Pyridine Derivatives, Methods of Making Pyridine Derivatives and Intermediates therefor

专利摘要:
Pyridine derivative (I) of formula (1), or a pharmaceutically acceptable salt thereof, which exhibits good bronchial contraction inhibitory action and / or anti-inflammatory action of the airways and is useful for the prevention or treatment of asthma: [Wherein A is a group of the formula: (WhereinOneAnd R2Are H, or protected or unprotected OH, respectively, and R31, R41And R42Is a protected or unprotected hydroxymethyl group, R32Is H, lower alkyl group, or protected or unprotected hydroxymethyl group, R33Is a substituted or unsubstituted lower alkyl group, and the dashed line means the presence or absence of a double bond.), R5And R6Is H, or a protected or unprotected amino group, or both, at their termini, combine with the adjacent nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic group.]
公开号:KR19980064040A
申请号:KR1019970067848
申请日:1997-12-11
公开日:1998-10-07
发明作者:우끼따다쓰조；스가하라마사까쓰；이께자와가쓰오；기까와히데오；나이또가주아끼
申请人:다나까도오시오；다나베세이야꾸가부시끼가이샤；
IPC主号:

专利说明:

Pyridine Derivatives, Methods of Making Pyridine Derivatives and Intermediates therefor
The present invention relates to novel pyridine derivatives, methods for preparing the pyridine derivatives thereof, and intermediates thereof which exhibit selective phosphodiesterase IV inhibitory action, and potential inhibitory action of bronchial contraction and / or anti-inflammatory action of the airways.
EP-557016-A1 (US patent 5342941) discloses that compounds such as 1- (3-pyridyl) -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene exhibit anti-asthmatic action Doing. EP-664289-A2 and EP-490823-A1 (US Patent 5177085) disclose 3,4-dihydro-6,7-dimethoxy-1- (3,5-dimethoxyphenyl) -3-hydroxymethyl-iso It has been disclosed that compounds such as quinoline show anti-asthmatic action. However, they do not disclose compounds such as compounds of the invention wherein the pyridine ring is substituted with a nitrogen-containing heterocyclic conjugate ring and a substituted or unsubstituted amino group.
In contrast, second intracellular messengers cAMP and cGMP are known to be degraded and inactivated by phosphodiesterase (abbreviated as PDE). At least seven different isozyme gene families are currently recognized, and these PDEs are widely distributed in various cell types and tissues of living bodies. PDE inhibitors inhibit the PDEs, thereby increasing cAMP and cGMP levels of tissue cells and consequently PDE inhibitors have a variety of pharmacological actions, such as vascular smooth muscle and bronchial smooth muscle relaxation, and positive muscular contractile action of the heart and Induction of morphogenic action is shown. Moreover, PDE inhibitors can regulate central function by increasing cAMP of the central system, ie it exhibits antidepressant action and improves memory learning function. PDE inhibitors also show inhibition of platelet aggregation and inhibition of inflammatory cells, in addition to the lipocatabolism of fat cells. (See Trends in Pharmacological Sciences, 12, 19-27, 1991)
Therefore, PDE inhibitors are thought to be useful for the treatment of various diseases, such as bronchial asthma, thrombosis, depression, central function decline after cerebral vascular occlusion, cerebral vascular dementia, Alzheimer's dementia, various inflammations, obesity and heart failure.
On the other hand, although various anti-asthma agents are known, these known anti-asthma agents have been required to develop new drugs because they have defects such as insufficient inhibitory effect of bronchial contraction and insufficient elimination of side effects to the heart.
To date, theophylline has been used as a PDE inhibitor in the treatment of asthma. However, since theophylline's PDE inhibitory action is not specific, it exhibits cardiac and central action in addition to the relaxation of bronchial smooth muscle. Therefore, theophylline should be wary of its side effects. For this reason, there has been a need for the development of novel therapeutic agents that selectively inhibit phosphodiesterase IV (PDE IV), which is present widely in bronchial smooth muscle and inflammatory cells, unlike other isozymes of PDE.
It is an object of the present invention to provide novel pyridine derivatives which exhibit selective PDE IV inhibitory action, and bronchial contraction potential inhibitory action and / or anti-inflammatory action of the respiratory tract, useful for the prevention or treatment of asthma. Another object of the present invention is to provide a method for producing a new pyridine derivative. Another object of the present invention is to provide an intermediate for the preparation of the new pyridine derivatives.
The present invention relates to a pyridine derivative (I) of formula (I), or a pharmaceutically acceptable salt thereof:
[Formula 1]
[Wherein A is a group of the formula:
Wherein R ¹ and R ² are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³¹ is a protected or unprotected hydroxymethyl group and R ³² is a hydrogen atom, a lower alkyl group Or a protected or unprotected hydroxymethyl group, R ³³ is a substituted or unsubstituted lower alkyl group, R ⁴¹ is a protected or unprotected hydroxymethyl group, and R ⁴² is a protected or unprotected hydroxide Oxymethyl group, dashed line means the presence or absence of double bond.)
R ⁵ and R ⁶ are the same or different and each is a hydrogen atom or a protected or unprotected amino group, or both are substituted or unsubstituted heterocyclic in combination with adjacent nitrogen atoms to which they are attached at their ends; Form a flag.]
Compound (I), or a pharmaceutically acceptable salt thereof, of the present invention is useful in the prevention or treatment of asthma because it exhibits selective PDE IV inhibitory action, and bronchial contraction potential inhibitory action, and / or anti-inflammatory action of the airways. For example, the present compound (I) shows more potent inhibitory effect on antigen-induced bronchial contraction than theophylline, and is characterized by a potential inhibitory effect on bronchial contraction but has no side effects on the heart.
When R ¹ and R ² of the present compound (I) are protected hydroxy groups, the protecting group for the hydroxy group may be any kind of protecting group for the pharmaceutically acceptable hydroxy group, for example substituted or unsubstituted lower egg A cannoyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted cycloalkyl group. Preferred protecting groups are alkyl groups, more preferably lower alkyl groups.
When R ³¹ , R ³² , R ³³ , R ⁴¹ and / or R ⁴² are a protected hydroxymethyl group, the protecting group for the hydroxy group of the hydroxymethyl group may be any kind of protecting group for the pharmaceutically acceptable hydroxy group, Examples include those that are readily hydrolyzed in the body but do not produce harmful byproducts, such as substituted or unsubstituted lower alkanoyl groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted lower alkoxycarbonyl groups or substituted Or an unsubstituted cycloalkyl group.
The substituted or unsubstituted lower alkanoyl group is a lower alkanoyl group which may be optionally substituted with one or two groups selected from protected or unprotected amino, carboxyl, lower alkoxycarbonyl, hydroxy and lower alkoxy groups. Include. Substituted or unsubstituted alkyl groups include alkyl groups which may be optionally substituted with groups selected from lower alkoxycarbonyl groups, lower alkoxy groups, aryl groups, and lower alkyl-substituted piperazinylcarbonyl groups. Aryl groups include, for example, phenyl groups, lower alkoxyphenyl groups and naphthyl groups.
The protecting group of a protected amino group which is one of the substituents of a substituted or unsubstituted lower alkanoyl group can be any kind of protecting group for an amino group, for example lower alkanoyl groups (e.g. acetyl, propionyl), lower alkoxy Acyl groups such as carbonyl groups or phenyl-lower alkoxycarbonyl groups such as benzyloxycarbonyl.
Substituted lower alkyl groups for R ³³ include lower alkyl groups substituted by groups selected from pyridyl groups, cyclo-lower alkyl groups and hydroxy groups.
Heterocyclic groups formed by R ⁵ and R ⁶ in combination with adjacent nitrogen atoms to which they are bonded at their termini, in addition to the adjacent nitrogen atoms, optionally contain hetero atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms Branches include heteromonocyclic, heterobicyclic or heterotricyclic groups.
Suitable examples of heterocyclic groups include pyridyl groups, quinolyl groups, isoquinolyl groups, cyclopenta [b] pyridyl groups, pyro [2,3-b] pyridyl groups, imidazo [4,5-b] pyrids Dyl, pyrido [2,3-d] thiazolyl, pyrido [2,3-d] oxazolyl, naphthyridinyl, quinoxazolinyl, phthalazinyl, quinazolinyl, indolyl, pyri Dazinyl, thieno [2,3-d] pyridazinyl, azepinyl, azetidyl, isoindolyl, pyrrolyl, benzazinyl, phenanthridinyl, benzothiadinyl, benz Imidazolinyl, pyrazinyl or morpholino groups. (These heterocyclic groups may be partially or wholly hydrogenated depending on the case.) Among these, pyridyl group, quinolyl group, isoquinolyl group, naphthyridinyl group, phthalazinyl group, quinozolinyl group or thieno [2 , 3-d] pyridazinyl group is preferred. (These heterocyclic groups are optionally partially or wholly hydrogenated.)
The protecting group for an amino group may be any kind of pharmaceutically acceptable protecting group for an amino group when one of R ⁵ and R ⁶ or both is a protected amino group, for example a lower alkanoyl group or a phenyl-lower alkoxycarbonyl group There is.
On the other hand, the above-mentioned heterocyclic group is (1) lower alkenyl group; (2) lower alkynyl groups; (3) lower alkylthio groups; (4) a cycloalkyl group; (5) trifluoromethyl group; (6) cyano group; (7) tetrazolyl group; (8) formyl groups; (9) amino groups; (10) mono- or di-substituted lower alkyl moieties may optionally be substituted by groups selected from morpholino groups, monocycloalkyl-substituted amino groups, pyridyl groups, imidazolyl groups, piperidyl groups and pyrrolidinyl groups Lower alkylamino groups; (11) pyridyl groups; (12) morpholino groups; (13) lower alkyl-substituted thiazolyl group; (14) bis (hydroxy-lower alkyl) aminocarbonyl groups; (15) bis (tri-lower alkylsilyloxy-lower alkyl) aminocarbonyl groups; (16) morpholinocarbonyl group; (17) lower alkyl-substituted piperazinylcarbonyl groups; (18) hydroxy-lower alkyl-substituted piperazinylcarbonyl groups; (19) tri-lower alkylsilyloxy-lower alkyl-substituted piperazinylcarbonyl groups; (20) lower alkoxycarbonyl group; (21) carboxyl group; (22) optionally a lower alkyl group which may be substituted with a morpholino group or a pyridyl group; (23) optionally a lower alkoxy group which may be substituted with a group selected from piperidyl group, pyridyl group, hydroxy group, or lower alkoxy group; (24) oxo groups; (25) a hydroxy group; (26) pyrimidinyl groups; (27) optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; (28) halogen atoms; (29) nitro groups; (30) imidazolyl group; (31) lower alkylenedioxy group; (32) thiazolyl group; And (33) optionally one or more groups selected from thienyl groups.
Among these, more preferable substituents include (1) an amino group; (2) pyridyl groups; (3) optionally a lower alkyl group which may be substituted with a morpholino group or a pyridyl group; (4) optionally a lower alkoxy group which may be substituted with a pyridyl group; (5) oxo groups; (6) pyrimidinyl groups; (7) optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; (8) halogen atoms; (9) thiazolyl group; And (10) one or more of the same or different groups selected from thienyl groups.
Among the substituted heterocyclic groups, pharmaceutically preferred heterocyclic groups are substituted with at least an oxo group, a hydroxy group or an amino group, in particular at least an oxo group. Heterocyclic groups substituted with at least an oxo group Heterocyclic group having a partial structure of, Suitable examples of such heterocyclic groups are as follows.
(These heterocyclic groups substituted with oxo groups are optionally (1) lower alkenyl groups; (2) lower alkynyl groups; (3) lower alkylthio groups; (4) cycloalkyl groups; (5) trifluoromethyl groups; (6) cyano groups; (7) tetrazolyl groups; (8) formyl groups; (9) amino groups; (10) lower alkyl moieties are optionally morpholino groups, monocycloalkyl-substituted amino groups, pyridyl groups, Mono- or di-lower alkylamino groups which may be substituted by a group selected from a dozolyl group, a piperidyl group and a pyrrolidinyl group; (11) pyridyl groups; (12) morpholino groups; (13) lower alkyl-substituted thia (14) bis (hydroxy-lower alkyl) aminocarbonyl groups; (15) bis (tri-lower alkylsilyloxy-lower alkyl) aminocarbonyl groups; (16) morpholinocarbonyl groups; (17) lower alkyl-substituted groups; Piperazinylcarbonyl groups; (18) hydroxy-lower alkyl-substituted piperazinylcarbonyl groups; (19) tri-low Alkylsilyloxy-lower alkyl-substituted piperazinylcarbonyl groups; (20) lower alkoxycarbonyl groups; (21) carboxyl groups; (22) optionally lower alkyl groups which may be substituted with morpholino groups or pyridyl groups; Lower alkoxy groups which may be substituted by groups selected from piperidyl, pyridyl, hydroxy, and lower alkoxy groups; (24) oxo groups; (25) hydroxy groups; (26) pyrimidinyl groups; (27) Thus a phenyl group which may be substituted with a di-lower alkylamino group or a halogen atom; (28) halogen atom; (29) nitro group; (30) imidazolyl group; (31) lower alkylenedioxy group; (32) thiazolyl And (33) may be further substituted with one or two groups selected from thienyl groups.)
When R ⁵ and R ⁶ of the present compound (I) combine at their terminals with adjacent nitrogen atoms to which they are bonded to form a substituted or unsubstituted heterocyclic group, the substituted or unsubstituted heterocyclic group As a suitable example, (1) an oxo-substituted dihydroquinolyl group which may be optionally substituted with a pyridyl group; (2) an oxo-substituted dihydroisoquinolyl group, which may optionally be substituted with a group selected from a morpholino-substituted lower alkoxy group or a pyridyl-substituted lower alkoxy group; (3) optionally a lower alkyl group which may be substituted with a pyridyl group; Pyrimidinyl groups; Lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group which may be optionally substituted with a group selected from thienyl group; (4) an oxo-substituted dihydropyridyl group, which may optionally be substituted with a pyridyl group; (5) oxo-substituted dihydronaphthyridinyl group; (6) a di-oxo-substituted dihydroquinazolinyl group which may be optionally substituted with a lower alkyl group; And (7) optionally an oxo-substituted thienopyridazinyl group which may be substituted with a tri-lower alkoxy-substituted phenyl group.
Among the compounds (I), preferred compounds are those in which A is a group selected from the formula:
(Wherein R ¹ and R ² may be the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group which may optionally be substituted with a lower alkylcarbonyl group, and R ³² is a hydrogen atom or hydroxy Is a methyl group, R ³³ is a cyclo-lower alkyl group or a methyl group substituted with a hydroxy group, R ⁴¹ is a hydroxymethyl group, R ⁴² is a hydroxymethyl group, and a dashed line means the presence or absence of a double bond.), R ⁵ And a substituted or unsubstituted heterocyclic group formed by combining R ⁶ at its terminals with an adjacent nitrogen atom to which they are attached as a group selected from (1) a morpholino-substituted lower alkoxy group and a pyridyl-substituted lower alkoxy group Substituted oxo-substituted dihydroisoquinolyl groups; (2) optionally a lower alkyl group which may be substituted with a pyridyl group; Pyrimidinyl groups; Lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group which may be optionally substituted with a group selected from thienyl group; (3) oxo-substituted dihydronaphthyridinyl groups; (4) di-oxo-substituted dihydroquinazolinyl group; And (5) a compound selected from an oxo-substituted thienopyridazinyl group substituted with a tri-lower alkoxy-substituted phenyl group.
Among the compounds (I), pharmaceutically preferred compounds are those wherein A is a group selected from the formula:
(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group which may optionally be substituted with a lower alkylcarbonyl group, and R ³² is a hydrogen atom or a hydroxymethyl group) , R ⁴² is a hydroxymethyl group and the dashed line means the presence or absence of a double bond.), R ⁵ and R ⁶ are substituted or unsubstituted heteros formed in combination with adjacent nitrogen atoms to which they are attached at their ends; An oxo-substituted dihydroisoquinolyl group in which the cyclic group is substituted with a group selected from (1) a morpholino-substituted lower alkoxy group and a pyridyl-substituted lower alkoxy group, and (2) an optionally lower alkyl group, pyrimidy Compound (I) is a group selected from an oxo-substituted dihydrophthalazinyl group which may be substituted with a group selected from a silyl group, a lower alkoxy group, a pyridyl group, a thiazolyl group, a phenyl group, and a thienyl group.
Among the compounds (I), pharmaceutically more preferred compounds are those wherein A is a group of the formula:
(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group which may optionally be substituted with a lower alkylcarbonyl group, and the dashed line means the presence or absence of a double bond) Oxo-substituted, wherein the substituted or unsubstituted heterocyclic group formed by R ⁵ and R ⁶ in combination with the adjacent nitrogen atom to which they are bonded is (1) a morpholino-substituted lower alkoxy group. Dihydroisoquinolyl group; And (2) a compound (I) which is optionally a group selected from an oxo-substituted dihydrophthalazinyl group which may be substituted with a group selected from a lower alkyl group, a pyridyl group, and a thiazolyl group.
Other pharmaceutically preferred compounds of these compounds are those wherein A is a group of the formula:
(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group which may optionally be substituted with a lower alkylcarbonyl group, and the dashed line means the presence or absence of a double bond) ), A substituted or unsubstituted heterocyclic group formed by R ⁵ and R ⁶ in combination with the adjacent nitrogen atom to which they are attached at (1) a morpholino-substituted lower alkoxy group and pyridyl-substituted An oxo-substituted dihydroisoquinolyl group substituted with a group selected from a lower alkoxy group, (2) a lower alkyl group; Lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group substituted with a group selected from a thienyl group, and (3) a group selected from an oxo-substituted thienopyridazinyl group substituted with a tri-lower alkoxy-substituted phenyl group.
Other pharmaceutically preferred compounds of these compounds are those wherein A is a group of the formula:
(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group, and the dashed line means the presence or absence of a double bond), R ⁵ and R ⁶ at their ends In which substituted or unsubstituted heterocyclic groups formed in combination with adjacent nitrogen atoms to which they are attached are substituted with groups selected from (1) morpholino-substituted lower alkoxy groups and pyridyl-substituted lower alkoxy groups. Hydroisoquinolyl groups, (2) lower alkoxy groups; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group substituted with a group selected from a thienyl group, and (3) a group selected from an oxo-substituted thienopyridazinyl group substituted with a tri-lower alkoxy-substituted phenyl group.
Other pharmaceutically more preferred of these compounds are those wherein A is a group of the formula:
(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group, and the dashed line means the presence or absence of a double bond), R ⁵ and R ⁶ at their ends In which the substituted or unsubstituted heterocyclic group formed in combination with the adjacent nitrogen atom to which they are bonded is (1) an oxo-substituted dihydroisoquinolyl group substituted with a morpholino-substituted lower alkoxy group, and (2) a pyri Compound (I) is a group selected from an oxo-substituted dihydrophthalazinyl group substituted with a group selected from a diyl group and a thiazolyl group.
Other pharmaceutically preferred compounds include those in which A is a group of the formula:
(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group, and the dashed line means the presence or absence of a double bond), R ⁵ and R ⁶ at their ends A lower alkyl group wherein a substituted or unsubstituted heterocyclic group formed in combination with adjacent nitrogen atoms to which they are bonded may optionally be substituted with a pyridyl group; Pyrimidinyl groups; Lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group which may be optionally substituted with a group selected from thienyl groups.
Other pharmaceutically preferred compounds are compounds (I) in which the heterocyclic group formed by combining R ⁵ and R ⁶ with the adjacent nitrogen atoms to which they are bonded at their termini is of the formula:
Wherein R ⁹¹ , R ⁹² and R ⁹³ are the same or different and each is a hydrogen atom; a thienyl group; a halogen atom; a lower alkoxy group; optionally a lower alkyl group substituted with a pyridyl group; in some cases di-lower Phenyl group which may be substituted by alkylamino group, lower alkoxy group or halogen atom; pyridyl group; pyrimidinyl group; or thiazolyl group.)
Among these compounds, more preferable compounds have the same or different R ⁹¹ , R ⁹² and R ⁹³ , and each hydrogen atom; Thienyl group; Halogen atom; Lower alkoxy group; Optionally a di-lower alkylamino group, or a phenyl group which may be substituted with a halogen atom; Pyridyl groups; Or a compound (I) which is a thiazolyl group.
The preferred substitution position of A in chemical (I) is the 4-position of the pyridine ring and the preferred substitution position of -NR ⁵ R ⁶ is the 2-position of the pyridine ring.
Of these pharmaceutically preferred compounds (I), R ¹ and R ² are the same or different and are each a lower alkoxy group, R ³¹ is a hydroxymethyl group, R ³² is a hydroxymethyl group, R ³³ is a hydroxymethyl group, Particular preference is given to compounds (I) in which R ⁴¹ is a hydroxymethyl group and R ⁴² is a hydroxymethyl group.
Compound (I) of the present invention exists in the form of optically active isomers because of its asymmetric carbon atoms, and the present invention also includes its optical isomers and mixtures thereof.
Compound (I) can be used clinically in free form or in the form of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloride, sulfate or hydrobromide, or salts of organic acids such as acetate, fumarate, oxalate, methanesulfonate or maleate. Compounds (I) having substituents such as carboxyl groups can be used clinically in the form of basic salts such as alkali metal salts (eg sodium salts, potassium salts) or alkaline earth metal salts (eg calcium salts).
Target compound (I) or salts thereof include intracellular salts or additives thereof and solvates or hydrates thereof.
The present compound (I) or a pharmaceutically acceptable salt thereof may be administered orally or parenterally and is prescribed in conventional pharmaceutical preparations such as tablets, granules, capsules, powders, injectables and inhalants. Can be.
The dosage of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may vary depending, for example, on the route of administration, age, weight and the condition of the patient, but is usually in the range of 0.001 to 10 mg / kg / day, Preferably in the range of 0.003 to 3 mg / kg / day.
Compounds (I) of the present invention can be prepared according to the following methods A, B and C.
Method A
Among the desired compounds (I), compound (Ia) of formula (I) reacts compound (II) of formula (II) with nitrogen-containing compound (III) of formula (3), and the product is a hydroxy group and / or a hydroxymethyl group Introducing a protecting group into the hydroxy portion of the product if necessary, or removing the protecting group from the product if necessary when the product has a protected hydroxy group and / or protected hydroxymethyl group, and if necessary It can be prepared by converting into a salt thereof, which is acceptable.
[Wherein A ¹ is a group selected from the formulas:
(Wherein R ¹ and R ² are the same or different and each is a hydrogen atom, or a protected or unprotected hydroxy group, R ³¹ is a protected or unprotected hydroxymethyl group, R ³² is a hydrogen atom, a lower alkyl group, or A protected or unprotected hydroxymethyl group, R ³³ is a substituted or unsubstituted lower alkyl group, R ⁴¹ is a protected or unprotected hydroxymethyl group, and R ⁴² is a protected or unprotected hydroxymethyl group. ), R ⁵ and R ⁶ are the same or different and each is a hydrogen atom or a protected or unprotected amino group, or both are substituted or unsubstituted hetero in combination with adjacent nitrogen atoms to which they are bonded at their termini; To form a cyclic group.]
[Wherein A ² is a group selected from the formulas:
(Wherein R ¹¹ and R ²¹ are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³⁴ is a protected or unprotected hydroxymethyl group, R ³⁵ is a hydrogen atom, a lower alkyl group, or A protected or unprotected hydroxymethyl group, R ³⁶ is a substituted or unsubstituted lower alkyl group, R ⁴³ is a protected or unprotected hydroxymethyl group, and R ⁴⁴ is a protected or unprotected hydroxymethyl group. ), X is a halogen atom.]
Wherein R ⁵ and R ⁶ are as defined above.
Method B
Among the desired compounds (I), compound (Ib) of formula (Ib) is an intramolecular cyclization reaction of compound (IV) of formula (IV) or a salt thereof, and a protecting group is added to the hydroxy group of the product if necessary when the product has a hydroxyl group. It may be prepared by introduction or by removing the protecting group from the product if necessary when the product has a protected hydroxy group and / or protected hydroxymethyl group, and if necessary then converting the product to a pharmaceutically acceptable salt thereof:
(Wherein R ⁵¹ and R ⁶¹ combine at their terminals with adjacent nitrogen atoms to which they are bonded to form a heterocyclic group substituted with at least an oxo group, other symbols being as defined above.)
Wherein R ³⁷ is a protected hydroxymethyl group and other symbols are as defined above.
Method C
Among the desired compounds (I), the compound (Ic) of the general formula (1c) or the compound (Id) of the general formula (1d) may be a compound (Ie) of the general formula (1e) or a salt thereof, and React with a salt thereof, or a carboxylic acid derivative (VI) of formula 6 or a salt thereof and introduce a protecting group into the hydroxy portion of the product if necessary when the product has a hydroxy group and / or a hydroxymethyl group, or When having a protected hydroxy group and / or protected hydroxymethyl group, it can be prepared by removing the protecting group from the product if necessary and then converting the product to its pharmaceutically acceptable salts if necessary:
Wherein R ⁹¹ , R ⁹² and R ⁹³ are the same or different and each is a hydrogen atom; a thienyl group; a halogen atom; a lower alkoxy group; optionally a lower alkyl group substituted with a pyridyl group; in some cases di-lower A phenyl group which may be substituted with an alkylamino group, a lower alkoxy group or a halogen atom; a pyridyl group; a pyrimidinyl group; or a thiazolyl group, other symbols being as defined above.)
Wherein R ⁹⁴ , R ⁹⁵ and R ⁹⁶ are the same or different and each is a hydrogen atom; a thienyl group; a halogen atom; a lower alkoxy group; optionally a lower alkyl group which may be substituted with a pyridyl group; A lower alkylamino group, a lower alkoxy group, or a phenyl group which may be substituted with a halogen atom; a pyridyl group; a pyrimidinyl group; or a thiazolyl group, A ¹ is as defined above.)
Wherein A ² is as defined above.
Wherein the symbols are as defined above.
Wherein the symbols are as defined above.
The above methods A, B and C can be carried out as follows.
Method A
The reaction of compound (II) and nitrogen-containing compound (III) is carried out in the presence of a base and a copper catalyst in a suitable solvent. The base includes, for example, alkali metal hydrides, alkali metal carbonates, and the copper catalyst is, for example, copper iodide (I), copper bromide (I), copper (0) powder, copper oxide ( I) and copper bromide (II). The solvent includes, for example, dimethylformamide, dimethylsulfoxide, dimethylacetamide, toluene, and xylene. The reaction is preferably carried out at a temperature of 80 to 160 ° C, more preferably at a temperature of 120 to 150 ° C.
Method B
Intramolecular cyclization of compound (IV) is carried out in the presence or absence of an acid catalyst in a suitable solvent. Such acid catalysts include, for example, phosphorus oxychloride, phosphorus pentachloride, aluminum chloride, thionyl chloride, chloroacetic anhydride, zinc chloride, alumina, phosphorus oxybromide, silica chloride, and polyphosphoric acid; , The solvent includes, for example, acetonitrile, toluene, xylene and chloroform. The reaction is preferably carried out at a temperature of 50 to 180 ° C, more preferably at a temperature of 80 to 120 ° C.
Method C
The reaction is carried out in a suitable solvent such as lower alkanols, ethylene glycol, dioxane, and toluene, preferably at a temperature of 100 to 140 ° C.
In methods A, B and C above, when R ¹¹ and / or R ²¹ are protected hydroxy groups and R ³⁴ , R ³⁵ , R ³⁶ , R ⁴³ and / or R ⁴⁴ are protected hydroxymethyl groups, Removal of these protecting groups is carried out by conventional methods such as hydrolysis, acid treatment, reduction and the like, and these methods should be selected according to the type of protecting group to be removed. Also 6- and / or 7-hydroxyl protection of the hydroxy portion, and the 2- and / or 3-hydroxy-part conventional method, that is, for each product ^{R 1, R 2, R 31} , R 32, R 33, R 41 And / or an acid hydride or acid halide of lower alkanoic acid or cycloalkanoic acid corresponding to a protecting group of R ⁴¹ , or optionally a lower alkyl halide which may be substituted with a lower alkoxycarbonyl group, or a protected or unprotected car This can be done by condensation with a compound-substituted lower alkyl sulfonate. The reaction is preferably carried out in the presence of a base (eg triethylamine, pyridine, dimethylaminopyridine, sodium hydride, hexamethylphosphoric triamide) in or without a suitable solvent (eg methylene chloride, tetrahydrofuran) Is performed.
Starting compound (II) of the present invention is a novel compound and can be prepared according to the following method.
In compound (II), isoquinoline compound (II-a) is prepared according to the following scheme 1:
(Wherein R ⁷¹ is a lower alkyl group, R ⁷² is a lower alkyl group, R ⁷³ is a lower alkyl group, X ¹ is a halogen atom, and other symbols are as defined above.)
In other words, compound (II-a) is prepared according to the following steps:
(i) condensation of the acetal compound (VII) with compound (VIII) to give compound (IX);
(ii) removing the protecting group from compound (IX) to give compound (X);
(iii) reacting compound (X) with an isonitrile derivative to produce compound (XI);
(iv) reducing compound (XI) to produce compound (XII);
(v) And if necessary, the 3-hydroxymethyl group of compound (XII) is protected to give compound (II-a).
In compound (II), isoquinoline compound (II-b) is prepared according to the following scheme 2:

(Wherein R ⁷⁴ is a lower alkyl group, R ⁷⁵ is a lower alkyl group, R ⁷⁶ is a lower alkyl group, X ² is a halogen atom, X ³ is a halogen atom, and other symbols are as defined above.)
In other words, compound (II-b) is prepared according to the following steps:
(i) condensing the acetal compound (VII) with compound (XIII) and removing the protecting group of the resulting compound (XIV);
(ii) oxidize the resulting compound (XV);
(iii) reacting the resulting compound (XVI) with a halogenomalonic acid diester derivative;
(iv) react the resulting compound (XVII) with ammonia;
(v) esterification of resultant compound (XVIII);
(vi) halogenating the resulting compound (XIX) to produce compound (XX);
(vii) dehalogenated compound (XX) to give compound (XXIII);
(viii) the resulting compound (XXIII) is reduced to give compound (XXIV);
(ix) Then, if necessary, protect the 3-hydroxymethyl group of the isoquinoline nucleus of compound (XXIV).
In compound (II), quinoline compound (II-c) is prepared according to the following scheme 3:

(Wherein R ⁷⁷ is a lower alkyl group, R ⁷⁸ is a lower alkyl group, R ⁷⁹ is a lower alkyl group, R ⁸⁰ is a lower alkyl group, and other symbols are as defined above.)
In other words, compound (II-c) is prepared according to the following steps:
(i) condensation of the acetal compound (VII) with compound (VIII) to yield compound (IX);
(ii) removing the protecting group of the resulting compound (IX) to give the compound (X);
(iii) oxidizing compound (X) and converting the resulting compound (XXV) to an acid azide compound and subjecting to a potential reaction to produce compound (XXVIII); or
(iv) condensation of the aniline compound (XXVI) with compound (XXVII) to give compound (XXVIII);
(v) reacting compound (XXVIII) with a lower alkoxymethylenemalonic acid diester compound and reducing compound (XXIX) to produce compound (XXX); or
(vi) alternatively, reacting compound (XXVIII) with a 3-oxo-lower alkylcarboxylic acid ester derivative and reducing the resulting compound (XXXI) to produce compound (XXXII); or
(vii) alternatively, compound (XXVIII) is reacted with tetronic acid and the resulting compound (XXXIII) is reduced to give compound (XXXIV);
(viii) Then, if necessary, the hydroxymethyl groups of compound (XXX), compound (XXXII) and compound (XXXIV) are protected.
Of compound (II), phthalazine compound (II-d) is prepared according to the following scheme 4:
Wherein the symbols are as defined above.
That is, compound (II-d) is prepared by condensing acetal compound (VII) with compound (VIII), removing protecting groups from the resulting compound (IX), and reacting the product with hydrazine.
Of the compound (II), the phthalazinone compound (II-e) is prepared according to the following scheme 5.
Wherein the symbols are as defined above.
In other words, compound (II-e) is prepared according to the following steps:
(i) condensing acetal compound (VII) with compound (VIII);
(ii) removing the protecting group from the resulting compound (IX);
(iii) oxidation of compound (X) yields compound (XXV);
(iv) reacting compound (XXV) with hydrazine to produce compound (XXXV);
(v) then protect the 2-position of the phthalazine nucleus of compound (XXXV).
Starting compound (IV) is a novel compound and is prepared according to the following Scheme 6:

(Wherein R ⁸¹ is a lower alkoxycarbonyl group, R ⁸² is a lower alkyl group and other symbols are as defined above.)
In other words, compound (IV) is prepared according to the following steps:
(i) reacting compound (XXXVI) with N-acetylglycine to produce compound (XXXVII);
(ii) hydrolysis of compound (XXXVII) to yield compound (XXXVIII);
(iii) hydrolysis of compound (XXXVIII) to yield compound (XXXIX);
(iv) hydrolysis of compound (XXXIX) to yield compound (XL);
(v) esterifying compound (XL) to produce compound (XLIII); or
(vi) In another method, the amino group of Compound (XL) is protected, the resulting Compound (XLI) is esterified, and the protecting group of the amino group of Compound (XLII) is removed to produce Compound (XLIII);
(vii) reducing compound (XLIII), condensing the resulting compound (XLIV) with a halogenopyridinecarboxylic acid, and hydrolyzing the resulting compound (XLV) to give compound (XLVII); or
(viii) alternatively reacting the resulting compound (XLIII) with a halogenopyridinecarboxylic acid and reducing the resulting compound (XLVI) to give a compound (XLVII);
(ix) Compound (XLVII) is reacted with compound (III-a) and, if necessary, protects the hydroxymethyl group of the resulting compound (XLVIII).
Compound (XLIII-a) and compound (XLIV-a) are prepared according to Scheme 7:
(Wherein R ⁸³ is a lower alkoxycarbonyl group, R ⁸⁴ is a lower alkyl group and other symbols are as defined above.)
That is, compound (XLIII-a) and compound (XLIV-a) are prepared according to the following steps:
(i) protecting the amino group of compound (XL-a) to produce compound (XLI-a);
(ii) esterifying compound (XLI-a) to give compound (XLII-a);
(iii) protecting the hydroxy group of compound (XLII-a) to produce compound (XLIII-b) (or alternatively protecting the hydroxy portion and the carboxyl portion of compound (XLI-a) simultaneously to give compound (XLIII -b) generate;);
(iv) the protecting group of the amino group of compound (XLIII-b) is removed; after that
(v) The produced compound (XLIII-a) is reduced to produce compound (XLIV-a).
In the preparation of compounds (II) and (IV), each intermediate for them can be used in its own form represented by the formula, but also salts or reactive derivatives thereof can be used so long as they do not inhibit the reaction.
Furthermore, in the preparation of the compounds of interest and starting compounds of the invention, when the starting compound or each intermediate has a functional group, it is possible to protect the functional groups by conventional methods used in the field of synthetic chemistry with appropriate protecting groups in addition to the groups described above, The protectors can be removed when the protectors are no longer needed.
In the present specification and claims, an alkyl group means a straight or branched chain alkyl group having 1 to 16 carbon atoms, in particular having 1 to 8 carbon atoms. Lower alkyl groups and lower alkoxy groups mean straight or branched chain groups each having 1 to 6 carbon atoms, in particular having 1 to 4 carbon atoms. Lower alkanoyl group means a straight or branched alkanoyl group having 2 to 7 carbon atoms, in particular having 2 to 5 carbon atoms. By cyclo lower alkyl group is meant a straight or branched cycloalkyl group having 3 to 8 carbon atoms, in particular having 3 to 6 carbon atoms. Halogen atom means chlorine, bromine, fluorine or iodine.
The invention will be described in more detail in the Examples and Reference Examples, but the scope is not limited.
Example 1
(1) potassium carbonate (103 mg), copper iodide (70 mg) in a solution of 4- (3-pyridyl) phthalazine-1 (2H) -one (167 mg) in dimethylformamide (5 mL) And 2-bromo-4- [6,7-dimethoxy-2- (4-pyridyl) methylphthalazine-1 (2H) -on-4-yl] pyridine (335 mg) continuously in a nitrogen atmosphere And the mixture is refluxed for 2 hours. The reaction mixture is cooled and aqueous ammonia is added. The mixture was extracted with chloroform, and the extract was washed, dried, concentrated and purified by silica gel column chromatography (solvent; chloroform: methanol = 19: 1) to give 4- [6,7-dimethoxy-2- (4 -Pyridyl) methylphthalazine-1 (2H) -on-4-yl] -2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] pyridine (216 mg).
(2) The compound (216 mg) obtained in the above (1) is dissolved in a mixture of chloroform and methanol (chloroform: methanol = 4: 1), 2M hydrochloric acid (0.18 mL) is added, and the mixture is concentrated. The mixture is azeotropically distilled with ethanol and chloroform is added to the residue. The mixture was filtered to afford 4- [6,7-dimethoxy-2- (4-pyridyl) methylphthalazine-1 (2H) -one-4-yl] -2- [4- (3-pyridyl) Produces phthalazine-1 (2H) -on-2-yl] pyridine dihydrochloride (106 mg).
M.p. 225-230 ℃ (decomposition)
Examples 2-5
4- (3-pyridyl) phthalazine-1 (2H) -one and compound (II-a) were treated in the same manner as in Examples 1- (1) and 1- (2), and are shown in Table 1 To produce compounds.
Example 6
2-bromo-4- (6,7-dimethoxyphthalazin-1-yl) pyridine and 4- (3-pyridyl) phthalazine-1 (2H) -one were prepared in Example 1- (1) And 4- (6,7-dimethoxyphthalazin-1-yl) -2- [4- (3-pyridyl) phthalazine-1 (2H)-by treating in the same manner as-(2). On-2-yl] pyridine hydrochloride.
M.p. 232-236 ℃ (decomposition)
Example 7
(1) To a solution of dimethylformamide (85 mL) of methyl isocyanoacetate (18 mL) is added ice cold sodium hydride (7.85 g, 62.4% in oil) in a nitrogen atmosphere, and the mixture is stirred at room temperature for 30 minutes. do. The solution was added dropwise to a solution of 3,4-dimethoxy-6- (2-chloroisonicotinoyl) benzaldehyde (52.0 g) in dimethylformamide (170 mL) at 40-50 ° C., and the mixture was heated at 50 ° C. 1 Stir for hours. The mixture is neutralized with 10% acetic acid, concentrated and extracted with chloroform. The extract is washed, insoluble materials are recovered by filtration and the filtrate is concentrated to dryness. The product and recovered insoluble materials were combined and recrystallized from ether-methanol to give 2-chloro-4- (3-methoxycarbonyl-6,7-dimethoxyisoquinolin-1-yl) pyridine (16.1 g) Create
M.p. 246-247 ℃
(2) The compound (12.9 g) obtained in the above (1) was suspended in tetrahydrofuran (300 mL), and tetrahydrofuran of sodium bis (methoxyethoxy) aluminum hydride (21.2 mL, 70% toluene solution) (50 mL) is added dropwise to the suspension at a temperature below −10 ° C. The mixture is gradually raised to room temperature and methanol is added. To the mixture is added 2M aqueous sodium hydroxide solution (90 mL) and the mixture is stirred at 40 ° C. for 30 minutes. The tetrahydrofuran layer is separated and the aqueous layer is extracted with ethyl acetate. All organic layers were combined, washed, dried and concentrated and the residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 2: 1) to give 2-chloro-4- (3-hydroxymethyl-6 To produce, 7-dimethoxyisoquinolin-1-yl) pyridine (7.44 g).
M.p. 162-163 ℃
(3) The solution of the compound (992 mg) obtained in the above (2) and hydrazine monohydrate (32.6 mL) were refluxed for 1 hour. The reaction mixture is cooled and the precipitate is recovered by filtration to give 2-hydrazino-4- (3-hydroxymethyl-6,7-dimethoxyisoquinolin-1-yl) pyridine (552 mg).
M.p. 157-159 ℃
(4) A mixture of the compound (1.63 g), 2-nicotinoyl benzoic acid (1.25 g) and ethylene glycol (50 mL) obtained in (3) above is heated with stirring at 120 ° C. for 3 hours. The reaction mixture is cooled and an aqueous sodium hydrogen carbonate solution is added to the mixture. The precipitate was recovered by filtration and purified by silica gel column chromatography (solvent; chloroform: methanol = 10: 1) to afford 4- (3-hydroxymethyl-6,7-dimethoxyisoquinolin-1-yl). To yield 2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] pyridine (1.68 g).
M.p. 250 ℃
(5) The compound (1.68 g) obtained in the above (4) is dissolved in a mixture of chloroform and methanol (chloroform: methanol = 10: 1), to which 2M hydrochloric acid (1.62 mL) is added, and the mixture is concentrated. The mixture is azeotropically distilled with ethanol and ether is added to the residue. The precipitate was recovered by filtration to give 4- (3-hydroxymethyl-6,7-dimethoxyisoquinolin-1-yl) -2- [4- (3-pyridyl) phthalazine-1 (2H)- On-2-yl] pyridine hydrochloride (1.83 g).
M.p. 257-260 ℃ (decomposition)
Examples 8-13
2-Hydrazino-4- (3-hydroxymethyl-6,7-dimethoxyisoquinolin-1-yl) pyridine and carboxylic acid compound (V) were treated in the same manner as in Example 7- (4) To yield the compounds shown in Table 2.
Example 14
3,4-diethoxy-6- (2-chloroisonicotinoyl) benzaldehyde was treated in the same manner as in Example 7- (1) to-(5) to give 4- (3-hydroxymethyl-6, To 7-diethoxyisoquinolin-1-yl) -2- [4- (3-pyridyl) phthalazine-1 (2H) -one-2-yl] pyridine hydrochloride.
M.p. 250 ℃
Examples 15-17
2-Hydrazino-4- (3-hydroxymethyl-6,7-diethoxyisoquinolin-1-yl) pyridine and carboxylic acid compound (V) with Examples 7- (4) to-(5) The same procedure is followed to produce the compounds shown in Table 3.
Example 18
2-hydrazino-4- (3-hydroxymethyl-6,7-diethoxyisoquinolin-1-yl) pyridine and 2- (3,4,5-trimethoxybenzoyl) -3-thiophenecarboxyl The acid was treated in the same manner as in Example 7- (4) to give 4- (3-hydroxymethyl-6,7-diethoxyisoquinolin-1-yl) -2- [7- (3,4,5- Trimethoxyphenyl) thieno [2,3-d] pyridazine-4 (5H) -one-5-yl] pyridine.
M.p. 250-251 ℃
Example 19
(1) 4- (1-chloro-6,7-dimethoxy-3-methoxycarbonylisoquinolin-4-yl) pyridine (6.11 g), sodium acetate (1.4 g) and 10% palladium-carbon (2.5 g) is added to acetic acid (80 mL) and the mixture is hydrogenated at 50 ° C., 2.7 atm for 19 h. Palladium-carbon is removed by filtration and the filtrate is concentrated to yield 4- (6,7-dimethoxy-3-methoxycarbonylisoquinolin-4-yl) pyridine (4.84 g).
M.p. 168-170 ℃ (decomposition)
(2) m-chloroperbenzoic acid (5.1 g) is added to a solution of methylene chloride (40 mL) of the compound (4.4 g) obtained in the above (1) at 0 ° C, and the mixture is stirred at 0 ° C for 2 hours, Stir at room temperature for 40 hours. An aqueous sodium thiosulfate solution is added to the reaction mixture, and the mixture is extracted with chloroform. The extract is washed, dried, and concentrated. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 20: 1) to give 4- (6,7-dimethoxy-3-methoxycarbonylisoquinolin-4-yl) pyridineN- To produce oxide (2.12 g).
M.p. 220-224 ℃ (decomposition)
(3) Phosphorus oxychloride (20 mL) is added to the compound (2.07 g) obtained in the above (2), and the mixture is refluxed for 1 hour. The reaction mixture is concentrated and chloroform is added to the residue. An aqueous sodium hydrogen carbonate solution is added to the mixture, and the mixture is extracted with chloroform. The extract was washed, dried, and concentrated and the residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 10: 1) to give 2-chloro-4- (6,7-dimethoxy-3-methoxy To produce oxycarbonylisoquinolin-4-yl) pyridine (1.05 g).
M.p. 164-168 ℃ (decomposition)
(4) 4- (6,7-dimethoxy-3-hydroxymethylisoquinolin-4-yl by treating the compound obtained in the above (3) in the same manner as in Example 7- (2) to-(5) ) -2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] pyridine hydrochloride (145 mg).
M.p. 231-233 ℃ (decomposition)
Example 20
(1) (2S) -1-acetoxy-3- (3,4-dimethoxyphenyl) -2- {2- [4- (3-pyridyl) phthalazine-1 (2H) -one-2 To a solution of acetonitrile (5 mL) of -yl] isonicotinoylamino} propane (150 mg) is added phosphorus oxychloride (0.29 mL) and the mixture is heated at reflux overnight. The reaction mixture is cooled to room temperature and neutralized with aqueous sodium hydrogen carbonate solution. The mixture is extracted with chloroform and the extract is washed, dried, and concentrated. The residue was crystallized from ethyl acetate to give the yellow crystals (3S) -4- (3-acetoxymethyl-3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl) -2- [4 To form-(3-pyridyl) phthalazine-1 (2H) -on-2-yl] pyridine (136 mg).
M.p. 177-179 ℃ (decomposition)
(2) The compound (200 mg) obtained in the above (1) was added to a dioxane (0.09 mL) 4M solution of hydrogen chloride, and (3S) -4- (3-acetoxymethyl-3,4-dihydro-6 Produces, 7-dimethoxyisoquinolin-1-yl) -2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] pyridine hydrochloride (200 mg).
M.p. 178-181 ℃ (decomposition)
Example 21-32
Compound (IV) is treated in the same manner as Example 20- (1) and-(2), or Example 20- (1) to give the compounds shown in Tables 4-6.

Example 33
(1) (3S) -4- (3-acetoxymethyl-3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl) -2- [4- (3-pyridyl) phthala Chin-1 (2H) -on-2-yl] pyridine (400 mg) was suspended in a mixture of methanol (20 mL) and tetrahydrofuran (10 mL), and 1M aqueous lithium hydroxide solution (1.43 mL) was added. Add dropwise in ice-cold. The mixture is stirred for 15 minutes on ice cooling and reacted for 3 hours at room temperature. The reaction mixture is concentrated and water is added to the residue. The mixture is extracted with methylene chloride and the extracts are washed, dried and concentrated. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 10: 1) to give (3S) -4- (3,4-dihydro-3-hydroxymethyl-6,7-dimethoxyiso Quinolin-1-yl) -2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] pyridine (230 mg).
M.p. 235-238 ℃ (decomposition)
(2) The compound (200 mg) obtained in the above (1) was reacted with a dioxane (0.1 mL) 4M solution of hydrogen chloride to give (3S) -4- (3,4-dihydro-3-hydroxymethyl-6 Produces, 7-dimethoxyisoquinolin-1-yl) -2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] pyridine hydrochloride (200 mg).
M.p. 225-228 ℃ (decomposition)
Examples 34-45
4- (3-acetoxymethyl-3,4-dihydro-6,7-di-lower alkoxyisoquinolin-1-yl) -2-substituted pyridine compound was prepared in Example 33- (1) and-(2) Treatment was carried out in the same manner as to produce the compounds shown in Tables 7-9.

Example 46
1-acetoxy-3- (3,4-dimethoxyphenyl) -2- {2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] isonicotinoyl Amino} propane was treated in the same manner as in Example 20- (1) and-(2) to give 4- (3-acetoxymethyl-3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl ) -2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] pyridine hydrochloride.
M.p. 183-186 ℃ (decomposition)
Example 47
4- (3-acetoxymethyl-3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl) -2- [4- (3-pyridyl) phthalazine-1 (2H)- On-2-yl] pyridine was treated in the same manner as in Examples 33- (1) and-(2) to give 4- (3,4-dihydro-3-hydroxymethyl-6,7-dimethoxyisoquinoline -1-yl) -2- [4- (3-pyridyl) phthalazine-1 (2H) -one-2-yl] pyridine hydrochloride.
M.p. 236-238 ℃ (decomposition)
Example 48
2-hydroxymethyl-4- (4-pyridyl) -6,7-dimethoxy-3-quinolinecarboxylic acid lactone (14 g) is suspended in tetrahydrofuran (50 mL), and sodium bis ( A tetrahydrofuran (10 mL) mixture of methoxyethoxy) aluminum hydride (20.3 mL, 70% toluene solution) is added dropwise at −10 ° C. over 30 minutes. The mixture is stirred at −10 ° C. for 1.5 hours and at 0 ° C. for 6 hours. Methanol is added to the mixture, and 2M aqueous sodium hydroxide solution (100 mL) is further added at 0 ° C. The mixture is evaporated to remove tetrahydrofuran and the residue is extracted with methylene chloride. The extract is washed, dried and concentrated. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 20: 1) to give 4- [2,3-bis (hydroxymethyl) -6,7-dimethoxyisoquinolin-4-yl] To yield pyridine (5.12 g).
M.p. 197-200 ℃
Example 49
2-Hydroxyno by treating 2-chloro-4- [2,3-bis (hydroxymethyl) -6,7-dimethoxyisoquinolin-4-yl] pyridine in the same manner as in Example 7- (3) To yield 4- [2,3-bis (hydroxymethyl) -6,7-dimethoxyisoquinolin-4-yl] pyridine.
M.p. 225-227 ℃
Example 50
2-Hydrazino-4- [2,3-bis (hydroxymethyl) -6,7-dimethoxyisoquinolin-4-yl] pyridine in the same manner as in Example 7- (4) and-(5) Treatment to 4- [2,3-bis (hydroxymethyl) -6,7-dimethoxyisoquinolin-4-yl] -2- [4- (3-pyridyl) phthalazine-1 (2H)- On-2-yl] pyridinehydrochloride.
M.p. 216-219 ℃ (decomposition)
Example 51
(1) a mixture of 3,4-dimethoxy-6- (2-chloroisonicotinoyl) aniline (2.93 g), methyl acetoacetate (2.16 mL), concentrated hydrochloric acid (0.1 mL) and acetic acid (30 mL) Heat at reflux for 2 hours. The reaction mixture is cooled to room temperature, and an aqueous sodium hydrogen carbonate solution is added thereto. The mixture is extracted with ethyl acetate and the extract is washed, dried and concentrated. The residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 9: 1) to give 2-chloro-4- (6,7-dimethoxy-3-methoxycarbonyl-2-methylquinoline- 4-yl) pyridine (3.0 g) is produced.
M.p. 145-147 ℃
(2) The same method as in Examples 7- (2) to-(5), with 2-chloro-4- (6,7-dimethoxy-3-methoxycarbonyl-2-methylquinolin-4-yl) pyridine 4- (3-hydroxymethyl-6,7-dimethoxy-2-methylquinolin-4-yl) -2- [4- (3-pyridyl) -phthalazine-1 (2H)- On-2-yl] pyridine hydrochloride.
M.p. 250 ℃
Example 52
(1) 2-chloro-4- (3-hydroxymethyl-6,7-dimethoxyquinolin-4-yl) pyridine was treated in the same manner as in Example 7- (3) to give 2-hydrazino-4- To yield (3-hydroxymethyl-6,7-dimethoxyquinolin-4-yl) pyridine.
M.p. 217-220 ℃
(2) 4- (3-hydroxymethyl-6,7-dimethoxyquinolin-4-yl) by treating the compound obtained in the above (1) in the same manner as in Example 7- (4) and-(5) To produce 2- [4- (3-pyridyl) phthalazine-1 (2H) -one-2-yl] pyridine hydrochloride.
M.p. 250 ℃
Reference Example 1
To a tetrahydrofuran (80 mL) solution of 2-bromo-4,5-dimethoxybenzaldehyde dimethyl acetal (21.8 g) was added n-butyl lithium (46.8 mL of 1.6 M hexane solution) at a temperature below −50 ° C. in a nitrogen atmosphere. Drop wise and the mixture is stirred for 20 minutes. The resulting solution is added dropwise to a tetrahydrofuran (80 mL) solution of 2-bromo-N, N-dimethylisonicotinamide (18.1 g) at a temperature below -60 ° C. and the mixture is stirred for 30 minutes. Acetic acid (4.5 mL) is added to the reaction mixture, the mixture is added to water and extracted with ethyl acetate. The extract was washed, dried, concentrated, and the residue was purified by silica gel column chromatography (solvent; hexanes: ethyl acetate = 2: 1) to give the oily product 3,4-dimethoxy-6- (2-bromoy Sonycotinoyl) benzaldehyde dimethyl acetal (13.9 g) is obtained.
Reference Example 2
3,4-Dimethoxy-6- (2-bromoisonicotinoyl) benzaldehyde dimethyl acetal (13.9 g) and 2M hydrochloric acid (1 mL) were added to a mixture of acetone (30 mL) and water (5 mL), and The mixture is stirred at room temperature for 2 hours. The mixture is evaporated to remove acetone and the remaining aqueous layer is extracted with chloroform. The extract is washed, dried and concentrated. The residue is purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 4: 1) to give 3,4-dimethoxy-6- (2-bromoisonicotinoyl) benzaldehyde (8.65 g). .
M.p. 133-134 ℃
Reference Example 3
Resorcinol (3.25 g) in dioxane (120 mL) solution of 3,4-dimethoxy-6- (2-bromoisonicotinoyl) benzaldehyde (8.61 g) in acetate buffer (pH 3.8, 60 mL) The solution is added dropwise at room temperature. To the mixture is gradually added dropwise aqueous sodium hypochlorite (3.1 g) solution (30 mL of water), and the mixture is stirred at room temperature for 2 hours. The pH of the reaction mixture is adjusted to about pH 1 with concentrated hydrochloric acid and extracted with chloroform. The extract is washed, dried and concentrated to yield 3.4-dimethoxy-6- (2-bromoisonicotinoyl) benzoic acid (8.07 g).
M.p. 199-200 ℃
Reference Example 4
3,4-Dimethoxy-6- (2-bromoisonicotinoyl) benzoic acid (15.2 g) and hydrazine monohydrate (15 mL) are added to ethanol (30 mL) and the mixture is heated at reflux for 1 h. The reaction mixture was cooled with ice and the precipitate was purified by filtration to afford 2-bromo-4- (6,7-dimethoxyphthalazine-1 (2H) -on-4-yl) pyridine (14.1 g). Create
M.p. 230 ℃
Reference Example 5
2-bromo-4- (6,7-dimethoxyphthalazine-1 (2H) -on-4-yl) pyridine (362 mg), 4-picolinyl chloride hydrochloride (180 mg) and potassium carbo Nate (359 mg) is added to dimethylformamide (10 mg) and the mixture is stirred and heated in a nitrogen atmosphere at 80 ° C. for 3 hours. Water is added to the reaction mixture and the mixture is extracted with methylene chloride. The extract was washed, dried and concentrated to give 2-bromo-4- [6,7-dimethoxy-2- (4-pyridyl) methylphthalazine-1 (2H) -on-4-yl] pyridine (355 mg).
M.p. 182-184 ℃
Reference Examples 6 to 8
2-Bromo-4- (6,7-dimethoxyphthalazine-1 (2H) -on-4-yl) pyridine and the corresponding halogeno compounds were treated in the same manner as in Reference Example 5 to Table 10 To produce the indicated compounds.
Reference Example 9
Sodium hydride (48 mg) in a dimethylformamide (2 mL) solution of 2-bromo-4- (6,7-dimethoxyphthalazine-1 (2H) -on-4-yl) pyridine (362 mg) , 62.4% in oil) is added under ice-cooling under a nitrogen atmosphere, and the mixture is stirred at room temperature for 30 minutes. Methyl bromoacetate (0.11 mL) is added to the mixture on ice cooling and the mixture is stirred for 15 minutes. Water is added to the mixture and extracted with ethyl acetate. The extract was washed, dried and concentrated to give 2-bromo-4- (6,7-dimethoxy-2-methoxycarbonylmethylphthalazine-1- (2H) -on-4-yl) pyridine (390 mg ).
M.p. 200-201 ℃
Reference Example 10
Tetrahydrofuran (20 mL) of 2-bromo-4- (6,7-dimethoxy-2-methoxycarbonylmethylphthalazine-1- (2H) -on-4-yl) pyridine (4.34 g) Sodium borohydride (0.76 g) is added to the solution, and a mixture of methanol (3.2 mL) and tetrahydrofuran (5 mL) is added dropwise over 1 hour with reflux heating. The reaction mixture is left to cool and water is added thereto on ice cooling. The mixture is extracted with chloroform and the extracts are washed, dried and concentrated. The residue was recrystallized from isopropyl ether to give 2-bromo-4- (6,7-dimethoxy-2-hydroxyethylphthalazine-1 (2H) -on-4-yl) pyridine (3.08 g) Create
M.p. 208-210 ℃
Reference Example 11
To a methanol (70 mL) solution of 3,4-dimethoxy-6- (2-bromoisonicotinoyl) benzaldehyde (4.5 g) is added dropwise hydrazine monohydrate (0.8 mL). The reaction mixture was cooled with ice, the precipitate was recovered by filtration, recrystallized from methanol, and yellow crystal product 2-bromo-4- (6,7-dimethoxyphthalazin-1-yl) pyridine (4.01 g ).
M.p. 157-159 ℃
Reference Example 12
2-Bromo-4,5-dimethoxybenzaldehyde dimethyl acetal and 2-chloro-N, N-dimethylisonicotinamide were treated in the same manner as in Reference Example 1 to obtain an oily product 3,4-dimethoxy-6- ( 2-chloroisonicotinoyl) benzaldehyde dimethyl acetal is obtained.
Reference Example 13
2-Bromo-4,5-dimethoxybenzaldehyde dimethyl acetal and 2-chloro-N, N-dimethylisonicotinamide were treated in the same manner as Reference Examples 1 and 2 to give 3,4-diethoxy-6- (2 -Chloroisonicotinoyl) benzaldehyde is produced.
M.p. 153-154 ℃
Reference Example 14
2-Bromo-4,5-dimethoxybenzaldehyde dimethyl acetal and N, N-dimethylisonicotinamide were treated in the same manner as Reference Examples 1 and 2 to give 3,4-dimethoxy-6- (2-isonicotino (1) Produce benzaldehyde.
M.p. 128-130 ℃
Reference Example 15
3,4-Dimethoxy-6- (2-isonicotinoyl) benzaldehyde was treated in the same manner as in Reference Example 3 to produce 3,4-dimethoxy-6- (2-isonicotinoyl) benzoic acid.
M.p. 258-260 ℃ (decomposition)
Reference Example 16
(1) Potassium carbonate in a dimethylformamide (500 mL) solution of 3,4-dimethoxy-6- (2-isonicotinoyl) benzoic acid (50.8 g) and diethyl bromomalonate (30 mL) (24 g) is added and the mixture is stirred at rt for 4 h. The mixture is concentrated under reduced pressure to remove the solvent and water is added to the residue. The mixture is extracted with ethyl acetate and the extracts are washed, dried and concentrated. The residue is crystallized from ether. The remaining crystals are added to a mixture of acetic acid (300 mL) and concentrated hydrochloric acid (300 mL). The mixture is heated to reflux for 5 hours and concentrated. The residue is recrystallized from tetrahydrofuran to give 3-carboxy-4- (4-pyridyl) -6,7-dimethoxyisocoumarin (23.4 g).
M.p. 250 ℃
(2) 3-carboxy-4- (4-pyridyl) -6,7-dimethoxyisocoumarin (1.86 g) was added to a methanol (100 mL) solution of 2.6 M ammonia, and the mixture was Leave for days. The reaction mixture is concentrated and water is added thereto. The pH of the mixture is adjusted to about pH 5 with 1 M hydrochloric acid and concentrated. To the residue is added 4M ethyl acetate solution of hydrochloric acid and the mixture is stirred at room temperature for 20 hours. The reaction mixture is concentrated, the residue is dissolved in a mixture of methanol and chloroform (3: 2) and the mixture is washed with saturated sodium chloride solution, dried and concentrated. The residue is recrystallized from methanol-ethyl acetate to give 3-carboxy-4- (4-pyridyl) -6,7-dimethoxyisoquinolin-1 (2H) -one hydrochloride (1.3 g).
M.p. 250 ℃
(3) 3-carboxy-4- (4-pyridyl) -6,7-dimethoxyisoquinolin-1 (2H) -one hydrochloride (12.6 g) is added to phosphorus oxychloride (200 mg), The mixture is stirred at 50 ° C. for 1.5 h. The reaction mixture is concentrated, toluene (200 mL) is added thereto, and methanol (100 mL) is further added. To the mixture is added triethylamine (15 mL) at 0 ° C. and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated and water is added to the residue. The mixture is extracted with chloroform and the extracts are washed, dried and concentrated. The residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 5: 1) to give 3-methoxycarbonyl-4- (4-pyridyl) -6,7-dimethoxyisoquinoline-1 (2H) -on (6.55 g) is produced.
M.p. 243-245 ℃ (decomposition)
(4) 3-methoxycarbonyl-4- (4-pyridyl) -6,7-dimethoxyisoquinolin-1 (2H) -one (6 g) is added to phosphorus oxychloride (100 mL), The mixture is heated to reflux for 2.5 hours. The reaction mixture is concentrated and chloroform is added thereto. To the mixture is further added saturated aqueous sodium hydrogen carbonate solution and the mixture is stirred for 20 minutes. The organic layer is recovered, dried and concentrated. The residue was purified by silica gel chromatography (solvent; chloroform: ethyl acetate = 5: 1) to give 1-chloro-3-methoxycarbonyl-4- (4-pyridyl) -6,7-dimethoxyiso Produces quinoline (5.17 g).
M.p. 220-222 ℃ (decomposition)
Reference Example 17
(1) Tetrahydrofuran (100 mL) of 3- (3,4-dimethoxyphenyl) -L-alanine methyl ester (12.2 g) in a tetrahydrofuran (200 mL) suspension of lithium aluminum hydride (7.75 g) The solution is added dropwise at 0 ° C. The reaction mixture is stirred at 0 ° C. for 30 min and thereto is added dropwise water (7.7 mL), 10% aqueous sodium chloride solution (7.7 mL) and water (23.1 mL). The reaction mixture is stirred at room temperature overnight and filtered through a pad of celite. The filtrate is concentrated to give (2S) -2-amino-3- (3,4-dimethoxyphenyl) -1-propanol (10.8 g) as a brown oily product.
(2) (2S) -2-amino-3- (3,4-dimethoxyphenyl) -1-propanol (2 g), 2-bromoisonicotinic acid (4.2 g), 1-hydroxybenzothiazole mono Hydrate (3.16 g) and 1,3-dicyclohexylcarbodiimide (4.26 g) are added to methylene chloride (20 mL) and the mixture is stirred at rt overnight. The reaction mixture is concentrated and ether is added thereto. Insoluble materials were removed by filtration and the filtrate was concentrated to give (2S) -1- (2-bromoisonicotinoyloxy) -2- (2-bromoisonicotinoylamino) -3- (3,4 To dimethoxyphenyl) propane (5 g).
(3) of (2S) -1- (2-bromoisonicotinoyloxy) -2- (2-bromoisonicotinoylamino) -3- (3,4-dimethoxyphenyl) propane (4.68 g) 1 M lithium hydroxide (8.1 mL) is added to the methanol (100 mL) suspension and the mixture is stirred for 15 h. The reaction mixture is concentrated under reduced pressure to remove methanol and the residue is extracted with methylene chloride. The extract is washed, dried and concentrated. The residue was purified by silica gel chromatography (solvent; chloroform: acetone = 5: 1) to give (2S) -2- (2-bromoisonicotinoylamino) -3- (3,4-dimethoxyphenyl)- Produces 1-propanol (1.2 g).
M.p. 151-153 ℃
(4) potassium in a dimethylformamide (40 mL) solution of (2S) -2- (2-bromoisonicotinoylamino) -3- (3,4-dimethoxyphenyl) -1-propanol (1.2 g) Carbonate (0.88 g) and copper (I) iodide (0.61 g) are added at room temperature under a nitrogen atmosphere. The mixture is heated with stirring at 120 ° C. for 30 minutes. 4- (3-pyridyl) phthalazine-1 (2H) -one (1.42 g) is added to the reaction mixture, and the mixture is stirred and heated at 130 ° C. for 2 hours. The reaction mixture is cooled to room temperature, to which aqueous ammonia is added. The mixture is extracted with chloroform and the extracts are washed, dried and concentrated. The residue was purified by silica gel chromatography (solvent; chloroform: acetone = 1: 1) to give (2S) -2- {2- [4- (3-pyridyl) phthalazine-1 (2H) -one- 2-yl] isonicotinoylamino} -3- (3,4-dimethoxyphenyl) -1-propanol (330 mg).
M.p. 135-137 ℃
(5) (2S) -2- {2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] isonicotinoylamino} -3- (3,4- To a solution of dimethoxyphenyl) -1-propanol (200 mg) in methylene chloride (5 mL) was added a catalytic amount of acetic anhydride (50 μL), triethylamine (80 μL), and dimethylaminopyridine at ice cooling, and the mixture was allowed to Stir for 2 hours. To the reaction mixture are added methanol and saturated sodium chloride solution on ice cooling and the mixture is extracted with chloroform. The extract is washed, dried and concentrated. The residue was recrystallized from ether to give (2S) -2- {2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] isonicotinoylamino} -3- ( To yield 3,4-dimethoxyphenyl) -1-acetoxypropane (200 mg).
M.p. 118-120 ℃
Reference Example 18
(1) Methylene chloride (120 mL) in 3- (3,4-dimethoxyphenyl) alanine ethyl ester (12.4 g), 2-bromoisonicotinic acid (10.9 g), 1-hydroxybenzotriazole monohydrate ( 8.23 g) and 1,3-dicyclohexylcarbodiimide (11.1 g) are added and the mixture is stirred at room temperature overnight. Insoluble materials are removed by filtration and the filtrate is concentrated. The residue was purified by silica gel chromatography (solvent; chloroform: acetone = 10: 1) to give the oily product N- (2-bromoisonicotinoyl) -3- (3,4-dimethoxyphenyl) alanine ethyl Obtain ester (13.9 g).
(2) Sodium borohydride (3.3 g) in a tetrahydrofuran (100 mL) solution of N- (2-bromoisonicotinoyl) -3- (3,4-dimethoxyphenyl) alanine ethyl ester (12.8 g) ) Is added dropwise over 3 hours with methanol (15 mL) heated to reflux. The reaction mixture is cooled with ice and water is added thereto. The mixture is extracted with chloroform and the extract is washed, dried and concentrated to give 2- (2-bromoisonicotinoylamino) -3- (3,4-dimethoxyphenyl) -1-propanol (10.2 g) do.
(3) 2- (2-bromoisonicotinoylamino) -3- (3,4-dimethoxyphenyl) -1-propanol in the same manner as in Reference Example 17- (4) to give 2- {2- To [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] isonicotinoylamino} -3- (3,4-dimethoxyphenyl) -1-propanol.
M.p. 147-148 ℃
(4) 2- {2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] isonicotinoylamino} -3- (3,4-dimethoxyphenyl) -1-propanol was treated in the same manner as in Reference Example 17- (5) to give 2- {2- [4- (3-pyridyl) phthalazine-1 (2H) -on-2-yl] isonicotino To monoamino} -3- (3,4-dimethoxyphenyl) -1-acetoxypropane.
M.p. 85-87 ℃
Reference Example 19
(1) 3- (3,4-dimethoxyphenyl) -L-alanine ethyl ester hydrochloride (66 g), triethylamine (33.3 mL), 2-bromoisonicotinic acid (50.6 g), 1-hydroxy Benzotriazole monohydrate (38.4 g) and 1,3-dicyclohexylcarbodiimide (51.7 g) are added to methylene chloride (660 mL) and the mixture is stirred at rt for 4 h. The reaction mixture is washed, dried and concentrated. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 10: 1) to give N- (2-bromoisonicotinoyl) -3- (3,4-dimethoxyphenyl) -L-alanine Ethyl ester (93.5 g) is obtained.
M.p. 108-109 ℃
(2) 2 (S) by treating N- (2-bromoisonicotinoyl) -3- (3,4-dimethoxyphenyl) -L-alanine ethyl ester in the same manner as in Reference Example 18- (2) To produce 2- (2-bromoisonicotinoylamino) -3- (3,4-dimethoxyphenyl) -1-propanol.
M.p. 136-138 ℃
Reference Examples 20 to 27
Reference Examples for Heterocyclic Compounds Corresponding to 2 (S) -2- (2-bromoisonicotinoylamino) -3- (3,4-dimethoxyphenyl) -1-propanol and Compound (III-a) The same procedure as for 17- (4) gave the compounds shown in Tables 11 and 12.

Reference Examples 28 to 35
The pyridine derivatives of compound (XLVIII) were treated in the same manner as Reference Example 17- (5) to afford the compounds shown in Tables 13 and 14.

Reference Example 36
(1) 3,4-diethoxybenzaldehyde (234.4 g), N-acetylglycine (95.4 g) and sodium acetate (49.5 g) are added to acetic anhydride (193 mL), and the mixture is heated to reflux for 1 hour, The reaction mixture is left to cool. The reaction mixture is then left in the fridge overnight and then water is added thereto. The mixture is extracted with chloroform and the extract is washed, dried and concentrated. The residue is recrystallized to yield 4- (3,4-diethoxybenzylidene) -2-methylroxazol-5 (4H) -one (100.9 g).
M.p. 117-119 ℃
(2) 4- (3,4-diethoxybenzylidene) -2-methylroxazol-5 (4H) -one (100 g) was added to acetone (200 mL) and water (400 mL) and the mixture was refluxed. Under heating for 3.5 hours. The mixture is evaporated to remove acetone and cooled to room temperature. The precipitate is recovered by filtration and washed with water to yield N-acetyl-3- (3,4-diethoxyphenyl) dihydroalanine (99 g).
M.p. 190-193 ℃
(3) To an acetic acid (1000 mL) suspension of N-acetyl-3- (3,4-diethoxyphenyl) dihydroalanine (100.2 g) was added 10% palladium-carbon (4 g) and the mixture was 40 ° C. It is hydrogenated at 3 atmospheres of hydrogen gas for 7 hours. The catalyst is removed by filtration and the filtrate is concentrated. The residue is crystallized from ether to yield N-acetyl-3- (3,4-diethoxyphenyl) alanine (70.1 g).
M.p. 149-151 ℃
(4) To 1M hydrochloric acid (600 mL) is added N-acetyl-3- (3,4-diethoxyphenyl) alanine (70 g) and the mixture is heated at reflux overnight. The reaction mixture is concentrated to dryness and the residue is suspended in ethanol (900 mL), to which acetyl chloride (200 mL) is added dropwise at -10 ° C. After addition, the mixture is slowly warmed to room temperature and stirred at room temperature overnight. The reaction mixture is concentrated, aqueous potassium carbonate solution is added to the residue, and the mixture is extracted with ethyl acetate. The extract is washed, dried, to which 4M ethyl acetate (60 mL) solution of hydrochloric acid is added and the mixture is concentrated, the residue is recrystallized from ether, 3- (3,4-dimethoxyphenyl) alanine ethyl ester hydro Produces chloride (63.4 g).
M.p. 151-152 ℃
(5) 2- (3-bromo-isonicotinoyl by treating 3- (3,4-dimethoxyphenyl) alanine ethyl ester hydrochloride in the same manner as in Reference Examples 19- (1) and-(2) To amino) -3- (3,4-diethoxyphenyl) -1-propanol.
M.p. 97-99 ℃
Examples 37 to 40
2- (2-Bromo-isonicotinoylamino) -3- (3,4-diethoxyphenyl) -1-propanol and heterocyclic compound (III-a) are the same as in Reference Example 17- (4) Treatment was carried out to produce the compounds shown in Table 15.
Reference Examples 41 to 44
The pyridine derivative of compound (XLVIII) was treated in the same manner as Reference Example 17- (5) to give the compounds shown in Table 16.
Reference Example 45
(1) 2-bromo-4,5-dimethoxybenzaldehyde dimethyl acetal and 2-chloro-N, N-diethylisonicotinamide were treated in the same manner as in Reference Examples 1, 2 and 3 to give 3,4-dimethy; To form oxy-6- (2-chloroisonicotinoyl) -benzoic acid.
M.p. 201-203 ℃
(2) To a tetrahydrofuran (1800 mL) solution of 3,4-dimethoxy-6- (2-chloroisonicotinoyl) -benzoic acid (70 g), triethylamine (45.5 mL) was added to a nitrogen atmosphere at room temperature. Add and add ethyl chloroformate (25 mL) dropwise at a temperature below −20 ° C. and stir the mixture at −20 ° C. for 10 minutes. To the reaction mixture is added 1.38 M aqueous sodium azide solution (500 mL) and the mixture is stirred at rt for 1.5 h and then extracted with ethyl acetate. Extracts are washed, dried and concentrated. The residue is dissolved in toluene (1300 mL) and the mixture is heated under reflux for 1 hour. Concentrated hydrochloric acid (450 mL) is added to the reaction mixture on ice cooling and the mixture is heated with stirring at 80 ° C. for 1 hour. Ice water is added to the reaction mixture, and the mixture is extracted with chloroform. Extracts are washed, dried and concentrated. The residue is recrystallized from ether to give 3,4-dimethoxy-6- (2-chloroisonicotinoyl) alanine (50.3 g).
M.p. 132-134 ℃
Reference Example 46
Boron chloride (25 g) is added to 1,2-dichloroethane (150 mL) on ice cooling and the mixture is stirred for 15 minutes. To the reaction mixture is added dropwise a solution of 1,2-dichloroethane (150 mL) of 3,4-dimethoxyaniline (36.3 g), to which 4-cyanopyridine (27.1 g) is added. The reaction mixture is heated under reflux overnight, to which 2M hydrochloric acid (160 mL) is added. The mixture is stirred and heated at 80 ° C. for 2 hours, to which 2 M aqueous sodium hydroxide solution (450 mL) is added at ice cooling. The mixture is separated to recover the 1,2-dichloroethane layer and the aqueous layer is extracted with ethyl acetate. The organic layer is recovered, washed, dried and concentrated. The residue is crystallized from ether to give 3,4-dimethoxy-6-isonicotinoylaniline (13.1 g).
M.p. 155-158 ℃
Reference Example 47
3,4-dimethoxyaniline and 4-cyanopyridine.N-oxide are treated in the same manner as in Reference Example 46 to produce 3,4-dimethoxy-6-isonicotinoylaniline.N-oxide. .
M.p. 192-194 ℃
Reference Example 48
To a toluene (100 mL) suspension of 3,4-dimethoxy-6-isonicotinoylaniline (13.1 g) is added tetronic acid (5.6 g) and p-toluenesulfonic acid monohydrate (9.66 g). The reaction mixture is heated at reflux for 10 hours, during which time the water produced is removed by a Dean-Stark apparatus. Insoluble materials are recovered by filtration and water is added thereto. The pH of the mixture is adjusted to pH 9 with aqueous potassium carbonate solution, and the precipitated crude crystals are recovered by filtration. The resulting crude crystals are recrystallized from dioxane to give 2-hydroxymethyl-4- (4-pyridyl) -6,7-dimethoxy-3-quinolinecarboxylic acid lactone (14.1 g).
M.p. 220 ℃
Reference Example 49
3,4-Dimethoxy-6-isonicotinoylanilineN-oxide was treated in the same manner as in Reference Example 48 to 2-hydroxymethyl-4- (4-pyridyl) -6,7-dimethoxy 3-Quinolinecarboxylic acid lactone N-oxide is produced.
M.p. 220 ℃
Reference Example 50
2-hydroxymethyl-4- (4-pyridyl) -6,7-dimethoxy-3-quinolinecarboxylic acid lactoneN-oxide (677 mL) and 2-chloroquinoline in xylene (3 mL) 1.3 g) is added and the mixture is heated under reflux for 16 h. The reaction mixture is cooled to room temperature and water is added thereto. The mixture is extracted with methylene chloride and the extracts are washed, dried and concentrated. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 2: 1) to give 2-hydroxymethyl-4- {4- [2- (quinolin-2 (1H) -one-1-yl) ] Pyridyl} -6,7-dimethoxy-3-quinolinecarboxylic acid lactone (340 mg).
M.p. 220 ℃
Reference Example 51
3,4-dimethoxy-6- (2-chloroisonicotinoyl) aniline (10 g) and tetronic acid (3.76 g) were added to a mixture of toluene (20 mL) and trifluoroacetic acid (15 mL) The mixture is heated at reflux with a Dean-Stark apparatus for 2 hours. The reaction mixture is cooled to room temperature, the pH of the mixture is adjusted to pH 9 with aqueous potassium carbonate solution, and the mixture is extracted with methylene chloride. The extract is washed, dried and concentrated. The residue is recrystallized from methanol to give 2-hydroxymethyl-4- [4- (2-chloropyridyl)]-6,7-dimethoxy-3-quinolinecarboxylic acid lactone (8.26 g).
M.p. 245-246 ℃
Reference Example 52
2-hydroxymethyl-4- [4- (2-chloropyridyl)]-6,7-dimethoxy-3-quinolinecarboxylic acid lactone was treated in the same manner as in Reference Example 48 to 2-chloro-4- To [2,3-bis (hydroxymethyl) -6,7-dimethoxyquinolin-4-yl)] pyridine.
M.p. 196-199 ℃
Reference Example 53
3,4-Dimethoxy-6- (2-chloroisonicotinoyl) aniline (10 g) and diethyl ethoxymethylenemalonate (8.2 mL) are stirred and heated at 120 to 130 ° C for 2 hours. Ether is added to the reaction mixture, and the precipitated crystals are recovered by filtration. The resulting crystals (15.1 g) and lithium chloride (6.9 g) are added to dimethylformamide (150 mL) and the mixture is heated to reflux for 45 minutes under a nitrogen atmosphere. The reaction mixture is cooled to room temperature and water is added thereto. The mixture is extracted with ethyl acetate and the extracts are washed, dried and concentrated. The residue is recrystallized from a mixture of methanol-methylene chloride to give 2-chloro-4- (3-ethoxycarbonylquinoline-6,7-dimethoxy-4-yl) pyridine (4.83 g).
M.p. 191-193 ℃
Reference Example 54
2-chloro-4- (3-ethoxycarbonylquinoline-6,7-dimethoxy-4-yl) pyridine was treated in the same manner as in Reference Example 7- (2) to give 2-chloro-4- (3- Hydroxymethyl-6,7-dimethoxyquinolin-4-yl) pyridine.
M.p. 183-185 ℃
Compounds (I) and pharmaceutically acceptable salts thereof of the present invention show good bronchial contraction inhibitory action and / or anti-inflammatory action of the airways and are useful for the prevention and treatment of asthma. That is, the target compound (I) of the present invention can effectively inhibit bronchial contraction induced by various spasmogens or antigens such as histamine.
In addition, the target compound (I) of the present invention and its pharmaceutically acceptable salt show little side effects to the heart, exhibit selective bronchial contraction inhibiting action and low toxicity, and also advantageously exhibit high stability as a therapeutic drug. . Although theophylline exhibits side effects such as hypertension, palpitations, etc. in the heart, Compound (I) of the present invention and its pharmaceutically acceptable salts do not substantially exhibit these side effects, but also exhibit excellent anti-asthmatic action.

权利要求:
Claims (20)
[1" claim-type="Currently amended] Pyridine derivative (I) of formula (1), or a pharmaceutically acceptable salt thereof:
[Formula 1]
[Wherein A is a group selected from the formula:

Wherein R ¹ and R ² are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³¹ is a protected or unprotected hydroxymethyl group and R ³² is a hydrogen atom, a lower alkyl group Or a protected or unprotected hydroxymethyl group, R ³³ is a substituted or unsubstituted lower alkyl group, R ⁴¹ is a protected or unprotected hydroxymethyl group, R ⁴² is a protected or unprotected hydroxy group Methyl group, and dashed line means presence or absence of double bond.)
R ⁵ and R ⁶ are the same or different and each is a hydrogen atom or a protected or unprotected amino group, or both are substituted or unsubstituted heterocyclic in combination with adjacent nitrogen atoms to which they are attached at their ends; Form a flag.] [2" claim-type="Currently amended] A compound according to claim 1, wherein R ¹ and R ² are the same or different and each is a hydrogen atom, a hydroxy group, or a lower alkoxy group, R ³¹ is a hydroxymethyl group which may be optionally substituted with a lower alkylcarbonyl group, and R ³² Is a hydrogen atom, a lower alkyl group, or a hydroxymethyl group, R ³³ is a lower alkyl group substituted with a group selected from a pyridyl group, a cyclo-lower alkyl group, and a hydroxy group, R ⁴¹ is a hydroxymethyl group, and R ⁴² is a hydroxymethyl group compound.
[3" claim-type="Currently amended] The heterocyclic group according to claim 1 or 2, wherein R ⁵ and R ⁶ are formed in combination with adjacent nitrogen atoms to which they are bonded at their ends, in addition to the adjacent nitrogen atom, optionally a nitrogen atom, an oxygen atom, And a heteromonocyclic, heterobicyclic or heterotricyclic group having a hetero atom selected from a sulfur atom.
[4" claim-type="Currently amended] 4. The heterocyclic group according to claim 3, wherein R ⁵ and R ⁶ are formed at their terminals in combination with adjacent nitrogen atoms to which they are bonded, pyridyl group, quinolyl group, isoquinolyl group, cyclopenta [b] pyridyl group, Pyro [2,3-b] pyridyl groups, imidazo [4,5-b] pyridyl groups, pyrido [2,3-d] thiazolyl groups, pyrido [2,3-d] oxazolyl groups, naphti Ridinyl group, quinoxalinyl group, phthalazinyl group, quinazolinyl group, indolyl group, pyridazinyl group, thieno [2,3-d] pyridazinyl group, azefinyl group, azetidyl group, isoindolinyl group , A pyrrolyl group, a benzazinyl group, a phenanthridinyl group, a benzothiadinyl group, a benzimidazolinyl group, a pyrazinyl group or a morpholinyl group, and these heterocyclic groups are optionally partially or wholly hydrogenated .
[5" claim-type="Currently amended] The heterocyclic group according to any one of claims 1 to 4, wherein the substituents of the heterocyclic groups formed by combining R ⁵ and R ⁶ with the adjacent nitrogen atoms to which they are bonded at the (1) lower alkenyl group; (2) lower alkynyl groups; (3) lower alkylthio groups; (4) a cycloalkyl group; (5) trifluoromethyl group; (6) cyano group; (7) tetrazolyl group; (8) formyl groups; (9) amino groups; (10) mono- or di-substituted lower alkyl moieties may optionally be substituted by groups selected from morpholino groups, monocycloalkyl-substituted amino groups, pyridyl groups, imidazolyl groups, piperidyl groups and pyrrolidinyl groups Lower alkylamino groups; (11) pyridyl groups; (12) morpholino groups; (13) lower alkyl-substituted triazolyl groups; (14) bis (hydroxy-lower alkyl) aminocarbonyl groups; (15) bis (tri-lower alkylsilyloxy-lower alkyl) aminocarbonyl groups; (16) morpholinocarbonyl group; (17) lower alkyl-substituted piperazinylcarbonyl groups; (18) hydroxy-lower alkyl-substituted piperazinylcarbonyl groups; (19) tri-lower alkylsilyloxy-lower alkyl-substituted piperazinylcarbonyl groups; (20) lower alkoxycarbonyl group; (21) carboxyl group; (22) optionally a lower alkyl group which may be substituted with a morpholino group or a pyridyl group; (23) optionally a lower alkoxy group which may be substituted with a group selected from a piperidyl group, a pyridyl group, a hydroxyl group, and a lower alkoxy group; (24) oxo groups; (25) a hydroxy group; (26) pyrimidinyl groups; (27) optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; (28) halogen atoms; (29) nitro groups; (30) imidazolyl group; (31) lower alkylenedioxy group; (32) thiazolyl group; And (33) the same or different one or two groups selected from thienyl groups.
[6" claim-type="Currently amended] ^{6. The} oxo-substituted dihydroqui of claim 5, wherein the heterocyclic groups formed by combining R ⁵ and R ⁶ with the adjacent nitrogen atoms to which they are bonded at their ends (1) may optionally be substituted with a pyridyl group Teasing; (2) an oxo-substituted dihydroisoquinolyl group, which may optionally be substituted with a group selected from a morpholino-substituted lower alkoxy group and a pyridyl-substituted lower alkoxy group; (3) optionally a lower alkyl group which may be substituted with a pyridyl group; Pyrimidinyl groups; Lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group which may be optionally substituted with a group selected from thienyl group; (4) an oxo-substituted dihydropyridyl group, which may optionally be substituted with a pyridyl group; (5) oxo-substituted dihydronaphthyridinyl group; (6) a di-oxo-substituted dihydroquinazolinyl group which may be optionally substituted with a lower alkyl group; And (7) a group selected from an oxo-substituted thienopyridazinyl group which may optionally be substituted with a tri-lower alkoxy-substituted phenyl group.
[7" claim-type="Currently amended] A compound according to claim 1 wherein A is a group selected from:

(Wherein R ¹ and R ² may be the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group which may optionally be substituted with a lower alkylcarbonyl group, and R ³² is a hydrogen atom or hydroxy Is a methyl group, R ³³ is a methyl group substituted with a group selected from a cyclo-lower alkyl group and a hydroxy group, R ⁴¹ is a hydroxymethyl group, R ⁴² is a hydroxymethyl group), and R ⁵ and R ⁶ are bonded at their terminals A heterocyclic group formed in combination with an adjacent nitrogen atom, which is (1) an oxo-substituted dihydroisoquinolyl group substituted with a group selected from a morpholino-substituted lower alkoxy group and a pyridyl-substituted lower alkoxy group; (2) optionally a lower alkyl group which may be substituted with a pyridyl group; Pyrimidinyl groups; Lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group which may be optionally substituted with a group selected from thienyl group; (3) oxo-substituted dihydronaphthyridinyl groups; (4) di-oxo-substituted dihydroquinazolinyl group; And (5) a group selected from an oxo-substituted thienopyridazinyl group substituted with a tri-lower alkoxy-substituted phenyl group.
[8" claim-type="Currently amended] The compound of claim 1, wherein A is a group selected from:

(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group which may optionally be substituted with a lower alkylcarbonyl group, and R ³² is a hydrogen atom or a hydroxymethyl group) , R ⁴² is a hydroxymethyl group.), A heterocyclic group formed by combining R ⁵ and R ⁶ with the adjacent nitrogen atom to which they are bonded at their terminals (1) Morpholino-substituted lower alkoxy group and pyridyl- Oxo-substituted dihydroisoquinolyl groups substituted with groups selected from substituted lower alkoxy groups, and (2) optionally lower alkyl groups, pyrimidinyl groups, lower alkoxy groups, pyridyl groups, thiazolyl groups, phenyl groups, and thienyl groups A compound selected from an oxo-substituted dihydrophthalazinyl group which may be substituted with a group selected from.
[9" claim-type="Currently amended] The compound of claim 1, wherein A is a group of formula:

(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, and R ³¹ is optionally a hydroxymethyl group which may be substituted with a lower alkylcarbonyl group.), R ⁵ and R ⁶ are their ends In which the heterocyclic group formed in combination with the adjacent nitrogen atom to which they are bonded is (1) an oxo-substituted dihydroisoquinolyl group substituted with a morpholino-substituted lower alkoxy group, and (2) a lower alkyl group, in some cases, A compound selected from a pyridyl group and an oxo-substituted dihydrophthalazinyl group which may be substituted with a group selected from a thiazolyl group.
[10" claim-type="Currently amended] The compound of claim 1, wherein A is a group of formula:

(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, and R ³¹ is optionally a hydroxymethyl group which may be substituted with a lower alkylcarbonyl group.), R ⁵ and R ⁶ are their ends An oxo-substituted dihydroisoquinolyl group in which the heterocyclic group formed in combination with the adjacent nitrogen atom to which they are bonded is substituted with a group selected from (1) a morpholino-substituted lower alkoxy group and a pyridyl-substituted lower alkoxy group, (2) lower alkyl groups; Lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group substituted with a group selected from a thienyl group, and (3) an oxo-substituted thienopyridazinyl group substituted with a tri-lower alkoxy-substituted phenyl group.
[11" claim-type="Currently amended] The compound of claim 1, wherein A is a group of formula:

(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group), and R ⁵ and R ⁶ are formed in combination with adjacent nitrogen atoms to which they are bonded at their ends; An oxo-substituted dihydroisoquinolyl group in which the heterocyclic group is substituted with a group selected from (1) a morpholino-substituted lower alkoxy group and a pyridyl-substituted lower alkoxy group, (2) a lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group substituted with a group selected from a thienyl group, and (3) an oxo-substituted thienopyridazinyl group substituted with a tri-lower alkoxy-substituted phenyl group.
[12" claim-type="Currently amended] The compound of claim 1, wherein A is a group of formula:

(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group), and R ⁵ and R ⁶ are formed in combination with adjacent nitrogen atoms to which they are bonded at their ends; Oxo-substituted dihydrophthalazinyl in which the heterocyclic group is substituted with a group selected from (1) a morpholino-substituted lower alkoxy group, and (2) a group selected from a pyridyl group and a thiazolyl group A group selected from the group.
[13" claim-type="Currently amended] 2. A compound according to claim 1 wherein A is a group of the formula:

(Wherein R ¹ and R ² are the same or different, each is a lower alkoxy group, R ³¹ is a hydroxymethyl group), and R ⁵ and R ⁶ are formed in combination with adjacent nitrogen atoms to which they are bonded at their ends; Lower alkyl groups in which the heterocyclic group may be optionally substituted with a pyridyl group; Pyrimidinyl groups; Lower alkoxy group; Halogen atom; Pyridyl groups; Thiazolyl group; Optionally a di-lower alkylamino group or a phenyl group which may be substituted with a halogen atom; And an oxo-substituted dihydrophthalazinyl group which may be optionally substituted with a group selected from thienyl groups.
[14" claim-type="Currently amended] In the method for preparing a pyridine derivative (Ia) of formula (Ia), or a pharmaceutically acceptable salt thereof, compound (II) of formula (2) is reacted with nitrogen-containing compound (III) of formula (3), and the product is a hydroxy group And / or introducing a protecting group to the hydroxy portion of the product, if necessary, or having a hydroxymethyl group, or removing the protecting group from the product, if necessary, when the product has a protected hydroxy group and / or a protected hydroxymethyl group, And, if necessary, then comprising converting the product into a pharmaceutically acceptable salt thereof:
[Formula 1a]
[Wherein A ¹ is a group selected from the formulas:

(Wherein R ¹ and R ² are the same or different and each is a hydrogen atom, or a protected or unprotected hydroxy group, R ³¹ is a protected or unprotected hydroxymethyl group, R ³² is a hydrogen atom, a lower alkyl group, or A protected or unprotected hydroxymethyl group, R ³³ is a substituted or unsubstituted lower alkyl group, R ⁴¹ is a protected or unprotected hydroxymethyl group, and R ⁴² is a protected or unprotected hydroxymethyl group. ), R ⁵ and R ⁶ are the same or different and each is a hydrogen atom or a protected or unprotected amino group, or both are substituted or unsubstituted hetero in combination with adjacent nitrogen atoms to which they are bonded at their termini; To form a cyclic group.] [Formula 2]
[Wherein A ² is a group selected from the formulas:

(Wherein R ¹¹ and R ²¹ are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³⁴ is a protected or unprotected hydroxymethyl group, R ³⁵ is a hydrogen atom, a lower alkyl group, or A protected or unprotected hydroxymethyl group, R ³⁶ is a substituted or unsubstituted lower alkyl group, R ⁴³ is a protected or unprotected hydroxymethyl group, and R ⁴⁴ is a protected or unprotected hydroxymethyl group. ), X is a halogen atom.] [Formula 3]
Wherein R ⁵ and R ⁶ are as defined above.
[15" claim-type="Currently amended] In the process for preparing the pyridine derivative (Ib) of formula (Ib), or a pharmaceutically acceptable salt thereof, the compound (IV) of formula (IV) is subjected to intramolecular cyclization reaction, and when the product has a hydroxyl group, When introducing a protecting group to a hydroxy group, or when the product has a protected hydroxy group and / or protected hydroxymethyl group, the protecting group is removed from the product if necessary, and, if necessary, thereafter, the product is converted into a pharmaceutically acceptable salt thereof. How to Include:
[Formula 1b]
Wherein R ¹ and R ² are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³¹ is a protected or unprotected hydroxymethyl group and R ⁵¹ and R ⁶¹ are at their ends In combination with adjacent nitrogen atoms to which they are attached to form a heterocyclic group substituted with at least an oxo group.)
[Formula 4]
Wherein R ¹¹ and R ²¹ are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³⁷ is a protected hydroxymethyl group and R ⁵¹ and R ⁶¹ are as defined above. )
[16" claim-type="Currently amended] In the process for preparing a pyridine derivative (Ic) of formula (Ic) or a pyrimidine derivative (Id) of formula (Id), or a pharmaceutically acceptable salt thereof, the compound of formula (Ie) (Ie) When reacted with a carboxylic acid derivative (V) or a salt thereof, or a carboxylic acid derivative (VI) or a salt thereof, and when the product has a hydroxy group and / or a hydroxymethyl group, the hydroxy portion of the product, if necessary When introducing a protecting group or when the product has a protected hydroxy group and / or protected hydroxymethyl group, removing the protecting group from the product if necessary, and then converting the product to a pharmaceutically acceptable salt thereof if necessary. How to Include:
[Formula 1c]
[Wherein A ¹ is a group selected from the formulas:

(Wherein R ¹ and R ² are the same or different and each is a hydrogen atom, or a protected or unprotected hydroxy group, R ³¹ is a protected or unprotected hydroxymethyl group, R ³² is a hydrogen atom, a lower alkyl group, or A protected or unprotected hydroxymethyl group, R ³³ is a substituted or unsubstituted lower alkyl group, R ⁴¹ is a protected or unprotected hydroxymethyl group, and R ⁴² is a protected or unprotected hydroxymethyl group. ), R ⁹¹ , R ⁹² and R ⁹³ are the same or different and each is a hydrogen atom; Thienyl group; Halogen atom; Lower alkoxy group; Optionally a lower alkyl group substituted with a pyridyl group; Optionally a phenyl group substituted with a group selected from a di-lower alkylamino group, a lower alkoxy group and a halogen atom; Pyridyl groups; Pyrimidinyl groups; Or a thiazolyl group.] [Formula 1d]
Wherein A ¹ is as defined above and R ⁹⁴ , R ⁹⁵ and R ⁹⁶ are the same or different and each is a hydrogen atom; a thienyl group; a halogen atom; a lower alkoxy group; optionally substituted with a pyridyl group Lower alkyl group; optionally a phenyl group substituted with a group selected from a di-lower alkylamino group, a lower alkoxy group and a halogen atom; a pyridyl group; a pyrimidinyl group; or a thiazolyl group.)
[Formula 1e]
[Wherein A ² is a group selected from the formulas:

(Wherein R ¹¹ and R ²¹ are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³⁴ is a protected or unprotected hydroxymethyl group, R ³⁵ is a hydrogen atom, a lower alkyl group, or A protected or unprotected hydroxymethyl group, R ³⁶ is a substituted or unsubstituted lower alkyl group, R ⁴³ is a protected or unprotected hydroxymethyl group, and R ⁴⁴ is a protected or unprotected hydroxymethyl group. )
[Formula 5]
^Wherein R ⁹¹ , R ⁹² and R ⁹³ are as defined above.
[Formula 6]
^Wherein R ⁹⁴ , R ⁹⁵ and R ⁹⁶ are as defined above.
[17" claim-type="Currently amended] Compound (II) of Formula 2
[Formula 2]
[Wherein A ² is a group selected from the formulas:

Wherein R ¹¹ and R ²¹ are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³⁴ is a protected or unprotected hydroxymethyl group and R ³⁵ is a hydrogen atom, a lower alkyl group Or a protected or unprotected hydroxymethyl group, R ³⁶ is a substituted or unsubstituted lower alkyl group, R ⁴³ is a protected or unprotected hydroxymethyl group, R ⁴⁴ is a protected or unprotected hydroxymethyl group X is a halogen atom.] [18" claim-type="Currently amended] Compound (IV) of Formula 4, or a salt thereof:
[Formula 4]
(Wherein R ¹¹ and R ²¹ are the same or different and each is a hydrogen atom or a protected or unprotected hydroxy group, R ³⁷ is a protected hydroxymethyl group, and R ⁵¹ and R ⁶¹ are bonded at their terminals) In combination with adjacent nitrogen atoms to form a heterocyclic group substituted at least with an oxo group.)
[19" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a pyridine derivative according to any one of claims 1 to 13 in a mixture with a pharmaceutically acceptable carrier or diluent.
[20" claim-type="Currently amended] Use of a pyridine derivative according to any one of claims 1 to 13 used for the prevention or treatment of asthma.

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同族专利:

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DK0848000T3|2002-09-30|

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1996-12-13|Priority to JP33335796

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1996-12-13|Priority to JP96-333357

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1997-12-11|Application filed by 다나까도오시오, 다나베세이야꾸가부시끼가이샤

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1998-10-07|Publication of KR19980064040A

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2004-05-24|Application granted

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2004-05-24|Publication of KR100416833B1

优先权:

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申请号 | 申请日 | 专利标题

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JP33335796|1996-12-13|

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JP96-333357|1996-12-13|