Pharmaceutically useful compounds

专利摘要:
The present invention relates to 2-arylpyrazoleisoquinoline and cinnaolinone derivatives, methods for their preparation, their use as medicaments and pharmaceutical compositions comprising them.
公开号:KR20000064716A
申请号:KR1019980707441
申请日:1997-03-20
公开日:2000-11-06
发明作者:존 밴틱；로저 보너트；피터 케이지；데이빗 도널드；마크 퍼버；시몬 허스트；매튜 페리；에이피온 필립스
申请人:니콜라스 피터 비가르트 (니크 비가르트), 콜린 레드롭；아스트라 파마슈티칼스 리미티드；
IPC主号:

专利说明:

Pharmaceutically useful compounds
Specific pyrazolo [4,3-c] isoquinolin-3-ones are described in Hinton et al., J. Chem. Soc. 599 (1959). Their use as drugs has not been proposed. The synthesis of certain pyrazolo [4,3-c] isoquinolin-3-ols and their ability to inhibit radioligand binding to benzodiazepine receptors are described in Allen et al., J. Med. Chem. 35, 368 (1992). Other specific pyrazolo [4,3-c] isoquinolin-3-ols have been disclosed in Qian Jian-hua et al., Gaodeng Xuexiao Huaxue Xuebao 1991, 12, 1620-1622. No pharmaceutical use of the compound is mentioned.
The present invention relates to pharmaceutically useful compounds, methods for their preparation, their use as medicaments and pharmaceutical compositions comprising them.
It has now been found that 2-arylpyrazoleisoquinoline and cinnalinone derivatives exhibit anti-allergic and anti-inflammatory activity. Accordingly, in a first aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable derivative thereof, useful as a drug.
Where
B, D, E and G each represent CH, CA or N, provided that only one of B, D, E and G represents CA and only one of B, D, E and G represents N;
X represents C═O, C═S, C═NR ¹⁵ , CR ³ R ⁶ or NR ⁴ ;
Y represents N or N ⁺ R ⁷ or CR ¹⁸ ;
Z represents OR ⁸ or O ⁻ ;
R ¹ represents OH or C _1-6 alkyl or forms a bond with R ² or R ⁵ ;
R ² represents H, C _1-6 alkyl (optionally substituted with phenyl, COOR ⁹ , NR ¹⁰ R ¹¹ , OR ¹² or F) or C _3-7 cycloalkyl or R ¹ , R ³ Or together with R ⁴ form a bond;
R ³ represents H or represents a bond with R ² ;
R ⁴ represents C _1-6 alkyl or represents a bond with R ² ;
R ⁵ represents a bond together with R ¹ or R ⁸ ;
R ⁶ is H, C _1-6 alkyl (optionally substituted with phenyl), C _3-7 cycloalkyl, phenyl, halogen, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Alkylsulfinyl, cyano or NR ¹³ R ¹⁴ ;
R ⁷ represents C _1-6 alkyl (which alkyl is optionally substituted with phenyl) or C _3-7 cycloalkyl, one of which is halogen, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, NR ¹⁶ R ^17, COOH, COO (C _1-6 alkyl), or cyano, or furnace be optionally substituted,
R ⁶ and R ⁷ together represent C _3-5 alkylene, such that X and Y form a 5-7 membered ring;
R ⁸ represents H or C _1-6 alkyl or represents a bond with R ⁵ ;
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently represent C _1-6 alkyl or H;
R ¹³ and R ¹⁴ independently represent C _1-6 alkyl or H, or together with the nitrogen atom to which they are attached form a three to seven membered saturated ring, which ring optionally further comprises an oxygen atom or a nitrogen atom And optionally substituted with C _1-6 alkyl);
Ar ¹ represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxalinyl, all of which are halo, nitro, cyano, phenyl, phenylsulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO (C _1-6 alkyl), a phenyl C _1-6 alkyl, or phenyl substituted with Optionally substituted with one or more substituents selected from wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl group may be optionally substituted with fluoro;
A represents halo, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy;
The phenyl group in the above definition of R ² , R ⁶ and R ⁷ or as a substituent on Ar ¹ may be optionally substituted with C _1-6 alkyl, halogen or C _1-6 alkoxy;
only,
(i) if X represents C═O, C═S or C═NR ¹⁵ , then Y represents N;
(ii) when R ⁴ represents a bond with R ² , then Y represents N ⁺ R ⁷ ;
(iii) Y represents that the N ⁺ R ^7, Z is O ^- represents a, R ² represents the bond with R ³ or R ^4, R ¹ and R ⁵ forms a bond;
(iv) when Y represents N, Z represents OR ⁸ ;
(v) when R ¹ represents OH, X represents C═O, Y represents N, Z represents OR ⁸ , and R ⁵ represents a bond with R ⁸ ;
(vi) when R ¹ represents alkyl, R ⁵ represents a bond with R ⁸ , Y represents N, R ² does not represent a bond, and X does not represent NR ⁴ ;
(vii) when R ¹ represents a bond with R ² , R ⁵ and R ⁸ form a bond, and when X represents NR ⁴ , R ⁴ represents alkyl;
(viii) when R ⁶ represents aryl, halogen, alkoxy or thioalkyl, R ² and R ³ form a bond;
(ix) when Y represents N or N ⁺ R ⁷ and R ² is substituted with any one of NR ¹⁰ R ¹¹ , OR ¹² or F, the substituents of Y and the ring nitrogen cannot bond to the same carbon atom of R ² ; ;
(x) when R ⁷ is substituted with any of NR ¹⁶ R ¹⁷ , OR ¹² or halogen, the substituent of Y and the ring nitrogen may not bond to the same carbon atom of R ⁷ ;
(xi) if one of B, D, E and G represents N, then X does not represent NR ⁴ ;
(xii) when Y represents CR ¹⁸ , X represents CR ³ R ⁶ ;
In addition,
B, D, E and G all represent CH, X represents CHR ³ , Y represents nitrogen, R ¹ and R ⁵ form a bond, R ⁸ represents H, R ² and R ³ When this represents a bond together, Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl.
Certain compounds of formula (I) are novel. According to the invention there is also provided a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
<Formula I>

Where
B, D, E and G each represent CH, CA or N, provided that only one of B, D, E and G represents CA and only one of B, D, E and G represents N;
X represents C═O, C═S, C═NR ¹⁵ , CR ³ R ⁶ or NR ⁴ ;
Y represents N or N ⁺ R ⁷ or CR ¹⁸ ;
Z represents OR ⁸ or O ⁻ ;
R ¹ represents OH or C _1-6 alkyl or forms a bond with R ² or R ⁵ ;
R ² represents H, C _1-6 alkyl (optionally substituted with phenyl, COOR ⁹ , NR ¹⁰ R ¹¹ , OR ¹² or F) or C _3-7 cycloalkyl or R ¹ , R ³ Or together with R ⁴ form a bond;
R ³ represents H or represents a bond with R ² ;
R ⁴ represents C _1-6 alkyl or represents a bond with R ² ;
R ⁵ represents a bond together with R ¹ or R ⁸ ;
R ⁶ is H, C _1-6 alkyl (optionally substituted with phenyl), C _3-7 cycloalkyl, phenyl, halogen, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Alkylsulfinyl, cyano or NR ¹³ R ¹⁴ ;
R ⁷ represents C _1-6 alkyl (which alkyl is optionally substituted with phenyl) or C _3-7 cycloalkyl, one of which is halogen, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, NR ¹⁶ R ^17, COOH, COO (C _1-6 alkyl), or cyano, or furnace be optionally substituted,
R ⁶ and R ⁷ together represent C _3-5 alkylene, such that X and Y form a 5-7 membered ring;
R ⁸ represents H or C _1-6 alkyl or represents a bond with R ⁵ ;
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently represent C _1-6 alkyl or H;
R ¹³ and R ¹⁴ independently represent C _1-6 alkyl or H, or together with the nitrogen atom to which they are attached form a three to seven membered saturated ring, which ring optionally further comprises an oxygen atom or a nitrogen atom And optionally substituted with C _1-6 alkyl);
Ar ¹ represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxalinyl, all of which are halo, nitro, cyano, phenyl, phenylsulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO (C _1-6 alkyl), a phenyl C _1-6 alkyl, or phenyl substituted with Optionally substituted with one or more substituents selected from wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl group may be optionally substituted with fluoro;
A represents halo, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy;
The phenyl group in the above definition of R ² , R ⁶ and R ⁷ or as a substituent on Ar ¹ may be optionally substituted with C _1-6 alkyl, halogen or C _1-6 alkoxy;
only,
(i) if X represents C═O, C═S or C═NR ¹⁵ , then Y represents N;
(ii) when R ⁴ represents a bond with R ² , then Y represents N ⁺ R ⁷ ;
(iii) Y represents that the N ⁺ R ^7, Z is O ^- represents a, R ² represents the bond with R ³ or R ^4, R ¹ and R ⁵ forms a bond;
(iv) when Y represents N, Z represents OR ⁸ ;
(v) when R ¹ represents OH, X represents C═O, Y represents N, Z represents OR ⁸ , and R ⁵ represents a bond with R ⁸ ;
(vi) when R ¹ represents alkyl, R ⁵ represents a bond with R ⁸ , Y represents N, R ² does not represent a bond, and X does not represent NR ⁴ ;
(vii) when R ¹ represents a bond with R ² , R ⁵ and R ⁸ form a bond, and when X represents NR ⁴ , R ⁴ represents alkyl;
(viii) when R ⁶ represents aryl, halogen, alkoxy or thioalkyl, R ² and R ³ form a bond;
(ix) when Y represents N or N ⁺ R ⁷ and R ² is substituted with any one of NR ¹⁰ R ¹¹ , OR ¹² or F, the substituents of Y and the ring nitrogen cannot bond to the same carbon atom of R ² ; ;
(x) when R ⁷ is substituted with any of NR ¹⁶ R ¹⁷ , OR ¹² or halogen, the substituent of Y and the ring nitrogen may not bond to the same carbon atom of R ⁷ ;
(xi) if one of B, D, E and G represents N, then X does not represent NR ⁴ ;
(xii) when Y represents CR ¹⁸ , X represents CR ³ R ⁶ ;
In addition,
(a) B, D, E and G all represent CH, X represents CHR ³ , Y represents N, R ¹ and R ⁵ form a bond, R ⁸ represents H, R ² and When R ³ together represent a bond, Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl;
(b) B, D, E and G all represent CH, X represents CHR ³ , Y represents N ⁺ R ⁷ , R ¹ and R ⁵ form a bond, and R ² and R ³ join When R ⁸ represents H and R ⁷ represents methyl, Ar ¹ does not represent unsubstituted phenyl;
(c) B, D, E and G all represent CH, X represents CH ₂ , Y represents N, R ¹ and R ⁵ form a bond, R ⁸ represents H, and R ² is When isopropyl, Ar ¹ does not represent unsubstituted phenyl or 4-bromophenyl;
(d) When B, D, E and G all represent CH, X and Y represent CH ₂ , and R ¹ and R ⁵ form a bond, Ar ¹ does not represent unsubstituted phenyl.
Preferably, Ar ¹ represents phenyl or pyridyl, most preferably phenyl. The phenyl group Ar ¹ preferably has a substituent in the para position, more preferably a Cl, Br, CF ₃ , C ₂ F ₅ , OCF ₃ or SCH ₃ substituent in the para position, in particular CF ₃ , It has a C ₂ F ₅ , OCF ₃ or SCH ₃ substituent.
Preferably, Y represents N ⁺ R ⁷ , X represents CR ³ R ⁶ , wherein R ³ together with R ² form a bond and R ⁶ represents alkyl. In that case, R ⁶ preferably represents branched alkyl. Alternatively, X can represent NR ⁴ , where R ⁴ represents a bond with R ² and Y represents N ⁺ R ⁷ .
Preferably, B represents CA. In that case, A preferably represents F.
When one of B, D, E and G represents N, it is preferable that D or G represents N.
Preferably, R ¹ represents a bond together with R ² or R ⁵ . In that case, R ¹ preferably represents a bond with R ⁵ .
Particularly preferred compounds of the present invention include those exemplified herein, including their free form and all salts and solvates.
Pharmaceutically acceptable derivatives include solvates and salts. Specific salts that may be mentioned include hydrochloride, hydrobromide, benzenesulfonate, tosylate and methanesulfonate.
Compounds of formula (I) may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the present invention. The compounds of formula (I) may also comprise one or more asymmetric carbon atoms and thus may exhibit optical and / or diastereo isomers. All diastereo isomers can be separated using conventional techniques, such as chromatography or fractional crystallization. Various optical isomers can be isolated by separating racemic mixtures or other mixtures of compounds by conventional techniques such as fractional crystallization or HPLC techniques. Alternatively, the desired optical isomers can be reacted with suitable optically active starting materials under conditions that will not cause racemization, or induced using, for example, homochiral acid followed by conventional means (e.g., on HPLC, silica Chromatography) to separate the diastereomer derivative. All stereoisomers are included within the scope of the present invention.
Can be represented by R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ . Or an alkyl group which may be substituted on one or more aromatic rings forming part of Ar ¹ may be saturated or unsaturated, and may be straight or branched. Thus, C _3-7 cycloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COO (C _1-6 alkyl) and C _3-5 alkylene are interpreted.
According to the invention, there is also provided a process for the preparation of a compound of formula (I) comprising the following methods:
(a) R ¹ and R ² both represent H, X represents CH ₂ or C═O, Y represents N, Z represents OR ⁸ , R ⁵ and R ⁸ form a bond, and B , D, E, the G and Ar ^1, for the corresponding compounds of formula (I) as defined above, for example, by oxidation using a suitable oxidizing agent (e.g., manganese dioxide) and an appropriate organic solvent at room temperature, X is CH ₂ Or C = O, Y represents N, Z represents OR ⁸ , R ⁵ and R ⁸ form a bond, and R ¹ and R ² form a bond.
(b) one of B, D, E and G represents CA, where A represents nitro, and X, Y, Z, Ar ¹ , R ¹ , R with the rest of B, D, E and G Corresponding compounds of formula I as ² and R ⁵ as defined above are reduced to, for example, iron powder and ammonium chloride in reflux ethanol such that one of B, D, E and G is CA (where A is amino To a compound of formula (I).
(c) one of B, D, E and G represents CA, where A represents amino, and X, Y, Z, Ar ¹ , R ¹ , R with the rest of B, D, E and G ² and R ⁵ diazotize the corresponding compounds of formula (I) as defined above, and the diazonium salt is decomposed in dichlorobenzene in reflux in the presence of a halogen anion or sodium tetrafluoride (to fluorine), B, D Prepare compounds of formula I, wherein one of E, G represents CA, where A represents halo.
(d) one of B, D, E and G represents CA, where A represents bromo, and X, Y, Z, Ar ¹ , R ¹ , R with the rest of B, D, E and G Corresponding compounds of formula (I) as defined above by ² and R ⁵ are reacted with copper cyanide (I) in N-methylpyrrolidone, for example at reflux, so that one of B, D, E and G Wherein A represents cyano).
(e) X represents CR ³ R ⁶ (wherein R ⁶ represents methylthio or halogen), Y represents N ⁺ R ⁷ , Z represents O ⁻ , and R ³ and R ² bond And R ¹ and R ⁵ form a bond and B, D, E, G and Ar ^{1 form} a corresponding compound of formula (I) as defined above in a suitable solvent (e.g. DMF) g., by substitution reaction the compound of formula II in the presence and of sodium hydride), X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents a, R ³ and R ² is bonded To form a compound of formula (I) wherein R ¹ and R ⁵ form a bond and R ⁶ represents alkylthio.
(Wherein R ^6a represents C _1-6 alkyl)
(f) X represents CR ³ R ⁶ (wherein R ⁶ represents methylthio or halogen), Y represents N ⁺ R ⁷ , Z represents O ⁻ , and R ³ and R ² bond And R ¹ and R ⁵ form a bond and B, D, E, G and Ar ^{1 form} a corresponding compound of formula (I) as defined above in a suitable solvent (e.g. DMF) g., to the presence of sodium hydride) by reacting the compound with a substituted of the formula III, X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents a, R ³ and R ² is bonded To form a compound of formula (I) wherein R ¹ and R ⁵ form a bond and R ⁶ represents alkoxy.
(Wherein R ^6a is as defined above)
(g) X represents CR ³ R ⁶ (wherein R ⁶ represents methylthio or halogen), Y represents N ⁺ R ⁷ , Z represents O ^- and R ³ and R ² bond And R ¹ and R ⁵ form a bond, and the corresponding compounds of formula (I) as defined by B, D, E, G and Ar ¹ as defined above in a suitable solvent (eg DMF) at 100 ° C. (e. g., sodium hydrogen carbonate sodium sodium) was to react the compound with the substitution of formula IV in the presence of, X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents a, R ³ And R ² form a bond, R ¹ and R ⁵ form a bond, and R ⁶ represents NR ¹³ R ¹⁴ .
Wherein R ¹³ and R ¹⁴ are as defined above.
(h) X represents C = S, Y represents N, Z represents OH, R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and B, D, E Corresponding compounds of formula (I), wherein G and Ar ¹ are as defined above, are reacted with a methylating agent (eg methyl iodide) at pure reflux, where X represents CR ³ R ⁶ and Y is N ⁺ R ⁷ represents Z, O represents O ⁻ , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and R ⁶ represents methylthio.
(i) X represents C = O, Y represents N, Z represents OH, R ¹ represents a bond with R ^5, and B, D, E, G, Ar ¹ and R ² are as defined above. Corresponding compounds of formula (I), such as those at reflux, in a suitable solvent (e.g. dioxane) using, for example, a Lawesson reagent, wherein X represents C = S and Y is Prepare a compound of formula (I) wherein N represents, Z represents OH, and R ¹ represents a bond with R ⁵ .
(j) X represents C═O, Y represents N, Z represents OR ⁸ , R ⁸ represents a bond with R ^5, and B, D, E, G, Ar ¹ , R ¹ and R ^2, for the corresponding compounds of formula (I) as defined above such as, for example, in pure 100 ℃, to halogenation reaction with oxy-halogenated phosphorus, X represents a CR ³ R ^6, Y a represents the N ⁺ R ⁷ To prepare a compound of formula I, wherein Z represents O ⁻ and R ⁶ represents halogen.
(k) X represents C═O, Y represents N, Z represents OH, R ¹ represents a bond with R ^5, and B, D, E, G and Ar ¹ are as defined above, Corresponding compounds of the formula (I) in which R ² represents a group corresponding to R ⁷ as defined above, for example, in a suitable solvent (eg dimethoxyethane) at reflux, for example a copper salt (eg, In the presence of copper bromide (I)), for example, by reacting with a nucleophilic alkylating agent such as a compound of the formula (V), X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , and Z represents O ⁻ To prepare a compound of formula I wherein R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and R ⁶ represents alkyl.
Wherein R ⁶ is as defined above and Hal represents halogen.
(l) X is CR ³ R ⁶ represents a (wherein, R ⁶ represents an H), Y a represents the N ⁺ R ^7, Z is O ^- represents a, and the R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and the corresponding compounds of formula I, wherein B, D, E, G and Ar ¹ are as defined above, for example at 0 ° C. in a suitable solvent (eg THF) for example, by reacting a nucleophilic alkylating agent and of the compound of formula V as defined above, X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents a, R ³ and R ² form a bond, and form a bond that R ¹ and R ^5, and to prepare a compound of formula I is R ⁶ represents an alkyl.
(m) Z represents OR ⁸ (where R ⁸ represents H), X represents C═O, Y represents N, R ¹ represents a bond with R ^5, and B, D, Corresponding compounds of formula I, wherein E, G, Ar ¹ and R ² are as defined above, in the presence of a base (for example sodium hydride), for example in a suitable solvent (for example DMF) To react with a compound of formula wherein X represents C═O, Y represents N, Z represents OR ⁸ , R ¹ represents a bond with R ^5, and R ⁸ represents alkyl do.
R ⁸ Hal
Wherein R ⁸ and Hal are as defined above.
(n) Z represents O ⁻ , R ¹ and R ⁵ form a bond, X represents C═O, Y represents N, and B, D, E, G, Ar ¹ and R ² are The corresponding compound of formula (I) as defined is treated with an oxidizing agent (e.g. ammonium nitrate with cerium) in an appropriate solvent (e.g. acetonitrile) at ambient temperature, for example, so that R ¹ Is prepared, wherein X represents C═O, Y represents N, Z represents OR ⁸ , and R ⁵ represents a bond with R ⁸ .
(o) Y represents N, Z represents OH, X represents CR ³ R ⁶ , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and B, D, Corresponding compounds of formula (I) as defined above by E, G, and Ar ¹ , for example, are compounds of the formula (IX) and bases (eg sodium hydride) in suitable solvents (eg DMF) at ambient temperature ) to give, X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents a, R ³ and R ² form a bond, and form a bond that R ¹ and R ⁵ To prepare a compound of formula (I).
R ⁷ Hal
Wherein R ⁷ and Hal are as defined above.
(p) R ² represents H, X represents C═O, Y represents N, Z represents OH, R ¹ represents a bond with R ^5, and B, D, E, G and Ar ^1, for the corresponding compounds of formula (I) as defined above, suitable solvent at ambient temperature and base in a (e. g., DMF) (for example, sodium hydride), and reacting a compound of formula VII, X Prepares compounds of formula I wherein C represents O, R ² does not represent H, Y represents N, Z represents OH, and R ¹ represents a bond with R ⁵ .
R ² Hal
Wherein R ² (excluding H) and Hal are as defined above.
(q) reacting a compound of formula (VIII) with a base (for example sodium hydride) and a compound of formula (IX) as defined above in an appropriate solvent (e.g. DMF) at ambient temperature, for example, B, D, E and G represents a CH or CA, X a represents an NR ^4, Y a represents the N ⁺ R ^7, Z is O ^- represents a, R ⁴ and R, ² form a bond, R ¹ and R ^Prepare compounds of formula (I) that form pentavalent bonds.
Wherein A and Ar ¹ are as defined above.
(r) reacting a compound of formula (VIII) as defined above with a base (for example sodium hydride) and a compound of formula (X) in a suitable solvent (eg DMF) at ambient temperature, for example, B, D, E and G represent CH or CA, X represents NR ⁴ , Y represents N, Z represents OR ⁸ , R ² and R ¹ form a bond, and R ⁵ and R ⁸ bond To prepare a compound of formula (I) which forms.
R ⁴ Hal
Wherein R ⁴ and Hal are as defined above.
(s) Y represents a N ⁺ R ^7, Z is O ^- represents a, R ⁷ is CH ₂ C ₆ H ₄ represents an O- alkyl, X a represents a CR ³ R ^6, R ³ and R ² is bonded And R ¹ represents a bond together with R ⁵ and B, D, E, G and Ar ¹ correspond to the corresponding compounds of the formula (I) as defined above, for example, at reflux, such as Fluoroacetic acid), X represents CR ³ R ⁶ , Y represents N, Z represents OH, R ³ and R ² form a bond, and R ¹ represents a bond with R ⁵ To prepare a compound of formula (I).
(t) Y represents a N ⁺ R ^7, Z is O ^- represents a, R ⁷ is CH ₂ - represents a phenyl (which is optionally substituted by C _1-6 alkyl or C _1-6 alkoxy), X is CR ³ R ⁶ represents R ³ and R ² form a bond, R ¹ represents a bond with R ^5, and B, D, E, G and Ar ¹ represent the corresponding compounds of formula I as defined above Treatment with hydrogen in the presence of a catalyst (eg palladium on carbon) such that X represents CR ³ R ⁶ , Y represents N, Z represents OH, and R ³ and R ² form a bond, Prepare compounds of formula I wherein R ¹ represents a bond with R ⁵ .
(u) Y represents a N ⁺ R ^7, Z is O ^- represents a, R ⁷ is CH ₂ C ₆ H ₄ represents an O- alkyl, X a represents a C = O, R ² a represents an H, R ¹ represents a bond together with R ⁵ and B, D, E, G and Ar ¹ correspond to the corresponding compounds of formula (I) as defined above, for example, at reflux to an acid (eg trifluoroacetic acid) Treatment produces a compound of formula I in which X represents C = 0, Y represents N, Z represents OH, R ² represents H, and R ¹ represents a bond with R ⁵ .
(v) reacting a compound of formula (XI) with a compound of formula (XII) in reflux, for example in xylene, where X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , and Z represents O ⁻ To prepare a compound of formula (I) wherein R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and R ⁶ represents H.
Ar ¹ NHNH ₂
Wherein X represents CH ₂ , R ¹ represents H, R ² represents a group corresponding to R ⁷ as defined above in the compound of formula I, and B, D, E, G and Ar ¹ are As defined and R represents alkyl.)
(w) X represents C═O, R ¹ represents H, R ² does not represent H, and B, D, E, G and R represent the corresponding compounds of Formula I as defined above at reflux For example, in xylene, reacted with a compound of formula XII as defined above (wherein Ar ¹ is as defined above), X represents C═O, R ² does not represent H, and Y represents N To prepare a compound of formula (I) wherein Z represents OH and R ¹ represents a bond with R ⁵ .
(x) a compound of formula XI as defined above, wherein X represents CH ₂ , R ¹ represents alkyl and B, D, E, G, R ² and R are as defined above at reflux; For example, in xylene, reacted with a compound of formula XII as defined above (wherein Ar ¹ is as defined above), X represents CH ₂ , Y represents N, Z represents OR ⁸ , Prepare compounds of formula I wherein R ⁸ and R ⁵ form a bond, and R ¹ represents alkyl.
(y) a compound of formula XI as defined above, wherein X represents C═O, R ¹ represents alkyl, R ² represents H or alkyl, and B, D, E, G and R are Is reacted at reflux with, for example, a compound of formula XII as defined above in xylene, wherein Ar ¹ is as defined above, where X represents C = 0 and Y represents N To prepare a compound of formula (I) wherein Z represents OR ⁸ , R ⁸ and R ⁵ form a bond, and R ¹ represents alkyl.
(z) X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ² and R ³ represent H, R ¹ and R ⁵ form a bond, and B, D, E, G, Ar ¹ , R ⁶ and R ¹⁸ oxidize the corresponding compounds of formula I as defined above, where X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, and R ¹ and R ⁵ form a bond, and R ² and R ³ form a bond to prepare a compound of formula I.
(aa) A compound of formula (XII) as defined above is reacted with a compound of formula (XX) wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, and R ² and R ³ are H To prepare a compound of formula (I) wherein R ¹ and R ⁵ form a bond.
Wherein B, D, E, G, R ⁶ , R ¹⁸ and R are as defined above.
X represents CHR ³ , R ² and R ³ together represent a bond, R ¹ and R ⁵ form a bond,
· Y represents the N ⁺ R ^7, Z is O ^- or indicate,
Compounds of formula I wherein Y represents N and Z represents OH are described in J. Med. Chem. 35, 368 (1992).
Compounds of formula (VIII) are known from European patent application EP-A-187551 or can be prepared analogously to the process described above.
Compounds of formula (XI) may be prepared by reacting a compound of formula (XIII) with a base (eg sodium hydride) at 60 ° C., for example in DMSO, in the presence of an alcohol.
Wherein B, D, E, G, R, R ² and X are as defined above and R 'is alkyl.
Compounds of formula (XI) wherein X represents C═O and R ² represents H are known from JP-B-82 54,152 or can be prepared analogously to the process described above.
A compound of formula (XIII), wherein X represents C═O, alkylates a compound of formula (XVI) with, for example, a compound of formula (XVII) at 50 ° C., for example in the presence of a base (eg, potassium carbonate) in acetone, for example Can be prepared.
(R'O) ₂ SO ₂
Wherein B, D, E, G, R, R ² and R 'are as defined above.
A compound of formula (XIII), wherein X represents CH ₂ , is reacted with a compound of formula (XV) in the presence of a base (eg, triethylamine) in a suitable solvent (eg, ether) at reflux It can manufacture.
(Wherein B, D, E, G, R, R ¹ , R ² and R ′ are as defined above.)
Compounds of formula (XIV) may be prepared by reacting a compound of formula (XVIII) with a brominating agent (eg, NBS) at reflux, for example in dichloroethane, with photodegradable irradiation.
Wherein B, D, E, G and R are as defined above.
Compounds of formula (XVI) are compounds of formula (XV) as defined above in a suitable solvent (eg acetone) at 50 ° C., wherein R ¹ , R ² and R ′ are as defined above. It can be prepared by reaction with.
Wherein B, D, E and G are as defined above.
Compounds of formula (II), (III), (IV), (V), (VI), (VII), (IX), (X), (XII), (XV), (XVI), (XVII), (XVIII) and (XX) are commercially available, well known in the literature, or obtained using known techniques. It is possible.
Those skilled in the art will appreciate that it may be necessary to protect the functional groups of the intermediate compounds with protecting groups in the process steps described above. Protection of the functional group may take place before any of the method steps described above. For example, the nitrogen atoms of the compounds of the formulas (XI), (XIII) and (XVI) can be further reacted after being protected using a suitable protecting group such as a benzyl group or preferably 4-methoxyphenylmethyl group. Protecting groups may be removed using techniques known to those skilled in the art after the reaction step or at the end of the reaction process (eg acid hydrolysis).
Since the compounds of the present invention have useful drug activity, they are pointed out as useful drugs for treatment.
There is also provided a compound of formula (I) as defined above, except that it does not have a proviso (c) useful as a drug according to the invention.
In particular, the compounds of the present invention have anti-allergic and anti-inflammatory activity, as shown, for example, in the tests described below. Thus, the compounds of the present invention may be used for asthma (eg bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma and efferent asthma), especially chronic or chronic asthma (eg late asthma and airway hypersensitivity), And allergic and inflammatory diseases of the airways, such as bronchitis and the like. In addition, the compounds of the present invention include acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis (including casein rhinitis), hypertrophic rhinitis, purulent rhinitis and dry rhinitis, drug rhinitis, membrane rhinitis (including crohnitis Inflammation, such as rhinitis, including all diseases characterized by inflammation of the nasal mucosa, such as fibrous and gastric rhinitis, adenoid rhinitis, seasonal rhinitis (including neural rhinitis (hay fever)), and vasomotor rhinitis Instructed in the treatment of diseases involving allergies.
The compounds of the present invention may also be used for chronic allergic disorders, atopic dermatitis, skin eosinophilia, eosinophilic fasciitis, high IgE syndrome, spring conjunctivitis, systemic lupus erythematosis, thyroiditis, nodular la disease, sezary syndrome, chronic hostess Instructed for use in the treatment of sex graft disease, myasthenia gravis and idiopathic thrombocytopenic purpura.
The compounds of the present invention have activity in the prophylaxis and treatment of AIDS, prevention of chronic allograft rejection mediated by humoral immunity, and treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Can be.
Of particular interest among the indications is the use of the compounds of the invention in the prevention of asthma, in particular, asthma and in rhinitis, especially allergic rhinitis and seasonal rhinitis (including neuronal rhinitis (hay fever)).
According to another aspect of the present invention, an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined above, which does not have the proviso (b) or (c), suffers from or is associated with an allergic or inflammatory disease Provided are methods of treating or preventing allergic or inflammatory diseases comprising administration to a patient susceptible to hypersensitivity.
The compounds of the present invention may be administered topically (eg by inhalation into the lungs). The compounds of the present invention may be inhaled as dry powder, which may or may not be pressurized.
In the unpressurized powder composition, the finely divided form of the active ingredient can be used as a mixture with a larger pharmaceutically acceptable inert carrier. Alternatively, the composition may be pressurized and may contain pressurized gas (eg, nitrogen) or liquefied gas propelant. In such pressurized compositions, the active ingredient is preferably finely divided. The pressurized composition may also contain a surfactant. Pressurized compositions can be prepared by conventional methods.
The composition of the present invention may be administered systemically (eg, by oral administration to the gastrointestinal tract). The active ingredient can be formulated with known excipients, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract. Examples of suitable excipients, diluents or carriers for oral administration in tablet, capsule and dragee form include microcrystalline cellulose, calcium phosphate, diatomaceous earth, sugars (eg lactose, dextrose or mantel), talc, silicic acid, starch , Sodium bicarbonate and / or gelatin.
According to yet another aspect of the present invention, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, as defined above, having no proviso provision (c), is contained as a mixture with a pharmaceutically acceptable excipient, diluent or carrier It provides a pharmaceutical composition.
Suitable dosages for topical or oral administration range from 0.01 to 30 mg / kg / day, for example 0.3 mg / kg / day.
Those skilled in the art will appreciate that certain functional groups of the compounds of the present invention may be protected with appropriate protecting groups to form "protected derivatives" of the compounds of the present invention. It will also be appreciated that such protected derivatives may not have drug activity by themselves, but may be metabolized in the body after administration to form compounds of the invention that are drug active. Thus, such derivatives may be referred to as "prodrugs". All protected derivatives and prodrugs of the compounds of formula I are included within the scope of the present invention.
The invention is illustrated by the following examples.
General caution
Column chromatography was typically run on silica (35-70 μM) under a gas pressure of 0.5 bar. The following hydrazines were used as intermediates in the following examples:
5-hydrazino-2-methylpyridine
A solution of sodium nitrite (0.3 g) in water (2 mL) was maintained at 5 &lt; 0 &gt; C, while 5-amino-2-methylpyridine in water (6 mL) and concentrated hydrochloric acid (1 mL) (J. Chem Soc. (C)., 1971, 3257]; 3.61 g). The mixture was stirred at 0 ° C. for 15 minutes and then cooled further to −10 ° C. Then a solution of tin (II) chloride (2.53 g) in concentrated hydrochloric acid (5 mL) was added dropwise. After stirring at −10 ° C. for 10 minutes, the solution was allowed to warm to room temperature and added until an slurry of anhydrous potassium carbonate was formed. The slurry was stirred with ethyl acetate, the organic phase was decanted and evaporated to give an oil. The slurry was then diluted with water and extracted with dichloromethane (three times). The organic layer was dried over sodium sulphate, filtered and evaporated and combined with the oil. Purification by column chromatography eluting with dichloromethane: methanol (20: 1) gave the title compound as a beige solid (0.09 g). Melting point 68-70 ° C.
¹ H NMR (CDCl ₃ ) δ 2.47 (3H, s), 3.60 (2H, br s), 5.13 (1H, br s), 7.03 (1H, d), 7.12 (1H, dd), 8.12 (1H, d ).
4- (pentafluoroethyl) phenyl hydrazine
Prepared according to the method used for 5-hydrazino-2-methylpyridine using 4- (pentafluoroethyl) aniline (J. Chem. Soc., Perkin Trans. 1. 1990, 2293). MS (EI) 226 (M ⁺ ).
¹ H NMR (CDCl ₃ ) δ 4.15 (2H, br), 6.87 (2H, d), 7.30 (2H, d), 7.45 (1H, br).
2-hydrazino-5-methylpyridine (J. Org. Chem., 1966, 31, 251)
2-chloro-5-hydrazinopyridine (Atti R. Accad. Dei Lincei, Roma, 1925, 2, 125; Chem. Zent., 1926, I, 672)
2-hydrazinopyrimidine (J. Chem. Soc., 1955, 3478)
Example 1
3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
(a) Methyl 2- [N- (methoxycarbonylmethyl) -N- (4-methoxyphenyl) methyl) amino] methylbenzoate
Methyl 2-bromomethylbenzoate (23.47 g; prepared analogously to the method described for ethyl ester in J. Med. Chem., 1992, 35, 368) and triethylamine (15.7 mL) were nitrogen It was dissolved in anhydrous diethyl ether (200 mL) under air. Methyl N-[(4-methoxyphenyl) methyl] glycinate (23.6 g; [J. Am. Chem. Soc., 1993, 115, 536]) was added dropwise. The mixture was heated at reflux for 16 h and cooled to room temperature. Water was added and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (3 times). The combined organic phases were washed with brine and dried over sodium sulfate. The solution was filtered and evaporated and the residue was further purified by column chromatography eluting with ethyl acetate: isohexane (1: 9) to give the lower title compound as an oil (27.85 g).
MS (APCI) 358 ((M + H) ⁺ ).
¹ H NMR (CDCl ₃ ) δ 3.23 (2H, s), 3.66 (3H, s), 3.71 (2H, s), 3.78 (3H, s), 3.88 (3H, s), 4.16 (2H, s), 6.8 (2H, d), 7.2 (2H, d), 7.3 (1H, td), 7.45 (1H, td), 7.6 (1H, dd), 7.75 (1H, dd).
(b) Methyl 1,2,3,4-tetrahydro-2- (4-methoxyphenyl) methyl-4-oxo-3-isoquinolinecarboxylate
Methyl 2- [N- (methoxycarbonylmethyl) -N- (4-methoxyphenyl) methyl) amino] methylbenzoate (27.85 g; from step (a) above) is dissolved in anhydrous toluene (150 mL) And added dropwise to reflux suspension of oil-free sodium hydride (from 4.37 g of 60% sodium hydride) in anhydrous toluene (300 mL) and 2-methylpropan-2-ol (2.0 mL). Heating continued for 12 hours. The mixture was cooled to rt, then poured into saturated ammonium chloride solution and extracted with ethyl acetate (3 times). The combined organic phases were then washed with brine and dried over sodium sulfate. After filtration and evaporation, the residue was purified by column chromatography eluting with diethyl ether: isohexane (1: 4) to give the lower title compound as an oil (20.41 g).
¹ H NMR (CDCl ₃ ) (main component-enol tautomer) δ 3.60 (2H, s), 3.81 (3H, s), 3.91 (5H, s), 6.86 (2H, d), 7.09 (1H, d) , 7.25 (2H, d), 7.35-7.43 (2H, m), 7.77 (1H, d) and 11.58 (1H, s).
(c) 3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide , Intramolecular inflammation
Methyl 1,2,3,4-tetrahydro-2- (4-methoxyphenyl) methyl-4-oxo-3-isoquinolinecarboxylate (1.0 g; from step (b) above), 4- (tri Fluoromethyl) phenylhydrazine (1.08 g) and a catalytic amount of 4-toluenesulfonic acid were fused together at 150 ° C. for 10 minutes. Xylene (20 mL) was then added and heating continued for an additional hour. After cooling to room temperature, the solvent was evaporated. The solid residue was triturated with diethyl ether to afford the title compound as a red solid (0.5 g). Melting point 220-221 ° C.
MS (APCI) 450 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 3.72 (3H, s), 6.08 (2H, s), 6.95 (2H, m), 7.7 (2H, m), 7.8 (3H, m), 7.95 (1H, td ), 8.15 (1H, d), 8.35 (1H, d), 8.6 (2H, d), 8.96 (1H, s).
Example 2
2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt (0.26 g; from step (c) above) was heated for 16 h at reflux in trifluoroacetic acid (2 mL) under a nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated. Toluene was added to the residue and then evaporated (twice). Methanol was added and evaporated and the red residue was triturated with ethyl acetate. Recrystallization from ethanol gave the title compound as a red solid (14 mg). Melting point> 250 ° C.
MS (APCI) 330 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.9 (3H, m), 8.0 (1H, t), 8.3 (4H, m), 9.03 (1H, bs).
Example 3
2- (4-chlorophenyl) -2,5-dihydro-5-methyl-3H-pyrazolo [4,3-c] cinnoline-3-one
2- (4-chlorophenyl) -2,5-dihydro-pyrazolo [4,3-c] cinnoline-3-one (0.33 g; European Patent Application EP-A-0187551) under a nitrogen atmosphere To a stirred suspension of oil-free sodium hydride (from 49 mg of 60% suspension) in anhydrous dimethylformamide (5 mL) was added portionwise. After 0.5 hour iodomethane (0.076 mL) was added dropwise and the resulting solution was stirred at room temperature for 2 hours. The solution was poured into brine and extracted with dichloromethane / methanol (three times). The organic phase was washed with 2M hydrochloric acid and brine, then dried over sodium sulfate, filtered and concentrated to give a red solid. Purification by column chromatography (3: 2 ethyl acetate: hexanes) and recrystallization from dimethylformamide gave the title compound as red crystals (55 mg). Melting point> 250 ° C.
MS (EI) 310, 312 (M &lt; ^{+ &} gt ^; ).
¹ H NMR (CDCl ₃ ) δ 4.33 (3H, s), 7.4 (2H, dd), 7.65 (2H, t), 7.75 (1H, td), 8.20 (2H, dd), 8.35 (1H, d).
Example 4
2- (4-chlorophenyl) -2,3a, 4,5-tetrahydro-3a, 4-dimethylpyrazolo [4,3-c] isoquinolin-3-one
(a) methyl 2-[((1-methoxycarbonyl) ethyl) methylamino] methyl benzoate
Methyl 2-bromomethylbenzoate (3.51 g) and diisopropylethylamine (5.86 mL) were dissolved in anhydrous diethyl ether (30 mL) under a nitrogen atmosphere and the solution was cooled to 0 ° C. N-methylalanine methyl ester trifluoroacetic acid salt (3.89 g) was dissolved in anhydrous diethyl ether (10 mL), anhydrous dichloromethane (5 mL) was added dropwise and the mixture was allowed to warm to room temperature overnight. Water was then added, the organic phase was separated, washed with brine and dried over sodium sulfate. After filtration and evaporation, column chromatography (1: 9 ethyl acetate: hexanes) afforded the lower title compound (2.87 g).
MS (EI) 265 (M ⁺ ).
(b) Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinoline carboxylate
Methyl 2-[((1-methoxycarbonyl) ethyl) methylamino] methyl benzoate (2 g) in anhydrous toluene (10 mL) was dissolved in anhydrous toluene (30 mL) and 2-methyl-2-propanol ( 5 drops) to reflux suspension of oil-free sodium hydride (from 0.42 g of 60% dispersion) dropwise. After heating at reflux for 45 minutes, the solution was cooled in ice and poured into saturated ammonium chloride solution, which was extracted with ethyl acetate (3 times). The organic phase was washed with brine and dried over sodium sulfate. After filtration and evaporation, column chromatography (1: 4 ethyl acetate: hexanes) gave the lower title compound as a yellow oil (0.95 g).
MS (EI) 234 ((M + H) ⁺ ).
(c) 2- (4-chlorophenyl) -2,3a, 4,5-tetrahydro-3a, 4-dimethylpyrazolo [4,3-c] isoquinolin-3-one
Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinoline carboxylate (0.84 g), 4-chlorophenylhydrazine (1.54 g) and 4-toluenesulfonic acid (20 Mg) were fused together at 150 ° C. for 10 minutes under a nitrogen atmosphere. Xylene (10 mL) was then added and the mixture was heated at 150 ° C. for an additional 6 hours. After cooling to room temperature, the solvent was removed and the residue was dissolved in dichloromethane / methanol. The solution was washed with 2M hydrochloric acid and brine and then dried over sodium sulfate. After filtration and evaporation, column chromatography (1:99 methanol: dichloromethane) gave the title compound as a colorless solid (50 mg).
Melting point 128-129 ° C.
MS (EI) 325, 327 (M ⁺ ).
Example 5
2- (4-chlorophenyl) -3a, 4-dihydro-3a, 4-dimethyl-2H-pyrazolo [4,3-c] isoquinoline-3,5-dione
(a) Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxo-3-isoquinolinecarboxylate
Methyl 1,2-dihydro-4-hydroxy-2-methyl-1-oxo-3-isoquinoline carboxylate (JP-B-82 54,152; 1.5 g) in anhydrous dimethylformamide (5 mL) was purged with nitrogen. To air was added dropwise to a stirred suspension of oil-free sodium hydride (from 0.28 g of 60% dispersion) in anhydrous dimethylformamide (10 mL) at room temperature. After 30 minutes, iodomethane (0.4 mL) was added dropwise. The solution was stirred at rt for 3 h, then poured into 2M hydrochloric acid and extracted with ethyl acetate (3 times). The organic phase was washed with brine and dried over sodium sulfate. After filtration and evaporation, column chromatography (1: 1 diethyl ether: hexane) afforded the lower title compound as a yellow oil (0.53 g).
MS (ESI) 248 ((M + H) ⁺ ).
(b) 2- (4-chlorophenyl) -3a, 4-dihydro-3a, 4-dimethyl-2H-pyrazolo [4,3-c] isoquinoline-3,5-dione
Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxo-3-isoquinolinecarboxylate (0.53 g), 4-chlorophenylhydrazine (0.92 g) and 4-toluene Sulfonic acid (10 mg) was fused together at 150 ° C. for 10 minutes under a nitrogen atmosphere. Xylene (5 mL) was then added and the mixture was heated at 150 ° C. for 10 h. After cooling to room temperature, the solvent was removed and the residue was dissolved in dichloromethane / methanol and washed with 2M hydrochloric acid, sodium bicarbonate solution and brine. The solution was dried over sodium sulphate, filtered and evaporated. Purification by column chromatography (1: 9 ethyl acetate: hexanes) and then recrystallization from propan-2-ol gave the title compound as a beige solid (0.13 g). Melting point 192-193 ° C.
MS (EI) 339, 341 (M ⁺ ).
Example 6
2- (4-chlorophenyl) -2,4-dihydro-3-hydroxy-4-methylpyrazolo [4,3-c] isoquinolin-5-one
Methyl 1,2-dihydro-4-hydroxy-2-methyl-1-oxo-3-isoquinolinecarboxylate (JP 82 54,152; 0.5 g), 4-chlorophenylhydrazine (0.91 g) and 4-toluene Sulfonic acid (10 mg) was fused at 150 ° C. for 10 minutes under a nitrogen atmosphere. Xylene (5 mL) was then added and the mixture was heated at 150 ° C. for 5 hours. After cooling to room temperature, a yellow precipitate was collected by filtration and washed with diethyl ether. Purification by column chromatography (1:49 methanol: dichloromethane) and recrystallization from ethanol gave the title compound as a beige solid (0.1 g). Melting point> 250 ° C.
MS (EI) 325, 327 (M ⁺ ).
Example 7
3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
The title compound was prepared according to the method described in Example 1 (c) using 3-hydrazinoquinoline. Melting point 232-233 ° C.
MS (APCI) 433 ((M + H) ⁺ ).
NMR (d ₆ -DMSO) δ 3.7 (3H, s), 6.1 (2H, s), 6.7 (2H, d), 7.65 (1H, t), 7.70 (3H, m), 7.80 (1H, t), 8.05 (3H, m), 8.20 (1H, d), 8.40 (1H, d), 9.00 (1H, s), 9.20 (1H, d), 9.90 (1H, d).
Example 8
2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
The title compound (0.21 g) is 3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide It was prepared according to the method described in Example 2 using a lockside, an intramolecular salt (0.66 g). Melting point 247-248 ° C.
MS (APCI) 313 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.70 (1H, td), 7.80 (1H, td), 7.90 (1H, bt), 8.00 (1H, t), 8.15 (2H, m), 8.35 (2H, m ), 8.90 (1 H, d), 9.05 (1 H), 9.70 (1 H, d), 12.20 (1 H, bs).
Example 9
2- (3,4-dichlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
The title compound was prepared according to the method described in Example 1 (c) using 3,4-dichlorophenylhydrazine. Melting point 239-240 ° C.
MS (APCI) 448, 450, 452 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 3.72 (3H, s), 6.06 (2H, s), 6.96 (2H, d), 7.70 (3H, m), 7.79 (1H, t), 7.97 (1H, t ), 8.16 (1 H, d), 8.37 (2 H, m), 8.72 (1 H, d), 8.97 (1 H, s).
Example 10
2- (3,4-dichlorophenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
The title compound (0.028g) is 2- (3,4-dichlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinoli Prepared according to the method described in Example 2 using nium hydroxide, intramolecular salt (0.26 g). Melting point> 230 ° C.
MS (APCI) 330, 332, 334 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.82 (1H, d), 7.86 (1H, t), 7.97 (1H, t), 8.13 (1H, dd), 8.24 (1H, d), 8.32 (1H, d ), 8.42 (1 H, d), 8.94 (1 H, s).
Example 11
2-([1,1'-biphenyl] -4-yl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
(a) 2-([1,1'-biphenyl] -4-yl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] Isoquinolinium hydroxide, intramolecular salt
The lower title compound was prepared in Example 1 (c) using [1,1′-biphenyl] -4-ylhydrazine (see J. Chem., Perkin Trans. I. (1975) 1280). It was prepared according to the method described.
(b) 2-([1,1'-biphenyl] -4-yl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
The title compound (0.082 g) is 2-([1,1'-biphenyl] -4-yl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4, 3-c] isoquinolinium hydroxide, intramolecular salt (0.29 g, from step (a) above) was prepared according to the method described in Example 2. Melting point> 220 ° C. (decomposition).
MS (APCI) 338 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.37 (1H, m), 7.51 (2H, m), 7.75 (2H, m), 7.89 (3H, m), 7.98 (1H, m), 8.05 (2H, m ), 8.31 (2H, m), 9.02 (1H, s, br).
Example 12
3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-methylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
The title compound was prepared according to the method described in Example 1 (c) using 4-methylphenylhydrazine. Melting point> 100 ° C. (decomposition).
MS (APCI) 396 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 2.34 (3H, s), 3.72 (3H, s), 6.10 (2H, s), 6.96 (2H, m), 7.26 (2H, m), 7.74 (3H, m ), 7.94 (1 H, m), 8.13 (1 H, d), 8.23 (2 H, d), 8.33 (1 H, d), 8.89 (1 H, s).
Example 13
2- (4-methylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
The title compound (0.043 g) is 3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-methylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide Seed, intramolecular salt (0.20 g), was prepared according to the method described in Example 2. Melting point 202-209 ° C. (decomposition).
MS (APCI) 276 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 2.37 (3H, s), 7.37 (2H, d), 7.88 (3H, m), 7.94 (1H, m), 8.29 (2H, m), 9.02 (1H, br ), 11.90 (1H, broad singlet).
Example 14
2- (4-bromophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
The title compound was prepared according to the method described in Example 1 (c) using 4-bromophenylhydrazine. Melting point> 220 ° C. (decomposition).
MS (APCI) 460, 462 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 3.70 (3H, s), 6.08 (2H, s), 6.96 (2H, m), 7.66 (2H, m), 7.76 (2H, m), 7.77 (1H, t ), 7.96 (1 H, m), 8.15 (1 H, d), 8.36 (3 H, m), 8.94 (1 H, s).
Example 15
2- (4-bromophenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
The title compound (0.053 g) is 2- (4-bromophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium Prepared according to the method described in Example 2 using hydroxide, intramolecular salt (0.164 g). Melting point> 250 ° C.
MS (APCI) 340, 342 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.76 (2H, d), 7.89 (1H, m), 8.02 (3H, m), 8.31 (2H, m), 9.07 (1H, br), 11.92 (1H, br ).
Example 16
2- (3-trifluoromethylphenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
The title compound was prepared according to the method described in Example 1 (c) using 3-trifluoromethylphenylhydrazine to give an oil, which was eluted first with ethyl acetate and second with an ether: ethyl acetate mixture. Purification twice by chromatography gave the title compound as an oil.
MS (APCI) 450 ((M + H) ⁺ ).
¹ H NMR (CDCl ₃ ) δ 3.81 (3H, s), 6.19 (2H, s), 6.96 (2H, d), 7.45 (1H, m), 7.54 (3H, m), 7.79 (2H, m), 7.86 (1 H, t), 8.52 (1 H, d), 8.68 (1 H, d), 8.72 (1 H, s).
Example 17
2- (3-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
The title compound is 2- (3-trifluoromethylphenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide And prepared according to the method described in Example 2 using an intramolecular salt. Melting point 250 ° C. (decomposition).
MS (APCI) 330 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.67 (1H, d), 7.81 (1H, t), 7.88 (1H, t), 7.99 (1H, t), 8.42 (3H, m), 8.48 (1H, s ), 9.01 (1 H, s).
Example 18
2- [4- (1,1-dimethylethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolin-3-ol
(a) 3-hydroxy-2- [4- (1,1-dimethylethyl) phenyl] -4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoqui Nolinium hydroxide, intramolecular salt
The lower title compound was prepared according to the method described in Example 1 (c) using 4-[(1,1-dimethylethyl) phenyl] hydrazine, and used in the next step without further purification.
(b) 2- [4- (1,1-dimethylethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolin-3-ol
The title compound is 3-hydroxy-2- [4- (1,1-dimethylethyl) phenyl] -4- (4-methoxyphenylmethyl) -2H-pyrazolo [4,3-c] isoquinolinium Prepared according to the method described in Example 2 using hydroxide, intramolecular salt. Melting point> 210 ° C. (decomposition).
MS (APCI) 318 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 1.33 (9H, s), 7.51 (2H, d), 7.75 (1H, t), 7.84 (1H, t), 8.01 (2H, d), 8.12 (1H, d ), 8.25 (1 H, d), 8.74 (1 H, s).
Example 19
2- (4-trifluoromethoxyphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
(a) 2- (4-trifluoromethoxyphenyl) -3-hydroxy-2-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide Seed, intramolecular salt
The lower title compound was prepared according to the method described in Example 1 (c) using 4-trifluoromethoxyphenylhydrazine, and used in the next step without further purification.
(b) 2- (4-trifluoromethoxyphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
The title compound is 2- (4-trifluoromethoxyphenyl) -3-hydroxy-2-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide Seed, an intramolecular salt, was prepared according to the method described in Example 2. Melting point> 230 ° C.
MS (APCI) 346 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.58 (2H, d), 7.91 (1H, t), 7.99 (1H, t), 8.14 (2H, d), 8.29 (2H, m), 9.03 (1H, br s).
Example 20
2- (4-chlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
Methyl 1,2,3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylate (0.5 g; I. G. Hinton and F. G. Mann (FG Mann), J. Chem. Soc., 1959, 599]), 4-chlorophenylhydrazine (0.98 g) and 4-toluenesulfonic acid (10 mg) were fused together at 150 ° C. for 10 minutes under a nitrogen atmosphere. Xylene (10 mL) was then added and the mixture was heated at 150 ° C. for an additional 6 hours. The reaction mixture was cooled down and the resulting red precipitate was filtered off and washed with diethyl ether. Recrystallization from methanol gave the title compound (0.27 g). Melting point 247-248 ° C.
MS (EI) 309, 311 (M ^&lt; ^{+ &} gt ^; ).
¹ H NMR (d ₆ -DMSO) δ 4.5 (3H, s), 7.5 (2H, d), 7.75 (1H, t), 7.95 (1H, t), 8.1 (1H, d), 8.3 (1H, d ), 8.4 (2H, d), 8.6 (1H, s).
Example 21
2- (4-chlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] cinnolinium hydroxide, intramolecular salt
2- (4-chlorophenyl) -2,5-dihydro-pyrazolo [4,3-c] cinnoline-3-one (0.33 g; European Patent Application EP-A-0187551) under a nitrogen atmosphere To a stirred suspension of oil-free sodium hydride (from 49 mg of 60% dispersion) in anhydrous dimethylformamide (5 mL) was added portionwise. After 0.5 h iodomethane (0.076 mL) was added and the resulting solution was stirred at rt for 2 h. The solution was poured into brine and extracted with dichloromethane: methanol mixture (3 times). The organic phase was washed with 2N hydrochloric acid and brine, then dried over sodium sulfate, filtered and concentrated to give a red solid. Purification by column chromatography (2: 3 ethyl acetate: hexanes) and then recrystallization from dimethylformamide gave the title compound as purple crystals (65 mg). Melting point 249-250 ° C.
MS (EI) 310, 312 (M &lt; ^{+ &} gt ^; ).
¹ H NMR (CDCl ₃ ) 4.81 (3H, s), 7.40 (2H, d), 7.75 (2H, m), 8.00 (1H, doublet), 8.25 (2H, d), 8.35 (1H, dd).
Example 22
2- (4-chlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
The title compound is methyl 1,2,3,4-tetrahydro-2- (4-methoxyphenyl) methyl-4-oxo-3-isoquinolinecarboxylate (this compound is described in I. G. Hinton and F. J. Chem. Soc., 1959, 599), which was prepared in the same manner as described in Example 20. Melting point 227-228 ° C.
MS (EI) 416, 418 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) 3.70 (3H, s), 6.08 (2H, s), 6.95 (2H, d), 7.50 (2H, d), 7.70 (2H, d), 7.75 (1H, t) , 7.95 (1H, t), 8.15 (1H, d), 8.35 (1H, d), 8.40 (2H, d), 8.93 (1H, s).
The compounds of Examples 23-56 below were prepared in a similar manner to Examples 20 and 22.
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 233-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt201-203344 (M + H) ⁺ 4.51 (3H, s), 7.80 (3H, m), 7.97 (1H, t), 8.10 (1H, d), 8.35 (1H, d), 8.60 (2H, d), 8.66 (1H, s). 243-hydroxy-4-methyl-2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250327 (M + H) ⁺ 4.55 (3H, s), 7.60 (1H, td), 7.70 (1H, td), 7.82 (1H, td), 8.00 (3H, m), 8.10 (1H, d), 8.40 (1H, d), 8.69 (1H, s), 9.13 (1H, d), 9.93 (1H, d). 252- (6-chloro-3-pyridyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250311/313 (M + H) ⁺ 4.50 (3H, s), 7.61 (1H, d), 7.80 (1H, t), 7.97 (1H, t), 8.12 (1H, d), 8.35 (1H, d), 8.68 (1H, s), 8.74 (1 H, dd), 9.37 (1 H, s). 262- (3,4-dichlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt223-229344/346/348 (M + H) ⁺ 4.49 (3H, s), 7.70 (1H, d), 7.78 (1H, t), 7.96 (1H, t), 8.11 (1H, d), 8.35 (2H, m), 8.67 (2H, m). 273-hydroxy-4-methyl-2- (4-methylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt247-248290 (M + H) ⁺ 2.33 (3H, s), 4.52 (3H, s), 7.24 (2H, m), 7.74 (1H, m), 7.93 (1H, m), 8.09 (1H, m), 8.20 (2H, m), 8.33 (1 H, d), 8.59 (1 H, s). 282- (4-bromophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt244354/356 (M + H) ⁺ 4.50 (3H, s), 7.63 (2H, d), 7.76 (1H, t), 7.96 (1H, t), 8.10 (1H, d), 8.34 (3H, m), 8.63 (1H, s). 293-hydroxy-4-methyl-2- (3-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt222-6344 (M + H) ⁺ 4.51 (3H, s), 7.53 (1H, d), 7.69 (1H, t), 7.78 (1H, t), 7.96 (1H, t), 8.12 (1H, d), 8.35 (1H, d), 8.63 (1H, d), 8.66 (1H, s), 8.81 (1H, s).
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 302- [4- (1,1-dimethylethyl) phenyl] -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 200 decomposition332 (M + H) ⁺ 1.35 (9H, s), 4.65 (3H, dt), 7.46 (2H, m), 7.62 (1H, dt), 7.71 (1H, s), 7.83 (2H, m), 8.15 (2H, m), 8.50 (1H, d). (CDCl ₃ instead of DMSO d ₆ ) 312- (6-chloro-3-pyridyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt223-224417/419 (M + H) ⁺ 3.72 (3H, s), 6.07 (2H, s), 6.97 (2H, d), 7.62 (1H, d), 7.70 (2H, d), 7.81 (1H, t), 8.00 (1H, t), 8.16 (1H, d), 8.36 (1H, d), 8.79 (1H, dd), 8.98 (1H, dd), 9.38 (1H, d). 323-hydroxy-4-methyl-2- (6-methyl-3-pyridyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250291 (M + H)2.50 (3H, s), 4.51 (3H, s), 7.33 (1H, d), 7.77 (1H, t), 7.98 (1H, t), 8.10 (1H, d), 8.34 (1H, d), 8.50 (1H, doublet), 8.64 (1H, s), 9.38 (1H, d). 332- (4-trifluoromethylphenyl) -3-hydroxy-4- (2-hydroxyethyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250374 (M + H) ⁺ 3.99 (2H, m), 4.92 (2H, m), 5.19 (1H, t), 7.79 (3H, m), 7.99 (1H, m), 8.20 (1H, d), 8.38 (1H, d), 8.60 (2H, d), 8.65 (1H, s). 343-hydroxy-4-methyl-2- (5-methyl-2-pyridyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt237-240291 (M + H) ⁺ 2.34 (3H, s), 4.50 (3H, s), 7.75 (2H, m), 7.98 (1H, t), 8.11 (1H, d), 8.18 (1H, d), 8.36 (1H, d), 8.40 (1 H, d), 8.59 (1 H, s). 353-hydroxy-4-methyl-2- [4- (1-methylethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt171-172318 (M + H) ⁺ 1.25 (6H, d), 2.92 (1H, m), 4.53 (3H, s), 7.34 (2H, d), 7.78 (1H, t), 7.97 (1H, t), 8.14 (3H, m), 8.35 (1 H, d), 8.69 (1 H, s). 363-hydroxy-4-methyl-2- (4-nitrophenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 230321 (M + H) ⁺ 3.93 (3H, s), 7.79 (1H, t), 7.99 (1H, t), 8.12 (1H, d), 8.33 (3H, m), 8.62 (2H, d), 8.71 (1H, s).
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 372- (4-cyanophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt225-227301 (M + H) ⁺ 4.49 (3H, s), 7.79 (1H, t), 7.89 (2H, t), 7.95 (1H, t), 8.00 (1H, d), 8.34 (1H, d), 8.56 (2H, d), 8.67 (1H, s). 382- (4-carboxyphenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 230320 (M + H) ⁺ 4.51 (3H, s), 7.78 (1H, t), 7.99 (1H, t), 8.01 (2H, d), 8.12 (1H, d), 8.09 (1H, d), 8.47 (2H, d), 8.64 (1H, s), 12.74 (1H, s). 392- (4-chloro-3-trifluoromethylphenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 230378/380 (M + H) ⁺ 4.50 (3H, s), 7.81 (2H, m), 8.00 (1H, t), 8.13 (1H, t), 8.38 (1H, d), 8.59 (1H, dd), 8.68 (1H, s), 8.98 (1H, d). 402- (4-trifluoromethoxyphenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt195-196360 (M + H) ⁺ 4.51 (3H, s), 7.46 (2H, d), 7.79 (1H, t), 7.96 (1H, t), 8.12 (1H, d), 8.35 (1H, d), 8.45 (2H, d), 8.64 (1H, s). 413-hydroxy-4-methyl-2- (4-methylthiophenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt197-198322 (M + H) ⁺ 2.50 (3H, s), 4.51 (3H, s), 7.33 (2H, d), 7.72 (1H, t), 7.91 (1H, t), 8.08 (1H, d), 8.27 (2H, d), 8.31 (1 H, d), 8.60 (1 H, s). 424-cyclopropyl-3-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250370 (M + H) ⁺ 1.33 (2H, m), 1.54 (2H, m), 5.03 (1H, m), 7.78 (3H, m), 7.96 (1H, m), 8.15 (1H, d), 8.34 (1H, d), 8.61 (2H, m), 8.65 (1H, s). 434-cyclopropyl-3-hydroxy-2- (6-methyl-3-pyridyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt226-240317 (M + H) ⁺ 1.32 (2H, d), 1.54 (2H, m), 2.51 (3H, s), 5.08 (1H, m), 7.33 (1H, d), 7.56 (1H, td), 7.94 (1H, td), 8.13 (1H, d), 8.32 (1H, d), 8.54 (1H, dd), 8.62 (1H, s), 9.40 (1H, d).
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 444-[(1,1-dimethyl-2-hydroxy) ethyl] -3-hydroxy-2-[(4-trifluoromethyl) phenyl] -2H-pyrazolo [4,3-c] isoqui Nolinium hydroxide, internal salt> 220402 (M + H) ⁺ 1.94 (6H, s), 4.28 (2H, d), 5.15 (1H, t), 7.79 (3H, m), 8.00 (1H, m), 8.37 (2H, t), 8.62 (2H, d), 8.77 (1H, s). 453-hydroxy-4- (2-methoxyethyl) -2-[(4-trifluoromethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt195-197388 (M + H) ⁺ 3.28 (3H, s), 3.96 (2H, t), 5.06 (2H, t), 7.79 (3H, m), 7.99 (1H, m), 8.18 (1H, d), 8.37 (1H, d), 8.58 (2H, d), 8.71 (1H, s). 462- (4-chlorophenyl) -3-hydroxy-4- [2- (methylthio) ethyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt187-188370/372 (M + H) ⁺ 2.19 (3H, s), 3.20 (2H, t), 5.03 (2H, t), 7.50 (2H, m), 7.79 (1H, m), 7.99 (1H, m), 8.15 (1H, d), 8.38 (3H, m), 8.77 (1H, s). 473-hydroxy-4- [2- (methylthio) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt193-195404 (M + H) ⁺ 2.20 (3H, s), 3.21 (2H, t), 5.04 (2H, t), 7.81 (3H, m), 8.01 (1H, m), 8.17 (1H, d), 8.39 (1H, d), 8.59 (2H, d), 8.80 (1H, s). 484-cyclopropyl-2- (4-trifluoromethoxyphenyl) -3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt188-189386 (M + H) ⁺ 1.34 (2H, m), 1.54 (2H, m), 5.08 (1H, m), 7.46 (2H, d), 7.78 (1H, t), 7.95 (1H, t), 8.15 (1H, d), 8.31 (1H, d), 8.46 (2H, d), 8.62 (1H, s). 492- (4-Chloro-3-trifluoromethylphenyl) -4-cyclopropyl-3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 220404/406 (M + H) ⁺ 1.33 (2H, m), 1.53 (2H, m), 4.98 (1H, m), 7.78 (2H, m), 7.97 (1H, t), 8.17 (1H, d), 8.36 (1H, d), 8.62 (1 H, dd), 8.67 (1 H, s), 9.03 (1 H, dd). 504-cyclopropyl-3-hydroxy-2- (4-methylthiophenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt166-167348 (M + H) ⁺ 1.30 (2H, m), 1.51 (2H, m), 2.51 (3H, s), 5.24 (1H, m), 7.37 (2H, d), 7.74 (1H, t), 7.93 (1H, t), 8.14 (1H, d), 8.33 (3H, m), 8.58 (1H, s).
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 513-hydroxy-4-phenyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt255406 (M + H) ⁺ 7.69 (3H, m), 7.76 (2H, m), 7.82 (3H, m), 8.05 (1H, m), 8.25 (1H, d), 8.45 (1H, d), 8.53 (2H, m), 8.85 (1H, s). 524-ethyl-3-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt192-198358 (M + H) ⁺ 1.63 (3H, d), 4.88 (2H, quart), 7.75 (1H, t), 7.79 (2H, d), 7.96 (1H, t), 8.09 (1H, d), 8.33 (1H, d), 8.59 (2H, d), 8.76 (1H, s). 532- (4-trifluoromethylphenyl) -4- (1-ethoxycarbonylmethyl) -3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt167-169416 (M + H) ⁺ 1.27 (3H, t), 4.27 (2H, q), 5.83 (2H, s), 7.82 (2H, d), 7.82 (1H, t), 8.04 (1H, t), 8.17 (1H, d), 8.39 (1H, d), 8.54 (2H, d), 8.71 (1H, d). 543-hydroxy-4-[(4-methoxyphenyl) methyl] -2-phenyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal saltFoam382 (M + H) ⁺ 3.72 (3H, s), 6.10 (2H, s), 6.95 (2H, d), 7.20 (1H, t), 7.48 (2H, t), 7.75 (3H, m), 7.95 (1H, t), 8.15 (1H, d), 8.35 (3H, m), 8.91 (1H, s). 553-hydroxy-4- (1-methylethyl) -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt201-203372 (M + H) ⁺ 1.70 (6H, d), 6.26 (1H, br s), 7.79 (1H, t), 7.79 (2H, d), 7.98 (1H, t), 8.22 (1H, d), 8.38 (1H, d), 8.62 (2 H, d), 8.93 (1 H, d). 563-hydroxy-4- (1-methylethyl) -2- (3-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt220-222372 (M + H) ⁺ 1.71 (6H, d), 6.27 (1H, br s), 7.54 (1H, d), 7.70 (1H, t), 7.78 (1H, t), 7.96 (1H, t), 8.22 (1H, d), 8.40 (1 H, d), 8.64 (1 H, d), 8.85 (1 H, s), 8.94 (1 H, s).
Example 57
3-hydroxy-2- (4-iodophenyl) -4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
Methyl 1,2,3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylate (0.485 g) and 4-iodophenylhydrazine (1.053 g) are mixed in ethanol (15 mL) And heated to reflux for 20 hours. Cooling precipitates a solid which is crystallized from ethanol followed by propan-2-ol to give the title compound (0.054 g). Melting point> 260 ° C.
MS (+ ve ESI) 402 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO): δ 4.50 (3H, s), 7.76 (1H, t), 7.77 (2H, d), 7.94 (1H, t), 8.09 (1H, d), 8.19 (2H, d), 8.32 (1 H, d), 8.62 (1 H, s).
The compounds of Examples 58 to 60 below were prepared according to methods analogous to those used for Example 2:
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 582- (6-chloro-3-pyridyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol> 250297/299 (M + H) ⁺ 7.71 (1H, d), 7.89 (1H, t), 8.00 (1H, t), 8.31 (2H, m), 8.56 (1H, br d), 9.00 (1H, br s), 9.13 (1H, s) . 592- [4- (1-methylethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolin-3-ol218-219304 (M + H) ⁺ 1.25 (6H, d), 2.97 (1H, m), 7.42 (2H, d), 7.93 (4H, m), 8.27 (2H, m), 9.00 (1H, s). 602- (4-pentafluoroethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol219-223380 (M + H) ⁺ 7.68 (1H, t), 7.76 (3H, m), 8.02 (1H, d), 8.24 (1H, d), 8.54 (3H, m).
The compounds of Examples 61 to 68 below were prepared according to methods analogous to those used for Example 6:
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 612,4-dihydro-3-hydroxy-4-methyl-2- (2-pyrimidinyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one> 250294 (M + H) ⁺ 3.79 (3H, s), 7.48 (1H, t), 7.75 (1H, t), 7.89 (1H, t), 8.18 (1H, d), 8.35 (1H, d), 8.92 (2H, d). 622-([1,1'-biphenyl] -4-yl) -2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo [4,3-c] isoquinoline-5- On241-244368 (M + H) ⁺ 3.83 (3H, s), 7.39 (1H, m), 7.50 (2H, t), 7.75 (3H, m), 7.91 (3H, m), 8.05 (3H, m), 8.38 (1H, d). 632,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one> 250360 (M + H) ⁺ 3.81 (3H, s), 7.77 (1H, t), 7.94 (3H, m), 8.05 (1H, d), 8.18 (2H, d), 8.37 (1H, d), 11.37 (1H, s). 642- (6-chloro-3-pyridyl) -2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo [4,3-c] isoquinolin-5-one> 250327/329 (M + H) ⁺ 3.79 (3H, s), 7.73 (1H, d), 7.76 (1H, t), 7.92 (1H, t), 8.02 (1H, d), 8.38 (2H, m), 8.97 (1H, d). 652,4-dihydro-3-hydroxy-2- (4-iodophenyl) -4-methyl-5H-pyrazolo [4,3-c] isoquinolin-5-one> 250418 (M + H) ⁺ 3.80 (3H, s), 7.74 (3H, m), 7.89 (3H, m), 8.02 (1H, d), 8.36 (1H, d). 662,4-dihydro-3-hydroxy-4- (4-methoxyphenylmethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinoline-5- On> 230 decomposition466 (M + H) ⁺ 3.68 (3H, s), 5.59 (2H, s), 6.83 (2H, d), 7.40 (2H, d), 7.75 (1H, t), 7.90 (3H, m), 8.07 (1H, d), 8.20 (2H, d), 8.38 (1H, d), 11.50 (1H, s). 672,4-dihydro-3-hydroxy-4- (1-methylethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one228-230 decomposition388 (M + H) ⁺ 1.59 (6H, d), 5.85 (1H, brs), 7.76 (1H, t), 7.92 (3H, d), 8.04 (1H, d), 8.18 (2H, d), 8.36 (1H, d). 682,4-dihydro-3-hydroxy-4-methyl-2- [4- (1-methylethyl) phenyl] -5H-pyrazolo [4,3-c] isoquinolin-5-one238-240334 (M + H) ⁺ 1.25 (6H, d), 2.96 (1H, hept), 3.81 (3H, s), 7.42 (2H, d), 7.72 (1H, t), 7.78 (2H, d), 7.89 (1H, t), 8.01 (1 H, d), 8.36 (1 H, d).
Example 69
2,4-dihydro-3-hydroxy-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one
Trifluoroacetic acid (4 mL) was added to 2,4-dihydro-3-hydroxy-4- (methoxyphenylmethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3- c] wasoquinolin-5-one (Example 66; 425 mg) and the mixture was heated at reflux for 12 h. After cooling to room temperature, the solvent was removed and the resulting residue was recrystallized from methanol / water to give a yellow solid which was triturated with isohexane to further purify to give the title compound (150 mg). Melting point> 200 ° C.
MS (APCI) 346 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.76 (1H, t), 7.92 (3H, m), 8.02 (1H, d), 8.18 (2H, d), 8.34 (1H, d), 11.20 (1H, s ).
The compounds of the following examples were prepared similarly to example 69.
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 702,4-dihydro-3-hydroxy-2- [4- (1-methylethyl) phenyl] -5H-pyrazolo [4,3-c] isoquinolin-5-one> 250320 (M + H) ⁺ 1.24 (6H, d), 2.95 (1H, m), 7.40 (2H, d), 7.70 (1H, t), 7.78 (2H, d), 7.88 (1H, t), 7.99 (1H, d), 8.32 (1H, d), 11.00 (1H, s). 712,4-dihydro-3-hydroxy-2-([1,1'-biphenyl] -4-yl) -5H-pyrazolo [4,3-c] isoquinolin-5-one275 Disassembly354 (M + H) ⁺ 7.39 (1H, t), 7.50 (2H, t), 7.74 (3H, d), 7.87 (3H, m), 8.01 (3H, m), 8.34 (1H, d), 11.13 (1H, s), 11.76 (1H, s).
Example 72
2- (4-chlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -5-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Molecular Inflammation
A 3M solution of methylmagnesium bromide in diethyl ether (2.0 ml) was added 2- (4-chlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] in anhydrous tetrahydrofuran (20 ml). Was added drop wise to an ice cold suspension of -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt (Example 22; 0.5 g) and copper bromide (I) (17 mg). The mixture was stirred for 1 hour under cooling, then saturated aqueous ammonium chloride and ethyl acetate were added. The mixture was stirred at rt for 16 h, then the aqueous phase was extracted with ethyl acetate (3 times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column chromatography (99: 1 dichloromethane: methanol) to give a purple solid (0.38 g). Sample (0.1 g) was recrystallized from ethanol to give the title compound (31 mg). Melting point 212-216 ° C.
MS (APCI) 430, 432 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 2.88 (3H, s), 3.71 (3H, s), 6.50 (2H, br s), 6.93 (2H, d), 7.32 (2H, d), 7.51 (2H, d), 7.76 (1 H, t), 7.98 (1 H, t), 8.32 (1 H, d), 8.43 (3 H, m).
Example 73
2- (4-chlorophenyl) -5-methyl-2H-pyrazolo [4,3-c] isoquinolin-3-ol
2- (4-chlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -5-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Intramolecular salt (0.29 g) was dissolved in trifluoroacetic acid (10 mL) and heated at reflux in a nitrogen atmosphere for 2 hours. Cool to room temperature, evaporate the solvent and evaporate the residue with toluene (three times). Purification by column chromatography (20: 1 dichloromethane: methanol) and trituration with methanol gave the title compound as an orange solid (0.07 g). Melting point> 250 ° C.
MS (APCI) 310, 312 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 2.77 (3H, s), 7.47 (2H, d), 7.68 (1H, t), 7.77 (1H, t), 8.10 (1H, d), 8.25 (1H, d ), 8.31 (2H, d).
The compounds of the following examples were prepared according to the method of example 72:
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 744-cyclopropyl-3-hydroxy-5-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250384 (M + H) ⁺ 1.32 (2H, m), 1.48 (2H, m), 3.07 (3H, s), 4.04 (1H, m), 7.76 (3H, m), 7.95 (1H, t), 8.36 (2H, m), 8.62 (2H, d). 753-hydroxy-4- (2-methoxyethyl) -5-methyl-2-[(4-trifluoromethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Internal inflammation202-204402 (M + H) ⁺ 3.00 (3H, s), 3.29 (3H, s), 4.08 (2H, t), 5.37 (2H, br s), 7.68 (3H, m), 7.88 (1H, t), 8.10 (1H, d), 8.56 (3 H, m).
Example 76
2- (4-chlorophenyl) -3-hydroxy-4,5-dimethyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
2- (4-chlorophenyl) -2,4-dihydro-3-hydroxy-4-methylpyrazolo [4,3-c] isoquinolin-5-one (0.48 g; Example 6) was dissolved in anhydrous 1 Suspended in, 2-dimethoxyethane (50 mL). A solution of methylmagnesium bromide (3 mL of 3M solution in ether) was added and the mixture was heated at reflux for 0.75 h. Additional methylmagnesium bromide (1 mL) was added and heating continued for 3 hours. The reaction was cooled to ambient temperature and then quenched by the slow addition of dilute hydrochloric acid. The mixture was basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 times). The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography (silica, 97: 3-95: 5 dichloromethane: methanol) to give a red solid, which was triturated with ether to give the title compound (0.060 g). Melting point> 250 ° C.
MS (APCI) 324/326 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 2.90 (3H, s), 4.63 (3H, s), 7.49 (2H, d), 7.77 (1H, t), 7.95 (1H, t), 8.39 (4H, m ).
The compounds of the following examples were prepared according to the method of example 72:
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 775-ethyl-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250372 (M + H) ⁺ 1.45 (3H, t), 3.32 (2H, q), 4.78 (3H, s), 7.68 (3H, m), 7.88 (1H, td), 8.03 (1H, d), 8.54 (2H, d), 8.58 (1H, dd). 783-hydroxy-5-methyl-4- (1-methylethyl) -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt205-210386 (M + H) ⁺ 1.76 & 1.90 (6H, 2 × m, Rotamer), 3.07 (3H, s), 5.42 & 7.40 (1H, 2 × br, Rotamer), 7.77 (3H, m), 7.97 (1H, t) , 8.41 (2H, m), 8.62 (2H, m). 794-methyl-5- (1-methylethyl) -3-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt236-238386 (M + H) ⁺ 1.61 (6H, d), 4.05 (1H, br), 4.75 (3H, s), 7.76 (1H, t), 7.80 (2H, d), 7.94 (1H, t), 8.43 (1H, dd), 8.52 (1H, d), 8.60 (2H, d). 803-hydroxy-4,5-dimethyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250358 (M + H) ⁺ 2.87 (3H, s), 4.72 (3H, s), 7.66 (3H, m), 7.86 (1H, t), 8.01 (1H, d), 8.53 (3H, m).
Example 81
5-chloro-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
Phosphorous oxychloride (5 mL) was added to 2,4-dihydro-3-hydroxy-4- (4-methoxyphenylmethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3 -c] wasoquinolin-5-one (Example 66; 350 mg) and heated to reflux for 1 hour. After cooling to room temperature, the solvent was removed and the residue was purified by column chromatography eluting with isohexane: ethyl acetate: acetic acid (80: 20: 2), then triturated with acetonitrile to give the title compound (25 mg). Got it.
Melting point> 250 ° C. Decomposition.
MS (APCI) 364/366 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.96 (5H, m), 8.07 (1H, t), 8.25 (1H, d), 8.43 (1H, d).
Example 82
3a, 4-dihydro-3a-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinoline-3,5-dione
Ammonium nitrate (700 mg) containing cerium was added to 2,4-dihydro-3-hydroxy-4- (4-methoxyphenylmethyl) -2 in acetonitrile (4 mL) and water (1 mL) at room temperature. To a suspension of-(4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one (Example 66; 200 mg). After 2 hours, the mixture was absorbed into silica gel and purified by HPLC eluting with isohexane: propan-2-ol (9: 1) followed by HPLC eluting with isohexane: ethyl acetate (4: 1). The title compound (50 mg) was obtained. Melting point 175-185 ° C.
MS (ESI) 360 (MH) ^- .
¹ H NMR (d ₆ -DMSO) δ 7.7-8.0 (5H, m), 8.08-8.12 (4H, m), 9.78 (1H, s).
Example 83
2,4-dihydro-3-methoxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one
2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinoline- in anhydrous dimethylformamide (5 mL) 5-one (0.2 g; Example 63) was added dropwise to a stirred suspension of oil-free sodium hydride (from 0.022 g of 60% dispersion) in anhydrous dimethylformamide (1 mL) at 0 ° C. After 0.5 h, methyl iodide (0.038 mL) was added. Stirring was continued for 16 hours. The mixture was diluted with water, acidified with diluted hydrochloric acid and extracted with ethyl acetate (3 times). The organic phase was washed with brine (7 times), then dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (25: 75-50: 50 ethyl acetate: dichloromethane, then 30:70 ethyl acetate: isohexane) gave the title compound as a colorless solid (0.015 g). Melting point 163-164 ° C.
MS (APCI) 374 ((M + H) ⁺ ).
¹ H NMR (CDCl ₃ ) δ 3.78 (3H, s), 3.83 (3H, s), 7.60 (1H, td), 7.74 (1H, td), 7.80 (2H, d), 8.04 (2H, d), 8.27 (1H, doublet), 8.48 (1H, doubled).
Example 84
2- (4-chlorophenyl) -4- {2- (N, N-dimethylamino) ethyl} -3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, molecule Flameproof
2- (4-chlorophenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol (0.3 g) in oil-free sodium hydride (60 mL) in anhydrous dimethylformamide (5 mL) under a nitrogen atmosphere (60 % Dispersion from 81 mg). After 30 minutes, 2-dimethylaminoethyl chloride hydrochloride (0.15 g) was added and the mixture was stirred at rt for 16 h. The mixture was diluted with water and extracted with ethyl acetate (3 times). The organic phase was washed with brine then dried over sodium sulfate, filtered and concentrated to give a purple solid. Purification by column chromatography (20: 1 dichloromethane: ethanol) and recrystallization from 4: 1 cyclohexane: ethyl acetate gave the title compound as a red solid (125 mg).
Melting point 173-174 ° C.
MS (APCI) 367, 369 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 2.32 (6H, s), 3.02 (2H, t), 5.03 (2H, t), 7.4 (2H, d), 7.65 (1H, t), 7.85 (3H, m ), 8.30 (2H, d), 8.50 (1H, d).
Example 85
3-hydroxy-4-methyl-2- (4-methylsulfinylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
3-hydroxy-4-methyl-2- (4-methylthiophenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt (0.10 g; Example 41) It was dissolved in methane (15 mL) and cooled to -78 ° C. 3-chloroperbenzoic acid (0.055 g) was added and the mixture was stirred for 10 minutes, then poured into aqueous sodium metabisulfite and extracted with ethyl acetate (3 times). The combined extracts were shaken with aqueous sodium bicarbonate, dried over sodium sulfate and evaporated to give a residue, which was purified by column chromatography (3: 2 ethyl acetate: methanol) to give the title compound as a red powder (0.012 g). Melting point> 230 ° C.
MS (APCI): 338 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO): δ 2.77 (3H, s), 4.52 (3H, s), 7.80 (3H, m), 7.96 (1H, t), 8.13 (1H, d), 8.37 (1H, d), 8.57 (2H, d), 8.64 (1H, s).
Example 86
2- (4-chlorophenyl) -3-hydroxy-4- [2- (methylsulfinyl) ethyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
3-chloroperbenzoic acid (0.86 g) was dissolved in dichloromethane (20 mL). 6 mL of the resulting solution was diluted 2- (4-chlorophenyl) -3-hydroxy-4- [2- (methylthio) ethyl] -2H-pyrazolo [4, in dichloromethane (20 mL) at -78 ° C. 3-c] dropwise to a solution of isoquinolinium hydroxide, intramolecular salt (0.43 g; Example 46). After 30 minutes, aqueous sodium metabisulfite was added and then the reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with aqueous sodium hydroxide, then dried (magnesium sulfate), filtered and evaporated. The residue was chromatographed using methanol in dichloromethane (2-6% by volume) as eluent to give a purple solid (0.46 g). Melting point 228-230 ° C.
MS (APCI +) 386, 388 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 2.69 (3H, s), 3.47 (1H, m), 3.64 (1H, m), 5.11 (1H, m), 5.34 (1H, m), 7.50 (2H, m ), 7.79 (1 H, m), 7.99 (1 H, m), 8.17 (1 H, d), 8.38 (3 H, m), 8.83 (1 H, s).
Example 87
3-hydroxy-4- [2- (methylsulfinyl) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
3-hydroxy-4- [2- (methylthio) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt ( Prepared according to the method of Example 86 from Example 47), the title compound was obtained as a purple solid. Melting point 241-243 ° C.
MS (APCI +) 420 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 2.70 (3H, s), 3.47 (1H, m), 3.64 (1H, m), 5.11 (1H, m), 5.36 (1H, m), 7.81 (3H, m ), 8.01 (1H, m), 8.19 (1H, d), 8.38 (1H, d), 8.60 (2H, d), 8.86 (1H, s).
Example 88
5- [2- (4-methoxyphenyl) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol, sodium salt
Methylmagnesium bromide (3M in ether, 8.6 mL) was dissolved in 2,4-dihydro-3-hydroxy-4- (4-methoxyphenylmethyl) -2- (1,2-dimethoxyethane (50 mL). 4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one (Example 66; 500 mg) and slowly added to a stirred suspension of copper bromide (I) (15 mg) Then heated at 100 ° C. for 24 h. After cooling to room temperature, the mixture was poured into cold dilute hydrochloric acid and then basified with sodium bicarbonate and sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over magnesium sulfate. The solution was filtered and evaporated, then purified by column chromatography eluting successively with isohexane: ethyl acetate (1: 1), ethyl acetate and ethyl acetate: methanol (9: 1) to afford the title compound as a red solid (90 Mg). Melting point> 200 ° C Decomposition.
MS (APCI) 464 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO / TFA) δ 3.08 (2H, t), 3.59 (2H, t), 3.73 (3H, s), 6.87 (2H, d), 7.25 (2H, d), 7.92 (3H , m), 8.05 (1H, t), 8.33 (2H, d), 8.40 (1H, d), 8.50 (1H, d), 12.05 (TFA / water / 1H).
Example 89
9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide Loxide, Inner Molecular Salt
(a) 2,6-difluoro-N- (2-hydroxy-1,1-dimethylethyl) benzamide
A solution of 2,6-difluorobenzoyl chloride (20 g) in anhydrous dichloromethane (100 mL) was maintained at a temperature below 5 ° C. with 2-amino-2-methylpropanol in anhydrous dichloromethane (150 mL) under a nitrogen atmosphere. (20.2 g) was added dropwise to an ice cold solution. After the addition was complete, the ice bath was removed and stirring continued for an additional 16 hours at room temperature. The organic phase was diluted with water and separated. The aqueous phase is then extracted with dichloromethane (twice). The combined organic phases were washed with brine, dried over sodium sulphate, filtered and evaporated. Trituration with hexanes gave the lower title compound (24.65 g).
MS (APCI) 230 ((M + H) ⁺ ).
¹ H NMR (CDCl ₃ ) δ 1.41 (6H, s), 3.70 (2H, d), 3.95 (1H, t), 6.00 (1H, br s), 6.95 (2H, m), 7.38 (1H, m) .
(b) 2- (2,6-difluorophenyl) -4,5-dihydro-4,4-dimethyloxazole
Thionyl chloride (12.6 mL) was ice-cold in 2,6-difluoro-N- (2-hydroxy-1,1-dimethylethyl) benzamide (24.65 g) in anhydrous dichloromethane (100 mL) under a nitrogen atmosphere. It was added dropwise to the solution. After addition, the ice bath was removed and stirring continued for 1 hour at room temperature. The solvent was then evaporated and the residue triturated with diethyl ether. The resulting solid was dissolved in a minimum amount of water (80 mL) and then basified with sodium hydroxide pellets. The base phase was then extracted with ethyl acetate (3 times). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give an oil which was purified by column chromatography (4: 1 hexanes: ethyl acetate) to give the lower title compound (20.86 g).
MS (EI) 211 (M ⁺ ).
¹ H NMR (CDCl ₃ ) δ 1.42 (6H, s), 4.14 (2H, s), 6.95 (2H, m), 7.40 (1H, m).
(c) 4,5-dihydro-2- (2-fluoro-6-methylphenyl) -4,4-dimethyloxazole
A 3M solution of methylmagnesium chloride in tetrahydrofuran (86 mL) was added 2- (2,6-difluorophenyl) -4,5-dihydro- in anhydrous tetrahydrofuran (60 mL) at 0 ° C. under nitrogen atmosphere. To the solution of 4,4-dimethyloxazole (18.23 g) was added dropwise. The solution was stirred at 0 ° C. for 1 hour and then warmed to room temperature over 16 hours. Saturated ammonium chloride solution was carefully added to the reaction mixture, which was then extracted with ethyl acetate (3 times). The organic extract was washed with brine, dried over sodium sulfate, filtered and evaporated to give the lower title compound as light yellow oil (18.18 g).
MS (APCI) 208 ((M + H) ⁺ ).
¹ H NMR (CDCl ₃ ) δ 1.42 (6H, s), 2.40 (3H, s), 4.12 (2H, s), 6.93 (1H, t), 7.00 (1H, d), 7.26 (1H, m).
(d) 2-fluoro-6-methylbenzoic acid
4,5-dihydro-2- (2-fluoro-6-methylphenyl) -4,4-dimethyloxazole (18.18 g) and excess iodomethane (20 mL) were added to 4 in acetonitrile (150 mL). Heated under reflux for hours and then cooled to room temperature. The solvent was evaporated and the solid residue triturated with diethyl ether. The resulting solid was then dissolved in a mixture of methanol (80 mL) and 10% sodium hydroxide solution (80 mL) and heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and then methanol was evaporated. The aqueous residue was washed with ethyl acetate (3 times) and then acidified to pH 1 with dilute hydrochloric acid. The acidic phase was extracted with ethyl acetate (3 times). The organic extract was washed with brine, dried over sodium sulfate, filtered and evaporated to afford 2-fluoro-6-methylbenzoic acid (10.85 g). Sample (0.27 g) was recrystallized from 4: 1 hexanes: ethyl acetate to give the lower title compound (0.15 g).
Melting point 123-124 ° C.
MS (EI) 154 (M ⁺ ).
¹ H NMR (CDCl ₃ ) δ 2.52 (3H, s), 7.02 (2H, m), 7.35 (1H, m).
(e) methyl 2-fluoro-6-methylbenzoate
Cesium carbonate (16 g) and iodomethane (4.6 mL) were added to a stirred solution of 2-fluoro-6-methylbenzoic acid (3.78 g) in anhydrous dimethylformamide (25 mL) under a nitrogen atmosphere. Stirring was continued for 16 hours at room temperature, then the reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine, then dried over sodium sulfate, filtered and evaporated to afford the lower title compound as a yellow oil (4.07 g).
MS (EI) 168 (M ⁺ ).
¹ H NMR (CDCl ₃ ) δ 2.40 (3H, s), 3.94 (3H, s), 6.94 (1H, t), 7.01 (1H, d), 7.30 (1H, m).
(f) methyl 2- (bromomethyl) -6-fluorobenzoate
Methyl 2-fluoro-6-methylbenzoate (35.53 g), N-bromosuccinimide (37.6 g) and azobis (isobutyronitrile) (2 g) in anhydrous dichloromethane (150 mL) were nitrogen atmosphere. Under irradiation for 4 hours (100 W halogen lamp). The resulting solution was poured into 10% sodium hydroxide solution and extracted with dichloromethane (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give a mixture of the lower title compound and starting material (52.33 g) as a yellow oil.
MS (EI) 246/248 (M ⁺ ).
¹ H NMR (CDCl ₃ ) δ 3.99 (3H, s), 4.66 (2H, s), 7.06 (1H, t), 7.23 (1H, d), 7.40 (1H, m).
(g) methyl 2-fluoro-6-{[(2-methoxy-2-oxoethyl)-(4-methoxyphenylmethyl) amino] methyl} benzoate
N- (4-methoxyphenylmethyl) glycine methyl ester (10.2 g) was added methyl 2- (bromomethyl) -6-fluorobenzoate (11 g) and triethylamine in anhydrous diethyl ether (50 mL). 6.8 ml) was added dropwise. The mixture was heated at reflux in a nitrogen atmosphere for 16 h. The reaction mixture was cooled down, then diluted with water and extracted with ethyl acetate (3 times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (20: 1 hexanes: ethyl acetate) to give the lower title compound as a colorless oil (8.82 g).
MS (APCI) 376 ((M + H) ⁺ ).
¹ H NMR (CDCl ₃ ) δ 3.21 (2H, s), 3.67 (3H, s), 3.68 (2H, s), 3.78 (3H, s), 3.88 (3H, s), 4.01 (2H, s), 6.82 (2H, d), 7.05 (1H, t), 7.18 (3H, m), 7.35 (1H, m).
(h) Methyl 5-fluoro-1,2,3,4-tetrahydro-2- (4-methoxyphenylmethyl) -4-oxo-3-isoquinolinecarboxylate
A solution of methyl 2-fluoro-6-{[(2-methoxy-2-oxoethyl)-(4-methoxyphenylmethyl) amino] methyl} benzoate (8.82 g) in anhydrous toluene (50 mL) was prepared. To a suspension of sodium hydride (1.32 g of 60% dispersion, no oil) and tert-butyl alcohol (1 mL) in anhydrous toluene (100 mL) heated under reflux in a nitrogen atmosphere was added dropwise. After further heating for 12 hours, the reaction mixture was cooled to room temperature. The mixture was then poured onto saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 times). The organic phase was washed with brine, dried over sodium sulphate, filtered and evaporated to afford the lower title compound (7.96 g). MS (APCI) 344 ((M + H) ⁺ ).
¹ H NMR (CDCl ₃ ) δ 3.60 (2H, s), 3.81 (3H, s), 3.89 (2H, s), 3.92 (3H, s), 6.86 (3H, m), 7.05 (1H, m), 7.22 (2H, m), 7.38 (1H, m), 11.83 (1H, s).
(h) 9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoqui Nolinium hydroxide, intramolecular salt
Methyl 5-fluoro-1,2,3,4-tetrahydro-2- (4-methoxyphenylmethyl) -4-oxo-3-isoquinolinecarboxylate (1.0 g), 4-trifluoromethylphenyl Hydrazine (1.03 g) and p-toluene sulfonic acid (20 mg) were fused together at 150 ° C. for 15 minutes under a nitrogen atmosphere. Xylene (20 mL) was then added and heating continued for a further 2 hours. Cooling at room temperature evaporated the solvent and the solid residue was purified by column chromatography (99: 1 dichloromethane: methanol) to give the title compound as purple needle crystals (0.425 g).
MS (APCI) 468 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 3.72 (3H, s), 6.10 (2H, s), 6.96 (2H, d), 7.70 (2H, d), 7.80 (4H, m), 8.00 (1H, dd ), 8.59 (2H, d), 8.98 (1H, s).
Example 90
9-fluoro-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol
9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide Loxide, intramolecular salt (0.43 g) was dissolved in trifluoroacetic acid (5 mL) and heated under reflux in a nitrogen atmosphere for 16 h. After cooling to room temperature, the solvent was evaporated and the residue was evaporated with toluene (three times). The residue was triturated successively with methanol followed by diethyl ether and finally recrystallized from ethyl acetate to give the title compound as a red solid (0.08 g).
Melting point> 250 ° C.
MS (APCI) 348 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 7.86 (2H, m), 7.95 (2H, d), 8.14 (1H, d), 8.24 (2H, br d), 9.09 (1H, br s), 11.85 (1H , br s).
The compounds of the following examples were prepared in a similar manner to Example 90:
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 912- (4-chlorophenyl) -7-fluoro-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250328/330 (M + H) ⁺ 4.51 (3H, s), 7.46 (2H, d), 7.77 (1H, td), 7.87 (1H, dd), 8.36 (3H, m), 8.45 (1H, s). 927-fluoro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250362 (M + H) ⁺ 4.51 (3H, s), 7.75 (2H, d), 7.80 (1H, m), 7.87 (1H, dd), 8.38 (1H, dd), 8.47 (1H, s), 8.54 (2H, d). 932- (4-chlorophenyl) -4-cyclopropyl-9-fluoro-3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 214-217354/356 (M + H) ⁺ 1.35 (2H, m), 1.54 (2H, m), 5.11 (1H, m), 7.51 (2H, d), 7.75 (2H, m), 7.95 (1H, dd), 8.38 (2H, d), 8.63 (1H, s). 944-cyclopropyl-9-fluoro-3-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250388 (M + H) ⁺ 1.36 (2H, m), 1.53 (2H, m), 5.06 (1H, m), 7.77 (4H, m), 7.97 (1H, m), 8.58 (2H, d), 8.66 (1H, s). 952- (4-chlorophenyl) -9-fluoro-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250328/330 (M + H) ⁺ 4.51 (3H, s), 7.51 (2H, d), 7.76 (2H, m), 7.91 (1H, m), 8.35 (2H, d), 8.65 (1H, s). 962- (4-Chlorophenyl) -9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250434/436 (M + H) ⁺ 3.72 (3H, s), 6.10 (2H, s), 6.95 (2H, d), 7.54 (2H, d) 7.70 (2H, d), 7.77 (2H, m), 7.97 (1H, m), 8.39 ( 2H, d), 8.96 (1H, s). 979-fluoro-3-hydroxy-4-methyl- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, internal salt> 250362 (M + H) ⁺ 4.51 (3H, s), 7.77 (4H, m), 7.93 (1H, m), 8.56 (2H, d), 8.68 (1H, s).
The following compounds (Examples 98-100) were prepared according to the method of Example 2:
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 982- (4-chlorophenyl) -9-fluoro-2H-pyrazolo [4,3-c] isoquinolin-3-ol> 250314/316 (M + H) ⁺ 7.63 (2H, d), 7.82 (2H, br m), 8.01 (2H, d), 8.11 (1H, br d), 9.05 (1H, br s), 11.80 (1H, br s). 997-fluoro-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol> 250348 (M + H) ⁺ 7.93 (3H, d), 8.14 (1H, d), 8.28 (2H, d), 8.41 (1H, dd), 9.02 (1H, br s). 1002- (4-chlorophenyl) -7-fluoro-2H-pyrazolo [4,3-c] isoquinolin-3-ol> 250314/3167.63 (2H, d), 7.91 (1H, br t), 8.05 (2H, d), 8.13 (1H, d), 8.40 (1H, dd), 9.00 (1H, br s), 12.00 (1H, br s ).
The following compounds were prepared according to the method of Example 69:
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 1019-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -5-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] iso Quinolinium Hydroxide, Internal Salt225-227482 (M + H) ⁺ 2.86 (3H, s), 3.73 (3H, s), 6.53 (2H, s), 6.92 (2H, d), 7.30 (2H, d), 7.74 (4H, m), 8.11 (1H, d), 8.58 (2H, d). 1022- (4-chlorophenyl) -9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -5-methyl-2H-pyrazolo [4,3-c] isoquinoli Nium hydroxide, internal salt222-223448/450 (M + H) ⁺ 2.85 (3H, s), 3.73 (3H, s), 6.53 (2H, s), 6.91 (2H, d), 7.29 (2H, d), 7.44 (2H, d), 7.70 (2H, m), 8.08 (1H, d), 8.37 (2H, d).
The following compounds were prepared according to the method of Example 2:
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 1039-fluoro-5-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol> 250362 (M + H) ⁺ 2.80 (3H, s), 7.79 (2H, m), 7.88 (2H, d), 8.10 (1H, d), 8.32 (2H, d). 1042- (4-chlorophenyl) -9-fluoro-5-methyl-2H-pyrazolo [4,3-c] isoquinolin-3-ol> 250328/330 (M + H) ⁺ 2.89 (3H, s), 7.58 (2H, d), 7.79 (2H, br m), 8.08 (3H, br m).
Example 105
2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinoline-5-thione
2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinoline-5- in dioxane (20 mL) A solution of warm (Example 63; 0.25 g) and Laweson reagent (0.7 g) was stirred for 18 hours under reflux and heated. The resulting mixture was cooled down and absorbed onto silica gel. Purification by chromatography (1: 99-3: 97 methanol: dichloromethane) gave the title compound, which was crystallized from ethanol to give a yellow solid (0.075 g). Melting point 255-259 ° C.
MS (APCI) 376 ((M + H) ⁺ ).
¹ H NMR (D ₂ O / NaOD) δ 8.47 (1H, d), 7.71 (2H, d), 7.60 (3H, m), 7.34 (1H, t), 7.22 (1H, t), 4.08 (3H, s).
Example 106
3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinoline-5-thione in acetone (50 mL) (0.46 g; Example 105) and a solution of iodomethane (0.095 mL) were stirred and refluxed for 4 h under reflux. Potassium carbonate (0.170 g) was added and the mixture was heated for a further 2 hours. The mixture was concentrated in vacuo. The residue was purified by chromatography (2:98 methanol: dichloromethane) to give the title compound as a purple solid (0.375 g).
MS (APCI) 390 ((M + H) ⁺ ).
¹ H NMR (CDCl ₃ ) δ 8.54 (4H, m), 7.86 (1H, t), 7.72 (3H, m), 4.98 (3H, s), 2.52 (3H, s).
Example 107
2- (4-trifluoromethylphenyl) -2,4-dihydro-5-imino-4-methyl-5H-pyrazolo [4,3-c] isoquinolin-3-ol
3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3- in ethanol (7 mL) and ammonia solution (0.880 specific gravity; 18 mL) c] A suspension of isoquinolinium hydroxide, intramolecular salt (0.013 g; Example 106) was stirred at 20 ° C. for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (5: 95-10: 90 methanol: dichloromethane) to give the title compound as an orange solid (0.043 g). Melting point 253-255 ° C.
MS (APCI) 717 ((2M + H) ⁺ ), 359 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) δ 8.60 (2H, d), 8.46 (1H, d), 8.29 (3H, m), 7.90 (1H, t), 7.71 (3H, m), 4.19 (3H, s ).
Example 108
3-hydroxy-4- (4-methoxyphenyl) methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4-f] [1,7] naphthyridinium hydroxide, Molecular Inflammation
(a) Methyl 2- (bromomethyl) nicotinate
Methyl 2-methylnicotinate (10.0 g) and N-bromosuccinimide (14.9 g) were mixed in 1,2-dichloroethane (80 mL). Acetic acid (3.8 mL) was added followed by 2,2'-azobis (2-methylpropionitrile) (1.0 g) and the mixture was heated to reflux with irradiation with a 500 W lamp. After 2 hours, the reaction was cooled and then poured onto sodium bicarbonate solution. The organic phase was separated, washed twice with brine, dried, filtered and evaporated to give an oil (18.2 g) which was used immediately in the next step.
(b) N-[(4-methoxyphenyl) methyl] -N-[(3-methoxycarbonyl-2-pyridyl) methyl] glycine methyl ester
Methyl 2- (bromomethyl) nicotinate (9.10 g), methyl N- (4-methoxyphenyl) methylglycine (10.2 g) and triethylamine (5.5 mL) in diethyl ether (100 mL) were used Prepared according to the method of step (a) of Example 1 to give the lower title compound (3.20 g).
MS (DESC SI) 358 (M ⁺ ).
¹ H NMR (d ₆ -DMSO) 3.17 (s, 2H), 3.34 (s, 3H), 3.58 (s, 2H), 3.71 (s, 3H), 3.82 (s, 3H), 4.23 (s, 2H) , 6.82 (d, 2H), 7.04 (d, 2H), 7.43 (dd, 1H), 8.03 (dd, 1H), 8.61 (dd, 1H).
(c) methyl 7,8-dihydro-5-hydroxy-7- (4-methoxyphenyl) methyl [1,7] naphthyridine-6-carboxylate
N-[(4-methoxyphenyl) methyl] -N-[(3-methoxycarbonyl-2-pyridyl) methyl] glycine methyl ester (1.00 g), sodium hydride (60% dispersion in oil; 160 mg ), 2-methylpropan-2-ol (0.10 mL) and toluene (15 mL) were prepared according to the method of Example (b) of Example 1 to give the lower title compound (790 mg).
MS (APCI) 327 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) 3.65-3.97 (m, 10H), 6.79 (m, 2H), 7.11-7.39 (m, 3H), 7.86-8.25 (m, 1H), 8.52-8.75 (m, 1H ), 11.25 (s, 1 H).
(d) 3-hydroxy-4- (4-methoxyphenyl) methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4-f] [1,7] naphthyridinium hydroxide Loxide, Inner Molecular Salt
Methyl 7,8-dihydro-5-hydroxy-7- (4-methoxyphenyl) methyl-1,7-naphthyridine-6-carboxylate (200 mg), 4-trifluoromethylphenylhydrazine (1.00 g) and ethanol (3 ml) were prepared according to the method of step (c) of Example 1 to give the title compound (21 mg).
Melting point 201-3 ° C.
MS (APCI) 451 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) 3.72 (s, 3H), 6.13 (s, 2H), 6.96 (d, 2H), 7.76 (d, 2H), 7.84 (d, 2H), 7.88 (dd, 1H) , 8.59 (d, 2H), 8.72 (dd, 1H), 9.00 (s, 1H), 9.05 (dd, 1H).
Example 109
2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4-f] [1,7] naphthyridin-3-ol
3-hydroxy-4- (4-methoxyphenyl) methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4-f] [1,7] naphthyridinium hydroxide, Prepared according to the method of Example 2 using an intramolecular salt (135 mg) and trifluoroacetic acid (5 mL) to give the title compound (19 mg).
Melting point 239-41 ° C. (decomposition).
MS (APCI) 331 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) 7.94 (d, 2H), 7.95 (m, 1H), 8.28 (d, 2H), 8.74 (d, 1H), 9.01 (br, 1H), 9.16 (d, 1H) .
The compounds of the following examples were prepared analogously to Example 109 using methyl 2- (bromomethyl) nicotinate, sarcosine methyl ester, and appropriate hydrazine.
ExampleCompound nameMelting point (℃)MS ¹ H NMR (d ₆ -DMSO) δ 1103-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4-f] [1,7] naphthyridinium hydroxide, internal salt> 260345 (M + H) ⁺ 4.56 (s, 3H), 7.82 (d, 2H), 7.88 (dd, 1H), 8.56 (d, 2H), 8.70 (s, 1H), 8.73 (s, 1H), 9.05 (d, 1H). 1112- (4-chlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [3,4-f] [1,7] naphthyridinium hydroxide, internal salt> 260311/313 (M + H) ⁺ 4.56 (s, 3H), 7.51 (d, 2H), 7.88 (dd, 1H), 8.35 (d, 2H), 8.68 (s, 1H), 8.70 (dd, 1H), 9.03 (dd, 1H).
Example 112
3-hydroxy-4-methyl-5- (dimethylamino) -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3- in acetone (10 mL) and 40% aqueous dimethylamine solution (2 mL) c] A solution of isoquinolinium hydroxide, intramolecular salt (0.39 g; Example 106) was stirred at 20 ° C. for 24 hours. The mixture was concentrated in vacuo. The residue was purified by chromatography (1: 99-2.5: 97.5 methanol: dichloromethane) to give the title compound as a red solid (0.129 g). Melting point 256-259 ° C.
MS (APCI) 387 ((M + H) ⁺ ).
¹ H NMR (DMSO) d 3.19 (6H, s), 4.52 (3H, s), 7.64 (3H, m), 7.84 (1H, td), 7.95 (1H, d), 8.54 (3H, d).
Example 113
3-hydroxy-4-methyl-5-morpholinyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3- in anhydrous tetrahydrofuran (7 mL) and morpholine (2.3 mL) c] A solution of isoquinolinium hydroxide, intramolecular salt (0.520 g; Example 106) was heated at 70 ° C. for 12 hours and then at 95 ° C. for 2 hours. The mixture was concentrated in vacuo. The residue was purified by chromatography (5:95 methanol: dichloromethane) to give the title compound as a red solid (0.165 g). Melting point 278-281 ° C.
MS (APCI) 429 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) d 3.49 (4H, m), 3.87 (4H, m), 4.49 (3H, s), 7.77 (2H, m), 7.94 (1H, t), 8.28 (1H, d ), 8.38 (1 H, d), 8.59 (2 H, d).
Example 114
3-hydroxy-4-methyl-5-piperazinyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt
3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide in toluene (20 mL), A solution of intramolecular salt (0.29 g; Example 106) was added dropwise to a stirred solution of piperazine (1.28 g) in toluene (50 mL) heated to 110 ° C. The resulting solution was stirred at 110 ° C. for 6 hours and then at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by chromatography (5: 95-10: 90 methanol: dichloromethane) and crystallized from ethanol to give the title compound as a red solid (0.107 g). Melting point 260-262 ° C.
MS (APCI) 428 ((M + H) ⁺ ).
¹ H NMR (DMSO) d 2.96 (4H, m), 3.37 (4H, m), 4.44 (3H, s), 7.76 (3H, m), 7.93 (1H, t), 8.27 (1H, d), 8.37 (1 H, d), 8.59 (2 H, d).
Example 115
4,5-dihydro-2- [4- (trifluoromethyl) phenyl] -2H-benz [g] indazol-3-ol
1-oxotetrahydronaphthalene-2-carboxylic acid methyl ester (Mander, LN) and Seti, SP; Tetrahedron Lett. 1983, 24, 5425- 2.0 g) and 4-trifluoromethylphenylhydrazine (3.47 g) were heated under reflux in xylene (15 mL) for 8 hours. After cooling the reaction mixture, the product was filtered off. The solid was washed with diethyl ether, dried and recrystallized from toluene to give the title compound as colorless crystals (1.45 g). Melting point 189-190 ° C.
MS (APCI) 331 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) d 2.67 (2H, m), 2.90 (2H, m), 7.29 (3H, m), 7.75 (1H, m), 7.84 (2H, d), 8.10 (2H, d ), 11.70 (1H, s, br).
Example 116
4,5-dihydro-2- (5-methyl-2-pyridinyl) -2H-benz [g] indazol-3-ol
1-oxotetrahydronaphthalene-2-carboxylic acid methyl ester (2.18 g) and 2-hydrazino-5-methylpyridine (2.85 g) were heated under reflux in xylene (15 mL) for 6 hours. After the reaction was cooled, the product was filtered and dried. Recrystallization from diethyl ether / isohexane gave the title compound as light brown needles (0.69 g). Melting point 112 ° C.
MS (APCI) 278 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) d 2.36 (3H, s), 2.73 (2H, t), 2.95 (2H, t), 7.29 (3H, m), 7.68 (1H, dd), 7.92 (1H, d ), 7.94 (1 H, m), 8.07 (1 H, s), 12.73 (1 H, s, br).
Example 117
2- [4- (trifluoromethyl) phenyl] -2H-benz [g] indazol-3-ol
4,5-dihydro-2- [4- (trifluoromethyl) phenyl] -2H-benz [g] indazol-3-ol (0.30 g) and 10% palladium on charcoal (0.10 g) are dimethylacet Heated under reflux in amide (5 mL) and cyclohexene (5 mL) for 1 h. Title compound (0.26 g). Melting point> 235 ° C. (decomposition).
MS (APCI) 329 ((M + H) ⁺ ).
¹ H NMR (d ₆ -DMSO) d 7.70 (4H, m), 7.85 (2H, d), 8.07 (1H, m), 8.27 (2H, d), 8.30 (1H, m), 11.70 (1H, s , br).
Example 118
2- (5-methyl-2-pyridinyl) -2H-benz [g] indazol-3-ol
4,5-Dihydro-2- (5-methyl-2-pyridinyl) -2H-benz [g] indazol-3-ol (0.40 g) and 10% palladium on charcoal (0.20 g) are dimethylacetamide (15 mL) and cyclohexene (15 mL) were heated at reflux for 8 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated (100 ° C./1 mm Hg) and the residue was recrystallized from ethyl acetate to give the title compound as pale orange crystals (0.12 g). Melting point 214 ° C.
MS (APCI) 276 ((MH) ⁺ ).
¹ H NMR (d ₆ -DMSO) d 2.36 (3H, s), 7.52 (1H, d), 7.66 (3H, m), 7.82 (1H, dd), 8.02 (1H, d), 8.41 (1H, s , br), 8.53 (2H, m).
Drug data
Test A-Chronic Host Host Test
Drug activity of the compounds of the present invention is described in J.M. J.M. Doutrelepont et al., Clin. Exp. Immunol., 1991, 83, 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse]. Test compounds were administered subcutaneously to mice as suspensions in saline with TWEEN-80 daily for 21 days.
Test B-Inhibition of Eosinophilia
The effect of the compounds of the present invention on inflammatory cells in mouse lungs is described in Bruselle et al., Clin. Exp. Allergy, 1994, 24, 73-80]. Measurement of eosinophil peroxidase as a marker for the number of eosinophils is described by Cheng et al., J. Pharmacol. Exp. Ther., 1993, 264, 922-929. Male Balb / c mice were sensitized to an ovalbumin / Al (OH) ₃ mixture. After 14 days of sensitization, administration of the compound was started. The compound was administered daily orally or subcutaneously as a suspension or solution (depending on the dosage and solubility of the compound) in 5% Tween 80. After 17 days of sensitization and 1 hour after administration of the fourth dose of the compound, mice were placed in a Perspex chamber sprayed with a solution of ovalbumin (2% w / v). Mice were inhaled with ovalbumin for 30-40 minutes. This attempt was repeated daily for the same number of times for an additional 3 or 7 days. If attempts were made for 4 days, ovalbumin was further administered 4 hours after the first dose on the last dose.
The next day the animals were sacrificed and the inhibition of the following parameters was measured in comparison with the control animals:
(1) Increase in the number of inflammatory cells, in particular eosinophils, in alveolar lavage (4 days after administration).
(2) Accumulation of eosinophils in lung tissue as measured by increased eosinophil peroxidase activity in homogenized lung tissue (after 8 days of administration).
(3) Increase in antibody titers (IgE, IgG1 and IgG2a) present in serum from whole blood (after 8 days of administration).
Certain compounds of the present invention exhibit activity with ED ₅₀ in the range of 0.1 to 10 mg / kg in chronic cohost test and inhibition of eosinophilia.

权利要求:
Claims (16)
[1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable derivative thereof, useful as a drug.
<Formula I>

Where
B, D, E and G each represent CH, CA or N, provided that only one of B, D, E and G represents CA and only one of B, D, E and G represents N;
X represents C═O, C═S, C═NR ¹⁵ , CR ³ R ⁶ or NR ⁴ ;
Y represents N or N ⁺ R ⁷ or CR ¹⁸ ;
Z represents OR ⁸ or O ⁻ ;
R ¹ represents OH or C _1-6 alkyl or forms a bond with R ² or R ⁵ ;
R ² represents H, C _1-6 alkyl (optionally substituted with phenyl, COOR ⁹ , NR ¹⁰ R ¹¹ , OR ¹² or F) or C _3-7 cycloalkyl or R ¹ , R ³ Or together with R ⁴ form a bond;
R ³ represents H or represents a bond with R ² ;
R ⁴ represents C _1-6 alkyl or represents a bond with R ² ;
R ⁵ represents a bond together with R ¹ or R ⁸ ;
R ⁶ is H, C _1-6 alkyl (optionally substituted with phenyl), C _3-7 cycloalkyl, phenyl, halogen, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Alkylsulfinyl, cyano or NR ¹³ R ¹⁴ ;
R ⁷ represents C _1-6 alkyl (which alkyl is optionally substituted with phenyl) or C _3-7 cycloalkyl, one of which is halogen, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, NR ¹⁶ R ^17, COOH, COO (C _1-6 alkyl), or cyano, or furnace be optionally substituted,
R ⁶ and R ⁷ together represent C _3-5 alkylene, such that X and Y form a 5-7 membered ring;
R ⁸ represents H or C _1-6 alkyl or represents a bond with R ⁵ ;
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently represent C _1-6 alkyl or H;
R ¹³ and R ¹⁴ independently represent C _1-6 alkyl or H, or together with the nitrogen atom to which they are attached form a three to seven membered saturated ring, which ring optionally further comprises an oxygen atom or a nitrogen atom And optionally substituted with C _1-6 alkyl);
Ar ¹ represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxalinyl, all of which are halo, nitro, cyano, phenyl, phenylsulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO (C _1-6 alkyl), a phenyl C _1-6 alkyl, or phenyl substituted with Optionally substituted with one or more substituents selected from wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl group may be optionally substituted with fluoro;
A represents halo, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy;
The phenyl group in the above definition of R ² , R ⁶ and R ⁷ or as a substituent on Ar ¹ may be optionally substituted with C _1-6 alkyl, halogen or C _1-6 alkoxy;
only,
(i) if X represents C═O, C═S or C═NR ¹⁵ , then Y represents N;
(ii) when R ⁴ represents a bond with R ² , then Y represents N ⁺ R ⁷ ;
(iii) Y represents that the N ⁺ R ^7, Z is O ^- represents a, R ² represents the bond with R ³ or R ^4, R ¹ and R ⁵ forms a bond;
(iv) when Y represents N, Z represents OR ⁸ ;
(v) when R ¹ represents OH, X represents C═O, Y represents N, Z represents OR ⁸ , and R ⁵ represents a bond with R ⁸ ;
(vi) when R ¹ represents alkyl, R ⁵ represents a bond with R ⁸ , Y represents N, R ² does not represent a bond, and X does not represent NR ⁴ ;
(vii) when R ¹ represents a bond with R ² , R ⁵ and R ⁸ form a bond, and when X represents NR ⁴ , R ⁴ represents alkyl;
(viii) when R ⁶ represents aryl, halogen, alkoxy or thioalkyl, R ² and R ³ form a bond;
(ix) when Y represents N or N ⁺ R ⁷ and R ² is substituted with any one of NR ¹⁰ R ¹¹ , OR ¹² or F, the substituents of Y and the ring nitrogen cannot bond to the same carbon atom of R ² ; ;
(x) when R ⁷ is substituted with any of NR ¹⁶ R ¹⁷ , OR ¹² or halogen, the substituent of Y and the ring nitrogen may not bond to the same carbon atom of R ⁷ ;
(xi) if one of B, D, E and G represents N, then X does not represent NR ⁴ ;
(xii) when Y represents CR ¹⁸ , X represents CR ³ R ⁶ ;
In addition,
B, D, E and G all represent CH, X represents CHR ³ , Y represents nitrogen, R ¹ and R ⁵ form a bond, R ⁸ represents H, R ² and R ³ When this represents a bond together, Ar ¹ does not represent 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl.
[2" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable derivative thereof.
<Formula I>

Where
B, D, E and G each represent CH, CA or N, provided that only one of B, D, E and G represents CA and only one of B, D, E and G represents N;
X represents C═O, C═S, C═NR ¹⁵ , CR ³ R ⁶ or NR ⁴ ;
Y represents N or N ⁺ R ⁷ or CR ¹⁸ ;
Z represents OR ⁸ or O ⁻ ;
R ¹ represents OH or C _1-6 alkyl or forms a bond with R ² or R ⁵ ;
R ² represents H, C _1-6 alkyl (optionally substituted with phenyl, COOR ⁹ , NR ¹⁰ R ¹¹ , OR ¹² or F) or C _3-7 cycloalkyl or R ¹ , R ³ Or together with R ⁴ form a bond;
R ³ represents H or represents a bond with R ² ;
R ⁴ represents C _1-6 alkyl or represents a bond with R ² ;
R ⁵ represents a bond together with R ¹ or R ⁸ ;
R ⁶ is H, C _1-6 alkyl (optionally substituted with phenyl), C _3-7 cycloalkyl, phenyl, halogen, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Alkylsulfinyl, cyano or NR ¹³ R ¹⁴ ;
R ⁷ represents C _1-6 alkyl (which alkyl is optionally substituted with phenyl) or C _3-7 cycloalkyl, one of which is halogen, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, NR ¹⁶ R ^17, COOH, COO (C _1-6 alkyl), or cyano, or furnace be optionally substituted,
R ⁶ and R ⁷ together represent C _3-5 alkylene, such that X and Y form a 5-7 membered ring;
R ⁸ represents H or C _1-6 alkyl or represents a bond with R ⁵ ;
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently represent C _1-6 alkyl or H;
R ¹³ and R ¹⁴ independently represent C _1-6 alkyl or H, or together with the nitrogen atom to which they are attached form a three to seven membered saturated ring, which ring optionally further comprises an oxygen atom or a nitrogen atom And optionally substituted with C _1-6 alkyl);
Ar ¹ represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxalinyl, all of which are halo, nitro, cyano, phenyl, phenylsulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO (C _1-6 alkyl), a phenyl C _1-6 alkyl, or phenyl substituted with Optionally substituted with one or more substituents selected from wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl group may be optionally substituted with fluoro;
A represents halo, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy;
The phenyl group in the above definition of R ² , R ⁶ and R ⁷ or as a substituent on Ar ¹ may be optionally substituted with C _1-6 alkyl, halogen or C _1-6 alkoxy;
only,
(i) if X represents C═O, C═S or C═NR ¹⁵ , then Y represents N;
(ii) when R ⁴ represents a bond with R ² , then Y represents N ⁺ R ⁷ ;
(iii) Y represents that the N ⁺ R ^7, Z is O ^- represents a, R ² represents the bond with R ³ or R ^4, R ¹ and R ⁵ forms a bond;
(iv) when Y represents N, Z represents OR ⁸ ;
(v) when R ¹ represents OH, X represents C═O, Y represents N, Z represents OR ⁸ , and R ⁵ represents a bond with R ⁸ ;
(vi) when R ¹ represents alkyl, R ⁵ represents a bond with R ⁸ , Y represents N, R ² does not represent a bond, and X does not represent NR ⁴ ;
(vii) when R ¹ represents a bond with R ² , R ⁵ and R ⁸ form a bond, and when X represents NR ⁴ , R ⁴ represents alkyl;
(viii) when R ⁶ represents aryl, halogen, alkoxy or thioalkyl, R ² and R ³ form a bond;
(ix) when Y represents N or N ⁺ R ⁷ and R ² is substituted with any one of NR ¹⁰ R ¹¹ , OR ¹² or F, the substituents of Y and the ring nitrogen cannot bond to the same carbon atom of R ² ; ;
(x) when R ⁷ is substituted with any of NR ¹⁶ R ¹⁷ , OR ¹² or halogen, the substituent of Y and the ring nitrogen may not bond to the same carbon atom of R ⁷ ;
(xi) if one of B, D, E and G represents N, then X does not represent NR ⁴ ;
(xii) when Y represents CR ¹⁸ , X represents CR ³ R ⁶ ;
In addition,
(a) B, D, E and G all represent CH, X represents CHR ³ , Y represents N, R ¹ and R ⁵ form a bond, R ⁸ represents H, R ² and When R ³ together represent a bond, Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl;
(b) B, D, E and G all represent CH, X represents CHR ³ , Y represents N ⁺ R ⁷ , R ¹ and R ⁵ form a bond, and R ² and R ³ join When R ⁸ represents H and R ⁷ represents methyl, Ar ¹ does not represent unsubstituted phenyl;
(c) B, D, E and G all represent CH, X represents CH ₂ , Y represents N, R ¹ and R ⁵ form a bond, R ⁸ represents H, and R ² is When isopropyl, Ar ¹ does not represent unsubstituted phenyl or 4-bromophenyl;
(d) When B, D, E and G all represent CH, X and Y represent CH ₂ , and R ¹ and R ⁵ form a bond, Ar ¹ does not represent unsubstituted phenyl.
[3" claim-type="Currently amended] 3. Compounds of formula I according to claim 1 or 2, wherein Ar ¹ represents phenyl or pyridyl.
[4" claim-type="Currently amended] 4. Compounds of formula I according to claim 3, wherein Ar ¹ represents phenyl.
[5" claim-type="Currently amended] The compound of formula I according to claim 3 or 4, wherein Ar ¹ has a substituent in the para position.
[6" claim-type="Currently amended] 6. Compounds of formula I according to claim 5, wherein Ar ¹ has a Cl, Br, CF ₃ , C ₂ F ₅ , OCF ₃ or SCH ₃ substituent in the para position.
[7" claim-type="Currently amended] 7. The compound of claim 1, wherein Y represents N ⁺ R ⁷ , X represents CR ³ R ⁶ , wherein R ³ together with R ² form a bond and R ⁶ represents alkyl. Compound of formula (I).
[8" claim-type="Currently amended] 8. Compounds of formula I according to claim 7, wherein R ⁶ represents branched alkyl.
[9" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 6, wherein X represents NR ⁴ , wherein R ⁴ represents a bond with R ^2, and Y represents N ⁺ R ⁷ .
[10" claim-type="Currently amended] 10. Compounds of formula I according to any one of claims 1 to 9, wherein B represents CA.
[11" claim-type="Currently amended] 11. Compounds of formula I according to claim 10, wherein A represents F.
[12" claim-type="Currently amended] 12. Compounds of formula I according to any one of claims 1 to 11, wherein D or G represents N.
[13" claim-type="Currently amended] 13. Compounds of formula I according to any one of claims 1 to 12, wherein R ¹ represents a bond together with R ² or R ⁵ .
[14" claim-type="Currently amended] The compound of formula I according to claim 13, wherein R ¹ represents a bond with R ⁵ .
[15" claim-type="Currently amended] The method of claim 2,
3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt ,
2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (4-chlorophenyl) -2,5-dihydro-5-methyl-3H-pyrazolo [4,3-c] cinnolin-3-one,
2- (4-chlorophenyl) -2,3a, 4,5-tetrahydro-3a, 4-dimethylpyrazolo [4,3-c] isoquinolin-3-one,
2- (4-chlorophenyl) -3a, 4-dihydro-3a, 4-dimethyl-2H-pyrazolo [4,3-c] isoquinoline-3,5-dione,
2- (4-chlorophenyl) -2,4-dihydro-3-hydroxy-4-methylpyrazolo [4,3-c] isoquinolin-5-one,
3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (3,4-dichlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt ,
2- (3,4-dichlorophenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2-([1,1'-biphenyl] -4-yl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-methylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-methylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (4-bromophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-bromophenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (3-trifluoromethylphenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt ,
2- (3-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- [4- (1,1-dimethylethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (4-trifluoromethoxyphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (4-chlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] cinnolinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-2- (3-quinolyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (6-chloro-3-pyridyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (3,4-dichlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-2- (4-methylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-bromophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-2- (3-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- [4- (1,1-dimethylethyl) phenyl] -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (6-chloro-3-pyridyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Molecular Infection,
3-hydroxy-4-methyl-2- (6-methyl-3-pyridyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-trifluoromethylphenyl) -3-hydroxy-4- (2-hydroxyethyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-2- (5-methyl-2-pyridyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-2- [4- (1-methylethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-2- (4-nitrophenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-cyanophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-carboxyphenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-chloro-3-trifluoromethylphenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-trifluoromethoxyphenyl) -3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-2- (4-methylthiophenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
4-cyclopropyl-3-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
4-cyclopropyl-3-hydroxy-2- (6-methyl-3-pyridyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
4-[(1,1-dimethyl-2-hydroxy) ethyl] -3-hydroxy-2-[(4-trifluoromethyl) phenyl] -2H-pyrazolo [4,3-c] isoqui Nolinium hydroxide, intramolecular salt,
3-hydroxy-4- (2-methoxyethyl) -2-[(4-trifluoromethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt ,
2- (4-chlorophenyl) -3-hydroxy-4- [2- (methylthio) ethyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4- [2- (methylthio) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
4-cyclopropyl-2- (4-trifluoromethoxyphenyl) -3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-chloro-3-trifluoromethylphenyl) -4-cyclopropyl-3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
4-cyclopropyl-3-hydroxy-2- (4-methylthiophenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-phenyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
4-ethyl-3-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-trifluoromethylphenyl) -4- (1-ethoxycarbonylmethyl) -3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-[(4-methoxyphenyl) methyl] -2-phenyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4- (1-methylethyl) -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4- (1-methylethyl) -2- (3-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-2- (4-iodophenyl) -4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (6-chloro-3-pyridyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- [4- (1-methylethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (4-pentafluoroethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2,4-dihydro-3-hydroxy-4-methyl-2- (2-pyrimidinyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one,
2-([1,1'-biphenyl] -4-yl) -2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo [4,3-c] isoquinoline-5- On,
2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one,
2- (6-chloro-3-pyridyl) -2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo [4,3-c] isoquinolin-5-one,
2,4-dihydro-3-hydroxy-2- (4-iodophenyl) -4-methyl-5H-pyrazolo [4,3-c] isoquinolin-5-one,
2,4-dihydro-3-hydroxy-4- (4-methoxyphenylmethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinoline-5- On,
2,4-dihydro-3-hydroxy-4- (1-methylethyl) -2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one,
2,4-dihydro-3-hydroxy-4-methyl-2- [4- (1-methylethyl) phenyl] -5H-pyrazolo [4,3-c] isoquinolin-5-one,
2,4-dihydro-3-hydroxy-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one,
2,4-dihydro-3-hydroxy-2- [4- (1-methylethyl) phenyl] -5H-pyrazolo [4,3-c] isoquinolin-5-one,
2,4-dihydro-3-hydroxy-2-([1,1'-biphenyl] -4-yl) -5H-pyrazolo [4,3-c] isoquinolin-5-one,
2- (4-chlorophenyl) -3-hydroxy-4-[(4-methoxyphenyl) methyl] -5-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Molecular Infection,
2- (4-chlorophenyl) -5-methyl-2H-pyrazolo [4,3-c] isoquinolin-3-ol,
4-cyclopropyl-3-hydroxy-5-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4- (2-methoxyethyl) -5-methyl-2-[(4-trifluoromethyl) phenyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide Seeds,
2- (4-chlorophenyl) -3-hydroxy-4,5-dimethyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
5-ethyl-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-5-methyl-4- (1-methylethyl) -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt ,
4-methyl-5- (1-methylethyl) -3-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt ,
3-hydroxy-4,5-dimethyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
5-chloro-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
3a, 4-dihydro-3a-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinoline-3,5-dione,
2,4-dihydro-3-methoxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinolin-5-one,
2- (4-chlorophenyl) -4- {2- (N, N-dimethylamino) ethyl} -3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, molecule Flameproof,
3-hydroxy-4-methyl-2- (4-methylsulfinylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -3-hydroxy-4- [2- (methylsulfinyl) ethyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4- [2- (methylsulfinyl) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt ,
5- [2- (4-methoxyphenyl) ethyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide Loxide,
2- (4-chlorophenyl) -7-fluoro-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
7-fluoro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -4-cyclopropyl-9-fluoro-3-hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
4-cyclopropyl-9-fluoro-3-hydroxy-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -9-fluoro-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -2H-pyrazolo [4,3-c] isoquinolinium hydroxide , Intramolecular salts,
9-fluoro-3-hydroxy-4-methyl- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -9-fluoro-2H-pyrazolo [4,3-c] isoquinolin-3-ol,
7-fluoro-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (4-chlorophenyl) -7-fluoro-2H-pyrazolo [4,3-c] isoquinolin-3-ol,
9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -5-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] iso Quinolinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -9-fluoro-3-hydroxy-4-[(4-methoxyphenyl) methyl] -5-methyl-2H-pyrazolo [4,3-c] isoquinoli Hydroxide, molecular salt,
9-fluoro-5-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2- (4-chlorophenyl) -9-fluoro-5-methyl-2H-pyrazolo [4,3-c] isoquinolin-3-ol,
2,4-dihydro-3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -5H-pyrazolo [4,3-c] isoquinoline-5-thione,
3-hydroxy-4-methyl-5-methylthio-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
2- (4-trifluoromethylphenyl) -2,4-dihydro-5-imino-4-methyl-5H-pyrazolo [4,3-c] isoquinolin-3-ol,
3-hydroxy-4- (4-methoxyphenyl) methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4-f] [1,7] naphthyridinium hydroxide, Molecular Infection,
2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4-f] [1,7] naphthyridin-3-ol,
3-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [3,4-f] [1,7] naphthyridinium hydroxide, intramolecular salt,
2- (4-chlorophenyl) -3-hydroxy-4-methyl-2H-pyrazolo [3,4-f] [1,7] naphthyridinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-5- (dimethylamino) -2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-5-morpholinyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
3-hydroxy-4-methyl-5-piperazinyl-2- (4-trifluoromethylphenyl) -2H-pyrazolo [4,3-c] isoquinolinium hydroxide, intramolecular salt,
4,5-dihydro-2- [4- (trifluoromethyl) phenyl] -2H-benz [g] indazol-3-ol,
4,5-dihydro-2- (5-methyl-2-pyridinyl) -2H-benz [g] indazol-3-ol,
2- [4- (trifluoromethyl) phenyl] -2H-benz [g] indazol-3-ol,
2- (5-methyl-2-pyridinyl) -2H-benz [g] indazol-3-ol and pharmaceutically acceptable derivatives thereof.
[16" claim-type="Currently amended] (a) R ¹ and R ² both represent H, X represents CH ₂ or C═O, Y represents N, Z represents OR ⁸ , R ⁵ and R ⁸ form a bond, and B , D, E, G and Ar ¹ oxidize the corresponding compound of formula I as defined in claim 1, wherein X represents CH ₂ or C═O, Y represents N, Z represents OR ⁸ To prepare a compound of formula (I) wherein R ⁵ and R ⁸ form a bond and R ¹ and R ² form a bond, or
(b) one of B, D, E and G represents CA, where A represents nitro, and X, Y, Z, Ar ¹ , R ¹ , R with the rest of B, D, E and G ² and R ⁵ reduce the corresponding compound of formula (I) as defined in claim 1 to form a compound of formula (I) wherein one of B, D, E and G represents CA, wherein A represents amino Manufacturing,
(c) one of B, D, E and G represents CA, where A represents amino, and X, Y, Z, Ar ¹ , R ¹ , R with the rest of B, D, E and G ² and R ⁵ diazotize the corresponding compounds of formula (I) as defined in claim 1 and decompose the diazonium salt in the presence of a halogen anion or a halogen anion source so that one of B, D, E and G is Preparing a compound of formula I wherein A represents halo, or
(d) one of B, D, E and G represents CA, where A represents bromo, and X, Y, Z, Ar ¹ , R ¹ , R with the rest of B, D, E and G Corresponding compounds of formula I as ² and R ⁵ as defined in claim 1 are reacted with copper cyanide (I) such that one of B, D, E and G is CA (where A represents cyano) Preparing a compound of formula (I)
(e) X represents CR ³ R ⁶ (wherein R ⁶ represents methylthio or halogen), Y represents N ⁺ R ⁷ , Z represents O ⁻ , and R ³ and R ² bond And a corresponding compound of formula I wherein R ¹ and R ⁵ form a bond and B, D, E, G and Ar ¹ are as defined in claim 1
<Formula II>

To substitution reaction with a compound of (wherein, R ^6a represents a C _1-6 alkyl), X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents a, and R ³ To prepare a compound of formula I wherein R ² forms a bond, R ¹ and R ⁵ form a bond, and R ⁶ represents alkylthio;
(f) X represents CR ³ R ⁶ (wherein R ⁶ represents methylthio or halogen), Y represents N ⁺ R ⁷ , Z represents O ⁻ , and R ³ and R ² bond And R ¹ and R ⁵ form a bond, and B, D, E, G and Ar ¹ correspond to the corresponding compounds of formula I as defined in claim 1
<Formula III>

To substitution reaction with a compound of (wherein, R ^6a is as defined above), X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents the, the R ³ and R ² To form a bond, wherein R ¹ and R ⁵ form a bond, and R ⁶ represents alkoxy;
(g) X represents CR ³ R ⁶ (wherein R ⁶ represents methylthio or halogen), Y represents N ⁺ R ⁷ , Z represents O ^- and R ³ and R ² bond And R ¹ and R ⁵ form a bond, and B, D, E, G and Ar ¹ correspond to the corresponding compounds of formula I as defined in claim 1
<Formula IV>

Wherein R ¹³ and R ¹⁴ are as defined in claim 1 for substitution reaction, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , and Z represents O ⁻ , To prepare a compound of Formula I wherein R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and R ⁶ represents NR ¹³ R ¹⁴ , or
(h) X represents C = S, Y represents N, Z represents OH, R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and B, D, E , G and Ar ¹ react with the methylating agent to the corresponding compound of formula (I) as defined in claim 1, where X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , and Z represents O ⁻ . To prepare a compound of formula (I) wherein R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and R ⁶ represents methylthio,
(i) X represents C = O, Y represents N, Z represents OH, R ¹ represents a bond with R ^5, and B, D, E, G, Ar ¹ and R ² are first Tionization of the corresponding compound of formula (I) as defined in the above, wherein X represents C = S, Y represents N, Z represents OH, and R ¹ represents a bond with R ⁵ To prepare a compound,
(j) X represents C═O, Y represents N, Z represents OR ⁸ , R ⁸ represents a bond with R ^5, and B, D, E, G, Ar ¹ , R ¹ and R ^{The divalent} halogenated reaction of the corresponding compound of formula (I) as defined in claim 1 wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- and R ⁶ represents halogen Preparing a compound of formula (I)
(k) X represents C = O, Y represents N, Z represents OH, R ¹ represents a bond with R ^5, and B, D, E, G and Ar ¹ are defined in claim 1 A corresponding compound of formula I, wherein R ² represents a group corresponding to R ⁷ as defined in claim 1,
<Formula V>

Reacted with a nucleophilic alkylating agent comprising a compound of formula wherein R ⁶ represents alkyl and Hal represents halogen, or another anion source corresponding to R ⁶ , wherein X represents CR ³ R ⁶ and Y is N To prepare a compound of Formula I wherein ⁺ represents R ⁷ , Z represents O ⁻ , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and R ⁶ represents alkyl;
(l) X is CR ³ R ⁶ represents a (wherein, R ⁶ represents an H), Y a represents the N ⁺ R ^7, Z is O ^- represents a, and the R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and B, D, E, G and Ar ¹ correspond to the compound of Formula V or R ⁶ as defined above as defined in claim 1 by reaction with a nucleophilic alkylating agent containing other anion sources, X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents a, and the R ³ and R ² form a bond, R To prepare a compound of formula I wherein ¹ and R ⁵ form a bond and R ⁶ represents alkyl, or
(m) Z represents OR ⁸ (where R ⁸ represents H), X represents C═O, Y represents N, R ¹ represents a bond with R ^5, and B, D, Corresponding compounds of Formula I, wherein E, G, Ar ¹ and R ² are as defined in claim 1
<Formula VI>
R ⁸ Hal
Where R ⁸ represents alkyl and Hal is as defined above, X represents C═O, Y represents N, R ¹ represents a bond with R ^5, and Z Prepares compounds of formula I wherein OR represents OR ⁸ and R ⁸ represents alkyl, or
(n) Z represents O ⁻ , R ¹ and R ⁵ form a bond, X represents C═O, Y represents N, R ² is as defined above, B, D, E, G and Ar ¹ treat the corresponding compounds of formula I as defined in claim ¹ with an oxidizing agent such that R ¹ represents OH, X represents C═O, Y represents N, and Z represents OR ⁸ To prepare a compound of formula I wherein R ⁵ represents a bond with R ⁸ , or
(o) Y represents N, Z represents OH, X represents CR ³ R ⁶ , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, and B, D, Corresponding compounds of formula I, wherein E, G and Ar ¹ are as defined in claim 1,
<Formula IX>
R ⁷ Hal
Wherein R ⁷ is as defined in claim 1 and Hal is as defined above, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , and Z represents O ⁻ To prepare a compound of formula (I) wherein R ³ and R ² form a bond, and R ¹ and R ⁵ form a bond,
(p) R ² represents H, X represents C═O, Y represents N, Z represents OH, R ¹ represents a bond with R ^5, and B, D, E, G and Ar ¹ to the corresponding compound of formula I as defined in claim 1
<Formula VII>
R ² Hal
Wherein R ² is as defined in claim 1 (excluding H) and Hal is as defined above, where X represents C═O, R ² does not represent H, To prepare a compound of Formula I wherein Y represents N, Z represents OH, and R ¹ represents a bond with R ⁵ , or
(q) Formula VIII
<Formula VIII>

Wherein A and Ar ¹ are as defined in claim ¹ and reacted with a compound of formula IX as defined above, wherein B, D, E and G represent CH or CA and X represents NR ⁴ represents a, Y a represents the N ⁺ R ^7, Z is O ^- represents a, R ⁴ and R ² a form a bond, to prepare a compound of formula (I) in which the R ¹ and R ⁵ form a bond, or
(r) a compound of formula VIII as defined above
<Formula X>
R ⁴ Hal
Wherein R ⁴ is as defined in claim 1 and Hal is as defined above, wherein B, D, E and G represent CH or CA, X represents NR ⁴ , and Y Prepares a compound of formula (I) wherein N represents, Z represents OR ⁸ , R ² and R ¹ form a bond, and R ⁵ and R ⁸ form a bond, or
(s) Y represents a N ⁺ R ^7, Z is O ^- represents a, R ⁷ is CH ₂ C ₆ H ₄ represents an O- alkyl, X a represents a CR ³ R ^6, R ³ and R ² is bonded Wherein R ¹ represents a bond with R ⁵ and B, D, E, G and Ar ¹ treat the corresponding compound of formula I as defined in claim 1 with an acid such that X is CR ³ R represents a ^6, the Y represents an N, Z a represents an OH, R ³ and R ² form a bond and, R ¹ is manufactured a compound of formula (I) represents a bond together with R ^5, or
(t) Y represents a N ⁺ R ^7, Z is O ^- represents a, R ⁷ is CH ₂ - represents a phenyl (which is optionally substituted by C _1-6 alkyl or C _1-6 alkoxy), X is CR ³ represents R ⁶ , R ³ and R ² form a bond, R ¹ represents a bond with R ^5, and B, D, E, G and Ar ¹ correspond to formula (I) as defined in claim 1 The compound to be treated with hydrogen, X represents CR ³ R ⁶ , Y represents N, Z represents OH, R ³ and R ² form a bond, and R ¹ represents a bond with R ⁵ Preparing a compound of Formula (I), or
(u) Y represents a N ⁺ R ^7, Z is O ^- represents a, R ⁷ is CH ₂ C ₆ H ₄ represents an O- alkyl, X a represents a C = O, R ² a represents an H, R ¹ represents a bond with R ⁵ and B, D, E, G and Ar ¹ treat the corresponding compound of formula I as defined in claim 1 with an acid such that X represents C═O and Y represents Preparing a compound of formula I wherein N represents Z, OH represents OH, R ² represents H, and R ¹ represents a bond with R ⁵ , or
(v) Formula XI
<Formula XI>

Wherein X represents CH ₂ , R ¹ represents H, R ² represents a group corresponding to R ⁷ as defined in the compound of formula I of claim 1, and B, D, E and G are the first A compound of formula (II)
<Formula XII>
Ar ¹ NHNH ₂
Reacting a compound of formula (wherein R, Ar ¹ is as defined in claim 1), X represents a CR ³ R ^6, Y a represents the N ⁺ R ^7, Z is O ^- represents a, R ³ and R Preparing a compound of Formula I wherein ^divalent bonds are formed, R ¹ and R ⁵ form bonds, and R ⁶ represents H, or
(w) a chemical formula wherein X represents C═O, R ¹ represents H, R ² does not represent H, R is as defined above, and B, D, E and G are as defined in claim 1 The corresponding compound of I is reacted with a compound of formula XII as defined above, wherein Ar ¹ is as defined in claim ¹ , wherein X represents C═O, R ² does not represent H, and Y Prepares compounds of formula (I) wherein N represents, Z represents OH, and R ¹ represents a bond with R ⁵ , or
(x) Formula XI as defined above, wherein X represents CH ₂ , R ¹ represents alkyl, R is as defined above, and B, D, E, G and R ² are defined in claim 1 A compound of formula XII as defined above, wherein Ar ¹ is as defined above, wherein X represents CH ₂ , Y represents N ⁺ R ⁷ , and Z is OR refers to ^8, R ⁸ and R ⁵ is to form a bond, R ¹ is manufactured a compound of formula (I) represents an alkyl or
(y) Formula XI as defined above, wherein X represents C═O, R ¹ represents alkyl, R ² represents H or alkyl, R is as defined above and B, D, E And G is as defined in claim 1, reacting a compound of formula XII as defined above, wherein Ar ¹ is as defined above, wherein X represents C = 0 and Y represents N Preparing a compound of Formula I wherein Z represents OR ⁸ , R ⁸ and R ⁵ form a bond, and R ¹ represents alkyl, or
(z) X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ² and R ³ represent H, R ¹ and R ⁵ form a bond, and B, D, E, G, Ar ¹ , R ⁶ and R ¹⁸ oxidize the corresponding compounds of formula I as defined in claim 1, wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , and Z represents OH. Preparing a compound of Formula I wherein R ¹ and R ⁵ form a bond and R ² and R ³ form a bond, or
(aa) a compound of formula XII as defined above is
<Formula XX>

Wherein R is as defined above and B, D, E, G, R ⁶ and R ¹⁸ are as defined in claim 1, wherein X represents CR ³ R ⁶ and Y is CR ¹⁸ , Z represents OH, R ² and R ³ represent H, and R ¹ and R ⁵ form a bond according to claim 1 or 2 comprising preparing a compound of formula (I). Process for the preparation of compounds of formula (I).

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JP2000506884A|2000-06-06|

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NZ331614A|2000-07-28|

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WO1997034893A1|1997-09-25|

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PL328921A1|1999-03-01|

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IL126271D0|1999-05-09|

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TR199801861T2|1998-12-21|

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BR9708103A|1999-07-27|

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NO984290D0|1998-09-16|

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CA2247814A1|1997-09-25|

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AU2186797A|1997-10-10|

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NO984290L|1998-10-27|

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EP0888347A1|1999-01-07|

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AR006520A1|1999-09-08|

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ID16283A|1997-09-18|

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IS4848A|1998-09-16|

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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:
1996-03-20|Priority to GBGB9605803.7A

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1996-03-20|Priority to GB9605803.7

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1996-05-18|Priority to GBGB9610474.0A

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1996-05-18|Priority to GB9610474.0

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1996-05-24|Priority to GB9610894.9

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1996-05-24|Priority to GBGB9610894.9A

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1997-01-16|Priority to GBGB9700862.7A

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1997-01-16|Priority to GB9700862.7

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1997-03-20|Application filed by 니콜라스 피터 비가르트 (니크 비가르트), 콜린 레드롭, 아스트라 파마슈티칼스 리미티드

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1997-03-20|Priority to PCT/SE1997/000471

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2000-11-06|Publication of KR20000064716A

优先权:

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申请号 | 申请日 | 专利标题

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GBGB9605803.7A|GB9605803D0|1996-03-20|1996-03-20|Pharmaceutically-active compound|

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GB9605803.7|1996-03-20|

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GBGB9610474.0A|GB9610474D0|1996-05-18|1996-05-18|Pharmaceutically active compounds|

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GB9610474.0|1996-05-18|

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GBGB9610894.9A|GB9610894D0|1996-05-24|1996-05-24|Pharmaceutically useful compounds|

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GB9610894.9|1996-05-24|

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GBGB9700862.7A|GB9700862D0|1997-01-16|1997-01-16|Pharmaceutically useful compounds|

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GB9700862.7|1997-01-16|

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PCT/SE1997/000471|WO1997034893A1|1996-03-20|1997-03-20|Pharmaceutically useful compounds|