Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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I
PHARMACEUTICALL,Y USEFUL COMPOUNDS
This invention relates to pharmaceutically useful compounds, methods for their
preparation, their use as medicaments, and pharrnaceutical formulations including them.
Certain pyrazolo[4,3-c~iso~uinolin-3-ones are known from J. Chem. Soc. 599 (1959)
(Hinton er al.). 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 al. ). Certain other
o pyrazolo[4,3-c3isoquinolin-3-ols are disclosed in Gaodeng XI~PYj(7Q Huaxue Xuebao 1991,
12, 162~16~2 (Qian Jian-hua et al.). 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-infl~mm~tQry activity. In a first aspect the invention therefore
provides a compound of formula I or a pharmaceutically acceptable derivative thereof for
use as a pharrnaceutical:
/ r
N - N
R ~xe~Rs
E~G 'Y' 2
(I)
wherein:
~ B, D, E and G each represent CH, CA or N provided that no more than one of B,
D, ~ and G represents CA and no more than one of B, D, E and G represenis N;
~ X represents C=O, C=S, C=NR'5, CR3R6 or NR4;
~ Y represents N or N' R7 or CRI8;
~ Z represents oR8 or O~;
~ Rl represents OH or C~_6 alkyl, or with either R- or R5 forrns a bond;
~ R- represents H, C~_6 alkyl (optionally substituted by phenyl, COOR9, NR~~R~ l,
ORI- or F) or C3 7 cycloalkyl, or with either R~, R3 or R4 forms a bond:
R3 represents H or a bond with R-;
~ R4 represents C,-6 alkyl or a bond with R-;
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WO 97/3~893 PCT/SE97/00471
R5 represents a bond with Rl or R8;
~ R6 represents H, C,~ alkyl (optionally substituted by phenyl), C3_7 cycloalkyl,
phenyl, halogen, Cl_6 alkoxy, C~_6 alkylthio, Cl_6 alkylsulfinyl, cyano or
NRI3R'4;
s ~ R7 represents Cl~ 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, Cl-6 alkylsulfinyl, NRI6Rl7, COOH, COO(C~_6 alkyl) or cyano;
~ or R6 and R7 together represent C3_s alkylene, X and Y thereby forrning a ring of
5--7 members;
o . R8 represents ~, Cl_6 alkyl or a bond with R5;
R9, Rl~, R'l, Rl, Rl5, Rl6, Rl7 and Rl8 independently ~G~Iesen
Ci_6 alkyl or H;
~ Rl3 and R~4 are independently Cl~ alkyl, H or together with the nitrogen atom to
which they are ~tt~ehe~l form a 3-7 membered saturated ring optionally
containing a further oxygen atom or a nitrogen atom optionally substituted by
Cl_6 alkyl;
~ Arl represents phenyl, pyridyi, 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, Cl~ alkyl,
Cl_6 alkoxy, C~-6 alkylthio, Cl_6 alkylsulfinyl, COOH, COO(C,_6 alkyl), Cl~
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, Cl_6 alkyl or Cl_6 alkoxy:
in which phenyl ~roups which are found in R-, R6, R7 or as substituents on Ar~ may be
2s ~ optionally substituted by Cl_6 alkyl, halogen or Cl_6 alkoxy;
with the provisos that:
(i) when X represents C=O, C=S or C=NRI5, then Y represents N;
(ii) when R4 represen~s a bond with R~, then Y represents N+R7;
(iii) when Y represents N~R7, then Z represents O~, R represents a bond with R3 or R4
and R' and Rs forrn a bond;
(iv) when Y represents N, then Z represents oR8;
(v) when Rl represents OH, then X represents C=O, Y represents N, Z represents oR8
and R5 represents a bond with R8;
(vi) when R~ represents alkyl, then R5 represents a bond with R8, Y represents N, R does
3s not represent a bond, and X does not represent NR4;
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(vii) when Rl represents a bond with R2, then R5 and R8 form a bond, and if X represents
NR4 then R4 represents alkyl;
(viii) when R6 represents aryl, halogen, alkoxy, thioalkyl, then R7 and R3 form a bond;
(ix) when Y represents N or N+R7 and R2 is substituted by any of NRI~Rll, oRl7 or F,
~hen the substituent and the ring nitrogen of Y may not be attached to the same
carbon atom of R-;
(x) when R7 is substituted by any of NRI6Rl7, ORI- or halogen then the substituent and
the ring nitrogen of Y may not be ~tt~hefl to the same carbon atom of R7;
(xi) when one of ~3, D, E and G represents N, then X does not represent NR4;
o (xii) when Y represents CR~8, then X represents CR3R6;
with the further proviso that:
~ when B, D, E and G all ,e~.Gsent CH, X represents CHR3, Y represents nitrogen, R' and
R5 forrn a bond, R8 ~G~l~sents H and R- and R3 together IGplGs~llt a bond, then Arl does
not .t~.esent unsubstituted phenyl, 4-chlorophenyl, ~fluorophenyl or 4-methoxyphenyl.
~5
Certain compounds of forrnula (I) are novel. According to the invention there is ~urther
provided a compound of formula I:
Arl
N--N
F~G 'Y' 2
(I)
wherein:
~ B, D, E and G each represent CH, CA or N provided that no more than one of B,
D, ~ and G represents CA and no more than one of B, D, E and G represents N;
~ ~ represents C=O, C=S, C=NRI5, CR3R6 or NR4;
~ Y represents N or N+R7 or CRI8;
Z represents oR8 or O~;
~ Rl represents OH or Cl_6 alkyl, or with either R- or R5 forms a bond;
~ R- represents H, Cl_6 alkyl (optionally substituted by phenyl, CooR9, NRI~Rl ~,
oRI7 or F) or C3 7 cycloalkyl, or with either Rl, R3 or R4 forms a bond;
~ R3 ,Gp-Gsellts H or a bond with R-;
~ R4 represents Cl_6 alkyl or a bond with R-;
~ R5 represents a bond with R' or R8;
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~ R6 represents H, Cl_6 alkyl (optionally s1~bstituted by phenyl), C3_7 cycloalkyl,
phenyl, halogen, C,_6 alkoxy, C,~ alkylthio, Ci_6 alkylsulfinyl, cyano or
NR'3R'4;
~ R7 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,
Cl~ alkylthio, Cl-6 alkylsulfinyl, NRI6Rl7, COOH, COO~C~_6 alkyl) or cyano;
~ or R6 and R7 together represent C3_s alkylene, X and Y thereby forrning a ring of
5-7 members;
~ R8 represents H, C~-6 alkyl or a bond with Rs;
~o . R9, Rl~, R~ ~, R~-, Rls, Rl6, Rl7 and Rl8 independently represent Cl_6 alkyl or ~;
~ R~3 and Rl4 are independently C~-6 alkyl, H or together with the nitrogen atom to
which they are attached forrn a 3-7 membered saturated ring optionally
containing a further oxygen atom or a nitrogen atom optional]y substi~uted by
Cl_6 alkyl;
~ Ar~ represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-~uinolyl or
2-quinoxalinyl, all of which are optionally substituted by one or more
substituents selected from halo, nitro, cyano, phenyl, phenylsulfonyl, C,_6 alkyl,
Cl_6 alkoxy, Cl_6 alkylthio, C~-6 alkylsulfinyl, COOH, COO(CI_6 alkyl), C~-6
alkyl substituted by phenyl, or phenyl, in which any alkyl, alkoxy, alkylthio and
20 = alkylsulfinyl groups may optionally be substituted by fluoro; and
~ A represents halo, cyano, amino, nitro, C,_6 alkyl or C,-6 alkoxy;
in which phenyl groups which are found in R2, R6, R7 or as substituents on Arl may be
optionally substituted by Cl_6 alkyl, halogen or C~_6 alkoxy;
with the provisos that--
(i) when X represents C=O, C=S or C=NRI5, then Y represents N;
(ii) when R4 represents a bond with R-, then Y represents N+R7;
~iii) when Y represents N+R7, then Z represents O~, R- represents a bond with R3 or R4
and R' and R5 forrn a bond;
(iv) when Y represents N, then Z represents oR8;
(v) when R~ represents O~I, then X represents C--O, Y represents N, Z represents oR8
and R5 represents a bond with R8;
(vi) when R' represents alkyl, then R5 represents a bond with R8~ y represents N, R- does
not represent a bond, and X does not represent NR4;
(vii) when Rl represents a bond with R-, then R5 and R8 forrn a bond, and if X represents
3s NR4 then R~ represents alkyl;
(viii) when R6 represents aryl, halogen, alkoxy, thioalkyl, then R- and R3 forrn a bond;
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s
(ix) when Y represents N or N+R7 and R- is substituted by any of NRI~R~ 1, ORI- or F,
then the substituent and the ring nitrogen of Y may not be attached to the same
carbon atom of R2;
~x~ when R7 is substituted by any of NRI6Rl7, ORI- or halogen then the substituent and
the ring nitrogen of Y may not be attached to the same carbon atom of R7;
(xi) when one of B, D, E and G represents N, then X does not ,~lese~lt NR4;
(xii) when Y represents CRI8, then X represents CR3~6;
with the further provisos that:
(a) when B, D, E and G all represent CH, X represents CHR3, Y represents N, Rl and Rs
o form a bond, R8 represents H and R- and R3 together represent a bond, then Ar~ does
not lepl~sGIlt unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or
4-methoxyphenyl;
(b) when B, D, E and G all represent CH, X represents CHR3, Y l~ ;sents N+R7, R~ and
Rs form a bond, R2 and R3 represents a bond, R3 represents H, and R7 represents
methyl, then Arl does not represent unsubstituted phenyl;
(c) when B, D, E and G all represent CH, X represents CH2, Y .~IGse.,L~ N, Rl and Rs
form a bond, R3 represents H, and R2 l~yl~s~l~ts isopropyl, then Arl does not represent
unsubstituted phenyi or 4-b~ulnophenyl; and
(d) when B, D, E and G all l~yl~;sellL CH, X and Y ~ ;S~.IL CH2 and Rl and R5 form a
bond, then Arl does not represent unsubstituted phenyl.
or a pharmaceutically acceptable derivative thereof.
Preferably Ar~ represents phenyl or pyridyl, most preferably phenyl. The phenyl group Ar~
preferably has a substituent in the para position, more preferably a Cl, Br, CF3, C2F5, OCF3
or SCH3 substituent in the para position especially a CF3, C2Fs~ OCF3 or SC~I3 substituent
in the para position.
Preferably Y represents N+R7, and X represents CR3R6 in which R3 forms a bond with R-
and R6 represents alkyl. In such a case, R6 preferably represents branched alkyl.
Alternatively, X may represent NR4 in which R4 represents a bond with R2 and Y represent
N+R7.
Preferably B represents CA. In such a case, A preferably represents F.
In the case where one of B, D, ~ and G represents N, preferably it is D or G that represents
N.
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Preferably Rl represents a bond with R2 or Rs. In such a case, R~ preferably represents a
bond with R5.
Particularly preferred compounds of the invention include those exemplified herein
including the free forrn and all salts and solvates thereof.
Pharn~elltically acceptable derivatives includes solvates and salts. Particular salts which
may be mentioned include hydrochloride, hydrobromide, benzenesulfonate, tosylate and
o methanesulfonate.
The compounds of forrnula 1 may exhibit tautomerism. All tautomeric forms and mixtures
thereof are included within the scope of the invention. The compounds of forrnula I may
also contain one or more asymmetric carbon atoms and may therefore exhibit optical
15 and/or diastereoisomerism. All diastereoisomers may be separated using conventional
techniques, for example chromatography or fractional cryst,.llis~t~on. The various optical
isomers may be isolated by separation of a racemic or other mixture of the compounds
using conventional, for example fractional crysf~'ilic,.ti~n or HPLC, techniques.
Alternatively the desired optical isomers may be made by reaction of the a~.op~iate
;o optically active starting m,.~eri~l~ under conditions which will not cause racemisation, or by
derivatisation, for example with a homochiral acid followed by separation of thediastereomeric derivatives by conventional means ~for example HP~C, chromatography
over silica). All stereoisomers are included within the scope of tne invention.
Alk I which Rl R2 R4 R6 R7 R8, R9, R~~, Rl ~, R~ 2, R13. R , R , R , ~ and R
may represent or which may be substituted on one or more of the aromatic rings forming
part of Arl may be saturated or unsaturated, and straighe chain or branched.
C37 cycloalkyl, C,~ alkoxy, C~ alkylthio, C~ alkylsulfinyl, COO(CI~ alkyl) ar d C3_5
alkylene are to be interpreted accordingly.
According to tne invention there is also provided a process for the preparation of
compounds of formula I which comprises:
(a) preparation of compounds of forrnula I where X represents CH2 or C--0, ~
represents N, Z represents oR8, R5 and R8 form a bond and Rl and R2 forrn a bond by
oxidation of a corresponding compound of forrnula I where R~ and R- both ~ Gsei~t H
and B, D, E, G, X, Y, Z, Ar~ and Rs are as'hereinbefore defined. for example at room
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W~ 97~4893 PCT/SE97/0047~
temperature using a suitable oxidising agent (for example manganese dioxide) and an
app,u~iate organic solvent;
(b) preparation of compounds of forrnula 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, ~ and G represents CA wherein A represents nitro and theremainder of B, D, E and G, and X, Y, Z, Ar~, R~, R- and R5, are as hereinbeforedefined, for example with iron powder and ammonium chloride in refluxing ethanol;
(c) 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,
,o where one of B, D, E and G represents CA wherein A represents amino and theremainder of B, D, E and G, and X, Y, Z, Arl, R3, R- and R5, are as hereinbeforedefined, and decomposition of the diazonium salt in the presence of the halide anion or
(for fluorine) sodium tetrafluoroborate in dichlorobenzene at reflux;
(d) 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 ~3, D, E and G represents CA wherein A represents bromo and the
remainder of B, D, E and G, and X. Y, Z, Arl, Rl, R- and R5, are as hereinbeforedefined, by reaction with copper(I) cyanide, for example at reflux in
N-methylpyrrolidone;
(e) preparation of compounds of formula I where X represents CR3R6, Y representsN+R7, Z represents 0~, R3 and R- forrn a bond, Rl and R5 forrn a bond and R6
represents alkylthio by displacement reaction of a corresponding compound of forrnula
I, where X represents CR3R6 wherein R6 represents methylthio or halogen and B, D, E,
G, Y, Z, Ar~. Rl, R-, R3 and R5 are as hereinbefore defined, with a compound of
2s formula II:
R6~S~H (Il)
wherein R63 l~ylGsents C~_6 alkyl, in the presence of a base, for example sodiumhydride, in an ~ o~,liate solvent, for example DM~;
(fl preparation of compounds of formula I where X represents CR3R6, Y representsN+R7, Z represents 0-, R3 and R~ forrn a bond, R~ and R5 form a bond and R6
- represents alkoxy by displacement reaction of a corresponding compound of forrnula I,
where X represents CR3R6 wherein R6 represents methylthio or halogen and B. D, E,
~ G, Y, Z, Arl, Rl, R-, R3 and R5 are as hereinbefore defined, with a compound of
3s forrnula m
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W O 97~.4893 PCT/SE97/00~71
R6a~~~ ~ l (111)
wherein R6a is as hereinbefore defined, in the presence of a base, for example sodium
hydride, in an a~,up.iate solvent, for example, DMF;
(g) preparation of compounds of formula I where X represents CR3R6, Y representsN+R7, Z represents O~, R3 and R2 forrn a bond, Rl and Rs forrn a bond and R6
represents NRI3R14 by displacement reaction of a corresponding compound of forrnula
I, where X represents CR3R6 wherein R6 represents methylthio or halogen and B, D, E,
G, Y, Z, Ar~, Rl, R2, R3 and R5 are as hereinbefore defined, with a compound of
forrnula IV:
R13
R1~N~H (IV)
wherein Rl3 and Rl4 are as hereinbefore defined, in the presence of a base, for example
sodium hydrogen carbonate, in an a~lu~liate solvent, for example, DMF at 100 ~C;(h) preparation of compounds of forrnula I where X ~ lesents CR3R6, Y representsN+R7, Z represents O~, R3 and RZ form a bond, Rl and R5 forrn a bond and R6
represents methylthio by reaction of a corresponding compound of forinula I, where X
-GsG..L~. C=S, Y represents N, Z represents OH and B, D, E, G, Ar~, R', RZ, and Rs
are as hereinbefore defined, with a methylating agent, for example, methyl iodide, for
example neat at reflux;
(i) preparation of compounds of formula I where X represents C=S, Y represents N, Z
represents OH and Rl represents a bond with R5 by reaction of a corresponding
compound of forrnula I, where X represents C=O and B, D, E, G, Y, Z, Ar~, R~, R-,
and Rs are as hereinbefore defined, by thionation, for example using Lawesson's
reagent in an ap~-u~liate solvent, for example dioxane at reflux;
Z5 (j3 preparation of compounds of ~orrnula I where X represents CR3R6, Y represents
N+R7, Z le~lt;se.lts O~ and R6 represents halogen by reaction of a correspondingcompound of forrnula I, where X represents C=O, Y represents N, Z represents oR8,
R8 represents a bond with R5 and B, D, E, G, Ar~, R' and R- are as hereinbefore
defined, by halogenation, for example with a phosphorus oxyhalide, for example neat
at 100 ~C;
(k) plGpa~Lion of compounds of formula I where X represents CR3R6, Y represents
N+R7, Z represents O~, R3 and RZ forrn a bond, R~ and Rs form a bond and R6
~t;pl~sents alkyl by reaction of a corresponding compound of forrnula I, where Xrepresents C=O, Y represents N, Z represents OH, R~ represents a bond with R~, B, D,
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E, G, and Arl are as hereinbefore defined and R~ ,Gp,esellts a group corresponding to
R7 as hereinbefore defined, by reaction with a nucleophilic alkylating reagent, for
example a compound of formula V:
R6~Mg~Hal
wherein R6 is as hereinbefore defined and Hal represents halogen, for example in the
presence of a copper salt, for example copper(I) bromide in an a~ropliate solvent, for
example dimethoxyethane, for example at reflux;
~o (I) preparation of compounds of formula I where X represents CR3R6, Y represents
N+R7, Z represents O-, R3 and R2 forrn a bond, Rl and Rs form a bond and R6
represents alkyl by reaction of a corresponding compound of formula I, where X
represents CR3R6 wherein R6 represents H and B, D, E, G, Y, Z, Ar', R ~, R-, and Rs
are as hereinbefore defined, with a nucleophilic allcylating reagent, for example a
compound of formula V as hereinbefore defined in an a~ Jpliate solvent, for example
THF, for example at 0 ~C;
(m) preparation of compounds of formula I where X represents C=O, Y represents N,
Z ,~,~,ese.lts oR8, Rl represents a bond with R5, and R8 ~ ICSGllts alkyl by reaction of
a corresponding compound of formula I, where Z represents oR8 wherein R8
represents H and B, D, E, G, X, Y, Ar~, Rl, R-, and R5 are as hereinbefore defined,
with a compound of formula VI:
R~Hal (Vl)
~5 wherein R8 and Hal are as hereinbefore defined, for example in the presence of a base,
for example sodium hydride, in an a~ iate solvent, for example DMF;
(n) preparation of compounds of formula I where Rl represents OH, X represents
C-O, Y represents N, Z represents oR8 and Rs represents a bond with R8 by reaction
of a cu"~s~onding compound of formula I, where Z represents O~, R~ and Rs form abond and B, D, E, G, X, Y, Arl and R- are as hereinbefore defined, by treatment with
an oxidising agent, for example ceric ammonium nitrate, in an a~ropliate solvent, for
example acetonitrile, for example at ambient temperature;
~o) L"~;~aldLion of compounds of forrnula I where X represents CR3R5, Y represents
N+R7, Z represents O~, R3 and R- form a bond and Rl and R5 form a bond by reaction
3s of a corresponding compound of formula I, where Y represents N, Z represents OH
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and B, D, E, G, X, Ar~ , R-, and R5 are as hereinbefore defined, with a compound of
formula IX:
R'Hal (IX~
wherein R7 and Hal are as hereinbefore defined and a base, for example sodium
hydride, in an a~ iate solvent, for example DMF, for example at ambient
temperature;
(p) preparation of compounds of forrnula I where X represents C=O, R- does not
o represent H, Y represents N, Z represents OH and Rl represents a bond with ~5 by
reaction of a corresponding compound of forrnula I, where R- represents H and B, D,
E, G, X, Y, Z, Ar~, R' and R5 are as hereinbefore defined, with a base, for example
sodium hydride, and a compound of formula VII:
RZHal (Vll)
wherein R, not representing H, and ~Ial are as hereinbefore defined, in an a~p~opliate
solvent, for example DMF, for example at ambient t~n,L,~,dture;
(q) preparation of compounds of formula I where B, D, E and G represent C~ or CA,
X represents NR4, ~ l~;p,~sents N+R7, Z represents O~, R4 and R- forrn a bond and R~
and Rs forrn a bond by reaction of a compound of formula vm
/ r
N - N
A ~ ~O
H (Vlll)
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 a~plop~iatesolvent, for exarnple DMF, for example at ambient temperature;
(r) p,~pa~ ion of compounds of formula I where B, D, E and G represent CH or CA,X represents NR4, Y represents N, Z represents oR8, R- and R~ form a bond and Rsand R8 forrn a bond by reaction of a compound of formula VIII as hereinbefore defined
with a base, for example sodium hydride, and a compound of for.nula X:
-
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W O 97~4893 11 PCT/SE97/00471
R6Hal (X)
wherein R~ and Hal are as hereinbefore defined, in an appropriate solvent, for example
DMF, for example at ambient ~ eldture;
(s) preparation of compounds of formula I where X represents CR3R6, Y represents N,
Z represents OH, R3 and R2 form a bond and Rl represents a bond with R5 by
treatment of a corresponding compound of formula I, where Y represents N+R7, Z
represents O~, R7 represents CH~C6H40alkyl and B, D, E, G, X, Ar~, Rl, R~, and R5 are
o as hereinbefore defined, with an acid, for example trifluoroacetic acid, for example at
reflux;
(t) preparation of co.l.L ou~lds of forrnula I where X represents CR3R6, Y represents N,
Z represents OH, R3 and R2 form a bond and R' represents a bond with Rs by
tre~tment of a corresponding compound of formula I, where Y represents N+R7, Z
represents O~, R7 represents C~2phenyl (optionally substituted by C~_s alkyl or Cl_6
alkoxy) and B, D, E, G, X, Ar~, Rl, R2, and R5 are as hereinbefore defined, withhydrogen in the presence of a catalyst, for example palladium on carbon;
(u~ preparation of compounds of formula I where X represents C=O, Y represents N, Z
represents OH, R2 represents H and R' represents a bond with Rs by treatment of a
corresponding compound of formula I, where Y represents N+R7, Z represents O~, R7
represents CH2C6II4Oalkyl and B, D. E, G, X, Arl, R~, R-, and R5 are as hereinbefore
defined, with an acid, for example trifluoroacetic acid, for example at reflux;
(v) preparation of compounds of formula I where X represents CR3R6, Y representsN+R7, Z represents C~~, R3 and R2 forr,n a bond, R' and R5 form a bond and R6
~s represents H by reaction of a compound of formula XI:
o
~B ~COOR
E~G X~N~R2 (Xl)
where X represents CH2, Rl represents H, R2 represents a group correspondin~ to R7 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'NHN~2 (Xll)
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WO 97~.4893 PCT/SE97/00471
12
wherein Ar~ is as hereinbefore defined, for example in xylene at reflux;
~w) preparation of compounds of formula I where X represents C=O, R- does not
represent H, Y represents N, Z represents O~ and R~ represents a bond with R5 by5 _ reaction of a compound of formula XI as hereinbefore defined, where X represents
C=O, Rl ~cL~lcsellts H, R2 is as hereinbefore defined and B, D, ~, 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;
(x) ~,G~a~dLion of compounds of fornula I where X le~lcscnts CH~, Y represents N, Z
o represents oR8, R8 and R5 form a bond and Rl represents alkyl by reaction of a
compound of formula XI as hereinbefore defined, where X represents CH2, R~
represents alkyl and B, D, E, G, R- and R are as hereinbefore defined, with a
compound of formula XII as hereinbefore de~med, wherein Arl is as hereinbefore
defined, for example in xylene at reflux; or
(y) p.el.alclLion of compounds of forrnula I where X .e~resents C=O, Y represents N, Z
represents ORg, R8 and R5 form a bond and R1 represents alkyl by reaction of a
compound of forrnula XI as hereinbefore defined, where X represents C=O, R~
sCIlts alkyl, R- lcpl~se~ts H or alkyl, and B, D, E, G and R are as hereinbeforedefined, with a compound of formula XII as hereinbefore defined, wherein Arl is as
hereinbefore defined, for example in xylene at reflux;
(z) preparation of compounds of formula I where X represents CR3R6, Y representsCRI8, Z represents OH, R~ and R5 forn a bond and R- and R3 form a bond by oxidation
of a corresponding colllpoll"d of for nula I where X represents CR3R6, Y represents
CRI8, Z represents OH, R- and R3 represent H, Rl and Rs forrn a bond and B, D, E, G,
Arl, R6 and Rl8 are as hereinbefore defined; or
(aa) preparation of compounds of formula I where ~ ,cpfGsents CR3R6, Y represents
CR~8, Z represents OH, R' and R3 represent H and Rl and R5 forrn a bond by reaction a
compound of formula XII as hereinbefore defined with a compound of formula XX:
OH o
R~ ~ ~R
E~ ~f Rl8
R6
(XX)
wherein B, D, E, G, R6, Rl8 and R are as hereinbefore defined
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WO 97/34893 13 PCT/SE97/00471
Compounds of formula I, wherein X represents CHR3, R2 and R3 together represent a
bond, Rl and R5 form a bond and either:
~ Y represents N~R7 and Z represents O~, or
~ Y represents N, and Z represents OH,
may be prepared analogousiy to the methods described in J. Med. Chem. 35, 368 ( 1992).
Compounds of formula vm are known from ~uropean Patent Application No.
EP-A- 187551, or may be prepared analogously to the methods described therein.
Compounds of formula XI may be pl~el~al~,d by reaction of a compound of formula XIII:
R,E,~G I 2
B~ ,N~COOR
COOR' (Xlll)
wherein B, D, E, G, R, R- 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 wllclGill X le~r~,sents C--O and R2 leplcsellts H are known from
Japanese Examined Patent Publication No. JP-B-82 54,152 or may L~lc~al-,d analogously to
s the methods described therein.
Compounds of formula XIII, where X ,e~ sellts C=O, may be prepared by reaction of a
compound of formula XVI:
~Bq~COOH
E~ ~N~COOR
~ (XVI)
wherein B, D, E, G, R and R2 are as hereinbefore defined, by alkylation, for example with a
compound of formula XVII:
(R'0~2S02 (XVII)
~5 wherein R' is as hereinbefore defined, in the presence of a base, for example potassium
carbonate, for example in acetone at 50 ~C.
ColllL)oLlllds of formula XIII, where ~ represents C~I2, may be prepared by reaction of a
compound of formula XIV:
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WO 97/34893 14
,B ~ COOR
E~ ~ ~ Br
G (XIV)
wherein B, D, E, G and R are as hereinbefore defined, with a compound of forrnula XV:
R'
R--NlCOOR'
H tXV)
s wherein R', R- and F~' are as hereinbefore defined, in the presence of a base for example
triethylarnine, in an ~p~ iate solvent, for example ether at reflux.
Compounds of formula XIV may be prepared by reaction of a compound of forrnula xvm
,B COOR
R '1'
~G~ (XVIII)
o wherein B, D, E, G and R are as hereinbefore defined with a bromin~ting agent, for
example NBS, for example in dichloroethane at reflux with photolytic irradiation.
Compounds of formula XVI may be prepared by reaction of a co~ ul~d of forrnula XI~:
o
~B
G
O (XIX~
5 wherein B, D, E; and G are as hereinbefqre defined, with a compound of formula XV as
hereinbefore defined, wherein R~, R- and R' are as hereinbefore defined, in an a~pro,t),iate
solvent, for example acetone at 50 ~C.
Compounds of formula II, m, IV, V, VI, VII, IX, X, XII, XV, XVI, XVII, XVIII and XX
~o 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 c~ o~lllds may need to be protected by protecting groups.
~s 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, xm and ~VI may
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W O 97/34893 15
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 techni~ues which are
well known to those s~cilled 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 (c), for use as a pharmaceutical.
~n particular the compounds of the invention possess antiallergic and anti-infl~mm~t~-ry
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 inflzlmm~fory ~iceaces
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 includin~
infl~mm~tions/allergies such as rhinitic, 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 pseudomem~ranous rhinitis, scrofoulous rhinitis, seasonal rhinitis
including rhinitis nervosa (hay fever) and vasomotor rhinitis.
~s
The compounds of the invention are also indicated for use in the treatment of chronic
allergic disorders, atopic derrnatitis, cutaneous eosinophilias, eosinophilic fascitis, hyper
IgE syndrome, vernal conjunctivitis, systemic lupus erythem~tosis, thyroiditis, lepromatous
leprosy, sezary syndrome, chronic graft versus host disease, myasthenia gravis, idiopathic
30 thrombocvtopenia 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 m~Ai~t~ by humoral immunity, and in the treatment of
autoimmune ~lice~cec such as multiple sclerosis and rhellm~toid arthritis.
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WO 97/34893 16
Of particular interest amongst the above indications are the use of the compounds of the
invention in ~cthrn~ 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 ;nflamm~fory disorder, which method com-
prises a-lmini.stration of a therapeutically effective amount of a compound of formu}a I as
defined above, but without provisos (b) or (c~, 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.
s In non-pressurised powder compositions, the active ingredient in finely divided form may
be used in admixture with a larger sized pharm~reutically acceptable inert carrier
The composition may alternatively be pressurised and contain a compressed gas, for
example nitrogen, or a lique~led gas propellant. In such pie~ ised compositions, the
active ingredient is preferably finely divided. The ~,~s~. ;ceA composition may also
=contain a surface active agent. The ~,cs~u~ised compositions may ~e made by conventional
methods.
The compounds of the invention may be ~min;.ctered syste~nically (for example by oral
aflminictratjon to the gastroint~stin~l tract). The active ingredient may be formul~terl
~5 together with lcnown adjuvants, diluents or carriers using conventional techniques to
produce tablets or capsules for oral ~iminictration to the gastrointestinal tract.
Examples of suitabIe adjuvants, dill~entc or carriers for oral ~-lminictration in the forrn of
tablets, capsules and dragees include microcrystalline cellulose, calcium phosphate,
diatomaceous earth, a sugar such as lactose, dextrose or mantel, talc, stearic acid, starch,
~codium bicarbonate and/or gelatine.
According to a further aspect of the invention there is provided a pharm~relTtic~
composition comprising a compound of formula I as hereinbefore defined, but without
proviso (c), or a phz~nn~reutically acceptable derivative thereof, in admixture with a
pharmaceutically acceptable adjuvant diluent or carrier.
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17
Suitable doses for ~lm;ni.~tration topical or orally are in the range 0.01 to 30 mg kg-l day~l,
for example 0.3 mg kg-l 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 ~ "iate protecting groups to forrn
"protected derivatives" of the compounds of the invention. lt will also be appreciated that,
although such protected derivatives may not possess pharmacological activity as such, they
may be ~rlrnini~tered and thereafter metabolised in the body to form the compound of the
invention which is pharmacologically active. Such derivatives may therefore be described
o 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 (35-70~M) under gas pressure, typically 0.5
bar. The following hydra~ines were used as intermediates in the subse~uent examples:
~5-Hy~lr~zil~o-2-methylpyridine
A solution of sodium nitrite (0.3 g) in water (2 ml3 was added to a cold solution of
S-amino-2-methylpyridine (J. Chem. Soc. (C)., 1971, 3257) (3.61 g) in water (6 ml) and
concentrated hydrochlo~ic acid ( I ml~ whilst mzlint~ining the temperature below 5 ~C. The
~s mixture was stirred at 0 ~C for 15 minutes then further cooled to -10 ~C. 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 warrn to room
temperature and anhydrous potassium carbonate was added until a thick slurry was forrned.
The slurry was stirred with ethyl acetate and the organic phase was decanted and30 evaporated to an oil. The slurry was then diluted with water and extracted with dichloro-
methane (thrice). The organic phase was dried over sodium sulphate, filtered andevaporated 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 g). m.p. 68--70 ~C
35 IH NMR (CDCl3) o 2.47 (3H, s), 3.60 (2H, br s), 5.13 (IH, br s), 7.03 (lH, d), 7.12 (lH,
dd)~ 8. 12 ( I H. d).
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18
4-(Pentafluoroethyl)phenyl hydrazine
Prepared following the method used for 5-Hydrazino-2-methylpyridine using 4-(penta-
fluoroethyl)aniline (J. C*em. Soc., Perkin Trans. 1, l990, 2293). MS (EI) 226 (M+)~H
NMR (CDCI3) ~ 4.15 (2H, br), 6.87 (2H, d), 7.30 (2H, d), 7.45 ( lH, br)
2-Hydrazino-5-methylpyridine (~. Org. C*em., 1966, 31, 251)
2-Chloro-~-hydrazinopyridine (Atti R. Accad. dei Lincei, Roma, 1925, 2, 125); Chem.
o Zent. 1926, I, 672
2-Hydrazinopyrimidine J. Chem. Soc. 1955, 3478
F,Ys~mp~ 1
3-~ydroxy-4-t(4-m~ henyl)methyl]-2-(4-tri~uoromethylphenyl)-2H-pyrazolo-
t4,3-c]isoqllino!inium hy~lru~ide, inrler salt
(a) Methyl
2-[N-(methoxycal l~u~yh~ethyl)-N-(4-1nethoxyphenyl)methyl)amino~methylbçn~o~t~.
Methyl 2-bromomethylbenzoate (23.47 g; prepared analogously to the method described
20 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-methoxyphenyl)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 ~ c;ldLu~e. Water was added and the organic phase was separated. The aqueous
25 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 coiumn chromatography, eluting with
ethyl acetate: isohexane (1:9), gave the subtitle compound as an oil (27.85 g);
MS(APCI) 358 ((M~H)+)
30 IH NMR (CDC13); o 3.23 (2H, s), 3.66 (3H, s), 3.71 (2H, s), 3.78 ~3H, s), 3.88 (3H, s), 4.16
(2H,s),6.8(2H,d),7.2(2H,d),7.3(1H,td),7.45(1H,td),7.6(1H,dd),7.75(IH,dd).
(b) Methyl I727374-tetrahydro-2-(4-methoxyphenyl)methyl-4-oxo-3-isoquinolin~rb
oxylate
35 Methyl-2-[N-(methoxycarbonylmethyl)-N-(4-methoxyphenyl)methyl)amino]methyl-
benzoate (27.85 g; from step (a) above) was dissolved in dry toluene (150 ml) and added
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WO 97/34893
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 ~elnpclature 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 (1:4), gave the subtitle compound as an oil (20.41 g).
lH NMR (CDC13) (major component--enol tautomer) S 3.60 (2H, s), 3.81 (3H, s), 3.91
(5H, s), 6.86 (2H, d), 7.09 (IH, d), 7.25 (2H, d), 7.35-7.43 (2H, m), 7.77 (IH, d) and 11.58
to (IH, s).
(c)
3-Hydroxy-4-[(4-methoxyphenyl3methyl~-2-~4-trifluoromelhyl~llenyl)-2H-pyrazolo-
[4,3-c~isoquinolinium hydroxide, inner salt
Methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenyl)methyl 4-oxo-3-isoquinolinecarboxylate
(1.0 g; from step (b) above), 4-(trifluoromethyl)phenylhydrazine (1.08 g) and a catalytic
amount of 4-toluenesulfonic acid were fused together at 150 ~C for 10 m;nut~s. Xylene
(20 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 llilu~ated with diethyl
20 ether to give the title compound as a red solid (0.5 g). m.p. 220-221 ~C
MS(APCI) 450 ((M+H)+)
'H NMR (d6-DMSO) o 3.72 (3H, s), 6.08 (2H, s), 6.95 (2H, m), 7.7 (2H, m), 7.8 (3H, m),
7.95(1H,td),8.15(1H,d),8.35(1H,d),8.6(2H,d),8.96(1H,s).
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Example 2
2-(4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c3isoquinolin-3-ol
3-Hydroxy-4-L(4-methoxyphenyl)methyl] -2-(4-trifluoromethylphenyl)-2H-pyrazolo-
[~,3-c]isoquinolinium hydroxide, inner salt (0.26 g; from step (c) 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 ~C
o MS (APCI) 330 ((M+H)+)
~H NMR (d6-DMSO) o 7.9 (3H, m), 8.0 (lH, t), 8.3 (4H, m), 9.03 (lH, bs).
F~ nple 3
2-(4-Chlorophenyl)-2,5-dihydro-5-methyl-3H-pyrazolo[4,3-c]cinnolin-3-one.
2-(4-Chlorophenyl)-2,5-dihydro-pyrazolo[4,3-c]cinnolin-3-one (0.33 g; European Patent
Application EP-A-0187551) was added portionwise to a stirred suspension of oil free
sodium hydride (from 49 mg of 60% dispersion) in dry dimethylformarnide (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 te,llye~dtulG for 2 h. The solution was poured into
~o 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 recryst~ c~tion from dimethylformamide, gave the title
compound as red crystals (55 mg).
m.p. >250 ~C
MS(EI) 310, 312 (M+)
IH NMR (CDCl3) o 4.33 (3H, s), 7.4 (2H, dd), 7.65 (2H, t), 7.75 (lH, td), 8.20 (2H, dd),
8.35 ~ 1H, d).
Example 4
2-(4-Chlorophenyl)-2,3a,4,5-tetrahydro-3a,4-~imethylpyrazolo{4,3-cliso~uinolin-3-
one
(a) Methyl 2-t((l-methoxycarbonyl)ethyl3methylamino]methyl ben~os~te
Methyl 2-bromomethylbenzoate (3.51 g) and diisopropylethylamine (5.86 ml) were
dissolved in dry diethyl ether (30 ml) under a nitrogen atmosphere and the solution was
cooled to 0 ~C. N-methylalanine methyl ester trifluoroacetic acid salt ~3.89 g) dissolved in
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W O 97t34893 PCT/SE97/00471
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. F~iltration
and evaporation followed by column chromatography (1:9 ethyl acetate: hexane) gave the
s subtitle compound (2.~7 g).
MS (EI) 265 (M~)
(b) Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinoline carboxylate
Methyl 2-[((1-methoxycarbonyl)ethyl)methylamino]methylbenzoate (2 g) in dry toluene
o (10 ml) was added dropwise to a re~luxing 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 reilux 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 ((M~H)+ )
(c) 2~ -chlo~opL~lyl)-2~3a~4~5-tetrahydro-3a~4-~ e~llyl~yrazolo~4~3-clisoquino~in
-3-one
Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-iso~uinolinecarboxylate (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
~5 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: dichloro-
methane) gave the title compound as a colourless solid (50 mg).
m.p. 128-129 ~C.
MS (EI~ ~25, 327 (M+)
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22
Example S
2-(4-Chlorophenyl)-3a,4-dihydro-3a,4-dimethyl-2H-pyrazolo[4,3-c~isoquinoline-
-3,5-dione
(a) Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxo-3-isoquinolinecarboxylate
Methyl 1,2-dihydro-4-hydroxy-2-methyl-1-oxo-3-isoquinolinecarboxylate
(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 Lt~ )cldlul~ under a nitrogen atmosphere. After 30
minutes, iodometh~n~ (0.4 ml) was added dropwise. The solution was stirred at room
o le~ e~dture 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 ((M+H)+~
(b) 2-(4-Chlorophenyl)-3a,4-dihydro-3a,4-dimethyl-~H-pyrazoloi4,3-c3isoquinoline-
-3,5-dione
Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxo-3-isoquinolinecarboxylate (0.53 g),
4-chlorophenylhydrazine (0.92 g) and 4-toluenesulfonic acid (10 mg) were fused together
20 at 150 ~C under a nitrogen atmosphere for 10 minutes. Xylene (5 rnl) was then added and
the mi~Lul~ was heated at I5() ~C for 10 hours. After cooling to room tenlp Idture 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, fïltered and evaporated. Purification by colurnn chromatography (1:9
2s ethyl acetate: hexane) followed by recryst~lli.~,.~ion from propan-2-ol gave the title
compound as a beige solid (0.13 g). m.p. 192-193 ~C
MS (EI) 33g, 341 (M+)
Example 6
30 2-(4-Chlorophenyl)-2,4-dihydro-3-hydroxy-4-methylpyrazolo[4,3-c]isoquinolin-~-one
Methyl 1,2-dihydro~hydroxy-2-methyl-1-oxo-3-isoquinolinecarboxylate (JP 82 54,152;
0.5 g), 4-chlorophenylhydrazine (0.91 g) and 4-toluenesulfonic acid ( 10 mg) were fused
together at 150 ~C for 10 minutes under a nitrogen atmosphere. Xylene (5 ml) was then
added and the mixture heated at 150 ~C for 5 hours. After cooling to room temperature a
35 yellow precipitate was collected by filtration and washed with diethyl ether. Purification by
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23
column chromatography (1 :4g methanol: dichloromethane) followed by recrystal}isation
from ethanol gave the title compound as a beige solid (0.1 g). m.p. >250~C
MS (EI) 325, 327 (M+)
FY~mple 7
3-Hydroxy-4-t(4-methoxyphenyl)methyl]-2-(3-quinolyl)-2H-pyrazolot4,3-cJiso-
quinolinium hydroxide, inner salt.
The title compound was prepared according to the method described in Example 1 (c) using
3-hydrazinoquinoline. m.p. 232-233 ~C.
o MS (APCI) 433 ((M+H)~)
NMR (d6-DMSO) ~ 3.7 (3H, s), 6.1 (2H, s), 6.7 (2H, d), 7.65 (lH, t), 7.70 (3H, m), 7.80
(lH,t),8.05(3H,m),8.20(1H,d),8.40(1H,d),9.00(1H,s),9.20(1H,d),9.90(lH,d).
FY~mp'~ 8
2-(3-Quinolyl)-2H-pyrazolo[4,3-c~isoquinolin-3-ol
The title compound (0.21 g) was prepared according to the method described in Example 2
using 3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(3-quinolyl)-2H-pyrazolo[4,3-c]iso-
quinolinium hydroxide, inner salt (0.66 g). m.p. 247--248 ~C
MS (APCI) 3}3 ((M+H)+)
20 IH NMR (d6-DMSO) ~ 7.70 (lH, td), 7.80 (lH, td), 7.90 (lH, bt), 8.00 (IH, t), 8.15 (2H,
m), 8.35 (2H, m), 8.90 (lH, d), 9.05 (lH), 9.70 (IH, d), 12.20 (IH, bs)
Example 9
2-(3,4-Dich10rophenyl~-3-hydroxy-4-r~4-m~t~o~yphenyl)methyl}-2H-pyrazolo[4,3-c] -
25 isoquinolinium Ly~ll u~ide, inner salt
The title compound was ~ al~d according to the method described in Example 1 (c) using
3,4-dichlorophenylhydr~ine. m.p. 239-240 ~C
MS (APCI) 448, 450, 452 ((M+H)+)
~I NMR (d6-DMSQ): ~ 3 72 (3H, s), 6.~!6 ~2H, s), 6.96 (2H, d), 7.70 (3H",l), 7.79 (;H, i),
30 7.97(1H,t),8.16(1H,d),8.37(2H,m),8.72(1H,d),8.97(1H,s).
Example 10
2-(3,4-Dichlorophenyl) -2H-pyrazolo[4,3-c]isoquinolin-3-ol
The title compound (0.028 g) was prepared according to the method described in Example
35 2 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-a~4-methoxyphenyl)methyl]-2H-pyrazolo-
[4,3-c~isoquinolinium hydroxide, inner salt (0.26 g). m.p. >230 ~C.
-
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MS (APCI) 330, 332, 334 ((M~H)+)
'H NMR (d6-DMSO) o 7.82 (lH, d), 7.86 (IH, t), 7.97 (lH, t), 8.13 (lH, dd), 8.24 (lH, d),
8.32 (lH, d), 8.42 (lH, d), 8.94 (lH, s).
Example 11
2-([1,1 '-Biphenyl]-4-yl)-2H-pyrazolo[4,3-c3isoquinolin-3-ol
(a) 2-([1,1'-Biphenyl]-4-yl)~3-hydroxy-4-rl4-methoxyphenyl)methyl3-2H-pyrazolo-
[4,3-c~iso(luinolinium hydroxide, inner salt
The sub-title compound was prepared according to the method described in Example 1 (c)
o using [l,l'-biphenyl~-4-ylhydrazine (see J. Chem. Soc., Perkin Trans. I, (1975) 1280).
(b) 2-([~ -Biphenyl]-4-yl)-2H-pyrazolot4~3-c]isoquinolin-3-ol
The title compound (0.082 g) was p~ a~ed according to the method described in Example
2 using 2-([1,1 '-biphenyl]-4-yl)-3-hydroxy4-[(4-methoxyphenyl3methyl3-2H-pyrazolo-
[4,3-clisoquinolinium hydroxide, inner salt (0.29 g; from step (a) above).
m.p. >220~ (dec.).
MS (APCI) 338 ((M+H)+)
IH NMR (d6-DMSO) ~ 7.37 (lH, m), 7.51 (2H, m), 7.75 (2H, m), 7.89 (3H, m), 7.98 (lH,
m), 8.05 (2H, m), 8.31 (2H, m), 9.02 (lH, s, br)
Example 12
3-Hy~roxy-4-[(4-methoxyphenyl)methyl}-2-(4-methylphenyl)-2H-pyrazolot4,3-c3 -
isoquinolinium hydroxide, inner salt
The title compound was prepared according to the method described in Example l(c) using
2s 4-methylphenylhydrazine.
m.p. >100 ~C (dec.)
MS (APCI) 396 ((M+H)+)
'H NMR (d6-DMSO) o 2.34 (3H, s), 3.72 (3H, s), 6.10 (2H, s)? 6.96 (2H, m), 7.26 (2H, m),
7.74(3H,m),7.94(1H,m),8.13(1H,d),8.23(2H,d)8.33(1H,d),8.89(~H,s)
E;xample 13
2-(4-Methylphenyl)-2H-pyrazolot4,3-c~isoquinolin-3-ol
The title compound (0.043 g) was prepared according to the method described in Example
2 using 3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-methylphenyl)-2H-pyrazolo[4,3-c]-
35 isoquinolinium hydroxide, inner salt (0.20 g). m.p. 202--209 ~C (dec.).
MS (APCI) 276 ((M~H)+)
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'H NMR (d6-DMSO) o 2.37 (3H, s), 7.37 ~2H, d), 7.88 (3H, m), 7.94 ~lH, m), 8.29 ~2H,
m), 9.02 (IH, br), 11.90 ~lH, br)
Example 14
2-(4-Bromophenyl)-3-hydroxy-4-{(4-1nethoxyphenyl)methyl]-2H-pyrazolo~4,3-c]iso-
quinolinium hydroxide, inner salt
The title compound was ~lGlJa~d according to the method described in Example l(c) using
4-bromophenylhydrazine. m.p. >220 ~C (dec.).
MS (APCI) 460, 462 ((M~H)+).
~H NMR (d6-DMSO) ~ 3.70 (3H, s), 6.08 (2H, s), 6.96 (2H, m), 7.66 (2H, m), 7.76 (2H,
m),7.77(1H,t),7.96(1H,m),8.15(1H,d),8.36(3H,m),8.94(1H,s)
FY~ 15
2-(4-Bromophenyl)-2H-I ~razol~4,3-c]iso~uinolin-3-ol
The title compound (0.()53 g) was prepared according to the method described in Example
2 using 2-(4-bromophenyl)-3-hydroxy-4-~(4-methoxyphenyl)methyl3-2H-pyrazolo[4,3-c]-
isoquinolinium hydroxide, inner salt (0.164 gm.p. > 250 ~C.
MS (APCI) 340, 342 ((M+H)+).
~H NMR (d6-DMSO) ;; 7.76 (2H, d), 7.89 (lH, m), 8.02 (3H, m), 8.31 (2H, m), 9.07 (lH,
br), 11.92 (lH, br)
Example 16
2-(3-Trifluoromethylphenyl)-3-hydroxy-4-1(4-methoxyphenyl)methyl l-2H-pyrazolo-
L4,3-c~iso(luino~inium hydroxide, inner salt
The title compound was ~cyal~d according to the method described in Example 1 (c) using
3-trifluoromethylphenylhydrazine 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 ((M~H)+)
IH NMR (CDC13) o 3.81 (3H, s), 6.19 (2H, s), 6.96 (2H, d), 7.45 (lH, m), 7.54 (3H, m),
7.79(2H,m),7.86(1H,t),8.52(1H,d),8.68(1H,d),8.72(1H,s)
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F,Y~plel7
2-(3-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c lisoquinolin -3-ol
The title compound was prepared according to the method described in E~xample 2 using
2-(3-trifluoromethylphenyl)-3-hydroxy-4-r(4-methoxyphenyl)methyl3-2H-pyrazolo~4,3-c}-
isoquinolinium hydroxide, inner salt. m.p. 250 ~C dec.
MS (APCI) 330 ((M+H)+)
'H NMR (d6-DMSO) ~ 7.67 (IH, d~, 7.81 (lH, t), 7.88 (lH, t~, 7.99 (lH, t), 8.42 (3H, m),
8.48 (lH, s), 9.01 (l~I, s)
o Example 1~
2-[4-(1,1 -Dimethylethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolin-3-ol
(a) 3-EIydroxy-2-[4-(1,1-dimethylethyl)phenyl]-4-r(4-methoxyphenyl)methyl]-2H-
-pyrazolo[4,3-c]iso~luinolinium hydroxide, inner salt
The sub-title compound was prepared according to the method described in Example l(c)
using 4-[(1,1-dimethylethyl)phenyl~hydrazine and was used without further purification in
the procee~lin~ step.
~b) 2-[4-(1,1-D,h-,etllylethyl)phenyl]-2H-pyrazolo[4,3-c~isoquinolin-3-ol
The title compound was ~ ,a.Gd according to the method described in Example 2 using
3-hydroxy-2-~4-(1,1-dimethylethyl) phenyl]-4-(4-methoxyphenylmethyl)-2H-pyrazolo-
[4,3-c]isoquinolinium hydroxide, inner salt. m.p. >21OG (dec.).
MS (APCI) 318 ((M~I)+)
IH NMR (d6-DMSO) ~ 1.33 (9H, s), 7.51 (2H, d), 7.75 (lH, t), 7.84 ~IH, t), 8.01 (2~I, d),
8.12 (lH, d), 8.25 (lH, d), 8.74 (1~, s)
F,Y~mple 19
2-(4-Trifluoromethoxyphenyl)-2H-pyrazolo[4,3-c~isoquinolin-3-ol
(a) 2-(4-Trifluoromethoxyphenyl)-3-HydroXy-2-[(4-lmetho~yphenyl)methyl}-2H-pyr
azolo[4,3-c~iso~luinolini1-m bydroxide, 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 purifîcation in the
proceeding step.
(b) 2-(4-Trifluoromethoxyphenyl~-2H-pyrazolo[4,3-c~isoquinolin-3-ol
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The title compound was prepared according to the method described in Example 2 using
2-(4-trifluoromethoxyphenyl)-3-hydroxy-2-[(~methoxyphenyl)methyl]-2H-pyrazolo-
~4,3-c~isoquinolinium hydroxide, inner salt. m.p. > 230 ~C.
MS (APCI) 346 ((M+H)+)
5 IH NM~ (d6-DMSO) ~ 7.58 (2H, d), 7.91 (IH, t), 7.99 (lH, t), 8.14 (2H, d), 8.29 (2H, m),
9.03 (lH, br s).
F.Y~mrle 20
2-(4-Chlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-cliso~uinolinium hydroxide,
Jo inner salt.
Methyl 1,2,3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylate (0.5 g) (I. G. Hinton
& F. G. Mann, J. C~2em. Soc. 1959, 599), 4-chlorophenylhydrazine (0.98 g) and
4-toluenesulfonic acid (10 mg) were fused together at 150 ~C 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 ~C. 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 g). m.p. 247--248 ~C.
MS (EI) 309, 311 (M+).
IH NMR (d6-DMSO~ o 4.5 (3H, s), 7.5 (2H, d), 7.75 (lH, t), 7.95 (lH, t), 8.1 (IH, d), 8.3
(lH, d), 8.4 (2H, d), 8.6 (lH, s~.
FY~mrle 21
2-(4-Chlorophenyl~-3-hydroxy-4-methyl-2H-pyrazolot4,3-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
resu}ting solution was stirred at room temperature for 2 h. The solution was poured into
brine and 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 recryst~Tic~ion from dimethylformamide gave the title
compound as purple crystals (65 mg). m.p. 249-250 ~C.
MS ~EI) 310, 312 ~M+).
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lH NMR (CDCI3) 4.81 ~3H, s), 7.40 (2H, d), 7.75 (2H, m), 8.00 (IH, dd), 8.25 (2H, d),
8.35 (lH, dd).
F,Y~mrle 22
2-(4-Chlorophenyl)-3-hydroxy-4-[(4-m~th~ypheny~)methyl-2H-pyrazolo[4,3-c]iso-
quinoliniu m hydroxide,inner salt.
The title compound was prepared according to the method descri~ed in Example 20, from
methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenyl)methyl-4-oxo-3-iso~uinolinecarboxylate
(which latter compound was prepared analogously to the methods described in I. G. Hinton
o & F. G. Mann, J. Chem. Soc. 1959, 599). m.p. 227--228 ~C.
MS (EI) 416, 418 ((M+H)+).
~H NMR (d6-DMSO) 3.70 (3H, s), 6.08 (2H, s), 6.95 (2H, d), 7.50 (2H, d), 7.70 (2H, d),
7.75(1H,t),7.95(1H,t),8.15(1H,d),8.35(1H,d),8.40(2H,d),8.93(1H,s).
The following compounds, Examples 23--56, were prepared by methods analogous to
examples 20 & 22:
Ex. Name m.p./~C MS lH NMR (d6-DMSO) ~i
23 3-Hydroxy-4-methyl-2-(4-tri- 201- 344 4.51 (3H, s), 7.80 (3H, m),
fluoromethylphenyl)-2H-pyr- 203 (M+H)+ 7.97 (lH, t), 8.10 (lH, d),
azolor4,3-c~isoquinolinium 8.35 (lH, d), 8.60(2H, d),
hydroxide, inner salt 8.66(1 H, s) .
24 3-Hydroxy-4-methyl-2- >250 327 4.55 (3H, s), 7.60 (lH, td),
-(3-quinolyl)-2H-pyrazolo- (M+H)+ 7.70 (lH, td), 7.82 (IH, td),
[4,3-c]isoquinolinium hydr- 8.00 (3H, m), 8.10 (lH, d),
oxide, inner salt 8.40 (lH, d), 8.69 (lH, s),
9.13 (lH, d), 9.93 (lH, d).
2-(6-Chloro-3-pyridyl)-3- >250 311/313 4.50(3H, s), 7.61(1H, d),
-hydroxy-4-methyl-2H-pyr- (M+H)+ 7.80(1H, t), 7.97(1H, t),
azolo[4,3-c~isoquinolinium 8.12(1H, d), 8.35(1H, d),
hydroxide, inner salt 8.68(1H, s), 8.74(1H, dd),
9.37(1H, s)
26 2-(3,4-Dichlorophenyl)-3- 2'73- 344/346/ 4.49 (3H, s), 7.70(1H, d),
-hydroxy-4-methyl-2H-pyr- 229 348 7.78 (lH, t), 7.96 (lH, t),
azolo[4,3-c~isoquinolinium (M+H)+ 8.11 (lH, d), 8.35 (2H, m),
hydroxide, inner salt 8.67 (2H, m)
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Fx. Name m.p./~C MS ~H NMR (d6-DMSO) â
27 3-Hydroxy~-methyl-2-(4- 247- 290 2.33 (3H, s), 4.52 (3H, s),
-methylphenyl)-2H-pyrazolo- 248 (M+H)+ 7.24 (2H, m), 7.74 (lH, m),
[4,3-c]isoquinolinium hydr- 7.93 (lH, m), 8.09 (lH, m),
oxide, inner salt 8.20 (2H, m), 8.33 (IH, d),
8.59 (lH, s)
28 2-(4-Bromophenyl)-3-hydr- 244 354/356 4.50 (3H, s), 7.63 (2H, d),
oxy-4-methyl-2H-pyrazolo- (M+H)+ 7.76 (lH, t), 7.96 (lH, t),
~4,3-cJisoquinolinium hydr- 8.10 (lH, d), 8.34 (3H, m),
oxide, inner salt 8.63 (1 H, s)
29 3-Hydroxy-4-methyl-2-(3-tri- 222-6 344 4.51 (3H, s), 7.53 (lH, d),
fluoromethylphenyl)-2H-pyr- (M+H)+ 7.69 (lH, t), 7.78 (IH, t),azolo~4,3-c]isoquinolinium 7.96 (IH, t), 8.12 (lH, d),
hydroxide, inner salt 8.35 (IH, d), 8.63 (IH, d),
8.66 (lH, s), 8.81 (lH, s)
2-{4-(1,1-Dimethylethyl)- >220~ 332 1.35 (9H, s), 4.65 (3H, dt),
phenyl]-3-hydroxy-4-methyl- (dec.) (M+H)+ 7.46 (2H, m), 7.62 (lH, dt),
2H-pyrazolo[4,3-c]iso- 7.71 (lH, s), 7.83 (2H, m),quinolinium hydroxide, inner 8.15 (2H, m), 8.50 (IH, d)
salt (CDCI3 not DMSO d6)
31 2-(6-Chloro-3-pyridyl)- 223- 417/419 3.72 (3H, s), 6.07 (2H, s),
-3-hydroxy4-[(4-methoxy- 224 (M+H)+ 6.97 (2H, d), 7.62 (lH, d)~
phenyl)methyl]-2H-pyrazolo- 7.70 (2H, d), 7.81 (IH, t),[4,3-c]isoquinolinium hydr- 8.00 ( IH, t), 8.16 ( lH, d),
oxide, inner salt 8.36 (lH, d), 8.79 (lH, dd),
8.98 (lH, dd), 9.38 (lH, d)
32 3-Hydroxy-4-methyl-2-(6- >250 291 2.50 (3H, s), 4.51 (3H, s),
-methyl-3-pyridyl)-2H-pyr- (M+H) 7.33 (lH, d), 7.77 (lH, t),
azolo[4,3-cJisoquinolinium 7.98 (lH, t), 8.10 (IH, d),
hydroxide, inner salt 8.34 (lH, d), 8.50 (IH, dd),
8.64(1H,s),9.38(1H,d)
33 2-(4- tri~luoromethylphenyl)- >250 374 3.99 (2H, m), 4.92 (2H, m),
-3-hydroxy-4-(2-hydroxy- (M+H)+ 5.19 (lH, t), 7.79 (3H, m),
ethyl)-2H-pyrazolo[4,3-c]iso- 7.99 (lH, m), 8.20 (lH, d),
quinolinium hydroxide, inner 8.38 (IH, d), 8.60 (2H, d),
salt 8.65 (IH, s)
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Ex. Name m.p./~C MS lH NMR (d6-DMSO) ~
34 3-Hydroxy-4-methyl-2-(5- 237- 291 2.34 (3H, s), 4.50 (3H, s),
-methyl-2-pyridyl)-2H-pyr- 240 (M+H)+ 7.75 (2H, m), 7.98 (lH, t),
azolo~4,3-c]isoquinolinium 8.11 ( I H, d), 8.18 (1 H, d),
hydroxide, inner salt 8.36 (IH, d), 8.40 (lH, d),
8.59 (lH, s)
3-Hydroxy-4-methyl-2-~4-(l- 171- 318 1.25 (6H, d), 2.92 (lH, m~,
-methylethyl)phenyl~-2H-pyr- 172 (M+H)+ 4.53 (3H, s), 7.34 (2H, d),
azolo[4,3-c]isoquinolinium 7.78 (lH, t), 7.97 (lH, t),
hydroxide, inner salt 8.14 (3H, m), 8.35 ( lH, d),
8.69 (lE~, s)
36 3-Hydroxy-4-methyl-2-(4- >230 321 3.93 (3H, s), 7.79 (IH, t),
-nitrophenyl)-2H-pyrazolo- (M+H)+ 7 99 (IH, t), 8.12 (lH, d),
~4,3-cJisoquinolinium hydr- 8.33 (3H, m), 8.62 (2H, d),
oxide, inner salt 8.71 (IH, s)
37 2-(4-Cyanophenyl)-3-hydr- 225- 301 4.49 (3H, s), 7.79 (lH, t),
oxy-4-methyl-2H-pyrazolo- 227 (M+H)+ 7.89 (2H, t), 7.95 (lH, t),
L4.3-c]isoquinolinium hydr- 8.00 (IH, d), 8.34 (IH, d),
oxide, inner salt 8.56 (2H, d), 8.67 (lH, s).
38 2-(4-Car~oxyphenyl)-3-hydr- >230 320 4.51 (3H, s), 7.78 (lH, t),
oxy-4-methyl-2H-pyrazolo- (M+H)+ 7.99 (IH, t), 8.01 (2H, d),
[4,3-c]isoquinolinium hydr- 8.12 (lH, d), 8.09 (IH, d),
oxide, inner salt 8.47 (2H, d), 8.64 (lH, s),
12.74 (lH, s)
39 2-(4-Chloro-3-trifluoro- >230 378/380 4.50 (3H, s), 7.81 (2H, m),
methylphenyl)-3-hydroxy- (M+H)+ 8.00 ( I H, t), 8.13 ( I H, t),
-4-methyl-2H-pyrazolo- 8.38 (lH, d), 8.59 (lH, dd),
[4,3-c]isoquinolinium hydr- 8.68 (lH, s), 8.98 (lH, d)
oxide, inner salt
2-(4-Trifluoromethoxy- 195- 360 4.51 ~3H, s), 7.46 (2H, d),
phenyl)-3-hydroxy-4-methyl- 196 (M+H)+ 7.79 (lH, t), 7.96 (lH, t),
-2H-pyrazolo~4,3-c]iso- 8.12 (lH, d), 8.35 (IH, d),
quinolinium hydroxide, inner 8.45 (2H, d), 8.64 (lH, s)
salt
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Ex. Name m.p./~C MS lH NM~ (d6-DMSO) ~
41 3-Hydroxy-4-methyl-2-~4- 197-- 322 2.50(3H,s),4.51 (3H,s),
-methylthiophenyl)-2~-pyr- 198 (M+H)+ 7.33 (2H, d), 7.72 (lH, t),
azolo[4,3-c]isoquinolinium 7.91 (lH, t), 8.08 (lH, d),
r hydroxide, inner salt 8.27 (2H, d), 8.31 (1 H, d),
8.6û ( lH, s)
42 4-Cyclopropyl-3-hydroxy-2- >250 370 1.33 (2H, m), 1.54 (2H, m),
-(4-trifluoromethylphenyl)- (M+H)+ 5.03 (lH, m), 7.78 (3H, m),
-2H-pyrazolo[4,3-cJiso- 7.96 (lH, m), 8.15 (lH, d),
quinolinium hydroxide. inner 8.34 (lH, d), 8.61 (2H, m),
salt 8.65 ( I H, s)
43 4-Cyclopropyl-3-hydroxy-2- 226- 317 1.32 (2H, d), 1.54 (2H, m),
-(6-methyl-3-pyridyl)-2H-pyr- 240 (M+H)+ 2.51 (3H, s), 5.08 (IH. m)7
azolo[4,3-c]isoquinolinium 7.33 (lH, d), 7.56 (lH, td),
hydroxide, innersalt 7.94 (lH, td), 8.13 (lH, d),
8.32 (lH, d), 8.54 (lH, dd),
8.62~1Hjs~,9.40(1H,d~
44 4-[(1,1-Dimethyl-2-hydroxy)- >220 402 1.94 (6H, s), 4.28 (2H, d~,
ethyl]-3-hydroxy-2-[(4-tri- (M+H)+ 5.15 (lH, t), 7.79 (3H, m),
fluoromethyl)phenyl]-2H-pyr- 8.00 (lH, m), 8.37 (2H, t),
azolo ~4,3-c]isoquinolinium 8.62 (2H, d), 8.77 (lH, s)
hydroxide, inner salt
3-Hydroxy~-(2-methoxy- 195-- 388 3.28 (3H, s), 3.96 (2H, t),
ethyl)-2-[(4-trifluoromethyl)- 197 (M+H)+ 5.06 (2H, t), 7.79 (3H, m),
phenyl]-2H-pyrazolo[4,3-c3- 7.99 (lH, m), 8.18 (lH, d),
isoquinolinium hydroxide, 8.37 (lH, d), 8.58 (2H, d),
inner salt 8.71 (1 H, s)
46 2-(4-Chlorophenyl)-3-hydr- 187-- 370/372 2.19 (3H, s), 3.20 (2H, t),
oxy-4-[2-(methylthio)ethyl]- 188 (M~H)+ 5.03 (2H, t), 7.50 (2H, m),
-2H-pyrazolo[4,3-c]iso- 7.79 (lH, m), 7.99 (lH, m),
quinolinium hydroxide, inner 8.15 (lH, d), 8.38 (3H, m),
salt 8.77 (lH, s)
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Ex. Name m.p./~C MS lH NMR (d6-DMSO) ~
47 3-Hydroxy-4-[2-(methylthio)- 193- 404 2.20 (3H, s), 3.21 (2H, t),
ethyll-2-(4-trifluoromethyl- 195 (M+H)+ 5.04 (2H, t), 7.81 (3H, m),
phenyl)-2H-pyrazolo[4,3-c]- 8.01 (lH, m~, 8.17 (IH, d),
isoquinolinium hydroxide, 8.39 (lH, d), 8.59 (2H, d),
inner salt 8.80 (lH, s)
48 4-Cyclopropyl-2-(4-trif~uoro- 188- 386 1.34 (2H, m), 1.54 (2H, m),
methoxyphenyl)-3-hydroxy- 189 (M+H)+ 5.08 (IH, m), 7.46 (2H, d),-2H-pyrazolo~4,3-c]iso- 7.78 (IH, t), 7.95 (lH, t),
quinolinium hydroxide, inner 8.15 (lH, d), 8.31 (lH, d),
salt 8.46 (2H, d), 8.62 (lH, s)
49 2-(4-Chloro-3-trifluoro- >220 404/406 1.33 (2H, m), 1.53 (2H, m),
methylphenyl)-4-cyclopropyl- (M+H)+ 4.98 (lH, m), 7.78 (2H, m),
-3-hydroxy-2H-pyrazolo- 7.97 (1 H, t), 8.17 (1 ~I, d),
E4,3-c3isoquinolinium hydr- 8.36 (lH, d), 8.62 (lH, dd),
oxide, inner salt 8.67 (lH, s), 9.03 (IH, dd)
4-Cyclopropyl-3-hydroxy-2- 166- 348 1.30 (2H, m), 1.51 (2H, m),
-(4-methylthiophenyl)-2H-pyr 167 (M+H)+ 2.51 (3H, s), 5.24 (lH, m),
azolo~4,3-c]isoquinolinium 7.37 (2H, d), 7.74 (IH, t),
hydroxide, inner salt 7.93 (lH, t), 8.14 (lH, d),
8.33 ~3H, m), 8.58 (lH, s)
51 3-Hydroxy-4-phenyl-2-(4-tri- 255 406 7.69(3H, m), 7.76(2H, m),
fluoromethylphenyl)-2H-pyr- (M+H)+ 7.82(3H, m), 8.05(1 H, m),
azolo[4,3-c]isoquinolinium 8.25(1H, d), 8.45(1H, d),
hydroxide, inner salt 8.53(2H, m), 8.85(1H, s)
52 4-Ethyl-3-Hydroxy-2-(4-tri- 192-- 358 1.63 (3H, d), 4.88 (2H,
fluoromethylphenyl)-2H-pyr- 198 (M+H)+ quart), 7.75 (lH, t), 7.79
azolo[4,3-c~isoquinolinium (2H, d), 7.96 (lH, t), 8.09
hydroxide, inner salt (lH, d), 8.33 (lH, d), 8.59
(2H, d), 8.76 (lH, s)
53 2-(4-Trifluoromethylphenyl)- 167- 416 1.27 (3H, t), 4.27 (2H, q),
-4-(1-ethoxycarbonylmethyl)- 169 (M+H)+ 5.83 (2H, s), 7.82 (2H, d),
3-hydroxy-2H-pyr- 7.82 (lH, t), 8.04 (lH, t),
azolo[4,3-c]isoquinolinium 8.17 (lH, d), 8.39 (lH, d),
hydroxide, inner salt 8.54 (2H, d), 8.71 (lH, d)
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33
Ex. Name m.p./~C MS lH NMR (d6-DMSO) ~
54 3-Hydroxy-4-[(4-methoxy- foam 382 3.72 (3H, s), 6.10 (2H, s),
phenyl)methyl]-2-phenyl-2H- (M+H)+ 6.95 (2H, d), 7.20 (lH, t~,pyrazolo[4,3-c~isoquinolin- 7.48 (2H, t), 7.75 (3H, m),
ium hydroxide, inner salt 7.g5 (1 H, t), 8.15 (1 H, d),
8.35 (3H, m), 8.91 (lH, s)
3-Hydroxy4-(1-methylethyl)- 201- 372 1.70 (6H, d), 6.26 (lH, br s),
-2-(4-trifluoromethylphenyl)- 203 (M+H)+ 7.79 (lH, t~, 7.79 (2H, d),-2H-pyrazolo[4,3-c]iso- 7.98 (IH, t), 8.22 (lH, d)~quinolinium hydroxide, inner 8.38 (lH, d), 8.62 (2H, d),salt 8.93 (lH, d)
56 3-Hydroxy-4-(1-methylethyl)- 220- 372 1.71 (6H, d), 6.27 (IH, brs),
-2-(3-trifluoromethylphenyl)- 222 (M+H)+ 7.54 (lH, d), 7.70 (lH, t),-2~-pyrazolo[4,3-c]iso- 7.78 (lH, t), 7.96 (lH, t),quinolinium hydroxide? inner 8.22 (lH, d), 8.40 (lH, d),salt 8.64 (lH, d), 8.85 (lH, s),
8.94(1H,s)
Example 57
3-Hydroxy-2-(4-iodophenyl)-4-methyl-2H-pyrazolo[4,3-c3iso~uinolinium hydroxide,
inner salt
Methyl 1,2,3,4-tetrahydro-2-methyl-4-oxo-3-iso~uinolinecarboxylate (0.485 g) and 4-iodo-
phenylhydrazine (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 g). m.p. ~260 ~C.
MS (+ve ESI) 402 ((M+H)+).
o IH NMR (d6-DMSO): o 4.50 (3H, s), 7.76 (lH, t), 7.77 (2H, d), 7.94 (lH, t), 8.09 ( lH, d),
8.19 (2H, d), 8.32 (lH, d), 8.62 (lH, s)
=
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34
The following compounds, examples 58--60, were prepared following methods analogous
to that used for example 2:
Ex. Name m.p./~C MS lHNMR (d6-DMSO) o
58 2-(6-Chloro-3-pyridyl)- > 250 297/ 7.71 (lH, d), 7.89 (lH, t), 8.00
-2H-pyrazolo~4,3-c~iso- 299 (lH, t), 8.31 (2H, m), 8.56 (lH, br
quinolin-3-ol ~M+H)~ d), 9.00 (lH, br s), 9.13 (IH, s)
59 2-[4-(1-Methylethyl)- 218- 304 1.25 (6H, d), 2.97 (lH, m), 7.42
phenyl]-2H-pyr~olo- 219 (M+H)' (2H, d), 7.93 (4H, m), 8.27 (2H,
t4,3-c~isoquinolin-3-ol m), 9.00 (IH, s)
2-~4-Pentafluoroethyl- 219-- 380 7.68 (lH, t), 7.76 (3H, m), 8.07
phenyl)-2H-pyrazolo- 223 (M+H)+ (lH, d), 8.24 (IH, d), 8.54 (3H,
[4,3-c] iso~uinolin-3-ol m)
The following compounds, examples 61-68, were ~,~L,ared following methods analogous
to that used ~or example 6:
Ex. Name m.p./~C MS IH NMR (d6-DMSO) ~
61 2,4-Dihydro-3-hydroxy-4- >250 294 3.79 (3H, s), 7.48 (lH, t),-methyl-2-(2-pyrimidinyl)-5H- (M+H)+ 7.7~ (lH, t), 7.89 (lH, t),
-pyr~olo[4,3-c]isoquinolin-5- 8.18 (lH, d), 8.35 (lH, d),
-one 8.92 (2H. d)
62 2-(~1,1'-biphenyl]-4-yl)-2,4-di- 241--244 368 3.83 (3H, s), 7.39 (lH, m),
hydro-3-hydroxy ~1-methyl-5H- (M+H)+ 7.50 (2H, t), 7.75 (3H, m),
-pyr~olo~4,3-c3isoc~uinolin-5- 7.91 (3H, m), 8.05 (3H,
-one m), 8.38 (lH, d)
63 2,4-Dihydro-3-hydroxy-4- ~250 360 3.81 (3H, s), 7.77 (lH, t),-methyl-2-(4-trifluoromethyl- (M+H)+ 7.94 (3H, m), 8.05 (lH, d),
phenyl)-5H-pyr~zolo[4,3-c3iso- 8.18 (2H, d), 8.37 (lH, d),
~uinolin-5-one 11.37 (lH, s)
64 2-(6-Chloro-3-pyridyl)-2,4-di- >250 327/329 3.79 (3H, s), 7.73 (lH, d),
hydro-3-hydroxy~-methyl- (M+H)t 7.76 (lH, t), 7.92 (lH, t),
-5H-pyra~olo~4,3-c]iso~uinolin- 8.02 (IH. d), 8.38 (2H, m),
-5-one 8.97 (lH, d)
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Ex. Name m.p./~C MS IH NMR (d6-DMSO) ~
2,4-Dihydro-3-hydroxy-2-(4- >250 418 3.80 (3H, s~, 7.74 (3H, m),
-iodophenyl)-4-methyl-5H-pyr- (M+H)+ 7.89 (3H, m), 8.û2 (IH, d),
azolo[4,3-c]isoquinolin-5-one 8.36 (lH, d)
66 2,4-Dihydro-3-hydroxy-4-(4- >230 466 3.68 (3H, s), 5.59 (2H, s),
-methoxyphenylmethyl)-2-(4- dec. (M+H)+ 6.83 (2H, d), 7.40 (2H, d),
-trifluoromethylphenyl)-5H- 7.75 (lH, t), 7:90 (3H~ m),
-pyrazolo~4,3-c]isoquinolin-5- 8.07 (lH, d), 8.20 (2H, d),
-one 8.38 (lH, d), 11.50 (lH, s)
67 2,4-Dihydro-3-hydroxy-4-(1- 228-230 388 1.59 (6H, d), 5.85 (lH,
-methylethyl)-2-(4-trifluoro- dec. (M+H)+ brs), 7.76 (lH, t), 7.g2methylphenyl)-5H-pyrazolo- ~3H, d3, 8.04 (lH, d), 8.18
[4,3-c]isoquinolin-5-one (2H, d), 8.36 (lH, d)
68 2,4-Dihydro-3-hydroxy-4- 238--240 334 1.25 (6H, d), 2.96 (lH,
-methyl-2-[4-(1-methylethyl)- (M+H)+ hept), 3.81 (3H, s), 7.42
phenyl}-5H-pyrazolo[4,3-c]iso- (2H, d), 7.72 (lH, t), 7.78
quinolin-5-one (2H, d), 7.89 (lH, t), 8.01(lH,d),8.36(1H,d)
Example 69
2,4-Dihydro-3-hydroxy-2-(4-trifluoromethylphenyl)-~H-py~azolo~4,3-c~iso(luinolin-
-5-one
Trifluoroacetic acid (4 ml) was added to 2,4-dihydro-3-hydroxy-4-(methoxyphenylmethyl~-
-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one (example 66) (425 mg)
and the mixture was heated at reflux for 12 hours. ~fter 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
o title compound (150 mg). m.p. >200 ~C.
MS (APCI) 346 ((M+H)+).
H NMR (d6-DMSO) ~ 7.76 (lH, t), 7.92 (3H, m), 8.02 (lH, d), 8.18 (2H, d), 8.34 (lH, d),
11.20 (lH, s)
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The following examples were prepared analogously to example 69:
Ex. Name m.p./~C MS IH NMR (d6-DMSO~ o
2,4-Dihydro-3-hydroxy-2-[4- >250~ 320 1.24 (6H, d), 2.95 (lH, m),
-(l-methylethyl)phenylJ-5H- (M+H)+ 7.40 (2H, d), 7.70 (1~, t), 7.78
-pyrazolo[4,3-c3iso~uinolin-5- (2~, d), 7.88 (IH, t), 7.99 (I~I,
-one d), 8.32 (IH, d), 11.00 (IH, s)
71 2,4-Dihydro-3-hydroxy-2- 275 354 7.39 (l~I, t), 7.50 (2H, t), 7.74
-([I,l'-biphenyl3-4-yl)-5H- dec. (M+H)+ (3H, d), 7.87 (3~I, m), 8.01
-pyrazolo[4,3-c~isoquinolin- (3H, m), 8.34 (1 H, d3, 11.13
-5-one (IH, s), 11.76 (IH, s)
Example 72
2-(4-Chlorophenyl)-3-hydroxy-4-t(4-methoxyphenyl)methyl~-5-methyl-2H-pyrazolo-
[4,3-c]isoquinolinil-rn hydroxide, inner salt
A 3M solution of methylm~gnesium bromide in diethyl ether (2.0 ml) was added dropwise
to an ice cooled suspension of 2-(4-chlorophenyl)-3-hydroxy-4-~(4-methoxyphenyl)-
methyl]-2H-pyrazolo[4,3-c~isoquinolinium hydroxidet inner salt (Ex. 22) (0.5 g) and
10 copper(I) bromide (17 mg) in dry tetrahydro~uran (20 ml). The mixture was stirred cold ~or
I hour before saturated aqueous ammonium chloride and ethyl acetate were added. This
mixture was stirred at room ~ peldture 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
15 chromatography (99:1 dichloromethane: methanol) to give a purple solid (0.38 g). A
sample (0.1 g) was recrystallised from ethanol to give the title compound (3 i mg).
m.p. 212-216 ~C
MS (APCI) 430, 432 ((M+H) ' )
'H NMR (d6-DMSO) o 2.88 (3H, s), 3.71 (3H, s), 6.50 (2H, br s), 6.93 (2H, d), 7.32 (2H,
~o d), 7.~1 (2H, d), 7.76 (lH, t), 7.98 (lH, t), 8.32 (1~, d), 8.43 (3H, m).
Example 73
2-(4-Chlorophenyl),5-methyl-2H-pyrazolo[4,3-c~isoquinolin-3-ol
2-(4-Chlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2H-pyrazolo-
'5 ~4,3-c]iso~uinolinium hydroxide, inner salt (0.29 g) was dissolved in trifluoroacetic acid
(10 ml) and heated under reflux in a nitrogen atrnosphere for 2 hours. On cooling to room
temperature the solvent was evaporated and the residue was co-evaporated with toluene
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(thrice). Purification by column chromatography (20: l 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 ((M+H)+)
iH NM~ (d6-DMSO) â 2.77 (3H, s~, 7.47 (2H, d), 7.68 (l~I, t), 7.77 (lH, t), 8.10 (lH, d),
8.25 (lH, d), 8.31 (2H, d).
The following examples were prepared following the method of example 72:
Ex. Name m.p./~C MS IH NMR (d6-DMSO) o
74 4-Cyclopropyl-3-hydroxy-5- ~250 384 1.32 (2H, m), 1.48 (2H, m),
-methyl-2-(4-trifluoromethyl- (M+H)+ 3.07 (3H, s), 4.04 (I H, m),
phenyl)-2H-pyrazolot4,3-c~- 7.16 (3H, m), 7.95 (lH, t),
iso~uinolinium hydroxide, 8.36 (2H, m), 8.62 (2H, d)
inner salt
3-Hydroxy~-(2-methoxy- 202- 402 3.00 (3H, s), 3.29 (3H, s), 4.08
ethyl)-5-methyl-2-~(4-tri- 204 (M~H)+ (2H, t), 5.37 (2H, br s), 7.68
fluoromethyl)phenyl]-2H-pyr- (3H, m), 7.88 (IH, t), 8.10
azolo [4,3-c]iso~uinolinium (IH, d), 8.56 (3H, m~
hydroxide, inner salt
Example 76
2-(4-Chlorophenyl)-3-hvdroxy-4,~-dimethyl-2~-pyrazolo[4,3-cJisoquinolinium
hydroxide, inner salt.
2-(4-Chlorophenyl)-2,4-dihydro-3-hydroxy-4-methylpyrazolo~4,3-c~isoquinolin-5-one
15 (0.48 g) (F.xample 6) was suspended in dry 1,2-dimethoxyethane (50 ml). A solution of
methylmagnesium brornide (3 ml of 3M solution in ether) was added and the mixture was
heated under reflux for 0.75 h. Further methy~m~esium 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
~o basified with a~ueous sodium bicarbonate solution and extracted with ethyl acetate (thrice).
The organic phase was washed with brine, dried over m~ne~ium sulfate, filtered and
evaporated. Purification of the residue by chromatography (silica, 97:3-95:5 dichloro-
methane: methanol) gave a red solid which was triturated with ether to give the title
compound (0.060 g). m.p. >250 ~C.
~s MS (APCI) 3241326 ((M+H)+).
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wo 97/34893 38 PCT/SE97/00471
IH NMR (d6-DMSO) ~ 2.90 ~3H, s), 4.63 (3H, s), 7.49 (2H, d), 7.77 (IH, t), 7.95 (lH, t),
8.39 (4H, m).
The following examples were prepared following the method of example 76:
Ex. Name m.p./~C MS lH NMR (d6-DMSO) ~
77 S-Ethyl-3-hydroxy-4-methyl- >250 372 1.45 (3H, t), 3.32 (2H, q), 4.78
-2-(4-trifluololllethylphenyl)- (M+H)+ (3H, s), 7.68 ~3H, m), 7.88
-2H-pyrazolo[4,3-c]iso- (lH, td), 8.03 (lH, d), 8.54
quinolinium hydroxide, inner (2H, d), 8.58 (lH, dd)
salt.
78 3-Hydroxy-S-methyl-4-(1- 205- 386 1.76 & 1.90 (6H, 2 x m,
-methylethyl)-2-(4-trifluoro- 210 (M+H)+ rotamers), 3.07 (3H, s), 5.42 &
methylphenyl)-2H-pyrazolo- 7.40 (lH, 2 x br, rotamers)
~4,3-c]isoquinolinium hydr- 7.77 (3H, m), 7.97 (lH, t),
oxide, inner salt 8.41 (2H, m), 8.62 (2H, m).
79 4-Methyl-S-(I-methylethyl)- 236-- 386 1.61 (6H,d),4.û5(1H,br),
-3-hydroxy-2-(4-trifluoro- 238 (M+H)+ 4.75 (3H, s), 7.76 (lH, t), 7.80methylphenyl)-2H-pyrazolo- (2H, d), 7.94 (lH, t), 8.43 (lEI,
[4,3-c3isoquinolinium hydr- dd), 8.52 (lH, d), 8.60 (2H, d)
oxide, inner salt
3-Hydroxy-4,5-dimethyl-2-(4- >250 358 2.87 (3H, s), 4.72 (3H, s), 7.66-trifluoromethylphenyl)-2~I- (M+H)' (3H, m), 7.86 (lH, t), 8.01
-pyrazolo[4,3-cJisoquinolin- (IH, d), 8.53 (3H, m)
ium hydroxide, inner salt
Example 81
',-Chloro-2-(4-t~ifluorometllyllJhenyl)-2N-pyrazolo[4,3-c]isoquinolin-3-ol
Phosphorous oxychloride (S ml) was added to 2,4-dihydro-3-hydroxy-4-(methoxyphenyl-
o methyl)-2-(4-trifluoromethylphenyl)-SH-pyrazolo[4,3-cJisoquinolin-S-one (example 66)
(350 mg) and heated to reflux for 1 hour. After cooling to room te~ e.ature the solvent
was removed and the residue was purified by column chromatography, eluting with
isohexane: ethyl acetate: acetic acid (80:20:2) followed by trituration with acetonitrile to
give the title compound (25 mg). m.p. >250 ~C dec.
MS (APCI) 36~/366 ((M+H~+).
IH NMR (d6-DMSO) ~ 7.96 (SH, m), 8.07 (lH, t), 8.25 (IH, d), 8.43 (lH, d)
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39
Example 82
3a,4-Dihydro-3a-hydroxy-2-(4-trifluoromethylphenyl)-2N-pyrazolo[4,3-c~isoquinolin-
-3,5-dione
Ceric ammonium nitrate (700 mg) was added to a suspension of 2,4-dihydro-3-hydroxy-
-4-(methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)-SH-pyr~olo~4,3-c]isoquinolin-
-5-one (example 66) (200 mg) in acetonitrile (4 ml) and water (1 ml) at room temperature.
After 2 hours the mixture was absorbed onto silica gel and purified by column
chromatography, eluting with isohexane: propan-2-ol (9:1), and then HPLC, eluting with
o isohexane: ethyl acetate (4: 1), to ~ive the title compound (S0 mg). m.p. 175-185 ~C
MS (ESl) 360 (M-H)-
IH NMR (d6-DMSO3 ~ 7.7-8.0 (5H, m), 8.08-8.12 ~4H, m), 9.78 (lH, s).
Example 83
2~4-Dihydro-3-methoxy-4-methyl-2-(4-trifluoromellly~ enyl)-s~l-pyrazolo[4~3-c]i
quinolin-5-one.
2,4-Dihydro-3-hydroxy-~methyl-2-(4-trifluolu~ Lhylphenyl)-5H-pyrazolo[4,3-cJiso-quinolin-5-one (0.2 g) (Example 63) in dry dimethylformamide (5 ml) was added dropwise
to a stirred suspension of oil-free sodium hydride (from 0.022 g 60% dispersion) in dry
20 dimethylform~mi~l~ (1 ml~ at 0 ~C. After 0.5 h methyl iodide (0.038 ml) was added.
Stirring was continued for 16 h. The mixture was diluted with water, acidified with dilute
hydrochloric acid and extracted with ethyl acetate (thrice). The organic phase was washed
with brine (seven times) then dried over m~gnecium sulfate, filtered and concentrated.
Purification by chromatography (25:75-SO:S0 ethyl acetate: dichlol~m~lllane then 30:70
~5 ethyl acetate: isohexane) gave the title compound as a colourless solid (0.015 g).
m.p. 163--164 ~C
MS (APCI) 374 ((M+H)~)
IH NMR ~CDCI3) o 3.78 (3H, s), 3.83 (3H, s), 7.60 (lH, td), 7.74 (lH, td), 7.80 (2H, d),
8.04 (2H, d), 8.27 (lH, dd), 8.48 (lH, dd).
FY~nlplE 84
2-(4-Chlorophenyl)-4-~2-(N,N-dimethylamino)ethyl}-3-hydroxy-2H-pyrazolo[4,3-c] -isoquinolinium hydroxide, inner salt
2-(4-Chlorophenyl)-2H-pyrazolo[4,3-c~isoquinolin-3-ol (0.3 g) was added to a stirred
3s suspension of oil-free sodium hydride (from 81 mg 60% dispersion) in dry
dimethylforrnamide ~5 ml) under a nitrogen atmosphere. After 30 minutes, 2-dimethyl-
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WO 97~4893 PCT/SE97/00471
aminoethyl chloride hydrochioride ~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 recryst~ilic:~ion 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 ((M+H)+).
lH NMR (d6-DMSO) â 2.32 (6~, s), 3.02 (2H, t), 5.03 (2H, t), 7.4 (2H, d), 7.65 (lH, t),
7.85 (3H, m), 8.30 (2H, d), 8.50 (IH, d).
Example 85
3-Hydroxy-4-methyl-2-(4-methylsulfinylphenyl) -2H-pyrazolor4,3-cJisoquinolinium
hydroxide, inner salt
3-Hydroxy-4-methyl-~-(4-methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide,
s inner salt (0.10 g) (example 41) was dissolved in dichloromethane (15 ml) and cooled to
-78 ~C. 3-Chloroperbenzoic acid (0.055 g) was added and the mixture was stirred ~or 10
minu~es 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
20 chromatography (3:2 ethyl acetate: methanol~ to give the t}tle compound as a red powder
(0.012 g). m.p. >230 ~C
MS(APCI): 338((M+H)+).
'H NMR (d6-DMSO): o 2.77 (3H, s), 4.52 (3H, s), 7.80 (3H, m), 7.96 (lH, t), 8.13 (lH, d),
8.37(1H,d),8.57(2H,d),8.64(1H,s).
F,Y~mrle86
2-(4-Chlorophenyl)-3-hydroxy-4-[2-(methylsul~myl)ethyl] -2H-pyrazolo[4,3-cJiso-
quinolini~ 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-r2-(methylthio)ethyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (example
46) (0.43 g) in dichloromethane ~20 ml) at -78 ~C. After 30 min aqueous sodium meta-
bisulfite 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 (2-6% by volume) in dichloromethane as the eluant to
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WO 97/34893 . PCT/SE97/00471
41
give a purple solid (0.46 g).
m.p. 228-230 ~C
MS (APCI+) 386, 388 ((M~H)+)
~HNMR(d6-DMSO)~2.69(3H,s),3.47(1H,m),3.64(1H,m),5.11 (IH,m),5.34(1H,
m),7.50(2H,m),7.79(1H,m),7.99(1H,m),8.17(1E~,d),8.38(3H,m),8.83(1H,s).
FY~-mr~e 87
3-Hy-lr~y-4-[2-(methylsulfinyl)ethyl]-2-(4-trifluoromethylphenyl)-2H pyrazolo[4,3 c
isoquinolinillm hydroxide, inner salt
o Prepared from 3-Hydroxy-4-[2-~methylthio)ethyl~-2-(4-trifluoromethylphenyl)-2H-
-pyr~oloL4,3-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 ((M+H)+).
'H NMR (d6-DMSO) o 2.70 (3H, s), 3.47 (IH, m), 3.64 (lH, m), 5.11 (lH, m), 5.36 (lH,
m),7.81 (3H,m),8.01 (lH,m),8.19(1H,d),8.38(1H,d),8.60(2H,d~,8.86(1H,s).
F.~ nrle 88
5-[2-(4-Methoky~h~ l)ethyll-2-(4-trifluoromethylphenyl)-2H-pyrazolo~4,3-c~iso-
quinolin-3-ol, sodium salt
Methylm~gnesium bromide (3M in ether, 8.6 ml) was added slowly to a stirred suspension
of 2,4-dihydro-3-hydroxy-4-(4-methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)-5H-
-pyrazolo{4,3-cJisoquinolin-5-one (example 66) (500 mg) and copper (I) bromide (15 mg)
in 1,2-dimethoxyethane (50 ml) and then heated at 100 ~C for 24 hours. After being
allowed to cool to room temperature the mixture was poured onto cold dilute hydrochloric
~5 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 m~necillm sulfate. Filtration and evaporation of the solution
followed by purification by column chromatography eluting successively with isohexane:
ethyl acetate (1: 1), ethyl acetate and ethyl acetate: methanol (9: 1), gave the title compound
as a red solid (90 mg). m.p. >200 ~C dec.
MS (APCI) 464 ((M+H)+)
lH NMR (d6-DMSOtI'FA) o 3.08 (2H, t), 3.59 (2H, t), 3.73 (3H, s), 6.87 (2H, d), 7.25 (2H,
d),7.92(3H,m),8.05(1H,t~,8.33(2H,d),8.40(1H,d),8.50(1H,d), 12.05
(TFA/water/l H) .
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Example 89
9-Fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo~4,3-c]iso~uinolinium hydroxide, inner salt
s ~a) 2,6 Difluoro-N-(2-hydroxy-1,1-dimethylethyl)ben7z~
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 ~C. After addition was complete the ice bath was removed and stirring
lO 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 ((M~H)+)
15 ~H NMR (CDCl3): ~ 1.41 (6H, s), 3.70 (2H, d), 3.95 (lH, t), 6.00 ~lH, ~r s), 6.95 (2H. m),
7.38 ( lH, m).
(b) 2-(2,6-D;lluvl o~henyl)-4,5-.lihydro-4,4-ciimethyloxazole
Thionyl chloride (12.6 ml) was added dropwise to an ice cooled solution of 2,6-difluoro-
20 -I\r-(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 stirrino
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 min;mllm
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) 21 1 (M+).
30 -IH NMR (CDCI3): o 1.42 (6H, s), 4.14 (2H, s), 6.95 (2H, m), 7.40 (lH, m).
(c) 4,5-Dihydro-2-(2-fluoro-6-methylphenyl)-4,4-dimethyloxazole
A 3M solution of methylmagnesium chloride in tetrahydrofuran (86 ml) was added
dropwise to a solution 2-(2,6-difluorophenyl)-4,5-dihydro~,4-dimethyloxazole ( 18.23 g) in
35 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 t~ pe,dture over 16 hours. Saturated
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43
ammonium chloride so}ution 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).
s MS (APCI) 208 ((M+H)+)
IH NMR (CDCI3): o 1.42 (6H, s), 2.40 (3H, s), 4.12 (2H, s), 6.93 (lH, t), 7.00 (lH, d), 7.26
(lH, m).
(d) 2-Fluoro-6-methylbenzoic acid
o 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
15 4 hours. The reaction mixture was allowed to cool to room te~ ture 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, fi}tered and evaporated to give 2-fluoro-6-methylbenzoic acid (10.85 g). A sample
20 (0.27 g) was recrystallised from 4: 1 hexane: ethyl acetate to give the subtitle compound
~0.15 g). m.p. 123-124 ~C.
MS (EI~ 154 (M+).
~H NMR (CDCI3) ~ 2.52 (3H, s), 7.02 (2H, m), 7.35 (lH, m).
25 (e) Methyl 2-fluoro-6-methylben7o~te
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 anatmosphere of nitrogen. Stirring was continued at room lt;mpeldture for 16 hours and then
the reaction mixture was diluted with water and extracted with ethyl acetate (thrice). The
30 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 (CDC}3~.o 2.40 (3H, s), 3.94 (3H, s), 6.94 (lH, t), 7.01 (IH, d), 7.30 (lH, m).
3~
(f) Methyl 2-(bromomethyl)-6-fluorob~n~o~te
-- --
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A suspension of methyl 2-fluoro-6-methylbenzoate (35.53 g), N-bromosuccinimide
(37.6 g) and azobis(isobutyronitrile) (2 g) in dry dichloromethane (150 ml) was irradiated
(lOOW halogen lamp) under an atmosphere of nitrogen for 4 hours. The resultant solution
was poured onto 10% sodium hydroxide solution and extracted with dichloromethane
(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 (52.3~ g) as a
yellow oil.
MS (EI) 246/248 (M ' )
lH NMR (CDCI3) S 3.99 (~H, s), 4.66 (2H, s), 7.06 (lH, t), 7.23 (IH, d), 7.40 (lH, m).
~g) Methyl 2-fluoro-6-{[(2-methoxy-2-oxoethyl)-(4-methoxyph~yl~.~et~.yl)amino~-
methyl}bPn~o~t~
N-(4-Methoxyphenylmethyl)glycine methyl ester ( 10.2 g) was added dropwise to a stirred
solution of methyl 2-(b-~.l--o--1cthyl)-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 ev~oldL~d. 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 ((M+H)+)
lH NMR (CDCI3): o 3.21 (2~I, s), 3.67 (3H, s), 3.68 (2H, s), 3.78 (3H, s), 3.88 (3H. s), 4.01
(2H,s),6.82(2H,d),7.05(1H,t),7.18(3H,m),7.35(1H,m).
(h3 Methyl 5-fluoro-1,2,3,4-tell ~Ly~lro-2-(4-methoxyphenylmethyl)4-oxo-3-iso-
~uinolinecarboxylate
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 ter~-butyl
~alcohol ( 1 ml) in dry toluene ( 100 ml) heated under reflux in a nitrogen atmosphere.
~ ting was continued a further 12 hours then the reaction nlib~Lul~ 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 g). MS (APCI) 344 ((M+H)+).
-
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H NMR (CDCI3): ~ 3.60 (2H, s), 3.81 (3H, s), 3.89 (2H, s), 3.92 (3H, s), 6.86 (3H, m),
~7.05(1H,m),7.22(2H,m),7.38(1H,m), 11.83(1H,s).
(i) 9-Fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl3-2-(4-trifluoromethylphenyl)-2H-
-pyrazolo[4,3-c]iso~uinolinium hydroxide, inner salt
Methyl 5-fluoro-1,2,3,4-tetrahydro-2-(4-methoxyphenylmethyl)-4-oxo-3-iso~uinolinecarb-
oxylate (1.0 g), 4-trifluoromethylphenylhydr~ine (1.03 g) and p-toluene sulfonic acid
(20 mg~ were fused together at 150 ~C under a nitrogen atmosphere for 15 minl-tPs. Xylene
(20 ml) was then added and heating was continued a further 2 hours. On cooling to room
telny~lature the solvent was evaporated and the solid residue was purified by column
chromatography (99: I dichloromethane: methanol) to give the title compound as purple
needles (0.425 g).
MS (APCI) 468 ((MtH)+)
'H NMR (d6-DMSO) o 3.72 (3H, s), 6.10 (2H, s), 6.96 (2H, d), 7.70 (2H, d), 7.80 (4H, m),
8.00 (lH, dd), 8.5g (2H, d), 8.98 (lH, s).
~,Y~n~ple 90
9-~luoro-2-(4-trifluoromelhyl~henyl)-2H-pyrazolo~4,3-c~isoquinolin-3-ol
9-Fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl] -2-(4-trifluoromethylphenyl)-2H-pyr-
20 azolor4,3-c]isoquinolinium hydroxide, inner salt (0.43 g) was dissolved in tnfluoroacetic
acid (5 ml) and heated under reflux in a nitrogen atmosphere ~or 16 hours. After being
cooled to room temperature the solvent was evaporated and the residue was co-evaporated
with toluene (thrice). The residue was lL;Lul~ed successively with methanol and then
diethyl ether and ~mally recryst~ ce~ from ethyl acetate to give the title compound as a red
2s solid (0.08 g). m.p. >250 ~C.
MS (APCI) 348 ((M+H)+).
~H NMR (d6-DMSO) ~ 7.86 (2H, m), 7.95 (2H, d), 8.14 (lH, d), 8.24 (2H, br d), 9.09 (lH,
br s), 11.85 (lH, br s).
30 The following compounds were made by methods analogous to example 90:
Ex. Name m.p./~C MS IH NMR (d6-DMSO) ~
91 2-(4-Chlorophenyl)-7-fluoro- >250 328/ 4.51 ~3H, s), 7.46 (2H, d), 7.77
-3-hydroxy-4-methyl-2H-pyr- 330 (lH, td), 7.87 (IH, dd), 8.36
azolor4,3-c]isoquinolinium (M+H)+ (3H, m), 8.45 (lH, s)
hydroxide, inner salt
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WO 97/3~893 46 PCT/SE97/00471
Ex. Name m.p./~C MS lH NMR (d~-DMSO) o
92 7-Fluoro-3-hydroxy-4-methyl- >250 362 4.51 (3H, s), 7.75 (2H, d), 7.80
-2-(4-trifluoromethylphenyl)- (M+H)+ (IH, m), 7.87 (lH, dd), 8.38
-2H-pyrazolor4,3-c3iso- (IH, dd), 8.47 (lH, s), 8.54
quinolinium hydroxide, inner (2H, d)
salt
93 2-(4-~hlorophenyl)-4-cyclo- >214- 354/ 1.35 (2H, m), 1.54 (2H, m),
propyl-9-fluoro-3-hydroxy- 217 356 5.11 (lH, m), 7.51 (2H, d),
-2H-pyrazolot4,3-c]iso- (M+H)+ 7.75 (2H, m), 7.g5 (IH, dd),
quinolinium hydroxide, inner 8.38 (2H, d), 8.63 (IEI, s).
salt
94 4-Cyclopropyl-9-fluoro-3- >250 388 }.36 (2H, m), 1.55 (2H, m),
-hydroxy-2-(4-trifluoro- (M+H)+ 5.06 (lH, m), 7.77 (4H, m),
methylphenyl)-2H-pyr- 7.97 (IH, m), 8.58 (2H, d),
azolot4,3-c]isoquinolinium 8.66 (IH, s)
hydroxide, inner salt
2-(4-Chlorophenyl)-9-fluoro- >250 328/ 4.51 (3H, s), 7.51 (2H, d), 7.76
-3-hydroxy~-methyl-2~-pyr- 330 (2H, m), 7.91 (IH, m), 8.35
azolo[4,3-c]isoquinolinium (I\~+H)+ (2H, d), 8.65 (IH, s)
hydroxide, inner salt
96 2-(4-Chlorophenyl)-9-fluoro- >250 434/ 3.72 (3H, s), 6.10 (2H, s), 6.~5
-3-hydroxy-4-r(4-methoxy- 436 (2H, d), 7.54 (2H, d), 7.70
phenyl)methyl]-2H-pyrazolo- (M~H)+ (2H, d), 7.77 (2H, m), 7.97
r4~3-c3isoquinolinium hydr- (lH, m), 8.39 (2H, d), 8.96
oxide, inner salt ( I H, s)
97 9-Fluoro-3-hydroxy-4-methyl- ~250 362 4.51 (3H, s), 7.77 (4H, m),
-(4-trifluoromethylphenyl)- (M+H)+ 7.93 (lH, m), 8.56 (2H, d),
-2H-pyrazolo[4,3-c]iso- 8.6~ (lH, s)
~uinolinium hydroxide, inner
salt
The following compounds (examples 98-100) were prepared following the methods ofexample 2:
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Ex Name m.p./~C MS 'H NMR (d6-DMSO) o
98 2-(4-Chlorophenyl)-9- >250 314/316 7.63 (2H, d), 7.82 (2H, brm),
-fluoro-2H-pyrazolo- ~M+H)+ 8.01 (2H, d), 8.11 (lH, br d),
[4,3-c]isoquinolin-3-ol 9.05 (lH, br s), 11.80 (lH, ~r s)
99 7-Fluoro-2-(4-trifluoro- >250 348 7.93 (3H, d), 8.14 (IH, d), 8.28methylphenyl)-2H-pyr- (M+H)+ (2H, d), 8.41 (1 H, dd), 9.02 (1 H,
azolo[4,3-c]iso~uinolin-3- br s)
-ol
100 2-(4-Chlorophenyl)-7- >250 314/316 7.63 (2H, d), 7.91 (I~I, brt),
-fluoro-2H-pyr~olo- 8.05 (2H, d), 8.13 (IH, d), 8.40
[4,3-c]isoquinolin-3-ol ~IH, dd), 9.00 (lH, br s~, 12.00
(IH. br s)
The following compounds were ~ Gd following the method of example 69:
Ex. Name m.p./~C MS IH NMR (d6-DMSO) ~
101 9-Fluoro-3-hydroxy-4-[(4-meth- 225-227 482 2.86 (3H, s), 3.73 (3H, s),
oxyphenyl)methyl~-5-methyl-2- (M+H)+ 6.53 (2H, s), 6.92 (2H, d),
-(4-trifluo.. "~ ylphenyl)-2H- 7.30 (2H, d), 7.74 (4H, m),
-pyrazolo~4,3-c]isoquinolinium 8.11 (lH, d), 8.58 (2H, d)
hydroxide, inner salt
102 2-(4-Chlorophenyl)-9-fluoro-3- 222-223 448/450 2.85 (3H, s), 3.73 (3H, s),
-hydroxy-4-[(4-methoxy- (M+H)+ 6.53 (2H, s), 6.91 (2H, d),
phenyl)methyl]-5-methyl-2H- 7.29 (2H, d), 7.44 (2H, d),
-pyr~olo[4,3-c~isoquinolinium 7.70 (2H, m), 8.08 (IH, d),
hydroxide, inner salt 8.37 (2H, d)
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The following compounds were prepared by the method of example 2:
Ex. Name m.p./~C MS IH NMR (d6-DMSO) ~
103 9-Fluoro-5-methyl-2-(4-tri- >250 362 2.80 (3H, s), 7.79 (2H, m),fluoromethylphenyl)-2H-pyr- ~M+H)+ 7.88 (2H, d), 8.10 (lH, d),
azolo~4,3-c3isoquinolin-3-ol 8.32 (2H, d)
104 2-~4-chlorophenyl~-9-fluoro-5- >250 328/330 2.89 (3H, s), 7.58 (2H, d),
-methyl-2H-pyr~olo[4,3-c]iso- (M+H)+ 7.79 (2H, br m), 8.08 (3H,
quinolin-3-ol br m)
Example 105
2,4-Dihydro-3-hydroxy-4-methyl-2-(4-trifluorom~tl.yl~ enyl)-5H-pyrazolo~4,3-cJiso-
quinoline-5-thione.
A solution of 2,4-dihydro-3-hydroxy-4-methyl-2-(4-kifluoromethylphenyl)-5H-pyrazolo-
[4,3-c]isoquinolin-5-one (example 63) (0.25 g) and Lawesson's reagent (0.7 g) in dioxane
o (20 ml) was stirred and heated under reflux for 18 hrs. The resnlting mixture was cooled
and absorbed onto silica gel. Purification by chromatography ( I :99-3:97 methanol:
dichloromethane) gave the title compound which was cryst~l~ice-l from ethanol to afford a
yellow solid (0.075 g). m.p. 255--259 ~C.
MS (APCI) 376 ((M+H)+).
'H NMR (D20/NaOD) ~ 8.47 (lH, d), 7.71 (2H, d), 7.60 (3H, m), 7.34 (IH, t), 7.22 (lH,
t), 4.08 (3H, s).
Example 106
3-H~droxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo~4,3-c~iso-
20 ~uinolinium hydroxide, inner salt.
A solution of 2,4-dihydro-3-hydroxy-4-methyl-2-(4-trilluoromethylphenyl)-5H-pyrazolo-
[4,3-c]iso~uinoline-5-thione (0.46 g) (example 105) and iodomethane (0.095 ml) in
acetone ~0 ml) was stirred and heated under reflux for 4 hr. Potassium carbonate (0.170 g)
was added and the mixture was heated for a further 2 hr. The mixture was concentrated in
~5 vacuo. Purification of the residue by chromatography (2:98 methanol: dichloromethane)
gave the title compound as a purple solid (0.375 g).
MS (APCI) 390 ((M+H)+)
IH NMR (CDCI3) o 8.54 (4H, m), 7.86 (lH, t), 7.72 (3H, m), 4.98 (3H, s), 2.52 (3H, s).
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Example 107
2-(4-Trifluoromethylphenyl)-2,4-dihydro-5-imino-4-methyl-5E~-pyrazolo[4,3-cJiso-~uinolin-3-ol.
A suspension of 3-hydroxy~-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2~-
-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.013 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 ma~nesium sulfate and concentrated in vacuo.
Purification of the residue by chromatography (5:95-10:90 methanol: dichloromethane)
o gave the title compound as an orange solid (0.043 g). m.p. 253--255 ~C.
MS (APCI) 717 ((2M+H)+), 359 ((M+H)+).
IH NMR (d6-DMSO) o 8.60 (2H, d), 8.46 (lH, d), 8.29 (3H, m), 7.90 (lH, t), 7.71 (3H, m),
4.19 (3H, s).
15 Example 108
3-Hydroxy-4-(4-n~thn~rypheny~ ell~yl-2-(4-trifluorome~ ênyl)-2El-pyra
r3,4-fl[1,7]naphthyri~1ini~m liy~ e, inner salt
(a~ Methyl 2-(bron~m~thyl)nirotin~fe
Methyl 2-methylnicotinate (10.0 g) and N-bromosuccinimide (14.9 g) were combined in
1,2-dichloroethane (80 ml). Acetic acid (3.8 ml) was added followed by 2,2'-azobis-
(2-methylpropionitrile) (1.0 g) and the mixture was heated to reflux 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 imm~Aiately for the
next step.
(b) N-[(4-methoxyphenyl)methyl]-N-t(3-methoxycarbonyl-2-pyridyl)methyl]glycine
methyl ester
Prepared fo!lowing the method of exarn,ple 1 step (z) using ,-lethyl 2-(bromomethyl)-
nicotinate (9.10 g), methyl N-(4-methoxyphenyl)methylglycine (10.2 g~ and triethylarnine
(5.5 ml) in diethyl ether (100 ml) to give the subtitle compound (3.20 g)
MS (DESC SI) 358 (M+)
lH NMR (d6-DMSO) 3.17 (s, 2H), 3.34 (s, 3H), 3.58 (s, 2H), 3.71 (s, 3H), 3.82 (s, 3H),
4.23 (s, 2H), 6.82 (d, 2H), 7.04 (d, 2H), 7.43 (dd, IH), 8.03 (dd, lH), 8.61 (dd, lH)
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(c) Methyl 7,8-dihydro-5-hydroxy-7-(4-methoxyphenyl)methyl[1,7Jnaphthyridine-
-6-carboxylate
Prepared following the method of example I step (b) using N-[(4-methoxyphenyl~methyl~-
-1~-[(3-methoxycarbonyl-2-pyridyl)methyl]glycine methyl ester (1.00 g), sodium hydride
(60% dispersion in oil) (160 mg), 2-methylpropan-2-ol (0.10 ml) and toluene (15 ml) to
give the subtit}e compound (790 mg).
MS (APCI) 327 ((M~H)+)
H NMR (d6-DMSO) 3.65-3.97 (m, lOH), 6.79 (m, 2H)7 7.11-7.39 (m, 3H), 7.8~8.25 (m7
lH), 8.52-8.75 (m, lH), 11.25 (s, lH)
(d) 3-Hydroxy-4-(4-methoxyphenyl)methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo-t3,4-.fl[1,7~}1aphthyri~1in;-lm hy~ xi.le, inner salt
Prepared following the method of example I step ~c3 using methyl 7,8-dihydro-5-hydroxy-
-7-(4-methoxyphenyl)methyl-1,7-naphthyridine-6-carboxy}ate (200 mg), 4-trifluoromethyl-
phenylhydrazine (1.00 g) and ethanol (3 ml) to give the title compound (21 mg).
m.p. 201-3 ~C.
MS (APCI) 451 ((M~H)+)
~H NMR (d6-DMSO) 3.72 (s, 3H), 6.13 (s, 2H), 6.96 (d, 2H), 7.76 (d, 2H), 7.84 (d, 2H),
7.88 (dd, lH), 8.59 (d, 2H), 8.72 (dd, lH), 9.00 (s, lH), 9.05 (dd, IH)
Example 109
2-(4-Trifluoromethylphenyl)-2H-pyrazolo[3,4-f l~1,7~naphth~1 i.lill-3'01
Prepared following the method of example 2 using 3-hydroxy-4-(4-methoxyphenyl)methyl-
-2-(4-trifluoromethylphenyl)-2H-pyrazolo[3,4-fl[1,7~naphthyridinium hydroxide, inner salt
2s (135 mg) and trilluoroacet-ic acid (5 ml) to give the title compound (19 mg). m.p. 239-41 ~C (dec.)
MS (APCI) 331 ((M+H)~)
lH NMR (d6-DMSO) 7.94 (d, 2H), 7.g5 (m, lH), 8.28 (d, 2H), 8.74 (d, lH), 9.01 (br, lH),
9.16(d, lH)
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The following examples were prepared analogously to example 109 using methyl
2-(bromomethyl)nicotinate, sarcosine methyl ester and the a~ iate hydrazine:
Ex. Name m.p./~C MS IH NME~ (d6-DMSO)
110 3-Hydroxy-4-methyl-2-(4-trifluoro- >260 345 4.56 (s, 3H), 7.82 (d,
methylphenyl)-2H-pyrazolo[3,4-fl- (M+H)+ 2H), 7.88 (dd, lH), 8.56
[1,7~naphthyridinium hydroxide, (d, 2~I), 8.70 (s, lH),
inner salt 8.73 (s, lH), 9.05 (d, IH)
111 2-(4-Chlorophenyl)-3-hydroxy- ~260 311/313 4.56 (s, 3H~, 7.51 (d,
-4-methyl-2~-pyrazolo[3,4-fl[1,7]- (M+H)+ 2H), 7.88 (dd, lH), 8.35
naphthyridinium hydroxide, inner (d, 2H), 8.6$ (s, lH),
salt 8.70 (dd, lH), 9.03 (dd,
lH)
s Example 112
3-Hydroxy-4-methyl-5-(dimethylamino)-
2-(4-trifluoromethylphenyl)-2E~-pyrazolo[4,3-c]isoquinol;ni-lm }-ydroxide inner salt.
A solution of 3-hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyr~olo-
[4,3-c3isoquinolinium hydroxide, inner salt (0.39 g) (example 106) in acetone (10 ml) and
40% aqueous dimethylamine solution (2 ml) was stirred at 20 ~C for 24 h. The mixture was
concentrated in vacuo. Purification of the residue by chromatography (1:99--2.5:97.5
methanol: dichloromethane) gave the title compound as a red solid (0.129 g). m.p. 25
259 ~C
MS (APCI) 387 ((M+H)+).
lH NMR (CDCl3) d 3.19 (6H, s), 4.52 (3H, s), 7.64 (3H, m), 7.84 (lH, td3, 7.95 (lH, d),
8.54 (3H, d)
~xample 113
3-Hydroxy-4-methyl-5-morpholinyl-2-(4-trifluoromethylphenyl~-2H-pyrazolo~4,3-c] -
isoquinolininnn hydroxide inner salt.
A solution of 3-hydroxy-4-methyl-5-methylthio-2-~4-trifluoromethylphenyl)-2H-pyr~olo-
[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 vacuo. Purification of the residue by chromatography (5:95
methanol: dichloromethane) gave the title compound as a red solid (0.165 g). m.p. 278-
281 ~C.
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MS (APCI) 429 ((M+H)+).
'H NMR ~d6-DMSO) d 3.49 (4H, m), 3.87 (4H, m), 4.49 (3H, s), 7.77 (2H, m), 7.94 (lE~,
t), g.28 (lH, d), 8.38 (lH, d), 8.59 (2H, d).
~Y~mple 114
3-Hydroxy-4-methyl-5-pil e~ ,yl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c~-
isoquinolini-lm hydroxide inner salt.
A solution of 3-hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl3-2H-pyrazolo-
~4~3-c]isoquinolinium hydroxide, inner salt (0.29 g) (example 106) in toluene (20 ml) was
10 added dropwise to a stirred solution of piperazine (1.28 g) in toluene (50 ml) heated at
110 ~C. The resulting solution was stirred at 110 ~C 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 (0.107g). m.p. 260--262 ~C.
MS (APCI) 428 ((M~H)+).
IH NMR (DMSO) d 2.96 (4H, m), 3.37 (4H~ m), 4.44 (3H, s), 7.76 (3H, m), 7.93 (lH, t),
8.27 (IH, d), 8.37 (lH, d), 8.59 (2H, d).
Example 115
20 4,5-Dihydro-2-L4-(tri~uoromethyl)~hellyl~-2H-benz~g~indazol-3-ol
l-Oxotetrahydronaphthalene-2-carboxylic acid methyl ester (Mander, L.N and Sethi, S.P;
Tetrahedron Lett. I983, 24, 5425-8) (2.0g) and 4-trifluoromethylphenylhydrazine (3.47g)
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
~5 recrystallised from toluene gave the title compound as colourless crystals. ~ 1.45g~. m.p.
189-lgO ~C.
MS (APCI) 331 ((M+H)+)
IH NMR {d6-DMSO) d 2.67 (2H, m), 2.90 (2H, m), 7.29 (3H, m), 7.75 (lH, m), 7.84 (2H,
d), 8.10 (2H, d), 11.70 (lH, s,br).
Example 116
4,~;-Dihydro-2-(5-methyl-2-py~ yl)-2H-benz~g]indazol-3-ol
I -Oxotetrahydronaphthalene-2-carboxylic acid methyl ester (2.18g) and 2-hydrazino-5-
methylpyridine (2.85g) were heated together in xylene (15ml) under reflux for 6h. The
35 reaction was allowed to cool and then the product was filtered and dried. Recryst~llic~tion
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from diethyl ether/isohexane gave the title compound as pale brown needles (0.69g). m.p.
112~C
MS (APCI) 278 ((M~H)+).
IH NMR (d6-DMSO) d 2.36 (3H, s), 2.73 (2H, t), 2.95 (2H, t), 7.29 (3H, m), 7.68 (lH, dd),
s 7.92 (IH, d), 7.94 (IH, m), 8.07 (lH, s), 12.73 (lH, s,br).
Flr~mrl~ 117
2-[4-(Trifluoromethyl~phenyl]-2H-benz[g]indazol-3-ol
4,5-Dihydro-2-[4-(trifluoromethyl)phenyl]-2H-benz[g~indazol-3-ol (0.30g) and 10%o palladium on charcoal (O.lOg) were heated in dimethyl~-~et~rnid~ (5ml) and cyclohexene
(Sml) under reflux for lh. the title compound (0.26g). m.p. >235 ~C (dec)
MS (APCI) 329 ((M~H)+)
iH NMR (d6-DMSO) d 7.70 (4H, m), 7.85 (21I, d), 8.07 (lH~ m), 8.27 (2H, d), 8.30 (lH,
m), 11.70 (lH, s, br).
l~xample 118
2-(~-Methyl-2.pyridinyl)-2H-benz[g]indazol-3-ol
4,5-Dihydro-2-(5-methyl-2-pyridinyl)-2H-benz~g~indazol-3-ol (0.40g) and 10% palladium
on charcoal (0.20g) were heated in dimethyl~ret~miA~ (15ml) and cyclohexene (15ml)
under reflux for 8h. The mixture was allowed to cool to ambient ~ e~:ture 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 (0.12g). m.p. 214 ~C.
MS (APCI) 276 ((MH)+)
lH NMR (d6-DMSO) d 2.36 (3H, s), 7.52 (lH, d), 7.66 (3H, m), 7.82 (lH, dd), 8.02 (lH,
2s d), 8.41 (lH1 s, br), 8.53 (2H, m).
Pharmacological Data
Test A - Chronic graft-versus-host test
Pharrnacological 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
~Aminictered to mice subcutaneously as a suspension in saline with TWEEN-80 every day
for21 days
_ _ _
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Test B - Inhibition of Eosinophilia
The effects of the compounds of the invention on inflamm~tory cells in mouse lungs was
~sesse~l by the following method, adapted from Brusselle et aL'., Clin. Exp. Allerg~, 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, 92')--929.
Male Balb/c mice were sensitised to ovalbumin/Al(OH)3 mixture.
14 days after sensitisation dosing with compound commenced. Compound was
~lm;ni.ctered daily either orally or subcutaneously as a suspension or solution (depending
on dose and compound solubility) in 5% TWEEN 80.
o 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 (2% 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 ch~ nge, on the final day of dosing an additional challenge with
ovalburnin was given 4 hours after the first.
~he following day the animals were sacrificed and inhibition of the following pala.lleters
was measured by co~ ~ison to control animals:
(1) Increase in the numbers of inll~mm~tory cells in the bronchioalveolar lavage, in
particular eosinophils (after the 4 day dosing).
,o (2) Accumulation of eosinophils within lung tissue, as measured by the increase in
eosinophil peroxidase activity in homogenised lung tissue (after the 8 day dosing).
(3) Increase in antibody titres (IgE, IgGl 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 ED50's in the range of 0.1 - 10 mg/kg.