AU712141B2 - Pharmaceutically useful compounds - Google Patents

Description

WO 97/34893 PCT/SE97/00471 1 PHARMACEUTICALLY USEFUL

COMPOUNDS

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

Certain pyrazolo[ 4 3 -c]isoquinolin-3-ones are known from J. Chem. Soc. 599 (1959) (Hinton et Their use as pharmaceuticals is not suggested. The synthesis and ability of certain pyrazolo[4,3-c]isoquinolin-3-ols to inhibit radioligand binding to benzodiazepine receptors has been detailed in J. Med. Chem. 35, 368 (1992) (Allen et Certain other pyrazolo[4,3-c]isoquinolin-3-ols are disclosed in Gaodeng Xuexiao Huaxue Xuebao 1991, 12, 1620-1622 (Qian Jian-hua et No pharmaceutical use of the compounds in question is mentioned.

It has now been found that 2 -arylpyrazolisoquinoline and cinnolinone derivatives exhibit anti-allergic 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 pharmaceutical: Ar 1

N-N

I/ z D B 1S 'G X "R 2

(I)

wherein: 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' 1

CR

3

R

6 or NR 4 Y represents N or NR 7 or CR 1 8 Z represents

OR

8 or O;

R

1 represents OH or C 1 6 alkyl, or with either R 2 or R 5 forms a bond; R- represents H, C1-6 alkyl (optionally substituted by phenyl, COOR 9

NRI'R'

OR

12 or F) or C3-7 cycloalkyl, or with either

R

3 or R 4 forms a bond:

R

3 represents H or a bond with R2;

R

4 represents Cl- 6 alkyl or a bond with R 2 WO 97/34893 PCT/SE97/00471 2

R

5 represents a bond with R' or R 8

R

6 represents H, Cl alkyl (optionally substituted by phenyl), C3- 7 cycloalkyl, phenyl, halogen,

CI-

6 alkoxy, C..

6 alkylthio, CI-6 alkylsulfinyl, cyano or NR3R 1 4;

R

7 represents C,-6 alkyl (optionally substituted by phenyl) or C3- 7 cycloalkyl, either of which may be optionally substituted by halogen, hydroxy, C -6 alkoxy,

C,-

6 alkylthio, CI-6 alkylsulfinyl,

NR

6 R1 7 COOH, COO(Ci_6 alkyl) or cyano; or R 6 and R 7 together represent C3- 5 alkylene, X and Y thereby forming a ring of 5-7 members;

R

8 represents H, Ci-6 alkyl or a bond with R 5

R

9 RiO, R 5 R 6 R, R and R' 8 independently represent C 6 alkyl or H;

R

1 3 and R' 4 are independently C,-6 alkyl, H or together with the nitrogen atom to which they are attached form a 3-7 membered saturated ring optionally containing a further oxygen atom or a nitrogen atom optionally substituted by Ci-6 alkyl; Ar' represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3 -quinolyl or 2 -quinoxalinyl, all of which are optionally substituted by one or more substituents selected from halo, nitro, cyano, phenyl, phenylsulfonyl, alkyl, C1- 6 alkoxy, CI-6 alkylthio, Cl 6 alkylsulfinyl, COOH, COO(C 1 alkyl), CI-6 alkyl substituted by phenyl, or phenyl, in which any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may optionally be substituted by fluoro; and A represents halo, cyano, amino, nitro, Ci-6 alkyl or C,-6 alkoxy; in which phenyl groups which are found in R 2

R

6

R

7 or as substituents on Ar' may be optionally substituted by C,-6 alkyl, halogen or C_-6 alkoxy; with the provisos that: when X represents C=O, C=S or C=NR' 5 then Y represents

N;

(ii) when R 4 represents a bond with R 2 then Y represents NR 7 (iii) when Y represents N R 7 then Z represents O0, R 2 represents a bond with R 3 or R 4 and R' and R 5 form a bond; (iv) when Y represents N, then Z represents

OR

8 when R' 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' 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 WO 97/34893 PCT/S97/ft471 3 (vii) when R' represents a bond with R 2 then R 5 and R 8 form a bond, and if 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 by any of NR'o°R, OR 1 2 or F, then the substituent and the ring nitrogen of Y may not be attached to the same carbon atom of R 2 when R 7 is substituted by any of NR 6 R17, OR 1 2 or halogen then the substituent and the ring nitrogen of Y may 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 lo (xii) when Y represents CR 1 8 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' does not represent unsubstituted phenyl, 4 -chlorophenyl, 4-fluorophenyl or 4 -methoxyphenyl.

Certain compounds of formula are novel. According to the invention there is further provided a compound of formula I: Ar 1

N-N

B z 1S II R' "G X YR2 (1) wherein: 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' 1

CR

3

R

6 or NR 4 Y represents N or N+R 7 orCR" 8 Z represents OR 8 or O-; R' represents OH or Ci-6 alkyl, or with either R 2 or R 5 forms a bond;

R

2 represents H, Ci_ 6 alkyl (optionally substituted by phenyl, COOR 9

NR'R",

OR

12 or F) or C3- 7 cycloalkyl, or with either R 3 or R 4 forms a bond; 3o R 3 represents H or a bond with R2;

R

4 represents Ci-6 alkyl or a bond with R 2

R

5 represents a bond with R' or R 8 WO 97/34893 PCT/SE97/00471 4 R 6 represents C 1 6 alkyl (optionally substituted by phenyl), C 3 7 cycloalkyl, phenyl. halogen. C 1 6 alkoxy, alkylthio, C 1 6 alkylsulfinyl, cyano or NR 13R":; R 7 represents C 1 6 alkyl (optionally substituted by phenyl sulbtiUted by a C 1 a~kylhalgenor C 1 6 alkoxry gr(xi) or C 3 7 cycloalicy, eitbher of wh-hra ect-aly ssttted by halog'en, 1ydroxY, C 1 6 a]JkDxy, CI- alkyithia. C 1 6 alkylsulfinyl, NR' 6

R

1 COOHK COO(C 1 4. alkyl1) or cyano; or R 6 and R 7 together represent C 3 5 alkvlene, X and Y thereby forming a ring of 5-7 members; 9 R 8 represents H, C 1 6 alkyl or a bond With R 5

*R

9

R'

0

R

1 1, Rl'. R1 5 Rl R 17and R1 8 independently represent Cj-. alkyl or H; *R1 3 and R 1 4 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 a further oxygen atom or a nitrogen atom optionaliv substituted by

C

1 6 alkylI.

Ar represents phenyl, pyridyl. pyrimidinyi, 2-benzothiazolyl, 2- or 3-quinolyl or *22-quinoxalinyl. all of which are optionally substituted by one or more :substituents selected from halo. nitro, cyano, phenyl, phenylsulfonyi, C 1 6 alkyl,

C

1 -6alkoxy, C 1 6 alkylthio. C 1 6 alkylsulfinyl, COOH. COO(C 1 6 alkyl), C 1 6 alkyl substituted by phenyl, or phenyl. in which any alkyl, alkoxy, alkvlthio and alky Isulfinvi g-roups may optionally be substituted by fluoro-, and A represents halo, cyano, amino, nitro, C 1 6 alkyl or C 1 6 alkoxy; ::in which phenyl groups which are found in R 2

R

6 or as substtets on Ar 1 mry be :~optionally substituted by C 1 4 alkyl. halogen or C 1 6 alkoxy;, with the provisos thatwhen X represents C=O, C=S or C=NR' 5 then Y represents N; 7; V. (ii) when R' represents a bond with R2, then Y represents N'R; (iii) when Y represents then Z represents R! represents a bond with Rj or R and R' and R 5 form a bond; (iv) when Y represents N, then Z represents OR 8 whtn R' represents OH, then X represents C=O, Y represents N, Z represents OR' an. R 5 represents a bond with R 8 (vi) when R' represents alkyl, then R 5 represents a bond with RS.. Y represents N, R 2 I does not represent a bond, and X does not represent NR", (vii) when R1 represents a bond with R2, then R3 and R 8 form a bond, and if X represents NR 4 then R represents alkyl; (viii) when R 6 represents arvi. halogen, alkoxy, thioalkyl. then R2 and R 3 form a bond; WO 97/34893 PCTSE97/00471 (ix) when Y represents N and R 2 is substiuted by any of NRR 1 1

CR

12 or F, then the substituent and the ring nitrogen of Y may not be attached to the same carbon atom of R 2 when R 7 is substituted by any of NR 6

R'

7

OR'

2 or halogen then the substiuent and the ring nitrogen of Y may 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"; (xii) when Y represents CR 1 8 then X represents CR R 6 with the further provisos that: when B, D, E and G all represent CH, X represents CHR 3 Y represents N, R' and R to form a bond. R 8 represents H and R- and R 3 together represent a bond, then Ar' does not represent unsubstituted phenyl. 4-chlorophenylorophen, -urophenyl or 4-methoxyphenyl; when B, D. E and G all represent CH. X represents CHR 3 Y represents NR R' and

R

5 form a bond. R 2 and R 3 represents a bond, R 3 represents H. and R' represents methyl, then Ar' does not represent unsubstituted phenyl; when B, D. E and G all represent CH. X represents CH:, Y represents N, R! and R form a bond, R 8 represents H, and R: represents isopropyl. then Ar' does not represent unsubstituted phenyl or 4-bromophenyl: and when B, D, E and G all represent CH, X and Y represent CH 2 and R' and R 5 form a t.v bond. then Ar' does not represent unsubstiruted phenyl.

or a pharmaceutically acceptable derivative thereof.

Preferably Ar t represents phenyl or pyridyl. most preferabiy phenyl. The phenyl group Ar' preferably has a substituent in the para position, more preferably a Cl, Br, CF 3

CF

5

OCF

3 *r 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.

a Preferably Y represents NR 7, and X represents CR 3

R

6 in which R 3 forms a bond with R: and R 6 represents alkyl. In such a case. R 6 preferably represents branched alkyl.

Alternatively, X may represent NR in which R 4 represents a bond with R 2 and Y represent

NTR

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

In the case where one of B, D. E and G represents N, preferably it is D or G that represents WO 97/34893 PCT/SE97/00471 6 Preferably R' represents a bond with R 2 or R s In such a case, R' preferably represents a bond with R 5 Particularly preferred compounds of the invention include those exemplified herein including the free form and all salts and solvates thereof.

Pharmaceutically acceptable derivatives includes solvates and salts. Particular salts which may be mentioned include 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 and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, for example chromatography or fractional crystallisation. The various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, for example fractional crystallisation or HPLC, techniques.

Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (for example HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

Alkyl groups which

R

2

R

4

R

6

R

7

R

8

R

9 R R RII, R R IR 4

RI

5

R

7 and R"' may represent or which may be substituted on one or more of the aromatic rings forming part of Ar' may be saturated or unsaturated, and straight chain or branched.

C

3 7 cycloalkyl, C1-6 alkoxy, Cl- alkylthio, C,4 alkylsulfinyl,

COO(C

1 6 alkyl) and C3alkylene are to be interpreted accordingly.

Accordi,;g to the invention there is also provided a process for the preparation of compounds of formula I which comprises: preparation of compounds of formula I where X represents

CH

2 or C=O, Y represents N, Z represents

OR

8

R

5 and R 8 form a bond and R' and R 2 form a bond by oxidation of a corresponding compound of formula I where R' and R 2 both represent

H

and B, D, E, G, X, Y, Z, Ar' and R 5 are as hereinbefore defined, for example at room WO 97/34893 PCT/SE97/00471 7 temperature using a suitable oxidising agent (for example manganese dioxide) and an appropriate organic solvent; preparation of compounds of formula I where one of B, D, E and G represents

CA

wherein A represents amino by reduction of a corresponding compound of formula

I,

S where 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', R 2 and R 5 are as hereinbefore defined, for example with iron powder and ammonium chloride in refluxing ethanol; preparation of compounds of formula I where one of B, D, E and G represents

CA

wherein A represents halo by diazotisation of a corresponding compound of formula

I,

where one of B, D, E and G represents CA wherein A represents amino and the remainder of B, D, E and G, and X, Y, Z, Ar',

R

2 and R 5 are as hereinbefore defined, and decomposition of the diazonium salt in the presence of the halide anion or (for fluorine) sodium tetrafluoroborate in dichlorobenzene at reflux; preparation of compounds of formula I where one of B, D, E and G represents

CA

wherein A represents cyano by reaction of a corresponding compound of formula

I,

where one of B, D, E and G represents CA wherein A represents bromo and the remainder of B, D, E and G, and X, Y, Z, Ar',

R

2 and R 5 are as hereinbefore defined, by reaction with copper(I) cyanide, for example at reflux in N-methylpyrrolidone; preparation of compounds of formula I where X represents

CR

3

R

6 Y represents

N'R

7 Z represents O, R 3 and R 2 form a bond, R' and R 5 form a bond and R 6 represents alkylthio by displacement reaction of a corresponding compound of formula I, where X represents

CR

3

R

6 wherein

R

6 represents methylthio or halogen and B, D, E, G, Y, Z, Ar', R 2

R

3 and R 5 are as hereinbefore defined, with a compound of formula

II:

R6a/

H

R S H(II) wherein

R

6a represents

C,,

6 alkyl, in the presence of a base, for example sodium hydride, in an appropriate solvent, for example

DMF;

preparation of compounds of formula I where X represents

CR

3

R

6 Y represents NR 7 Z represents

R

3 and R 2 form a bond, R' and R 5 form a bond and R 6 represents alkoxy by displacement reaction of a corresponding compound of formula

I,

where X represents

CR

3

R

6 wherein

R

6 represents methylthio or halogen and B, D, E, G, Y, Z, Ar 1

R

2

R

3 and R 5 are as hereinbefore defined, with a compound of formula

III:

WO 97/34893 PCT/SE97/00471 8 R6a/' H (111) wherein R 6a is as hereinbefore defined, in the presence of a base, for example sodium hydride, in an appropriate solvent, for example, DMF; preparation of compounds of formula I where X represents CR 3

R

6 Y represents

NR

7 Z represents O0, R 3 and R 2 form a bond, R' and R s form a bond and R 6 represents

NR

13

R'

4 by displacement reaction of a corresponding compound of formula I, where X represents

CR

3

R

6 wherein

R

6 represents methylthio or halogen and B, D, E, G, Y, Z, Ar', R 2

R

3 and R 5 are as hereinbefore defined, with a compound of formula IV:

R

13

H

S

1

(IV)

wherein R 13 and R' 4 are as hereinbefore defined, in the presence of a base, for example sodium hydrogen carbonate, in an appropriate solvent, for example, DMF at 100 °C; preparation of compounds of formula I where X represents CR 3

R

6 Y represents

N'R

7 Z represents O, R 3 and R 2 form a bond, R' and R 5 form a bond and R 6 represents methylthio by reaction of a corresponding compound of formula I, where X represents C=S, Y represents N, Z represents OH and B, D, E, G, Ar', R 2 and R are as hereinbefore defined, with a methylating agent, for example, methyl iodide, for example neat at reflux; preparation of compounds of formula I where X represents C=S, Y represents N, Z represents OH and R' represents a bond with R 5 by reaction of a corresponding compound of formula I, where X represents C=O and B, D, E, G, Y, Z, Ar', R 2 and R 5 are as hereinbefore defined, by thionation, for example using Lawesson's reagent in an appropriate solvent, for example dioxane at reflux; preparation of compounds of formula I where X represents

CR

3

R

6 Y represents

N+R

7 Z represents 0- and R 6 represents halogen by reaction of a corresponding compound of formula I, where 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' and R 2 are as hereinbefore defined, by halogenation, for example with a phosphorus oxyhalide, for example neat at 100 °C; preparation of compounds of formula I where X represents

CR

3

R

6 Y represents

N'R

7 Z represents

R

3 and R 2 form a bond, R' and R 5 form a bond and R 6 represents alkyl by reaction of a corresponding compound of formula I, where X represents C=O, Y represents N, Z represents OH, R' represents a bond with R 5 B, D, WO 97/34893 PCT/SE97/00471 9 E, G, and Ar' are as hereinbefore defined and R 2 represents a group corresponding to

R

7 as hereinbefore defined, by reaction with a nucleophilic alkylating reagent, for example a compound of formula

V:

R ,Mg Hal

(V)

wherein

R

6 is as hereinbefore defined and Hal represents halogen, for example in the presence of a copper salt, for example copper(I) bromide in an appropriate solvent, for example dimethoxyethane, for example at reflux; preparation of compounds of formula I where X represents

CR

3

R

6 Y represents

N*R

7 Z represents O0, R 3 and R 2 form a bond, R' and R 5 form a bond and R 6 represents alkyl by reaction of a corresponding compound of formula I, where X represents

CR

3

R

6 wherein

R

6 represents H and B, D, E, G, Y, Z, Ar', R 1

R

2 and R are as hereinbefore defined, with a nucleophilic alkylating reagent, for example a compound of formula V as hereinbefore defined in an appropriate solvent, for example THF, for example at 0 °C; preparation of compounds of formula I where X represents C=O, Y represents

N,

Z represents

OR

8 R' represents a bond with R 5 and R 8 represents alkyl by reaction of a corresponding compound of formula I, where Z represents

OR

8 wherein R 8 represents H and B, D, E, G, X, Y, Ar',

R

2 and R 5 are as hereinbefore defined, with a compound of formula

VI:

R'Hal

(VI)

wherein

R

8 and Hal are as hereinbefore defined, for example in the presence of a base, for example sodium hydride, in an appropriate solvent, for example

DMF;

preparation of compounds of formula I where R' represents OH, X represents C=O, Y represents N, Z represents

OR

8 and R 5 represents a bond with R 8 by reaction of a corresponding compound of formula I, where Z represents R' and R 5 form a bond and B, D, E, G, X, Y, Arl and R 2 are as hereinbefore defined, by treatment with an oxidising agent, for example ceric ammonium nitrate, in an appropriate solvent, for example acetonitrile, for example at ambient temperature; preparation of compounds of formula I where X represents

CR

3

R

6 Y represents

N'R

7 Z represents O0, R 3 and R 2 form a bond and R' and R 5 form a bond by reaction of a corresponding compound of formula I, where Y represents N, Z represents

OH

WO 97/34893 DP 'I /nn i

UU/

and B D, E, G, X, Ar',

R

2 and R 5 are as hereinbefore defined, with a compound of formula IX: R'Hal

(IX)

wherein

R

7 and Hal are as hereinbefore defined and a base, for example sodium hydride, in an appropriate solvent, for example DMF, for example at ambient temperature; preparation of compounds of formula I where X represents C=O, R 2 does not 0o represent H, Y represents N, Z represents OH and R 1 represents a bond with R- by reaction of a corresponding compound of formula I, where R 2 represents H and B, D, E, G, X, Y, Z, Ar', R' and R 5 are as hereinbefore defined, with a base, for example sodium hydride, and a compound of formula

VII:

R

2 Hal

(VII)

wherein R not representing H, and Hal are as hereinbefore defined, in an appropriate solvent, for example DMF, for example at ambient temperature; preparation of compounds of formula I where B, D, E and G represent CH or CA, X represents

NR

4 Y represents

N+R

7 Z represents 0, R 4 and R 2 form a bond and R 1 and R 5 form a bond by reaction of a compound of formula

VII:

Ar' A O

N/N

H

(VIII)

wherein A and Ar' are as hereinbefore defined, with a base, for example sodium hydride, and a compound of formula IX as hereinbefore defined, in an appropriate solvent, for example DMF, for example at ambient temperature; preparation of compounds of formula I where B, D, E and G represent CH or CA, X represents

NR

4 Y represents N, Z represents

OR

8

R

2 and R' form a bond and R and R 8 form a bond by reaction of a compound of formula VIII as hereinbefore defined with a base, for example sodium hydride, and a compound of formula

X:

WO 97/34893 PCT-rI Q7/n471 11 R'Hal

(X)

wherein R 4 and Hal are as hereinbefore defined, in an appropriate solvent, for example DMF, for example at ambient temperature; preparation of compounds of formula I where X represents

CR

3

R

6 Y represents

N,

Z represents OH, R 3 and R 2 form a bond and R' represents a bond with R 5 by treatment of a corresponding compound of formula I. where Y represents

N"R

7

Z

represents 0, R 7 represents

CH

2

C

6 HaOalkyl and B, D. E, G, X. Ar 1 and R 5 are as hereinbefore defined, with an acid. for example trifluoroacetic acid, for example at reflux; preparation of compounds of formula I where X represents CR3R 6 Y represents

N,

Z represents OH. R 3 and R: form a bond and R' represents a bond with R 5 by treatment of a corresponding compound of formula I, where Y represents

NR

7

Z

represents R' represents CH 2 phenyl substituted by C 1 6 alkyl or C6 i alkoxy, and B, D, E, G, X. Ar', R 2 and R 5 are as hereinbefore defined, with hydrogen in the presence of a catalyst, for example palladium on carbon; preparation of compounds of formula I where X represents C=O. Y represents N, Z represents OH. R' represents H and R' represents a bond with R 5 by treatment of a corresponding compound of formula I, where Y represents N-R. Z represents

R'

represents CH2C 6 HaOalkyl and B. D, E. G, X. Ar 1

R

1

R

2 and R 5 are as hereinbefore defined, with an acid, for example trifluoroacetic acid. for example at reflux: preparation of compounds of formula I where X represents CR'R', Y represents :N

R

7 Z represents 0O, R and R- form a bond, R' and R 5 form a bond and R' represents H by reaction of a compound of formula XI: 0 D/8 COOR G X R

(XI)

where X represents CH 2 R' represents H. R 2 represents a group corresponding to R' as hereinbefore defined in the compound of formula I. B, D, E and G are as hereinbefore defined and R is alkyl, with a compound of formula XII: Ar'NHNH (XII) WO 97/34893 PCT/SE97/00471 12 wherein Ar' is as hereinbefore defined, for example in xylene at reflux; preparation of compounds of formula I where X represents C=O, R 2 does not represent H, Y represents N, Z represents OH and R' represents a bond with R 5 by reaction of a compound of formula XI as hereinbefore defined, where X represents C=O, R' represents H, R 2 is as hereinbefore defined and B, D, E, G and R are as hereinbefore defined, with a compound of formula XII as hereinbefore defined, wherein Ar' is as hereinbefore defined, for example in xylene at reflux; preparation of compounds of formula I where X represents

CH

2 Y represents N, Z t0 represents

OR

8

R

8 and R 5 form a bond and R' represents alkyl by reaction of a compound of formula XI as hereinbefore defined, where X represents

CH

2

R'

represents alkyl and B, D, E, G, R 2 and R are as hereinbefore defined, with a compound of formula XII as hereinbefore defined, wherein Ar' is as hereinbefore defined, for example in xylene at reflux; or preparation of compounds of formula I where X represents C=O, Y represents N, Z represents

OR

8

R

8 and R 5 form a bond and R' represents alkyl by reaction of a compound of formula XI as hereinbefore defined, where X represents C=O, R 1 represents alkyl, R 2 represents H or alkyl, and B, D, E, G and R are as hereinbefore defined, with a compound of formula XII as hereinbefore defined, wherein Ar' is as hereinbefore defined, for example in xylene at reflux; preparation of compounds of formula I where X represents CR R 6 Y represents

CR

8 Z represents OH, R' and R 5 form a bond and R 2 and R 3 form a bond by oxidation of a corresponding compound of formula I where X represents

CR

3

R

6 Y represents CR 8 Z represents OH, R 2 and R 3 represent H, R' and R form a bond and B, D, E, G, Ar', R and R 18 are as hereinbefore defined; or (aa) preparation of compounds of formula I where X represents

CR

3

R

6 Y represents CR 8 Z represents OH, R 2 and R 3 represent H and R' and R 5 form a bond by reaction a compound of formula XII as hereinbefore defined with a compound of formula

XX:

OH O IB

O/R

E 0 E'G

R

1 8

R

6

(XX)

wherein B, D, E, G, R 6

R

18 and R are as hereinbefore defined.

WO 97/34893 PCT/SE97/00471 13 Compounds of formula I, wherein X represents

CHR

3 R and R 3 together represent a bond, R' and R s form a bond and either: Y represents N R 7 and Z represents or Y represents N, and Z represents

OH,

may be prepared analogously to the methods described in J. Med. Chem. 35, 368 (1992).

Compounds of formula VIII are known from European Patent Application No.

EP-A-187551, or may be prepared analogously to the methods described therein.

Compounds of formula XI may be prepared by reaction of a compound of formula

XIII:

DE G R 2 S XN COOR

COOR'

wherein B, D, E, G, R, R 2 and X are as hereinbefore defined 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 wherein X represents C=O and R 2 represents H are known from Japanese Examined Patent Publication No. JP-B-82 54,152 or may prepared analogously to the methods described therein.

Compounds of formula XII, where X represents C=O, may be prepared by reaction of a compound of formula

XVI:

8 COOH E. N. COOR 0

(XVI)

wherein B, D, E, G, R and R are as hereinbefore defined, by alkylation, for example with a compound of formula

XVII:

(XVII)

wherein R' is as hereinbefore defined, in the presence of a base, for example potassium carbonate, for example in acetone at 50 OC.

Compounds of formula XIII, where X represents

CH

2 may be prepared by reaction of a compound of formula

XIV:

WO 97/34893 PCT/SE97/00471 14 DB COOR D N EGI Br

(XIV)

wherein B, D, E, G and R are as hereinbefore defined, with a compound of formula

XV:

R

1 N "COOR'

H

2 (XV) S wherein R and R' are as hereinbefore defined, in the presence of a base for example triethylamine, in an appropriate solvent, for example ether at reflux.

Compounds of formula XIV may be prepared by reaction of a compound of formula

XVIII:

D"B COOR

E

G (XVIII) wherein B, D, E, G and R are as hereinbefore defined with a brominating agent, for example NBS, for example in dichloroethane at reflux with photolytic irradiation.

Compounds of formula XVI may be prepared by reaction of a compound of formula

XIX:

0B

D

11 0

E

G

O 0

(XIX)

wherein B, D, E and G are as hereinbefore defined, with a compound of formula XV as hereinbefore defined, wherein

R

2 and R' are as hereinbefore defined, in an appropriate solvent, for example acetone at 50 °C.

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

It will be appreciated by those skilled in the art that in the process steps described above the functional groups of intermediate compounds may need to be protected by protecting groups.

The protection of functional groups may take place before any the process steps hereinbefore described. For example the nitrogen atom of compounds of formula XI, XIII and XVI may WO 97/34893 PCT/SE97/00471 be protected before further reaction using a suitable protecting group, for example a benzyl group or preferably a 4 -methoxyphenylmethyl group. Protecting groups may be removed following a reaction step or at the end of the reaction process using techniques which are well known to those skilled in the art (for example acid hydrolysis).

The compounds of the invention are useful possess pharmacological activity and are therefore indicated as pharmaceuticals useful in therapy.

According to the invention there is further provided a compound of formula I as .o hereinbefore defined, but without proviso for use as a pharmaceutical.

In particular the compounds of the invention possess antiallergic and anti-inflammatory activity, for example as shown in the tests described below. The compounds of the invention are thus indicated for use in the treatment of allergic and inflammatory diseases is of the airways such as asthma (for example bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example late asthma and airway hyper-responsiveness), bronchitis and the like.

Further, the compounds of the invention are indicated in the treatment of diseases including inflammations/allergies such as rhinitis, including all conditions characterised by inflammation of the nasal mucus membrane, 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, scrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis.

The compounds of the invention are also indicated for use in the treatment of chronic allergic disorders, atopic dermatitis, cutaneous eosinophilias, eosinophilic fascitis, hyper IgE syndrome, vernal conjunctivitis, systemic lupus erythematosis, thyroiditis, lepromatous leprosy, sezary syndrome, chronic graft versus host disease, myasthenia gravis, idiopathic thrombocytopenia pupura and the like.

The compounds of the invention may also have activity in both the prophylactic and therapeutic treatment of acquired immunodeficiency syndrome (AIDS), the prevention of chronic rejection of allografts mediated by humoral immunity, and in the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

WO 97/34893 PCT/SE97/00471 16 Of particular interest amongst the above indications are the use of the compounds of the invention in asthma, especially the prophylaxis of asthma, and in rhinitis, most particularly allergic rhinitis and seasonal rhinitis including rhinitis nervosa (hay fever).

According to a further aspect of the present invention, there is provided a method of treatment or prophylaxis of an allergic or an inflammatory disorder, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined above, but without provisos or or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to such a disease.

Administration of the compounds of the invention may be topical (for example by inhalation to the lung). The compounds of the invention may be inhaled as a dry powder which may be pressurised or non-pressurised.

Is In non-pressurised powder compositions, the active ingredient in finely divided form may be used in admixture with a larger sized pharmaceutically acceptable inert carrier The composition may alternatively be pressurised and contain a compressed gas, for example nitrogen, or a liquefied gas propellant. In such pressurised compositions, the active ingredient is preferably finely divided. The pressurised composition may also contain a surface active agent. The pressurised compositions may be made by conventional methods.

The compounds of the invention may be administered systemically (for example by oral administration to the gastrointestinal tract). The active ingredient may be formulated together with known adjuvants, diluents or carriers using conventional techniques to produce 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, a sugar such as lactose, dextrose or mantel, talc, stearic acid, starch, sodium bicarbonate and/or gelatine.

According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I as hereinbefore defined, but without proviso or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant diluent or carrier.

WO 97 34893 PCT/SE97/00471 17 Suitable doses for administration topical or orally are in the range 0.01 to 30 mg kg-' dayfor example 0.3 mg kg' day It will be understood by those skilled in the art that certain functional groups in the compounds of the invention may be protected using appropriate protecting groups to form "protected derivatives" of the compounds of the invention. It will also be appreciated that, although such protected derivatives may not possess pharmacological activity as such, they may be administered and thereafter metabolised in the body to form the compound of the invention which is pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds of formula I are included within the scope of the invention.

The invention is illustrated by the following examples.

General Notes: Column chromatography was run on silica (35-70gM) under gas pressure, typically bar. The following hydrazines were used as intermediates in the subsequent 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 Chem. Soc. 1971, 3257) (3.61 g) in water (6 ml) and concentrated hydrochloric acid (1 ml) whilst maintaining the temperature below 5 The mixture was stirred at 0 oC for 15 minutes then further cooled to -10 A solution of tin(II)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 slurry was formed.

The slurry was stirred with ethyl acetate and the organic phase was decanted and evaporated to an oil. The slurry was then diluted with water and extracted with dichloromethane (thrice). The organic phase was dried over sodium sulphate, filtered and evaporated then combined with the oil above. Purification by column chromatography eluting with dichloromethane methanol (20:1) gave the title compound as a beige solid (0.09 m.p. 68-70 °C IH NMR (CDC13) 5 2.47 (3H, 3.60 (2H, br 5.13 (1H, br 7.03 (1H, 7.12 (1H, dd), 8.12 (1H, d).

WO 97/34893 PCT/SE97/00471 18 4 -(Pentafluoroethyl)phenyl hydrazine Prepared following the method used for 5-Hydrazino-2-methylpyri dine using 4 -(penta.

fluoroethyl)aniline Chem. Soc., Perkin Trans. 1, 1990, 2293). MS (El) 226 11 NMR (CDCI 3 8 4.15 (2H, br), 6.87 (2H4, 7.30 (2H, 7.45 (11-H, br) 2 -Hydrazino-5-methylpyridine Org. Chem., 1966, 31, 25 1) 2 -Chloro-5-hydrazinopyridine (Atti R. Accad. dei Lincei, Roma, 1925, 2, 125); Chem.

Zent. 1926, L, 672 2 -Hydrazinopyrimidine J. Chem. Soc. 1955, 3478 Example 1 3 -Hydroxy4[(4.ethoxypheny)methyl] 2 4 tifluooehlhnl-f-yaoo 4 3 -cjisoquinouinium hydroxide, inner salt Methyl 2 -[N(xethoxycarbonymethyl) moypehy)mtyainlehbnzt.

Methyl 2 -brornomethylbenzoate (23.47 g; prepared analogously to the method described for the ethyl ester in J. Med Chem., 1992, 35, 368) and triethylamine (15.7 ml) were dissolved in dry diethyl ether (200 ml) under a nitrogen atmosphere. Methyl

N+[

4 -methoxyphenyI)methyl] glycinate (23.6 g; J. Am. Chem. Soc., 1993, 115, 536) was added dropwise. The mixture was heated under 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 (thrice). The combined organic phase was washed with brine and dried over sodium sulfate. Filtration and evaporation of the solution followed by further purification of the residues by column chromatography, eluting with ethyl acetate: isohexane gave the subtitle compound as an oil (27.85 g); MS(APCI) 358 'H NMR (CDCI 3 8 3.23 (2H, 3.66 (3H1, 3.71 (2H, 3.78 (3H, 3.88 (31, 4.16 (2H4, 6.8 (2H, 7.2 (2H, 7.3 (1IH, td), 7.45 (1 H, td), 7.6 (1 H, dd), 7.75 (1IH, dd).- Methyl 1,,,-erhdo2(-ehxpeylmty--x--sqioieab oxylate Mehl2[-mtoyabnlehl--4mtoyhnlmty~mn~ehl benzoate (27.85 g; from step above) was dissolved in dry toluene (150 ml) and added WO 97/34893 PCT/SE97/00471 19 dropwise to a refluxing suspension of oil-free sodium hydride (from 4 .37g of 60% sodium hydride) in dry toluene (300 ml) and 2 -methylpropan-2-ol (2.0 ml). The heating was continued for 12 hours. The mixture was allowed to cool to room temperature and was then poured onto saturated ammonium chloride solution and extracted with ethyl acetate (thrice). 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 gave the subtitle compound as an oil (20.41 g).

1H NMR (CDC13) (major component--enol tautomer) 6 3.60 (2H, 3.81 (3H, 3.91 6.86 (2H, 7.09 (IH, 7.25 (2H, 7.35-7.43 (2H, 7.77 (1H, d) and 11.58 (1H, s).

(c) 3-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2Hpyrazoio- 4 3 -c]isoquinolinium hydroxide, inner salt Methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenyl)methyl-4-oxo-3-isoquinolinecarboxylate g; from step above), 4-(trifluoromethyl)phenylhydrazine (1.08 g) and a catalytic amount of 4 -toluenesulfonic acid were fused together at 150 °C for 10 minutes. Xylene ml) was then added and heating was continued for a further 1 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 m.p. 220-221

'C

MS(APCI) 450 'H NMR (d 6 -DMSO) 6 3.72 (3H, 6.08 (2H, 6.95 (2H, 7.7 (2H, 7.8 (3H, m), 7.95 (1H, td), 8.15 (1H, 8.35 (1H, 8.6 (2H, 8.96 (1H, s).

WO 97/34893 PCT/SE97/00471 Example 2 2 4 -Trifluoromethylphenyl).2Hpyrazolo[4,3.c]isoquinolin 3 ol 3 -Hydroxy-4[(4methoxyphenyl)methyl] 2(4t-rilurifluthylhl)-2-przo 4 ,3-clisoquinolinium hydroxide, inner salt (0.26 g; from step above) was heated at reflux in trifluoroacetic acid (2 ml) under a nitrogen atmosphere 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 and evaporated and the red residue was triturated with ethyl acetate. Recrystallisation from ethanol gave the title compound as a red solid (14 mg). m.p. >250 OC MS (APCI) 330 'H NMR (d 6 -DMSO) 5 7.9 (31, in), 8.0 (lIH, 8.3 (4H, in), 9.03 (111, bs).

Example 3 2 4 -Chlorophenyl)2,S.dihydro.5methyl.3Hpyrazolo[ 4 3 ccini 3 -oe 2 4 -Chlorophenyl)2,sdhydropyrzolo[43c]cinnolin- 3 -one (0.33 g; European Patent Application EP-A-0 187551) was added portionwise to a stirred suspension of oil free sodium hydride (from 49 mg of 60% dispersion) in dry dimethylformarnide (5 ml) under a nitrogen atmosphere. lodomethane (0.076 ml) was added dropwise after 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 (thrice). The organic phase was washed with 2M hydrochloric acid and brine, and then dried over sodium sulfate, filtered and concentrated to give a red solid. Purification by column chromatography (3:2 ethyl acetate hexane), followed by recrystallisation from dimethylformamide, gave the title compound as red crystals (55 mg).

m.p. >250 aC MS(EI) 310, 312 'H NMR (CDC1 3 8 4.33 (3H, 7.4 (2H, dd), 7.65 (211, 7.75 (1 H, td), 8.20 (2H, dd), 8.3 5 (1IH, d).

Example 4 2 4 Chlorophenyl)2,3a,4,5tetrahydro.3a4dimethylpyl[ 4 3 cisounln one Methyl -methoxycarbonyl)ethyl)methylaminolmethyI benzoate Methyl 2 -bromomethylbenzoate (3.51 g) and diisopropylethylamijne (5.86 ml) were dissolved in dry diethyl ether (30 ml) under a nitrogen atmosphere and the solution was cooled to 0 IC. N-methylalanine methyl ester trifluoroacetic acid salt (3.89 g) dissolved in WO 97/34893 PCT/SE97/00471 21 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 separated, washed with brine and dried over sodium sulfate. Filtration and evaporation followed by column chromatography (1:9 ethyl acetate hexane) gave the subtitle compound (2.87 g).

MS (EI) 265 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 60% dispersion) in dry toluene (30 ml) and 2 -methyl-2-propanol (5 drops) under a nitrogen atmosphere. After being heated at reflux for 45 minutes the solution was cooled in ice and poured into saturated ammonium chloride solution which was extracted with ethyl acetate (thrice). The organic phase was washed with brine and dried over sodium sulfate. Filtration and evaporation followed by column chromatography (1:4 ethyl acetate hexane) gave the subtitle compound as a yellow oil (0.95 g).

MS (EI) 234 2 4 -Chlorophenyl)-2,3a,4,5-tetrahydro-3a,4-dimethylpyrazolo[ 4 ,3-c]isoquinolin- 3 -one Methyl 1,2,3,4-tetrahydro-23-dimethyl-4-oxo-3-isoquinolinecarboxylate (0.84 g), 4 -chlorophenylhydrazine (1.54 g) and 4 -toluenesulfonic acid (20 mg) were fused together at 150 'C for 10 minutes under a nitrogen atmosphere. Xylene (10 ml) was then added and the mixture was heated at 150 °C a further 6 hours. After cooling to room temperature the solvent was removed and the residue was dissolved in dichloromethane/methanol. The solution was washed with 2M hydrochloric acid and brine, then dried over sodium sulfate.

Filtration and evaporation followed by column chromatography (1:99 methanol dichloromethane) gave the title compound as a colourless solid (50 mg).

m.p. 128-129 oC.

MS (El) 325, 327 (M WO 97/34893 PCT/SE97/00471 22 Example 2-( 4 -Chlorophenyl)-3a,4-dihydro-3a,4-dimethyl-2Hpyrazolo[4,3.c]isoquinoline- Methyl l,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxo-3-isoquinolinecarboxylate Methyl 1, 2 -dihydro-4-hydroxy-2-methyl-l-oxo- 3 -isoquinoline carboxylate (JP-B-82 54,152; 1.5 g) in dry dimethylformamide (5 ml) was added dropwise to a stirred suspension of oil free sodium hydride (from 0.28g 60% dispersion) in dry dimethylformamide (10 ml) at room temperature under a nitrogen atmosphere. After minutes, iodomethane (0.4 ml) was added dropwise. The solution was stirred at room 0o temperature for 3 hours, then poured into 2M hydrochloric acid and extracted with ethyl acetate (thrice). The organic phase was washed with brine and dried over sodium sulfate.

Filtration and evaporation followed by column chromatography (1:1 diethyl ether: hexane) gave the subtitle compound as a yellow oil (0.53 g).

MS (ESI) 248 2 4 -Chlorophenyl)-3a4-dihydro-3a,4-dimethyl2Hpyrazolo4,3-c]isoquinoline Methyl 1,2,3, 4 -tetrahydro-2,3-dimethyl-1,4-dioxo-3-isoquinolinecarboxylate (0.53 g), 4 -chlorophenylhydrazine (0.92 g) and 4 -toluenesulfonic acid (10 mg) were fused together at 150 'C under a nitrogen atmosphere for 10 minutes. Xylene (5 ml) was then added and the mixture was heated at 150 °C for 10 hours. After cooling to room temperature the solvent was removed and the residue dissolved in dichloromethane/methanol, was washed with 2M hydrochloric acid, sodium bicarbonate solution and brine. The solution was dried over sodium sulfate, filtered and evaporated. Purification by column chromatography (1:9 ethyl acetate hexane) followed by recrystallisation from propan-2-ol gave the title compound as a beige solid (0.13 m.p. 192-193

°C

MS (EI) 339, 341 Example 6 2-( 4 -Chlorophenyl)-2, 4 -dihydro-3-hydroxy-4-methylpyrazoo[ 4 Methyl 1,2-dihydro-4-hydroxy-2-methyl- 1-oxo-3-isoquinolinecarboxylate (JP 82 54,152; 4 -chlorophenylhydrazine (0.91 g) and 4 -toluenesulfonic acid (10 mg) were fused together at 150 °C for 10 minutes under a nitrogen atmosphere. Xylene (5 ml) was then added and the mixture heated at 150 OC for 5 hours. After cooling to room temperature a yellow precipitate was collected by filtration and washed with diethyl ether. Purification by

M

WO 97/34893 PCT/SE97/00471 23 column chromatography (1:49 methanol dichioromethane) followed by recrystallisation from ethanol gave the title compound as a beige solid 1 m.p. >250'C MS (El) 325, 327 (M Example 7 3-yrx--(-ehxpey~ehl--3qioy)2-yaoo43cio quinolinium hydroxide, inner salt.

The title compound was prepared according to the method described in Example 1 using 3-hydrazinoquinoline. m.p. 232-233 *C.

MIS (APCI) 433 NMR (d 6 -DMSO) 5 3.7 (3H, 6.1 (2H, 6.7 (2H, 7.65 (1H, 7.70 (3H, in), 7.80 (IH, 8.05 (3H, in), 8.20 (IH4, 8.40 (lH, 9.00 (IH, 9.20 (IH, 9.90 (1H, d).

Example 8 2 3 -Quinolyl)-2H-pyrazolo[4,3.c]isoqunoil.3.

0 The title compound (0.21 g) was prepared according to the method described in Example 2 using 3 -hydroxy-4[(4methoxyphenyl)methyl-2(3quinoly)2flpyrazolo [4,3-c]isoquinolinium hydroxide, inner salt (0.66 m.p. 247-248 'C MS (APCI) 313 4 'H NMR (d,-DMSO) 8 7.70 (1H, td), 7.80 (11H, td), 7.90 (1H, bt), 8.00 (1H, 8.15 (211, mn), 8.35 (211, in), 8.90 (1lH, 9.05 (1 9.70 (1IH, 12.20 (1IH, bs) Example 9 2 3 4 Dichlorophenyl).3 hoydrox4-methoheylphenyljmtHlI..

2 H.lo[4,isoquinolinium hydroxide, inner salt The title compound was prepared according to the method described in Example 1 using 3 4 -dichlorophenylhydrazine. m.p. 239-240 'C MS (APCI) 448, 450, 452 'H NMR (d 6 -DMSO): 8 3.72 (3H, 6.06 (2H, 6.96 7.70 (3H, in), 7.79 (1IH, t), 7.97 (111, 8.16 (IH, 8.37 (2H, in), 8.72 (1H, 8.97 (1H, s).

Example 2 3 4 Dichlorophenyl)2H-.pyrazolo[4,3..c~isoquinolin.

3 -oI The title compound (0.028 g) was prepared according to the method described in Example 2 using, 2-34dclrpey)3hdoy4[4mtoyhnlmty]2-yaoo 4 3 -c]isoquinoliniuin hydroxide, inner salt (0.26 m.p. >230 'C.

WO 97/34893 PCT/SE97/00471 24 MS (APCI) 330, 332, 334 'H NMR (d,-DMSO) 6 7.82 (1 H, 7.86 (1 H, 7.97 (1IH, 8.13 (1iH, dd), 8.24 (1 H, d), 8.32 (1 H, 8.42 (11-H, 8.94 (1IH, s).

Example 11 '-Biphenyl]-4-yl)-2Hpyrazoo[4,3c~isoquinolin- 3 .o -ihnl--l--yrx--(-mtoyhnlmty]2-yaoo [4,3-c]isoquinolinium hydroxide, inner salt The sub-title compound was prepared according to the method described in Example I1(c) using [I,lI-biphenyJ-4-ylhydrazine (see J. Chem. Soc., Perkin Trans. 1, (1975) 1280).

'-Biphenyl]-4.yl)-2Hpyrazoo[43.cisoquinoin 3 oI The title compound (0.082 g) was prepared according to the method described in Example 2 using 1,1 -ihnl--l--yrx--(-mtoyhnlmty]2-yaoo 's 4 3 -clisoquinolinium hydroxide, inner salt (0.29 g; from step above).

m.p. >220' (dec.).

MS (APCI) 338 'H NMR (d 6 -DMSO) 6 7.37 (1IH, in), 7.51 (2H, in), 7.75 (2H, mn), 7.89 (311, in), 7.98 (1IH, mn), 8.05 (2H, in), 8.31 (2H, mn), 9.02 (1IH, s, br) Example 12 3 -Hydrox-4[(4methoxyphenymethyI..2-( meth yl)H-y..H.l[ 4 3 isoquinolinium hydroxide, inner salt The title compound was prepared according to the method described in Example 1 using 4 -methylphenylhydrazine.

m.p. >100'C (dec.) MS (APCI) 396 'H NMR (d 6 -DMSO) 6 2.34 (3H4, 3.72 (3H, 6.10 (211, 6.96 (2H, mn), 7.26 (2H, mn), 7.74 (3H, in), 7.94 (lH, in), 8.13 (1H, 8.23 (2H1, d) 8.33 (1H, 8.89 (111, s) Example 13 2 4 -Methylphenyl)-2Hpyrazolo[4,3-c]isoquinolin- 3 oI The title compound (0.043 g) was prepared according to the method described in Example 2 using 3-hydroxy-4- 4 -methoxyphenyl)iethyl2(4meffiypheny)2Hpyrzolo[ 4 3 -c] isoquinolinium hydroxide, inner salt (0.20 m.p. 202-209 'C (dec.).

MS (APCI) 276 WO 97/34893 PCT/SE97/00471 'H NMR (d 6 -DMSO) 5 2.37 (3H1, 7.37 (211, 7.88 (3H, in), 7.94 (11H, in), 8.29 (2H1, in), 9.02 (1 H, br), 11.90 (1 H, br) Example 14 2 4 Bromopheny).3hydroxy.[4m(4..mpehoypehymetHpyrazHp[ 4 3 ]is quinolinium hydroxide, inner salt The title compound was prepared according to the method described in Example 1 using 4-bromophenylhydrazine. m.p. >220 'C (dec.).

MIS (APCI) 460, 462 'H NMR (d 6 -DMSO) 8 3.70 (3H, 6.08 (2H, 6.96 (2H4, mn), 7.66 (2H4, in), 7.76 (2H, in), 7.77 (114, 7.96 (lH, in), 8.15 (lH, 8.36 (3H, in), 8.94 (1H, s) Example 2 4 -Bromopheny1)..2Hpyrazolo[4,3..clisoquinolin 3 oI The title compound (0.053 g) was prepared according to the method described in Example 2 using 2 4 -bromophenyl)3hydroxy4[(4methoxyphenyl)inethyl] 2H-priol[43] isoquinolinium hydroxide, inner salt 164 gm.p. 250 'C.

MS (APCI) 340, 342 'H NMR (d 6 -DMSO) 587.76 (2H, 7.89 (1H, in), 8.02 (3H4, in), 8.31 (2H, in), 9.07 (IH, br), 11.92 (1H, br) Example 16 2 3 -TrifluoromethylphenyI)..3.hydroxy-4-[(4-methoxyphenyl)mthyI] 2Hpyao- 4 3 -clisoquinoliniurn hydroxide, inner salt The title compound was prepared according to the method described in Example 1 using 3 -trifluoroinethylphenylhydrazine to give an oil which was purified twice by chromatography, eluting the first time with ethyl acetate and the second time with ether: ethyl acetate mixtures, to give the title compound as an oil.

MS (APCI) 450 'H NMR (CDCl,) 8 3.81 (3H, 6.19 (2H, 6.96 (214, 7.45 (1 H, in), 7.54 (3H, in), 7.79 in), 7.86 (IH, 8.52 (111, 8.68 (IH, 8.72 (114, s)

I

WO 97/34893 PCT/SE97/00471 26 Example 17 2 3 -Trifluoromethylphenyl)>2H-pyrazolo[4,3..clisoquinolin.

3 -oI The title compound was prepared according to the method described in Example 2 using 2 3 trifluoromethypheny3-yroydroy4methoxeyphyl]metH-prl] 2 Hl -c] isoquinolinium hydroxide, inner salt. m.p. 250 'C dec.

MS (APCI) 330 'H NMR (d 6 -DMSO) 8 7.67 (1WH, 7.81 (1IH, 7.88 (1 H, 7.99 (1IH, 8.42 (3H, in), 8.48 (1WH, 9.01 (1IH, s) Example 18 2-[ 4 (,l-DimethylethyphenyI].2Hpyrazolo[4,3..c]isoquinolin.

3 -oI 3-Hydroxy-2-4.(.,1 -dimethylethyl)pheny]4-[(4-methoxyphenyI)methyl]- 2

H-

-pyrazolo[4,3-c)isoquinolinium hydroxide, inner salt The sub-title compound was prepared according to the method described in Example 1 (c) using 1, 1 -dimethylethyl)phenyl]hydrazine and was used without further purification in the proceeding step.

2 4 -(ll-Dimethylethyl)phenyII.2Hpyrazolo[4,3.cisoquinoin 3 -o The title compound was prepared according to the method described in Example 2 using 3-hydroxy-2-[4-(, 1, -dimethylethyl) phenylI- 4 (4iethoxyphenymethy)2Hpyrazolo- 4 3 -c]isoquinolinium hydroxide, inner salt. m.p. >2100 (dec.).

MS (APCI) 318 'HWNMR (d,-DMSO) 5 1.33 (9H, 7.51 (211, 7.75 (1W, 7.84 (1W, 8.01 (2H, d).

8.12 (1 H, 8.25 (1WH, 8.74 (1IH, s) Example 19 2 4 Trifluoromethoxy henyI)..Hpyra az,-cioqio 3 li 3 Jo 2 4 Trifluoromethoxypheny 3rHydroxy2[(4mxypeoyi)thl]-Hp azoloj4,3-c]isoquinolinium hydroxide, inner salt The sub-title compound was prepared according to the method described in Example 1 (c) using 4 -trifluoromethoxyphenylhydrazine and was used without further purification in the proceeding step.

2 4 -Trifluoromethoxyphenyl)..2H-pyrazolo[4,3..c~isoquinolin.

3 -oI N -1 1 0 WO 97/34893 PCT/SE97/00471 27 The title compound was prepared according to the method described in Example 2 using 2-( 4 -trifluoromethoxyphenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]- 2 H-pyrazolo- 4 3 -c]isoquinolinium hydroxide, inner salt. m.p. 230 °C.

MS (APCI) 346 'H NMR (d 6 -DMSO) 5 7.58 (2H, 7.91 (1H, 7.99 (1H, 8.14 (2H, 8.29 (2H, m), 9.03 (1H, br s).

Example 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) G. Hinton F. G. Mann, J. Chem. Soc. 1959, 599), 4 -chlorophenylhydrazine (0.98 g) and 4-toluenesulfonic acid (10 mg) were fused together at 150 OC for ten minutes under a nitrogen atmosphere. Xylene (10 ml) was then added and the mixture was heated for a further 6 h at 150 oC. The reaction mixture was cooled and the resulting red precipitate filtered off and washed with diethyl ether. Recrystallisation from methanol gave the title compound (0.27 m.p. 247-248 °C.

MS (EI) 309, 311 'H NMR (d 6 -DMSO) 84.5 (3H, 7.5 (2H, 7.75 (1H, 7.95 (1H, 8.1 (1H, 8.3 (1H, 8.4 (2H, 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 60% dispersion) in dry dimethylformamide (5 ml) under a nitrogen atmosphere. Iodomethane (0.076 ml) was added dropwise after 0.5 h and the resulting solution was stirred at room temperature for 2 h. The solution was poured into brine an, extracted with dichloromethane/methanol mixtures (thrice). The organic phase was washed with 2N hydrochloric acid and brine then dried over sodium sulfate, filtered and concentrated to give a red solid. Purification by column chromatography (2:3 ethyl acetate hexane), followed by recrystallisation from dimethylformamide gave the title compound as purple crystals (65 mg). m.p. 249-250 "C.

MS (EI) 310, 312 (M WO 97/34893 WO 9734893PCT/SE97/00471 'H NMR (CDCI,) 4.81 (3H, 7.40 (2H, 7.75 (2H, in), 8.00 (1 H, dd), 8.25 (2H, d), 8.35 (1 H, dd).

Example 22 2-4Clrpey)3hdoy4[4mtoxpey~ehl2-yaoo43cio quinolinium hydroxide, inner salt.

The title compound was prepared according to the method described in Example 20, from methyl 1,2,3,4ttayr--4mtoxpey ehl4oo3-sqioieabxlt (which latter compound was prepared analogously to the methods described in I. G. Hinton F. G. Mann, J. Chem. Soc. 1959, 599). m.p. 227-228 'C.

MS (El) 416, 418 'H NMR (d 6 -DMSO) 3.70 (3H, 6.08 (2H, 6.95 (2H, 7.50 (2H, 7.70 (2H, d), 7.75 (1H, 7.95 (ili, 8.15 (LH, 8.35 (1H, 8.40 (2H, 8.93 (1H, s).

The following compounds, Examples 23-56, were prepared by methods analogous to examples 20 22: 1 x.

Name Im.p./ 0 C I MS 24 3 -Hydroxy-4-methyl-2-(4-tri.

fluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3 -Hydroxy-4-methyl-2- 3 -quinolyl)-2H-pyrazolo- 4 3 -clisoquinolinium hydroxide, inner salt 201- 203 344 327 >250 'H NMR (d 6 -DMSO) 4.51 (3H, 7.80 (3H, in), 7.97 (1 H, 8. 10 (1 H, d), 8.35 (1 H, 8.60(2H, d), 8.66(1H, s).

4.55 (3H, 7.60 (1IH, td), 7.70 (1 H, td), 7.82 (1 H, td), 8.00 (3H, in), 8. 10 (1lH, d), 8.40 (1IH, 8.69 (1 H, s), I 1 1 IkIn, Y.Y1kI 2 6 -Chloro-3-pyridyl)-3- >250 311/313 4.50(3H, 7.61 (1 H, d), -hydroxy-4-methyl-2H-pyr- 7.80(1 H, 7.97(1 H, t), azolo[4,3-clisoquinoliniuin 8.12(1H, 8.35(1H, d), hydroxide, inner salt 8.68(1H, 8.74(1H, dd), 9.37 (1 H, s) 26 2 3 4 -Dichlorophenyl)-3- 223- 344/346/ 4.49 (3H, 7.70 (1 H, d), -hydroxy-4-methyl-2H-pyr- 229 348 7.78 (11-H, 7.96 (1 H, t), azolo[4,3-clisoquinolinium 8.11 (IH, 8.35 (2H, in), hydroxide inner salt 8.67 (2H, m) WO 97/34893 PCT/SE97/00471 29 Ex. amem.p./OC MS 'H NMR (d 6

-DMSO)

T27 3 -Hydroxy-4 methyl-2-(4- 247- 290 2.33 (3H, 4.52 (3H, s), -methylphenyl)2H-pyrzolo- 248 7.24 (2H, in), 7.74 (1WH, in), 4 3 -clisoquinolinium hydr- 7.93 (1 H, in), 8.09 0IH, in), oxide, inner salt 8.20 (2H, in), 8.33 (1IH, d), 8.59 (I1H, s) 28 2 4 -Broinophenyl)-3-hydr7 244 354/356 4.50 (3H, 7.63 (2H, d), oxy- 4 -methyl-2H-pyrazolo- 7.76 (1WH, 7.96 (1WH, t), 4 3 -cjisoquinolinium hydr- 8. 10 (1 H, 8.34 (3H, in), oxide, inner salt 8.63 (1WH, s) 29 3 -Hydroxy-4 methylI2-(3-tri. 222-6 344 4.51 (3H, 7.53 (OH, d), fuoromethylphenyl)2H-pyr- (M H) 7.69 (1 H, 7.78 (1 H, t), azoio[ 4 3 -clisoquinolinium 7.96 (1IH, 8.12 (1 H, d), hydroxide, inner salt 8.35 (1WH, 8.63 (1W, d), 8.66 (1WH, 8.81 (1WH, s) 2 4 1-Diinethylethyl)- >22200 332 1.35 (9H, 4.65 (3W, dt), Phenyll-3-hydroxy-4melthyl (dec.) 7.46 (2H, mn), 7.62 (1WH, dt), 2H-pyrazolo[4,3c]iso- 7.71 (1W, 7.83 (2H, in), quinoliniuin hydroxide, inner 8.15 (2H, in), 8.50 (1WH, d) salt (CDC1 3 not DMSO d 6 31 2 6 -Chloro-3-pyridyl)- 223- 417/419 3.72 (3H, 6.07 (2H, s), 3 -hydroxy..4+[4-methoxy. 224 6.97 (2H, 7.62 (1WH, d), phenyl)methyl1.2Hpyrazolo- 7.70 (2H, 7.81 (1WH, t), 1 4 3 -c)isoquinoliniuin hydr- 8.00 (1LW, 8.16 (1WH, d), oxide, inner salt 8.36 (1W, 8.79 (1W, dd), 8.98 (1W, dd), 9.38 (1W, d) 32 3 -Hydroxy-4-methyl-2(6- >250 291 2.50 (3W, 4.51 s), -inethyl-3-pyridyl)-2THpyr. 7.33 (1WH, 7.77 (1WH, t), azolo[ 4 ,3-c]isoquinoliniuin 7.98 (1WH, 8. 10 (1WH, d), hydroxide, inner salt 8.34 (1WH, 8.50 Q1H, dd), 8.64 (1WH, 9.38 (1WH, d) 33 trifluoromethylphenyl)- >250 374 3.99 (2H, in), 4.92 (2H, in), 3 -hydroxy-4-(2-hydroxy.

(M+W)

4 5.19 (1W, 7.79 (3H, in), ethyl)-2H-pyrazolo[43-ciso- 7.99 (1WH, in), 8.20 (1LH, d), quinoliniurn hydroxide, inner 8.38 (1WH, 8.60 (2H, d), salt 8.65 s) WO 97/34893 PCT/SE97/00471 Ex. Name mn/IC I MR m n 1 0r r 3 -H-ydroxy-4-methyl-2-(5 -methyl-2-pyridyl)-2H-pyrazolo[ 4 ,3-clisoquinolinium hydroxide, inner salt 237- 240 I 36 37 38 39 3-Hydroxy-4-methyl-2-[4-( 1- -methylethyl)phenyl]-2Hpyrazolo[ 4 3 -clisoquinolinium hydroxide, inner salt 3 -Hydroxy-4-methyl-2-(4- -nitrophenyl)-2H-pyrazobo- 4 3 -c]isoquinolinium hydroxide, inner salt 2 4 -Cyanophenyl)-3-hydroxy- 4 -methy1-2H-pyrazolo- 4 3 -clisoquinolinium hydroxide, inner salt 2 4 -Carboxyphenyl)-3-hydroxy-4-methy-2H-pyrazolo.

4 3 -cjisoquinolinium hydroxide, inner salt 2 -(4-Chloro-3-trifluoromethylphenyl)-3-hydroxy- 4 -methyl-2H-pyrazolo- 4 3 -c]isoquinolinium hydroxide, inner salt 2 4 -Trifluoromethoxyphenyl)-3-hydroxy-4-methyl.

2 H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 171- 172 >230 225- 227 >230 >230 195- 196 291 318 321 301 (M+11)+ 320 378/380 360 'H NMR (d 6 -DMSO) 2.34 (3H, 4.50 (3H, s), 7.75 (2H, in), 7.98 (111, t), 8.11 (11H, 8.18 (1 H, d), 8.3 6 (1IH, 8.40 (1 H, d), 8.59 (111, s) 1.25 (6H, 2.92 (1 H, mn), 4.53 (3H, 7.34 (2H, d), 8.14 (3H, in), 8.35 (11H, d), 8.69 (1IH, s) 3.93 (3H1, 7.79 (1IH, 0), 7.99 (1lH, 8.12 (11-H, d), 8.33 (3H, in), 8.62 (2H, d), 8.71 (1 H, s) 4.49 (311, 7.79 (11H, t), 7.8 9 (2H, 7.95 (11H, t), 8.00 (1H1, 8.34 (1 H, d), 8.56 (2H, 8.67 (111, s).

4.51 (3H1, 7.78 (1IH, t), 7.99 (11H, 8.01 (2H, d), 8.12 (1 H, 8.09 (11H, d), 8.47 8.64 (1H, s), 12.74 (111, s) 4.50 (3H, 7.81 (2H, in), 8.38 (1H, 8.59 (IH, dd), 8.68 (1 H, 8.98 (11H, d) 4.51 (3H, 7.46 (2H1, d), 7.79 (1IH, 7.96 (11H, t), 8.12 (11H, 8.3 5 (1lH, d), 8.45 (211, 8.64 (11H, s) WO 97/34893 PCT/SE97/00471 IE.IName M n I m n/ 0

F

3-Hydroxy-4-methyl-2-(4- -methylthiophenyl)-2H-pyrazolo[ 4 3 -clisoquinolinium hydroxide, inner salt 197i198 jMS 322 t i 4-Cyclopropyl-3-hydroxy-2- -(4-trifluoromethylphenyl)- -2H-pyrazolo[4,3-c] isoquinolinium hydroxide, inner salt >250 370 (MH) 'H NMR (d 6 DMSO)6 2.50 (3H, 4.51 (3H, s), 7.33 (2H1, 7.72 (11H, t), 7.91 (111, 8.08 (1 H, d), 8.27 (2H1, 8.31 (11H, d), 8.60 (11H, s) 1.33 (211, in), 1.54 (2H4,i) 5.03 (11H, in), 7.78 (3H1,i) 7.96 (1 H, mn), 8.15 (11H, d), 8.34 (11H, 8.61 (214, i) 8.65 (11H, s) 1.32 (2H, 1.54 (2H, i) 2.51 (3H, 5.08 (1H, i) 7.33 0IH, 7.56 (11H, td), 7.94 (111, td), 8.13 (11H, d), 8.32 (111, 8.54 (11H, dd), 8.62 (1 H, 9.40 (1 H, d) 1.94 (6H4, 4.28 (2H1, d), 5.15 (1 H, 7.79 (3H, in), 8.00 OIH, in), 8.37 (2H, t), 8.62 (211, 8.77 (1IH, s)

I

I

4 -Cyclopropyl-3-hydroxy-2- 6 -methyl-3-pyridyl)-2H-pyrazolo[4,3-cjisoquinolinium hydroxide, inner salt 226- 240 1~ 4. 44 1 -Dimethyl-2-hydroxy)ethyl] -3-hydroxy-2- [(4-tri fluoromethyl)phenyl]-2H-pyrazolo 4 ,3-c]isoquinolinium hydroxide, inner salt 3 -Hydroxy.-4-(2-methoxyethyl)-2-[(4-trifluoromethyl)phenyl] -2H-pyrazolo[4,3-c]isoquinoliniuin hydroxide, inner salt >220 195- 197 402 388 (M+11)+ ~1 J I

I

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

I

3.28 (311, 3.96 (214, 0), 5.06 (211, 7.79 (3H, in), 7.99 (1 H, in), 8.18 (1 H, d), 8.37 (111, 8.58 (2H, d), 8.71 (11H, s) 2.19 (314, 3.20 (2H, 0), 5.03 (211, 7.50 (2H1, in), 7.79 (11H, in), 7.99 (1 H, in), 8.15 (11H, 8.38 (3H1, m), 8.77 (11H, s) 187- 188 3 70/3 72 (M+11)+ I- I I WO 97/34893 WO 9734893PCT/SE97/00471 Ex. Name m.p.1 0 C MS 'H NMR (d 6 -DMSO) 6 47 3-Hydroxy-4-[2-(methylthio)- 193- 404 2.20 (3H, 3.21 (2H, t), ethylJ-2-(4-trifluoromethyl- 195 5.04 (2H, 7.81 (3H, mn), phenyl)-2H-pyrazolof4,3-c]- 8.01 (1 H, mn), 8.17 (1IH, d), isoquinolinium hydroxide, 8.39 (1H, 8.59 (2H, d), inner salt 8.80 011H, s) 48 4-Cyclopropyl-2-(4-trifluoro- 188- 386 1.34 (2H, in), 1.54 (2H, in), inethoxyphenyl)-3-hydroxy- 189 5.08 0IH, mn), 7.46 (2H, d), -2H-pyrazolo[4,3-cjiso- 7.78 (1H, 7.95 (1 H, t), quinoliniuin hydroxide, inner 8.15 (1 H, 8.31 (1 H, d), salt (2H, 8.62 (11H, s) 49 2-(4-Chloro-3-trifluoro- >220 404/406 1.33 (2H, in), 1.53 (2H, m), inethylphenyl)-4-cyclopropyl- (M 4.98 (IH, mn), 7.78 (2H, mn), -3-hydroxy-2H-pyrazolo- 7.97 (1 H, 8.17 (1 H, d), 4 ,3-clisoquinolinium hydr- 8.3 6 (1IH, 8.62 (1LH, dd), ___oxide, inner salt 8.67 (1 H, 9.03 (1 H, dd) 4-Cyclopropyl-3-hydroxy-2- 166- 348 1.30 (2H, in), 1.51 (2H, in), -(4-inethylthiophenyl)-2H-pyr 167 2.51 (3H, 5.24 (1K, in), azolo[4,3-c]isoquinoliniuin 7.37 (2H, 7.74 (1 H, t), hydroxide, inner salt 7.93 (1 H, 8.14 (1IH, d), (3H, mn), 8.58 (1 H, s) 51 3-Hydroxy-4-phenyl-2-(4-tri- 255 406 7.69(3H, in), 7.76(2H, in), fluoromethylphenyl)-2H-pyr- 7.82(3H, in), 8.05(IH, in), azolo[4,3-clisoquinolinium 8.25(1 H, 8.45(1 H, d), hydroxide, inner salt in), 8.85(1K, s) 52 4-Ethyl-3-Hydroxy-2-(4-tri- 192- 358 1.63 (3H, 4.88 (2H, fluoromethylphenyl)-2H-pyr- 198 quart), 7.75 (1K, 7.79 azolo[4,3-c]isoquinoliniuin (2H, 7.96 (1 H, 8.09 hydroxide, inner salt (1H, 8.33 (1H, 8.59 8.76 (1KH, s) 53 2 -(4-Trifluoromethylphenyl)- 167- 416 1.27 (311, 4.27 (2H, q), 1 -ethoxycarbonylinethyl)- 169 (M+H) 4 5.83 (2K, 7.82 (2H, d), 3-hydroxy-2H-pyr- 7.82 (1 H, 8.04 (1KH, t), azolo[4,3-c]isoquinoliniuin 8.17 (1 H, 8.39 (111, d), hydroxide, inner 8.54 (2K, d),8.71 (I H, d) WO 97/34893 PCT/SE97/00471 Ex. Name 54 3-Hydroxy-4-[(4-methoxyphenyl)methylj-2-phenyl-2Hpyrazolo[4,3-c~isoquinolinium hydroxide, inner salt 3-Hydroxy-4-( 1 -methylethyl)- -2-(4-trifluoromethylphenyl -2H-pyrazolo[4,3-ciso.

quinolinium hydroxide, inner salt 56 3-Hydroxy-4-( 1 -methylethyl)- 2 3 -trifluoromethylphenyl)- -2H-pyrazolo isoquinoliniumn hydroxide, inner salt 'H NMR (d 6 -DMSO) 8 3.72 (31-1, 6.10 (2H, s), 6.95 (2H, 7.20 (1 H, t), 7.48 (2H, 7.75 (3H, in), 7.95 (1 H, 8.15 (1IH, d), 8.35 (3H, in), 8.91 (lH, s) 1.70 (611, 6.26 (1IH, br s), 7.79 (1H, 7.79 d), 7.98 (1WH, 8.22 (1WH, d), 8.38 (1 H, 8.62 (2H, d), 8.93 (1IH, d) 1.71 (6H, 6.27 (1WH, br s), 7.54 (1WH, 7.70 7.78 (1IH, 7.96 (1W H, 8.22 (1WH, 8.40 (1IH, d), 8.64 (1WH, 8.85 (1WH, s), 8.94 G1W, s) Example 57 3 -Hydroxy-2(4iodopheny).4methy2Hpyrazoo[43.c]isoquinoinim hydroxide, inner salt Methyl 1,,,-erhdo2mty 4oo3iounlncroylt (0.485 g) and 4-iodophenyihydrazine (1.053 g) were combined in ethanol (15 ml) and heated to reflux for 20 h.

A solid precipitated on cooling, this was crystallised from ethanol and then propan-2-ol to give the title compound (0.054 m.p. >260 0

C.

MS (+ve ESI) 402 4 'H NMR (d 6 -DMSO0): 864.50 7.76 (1WH, 7.77 (2H, 7.94 (1WH, 8.09 (1WH, d), 8.19 (211, 8.32 (1W, 8.62 (111, s) WO 97/34893 PCT/SE97/00471 34 The following compounds, examples 58-60, were prepared following methods analogous to that used for example 2: Ex. Name M.p./OC 6 -Chloro-3-pyridyl). 2 H-pyrazolo[4,3-cjisoquinolin-3-ol 59 2-[4-(lI -Methylethyl)- 218phenyl]-2H-pyrazolo 219 4 3 -'c)isoquinolin-3-ol 2 4 -Pentafluoroethyl. 219phenyl)-2H-pyrazolo- 223 4 3 -clisoquinolin-3-oll The following compounds, examples 61-68, to that used for example 6: 304/ 1.25 (6H, 2.9 (18, 78.42 299) (28, 7.31 (4H, in), 8.27 (28, b in), 9.00 (1IH, s) =380 7.68 (IH, 7.76 (3H, in), 8.02 (18, 8.24 (18, 8.54 (3H, in)M were prepared following methods analogous Ex Nae 8.9 (28 8 m'8) 7.50 t) 7.7 (39 in), 6 2 4 -Dihydro.3hydroxy--4- >250 360 3.1 (38 7.77 (18, t), yanoin--on 11.3-7 s 7.7 (18, 7.9 (18, t), -S-pyrazolo[4,3cisoquinolin5- 8.2 8.3 (28, in), one (1H, d)

I

b WO 97/34893 PCT/SE97/00471 Ex. Name 0

C

2 ,4-Dihydro-3-hydroxy-2(4- >250 -iodophenyl)-4..methyl..sHpyrazolo[ 4 3 -clisoquinolin-5-one 66 2 4 -Dihydro-3-hydroxy..4-(4- >230 -methoxyphenylmethyl).2-(4- dec.

-pyrazoio[4,3-clisoquinolin-5- -one 67 2 ,4-Dihydro-3-hydroxy.4.(l 1- 228-230 -methylethyl)-2-(4-trifluoro- dec.

0 4 3 -clisoquinolin-5-one 68 2 4 -Dihydro-3-hydroxy.4 238-240 -methyl-2-[4-( 1 -methylethyl)phenyll-5H-pyrazolo[4,3..cliso- M S'H N M 6 ~s8 418 3.80 (3H, 7.74 (3H, in), 7.8 9 (3 H, in), 8.02 (1 H, d), 8.3 H1-, d) 466 3.68 (3H, 5.59 (2H, s), 6.83 (2H, 7.40 (2H, d), 7.75 (1IH, 7.90 (3H,i) 8.07 (OH, 8.20 (2H, d), 8.38 (11H, 11.50 (1H, s) 388 1.59 (611, 5.85 (14, brs), 7.76 (1iH, 7.92 Q3H, 8.04 (INH, 8.18 (2H, 8.36 (1H, d) 334 1.25 (6H, 2.96 (1iH, (M+H)j hept), 3.81 (3H, 7.42 (2H4, 7.72 (iN, 7.78 (2H, 7.89 (1iH, 8.01 0lH, 8.36 (1H, d) Example 69 2 4 -Dihydro-3hydroxy.2..4trifluoroethyphenYl).5h-.pyrazoo[ 4 3 c]isoquinoin Trifluoroacetic acid (4 ml) was added to 2 4 -dihydro3hydroxy4(methoxyphenylmethyl)- 2 4 -trifluoromethylphenyl)s5H.pyrazolo[4, 3 -cisoquinolin-5-one (example 66) (425 mng) and the mixture was heated at reflux for 12 hours. After cooling to room temperature the solvent was removed and the resultant residue was recrystallised from methanol/water to give a yellow solid, which was further purified by trituration with isohexane to give the io title compound (150 mg). in.p. >200 'C.

MS (APCI) 346 'H NMR (d,-DMSO0) 5 7.7 6 (1iH, 7.92 (3H, in), 8.02 (1iH, 8.18 (2H, 8.34 (1iH, d), 11.20 (1IH, s) WO 97/34893 PCT/SE97/00471 The following examples were prepared analogously to example 69: Ex. Name 2 ,4-Dihydro-3-hydroxy.2-[4 E -mthylethyl)phenyly5H- -pyrazolo[4,3-clisoquinolin-5- -one 71 2,4-Dihydro-3-hydroxy.2 1,1 '-biphenyll-4-yl)-5H- -pyrazolo[4,3-clisoquinolin- M.p.1 0

C

>2500 275 dec.

MIS 'Hl NMR (d 6 -DMSO) 8 320 1.24 (6H, 2.95 (1N i, 7.40 (2H, 7.70 (1iH, 7.78 7.88 (1I-H, 7.99 (1IH, 8.3 2 (INH, I11.00 (1IH, s) 354 7.39 O1H, 7.50 t0, 7.74 (3H, 7.87 (3H, in), 8.01 Q3H, in), 8.34 (1IH, 11. 13 (I H, 11. 76 (1I-H, s) Example 72 2 4 -Chloropheny)3.hydroxy4[(4methoxypheny)thy 115meh-2pyao- 4 3 -clisoquinoliniurn hydroxide, inner salt A 3M solution of methylmagnesium bromide in diethyl ether (2.0 ml) was added dropwise to an ice cooled suspension of 2-4clrpey)3hdox--(-ehxpey) methyI3- 2 Hpyrazoo43c]isoquinolinium hydroxide, inner salt (Ex. 22) (0.5 g) and copper(I) bromide (17 mg) in dry tetrahydrofuran (20 ml). The mixture was stirred cold for 1 hour before saturated aqueous amnmonium chloride and ethyl acetate were added. This mixture was stirred at room temperature for 16 hours then the aqueous phase was extracted with ethyl acetate (thrice). The organic phase was washed with brine, dried over sodium sulphate, filtered and evaporated. The solid residue was purified by column chromatography (99:1 dichloromethane methanol) to give a purple solid (0.38

A

sample 1 g) was recrystallised from ethanol to give the title compound (31 mng).

m.p. 212-2 16 'C MS (APCI) 430, 432 'H NMR (d 6 -DMSO) 582.88 (3H, 3.71 (3H1, 6.50 (2H, br 6.93 (211, 7.32 (2H, 7.51 (2H1, 7.76 (1 H, 7.98 (11H, 8.32 (1IH, 8.43 (3H1, in).

Example 73 2 4 -Chorophenyl)..s.methyl.2Hpyrazolo[4,3.c]isoquinolin 3 -o 2 4 -Chlorophenyl)--yrx--(-etoyhnlmty]5-ehl2-yaoo [4, 3 -c]isoquinolinium hydroxide, inner salt (0.29 g) was dissolved in trifluoroacetic acid ml) and heated under reflux in a nitrogen atmosphere for 2 hours. On cooling to room temperature the solvent was evaporated and the residue was co-evaporated with toluene WO 97/34893 PCT/SE97/00471 (thrice). Purification by column chromatography (20:1 dichloromethane methanol) followed by trituration with methanol gave the title compound as an orange solid (0.07 g) m.p. >250 °C MS (APCI) 310, 312 'H NMR (d 6 -DMSO) 6 2.77 (3H, 7.47 (2H, 7.68 (1H, 7.77 (1H, 8.10 (1H, d), 8.25 (1H, 8.31 (2H, d).

The following examples were prepared following the method of example 72: Ex. Name m.p./oC

MS

74 4-Cyclopropyl-3-hydroxy-5- >250 384 -methyl-2-(4-trifluoromethyl-

(M+H)

phenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 3 -Hydroxy-4-(2-methoxy- 202- 402 ethyl)-5-methyl-2-[(4-tri- 204

(M+H)

fluoromethyl)phenyl]-2H-pyrazolo 4 3 -c]isoquinolinium hydroxide, inner salt 'H NMR (d 6 -DMSO) 8 1.32 (2H, 1.48 (2H, m), 3.07 (3H, 4.04 (1H, m), 7.76 (3H, 7.95 (1H, t), 8.36 (2H, 8.62 (2H, d) 3.00 (3H, 3.29 (3H, 4.08 (2H, 5.37 (2H, br 7.68 (3H, 7.88 (1H, 8.10 (1H, 8.56 (3H, m) (111 d),8.56(311 in Example 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 3M solution in ether) was added and the mixture was heated under reflux for 0.75 h. Further methylmagnesium bromide (1 ml) was added and heating was continued for 3 h. The reaction was allowed to cool to ambient temperature and was then quenched by the slow addition of dilute hydrochloric acid. The mixture was basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (thrice).

The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. Purification of the residue by chromatography (silica, 97:3-95:5 dichloromethane methanol) gave a red solid which was triturated with ether to give the title compound (0.060 m.p. >250 "C.

MS (APCI) 324/326 WO 97/34893 PTS9/07 38 PTS9/07 'H NMR (d 6 -DMSO) 5 2.90 (3H, 4.63 (3H, 7.49 (2H, 7.77 7.95 (IH, t), 8.39 (4H, in).

The following examples were prepared following the method of example 76: Ex. Name m-p./ 0 C MIS 'H NMR (d,-DMSO)

A

77 5-Ethyl-3-hydroxy4methyl- >250 372 1.45 (3H, 3.32 (2H, 4.78 2 4 -trifluoromethylphenyl)- (3H, 7.68 (3H, in), 7.88 2 H-pyrazolo[4,3-cliso- 0IH, td), 8.03 01H, 8.54 quinolinium hydroxide, inner (2H, 8.58 (1 H, dd) salt.

78 3 -Hydroxy-5-methyl4-( I -205-- 386 1.76 1.90 (6H, 2 x m, -methylethyl)-2-(4-trifluoro- 210 rotamers), 3.07 (3H, 5.42 methylphenyl)-2Hpyrazolo- 7.40 (1 H, 2 x br, rotamers) 4 3 -c]isoquinolinium hydr- 7.77 (3H, in), 7.97 (1 H, t), oxide,' inner salt 8.41 (2H1, in), 8.62 (2H, in).

79 4 -Methyl-5-(1 -methylethyl)- 236- 386 1.61 (614, 4.05 (IH, br), hydroxy-2-(4-trifluoro- 238 4.75 (31, 7.76 (1IH, 7.80 methylphenyl>2Hpyrzolo- (2H, 7.94 (11H, 8.43 (1 H, 4 3 -c]isoquinolinium hydr- dd), 8.52 (1IH, 8.60 (2H, d) oxide, inner salt 3 -Hydroxy-4,5-dimethyl2(4- >250 358 2.87 (311, 4.72 (3H, 7.66 -trifluoromethylphenyl)-2H- (3H, in), 7.86 (LH, 8.01 -pyrazolo[4,3-clisoquinolin- (lH4, 8.53 (3H, m) ium hydroxide, inner salt Example 81 S5-Chloro2(4trifluoroinethylpheny).2H.pyrazoo[4 3 .c]isoquinoin 3 o Phosphorous oxychloride (5 was added to 2 4 -dihydro-3hydroxy4-(iethoxyphenylmty)2(-rfurmtypey)-Hprzl[,-~sqioi--n (example 66) (350 mg) and heated to reflux for 1 hour. After cooling to room temperature the solvent was removed and the residue was purified by column chromatography, eluting with isohexane ethyl acetate acetic acid (80:20:2) followed by trituration with acetonitrile to give the title compound (25 mng). m.p. >250 0 C dec.

13 MS (APCI) 364/366 'H NMR (d 6 -DMSO) 5 7.96 (5H, mn), 8.07 (IH, 8.25 (111, 8.43 (11H, d) WO 97/34893 PCT/SE97/00471 39 Example 82 3a,4-Dih dro-3a-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolins Ceric ammonium nitrate (700 mg) was added to a suspension of 2 4 -dihydro-3-hydroxy- -4-(methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)-5H-pyrazolol4,3-cisoquinoli (example 66) (200 mg) in acetonitrile (4 mi) and water (1 ml) at room temperature After 2 hours the mixture was absorbed onto silica gel and purified by column chromatography, eluting with isohexane propan-2-ol and then HPLC, eluting with isohexane ethyl acetate to give the title compound (50 mg). m.p. 175-185

O

C

MS (ESI) 360 'H NMR (d 6 -DMSO) 6 7.7-8.0 (5H, 8.08-8.12 (4H, 9.78 (1H, s).

Example 83 2 ,4-Dihydro-3methoxy-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo4,3-c]isooehihnl-N~yaoo43cio 2,4-Dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-ciso- (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 60% dispersion) in dry dimethylformamide (1 mi) at 0 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 (thrice). The organic phase was washed with brine (seven times) then dried over magnesium sulfate, filtered and concentrated.

Purification by chromatography (25:75-50:50 ethyl acetate dichloromethane then 30:70 ethyl acetate isohexane) gave the title compound as a colourless solid (0.015 g).

m.p. 163-164

'C

MS (APCI) 374 'H NMR (CDC1 3 6 3.78 (3H, 3.83 (3H, 7.60 (IH, td), 7.74 (1H, td), 7.80 (2H, d), 8.04 (2H, 8.27 (1H, dd), 8.48 (1H, dd).

Example 84 2-( 4 -Chlorophenyl)4-{2-(NN-dimethylamino)ethyl}-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 2-(4-Chlorophenyl)-2H-pyrazolol4,3-c]isoquinolin-3-ol (0.3 g) was added to a stirred suspension of oil-free sodium hydride (from 81 mg 60% dispersion) in dry dimethylformamide (5 ml) under a nitrogen atmosphere. After 30 minutes, 2-dimethyl- WO 97/34893 PCT/SE97/00471 aminoethyl 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 (thrice). The organic phase was washed with brine then dried over sodium sulphate, filtered and concentrated to give a purple solid. Purification by column chromatography (20:1 dichloromethane ethanol), followed by recrystallisation from 4:1 cyclohexane ethyl acetate gave the title compound as a red solid (125 mg). m.p. 173-174

°C.

MS (APCI) 367, 369 'H NMR (d 6 -DMSO) 8 2.32 (6H, 3.02 (2H, 5.03 (2H, 7.4 (2H, 7.65 (1H, t), 7.85 (3H, 8.30 (2H, 8.50 (IH, d).

Example 3-Hydroxy-4-methyl-2-(4methylsufinylphenyl)2H-pyrazolo[4,3]isoquinolinium hydroxide, inner salt 3-Hydroxy-4-methyl-2-(4-methylthiophenyl)-2Hpyrazolo[4,3-cisoquinolinium hydroxide, inner salt (0.10 g) (example 41) was dissolved in dichloromethane (15 ml) and cooled to -78 3 -Chloroperbenzoic acid (0.055 g) was added and the mixture was stirred for minutes before being poured into aqueous sodium metabisulfite and extracted with ethyl acetate (thrice). The combined extracts were shaken with aqueous sodium bicarbonate, dried with sodium sulfate and evaporated to give a residue which was purified by column chromatography (3:2 ethyl acetate methanol) to give the title compound as a red powder (0.012 m.p. >230 °C.

MS(APCI): 338((M+H) 'H NMR (d 6 -DMSO): 8 2.77 (3H, 4.52 (3H, 7.80 (3H, 7.96 (1H, 8.13 (1H, d), 8.37 (1H, 8.57 (2H, 8.64 (1H, s).

Example 86 2-( 4 -Chlorophenyl)-3-hydroxy-4-[2-(methylsulfinyl)ethyl]- 2 Hpyrazolo[4,3c]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 After 30 min 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 and then dried (magnesium sulfate), filtered, and evaporated. The residue was subjected to chromatography using methanol by volume) in dichloromethane as the eluant to 1 WO 97/34893 PCT/SE97/00471 41 give a purple solid (0.46 g).

m.p. 228-230 °C MS (APCI+) 386, 388 'H NMR (d 6 -DMSO) 5 2.69 (3H, 3.47 (IH, 3.64 (1H, 5.11 (1H, 5.34 (1H, 7.50 (2H, 7.79 (1H, 7.99 (1H, 8.17 (1H, 8.38 (3H, 8.83 (1H, s).

Example 87 3-Hydroxy-4-[2-(methylsufinyl)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c ]isoquinolinium hydroxide, inner salt Prepared from 3-Hydroxy-4-[2-(methylthio)ethylJ-2-(4-trifluoromethylphenyl)-2H- -pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (example 47) following the method of example 86 to give the title compound as a purple solid. m.p. 241-243

°C.

MS (APCI+) 420 'H NMR (d 6 -DMSO) 62.70 (3H, 3.47 (1H, 3.64 (1H, 5.11 (1H, 5.36 (1H, 7.81 (3H, 8.01 (1H, 8.19 (1H, 8.38 (1H, 8.60 (2H, 8.86 (1H, s).

Example 88 2 4 -Methoxyphenyl)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[ 4 ,3-c]isoquinolin-3-ol, sodium salt Methylmagnesium bromide (3M in ether, 8.6 ml) was added slowly to a stirred suspension of 2,4-dihydro-3-hydroxy-4-(4-methoxyphenylmethyl)-2-(4trifluoromethylphenyl)-5 -pyrazolo[ 4 ,3-c]isoquinolin-5-one (example 66) (500 mg) and copper bromide (15 mg) in 1, 2 -dimethoxyethane (50 ml) and then heated at 100 °C for 24 hours. After being allowed to cool to room temperature the mixture was poured onto cold dilute hydrochloric acid and then basified with sodium hydrogen carbonate 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 ethyl acetate and ethyl acetate methanol gave the title compound as a red olid (90 mg). m.p. >200 °C dec.

MS (APCI) 464 'H NMR (d 6 -DMSO/TFA) 5 3.08 (2H, 3.59 (2H, 3.73 (3H, 6.87 (2H, 7.25 (2H, 7.92 (3H, 8.05 (IH, 8.33 (2H, 8.40 (IH, 8.50 (1H, 12.05 (TFA/water/1H).

WO 97/34893 PCT/SE97/00471 42 Example 89 9-Fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifuoromethylphenyl)-2H-py razolo[4,3-c]isoquinolinium hydroxide, inner salt 2,6 Difluoro-N-(2-hydroxy-l,l-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 an atmosphere of nitrogen whilst maintaining the temperature below 5 After addition was complete the ice bath was removed and stirring was continued 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 then evaporated. Trituration with hexane gave the subtitle compound (24.65 g), MS (APCI) 230 'H NMR (CDCI 3 8 1.41 (6H, 3.70 (2H, 3.95 (1H, 6.00 (1H, br 6.95 (2H, m), 7.38 (1H, m).

2 2 ,6-Difluorophenyl)-4,5-dihydro-4,4-dimethyloxazole Thionyl chloride (12.6 ml) was added dropwise to an ice cooled solution of 2,6-difluoro- -N-(2-hydroxy-1,1-dimethylethyl)benzamide (24.65 g) in dry dichloromethane (100 ml) under an atmosphere of nitrogen. 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 resultant solid was dissolved in the minimum amount of water (80 ml) and then basified with sodium hydroxide pellets. The basic phase was then extracted with ethyl acetate (thrice). The organic extracts were combined and then washed with brine, dried over sodium sulfate, filtered and evaporated to give an oil which was purified by column chromatography (4:1 hexane ethyl acetate) to give the subtitle compound (20.86 g).

MS (EI) 211 (M 'H NMR (CDC13): 8 1.42 (6H, 4.14 (2H, 6.95 (2H, 7.40 (1H, m).

4,5-Dihydro-2-(2-fluoro-6-methylphenyl)-4,4-dimethyoxazole A 3M solution of methylmagnesium chloride in tetrahydrofuran (86 ml) was added dropwise to a solution 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 WO 97/34893 PCT/SE97/00471 43 ammonium chloride solution was added carefully to the reaction mixture which was then extracted with ethyl acetate (thrice). The organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the subtitle compound as a pale yellow oil (18.18 g).

MS (APCI) 208 'H NMR (CDC13): 5 1.42 (6H, 2.40 (3H, 4.12 (2H, 6.93 (1H, 7.00 (1H, 7.26 (1H, m).

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 under reflux in acetonitrile (150 ml) for 4 h and then allowed to cool to room temperature. The solvent was evaporated and the solid residue was triturated with diethyl ether. The resultant solid was then dissolved in a mixture of methanol (80 ml) and 10% sodium hydroxide solution (80 ml) and heated under reflux for Is 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 (thrice) and then acidified with dilute hydrochloric acid to pH 1. The acidic phase was extracted with ethyl acetate (thrice). The organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give 2 -fluoro-6-methylbenzoic acid (10.85 A sample (0.27 g) was recrystallised from 4:1 hexane ethyl acetate to give the subtitle compound (0.15 m.p. 123-124 °C.

MS (EI) 154 'H NMR (CDCI 3 8 2.52 (3H, 7.02 (2H, 7.35 (1H, m).

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 an atmosphere of nitrogen. Stirring was continued at room temperature for 16 hours and then the reaction mixture was diluted with water and extracted with ethyl acetate (thrice). The organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution, and brine, then dried over sodium sulfate, filtered and evaporated to give the subtitle compound as a yellow oil (4.07 g).

MS (EI) 168 (M 'H NMR (CDC1 3 2.40 (3H, 3.94 (3H, 6.94 (1H, 7.01 (1H, 7.30 (IH, m).

Methyl 2 -(bromomethyl)-6-fluorobenzoate WO 97/34893 PCT/SE97/00471 44 A suspension of methyl 2 -fluoro- 6 -methylbenzoate (35.53 N-bromosuccinimide (37.6 g) and azobis(isobutyronitrile) (2 g) in dry dichloromethane (150 ml) was irradiated (100W halogen lamp) under an atmosphere of nitrogen for 4 hours. The resultant solution was poured onto 10% sodium hydroxide solution and extracted with dichloromethane s (thrice). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give a mixture of subtitle compound and starting material (52.33 g) as a yellow oil.

MS (EI) 246/248 (Mt) H NMR (CDC13) 5 3.99 (3H, 4.66 (2H, 7.06 (IH, 7.23 (1H, 7.40 (IH, m).

Methyl 2-fluoro-6-{ [(2-methoxy-2-oxoethyl)-(4-methoxyphenylmethyl)amino]methylbenzoate 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 under reflux in a nitrogen atmosphere for 16 hours. The reaction mixture was allowed to cool and was then diluted with water and extracted with ethyl acetate (thrice). The organic phase was washed with brine, dried over sodium sulfate, filtered and then evaporated. The residue was purified by column chromatography (20:1 hexane ethyl acetate) to give the subtitle compound as a colourless oil (8.82 g).

MS (APCI) 376 IH NMR (CDCI 3 6 3.21 (2H, 3.67 (3H, 3.68 (2H, 3.78 (3H, 3.88 (3H, 4.01 (2H, 6.82 (2H, 7.05 (1H, 7.18 (3H, 7.35 (1H, m).

Methyl 5-fluoro-1,2,3,4-tetrahydro2-(4ethoxyphenylmethyl)4oxo-3iso quinolinecarboxylate 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% dispersion, freed from oil) and tert-butyl alcohol (1 ml) in dry toluene (100 ml) heated under reflux in a nitrogen atmosphere.

Heating was continued a further 12 hours then the reaction mixture was allowed to cool to room temperature. The mixture was then poured onto saturated aqueous ammonium chloride solution and extracted with ethyl acetate (thrice). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give the subtitle compound (7.96 MS (APCI) 344 WO 97/34893 PCT/SE97/00471 NMR (CDCI 3 8 3.60 (211, 3.81 (31, 3.89 (2H, 3.92 (3H, 6.86 (31, i) 17.05 (1H, in), 7.22 (2H1, mn), 7.38 (114, in), 11.83 (111, s).

9 -Fluoro3-hydroxy-4-[(4.methoxypheny)ieth] 2 4 tffiurmtyphnl- -pyrazolo[ 4 ,3-cjisoquinolinium hydroxide, inner salt Methyl 5-fl uoro-1,,,-erhdo2 -ehxpeylehl--x--sqioieab oxylate (1.0 4 -trifluoromethylphenylhydrazine (1.03 g) and p-toluene sulfonic acid mg) were fused together at 150 *C under a nitrogen atmosphere for 15 minutes. Xylene mn]) was then added and heating was continued a further 2 hours. On cooling to room temperature the solvent was evaporated and the solid residue was purified by column chromatography (99:1 dichloromethane :methanol) to give the title compound as purple needles (0.425 g).

MS (APCI) 468 'H NMR (d 6 -DMSO) 563.72 (311, 6.10 (2H, 6.96 (214, 7.70 (2H, 7.80 (4H4, m), 8.00 (111, dd), 8.59 (2H, 8.98 (1H, s).

Example 9 -Fluoro-2(4-trifluoromethypheny)2H.pyrazoo[4 3 cisoquinolin 3 -o 9 -Fluoro3hydroxy4(4methoxyphenyl)nethI 2 4 trfluooehlhnl-H azolo[ 4 3 -c]isoquinolinium hydroxide, inner salt (0.43 g) was dissolved in trifluoroacetic acid (5 ml) and heated under reflux in a nitrogen atmosphere for 16 hours. After being cooled to room temperature the solvent was evaporated and the residue was co-evaporated with toluene (thrice). The residue was triturated successively with methanol and then diethyl ether and finally recrystallised from ethyl acetate to give the title compound as a red solid (0.08 in.p. >250 *C.

MS (APCI) 348 'H1 NMR (d 6 -DMSO) 8 7.86 (211, mn), 7.95 (211, 8.14 (114, 8.24 (211, br 9.09 (111, br 11.85 (11H, hr s).

The following compounds were made by methods analogous to example Ex. Name in.pP/C MS 'H NMR (d 6 -DMSO) 8 91 2 4 -Chlorophenyl)-7-nluoro- >250 328/ 4.51 (3H, 7.46 (2H1, 7.77 3 -hydroxy..4.methyl-2H..pyr. 330 (lH, td), 7.87 (111, dd), 8.36 azolo[ 4 ,3-c]isoquinolinium (M+11) 4 (31, in), 8.45 (11H, s) hydroxide, inner saltI WO 97/34893 PCT/SE97/00471 Ex. Name 92 7 -Fluoro-3-hydroxy-4..methy[- 2 4 -trifluoromethylphenyl)- 2 H-pyrazolo[4,3-cjisoquinolinium hydroxide, inner salt 93 2 -(4-Chlorophenyl)-4-cyclopropyl-9-fluoro-3-hydroxy.

2 H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 94 4 -Cyclopropyl-9-fluoro.3 -hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[ 4 ,3-clisoquinolinium hydroxide, inner salt 2 4 -Chlorophenyl)-9-fluoro.

3 -hydroxy-4-methyl-2H-pyr.

azolo[ 4 3 -c]isoquinolinium hydroxide, inner salt 96 2 4 -Chlorophenyl)-9-fluoro- 3 -hydroxy-4-[4-methoxyphenyl)methyl]-2H-pyrazolo- 4 3 -c]isoquinolinium hydroxide, inner salt 97 9 -Fluoro-3-hydroxy.4-methyl.

4 -trifluoromethylphenyl).

21 1 -pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt m.p./ 0 C MS >250 362

(M+H)

4 >214- 217 >250 >250 >250 354/ 356 388 328/ 330 434/ 436 362 'H NMR (d 6 -DMSO) 4.51 (3H, 7.75 7.80 in), 7.87 (OH, dd), 8.38 (OH, dd), 8.47 (IH, 8.54 (2H, d) 1.35 (2H, mn), 1.54 i) 5.11 (1 H, in), 7.51 (2H, d), 7.75 (2H, in), 7.95 (1H, dd), 8.38 (2H, 8.63 (1WH,s) 1.36 (2H, mn), 1.55 (2H, i) 5.06 (1lH, in), 7.77 (4H, i) 7.97 (1IH, in), 8.58 (2H, d), 8.66 (1WH, s) 4.51 (3W, 7.51 (2H, 7.76 mn), 7.91 (1WH, in), 8.35 (2H, 8.65 (1WH, s) 3.72 (3H, 6.10 (2H, 6.95 (2H, 7.54 (2H, 7.70 (2H, 7.77 (2H, in), 7.97 (1W, in), 8.39 (2H, 8.96 (I1H, s) 4.51(3W, 7.77 (411,i) 7.93 01H, in), 8.5 6 (2H, d), 8.68 (1WH, s) The following compounds (examples 98-100) were prepared following the methods of example 2: WO 97/34893 PCT/SE97/00471 Ex. Name

M.D.FC

m.D1 0 C MS 98 2 -(4-Chlorophenyl)-9- >250 31/316 -fluoro-2H-pyrazolo- 4 3 -clisoquinolin-3-ol 7-Fluoro-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-clisoquinolin-3- -ol >250 348 (M+11)+ 'H NMR (d 6 -DMSO) 7.63 (2H, 7.82 (2H1, br mn), 8.01 (211, 8.1 1 (11H, br d), 19.05 (1 H, br 11 .80 (11H, br s) 7.63 (2H, 7.91 (1 H, br t), 8.05 (2H, 8.13 (IH, 8.40 (I H, dd), 9.00 (11H, br 12.00 1II 2-(4-Chlorophenyl)-7- -fluoro-2H-pyrazoloisoquinolin-3-ol >250 3 14/3 16 f

I

(111. brs) The following compounds were prepared following the method of example 69:

I

VtX.

Name M lor 4 -I I -Aj. I 9 -Fluoro-3-hydroxy-4-[(4-meth.

oxyphenyl)methyll-5-methyl-2- -(4-trifluoromethylphenyl)-2H- -pyrazolo[4,3-clisoquinolinium hydroxide, inner salt 225-227 482 'H NMR (d 6 -DMSO) 2.86 (311, 3.73 (311, s), 6.53 (2H, 6.92 (211, d), 7.30 (2H1, 7.74 (4H, in), 8.11 (1H, 8.58 (2H, d) 2.85 (3H, 3,73 (3H, s), 6.53 (2H, 6.91 (2H, d), 7.29 (211, 7.44 (2H, d), 7.70 (211, in), 8.08 (11H, d), 8.37 (211, d) ~1- 2 -(4-Chiorophenyl)-9-fluoro-3- -hydroxy-4-[(4-methoxyphenyl)methyl]-5-netiyl-2H.

-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt I

I

222-223 448/45 0

(M+H)

4

I

W9738348 PCT/SE97/00471 The following compounds were prepared by the method of example 2: Ex. Name m.p.1 0 C MS 'H NMR (d 6 -DMSO0) 103 9 -Fluoro-5-methyl2(4-tri- >250 362 2.80 (3H, 7.79 (2H, in), fluoromethylphenyl)2H-pyr- 7.88 8.10 (11, d), azolo[4,3-c),isoquinolin-3.ol 8.32 (211, d) 104 2 4 -chlorophenyly9fluoro-5 >250 328/330 2.89 (3H, 7.58 (21H, d), -methyl-2H..pyrazolo[4,3-cliso- 7.79 (2H, br in), 8.08 (31, quinolin-3-ol .br m) Example 105 2 4 Dihdro3hydroxy4-et..me(4tY12(4.rifltylphey)H-rao[43c A solution of 2 4 dihydro3 hoydroxeyl-4ethl2(4omtjhlhey)5-raoo 4 3 -clisoquinolin-5-one (example 63) (0.25 g) and Lawesson's reagent (0.7 g) in dioxane (20 ml) was stirred and heated under reflux for 18 hrs. The resulting mixture was cooled and absorbed onto silica gel. Purification by chromatography (1:99-3:97 methanol dichloromethane) gave the title compound which was crystallised from ethanol to afford a yellow solid (0.075 in.p. 255-259

'C.

MS (APCI) 376 'H NMR (D2OfNaOD) 868.47 (11H, 7.71 (211, 7.60 (3H1, 7.34 (11H, 7.22 (111, 4.08 (31, s).

Example 106 3 -Hydroxy-4methy.5methylthio2.(4trifluoromthlhen1)-2H-yaoo43ci quinolinium hydroxide, inner salt.

A solution of 2 4 dihydro3hoydroxetyl-4etyluotrilhlhey)5-rao- 4 3 -clisoquinoline-5.thione (0.46 g) (example 105) and iodomethane (0.095 ml) in acetone '9 ml) was stirred and heated under reflux for 4 hr. Potassium carbonate 170 g) was added and the mixture was heated for a further 2 hr. The mixture was concentrated in vacuc. Purification of the residue by chromatography (2:98 methanol dichioromethane) gave the title compound as a purple solid (0.375 g).

MS (APCI) 390 'H1 NMR (CDCl 3 5 8.54 (4H1, mn), 7.86 (111, 7.72 (31, in), 4.98 (311, 2.52 (311, s).

WO 97/34893 PCT/SE97/00471 49 Example 107 2 4 Triluoromethylpheny l)..2,4ihdoiyr..inoo metl-H-yrlofl 4 3 -ci quinolin-3-ol.

A suspension of 3 -hydroxy-4methyl5methythio2(4trifluoromethlhl)- 2

H

-pyrazolo[ 4 3 -cjisoquinolinium hydroxide, inner salt (0.0 13 g) (example 106) in ethanol (7 ml) and ammonia solution (0.880 specific gravity; 15 ml) was stirred at 20 'C for 24 hr.

The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo.

Purification of the residue by chromatography (5:95-10:90 methanol dichioromethane) gave the title compound as an orange solid (0.043 mn.p. 253-255 0

C.

MS (APCI) 717 359 'H NMR (d 6 -DMSO) 868.60 (21H, 8.46 8.29 (3H, in), 7.90 (1IH, 7.71 (3H, in), 4.19 (3H, s).

Example 108 3 -Hydroxy-4(4methoxyphenyl)methy I..2(4..uoomtinuoroetylHpealo 3 4 -I][l,7lnaphthyridinium hydroxide, inner salt Methyl 2 -(bromomethyl)nicotinate Methyl 2 -methylnicotinate (10.0 g) and N-bromosuccinimide (14.9 g) were combined in

I,

2 -dichloroethane (80 ml). Acetic acid (3.8 ml) was added followed by 2,2'-azob is- 2 -methyipropionitrile) (1.0 g) and the mixture was heated to reflux whilst being irradiated with a 500W lamp. After 2 h the reaction was allowed to cool and then poured onto sodium bicarbonate solution. The organic phase was separated and was washed with brine twice, then dried, filtered and evaporated to an oil (18.2 g) which was used immediately for the next step.

N-(-ntoyhnlmty]N[3mtoyabnl2prdlmty~lcn methyl ester Prepared following the method of example I step using methyl 2 -(bromomethyl).

nicotinate 10 methyl N-4mtoyhny~ehllcn (10.2 g) and triethylanine ml) in diethyl ether (100 ml) to give the subtitle compound (3.20 g) MS (DESC SI) 358 'HNMR (d 6 -DMSO) 3.17 3.34 3H), 3.58 2H), 3.71 3H), 3.82 311), 4.23 2H), 6.82 2H), 7.04 2H), 7.43 (dd, 1W), 8.03 (dd, 111), 8.61 (dd, 1H) WO 97/34893 PCT/SE97/00471 Methyl 7 8 dihydro5hydroxy7(4.methoxypheny)methy1l 7 hthidin 6 -carboxylate Prepared following the method of example I step using 4 -methoxyphenyl)methyl]- 3 -methoxycarbonyl2pyridyl)methyl]glycine methyl ester (1.00 sodium hydride s (60% dispersion in oil) (160 mg), 2 -methylpropan-2-ol 10 ml) and toluene (15 ml) to give the subtitle compound (790 mg).

MS (APCI) 327 'H NMR (d 6 -DMSO) 3.65-3.97 (in, 1OH), 6.79 (mn, 2H), 7.11-7.39 (mn, 3H1), 7.86-8.25 (in, 11-1), 8.52-8.75 (in, IH), 11.25 111) 3 -Hydroxy4(4.methoxyphenyIethyl-4til2(4tifthylhI l-H-yaoo 3 4 -fllh, 7 naphthyridiniumn hydroxide, inner salt Prepared following the method of example I step using methyl 7 7 4 -methoxyphenyl)methyl-1, 7 -naphthyridine-6carboxylate (200 4 -trifluoroinethylphenyihydrazine (1.00 g) and ethanol (3 ml) to give the title compound (21 mng).

m.p. 20 1-3 0

C.

MS (APCI) 451 'H NMR (d,-DMSO) 3.72 3H1), 6.13 21H), 6.96 2H), 7.76 2H), 7.84 2H1), 7.88 (dd, 111), 8.59 2H1), 8.72 (dd, 111), 9.00 IH), 9.05 (dd, IH) Example 109 2-4Tilooehlhnl-Hpraoo34j[,]ahhrdn3o Prepared following the method of example 2 using 3 -hydroxy-4-(4-inethoxyphenyI)methyJ- 2 4 -trifluoromethyphenyl)2Hpyrzoo[3 4 ,7lnaphthyridiniuin hydroxide, inner salt (135 mg) and trifluoroacetic acid (5 ml) to give the title compound (19 ing).

m.p. 239-41 0 C (dec.) MIS (APCI) 331 'H NMR (d,-DMSO) 7.94 2H1), 7.95 (in, 111), 8.28 2H1), 8.74 111), 9.01 (br, 11H), 9.16 11H) M

M

WO 97/34893 PCT/SE97/00471 51 The following examples were prepared analogously to example 109 using methyl 2 -(bromomethyl)nicotinate, sarcosine methyl ester and the appropriate hydrazine: Ex Name ]ntm/oCl MS 1H NN AL tl3J 110 3 -Hydroxy-4-methyl-2-(4-trifluoro- >260 345 4.56 3H), 7.82 (d, methylphenyl)-2H-pyrazolo[3 2H), 7.88 (dd, IB), 8.56 1,7]naphthyridinium hydroxide, 2H), 8.70 I H), innersalt 8.73 I1H), 9.05 IRH) 111 2 4 -Chlorophenyl)-3-hydroxy- >260 311/313 4.56 3H), 7.51 (d, -4-methyl-2H-pyrazolo[3,4A[ 1,71- 2H), 7.88 (dd, 1H), 8.35 naphthyridinium hydroxide, inner 2H), 8.68 1H), salt 8.70 (dd, 111), 9.03 (dd, 1H)_ Example 1112 3 2 4 -trifluoromethylpheny)2H-pyrazolo[4,3.clisoquinolinium hydroxide inner salt.

A solution of 3-yrx--ehl5mtyti--4-rfurmtypey)2-yaoo 4 3 -clisoquinolinium hydroxide, inner salt (0.39 g) (example 106) in acetone (10 ml) and i0 40% aqueous dimethylamine solution (2 ml) was stirred at 20 'C for 24 h. The mixture was concentrated in vacuc. Purification of the residue by chromatography (1:99-2.5:97.5 methanol dichloromethane) gave the title compound as a red solid 129 m.p. 256- 259 0

C.

MS (APCI) 387 'H NMR (CDCl 3 d 3.19 (6H, 4.52 (3H, 7.64 (3H, in), 7.84 (1lH, td), 7.95 (1IH, d), 8.54 (3H, d) Example 113 3 -Hvdroxy-4methy-5..mrpholn linyl2(4trifluoromethyyl-Hpeya) 2

H[

4 3 isoquinolinium hydroxide inner salt.

A solution of 3 -hydroxy- 4 methyl-methylthio.2(4trifluoromethylphenyl) 2 pyoo 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 12h and then at 95 "C for 2h. The mixture was concentrated in vacuc. Purification of the residue by chromatography (5:95 methanol dichioromethane) gave the title compound as a red solid 165 m.p. 278- 281 0

C.

I

I

WO 97/34893 PCT/SE97/00471 52 MS (APCI) 429 'H NMR (d6-DMSO) d 3.49 (4H, 3.87 (4H, 4.49 (3H, 7.77 (2H, 7.94 (1H, 8.28 (1H, 8.38 (1H, 8.59 (2H, d).

Example 114 3-Hydroxy-4-methyl-5-piperazinyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide inner salt.

A solution of 3-hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)- 2 H-pyrazolo- 1[ 4 3 -c]isoquinolinium hydroxide, inner salt (0.29 g) (example 106) in toluene (20 ml) was 1o added dropwise to a stirred solution of piperazine (1.28 g) in toluene (50 ml) heated at 110 The resulting solution was stirred at 110 OC for 6h. then at room temperature for 16h. The mixture was concentrated in vacuo.. Purification of the residue by chromatography (5:95-10:90 methanol dichloromethane) followed by crystallisation from ethanol gave the title compound as a red solid 107g). m.p. 260-262 'C.

MS (APCI) 428 'H NMR (DMSO) d 2.96 (4H, 3.37 (4H, 4.44 (3H, 7.76 (3H, 7.93 (1H, t), 8.27 (1H, 8.37 (1H, 8.59 (2H, d).

Example 115 4,5-Dihydro-2-[4-(trifluoromethyl)phenyl-2H-benz[g]indazol-3-ol 1I-Oxotetrahydronaphthalene-2-carboxylic acid methyl ester (Mander, L.N and Sethi, S.P; Tetrahedron Lett. 1983, 24, 5425-8) (2.0g) and 4 -trifluoromethylphenylhydrazine (3.

4 7g) were heated in xylene (15ml) under reflux for 8h. The reaction mixture was allowed to cool and then the product was filtered. The solid was washed with diethyl ether, dried and recrystallised from toluene gave the title compound as colourless crystals. (1.45g). m.p.

189-190 oC.

MS (APCI) 331 1 H NMR (d 6 -DMSO) d 2.67 (2H, 2.90 (2H, 7.29 (3H, 7.75 (1H, 7.84 (211, 8.10 (2H, 11.70 (1H, s,br).

Example 116 4,5-Dihydro-2-(5-methyl-2-pyridinyl)-2H-benz[g]indazol-3-o I-Oxotetrahydronaphthalene-2-carboxylic acid methyl ester (2.18g) and methylpyridine (2.85g) were heated together in xylene (15ml) under reflux for 6h. The reaction was allowed to cool and then the product was filtered and dried. Recrystallisation WO 97/34893 PCT/SE97/00471 53 from diethyl ether/i sohexane gave the title Compound as pale brown needles (0.

6 9g). M.P.

I 12 0

C.

MS (APCI) 278 'H NMR (d,-DMSO) d 2.36 (3H, 2.73 (2H1, 2.95 (2H, 7.29 (3H, in), 7.68 (111, dd), 7.92 (1IH, 7.94 (1IH, in), 8.07 (1lH, 12.73 (1IH, s,br).

Example 117 2 4 -(Trifluoromethy1)pheny1]..2n.benzfgindazo.

3 .oI 4 ,5-Dihydro-2-[4-(trifluoromethyl)phenyl] 2 H-benz[gindazol3oI (0.

3 0g) and palladium on charcoal l0g) were heated in dimethylacetamide (5ml) and cyclohexene under reflux for Ilh. the title compound (0.26g). m.p. >235 'C (dec) MS (APCI) 329 'H NMR (d 6 -DMSO) d 7.70 (4H, mn), 7.85 (2H, 8.07 (IH4, mn), 8.27 (2H. 8.30 (111, in), 11.70 01H, s, br).

Example 118 4,-iyr--5mty--yiiy)2-ezgidzl3o (0.

4 0g) and 10% palladium on charcoal (0.20g) were heated in dimethylacetamide, (I15m1) and cyclohexene (15in1) under reflux for 8h. The mixture was allowed to cool to ambient temperature and then filtered. The filtrate was evaporated (100 'C /lmmHg) and the residue was recrystallised from ethyl acetate to give the title compound as pale orange crystals 12g). m.p. 214 'C.

MS (APCI) 276 'H NMR (d,-DMSO) d 2.36 (3H, 7.52 (1lH, 7.66 (3H, mn), 7.82 (1 H, dd), 8.02 (1 H, 8.410 s, br), 8.53 (2H, in).

Pharmacological Data Test A Chronic graft-versus-host test Pharmacological activity of the compounds of the invention may be demonstrated using the method of J. M. Doutrelepont et al. ([Clin. Exp. Immunol., 1991, vol. 83, 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse]. Test compound was administered to mice subcutaneously as a suspension in saline with TWEEN-80 every day for 21 days.

WO 97/34893 PCT/SE97/00471 54 Test B Inhibition of Eosinophilia The effects of the compounds of the invention on inflammatory cells in mouse lungs was assessed by the following method, adapted from Brusselle et al., Clin. Exp. Allergy, 1994, 24, 73-80. The measurement of eosinophil peroxidase as a marker for eosinophil numbers was adapted from Cheng et al., J. Pharmacol. Exp. Ther. 1993, 264, 922-929.

Male Balb/c mice were sensitised to ovalbumin/Al(OH) 3 mixture.

14 days after sensitisation dosing with compound commenced. Compound was administered daily either orally or subcutaneously as a suspension or solution (depending on dose and compound solubility) in 5% TWEEN 17 days after sensitisation and one hour after the fourth dose of compound, the mice were placed in Perspex chambers into which a solution of ovalbumin w/v) was nebulised.

The mice were allowed to inhale the ovalbumin for a period of 30-40 min. This challenge was repeated daily at the same time for a further 3 or 7 days.

In the case of the 4 day challenge, on the final day of dosing an additional challenge with s1 ovalbumin was given 4 hours after the first.

The following day the animals were sacrificed and inhibition of the following parameters was measured by comparison to control animals: Increase in the numbers of inflammatory cells in the bronchioalveolar lavage, in particular eosinophils (after the 4 day dosing).

Accumulation of eosinophils within lung tissue, as measured by the increase in eosinophil peroxidase activity in homogenised lung tissue (after the 8 day dosing).

Increase in antibody titres (IgE, IgG1 and IgG2a) present in the serum obtained from whole blood (after the 8 day dosing).

Certain compounds of the invention show activities in the chronic graft versus host test and the inhibition of eosinophilia test with EDso's in the range of 0.1 10 mg/kg.

Claims (8)

1. A compoulnd of formuila I: Ar' I z D E G X GI) wherein- e B, D. E and G each represent OH, 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=0, C=S, C=NR, CR3R 6 or N 4 Y represents N orN'sR' or CR' 8 *Z represents OR 8 or 0'; R'represents OH or Cj-. alkyl. or with either R2 or RS forms a bond; e R ,represents H. CI- alkyl (optionally substituted by phenyi. COOR'..NR'GR", 0R 1 2 or F) or cycloalkyl, or with either R 3 or R" forms a bond; R3represents H or a bond with R:; R- represents Cj-. alkyl or a bond with R'; R5 represents a bond with R' or R 8 R 6 represents H. CI- alkyl (optionally substituted by phenyl), CI-.7 cvcloalkvl. phenyl. halogen. CI- alkoxy, alkylthio, Cj.- alkylsulfinyl. cyano or R' represents CI- alkyl (optionally substituted by phenyl sibstibited by ~a CI 1 6 alkyl, -baTlcen Or C 1 6 alkOxY gr~p) or C 3 7 Cycloajkyl, eiLther of which may be cptiorially subetituted by halogeni, h-ydrcoxy, alkox, Cj,.6alkvlthio, Cj- alkylsulfinyl, NR1 6 R 0001., COO(C 1-6 alkyl) or cyano; *or R 6 and R 7 together represent C3-5 alkylene, X and Y thereby forming, a rinz

5-7 members; represents H, C14 alkyl or a bond with R 5 *R 9 R1 0 R" R'z, R1 5 R16 R 1 and R independently represent CI..-6 alkyl or H; R R' and R *are independently CI- alkyl, H or together with the nitrozen atom to PRA41 which they are attached form a 3-7 mnembered saturated ring optionally WO 97/34893 PCT/SE9700471 56 containing a further oxygen atom or a nitrogen atom optionally substituted by C 1 alkyl; Ar' represents phenyl, pyridyl, pyrimidinyl. 2-benzothiazolyl. 2- or 3-quinolyl or 2-quinoxalinyl. all of which are optionally substituted by one or more substituents selected from halo, nitro, cyano, phenyl, phenylsulfonyl, Ci,. alkyl, Ci- alkoxy, Ci-, alkylthio, Ci, alkylsulfinyl, COOH, COO(CI 4 alkyl), Ci4 alkyl substituted by phenyl, or phenyl, in which any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may optionally be substituted by fluoro; and A represents halo. cyano, amino, nitro, Ci-. alkyl or CI.. alkoxy; in which phenyl groups which are found in R 2 R 6 or as substituents on Ar may be optionally substituted by C1i_ alkyl, halogen or Ci_6 alkoxy; with the provisos that- when X represents C=O, C=S or C=NR 1 5 then Y represents N; (ii) when R' represents a bond with R 2 then Y represents N'R'; (iii) when Y represents then Z represents R: represents a bond with R 3 or R" and R' and R 5 form a bond; (iv) when Y represents N, then Z represents OR 8 when R' 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' represents alkyl, then R 5 represents a bond with R 8 Y represents N, R: does not represent a bond. and X does not represent NR (vii) when R' represents a bond with R 2 then R 5 and R 8 form a bond. and if X represents NR 4 then R" represents alkyi: (viii) when R 6 represents aryl. halogen. alkoxy, thioalkyl, then R 2 and R 3 form a bond; (ix) when Y represents N and R 2 is sbstituted by any of NO 1 1 CR12 or F, then the substituent and the ring nitrogen of Y may not be attached to the same carbon atom of R:; when R' is substituted by any of NR" 6 OR' or halogen then the substituent and the ring nitrogen of Y may 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-; (xii) when Y represents CR' 1 then X represents CR 3 R 6 with the further provisos tha:: when B, D. E and G all represent CH. X represents CHR 3 Y represents N, R' and R form a bond. R 8 represents H and R 2 and R 3 together represent a bond. then Ar' does 3s not represent unsubstituted phenyl, 4-chlorophenyl. 4-fluorophenyl or 4-methoxyphenyl; WO 97/34893 PCT/SE97/00471 57 when B, D, E and G all represent CH, X represents CHR 3 Y represents N'R 7 R' and R 5 form a bond. R 2 and R 3 represents a bond, R 8 represents H, and R 7 represents methyl, then Ar' does not represent unsubstituted phenyl; when B, D. E and G all represent CH, X represents CH 2 Y represents N, R' and R form a bond, R 8 represents H, and R 2 represents isopropyl, then Ar 1 does not represent unsubstituted phenyl or 4-bromophenyl and when B. D. E and G all represent CH, X and Y represent CH and R' and R 5 form a bond, then Ar' does not represent unsubstituted phenyl. or a pharmaceutically acceptable derivative thereof. 2 A compound of formula I as claimed in claim I wherein Ar represents phenyl or pyridyl. 3 A compound of formula I as claimed in claim 2 wherein Ar' represents phenyl. 4. A compound of formula I as claimed in claim 2 or claim 3 wherein Ar' has a substituent in the para position. S: 5. A compound of formula I as claimed in claim 4 wherein Ar' has a CI. Br, CF 3 C.Fs, z2 OCF 3 or SCH3 substiruent in the para position. 6 A compound of formula I as claimed in any preceding claim, wherein Y represents and X represents CR 3 R 6 in which R 3 forms a bond with R 2 and R 6 represents alkyl.

7. A compound of formula I as claimed in claim 6, wherein R 6 represents branched alkyl.

8. A compound of formula I as claimed in any one of claims 1 to 6, wherein X represents NR 4 in which R 4 represents a bond with R 2 and Y represent N"R 7 9 A compound of formula I as claimed in any preceding claim, wherein B represents CA. A compound of formula I as claimed in claim 9 wherein A represents F.

11. A compound of formula I as claimed in any preceding claim, wherein D or G represents N. I I -M WO 97/34893 PCT/SE97100471 58

12. A compound of formula I as claimed in any preceding claim, wherein R' represents a bond with R 2 or R 5

13. A compound of formula I as claimed in claim 12, wherein R' represents a bond with R 5

14. A compound accordingr to claim 1 which is: 3-Hydroxv-4I-[(4-rnerhoxyphenyl)methyl]-2-(4-trifluoromehylpheny)-2i-prazolo(4,3-c]. isoquinolinium hydroxide. inner salt. 2-(4-Trifluoromethylphenyl)-2H-pyrazolo14,3-c]isoquinolin-3-ol, 2-(4-Chlorop)hen vl)-2,5 -dihvdro-5-methy 1-3 H-pyrazo lo (4,3 -cjcinnolin-3-one, Chlorop'nenvb)-2.3 ,4.5-tetrahvdro-3a.4'-dimethylpyrazolo(4.3-c]isocuinolin-3 one, 2-(4-Chl orochen v l)-3 a.4-dihydro-3 a,4-dimethyl-2H-pyrazolo (4.3-chisoquinoiline -3 2-(4-Chl oroo heny v)-2,4'-dihydro-3 -hydroxv-4-meth ylpyrazolo (4,3 isoquinolin- -Hvdroxv-4- [(4-methoxyphenyl)methyll-2-(3-quinolyl)-2H-pyrazolo(4,3-cliso- :::quinolinium hydroxide, inner salt, -(3-Quinolyl)-2H-pyrazolo(4.3-c)isoquinolin-3-ol, ,4-Dichiorophenvl)-3-hvdroxv-4-[(4-methoxyphenyl)methvl]-2H-pyrazolo(4.3 isoquinoliniumn hydroxide, inner salt, 1,4l-Dilorhenvly)-2H-pyrazolo(4,3)-cisoquinoin-3-ol 3-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-methylpheflyI)-2H-pyrazoiof 4.3-cl- isoquinolinium hydroxide, inner salt, :2-(4-Methvlphenvl)-2H-pyrazolo(4,3-cisoquinoin-3-ol, S. 2-(4-Bromophenyl)-3-hydroxy4-(4-ethoxpheyl)mthyl-2H-pyrazolo E4.3-cl iso- quinoliniurn hydroxide, inner salt, 2-(4-Bromophenv)-21-pyrazoloE4,3"-cJ isoquinolin-3-ol, 2-(3-TrV oromethylphenyl)-3-hydroxy4-((4-methoxypheyl)methlJ-2H-oyrazolo(4,3-c]- isoquinotinium hydroxide, inner salt, 2-(3-Trifluoromethyvhenyl)-2H-pyrazolot4,3-c] isoquinolin-3-oI. 1, 1 -Dimethy iethyl)phenyfl-2H-pyrazolo(4,3-cisoquilolin- 3 -ol. 2-(4-Trifluoromethoxyphenyi,)-2H-pyrazolo(4,3-cjisoquilolin- 3 -ol, 2-4Clrthnl--yrx--ehl2-yaoo43ciounlnu hydroxide, inner salt, -M m WO 97I34893 PCT/SE97/00471 59 2-(4-Chlorophenyl)-3-hydroxy-4-methyl -2H-pyrazolo E4,3-c]cinnolinium hydroxide, inner salt, 2-(4-Chlorophenyl )-3-hydroxy-4-(4-rnethoxyphenyl)rnethyl-2H-pyrazolo iso- quinoliniurn hydroxide, inner salt, 3-Hydroxy-4-merhyl-2-(4-trifluorornethylphenyl)-2H-pyrazolo 4 isoquinolinium hydroxide, inner salt, 3-Hvdroxy-4-methyvl-2-(3-quinolyl)-2H-pyrazoiof4,3-c]isoquinolinium hydroxide, inner salt, 2.(6-Chloro-3-pvridyl)-3-hydroxy-4-rnethyl-2H-pyrazo 10(4,3-clisoquinoliniuni t0 hydroxide, inner salt, 2-(3,4-Dichlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo(4.3-clisoquinolinium hydroxide, inner salt, 3-Hydroxv-4-methyl-2-(4-methylp~henfl)-2H-pyrazolo[4.3 -clisoquinoliniurn hydroxide. inner salt. 2-44-B romrohen vl)-3 -hydroxyv-4- methylI-2H-pyrazolo isoquino iinium :;:hydroxide, inner salt. *3-Hvdroxv-4-methyl-2-(3-rrifluorornethylphenyl)-2H-pyrazolo[4,3-cisoquinolinium hydroxide. inner salt, 1, 1 -Dimethvlethyl)phenyl]-3-hydroxy-4-methyl-2H-pyrazolol4.3-cjisoquinoliniurn hydroxide, inner salt. -(6.Chl oro- 3-pyridyl1)- 3-hvdroxy-4- ((4-methoxyphenv l)me thy I]-2H- vrazolo 4.3-c iso- quinolinium hydroxide, inner salt. 3-Hydroxv--4'-methyl-2-(6-mnethyl-3-pyridyl )-2H-pyr azolo(4,3-clisoquinoli nium hydroxide, inner salt. 2-(4-trifluororethylphenyl).3 -hydroxy-4-(2-hydroxyethyl)-2H-pyrazolo(4,3c1 iso- quinolinium hydroxide, inner salt, 3-Hydroxy4..rn-ethl-2-(5-nethyl-2-pridyl)-2H-pyralZol(4.3'-c~isoquinoiinium hydroxide, inner salt, 3-Hydroxy-4-methyl-2-(4-( I -merhylethvl)phenyl]-2H-pyrazolo[4,3-cjisoquinolinium 3o hydroxide, inner salt, 3-Hydroxy--methyl-2-(4-nitrophenyl)-2H-pyrazoo( 4 3 isoquinoliniurn hydroxide, inner salt, 2-(4-Cyanophenyl )-3-hydroxy-4-methyI -2H-pyrazolo(4.3-cjisoquinoliniuzn hydroxide, inner salt, 2-4Croyhni--yrx--ehl2-yaoo43ciounlnu hydroxide. inner salt, WO 97/34893 PCT/SE97/00471 2-(4-Chloro-3-trifluoromethylphely l)-3-hydroxy-4-methyl-2H-pyrazolo(4,3-c)- isoquinolinium hydroxide, inner salt, hydroxide, inner salt, 3-yrx--ehl2(-ehltipey) -yaoo43cisoquinoliniurn hydroxide, inner salt, 4-Cyclopropy l-3-hydroxy-2-(4-tfluoromethylpheflyl)-2H-PYrazolo f4,3-c] isoquinoliniurn hydroxide, inner salt, 4 -Cccopropyl-'3-hvdrox-2(6methvl13pvrdyl) 2 Hpyraolo[ 4 ,3-cisoquinouinium hydr- oxide, inner salt, 44(1, 1 -Dimnethy 1-2-hvdroxy)ethyl] -hydroxy-2-[(4-trifluoromethyl)phell]-2H-pyrazolo [4.3-c]isoquinoliliut hydroxide, inner salt, 3-yrx--2mtovty)2(4tifurm y~hnl-Hprzi(,-] isoquinoliniurn hydroxide, inner salt, is 2-4-h orpbny1- hdoy4 2-mtytio ehlI-Hprzl 43)ciounln :hydroxide, inner salt. 3-Hvdroxy-4- [2-(rnethy lthio)ethylI] 2-(4-trifluoromethylphenyl)-2H-pyrazolo[ 4 3 :::isoquinolinium hydroxide, inner salt, *:*~4-Cvclopropy j-2-(4-trifluoromfethoxyphenyl-3hydroxy-2H-pyrazoIo( 4 3 -cisoquinolinur :.2cr hvdroxide, inner salt, 2-(4-Chloro-3- rtjluoromethylphefl)-4-cyclopropy l-3-hydroxy-2H-pyrazolo- 4,3 -clisoquinolinium hydroxide. inner salt, hydroxide, inner salt. hydroxide. inner salt, [ooehlhey)2-yaoo4,3-c] isoquinolinium hydroxide, inner salt, 2-(4-TrifluoromethylphenI) 4 r(l -ethoxycarbornylrfethyl)-3-hydroxy- 2 THpyr azolo(4,3'-clisoquinoliniurn hydroxide, inner salt, 3-Hdoy4 4mtoyhnlmty]2phnl2-yaoo43ciountnu hydroxide, inner" salt. 3-Hydrox y- 4 -mtyehl--4tilooehlpey)2-yaoo4- ci quinoliniurn hydroxide. inner salt, 3-Hvdroxy-4-(l -mtyehy)2(-ti.oomtypenl .pyrazolot4.3-c] iso- quinoliniurn hydroxide, inner salt, W GIMLA901 Dt-r/Crn-tm 3-Hydroxy-2-(4-iodophenyl)-4mehyl-2H-pyrazoko isoquinoliniurn hydroxide, inner salt, 2-(6-Chloro-3-pyridvl)-2H-pyrazolo(4,3'-clisoquinolin-3-ol, 24[4-0 -,Methy Iethvyphenyi]-2H-pyrazolof4,3-clisocuinolin-3-ol. 2-(4-PentafluoroehylphenyI)-2H-pyrazolo(4,3-cisouinoin- )ol, 2,4-Dihvdro-3 -hydroxy-4-rnerthy- 2 2 -pyrirnidinyI)-5H-pyrazolo[4,3 1. I-b iphenyl 1 -4-y I)-2,4-di hy dro-3-hydroxy-4-methyI1-5H-pyrazo o (4,3 cj iso quino one. 2.4-Dihydro-3 )-hydroxy-4-methyl-2-(4-trifluoromethylphenvl)-5H-pyrazolo(4.3-ciso. 2-(6-Chloro-3 -pyridvl)-2.4-dihvdro-3-hvdroxy-4-nerhvl-5H-pyrazolof 4.3-c] isocuinolin- -a-one, 2.4-Dihvd-o-3 -hydroxy-2-(4-iodophenyl)-4-merhyl-5H-pyrazolo[4.3-c isocuinolin- 2.4-Dihvdro-3--hvdroxv-4-(4-methoxyphenyirnethvl)-2 azoiof4.3'-c]isoouinoiin-5-one. 00 1. ihd-3hvadroxv-4-( I-methylerhy i)-2-(4-rrifluorornethvlphenvl)-5H-pyrazolo- 4,3-c]isoquinoin-5-one, 2.4-Dihvdro-3- hydroxy-4-merbvl-2-[4-( I -methylethyl)phenvil-5H-pvrazoio[4.3-ciso- 2.4-Dihvdro-3. hvdroxy-2-(4-rrfluoroznethy Iphenyl )-5H-pyrazolo[4.3-cjisoquinoli-5-one, 2.4-Dihvdro-3'-hvdroxy-2- I -merhy Iethyl)phenfl-5H-pyrazolo[4,3-c]isoquinolin-5one. 2.4A-Dihvdro-3-hydroxy-2-([ 1.I'-biphenyl]-4-yl)-5H-pyrazolo(4.3-cjisoquinolin-5-one. 2-(4-Chlorophenyl)-3-hydroxy4-f(4-mehoxyphenvl)nethvl]-5-nethvl-2H-pyrazolo- (4.3-clisocuinoliniurn hydroxide. inner salt, *:s0 2-(4-Chl orop hen vl0-5-methy 1-2H-p yrazolIo[4.3 isoquinoli n-3-oI. 4-CyclopropylI-3-hydroxy-5-rnerhyl-2-(4-E-ifluorornerhylphenvl)-2H-pvrazolo[4,3-c]- isoquinoliniurn hydroxide, inner salt, 3-Hydroxv-4-(2-methoxyethyl)-5-merhy I-2-((4-crifluorornethyl)phenv IJ-2H-pyrazolo (4,3 -clisoquinoliniurn hydroxide. inner salt, 2-(4-Chlorophenvl -hydroxy-4,5-dirnerhyl-2R-pyrazolo isoquinoliniurn hydroxide, inner salt. 5-EthvI-3-hydroxv-methyI1-2 -(4-trifluorone thy I hen vI)-2H-pyrazol o[4,3 isoqu inolin- ium hydroxide, inner salt, 3 -Hydroxv-5-methyl 14-( I -rnerhvlethyl)-2-(4-trifluorornerhylphcnvl)-2H-pyrazolo- (4,3-clisoquinoliniumn hydroxide, inner salt. WO 97134893 PC-f/SE97/00471 62 4-Merhy 1 -methylethyl)-3-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo- [4,3 -clisoquinoliniurn hydroxide, inner salt. 3-Hydroxy-4,5-dinethyl-2-(4-trifluororfethylphenyl)-2H-pyrazolo[4,3-clisoquinoiiniun hydroxide, inner salt, 5-Chloro-2-(4-trifluoromethylpheflyl)-2H-pyrazOoo4.3-clisoquinolin-3-ol, 3a.4-Dihvdro-3a-hydroxy 2-(4-trifluorornethylphenyI )-2H-pyrazolo(4,3I-clisoquinolin- -3 2,4-Dihvdro-3 -methaxy-4-ethyl-2-(4-rifluoromcthylpheny)-5H-pyrazolo[4,3-cliso- -one, to 2-(4-Chlorophenyl 2-(N,N-dimethylamina)ethyl J-3-h ydroxy-2H-pyrazolo(4,3-c] isoquinoliniurn hydroxide, inner salt. 3-Hydroxy-4-mechy 1-2-(4-methy lsul fin ylph eny l)-2H-rpyrazoiol4,3-c] isoquinoin Ium hydroxide, inner salt, 2-1.4-Chioraphenyl )-3-hydroxy-442-( rethvisulfinvyI)ethyl]-2I1-pyrazolo(4.3'-c] iso- quinoiiniurn hydroxide, inner salt. 3-Hy droxy-4- [2-(methvlsulfinyl)e,,hyII-2-(4I-trifluaramethylphenyl )-2H-pvrazala(4'.3-cj isa- quinaliniurn hvdroxide, inner salt. :5-[2-(4-Methoxvph lehl-2-(4-crifluorornerhylphenyl )-2H-pyrazolo[4.3-clisocuinolin- 3-al, *ai '9-Fiuaro-3-h-v droxv-4-[(4-methoxyphenyl)rnethy l1-2-(4-trifluoromethylphenyl)-2H-pyr- azola(4,3'-cjisoquinolinium hydroxide. inner salt. :2-(4-Chlorophenvl)-7-fluoro-3)-hydroxy-4-ethl-2H-pyrazolo(4.-cjisoqunolinium hydr- oxide, inner salt. 0,7-Fiuoro-3 -hydroxy-4-rehyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4.3:c]iso- quinolinium hydroxide, inner salt, 2-(4,qChlarophenyl)-4-cyclopropyl-9-fluoro-3-hydroxy-2H-pytaolo( 4 isoquinoliniurn hydroxide, inner salt, 4-Cyclopropy l-9-fluoro-3 .hydroxy-2-(4-rrifluoromethylphenyl)-2H-pyr- azolo(4,3)-c]isoquinoliniurn hydroxide. inner salt, 2-(4"-Chlorophenyl)-9-fluoro--hydroxy-4-methY l-2H-pyrazolo(4,3-clisoquinolinium hydroxide, inner salt, 2-4Clrpev)9fur- -yrx-4[4mtoyhnlmty]2-yaoo E4,-c)isoquinolinium hydroxide, inner salt, 9-ioo3hdov4mty-4tilooehypey)2-yaoo43ciounlnu hydroxide. inner salt. ,-4Clrpev)9fur-Hprzl(.-~sqioi--l WO 97/34893 PCT/SE97/00471 63 7-Fluoro-2-(4-trifluoromethylphenyl)-21i-pyrazolo(4,3-clisoquinolin.3-o1 2-(4-Chlorophenyl )-7-fluoro-2H-pyrazolo isoquinolin-3-ol, 9-Fluoro-3-hydroxy-4-[(4-nechoxyphenyl)ncthy]-5-methy..2 4 -trifluoromethyiphenyl)-2R-pyrazolo(4,3-c~isoquinolinjum hydroxide, inner salt, 2-( 4 -Chlorophenyl)-9-fluoro-3-hydroxY- 4 -[(4-methoxyphenvl)rnethy1]-5merIhy1-2Hpyr- azolo(4.3-c~isoquinolinium hydroxide, inner salt, 9-Fluoro-5-methv1-2-(4-trifluoromethylpheny)-2H-pyrazolo4,3'Icjisoaujnojjn-3-olj 2-(4-chlorophenvl)-9-fluoro-5-methyl-2H-pyrazoio[4,3-c] isoquinolin-3-ol, 2.4-Dihvdro-)- hydroxv-4-rnethvl-2-(4-trifluoromethyiphenvl)-5H-pyrazoio(4,..Ciiso- 3-Hydroxv-4-merhyli.5-methylthio-2-(4-trifluoromethylphenyl)-2Horvrazo lo(4.3-cjiso- cuinoliniurn hydroxide, inner salt, 2-(4-Tri f uoromethy lDhenyl )-2.4-di hydro-5-irnino-4-methvlI-5H- [vrazolo[4.3-cj iso- quinoiin-3-ol, 3: 3-Hydrox 4- metho xvphen v )mechy 1-2 trifl uorometh v phen v I)-2H-pyrazo Io( 1,71naphthyridiniumn hydroxide, inner salt, 2--(4-Trirluoromethylphenyl)-2H-prazoo3,4-fl ,7naphthyridin3ol, -Hydrox v-4-rnethvl-2-(4-trifiuoromethvlphenyl)-2H-pyrazolo(3 /31[ I ,71naphthvridiniurn hydroxide, inner salt. 2--(4-Chlorophenv l)-3-hydroxy-4-methvl-2H-pyrazolo[3,.4--][1 .7]narhhridinium :hydroxide-. inner salt, -Hydrov4mtv -dmehlmn)2(-rilooe ypev)-2H-pyrazolo(4.3-c] :::isoquinolinium hydroxide inner salt, 3-Hydroxv -4-methvl-5-rnorpholiny l-2-(4-trifluoromethylphenyl )-2H-pyrazolo(42.3-c) iso- quinolinium hydroxide inner salt, -Hvdroxv-4-rnethvl-S-piperazinvl-2-(4-Erifluoromethylphenyl)-2H-ovrazolo( 1.3 -cjiso- quinolinium hydroxide inner salt, 4,5-Dihydro-2 -f4-(trifluoromethvl )phenyl]-2H-benz[-jindazol-3 -ol, 4.5-Dihvdro-2-( 5-merhyl-2-pyridinyl)-2H-benz(glindazol-3-ol, 2-[4-(Trifluoromethyl)phenyl]-2H-benz~g] indazol-3-ol, 2-(5-Methyl-2-p yridinyl)-2H-benz~cgjindazol-3-ol, and pharmaceutically acceptable derivatives thereof. A process for the preparation of compounds of formula I as defined in claim 1 which comprises: \u/n o7/ 4ro l--r ri gr. iiuun 0i I 64 Z- 1- I lazy/UU4i preparation of compounds of formula I where X represents CH 2 or C=O, Y represents N. Z represents OR 8 R 5 and R 8 form a bond and R' and R 2 form a bond by oxidation of a corresponding compound of formula I where R' and R: both represent H. X, Y. Z and R 5 are as defined above and B, D. E. G and Ar' are as defined in claim 1; preparation of compounds of formula I where one of B, D, E and G represents CA wherein A represents amino by reduction of a corresponding compound of formula I. where 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', R: and R 5 are as defined in claim 1; preparation of compounds of formula I where one of B. D, E and G represents CA wherein A represents halo by diazotisation of a corresponding compound of formula I. where one of B, D, E and G represents CA wherein A represents amino and the remainder of B, D, E and G, and X, Y, Z, Ar.' R: and R' are as defined in claim 1. and decomposition of the diazonium salt in the presence of the halide anion or a source thereof; preparation of compounds of formula I where one of E. D. E and G represents CA wherein A represents cyano by reaction of a corresponding compound of formula I, where one of B. D, E and G represents CA wherein A represents bromo and the remainder of B. D, E and G, and X, Y, Z, Ar', R: and R 5 are as defined in claim 1; preparation of compounds of formula I where X represents CR 3 R 6 Y represents Z represents R' and R" form a bond, R' and R 5 form a bond and R 6 'represents alkylthio by displacement reaction of a corresponding compound of formula I, where X represents CR R 6 wherein R 6 represents methylthio or halogen. Y. Z. R'. R' and R4 are as defined above and B, D. E. G and Ar t are as defined in claim 25 with a compound of formula II: R6-S' H H(II) wherein R" represents alkyl; (f preparation of compounds of formula I where X represents CR3R 6 Y represents NR' 7 Z represents .R 3 and R 2 form a bond. R' and R 5 form a bond and R 6 represents alkoxy by displacement reaction of a corresponding compound of formula I, where X represents CR3R 6 wherein R 6 represents methylthio or halogen, Y. Z. R 2 R 3 and R 5 are as defined above and B, D, E. G and Arl are as defined in claim 1. with a compound of formula m: WO 97/34893 PCT/SE97/00471 Rsa/O'H wherein R" is as defined above; preparation of compounds of formula I where X represents CR3R 6 Y represents Z represents R 3 and R 2 form a bond, R' and R 5 form a bond and R 6 represents NRIR 14 by displacement reaction of a corresponding compound of formula I, where X represents CR 3 R 6 wherein R 6 represents methylthio or halogen, Y, Z, R', R 3 and R 5 are as defined above, and B, D, E, G Ar' are as defined in claim 1, with a compound of formula IV: R 1 3 RH SIV) wherein R 1 3 and R" are as defined in claim 1; preparation of compounds of formula I where X represents CR3R 6 Y represents Z represents R 3 and R 2 form a bond, R' and R 5 form a bond and RO represents methylthio by reaction of a corresponding compound of formula I. where X represents C=S. Y represents N. Z represents OH. and R 5 are as defined above and B, D. E. G and Arl are as defined in claim 1, with a methylating agent: preparation of compounds of formula I where X represents C=S. Y represents N, 20o Z represents OH and R' represents a bond with R 5 by reaction of a corresponding compound of formula I. where X represents C=O, Y, Z, R i and R' are as deined above and B, D, E. G, Ar' and R: are as defined in claim 1, by thionation: preparation of compounds of formula I where X represents CR 3 R 6 Y represents 7* NR', Z represents 0' and R 6 represents halogen by reaction of a corresponding compound of formula I, where 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', R' and R 2 are as defined in claim 1, by halogenation: preparation of compounds of formula I where X represents CR3R 6 Y represents N'R, Z represents R' and R 2 form a bond. R' and R 5 form a bond and R 6 represents alkyl by reaction of a corresponding compound of formula I. where X represents C=O, Y represents N, Z represents OH, R' represents a bond with R 5 B, D, E. G. Ar' are as defined in claim 1 and R' represents a group corresponding to R 7 as defined in claim 1, by reaction with a nucleophilic alkylating reagent comprising a compound of formula V: WO 97/34893 PMSE97/00471 66 R 5 gHal (V) wherein R 6 is as defined above and Hal represents halogen, or another source of the s anion corresponding to R6; preparation of compounds of formula I where X represents CR3R 6 Y represents NIR 7 Z represents R 3 and R 2 form a bond, R' and R 5 form a bond and R 6 represents alkyl by reaction of a corresponding compound of formula I, where X represents CR3R 6 wherein R 6 represents H, Y, Z. R 2 and R 5 are as defined above and B, D, E, G and Ar' are as defined in claim 1, with a nucleophilic alkylating reagent comprising a compound of formula V as defined, or another source of the anion corresponding to R6; preparation of compounds of formula I where X represents C=O, Y represents N, Z represents OR 8 R' represents a bond with R 5 and R 8 represents alkyl by reaction of a corresponding compound of formula I, where Z represents OR 8 wherein R 8 represents H. X. Y. and R 5 are as defined above and B. D. E, G. Arl and R: are as defined in claim I, with a compound of formula VI: R'Hal (VI) wherein R 8 reoresents alkvl and Hal is as defined above: preparation of compounds of formula I where R' represents OH. X represents C=0, Y represents N, Z represents OR 8 and R' represents a bond with R 8 by reaction of a corresponding compound of formula I. where Z represents R' and R 5 form a bond, X. Y, and R 2 are as defined above and B, D, E. G and Ar' are as defined in claim 1, by treatment with an oxidising agent; preparation of compounds of formula I where X represents CR' 3 R, Y represents N'R 7 Z represents R' and R 2 form a bond and R' and R 5 form a bond by reaction of a corresponding compound of formula I, where Y represents N, Z represents OH, X, R 2 and R 5 are as defined above and B, D, E, G and Ar' are as defined in claim 1, with a compound of formula IX: R T Hal (IX) wherein R' is as defined in claim 1 and Hal are as defined: WO 97/34893 PCT/SE97/00471 67 preparation of compounds of formula I where X represents C=O, R 2 does not represent H, Y represents N, Z represents OH and R' represents a bond with R 5 by reaction of a corresponding compound of formula I, where R 2 represents H. X, Y, Z, R' and R 5 are as defined above and B, D, E, G and Ar' are as defined in claim 1, with a s compound of formula VII: R'Hal (VII) wherein R 2 not representing H, is as defined in claim I and Hal is as defined above: preparation of compounds of formula I where B, D, E and G represent CH or CA, X represents NR". Y represents N*R 7 Z represents R 4 and R 2 form a bond and R' and R 5 form a bond by reaction of a compound of formula VIII: Ar' N-N I A (Vill) wherein A and Ar t are as defined in claim 1, with a compound of formula IX as R'Hal (X) wherein R is as defined in claim I and Hal is as defined above; defined above; preparation of compounds of formula I where D, E and G represent CH oresents CA, represents OH, R and R 2 form a bond and R represents a bond with R s by 20 R and R form a bond by reaction of a compound of formula Vi as defined above with a compound of formula X: R'Hal (X) wherein R' is as defined in claim 1 and Hal is as defined above; preparation of compounds of formula I where X represents CR'R 6 Y represents N, Z represents OH, R 3 and R 2 form a bond and R' represents a bond with R 5 by treatment of a corresponding compound of formula I, where Y represents N"R 7 Z represents R 7 represents CH 2 CsHAOalkyl. X, R1. R 2 and R 5 are as defined above, a and B, D, E, G and Ar' are as defined in claim 1, with an acid; WO 97/34893 PCT/SE97/00471 68 preparation of compounds of formula I where X represents CR 3 R 6 Y represents N, Z represents OH, R 3 and R 2 form a bond and R' represents a bond with R 5 by treatment of a corresponding compound of formula I, where Y represents N'R 7 Z represents R 7 represents CH 2 phenyl substituted by C1 6 alkyl or Cis. alkoxy, X, R 2 and Rs are as defined above, and B, D, E, G and Ar' are as defined in claim 1, with hydrogen; preparation of compounds of formula I where X represents C=O, Y represents N, Z represents OH, R 2 represents H and R' represents a bond with R 5 by treatment of a corresponding compound of formula I. where Y represents Z represents R 7 represents CH 2 C 6 HaOalkyl, R 2 and R 5 are as defined above, and B, D, E, G and Ar' are as defined in claim 1, with an acid; preparation of compounds of formula I where X represents CR3R 6 Y represents Z represents R 3 and R! form a bond. R' and R 5 form a bond and R 6 represents H by reaction of a compound of formula XI: R B COOR I S* G (X) where X represents CH 2 R' represents H. R: represents a group corresponding to R: as a: defined in claim 1 in the compound of formula I. B. D, E and G are as defned in claim 1 and R is alkyl, with a compound of formula XII: Ar'NHNH, (XII) wherein Ar' is as defined in claim 1; s preparation of compounds of formula I where X represents C=O. R: does not represent H. Y represents N, Z represents OH and R' represents a bond with R 5 by reaction of a compound of formula XI as defined above, where X represents C=O, R' represents H, R 2 is as defined above. R is as defined above and B. D. E and G are as defined in claim 1, with a compound of formula XII as defined above, wherein Art is as defined in claim 1; preparation of compounds of formula I where X represents CH 2 Y represents N'R 7 Z represents OR 8 R 8 and R 5 form a bond and R' represents alkyl by reaction of a compound of formula XI as defined above, where X represents CHI. R' represents WO 97/34893 PCTSE97/00471 alkyl, R is as defined above and B, D, E, G and R 2 are as defined in claim 1, with a compound of formula XII as defined above, wherein Ar' is as defined above; preparation of compounds of formula I where X represents C=O, Y represents N, Z represents OR 8 R 8 and R 5 form a bond and R' represents alkyl by reaction of a s compound of formula XI as defined above, where X represents C=O, R' represents alkyl, R 2 represents H or alkyl, R is as defined above and B, D, E and G are as defined in claim 1, with a compound of formula XII as defined above, wherein Ar' is as defined above; preparation of compounds of formula I where X represents CR 3 R 6 Y represents CR 1 8 Z represents OH, R' and R 5 form a bond and R 2 and R 3 form a bond by oxidation of a corresponding compound of formula I where X represents CR 3 R 6 Y represents CR 1 8 Z represents OH, R 2 and R 3 represent H, R' andR 5 form a bond and B, D, E. G, Ar', R 6 and R 18 are as defined in claim 1; or (aa) preparation of compounds of formula I where X represents CR 3 R 6 Y represents CR 1 8 Z represents OH, R 2 and R' represent H and R" and R 5 form a bond by reaction a compound of formula XII as defined above with a compound of formula XX: OH 0 a.D OR I II wherein R is as defined above and B, D, E, G, R 6 and R 18 are as defined in claim 1. ID this 31st day of Augst 1999 SAS PHAIRMIjCAlHS LD., By its Patent Attorneys, F/F. MIIJER (Bnce lngton)