SK118798A3 - Pharmaceutically useful compounds - Google Patents

Abstract

The invention relates to 2-arylpyrazolisoquinoline and cinnolinone derivatives, methods for their preparation, their use as medicaments, and pharmaceutical formulations including them.

Description

Pharmaceutically useful compounds and method for their preparation

Field of technology

This invention relates to pharmaceutically useful compounds, methods for their preparation, their use as medicaments, and pharmaceutical formulations containing them.

State of the art

Some pyrazolo[4,3-c]isoquinolin-3-ones are known from J. Chem. Soc. 599 (1959) (Hinton et al.). Their use as drugs is not mentioned. The synthesis and ability of certain pyrazolo[4,3-c]isoquinolin-3-ols to inhibit binding to benzodiazepine receptors has been described in detail in J. Med. Chem. , 368 (1992) (Alien et al.). Some other pyrazolo[4,3-c]isoquinolin-3-ols are mentioned in Gaodeng Xuexiao Huaxue Xuebao 1991, , 1620-1622 (Qian Jian-hua et al.). No pharmaceutical use of these compounds is mentioned.

The essence of the invention

It has now been found that 2-arylpyrazolisoquinoline and cinnolinone derivatives exhibit antiallergic and anti-inflammatory activity. In a first aspect, the invention therefore provides a compound of formula I or a pharmaceutically acceptable derivative thereof for use as a medicament:

(I) where:

• B, D, E and G each represent CH, CA or N, with the proviso that no more than one of B, D, E and G represents CA and no more than 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 one of 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 forms a bond with one of R ¹ , R ³ or R ⁴ ;

• R ³ represents H or a bond with R ² ;

• R ⁴ represents C 1-6 alkyl or a bond with R ² ;

® R ⁵ represents a bond with R ¹ or R ⁸ ;

• R ⁶ represents 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 (optionally substituted with phenyl) or C 3-7 cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, 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 R ⁶ and R ⁷ together represent _{C 3-5} alkylene, X and Y forming a 5-7 membered ring;

• R ⁸ represents H, C _1-6 alkyl or 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 are independently C 1-6 alkyl, H or together with the nitrogen atom to which they are attached form a 3-7 membered saturated ring optionally containing another oxygen atom or a nitrogen atom 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 optionally substituted with one or more substituents selected from the following: halogen, nitro, cyano, phenyl, phenylsulfonyl, C 6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO(C _1-6 alkyl), C _1-6 alkyl substituted with phenyl or phenyl, in which any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may be optionally substituted with fluorine; and • A represents halogen, cyano, amino, nitro, C 1-6 alkyl or C _1-6 alkoxy;

wherein the phenyl groups present in R ² , R ⁶ , R ⁷ or as substituents on Ar ¹ may be optionally substituted with C _1-6 alkyl, halogen or C _1-6 alkoxy;

with the reservations that:

(i) when 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) when Y represents N ⁺ R ⁷ , then Z represents O', R ² represents a bond with R ³ or R ⁴ , and R ¹ and R ⁵ form a bond;

(iv) when Y represents N, then Z represents OR ⁸ ;

(v) when R ¹ represents OH, then 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, then 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 , then R ⁵ and R ⁸ form a bond, and when X represents NR ⁴ , then R ⁴ represents alkyl;

I (viii) when R ⁶ represents aryl, halogen, alkoxy, thioalkyl, then R ² and R ³ form a bond;

(ix) when Y represents N or N ⁺ R ⁷ and R ² is substituted with any of NR ¹⁰ R ¹¹ , OR ¹² or F, then the substituent and the ring nitrogen of Y must not be attached to the same carbon atom of R ² ;

(x) when R ⁷ is substituted with any of NR ^1S R ¹⁷ , OR ¹² or halogen, then the substituent and the ring nitrogen of Y must not be attached to the same carbon atom of R ⁷ ;

(xi) when one of B, D, E and G represents N, then X does not represent NR ⁴ ;

(xii) · when Y represents CR ¹⁸ , then X represents CR ³ R ⁶ ;

i · · with the further proviso that:

« when 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 and R ² and R ³ together represent a bond, then Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or

4-methoxyphenyl.

Some of the compounds of formula (I) are novel. The invention further provides a compound of formula (I):

(l)

where:

• B, D, E and G each represent CH, CA or N, provided that no more than one of B, D, E and G represents CA and no more than 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 either 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 forms a bond with either R ¹ , R ³ or R ⁴ ;

• R ³ represents H or a bond with R ² ;

• R ⁴ represents C _1-6 alkyl or a bond with R ² ;

• R ⁵ represents a bond with R ¹ or R ⁸ ;

• R ⁶ represents 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 (optionally substituted with phenyl) or C 3-7 cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, 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 R ⁶ and R ⁷ together represent C 3-5 alkylene, X and Y forming a 5-7 membered ring;

• R ⁸ represents H, C _1-6 alkyl or 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 are independently C _1-6 alkyl, H or together with the nitrogen atom to which they are attached form a 3-7 membered saturated ring optionally containing another oxygen atom or a nitrogen atom 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 optionally substituted with one or more substituents selected from the following: halogen, 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), _{C 1-6 alkyl} substituted with phenyl or phenyl, in which any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may be optionally substituted with fluorine; and • A represents halogen, cyano, amino, nitro, C 1-6 alkyl or C _1-6 alkoxy;

wherein the phenyl groups present in R ² , R ⁶ , R ⁷ or as substituents on Ar ¹ may be optionally substituted with C _1-6 alkyl, halogen or C 1-6 alkoxy;

with the reservations that:

(i) when 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) when Y represents N ⁺ R ⁷ , then Z represents O-, R ² represents a bond with R ³ or R ⁴ and R ¹ and R ⁵ form a bond;

(iv) when Y represents N, then Z represents OR ⁸ ;

(v) when R ¹ represents OH, then X represents O=O, Y represents N, Z represents OR ⁸ and R ⁵ represents a bond with R ⁸ ;

(vi) when R ¹ represents alkyl, then 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 , then R ⁵ and R ⁸ form a bond, and when X represents NR ⁴ , then R ⁴ represents alkyl;

(viii) when R ⁶ represents aryl, halogen, alkoxy, thioalkyl, then R ² and R ³ form a bond;

(ix) when Y represents N or N ⁺ R ⁷ and R ² is substituted with any of NR ¹⁰ R ¹¹ , OR ¹² or F, then the substituent and the ring nitrogen of Y must not be attached 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, then the substituent and the ring nitrogen of Y must not be attached to the same carbon atom of R ⁷ ;

(xi) when one of B, D, E and G represents N, then X does not represent NR ⁴ ;

(xii) when Y represents CR ¹⁸ , then X represents CR ³ R ⁶ ;

with the further reservations that:

(a) when 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 and R ² and R ³ together represent a bond, then Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl;

(b) when 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, R ² and R ³ represent a bond, R ⁸ represents H and R ⁷ represents methyl, then Ar ¹ does not represent unsubstituted phenyl;

(c) when B, D, E and G all represent CH, X represents CH ₂₁ Y represents N, R ¹ and R ⁵ form a bond, R ⁸ represents H and R ² represents isopropyl, then Ar ¹ does not represent unsubstituted phenyl or 4-bromophenyl; and (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, then Ar ¹ does not represent unsubstituted phenyl.

or a pharmaceutically acceptable derivative thereof. ¹ '

Ar ¹ preferably 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, especially a CF ₃ , C ₂ F ₅ , OCF ₃ or SCH ₃ substituent in the para position.

Y preferably represents N ⁺ R ⁷ and X represents CR ³ R ⁶ , in which R ³ forms a bond with R ² , and R ⁶ represents alkyl. In such a case, R ⁶ preferably represents . branched alkyl. Alternatively, X may represent NR ⁴ , in which R ⁴ represents a bond with R ² , and Y represents N ⁺ R ⁷ .

B preferably represents CA. In such a case, A preferably represents F.

In the case where one of B, D, E and G represents N, then the one representing N is preferably D or G.

R ¹ preferably represents a bond with R ² or R ⁵ In such a case, R ¹ preferably represents a bond with R ⁵ .

Particularly preferred compounds of the invention include those exemplified herein, including their free form and all salts and solvates thereof.

Pharmaceutically acceptable derivatives include solvates and salts. Particular salts which may be mentioned include _the hydrochloride, hydrobromide, benzenesulfonate, tosylate and methanesulfonate.

The compounds of formula I may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical isomerism and/or diastereoisomerism. All diastereomers may be separated by conventional techniques, for example by chromatography or fractional crystallization. The different optical isomers may be isolated by resolution of racemic or other mixtures of the compounds by conventional techniques, for example by fractional crystallization or HPLC. Alternatively, the desired optical isomers may be prepared by reaction of the appropriate optically active starting materials under conditions that do not cause racemization, or by derivatization, for example with a homochiral acid, followed by separation of the diastereomeric derivatives by conventional means (for example by HPLC, silica chromatography). All stereoisomers are included within the scope of the invention.

Alkyl groups, which may represent 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 which may be substituted by one or more aromatic rings forming part of Ar ¹ , may be saturated or unsaturated and may be linear or branched. C3-7 cycloalkyl, C6 alkoxy, C4-6 alkylthio, _C1-6 alkylsulfinyl, C1-6 alkyl and C3-5 alkyl are to be interpreted accordingly.

The invention also provides a process for preparing compounds of formula I, which comprises the following steps:

(a) the preparation of compounds of formula I, wherein X represents 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, by oxidizing the corresponding compound of formula I, where both R ¹ and R ² represent H and B, D, E, G, X, Y, Z, Ar ¹ and R ⁵ have the above meanings, for example at room temperature

-8using a suitable oxidizing agent (for example manganese dioxide) and a suitable organic solvent;

(b) preparing compounds of formula I, wherein one of B, D, E and G represents CA, wherein A represents amino, by reducing the corresponding compound of formula I, wherein one of B, D, E and G represents CA, wherein A represents nitro and the remainder of B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above, for example with iron powder and ammonium chloride in refluxing ethanol;

(c) preparing compounds of formula I, wherein one of B, D, E and G represents CA, wherein A represents halogen, by diazotizing the corresponding compound of formula I, wherein one of B, D, E and G represents CA, wherein A represents amino and the residue B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ have the meanings given above, and decomposing the diazonium salt in the presence of a halide anion or (for fluorine) sodium tetrafluoroborate in dichlorobenzene under reflux;

(d) preparing compounds of formula I, wherein one of B, D, E and G represents CA, wherein A represents cyano, by reacting the corresponding compound of formula I, wherein one of B, D, E and G represents CA, wherein A represents bromine and the remainder of B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above, with copper cyanide, for example under reflux in N-methylpyrrolidone;

(e) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 alkylthio, by substitution reaction of the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² , R ³ and R ⁵ have the above meanings, with a compound of formula II:

R6a ^xSx H (II) where ^R6a represents _C1-6 alkyl, in the presence of a base, for example sodium hydride, in a suitable solvent, for example DMF;

(f) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 alkoxy, by substitution reaction of the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² , R ³ and R ⁵ have the above meanings, with a compound of formula III:

(g) (h) (i)

G)

R6a ^x ^H ^π (III) where ^R6a is as defined above, in the presence of a base, for example sodium hydride, in a suitable solvent, for example DMF;

preparation of compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 NR ¹³ R ¹⁴ , by substitution reaction of the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² , R ³ and R ⁵ have the above meaning, with a compound of formula IV:

R13 (IV) where ^R13 and ^R14 are as defined above, in the presence of a base, for example sodium bicarbonate, in a suitable solvent, for example DMF, at 100°C;

preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 methylthio, by reacting the corresponding compound of formula I, wherein X represents C=S, Y represents N, Z represents OH and B, D, E, G, Ar ¹ , R ¹ , R ² and R ⁵ have the above meanings, with a methylating agent, for example methyl iodide, for example near reflux;

the preparation of compounds of formula I, where X represents C=S, Y represents N, Z represents OH and R ¹ represents a bond with R ⁵ , by reacting the corresponding compound of formula I, where X represents C=O and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ have the meanings given above, by thionation, for example using Lawesson's reagent, in a suitable solvent, for example in dioxane at reflux;

the preparation of compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O' and R ⁶ represents halogen, by reacting the corresponding compound of formula I, wherein 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 have the meanings given above, with halogenation, for example with phosphorus oxyhalide, for example near 100 °C;

-10(k) preparation of compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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, by reacting the corresponding compound of formula I, wherein X represents C=O, Y represents N, Z represents OH, R ¹ represents a bond with R ⁵ , B, D, E, G and Ar ¹ have the above meaning and R ² represents a group corresponding to R ⁷ defined above, by reaction with a nucleophilic alkylating agent, for example a compound of formula V:

Hal (VI) where R ⁶ is as defined above and Hal represents halogen, for example in the presence of a copper salt, for example copper (I) bromide, in a suitable solvent, for example dimethoxyethane, for example at reflux;

(I) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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, by reacting the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents H, and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ have the above i

meaning, with a nucleophilic alkylating agent, for example a compound of formula V as defined above, in a suitable solvent, for example THF, for example at 0°C;

(m) preparing compounds of formula I, 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, by reacting the corresponding compound of formula I, wherein Z represents OR ⁸ , wherein R ⁸ represents H, and B, D, E, G, X, Y, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above, with a compound of formula VI:

R ⁸ Hal (VI) where R ⁸ and Hal are as defined above, for example in the presence of a base, for example sodium hydride, in a suitable solvent, for example DMF;

(n) preparing compounds of formula I, wherein R ¹ represents OH, X represents C=O, Y represents N, Z represents OR ⁸ and R ⁵ represents a bond with R ⁸ , by reacting the corresponding compound of formula I, wherein Z represents O', R ¹ and R ⁵ form a bond and B, D, E, G, X, Y, Ar ¹ and R ² have the meanings given above, with an oxidizing agent, for example ammonium cerium nitrate, in a suitable solvent, for example acetonitrile, for example at room temperature;

-11 (o) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O', R ³ and R ² form a bond and R ¹ and R ⁵ form a bond, by reacting the corresponding compound of formula I, wherein Y represents N, Z represents OH and B, D, E, G, X, Ar ¹ , R ¹ , R ² and R ⁵ have the meanings given above, with a compound of formula IX: ,,

R ⁷ Hal (IX) where R ⁷ and Hal are as defined above, and a base, for example sodium hydride, in a suitable solvent, for example DMF, for example at room temperature;

(p) the preparation of compounds of formula I, wherein X represents C=O, R ² does not represent H, Y represents N, Z represents OH and R ¹ represents a bond with R ⁵ , by reacting the corresponding compound of formula I, wherein R ² represents H and B, D, E, G, X, Y, Z, Ar ¹ , R ¹ and R ⁵ are as defined above, with a base, for example sodium hydride, and a compound of formula VII:

R ² Hal (VII) where R ² , which is not H, and Hal are as defined above, in a suitable solvent, for example DMF, for example at room temperature;

(q) preparing compounds of formula I, wherein B, D, E and G represent CH or CA, X represents NR ⁴ , Y represents N ⁺ R ⁷ , Z represents O', R ⁴ and R ² form a bond and R ¹ and R ⁵ form a bond, by reacting a compound of formula VIII:

(VIII) where A and Ar ¹ are as defined above, with a base, for example sodium hydride, and a compound of formula IX as defined above, in a suitable solvent, for example DMF, for example at room temperature;

(r) preparing compounds of formula I, wherein 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 form a bond, by reacting a compound of formula VIII as defined above with a base, for example sodium hydride, and a compound of formula X:

-12R ⁴ Hal (X) where R ⁴ and Hal are as defined above, in a suitable solvent, for example DMF, for example at room temperature;

(s) preparing compounds of formula I, wherein 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 , by treating the corresponding compound of formula I, wherein Y represents N ⁺ R ⁷ , Z represents O', R ⁷ represents CH ₂ C ₆ H ₄ Oalkyl and B, D, E, G, X, Ar ¹ , R ¹ , R ² and R ⁵ have the meanings given above, for example under reflux, with an acid, for example trifluoroacetic acid;

(t) preparing compounds of formula I, wherein 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 , by reacting the corresponding compound of formula I, wherein Y represents N ⁺ R ⁷ , Z represents O', R ⁷ represents CH ₂ phenyl (optionally substituted with C _1-6 alkyl or C _1-6 alkoxy) and B, D, E, G, X, Ar ¹ , R ¹ and R ⁵ are as defined above, with hydrogen in the presence of a catalyst, for example palladium on carbon;

(u) preparing compounds of formula I, wherein X represents C=O, Y represents N, Z represents OH, R ² represents H and R ¹ represents a bond with R ⁵ , by reacting the corresponding compound of formula I, wherein Y represents N ⁺ R ⁷ , Z represents O', R ⁷ represents CH ₂ C ₆ H ₄ 0alkyl and B, D, E, G, X, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above, with an acid, for example trifluoroacetic acid, for example under reflux;

(v) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 H, by reacting a compound of formula XI;

(XI) where X represents CH ₂ , R ¹ represents H, R ² represents a group corresponding to R ⁷ with the above meaning in the compound of formula I, B, D,

E and G are as defined above and R is alkyl, with a compound of formula XII: Ar ¹ NHNH ₂ (XII) where Ar ¹ is as defined above, for example in xylene at reflux;

- 13(w) preparation of compounds of formula I, wherein X represents C=O, R ² does not represent H, Y represents N, Z represents OH and R ¹ represents a bond with R ⁵ , by reacting a compound of formula XI with the above meaning, wherein X represents C=O, R ¹ represents H, R ² has the above meaning and B, D, E, G and R have the above meaning, with a compound of formula XII with the above meaning, wherein Ar ¹ has the above meaning, for example in xylene at reflux;

(x) the preparation of compounds of formula I, wherein X represents CH ₂ , Y represents N, Z represents OR ⁸ , R ⁸ and R ⁵ form a bond and R ¹ represents alkyl, by reacting a compound of formula XI with the above meaning, wherein X represents CH ₂ , R ¹ represents alkyl and B, D, E, G, R ² and R have the above meaning, with a compound of formula XII with the above meaning, wherein Ar ¹ has the above meaning, for example in xylene at reflux; or (y) the preparation of compounds of formula I, wherein X represents C=O, Y represents N, Z represents OR ⁸ , R ⁸ and R ⁵ form a bond and R ¹ represents alkyl, by reacting a compound of formula XI with the above meaning, wherein X represents C=O, R ¹ represents alkyl, R ² represents H or alkyl, and B, D, E, G and R have the above meaning, with a compound of formula XII with the above meaning, wherein Ar ¹ has the above meaning, for example in xylene at reflux;

(z) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ¹ and R ⁵ form a bond and R ² and R ³ form a bond, by oxidizing the corresponding compound of formula I, wherein 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 have the meanings given above; or (aa) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ² and R ³ represent H and R ¹ and R ⁵ form a bond, by reacting a compound of formula XII with a compound of formula XX:

wherein B, D, E, G, R ⁶ , R ¹⁸ and R have the above meanings.

-14Compounds of formula I, wherein X represents CHR ³ , R ² and R ³ together represent a bond, R ¹ and R ⁵ form a bond and either:

«> Y represents N ⁺ R ⁷ and Z represents O', or » Y represents N and Z represents OH, can be prepared analogously to the methods described in J. Med. Chem. , 368 (1992). Compounds of formula VIII are known from European Patent Application No. EPA-187551 or can be prepared analogously to the methods described therein. Compounds of formula XI can be prepared by reacting a compound of formula XIII:

COOR (xiii) where B, D, E, G, R, R ² and X are as defined above and R', is alkyl, with a base, for example sodium hydride, for example in DMSO at 60°C in the presence of an alcohol. Compounds of formula XI, where X is C=O and R ² is H, are known from Japanese Examined Patent Publication No. JP-B-82 54,152, or can be prepared analogously to the methods described therein.

Compounds of formula XIII, where X represents C=O, can be prepared by reacting a compound of formula XVI:

COOR (XVI) where B, D, E, G, R and R ² are as defined above, by alkylation, for example with a compound of formula XVII:

(RO) ₂ SO ₂ (XVII)

-15where R' has the above meaning, in the presence of a base, for example potassium carbonate, for example in acetone at 50°C.

Compounds of formula XIII, where X represents CH ₂ , can be prepared by reacting a compound of formula XIV: ' . , .3. . COOFi

D

(XIV) where B, D, E, G and R are as defined above, with a compound of formula XV:

(XV) where R ¹ , R ² and R' are as defined above, in the presence of a base, for example triethylamine, in a suitable solvent, for example ether at reflux.

Compounds of formula XIV can be prepared by reacting a compound of formula XVIII:

(XVIII) where B, D, E, G and R are as defined above, with a brominating agent, for example NBS, for example in dichloromethane at reflux with photolytic radiation.

*

Compounds of formula XVI can be prepared by reacting compounds of formula XIX:

(XIX) wherein B, D, E and G are as defined above, with a compound of formula a and as defined above, wherein R ¹ , R ² and R' are as defined above, in a suitable solvent, for example acetone at 50°C.

-16Compounds of formula II, III, IV, V, VI, VII, IX, X, XII, XV, XVI, XVII, XVIII and XX are either commercially available or known from the literature, or are available using known techniques.

It will be apparent to those skilled in the art that in the process steps described above, the functional groups of the intermediates may require protection with protecting groups. Protection of the functional groups may be effected prior to any step of the process described above. For example, the nitrogen atom of compounds of formula XI, XIII and XVI may be protected from further reaction by a suitable protecting group, for example a benzyl group or preferably a 4-methoxyphenylmethyl group. The protecting groups may be removed after the reaction step or at the end of the reaction process by techniques known to those skilled in the art (for example, acid hydrolysis).

The compounds of the invention are useful, have pharmacological activity and are therefore indicated as drugs useful in therapy.

The invention further provides a compound of formula I with the above meaning, but without proviso (c), for use as a medicament.

The compounds of the invention have in particular antiallergic and anti-inflammatory activity, as shown, for example, in the tests described below. The compounds of the invention are therefore indicated for use in the treatment of allergic and inflammatory diseases of the respiratory tract, such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), especially chronic or severe asthma (for example, recent asthma and airway hyperresponsiveness), bronchitis and the like. Furthermore, the compounds of the invention are indicated in the treatment of diseases including inflammations or allergies such as rhinitis, including all conditions characterized by inflammation of the nasal mucosa, such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta and rhinitis sicca, rhinitis medicamentosa, membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis, scrofulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis.

-17The compounds of the invention are also indicated for use in the treatment of chronic allergic disorders, atopic dermatitis, cutaneous eosinophilia, eosinophilic fasciitis, hyper IgE syndrome, vernal conjunctivitis, systemic lupus erythematosis, thyroiditis, lepromatous leprosy, Sézary syndrome, chronic graft-versus-host disease, myasthenia gravis, idiopathic thrombocytopenic purpura and the like.

The compounds of the invention may also have activity in the prophylactic and therapeutic treatment of acquired immune deficiency syndrome (AIDS), the prevention of chronic humoral immune-mediated allograft rejection, and in the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Of particular interest among the above-mentioned indications is the use of the compounds of the invention in asthma, in particular in the prophylaxis of asthma, and in rhinitis, in particular allergic rhinitis and seasonal rhinitis including rhinitis nervosa (hay fever).

As a further aspect of the present invention, there is provided a method of treating or prophylactic treating an allergic or inflammatory disorder, which method comprises administering to a subject suffering from or susceptible to such a disease a therapeutically effective amount of a compound of formula I as defined above, but without the proviso (b) or (c), or a pharmaceutically acceptable derivative thereof.

Administration of the compounds of the invention may be local (e.g., by inhalation into the lungs). The compounds of the invention may be inhaled as a dry powder, which may be aerosolized or non-aerosolized.

In non-aerosol powder compositions, finely divided active ingredient may be used in admixture with a pharmaceutically acceptable carrier of larger particle size. Alternatively, the composition may be formulated as an aerosol and may contain a pressurized gas, such as nitrogen, or a liquefied gaseous propellant. In such aerosol compositions, the active ingredient is preferably finely divided. The aerosol composition may also contain a surfactant. Aerosol compositions may be prepared by conventional methods.

-18The compounds of the invention can be administered systemically (for example, by oral administration to the gastrointestinal tract). The active ingredient can be formulated together with known adjuvants, diluents or carriers using conventional techniques to form tablets or capsules for oral administration to the gastrointestinal tract. Examples of suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and dragees include microcrystalline cellulose, calcium phosphate, diatomaceous earth, sugar such as lactose, dextrose or mantel, talc, stearic acid, starch, sodium bicarbonate and/or gelatin.

As a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I as defined above, but without proviso (c), or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable doses for topical or oral administration are in the range of 0.01 to 30 mg.kg ^-1 .day ¹ , for example 0.3 mg.kg ^-1 .day ¹ .

It will be apparent to those skilled in the art that certain functional groups in the compounds of the invention may be protected by suitable protecting groups, thereby forming “protected derivatives” of the compounds of the invention. It will also be apparent that, although such protected derivatives may not have pharmacological activity per se, they may be administered and then metabolized in the body to form a compound of the invention that is pharmacologically active. Such derivatives may therefore be described 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.

-19Examples of the invention

General notes:

Column chromatography was performed on silica (35-70 pm) under gas pressure, usually 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 added to a cold solution of 5-amino-2-methylpyridine (J. Chem. Soc. (C)., 1971, 3257) (3.61 g) in water (6 ml) and concentrated hydrochloric acid (1 ml), keeping the temperature below 5 °C. The mixture was stirred at 0 °C for 15 minutes and then further cooled to -10 °C. A solution of stannous chloride (2.53 g) in concentrated hydrochloric acid (5 ml) was then added dropwise. After stirring at -10 °C for 10 minutes, the solution was allowed to warm to room temperature and anhydrous potassium carbonate was added until a thick suspension was formed. The suspension was stirred with ethyl acetate and the organic phase was decanted and evaporated to an oil. The suspension was then diluted with water and extracted with dichloromethane (three times). The organic phase was dried over sodium sulfate, filtered and evaporated, and then combined with the above oil. Purification by column chromatography, eluting with dichloromethane:methanol (20:1), gave the title compound as a beige solid (0.09 g), mp 1.1. 68-70 °C.

. ¹ H NMR (CDCIa): δ 2.47 (3H, s), 3.60 (2H, br s), 5.13 (1 H, 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. , 1990, 2293). MS (El) 226 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ 4.15 (2H, br), 6.87 (2H, d), 7.45 ( ¹ H, br)

2-Hydrazino-5-methylpyridine (J. Org. Chem., 1966,, 251)

2- Chloro-5-hydrazinopyridine (Atti R. Accad. dei Lincei, Rome, 1925,, 125); Chem. Zent. 1926, I, 672

I

Hydrazinopyrimidine J. Chem. Soc. 1955, 3478

Example 1

3-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2N-pyrazolo-[4,3-isoquinoline hydroxide, inner 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 the ethyl ester in J. Med. Chem., 1992, , 368) and triethylamine (15.7 ml) were dissolved in dry diethyl ether (200 ml) under a nitrogen atmosphere. Methyl N-[(4-methoxyphenyl)methyl]glycinate (23.6 g; J. Am. Chem. Soc., 1993, , 536) was added dropwise. The mixture was heated at reflux for 16 hours and allowed to cool to room temperature. Water was added and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (three times). The combined organic phase was washed with brine and dried over sodium sulfate. Filtration and evaporation of the solution followed by purification of the residue by column chromatography eluting with ethyl acetate:isohexane (1:9) gave the title compound as an oil (27.85 g);

MS (APCI) 358 ((M + H) ⁺ ) ¹ H NMR (CDCl): 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) was dissolved in dry toluene (150 ml) and added dropwise to a refluxing suspension of the sodium hydride-free oil (from 4.37 g of 60% sodium hydride) in dry toluene (300 ml) and 2-methylpropan-2-ol (2.0 ml). Heating was continued for 12 hours. The mixture was allowed to cool to room temperature and then poured into saturated ammonium chloride solution and extracted with ethyl acetate (three times). The combined organic phase was then washed with brine and dried over sodium sulfate. Filtration and evaporation followed by purification by column chromatography eluting with diethyl ether:isohexane (1:4) gave the title compound as an oil (20.41 g). ¹ H NMR (CDCl ₃ ) (major component - enolic 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]isoquinolinium hydroxide, inner salt

Methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenyl)methyl-4-oxo-3-isoquinolinecarboxylate (1.0 g; from step (b) above), 4-(trifluoromethyl)phenylhydrazine (1.08 g) and a catalytic amount of 4-toluenesulfonic acid were melted together at 150 °C for 10 minutes. Xylene (20 ml) was then added and heating continued for another hour. After cooling to room temperature, the solvent was evaporated. The solid residue was triturated with diethyl ether to give the title compound as a red solid (0.5 g), m.p. 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, inner salt (0.26 g; from step (c) above) was heated to reflux in trifluoroacetic acid (2 ml) under nitrogen for 16 hours. After cooling to room temperature, the solvent was evaporated. Toluene was added to the residue and then evaporated (twice). Methanol was added, evaporated and the red residue was triturated with ethyl acetate. Recrystallization from ethanol gave the title compound as a red solid (14 mg), m.p. >250 °C.

MS (APCI) 330 ((M + H) ⁺ ) ¹ H NMR (ds-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-3/7-pyrazolo[4,3-c]cinnolin-3-one

2-(4-Chlorophenyl)-2,5-dihydro-pyrazolo[4,3-c]cinnoline-3-one (0.33 g; European Patent Application EP-A-0187551) was added portionwise to a stirred suspension of oil-free sodium hydride (from 49 mg of a 60% dispersion) in dry dimethylformamide (5 ml) under a nitrogen atmosphere. Iodomethane (0.076 ml) was added dropwise over 0.5 h and the resulting solution was stirred at room temperature for 2 h. The solution was poured into brine and extracted with dichloromethane/methanol (three times). The organic phase was washed with 2 M hydrochloric acid and brine and then dried over sodium sulfate, filtered and concentrated to give a red solid. Purification by column chromatography (ethyl acetate and hexane 3:2) followed by recrystallization from dimethylformamide gave the title compound as red crystals (55 mg), mp >250 °C.

MS (E1) 310, 312 (M ⁺ ) 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]methylbenzoate

Methyl 2-bromomethylbenzoate (3.51 g) and diisopropylethylamine (5.86 ml) were dissolved in dry 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) dissolved in dry diethyl ether (10 ml) and dry dichloromethane (5 ml) was added dropwise and the mixture was allowed to warm to room temperature overnight. Water was then added and the organic phase was separated, washed with brine and dried over sodium sulfate. Filtration and evaporation followed by column chromatography (ethyl acetate and hexane 1:9) gave the title compound (2.87 g).

MS (El) 265 (M ⁺ ) (b) Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinoline carboxylate

Methyl 2-(((1-methoxycarbonyl)ethyl)methylamino]methylbenzoate (2 g) in dry toluene (10 ml) was added dropwise to a refluxing suspension of oil-free sodium hydride (from 0.42 g of a 60% dispersion) in dry toluene (30 ml) and 2-methyl-2-propanol (5 drops) under nitrogen. After heating at reflux for 45 min, the solution was cooled in ice and poured into saturated ammonium chloride solution, which was extracted with ethyl acetate (three times). The organic phase was washed with brine and dried over sodium sulfate. Filtration and evaporation followed by column chromatography (ethyl acetate and hexane 1:4) gave the title compound as a yellow oil (0.95 g).

-24MS (EI) 234 (M ⁺ ) (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 melted 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 a further 6 hours. After cooling to room temperature, the solvent was removed and the residue was dissolved in dichloromethane with methanol. The solution was washed with 2M hydrochloric acid and brine and dried over sodium sulfate. Filtration and evaporation followed by column chromatography (methanol and dichloromethane 1 : 99) gave the title compound as a colourless solid (50 mg), m.p. 128-129 °C.

MS (EI) 325, 327 (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-toluenesulfonic acid (10 mg) were melted 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 5 hours. After cooling to room temperature, a yellow precipitate was collected by filtration and washed with diethyl ^ether . Purification by column chromatography (methanol and dichloromethane 1:49) followed by recrystallization from ethanol gave the title compound as a beige solid (0.1 g), m.p. >250 °C.

MS (EI) 325, 327 (M ⁺ )

-25Example 7

3-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-(3-quinolyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using 3-hydrazinoquinoline. M.p. 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) was prepared according to the method described in Example 2 using 3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(3-quinolyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.66 g). M.p. 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 (1H, d), 9.05 (1H), 9.70 (1H, d), 12.20 (1H, bs).

Example 9

2-(3,4-Dichlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using 3,4-dichlorophenylhydrazine. M.p. 239-240°C.

-26MS (APCI) 448, 450, 452 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 3.72 (3H, s), 6.06 (2H, s), 6.69 (2H, d), 7.70 (3H, m),

7.79 (1H, t), 7.97 (1H, t), 8.16 (1H, d), 8.37 (2H, m), 8.72 (1H, d), 8.97 (1H, s).

Example 10

2-(3,4-Dichlorophenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

The title compound (0.028 g) was prepared according to the method described in Example 2 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.26 g). M.p. >230 °C.

MS (APCI) 330, 332, 334 ((M + H) ⁺ ) ¹ H NMR (d ₅ -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 (1H, d), 8.94 (1H, 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'-isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using [1,1'-biphenyl]-4-ylhydrazine (see J. Chem. Soc., Perkin Trans. , (1975) 1280).

(b) 2-([1,1'-Biphenyl]-4-yl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

The title compound (0.082 g) was prepared according to the method described in Example 2 using 2-([1,1'-biphenyl]-4-yl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]

-27 2/7-Pyrazolo-[4,5-c]isoquinolinium hydroxide, inner salt (0.29 g; from step (a) above). M.p. >220°C (with 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, with, br).

Example 12

3-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-methylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using 4-methylphenylhydrazine. M.p. > 100 °C (dec.)

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 (1H, m), 8.13 (1H, d), 8.23 (2H, d), 8.33 (1H, d), 8.89 (1H, s).

Example 13

2-(4-Methylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

The title compound (0.043 g) was prepared according to the method described in Example 2 using 3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-methylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.20 g). M.p. 202-209 °C (dec.)

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, br).

Example 14

2-(4-Bromophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using 4-bromophenylhydrazine. M.p. > 220 °C (dec.)

MS (APCl) 460, 462 ((M + H) ⁺ ) ¹ H NMR (de-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 (1H, m), 8.15 (1H, d), 8.36 (3H, m), 8.94 (1H, s).

Example 15

2-(4-Bromophenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

The title compound (0.053 g) was prepared according to the method described in Example 2 s. using 2-(4-bromophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2 H -pyrazolo[4,3-c]-isoquinolinium hydroxide, inner salt (0.164 g). M.p. > 250 °C.

MS (APCl) 340, 342 ((M + H) ⁺ ) ¹ H NMR (ds-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).

í

Example 16 '

2-(3-Trifluoromethylphenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using 3-trifluoromethylphenylhydrazine to give an oil which was purified twice by chromatography, eluting first with ethyl acetate and secondly with mixtures of ether and ethyl acetate to give the title compound as an oil.

-29MS (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 (1H, 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 was prepared according to the method described in Example 2 using 2-(3-trifluoromethylphenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt. M.p. 250°C (dec.).

MS (APCI) 330 ((M + H) ⁺ ) ¹ H NMR (dg-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 (1H, 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]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using 4-((1,1-dimethylphenyl)phenyl]hydrazine and was used without further purification in the next step.

(b) 2-(4-(1,1-Dimethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinol ηη-3-ol

The title compound was prepared according to the method described in Example 2 using 3-hydroxy-2-[4-(1,1-dimethylethyl)phenyl]-4-(4-methoxyphenylmethyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt. M.p. > 210 °C (dec.)

-30MS (APCI) 318 ((Μ + Η) ⁺ ) ¹ H NMR (d _s -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 (1H, d), 8.74 (1H, 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, inner salt

The title compound was prepared according to the method described in Example 1(c) using 4-trifluoromethoxyphenylhydrazine and was used without further purification in the next step.

(b) 2-(4-Trifluoromethoxyphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

The title compound was prepared according to the method described in Example 2 using 2-(4-trifluoromethoxyphenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt. M.p. >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). ' ,

Example 20

2-(4-Chlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

Methyl 1,2,3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylate (0.5 g) (I. G. Hinton and F. G. Mann, J. Chem. Soc. 1959, 599), 4-chlorophenylhydrazine (0.98 g) and

-31 4-toluenesulfonic acid (10 mg) were melted together at 150°C for ten minutes under a nitrogen atmosphere. Xylene (10 ml) was then added and the mixture was heated at 150°C for a further 6 hours. The reaction mixture was cooled and the resulting red precipitate was filtered off and washed with diethyl ether. Recrystallization from methanol gave the title compound (0.27 g). M.p. 247-248°C.

MS (E1) 309, 311 ((M + H) ⁺ ) 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, inner salt

2-(4-Chlorophenyl)-2,5-dihydro-pyrazolo[4,3-c]cinnolin-3-one (0.33 g) (European Patent Application EP-A-0187551) was added portionwise to a stirred suspension of oil-free sodium hydride (from 49 mg of a 60% dispersion) in dry dimethylformamide (5 ml) under a nitrogen atmosphere. After 0.5 h, iodomethane (0.076 ml) was added and the resulting solution was stirred at room temperature for 2 h. The solution was poured into brine and extracted with a mixture of dichloromethane and methanol (three times). The organic phase was washed with 2 N hydrochloric acid and brine and dried over sodium sulfate, filtered and concentrated to give a red solid. Purification by column chromatography (ethyl acetate and hexane 2:3) followed by recrystallization from dimethylformamide gave the title compound as purple crystals (65 mg). M.p. 249-250°C.

MS (E1) 310, 312 ((M + H) ⁺ ) ¹ H NMR (CDCl ₃ ) 4.81 (3H, s), 7.40 (2H, d), 7.75 (2H, m), 8.00 (1H, dd), 8.25 (2H, d), 8.35 (1H, dd).

-32Example 22

2-(4-Chlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl-2H-[4,3]-pyrazolo[4,3]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 20 from methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenyl)methyl-4-oxo-3-isoquinolinecarboxylate (which was prepared analogously to the method described in I. G. Hinton and F. G. Mann, J. Chem. Soc. 1959, 599). M.p. 227-228 °C.

MS (E1) 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 following compounds, Examples 23-56, were prepared by methods analogous to Examples 20 and 22:

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 23. 3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2/7pyrazolo[4,3]isoquinolinium hydroxide, inner salt 201 - 203 344 (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). 24. 3-hydroxy-4-methyl-2-(3-quinolyl)-2H-pyrazolo[4,3-]isoquinolinium hydroxide, ' inner salt >250 327 (M+H) ⁺ 4.55 (3H, s), 7.60 (1H, td), 7.70(1,H, 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). 25. 2-(6-chloro-3-pyridyl)-3hydroxy-4-methyl-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt >250 311/313 (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 (1H, dd), 9.37(1H, s).

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 26. 2-(3,4-dichlorophenyl)-3hydroxy-4-methyl-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 223- 229 tons 344/346/348 (M+H) ⁺ 4.49 (3H, s), 7.70(1H, d), 7.78(1 H, t), 7.96(1 H, t), 8.11 (1H, d), 8.35 (2H, m), 8.67 (2H, m). 27. 3-hydroxy-4-methyl-2-(4methylphenyl)-2/-/-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 247- 248 290 (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(1H, d), 8.59(1H, s). 28. 2-(4-bromophenyl)-3-hydroxy4-methyl-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 244 354/356 (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). 29. 3-hydroxy-4-methyl-2-(3-trifluoromethylphenyl)-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 222-6 344 (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). 30. 2- (4-(1,1 -dimethylethyl)phenyl)- 3- hydroxy-4-methyl-2Hpyrazolo[4,3c]isoquinolinium hydroxide, inner salt >220 (decomposed) 332 (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), (CDCIs not DMSO d ₆ ). 31. 2-(6-chloro-3-pyridyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2/-/pyrazolo[4,3]isoquinolinium hydroxide, inner salt 223- 224 417/419 (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). 32. 3-hydroxy-4-methyl-2-(6methyl-3-pyridyl)-2Hpyrazolo[4,3c]isoquinolinium hydroxide, inner salt >250 291 (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, dd), 8.64 (1H, s), 9.38(1H, d).

Ex. Name 1.1. (°C) World Cup 'H NMR ( _d6 -DMSO) δ 33. 2-(4-trifluoromethylphenyl)-3hydroxy-4-(2-hydroxyethyl)2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt >250 374 (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). 34. 3-hydroxy-4-methyl-2-(5-methyl-2-pyridyl)-2/7pyrazolo[4,3]isoquinolinium hydroxide, inner salt 237 - 240 291 (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(1H, d), 8.59(1H, s). 35. 3-hydroxy-4-methyl-2-[4-(1 methylethyl)phenyl]-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 171 - 172 318 (M+H) ⁺ 1.25 (6H, s), 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(1H, d), 8.69(1 H, s). 36. 3-hydroxy-4-methyl-2-(4-nitrophenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt >230 321 (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). 37. 2-(4-cyanophenyl)-3-hydroxy4-methyl-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 225- 227 301 (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). 38. 2-(4-carboxyphenyl)-3hydroxy-4-methyl-2Hpyrazolo[4,3c]isoquinolinium hydroxide, inner salt >230 320 (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). 39. 2-(4-chloro-3-trifluoromethylphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt >230 378/380 (M+H) ⁺ 4Í50 (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). 40. 2-(4-trifluoromethoxyphenyl)-3-hydroxy-4-methyl-2/-/pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 195- 196 360 (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).

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 41. 3-hydroxy-4-methyl-2-(4-methylthiophenyl)-2/7pyrazolo[4,3]isoquinolinium hydroxide, inner salt 197 - 198 322 (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 (1H, d), 8.60(1H, s). ¹ 42. 4-cyclopropyl-3-hydroxy-2(4-trifluoromethylphenyl)-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt >250 370 (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). 43. 4-cyclopropyl-3-hydroxy-2(6-methyl-3-pyridyl)-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 226- 240 317 (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). 44. 4-[(1,1 -dimethyl-2-hydroxy)ethyl]-3-hydroxy-2[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3-]isoquinolinium hydroxide, inner salt >220 402 (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). 45. 3-hydroxy-4-(2-methoxyethyl)- 2-[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 195 - 197 388 (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). 46. ι 2-(4-chlorophenyl)-3-hydroxy- 4-[2-(methylthio)ethyl]-2/7pyrazolo[4,3]isoquinolinium hydroxide, inner salt 187- 188 370/372 (MťHf 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). 47. 3-hydroxy-4-[2-(methylthio)ethyl]-2-(4-trifluoromethylphenyl)-2/-/pyrazolo[4,3]isoquinolinium hydroxide, inner salt 193 - 195 404 (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).

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 48. 4-cyclopropyl-2-(4-trifluoromethoxyphenyl)-3-hydroxy-2/-/-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 188- 189 386 (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). 49. 2-(4-chloro-3-trifluoromethylphenyl)-4-cyclopropyl-3-hydroxy-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt >220 404/406 (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(1H, dd), 8.67 (2H, s), 9.03(1H, dd). 50. 4-cyclopropyl-3-hydroxy-2(4-methylthiophenyl)-2/-/pyrazolo[4,3]isoquinolinium hydroxide, inner salt 166- 167 348 (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). 51. 3-hydroxy-4-phenyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 255 406 (M+H) ⁺ 7.69 (3H, m), 7.76 (2H, m), 7.82 (3H, m), 8.05(1H, m), 8.25(1 H, d), 8.45(1 H, d), 8.53 (2H, m), 8.45 (1H, d). 52. 4-ethyl-3-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 192- 198 358 (M+H) ⁺ 1.63 (3H, d), 4.88 (2H, quart), 7.55(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). 53. 2-(4-trifluoromethylphenyl)-4-(1-ethoxycarbonylmethyl)-3-hydroxy-2/7-pyrazolo[4,3-]isoquinolinium hydroxide, inner salt 167- 169 416 (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). 54. 3-hydroxy-4-[(4methoxyphenyl)methyl]-2-phenyl2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt foam 382 (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).

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 55. 3-hydroxy-4-(1-methylethyl)-2(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 201 - 203 372 (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 (2H, d), 8.93 (1H, d). 56. 3-hydroxy-4-(1-methylethyl)-2(3-trifluoromethylphenyl)-2H-pyrazolo[4,3-]isoquinolinium hydroxide, inner salt 220- 222 372 (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 (1H, d), 8.64(1H, d), 8.85(1H, s), 8.94(1H, s).

Example 57

3-Hydroxy-2-(4-iodophenyl)-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >

Methyl 1,2- ₍ 3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylate (0.485 g) and 4-iodophenylhydrazine (1.053 g) were mixed in ethanol (15 ml) and heated at reflux for 20 hours. On cooling, a solid precipitated which was recrystallized from ethanol and then from 2-propanol to give the title compound (0.054 g). M.p. >260 °C.

MS (+ve ESI) 402 ((M + H) ⁺ ) ¹ H NMR (de-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 (1H, d), 8.62 (1H, with).

The following compounds, Examples 58-60, were prepared in an analogous manner to Example 2:

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 58. 2-(6-chloro-3-pyridyl)-2/-/pyrazolo[4,3-c]isoquinolin-3-ol >250 297/299 (M+H) ⁺ 7.71 (1H, d), 7.89 (1H, t), 8.00(1H, t), 8.31 (2H, m), 8.56(1 H, br d), 9.00(1 H, br s), 9.13(1 H, s).· 59. 2-(4-(1-methylethyl)pheny IJ-2/Vpyrazolo[4,3-c]isoquinolin-3ol 218 - 219 304 (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). 60. 2-(4-pentafluoroethylphenyl)-2Hpyrazolo[4,3-c]isoquinolin-3ol 219- 223 380 (M+H) ⁺ 7.68(1H, t), 7.76 (3H, m), 8.02 (1H, d), 8.24(1H, d), 8.54 (3H, m).

The following compounds, Examples 61-68, were prepared in an analogous manner to Example 6:

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 61. 2,4-dihydro-3-hydroxy-4- methyl 2-(2-pyrimidinyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one >250 294 (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). i 62. 2-((1, 1'-biphenyl]-4-yl)-2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo[4,3c]isoquinolin-5-one 241 - 244 368 (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). 63. 2,4-dihydro-3-hydroxy-4methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one >250 360 (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). 64. 2-(6-chloro-3-pyridyl)-2,4-dihydro-3-hydroxy-4-methyl-5/N-pyrazolo[4,3c]isoquinolin-5-one >250 327/329 (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(1 H, d).

Ex. Name 1.1. (°C) World Cup ¹ H NMR (de-DMSO) δ 65. 2,4-dihydro-3-hydroxy-2-(4-iodophenyl)-4-methyl-5H-pyrazolo[4,3-c]isoquinolin-5-one . >250 418 (M+H) ⁺ 3.80 (3H, s), 7.74 (3H, m), 7.89 (3H, m), 8.02 (1H, d), 8.36(1H, d). 66. 2,4-dihydro-3-hydroxy-4-(4methoxyphenylmethyl)-2-(4trifluoromethylphenyl)-5Hpyrazolo[4,3-c]isoquinolin-5one >230 466 (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). 67. 2,4-dihydro-3-hydroxy-4-(1 methylethyl)-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one 228230 split 388 (M+H) ⁺ 1.59 (6H, d), 5.85(1H, br s), 7.76(1H, t), 7.92 (3H, d), 8.04(1H, d), 8.18 (2H, d), 8.36(1H, d). 68. 2,4-dihydro-3-hydroxy-4methyl-2-[4-(1methylethyl)phenyl-5Hpyrazolo[4,3-c]isoquinolin-5one 238- 240 334 (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 (1H, d), 8.36(1H, 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]isoquinolin-5-one (Example 66) (425 mg) and the mixture was heated to reflux for 12 hours. 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 further purified by trituration with isohexane to give the title compound (150 mg). M.p. >200°C.

MS (APCI) 346 ((M + H) ⁺ ) ¹ H NMR (de-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).

-40The following compounds were prepared analogously to Example 69:

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 70. 2,4-dihydro-3-hydroxy-2-[4-(1-methylethyl)phenyl]-5Hpyrazolo[4,3-c]isoquinolin-5-one >250 320 (M+H) ⁺ I. 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), II. 00 (1H, s). 71. 2,4-dihydro-3-hydroxy-2- ([1,1'-biphenyl]-4-yl]-5Hpyrazolo[4,3-c]isoquinolin-5-one 275 split 354 (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]isoquinolinium hydroxide, inner salt

A 1 M solution of methylmagnesium bromide in diethyl ether (2.0 ml) was added dropwise to an ice-cooled suspension of 2-(4-chlorophenyl)-3-hydroxy-4-[(4methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinoline hydroxide, inner salt (Example 22) (0.5 g) and copper (I) bromide (17 mg) in dry tetrahydrofuran (20 ml). The mixture was stirred with cooling for 1 hour and saturated aqueous ammonium chloride solution and ethyl acetate were added. This mixture was stirred at room temperature for 16 hours and then the aqueous phase was extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column chromatography (dichloromethane and methanol 99:1) to give a purple solid (0.38 g). A sample (0.1 g) was recrystallized from ethanol to give the title compound (31 mg). M.p. 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 (1H, t), 7.98 (1H, t), 8.32 (1H, d), 8.43 (3H, m).

-41 Example 73

2-(4-Chlorophenyl)-5-methyl-2H-pyrazolo[4,3-c]isoquinolin-2-ol

2-(4-Chlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.29 g) was dissolved in trifluoroacetic acid (10 ml) and heated to reflux under nitrogen for 2 hours. After cooling to room temperature, the solvent was evaporated and the residue was co-evaporated with toluene (three times). Purification by column chromatography (dichloromethane and methanol 20:1) followed by trituration with methanol gave the title compound as an orange solid (0.07 g). M.p. >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 following compounds were prepared according to the method of Example 72:

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 74. 4-cyclopropyl-3-hydroxy-5-methyl-2-(4-trifluoromethylphenyl)-2/7-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt >250 384 (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). 75. 3-hydroxy-4-(2-methoxyethyl)5-methyl-2-[(4- ’ trifluoromethyl)phenyl]-2/7pyrazolo[4,3j]isoquinolinium hydroxide, inner salt 202- 204 402 (M+H) ⁺ 3.00 (3H, s), 3.29 (3H, s), 4.08 (2Η, t), 5.37 (2H, br s), 7.68 (3H, m), 7.88(1H, t), 8.10 (1H, d), 8.56 (3H, m).

-42Example 76

2-(4-Chlorophenyl)-3-hydroxy-4,5-dimethyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

2-(4-Chlorophenyl)-2,4-dihydro-3-hydroxy-4-methylpyrazolo[4,3-c]isoquinolin-5-one (0.48 g) (Example 6) was suspended in dry 1,2-dimethoxyethane (50 ml). A solution of methylmagnesium bromide (3 ml of a 3 M solution in ether) was added and heating continued for 3 hours. The reaction mixture was allowed to cool to room temperature and then neutralized by slow addition of dilute hydrochloric acid. The mixture was made basic with aqueous sodium bicarbonate and extracted with ethyl acetate (three times). The organic layer was washed with brine and dried over magnesium sulfate, filtered and evaporated. Purification of the residue by chromatography (silica, dichloromethane and methanol 97:3 - 95:5) gave a red solid which was triturated with ether to give the title compound (0.060 g). Mp >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 following compounds were prepared according to the method of Example 76:

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 77. 5-ethyl-3-hydroxy-4-methyl-2(4-trifluoromethylphenyl)-2Hpyrazolo[4,3]isoquinolinium hydroxide, inner salt >250 372 (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). 78. 3-hydroxy-5-methyl-4-(1-methylethyl)-2-(4-trifluoromethylphenyl)-2-pyrazolo[4,3-]isoquinolinium hydroxide, inner salt 205- 210 386 (M+H) ⁺ 1.76 and 1.90 (6H, 2 x m, rotamers), 3.07 (3H, s), 5.42 and 7.40 (1 H, 2 x br, rotamers), 7.77 (3H, m), 7.97 (1 H, t), 8.41 (2H, m), 8.62 (2H, m).

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 79. 4-methyl-5-(1-methylethyl)-3-hydroxy-2-(4-trifluoromethylphenyl)-2/7-pyrazolo[4,3-]isoquinolinium hydroxide, inner salt 236- 238 386 (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). 80. 3-hydroxy-4,5-dimethyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-]isoquinolinium hydroxide, inner salt >250 358 (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

Phosphorus oxychloride (5 ml) was added to 2,4-dihydro-3-hydroxy-4-(4methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one (Example 66) (350 mg) and heated at 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) followed by trituration with acetonitrile to give the title compound (25 mg). M.p. >250 °C (dec.).

MS (APCI) 364/366 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 7.96 (5H, m), 8.07 (1 H, t), 8.25 (1 H, d), 8.43 (1 H, d).

-44Example 82

3a,4-Dihydro-3a-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[ _4L3 -c]isoquinoline-3,5-dione

Ceric ammonium nitrate (700 mg) was added to a suspension of 2,4-dihydro-3-hydroxy-4-(4-methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one (Example 66) (200 mg) in acetonitrile (4 mL) and water (1 mL) at room temperature. After 2 hours, the mixture was adsorbed onto silica gel and purified by column chromatography eluting with isohexane and 2-propanol (9:1) followed by HPLC eluting with isohexane and ethyl acetate (4:1) to give the title compound (50 mg). M.p. 175-185 °C

MS (El) 360 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 7.7 to 8.0 (5H, m), 8.08 to 8.12 (4H, m), 9.78 (1 H, s).

Example 83

2 ₁ 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]isoquinolin-5-one (0.2 g) (Example 63) in dry dimethylformamide (5 ml) was added dropwise to a stirred suspension of oil-free sodium hydride (from 0.022 g of a 60% dispersion) in dry dimethylformamide (1 ml) at 0 °C. After 0.5 h, methyl iodide (0.038 ml) was added. Stirring was continued for 16 h. The mixture was diluted with water, acidified with dilute hydrochloric acid and extracted with ethyl acetate (three times). The organic phase was washed with brine (seven times) and then dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (ethyl acetate, dichloromethane 25:75 - 50:50 and then ethyl acetate, isohexane 30:70) gave the title compound as a colorless solid (0.015 g). M.p. 163-164 °C

MS (APCI) 374 ((M + H) ⁺ )

-45 ¹ H NMR (CDCl): 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, dd), 8.48 (1H, dd).

Example 84 _t ' I

2-(4-Chlorophenyl)-4-{2-(N,N-dimethylamino)ethyl}-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

2-(4-Chlorophenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol (0.3 g) was added to a stirred suspension of oil-free sodium hydride (from 81 mg of a 60% dispersion) in dry dimethylformamide (5 mL) under nitrogen. After 30 min, 2-dimethylaminoethyl chloride hydrochloride (0.15 g) was added and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with ethyl acetate (three times). The organic phase was washed with brine and then dried over sodium sulfate, filtered, and concentrated to give a purple solid. Purification by column chromatography (dichloromethane, ethanol 20:1) followed by recrystallization from cyclohexane:ethyl acetate 4:1 gave the title compound as a red solid (125 mg). M.p. 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, inner salt

3-Hydroxy-4-methyl-2-(4-methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.10 g) (Example 41) was dissolved in dichloromethane (15 ml) and cooled to -78 °C. 3-Chloroperbenzoic acid (0.055) was added and the mixture was stirred for 10 minutes, poured into aqueous sodium metabisulfite and extracted with ethyl acetate (three times). The combined extracts were shaken with aqueous sodium bicarbonate, dried over sodium sulfate and evaporated. The residue obtained was purified by column chromatography (ethyl acetate, methanol 3:2) to give the title compound as a red powder. M.p. >230 °C.

MS (APCl) 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, with).

Example 86

2-(4-Chlorophenyl)-3-hydroxy-4-[2-(methylsulfinyl)ethyl]-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt

3-Chloroperbenzoic acid (0.86 g) was dissolved in dichloromethane (20 ml). 6 ml of the resulting solution was added dropwise to a solution of 2-(4-chlorophenyl)-3-hydroxy-4-[2-(methylthio)ethyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (Example 46) (0.43 g) in dichloromethane (20 ml) at -78 °C. After 30 minutes, aqueous sodium metabisulfite was added and the reaction mixture was then partitioned between water and dichloromethane. The organic layer was washed with aqueous sodium hydroxide solution and then dried (magnesium sulfate), filtered and evaporated. The residue was chromatographed using methanol (2-6% v/v) in dichloromethane as eluent to give a purple solid (0.46 g). M.p. 228 - 230 °C.

MS (APCI+) 386, 388 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 2Ό9 (3H, s), 3.47 (1H, m),'3.64(1H, m), 5.11 (1H, m), 5.34 (1H, m), 7.50 (2H, m), 7.79 (1H, m), 7.99 (1H, m), 8.17 (1H, d), 8.38 (3H, m), 8.83(1H, s).

Example 87

3-Hydroxy-4-[2-(methylsulfinyl)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt

Prepared from 3-hydroxy-4-[2-(methylthio)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (Example 47), according to the method of Example 86 to give the title compound as a purple solid. M.p. 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]isoquinoline-3-yl, sodium salt

Methylmagnesium bromide (3 M in ether, 8.6 mL) was added slowly to a stirred suspension of 2,4-dihydro-3-hydroxy-4-(4-methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)5H-pyrazolo[4,3-c]isoquinolin-5-one (Example 66) (500 mg) and copper (I) bromide (15 mg) in 1,2-dimethoxyethane (50 mL) and then heated at 100 °C for 24 h. After cooling to room temperature, the mixture was poured into cold dilute hydrochloric acid and the pH was adjusted to basic with sodium bicarbonate and sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over magnesium sulfate. Filtration and evaporation of the solution followed by purification by column chromatography eluting successively with isohexane/ethyl acetate (1:1), ethyl acetate and ethyl acetate/methanol (9:1) gave the title compound as a red solid (90 mg). M.p. >200 °C (dec.).

MS (APCI) 464 ((M + H) ⁺ )

-48 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).

and

Example 89

2-Fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt (a) 2,6-Difluoro-N-(2-hydroxy-1,1-dimethylethyl)benzamide

A solution of 2,6-difluorobenzoyl chloride (20 g) in dry dichloromethane (100 ml) was added dropwise to an ice-cooled solution of 2-amino-2-methylpropanol (20.2 g) in dry dichloromethane (150 ml) under a nitrogen atmosphere, maintaining the temperature below 5 °C. After the addition was complete, the ice bath was removed and stirring was continued for a further 16 hours at room temperature. The organic phase was diluted with water and separated. The aqueous phase was then extracted with dichloromethane (twice). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. Trituration with hexane gave the title compound (24.65 g).

MS (APCI) 230 ((M + H) ⁺ ) ¹ H NMR (CDCIa) δ 1.41 (6H, s), 3.70 (2H, d), 3.95 (1H, t), 6.00 (1H, br s), 6:95 (2H, m), 7.38 (i H, m). , (b) 2-(2,6-Difluorophenyl)-4,5-dihydro-4,4-dimethyloxazole

Thionyl chloride (12.6 ml) was added dropwise to the ice-cooled solution

2,6-difluoro-N-(2-hydroxy-1,1-dimethylethyl)benzamide (24.65 g) in dry dichloromethane (100 ml) under a nitrogen atmosphere. After the addition, the ice bath was removed and stirring was continued for 1 hour at room temperature. The solvent was then evaporated and the residue was triturated with diethyl ether. The solid obtained was dissolved in a minimum amount of water (80 ml) and the pH was adjusted to basic using sodium hydroxide tablets. The basic phase was then extracted with ethyl acetate (three times). The organic extracts were combined and then washed with brine, dried over sodium sulfate, filtered and evaporated. The oil obtained was purified by column chromatography (hexane and ethyl acetate 4:1) to give the title compound (20.86 g).

I I

MS (E1) 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 1 M solution of methylmagnesium chloride in tetrahydrofuran (86 ml) was added dropwise to a solution of 2-(2,6-difluorophenyl)-4,5-dihydro-4,4-dimethyloxazole (18.23 g) in dry tetrahydrofuran (60 ml) at 0 °C under a nitrogen atmosphere. The solution was stirred at 0 °C for 1 hour and then allowed to warm to room temperature over 16 hours. Saturated ammonium chloride solution was carefully added to the reaction mixture. The mixture was then extracted with ethyl acetate (three times). The organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound as a pale 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 heated at reflux in acetonitrile (150 ml) for 4 hours and then allowed to cool to room temperature. The solvent was evaporated and the solid residue was triturated with diethyl ether. The solid obtained 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 allowed to cool to room temperature and then the methanol was evaporated. The aqueous residues were washed with ethyl acetate (three times) and then acidified with dilute hydrochloric acid to pH 1. The acidic phase was extracted with ethyl acetate (three times). The organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give 2-fluoro-6-methylbenzoic acid (10.85 g). A sample (0.27 g) was recrystallized from 4:1 hexane/ethyl acetate to give the title compound (0.15 g). M.p. 123-124 °C.

MS (E1) 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 dry dimethylformamide (25 ml) under nitrogen. Stirring was continued at room temperature for 16 hours, and then the reaction mixture was diluted with water and extracted with ethyl acetate (three times). The organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated to give the title compound as a yellow oil (4.07 g).

MS (El) 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

A suspension of methyl 2-fluoro-6-methylbenzoate (35.53 g), N-bromosuccinimide (37.6 g) and azobis(isobutyronitrile) (2 g) in dry dichloromethane (150 ml) was irradiated (100 W halogen lamp) under a nitrogen atmosphere for 4 h. Obtained

The 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 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 dropwise to a stirred solution of methyl 2-(bromomethyl)-6-fluorobenzoate (11 g) and triethylamine (6.8 ml) in dry diethyl ether (50 ml). The mixture was heated to reflux under nitrogen for 16 hours. The reaction mixture was allowed to cool and then diluted with water and extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (hexane and ethyl acetate 20:1) to give the title compound as a colorless oil (8.82 g).

MS (APCI) 376 ((M + H) ⁺ ) ¹ H NMR (CDCIa): 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 dry toluene (50 ml) was added dropwise to a suspension of sodium hydride (1.32 g of a 60% oil-free dispersion) and tert-butyl alcohol (1 ml) in dry toluene (100 ml) heated to reflux under nitrogen. Heating was continued for a further 12 hours and then the reaction mixture was allowed to cool to room temperature. The mixture was poured into

-52 saturated aqueous ammonium chloride solution and extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give the 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).

(i) 9-Fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

Methyl 5-fluoro-1,2,3,4-tetrahydro-2-(4-methoxyphenylmethyl)-4-oxo-3-isoquinolinecarboxylate (1.0 g), 4-trifluoromethylphenylhydrazine (1.03 g) and p-toluenesulfonic acid (20 mg) were melted together at 150 °C under nitrogen for 15 minutes. Xylene (20 ml) was added and heating was continued for another 2 hours. After cooling to room temperature, the solvent was evaporated and the solid residue was purified by column chromatography (dichloromethane and methanol 99:1) to give the title compound as purple needles (0.425 g).

MS (APCI) 468 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 3.72 (3H, s), 6.10 (2H, s), 6.69 (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, inner salt (0.43 g), was dissolved in trifluoroacetic acid (5 ml) and heated to reflux under nitrogen for 16 hours. After cooling to room temperature, the solvent was evaporated and the residue was co-evaporated with toluene (three times). The residue was successively triturated with methanol and

-53then with diethyl ether and finally recrystallized from ethyl acetate to give the title compound as a red solid (0.08 g). Mp >250°C.

MS (APCI) 348 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 7.86 (2H, m), 7.95 (2H, d), 8.14 (1 H, d), 8.24 (2H, br d), 9.09 (1 H, br d), 11.85 (1H, br s).

The following compounds were prepared analogously to Example 90:

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 91. 2-(4-chlorophenyl)-7-fluoro-3-hydroxy-4-methyl-2/7-pyrazolo[4,3]isoquinolinium hydroxide, inner salt >250 328/330 (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). 92. 7-fluoro-3-hydroxy-4-methyl-2(4-trifluoromethylphenyl)-2Hpyrazolo[4,3]isoquinolinium hydroxide, inner salt >250 362 (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). 93. 2-(4-chlorophenyl)-4-cyclopropyl-9-fluoro-3-hydroxy-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt >214- 217 354/356 (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). 94. 4-cyclopropyl-9-fluoro-3-hydroxy-2-(4-trifluoromethylphenyl)-2-pyrazolo[4,3-]isoquinolinium hydroxide, inner salt >250 388 > (M+H) ⁺ 1.36 (2H, m), 1.55 (2H, m), 5.06(1H, m), 7.77 (4H, m), 7.97(1H, m), 8.58 (2H, d), 8.66(1H, s). 95. 2-(4-chlorophenyl)-9-fluoro-3-hydroxy-4-methyl-2/-/pyrazolo[4,3]isoquinolinium hydroxide, inner salt >250 328/330 (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).

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 96. 2-(4-chlorophenyl)-9-fluoro-3-hydroxy-4-[(4methoxyphenyl)methyl]-2/-A pyrazolo[4,3]isoquinolinium hydroxide, inner salt > 250 434/436 (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). 97. 9-fluoro-3-hydroxy-4-methyl(4-trifluoromethylphenyl)-2Hpyrazolo[4,3c]isoquinolinium hydroxide, inner salt >250 362 (M+H) ⁺ 4.51 (3H, s), 7.77 (4H, m), 7.93(1H, m), 8.56 (2H, d), 8.68(1 H, s).

The following compounds (Examples 98-100) were prepared according to the procedures of Example 2:

Ex. Name 1.1. (°C) World Cup ¹ H NMR (de-DMSO) δ 98. 2- (4-chlorophenyl)-9-fluoro-2Hpyrazolo[4,3-c]isoquinoline- 3- o I >250 314/316 (M+H) ⁺ 7.63 (2H, d), 7.82 (2H, br m), 8.01 (2H, d), 8.11 (1H, br d), 9.05 (1 H, br s), 11.80 (1H, br s). 99. 7-fluoro-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin- 3-ol >250 348 (M+H) ⁺ 7.93 (3H, d), 8.14(1H, d), 8.28 (2H, d), 8.41 (1H, dd), 9.02(1H, br s). 100. 2-(4-chlorophenyl)-7-fluoro-2Hpyrazolo[4,3-c]isoquinoline- 3- bl >250 314/316 7.63 (2H, d), 7.91 (1H, br t), 8.05 (2H, d), 8.13(1H, d), 8.40(1H, dd); 9.00 (1 H, br s), 12.00 (1 H, br s).

The following compounds were prepared according to the procedures of Example 69:

Ex. Name 1.1. (°C) World Cup ¹ H NMR (ds-DMSO) δ 101. 9-fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 225- 227 482 (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). 102. 2-(4-chlorophenyl)-9-fluoro-3-hydroxy-4-[(4methoxyphenyl)methyl]-5-methyl2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 222- 223 448/450 (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 procedures of Example 2:

Ex. Name 1.1. (°C) World Cup ¹ H NMR ( _d6 -DMSO) δ 103. 9-fluoro-5-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol >250 362 (M+H) ⁺ 2.80 (3H, s), 7.79 (2H, m), 7.88 (2H, d), 8.10 (1H, d), 8.32 (2H, d). 104. 2-(4-chlorophenyl)-9-fluoro-5-methyl-2H-pyrazolo[4,3c]isoquinolin-3-ol >250 328/330 (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

A solution of 2,4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one (Example 63) (0.25 g) and Lawesson's reagent (0.7 g) in dioxane (20 ml) was stirred and heated to reflux for 18 hours. The resulting mixture was cooled and adsorbed onto silica gel. Purification by chromatography (methanol

-56 with dichloromethane 1:99-3:97) gave the title compound which crystallized from ethanol to give yellow crystals (0.075 g). M.p. 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)-2/7-pyrazolo[4,3]isoquinolinium hydroxide, inner salt

A solution of 2,4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-5/7-pyrazolo[4,3-c]isoquinoline-5-thione (0.46 g) (Example 105) and iodomethane (0.095 ml) in acetone (50 ml) was stirred and heated to reflux for 4 hours. Potassium carbonate (0.170 g) was added and the mixture was heated to reflux for a further 2 hours. The mixture was concentrated in vacuo. Purification of the residue by chromatography (methanol:dichloromethane 2:98) gave the title compound as a purple solid (0.375 g).

MS (APCI) 390 ((M + H) ⁺ ) ¹ H NMR (CDCl 2 ) δ 8.54 (4H, m), 7.86 (1H, t), 7.72 (3H, m), 4.98 (3H, s), 2.52 (3H, s).

Example 107 l ,

2-(4-Trifluoromethylphenyl)-2,4-dihydro-5-imino-4-methyl-5H-pyrazolo[4,3-c]isoquinoline-

3-ol

A suspension of 3-hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2/7-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.013 g) (Example 106) in ethanol (7 ml) and ammonia solution (specific gravity 0.880; 15 ml) was stirred at 20 °C for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic

The -57 phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by chromatography (methanol:dichloromethane 5:95 - 10:90) gave the title compound as an orange solid (0.043 g). M.p. 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]naphthhydrinium hydroxide, inner salt (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 while irradiated with a 500 W lamp. After 2 hours, the reaction mixture was allowed to cool and then poured into sodium bicarbonate solution. The organic phase was separated and washed twice with brine, then 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

Prepared according to the method of Example 1, step (a) using 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) to give the title compound (3.20 g).

MS (DESC SI) 358 (M ⁺ )

-58 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

Prepared according to the method of Example 1, step (b), using Λ/[(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) to give the title compound (790 mg).

MS (APCI) 327 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) 3.65 to 3.97 (m, 10H), 6.79 (m, 2H), 7.11 to 7.39 (m, 3H), 7.86 to 8.25 (m, 1H), 8.52 to 8.75 (m, 1H), 11.25 (s, 1H).

(d) 3-Hydroxy-4-(4-methoxyphenyl)methyl-2-(4-trifluoromethylphenyl)-2N-pyrazolo[3,4/][1,7]naphthhydrinium hydroxide, inner salt

Prepared according to the method of Example 1, step (c), using methyl 7,8-dihydro-5-hydroxy-7-(4-methoxyphenyl)methyl-1,7-naphthhydrin-6-carboxylate (200 mg), 4-trifluoromethylphenylhydrazine (1.00 g) and ethanol (3 ml) to give the title compound (21 mg). M.p. 201-203 °C.

MS (APCI) 451 ((M + H) ⁺ ) ¹ H NMR (de-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).

-59Example 109

2-(4-Trifluoromethylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthhydrin-3-ol

Prepared according to the method of Example 2 using 3-hydroxy-4-(4-methoxyphenyl)methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[3,4- f ][1,7]naphthhydrinium hydroxide, inner salt (135 mg) and trifluoroacetic acid (5 ml) to give the title compound (19 mg). M.p. 239-241 °C (dec.).

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 (s, 1H).

The following compounds were prepared analogously to Example 109 using methyl 2-(bromomethyl)nicotinate, sarcosine methyl ester and the corresponding hydrazine:

Ex. Name 1.1. (°C) World Cup ¹ H NMR (ds-DMSO) δ 110. 3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2/-/pyrazolo[3,4- f)[1,7]naphthhydrinium hydroxide, inner salt >260 345 (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) 111. 2-(4-chlorophenyl)-3-hydroxy- 4-methyl-2H-pyrazolo[3,4/][1,7]naphthhydrinium hydroxide, inner salt >260 311/330 (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)

-60Example 112

3-Hydroxy-4-methyl-5-(dimethylamino)-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt

A solution of 3-hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.39 g) (Example 106), in acetone (10 ml) and 40% aqueous dimethylamine (2 ml) was stirred at 20 °C for 24 hours. The mixture was concentrated in vacuo. Purification of the residue by chromatography (methanol and dichloromethane, 1 : 99 - 2.5 : 97.5) gave the title compound as a red solid (0.129 g). M.p. 256 - 259 °C.

MS (APCI) 387 ((M + H) ⁺ ) ¹ H NMR (CDCIs) δ 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]isoquinolinium hydroxide, inner salt

A solution of 3-hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.520 g) (Example 106), in dry tetrahydrofuran (7 ml) and morpholine (2.3 ml) was heated to 70 °C for 12 hours and then to 95 °C for 2 hours. The mixture was concentrated in vacuo. Purification of the residue by chromatography (methanol and dichloromethane, 5:95) gave the title compound as a red solid (0.165 g). M.p. 278-281 °C.

MS (APCI) 429 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 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 (1H, d), 8.59 (2H, d).

-61 Example 114

3-Hydroxy-4-methyl-5-piperazinyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt

I'

A solution of 3-hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.29 g) (Example 106), in toluene (20 ml) 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. Purification of the residue by chromatography (methanol and dichloromethane, 5:95-10:90) followed by crystallization from ethanol gave the title compound as a red solid (0.107 g). M.p. 260-262 °C.

MS (APCI) 428 ((M + H) ⁺ ) ¹ H NMR (DMSO) δ 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 (1H, d), 8.59 (2H, d).

Example 115

4,5-Dihydro-2-[4-(trifluoromethyl)phenyl]-2H-benz[g]indazol-3-ol

1-Oxotetrahydronaphthalene-2-carboxylic acid methyl ester (Mander, L. N. and Sethi, S. P.; Tetrahedron Lett. 1983, 24, 5425-8) (2.0 g) and 4-trifluoromethylphenylhydrazine (3.47 g) were heated in xylene (15 ml) at reflux for 8 hours. The reaction mixture was allowed to cool and 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). M.p. 189-190 °C.

MS (APCI) 331 ((M + H) ⁺ ) ¹ H NMR (de-DMSO) δ 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).

-62Example 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 together in xylene (15 ml) at reflux for 6 hours. The reaction mixture was allowed to cool and the product was then filtered off and dried. Recrystallization from diethyl ether/isohexane gave the title compound as light brown needles (0.69 g). M.p. 112 °C.

MS (APCI) 278 ((M + H) ⁺ ) ¹ H NMR (d _s -DMSO) δ 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 (1H, m), 8.07 (1H, s), 12.73 (1H, 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 carbon (0.10 g) were heated in dimethylacetamide (5 ml) and cyclohexene (5 ml) at reflux for 1 hour. The title compound (0.26 g), 1.1. > 235 °C (dec.).

MS (APCI) 329 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 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)?

Example118

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 carbon (0.20 g) were heated in dimethylacetamide (15 ml) and cyclohexene (15 ml) at reflux for 8 hours. The mixture was then allowed to cool to room temperature and then filtered. The filtrate was evaporated (100 °C/1 mm Hg) and the residue was recrystallized from ethyl acetate to give the title compound as light orange crystals (0.12 g). M.p. 214 °C.

MS (APCI) 276 ((M + H) ⁺ ) ¹ H NMR (d ₆ -DMSO) δ 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).

Pharmacological data

Test A - chronic graft-versus-host disease

The pharmacological activity of the compounds of the invention can be demonstrated using the method of J. M. Doutrelepnot et al. [Clin. Exp. Immunol., 1991, , 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse]. The test compound was administered to mice subcutaneously as a suspension in saline with TWEEN-80 every day for 21 days.

Test B - Eosinophilia Inhibition

The effects of the compounds of the invention on inflammatory cells in the mouse lung were evaluated by the following method adapted from Brusselle et al. Clin. Exp. Allergy, 1994, , 73-80. Measurement of eosinophil peroxidase as a marker for eosinophil counts was adapted from Cheng et al., J. Pharmacol. Exp. Ther. 1993, , 922-929. Male Balb/c mice were sensitized to a mixture of ovalbumin/Al(OH) ₃ .

I

Compound administration began 14 days after sensitization. The compound was administered daily either orally or subcutaneously as a suspension or solution (depending on the dose and solubility of the compound) in 5% TWEEN 80.

Days after sensitization and one hour after the fourth dose of compound, mice were placed in Prespex chambers into which a solution of ovalbumin (2% w/v) had been sprayed. Mice were allowed to inhale ovalbumin for 30-40 minutes. This treatment was repeated daily at the same time for a further 3 or 7 days.

-64 In the case of a four-day treatment, a further ovalbumin treatment was performed on the last day of administration 4 hours after the first.

The following day, the animals were sacrificed and the inhibition of the following parameters was measured by comparison with control animals:

I ;

1. Increase in the number of inflammatory cells in bronchoalveolar lavage, especially eosinophils (after four days of administration);

2. Accumulation of eosinophils in lung tissue (after 8 days of administration);

3.. Increase in antibody titers (IgE, IgGI and IgG2a) present in serum obtained from whole blood (after 8 days of administration).

Some compounds of the invention show activity in the chronic graft-versus-host disease assay and the eosinophil inhibition assay with ED _50s in the range of 0.1-10 mg/kg.

Claims (15)

PATENT CLAIMS 1. A compound of formula I or a pharmaceutically acceptable derivative thereof for use as a medicament: Oh! (i) where: • B, D, E and G each represent CH, CA or N, with the proviso that no more than one of B, D, E and G represents CA and no more than 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 1-4 alkyl, or forms a bond with one of 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 forms a bond with one of R ¹ , R ³ or R ⁴ ; • R ³ represents H or a bond with R ² ; • R ⁴ represents C 1-6 alkyl or a bond with R ² ; o R ⁵ represents a bond with R ¹ or R ⁸ ; o R ⁶ represents 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 (optionally substituted with phenyl) or _{C 3-7 cycloalkyl} , each of which may be optionally substituted with halogen, hydroxyl, 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 R ⁶ and R ⁷ together represent C 3-5 alkylene, X and Y forming a 5-7 membered ring; • R ⁸ represents H, C 1-6 alkyl or 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 are independently C 1-6 alkyl, H or together with the nitrogen atom to which they are attached form a 3-7 membered saturated ring optionally containing another oxygen atom or a nitrogen atom 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 optionally substituted with one or more substituents selected from the following: halogen, 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), C 1-6 alkyl substituted with phenyl or phenyl, in which any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may be optionally substituted with fluorine; and • A represents halogen, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy; wherein the phenyl groups present in R ² , R ⁶ , R ⁷ or as substituents on Ar ¹ may be optionally substituted with C 1-6 alkyl, halogen or C 1-6 alkoxy; with the reservations that: (i) when X represents C=O, C=S or C=NR ¹⁵ , then Y represents N; ¹ '' ¹ ' . ' (ii) when R ⁴ represents a bond with R ² , then Y represents N ⁺ R ⁷ ; (iii) when Y represents N ⁺ R ⁷ , then Z represents O', R ² represents a bond with R ³ or R ⁴ , and R ¹ and R ⁵ form a bond; (iv) when Y represents N, then Z represents OR ⁸ ; (v) when R ¹ represents OH, then 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, then 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 , then R ⁵ and R ⁸ form a bond, and when X represents NR ⁴ , then R ⁴ represents alkyl; (viii) when R ⁶ represents aryl, halogen, alkoxy, thioalkyl, then R ² and R ³ form a bond; (ix) when Y represents N or N ⁺ R ⁷ and R ² is substituted with any I of NR ¹⁰ R ¹¹ , OR ¹² or F, then the substituent and the ring nitrogen of Y must not be attached 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, then the substituent and the ring nitrogen of Y must not be attached to the same carbon atom of R ⁷ ; (xi) when one of B, D, E and G represents N, then X does not represent NR ⁴ ; (xii) when Y represents CR ¹⁸ , then X represents CR ³ R ⁶ ; with the further proviso that: • when 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 and R ² and R ³ together represent a bond, then Ar ¹ does not represent 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl. 2. Compound of formula I: AH N—N 7 (D where ® B, D, E and G each represent CH, CA or N provided that not more than one of B, D, E and G represents CA and not more than 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 either 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 forms a bond with either R ¹ , R ³ or R ⁴ ; • R ³ represents H or a bond with R ² ; • R ⁴ represents C _1-6 alkyl or a bond with R ² ; • R ⁵ represents a bond with R ¹ or R ⁸ ; • R ⁶ represents 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 (optionally substituted with phenyl) or C 3-7 cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkylthio, alkylsulfinyl, NR ¹⁶ R ¹⁷ , COOH, COO(C 1-6 alkyl) or cyano; • or R ⁶ and R ⁷ together represent C 3-5 alkylene, X and Y forming a 5-7 membered ring; • R ⁸ represents H, 0 _{ν 6} alkyl or 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 are independently C _1-6 alkyl, H or together with the nitrogen atom to which they are attached form a 3-7 membered saturated ring optionally containing another oxygen atom or a nitrogen atom 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 optionally substituted with one or more substituents selected from the following: halogen, 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), C 1-6 alkyl substituted with phenyl or phenyl, in which any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may be optionally substituted with fluorine; and • A represents halogen, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy; wherein the phenyl groups present in R ² , R ⁶ , R ⁷ or as substituents on Ar ¹ may be optionally substituted with C _1-6 alkyl, halogen or C 1-6 alkoxy; with the reservations that: (i) when 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) when Y represents N ⁺ R ⁷ , then Z represents O-, R ² represents a bond with R ³ or R ⁴ and R ¹ and R ⁵ form a bond; (iv) when Y represents N, then Z represents OR ⁸ ; (v) when R ¹ represents OH, then 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, then 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 , then R ⁵ and R ⁸ form a bond, and when X represents NR ⁴ , then R ⁴ represents alkyl; (viii) when R ⁶ represents aryl, halogen, alkoxy, thioalkyl, then R ² and R ³ form a bond; (ix) when Y represents N or N ⁺ R ⁷ and R ² is substituted with any of NR ¹⁰ R ¹¹ , OR ¹² or F, then the substituent and the ring nitrogen of Y must not be attached 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, then the substituent and the ring nitrogen of Y must not be attached to the same carbon atom of R ⁷ ; (xi) when one of B, D, E and G represents N, then X does not represent NR ⁴ ; (xii) when Y represents CR ¹⁸ , then X represents CR ³ R ⁶ ; with the further reservations that: (a) when 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 and R ² and R ³ together represent a bond, then Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl; (b) when 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, R ² and R ³ represent a bond, R ⁸ represents H and R ⁷ represents methyl, then Ar ¹ does not represent unsubstituted phenyl; (c) when 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 represents isopropyl, then Ar ¹ does not represent unsubstituted phenyl or 4-bromophenyl; and (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, then Ar ¹ does not represent unsubstituted phenyl. or a pharmaceutically acceptable derivative thereof. A compound of formula I according to claim 1 or claim 2, wherein Ar ¹ represents phenyl or pyridyl. A compound of formula I according to claim 3, wherein Ar ¹ represents phenyl. A compound of formula I according to claim 3 or claim 4, wherein Ar ¹ has a substituent in the para position. 6. A compound 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. A compound of formula I according to any one of the preceding claims 1 to 6, wherein Y represents N ⁺ R ⁷ and X represents CR ³ R ⁶ , wherein R ³ forms a bond with R ² and R ⁶ represents alkyl. >. , 8. A compound of formula I according to claim 7, wherein R ⁶ represents branched alkyl. A 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 . A compound of formula I according to any one of the preceding claims 1 to 10, wherein B represents CA. 11. A compound of formula I according to claim 10, wherein A represents F. A compound of formula I according to any one of the preceding claims 1 to 11, wherein D or G represents N. 13.) A compound of formula I according to any one of the preceding claims 1 to 12, wherein R ¹ represents a bond with R ² or R ⁵ . 14. A compound of formula I according to claim 13, wherein R ¹ represents a bond with R ⁵ . 15. A compound according to claim 2, which is: 3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo-[4,3-]isoquinoline hydroxide, inner 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]isoquinolinium hydroxide, inner 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, inner 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, inner 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, inner 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]isoquinolinium hydroxide, inner salt 2-(3-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol 2-(4-(1,1-dimethylethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinoline-3-pl 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, inner salt 2-(4-chlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]cinnolinium hydroxide, inner salt 2-(4-chlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl-2H-pyrazolo(4,3- c)isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2/7-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-(3-quinolyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt -732-(6-chloro-3-pyridyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(3,4-Dichlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt I 3-hydroxy-4-methyl-2-(4-methylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-bromophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-(3-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-(1,1-dimethylethyl)phenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 2-(6-chloro-3-pyridyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3- c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-(6-methyl-3-pyridyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-Trifluoromethylphenyl)-3-hydroxy-4-(2-hydroxyethyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-(5-methyl-2-pyridyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-[4-(1-methylethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-(4-nitrophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt -742-(4-cyanophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-Carboxyphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-chloro-3-trifluoromethylphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 2-(4-Trifluoromethoxyphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-(4-methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 4-cyclopropyl-3-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 4-cyclopropyl-3-hydroxy-2-(6-methyl-3-pyridyl)-2H-pyrazolo[4,3- c]isoquinolinium hydroxide, inner salt 4-((1,1-dimethyl-2-hydroxy)ethyl]-3-hydroxy-2-[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-(2-methoxyethyl)-2-[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3- c isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-3-hydroxy-4-[2-(methylthio)ethyl]-2H-pyrazolo[4,3- c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-[2-(methylthio)ethyl]-2-(4-trifluoromethylphenyl)-2/-/-pyrazolo[4,3- c]isoquinolinium hydroxide, inner salt 4-cyclopropyl-2-(4-trifluoromethoxyphenyl)-3-hydroxy-2H-pyrazolo[4,3- c]isoquinolinium hydroxide, inner salt 2-(4-chloro-3-trifluoromethylphenyl)-4-cyclopropyl-3-hydroxy-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 4-cyclopropyl-3-hydroxy-2-(4-methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-phenyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 4-ethyl-3-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-Trifluoromethylphenyl)-4-(1-ethoxycarbonylmethyl)-3-hydroxy-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-phenyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-(1-methylethyl)-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-hydroxy-4-(1-methylethyl)-2-(3-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-hydroxy-2-(4-iodophenyl)-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner 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[4,3c]isoquinolin-5-one 2-([1,1'-biphenyl]-4-yl)-2,4-dihydro-3-hydroxy-4-methyl-5 H -pyrazolo[4,3c]isoquinolin-5-one 2.4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3- c]isoquinolin-5-one J 2-(6-chloro-3-pyridyl) _-2,1,4 -dihydro-3-hydroxy-4-methyl-5H-pyrazolo[4,3c]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]isoquinolin-5-one 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]isoquinoline- 5-one 2 _l 4-dihydro-3-hydroxy-2-([1,1'-biphenyl]-4-yl]-5 H -pyrazolo[4,3-c]isoquinolin-5-one 2-(4-chlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-5-methyl-2H-pyrazolo[4,3-c]isoquinolin-2-ol -Ί7 - 4-cyclopropyl-3-hydroxy-5-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-(2-methoxyethyl)-5-methyl-2-[(4-trifluoromethyl)phenyl]-2/7-pyrazolo[4,3- c isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-3-hydroxy-4,5-dimethyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 5-ethyl-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-hydroxy-5-methyl-4-(1-methylethyl)-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3- c]isoquinolinium hydroxide, inner salt 4-methyl·5-(1-methylethyl)-3-hydroxy-2-(4-trifluoromethylphenyl)-2/7-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 3-hydroxy-4,5-dimethyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3- c]isoquinolinium hydroxide, inner salt 5-chloro-2-(4-trifluoromethylphenyl)-2/7-pyrazolo[4,3-c]isoquinolin-3-ol 3a,4-dihydro-3a-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3c]isoquinoline-3,5-dione 2,4-dihydro-3-methoxy-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3- c]isoquinoline-5-one 2-(4-chlorophenyl)-4-(N,N-dimethylamino)ethyl}-3-hydroxy-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-2-(4-methylsulfinylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-3-hydroxy-4-[2-(methylsulfinyl)ethyl]-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-hydroxy-4-[2-(methylsulfinyl)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner salt 5-[2-(4-Methoxyphenyl)ethyl]-2-(4-trifluoromethylphenyl)-2/-/-pyrazolo[4,3c]isoquinolin-3-ol 9-Fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-7-fluoro-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 7-Fluoro-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-4-cyclopropyl-9-fluoro-3-hydroxy-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 4-cyclopropyl-9-fluoro-3-hydroxy-2-(4-trifluoromethylphenyl)-2/7-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-9-fluoro-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-9-fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 9-Fluoro-3-hydroxy-4-methyl-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3c]isoquinolinium hydroxide, inner 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]isoquinolinium hydroxide, inner salt 2-(4-chlorophenyl)-9- _fluoro- 3-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner 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[4,3c]isoquinoline-5-thione 3-hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3- c]isoquinolinium hydroxide, inner 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-η[1,7]naphthhydrinium hydroxide, inner salt 2-(4-Trifluoromethylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthhydrin-3-ol 3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthhydrinium hydroxide, inner salt 2-(4-chlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[3,4-f][1,7]naphthhydrinium hydroxide, inner salt 3-hydroxy-4-methyl-5-(dimethylamino)-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3- c]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-5-morpholinyl-2-(4-trifluoromethylphenyl)-2H-H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-hydroxy-4-methyl-5-piperazinyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3]isoquinolinium hydroxide, inner 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. 15. A process for the preparation of compounds of formula I according to claim 1 or claim 2, characterized in that it comprises: (a) preparing compounds of formula I, wherein X represents 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, by oxidizing the corresponding compound of formula I, wherein R ¹ and R ² both represent H, X, Y, Z and R ⁵ have the above meaning and B, D, E, G and Ar ¹ have the meaning according to claim 1; (b) preparing compounds of formula I, wherein one of B, D, E and G represents CA, wherein A represents amino, by reducing the corresponding compound of formula I, wherein one of B, D, E and G represents CA, wherein A represents nitro and the residue B, D, E and G, and X, Y, Z, Ar ¹ ,,R ¹ , R ² and R ⁵ are as defined in claim 1; (c) preparing compounds of formula I, wherein one of B, D, E and G represents CA, wherein A represents halogen, by diazotizing the corresponding compound of formula I, wherein one of B, D, E and G represents CA, wherein A represents amino and the residue B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined in claim 1, and decomposing the diazonium salt in the presence of a halide anion or source thereof; (d) preparing compounds of formula I, wherein one of B, D, E and G represents CA, wherein A represents cyano, by reacting the corresponding compound of formula I, wherein one of B, D, E and G represent CA, where A represents bromine and the remainder of B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ have the meaning according to claim 1; (e) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 alkylthio, by substitution reaction of the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen, Y, Z, R ¹ , R ² , R ³ and R ⁵ have the above meaning and B, D, E, G and Ar ¹ have the meaning according to claim 1, with a compound of formula II: wherein R ^6a represents C _1-6 alkyl; (f) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 alkoxy, by substitution reaction of the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen, Y, Z, R ¹ , R ² , R ³ and R ⁵ have the above meaning and B, D, E, G and Ar ¹ have the meaning according to claim 1, with a compound of formula III: wherein R ^6a has the above meaning; (g) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 NR ¹³ R ¹⁴ , by substitution reaction of the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen, Y, Z, R ¹ , R ² , R ³ and R ⁵ have the above meaning and B, D, E, G and Ar ¹ have the meaning according to claim 1, with a compound of formula IV: R13 (IV) wherein ^R13 and ^R14 have the meaning according to claim 1; (h) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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 methylthio, by reacting the corresponding compound of formula I, wherein X -82 represents C=S, Y represents N, Z represents OH, R ¹ , R ² and R ⁵ have the meanings given above and B, D, E, G and Ar ¹ have the meanings according to claim 1, with a methylating agent; (i) preparing compounds of formula I, wherein X represents C=S, Y represents N, Z represents OH and R ¹ represents a bond with R ⁵ , by reacting the corresponding 'à' compound of formula I, wherein X represents C=O, Y, Z, R ¹ and R ⁵ have the above meaning and B, D, E, G, Ar ¹ and R ² have the meaning according to claim 1, with thionation; (j) preparing compounds of formula I, wherein X represents ^CR3R6 , Y represents N ^{+ R7} , Z represents O' and ^R6 represents halogen, by reacting the corresponding compound of formula I, wherein X represents C=O, ^Y represents N, Z represents ^OR8 , ^R8 represents a bond with ^R5 and B, D, E, G, ^Ar1 , ^R1 and ^R2 are as defined in claim 1, with halogenation; (k) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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, by reacting the corresponding compound of formula I, wherein X represents C=O, Y represents N, Z represents OH, R ¹ represents a bond with R ⁵ , B, D, E, G, Ar ¹ are as defined in claim 1 and R ² represents a group corresponding to R ⁷ as defined in claim 1, with a nucleophilic alkylating agent comprising a compound of formula V: _c Mg R6' ^and Hal _(V|) where ^R6 has the above meaning and Hal represents halogen or another source of anion corresponding to ^R6 ; , '. (l) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ 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, by reacting the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents H, Y, Z, R ¹ , R ² and R ⁵ are as defined above and B, D, E, G and Ar ¹ are as defined in claim 1, with a nucleophilic alkylating agent comprising a compound of formula V as defined above or with another source of anion corresponding to R ⁶ ; (m) preparing compounds of formula I, 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, by reacting the corresponding compound of formula I, wherein Z represents OR ⁸ , wherein R ⁸ represents H, X, Y, R ¹ and R ⁵ have the meanings given above and B, D, E, G, Ar ¹ and R ² have the meanings according to claim 1, with a compound of formula VI; > R ⁸ Hal (VI) where R ⁸ represents alkyl and Hal has the above meaning; (n) the preparation of compounds of formula I, wherein R ¹ represents OH, X represents C=O, Y represents N, Z represents OR ⁸ and R ⁵ represents a bond with R ⁸ , by reacting the corresponding compound of formula I, where Z represents O', R ¹ and R ⁵ form a bond, X, YR ² have the above meaning and B, D, E, G and Ar ¹ have the meaning according to claim 1, with the action of an oxidizing agent; (o) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O', R ³ and R ² form a bond and R ¹ and R ⁵ form a bond, by reacting the corresponding compound of formula I, wherein Y represents N, Z represents OH, X, R ¹ , R ² and R ⁵ have the above meaning and B, D, E, G and Ar ¹ have the meaning according to claim 1, with a compound of formula IX: R ⁷ Hal (IX) where R ⁷ has the meaning according to claim 1 and Hal has the meaning given above; (p) preparing compounds of formula I, wherein X represents C=O, R ² does not represent H, Y represents N, Z represents OH and R ¹ represents a bond with R ⁵ , by reacting the corresponding compound of formula I, where R ² represents H, X, Y, Z, R ¹ and R ⁵ have the above meaning and B, D, E, G and Ar ¹ have the meaning according to claim 1, with a compound of formula VII: R ² Hal (VII) where R ² , which does not represent H, has the meaning according to claim 1 and Hal has the meaning given above; (q) preparing compounds of formula I, wherein B, D, E and G represent CH or CA, X represents NR ⁴ , Y represents N ⁺ R ⁷ , Z represents O', R ⁴ and R ² form a bond and R ¹ and R ⁵ form a bond, by reacting a compound of formula VIII: (VIII) wherein A and Ar ¹ have the meaning according to claim 1, with a compound of formula IX having the above meaning; (r) preparing compounds of formula I, wherein 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 form a bond, by reacting a compound of formula VIII as defined above with a compound of formula X: R ⁴ Hal (X) where R ⁴ has the meaning according to claim 1 and Hal has the meaning given above; (s) preparing compounds of formula I, wherein 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 , by treating with an acid the corresponding compound of formula I, wherein Y represents N ⁺ R ⁷ , Z represents O', R ⁷ represents CH ₂ C _s H ₄ 0alkyl, X, R ¹ , R ² and R ⁵ have the meanings given above and B, D, E, G and Ar ¹ have the meanings according to claim 1; (t) preparing compounds of formula I, wherein 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 , by reacting the corresponding compound of formula I, wherein Y represents N ⁺ R ⁷ , Z represents O', R ⁷ represents CH ₂ phenyl (optionally substituted with C 1-6 alkyl or C _1-6 alkoxy), X, R ¹ , R ² and R ⁵ are as defined above and B, D, E, G and Ar ¹ are as defined in claim 1, with hydrogen; (u) preparing compounds of formula I, wherein X represents C=O, Y represents N, Z represents OH, R ² represents H and R ¹ represents a bond with R ⁵ , by reacting the corresponding compound of formula I, wherein Y represents N ⁺ R ⁷ , Z represents O', R ⁷ represents CH ₂ C6H ₄ Oalkyl, X, R ¹ , R ² and R ⁵ have the meanings given above and B, D, E, G and Ar ¹ have the meanings according to claim 1, with an acid; (v) the preparation of compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O', R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ -85(XI) represents H, by reaction of the compound of formula XI: where X represents CH ₂₎ R ¹ represents H, R ² represents a group corresponding to R ⁷ with the meaning according to claim 1 in the compound of formula I, B, D, E and G are as defined in claim 1 and R is alkyl, with a compound of the formula XII: Ar ¹ NHNH ₂ (XII) where Ar ¹ has the meaning according to claim 1; (w) preparing compounds of formula I, wherein X represents C=O, R ² does not represent H, Y represents N, Z represents OH and R ¹ represents a bond with R ⁵ , by reacting a compound of formula XI with the above meaning, wherein X represents 0=0, R ¹ represents H, R ² has the above meaning, R has the above meaning and B, D, E and G have the meaning according to claim 1, with a compound of formula XII with the above meaning, wherein Ar ¹ has the meaning according to claim 1; (x) preparing compounds of formula I, wherein X represents CH ₂ , Y represents N ⁺ R ⁷ , Z represents OR ⁸ , R ⁸ and R ⁵ form a bond and R ¹ represents alkyl, by reacting a compound of formula XI with the above meaning, wherein X represents CH ₂ , R ¹ represents alkyl, R has the above meaning and B, D, E, G and R ² have the meaning according to claim 1, with a compound of formula XII with the above meaning, wherein Ar ¹ has the above meaning; (y) 'preparation of compounds of formula I, wherein X represents O=O, Y represents N, Z represents OR ⁸ , R ⁸ and R ⁵ form a bond and R ¹ represents alkyl, by reacting a compound of formula XI with the above meaning, wherein X represents O=O, R ¹ represents alkyl, R ² represents H or alkyl, R has the above meaning and B, D, E and G have the meaning according to claim 1, with a compound of formula XII with the above meaning, wherein Ar ¹ has the above meaning; (z) preparing compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ¹ and R ⁵ form a bond and R ² and R ³ form a bond, by oxidizing the corresponding compound of formula I, wherein 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 have the meaning according to claim 1; or (aa) preparing compounds of formula I, wherein X represents CR ³ R ^S , Y represents CR ¹⁸ , Z represents OH, R ² and R ³ represent H and R ¹ and R ⁵ form a bond, by reacting a compound of formula XII as defined above with a compound of formula XX: to OH 0 • A ₀ ' ^R M R6 R18 (XX)