U.S. patent application number 10/109629 was filed with the patent office on 2002-11-21 for substituted azabicyclic compounds.
Invention is credited to Astles, Peter Charles.
Application Number | 20020173527 10/109629 |
Document ID | / |
Family ID | 26309536 |
Filed Date | 2002-11-21 |
United States Patent
Application |
20020173527 |
Kind Code |
A1 |
Astles, Peter Charles |
November 21, 2002 |
Substituted azabicyclic compounds
Abstract
This invention is directed to physiologically active compounds
of formula (I) 1 wherein 2 represents a bicyclic ring, system, of 9
ring members, in which the ring 3 is an oxazole, and the ring 4 is
a benzene ring; R.sup.1 represents hydrogen or a straight- or
branched-chain alkyl group of 1 to about 4 carbon atoms, optionally
substituted by hydroxy or one or more halogen atoms, or when
Z.sup.1 represents a direct bond R.sup.1 may also represent a lower
alkenyl or lower alkynyl group, or a formyl group; R.sup.2
represents hydrogen, alkenyl, alkoxy, alkyl, alkylsulphinyl,
alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl,
arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl,
arylsulphonyl, arylthio, cyano, cycloalkenyl, cycloalkenyloxy,
cycloalkyl, cycloalkyloxy, hydroxy, --SO.sub.2NR.sup.4R.sup.5,
--NR.sup.4SO.sub.2R.sup.5, --NR.sup.4R.sup.5, --C(.dbd.O)R.sup.5,
--C(.dbd.O)C(.dbd.O)R.sup.5, --C(.dbd.O)NR.sup.4R.sup.5,
--C(.dbd.O)OR.sup.5, --O(C.dbd.O)NR.sup.4R.sup.5, or
--NR.sup.4C(.dbd.O)R.sup.5; R.sup.3 represents
--C(.dbd.Z)--N(R.sup.7)R.sup.6; A.sup.1 represents a straight or
branched C.sub.1-6alkylene chain optionally substituted by
hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl; Z.sup.1
represents a direct bond, an oxygen or sulphur atom or NH; n is
zero; and mis 1; and N-oxides thereof, and their prodrugs, and
pharmaceutically acceptable salts and solvates of the compounds of
formula (I) and N-oxides thereof, and their prodrugs. Such
compounds inhibit the production or physiological effects of TNF
and inhibit cyclic AMP phosphodiesterase. The invention is also
directed to pharmaceutical compositions comprising compounds of
formula (I), their pharmaceutical use and methods for their
preparation.
Inventors: |
Astles, Peter Charles;
(Dagenham, GB) |
Correspondence
Address: |
AVENTIS PHARMACEUTICALS, INC.
PATENTS DEPARTMENT
ROUTE 202-206, P.O. BOX 6800
BRIDGEWATER
NJ
08807-0800
US
|
Family ID: |
26309536 |
Appl. No.: |
10/109629 |
Filed: |
March 28, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10109629 |
Mar 28, 2002 |
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09612530 |
Jul 7, 2000 |
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09612530 |
Jul 7, 2000 |
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09216392 |
Dec 18, 1998 |
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6303600 |
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09216392 |
Dec 18, 1998 |
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PCT/GB97/01639 |
Jun 19, 1997 |
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60023047 |
Aug 2, 1996 |
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Current U.S.
Class: |
514/375 ;
514/379; 548/217; 548/241 |
Current CPC
Class: |
A61P 9/00 20180101; C07D
417/14 20130101; A61P 29/00 20180101; A61P 31/00 20180101; C07D
209/42 20130101; C07D 401/14 20130101; A61P 25/04 20180101; A61P
3/10 20180101; A61P 17/04 20180101; A61P 17/06 20180101; A61P 33/00
20180101; A61P 37/00 20180101; A61P 37/06 20180101; C07D 409/14
20130101; C07D 405/14 20130101; A61P 25/16 20180101; A61P 11/06
20180101; A61P 25/28 20180101; C07D 235/24 20130101; C07D 403/12
20130101; C07D 413/12 20130101; A61P 35/00 20180101; A61P 11/00
20180101; C07D 209/12 20130101; C07D 403/04 20130101; C07D 413/14
20130101; A61P 13/12 20180101; A61P 31/12 20180101; A61P 37/02
20180101; A61P 1/00 20180101; A61P 19/08 20180101; A61P 17/00
20180101; A61P 25/14 20180101; A61P 25/00 20180101; A61P 1/04
20180101; C07D 401/06 20130101; A61P 31/04 20180101; C07D 401/12
20130101; A61P 17/12 20180101; A61P 7/12 20180101; A61P 19/02
20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/375 ;
514/379; 548/217; 548/241 |
International
Class: |
C07D 263/52; C07D
263/60; C07D 261/20; A61K 031/423; A61K 031/42 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 19, 1996 |
GB |
9612760.0 |
Claims
1. A compound of the general formula (I): 172wherein 173 represents
a bicyclic ring system, of 9 ring members, in which the ring 174 is
an oxazole, and the ring 175 is a benzene ring; R.sup.1 represents
hydrogen or a straight- or branched-chain alkyl group of 1 to about
4 carbon atoms, optionally substituted by hydroxy or one or more
halogen atoms, or when Z.sup.1 represents a direct bond R.sup.1 may
also represent a lower alkenyl or lower alkynyl group, or a formyl
group; R.sup.2 represents hydrogen, alkenyl, alkoxy, alkyl,
alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy,
arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy,
arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl,
cycloalkenyloxy, cycloalkyl, cycloalkyloxy, hydroxy,
--SO.sub.2NR.sup.4R.sup.5, --NR.sup.4SO.sub.2R.sup.5,
--NR.sup.4R.sup.5, --C(.dbd.O)R.sup.5, --C(.dbd.O)C(.dbd.O)R.sup.5,
--C(.dbd.O)NR.sup.4R.sup- .5, --C(.dbd.O)OR.sup.5,
--O(C.dbd.O)NR.sup.4R.sup.5, or --NR.sup.4C(.dbd.O)R.sup.5; R.sup.3
is: --C(.dbd.Z)--N(R.sup.7)R.sup.6 R.sup.4 and R.sup.5, which may
be the same or different, each represent a hydrogen atom, or an
alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl
group; R.sup.6 is optionally substituted pyridyl; R.sup.7 is a
hydrogen atom or an alkyl or amino group; R.sup.8 and R.sup.9,
which may be the same or different, is each a hydrogen atom or
alkyl, --CO.sub.2R.sup.5, --C(.dbd.Z)NR.sup.26R.sup.27 (where
R.sup.26 and R.sup.27 may be the same or different and each is as
described for R.sup.5), --CN or --CH.sub.2CN; R.sup.10 and
R.sup.11, which may be the same or different, is each a group
--(CH.sub.2).sub.pR.sup.6; R.sup.12 is a hydrogen atom or an alkyl
group; R.sup.13 is a hydrogen or halogen atom or an --OR.sup.28
group (where R.sup.28 is a hydrogen atom or an alkyl, alkenyl,
alkoxyalkyl, acyl, carboxamido or thiocarboxamido group); R.sup.14
is a hydrogen atom or an alkyl group; R.sup.15 is a hydrogen atom
or a hydroxyl group; R.sup.16 is a hydrogen atom or an alkyl,
amino, aryl, arylalkyl or hydroxy group; R.sup.17 is a hydrogen
atom or a C.sub.1-4alkyl or arylC.sub.1-4alkyl group; R.sup.18 is
an amino, alkylamino, arylamino, alkoxy or aryloxy group; R.sup.19
is an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group;
R.sup.20 is R.sup.5, (CH.sub.2).sub.pCO.sub.2R.sup.5 or
(CH.sub.2).sub.pCOR.sup.5; R.sup.21 is a group L.sup.1--R.sup.29,
or R.sup.21 is an optionally substituted cycloalkyl, cycloalkenyl
or heterocycloalkyl group which may optionally be fused to an
additional optionally substituted aromatic, heteroaromatic,
carbocyclic or heterocycloalkyl ring (where the one or more
optional substituents, for either or both rings, may be represented
by -L.sup.1--R.sup.29); L.sup.1 is a straight or branched
C.sub.16alkylene chain, a straight or branched C.sub.2-6alkenylene
chain, a straight or branched C.sub.2-6alkynylene chain or a
straight or branched C.sub.1-6alkylene chain containing an oxygen
or sulphur atom, a phenylene, imino (--NH--) or alkylimino linkage,
or a sulphinyl or sulphonyl group, in which each of the alkylene,
alkenylene and alkynylene chains may be optionally substituted, the
substituents chosen from alkoxy, aryl, carboxy, cyano, cycloalkyl,
halogen, heteroaryl, hydroxyl or oxo; and R.sup.29 is hydrogen, or
arylalkoxycarbonyl, carboxy or an acid bioisostere, cyano,
--NY.sup.1Y.sup.2; Y.sup.1 and Y.sup.2 are independently hydrogen,
alkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl or
heteroarylalkyl, or the group --NY.sup.1Y.sup.2 may form a 4-6
membered cyclic amine (which may optionally contain a further
heteroatom selected from O, S, or NY.sup.1, or which may be fused
to an additional aromatic or heteroaromatic ring); R.sup.22 is a
hydrogen atom, a group -L.sup.1--R.sup.29, or an optionally
substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl group which may optionally be fused to an
additional optionally substituted aromatic, heteroaromatic,
carbocyclic or heterocycloalkyl ring (where the one or more
optional substituents, for either or both rings, may be represented
by -L.sup.1--R.sup.29); or both R.sup.21 and R.sup.22 represent
aryl or heteroaryl each optionally substituted by
-L.sup.1--R.sup.29; or the group --NR.sup.21R.sup.22 represents an
optionally substituted, saturated or unsaturated 3 to 8 membered
cyclic amine ring, which may optionally contain one or more
heteroatoms selected from O, S or N, and may also be fused to an
additional optionally substituted aromatic, heteroaromatic,
carbocyclic or heterocycloalkyl ring (where the one or more
optional substituents, for any of the rings, may be represented by
-L.sub.1--R.sup.29); 176 where: R.sup.30 is hydrogen atom or an
alkyl, hydroxyalkyl or alkoxyalkl group; R.sup.31 is a hydrogen
atom or an alkyl, carboxy, CONHOR.sup.14, N-alkylaminoalkyl,
N,N-dialkylaminoalkyl or alkoxyalkyl group; or R.sup.30 and
R.sup.31 together represent a
--CH.sub.2--O--CH.sub.2--O--CH.sub.2-- group; R.sup.32 is a
hydrogen atom, or amino, alkyl, aminoalkyl, hydroxyalkyl, hydroxy,
acyl, alkoxycarbonyl, methoxycarbonylalkyl,
--(CH.sub.2).sub.pCONY.sup.3Y.sup.4- ; Y.sup.3 and Y.sup.4 are each
independently hydrogen or alkyl;
--(CH.sub.2).sub.pSO.sub.2NY.sup.3Y.sup.4,
--(CH.sub.2).sub.pPO.sub.3H.su- b.2,
--(CH.sub.2).sub.pSO.sub.2NHCOalkyl, or
--(CH.sub.2).sub.pSO.sub.2NHC- OR.sup.6; R.sup.33 is
C.sub.1-4alkyl, CH.sub.2NHCOCONH.sub.2,
CH.dbd.--C(R.sup.43)R.sup.44, cyclopropyl (optionally substituted
by R.sup.43), CN, CH.sub.2OR.sup.44 or CH.sub.2NR.sup.44R.sup.45;
R.sup.43 is R.sup.44 or fluorine and R.sup.44 is hydrogen or
C.sub.1-4alkyl optionally substituted by 1 to 3 fluorine atoms;
R.sup.45 is hydrogen, OR.sup.44, or C.sub.1-4alkyl optionally
substituted by 1 to 3 fluorine atoms; NR.sup.44R.sup.45 represents
a 5 to 7 membered cyclic amine optionally containing one or more
additional heteroatoms selected from O, N, and S; R.sup.34 is
methyl or ethyl optionally substituted by 1 or more halogen atoms;
R.sup.35 is R.sup.14, --OR.sup.14, --C.sub.2R.sup.14, --COR.sup.14,
--CN, --CONY.sup.3Y.sup.4 or --NY.sup.3Y.sup.4; R.sup.36 is
--C(.dbd.Z)R.sup.14, --CO.sub.2R.sup.14, --CONY.sup.3Y.sup.4 or
--CN; R.sup.37 and R.sup.39, which may be the same or different, is
each a hydrogen atom, alkyl, acyl, arylalkyl,
--(CH.sub.2).sub.pCO.sub.2R.sup.5, --CONHR.sup.5, heteroarylalkyl,
aryl, or heteroaryl; R.sup.38 is acyl, aroyl,
--C(.dbd.O)cycloalkyl, alkoxycarbonyl, cycloalkoxycarbonyl,
carboxy, alkoxyalkyl, --NO.sub.2, --CH.sub.2H, --CN,
--NR.sup.14COR.sup.5, --NR.sup.14CONY.sup.5Y.sup.6,
--NR.sup.14SO.sub.2R.sup.46, --SO.sub.2R.sup.46 or
--CONY.sup.5Y.sup.6; R.sup.46 is alkyl, cycloalkyl,
trifluoromethyl, aryl, arylalkyl or --NY.sup.5Y.sup.6; Y.sup.5 and
Y.sup.6 are independently selected from hydrogen, alkyl,
cycloalkyl, aryl or arylalkyl, or Y.sup.5 and Y.sup.6 together form
a 4- to 7-membered heterocyclic or carbocyclic ring; R.sup.40 is
hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, acyl, aroyl,
--C(.dbd.O)cycloalkyl, --CH.sub.2OH, alkoxyalkyl, alkoxycarbonyl,
cycloalkoxycarbonyl, aryloxycarbonyl, --CN, --NO.sub.2, or
--SO.sub.2R.sup.46; R.sup.41 is --CN, --C(Z)R.sup.47 (where
R.sup.47 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl,
arylalkyl, heteroaryl, C.sub.1-6alkoxy, arylalkoxy, aryloxy or
--NY.sup.5Y.sup.6) or SO.sub.2R.sup.46; R.sup.42 is hydrogen,
alkyl, cycloalkyl, acyl, aroyl, --C(.dbd.O)cycloalkyl,
alkoxycarbonyl, cycloalkoxycarbonyl, carboxy, --CN,
--SO.sub.2R.sup.46 or --CONY.sup.5Y.sup.6; W is (CH.sub.2).sub.r or
NR.sup.39; Z.sup.3 is an oxygen atom, NR.sup.14 or NOR.sup.14; s is
zero or an integer 1 to 4; r is 1 to 4; and Y is an oxygen atom,
C(.dbd.O), CH(OH) or C(OR.sup.14)(CH.sub.2).sub.pR.sup.6; R.sup.24
is R.sup.5 or CONHR.sup.25; R.sup.25 is hydrogen, C.sub.1-3alkyl or
(CH.sub.2).sub.qR.sup.6; p is zero or an integer from 1 to 5; q is
zero or 1; X.sup.1 and X.sup.2, which may be the same or different,
is each a hydrogen or fluorine atom; X.sup.3 is a chlorine or
fluorine atom, alkoxy, aryloxy, heteroaryloxy, arylalkyloxy or
heteroarylalkyl; X.sup.4 is a halogen atom or hydroxy; Z represents
an oxygen or sulphur atom; A.sup.1 is a straight or branched
C.sub.1-6alkylene chain optionally substituted by hydroxyl, alkoxy,
oxo, cycloalkyl, aryl or heteroaryl; Z.sup.1 represents a direct
bond, an oxygen or sulphur atom or NH; n is zero; and m is 1; and
N-oxides thereof, and their prodrugs, and pharmaceutically
acceptable salts and solvates of the compounds of formula (I) and
N-oxides thereof, and their prodrugs.
2. A compound according to claim 1 in which R.sup.1 represents
C.sub.1-4alkyl optionally substituted by one or more halogen
atoms.
3. A compound according to claim 1 in which Z.sup.1represents a
direct bond or an oxygen atom.
4. A compound according to claim 1 in which A.sup.1 represents a
direct bond or a straight- or branched-chain alkylene linkage
containing from 1 to 6 carbon atoms and optionally substituted by
alkoxy.
5. A compound according to claim 1 in which R.sup.3 represents
--C(.dbd.O)NHR.sup.6.
6. A compound according to claim 5 in which R.sup.6 is substituted
on both positions adjacent to the position of attachment of R.sup.6
to the rest of the molecule.
7. A compound according to claim 5 in which R.sup.6 is substituted
by two methyl or halogen moieties on both positions adjacent to the
position of attachment of R.sup.6 to the rest of the molecule.
8. A compound according to claim 5 in which R.sup.6 is
3,5-dimethylpyrid-4-yl, 3,5-dihalopyrid-4-yl or an N-oxide of such
groups.
9. A compound of formula (Ia) 177wherein R.sup.1, R.sup.2, R.sup.3,
A.sup.1 and Z.sup.1 are as defined in claim 1, Q.sup.1 is CH,
CX.sup.5 (where X.sup.5 is halogen), a nitrogen atom or
N.sup.+--O.sup.- and 178 (where R.sup.5 represents a hydrogen atom
or a methyl group), and N-oxides thereof, and their prodrugs, and
pharmaceutically acceptable salts and solvates of the compounds of
formula (I) and N-oxides thereof and their prodrugs.
10. A compound according to claim 9 in which R.sup.1 represents
C.sub.1-4alkyl optionally substituted by one or more halogen
atoms.
11. A compound according to claim 9 in which R.sup.1 represents
methyl or difluoromethyl.
12. A compound according to claim 9 in which R.sup.2 represents a
straight- or branched-chain C1-4alkyl group, or cycloalkyl, alkoxy,
aryl, or aryloxy.
13. A compound according to claim 9 in which R.sup.3 represents
--C(.dbd.O)--NHR.sup.6.
14. A compound according to claim 13 in which R.sup.6 is
substituted on both positions adjacent to the position of
attachment of R.sup.6 to the rest of the molecule.
15. A compound according to claim 13 in which R.sup.6 is
substituted by two methyl or halogen moieties on both positions
adjacent to the position of attachment of R.sup.6 to the rest of
the molecule.
16. A compound according to claim 13 in which R.sup.6 is
3,5-dimethylpyrid-4-yl, 3,5-dihalopyrid-4-yl or an N-oxide of such
groups.
17. A compound according to claim 9 in which A.sup.1 represents a
straight- or branched-chain alkylene linkage containing 1 to 6
carbon atoms optionally substituted by alkoxy.
18. A compound according to claim 9 in which 179represents 180 and
where R.sup.5 is a hydrogen atom.
19. A compound according to claim 9 in which Q.sup.1 is a CH
linkage.
20. A compound according claim 9 in which Z.sup.1 is an oxygen
atom.
21. A compound according to claim 9 in which R.sup.1 is methyl or
difluoromethyl, R.sup.2 is C.sub.1-4alkyl, C.sub.3-6cycloalkyl,
C.sub.1-4alkoxy, aryl, or aryloxy, R.sup.3 is
--C(.dbd.O)--NIR.sup.6, A.sup.1 is a methylene linkage; 181Q.sup.1
is a CH linkage and Z.sup.1 is an oxygen atom, and N-oxides
thereof, and their prodrugs, and pharmaceutically acceptable salts
and solvates of the compounds of formula (Ia) herein and N-oxides
thereof, and their prodrugs.
22. A compound of formula (Ib) 182wherein R.sup.1, R.sup.2,
R.sup.3, A.sup.1 and Z.sup.1 are as defined in claim 1, and Q
represents a CH linkage or a nitrogen atom, and N-oxides thereof,
and their prodrugs, and pharmaceutically acceptable salts and
solvates of the compounds of formula (Ib) and N-oxides thereof, and
their prodrugs.
23. A compound according to claim 22 in which R.sup.1 is hydrogen
or methyl, R.sup.2 is C.sub.4-9alkyl, C.sub.3-7cycloalkyl, or aryl,
R.sup.3 is --C(.dbd.O)--NHR.sup.6, A.sup.1 is a methylene linkage,
Z.sup.1 is a direct bond, and Q is a CH linkage or a nitrogen atom,
and N-oxides thereof, and their prodrugs, and pharmaceutically
acceptable salts and solvates of the compounds of formula (Ib)
herein and N-oxides thereof, and their prodrugs.
24. A compound of formula (Ic) 183wherein R.sup.1, R.sup.2,
R.sup.3, A.sup.1 and Z.sup.1 are as defined in claim 1, Q.sup.1 is
CH, CX.sup.5 (where X.sup.5 is halogen), a nitrogen atom or
N.sup.+--O.sup.- and Z is an oxygen or sulphur atom, and N-oxides
thereof, and their prodrugs, and pharmaceutically acceptable salts
and solvates of the compounds of formula (Ic) and N-oxides thereof,
and their prodrugs.
25. A compound according to claim 24 in which R.sup.1 is methyl or
difluoromethyl, R.sup.2 is C.sub.1-4alkyl, C.sub.3-6cycloalkyl,
C.sub.1-4alkoxy, aryl, or aryloxy, R.sup.3 is
--C(.dbd.O--NHR.sup.6, or A.sup.1 is a methylene linkage, Q.sup.1
is a CH linkage, and Z and Z.sup.1 are both oxygen atoms, and
N-oxides thereof, and their prodrugs, and pharmaceutically
acceptable salts and solvates of the compounds of formula (Ic)
herein and N-oxides thereof, and their prodrugs.
26. A compound of formula (Id) 184wherein R.sup.1, R.sup.2,
R.sup.3, A.sup.1 and Z.sup.1 are as defined in claim 1, Q.sup.1 is
CH, CX.sup.5 (where X.sup.5 is halogen), a nitrogen atom or
N.sup.+--O.sup.- and Z is an oxygen or sulphur atom, and N-oxides
thereof, and their prodrugs, and pharmaceutically acceptable salts
and solvates of the compounds of formula (Id) and N-oxides thereof,
and their prodrugs.
27. A compound according to claim 26 in which R.sup.1 is methyl or
difluoromethyl, R.sup.2 is C.sub.1-4alkyl, C.sub.3-6cycloalkyl,
C.sub.1-4alkoxy, aryl, or aryloxy, R.sup.3 is
--C(.dbd.O)--NHR.sup.6, A.sup.1 is a methylene linkage, Q.sup.1 is
a CH linkage, and Z and Z.sup.1 are both oxygen atoms, and N-oxides
thereof, and their prodrugs, and pharmaceutically acceptable salts
and solvates of the compounds of formula (Id) herein and N-oxides
thereof, and their prodrugs.
28. A compound of formula (Ie) 185wherein R.sup.1, R.sup.2,
R.sup.3, A.sup.1 and Z.sup.1 are as defined in claim 1, and
N-oxides thereof, and their prodrugs, and pharmaceutically
acceptable salts and solvates of the compounds of formula (Ie) and
N-oxides thereof, and their prodrugs.
29. A compound according to claim 28 in which R.sup.1 is hydrogen
or methyl, R.sup.2 is C.sub.4-9alkyl, C.sub.3-7cycloalkyl, or aryl,
R.sup.3 is --C(.dbd.O)--NHR.sup.6, A.sup.1 is a methylene linkage
and Z.sup.1 is a direct bond, and N-oxides thereof, and their
prodrugs, and pharmaceutically acceptable salts and solvates of the
compounds of formula (Ie) herein and N-oxides thereof, and their
prodrugs.
30. 186wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1 and Z.sup.1 are
as defined in claim 1, and N-oxides thereof, and their prodrugs,
and pharmaceutically acceptable salts and solvates of the compounds
of formula (If) and N-oxides thereof, and their prodrugs.
31. A compound according to claim 30 in which R.sup.1 is hydrogen
or methyl, R.sup.2 is C.sub.1-4alkyl, C.sub.3-7cycloalkyl, or aryl,
R.sup.3 is --C(.dbd.O)--NHR.sup.6, A.sup.1 is a methylene linkage
and Z.sup.1 is an oxygen atom, and N-oxides thereof, and their
prodrugs, and pharmaceutically acceptable salts and solvates of the
compounds of formula (If) herein and N-oxides thereof, and their
prodrugs.
32. A compound according to claim 1 selected from the group
consisting of:
N-(3,5-dichloro-4-pyridyl)-4-methoxy-2-methoxymethyl-benzoxazole-7-carbox-
amide;
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazo-
le-4-carboxamide;
N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazol-
e-4-carboxamide;
2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-ben-
zimidazole-4-carboxamide;
2-isopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-
-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-N-(3,5-dimethyl-4-isoxazoly-
l)-7-methoxy-3H-benzimidazole-4-carboxamide;
N-(3,5-dimethyl-4-isoxazolyl)-
-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;
2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazol-
e;
4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimid-
azole; and the corresponding pyridine N-oxides, and their prodrugs,
and pharmaceutically acceptable salts and solvates thereof.
33. A compound according to claim 1 which is selected from
2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazol-
e; and its corresponding pyridine N-oxide, and its prodrugs, and
pharmaceutically acceptable salts and solvates thereof.
34. A pharmaceutical composition comprising an effective amount of
a compound according to claim 1 or a prodrug thereof, and
pharmaceutically acceptable salts and solvates thereof in
association with a pharmaceutically acceptable carrier or
excipient.
35. A method of treating a patient suffering from, or subject to,
conditions which can be ameliorated by the administration of an
inhibitor of TNF, comprising administering to said patient a
compound of formula (I) or a prodrug thereof, or a pharmaceutically
acceptable salt or solvate thereof as claimed in claim 1.
36. A method of treating a patient suffering from, or subject to,
conditions which can be ameliorated by the administration of an
inhibitor of type IV cyclic AMP phosphodiesterase, comprising
administering to said patient a compound of formula (I)or a prodrug
thereof, or a pharmaceutically acceptable salt or solvate thereof
as claimed in claim 1.
37. A method of treating a patient suffering from, or subject to,
conditions which can be ameliorated by the administration of an
inhibitor of type IV cyclic AMP phosphodiesterase or of TNF,
comprising administering to said patient an effective amount of a
compound of formula (I) or a prodrug thereof, or a pharmaceutically
acceptable salt or solvate thereof as claimed in claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 09/612,530, filed Jul. 7, 2000, which
application is, in turn, a continuation of U.S. patent application
Ser. No. 09/216,392 filed Dec. 18, 1998, now U.S. Pat. No.
6,303,600 which in turn is a continuation of International Patent
Application No. PCT/GB97/01639, filed Jun. 19, 1997, which claims
the benefit of U.S. provisional patent application No. 60/023,047,
filed Aug. 2, 1996, now abandoned.
TECHNICAL FIELD
[0002] This invention is directed to substituted azabicyclic
compounds, their preparation, pharmaceutical compositions
containing these compounds, and their pharmaceutical use in the
treatment of disease states associated with proteins that mediate
cellular activity.
BACKGROUND OF THE INVENTION
[0003] Tumour necrosis factor (TNF) is an important
pro-inflammatory cytokine which causes hemorrhagic necrosis of
tumors and possesses other important biological activities. TNF is
released by activated macrophages, activated T-lymphocytes, natural
killer cells, mast cells and basophils, fibroblasts, endothelial
cells and brain astrocytes among other cells.
[0004] The principal in vivo actions of TNF can be broadly
classified as inflammatory and catabolic. It has been implicated as
a mediator of endotoxic shock, inflammation of joints and of the
airways, immune deficiency states, allograft rejection, and in the
cachexia associated with malignant disease and some parasitic
infections. In view of the association of high serum levels of TNF
with poor prognosis in sepsis, graft versus host disease and adult
respiratory distress syndrome, and its role in many other
immunologic processes, this factor is regarded as an important
mediator of general inflammation.
[0005] TNF primes or activates neutrophils, eosinophils,
fibroblasts and endothelial cells to release tissue damaging
mediators. TNF also activates monocytes, macrophages and
T-lymphocytes to cause the production of colony stimulating factors
and other pro-inflammatory cytokines such IL.sub.1, IL.sub.6,
IL.sub.8 and GM-CSF, which in some case mediate the end effects of
TNF. The ability of TNF to activate T-lymphocytes, 10 monocytes,
macrophages and related cells has been implicated in the
progression of Human Immunodeficiency Virus (HIV) infection. In
order for these cells to become infected with HIV and for HIV
replication to take place the cells must be maintained in an
activated state. Cytokines such as TNF have been shown to activate
HIV replication in monocytes and macrophages. Features of endotoxic
shock such as fever, metabolic acidosis, hypotension and
intravascular coagulation ate thought to be mediated through the
actions of TNF on the hypothalamus and in reducing the
anti-coagulant activity of vascular endothelial cells. The cachexia
associated with certain disease states is mediated through indirect
effects on protein catabolism. TNF also promotes bone resorption
and acute phase protein synthesis.
[0006] The discussion herein relates to disease states associated
with TNF including those disease states related to the production
of TNF itself, and disease states associated with other cytokines,
such as but not limited to IL-1, or L-6, that are modulated by
associated with TNF. For example, a IL-1 associated disease state,
where IL-1 production or action is exacerbated or secreted in
response to TNF, would therefore be considered a disease state
associated with TNF. TNF-alpha and TNF-beta are also herein
referred to collectively as "TNF" unless specifically delineated
otherwise, since there is a close structural homology between
TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them
has a capacity to induce similar biological responses and bind to
the same cellular receptor.
[0007] Cyclic AMP phosphodiesterases are important enzymes which
regulate cyclic AMP levels and in turn thereby regulate other
important biological reactions. The ability to regulate cyclic AMP
phosphodiesterases therefore, has been implicated as being capable
of treating assorted biological conditions. In particular,
inhibitors of type IV cyclic AMP phosphodiesterase have been
implicated as being bronchodilators agents, prophylactic agents
useful against asthma and as agents for inhibiting eosinophil
accumulation and of the function of eosinophils, and for treating
other diseases and conditions characterised by, or having an
etiology involving, morbid eosinophil accumulation. Inhibitors of
cyclic AMP phosphodiesterase are also implicated in treating
inflammatory diseases, proliferative skin diseases and conditions
associated with cerebral metabolic inhibition.
[0008] It has already been reported that certain substituted
monocyclic aromatic compounds have valuable pharmaceutical
properties, in particular the ability to regulate proteins that
mediate cellular activity, for example, type IV cyclic AMP
phosphodiesterase and/or TNF, as described, for example, in the
specification of International Patent Application Publication No.
WO 95/04045.
[0009] Certain substituted bicyclic aromatic compounds, for example
amino-substituted benzofurans and benzothiophenes, are reported in
European Patent Application EP-A-0685475, to have the ability to
regulate elevated cellular cyclic AMP levels probably due to
inhibition of type IV cyclic AMP phosphodiesterase.
[0010] Further examples of substituted bicyclic aromatic compounds
with type IV cyclic AMP phosphodiesterase and/or TNF inhibitory
activity include dihydrobenzofurans reported in WO 96/36625 and WO
96/36626.
SUMMARY OF THE INVENTION
[0011] We have now found a novel group of azabicyclic compounds
which have valuable pharmaceutical properties, in particular the
ability to regulate proteins that mediate cellular activity, for
example, cyclic AMP phosphodiesterases (in particular type IV
and/or TNF.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Thus, in one aspect, the present invention is directed to
compounds of general formula (I): 5
[0013] wherein 6
[0014] represents a bicyclic ring system, of about 10 to about 13
ring members, in which the ring 7
[0015] is an azaheterocycle, and the ring 8
[0016] represents an azaheteroaryl ring, or an optionally halo
substituted benzene ring;
[0017] R.sup.1 represents hydrogen or a straight- or branched-chain
alkyl group of 1 to about 4 carbon atoms, optionally substituted by
hydroxy or one or more halogen atoms, or when Z.sup.1 represents a
direct bond R.sup.1 may also represent a lower alkenyl or lower
alkynyl group, or a formyl group;
[0018] R.sup.2 represents hydrogen, alkenyl, alkoxy, alkyl,
alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy,
arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy,
arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl,
cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl,
heteroarylalkyloxy, heteroaryloxy, hydroxy,
--SO.sub.2NR.sup.4R.sup.5, --NR.sup.4SO.sub.2R.sup.5,
--NR.sup.4R.sup.5, --C(.dbd.O)R.sup.5, --C(.dbd.O)C(.dbd.O)R.sup.5,
--C(.dbd.O)NR.sup.4R.sup.5, --C(.dbd.O)OR.sup.5,
--O(C.dbd.O)NR.sup.4R.sup.5, or --NR.sup.4C(.dbd.O)R.sup.5 (where
R.sup.4 and R.sup.5, which may be the same or different, each
represent a hydrogen atom, or an alkyl, aryl, arylalkyl,
cycloalkyl, heteroaryl, or heteroarylalkyl group);
1 R.sup.3 represents a group selected from: (i)
--C(.dbd.Z)--N(R.sup.7)R.sup.6 (ii) --C(.dbd.Z)--CHR.sup.12R.sup.6
(iii) --C(.dbd.Z)--R.sup.6 (iv)
--CR.sup.8.dbd.C(R.sup.9)(CH.sub.2).sub.p--R.sup.6 (v)
--C(R.sup.10).dbd.C(R.sup.11)R.sup.12 (vi)
--C(R.sup.13)(R.sup.10)C(R.sup.11)(R.sup.14)R.sup.12 (vii)
--C(R.sup.8)(R.sup.15)CH(R.sup.9)(CH.sub.2).sub.p--R.sup.6 (viii)
--R.sup.6 (ix) --N(R.sup.16)C(.dbd.Z)R.sup.6 (x)
--C(R.sup.17).dbd.N--OC(=0)R.sup.18 (xi) --C(.dbd.O)--N(R.sup.19)-
OR.sup.20 (xii) --C.ident.C--R.sup.6 (xiii)
--CH.sub.2--C(.dbd.Z)--R.sup.6 (xiv) --C(.dbd.Z)--C(.dbd.Z)R.sup.-
6 (xv) --CH.sub.2--NHR.sup.6 (xvi) --CH.sub.2--ZR.sup.6 (xvii)
--CH.sub.2--SOR.sup.6 (xviii) --CH.sub.2--SO.sub.2R.s- up.6 (xix)
--CF.sub.2--OR.sup.6 (xx) --NH--CH.sub.2R.sup.6 (xxi)
--Z--CH.sub.2R.sup.6 (xxii) --SO--CH.sub.2R.sup.6 (xxiv)
--SO.sub.2--CH.sub.2R.sup.6 (xxv) --O--CF.sub.2R.sup.6 (xxiii)
--O--C(.dbd.Z)R.sup.6 (xxvi) --N.dbd.N--R.sup.6 (xxvii)
--NH--SO.sub.2R.sup.6 (xxviii) --SO.sub.2--NR.sup.21R.sup.22 (xxix)
--CZ--CZ--NHR.sup.6 (xxx) --NH--CO--OR.sup.6 (xxxi)
--O--CO--NHR.sup.6 (xxxii) --NH--CO--NHR.sup.6 (xxxiii) --R.sup.23
(xxxiv) --CX.sup.1.dbd.CX.sup.2R.sup.6 (xxxv)
--C(.dbd.NOR.sup.24)--(CH.s- ub.2).sub.qR.sup.6 (xxxvi)
--CH.sub.2--CO--NH(CH.sub.2).sub.qR.sup- .6 (xxxvii)
--CH.sub.2--NH--CO(CH.sub.2).sub.qR.sup.6 (xxxviii)
--CH.sub.2--CO--CH.sub.2R.sup.6 (xxxix)
--C(.dbd.NR.sup.25)--NH(CH.sub.2).sub.qR.sup.6 (xxxx)
--C(X.sup.3).dbd.N--(CH.sub.2).sub.qR.sup.6 (xxxxi)
--CH(X.sup.4)--CH.sub.2R.sup.6
[0019] [where:
[0020] R.sup.6 is aryl or heteroaryl;
[0021] R.sup.7 is a hydrogen atom or an alkyl or amino group;
[0022] R.sup.8 and R.sup.9, which may be the same or different, is
each a hydrogen atom or alkyl, --CO.sub.2R.sup.5,
--C(.dbd.Z)NR.sup.26R.sup.27 (where R.sup.26 and R.sup.27 may be
the same or different and each is as described for R.sup.5), --CN
or --CH.sub.2CN;
[0023] R.sup.10 and R.sup.11, which may be the same or different,
is each a group --(CH.sub.2).sub.pR.sup.6;
[0024] R.sup.12 is a hydrogen atom or an alkyl group;
[0025] R.sup.13 is a hydrogen or halogen atom or an --OR.sup.28
group (where R.sup.28 is a hydrogen atom or an alkyl, alkenyl,
alkoxyalkyl, acyl, carboxamido or thiocarboxamido group);
[0026] R.sup.14 is a hydrogen atom or an alkyl group;
[0027] R.sup.15 is a hydrogen atom or a hydroxyl group;
[0028] R.sup.16 is a hydrogen atom or an alkyl, amino, aryl,
arylalkyl, or hydroxy group;
[0029] R.sup.17 is a hydrogen atom or a C.sub.1-4alkyl or
arylC.sub.1-4alkyl group;
[0030] R.sup.18 is an amino, alkylamino, arylamino, alkoxy or
aryloxy group;
[0031] R.sup.19 is an alkyl, aryl, heteroaryl, arylalkyl or
heteroarylalkyl group;
[0032] R.sup.20 is R.sup.5, (CH.sub.2).sub.pCO.sub.2R.sup.5 or
(CH.sub.2).sub.pCOR.sup.5;
[0033] R.sup.21 is a group -L.sup.1--R.sup.29 [where L.sup.1 is a
straight or branched C.sub.1-6alkylene chain, a straight or
branched C.sub.2-6alkenylene chain, a straight or branched
C.sub.2-6alkynylene chain or a straight or branched
C.sub.1-6alkylene chain containing an oxygen or sulphur atom, a
phenylene, imino (--NH--) or alkylimino linkage, or a sulphinyl or
sulphonyl group, in which each of the alkylene, alkenylene and
alkynylene chains may be optionally substituted, the substituents
chosen from alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen,
heteroaryl, hydroxyl or oxo; and R.sup.29 is hydrogen, or
arylalkoxycarbonyl, carboxy or an acid bioisostere, cyano,
--NY.sup.1Y.sup.2, {where Y.sup.1 and Y.sup.2 are independently
hydrogen, alkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl or
heteroarylalkyl, or the group --NY.sup.1Y.sup.2 may form a 4-6
membered cyclic amine (which may optionally contain a further
heteroatom selected from O, S, or NY.sup.1, or which may be fused
to an additional aromatic or heteroaromatic ring)}], or R.sup.21 is
an optionally substituted cycloalkyl, cycloalkenyl or
heterocycloalkyl group which may optionally be fused to an
additional optionally substituted aromatic, heteroaromatic,
carbocyclic or heterocycloalkyl ring (where the one or more
optional substituents, for either or both rings, may be represented
by -L.sup.1 --R.sup.29);
[0034] R.sup.22 is a hydrogen atom, a group -L.sup.1--R.sup.29, or
an optionally substituted aryl, heteroaryl, cycloalkyl,
cycloalkenyl or heterocycloalkyl group which may optionally be
fused to an additional optionally substituted aromatic,
heteroaromatic, carbocyclic or heterocycloalkyl ring (where the one
or more optional substituents, for either or both rings, may be
represented by -L.sup.1--R.sup.29); or both R.sup.21 and R.sup.22
represent aryl or heteroaryl each optionally substituted by
-L.sup.1--R.sup.29; or the group --NR.sup.21R.sup.22 represents an
optionally substituted saturated or unsaturated 3 to 8 membered
cyclic amine ring, which may optionally contain one or more
heteroatoms selected from O, S or N, and may also be fused to an
additional optionally substituted aromatic, heteroaromatic,
carbocyclic or heterocycloalkyl ring (where the one or more
optional substituents, for any of the rings, may be represented by
-L.sup.1--R.sup.29); 9
[0035] {where:
[0036] R.sup.30 is a hydrogen atom or an alkyl, hydroxyalkyl or
alkoxyalkyl group;
[0037] R.sup.31 is a hydrogen atom or an alkyl, carboxy,
CONHOR.sup.14, N-alkylaminoalkyl, N,N-dialkylaminoalkyl or
alkoxyalkyl group; or R.sup.30 and R.sup.31 together represent a
--CH.sub.2--O--CH.sub.2--O--CH- .sub.2-- group;
[0038] R.sup.32 is a hydrogen atom, or amino, alkyl, aminoalkyl,
hydroxyalkyl, hydroxy, acyl, alkoxycarbonyl, methoxycarbonylalkyl,
--(CH.sub.2).sub.pCONY.sup.3Y.sup.4 (where Y.sup.3 and Y.sup.4 are
each independently hydrogen or alkyl),
--(CH.sub.2).sub.pSO.sub.2NY.sup.3Y.sup- .4,
--(CH.sub.2).sub.pPO.sub.3H.sub.2, --(CH2).sub.pSO.sub.2NHCOalkyl,
or --(CH2).sub.pSO2NHCOR.sup.6;
[0039] R.sup.33 is C.sub.1-4alkyl, CH.sub.2NHCOCONH.sub.2,
CH.dbd.C(R.sup.43)R.sup.44 (where R.sup.43 is R.sup.44 or fluorine
and R.sup.44 is hydrogen or C.sub.1-4alkyl optionally substituted
by 1 to 3 fluorine atoms), cyclopropyl (optionally substituted by
R.sup.43), CN, CH.sub.2OR.sup.44 or CH.sub.2NR.sup.44R.sup.45
(where R.sup.45 is hydrogen, OR.sup.44, or C.sub.1-4alkyl
optionally substituted by 1 to 3 fluorine atoms, or the group
NR.sup.44R.sup.45 represents a 5 to 7 membered cyclic amine
optionally containing one or more additional heteroatom selected
from O, N, or S);
[0040] R.sup.34 is methyl or ethyl optionally substituted by 1 or
more halogen atoms;
[0041] R.sup.35 is R.sup.14, --OR.sup.14, --CO.sub.2R.sup.14,
--COR.sup.14, --CN, --CONY.sup.3Y.sup.4 or --NY.sup.3Y.sup.4;
[0042] R.sup.36 is --C(.dbd.Z)R.sup.14, --CO.sub.2R.sup.14,
--CONY.sup.3Y.sup.4 or --CN;
[0043] R.sup.37 and R.sup.39, which may be the same or different,
is each a hydrogen atom, alkyl, acyl, arylalkyl,
--(CH.sub.2).sub.pCO.sub.2R.sup.- 5, --CONHR.sup.5,
heteroarylalkyl, aryl, or heteroaryl;
[0044] R.sup.38 is acyl, aroyl, --C(.dbd.O)cycloalkyl,
alkoxycarbonyl, cycloalkoxycarbonyl, carboxy, alkoxyalkyl,
--NO.sub.2, --CH.sub.2OH, --CN, --NR.sup.14COR.sup.5,
--NR.sup.14CONY.sup.5Y.sup.6, --NR.sup.14SO.sub.2R.sup.46 [where
R.sup.46 is alkyl, cycloalkyl, trifluoromethyl, aryl, arylalkyl or
--NY.sup.5Y.sup.6 (where Y.sup.5 and Y.sup.6 are independently
selected from hydrogen, alkyl, cycloalkyl, aryl or arylalkyl, or
Y.sup.5 and Y.sup.6 together form a 4- to 7-membered heterocyclic
or carbocyclic ring)], --SO.sub.2R.sup.46 or
--CONY.sup.5Y.sup.6;
[0045] R.sup.40 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl,
acyl, aroyl, --C(.dbd.O)cycloalkyl, --CH.sub.2OH, alkoxyalkyl,
alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, --CN,
--NO.sub.2, or --SO.sub.2R.sup.46;
[0046] R.sup.41 is --CN, --C(Z)R.sup.47 (where R.sup.47 is
hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, C.sub.1-6alkoxy, arylalkoxy, aryloxy or --NY.sup.5Y6)
or SO.sub.2R.sup.46;
[0047] R.sup.42 is hydrogen, alkyl, cycloalkyl, acyl, aroyl,
--C(.dbd.O)cycloalkyl, alkoxycarbonyl, cycloalkoxycarbonyl,
carboxy, --CN, --SO.sub.2R.sup.46 or --CONY.sup.5Y.sup.6;
[0048] W is (CH2).sub.r or NR.sup.39;
[0049] Z.sup.3 is an oxygen atom, NR.sup.14 or NOR.sup.14;
[0050] s is zero or an integer 1 to 4;
[0051] r is 1 to 4; and
[0052] Y is an oxygen atom, C(.dbd.O), CH(OH) or
C(OR.sup.14)(CH.sub.2).su- b.pR.sup.6};
[0053] R.sup.24 is R.sup.5 or CONHR.sup.25;
[0054] R.sup.25 is hydrogen, C.sub.1-3alkyl or
(CH.sub.2).sub.qR.sup.6;
[0055] p is zero or an integer 1 to 5;
[0056] q is zero or 1;
[0057] X.sup.1 and X.sup.2, which may be the same or different, is
each a hydrogen or fluorine atom;
[0058] X.sup.3 is a chlorine or fluorine atom, alkoxy, aryloxy,
heteroaryloxy, arylalkyloxy or heteroarylalkyl;
[0059] X.sup.4 is a halogen atom or hydroxy;
[0060] Z represents an oxygen or sulphur atom];
[0061] A.sup.1 represents a direct bond, or a straight or branched
C.sub.1-6alkylene chain optionally substituted by hydroxyl, alkoxy,
oxo, cycloalkyl, aryl or heteroaryl, or A.sup.1 represents a
straight or branched C.sub.2-6alkenylene or C.sub.2-6alkynylene
chain;
[0062] Z.sup.1 represents a direct bond, an oxygen or sulphur atom
or NH;
[0063] n and m each represent zero or 1, provided that n is 1 when
m is zero and n is zero when m is 1;
[0064] and N-oxides thereof, and their prodrugs, and
pharmaceutically acceptable salts and solvates (erg. hydrates) of
the compounds of formula (I) and N-oxides thereof, and their
prodrugs.
[0065] In the present specification, the term "compounds of the
invention", and equivalent expressions, are meant to embrace
compounds of general formula (I) as hereinbefore described, which
expression includes the N-oxides, the prodrugs, the
pharmaceutically acceptable salts, and the solvates, e.g. hydrates,
where the context so permits. Similarly, reference to
intermediates, whether or not they themselves are claimed, is meant
to embrace their N-oxides, salts, and solvates, where the context
so permits. For the sake of clarity, particular instances when the
context so permits are sometimes indicated in the text, but these
instances are purely illustrative and it is not intended to exclude
other instances when the context so permits.
[0066] It is to be understood that R.sup.2A.sup.1,
(R.sup.1Z.sup.1).sub.n and (R.sup.1Z.sup.1).sub.m may be attached
at either a ring carbon or nitrogen atom whereas R.sup.3 is
attached at a ring carbon.
[0067] As used above, and throughout the description of the
invention, the following terms, unless otherwise indicated, shall
be understood to have the following meanings:
[0068] "Patient" includes both human and other mammals.
[0069] "Acyl" means an H--CO-- or alkyl-CO-- group in which the
alkyl group is as described herein. Preferred acyls contain a
C.sub.1-4alkyl. Exemplary acyl groups include formyl, acetyl,
propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
[0070] "Acylamino" is an acyl-NH-- group wherein acyl is as defined
herein.
[0071] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as described herein. Exemplary alkoxy groups include methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
[0072] "Alkoxycarbonyl" means an alkyl-O--CO-- group in which the
alkyl group is as described herein. Exemplary alkoxycarbonyl groups
include methoxy- and ethoxycarbonyl.
[0073] "Alkyl" means, unless otherwise specified, an aliphatic
hydrocarbon group which may be straight or branched having about 1
to about 15 carbon atoms in the chain, optionally substituted by
one or more halogen atoms. Particular alkyl groups have 1 to about
12 carbon atoms in the chain, more particularly from 1 to about 6
carbon atoms. Exemplary alkyl groups for R.sup.1 include methyl,
fluoromethyl, difluoromethyl, trifluoromethyl and ethyl. Exemplary
alkyl groups for R.sup.2 include methyl, ethyl, n-propyl, i-propyl,
n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl,
nonyl, decyl and dodecyl.
[0074] "Alkylsulphonyl" means an alkyl-SO.sub.2-- group in which
the alkyl group is as previously described. Preferred groups are
those in which the alkyl group is C.sub.1-4alkyl.
[0075] "Alkylsulphinyl" means an alkyl-SO-- group in which the
alkyl group is as previously described. Preferred groups are those
in which the alkyl group is C.sub.1-4alkyl.
[0076] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Exemplary alkylthio groups
include methylthio, ethylthio, isopropylthio and heptylthio.
[0077] "Aroyl" means an aryl--CO-- group in which the aryl group is
as described herein.
[0078] Exemplary groups include benzoyl and 1- and 2-naphthoyl.
[0079] "Aroylamino" is an aroyl-NH-- group wherein aroyl is as
previously defined.
[0080] "Aryl" as a group or part of a group denotes an optionally
substituted monocyclic or multicyclic aromatic carbocyclic moiety
of about 6 to about 10 carbon atoms. When R.sup.3 contains an
optionally substituted aryl group this may particularly represent
an aromatic carbocyclic moiety of about 6 to about 10 carbon atoms
such as phenyl or naphthyl optionally substituted with one or more
aryl group substituents which may be the same or different, where
"aryl group substituent" includes, for example, acyl, acylamino,
alkyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulphinyl,
alkylsulphonyl, aroyl, aroylamino, aryl, arylalkyl, arylalkyloxy,
arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl,
arylsulphinyl, arylsulphonyl, carboxy, cyano, halo, heteroaroyl,
heteroaryl, heteroarylalkyl, heteroarylamino, heteroaryloxy,
hydroxy, hydroxyalkyl, nitro, arylthio, Y.sup.7Y.sup.8N--,
Y.sup.7Y.sup.8NCO-- or Y.sup.7Y.sup.8NSO.sub.2-- (where Y.sup.7 and
Y.sup.8 are independently hydrogen, alkyl, aryl, and arylalkyl).
Preferred aryl group substituents within R.sup.3 include acyl,
acylamino, alkoxycarbonyl, alkyl, alkylthio, aroyl, cyano, halo,
hydroxy, nitro, Y.sup.7Y.sup.8N--, Y.sup.7Y.sup.8NCO-- and
Y.sup.7Y.sup.8NSO.sub.2-- (where Y.sup.7 and Y.sup.8 are
independently hydrogen or alkyl). When R.sup.2 contains an
optionally substituted aryl group this may particularly represent a
phenyl group optionally substituted by one or more substituents
selected from the "aryl group substituents" listed above. Preferred
aryl group substituents within R.sup.2 include halogen, alkoxy,
carboxamido, cyano and heteroaryl.
[0081] "Arylalkyl" means an aryl-alkyl-group in which the aryl and
alkyl moieties are as previously described. Preferred arylalkyl
groups contain a C.sub.1-4alkyl moiety. Exemplary arylalkyl groups
include benzyl, 2-phenethyl and naphthlenemethyl.
[0082] "Arylalkylsulphinyl" means an aryl-alkyl-SO-- group in which
the aryl and alkyl moieties are as previously described.
[0083] "Arylalkylsulphonyl" means an aryl-alkyl-SO-- group in which
the aryl and alkyl moieties are as previously described.
[0084] "Arylalkyloxy" means an arylalkyl-O-- group in which the
arylalkyl groups is as previously described. Exemplary arylalkyloxy
groups include benzyloxy and 1- or 2-naphthalenemethoxy.
[0085] "Arylalkyloxycarbonyl" means an arylalkyl-O-CO-- group in
which the arylalkyl groups is as previously described. An exemplary
arylalkyloxycarbonyl group is benzyloxycarbonyl.
[0086] "Arylalkylthio" means an arylalkyl-S-- group in which the
arylalkyl group is as previously described. An exemplary
arylalkylthio group is benzylthio.
[0087] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Exemplary aryloxy groups include
optionally substituted phenoxy and naphthoxy.
[0088] "Aryloxycarbonyl" means an aryl--O--CO-- group in which the
aryl group is as previously described. Exemplary aryloxycarbonyl
groups include phenoxycarbonyl and naphthoxycarbonyl.
[0089] "Arylsulphinyl" means an aryl-SO-- group in which the aryl
group is as previously described.
[0090] "Arylsulphonyl" means an aryl-SO.sub.2-- group in which the
aryl group is as previously described.
[0091] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Exemplary arylthio groups include
phenylthio and naphthylthio.
[0092] "Azaheterocycle" means a heterocycle of about 5 to about 7
ring members in which one of the ring members is nitrogen and the
other ring members are chosen from carbon, oxygen, sulphur,
nitrogen and NR.sup.5, but excluding compounds where two O or S
atoms are in adjacent positions. Exemplary azaheterocycles include
pyridyl, imidazolyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl,
pyrazolyl, pyridazyl, pyrimidinyl, morpholinyl, piperidinyl.
[0093] "Azaheteroaryl" means an aromatic carbocyclic moiety of 5 or
6 ring members in which one of the ring members is nitrogen and the
other ring members are chosen from carbon, oxygen, sulphur, or
nitrogen. Exemplary azaheteroaryl rings include isoxazolyl, pyridyl
and pyrimidinyl.
[0094] "Cycloalkenyl" means a non-aromatic monocyclic ring system
containing a carbon-carbon double bond and having about 3 to about
10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include
cyclopentenyl, cyclohexenyl and cycloheptenyl.
[0095] "Cycloalkenyloxy" means a cycloalkenyl-0- group in which the
cycloalkenyl moiety is as previously defined. Exemplary
cycloalkyloxy groups include cyclopentenyloxy, cyclohexenyloxy and
cycloheptenyloxy.
[0096] "Cycloalkyl" means a saturated monocyclic or bicyclic ring
system of about 3 to about carbon atoms. Exemplary monocyclic
cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0097] "Cycloalkyloxy" means a cycloalkyl-0- group in which the
cycloalkyl moiety is as previously defined. Exemplary cycloalkyloxy
groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and
cycloheptyloxy.
[0098] "Heteroaroyl" means a heteroaryl-CO-- group in which the
heteroaryl group is as described herein. Exemplary groups include
pyridylcarbonyl.
[0099] "Heteroaryl" as a group or part of a group denotes an
optionally substituted aromatic monocyclic or multicyclic organic
moiety of about 5 to about 10 ring members in which one or more of
the ring members is/are element(s) other than carbon, for example
nitrogen, oxygen or sulphur. Examples of suitable optionally
substituted heteroaryl groups include furyl, isoxazolyl,
isoquinolinyl, isothiazolyl, oxadiazole, pyrazinyl, pyridazinyl,
pyridyl, pyrimidinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl,
thienyl, and 1,2,4-triazinyl groups, optionally substituted by one
or more aryl group substituents as defined above. When R.sup.2 or
R.sup.3 contains an optionally substituted heteroaryl group this
may particularly represent an optionally substituted
"azaheteroaryl" group. Optional substituents for the heteroaryl
group within R.sup.2 or R.sup.3 include, for example, halogen atoms
and alkyl, aryl, arylalkyl, hydroxy, oxo, hydroxyalkyl, haloalkyl
(for example trifluoromethyl), alkoxy, haloalkoxy (for example
trifluoromethoxy), aryloxy and arylalkyloxy groups. Preferred
heteroaryl groups within R.sup.2 or R.sup.3 include optionally
substituted pyridyl. Preferred heteroaryl groups represented by
R.sup.6 within the groups --C(.dbd.Z)NHR.sup.6 and
--C(.dbd.Z)CH.sub.2R.sup.6 are optionally substituted pyridyl
groups, especially wherein the optional substituents are alkyl
groups or, more particularly, halogen atoms. Preferred heteroaryl
groups represented by R.sup.6 within the group --C(.dbd.Z)R.sup.6
are optionally substituted pyridyl groups, especially wherein the
optional substituent is an aryloxy group.
[0100] "Heteroarylalkyl" means a heteroaryl-alkyl- group in which
the heteroaryl and alkyl moieties are as previously described.
Preferred heteroarylalkyl groups contain a C.sub.1-4alkyl moiety.
Exemplary heteroaryl alkyl groups include pyridylmethyl.
[0101] "Heteroaryloxy" means an heteroaryl-O-- group in which the
heteroaryl group is as previously described. Exemplary
heteroaryloxy groups include optionally substituted pyridyloxy.
[0102] "Heteroarylalkoxy" means an heteroarylalkyl-O-- group in
which the heteroarylalkyl group is as previously described.
Exemplary heteroaryloxy groups include optionally substituted
pyridylmethoxy.
[0103] "Heterocycloalkyl" means a cycloalkyl group which contains
one or more heteroatoms selected from O, S or NY.sup.1.
[0104] "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as
previously defined. Preferred hydroxyalkyl groups contain
C.sub.1-4alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl
and 2-hydroxyethyl.
[0105] "Y.sup.7Y.sup.8N--" means a substituted or unsubstituted
amino group, wherein Y.sup.7 and Y.sup.8 are as previously
described. Exemplary groups include amino (H.sub.2N--),
methylamino, ethylmethylamino, dimethylamino and diethylamino.
[0106] "Y.sup.7Y.sup.8NCO--" means a substituted or unsubstituted
carbamoyl group, wherein Y.sup.7 and Y.sup.8 are as previously
described. Exemplary groups are carbamoyl (H.sub.2NCO--) and
dimethylcarbamoyl (e.sub.2NCO--).
[0107] "Y.sup.7Y.sup.8NSO.sub.2--" means a substituted or
unsubstituted sulphamoyl group, wherein Y.sup.7 and Y.sup.8 are as
previously described. Exemplary groups are sulphamoyl
(H.sub.2NSO.sub.2--) and dimethylsulphamoyl
(Me.sub.2NSO.sub.2--).
[0108] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo.
Preferred are fluoro or chloro.
[0109] "Prodrug" means a compound which is convertible in vivo by
metabolic means (e.g. by hydrolysis) to a compound of formula (I),
including N-oxides thereof, for example an ester of a compound of
formula (I) containing a hydroxy group.
[0110] Suitable esters are of many different types, for example
acetates, citrates, lactates, tartrates, malonates, oxalates,
salicylates, propionates, succinates, fumarates, maleates,
methylene-bis-p-hydroxynaph- thoates, gentisates, isethionates,
di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,
benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and
quinates.
[0111] An especially useful class of esters may be formed from acid
moieties selected from those described by Bundgaard et. al., J.
Med. Chem., 1989, 32, page 2503-2507, and include substituted
(aminomethyl)-benzoates, for example dialkylamino-methylbenzoates
in which the two alkyl groups may be joined together and/or
interrupted by an oxygen atom or by an optionally substituted
nitrogen atom, e.g. an alkylated nitrogen atom, more especially
(morpholino-methyl)benzoates, e.g. 3- or
4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)ben-
zoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
[0112] Some of the compounds of the present invention are basic,
and such compounds are useful in the form of the free base or in
the form of a pharmaceutically acceptable acid addition salt
thereof.
[0113] Acid addition salts are a more convenient form for use; and
in practice, use of the salt form inherently amounts to use of the
free base form. The acids which can be used to prepare the acid
addition salts include preferably those which produce, when
combined with the free base, pharmaceutically acceptable salts,
that is, salts whose anions are non-toxic to the patient in
pharmaceutical doses of the salts, so that the beneficial
inhibitory effects inherent in the free base are not vitiated by
side effects ascribable to the anions. Although pharmaceutically
acceptable salts of said basic compounds are preferred, all acid
addition salts are useful as sources of the free base form even if
the particular salt, per se, is desired only as an intermediate
product as, for example, when the salt is formed only for purposes
of purification, and identification, or when it is used as
intermediate in preparing a pharmaceutically acceptable salt by ion
exchange procedures. Pharmaceutically acceptable salts within the
scope of the invention include those derived from mineral acids and
organic acids, and include hydrohalides, e.g. hydrochlorides and
hydrobromides, sulphates, phosphates, nitrates, sulphamates,
acetates, citrates, lactates, tartrates, malonates, oxalates,
salicylates, propionates, succinates, fumarates, maleates,
methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,
di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates,
benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and
quinates.
[0114] Where the compound of the invention is substituted with an
acidic moiety, base addition salts may be formed and are simply a
more convenient form for use; and in practice, use of the salt form
inherently amounts to use of the free acid form. The bases which
can be used to prepare the base addition salts include preferably
those which produce, when combined with the free acid,
pharmaceutically acceptable salts, that is, salts whose cations are
non-toxic to the patient in pharmaceutical doses of the salts, so
that the beneficial inhibitory effects inherent in the free base
are not vitiated by side effects ascribable to the cations.
Pharmaceutically acceptable salts, including those derived from
alkali and alkaline earth metal salts, within the scope of the
invention include those derived from the following bases: sodium
hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide,
aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc
hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine,
arginine, ornithine, choline, N,N'-dibenzylethylenediamine,
chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,
diethylamine, piperazine, tris(hydroxymethyl)amin- omethane,
tetramethylarnmonium hydroxide, and the like.
[0115] As well as being useful in themselves as active compounds,
salts of compounds of the invention are useful for the purposes of
purification of the compounds, for example by exploitation of the
solubility differences between the salts and the parent compounds,
side products and/or starting materials by techniques well known to
those skilled in the art.
[0116] It will be appreciated that compounds of the present
invention may contain asymmetric centres. These asymmetric centres
may independently be in either the R or S configuration. It will be
apparent to those skilled in the art that certain compounds of the
invention may also exhibit geometrical isomerism. It is to be
understood that the present invention includes individual
geometrical isomers and stereoisomers and mixtures thereof,
including racemic mixtures, of compounds of formula (I)
hereinabove. Such isomers can be separated from their mixtures, by
the application or adaptation of known methods, for example
chromatographic techniques and recrystallization techniques, or
they are separately prepared from the appropriate isomers of their
intermediates. Additionally, in situations where tautomers of the
compounds of formula (I) are possible, the present invention is
intended to include all tautomeric forms of the compounds.
[0117] With reference to formula (I) above, the following are
particular and preferred groupings:
[0118] R.sup.1 preferably represents a C.sub.1-4alkyl group
optionally substituted by one or more halogen (e.g. chlorine or
fluorine) atoms. R.sup.1 more preferably represents methyl or
difluoromethyl.
[0119] R.sup.2 may particularly represent C.sub.1-7alkyl (for
example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl).
[0120] R.sup.2 may also particularly represent C.sub.1-4alkoxy (for
example methoxy).
[0121] R.sup.2 may also particularly represent C.sub.3-7cycloalkyl
(for example cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl).
[0122] R.sup.2 may also particularly represent aryl (for example
optionally substituted phenyl or naphthyl).
[0123] R.sup.2 may also particularly represent aryloxy (for example
optionally substituted phenoxy).
[0124] R.sup.2 may also particularly represent heteroaryl (for
example optionally substituted thienyl, pyridyl, furanyl).
[0125] R.sup.2 may also particularly represent heterocycloalkyl
(for example tetrahydrofuranyl, tetrahydropyranyl).
[0126] R.sup.2 may also particularly represent arylalkylsulphonyl
(for example 4-methylphenylsulphonyl and 4-methoxyphenylsulphonyl)
when the group R.sup.2A.sup.1- is attached to a ring nitrogen
atom.
[0127] It is to be understood that the aforementioned heteroaryl
and heterocycloalkyl moieties represented by R.sup.2 when
containing at least one nitrogen atom may be presented as the
corresponding N-oxides.
[0128] R.sup.3 may particularly represent --OCH.sub.2R.sup.6,
--C(.dbd.Z)--N(R.sup.7)R.sup.6, preferably wherein R.sup.7
represents a hydrogen atom, or --C(.dbd.Z)--CHR.sup.12R.sup.6
especially where R.sup.12 is hydrogen. Within such groups R.sup.6
may preferably represent substituted phenyl, especially a phenyl
group substituted on one or both, more preferably on both, of the
positions adjacent to a position of attachment of R.sup.6 to the
rest of the molecule. It is also .preferred that the phenyl
substituent is alkyl, especially methyl, or halo, especially chloro
or fluoro. Within such groups R.sup.6 may also preferably represent
substituted azaheteroaryl, where the azaheteroaryl group is
preferably substituted on one or both, more preferably on both, of
the positions adjacent to a position of attachment of R.sup.6 to
the rest of the molecule. It is also preferred that the heteroaryl
substituent is alkyl, especially methyl, or halo, especially chloro
or fluoro.
[0129] R.sup.3 may also particularly represent --C(.dbd.Z)--R.sup.6
wherein R.sup.6 is preferably azaheteroaryl (e.g. pyridyl),
particularly when substituted by aryloxy (e.g.
3-chlorophenoxy).
[0130] R.sup.3 may also particularly represent
--CR.sup.8.dbd.C(R.sup.9)(C- H.sub.2).sub.p--R.sup.6 where R.sup.8
is preferably CH.sub.3 or more preferably hydrogen, R.sup.9 is
preferably hydrogen, CN or CH.sub.3 and p is zero, 1 or 2,
especially zero and R.sup.6 is as defined above.
[0131] R.sup.3 may also particularly represent
--C(R.sup.10).dbd.C(R.sup.1- 1)R.sup.12 where R.sup.10 and R.sup.11
are each preferably CH.sub.2R.sup.6 or especially R.sup.6 (where
R.sup.6 is as defined above), and R.sup.12 is hydrogen.
[0132] R.sup.3 may also particularly represent
--C(R.sup.13)(R.sup.10)C(R.- sup.11)(R.sup.14)R.sup.12 where
R.sup.10 and R.sup.11 are each preferably CH.sub.2R.sup.6 or
especially R.sup.6 (where R.sup.6 is as defined above), R.sup.13 is
preferably hydrogen or hydroxy, R.sup.12 and R.sup.14 are
preferably methyl or more especially hydrogen.
[0133] R.sup.3 may also particularly represent
--C(R.sup.8)(R.sup.15)CH(R.- sup.9)(CH.sub.2).sub.p--R.sup.6 where
R.sup.8 is preferably CH.sub.3 or more preferably hydrogen, R.sup.9
and is preferably hydrogen, CN or CH.sub.3, more preferably
hydrogen, p is zero, 1 or 2, especially zero, R.sup.15 is
preferably hydrogen and R.sup.6 is as defined above.
[0134] R.sup.3 may also particularly represent --R.sup.6 where
R.sup.6 is as defined above.
[0135] R.sup.3 may also particularly represent
--N(R.sup.16)C(.dbd.Z)R.sup- .6 where R.sup.16 is hydrogen and
R.sup.6 is as defined above.
[0136] R.sup.3 may also particularly represent
--C(R.sup.17).dbd.N--OC(=0)- R.sup.18 where R.sup.17 is
C.sub.1-4alkyl and R.sup.18 is amino.
[0137] R.sup.3 may also particularly represent
--C(.dbd.O)--N(R.sup.19)OR.- sup.20 where R.sup.19 is
C.sub.1-4alkyl or aryl and R.sup.20 is C.sub.1-4alkyl or
arylalkyl.
[0138] R.sup.3 may also particularly represent --C.dbd.C--R.sup.6,
--CH.sub.2--NHR.sup.6, --CH.sub.2--SOR.sup.6,
--CH.sub.2--SO.sub.2R.sup.6- , --CF.sub.2OR.sup.6,
--NH--CH.sub.2R.sup.6, --SO--CH.sub.2R.sup.6,
--SO.sub.2--CH.sub.2R.sup.6, --O--CF.sub.2R.sup.6,
--N.dbd.N--R.sup.6, --NH--SO.sub.2R.sup.6, ----NH--CO--OR.sup.6,
--O--CO--NHR.sup.6, --NH--CO--NHR.sup.6 or --CH.sub.2--,
CO--CH.sub.2R.sup.6 where R.sup.6 is as defined above.
[0139] R.sup.3 may also particularly represent
--SO.sub.2--NR.sup.21R.sup.- 22 where R.sup.21 and R.sup.22 are as
defined above.
[0140] R.sup.3 may also particularly represent
--CH.sub.2--C(.dbd.Z)--R.su- p.6,
--C(.dbd.Z)--C(.dbd.Z)R.sup.6,--CH.sub.2--ZR.sup.6,
--Z--CH.sub.2R.sup.6, CZ--CZ--NHR.sup.6 or --O--C(.dbd.Z)R.sup.6
where Z and R.sup.6 are as defined above.
[0141] R.sup.3 may also particularly represent
--CX.sup.1.dbd.CX.sup.2R.su- p.6 where X.sup.1, X.sup.2 and R.sup.6
are as defined above.
[0142] R.sup.3 may also particularly represent
--C(.dbd.NOR.sup.24)--(CH.s- ub.2).sub.qR.sup.6 where R.sup.24, q
and R.sup.6 are as defined above.
[0143] R.sup.3 may also particularly represent
--CH.sub.2--CO--NH(CH.sub.2- ).sub.qR.sup.6 or
--CH.sub.2--NH--CO(CH.sub.2).sub.qR.sup.6 where q and R.sup.6 are
as defined above.
[0144] R.sup.3 may also particularly represent
--C(.dbd.NR.sup.25)--NH(CH.- sub.2).sub.qR.sup.6 where R.sup.25, q
and R.sup.6 are as defined above.
[0145] R.sup.3 may also particularly represent
--C(X.sup.3).dbd.N--(CH.sub- .2).sub.qR.sup.6 or where X.sup.3, q
and R.sup.6 are as defined above.
[0146] R.sup.3 may also particularly represent
--CH(X.sup.4)--CH.sub.2R.su- p.6 where X.sup.4 and R.sup.6 are as
defined above.
[0147] R.sup.3 may also particularly represent 10
[0148] where R.sup.30 and R.sup.32 are hydrogen and R.sup.31 is
--CO.sub.2H or --CONHOH.
[0149] R.sup.3 may also particularly represent 11
[0150] R.sup.3 may also particularly represent 12
[0151] R.sup.3 may also particularly represent 13
[0152] R.sup.3 may also particularly represent 14
[0153] where R.sup.33 is CN, s is zero and Z.sup.3 is an oxygen
atom.
[0154] R.sup.3 may also particularly represent 15
[0155] where R.sup.33 is CN, s is zero and Z.sup.3 is an oxygen
atom.
[0156] R.sup.3 may also particularly represent 16
[0157] where R.sup.33 is CN, s is zero,
[0158] R.sup.35 is hydrogen and R.sup.36 is CO .sub.2H.
[0159] R.sup.3 may also particularly represent 17
[0160] where R.sup.33 is CN, s is zero and R.sup.5 is hydrogen or
C.sub.1-4alkyl, especially methyl.
[0161] R.sup.3 may also particularly represent 18
[0162] where R.sup.33 is CN, s is zero and R.sup.5 is hydrogen or
C.sub.1-4alkyl, especially methyl.
[0163] R.sup.3 may also particularly represent 19
[0164] where W is NR.sup.39 [where R.sup.39 is C.sub.1-4alkyl,
especially methyl] and R.sup.37 is CONHR.sup.5 [where R.sup.5 is
heteroarylalkyl, especially pyridylmethyl].
[0165] R.sup.3 may also particularly represent 20
[0166] where W is CH.sub.2 and R.sup.37 is hydrogen.
[0167] R.sup.3 may also particularly represent 21
[0168] where W is CH.sub.2 and R.sup.38 is hydroxymethyl.
[0169] R.sup.3 may also particularly represent 22
[0170] where W is CH.sub.2 and R.sup.38 is carboxy.
[0171] R.sup.3 may also particularly represent 23
[0172] where R.sup.37 is hydrogen.
[0173] R.sup.3 may also particularly represent 24
[0174] where R.sup.37 and R.sup.39 are alkoxycarbonyl.
[0175] R.sup.3 may also particularly represent 25
[0176] where R.sup.37 is hydroxy and R.sup.39 is hydrogen.
[0177] R.sup.3 may also particularly represent 26
[0178] where R.sup.40 is hydrogen, R.sup.41 is
C.sub.1-4alkoxycarbonyl, especially methyl, R.sup.42 is
C.sub.1-4alkyl, especially methyl, and R.sup.38 is C.sub.1-4acyl,
especially acetyl.
[0179] R.sup.3 may also particularly represent 27
[0180] where Y is defined above.
[0181] The moiety A.sup.1 may particularly represent a direct bond
or a straight- or branched-chain alkylene linkage containing from 1
to 6 carbon atoms, optionally substituted by alkoxy.
[0182] Z.sup.1 may particularly represents an oxygen atom.
[0183] Z.sup.1 may also particularly represents a direct bond.
[0184] The moiety R.sup.3 is preferably --C(.dbd.O)--NHR.sup.6,
--C(.dbd.O)--CH.sub.2R.sup.6 or --OCH.sub.2R.sup.6 wherein R.sup.6
represents an optionally substituted azaheteroaryl group,
especially a pyridyl or isoxazolyl, substituted (by one or two
methyl groups or halogen, e.g. chlorine atoms) on one or both, more
preferably both, of the positions adjacent to the position of
attachment of R.sup.6 to the rest of the molecule. Particular
examples of R.sup.6 include a 3,5-dimethyl- or 3,5-dihalopyrid-4-yl
moiety (more especially a 5 3,5-dimethylpyrid-4-yl moiety) or
3,5-dimethyl-isoxazol-4-yl.
[0185] It is to be understood that the aforementioned heteroaryl
moieties present within R.sup.3 when containing at least one
nitrogen atom may be presented as the corresponding N-oxides, and
such N-oxides are also preferred. Thus, R.sup.3 may preferably
contain a 3,5-dialkyl- or 3,5-dihalo-1-oxido-4-pyridinio group,
such as a 3,5-dimethyl- or 3,5-dichloro-l-oxido-4-pyridinio
group.
[0186] In compounds of formula (I) ring 28
[0187] may particularly represent a 5-membered azaheterocycle
containing at least one nitrogen atom, and ring 29
[0188] may particularly represent a 6-membered azaheteroaryl or
preferably a benzene ring. Such compounds in which n is zero and m
is I are preferred.
[0189] The bicycle 30
[0190] may particularly represent 31
[0191] where Q.sup.1 is a CH or CX.sup.5 linkage (where X.sup.5 is
halogen), or a nitrogen atom, or N.sup.+--O--, especially a CH
linkage, and the moiety 32
[0192] especially where R.sup.5 represents a hydrogen atom or a
methyl group, more especially where R.sup.5 is hydrogen. Preferred
compounds have R.sup.2A.sup.1 attached to position 2 of the
benzimidazole ring.
[0193] It will be appreciated that compounds of formula (I) in
which the bicycle 33
[0194] represents 34
[0195] where the moiety 35
[0196] where R.sup.5 represents a hydrogen atom, are tautomers.
[0197] The bicycle 36
[0198] may also particularly represent 37
[0199] especially where R.sup.2A.sup.1 is attached to the ring
nitrogen atom.
[0200] The bicycle 38
[0201] may also particularly represent 39
[0202] especially where R.sup.2A.sup.1 is attached to the ring
nitrogen atom.
[0203] The bicycle 40
[0204] may also particularly represent 41
[0205] (wherein Z is as hereinbefore defined, especially an oxygen
atom ) especially where R.sup.2A.sup.1 is attached to position 2 of
the benzoxazole ring.
[0206] The bicycle 42
[0207] may also particularly represent 43
[0208] especially where R.sup.2A.sup.1 is attached to the ring
nitrogen atom.
[0209] The bicycle 44
[0210] may also particularly represent 45
[0211] especially where R.sup.2A.sup.1 is attached to position 2 of
the quinoline ring.
[0212] It is to be understood that this invention covers all
appropriate combinations of the particular and preferred groupings
referred to herein.
[0213] A further particular group of compounds of the present
invention are compounds of formula (Ia): 46
[0214] wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1, 47
[0215] Z.sup.1 and Q.sup.1 are as defined previously, and N-oxides
thereof, and their prodrugs, and pharmaceutically acceptable salts
and solvates (e.g. hydrates) of the compounds of formula (Ia) and
N-oxides thereof, and their prodrugs.
[0216] Compounds of formula (Ia) in which R.sup.1 represents
C.sub.1-4alkyl optionally substituted by one or more halogen atoms
(especially methyl or difluoromethyl) are preferred.
[0217] Compounds of formula (Ia) in which R.sup.2 represents a
straight- or branched-chain C.sub.1-4alkyl group (e.g. isopropyl),
or cycloalkyl (e.g. cyclopropyl), alkoxy (e.g. methoxy), aryl,
aryloxy or heteroaryl (e.g. pyridyl) are preferred.
[0218] Compounds of formula (Ia) in which R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 represents a disubstituted
azaheteroaryl group, or an N-oxide thereof, more particularly a
dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are
preferred. Azaheteroaryl groups substituted on both of the
positions adjacent to the position of attachment of R.sup.6 to the
rest of the molecule, for example 3,5-dimethyl-isoxazol-4-yl, or
3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are
most preferred.
[0219] Compounds of formula (Ia) in which A.sup.1 represents a
direct bond are a preferred group of compounds.
[0220] Compounds of formula (Ia) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms, for example a methylene, ethylene, propylene,
methylmethylene, or butylmethylene linkage, (especially methylene)
are also a preferred group of compounds.
[0221] Compounds of formula (Ia) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms which is substituted by alkoxy, for example a
methoxymethylene or methoxypropylmethylene, are a further preferred
group of compounds.
[0222] Compounds of formula (Ia) in which the moiety 48
[0223] represents 49
[0224] where R.sup.5 represents a hydrogen atom or a methyl group
(especially a hydrogen atom) are preferred.
[0225] Compounds of formula (Ia) in which Q.sup.1 is a CH linkage
are preferred.
[0226] Compounds of formula (Ia) in which Z.sup.1 is an oxygen atom
are preferred.
[0227] A preferred group of compounds of the invention are
compounds of formula (Ia) in which: R.sup.1 is methyl or
difluoromethyl; R.sup.2 is C.sub.1-4alkyl (e.g. isopropyl),
C.sub.3-6cycloalkyl (e.g. cyclopropyl), C.sub.1-4alkoxy (e.g.
methoxy), aryl, aryloxy or azaheteroaryl; R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 is a dimethyl- or
dihalo-azaheteroaryl (e.g. 3,5-dimethyl- isoxazol-4-yl, or
3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof);
A.sup.1 is a direct bond or a methylene linkage 50
[0228] Q.sup.1 is a CH linkage and Z.sup.1 is an oxygen atom, and
N-oxides thereof, and their prodrugs, and pharmaceutically
acceptable salts and solvates (e.g. hydrates) of the compounds of
formula (Ia) and N-oxides thereof, and their prodrugs.
[0229] A further particular group of compounds of the present
invention are compounds of formula (Ib): 51
[0230] wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1 and Z.sup.1 are
as defined previously, and Q represents a CH linkage or a nitrogen
atom, and N-oxides thereof, and their prodrugs, and
pharmaceutically acceptable salts and solvates (e.g. hydrates) of
the compounds of formula (Ib) and N-oxides thereof, and their
prodrugs.
[0231] Compounds of formula (Ib) in which R.sup.1 represents methyl
is preferred.
[0232] Compounds of formula (Ib) in which R.sup.2 represents a
straight- or branched-chain C.sub.4-9-alkyl group (e.g. heptyl), a
cycloalkyl group (e.g. cyclopentyl, cyclohexyl), an aryl (e.g.
optionally substituted phenyl), a heteroaryl (e.g. optionally
substituted thienyl) or heterocycloalkyl (e.g. tetrahydofaranyl,
tetrahydropyranylmethyl) are preferred.
[0233] Compounds of formula (Ib) in which R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 represents a disubstituted
azaheteroaryl group, or a N-oxide thereof, more particularly a
dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are
preferred. Azaheteroaryl groups substituted on both of the
positions adjacent to the position of attachment of R.sup.6 to the
rest of the molecule, for example 3,5-dimethyl-isoxazolyl, or
3,5-dimethyl- or 3,5-chloro-pyridyl or an N-oxide thereof, are most
preferred.
[0234] Compounds of formula (Ib) in which A.sup.1 represents a
direct bond are a preferred group of compounds.
[0235] Compounds of formula (Ib) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms, for example a methylene, ethylene, propylene,
methylmethylene, butylmethylene linkage, (especially methylene) are
also a preferred group of compounds.
[0236] Compounds of formula (Ib) in which Q represents a CH linkage
or a nitrogen atom are preferred.
[0237] Compounds of formula (Ib) in which Z.sup.1 represents a
direct bond are preferred.
[0238] A preferred group of compounds of the invention are
compounds of formula (Ib) in which: R.sup.1 is hydrogen or methyl;
R.sup.2 is C.sub.4-9alkyl (e.g. heptyl), C.sub.3-7cycloalkyl (e.g.
cyclopentyl, cyclohexyl), aryl, heteroaryl (e.g. optionally
substituted thienyl), heterocycloalkyl (e.g. tetrahydofuranyl,
tetrahydropyranylmethyl); R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 is a dimethyl- or
dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or
3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof);
A.sup.1 is a direct bond or a methylene linkage and Z.sup.1 is a
direct bond and Q is a CH linkage or a nitrogen atom, and N-oxides
thereof, and their prodrugs, and pharmaceutically acceptable salts
and solvates (e.g. hydrates) of the compounds of formula (Ib) and
N-oxides thereof, and their prodrugs.
[0239] A further particular group of compounds of the present
invention are compounds of formula (Ic): 52
[0240] wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1, Q.sup.1, Z and
Z.sup.1 are as defined previously, and N-oxides thereof, and their
prodrugs, and pharmaceutically acceptable salts and solvates (e.g.
hydrates) of the compounds of formula (Ic) and N-oxides thereof,
and their prodrugs.
[0241] Compounds of formula (Ic) in which R.sup.1 represents methyl
or difluoromethyl are preferred.
[0242] Compounds of formula (Ic) in which R.sup.2 represents a
straight- or branched-chain C.sub.1-4alkyl group (e.g. isopropyl),
a cycloalkyl group (e.g. cyclopropyl), alkoxy (e.g. methoxy), aryl,
aryloxy, heteroaryl (e.g. pyridyl) are preferred.
[0243] Compounds of formula (Ic) in which R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 represents a disubstituted
azaheteroaryl group, or a N-oxide thereof, more particularly a
dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are
preferred. Azaheteroaryl groups substituted on both of the
positions adjacent to the position of attachment of R.sup.6 to the
rest of the molecule, for example 3,5-dimethyl-isoxazol-4-yl, or
3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are
most preferred.
[0244] Compounds of formula (Ic) in which A.sup.1 represents a
direct bond are a preferred group of compounds.
[0245] Compounds of formula (Ic) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms, for example a methylene, ethylene, propylene,
methylmethylene, or butylmethylene linkage, (especially methylene)
are also a preferred group of compounds.
[0246] Compounds of formula (Ic) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms which is substituted by alkoxy, for example a
methoxymethylene or methoxypropylmethylene, are a further preferred
group of compounds.
[0247] Compounds of formula (Ic) in which Q.sup.1 is a CH linkage
are preferred.
[0248] Compounds of formula (Ic) in which Z is an oxygen atom are
preferred.
[0249] Compounds of formula (Ic) in which Z.sup.1 is an oxygen atom
are preferred.
[0250] A preferred group of compounds of the invention are
compounds of formula (Ic) in which: R.sup.1 is methyl or
difluoromethyl; R.sup.2 is C.sub.1-4alkyl (e.g. isopropyl),
C.sub.3-6cycloalkyl (e.g. cyclopropyl), C.sub.1-4alkoxy (e.g.
methoxy), aryl, aryloxy or azaheteroaryl; R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 is a dimethyl- or
dihalo-azaheteroaryl (e.g. 3,5-dimethyl- isoxazol-4-yl, or
3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof);
A.sup.1 is a direct bond or a methylene linkage; Q.sup.1 is a CH
linkage; and Z and Z.sup.1 are both oxygen atoms, and N-oxides
thereof, and their prodrugs, and pharmaceutically acceptable salts
and solvates (e.g. hydrates) of the compounds of formula (Ic) and
N-oxides thereof, and their prodrugs.
[0251] A further particular group of compounds of the present
invention are compounds of formula (Id): 53
[0252] wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1, Q.sup.1, Z and
Z.sup.1 are as defined previously, and N-oxides thereof, and their
prodrugs, and pharmaceutically acceptable salts and solvates (e.g.
hydrates) of the compounds of formula (Id) and N-oxides thereof,
and their prodrugs.
[0253] Compounds of formula (Id) in which R.sup.1 represents methyl
or difluoromethyl are preferred.
[0254] Compounds of formula (Id) in which R.sup.2 represents a
straight- or branched-chain C.sub.1-4alkyl group (e.g. isopropyl),
a cycloalkyl group (e.g. cyclopropyl), alkoxy (e.g. methoxy), aryl,
aryloxy, heteroaryl (e.g. pyridyl) are preferred.
[0255] Compounds of formula (Id) in which R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 represents a disubstituted
azaheteroaryl group, or a N-oxide thereof, more particularly a
dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are
preferred. Azaheteroaryl groups substituted on both of the
positions adjacent to the position of attachment of R.sup.6 to the
rest of the molecule, for example 3,5-dimethyl-isoxazol-4-yl or
3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are
most preferred.
[0256] Compounds of formula (Id) in which A.sup.1 represents a
direct bond are a preferred group of compounds.
[0257] Compounds of formula (Id) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms, for example a methylene, ethylene, propylene,
methylmethylene, or butylmethylene linkage, (especially methylene)
are also a preferred group of compounds.
[0258] Compounds of formula (Id) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms which is substituted by alkoxy, for example a
methoxymethylene or methoxypropylmethylene, are a further preferred
group of compounds.
[0259] Compounds of formula (Id) in which Q.sup.1 is a CH linkage
are preferred.
[0260] Compounds of formula (Id) in which Z is an oxygen atom are
preferred.
[0261] Compounds of formula (Id) in which Z.sup.1 is an oxygen atom
are preferred.
[0262] A preferred group of compounds of the invention are
compounds of formula (Id) in which: R.sup.1 is methyl or
difluoromethyl; R.sup.2 is C.sub.1-4alkyl (e.g. isopropyl),
C.sub.3-6cycloalkyl (e.g. cyclopropyl), C.sub.1-4alkoxy (e.g.
methoxy), aryl, aryloxy or azaheteroaryl; R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 is a dimethyl- or
dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or
3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof);
A.sup.1 is a direct bond or a methylene linkage; Q.sup.1 is a CH
linkage; and Z and Z.sup.1 are both oxygen atoms, and N-oxides
thereof, and their prodrugs, and pharmaceutically acceptable salts
and solvates (e.g. hydrates) of the compounds of formula (Id) and
N-oxides thereof, and their prodrugs.
[0263] A further particular group of compounds of the present
invention are compounds of formula (Ie) 54
[0264] wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1 and Z.sup.1 are
as defined previously, and N-oxides thereof, and their prodrugs,
and pharmaceutically acceptable salts and solvates (e.g. hydrates)
of the compounds of formula (Ie) and N-oxides thereof, and their
prodrugs.
[0265] Compounds of formula (Ie) in which R.sup.1 represents methyl
are preferred.
[0266] Compounds of formula (Ie) in which R.sup.2 represents a
straight- or branched-chain C.sub.4-9alkyl group (e.g. heptyl), a
cycloalkyl group (e.g. cyclopentyl, cyclohexyl), an aryl (e.g.
optionally substituted phenyl), a heteroaryl (e.g. optionally
substituted thienyl) or heterocycloalkyl (e.g. tetrahydofuranyl,
tetrahydropyranylmethyl) are preferred.
[0267] Compounds of formula (Ie) in which R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 represents a disubstituted
azaheteroaryl group, or a N-oxide thereof, more particularly a
dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are
preferred. Azaheteroaryl groups substituted on both of the
positions adjacent to the position of attachment of R.sup.6 to the
rest of the molecule, for example 3,5-dimethyl-isoxazolyl, or
3,5-dimethyl- or 3,5-chloro-pyridyl or an N-oxide thereof, are most
preferred.
[0268] Compounds of formula (Ie) in which A.sup.1 represents a
direct bond are a preferred group of compounds.
[0269] Compounds of formula (Ie) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms, for example a methylene, ethylene, propylene,
methylmethylene, butylmethylene linkage, (especially methylene) are
also a preferred group of compounds.
[0270] Compounds of formula (Ie) in which Z.sup.1 represents a
direct bond are preferred.
[0271] A preferred group of compounds of the invention are
compounds of formula (Ie) in which: R.sup.1 is hydrogen or methyl;
R.sup.2 is C.sub.4-9alkyl (e.g. heptyl), C.sub.3-7cycloalkyl (e.g.
cyclopentyl, cyclohexyl), aryl, heteroaryl(e.g. optionally
substituted thienyl) or heterocycloalkyl (e.g. tetrahydofuranyl,
tetrahydropyranylmethyl); R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--0--CH.sub.2R.sup.6 where R.sup.6 is a dimethyl- or
dihalo-azaheteroaryl (e.g. 3,5-dimethyl-isoxazol-4-yl, or
3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl, or an N-oxide thereof);
A.sup.1 is a direct bond or a methylene linkage and Z.sup.1 is a
direct bond, and N-oxides thereof, and their prodrugs, and
pharmaceutically acceptable salts and solvates (e.g. hydrates) of
the compounds of formula (Ie) and N-oxides thereof, and their
prodrugs.
[0272] A further particular group of compounds of the present
invention are compounds of formula (If) 55
[0273] wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1 and Z.sup.1 are
as defined previously, and N-oxides thereof, and their prodrugs,
and pharmaceutically acceptable salts and solvates (e.g. hydrates)
of the compounds of formula (If) and N-oxides thereof, and their
prodrugs.
[0274] Compounds of formula (If) in which R.sup.1 represents methyl
or difluoromethyl are preferred.
[0275] Compounds of formula (If) in which R.sup.2 represents a
straight- or branched-chain C.sub.1-4alkyl group (e.g. propyl), a
cycloalkyl group (e.g. cyclopropyl), aryl, heteroaryl, or
heterocycloalkyl are preferred.
[0276] Compounds of formula (If) in which R.sup.3 represents
--C(.dbd.O)--NHR.sup.6, --C(.dbd.O)--CH.sub.2R.sup.6 or
--O--CH.sub.2R.sup.6 where R.sup.6 represents a disubstituted
azaheteroaryl group, or a N-oxide thereof, more particularly a
dialkyl- or dihalo-azaheteroaryl group or an N-oxide thereof, are
preferred. Azaheteroaryl groups substituted on both of the
positions adjacent to the position of attachment of R.sup.6 to the
rest of the molecule, for example 3,5-dimethyl-isoxazolyl, or
3,5-dimethyl- or 3,5-chloro-pyridyl or an N-oxide thereof, are most
preferred.
[0277] Compounds of formula (If) in which A.sup.1 represents a
direct bond are a preferred group of compounds.
[0278] Compounds of formula (If) in which A.sup.1 represents a
straight or branched chain alkylene linkage containing from 1 to 6
carbon atoms, for example a methylene, ethylene, propylene,
methylmethylene, butylmethylene linkage, (especially methylene) are
also a preferred group of compounds.
[0279] Compounds of formula (If) in which Z.sup.1 represents an
oxygen atom are preferred.
[0280] A preferred group of compounds of the invention are
compounds of formula (If) in which: R.sup.1 is hydrogen or methyl;
R.sup.2 is C.sub.1-4alkyl (e.g. propyl), C.sub.3-7cycloalkyl (e.g.
cyclopentyl, cyclohexyl), aryl, heteroaryl or heterocycloalkyl;
R.sup.3 represents --C(.dbd.O)--NHR.sup.6,
--C(.dbd.O)--CH.sub.2R.sup.6 or --O--CH.sub.2R.sup.6 where R.sup.6
is dimethyl- or dihalo-azaheteroaryl (e.g.
3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or
3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A.sup.1 is a
direct bond or a methylene linkage and Z.sup.1 is an oxygen atom,
and N-oxides thereof, and their prodrugs, and pharmaceutically
acceptable salts and solvates (e.g. hydrates) of the compounds of
formula (If) and N-oxides thereof, and their prodrugs.
[0281] A further preferred group of compounds of the invention are
compounds of formula (Ig) 56
[0282] wherein
[0283] R.sup.1 represents hydrogen, or a straight- or
branched-chain alkyl group of 1 to about 4 carbon atoms, optionally
substituted by one or more halogen atoms;
[0284] R.sup.2 represents hydrogen, alkoxy, alkyl, alkylsulphinyl,
alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl,
arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl,
arylsulphonyl, arylthio, cycloalkenyl, cycloalkenyloxy, cycloalkyl,
cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy,
hydroxy, --SO.sub.2NR.sup.4R.sup.5, --NR.sup.4SO.sub.2R.sup.5,
--NR.sup.4R.sup.5, --C(.dbd.O)R.sup.5, --C(.dbd.O)C(.dbd.O)R.sup.5,
--C(.dbd.O)NR.sup.4R.sup- .5, --C(.dbd.O)OR.sup.5,
--O(C.dbd.O)NR.sup.4R.sup.5, or --NR.sup.4C(.dbd.O)R.sup.5 where
R.sup.4 and R.sup.5, which may be the same or different, each
represent a hydrogen atom, or an alkyl, aryl, heteroaryl, arylalkyl
or heteroarylalkyl group;
[0285] R.sup.3 represents a group selected from:
[0286] (i) --C(.dbd.Z)--N(R.sup.a)R.sup.6
[0287] (ii) --C(.dbd.Z)--CH.sub.2R.sup.6
[0288] (iii) --C(.dbd.Z)--R.sup.6
[0289] (iv) --CR.sup.7.dbd.C(R.sup.8)(CH.sub.2).sub.n--R.sup.6
[0290] (v) --C(R.sup.9).dbd.C(R.sup.10)R.sup.11
[0291] (vi) --C(R.sup.12)(R.sup.9)C(R.sup.10)(R.sup.13)R.sup.17
[0292] (vii)
--C(R.sup.7)(R.sup.14)CH(R.sup.8)(CH.sub.2).sub.n--R.sup.6
[0293] (viii) --R.sup.6
[0294] (ix) --N(R.sup.15)C(.dbd.Z)R.sup.6
[0295] (x) --C(CH.sub.3).dbd.N--OC(.dbd.0)NH.sub.2
[0296] (xi) --C(.dbd.O)--N(CH.sub.3)OCH.sub.3
[0297] (xii) --C.ident.C--R.sup.6
[0298] (xiii) --CH.sub.2--C(.dbd.Z)--R.sup.6
[0299] (xiv) --C(.dbd.Z)--C(.dbd.Z)R.sup.6
[0300] (xv) --CH.sub.2--NHR.sup.6
[0301] (xvi) --CH.sub.2--ZR.sup.6
[0302] (xvii) --CF.sub.2--OR.sup.6
[0303] (xviii) --NH--CH.sub.2R.sup.6
[0304] (xix) --Z--CH.sub.2R.sup.6
[0305] (xx) --SO--CH.sub.2R.sup.6
[0306] (xxi) --SO.sub.2--CH.sub.2R.sup.6
[0307] (xxii) --O--CF.sub.2R.sup.6
[0308] (xxiii) --O--C(.dbd.Z)R.sup.6
[0309] (xxiv) --N.dbd.N--R.sup.6
[0310] (xxv) --NH-SO.sub.2R.sup.6
[0311] (xxvi) --SO.sub.2--NHR.sup.6
[0312] (xxvii) --CZ--CZ--NHR.sup.6
[0313] (xxviii) --NH--CO--OR.sup.6
[0314] (xxix) --O--CO--NHR.sup.6
[0315] (xxx) --NH--CO--NHR.sup.6
[0316] (xxxi) --R.sup.16
[0317] (xxxii) --CX.sup.2.dbd.CX.sup.3R.sup.6
[0318] [where R.sup.a is a hydrogen atom or alkyl, hydroxy or
amino;
[0319] R.sup.6 is aryl or heteroaryl;
[0320] R.sup.7 and R.sup.8, which may be the same or different, is
each a hydrogen atom or alkyl, --CO.sub.2R.sup.17 (where R.sup.17
is hydrogen or an alkyl, arylalkyl or aryl group),
--C(.dbd.Z)NR.sup.18R.sup.19 (where R.sup.18 and R.sup.19 may be
the same or different and each is as described for R.sup.17), --CN
or --CH.sub.2CN;
[0321] n is zero or an integer 1, 2 or 3;
[0322] R.sup.9 and R.sup.10, which may be the same or different, is
each a group --(CH.sub.2).sub.nR.sup.6;
[0323] R.sup.11 is a hydrogen atom or alkyl;
[0324] R.sup.12 is a hydrogen or halogen atom or an --OR.sup.20
group (where R.sup.20 is a hydrogen atom or an alkyl, alkenyl,
alkoxyalkyl or acyl group, or carboxamido or thiocarboxamido
group);
[0325] R.sup.13 represents hydrogen or alkyl;
[0326] R.sup.14 is hydrogen or hydroxyl;
[0327] R.sup.15 is hydrogen, alkyl, amino, aryl, arylalkyl, or
hydroxy; 57
[0328] where W is (CH.sub.2).sub.m or NR.sup.22;
[0329] R.sup.21 and R.sup.22 which may be the same or different is
each a hydrogen atom, alkyl, acyl, arylalkyl, --CO.sub.2R.sup.17,
heteroarylalkyl, aryl, or heteroaryl; m is 1 to4;
[0330] X.sup.2 and X.sup.3 which may be the same or different is
each a hydrogen or fluorine atom; Z represents an oxygen or sulphur
atom];
[0331] A.sup.1 represents a direct bond, or a straight or branched
C.sub.1-6alkylene chain optionally substituted by hydroxyl, alkoxy,
oxo, cycloalkyl, aryl or heteroaryl. 58
[0332] represents 59
[0333] where R.sup.23 represents a hydrogen atom or a
C.sub.1-4straight- or branched-chain alkyl, aryl,
arylC.sub.1-4alkyl, heteroaryl or heteroarylC.sub.1-4alkyl
group;
[0334] Z.sup.1 represents a direct bond, or an oxygen or sulphur
atom, or NH;
[0335] Q.sup.1 represents a CH or CX.sup.1 linkage or a nitrogen
atom; and
[0336] X.sup.1 represents a halogen atom;
[0337] and N-oxides thereof, and their prodrugs, pharmaceutically
acceptable salts, and solvates (e.g. hydrates), thereof.
[0338] Particular compounds of the invention are selected from the
following:
[0339]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazo-
le-4-carboxamide;
[0340]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenyl-3H-benzimidazole-4-ca-
rboxamide;
[0341]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenethyl-3H-benzimidazole-4-
-carboxamide;
[0342]
2-benzyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-ca-
rboxamide;
[0343]
(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benz-
imidazole-4-carboxamide;
[0344]
(R)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzi-
midazole-4-carboxamide;
[0345]
(S)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzi-
midazole-4-carboxamide;
[0346]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxybenzyl)-3H-benzimi-
dazole-4-car boxamide;
[0347]
(RS)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-meth-
oxy-3H-benzimidazole-4-carboxamide;
[0348] (R)-2-(cyclohexyl-phenyl-methyl)-N-(3
,5-dichloro-4-pyridyl)-7-meth-
oxy-3H-benzimidazole-4-carboxamide;
[0349]
(S)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-metho-
xy-3H-benzimidazole-4-carboxamide;
[0350]
(RS)-N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H--
benzimidazole-4-carboxamide;
[0351] (R)-N-(3,5-dichloro-4-pyridyl)-2-(
1,2-diphenylethyl)-7-methoxy-3H-- benzimidazole-4-carboxamide;
[0352] (S)-N-(3,5-dichloro-4-pyridyl)-2-(
1,2-diphenylethyl)-7-methoxy-3H-- benzimidazole-4-carboxamide;
[0353]
(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-ben-
zimidazole-4-carboxamide;
[0354]
(R)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benz-
imidazole-4-carboxamide;
[0355]
(S)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benz-
imidazole-4-carboxamide;
[0356]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxyphenoxymethyl)-3H--
benzimidazole-4-carboxamide;
[0357]
(RS)--N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-ben-
zimidazole-4-carboxamide;
[0358]
(R)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzi-
midazole-4-carboxamide;
[0359]
(S)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzi-
midazole-4-carboxamide;
[0360]
2-(4-bromobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimida-
zole-4-carboxamide;
[0361]
(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylprop-
yl]-3H-benzi midazole-4-carboxamide;
[0362]
(R)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropy-
l]-3H-benzimidazole-4-carboxamide;
[0363]
(S)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropy-
l]-3H-benzimidazole-4-carboxamide;
[0364] 2-(4-cyanobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy -3H-
benzimidazole-4- carboxamide;
[0365]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[4-(3-pyridyl)benzyl]-3H-ben-
zimidazole-4-carboxamide;
[0366]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxybenzyl)-3H-benzimi-
dazole-4-car boxamide;
[0367]
(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(methoxy-phenyl)methyl--
3H-benzimidazole-4-carboxamide;
[0368]
(R)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxy-phenyl)methyl-
-3H-benzimidazole-4-carboxamide;
[0369]
(S)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxy-phenyl)methyl-
-3H-benzimidazole-4-carboxamide;
[0370]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxyphenoxy)methyl-3H--
benzimidazole-4-carboxamide;
[0371]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(3-pyridyl)-3H-benzimidazole-
-4-carboxamide;
[0372]
N-(3,5-dichloro-4-pyridyl)-2-isopropyl-7-methoxy-3H-benzimidazole-4-
-carboxamide;
[0373]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methyl-3H-benzimidazole-4-ca-
rboxamide;
[0374]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenoxymethyl-3H-benzimidazo-
le-4-carboxamide;
[0375]
2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-
-4-carboxamide;
[0376]
2-benzyl-N-(3,5-dichloro-4-pyridyl)-3H-benzimidazole-4-carboxamide;
[0377]
2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-1-methyl-benzimi-
dazole-4-carboxamide;
[0378]
2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3-methyl-3H-benz-
imidazole-4-carboxamide;
[0379]
N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxa-
mide;
[0380]
2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-
-4-carboxamide;
[0381]
2-cyclopropyl-N-(2,6-difluorophenyl)-7-methoxy-3H-benzimidazole-4-c-
arboxamide;
[0382]
2-cyclopropyl-N-(2,6-dibromophenyl)-7-methoxy-3H-benzimidazole-4-ca-
rboxamide;
[0383]
2-cyclopropyl-N-(2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-c-
arboxamide;
[0384]
2-cyclopropyl-N-(2,4,6-trifluorophenyl)-7-methoxy-3H-benzimidazole--
4-carboxamide;
[0385]
2-cyclopropyl-N-(2,6-dichlorophenyl)-7-methoxy-3H-benzimidazole-4-c-
arboxamide;
[0386]
2-cyclopropyl-N-(3,5-dimethyl-4-pyridyl)-7-methoxy-3H-benzimidazole-
-4-carboxamide;
[0387]
2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidaz-
ole-4-carboxamide;
[0388]
N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimid-
azole-4-carboxamide;
[0389]
2-cyclopropyl-N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-3H-benzimi-
dazole-4-carboxamide;
[0390]
N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-2-methoxymethyl-3H-benzi-
midazole-4-carboxamide;
[0391]
N-(3-chloro-4-pyridyl)-7-methoxy-2-propyl-3H-benzimidazole-4-carbox-
amide;
[0392] N-(3,5-dichloro-4-pyridyl)-8-methoxy-2-n-propyl
quinoline-5-carboxamide;
[0393]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;
[0394]
1-butyloxycarbonyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-indole-6-car-
boxamide;
[0395] N-(3,5-dichloro-4-pyridyl)-1H-indole-6-carboxamide;
[0396] 1-(6,6-dimethyl-bicyclo[3
1.1]hept-2-ylmethyl)-3-methyl-N-(4-pyridy-
l)-1H-indole-6-carboxamide;
[0397]
1-benzyl-N-(4-hydroxyphenyl)-3-methyl-1H-indole-6-carboxamide;
[0398]
1-(2-cyclohexyl)ethyl-3-methyl-N-(4-pyrimidinyl)-1H-indole-6-carbox-
amide;
[0399]
1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-N-(3,5-dimethyl-[1,2-
,4]-triazol-4-yl) -3-methyl-1H-indole-6-carboxamide;
[0400]
1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indoline-6-carboxam-
ide;
[0401]
1-(2-cyclopentyl-7-methoxy-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethan-
one;
[0402]
2-(3,5-dichloro-4-pyridyl)-1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-
-6-yl]-ethanone;
[0403]
2-(3,5-dichloro-pyridin-4-yl)-1-[1-(1-toluene-4-sulphonyl)-3-methyl-
-1H-indol-6-yl]-ethanone;
[0404]
1-[l-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-2-(4-pyridyl)-ethano-
ne;
[0405]
1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)eth-
anone;
[0406]
1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4--
yl)-propan-2-ol;
[0407]
7-methoxy-2-methoxymethyl-4-[2-(4-pyridyl)ethyl]-3H-benzimidazole;
[0408]
2-(4-carboxamidobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-ben-
zimidazole-4-carboxamide;
[0409]
[2-(3-chlorophenoxy)-pyridin-3-yl]-(7-methoxy-2-methoxymethyl-3H-be-
nzimidazol-4-yl)-methanone;
[0410]
2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzim-
idazole;
[0411]
4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benz-
imidazole;
[0412] ethyl
5-(2-cyclopropyl-7-methoxy-benzimidazole-4-yl)pyridine-2-carb-
oxylate;
[0413]
2-cyclopropyl-7-methoxy-4-(4-morpholinosulphonyl)-3H-benzimidazole;
[0414]
1-benzyl-7-methoxy-2-methoxymethyl-4-(2-(4-pyridyl)ethyl)-1H-benzim-
idazole;
[0415]
1-cyclohexylmethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6--
carboxamide;
[0416]
1-(2-cyclohexyl)ethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-
-6-carboxamide;
[0417]
1-[3-(cyclohexyl)propyl]-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-ind-
ole-6-carboxamide;
[0418]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-heptyl-1H-indole-6-carboxamid-
e;
[0419]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)met-
hyl-1H-indole-6-carboxamide;
[0420]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-2-yl)methyl--
1H-indole-6-carboxamide;
[0421]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(toluene-4-sulphonyl)-1H-indo-
le-6-carboxamide;
[0422]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-3-yl)-1H-ind-
ole-6-carboxamide;
[0423]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-methoxy)cyclopentyl-1H-ind-
ole-6-carboxamide;
[0424]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-chlorothiophen-2-yl)methyl-
-1H-indole-6-carboxamide;
[0425]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3,5-dimethylisoxazol-4-yl)me-
thyl-1H-indole-6-carboxamide;
[0426]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-methyl-thiazol-4-yl)methyl-
-l1H-indole-6-carboxamide;
[0427] methyl
5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indol-1-y-
lmethyl]-furan-2-carboxylate;
[0428]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-phenyl-[1,2,4]oxadiazol-3--
yl)methyl-1H-indole-6-carboxamide;
[0429]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-morpholin-4-yl)ethyl-1H-in-
dole-6-carboxamide;
[0430] methyl
5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indole-1--
yl]-pentanoate;
[0431]
N-(3,5-dichloro-4-pyridyl)-1-(4-trifluorobenzyl)-3-methyl-1H-indole-
-6-carboxamide;
[0432]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(4-methylsulphonylbenzyl)-1H--
indole-6-carboxamide;
[0433]
N-(3,5-dichloro-4-pyridyl)-1-(4-methoxycarbonylbenzyl)-3-methyl-1H--
indole-6-carboxamide;
[0434]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-nitrobenzyl)-1H-indole-6-c-
arboxamide;
[0435]
N-(3,5-dichloro-4-pyridyl)-1-(naphthalen-2-yl)methyl-3-methyl-1H-in-
dole-6-carboxamide;
[0436]
N-(3,5-dichloro-4-pyridyl)-1-(biphenyl-4-yl)methyl-3-methyl-1
H-indole-6-carboxamide;
[0437]
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(1-benzyl-imidazol-2-yl)methy-
l-1H-indole-6-carboxamide;
[0438]
N-(3,5-dichloro-pyridin-4-yl)-3-ethyl-1-(toluene-4-sulphonyl)-1H-in-
dole-6-carboxamide;
[0439]
N-(3,5-dichloro-pyridin-4-yl)-3-isopropyl-1-(toluene-4-sulphonyl)-1-
H-indole-6-carboxamide;
[0440]
N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-(toluene-4-sulph-
onyl)-1H-indole-6-carboxamide;
[0441]
N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyisopropyl)-1-(toluene-4-s-
ulphonyl)-1H-indole-6-carboxamide;
[0442]
N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-i-
ndole-6-carboxamide;
[0443]
N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide;
[0444]
1-benzyl-4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidin-
e-2-one;
[0445]
4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one;
[0446]
1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-ethyl)-1H-i-
ndole;
[0447] cis- and
trans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin--
4-yl-vinyl)-1H-indole;
[0448]
6-(1-hydroxy-1-phenyl-2-pyridin-4-yl)ethyl-1-(4-methoxybenzyl)-3-me-
thyl-1H-indole;
[0449] [1-(4-methoxy-benzyl)-3-methyl-1H-indol-6-yl]-phenyl
methanone;
N-methoxy-1-(4-methoxybenzyl)-3-methyl-N-methyl-1H-indole-6-carboxamide;
1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indazole-6-carboxamide;
[0450]
N-(3,5-dichloro-4-pyridyl)-1-(4-methoxybenzyl)-3-methyl-1H-indazole-
-6-carboxamide;
[0451]
N-(3,5-dichloro-4-pyridyl)-4-methoxy-2-methoxymethyl-benzoxazole-7--
carboxamide;
[0452]
N-(3,5-dichloro-4-pyridyl)-3-isopropyl-1-methyl-1H-indole-5-carboxa-
mide; and the corresponding pyridine N-oxides, and their prodrugs
and pharmaceutically acceptable salts and solvates (e.g. hydrates)
thereof.
[0453] Preferred compounds of the invention include:
[0454]
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazo-
le-4-carboxamide;
[0455]
N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxa-
mide;
2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole--
4-carboxamide;
[0456]
N-(3,5-dichloro-4-pyridyl)-2-isopropyl-7-methoxy-3H-benzimidazole-4-
-carboxamide;
[0457]
2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidaz-
ole-4-carboxamide;
[0458]
N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimid-
azole-4-carboxamide;
[0459]
2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzim-
idazole;
4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-be-
nzimidazole;
[0460] and the corresponding pyridine N-oxides, and their prodrugs,
and pharmaceutically acceptable salts and solvates (e.g. hydrates)
thereof.
[0461] A more preferred compound of the invention is:
[0462]
2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzim-
idazole; and its corresponding pyridine N-oxide, and its prodrugs,
and pharmaceutically acceptable salts, and solvates (e.g. hydrates)
thereof.
[0463] The compounds of the invention exhibit useful
pharmacological activity and accordingly are incorporated into
pharmaceutical compositions and used in the treatment of patients
suffering from certain medical disorders. The present invention
thus provides, according to a further aspect, compounds of the
invention and compositions containing compounds of the invention
for use in therapy.
[0464] Compounds within the scope of the present invention exhibit
marked pharmacological activities according to tests described in
the literature which tests results are believed to correlate to
pharmacological activity in humans and other mammals. Detailed in
vitro and in vivo procedures are described hereinafter.
[0465] Compounds of the invention are inhibitors of tumor necrosis
factor, especially TNF-alpha. Thus, in a further embodiment, the
present invention provides compounds of the invention and
compositions containing compounds of the invention for use in the
treatment of a patient suffering from, or subject to, conditions
which can be ameliorated by the administration of an inhibitor of
TNF, especially of TNF-alpha.
[0466] For example, compounds of the present invention are useful
in joint inflammation, including arthritis, rheumatoid arthritis
and other arthritic conditions such as rheumatoid spondylitis and
osteoarthritis. Additionally, the compounds are useful in the
treatment of sepsis, septic shock, gram negative sepsis, toxic
shock syndrome, adult respiratory distress syndrome, asthma and
other chronic pulmonary diseases, bone resorption diseases,
reperfusion injury, graft vs. host reaction, allograft rejection
and leprosy. Furthermore, the compounds are useful in the treatment
of infections such as viral infections and parasitic infections,
for example malaria such as cerebral malaria, fever and myalgias
due to infection, HIV, AIDS, cachexia such as cachexia secondary to
AIDS or to cancer.
[0467] Compounds of the invention are also cyclic AMP
phosphodiesterase inhibitors, in particular type IV cyclic AMP
phosphodiesterase inhibitors. Thus, in another embodiment of the
invention, we provide compounds of the invention and compositions
containing compounds of the invention for use in the treatment of a
patient suffering from, or subject to, conditions which can be
ameliorated by the administration of an inhibitor of cyclic AMP
phosphodiesterase, especially type IV cyclic AMP phosphodiesterase.
For example, compounds within the present invention are useful as
bronchodilators and asthma-prophylactic agents and agents for the
inhibition of eosinophil accumulation and of the function of
eosinophils, e.g. for the treatment of inflammatory airways
disease, especially reversible airway obstruction or asthma, and
for the treatment of other diseases and conditions characterised
by, or having an etiology involving, morbid eosinophil
accumulation. As further examples of conditions which can be
ameliorated by the administration of inhibitors of cyclic AMP
phosphodiesterase such as compounds of the invention there may be
mentioned inflammatory diseases, such as atopic dermatitis,
urticaria, allergic rhinitis, psoriasis, rheumatoid arthritis,
inflammatory diseases (e.g. ulcerative colitis and Crohn's
disease), adult respiratory distress syndrome and diabetes
insipidus, other proliferative skin diseases such as keratosis and
various types of dermatitis, conditions associated with cerebral
metabolic inhibition, such as cerebral senility, multi-infarct
dementia, senile dementia (Alzheimer's disease), and memory
impairment associated with Parkinson's disease, and conditions
ameliorated by neuroprotectant activity, such as cardiac arrest,
stroke, and intermittent claudicatidn.
[0468] Another group of conditions which may be treated with the
compounds of the present invention includes diseases and disorders
of the central nervous system such as brain trauma, ischaemia,
Huntington's disease and tardive dyskinaesia.
[0469] Other disease states which may be treated with the compounds
of the present invention include pyresis, autoimmune diseases (e.g.
systemic lupus erythematosus, allergic erythematosus, multiple
sclerosis), type I diabetes mellitus, psoriasis, Bechet's disease,
anaphylactoid purpura nephritis, chronic glomerulonephritis and
leukemia.
[0470] A special embodiment of the therapeutic methods of the
present invention is the treating of asthma.
[0471] Another special embodiment of the therapeutic methods of the
present invention is the treating of joint inflammation.
[0472] According to a further feature of the invention there is
provided a method for the treatment of a human or animal patient
suffering from, or subject to, conditions which can be ameliorated
by the administration of an inhibitor of cyclic AMP
phosphodiesterase or of TNF, especially TNF-alpha, for example
conditions as hereinbefore described, which comprises the
administration to the patient of an effective amount of compound of
the invention or a composition containing a compound of the
invention. "Effective amount" is meant to describe an amount of
compound of the present invention effective in inhibiting cyclic
AMP phosphodiesterase and/or TNF and thus producing the desired
therapeutic effect.
[0473] According to another aspect of the invention, there is
provided the use of a compound of the invention in the manufacture
of a medicament for the treatment of a patient suffering from, or
subject to, conditions which can be ameliorated by the
administration of an inhibitor of cyclic AMP phosphodiesterase,
especially type IV cyclic AMP phosphodiesterase.
[0474] According to a further aspect of the invention, there is
provided the use of a compound of the invention in the manufacture
of a medicament for the treatment of a patient suffering from, or
subject to, conditions which can be ameliorated by the
administration of an inhibitor of TNF, especially of TNF-alpha.
[0475] References herein to treatment should be understood to
include prophylactic therapy as well as treatment of established
conditions.
[0476] The present invention also includes within its scope
pharmaceutical compositions comprising at least one of the
compounds of the invention in association with a pharmaceutically
acceptable carrier or excipient.
[0477] Compounds of the invention may be administered by any
suitable means. In practice compounds of the present invention may
generally be administered parenterally, topically, rectally, orally
or by inhalation, especially by the oral route.
[0478] Compositions according to the invention may be prepared
according to the customary methods, using one or more
pharmaceutically acceptable adjuvants or excipients. The adjuvants
comprise, inter alia, diluents, sterile aqueous media and the
various non-toxic organic solvents. The compositions may be
presented in the form of tablets, pills, granules, powders, aqueous
solutions or suspensions, injectable solutions, elixirs or syrups,
and can contain one or more agents chosen from the group comprising
sweeteners, flavourings, colourings, or stabilisers in order to
obtain pharmaceutically acceptable preparations. The choice of
vehicle and the content of active substance in the vehicle are
generally determined in accordance with the solubility and chemical
properties of the active compound, the particular mode of
administration and the provisions to be observed in pharmaceutical
practice. For example, excipients such as lactose, sodium citrate,
calcium carbonate, dicalcium phosphate and disintegrating agents
such as starch, alginic acids and certain complex silicates
combined with lubricants such as magnesium stearate, sodium lauryl
sulphate and talc may be used for preparing tablets. To prepare a
capsule, it is advantageous to use lactose and high molecular
weight polyethylene glycols. When aqueous suspensions are used they
can contain emulsifying agents or agents which facilitate
suspension. Diluents such as sucrose, ethanol, polyethylene glycol,
propylene glycol, glycerol and chloroform or mixtures thereof may
also be used.
[0479] For parenteral administration, emulsions, suspensions or
solutions of the products according to the invention in vegetable
oil, for example sesame oil, groundnut oil or olive oil, or
aqueous-organic solutions such as water and propylene glycol,
injectable organic esters such as ethyl oleate, as well as sterile
aqueous solutions of the pharmaceutically acceptable salts, are
used. The solutions of the salts of the products according to the
invention are especially useful for administration by intramuscular
or subcutaneous injection. The aqueous solutions, also comprising
solutions of the salts in pure distilled water, may be used for
intravenous administration with the proviso that their pH is
suitably adjusted, that they are judiciously buffered and rendered
isotonic with a sufficient quantity of glucose or sodium chloride
and that they are sterilised by heating, irradiation or
microfiltration.
[0480] For topical administration, gels (water or alcohol based),
creams or ointments containing compounds of the invention may be
used. Compounds of the invention may also be incorporated in a gel
or matrix base for application in a patch, which would allow a
controlled release of compound through the transdermal barrier.
[0481] For administration by inhalation compounds of the invention
may be dissolved or suspended in a suitable carrier for use in a
nebuliser or a suspension or solution aerosol, or may be absorbed
or adsorbed onto a suitable solid carrier for use in a dry powder
inhaler.
[0482] Solid compositions for rectal administration include
suppositories formulated in accordance with known methods and
containing at least one compound of the invention.
[0483] The percentage of active ingredient in the compositions of
the invention may be varied, it being necessary that it should
constitute a proportion such that a suitable dosage shall be
obtained. Obviously, several unit dosage forms may be administered
at about the same time. The dose employed will be determined by the
physician, and depends upon the desired therapeutic effect, the
route of administration and the duration of the treatment, and the
condition of the patient. In the adult, the doses are generally
from about 0.001 to about 50, preferably about 0.001 to about 5,
mg/kg body weight per day by inhalation, from about 0.01 to about
100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body
weight per day by oral administration, and from about 0.001 to
about 10, preferably 0.01 to 1, mg/kg body weight per day by
intravenous administration. In each particular case, the doses will
be determined in accordance with the factors distinctive to the
subject to be treated, such as age, weight, general state of health
and other characteristics which can influence the efficacy of the
medicinal product.
[0484] The compounds according to the invention may be administered
as frequently as necessary in order to obtain the desired
therapeutic effect. Some patients may respond rapidly to a higher
or lower dose and may find much weaker maintenance doses adequate.
For other patients, it may be necessary to have long-term
treatments at the rate of I to 4 doses per day, in accordance with
the physiological requirements of each particular patient.
Generally, the active product may be administered orally 1 to 4
times per day. Of course, for some patients, it will be necessary
to prescribe not more than one or two doses per day.
[0485] The compounds of the present invention may also be
formulated for use in conjunction with other therapeutic agents
such as agents which increase cyclic AMP production including
.beta.-agonists and PGE.sub.2. It is to be understood that the
present invention includes combinations of compounds of the present
invention with one or more of the aforementioned therapeutic
agents.
[0486] Compounds of the invention may be prepared by the
application or adaptation of known methods, by which is meant
methods used heretofore or described in the literature.
[0487] In particular, compounds of the invention in which the
moiety R.sup.3 is group (iv) may be prepared by methods similar to
those described in WO 94/20455.
[0488] Compounds of the invention in which the moiety R.sup.3 is
group (v) may be prepared by methods similar to those described in
WO 94/14800.
[0489] Compounds of the invention in which the moiety R.sup.3 is
group (vi) may be prepared by methods similar to those described in
WO 94/14742.
[0490] Compounds of the invention in which the moiety R.sup.3 is
group (vii) may be prepared by methods similar to those described
in WO 94/20446.
[0491] Compounds of the invention in which the moiety R.sup.3 is
group (viii) may be prepared by methods similar to those described
in WO 94/10118 and WO 95/22520.
[0492] Compounds of the invention in which the moiety R.sup.3 is
group (ix) may be prepared by methods similar to those described in
WO 93/25517.
[0493] Compounds of the invention in which the moiety R.sup.3 is
group (x) may be prepared by methods similar to those described in
EP-A-0470805.
[0494] Compounds of the invention in which the moiety R.sup.3 is
group (xxviii) may be prepared by methods similar to those
described in WO 96/36595, WO 96/36596 and WO 96/36611.
[0495] Compounds of the invention in which the moiety R.sup.3 is
group (xxxiii) wherein R.sup.23 is 60
[0496] may be prepared by methods similar to those described in WO
95/14681.
[0497] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 61
[0498] may be prepared by methods similar to those described in
EP-A-0523513.
[0499] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 62
[0500] may be prepared by methods similar to those described in
EP-A-0510562.
[0501] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 63
[0502] may be prepared by methods similar to those described in
EP-A-0428313.
[0503] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 64
[0504] may be prepared by methods similar to those described in
U.S. Pat. No. 5,449,686.
[0505] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 65
[0506] may be prepared by methods similar to those described in WO
95./09624.
[0507] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 66
[0508] may be prepared by methods similar to those described in WO
93/19749.
[0509] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 67
[0510] may be prepared by methods similar to those described in WO
95/03794.
[0511] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 68
[0512] where W is CH.sub.2 and R.sup.37 is hydrogen, may be
prepared by methods similar to those described in U.S. Pat. No.
5,420,154.
[0513] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 69
[0514] where W is NR.sup.39 and R.sup.37 and R.sup.39 are as
hereinbefore defined, may be prepared by methods similar to those
described in EP-A-0511865.
[0515] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 70
[0516] and R.sup.37 is hydrogen or --CO.sub.2Me, may be prepared by
methods similar to those described by R. D. Miller and P. Goelitz,
J. Org.Chem., 1981, 46, page 1616-1618.
[0517] Compounds of the invention in which moiety R.sup.3 is group
(xxxiii) wherein R.sup.23 is 71
[0518] and R.sup.37 and R.sup.39 are as hereinbefore defined, may
be prepared by methods similar to those described in WO
95/08534.
[0519] In the reactions described hereinafter it may be necessary
to protect reactive functional groups, for example hydroxy, amino,
imino, thio or carboxy groups, where these are desired in the final
product, to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with
standard practice, for examples see T. W. Green and P. G. M. Wuts
in "Protective Groups in Organic Chemistry" John Wiley and Sons,
1991.
[0520] Compounds of this invention may be represented by the
formula (Iz):
T.sup.1--R.sup.3 (Iz)
[0521] wherein R.sup.3 is as hereinbefore defined and T.sup.1
represents a group of the formula 72
[0522] wherein 73
[0523] R.sup.1, R.sup.2, A.sup.1, Z.sup.1, n and m are as
hereinbefore defined.
[0524] In a process (A), compounds of formula (I) wherein R.sup.3
represents a --C(.dbd.O)--NHR.sup.6 group in which R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (II)
T.sup.1--C(.dbd.O)X.sup.6 (II)
[0525] wherein T.sup.1 is as hereinbefore defined and X.sup.6
represents an azido, O-benzotriazol-1-yl, or alkoxy group, such as
methoxy, or a halogen atom, such as a bromine, or preferably, a
chlorine atom, with compounds of the general formula (III)
R6NHR.sup.48 (III)
[0526] wherein R.sup.6 is as hereinbefore described, including
N-oxides of heteroaryl groups, and R.sup.48 represents a hydrogen
atom or an alkanoyl, e.g. acetyl group. The reaction may be carried
out in the presence of a base such as an alkali metal
dialkyldihydroaluminate, e.g. sodium diethyldihydroaluminate or an
alkali metal hydride, e.g. sodium hydride, or in the presence of
trimethylaluminium, optionally in an inert solvent, or mixture of
inert solvents, chosen from for example a halogenated hydrocarbon
(such as dichloromethane), toluene, dimethylformamide, or an ether
(e.g. diethyl ether or tetrahydrofuran), preferably at a
temperature from 0.degree. C. to the reflux temperature or at the
melting point of the reaction mixture. The use of sodium
diethyldihydroaluminate is preferred when R.sup.6 represents a
heteroaryl group containing at least one nitrogen atom.
[0527] As another example, in a process (B), compounds of formula
(I) wherein R.sup.3 represents a --C(.dbd.O)--CH.sub.2R.sup.6 group
in which R.sup.6 is as hereinbefore defined, together with
compounds of formula (I) wherein R.sup.3 represents a
--C(R.sup.13)(R.sup.10)C(R.sup.11)(R.sup- .14)R.sup.12 group in
which R.sup.10 and R.sup.11 each represents a
--(CH.sub.2).sub.pR.sup.6 group (where R.sup.6 is as hereinbefore
defined and p is 1), R.sup.12 and R.sup.14 represent hydrogen atoms
and R.sup.13 represents a hydroxy group, may be prepared by the
reaction of compounds of the general formula (IV)
T.sup.1--CO.sub.2R.sup.49 (IV)
[0528] wherein T.sup.1 is as hereinbefore defined and R.sup.49
represents a C.sub.1-5alkyl group with compounds of the general
formula (V)
R.sup.6--CH.sub.3 (V)
[0529] wherein R.sup.6 is as hereinbefore defined, in the presence
of a strong base such as lithium diisopropylamide (usually prepared
in situ from butyl lithium and diisopropylamine), in an inert
solvent, for example an ether, e.g. tetrahydrofuran, preferably at
a temperature from -65.degree. C. to 0.degree. C.
[0530] Alternatively compounds of formula (I) wherein R.sup.3
represents a --C(.dbd.O)--CH.sub.2R.sup.6 group and R.sup.6 is as
hereinbefore defined, may be prepared by the oxidation of compounds
of the general formula (VI)
T.sup.1--CH(OH)CH.sub.2R.sup.6 (VI)
[0531] wherein T.sup.1 and R.sup.6 are as hereinbefore defined, by
the application or adaptation of known methods. The oxidation can
be carried out, for example. by reaction with oxalyl chloride and
dimethyl sulphoxide, in a solvent such as dichloromethane, and
preferably at a temperature lower than -65.degree. C. These
conditions are especially convenient for the preparation of
compounds wherein Z.sup.1 represents a direct bond or an oxygen
atom.
[0532] As another example, in a process (C), compounds of formula
(I) wherein R.sup.3 represents a --C(.dbd.O)--R.sup.6 group and
R.sup.6 is as hereinbefore defined may be prepared by reaction of
compounds of formula (I), wherein R.sup.3 represents a group
--C(.dbd.O)--N(CH.sub.3)OCH.sub.3- , with compounds of the general
formula (VII)
R.sup.6--MgBr (VII)
[0533] wherein R.sup.6 is as hereinbefore defined, in an inert
solvent, for example an ether, e.g. tetrahydrofuran, preferably at
a temperature from about 0.degree. C. to about reflux
temperature.
[0534] Alternatively, in a process (D), compounds of formula (I)
wherein R.sup.3 represents a --C(.dbd.O)--R.sup.6 group and R.sup.6
is as hereinbefore defined may be prepared by reaction of compounds
of formula (II), especially where X.sup.6 represents
O-benzotriazolyl, with the anion derived from reaction of compounds
of formula R.sup.6--Br (where R.sup.6 is as hereinbefore defined)
and butyllithium. The reaction is carried out in an inert solvent
such as an ether, e.g. tetrahydrofuran, and at a temperature at
about -70.degree. C.
[0535] As another example, compounds of formula (I), wherein
R.sup.3 represents a
--CR.sup.8.dbd.C(R.sup.9)(CH.sub.2).sub.p--R.sup.6 group and
R.sup.6, R.sup.8, R.sup.9 and p are as hereinbefore defined, may be
prepared by the reaction of compounds of formula (VIII)
T.sup.1--C(.dbd.O)R.sup.8 (VIII)
[0536] wherein T.sup.1 and R.sup.8 are as hereinbefore defined,
with the reaction product of a compound of the formula (IX)
[(R.sup.50).sub.3PCH(R.sup.9)(CH.sub.2).sub.pR.sup.6].sup.+X.sup.-
(IX)
[0537] wherein R.sup.9, R.sup.6 and p are as hereinbefore defined,
R.sup.50 represents an aryl, such as phenyl group, and X represents
halo, preferably bromo, with a base such as an alkali metal
alkoxide (for example potassium t-butoxide), or an alkali metal
hydride (for example sodium hydride), or butyl lithium. The
reaction is preferably carried out in a solvent such as
dimethylformamide or tetrahydrofuran.
[0538] Compounds of formula (I) wherein R.sup.3 represents a
--C(R.sup.10).dbd.C(R.sup.11)R.sup.12 group and R.sup.10, R.sup.11
and R.sup.12 are as hereinbefore defined, may be similarly prepared
by the reaction of compounds of formula (X):
T.sup.1--C(.dbd.O)R.sup.10 (X)
[0539] wherein T.sup.1 and R.sup.10 are as hereinbefore defined,
with the phosphorane obtained by treating a compound of the formula
(XI):
[(R.sup.50).sub.3PCH(R.sup.11)R.sup.12].sup.+ X.sup.31 (XI)
[0540] wherein R.sup.11 and R.sup.12 and R.sup.50 are as
hereinbefore defined with a base as described above.
[0541] As another example, compounds of formula (I) wherein R.sup.3
represents a --CR.sup.8.dbd.C(R.sup.9)(CH.sub.2).sub.p--R.sup.6
group, where R.sup.6, R.sup.8,R.sup.9 and p are as hereinbefore
defined, may be prepared by the reaction of compounds of formula
(VIII), wherein T.sup.1 is as hereinbefore defined, with the
reaction product of a compound of the formula (XII):
(R.sup.51O).sub.2P(.dbd.O)CH(R.sup.9)(CH.sub.2).sub.pR.sup.6
(XII)
[0542] wherein R.sup.6, R.sup.9 and p are as hereinbefore defined
and R.sup.51 represents a C.sub.1-4alkyl group, with a base such as
an alkali metal alkoxide (for example potassium t-butoxide), or an
alkali metal hydride (for example sodium hydride). The reaction is
preferably carried out in a solvent such as dimethylformamide or
tetrahydrofuran.
[0543] Compounds of formula (I) wherein R.sup.3 represents a
--C(R.sup.10).dbd.C(R.sup.11)R.sup.12 group and R.sup.10, R.sup.11
and R.sup.12 are as hereinbefore defined may be prepared in a
similar manner to that described above from compounds of formula
(X), wherein T.sup.1 and R.sup.10 are as hereinbefore defined, and
compounds of formula (XIII):
(R.sup.51O).sub.2P(.dbd.O)CH(R.sup.11)R.sup.12 (XIII)
[0544] wherein R.sup.11, R.sup.12 and R.sup.51 are as hereinbefore
defined.
[0545] As another example, compounds of formula (I) wherein R.sup.3
represents a --C(R.sup.10).dbd.C(R.sup.11)R.sup.12 group where
R.sup.10, R.sup.11 and R.sup.12 are as hereinbefore defined may
also conveniently be prepared from compounds of formula (XIV):
T.sup.1--C(R.sup.10)(OH)CH(R.sup.11)R.sup.12 (XIV)
[0546] wherein T.sup.1, R.sup.10, R.sup.11 and R.sup.12 are as
hereinbefore defined, by dehydration using an acid such as a Lewis
acid (e.g. thionyl bromide) at an elevated temperature, for example
the reflux temperature, optionally in the presence of a suitable
base such as 1,8-diazabicyclo-[5.4.0]undec-7-ene.
[0547] Compounds of formula (I) wherein R.sup.3 represents
--C(R.sup.8).dbd.C(R.sup.9)(CH.sub.2).sub.pR.sup.6 where R.sup.6,
R.sup.8, R.sup.9 and p are as hereinbefore defined may be prepared
by dehydration of compounds of formula (XV):
T.sup.1--C(R.sup.8)(OH)CH(R.sup.9)(CH.sub.2).sub.pR.sup.6 (XV)
[0548] wherein T.sup.1, R.sup.6, R.sup.8, R.sup.9 and p are as
hereinbefore defined, using an acid such as a Lewis acid (e.g.
thionyl bromide) at an elevated temperature, for example the reflux
temperature, optionally in the presence of a suitable base such as
1,8-diazabicyclo-[5.4.0]undec-7-ene. Alternatively the dehydration
may be carried out using an acid catalyst, such as
4-toluenesulphonic acid, in an inert solvent, such as benzene, at a
temperature from about 0.degree. C. to about reflux
temperature.
[0549] As another example, compounds of formula (I) wherein R.sup.3
represents a --C(R.sup.13)(R.sup.10)C(R.sup.11)(R.sup.14)R.sup.12
group where R.sup.10, R.sup.11 and R.sup.12 are as hereinbefore
defined, and R.sup.13 and R.sup.14 each represent a hydrogen atom,
may be prepared by hydrogenation of compounds of the general
formula (I) wherein R.sup.3 represents a
--C(R.sup.10).dbd.C(R.sup.11)R.sup.12 where R.sup.10, R.sup.11 and
R.sup.12 are as hereinbefore defined. The hydrogenation may be
carried out using hydrogen in the presence of a suitable metal
catalyst, e.g. platinum or palladium optionally supported on an
inert carrier such as carbon, preferably in a solvent such as
methanol or ethanol. Compounds of formula (I) wherein R.sup.3
represents a
--C(R.sup.8)(R.sup.15)CH(R.sup.9)(CH.sub.2).sub.p--R.sup.6 group
where R.sup.8, R.sup.9 and p are as hereinbefore defined and
R.sup.15 represents a hydrogen atom, may be prepared in a similar
manner to that described above by hydrogenation of compounds of the
general formula (I) wherein R.sup.3 represents a
--C(R.sup.8).dbd.C(R.sup.9)(CH.sub.2).sub.pR- .sup.6 where R.sup.8,
R.sup.9 and p are as hereinbefore defined.
[0550] Compounds of formula (I), wherein R.sup.3 represents a
--C(R.sup.8)(R.sup.15)CH(R.sup.9)(CH.sub.2).sub.p--R.sup.6 group
where R.sup.6 is as hereinbefore defined and R.sup.8, R.sup.9 and
R.sup.15 represent hydrogen atoms and p is zero, may be prepared by
reduction of compounds of the general formula (I) wherein R.sup.3
represents a --C(.dbd.O)--CH.sub.2R.sup.6, where R.sup.6 is as
hereinbefore defined. The reduction may be carried out with
hydrazine hydrate, in the presence of an alkali metal hydroxide,
such a potassium hydroxide, in an inert solvent, such as diethylene
glycol, at a temperature up to about 100.degree. C.
[0551] As another example, compounds of formula (1) wherein R.sup.3
represents a R.sup.6 group may be prepared by the reaction of
compounds of the general formula (XVI):
T.sup.1--B(OH).sub.2 (XVI)
[0552] wherein T.sup.1 is as hereinbefore defined, with a compound
of the general formula (XVII):
R.sup.6--X.sup.7 (XVII)
[0553] wherein R.sup.6 is as hereinbefore described and X.sup.7
represents a halogen atom for example a bromine or chlorine atom,
or a triflate group, in the presence of a complex metal catalyst
such as tetrakis(triphenylphosphine)palladium(0).
[0554] Alternatively compounds of formula (I) wherein R.sup.3
represents a R.sup.6 group may be similarly prepared by the
reaction of compounds of the general formula (XVIII):
T.sup.1--X.sup.7 (XVIII)
[0555] wherein T.sup.1 and X.sup.7 are as hereinbefore defined,
with a compound of the general formula (XIX):
R.sup.6--B(OH).sub.2 (XIX)
[0556] wherein R.sup.6 is as hereinbefore defined in the presence
of a complex metal catalyst such as
tetrakis(triphenylphosphine)palladium(0).
[0557] Compounds of formula (I) wherein R.sup.3 represents a
R.sup.6 group may also be prepared by reaction of compounds of
formula (XVIII) wherein T.sup.1 is as hereinbefore defined and
X.sup.7 is a bromine atom, with a solution of butyllithium in
hexane, in an inert solvent such as tetrahydrofuran, at a
temperature at about -70.degree. C., followed by reaction with
tributyltin chloride and subsequent reaction of the tributyltin
intermediate with compounds of formula (XVII) wherein R.sup.6 is as
hereinbefore defined and X.sup.7 is a bromine atom, in the presence
of bis(dibenzylidene)acetone palladium(0) and triphenylphosphine in
dimethylformamide at a temperature up to about 120.degree. C.
[0558] As another example, compounds of formula (I) wherein R.sup.3
represents a --NHC(.dbd.O)R.sup.6 group where R.sup.6 is as
hereinbefore defined, may be prepared by the reaction of compounds
of the general formula (XX):
T.sup.1--NH.sub.2 (XX)
[0559] wherein T.sup.1 is as hereinbefore defined with compounds of
formula (XXII):
R.sup.6C(.dbd.O)X.sup.8 (XXI)
[0560] wherein R.sup.6 is as hereinbefore defined and X.sup.8
represents an azido group or a halogen atom, e.g. bromine or,
preferably, chlorine atom, are as hereinbefore defined, preferably
in the presence of a base such as a tertiary amine, e.g.
triethylamine, preferably in a solvent such as dichloromethane.
[0561] As another example, compounds of formula (I) wherein R.sup.3
represents a --C(CH.sub.3).dbd.N--OC(=0)NH.sub.2 group may be
prepared by the reaction of compounds of the general formula
(XXII):
T.sup.1--C(.dbd.NOH)CH.sub.3 (XXII)
[0562] wherein T.sup.1 is as hereinbefore defined, with sodium
cyanate in an inert solvent such as dichloromethane in the presence
of an acid such as acetic acid or trifluoroacetic acid at a
temperature at about ambient temperature.
[0563] As another example, compounds of formula (I) wherein R.sup.3
represents a --C(.dbd.O)--N(Me)OCH.sub.3 group may be prepared by
the reaction of compounds of the general formula (II), wherein
T.sup.1 is as hereinbefore defined and X.sup.6 is a halogen atom,
such as a chlorine atom, with N-methyl-O-methylhydroxylamine in an
inert solvent such as dimethylformamide.
[0564] As another example, compounds of formula (I) wherein R.sup.3
represents a --C.ident.C--R.sup.6 group where R.sup.6 is as
hereinbefore defined, may be prepared by the reaction of compounds
of the general formula (XXIII):
T.sup.1--I (XXIII)
[0565] wherein T.sup.1, is as hereinbefore defined, with acetylenes
of the general formula (XXIV):
R.sup.6C.ident.CH (XXIV)
[0566] wherein R.sup.6 is as hereinbefore defined. Preferably the
reaction is carried out with the aid of a catalyst, e.g. palladium
on carbon and cuprous iodide, preferably with the aid of a base
such as a tertiary amine, e.g. triethylamine, preferably in a
solvent such as dimethylformamide.
[0567] As another example, compounds of formula (I) wherein R.sup.3
represents a --CH.sub.2--C(.dbd.O)--R.sup.6 group where R.sup.6 is
as hereinbefore defined may be prepared by oxidation of compounds
of the general formula (XXV):
T.sup.1--CH.sub.2CH(OH)R.sup.6 (XXV)
[0568] wherein T.sup.1 and R.sup.6 are as hereinbefore defined. The
oxidation may conveniently be carried out, for example, by reaction
with oxalyl chloride and dimethyl sulphoxide, in a solvent such as
dichloromethane, and preferably at a temperature lower than
-65.degree. C. Alternatively, the oxidation may be carried out by
reaction with chromium trioxide in the presence of
3,5-dimethylpyrazole.
[0569] As another example, compounds of formula (I) wherein R.sup.3
represents a --C(.dbd.O)--C(.dbd.O)R.sup.6 group where R.sup.6 is
as hereinbefore defined may be prepared by the oxidation of
compounds of formula (I) wherein R.sup.3 represents a
--C(.dbd.O)--CH.sub.2R.sup.6 group where R.sup.6 is as hereinbefore
defined. The oxidation may be carried out, for example, by reaction
with pyridinium dichromate, preferably in a solvent such as
dichloromethane. This reaction is particularly suitable for the
preparation of compounds wherein R.sup.6 represents a heteroaryl,
for example an optionally substituted pyridyl, group.
[0570] As another example, compounds of formula (I) wherein R.sup.3
represents --CH.sub.2--NHR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXVI):
T.sup.1--C(.dbd.O)H (XXVI)
[0571] wherein T.sup.1 is as hereinbefore defined, with compounds
of formula (III) wherein R.sup.6 is as hereinbefore defined and
R.sup.48 is hydrogen, followed by reduction with sodium
cyanoborohydride. This reaction is especially suitable for the
preparation of compounds wherein R.sup.6 represents an optionally
substituted phenyl or naphthyl group.
[0572] Alternatively, compounds of formula (I) wherein R.sup.3
represents --CH.sub.2--NHR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXVII):
T.sup.1--CH.sub.2X.sup.9 (XXVII)
[0573] wherein T.sup.1 is as hereinbefore defined and X.sup.9
represents halogen, preferably a bromine atom, with compounds of
formula (III) wherein R.sup.6 is as hereinbefore defined and
R.sup.48 is hydrogen. The reaction preferably takes place in the
presence of a base such as sodium hydride. The reaction is
especially suitable for the preparation of compounds wherein
R.sup.6 represents an optionally substituted heteroaryl group.
[0574] As another example, compounds of formula (I) wherein R.sup.3
represents --CH.sub.2--OR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXVII) wherein T.sup.1 and X.sup.9 are as
hereinbefore defined with compounds of formula (XXVIII):
R.sup.6--OH (XXVIII)
[0575] wherein R.sup.6 is as hereinbefore defined, preferably with
the aid of a base such as an alkali metal alkoxide, e.g. potassium
t-butoxide.
[0576] Alternatively compounds of formula (I) wherein R.sup.3
represents a --CH.sub.2--OR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXIX):
T.sup.1--CH.sub.2OH (XXIX)
[0577] wherein T.sup.1 is as hereinbefore defined, with compounds
of formula (XVII) wherein R.sup.6 and X.sup.7 are as hereinbefore
defined, preferably with the aid of a base such as an alkali metal
alkoxide, e.g. potassium t-butoxide. The reaction is preferably
carried out in a solvent such as tetrahydrofuran.
[0578] Alternatively compounds of formula (I) wherein R.sup.3
represents a --CH.sub.2--OR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by reaction of compounds of
the general formula (XXIX) with compounds of formula (XXVIII)
wherein R.sup.6 is as hereinbefore defined, in the presence of a
dialkyl azodicarboxylate, such as diethyl azodicarboxylate, and
triphenylphosphine, preferably in a dry ethereal solvent, e.g.
diethyl ether or tetrahydrofuran, preferably at or near room
temperature.
[0579] As another example, compounds of formula (I) wherein R.sup.3
represents a --CH.sub.2--SR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXVII), wherein T.sup.1 and X.sup.9 are as
hereinbefore defined with compounds of the general formula
(XXX):
R.sup.6--SH (XXX)
[0580] wherein R.sup.6 is as hereinbefore defined, preferably with
the aid of a base such as an alkali metal carbonate, e.g. potassium
carbonate.
[0581] As another example, compounds of formula (I) wherein R.sup.3
represents a --CF.sub.2--OR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXXI):
T.sup.1--CF.sub.2Br (XXXI)
[0582] with compounds of the general formula (XXVIII) wherein
R.sup.6 is as hereinbefore defined, preferably with the aid of a
base such as sodium hydride, preferably in a solvent such as
dimethylformamide.
[0583] As another example, compounds of formula (I) wherein R.sup.3
represents a --NH--CH.sub.2R.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XX) wherein T.sup.1 is as hereinbefore
defined, with compounds of the general formula (XXXII):
R.sup.6CHO (XXXII)
[0584] wherein R.sup.6 is as hereinbefore defined, in the presence
of a reducing agent such as sodium cyanoborohydride.
[0585] As another example, compounds of formula (I) wherein R.sup.3
represents a --O--CH.sub.2R.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXXIII):
T.sup.1--OH (XXXIII)
[0586] wherein T.sup.1 is as hereinbefore defined, with compounds
of the general formula (XXXIV):
R.sup.6CH.sub.2X.sup.10 (XXXIV)
[0587] wherein R.sup.6 is as hereinbefore defined and X.sup.10
represents hydroxy or a halogen atom.
[0588] When X.sup.10 represents hydroxy the reaction is
conveniently carried out in the presence of a dialkyl
azodicarboxylate, such as diethyl azodicarboxylate, and
triphenylphosphine, preferably in a dry ethereal solvent, e.g.
diethyl ether or tetrahydrofuran, preferably at or near room
temperature. When X.sup.10 represents a halogen atom, especially a
chlorine atom, the reaction is preferably carried out in the
presence of a base such as an alkali metal carbonate, e.g.
potassium carbonate, preferably in an solvent such as
dimethylformamide, and at a temperature from about room temperature
to about 80.degree. C.
[0589] As another example, compounds of formula (I) wherein R.sup.3
represents a --S--CH.sub.2R.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXXV):
T.sup.1--SH (XXXV)
[0590] wherein T.sup.1 is as hereinbefore defined, with compounds
of formula (XXXIV) wherein R.sup.6 is as hereinbefore defined and
X.sup.10 is a halogen atom, preferably a bromine atom. The reaction
is preferably carried out in the presence of a base such as an
alkali metal alkoxide, e.g. sodium methoxide.
[0591] As another example, compounds of formula (1) wherein R.sup.3
represents a --O--CF.sub.2R.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXXIII) wherein T.sup.1 is as hereinbefore
defined with compounds of the general formula (XXXVI):
R.sup.6CF.sub.2Br (XXXVI)
[0592] wherein R.sup.6 is as hereinbefore defined, preferably with
the aid of a base such as sodium hydride, preferably in a solvent
such as dimethylformamide.
[0593] As another example, compounds of formula (I) wherein R.sup.3
represents a --O--C(.dbd.O)R.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXXIII), wherein T.sup.1 is as hereinbefore
defined, with compounds of the general formula (XXI) wherein
R.sup.6 is as hereinbefore defined, and X.sup.8 represents a
halogen atom, for example a bromine or, preferably, a chlorine
atom, preferably in the presence of a base such as a tertiary
amine, e.g. triethylamine, preferably in a solvent such as
dichloromethane.
[0594] As another example, compounds of formula (I) wherein R.sup.3
represents a trans --N.dbd.N--R.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXXVII):
T.sup.1--N.sub.2.sup.+BF.sub.4.sup.- (XXXVII)
[0595] wherein T.sup.1 is as hereinbefore defined, with compounds
of the general formula (XXXVIII):
R.sup.6H (XXXVIII)
[0596] wherein R.sup.6 is as hereinbefore defined, preferably with
the aid of a base such as lithium diisopropylamide.
[0597] As another example, compounds of formula (I) wherein R.sup.3
represents a --NH--SO.sub.2R.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XX), wherein T.sup.1 is as hereinbefore
defined, with compounds of the general formula (XXXIX):
R.sup.6SO.sub.2X.sup.11 (XXXIX)
[0598] wherein R.sup.6 is as hereinbefore defined and X.sup.11
represents a halogen, preferably chlorine, atom, preferably with
the aid of a base such as a tertiary amine, e.g. triethylamine,
preferably in a solvent such as tetrahydrofuran.
[0599] As another example, compounds of formula (I) wherein R.sup.3
represents a --SO.sub.2--NR.sup.21R.sup.22 group where R.sup.21 and
R.sup.22 are as hereinbefore defined may be prepared by the
reaction of compounds of the general formula (XXXX):
T.sup.1SO.sub.2Cl (XXXX)
[0600] wherein T.sup.1 is as hereinbefore defined with compounds of
the general formula (XXXXI):
R.sup.21--NH--R.sup.22 (XXXXI)
[0601] wherein R.sup.21 and R.sup.22 are as hereinbefore defined,
preferably with the aid of a base such as a tertiary amine, e.g.
triethylamine, preferably in a solvent such as tetrahydrofuran.
[0602] As another example, compounds of formula (I) wherein R.sup.3
represents a --C(.dbd.O)--C(.dbd.O)--NHR.sup.6 group where R.sup.6
is as hereinbefore defined may be prepared by the reaction of
compounds of the general formula (XXXXII)
T.sup.1--COCOOH (XXXXII)
[0603] wherein T.sup.1 is as hereinbefore defined, with thionyl
chloride in an inert solvent such as dichloromethane, followed by
reaction with compounds of formula (D) wherein R.sup.6 is as
hereinbefore defined and R.sup.48 is hydrogen.
[0604] As another example, compounds of formula (I) wherein R.sup.3
represents a --NH--CO--OR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXXXIII)
T.sup.1--NCO (XXXXIII)
[0605] wherein T.sup.1 is as hereinbefore defined, with compounds
of formula (XXVIII) wherein R.sup.6 is as hereinbefore defined,
preferably with the aid of a base such as a tertiary amine, e.g.
triethylamine, preferably in a solvent such as dichloromethane.
[0606] As another example, compounds of formula (I) wherein R.sup.3
represents a --O--CO--NHR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XXXII) wherein T.sup.1 is as hereinbefore
defined, with compounds of formula (III) wherein R.sup.6 is as
hereinbefore defined and R.sup.48 is hydrogen, together with
phosgene or a source thereof, preferably,
bis(trichloromethyl)carbonate, preferably with the aid of a base
such as a tertiary amine, e.g. triethylamine, preferably in a
solvent such as dichloromethane.
[0607] As another example, compounds of formula (I) wherein R.sup.3
represents a --NH--CO--NHR.sup.6 group where R.sup.6 is as
hereinbefore defined may be prepared by the reaction of compounds
of the general formula (XX), wherein T.sup.1 is as hereinbefore
defined with compounds of the general formula (XXXXIV)
R.sup.6NCO (XXXXIV)
[0608] wherein R.sup.6 is as hereinbefore defined, preferably in
the presence of a base such as a tertiary amine, e.g.
triethylamine, preferably in a solvent such as dichloromethane.
[0609] According to a further feature of the present invention,
compounds of formula (I) wherein R.sup.3 represents a
--NH--CO--NHR.sup.6 group where R.sup.6 is as hereinbefore defined
may be prepared by the reaction of compounds of formula (XX)
wherein T.sup.1 is as hereinbefore defined with compounds of
formula (m) wherein R.sup.6 is as hereinbefore defined and R.sup.48
is hydrogen, together with phosgene or a source thereof. The
reaction is preferably carried out by reacting the compound of
formula (XX) with phosgene or, preferably, bis(trichloromethyl)
carbonate, and by then reacting the product of that reaction with
the anion derived from the compound of formula (III), for example
by reaction with a base such as sodium hydride. The reactions may
be preferably carried out in suitable solvents such as
dichloromethane and tetrahydrofuran.
[0610] According to a further feature of the present invention,
compounds of formula (Ia) wherein 74
[0611] A.sup.1, R.sup.1, R.sup.2, R.sup.3, Q.sup.1 and Z.sup.1 are
as hereinbefore defined, (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), may be prepared by reaction of compounds of formula
(XXXXV): 75
[0612] wherein A.sup.1, R.sup.1, R.sup.2, R.sup.3, Q.sup.1 and
Z.sup.1 are as hereinbefore defined, (with the proviso that when
A.sup.1 is a direct bond then R.sup.2 is alkyl, cycloalkyl, aryl,
or heteroaryl), with sodium hypochlorite in the presence of an
aqueous acid such as dilute hydrochloric acid, in an alcohol, such
as methanol, and at a temperature at about ambient temperature,
followed by treatment with an alkali metal carbonate, such as
sodium carbonate, at a temperature of about reflux temperature.
[0613] According to a further feature of the present invention,
compounds of formula (Ia), wherein 76
[0614] represents 77
[0615] A.sup.1, R.sup.1, R.sup.2, R.sup.3, Q.sup.1 and Z.sup.1 are
as hereinbefore defined, (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), may be prepared by reaction of compounds of formula
(XXXXVI): 78
[0616] wherein R.sup.1, R.sup.3, Q.sup.1 and Z.sup.1 are as
hereinbefore described, with compounds of formula (XXXXVII)
R.sup.2A.sup.1C(.dbd.O)X.sup.12 (XXXXVI)
[0617] wherein R.sup.2 and A.sup.1 are as hereinbefore defined,
(with the proviso that when A.sup.1 is a direct bond then R.sup.2
is alkyl, cycloalkyl, aryl, or heteroaryl), and X.sup.12 represents
a hydroxy group or a halogen atom, preferably a chlorine atom. When
X.sup.12 represents a hydroxy group the reaction is preferably
carried out in the hydrochloric acid at a temperature at about
125.degree. C. When X.sup.12 represents a halogen atom the reaction
is preferably carried out in an inert solvent, such as
dichloromethane, optionally in the presence of triethylamine and at
a temperature from about 0.degree. C. to about ambient temperature,
followed by reaction of the product with acetic acid at a
temperature at about reflux.
[0618] According to a further feature of the present invention,
compounds of formula (Ia), wherein R.sup.1, R.sup.3, Q.sup.1 and
Z.sup.1 are as hereinbefore defined, R.sup.2 represents a
C.sub.1-5alkoxy group optionally substituted by one or more
fluorine atoms, A.sup.1 represents a direct bond and 79
[0619] represents 80
[0620] may be prepared by reaction of compounds of formula (XXXXVI)
wherein R.sup.1, R.sup.3, Q.sup.1 and Z.sup.1 are as hereinbefore
described, with compounds of formula (XXXXVII)
(R.sup.49O).sub.4C (XXXXVIII)
[0621] wherein R.sup.49 is a C.sub.1-5alkyl group optionally
substituted by one or more fluorine atoms. The reaction may
conveniently be carried out in acetic acid at a temperature up to
about reflux temperature.
[0622] As another example, compounds of formula (Ia) wherein 81
[0623] R.sup.1, R.sup.3, Q.sup.1 and Z.sup.1 are as hereinbefore
described, R.sup.2 is alkylthio, arylthio or arylalkylthio and
A.sup.1 represents a direct bond, may be prepared by reaction of
compounds of formula (XXXXIX): 82
[0624] wherein 83
[0625] R.sup.1, R.sup.3, Q.sup.1 and Z.sup.1 are as hereinbefore
described, with the appropriate alkyl- or aryl- or arylalkylthiol.
The reaction may conveniently be carried out in an inert solvent
such as methanol or dimethylformamide, at a temperature from about
room temperature to about 80.degree. C., optionally in the presence
of an alkali metal carbonate, such as potassium carbonate.
[0626] Alternatively compounds of formula (Ia) wherein 84
[0627] R.sup.1, R.sup.3, Q.sup.1 and Z.sup.1 are as hereinbefore
described, R.sup.2 represents alkylthio or arylalkylthio and
A.sup.1 represents a direct bond, may be prepared by reaction of
compounds of formula (L): 85
[0628] wherein R.sup.1, R.sup.3, 86
[0629] Q.sup.1 and Z.sup.1 are as hereinbefore described, with the
appropriate alkyl- or arylalkylhalide. The reaction may
conveniently be carried out in an inert solvent such as methanol or
dimethylformamide, at a temperature from about room temperature to
about 80.degree. C., optionally in the presence of an alkali metal
carbonate, such as potassium carbonate.
[0630] As another example, compounds of formula (Ia) wherein 87
[0631] R.sup.1, R.sup.3, Q.sup.1 and Z.sup.1 are as hereinbefore
described, R.sup.2 represents NR.sup.4R.sup.5 where R.sup.4 and
R.sup.5 are as hereinbefore described and A.sup.1 represents a
direct bond, may be prepared by reaction of compounds of formula
(XXXXIX) wherein 88
[0632] R.sup.1, R.sup.3, Q.sup.1 and Z.sup.1 are as hereinbefore
described, with compounds of formula (LI)
HNR.sup.4R.sup.5 (LI)
[0633] wherein R.sup.4 and R.sup.5 are as hereinbefore described.
The reaction may conveniently be carried out in an inert solvent
for example an alcohol such as isopropanol, at a temperature from
about room temperature to about 80.degree. C., optionally in the
presence of an alkali metal carbonate, such as potassium
carbonate.
[0634] As another example, compounds of formula (Ia) wherein 89
[0635] R.sup.1, R.sup.3, Q.sup.1 and Z.sup.1 are as hereinbefore
described, R.sup.2 represents --C(.dbd.O)R.sup.5, in which R.sup.5
is aryl or heteroaryl, and A.sup.1 represents a direct bond, may be
prepared by reaction of compounds of formula (LII): 90
[0636] wherein R.sup.1, R.sup.3 91
[0637] Q.sup.1 and Z.sup.1 are as hereinbefore described, with
compounds of formula (LIII)
R.sup.5C(.dbd.O)X.sup.13 (LIII)
[0638] wherein R.sup.5 is aryl or heteroaryl and X.sup.3 is a
chlorine atom. There action may conveniently be carried out in an
inert solvent for example dimethylformamide, at a temperature up to
about 150.degree. C., under vacuo, optionally in the presence of
triethylamine.
[0639] As another example, compounds of formula (I) wherein R.sup.3
represents a 92
[0640] group may be prepared by reaction of compounds of formula
(I) wherein R.sup.3 represents a 93
[0641] in which R.sup.52 is a methyl or ethyl group, with
hydroxylamine hydrochloride in the presence of sodium methoxide, in
a solvent such as an alcohol, for example methanol, and at a
temperature at about room temperature.
[0642] As another example, compounds of formula (I) wherein T.sup.1
is as hereinbefore described and the moiety R.sup.3 represents a
94
[0643] group may be prepared by reaction of compounds of formula
(VIII) wherein R.sup.8 is methyl, with glyoxylic acid monohydrate
at about 100.degree. C. to 150.degree. C., followed by treatment
with hydrazine hydrate at reflux.
[0644] As another example, compounds of formula (I) wherein R.sup.3
represents a 95
[0645] group may be prepared by reaction of compounds of formula
(LIV)
T.sup.1--C(CN)[(CH.sub.2).sub.2CO.sub.2R.sup.52].sub.2 (LIV)
[0646] wherein T.sup.1 is as hereinbefore described and R.sup.52 is
a methyl or an ethyl group, with an alkali metal hydride, for
example sodium hydride, in an inert solvent, such as
1,2-dimethoxyethane, at a temperature at about reflux temperature,
followed by heating the product with a mixture of concentrated
hydrochloric acid and 20% sulphuric acid in ethanol at reflux
temperature.
[0647] As another example, compounds of formula (I) wherein R.sup.3
represents a 96
[0648] group may be prepared by reaction of compounds of formula
(I), wherein T.sup.1 is as hereinbefore described and the moiety
R.sup.3 represents a 97
[0649] group, with diethyl aluminium cyanide in an inert solvent,
such as toluene, and at a temperature at about room
temperature.
[0650] Compounds of formula (I), wherein R.sup.3 represents a
98
[0651] group may be prepared by reaction of compounds of formula
(XVIII), wherein T.sup.1 is as hereinbefore described and X.sup.7
is a bromine atom, with an alkyl lithium, such as n-butyl lithium
at -78.degree. C., in an inert solvent, such as tetrahydrofuran,
followed by reaction with 3-methoxycyclohex-2-enone (prepared
according to the method of A. J. Pearson et al., J.Org.Chem., 1984,
49, pages 3887-3891) at a temperature at about 0.degree. C.
[0652] As another example, compounds of formula (I) wherein R.sup.3
represents a 99
[0653] group may be prepared by hydrolysis of compounds of formula
(I) wherein R.sup.3 represents a 100
[0654] group, with an alkali metal hydroxide such as potassium
hydroxide in an aqueous alcohol such as aqueous methanol and at a
temperature from about room temperature to about reflux.
[0655] Compounds of formula (I), wherein R.sup.3 represents a
101
[0656] group, may be prepared by reaction of compounds of formula
(I), wherein R.sup.3 represents a 102
[0657] group, with triflic anhydride in the presence of an
appropriate tertiary amine base, or with lithium diisopropylamide
at -78.degree. C., in an inert solvent such as tetrahydrofuran,
followed by treatment with N-phenyl trifluorosulphonimide. The
resulting enol triflate may then be reacted with carbon monoxide in
an alcohol such as methanol, optionally mixed with
dimethylformamide, in the presence of an amine, such as
triethylamine, and an appropriate palladium catalyst, such as
tetrakis(triphenylphosphine)palladium, at a temperature at about
room temperature.
[0658] As another example, compounds of formula (I) wherein R.sup.3
represents a 103
[0659] group, in which R.sup.39 is hydrogen, alkyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, may be prepared by
reaction of compounds of formula (LV)
T.sup.1--CH.dbd.CH--CO.sub.2H (LV)
[0660] wherein T.sup.1 is as hereinbefore described, with a
hydrazine of formula (LVI)
R.sup.39NH--NH.sub.2 (LVI)
[0661] wherein R.sup.39 is hydrogen, alkyl aryl, arylalkyl,
heteroaryl, or heteroarylalkyl. The reaction is preferably carried
out in an inert solvent, such as toluene, at a temperature at about
100.degree. C.
[0662] As another example, compounds of formula (I) wherein R.sup.3
represents a 104
[0663] group may be prepared by reduction of compounds of the
general formula (LVII)
T.sup.1--CH(CH.sub.2NO.sub.2)CH.sub.2CO.sub.2R.sup.49 (LVII)
[0664] wherein T.sup.1 and R.sup.49 are as hereinbefore described,
followed by hydrolysis with sodium hydroxide. The reduction may be
carried out using hydrogen in the presence of Raney Nickel
preferably in a solvent such as methanol or ethanol and at a
temperature at about room temperature.
[0665] As another example, compounds of formula (I) wherein R.sup.3
represents a group 105
[0666] may be prepared by oxidation of compounds of formula
(LVIII)
T.sup.1--CH(NHCO.sub.2Me)CH.sub.2CH.sub.2CH.sub.2OH (LVIII)
[0667] wherein T.sup.1 is as hereinbefore described, with Jones
reagent in acetone at room temperature.
[0668] According to a further feature of the present invention, in
a process (E), compounds of the present invention of formula (Ia)
wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1, Q.sup.1 and Z.sup.1 are
as hereinbefore defined, and 106
[0669] represents 107
[0670] may be prepared by deprotection of compounds of formula
(LIX): 108
[0671] wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1, Q.sup.1 and
Z.sup.1 are as hereinbefore defined and 109
[0672] is a suitable protecting group, for example a
2-trimethylsilanyl-ethoxymethyl group. When 110
[0673] is a 2-trimethylsilanyl-ethoxymethyl group the deprotection
reaction may conveniently be carried out by treatment with
hydrochloric acid, in an alcohol, such as ethanol, and at a
temperature at about reflux temperature. This process is
particularly convenient for compounds of formula (Ia) wherein
R.sup.3 is a group --O--CH.sub.2--R.sup.6 in which R.sup.6 is as
hereinbefore defined.
[0674] According to a further feature of the present invention, in
a process (F) compounds of the invention may be prepared by
interconversion of other compounds of the invention.
[0675] For example compounds of the invention containing an imino
group may be alkylated with an alkyl halide, arylalkyl halide or
heteroarylalkyl halide. Thus compounds of formula (Ia) wherein
111
[0676] represents 112
[0677] and R.sup.5 represents C.sub.1-4straight- or branched-chain
alkyl, an arylC.sub.1-4alkyl or a heteroarylC.sub.1-4alkyl group
may be prepared by reaction of compounds of formula (Ia) wherein
113
[0678] represents 114
[0679] with a C.sub.1-4straight- or branched-chain alkyl halide, an
arylC.sub.1-4alkyl halide or a heteroarylC.sub.1-4alkyl halide. The
alkylation may for example be carried out in the presence of a
base, such as an alkali metal hydride, e.g. sodium hydride, in
dimethylformamide, or dimethyl sulphoxide, at a temperature from
about 0.degree. C. to about 100.degree. C.
[0680] As another example of the interconversion process, compounds
of the invention containing an imino group may be acylated with an
acyl halide, aroyl halide or heteroaroyl halide. The acylation may
for example be carried out in the presence of a suitable base, such
as triethylamine or pyridine, optionally in dimethylformamide, at a
temperature from about 0.degree. C. to about 100.degree. C.
[0681] As another example of the interconversion process, compounds
of the invention containing a heterocyclic group wherein the hetero
atom is a nitrogen atom may be oxidised to their corresponding
N-oxides. This interconversion is especially convenient for the
preparation of compounds of the invention wherein Z.sup.1
represents an oxygen atom and wherein neither R.sup.2 or R.sup.3
contain an oxidisable groups such as a thioether. The oxidation may
conveniently be carried out by means of reaction with a mixture of
hydrogen peroxide and an organic acid, e.g. acetic acid, preferably
at or above room temperature, for example at a temperature of about
60-90.degree. C. Alternatively, the oxidation may be carried out by
reaction with a peracid, for example peracetic acid or
m-chloroperoxybenzoic acid, in an inert solvent such as chloroform
or dichloromethane, at a temperature from about room temperature to
reflux, preferably at elevated temperature. The oxidation may
alternatively be carried out by reaction with hydrogen peroxide in
the presence of sodium tungstate at temperatures between room
temperature and about 60.degree. C.
[0682] As another example of the interconversion process, an
N-oxide group within a compound of formula (I) may be reduced to a
nitrogen atom. More particularly, one or more of the N-oxide groups
in a compound of formula (I) wherein Q.sup.1 represents a nitrogen
atom in its oxidised form and R.sup.2 and/or R.sup.3 represents a
heteroaryl group containing one or more nitrogen ring atoms in its
oxidised form, may be reduced to a nitrogen atom. The reduction of
an N-oxide group may be carried out by reaction with diphosphorus
tetraiodide in an inert solvent, such as dichloromethane,
preferably at or near room temperature, or by reaction with a
chlorotrialkylsilane, preferably chlorotrimethylsilane, in the
presence of zinc and an alkali metal iodide, e.g. potassium iodide,
in an inert solvent, e.g. acetonitrile, at a temperature between
about 0.degree. C. and about room temperature, preferably below
room temperature.
[0683] According to a further example of the interconversion
process, compounds of the invention containing hydroxy moieties may
be converted to esters by the application or adaptation of known
methods of esterification, for example, by reaction with an acid
chloride (prepared by treatment of the appropriate acid with
thionyl chloride or oxalyl chloride), preferably in the presence of
a base, for example a tertiary amine, e.g. triethylamine.
Alternatively, compounds of the invention containing hydroxy
moieties may be reacted with the appropriate acid in the presence
of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate,
and triphenylphosphine, preferably in a dry ethereal solvent, e.g.
diethyl ether or tetrahydrofuran, preferably at or near room
temperature.
[0684] As another example of the interconversion process, compounds
of the invention containing hydroxy moieties may be prepared by
hydrolysis of corresponding esters of the invention. The hydrolysis
may conveniently be carried out by alkaline hydrolysis using a
base, such as an alkali metal hydroxide or carbonate, in the
presence of an aqueous/organic solvent mixture, using organic
solvents such as dioxan, tetrahydrofuran or methanol, at a
temperature from about ambient to about reflux. The hydrolysis of
the esters may also be carried out by acid hydrolysis using an
inorganic acid, such as hydrochloric acid, in the presence of an
aqueous/inert organic solvent mixture, using organic solvents such
as dioxan or tetrahydrofuran, at a temperature from about
50.degree. C. to about 80.degree. C.
[0685] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.3 represents a group containing
R.sup.6 which is substituted by a formyl group may be prepared by
oxidising the corresponding compounds of formula (I) wherein
R.sup.3 represents a group containing R.sup.6 which is substituted
by a hydroxymethyl group for example with oxalyl chloride and
dimethyl sulphoxide, in a solvent such as dichloromethane, and
preferably at a temperature lower than about -65.degree. C., or,
preferably, by reaction with a complex of sulphur trioxide with an
amine such as pyridine, preferably in the presence of an amine such
as triethylamine, preferably at about room temperature.
[0686] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.3 represents a group containing
R.sup.6 which is substituted by an amino group may be prepared by
reducing the corresponding compounds of formula (I) wherein R.sup.3
represents a group containing R.sup.6 which is substituted by a
nitro group, preferably with iron in acidic conditions, such as in
acetic acid, preferably at or above room temperature, more
especially at the reflux temperature. Alternatively the reduction
may be carried out by reaction with hydrazine hydrate in the
presence of ferric chloride and activated carbon, conveniently in a
solvent such as methanol, at temperatures from about 25.degree. C.
to about 80.degree. C.
[0687] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.3 represents a group containing
R.sup.6 which is substituted by an acylamino or aroylamino group
may be prepared from compounds of formula (I) wherein R.sup.3
represents a group containing R.sup.6 which is substituted by an
amino group, preferably by means of reaction with the appropriate
acid halide or acid anhydride in the presence of a tertiary base,
such as triethylamine, optionally in an inert solvent, and
preferably at a temperature from about 0.degree. C. to reflux.
[0688] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.3 represents a group containing
R.sup.6 which is substituted by a carboxamido group may be prepared
from compounds of formula (I) wherein R.sup.3 represents a group II
containing R.sup.6 which is substituted by a cyano group, by means
of reaction with hydrogen peroxide and potassium carbonate in
dimethyl sulphoxide.
[0689] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.3 represents a group containing
R.sup.6 which is substituted by a cyano group may be prepared from
compounds of formula (I) wherein R.sup.3 represents a group
containing R.sup.6 which is substituted by a bromine atom, by means
of reaction with zinc cyanide in the presence of
tetrakis(triphenylphosphine) palladium(O) in an inert solvent, such
as dimethylformamide, at a temperature at about 100.degree. C.
[0690] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.1 is substituted by fluorine on a
carbon atom thereof alpha to the attachment of R.sup.1 to Z.sup.1
as sulphur, may be prepared by reacting xenon difluoride with
corresponding compound of formula (I) wherein said alpha-carbon
atoms carry hydrogen atoms instead of said fluorine atoms. The
reaction is conveniently carried out in a solvent, such as
dichloromethane, in the presence of a molecular sieve. and in an
inert atmosphere, at a low temperature, such as at about 0.degree.
C.
[0691] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.1 is a difluoromethyl group and
Z.sup.1 is an oxygen or sulphur atom, may be prepared by reacting a
compound of formula (I) wherein R.sup.1 is a hydrogen atom and
Z.sup.1 is an oxygen or sulphur atom, with HCBrF.sub.2 in the
presence of a strong base in an inert solvent.
[0692] As another example, compounds of formula (I) wherein R.sup.3
represents a group containing R.sup.6 which is a heteroaryl group
containing one or more nitrogen ring atoms but carrying no halogen
substituents may be prepared by the reduction of the corresponding
compounds of formula (I) wherein R.sup.3 represents a group
containing R.sup.6 which does carry one or more halo, such as
chloro, substituents, for example by means of ammonium formate in
the presence of a palladium catalyst.
[0693] As another example, compounds of formula (I) wherein the
moiety R.sup.3 contains a cis alkenyl group may be prepared by the
action of ultraviolet radiation upon the trans-isomer.
[0694] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.3 contains a cis --N.dbd.N-- linkage
may be prepared by the action of ultraviolet radiation upon their
trans-isomers.
[0695] As another example of the interconversion process, compounds
of formula (I) containing sulphoxide linkages may be prepared by
the oxidation of corresponding compounds containing --S-- linkages.
For example, the oxidation may conveniently be carried out by means
of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid,
preferably in an inert solvent, e.g. dichloromethane, preferably at
or near room temperature, or alternatively by means of potassium
hydrogen peroxomonosulphate in a medium such as aqueous methanol,
buffered to about pH5, at temperatures between about 0.degree. C.
and room temperature. This latter method is preferred for compounds
containing an acid-labile group.
[0696] As another example of the interconversion process, compounds
of formula (I) containing sulphone linkages may be prepared by the
oxidation of corresponding compounds containing --S-- or sulphoxide
linkages. For example, the oxidation may conveniently be carried
out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic
acid, preferably in an inert solvent, e.g. dichloromethane,
preferably at or near room temperature.
[0697] As another example of the interconversion process, compounds
of formula (I) wherein R.sup.3 represents a group containing a
--CSCH.sub.2-- linkage may be prepared from compounds of formula
(I) wherein R.sup.3 represents a group containing a --COCH.sub.2--
linkage by reaction with phosphorus pentasulphide or
2,4-bis(4-methoxyphenyl)-1,3-di-
thia-2,4-diphosphetane-2,4-disulphide, preferably in a solvent such
as pyridine or toluene, and preferably at a temperature from
0.degree. C. to the reflux temperature.
[0698] As another example of the interconversion process, compounds
of formula (I) containing a hydroxymethyl group may be prepared by
the reduction of the corresponding compounds of formula (I)
containing an aryloxycarbonyl or, particularly, alkoxycarbonyl
group, preferably by means of reaction with an alkali metal
borohydride, preferably in an inert solvent, e.g. tetrahydrofuran,
and preferably at or near room temperature.
[0699] As another example of the interconversion process, compounds
of formula (Ib) in which R.sup.2 is hydrogen and A.sup.1 is a
direct bond may be prepared by heating compounds of formula (Ib) in
which the group R.sup.2 is a butyloxycarbonyl group and A.sup.1 is
a direct bond.
[0700] According to a further feature of the invention, acid
addition salts of the compounds of this invention may be prepared
by reaction of the free base with the appropriate acid, by the
application or adaptation of known methods. For example, the acid
addition salts of the compounds of this invention may be prepared
either by dissolving the free base in water or aqueous alcohol
solution or other suitable solvents containing the appropriate acid
and isolating the salt by evaporating the solution, or by reacting
the free base and acid in an organic solvent, in which case the
salt separates directly or can be obtained by concentration of the
solution.
[0701] The acid addition salts of the compounds of this invention
can be regenerated from the salts by the application or adaptation
of known methods. For example, parent compounds of the invention
can be regenerated from their acid addition salts by treatment with
an alkali, e.g. aqueous sodium bicarbonate solution or aqueous
ammonia solution.
[0702] According to a further feature of the invention, base
addition salts of the compounds of this invention may be prepared
by reaction of the free acid with the appropriate base, by the
application or adaptation of known methods. For example, the base
addition salts of the compounds of this invention may be prepared
either by dissolving the free acid in water or aqueous alcohol
solution or other suitable solvents containing the appropriate base
and isolating the salt by evaporating the solution, or by reacting
the free acid and base in an organic solvent, in which case the
salt separates directly or can be obtained by concentration of the
solution.
[0703] Compounds of this invention can be regenerated from their
base addition salts by the application or adaptation of known
methods. For example, parent compounds of the invention can be
regenerated from their base addition salts by treatment with an
acid, e.g. hydrochloric acid.
[0704] Compounds of the present invention may be conveniently
prepared, or formed during the process of the invention, as
solvates (e.g. hydrates). Hydrates of compounds of the present
invention may be conveniently prepared by recrystallisation from
water.
[0705] The starting materials and intermediates may be prepared by
the application or adaptation of known methods, for example methods
as described in the Reference Examples or their obvious chemical
equivalents.
[0706] Intermediates of formula (II, T.sup.1--C(.dbd.O)X.sup.6)
wherein T.sup.1 is as hereinbefore defined and X.sup.6 represents
an O-benzotriazol-1-yl group may be prepared by reaction of
compounds of formula (1)
T.sup.1--CO.sub.2H (1)
[0707] wherein T.sup.1 is as hereinbefore defined, with
O-benzotriazol-1-yl-N,N,N',N',-bis(tetramethylene)uronium
tetrafluoroborate in an inert solvent, for example dichloromethane,
at a temperature at about ambient temperature.
[0708] Intermediates of formula (II, T.sup.1--C(.dbd.O)X.sup.6)
wherein T.sup.1 is as hereinbefore defined and X.sup.6 represents
an azido group may be prepared from compounds of formula (1)
wherein T.sup.1 is as hereinbefore defined by the application or
adaptation of known methods for the preparation of acid azides from
carboxylic acids. For example, the reaction may be carried out by
means of diphenylphosphoryl azide in the presence of triethylamine
in dimethylformamide.
[0709] Intermediates of formula (II, T.sup.1--C(.dbd.O)X.sup.6)
wherein T.sup.1 Is as hereinbefore defined and X.sup.6 represents a
halogen atom may be prepared from compounds ox the general formula
(I) wherein T.sup.1 is as hereinbefore defined, by the application
or adaptation of known methods for the preparation of acid halides
from carboxylic acids. For example, when X.sup.6 represents a
chlorine atom, the reaction may be carried out by means of thionyl
chloride or, preferably, oxalyl chloride, optionally in the
presence of a small amount of dimethylformamide.
[0710] Compounds of formula (1, T.sup.1--CO.sub.2H), wherein
T.sup.1 is as hereinbefore defined may be prepared by hydrolysis of
compounds of formula (IV, T.sup.1--CO.sub.2R.sup.49) wherein
T.sup.1 and R.sup.49 are as hereinbefore defined. The hydrolysis
may for example be carried out by reaction with a base, such as an
alkali metal hydroxide, e.g. sodium or lithium hydroxide, or an
alkali metal carbonate, e.g. potassium carbonate, in the presence
of water, in an alcohol such as methanol and at a temperature from
about ambient to about reflux, followed by reaction with an aqueous
acid such as dilute hydrochloric acid.
[0711] Intermediates of the general formula (III,
R.sup.6NHR.sup.48) wherein R.sup.6 is as hereinbefore described,
including N-oxides of heteroaryl groups, and R.sup.48 represents an
alkanoyl group, e.g. acetyl group may be prepared for example, by
the application or adaptation of known methods for the acylation or
aromatic amines.
[0712] Intermediates of formula (IV) represented by the formula
(2): 115
[0713] wherein 116
[0714] represents 117
[0715] R.sup.53 represents CO.sub.2R.sup.49 (in which R.sup.49 is
as hereinbefore defined), and R.sup.1, A.sup.1, Q.sup.1 and Z.sup.1
are as hereinbefore defined (with the proviso that when A.sup.1 is
a direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), may be prepared by reaction of compounds of formula
(3): 118
[0716] wherein R.sup.1, R.sup.2, A.sup.1, Q.sup.1 and Z.sup.1 are
as hereinbefore described (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), and R.sup.53 represents --CO.sub.2R.sup.49 (in which
R.sup.49 is as hereinbefore defined), with sodium hypochlorite in
the presence of an aqueous acid such as dilute hydrochloric acid,
in an alcohol, such as methanol, and at a temperature at about
ambient temperature, followed by treatment of the resultant
chloroimine with an alkali metal carbonate, such as sodium
carbonate, at a temperature of about reflux temperature.
[0717] Intermediates of formula (VIII) represented by the formula
(2), wherein 119
[0718] represents 120
[0719] R.sup.53 represents --C(.dbd.O)--R.sup.8 (in which R.sup.8
is optionally substituted alkyl), and R.sup.1, R.sup.2 and A.sup.1
are as hereinbefore defined, Q.sup.1 is CH and Z.sup.1 is an oxygen
atom (with the proviso that when A.sup.1 is a direct bond then
R.sup.2 is alkyl, cycloalkyl, aryl, or heteroaryl), may be
similarly prepared from compounds of formula (3) wherein R.sup.1,
R.sup.2 and A.sup.1 are as hereinbefore defined, R.sup.53 is a
group --C(.dbd.O)--R.sup.8 (in which R.sup.8 is optionally
substituted alkyl), Q.sup.1 is a CH linkage and Z.sup.1 is an
oxygen atom (with the proviso that when A.sup.1 is a direct bond
then R.sup.2 is alkyl, cycloalkyl, aryl, or heteroaryl).
[0720] Intermediates of formula (X) represented by the formula (2),
wherein 121
[0721] represents 122
[0722] R.sup.53 represents --C(.dbd.O)--R.sup.10 (in which R.sup.10
is a group --(CH.sub.2).sub.pR.sup.6 where R.sup.6 and n are as
hereinbefore defined); R.sup.1, R.sup.2 and A.sup.1 are as
hereinbefore defined; Q.sup.1 is CH and Z.sup.1 is an oxygen atom
(with the proviso that when A.sup.1 is a direct bond then R.sup.2
is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarly
prepared from compounds of formula (3) wherein R.sup.1, R.sup.2 and
A.sup.1 are as hereinbefore defined, R.sup.53 is a group
--C(.dbd.O)--R.sup.10 (in which R.sup.10 is a group
--(CH.sub.2).sub.pR.sup.6 in which R.sup.6 and n are as
hereinbefore defined), Q.sup.1 is a CH linkage and Z.sup.1 is an
oxygen atom (with the proviso that when A.sup.1 is a direct bond
then R.sup.2 is alkyl, cycloalkyl, aryl, or heteroaryl).
[0723] Intermediates of formula (XVIII) represented by the formula
(2), wherein 123
[0724] represents 124
[0725] R.sup.53 represents a halogen atom, Q.sup.1 is a CH linkage,
Z.sup.1 is an oxygen atom and R.sup.1, R.sup.2 and A.sup.1 are as
hereinbefore defined, (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl). may be similarly prepared from compounds of formula
(3) wherein 125
[0726] represents 126
[0727] R.sup.53 is a halogen atom, Q.sup.1 is a CH linkage, Z.sup.1
is an oxygen atom and R.sup.1, R.sup.2 and A.sup.1 are as
hereinbefore defined (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl).
[0728] Compounds of formula (18) represented by the formula (2),
wherein R.sup.53 is a nitro group and 127
[0729] R.sup.1, R.sup.2, A.sup.1, Q.sup.1 and Z.sup.1 are as
hereinbefore defined (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), may be similarly prepared from compounds of formula
(3) wherein R.sup.53 is a nitro group and R.sup.1, R.sup.2,
A.sup.1, Q.sup.1 and Z.sup.1 are as hereinbefore defined (with the
proviso that when A.sup.1 is a direct bond then R.sup.2 is alkyl,
cycloalkyl, aryl, or heteroaryl).
[0730] Compounds of formula (19), represented by the formula (2),
wherein R.sup.53 is a methyl group and 128
[0731] R.sup.1, R.sup.2, A.sup.1, Q.sup.1 and Z.sup.1 are as
hereinbefore defined (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), may be similarly prepared from compounds of formula
(3) wherein R.sup.53 is a methyl group and R.sup.1, R.sup.2,
A.sup.1, Q.sup.1 and Z.sup.1 are as hereinbefore defined (with the
proviso that when A.sup.1 is a direct bond then R.sup.2 is alkyl,
cycloalkyl, aryl, or heteroaryl).
[0732] Compounds of formula (3), wherein R.sup.1, R.sup.2,
R.sup.53, A.sup.1, Q.sup.1 and Z.sup.1 are as hereinbefore defined
(with the proviso that when A.sup.1 is a direct bond then R.sup.2
is alkyl, cycloalkyl, aryl, or heteroaryl), may be prepared by
reaction of compounds of formula (4): 129
[0733] wherein R.sup.1, R.sup.53, Q.sup.1 and Z.sup.1 are as
hereinbefore defined, with compounds of formula
R.sup.2A.sup.1C.ident.N, wherein R.sup.2 and A.sup.1 are as
hereinbefore defined (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), in the presence of an acid catalyst, such as
4-toluenesulphonic acid, at a temperature up to about 180.degree.
C.
[0734] Intermediates of formula (XXXXV) wherein R.sup.1, R.sup.2,
R.sup.3, A.sup.l, Q.sup.1 and Z.sup.1 are as hereinbefore defined
(with the proviso that when A.sup.1 is a direct bond then R.sup.2
is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarly
prepared by reaction of compounds of formula (4) wherein R.sup.1,
Q.sup.1 and Z.sup.1 are as hereinbefore defined and R.sup.53 is a
group --R.sup.3, with compounds of formula R.sup.2A.sup.1C.ident.N,
wherein R.sup.2 and A.sup.1 are as hereinbefore defined (with the
proviso that when A.sup.1 is a direct bond then R.sup.2 is alkyl,
cycloalkyl, aryl, or heteroaryl), in the presence of an acid
catalyst, such as 4-toluenesulphonic acid, at a temperature up to
about 180.degree. C.
[0735] Compounds of formula (4) wherein R.sup.1 is as hereinbefore
defined, R.sup.53 represents a group --CO.sub.2R.sup.49 in which
R.sup.49 is as hereinbefore defined, Z.sup.1 represents an oxygen
atom and Q.sup.1 represents a nitrogen atom, may be prepared by
reaction of compounds of formula (5): 130
[0736] wherein R.sup.1 and R.sup.49 are as hereinbefore defined,
with ammonium hydroxide in the presence of sulphur dioxide
according to the procedure of H.King, J.Chem.Soc, 1946, page
523.
[0737] Compounds of formula (4) wherein R.sup.1 and R.sup.53 are as
hereinbefore defined, Z.sup.1 represents an oxygen atom or a direct
bond and Q.sup.1 represents a CH or a CF linkage, may be prepared
by reduction of compounds of formula (6): 131
[0738] wherein R.sup.1 and R.sup.53 are as hereinbefore defined,
Z.sup.1 represents an oxygen atom or a direct bond and Q.sup.1
represents a CH or a CF linkage. The reduction may conveniently be
carried out using hydrogen in the presence of a suitable metal
catalyst, e.g. platinum or palladium optionally supported on an
inert carrier such as carbon, preferably in a solvent such as
methanol or ethanol. Alternatively the reduction may be carried out
ammonium chloride and iron, in an aqueous/organic solvent mixture,
for example aqueous methanol, at a temperature at about reflux.
[0739] Compounds of formula (6), wherein R.sup.1 and R.sup.53 are
as hereinbefore defined, Z.sup.1 represents an oxygen atom or a
direct bond and Q.sup.1 represents a CH or a CF linkage, may be
prepared by nitration of compounds of formula (7): 132
[0740] wherein R.sup.1 and R.sup.53 are as hereinbefore defined,
Z.sup.1 represents an oxygen atom or a direct bond and Q.sup.1
represents a CH or a CF linkage, with fuming nitric acid at a
temperature from about ambient temperature to about 60.degree. C.,
and separation of the required nitro-isomer (6).
[0741] Compounds of formula (6), wherein R.sup.1 is C.sub.1-4alkyl,
R.sup.53 is a bromine atom, Q.sup.1 represents a CH linkage and
Z.sup.1 represents an oxygen atom, may be prepared by bromination
of the appropriate 2-(C.sub.1-4alkoxy)nitrobenzene according to the
procedure of S. Kajigaeshi et.al. J. C. S. Perkin Trans.I, 1990,
page 897.
[0742] Compounds of formula (6), wherein R.sup.1 is C.sub.1-4alkyl,
R.sup.53 is an iodine atom, Q.sup.1 represents a CH linkage and
Z.sup.1 represents an oxygen atom, may be prepared by thallation of
the appropriate 2-(C.sub.1-4alkoxy)-nitrobenzene with thallium
trifluoroacetate in trifluoroacetic acid followed by iodination
with aqueous potassium iodide according to the procedure of A.
Mckillop et.al. Tetrahedron. Letters, 1969, page 2427.
[0743] Compounds of formula (4), wherein R.sup.1 is as hereinbefore
defined and R.sup.53 is a group --SO.sub.2NR.sup.21R.sup.22 in
which R.sup.21 and R.sup.22 are as hereinbefore described, Q.sup.1
is a CH linkage and Z.sup.1 is an oxygen atom, may be prepared from
reaction of 3-acetamido-4-methoxybenzene sulphonyl chloride
(prepared according to the procedure of B. M.Culbertson,
J.Chem.Soc., 1968, page 992) with amines of formula
R.sup.21R.sup.22NH wherein R.sup.21 and R.sup.22 are as
hereinbefore described and subsequent treatment with sodium
hydroxide.
[0744] Compounds of formula (7), wherein R.sup.1 is as hereinbefore
defined, R.sup.53 represents --CO.sub.2R.sup.49 (in which R.sup.49
is as hereinbefore defined), Z.sup.1 represents an oxygen atom and
Q.sup.1 represents a CF linkage may be prepared by reaction of
compounds of formula (8): 133
[0745] wherein R.sup.1 is as hereinbefore defined, with the
appropriate C.sub.1-5alkyl alcohol, in the presence of hydrogen
chloride at a temperature up to about reflux.
[0746] Compounds of formula (8), wherein R.sup.1 is as hereinbefore
defined, may be prepared by reaction of
4-hydroxy-2-fluorobenzonitrile with compounds of the formula
(9)
R.sup.1X.sup.12 (9)
[0747] wherein R.sup.1 is as hereinbefore described and X.sup.12 is
a bromine or chlorine atom, or a triflate group. The reaction may
be carried out in the presence of an alkali metal carbonate, such
as potassium carbonate, in an inert solvent such as
dimethylformamide, and at a temperature from about room temperature
to about 80.degree. C.
[0748] Intermediates of formula (2), wherein 134
[0749] represents 135
[0750] R.sup.53 represents --CO.sub.2R.sup.49 (in which R.sup.49 is
as hereinbefore defined), A.sup.1 is a direct bond, R.sup.2 is an
alkoxy group, and R.sup.1, Q.sup.1 and Z.sup.1 are as hereinbefore
defined, may be prepared by reaction of compounds of formula (10):
136
[0751] wherein R.sup.1, R.sup.49, Q.sup.1 and Z.sup.1 are as
hereinbefore described, with compounds of formula (XXXXVII),
wherein R.sup.49 is as hereinbefore defined. The reaction is
carried out in acetic acid at a temperature up to about reflux
temperature.
[0752] Intermediates of formula (2), wherein 137
[0753] represents 138
[0754] R.sup.53 represents --CO.sub.2R.sup.49 (in which R.sup.49 is
as hereinbefore defined), and R.sup.1, A.sup.1, Q.sup.1 and Z.sup.1
are as hereinbefore defined (with the proviso that when A.sup.1 is
a direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), may be prepared by reaction of compounds of formula
(10), wherein R.sup.1, R.sup.49, Q.sup.1 and Z.sup.1 are as
hereinbefore described, with compounds of formula (XXXXVII,
R.sup.2A.sup.1C(.dbd.O)X.sup.10), wherein R.sup.2 and A.sup.1 are
as hereinbefore defined (with the proviso that when A.sup.1 is a
direct bond then R.sup.2 is alkyl, cycloalkyl, aryl, or
heteroaryl), and X.sup.10 represents a hydroxy group or a halogen
atom, preferably a chlorine atom. When X.sup.10 represents a
hydroxy group the reaction is preferably carried out in the
hydrochloric acid at a temperature at about 125.degree. C. When
X.sup.10 represents a chlorine atom the reaction is preferably
carried out in an inert solvent, such as dichloromethane,
optionally in the presence of triethylamine and at a temperature
from about 0.degree. C. to about ambient temperature, followed by
reaction of the product with acetic acid at a temperature at about
reflux.
[0755] Compounds of formula (10), wherein R.sup.1, R.sup.49 and
Z.sup.1 are as hereinbefore defined and Q.sup.1 represents a CH
linkage, may be prepared by reduction of compounds of formula (11):
139
[0756] wherein R.sup.1, R.sup.49 and Z.sup.1 are as hereinbefore
described. The reduction may be carried out using hydrogen in the
presence of a suitable metal catalyst, e.g. platinum or palladium
optionally supported on an inert carrier such as carbon, preferably
in a solvent such as methanol or ethanol.
[0757] Compounds of formula (11) wherein R.sup.1, R.sup.49 and
Z.sup.1 are as hereinbefore described may be prepared by conversion
of the carboxy group in compounds of formula (12): 140
[0758] wherein R.sup.1, R.sup.49 and Z.sup.1 are as hereinbefore
described, into an amino group. The process involves initial
reaction with thionyl chloride, in an inert solvent such as
toluene, in the presence of dimethylformamide and at a temperature
at about reflux, to form the corresponding acid chloride. The acid
chloride is then reacted with a sodium azide in aqueous acetone at
a temperature from about 0.degree. C. to about ambient temperature
to form the corresponding acid azide, which is heated in an aqueous
alcohol, such as t-butanol, at a temperature at about reflux.
[0759] Compounds of formula (12) wherein R.sup.1, R.sup.49 and
Z.sup.1 are as hereinbefore described may be prepared by
esterification of the corresponding phthalic acid of formula (13):
141
[0760] wherein R.sup.1 and Z.sup.1 are as hereinbefore described
with the appropriate C.sub.1-5alkyl alcohol.
[0761] Compounds of formula (13) wherein R.sup.1 and Z.sup.1 are as
hereinbefore described may be prepared by nitration of the
corresponding phthalic acid of formula (14): 142
[0762] wherein R.sup.1 and Z.sup.1 are as hereinbefore described,
with fuming nitric acid at a temperature from about ambient
temperature to about 60.degree. C.
[0763] Intermediates of formula (2), wherein 143
[0764] represents 144
[0765] (in which R.sup.5 represents a C.sub.1-4straight- or
branched-chain alkyl, an arylC.sub.1-4alkyl or a
heteroarylC.sub.1-4alkyl group), R.sup.53 represents
--CO.sub.2R.sup.49 (in which R.sup.49 is as hereinbefore defined),
and R.sup.1, R.sup.2, A.sup.1, Q.sup.1 and Z.sup.1 are as
hereinbefore defined, may be prepared by reaction of compounds of
formula (2), wherein 145
[0766] represents 146
[0767] , R.sup.53 represents --CO.sub.2R.sup.49 (in which R.sup.49
is as hereinbefore defined), and R.sup.1, R.sup.2, A.sup.1, Q.sup.1
and Z.sup.1 are as hereinbefore defined, with a C.sub.1-4straight-
or branched-chain alkyl halide or a arylC.sub.1-4alkyl halide or a
heteroarylC.sub.1-4alkyl halide respectively. The alkylation may
for example be carried out in the presence of a base, such as an
alkali metal hydride, e.g. sodium hydride, in dimethylformamide at
a temperature from about 0.degree. C. to about ambient
temperature.
[0768] Intermediates of formula (IV) or (XXXI) represented by
formula (15): 147
[0769] wherein R.sup.1, R.sup.2, A.sup.1, and Z.sup.1 are as
hereinbefore defined, R.sup.53 represents --CO.sub.2R.sup.49 (in
which R.sup.49 is as hereinbefore defined) or OH, and Q is CH or N,
may be prepared for example by the application or adaptation of
known methods for the substitution of the imino (NH) group in
indoles or indazines of general formula (16): 148
[0770] wherein R.sup.1 and Z.sup.1 are as defined previously,
R.sup.53 represents --CO.sub.2R.sup.49 (in which R.sup.49 is as
hereinbefore defined), and Q is CH or N.
[0771] Intermediates of formula (16) wherein R.sup.1 and Z.sup.1
are as defined previously, R.sup.53 represents CO.sub.2R.sup.49 (in
which R.sup.49 is as hereinbefore defined) and Q is N may be
prepared from compounds of general formula (17), wherein R.sup.1
and Z.sup.1 are as hereinbefore defined, as shown in Scheme (I):
149
[0772] Reaction conditions:
[0773] (i) treatment with boron tribromide in an inert solvent,
such as dichloromethane, at a temperature from about 0.degree. C.
to about reflux temperature.
[0774] (ii) treatment with N-phenyltrifluoromethane sulphonimide in
the presence of a suitable base such as sodium hydride in an inert
solvent, such as tetrahydrofuran, at a temperature at about
50.degree. C.
[0775] (iii) treatment with carbon monoxide in the presence of
palladium acetate, diphenylphosphine ferrocene, triethylamine and
methanol.
[0776] (iv) treatment with a suitable base, e.g. an alkali metal
carbonate, such as potassium carbonate, in a mixture of an alcohol,
such as methanol, and water at a temperature up to about reflux
temperature.
[0777] (v) treatment with the appropriate alcohol R.sup.49--OH in
the presence of hydrogen chloride at room temperature.
[0778] Compounds of general formula (17), wherein R.sup.1 is methyl
and Z.sup.1 is a direct bond may be prepared by treatment of
2-fluoro-4-methoxyacetophenone with hydrazine at a temperature up
to about reflux temperature.
[0779] Compounds of formula (16) wherein R.sup.1 and Z.sup.1 are as
defined previously, R.sup.53 represents OH and Q is N may be
prepared from compounds of general formula (17), wherein R.sup.1
and Z.sup.1 are as hereinbefore defined, as shown in the first step
of Scheme (I).
[0780] Intermediates of formula (VI), wherein T.sup.1 and R.sup.6
are as hereinbefore defined, may be prepared by reaction of
compounds of formula (XXVI) wherein T.sup.1 is as hereinbefore
defined with compounds of general formula (V), wherein R.sup.6 is
as hereinbefore described, in the presence of a strong base such as
lithium diisopropylamine, in an inert solvent, for example an ether
such as tetrahydrofuran, preferably at a temperature from
-65.degree. C. to 0.degree. C.
[0781] Intermediates of formula (VII), wherein T.sup.1 is as
hereinbefore defined, and R.sub.8 is hydrogen [i.e.
T.sup.1--C(.dbd.O)H, compounds of formula (XXVI)] may be prepared
by oxidation of compounds of formula (XXIX) with manganese dioxide
in an inert solvent, such as dichloromethane or toluene (or a
mixture of both), and at a temperature from about room temperature
to about 85.degree. C.
[0782] Intermediates of formula (XIV), wherein T.sup.1, R.sup.10,
R.sup.1 and R.sup.12 are as hereinbefore defined, may be prepared
by reaction of compounds of formula (X) wherein T.sup.1 and
R.sup.10 are as hereinbefore defined, with an organometallic
reagent R.sup.11(R.sup.2)CHM [where M is a metal atom, for example
a lithium atom] in a solvent such as an ether (e.g.
tetrahydrofuran) at a low temperature, e.g. about -78.degree. C. to
ambient temperature. Reagents R.sup.11(R.sup.12)CHM are either
known compounds or may be prepared, preferably in situ during the
above process, by reaction of a compound AlkCH.sub.2M or
[Alk].sub.2NM [where Alk is an alkyl group such as n-propyl or
i-propyl] with a compound R.sup.11CH.sub.2R.sup.12 using the just
mentioned conditions. Intermediates of formula (XV,
T.sup.1--C(R.sup.8)(OH)CH(R.sup.9)(CH.sub.2- ).sub.pR.sup.6),
wherein T.sup.1, R.sup.6, R.sup.8 and R.sup.9 are as hereinbefore
defined, may be similarly prepared by reaction of compounds of
formula (VIII) wherein T.sup.1 and R.sup.8 are as hereinbefore
defined, with an organometallic reagent
R.sup.6(CH.sub.2).sub.p(R.sup.9)C- HM [where M is a metal atom, for
example a lithium atom].
[0783] Intermediates of formula (XVI, T.sup.1--B(OH).sub.2),
wherein T.sup.1 is as hereinbefore defined, may be prepared by
reaction of compounds of formula (XVIII), wherein T.sup.1 is as
hereinbefore defined, with n-butyl lithium, in an inert solvent
such as tetrahydrofuran, at a temperature about -78.degree. C.,
followed by reaction with a trialkylborate, such as triethyl
borate, and subsequent hydrolysis with a dilute mineral acid such
as hydrochloric acid.
[0784] Intermediates of formula (XX, T.sup.1--NH.sub.2), wherein
T.sup.1 is as hereinbefore defined, may be prepared by
hydrogenation of compounds of formula (18)
T.sup.1--NO.sub.2 (18)
[0785] wherein T.sup.1 is as hereinbefore defined. The
hydrogenation may be carried out using hydrogen in the presence of
a suitable metal catalyst, e.g. palladium optionally supported on
an inert carrier such as carbon, preferably in a solvent such as
methanol or ethanol.
[0786] Intermediates of formula (XXII,
T.sup.1--C(.dbd.NOH)CH.sub.3), wherein T.sup.1 is as hereinbefore
defined, may be prepared by reaction of compounds of formula (VII)
wherein T.sup.1 is as hereinbefore described and R.sup.8 is methyl,
with hydroxylamine hydrochloride in the presence of pyridine, in an
inert solvent, such as dichloromethane, at a temperature at about
room temperature.
[0787] Intermediates of formula (XXV,
T.sup.1--CH.sub.2CH(OH)R.sup.6), wherein T.sup.1 and R.sup.6 are as
hereinbefore defined, may be prepared by reaction of compounds of
formula (19)
T.sup.1--CH.sub.3 (19)
[0788] wherein T.sup.1 is as hereinbefore described, with a strong
base such as lithium diisopropylamide, in an inert solvent, such as
tetrahydrofuran at a temperature at about -78.degree. C. followed
by reaction of with compounds of formula (XXXII, R.sup.6CHO)
wherein R.sup.6 is as hereinbefore described.
[0789] Intermediates of formula (XXVII, T.sup.1--CH.sub.2X.sup.7),
wherein T.sup.1 is as hereinbefore described and X.sup.7 is a
bromine atom, may be prepared by bromination of compounds of
formula (19), wherein T .sup.1 is as hereinbefore described, with
N-bromosuccinimide, optionally in the presence of a catalyst, such
as benzoyl peroxide, in an inert solvent such as dichloromethane
and at a temperature at about room temperature.
[0790] Alternatively intermediates of formula (XXVII,
T.sup.1--CH.sub.2X.sup.7), wherein T.sup.1 is as hereinbefore
described and X.sup.7 is a bromine atom, may be prepared by
reaction of compounds of formula (XXIX, T.sup.1CH.sub.2OH), wherein
T.sup.1 is as hereinbefore described, with N-bromosuccinimide,
optionally in the presence of a catalyst, such as benzoyl peroxide,
in an inert solvent such as dichloromethane and at a temperature at
about room temperature.
[0791] Intermediates of formula (XXIX, T.sup.1--CH.sub.2OH),
wherein T.sup.1 is as hereinbefore described may be prepared by
reduction of compounds of formula (IV, T.sup.1--CO.sub.2R.sup.49)
wherein T.sup.1 and R.sup.49 are as hereinbefore described. The
reduction may conveniently be carried out with diisobutylaluminium
hydride in an inert solvent, such as tetrahydrofuran, at a
temperature from about -78.degree. C. to about room temperature.
The reduction may also be carried out with lithium aluminium
hydride in an inert solvent, such as an ether, for example diethyl
ether, at a temperature from about room temperature to about
reflux.
[0792] Intermediates of formula (XXXI) wherein T.sup.1 is as
hereinbefore defined may be prepared from compounds of the general
formula (20)
T.sup.1--CHF.sub.2 (20)
[0793] wherein T.sup.1 is as hereinbefore defined, by reaction with
bromine in carbon tetrachloride and ultraviolet radiation, at a
temperature from about ambient to about reflux.
[0794] Compounds of formula (20) wherein T.sup.1 is as hereinbefore
defined may be prepared by the action of sulphur tetrafluoride and
hydrofluoric acid on compounds of formula (XXVI) wherein T.sup.1 is
as hereinbefore defined, optionally in the presence of pyridine, at
a temperature from about room temperature to about 125.degree. C.,
or alternatively by the action of diethylaminosulphur trifluoride,
preferably in an inert solvent, such as dichloromethane, preferably
at a temperature from about 0.degree. C. to about room
temperature.
[0795] Intermediates of formula (XXXVII,
T.sup.1--N.sub.2.sup.+BF.sub.4.su- p.-), wherein T.sup.1 is as
hereinbefore defined may be prepared by diazotisation of compounds
of formula (XX) with sodium nitrite in the presence of hydrochloric
acid, followed by treatment with sodium tetrafluoroborate.
[0796] Intermediates of formula (XXXX, T.sup.1--SO.sub.2Cl),
wherein T.sup.1 is as hereinbefore defined may be prepared by
reaction of compounds of formula (XVIII, T.sup.1--X.sup.7), wherein
T.sup.1 is as hereinbefore defined and X.sup.7 is a bromine atom
with butyllithium in tetrahydrofuran at a temperature at about
-70.degree. C. followed by treatment with sulphur dioxide at about
the same temperature and subsequent reaction of the resulting
lithium sulphinate salt with sulphuryl chloride in an inert solvent
such as dichloromethane at a temperature at about 0.degree. C.
[0797] Intermediates of formula (XXXXII,
T.sup.1--C(.dbd.O)CO.sub.2H), wherein T.sup.1 is as hereinbefore
defined may be prepared by the oxidation of compounds of formula
(VIII, T.sup.1--C(.dbd.O)R.sub.8) wherein T.sup.1 is as
hereinbefore described and R.sub.8 is methyl, by reaction with
selenium dioxide in the presence of pyridine, using mild
conditions, e.g. in a solvent such as ethanol, at or below room
temperature.
[0798] Intermediates of the general formula (XXXXIII) wherein
T.sup.1 is as hereinbefore defined may be prepared by treatment of
compounds of formula (XX) wherein T.sup.1 is as hereinbefore
defined with the phosgene equivalent (ClC(.dbd.O)OCCl.sub.3) in an
inert solvent such as dioxan at a temperature at about 60.degree.
C.
[0799] Intermediates of formulae (XXXXIX), (L) and (LII) wherein
R.sup.1, R.sup.3, 150
[0800] Q.sup.1 and Z.sup.1 are as hereinbefore described, may be
prepared by the application or adaptation of methods for the
reactions of o-arylenediamines described in Comprehensive
Heterocyclic Chemistry, page 470.
[0801] Intermediates of formula (LIV,
T.sup.1--C(CN)[(CH.sub.2).sub.2CO.su- b.2R.sup.52].sub.2), wherein
T.sup.1 is as hereinbefore described, may be prepared by reaction
of compounds of formula (21)
T.sup.1--CH.sub.2CN (21)
[0802] wherein T.sup.1 is as hereinbefore described, with methyl
(or ethyl) acrylate in methanol, in the presence of a suitable
catalyst, such as Triton-B, and at reflux temperature.
[0803] Compounds of formula (21), wherein T.sup.1 is as
hereinbefore described, may be prepared by reaction of compounds of
formula (XXVII), wherein T.sup.1 is as hereinbefore described and
X.sup.7 represents a chlorine atom, with sodium cyanide in
dimethylformamide.
[0804] Intermediates of the general formula (LV,
T.sup.1--CH.dbd.CH--CO.su- b.2H) wherein T.sup.1 is as hereinbefore
described may be prepared by reaction of compounds of formula
(XXVI, T.sup.1--CHO) with malonic acid in the presence of
piperidine in a solvent such as pyridine at a temperature up to
about reflux.
[0805] Intermediates of the general formula (LVII), wherein T.sup.1
is as hereinbefore described may be prepared by reaction of
compounds of formula (22)
T.sup.1--CH.dbd.CHCO.sub.2R.sup.49 (22)
[0806] wherein T.sup.1 and R.sup.49 are as hereinbefore described,
with an nitromethane in the presence of tetramethylguanidine at a
temperature at about 65.degree. C.
[0807] Compounds of formula (22), wherein T.sup.1 and R.sup.49 are
as hereinbefore described may be prepared by reaction of compounds
of formula (XXVI) with a carboalkoxymethylene triphenylphosphorane,
e.g. carbomethoxymethylene triphenylphosphorane, in an inert
solvent, such as toluene, and at a temperature from about room
temperature to about 80.degree. C.
[0808] Intermediates of formula (LVIII), wherein T.sup.1 is as
hereinbefore described, may be prepared from compounds of formula
(23)
T.sup.1--CH(NHCO.sub.2Me)CH.sub.2CH.dbd.CH.sub.2 (23)
[0809] wherein T.sup.1 is as hereinbefore described, following
hydroboration of the double bond with for example diisoamylborane
in tetrahydrofuran at 0.degree. C. and subsequent treatment with
sodium hydroxide and hydrogen peroxide at 0.degree. C.
[0810] Compounds of formula (23), wherein T .sup.1 is as
hereinbefore described, maybe prepared by reaction of compounds of
formula (24)
T.sup.1--CH(CO.sub.2H)CH.sub.2CH.dbd.CH.sub.2 (24)
[0811] wherein T.sup.1 is as hereinbefore described, with thionyl
chloride, at room temperature, followed by reaction of the
resulting acid chloride with sodium azide in acetone at 0.degree.
C. to room temperature then thermolysis by refluxing in an inert
solvent such as benzene to furnish the isocyanate which may be
converted to the required urethane by refluxing in methanol.
[0812] Compounds of formula (24,
T.sup.1--CH(CO.sub.2H)CH.sub.2CH.dbd.CH.s- ub.2), wherein T.sup.1
is as hereinbefore described, may be prepared by alkylation of the
acid dianion (obtained following treatment with two equivalents of
lithium diisopropylamine in tetrahydrofuran) derived from compounds
of formula (25)
T.sup.1--CH.sub.2CO.sub.2H (25)
[0813] wherein T.sup.1 is as hereinbefore described, with allyl
bromide.
[0814] Intermediates of formula (Iz) wherein T.sup.1 is as
hereinbefore described and the moiety R.sup.3 represents a 151
[0815] group in which R.sup.52 is a methyl or ethyl group, may be
prepared from compounds of formula (XXVI) by reaction with
hydroxylamine hydrochloride in the presence of pyridine, followed
by treatment of the so formed oxime with N-chlorosuccinimide and
pyridine in an inert solvent, such as dichloromethane, and
subsequent reaction of the chloroamidoxime with methyl or ethyl
acrylate in the presence of triethylamine.
[0816] Intermediates of formula (LIX), wherein R.sup.1, R.sup.2,
A.sup.1, Q.sup.1 and Z.sup.1 are as hereinbefore defined, R.sup.3
represents a --O--CH.sub.2--R.sup.6 group where R.sup.6 is as
hereinbefore defined, and 152
[0817] is a suitable protecting group, for example a
2-trimethylsilanyl-ethoxymethyl group, may be prepared by reaction
of compounds of formula (26): 153
[0818] wherein R.sup.1, R.sup.2, A.sup.1, Q.sup.1 and Z.sup.1 are
as hereinbefore defined, and 154
[0819] is a suitable protecting group, for example a
2-trimethylsilanyl-ethoxymethyl group, with compounds of formula
(27)
R.sup.6CH.sub.2OH (27)
[0820] wherein R.sup.6 is as hereinbefore defined, in the presence
of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate,
and triphenylphosphine, preferably in a dry ethereal solvent, e.g.
diethyl ether or tetrahydrofuran, preferably at or near room
temperature.
[0821] Compounds of formula (26) wherein R.sup.1, R.sup.2, A.sup.1,
Q.sup.1 and Z.sup.1 are as hereinbefore defined, and 155
[0822] is a suitable protecting group, for example a
2-trimethylsilanyl-ethoxymethyl group, may be prepared by reaction
of compounds of formula (28): 156
[0823] wherein R.sup.1, R.sup.2, A.sup.1, Q.sup.1 and Z.sup.1 are
as hereinbefore defined, and 157
[0824] is a suitable protecting group, for example a
2-trimethylsilanyl-ethoxymethyl group, with m-chloroperbenzoic acid
in an inert solvent such dichloromethane and at a temperature from
about 0.degree. C. to about room temperature followed by treatment
with sodium hydrogen carbonate.
[0825] Intermediates of formula (XXXIII), wherein T.sup.1 is as
hereinbefore defined, may be similarly prepared by reaction of
compounds of formula (XXVI), wherein T.sup.1 is as hereinbefore
defined, with m-chloroperbenzoic acid.
[0826] Compounds of formula (28) wherein R.sup.1, R.sup.2, A.sup.1,
Q.sup.1 and Z.sup.1 are as hereinbefore defined, and 158
[0827] is a 2-trimethylsilanyl-ethoxymethyl group, may be prepared
by reaction of compounds of formula (2), wherein 159
[0828] represents 160
[0829] represents a formyl group, and R.sup.1, R.sup.2, A.sup.1,
Q.sup.1 and Z.sup.1 are as hereinbefore defined, with
2-(trimethylsilyl)ethoxymet- hyl chloride in the presence of sodium
hydride, in an inert solvent such as dimethylformamide, and at a
temperature at about room temperature.
[0830] Compounds of formula (XXXIV) wherein R.sup.6 is as
hereinbefore defined and X.sup.8 is hydroxy may be prepared by
reduction of compounds of formula (XXXII) wherein R.sup.6 is as
hereinbefore defined. The reduction may conveniently be carried out
with sodium borohydride in an alcohol such as ethanol at a
temperature at about room temperature.
[0831] Compounds of formula (XXXI) wherein R.sup.6 is heteroaryl,
such as a substituted pyridyl, for example 3,5-dimethylpyridyl, may
be prepared by reaction of compounds of formula (29)
R.sup.6Br (29)
[0832] wherein R.sup.6 is heteroaryl, such as a substituted
pyridyl, for example 3,5-dimethylpyridyl, with butyl lithium in an
inert solvent, such as diethyl ether, at -78.degree. C., and
subsequent treatment of the resulting anion with
dimethylformamide.
[0833] Compounds of formula (29) wherein R.sup.6 is
3,5-dimethylpyridyl, may be prepared by reaction of
4-nitro-3,5-dimethylpyridine-N-oxide with phosphorous tribromide in
a similar manner to the procedures described in J.Chem.Soc., 1956,
page 771.
[0834] Intermediates of formula (IV) represented by formula (30):
161
[0835] wherein R.sup.1, R.sup.2, A.sup.1, and Z.sup.1 are as
hereinbefore defined, R.sup.53 is CO.sub.2R.sup.49 (in which
R.sup.49 is as hereinbefore defined), may be prepared for example
by reaction of compounds of formula (4), wherein R.sup.1 and
Z.sup.1 are as hereinbefore defined, R.sup.53 is CO.sub.2R.sup.49
(in which R.sup.49 is as hereinbefore defined) and Q is CH, with
compounds of formula (31)
R.sup.2A.sup.1--CH.dbd.CH--CHO (31)
[0836] wherein R.sup.2 and A.sup.1 are as hereinbefore defined, in
the presence of p-chloranil in a alcohol, such as butanol, and at a
temperature at about reflux temperature.
[0837] Intermediates of formula (IV) represented by formula (32):
162
[0838] wherein R.sup.1 is hydrogen, R.sup.2 is alkyl, aryl or
heteroaryl, R.sup.53 is CO.sub.2R.sup.49 (in which R.sup.49 is as
hereinbefore defined), Z.sup.1 is a direct bond, and A.sup.1 is
--CH.sub.2-- or --CH(CH.sub.3)--, may be prepared for example by
reaction of compounds of formula (33): 163
[0839] wherein R.sup.49 is as hereinbefore defined, R.sup.2 is
alkyl, aryl or heteroaryl, and R.sup.54 is hydrogen or methyl, with
palladium acetate in the presence of triethylamine in an inert
solvent such as acetonitrile, sealed in a bomb, and at a
temperature up to about 110.degree. C.
[0840] Compounds of formula (33), wherein R.sup.2, R.sup.53 and
A.sup.1 are as hereinbefore defined, may be prepared by reaction of
compounds of formula (34): 164
[0841] wherein R.sup.53 is as hereinbefore defined with an allyl
bromide of formula (35)
R.sup.2(R.sup.54)C.dbd.CH--CHBr (35)
[0842] wherein R.sup.2 and R.sup.54 are as defined above, in the
presence of lithium diisopropylamide in an inert solvent such as an
ether, e.g. tetrahydrofuran, at a temperature from about
-78.degree. C. to about room temperature.
[0843] Compounds of formula (34) may be prepared according to the
method of Hill, Tetrahedron, 1990, 46, page 4587.
[0844] Intermediates of formula (IV) represented by formula (36):
165
[0845] wherein R.sup.1, R.sup.2, A.sup.1, and Z.sup.1 are as
hereinbefore defined, and R.sup.53 is CO.sub.2R.sup.49, may be
prepared for example by reaction of compounds of formula (37):
166
[0846] wherein R.sup.1, R.sup.49 and Z.sup.1 are as hereinbefore
defined, with compounds of formula R.sup.2A.sup.1C.ident.N, wherein
R.sup.2 and A.sup.1 are as hereinbefore defined (with the proviso
that when A.sup.1 is a direct bond then R.sup.2 is alkyl,
cycloalkyl, aryl, or heteroaryl), in the presence of an acid
catalyst, such as 4-toluenesulphonic acid, at a temperature up to
about 180.degree. C.
[0847] Compounds of formula (37), wherein R.sup.1 and Z.sup.1 are
as hereinbefore defined, may be prepared by reduction of compounds
of formula (38): 167
[0848] wherein R.sup.1, R.sup.49 and Z.sup.1 are as hereinbefore
defined. The reduction may be carried out using hydrogen in the
presence of a suitable metal catalyst, e.g. platinum or palladium
optionally supported on an inert carrier such as carbon, preferably
in a solvent such as ethyl acetate.
[0849] Compounds of formula (38), wherein R.sup.49 is as
hereinbefore defined, R.sup.1 is methyl and Z.sup.1 is an oxygen
atom, may be prepared by nitration of methyl 4-methoxysalicylate
followed by separation of the required nitro-isomer. The nitration
may be conveniently carried out using concentrated nitric acid in
acetic acid at a temperature at about room temperature.
[0850] Intermediates of formula (IV) represented by formula (39):
168
[0851] wherein R.sup.1 is alkyl, R.sup.2 is alkyl, aryl or
heteroaryl, R.sup.53 is CO.sub.2R.sup.49 (in which R.sup.49 is as
hereinbefore defined), Z.sup.1 is a direct bond, and A.sup.1 is as
hereinbefore defined, may be prepared for example by reduction of
compounds of formula (15), wherein R.sup.1 is alkyl, R.sup.2 is
alkyl, aryl or heteroaryl, R.sup.53 is CO.sub.2R.sup.49 (in which
R.sup.49 is as hereinbefore defined), Q is CH, Z.sup.1 is a direct
bond, and A.sup.1 is as hereinbefore defined, using a solution of
borane-tetrahydrofuran complex in tetrahydrofuran. The reaction may
conveniently be carried out in trifluoroacetic acid at a
temperature at about 0.degree. C.
[0852] Intermediates of formula (IV) represented by formula (40):
169
[0853] wherein R.sup.1, R.sup.2, A.sup.1 and Z.sup.1 are as
hereinbefore defined, and R.sup.53 is CO.sub.2R.sup.49 (in which
R.sup.49 is as hereinbefore defined), may be prepared for example
by reaction of compounds of formula (37), wherein R.sup.1, R.sup.49
and Z.sup.1 are as hereinbefore defined, with compounds of formula
(41)
R.sup.2A.sup.1CH(Cl)C(.dbd.O)Cl (41)
[0854] wherein R.sup.1 and A.sup.1 are as hereinbefore defined, in
an inert solvent such as dichloromethane, in the presence of a
base, such as sodium hydrogen carbonate, and at a temperature from
about 0.degree. C. to about room temperature, followed by heating
the intermediate with potassium carbonate in dimethylformamide at
100.degree. C. and then reduction with borane-dimethylsulphide
complex in tetrahydrofuran at room temperature.
[0855] Intermediates of formula (IV) represented by formula (41):
170
[0856] wherein R.sup.1, R.sup.49 and Z.sup.1 are as hereinbefore
defined, R.sup.2 is alkoxy, arylalkyloxy, heteroarylalkyloxy or
hydroxy and A.sup.1 is methylene may be prepared for example by
reaction of compounds of formula (42): 171
[0857] wherein R.sup.1, R.sup.49 and Z.sup.1 are as hereinbefore
defined, with with sodium hypochlorite in the presence of an
aqueous acid such as dilute hydrochloric acid, in an alcohol, such
as methanol, and at a temperature at about reflux temperature,
followed by treatment of the resultant chloroimine with water or an
alcohol of formula R.sup.2--OH where R.sup.2 is as defined
immediately above, in the presence of an alkali metal carbonate,
such as potassium carbonate, at a temperature at about reflux
temperature
[0858] Compounds of formula (42) wherein R.sup.1, R.sup.49 and
Z.sup.1 are as hereinbefore defined, may be prepared by reaction of
compounds of formula (4) wherein R.sup.1 and Z.sup.1 are as
hereinbefore defined, R.sup.53 is CO.sub.2R.sup.49 (in which
R.sup.49 is as hereinbefore defined) and Q.sup.1 is CH, with
chlorocetonitrile in the presence of an acid catalyst, such as
4-toluenesulphonic acid, and at a temperature at about 180.degree.
C.
[0859] Intermediates of formulae (II), (IV), (VI), (VIII), (X),
(XIV), (XV), (XVI), (XVIII), (XX), (XXII), (XXIII), (XXV), (XXVI),
(XXVII), (XXIX), (XXXI), (XXXI), (XXXV), (XXXVII), (XXXX),
(XXXXII), (XXXXIII), (XXXXV), (XXXXIX), (L), (LII), (LIV), (LV),
(LVI) and (LIX) are novel compounds and, as such, they and their
processes described herein for their preparation constitute further
features of the present invention.
[0860] The present invention is further Exemplified but not limited
by the following illustrative Examples and Reference Examples.
[0861] In the nuclear magnetic resonance spectra (NMR) the chemical
shifts are expressed in ppm relative to tetramethylsilane.
Abbreviations have the following significances: s=singlet;
d=doublet; t=triplet; m=multiplet; dd=doublet of doublets;
b=broad.
EXAMPLE 1
[0862] (a) N-(3,5-Dichloro-4-pyridyl)-7-methoxy-2-methoxy methyl
3H-benzimidazole-4-carboxamide
[0863] A solution of 4-amino-3,5-dichloropyridine (24.3 g) in
tetrahydrofuran (100 ml) was diluted with toluene (150ml) and the
mixture treated dropwise with a solution of sodium diethylaluminate
in toluene (36 ml; 2M, caution pyrophoric reagent). The mixture was
stirred at ambient temperature for 30 minutes, then heated at
reflux with stirring for a further 30 minutes. The resulting
solution was cooled to room temperature and then treated with a
solution of 1'-benzotriazolyl
7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [Reference
Example 1(a)] in tetrahydrofuran (40 ml). The resulting mixture was
refluxed for 2 hours, then cooled to ambient temperature, then
diluted with chloroform and then washed with a dilute solution of
sodium tartrate followed by brine. The organic phase was dried over
magnesium sulphate and then evaporated. The solid residue was
triturated overnight with ethyl acetate and the insoluble material
was recrystallised from a mixture of methanol and toluene to give
the title compound (6.06 g) as a white solid, m.p. 230-231.degree.
C. [Elemental analysis: C,50.0; H,3.60; N,14.4%. Calculated:
C,50.4; H,3.70; N,14.7%].
[0864] (b) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(b), there was prepared
N-(3,5-dichloro-4-pyridyl-7-me-
thoxy-2-phenyl-3H-benzimidazole-4-carboxamide as a white solid,
m.p. 344-345.degree. C. [Elemental analysis: C,57.9; H,3.40;
N,13.2%. Calculated: C,58.1; H,3.41; N,13.6%].
[0865] (c) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(c), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-phenethyl-3H-benzimidazole-4-carboxamide as a white solid,
m.p. 211.degree. C. [Elemental analysis: C,60.0; H,4.20; N,12.5%.
Calculated: C,59.9; H,4.11; N,12.7%].
[0866] (d) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(d), there was prepared
2-benzyl-N-(3,5-dichloro-4-pyr-
idyl)-7-methoxy-3H-benzimidazole-4-carboxamide as a white solid,
m.p. 200-201.degree. C. [Elemental analysis: C,59.4; H,3.80;
N,12.8%. Calculated: C,59.0; H,3.77; N,13.1%].
[0867] (e) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(e), there was prepared
(RS)-N-(3,5-dichloro-4-pyridyl-
)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide as a
white solid, m.p. 220-222.degree. C. [Elemental analysis: C,60.3;
H,4.10; N,12.4%. Calculated: C,59.9; H,4.11; N,12.7%]. NMR
(CDCl.sub.3): .delta.1.90(d,J=7.5Hz,3H), 3.97(s,3H),
4.41(q,J=7.5Hz,1H), 6.80(d,J=8Hz,1H), 7.4(m,5H), 8.19(d,J=8Hz,1H),
8.8(s,2H), 9.05(bs,1H).
[0868] (f) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(f), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-car boxamide as a
white solid, m.p. 225-226.degree. C. [Elemental analysis: C,57.6;
H,3.90; N,12.2%. Calculated: C,57.8; H,3.97; N,12.3%]. NMR
(CDCl.sub.3): .delta.3.8(s,3H), 3.95(s,3H), 4.28(s,2H),
6.79(d,J=8Hz,1H), 6.92(d,J=8Hz,2H), 7.26(d,J=8Hz,2H),
8.17(d,J=8Hz,1H), 8.55(s,2H), 9.4(bs,1H).
[0869] (g) By proceeding in a similar manner to Example I1(a) but
using Reference Example 1(g), there was prepared
(RS)-2-(cyclohexyl-phenyl-meth-
yl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide
as a white solid, m.p. 281.degree. C. with decomposition.
[Elemental analysis: C,63.5; H,5.30; N,10.9%. Calculated: C,63.7;
H,5.14; N,11.0%].
[0870] (h) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(h), there was prepared
(RS)-N-(3,5-dichloro-4-pyridyl-
)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide as
a white solid, m. p. 225-226 8.degree. C. [Elemental analysis:
C,64.2; H,4.40; N,10.5; H.sub.2O,2.0%. Calculated for
C.sub.28H.sub.22Cl.sub.2N.s- ub.4O.sub.2.0.5H.sub.2O: C,63.8;
H,4.37; N,10.6; H.sub.2O,1.7%].
[0871] (i) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(i), there was prepared
(RS)-N-(3,5-dichloro-4-pyridyl- )-7-methoxy-2-(2-2phenylpropyl)-3H
-benzimidazole-4-carboxamide as a white solid, m.p .
103-105.degree. C. [Elemental analysis: C,60.3; H,4.50; N,12.0%.
Calculated: C,60.1; H,4.43; N,12.3%].
[0872] (j) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(j), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxamide as
a white solid, m.p. 185-186.degree. C. [Elemental analysis: C,55.2;
H,3.90; N,11.4%. Calculated: C,55.8; H,3.83; N,11.8%].
[0873] (k) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(k), there was prepared
(RS)-N-(3,5-dichloro-4-pyridyl-
)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide as a
white solid, m.p. 223-224.degree. C. [Elemental analysis: C,61.0;
H,4.70; N,11.7%. Calculated: C,61.4; H,4.72; N,11.9%].
[0874] (l) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(l), there was prepared
2-(4-bromobenzyl-N-(3,5-dichlo-
ro-4-pyridyl-7-methoxy-3H-benzimidazole-4-carboxamide as a yellow
solid, m.p. 273-275.degree. C. [Elemental analysis: C,49.8; H,2.90;
N,10.6%. Calculated: C,49.8; H,2.99; N,11.1%]. NMR
{(CD.sub.3).sub.2SO}: .delta.4.00(s,3H), 4.25(s,2H), 7.00(d,1H),
7.35(d,2H), 7.50(d,2H), 7.90(d,1H), 8.74(s,1H), 12.95(s,1H),
13.40(s,1H).
[0875] (m) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(m), there was prepared
(RS)-N-(3,5-dichloro-4-pyridyl-
)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzi
midazole-4-carboxamide as a white solid, m.p. 167-169.degree. C.
[Elemental analysis: C,59.1; H,4.60; N,11.3%. Calculated: C,59.3;
H,4.57; N,11.5%]. NMR (CDCl.sub.3): .delta.2.33(m,1H), 2.75(m,1H),
3.31(m,1H), 3.33(s,3H), 3.45(m,1H), 4.0(s,3H), 4.50(t,J=8Hz,1H),
6.82(d,J=8Hz,1H), 7.35(m,5H), 8.18(d,J=8Hz,1H), 8.60(s,2H),
9.63(bs,1H).
[0876] (n) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(n), there was prepared
2-(4-cyanobenzyl)-N-(3,5-dichl-
oro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide as a white
solid, m.p. 225-227.degree. C. [Elemental analysis: C,58.4; H,3.60;
N,14.8%. Calculated: C,58.4; H,3.34; N,15.5%]. NMR
{(CD.sub.3).sub.2SO}: .delta.4.05(s,3H), 4.35(s,2H), 7.00(d,1H),
7.60(d,2H), 7.75(d,2H), 7.90(d,1H), 8.70(s,2H), 11.90(s,1H),
13.45(s,1H).
[0877] (o) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(o), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-[4-(3-pyridyl)benzyl]-3H-benzimidazole-4-carboxamide as a
tan coloured solid, m.p. 255.degree. C. with decomposition.
[Elemental analysis: C,61.3; H,4.10; N,13.2; H.sub.2O,0.90%.
Calculated for C.sub.26H.sub.19Cl.sub.2N.sub.5O.sub.2.0.25H.sub.2O:
C,60.8; H,3.70; N,13,6, H.sub.2O,0.88%]. NMR {(CD.sub.3).sub.2SO}:
.delta.4.10(s,3H), 4.35(s,2H), 7.00(d,1H), 7.50(m,3H), 7.70(d,2H),
7.90(d,1H), 8.10(d,1H), 8.55(d,1H), 8.70(s,1H), 8.85(d,1H),
1200(s,1H), 13.40(s,1H).
[0878] (p) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(p), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-car boxamide as a
white solid, m.p. 211-212.degree. C. [Elemental analysis: C,57.7;
H,3.70; N,12.0%. Calculated: C,57.8; H,3.97; N,12.3%].
[0879] (q) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(q), there was prepared
(RS)-N-(3,5-dichloro-4-pyridyl-
)-7-methoxy-2-(methoxy-phenyl-methyl)-3H-benzimidazole-4-carboxamide
as a white solid, m.p. 227-229.degree. C. [Elemental analysis:
C,57.8; H,3.50; N,12.0%. Calculated: C,57.8; H,3.97; N,12.3%].
[0880] (r) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(r), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-(2-methoxyphenoxymethyl-3H-benzimidaz ole-4-carboxamide as
a white solid, m.p. 222-223.degree. C. NMR (CDCl.sub.3):
.delta.4.0(s,3H), 4.07(s,3H), 5.5(s,2H), 6.86(d,J=8Hz,1H),
6.97(m,2H), 7.09(m,2H), 8.2(d,J=8Hz,1H), 8.59(s,2H).
[0881] (s) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(s), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxamide as an off-white
solid, m.p. 315.degree. C. [Elemental analysis: C,54.4; H,3.30;
N,16.3; H.sub.2O,1.10%. Calculated for
C.sub.19H.sub.13Cl.sub.2N.sub.5O.sub.2.0.2- 5H.sub.2O: C,54.5;
H,3.25; N,16.7, H.sub.2O,1.07%].
[0882] (t), By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(t), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-isopropyl-3H-benzimidazole-4-carboxamide as a white solid,
m.p. 266.degree. C. [Elemental analysis: C,53.7; H,4.40; N,14.5%.
Calculated: C,53.8; H,4.25; N,14.8%].
[0883] (u) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(u), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-methyl-3H-benzimidazole-4-carboxamide as a white solid,
m.p. 235.degree. C. [Elemental analysis: C,51.3; H,3.40; N,15.8%.
Calculated: C,51.3; H,3.44; N,16.0%].
[0884] (v) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(v), there was prepared
N-(3,5-dichloro-4-pyridyl)-7-m-
ethoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxamide as a white
solid, m.p. 215-219.degree. C. with decomposition. [Elemental
analysis: C,56.4; H,3.90; N,12.4%. Calculated: C,56.9; N,3.64;
6.95(m,1H), 7.1(m,3H), 7.32(m,2H), 7.98(d,J=8Hz,1H), 8.75(s,2H),
11.75(bs,1H),
[0885] (w) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(w), there was prepared
2-cyclopentyl-N-(3,5-dichloro--
4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide as a white
solid, m.p. >250.degree. C. [Elemental analysis: C,56.4; H,4.40;
N,13.5%. Calculated: C,56.3; H,4.48; N,13.8%].
[0886] (x) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(x), there was prepared
2-benzyl-N-(3,5-dichloro-4-pyr-
idyl)-3H-benzimidazole-4-carboxamide as a white solid, m.p.
162.degree. C. [Elemental analysis: C,60.5; H,3.80; N,13.9%.
Calculated: C,60.5; H,3.55; N,14.1%].
[0887] (y) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(y), there was prepared
2-cyclopentyl-N-(3,5-dichloro--
4-pyridyl)-7-methoxy-1-methyl-1H-benzimidazole-4-carboxamide as a
white solid, m.p. 212.degree. C. [Elemental analysis: C,57.2;
H,4.80; N,13.2%. Calculated: C,57.3; H,4.81; N,13.4%].
[0888] (z) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(z), there was prepared
2-cyclopentyl-N-(3,5-dichloro--
4-pyridyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxamide as a
white solid, m.p. 180.degree. C. [Elemental analysis: C,57.2;
H,4.80; N,13.3%. Calculated: C,57.3; H,4.81; N,13.4%].
[0889] (aa) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(aa), there was prepared
N-(3,5-dichloro-4-pyridyl)-2,-
7-dimethoxy-3H-benzimidazole-4-carboxamide as a white solid, m.p.
238-239.degree. C. [Elemental analysis: C,48.8; H,3.20; N,15.1%.
Calculated: C,49.1; H,3.29; N,15.3%].
[0890] (ab) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(ab), there was prepared
2-cyclopropyl-N-(3,5-dichloro-
-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide as a white
solid, m.p. 253-254.degree. C. [Elemental analysis: C,54.13;
H,3.74; N,14.85%. Calculated: C,54.07; H,3.71; N,14.85%].
[0891] (ac) By proceeding in a similar manner to Example 1(a) but
using 2,6-difluoroaniline and Reference Example 1(ab), there was
prepared
2-cyclopropyl-N-2,6-difluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxam-
ide as a white solid, m.p. 133-135.degree. C. [Elemental analysis:
C,62.81; H,4.71; N,10.42%; F,11.55%. Calculated for
C.sub.18H.sub.15F.sub.2N.sub.3O.sub.2.0.25CH.sub.3OH: C,62.39;
H,4.59; N,10.82%; F,11.96%].
[0892] (ad) By proceeding in a similar manner to Example 1(a) but
using 2,6-dibromoaniline and Reference Example 1(ab), there was
prepared
2-cyclopropyl-N-(2,6-dibromophenyl)-7-methoxy-3H-benzimidazole-4-carboxam-
ide as a white solid, m.p. 258-260.degree. C. [Elemental analysis:
C,45.71; H,3.75; N,9.33%. Calculated for
C.sub.18H.sub.15Br.sub.2N.sub.3O- .sub.2.CH.sub.3OH: C,45.90;
H,3.85; N,8.45%].
[0893] (ae) By proceeding in a similar manner to Example 1(a) but
using 2,6-dimethylaniline and Reference Example 1(ab), there was
prepared
2-cyclopropyl-N-(2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxa-
mide as a white solid, m.p. 247-249.degree. C. [Elemental analysis:
C,71.51; H,6.54; N,12.33%. Calculated: C,71.62; H,6.31;
N,12.53%].
[0894] (af) By proceeding in a similar manner to Example 1(a) but
using 2,4,6-trifluoraniline N and Reference Example 1(ab), there
was prepared
2-cyclopropyl-N-(2,4,6-trifluorophenyl)-7-methoxy-3H-benzimidazole-4-carb-
oxamide as a white solid, m.p. 161-163.degree. C. [Elemental
analysis: C,59.79; H,3.65; N,11.52%; F,11.52%. Calculated: C,59.83;
H,3.91; N,11.63%; F,11.63%].
[0895] (ag) By proceeding in a similar manner to Example 1(a) but
using 2,6-dichloroaniline and Reference Example 1(ab), there was
prepared
2-cyclopropyl-N-(2,6-dichlorophenyl)-7-methoxy-3H-benzimidazole-4-carboxa-
mide as a white solid, m.p. 225-227.degree. C. [Elemental analysis:
C,57.35; H,4.04; N,11.10%; Cl,18.78%. Calculated: C,57.46; H,4.02;
N,11.17%; Cl,18.85%].
[0896] (ah) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dimethylpyridine and Reference Example 1(ab),
there was prepared
2-cyclopropyl-N-(3,5-dimethyl-4-pyridyl)-7-methoxy-3H-benzimidaz-
ole-4-carboxamide as a white solid, m.p. 268-270.degree. C.
[Elemental analysis: C,65.31; H,5.80; N,15.88%. Calculated for
C.sub.19H.sub.20N.sub.4O.sub.2.0.2CH.sub.2Cl.sub.2: C,65.26;
H,5.82; N,15.86%].
[0897] (ai) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dimethylisoxazole and Reference Example 1(ab),
there was prepared
2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl-7-methoxy-3H-benzimid-
azole-4-carboxamide as a white solid, m.p. 232-234.degree. C.
[Elemental analysis: C,62.32; H,5.85; N,17.08%. Calculated:
C,62.56; H,5.56; N,17.17%].
[0898] (aj) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dimethylisoxazole, there was prepared
N-(3,5-dimethyl-4-isoxa- zolyl
-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide as a
white solid, m.p. 232-234.degree. C. [Elemental analysis: C,58.69;
H,5.50; N,16.81%. Calculated: C,58.17; H,5.49; N,16.96%].
[0899] (ak) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dimethylpyridine and Reference Example 1(ab),
there was prepared
2-cyclopropyl-N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-3H-benz-
imidazole-4-carboxamide as a white solid, m.p. 190-192.degree. C.
[Elemental analysis: C,62.26; H,5.74; N,10.21%. Calculated for
C.sub.21H.sub.21N.sub.3O.sub.4.1.5H.sub.2: C,62.06; H,5.95;
N,10.33%].
[0900] (al) By proceeding in a similar manner to Example 1(a) but
using 4-carboxy-2,6-dimethylaniline, there was prepared
N-(4-carboxy-2,6-dimeth-
ylphenyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide
as a white solid, m.p. 251-253.degree. C. [Elemental analysis:
C,61.73; H,5.57; N,10.59%. Calculated for
C.sub.20H.sub.21N.sub.3O.sub.5.0.25H.sub- .2: C,61.92; H,5.59;
N,10.83%].
[0901] (am) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3-chloropyridine and Reference Example 1(ax), there
was prepared
N-(3-chloro-4-pyridyl)-7-methoxy-2-n-propyl-3H-benzimidazole-4-carboxamid-
e as a green solid, m.p. 272-274.degree. C. [Elemental analysis:
C,59.04; H,4.99; N,15.99%. Calculated: C,59.22; H,4.97;
N,16.24%].
[0902] (an) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(as), there was prepared
N-(3,5-dichloro-4-pyridyl)-8--
methoxy-2-n-propylquinoline-5-carboxamide as a white solid, m.p.
227-230.degree. C. [Elemental analysis: C,58.43; H,4.12%.
Calculated for C.sub.19H.sub.17Cl.sub.2N.sub.3O.sub.2: C,58.47;
H,4.39%].
[0903] (ao) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1
(ac), there was prepared
1-cyclohexylmethyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridi-
nio)-1H-indole-6-carboxamide as a white solid, m.p. 226-228.degree.
C. [Elemental analysis: C,61.06; H,5.23; N,9.59%. Calculated for
C.sub.22H.sub.23Cl.sub.2N.sub.3O.sub.2: C,61.12; H,5.36;
N,9.72%].
[0904] (ap) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ad), there was prepared
1-cyclohexyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1-
H-indole-6-carboxamide as a white solid, m.p. 165-170.degree. C.
[Elemental analysis: C,60.95; H,5.85; N,9.20%. Calculated for
C.sub.21H.sub.21Cl.sub.2N.sub.3O.sub.2: C,60.30; H,5.06;
N,10.04%].
[0905] (aq) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ae), there was prepared
1-(2-cyclohexyl)ethyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyr-
idinio)-1H-indole-6-carboxamide as an off-white solid, m.p
125-140.degree. C. [Elemental analysis: C,60.95; H,5.85; N,9.20%.
Calculated for C.sub.23H.sub.25Cl.sub.2N.sub.3O.sub.2: C,61.87;
H,5.65; N,9.41%].
[0906] (ar) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(af), there was prepared
1-(3-cyclohexyl)propyl-3-methyl-N-(3,5-dichloro-1-oxido-4-py-
ridinio)-1H-indole-6-carboxamide as a white solid, m.p 178.degree.
C. [Elemental analysis: C,62.63; H,5.99; N,8.87%. Calculated for
C.sub.24H.sub.27Cl.sub.2N.sub.3O.sub.2: C,62.61; H,5.91;
N,9.13%].
[0907] (as) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ag), there was prepared
1-heptyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-in-
dole-6-carboxamide as a white solid, m.p 170.degree. C. [Elemental
analysis: C,60.72; H,5.83; N,9.51%. Calculated for
C.sub.22H.sub.25Cl.sub.2N.sub.3O.sub.2: C,60.83; H,5.80;
N,9.67%].
[0908] (at) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ah), there was prepared
1-cycloheptylmethyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyrid-
inio)-1H-indole-6-carboxamide as a yellow solid, m.p 185.degree. C.
[Elemental analysis: C,61.89; H,5.65; N,9.41%. Calculated for
C.sub.23H.sub.25Cl.sub.2N.sub.3O.sub.2: C,61.6; H,5.40;
N,9.70%].
[0909] (au) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ai), there was prepared 1-(6,6-dimethyl-bicyclo[3.1.1
.]hept-3-ylmethyl)-3-methyl-N--
(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamide as an
off-white solid, m.p 125-140.degree. C. [Elemental analysis:
C,62.37; H,5.78; N,8.51%. Calculated for
C.sub.23H.sub.25Cl.sub.2N.sub.3O.sub.2: C,63.50; H,5.76; N,8.89%].
NMR (CDCl.sub.3): .delta.0.65(s,3H), 1.20(s,3H), 1.30-1.40(m,1H),
1.40-1.50(m,1H), 1.65-1.70(m,1H), 1.75-1.85(m,2H), 1.90-1.95(m,1H),
2.10-2.20(m,1H), 2.50-2.60(m,1H), 3.90-4.00(m,2H), 7.00(s,1H),
7.50-7.70(m,2H), 7.80(s,1H), 8.00(s,1H), 8.30(s,2H).
[0910] (av) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(aj), there was prepared
1-(3-phenyl)butyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridin-
io)-1H-indole-6-carboxamide as a white solid, m.p 179.degree. C.
[Elemental analysis: C,64.24; H,5.12; N,8.99%. Calculated for
C.sub.25H.sub.23Cl.sub.2N.sub.3O.sub.2: C,64.11; H,4.95;
N,8.97%].
[0911] (aw) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ak), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(4-trifluoro-
methylbenzyl)-1H-indole-6-carboxamide as a white solid, m.p
135.degree. C. [Elemental analysis : C,55.08; H,3.37; N,8.32%.
Calculated for
C.sub.23H.sub.16Cl.sub.2F.sub.3N.sub.3O.sub.2.0.5H.sub.2O: C,54.86;
H,3.41; N,8.35%]. NMR {(CD.sub.3).sub.2SO}: .delta.2.30(s,3H),
5.52(s,1H), 7.20-7.30(m,2H), 7.52(s,1H), 7.70-7.80(m,4H),
8.12(s,1H), 8.72(s,2H), 10.30(s,1H).
[0912] (ax) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(al), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(4-methylsul-
phonylbenzyl)-1H-indole-6-carboxamide as a yellow solid, m.p
157-160.degree. C. [Elemental analysis: C,54.72; H,4.27; N,8.65%.
Calculated for C.sub.23H.sub.19Cl.sub.2N.sub.3O.sub.4S: C,54.77;
H,3.80; N,8.33%].
[0913] (ay) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(am), there was prepared
1-(1,3-benzodioxol-5-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyr-
idinio)-3-methyl-1H-indole-6-carboxamide as a white solid, m.p.
>245.degree. C. [Elemental analysis: C,58.53; H,3.77; N,8.69%.
Calculated for C.sub.23H.sub.17Cl.sub.2N.sub.3O.sub.4: C,58.74;
H,3.64;N,8.93%].
[0914] (az) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(an), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(naphthalen--
2-yl)methyl-1H-indole-6-carboxamide as a white solid, m.p
>230.degree. C. NMR {(CD.sub.3).sub.2SO)}: .delta.2.30(s,3H);
5.60(s,2H); 7.35-7.40,7.45-7.55,7.60-7.80 and 7.80-7.90(m,10H);
8.20(s,1H); 8.70(s,2H); 10.30(s,1H).
[0915] (ba) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ao), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(tetrahydro--
2H-pyran-2-yl)methyl-1H-indole-6-carboxamide as a beige coloured
solid, m.p >150.degree. C. with decomposition. [Elemental
analysis: C,57.60; H,5.30; N,10.00%. Calculated for
C.sub.21H.sub.21Cl.sub.2N.sub.3O.sub.3: C,58.08; H,4.87;
N,9.67%].
[0916] (bb) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ap), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(tetrahydrof-
urfuryl)methyl-1H-indole-6-carboxamide as a yellow solid, m.p
136.degree. C. with decomposition. [Elemental analysis: C,55.08;
H,3.37; N,8.32%. Calculated for
C.sub.23H.sub.16Cl.sub.2F.sub.3N.sub.3O.sub.2.0.425H.sub.2- O:
C,55.89; H,3.26; N,8.50%]. M.sup.+419.
[0917] (bc) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(aq), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(4-toluenesu-
lfonyl)-1H-indole-6-carboxamide as a light brown solid, m.p.
>127.degree. C. with decomposition. [Elemental analysis:
C,53.90; H,3.60; N,8.40%. Calculated for
C.sub.22H.sub.17Cl.sub.2N.sub.3O.sub.4: C,53.89; H,3.49;
N,8.57%].
[0918] (bd) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(ar), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(tetrahydrof-
uran-3-yl)-1H-indole-6-carboxamide as a beige coloured solid, m.p.
>135.degree. C. with decomposition. [Elemental analysis:
C,56.00; H,4.60; N,9.80%. Calculated for
C.sub.19H.sub.17Cl.sub.2N.sub.3O.sub.3: C,56.17; H,4.22;
N,10.34%].
[0919] (be) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(at), there was prepared
N-(3,5-dichloro-4-pyridyl)-3-- methyl-1H-indole-6-carboxamide as a
white solid, m.p. 223-225.degree. C. [Elemental analysis: C,56.00;
H,3.50; N,12.90%. Calculated for C.sub.15H.sub.11Cl.sub.2N.sub.3O:
C,56.27; H,3.46; N,13.12%].
[0920] (bf) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dichloro-pyridine N-oxide and Reference Example
1(au), there was prepared
1-butyloxycarbonyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-me-
thyl-indole-6-carboxamide as a white solid. NMR
{(CD.sub.3).sub.2SO}: .delta.1.60(s), 2.30(s), 7.60-7.70(m),
7.80-7.90(s), 8.70(s), 10.50(s).
[0921] (bg) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(aw), there was prepared
N-(3,5-dichloro-4-pyridyl)-1H- -indole-6-carboxamide as a white
solid.
[0922] (bh) By proceeding in a similar manner to Example 1(a) but
using Reference Example 1(av), there was prepared
1-benzyl-N-(3,5-dichloro-4-py-
ridyl)-3-methyl-1H-indoline-6-carboxamide as a yellow solid, m.p.
223-225.degree. C. [Elemental analysis: C,63.56; H,4.94; N,9.53%.
Calculated for C.sub.22H.sub.19Cl.sub.2N.sub.3O: C,64.09; H,4.69;
N,10.19%]. NMR (CD.sub.3Cl): .delta.1.20-1.30(m,1H); 1.30(m,1H);
2.90-3.00(m,1H); 3.30-3.40(m,1H); 3.50-3.60(m,1H); 4.20-4.30 and
4.40-4.50(m,2H); 7.00(m,1H);7.10-7.40(m,7H); 7.70(s,1H);
8.60(s,2H).
[0923] (bi) By proceeding in a similar manner to Example 1(a) but
using 4-aminopyridine and Reference Example 1(ai), there was
prepared
1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-3-methyl-N-(4-pyridyl)-1H--
indole-6-carboxamide as a white solid. [Elemental analysis:
C,76.08; H,7.47, N,10.50%. Calculated for
C.sub.25H.sub.29N.sub.3O.0.5H.sub.2O: C,75.66; H,7.63; N,10.60%].
NMR (CDCl.sub.3): .delta.0.75(s,3H), 1.1(s,3H), 1.3-1.4(m,1H),
1.4-1.5(m,1H), 1.6-1.8(m,4H), 1.8-1.9(m,1H), 2.05-2.15(m,1H),
2.3(s,3H), 2.45-2.55(m,1H), 3.8-3.9(m,2H), 7.0(s,1H),
7.4-7.5(m,1H), 7.55-7.60, 7.6-7.65(m,3H), 8.0(s,1H), 8.2(s,1H),
8.5(m,2H).
[0924] (bj) By proceeding in a similar manner to Example 1(a) but
using 4-hydroxyaniline and Reference Example 1(av), there was
prepared
1-benzyl-N-(4-hydroxyphenyl)-3-methyl-1H-indole-6-carboxamide as a
white solid, m.p. 230-231.degree. C. [Elemental analysis: C,75.46;
H,6.17; N,7.05%. Calculated for
C.sub.23H.sub.20N.sub.2O.0.6H.sub.2O: C,75.16; H,5.82; N,7.63%].
NMR [(CD.sub.3).sub.2CO]: .delta.2.2(s,3H), 5.5(s,2H),
6.8-6.85(m,2H), 7.2-7.3(m,5H), 7.55-7.6(m,3H), 7.7-7.75(m,1H),
8.1(s,1H), 9.4(s, 1H).
[0925] (bk) By proceeding in a similar manner to Example 1(a) but
using 4-aminopyrimidine and Reference Example 1(ae), there was
prepared
1-(2-cyclohexyl)ethyl-3-methyl-N-(4-pyrimidinyl)-1H-indole-6-carboxamide
as a white solid, m.p. 192-194.degree. C. [Elemental analysis:
C,73.22; H,7.24; N,15.18%. Calculated for C.sub.22H.sub.26N.sub.4O:
C,72.90; H,7.23; N,15.46%]. NMR [(CD.sub.3).sub.2CO]:
.delta.0.9-1.1, 1.1-1.3 (m,6H), 1.6-1.9(m,7H), 2.3(s,3H),
4.3-4.4(m,2H), 7.3(s,1H(, 7.6-7.65, 7.8-7.85(m,2H), 8.3-8.4(m,2H),
8.6-8.7(m,1H), 8.9(s,1H), 9.8(m,1H).
[0926] (bl) By proceeding in a similar manner to Example 1(a) but
using 4-amino-3,5-dimethyl-[1,2,4]-triazole and Reference Example
1(ai), there was prepared
1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-N-(3,5-dimeth-
yl-[1,2,4]-triazol-4-yl)-3-methyl-1H-indole-6-carboxamide as a
white solid, m.p. 135-140.degree. C. [Elemental analysis: C,69.61;
H,7.64; N,17.71%. Calculated for C.sub.24H.sub.31N.sub.5O: C,71.13;
H,7.71; N,17.28%]. NMR( CDCl.sub.3): .delta.0.7(s,3H), 1.19(s,3H),
1.25-1.4, 1.4-1.45, 1.45-1.6, 1.6-1.7, 1.7-1.8, 1.8-1.9 (m,7H),
2.0-2.1(s,1H), 2.3(s,3H), 2.35(s 3H), 2.4-2.55(m,1H), 3.-4.1(m,2H),
7.0(s,1H), 7.65-7.7, 7.9-7.95(m,2H), 8.35(s,1H).
EXAMPLE 2
[0927] (a)
(RS)-2-(Cyclohexyl-phenyl)methyl-N-(3,5-dichloro-1-oxido-4-pyri-
dinio)-7-methoxy-3H-benzimidazole-4-carboxamide
[0928] A solution of
(RS)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-p-
yridyl)-7-methoxy-3H-benzimidazole-4-carboxamide [0.545 g, Example
1(g)] in chloroform (15 ml)was treated with meta-chloroperbenzoic
acid (1.6 g, 70%). The reaction mixture was stirred at ambient
temperature for 15 hours, then diluted with chloroform. The mixture
was washed with saturated sodium bicarbonate solution, then with
water and then with brine. The organic phase was dried over
magnesium sulphate and then evaporated. The residue was subjected
to flash chromatography on silica eluting with a mixture of ethyl
acetate and hexanes (2:1, v/v) to give the title compound (0.12 g)
as a tan coloured solid, m.p. 310-312.degree. C. [Elemental
analysis: C,61.0; H,5.00; N,10.2; H.sub.2O,1.70%. Calculated for
C.sub.27H.sub.26Cl.sub.2N.sub.4O.sub.3.0.5H.sub.2O: C,60.6; H,5.09;
N,10.5, H.sub.2O,1.07%].
[0929] (b) By proceeding in a similar manner to Example 2(a) but
using Example 1(i), there was prepared
(RS)-N-(3,5-dichloro-1-oxido-4-pyridinio-
)-7-methoxy-2-(2-phenyl)propyl-3H-benzimidazole-4-carboxamide as a
yellow solid, m.p. 256-258.degree. C. [Elemental analysis: C,57.4;
H,4.40; N,11.4%. Calculated for
C.sub.23H.sub.20Cl.sub.2N.sub.4O.sub.3.90.5H.sub.- 2O: C,57.1;
H,4.41; N,11.7%].
[0930] (c) By proceeding in a similar manner to Example 2(a) but
using Example 1(1), there was prepared
2-(4-bromobenzyl)-N-(3,5-dichloro-1-oxid-
o-4-pyridinio)-7-methoxy-3H-benzimidazole-4-carboxamide as a pale
yellow solid, m.p. 248.degree. C. [Elemental analysis: C,48.1;
H,3.10; N,10.0%. Calculated for
C.sub.21H.sub.15BrCl.sub.2N.sub.4O.sub.3.0.5H.sub.2O: C,57.1;
H,4.41; N,11.7%].
[0931] (d) By proceeding in a similar manner to Example 2(a) but
using Example 1(n), there was prepared
2-(4-cyanobenzyl)-N-(3,5-dichloro-1-oxid-
o-4-pyridinio)-7-methoxy-3H-benzimidazole-4-carboxamide as a white
solid, m.p. 253.degree. C. with decomposition. [Elemental analysis:
C,53.9; H,3.50; N,13.8; H.sub.2O,4.60%. Calculated for
C.sub.22H.sub.15Cl.sub.2N.- sub.4O.sub.3.1.25H.sub.2O: C,53.8;
H,3.59; N,14.3; H.sub.2O,4.59%].
[0932] (e) By proceeding in a similar manner to Example 2(a) but
using Example 1(a), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-7-m-
ethoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide as a white
solid, m.p. 244-247.degree. C. [Elemental analysis: C,48.5; H,3.60;
N,13.9%. Calculated: C,48.4; H,3.55; N,14.1%].
[0933] (f) By proceeding in a similar manner to Example 2(a) but
using Example 1(e), there was prepared
(RS)-N-(3,5-dichloro-1-oxido-4-pyridinio-
)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide as an
off-white solid. [Elemental analysis: C,57.1; H,3.90; N,12.0%.
Calculated for C.sub.22H.sub.18Cl.sub.2N.sub.4O.sub.3.0.25H2O:
C,57.2; H,4.04; N,12.1%]. NMR {(CD.sub.3).sub.2SO}:
.delta.1.75(d,J=7.5 Hz,3H), 4.03-4.46(q,J=7.5 Hz,1H), 6.98(d,J=8
Hz,1H), 7.3(m,5H), 7.88(d,J=8Hz,1H), 8.77(s,2H).
EXAMPLE 3
[0934] (a)
1-(2-Cyclopentyl-7-methoxy-3H-benzimidazol-4-yl)-2-(4-pyridyl)e-
thanone
[0935] A solution of diisopropylamine (0.47 ml) in tetrahydrofuran
(6 ml), cooled to -10.degree. C., was treated dropwise, with a
solution of butyl lithium in hexanes (1.2 ml, 2.5M). The resulting
solution was stirred for 10 minutes, then cooled to -78.degree. C.
and then treated dropwise with a solution of 4-picoline (0.29 ml)
in tetrahydrofuran (1 ml). This solution was stirred for 30 minutes
then treated with a solution of methyl
2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [0.274 g,
Reference Example 3(t)] in tetrahydrofuran (2 ml). The cold bath
was removed and the reaction mixture stirred for 15 minutes at
ambient temperature. The mixture was quenched with water, then
diluted with ethyl acetate. The organic phase was separated then
washed with brine, then dried over magnesium sulphate and then
evaporated. The residue was subjected to flash chromatography on
silica, eluting with a mixture of methanol and dichloromethane
(8:92,v/v), to give the title compound (0.126 g) as a white solid.
[Elemental analysis: C,71.7; H,6.40; N,12.5%. Calculated: C,71.6;
H,6.31; N,12.5%]. NMR (CDCl.sub.3): .delta.1.63-2.05(m,6H),
2.2(m,2H), 3.33(m,1H), 4.11 (s,3H), 4.35(s,2H), 6.72(d,J=8 Hz, 1H),
7.23(m,2H), 7.82(d,J=8 Hz 8.6(m,2H).
[0936] (b) By proceeding in a similar manner to Reference Example
3(a), but using 3,5-dichloro-4-methylpyridine and Reference Example
3(l), there was prepared
2-(3,5-dichloro-4-pyridyl)-1-[1-(4-methoxybenzyl)-3-methyl-1-
H-indol-6-yl]-ethanone as a white solid, m.p. 165-167.degree. C.
[Elemental analysis: C,65.60; H,4.80; N,6.20%. Calculated for
C.sub.24H.sub.20Cl.sub.2N.sub.2O.sub.2: C,65.61; H,4.59;
N,6.38%].
[0937] (c) By proceeding in a similar manner to Reference Example
3(a), but using 3,5-dichloro-4-methylpyridine and Reference Example
3(s), there was prepared
2-(3,5-dichloro-pyridin-4-yl)-1-[1-(1-toluene-4-sulphonyl)-3-
-methyl-1H-indol-6-yl]-ethanone as a yellow solid, m.p.
193-198.degree. C. [Elemental analysis: C,57.90; H,3.90; N,5.80%.
Calculated for C.sub.23H.sub.18Cl.sub.2N.sub.2O.sub.3S: C,58.36;
H,3.83; N,5.92%].
[0938] (d) By proceeding in a similar manner to Reference Example
3(a), but using Reference Example 3(l), there was prepared
1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-2-(4-pyridyl)-ethanone
as a yellow solid, m.p 109-110.degree. C. [Elemental analysis:
C,77.20; H,6.30; N,7.40%. Calculated for
C.sub.24H.sub.22N.sub.2O.sub.2O.0.25H.sub- .2O: C,76.86; H,6.05;
N,7.48%]. NMR (CDCl.sub.3): .delta.2.30(s,3H); 3.80(s,3H);
4.30(s,2H); 5.20(s,2H); 6.80(s,2H); 7.00-7.05(m,3H);
7.15-7.20(m,2H); 7.55-7.60(m,1H): 7.70-7.75(m,1H); 8.00(s,1H);
8.45-8.50(m,2H).
EXAMPLES 4 and 5
[0939]
1-(7-Methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)eth-
anone and
1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-
-4-yl)-propan-2-ol
[0940] A solution of diisopropylamine (1.51 g) in tetrahydrofuran
(15 ml), under nitrogen, cooled to --10.degree. C. was treated with
butyl lithium in hexane (6 ml, 2.5M). The solution was cooled to
-78.degree. C. then treated dropwise with a solution of 4-picoline
(1.40 g) in tetrahydrofuran (10 ml) followed by a solution of
methyl 7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate
[1,25 g, Reference Example 3(a)] in tetrahydrofuran (15 ml). The
brown solution was allowed to warm to room temperature and the
resulting yellow suspension was filtered. The insoluble material
was washed with a little tetrahydrofuran then air dried. The yellow
solid (2.3 g) was dissolved in water (75 ml) and the solution
extracted three times with dichloromethane (25 ml). The combined
extracts were dried over magnesium sulphate and then evaporated.
The resulting yellow solid (1.53 g) was subjected to flash
chromatography on silica eluting initially with a mixture of
methanol and dichloromethane (5:95, v/v) to give
1-(7-methoxy-2-methoxyme-
thyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone (0.39 g)
recrystallised from toluene as a yellow solid, m.p. 218-220.degree.
C. with decomposition. [Elemental analysis: C,66.58; H,5.53;
N,13.76%. Calculated: C,66.45; H,5.50; N,13.5%]; then eluting with
a mixture of methanol and dichloromethane (1:9, v/v) to give
1,3-bis-(4-pyridyl)-2-(7--
methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-propan-2-ol (0.4 g)
recrystallised from methanol as a white solid, m.p. 210.degree. C.
with decomposition. [Elemental analysis: C,68.40; H,5.94; N,13.85%.
Calculated: C,68.30; H,5.98; N,14.00%].
EXAMPLE 6
[0941]
7-Methoxy-2-methoxymethyl-4-[2-(4-pyridyl)ethyl]-3H-benzimidazole
[0942] A mixture of
1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(-
4-pyridyl)ethanone (0.92 g, Example 4), hydrazine hydrate (0.8 ml,
98%) and potassium hydroxide (1.6 g) in diethylene glycol (10 ml)
was heated at 100.degree. C. for 5 minutes. The resulting clear
solution was the heated at 160.degree. C. for 1 hour, then heated
at 180.degree. C. for 2 hours whilst removing water at intervals
from an attached air condenser. The red solution was cooled to room
temperature then poured into water (200 ml). The mixture was
extracted three times with dichloromethane (100 ml). The combined
extracts were dried over magnesium sulphate and then evaporated.
The residue was subjected to flash chromatography on silica eluting
with a mixture of methanol and dichloromethane (5:95, v/v).
Fractions containing the required product were combined and
evaporated. The resulting solid was combined with material
similarly prepared from 0.47 g of
1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl-
)ethanone and dissolved in dichloromethane (50 ml). The solution
was washed with water (100 ml) then dried over magnesium sulphate
and then evaporated. The residual white solid (1.03 g) was
recrystallised from toluene to give the title compound (0.95 g) as
a white solid, m.p. 154-156.degree. C. [Elemental analysis:
C,68.09; H,6.43; N,13.87%. Calculated: C,68.67; H,6.44;
N,14.13%].
EXAMPLE 7
2-(4-carboxamidobenzyl
-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidaz-
ole-4-carboxamide
[0943] A solution of
2-(4-cyanobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methox-
y-3H-benzimidazole-4-carboxamide [0.1 g, Example 1(n)] in dimethyl
sulphoxide (0.3 ml) was treated with potassium carbonate (6mg) and
hydrogen peroxide (0.05 ml, 30%). The reaction mixture was stirred
at ambient temperature for 12 hours then treated with water (50
ml). The resulting solid was filtered and air dried to give the
title compound (77%) as a white solid, m.p. 292-293.degree. C.
[Elemental analysis: C,55.2; H,3.70; N,13.9; H20,1.90%. Calculated
for C.sub.22H.sub.17Cl.sub.- 2N.sub.5O.sub.3.0.5H.sub.2O: C,55.1;
H,3.79; N,13.9, H2O,1.88%]. NMR {(CD.sub.3).sub.2SO}:
.delta.4.00(s,3H), 4.35(s,2H), 5.75(s,2H), 7.00(d,1H), 7.45(d,2H),
7.80(d,2H), 7.90(d,1H), 8.70(s,2H), 11.90(s,1H), 13.45(s,1H).
EXAMPLE 8
[2-(3-Chlorophenoxy)-pyridin-3-yl]-(7-methoxy-2-methoxymethyl-1H-benzimida-
zol-4-yl)-methanone
[0944] A solution of 3-bromo-2-(3-chlorophenoxy)pyridine (0.43 g,
Reference Example 16) in dry tetrahydrofuran (6 ml), at -70.degree.
C., was treated with butyl lithium in hexane (0.64 ml, 2.5M). The
mixture was then stirred at -70.degree. C. for 45 minutes then
treated with a solution of 1-benzotriazolyl
7-methoxy-2-methoxymethyl-3H-benzimidazole-4- -carboxylate [0.177
g, Reference Example 1(a)] in dry tetrahydrofuran (2 ml) and
stirring was continued at -70.degree. C. for 10 minutes. The
reaction mixture was allowed to warm to room temperature, then
stirred at this temperature for 2 hours, then treated with aqueous
ammonium chloride solution, and then extracted with ethyl acetate
(20 ml). The organic extract was dried and concentrated to give a
brown syrup which was purified by flash chromatography on silica
eluting initially with a mixture of diethyl ether and pentane (1:1,
v/v), then with a mixture of diethyl ether and pentane (7:3, v/v)
and then with diethyl ether to give the title compound (0.04 g) as
white solid, m.p. 181-183.degree. C. [Elemental analysis: C,62.17,
H,4.32, N,10.15%. Calculated : C,62.35, H,4.28, N,9.91%]. NMR
(CDCl.sub.3): .delta.3.52(s,3H), 4.13(s,3H), 4.85(s,2H), 6.73(d,J=8
Hz,1H), 7.00(m,1H), 7.12(t,J=2Hz,1H), 7.16(m,1H), 7.2(dd,J=7 Hz,J=5
Hz,1H), 7.28(t,J=8 Hz,1H), 7.55(d,J=8 Hz,1H), 7.85(dd,J=8
Hz,J=2Hz,1H), 8.83(dd,J=4 Hz,J=1 Hz,1H).
EXAMPLE 9
[0945] (a)
N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-2-methoxymethyl--
3H-benzimidazole-4-carboxamide
[0946] A suspension of
N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethy-
l-3H-benzimidazole-4-carboxamide [17.9 g, Example 1(a)] in
dichloromethane (325 ml) was treated with a peracetic acid (140 ml,
37% in acetic acid) giving a pale yellow solution which was stirred
at ambient temperature for 48 hours. The solution was concentrated
under reduced pressure, at ambient temperature, to remove the
volatile solvent and the remaining solution was neutralised by the
slow addition of a saturated aqueous sodium hydrogen carbonate
solution (500 ml). The solid which precipitated was collected by
filtration then washed with water and then recrystallised from
ethanol to give the title compound (12.7 g) as a white solid.
[0947] (b) By proceeding in a similar manner to Example 9(a) but
using Example 1 (t), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-2--
isopropyl-7-methoxy-3H-benzimidazole-4-carboxamide recrystallised
from ethanol as a white crystalline solid, m.p. 255-258.degree. C.
with decomposition. [Elemental analysis: C,51.14; H,4.13; N,13.95%.
Calculated: C,51.60; H,4.05; N,14.17%].
[0948] (c) By proceeding in a similar manner to Example 9(a) but
using Example 1(aa), there was prepared
N-(3,5-dichloro-1-oxido-4-pyridinio)-2,-
7-dimethoxy-3H-benzimidazole-4-carboxamide as a cream coloured
solid, m.p. decomposes above 247.degree. C. [Elemental analysis:
C,45.90; H,3.06; N,14.28%. Calculated: C,46.97; H,3.13;
N,14.62%].
EXAMPLE 10
[0949]
2-Cyclopropyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-3H-ben-
zimidazole-4-carboxamide
[0950]
2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-
-4-carboxamide [0.45 g, Example 1(ab)] was treated with peracetic
acid (3 ml, 32% in acetic acid) and the mixture heated at
60.degree. C. for 2.25 hours then left at room temperature for 18
hours. The reaction mixture was diluted with diethyl ether (60 ml),
then cooled and then filtered. The yellow solid was heated with
ethanol (40 ml) then filtered to remove a small amount of insoluble
solid. The filtrate was concentrated to about 25 ml volume and
stood at ambient temperature. The resulting yellow crystals were
filtered and combined with a separate batch synthesised in a
similar manner from 0.40 g of
2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)--
7-methoxy-3H-benzimidazole-4-carboxamide. The combined material was
heated with methanol (50 ml) then filtered to remove a small amount
of insoluble solid. The filtrate was concentrated to about 25 ml
volume and stood at ambient temperature.
[0951] The resulting yellow crystals were filtered, washed with
methanol and then with diethyl ether to give the title compound
(0.185 g) as cream coloured crystals, m.p. 271-274.degree. C.
[Elemental analysis: C,51.91; H,3.59; N,14.24%. Calculated:
C,52.12; H,3.53; N,14.26%].
EXAMPLE 11
[0952] (a)
2-Cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-be-
nzimidazole
[0953] A stirred solution of
2-cyclopropyl-7-(3,5-dimethyl-4-pyridylmethox- y)-4-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole (3.49
mMol, Reference Example 17) in methylated spirits (50 ml) was
treated with hydrochloric acid (50 ml, 5M) and the mixture was then
heated at reflux for 5 hours. The resulting solution was cooled to
room temperature and then evaporated. The residue was partitioned
between water (10 ml) and ethyl acetate (50 ml). The pH of the
aqueous phase was adjusted to 8, with cooling, and the resulting
white solid was washed with water, then with ethyl acetate, then
dried at 70.degree. C. to afford the title compound (0.47 g) as a
cream coloured solid, m.p. 152-155.degree. C. [Elemental analysis:
C,62.60; H,6.65; N,11.52%. Calculated: C,70,57; H,6.55;
N,12.99%].
[0954] (b) By proceeding in a similar manner to Example 11(a) but
using Reference Example 18, there was prepared
4-(3,5-dimethyl-4-pyridylmethoxy-
)-7-methoxy-2-methoxymethyl-3H-benzimidazole as a cream coloured
solid, m.p. 196-198.degree. C. [Elemental analysis: C,65.74;
H,6.63; N,12.77%. Calculated: C,66.04; H,6.47; N,12.83%].
[0955] (c) By proceeding in a similar manner to Example 11(a) but
using Reference Example 36, there was prepared ethyl
5-(2-cyclopropyl-7-methoxy-
-benzimidazole-4-yl)pyridine-2-carboxylate as cream coloured solid,
m.p. 126-128.degree. C.
[0956] (d) By proceeding in a similar manner to Example 11(a) but
using Reference Example 34 there was prepared
2-cyclopropyl-7-methoxy-4-(4-morp-
holinosulphonyl)-3H-benzimidazole as white solid, m.p.
294-295.degree. C.
EXAMPLE 12
[0957] (a)
1-Benzyl-7-methoxy-2-methoxymethyl-4-(2-(4-pyridylmethyl)-1H-be-
nzimidazole hydrochloride dihydrate
[0958] A solution of
7-methoxy-2-methoxymethyl-4-[2-(4-pyridyl)ethyl]-3H-b- enzimidazole
(0.35 g, Example 6) and dimethylformamide (10 ml) was treated with
sodium hydride (0.06 g, 60% dispersion in mineral oil) under argon.
After stirring at room temperature the mixture was treated with
benzyl bromide (0.15 ml) and stirring was continued for 16 hours.
The reaction mixture was evaporated and the residue was treated
with hydrochloric acid solution (20 ml, 1M) then washed with three
portions of ethyl acetate (20 ml). The pH of the aqueous phase was
adjusted to 12 by addition of sodium hydroxide solution (1M). The
resulting solid was filtered, then dried, then dissolved in
isopropanol (2 ml) and then treated with a few drops of
concentrated hydrochloric acid. The mixture was allowed to stand at
room temperature for 16 hours and the solid formed was filtered,
then washed with isopropanol and then dried at 90.degree. C. under
vacuum to give the title compound as a white solid (0.2 g), m.p.
193-196.degree. C. (decomposed). [Elemental analysis: C,61.3;
H,6.1; N,9.2%. Calculated: C,62.6; H,6.3; N,9.1]%.
[0959] (b) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and chloromethylcyclohexane there was prepared
1-cyclohexylmethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carbox-
amide as a yellow solid, m.p. 147-151.degree. C. [Elemental
analysis: C,62.97; H,5.83; N,9.52%. Calculated for
C.sub.22H.sub.23Cl.sub.2N.sub.3O- .0.3H.sub.2O: C,62.63; H,5.64;
N,9.97%].
[0960] (c) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and (2-chloroethyl)-cyclohexane, there was
prepared
1-(2-cyclohexyl)ethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-H-indole-6-carb-
oxamide as a white solid, m.p. 163-165.degree. C. [Elemental
analysis: C,63.00; H,5.79; N,9.71%. Calculated for
C.sub.23H.sub.25Cl.sub.2N.sub.3O- .0.25H.sub.2O: C,63.50; H,5.91;
N,9.97%].
[0961] (b) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 3-cyclohexyl-chloropropane there was
prepared
1-[3-(cyclohexyl)propyl]-N-(3.5-dichloro-4-pyridyl)-3-methyl-1H-indole-6--
carboxamide as a white solid, m.p. 174-176.degree. C. [Elemental
analysis: C,64.69; H,5.98; N,9.43%. Calculated for
C.sub.24H.sub.27Cl.sub.2N.sub.3O- : C,64.89; H,6.12; N,9.46%].
[0962] (e) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 1-chloroheptane there was prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-heptyl-1H-indole-6-carboxamide
as a white solid, m.p. 151-152.degree. C. [Elemental analysis:
C,62.94; H,5.80; N,9.84%. Calculated for
C.sub.22H.sub.25Cl.sub.2N.sub.3O: C,63.16; H,6.02; N,10.04%].
[0963] (i) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 2-(chloromethyl)tetrahydro-2H-pyran there
was prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydro-2H1-pyran-2-yl)methyl-1-
H-indole-6-carboxamide as a white solid, m.p. 159-161.degree. C.
[Elemental analysis: C,60.20; H,5.30; N,9.80%. Calculated for
C.sub.21H.sub.21Cl.sub.2N.sub.3O.sub.2: C,60.30; H,5.06;
N,10.04%].
[0964] (j) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 2-(chloromethyl)-tetrahydrofuran there was
prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-2-yl)methyl-1H-ind-
ole-6-carboxamide as a yellow solid, m.p. 189-191.degree. C.
[Elemental analysis: C,59.40; H,4.90; N,10.00%. Calculated for
C.sub.20H.sub.19Cl.sub.2N.sub.3O.sub.2: C,59.42; H,4.74;
N,10.39%].
[0965] (k) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 4-toluenesulphonyl chloride there was
prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(toluene-4-sulphonyl)-1H-indole-6-c-
arboxamide as a white solid, m.p. 186-190.degree. C. [Elemental
analysis: C,55.48; H,3.95; N,8.43%. Calculated for
C.sub.22H.sub.17Cl.sub.2N.sub.3O- .sub.3S: C,55.70; H,3.61;
N,8.86%].
[0966] (l) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 3-chlorotetrahydrofuran there was prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6--
carboxamide as a beige coloured solid, m.p. 184.degree. C.
[Elemental analysis: C,58.30; H,4.60; N,10.30%. Calculated for
C.sub.19H.sub.17Cl.sub.2N.sub.3O.sub.2: C,58.48; H,4.39;
N,10.77%].
[0967] (m) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 3-methoxy-chlorocyclopentane there was
prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-methoxy)cyclopentyl-1H-indole-6--
carboxamide as a beige coloured solid, m.p. 100-120.degree. C. with
decomposition. [Elemental analysis: C,59.90; H,5.10; N,9.80%.
Calculated for C.sub.21H.sub.21Cl.sub.2N.sub.3O.sub.2: C,60.30;
H,5.06; N,10.04%].
[0968] (n) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 5-chloro-2-chloromethyl-thiophene there was
prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-chlorothiophen-2-ylmethyl-1H-ind-
ole-6carboxamide as a yellow solid, m.p. >165.degree. C. with
decomposition. [Elemental analysis: C,52.84; H,2.98; N,9.04%.
Calculated for C.sub.20H.sub.14Cl.sub.3N.sub.3O: C,53.29; H,3.13;
N,9.32%].
[0969] (o) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 4-(chloromethyl)-3,5-dimethylisoxazole
there was prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3,5-dimethylisoxazol-4-yl-
)methyl-1H-indole-6-carboxamide as a white solid, m.p.
243-246.degree. C. [Elemental analysis: C,58.62; H,4.43; N,12.72%.
Calculated for C.sub.21H.sub.18Cl.sub.2N.sub.4O.sub.2: C,58.75;
H,4.23; N,13.05%].
[0970] (p) By proceeding in a similar manner to Example 12(a) but
using N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide
[Example 1(be)] and 4-chloromethyl-2-methyl-thiazole there was
prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-methyl-thiazol-4-yl)methyl-1H-in-
dole-6-carboxamide as a white solid, m.p. 217-219.degree. C.
[Elemental analysis: C,55.22; H,3.63; N,12.74%. Calculated for
C.sub.20H.sub.16Cl.sub.2N.sub.4OS.0.25H2O: C,55.10; H,3.82;
N,12.86%].
[0971] (q) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and methyl 2-chloromethylfuran-2-carboxylate
there was prepared methyl
5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indol--
1-ylmethyl]-furan-2-carboxylate as a white solid, m.p. 217.degree.
C. [Elemental analysis: C,57.03; H,3.50; N,8.88%. Calculated for
C.sub.22H.sub.17Cl.sub.2N.sub.3O.sub.4.0.25H2O: C,57.05; H,3.81;
N,9.08%].
[0972] (r) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 3-chloromethyl-5-phenyl-[1,2,4]-oxadiazole
there was prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-phenyl-[1,2,4]oxadiazol-
-3-yl)methyl-1H-indole-6-carboxamide as a white solid, m.p.
225-227.degree. C. [Elemental analysis: C,59.24; H,3.73; N,14.09%.
Calculated for C.sub.24H.sub.17Cl.sub.2N.sub.5O.sub.2.0.5H.sub.2O:
C,59.13; H,3.72; N,14.38%].
[0973] (s) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 4-(2-chloroethyl)-morpholine there was
prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-morpholin-4-yl)ethyl-1H-indole-6-
-carboxamide as a yellow solid, m.p. 172.degree. C. [Elemental
analysis: C,57.78; H,5.07; N,12.76%. Calculated for
C.sub.21H.sub.22Cl.sub.2N.sub.4- O.sub.2: C,58.21; H,5.12;
N,12.93%].
[0974] (t) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and methyl 5-chloro-pentanoate there was
prepared methyl
5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indole-1-yl]-pentanoat-
e as a white solid, m.p. 134.degree. C. [Elemental analysis:
C,58.09; H,5.05; N,9.50%. Calculated for
C.sub.21H.sub.21Cl.sub.2N.sub.3O.sub.3: C,58.07; H,4.87;
N,9.67%].
[0975] (u) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 4-trifluoromethylbenzyl chloride there was
prepared
N-(3,5-dichloro-4-pyridyl)-1-(4-trifluorobenzyl)-3-methyl-1H-indole-6-car-
boxamide as a white solid, m.p. 221-222.degree. C. [Elemental
analysis: C,57.63; H,3.39; N,8.81%. Calculated for
C.sub.23H.sub.16Cl.sub.2F.sub.3N- .sub.3O: C,57.76; H,3.37;
N,8.79%].
[0976] (v) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 4-methylsulphonylbenzyl chloride there was
prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(4-methylsulphonylbenzyl)-1H-indole-
-6-carboxamide as a white solid, m.p. 125-140.degree. C.
NMR(CDCl.sub.3): .delta.2.3(3H,s), 3.2(3H,s), 5.6(2H,s),
7.3-7.4(2H,m), 7.5(1H,s), 7.6-7.75(2H,m), 7.9(2H,m), 8.1(1H,s),
8.7(2H,s).
[0977] (w) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 4-methoxycarbonylbenzyl chloride there was
prepared
N-(3,5-dichloro-4-pyridyl)-1-(4-methoxycarbonylbenzyl)-3-methyl-1H-indole-
-6-carboxamide as a white solid, m.p. 172-174.degree. C. [Elemental
analysis: C,61.10; H,4.02; N,8.81%. Calculated for
C.sub.24H.sub.19Cl.sub.2N.sub.3O.sub.3: C,61.55; H,4.09;
N,8.97%].
[0978] (x) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 3-nitrobenzyl chloride there was prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-nitrobenzyl)-1H-indole-6-carboxa-
mide as a yellow solid, m.p. 239-240.degree. C. [Elemental
analysis: C,57.63; H,3.75; N,11.80%. Calculated for
C.sub.22H.sub.16Cl.sub.2N.sub.4- O.sub.3.0.25H.sub.2O: C,57.45;
H,3.62; N,12.19%].
[0979] (y) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 2-chloromethylnaphthalene there was
prepared
N-(3,5-dichloro-4-pyridyl)-1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-
-carboxamide as a white solid, m.p. 241-243.degree. C. [Elemental
analysis: C,67.32; H,4.02; N,9.06%. Calculated for
C.sub.26H.sub.19Cl.sub.2N.sub.3O.0.25H2O: C,67.15; H,4.23;
N,9.05%].
[0980] (z) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 2-chloromethyl-4-biphenyl there was
prepared
N-(3,5-dichloro-4-pyridyl)-1-(biphenyl-4-yl)methyl-3-methyl-1H-indole-6-c-
arboxamide as a white solid, m.p. 229-230.degree. C. [Elemental
analysis: C,68.63; H,4.63; N,8.26%. Calculated for
C.sub.28H.sub.21Cl.sub.2N.sub.3O- .0.25H.sub.2O: C,68.48; H,4.42;
N,8.57%].
[0981] (aa) By proceeding in a similar manner to Example 12(a) but
using Example 1(be) and 1-benzyl-2-(chloromethyl)-imidazole there
was prepared
N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(1-benzyl-imidazol-2-yl)methyl-1H-i-
ndole-6-carboxamide as a yellow solid, m.p. 92-94.degree. C.
EXAMPLE 13
[0982] (a)
1-Cyclohexylmethyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinyl-
-1H-indole-6-carboxamide
[0983] A solution of
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indo-
le-6-carboxamide (0.25 g, Example 14) in a mixture of dimethyl
sulphoxide (5 ml) and tetrahydrofuran (5 ml) was added to a
suspension of sodium hydride (0.045 g) in a mixture of dimethyl
sulphoxide (2 ml) and tetrahydrofuran (2 ml) at 0.degree. C. The
mixture was stirred for 15 minutes then treated with
cyclohexylbromide (0.142 g) in a mixture of dimethyl sulphoxide (3
ml) and tetrahydrofuran (3 ml). This mixture was stirred at
0.degree. C. for 10 minutes then allowed to warm to room
temperature. The reaction mixture was quenched with ice-water then
diluted with water and then extracted three times with
dichloromethane (15 ml). The combined extracts were washed three
times with water (25 ml), then with brine (15 ml), then dried over
sodium sulphate and then evaporated. The residue was subjected to
flash column chromatography on silica eluting with a mixture of
ethyl acetate and hexane (gradient elution, 4:1 to 4:0, v/v) to
give the title compound (0.19 g) as a white solid, m.p. 127.degree.
C.
[0984] (b) By proceeding in a similar manner to Example 13(a) but
using 4-methoxycarbonylbenzyl bromide there was prepared
1-(4-methoxycarbonylbenzyl)-3-methyl-N-(3.5-dichloro-1-oxido-4-pyridinio)-
-1H1-indole-6-carboxamide as a white solid, m.p 169-172.degree. C.
[Elemental analysis: C,57.43; H,4.26; N,8.15%. Calculated for
C.sub.24H.sub.19Cl.sub.2N.sub.3O.sub.4.H.sub.2O C,57.36; H,4.22;
N,8.37%]. NMR {(CD.sub.3).sub.2CO}: .delta.2.30(s,3H); 3.80(s,3H);
5.60(s,2H); 7.20-7.30(s,2H); 7.40(s,1H); 7.60-7.65 (m,1H);
7.75-7.80(m,1H); 7.85-7.90(m,2H); 8.29(s,1H); 8.35(s,2H); 9.50
(bs,1H).
[0985] (c) By proceeding in a similar manner to Example 13(a) but
using 4-carboxybenzyl bromide there was prepared
1-(4-carboxybenzyl)-3-methyl-N-
-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamide as a
white solid, m.p 255-257.degree. C. with decomposition. [Elemental
analysis: C,58.05; H,3.84; N,8.66%. Calculated for
C.sub.23H.sub.17Cl.sub.2N.sub.3O- .sub.4: C,58.74; H,3.64;
N,8.93%].
[0986] (d) By proceeding in a similar manner to Example 13(a) but
using (5-chlorothiophen-2-yl)methyl bromide there was prepared
1-(5-chlorothiophen-2-yl)methyl-N-(3.5-dichloro-1-oxido-4-pyridinio)-3-me-
thyl-1H-indole-6-carboxamide as a beige coloured solid, m.p
140-142.degree. C. with decomposition. [Elemental analysis:
C,50.95;H,3.13; N,8.38%. Calculated for
C.sub.20H.sub.14Cl.sub.3N.sub.3O.- sub.2S.0.4H.sub.2O: C,50.65;
H,3.152; N,8.87%]. NMR {(CD.sub.3).sub.2SO)}: .delta.2.30(s,3H);
5.50(s,2H); 7.00(s,2H); 7.40-7.45(m,1H); 7.60-7.65 and
7.70-7.75(m,2H); 8.20(s,1H); 8.70(s,2H); 10.30(bs,1H).
[0987] (e) By proceeding in a similar manner to Example 13(a) but
using 1-benzyl-2-(chloromethyl)imidazole there was prepared
1-(1-benzyl-imidazol-2-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-m-
ethyl-1H-indole-6-carboxamide as a white solid, m.p >112.degree.
C. with decomposition. NMR {(CD.sub.3).sub.2CO)}:
.delta.2.20(s,3H); 5.20(s,2H); 5.40(s,2H); 6.90-7.00(m,3H);
7.10-7.15(m,2H); 7.15-7.20(m,3H); 7.50-7.55 and 7.70-7.75(m,1H);
8.30(s,1H); 8.40(s,2H); 9.60(bs,1H).
[0988] (f) By proceeding in a similar manner to Example 13(a) but
using 4-(chloromethyl)-2-methylthiazole there was prepared
1-(2-methylthiazol-4-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-met-
hyl1H-indole-6-carboxamide as a yellow solid, m.p 125-127.degree.
C. with decomposition. [Elemental analysis: C,53.25; H,3.65;
N,12.25%. Calculated for C.sub.20H.sub.16Cl.sub.2N.sub.4O.sub.2:
C,53.70;H,3.61; N,12.52%](g) By proceeding in a similar manner to
Example 13(a) but using methyl 5-(bromomethyl)-furan-2-carboxylate
there was prepared methyl
5-[6-N-(3,5-dichloro-1-oxido-4-pyridinio)carbamoyl-3-methyl-indol-1-ylmet-
hyl]-furan-2-carboxylate as a white solid, m.p 196-198.degree. C.
[Elemental analysis: C,57.20;H,4.80; N,9.70%. Calculated for
C.sub.20H.sub.19Cl.sub.2N.sub.3O.sub.4: C,57.16;H,4.56;
N,10.00%].
[0989] (h) By proceeding in a similar manner to Example 13(a) but
using 4-(chloromethyl)-3,5-dimethylisoxazole there was prepared
1-(3,5-dimethylisoxazol-4-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)--
3-methyl-1H-indole-6carboxamide as a yellow solid, m.p
145-148.degree. C. [Elemental analysis: C,55.16; H,4.02; N,12.10%.
Calculated for C.sub.21H.sub.18Cl.sub.2N.sub.3O.sub.3: C,56.64,
H,4.07, N,12.58%].
[0990] (i) By proceeding in a similar manner to Example 12(a) but
using 4-(chloromethyl)-2-methylthiazole there was prepared
1-(2-methylthiazol-4-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-met-
hyl-1H-indole-6-carboxamide as a yellow solid, m.p 125-127.degree.
C. with decomposition. [Elemental analysis: C,53.25; H,3.65;
N,12.25%. Calculated for C.sub.20H.sub.16Cl.sub.2N.sub.4O.sub.2:
C,53.70;H,3.61; N,12.52%].
EXAMPLE 14
[0991]
N-(3,5-Dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxami-
de
1-Butyloxycarbonyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-indole-
-6-carboxamide (0.2 g, Example 1(bf) was heated at 170-180.degree.
C. for 10 minutes to give the title compound as a white solid which
was used without further purification. NMR {(CD.sub.3).sub.2SO}:
.delta.2.30(s), 7.30(s), 7.50-7.60(m), 8.00(s), 8.70(s), 10.30(s),
11.20(s).
EXAMPLE 15
[0992] (a)
N-(3,5-Dichloro-pyridin-4-yl)-3-ethyl-1-(toluene-4-sulphonyl)1H-
-indole-6-carboxamide
[0993] A stirred solution of
N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyeth-
yl)-1-(toluene-4-sulphonyl)-1-H-indole-6-carboxamide [0.06 g,
Example 16(a)] in dichloromethane (2ml), under nitrogen and at
0.degree. C., was treated with triethylsilane (0.028 g,) and boron
trifluoride dietherate (0.015 ml). The mixture was allowed to warm
to room temperature and then stirred at this temperature for 3
hours. The solution was partitioned between ethyl acetate (15 ml)
and saturated sodium bicarbonate solution (15 ml). The organic
layer was dried over sodium sulphate then evaporated. The residue
was subjected to flash column chromatography on silica eluting with
a mixture of ethyl acetate and hexane (gradient elution, 1:3 to
2.1, v/v) to give the title compound (22 mg) as a white solid, m.p.
147-149.degree. C. [Elemental analysis: C,56.69; H, 4.04; N,8.15%.
Calculated for C.sub.23H.sub.19Cl.sub.2N.sub.3O.sub.3S:
C,56.56;H,3.92; N,8.60%]
[0994] (b) By proceeding in a similar manner to Example 15(a) but
using
N-(3,5-dichloro-pyridin-4-yl)-3-(-1-hydroxy-1-methyl-propyl)-1-(toluene-4-
-sulphonyl)-1H indole-6-carboxamide, Example 16(b), there was
prepared
N-(3,5-dichloro-pyridin-4-yl)-3-(2-methyl-propyl)-1-(toluene-4-sulphonyl)-
-1H-indole-6-carboxamide as a white solid, m.p. 104-108.degree. C.
[Elemental analysis: C,58.84;H,4.67; N,7.80%. Calculated for
C.sub.25H.sub.23Cl.sub.2N.sub.3O.sub.3S: C,58.14;H,4.49;
N,8.14%].
EXAMPLE 16
[0995] (a) N-(3,5-Dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-
(toluene-4-sulphonyl)-1H-indole-6-carboxamide
[0996] A stirred solution of
N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(tol-
uene-4-sulphonyl)-1H-indole-6-carboxamide (0.1 g, Example 17) in
tetrahydofuran (3 ml), at 0.degree. C., was treated with a solution
of methylmagnesium bromide in diethyl ether (0.11 ml, 3M). The
mixture was allowed to warm to room temperature then stirred for 2
hours. The reaction mixture was quenched with water (15 ml) and
then extracted with ethyl acetate (15 ml). The organic extract was
dried over sodium sulphate then evaporated. The residue was
subjected to flash column chromatography on silica eluting with a
mixture of ethyl acetate and hexane (2:1, v/v) to yield the title
compound (68 mg) as a white solid, m.p. 206-211.degree. C.
[Elemental analysis: C,55.07;H,4.00; N,7.92%. Calculated for
C.sub.23H.sub.19Cl.sub.2N.sub.3O.sub.4S: C,54.77;H,3.80;
N,8.33%].
[0997] (b) By proceeding in a similar manner to Example 16(a) but
using isopropylmagnesium chloride there was prepared
N-(3,5-dichloro-pyridin-4--
yl)-3-(1-hydroxy-2-methyl-propyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carb-
oxamide.
EXAMPLE 17
N-(3,5-Dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-
-carboxamide
[0998] A stirred solution of
N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1H-ind- ole-6-carboxamide
(0.518 g, Example 18) in dimethylformamide at 0.degree. C. was
treated with sodium hydride (0.136 g). The mixture was stirred for
15 minutes, then cooled to -40.degree. C. and then treated with
4-toluenesulphonyl chloride (0.325 g). The reaction mixture was
gradually allowed to warm to -20.degree. C. over a period of 90
minutes, then quenched with water (20 ml), then extracted three
times with ethyl acetate (25 ml). The combined extracts were dried
over sodium sulphate then evaporated to give the title compound
(800 mg), which was used without further purification as a white
solid, m.p. 245.degree. C. [Elemental analysis: C,53.91;H,3.34;
N,8.30%. Calculated for C.sub.22H.sub.15Cl.sub.2N.sub.3O.sub.4S:
C,54.11;H,3.10; N,8.60%].
EXAMPLE 18
N-(3,5-Dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide
[0999] A stirred solution of dimethylformamide (10 ml), under
nitrogen and at 0.degree. C., was treated with phosphorus
oxychloride (0.6 ml). After stirring for 30 minutes at 0.degree. C.
the mixture was treated with a solution of
N-(3,5-dichloro-pyridin-4-yl)1H-indole-6-carboxamide [1.55 g,
Example 1(bg)] in dimethylformamide (5 ml). The mixture was then
heated at 40.degree. C. for 45 minutes then cooled to room
temperature and then partitioned between ethyl acetate (25 ml) and
saturated sodium bicarbonate (50 ml). The organic layer was washed
with water (75 ml) then dried over sodium sulphate then evaporated.
The residue was subjected to flash chromatography on silica eluting
with a mixture of ethyl acetate and hexane (1:2, v/v) to yield the
title compound (0.53 g) as a white solid. [Elemental analysis:
C,53.83;H,2.99; N,12.31%. Calculated for
C.sub.15H.sub.9Cl.sub.2N.sub.3O.sub.2: C,53.92;H,2.71;
N,12.57%].
EXAMPLE 19
1-Benzyl-4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6yl]-pyrrolidine-2-one
[1000] A solution of sodium hydride (0.013 g) in tetrahydrofuran at
0.degree. C., under argon, was treated with a solution of
4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one
(0.184 g, Example 20) and benzyl bromide (0.094 g) in dry
tetrahydrofuran. The mixture was allowed to warm to room
temperature then treated with N,N'-dimethylpropyleneurea (0.05 g).
After stirring at room temperature overnight the solution was
partitioned between ethyl acetate (15 ml)and 1N hydrochloric acid
(15 ml). The organic phase was dried over magnesium sulphate then
evaporated. The residue was subjected to preparative layer
chromatography on silica using a mixture of ethyl acetate and
hexane (3:7, v/v) as eluent to yield the title compound (0.18 g) as
an oil. [Elemental analysis: C, 79.16;H, 6.98; N, 6.14%. Calculated
for C.sub.29H.sub.30N.sub.2O.H.sub.2O: C,79.04;H,7.33;
N,6.36%].
EXAMPLE 20
4-3-Methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one
[1001] A solution of methyl
3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl-
)-3-nitromethyl-propionate (0.296 g, Reference Example 38) in
methanol (100 ml), under argon, was treated with excess Raney.RTM.
nickel. The argon atmosphere was replaced by hydrogen at 1
atmosphere then the mixture was stirred at room temperature for 2
hours. The reaction mixture was filtered through celite. The
filtrate was evaporated and the residual crude methyl
3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-3-aminomethy-
l-propionate was dissolved in sodium hydroxide solution (15 ml,
1N). After stirring at room temperature for 1 hour the reaction
mixture was extracted three times with ethyl acetate (15 ml). The
combined extracts were dried over sodium sulphate then evaporated.
The residue was subjected to preparative layer chromatography on
silica using a mixture of ethyl acetate and hexane (1:1, v/v) as
eluent to yield the title compound (0.198 g) as an oil. NMR
(CDCl.sub.3): .delta.2.05-2.15(m); 2.30(s); 2.55-2.60(m);
2.65-2.70(m); 2.85-2.95(m); 3.30-3.40(m); 3.60-3.70(m);
3.90-4.00(m); 4.40-4.60(m); 6.80-7.40(m). M.sup.+332.1941.
EXAMPLE 21
1-(4-Methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-ethyl)-1H-indole
[1002] A solution of cis- and
trans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phe-
nyl-2-pyridin-4-yl-vinyl)-1H-indole (70 mg, Example 22) in a
mixture of tetrahydrofuran and methanol (20 ml; 1:1, v/v) was
heated at 45-50.degree. C. under an atmosphere of hydrogen in the
presence of 6% palladium on activated charcoal then stirred
overnight at room temperature. The mixture was filtered through
celite then evaporated. The residue was subjected to high pressure
liquid chromatography using a hypersilC18 BDS column (250.times.20
ml, 8 micron) and eluting with methanol containing 0.1% ammonium
hydroxide to yield the title compound (13 mg) as an oil. NMR
(CDCl.sub.3): .delta.2.30(s,3H); 3.30-3.40(m,2H); 3.70(s,3H);
4.30-4.40(m,1H); 5.10(s,2H); 6.80-7.50 (m,13H); 8.30-8.35(m,2H);
8.50(bs,2H).
EXAMPLE 22
cis- and
trans-[1-(4-Methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vi-
nyl)-1H-indole
[1003] A stirred solution of
6-(1-hydroxy-1-phenyl-2-pyridin-4-yl)ethyl-1--
(4-methoxybenzyl)-3-methyl-1H-indole (50 mg, Example 23) in benzene
(1.5 ml) at 0.degree. C. was treated with 4-toluenesulphonic acid
(42 mg). After stirring at 0.degree. C. for 20 minutes the reaction
mixture was partitioned between ethyl acetate (10 ml) and saturated
sodium bicarbonate solution (10 ml). The organic layer was dried
over sodium sulphate then evaporated to yield the title compound
(45 mg) as a yellow solid. [Elemental analysis: C,82.40;H,6.20;
N,6.30%. Calculated for C.sub.30H.sub.26N.sub.2O.0.0.5H.sub.2O:
C,81.96;H,6.20; N,6.38%]. NMR(CDCl.sub.3): [3:1, trans:cis
isomers].delta.2.30 and 2.32(s,3H); 3.78 and 3.79(s,3H); 5.05 and
5.07(s,2H); 6.70-6.95, 6.95-7.05, 7.10-7.25 and 7.30-7.50 (m,11H);
8.35 (bs,2H).
EXAMPLE 23
6-(1-hydroxy-1-phenyl-2-pyridin-4-yl)ethyl-1-(4-methoxybenzyl)-3-methyl-1H-
-indole
[1004] A stirred solution of 4-methylpyridine (60 mg) in
tetrahydrofuran (3 ml), under nitrogen and at -78.degree. C., was
treated dropwise with a solution of n-butyllithium in hexane (0.385
ml). After 30 minutes a solution of
1-(4-methoxybenzyl)-3-methyl1H-indol-6-yl]-1-phenylmethanone (200
mg, Example 24) in tetrahydrofuran (3 ml) was added and the mixture
was stirred at -78.degree. C. for 1 hour, then warmed to room
temperature and then stirred overnight. The reaction mixture was
quenched with water (15 ml) and then extracted three times with
ethyl acetate (15 ml). The combined extracts were dried over sodium
sulphate and then evaporated. The residue was subjected to flash
column chromatography on silica eluting with a mixture of ethyl
acetate and hexane (gradient elution, 1:3 to 3:1, v/v) to yield the
title compound (115 mg) as a white solid. [Elemental analysis:
C,79.5;H,6.30; N,6.10%. Calculated for
C.sub.30H.sub.28N.sub.2O.sub.2.0.25H.sub.2O: C,79.5;H,6.34;
N,6.18%]. NMR (CDCl.sub.3): .delta.2.30(3H,s), 3.5-3.7(2H,m),
3.75(3H,s), 5.05(2H,s), 6.75-7.55 (m), 8.15-8.20(m,2H)
EXAMPLE 24
[1-(4-Methoxy-benzyl)-3-methyl-1H-indol-6-yl]-phenyl methanone
[1005] A stirred solution of
N-methoxy-1-(4-methoxybenzyl)-3-methyl-N-meth-
yl-1H-indole-6-carboxamide (2.215 g, Example 25) in tetrahydrofuran
(55 ml) was treated with a solution of phenylmagnesium chloride in
tetrahydrofuran (9.83 ml, 2M). The solution was stirred at
0.degree. C. for 2 hours then poured into a mixture of ice and 1N
hydrochloric acid (10 ml) and then partitioned between ethyl
acetate (50 ml) and water (50 ml). The organic layer was dried over
sodium sulphate then evaporated. The residue was subjected to flash
chromatography on silica eluting with a mixture of ethyl acetate
and hexane (1:2, v/v) to yield the title compound (2.05 g) as a
yellow solid, m.p. 146-147.degree. C. [Elemental analysis:
C,80.80;H,6.00; N,3.80%. Calculated for C.sub.24H.sub.21NO.sub.- 2:
C,81.10;H,5.96; N,3.94%].
EXAMPLE 25
N-methoxy-1-(4-methoxybenzyl)-3-methyl-N-methyl-1H-indole-6-carboxamide
[1006] A stirred solution of
1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carb- onyl chloride [2.8
g, Reference Example 42(b)] in chloroform (90 ml) at 0.degree. C.
was treated with N,O-dimethylhydroxylamine hydrochloride (0.982 g)
and pyridine (1.55 ml). The solution was stirred at room
temperature for 1 hour then evaporated. The residue was partitioned
between dichloromethane (100 ml) and brine (50 ml). The organic
layer was dried over sodium sulphate then evaporated. The residue
was subjected to flash chromatography on silica eluting with a
mixture of ethyl acetate and hexane (1:2, v/v) to yield the title
compound (2.8 g).
EXAMPLE 26
[1007] (a) 1-Benzyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-
methyl-1H-indazole-6-carboxamide
[1008] A solution of 4-amino-3,5-dichloropyridine-N-oxide (0.501 g,
prepared as described in the specification of International Patent
Application Publication No. WO 92/12961) in a mixture of toluene
and tetrahydrofuran (20 ml; 1:1, v/v) was treated with
trimethylaluminium (2.8 ml). After stirring at ambient temperature
for 1 hour the mixture was treated dropwise with a solution of
1-benzyl-3-methyl-1H-indazole carbonyl chloride (0.16 g, Reference
Example 42(a) in dry tetrahydrofuran (25 ml). Stirring was
continued at ambient temperature for 2 hours then the mixture was
heated at 90.degree. C. for 12 hours. The reaction mixture was
cooled to room temperature then poured into water (15 ml) then
extracted three times with ethyl acetate (45 ml). The combined
extracts were dried over sodium sulphate then evaporated. The
residue was subjected to preparative layer chromatography on silica
using a mixture of ethyl acetate and hexane (2:1, v/v) as eluent to
yield the title compound (0.071 g) as a white solid. [Elemental
analysis: C,58.03;H,3.78; N,12.60%. Calculated for
C.sub.21H.sub.16Cl.sub.2N.sub.4O.sub.2.0.5H.sub.- 2O:
C,57.79;H,3.93; N,12.85%].
[1009] (b) By proceeding in a similar manner to Example 26(a) but
using 4-amino-3,5-dichloropyridine and Reference Example 42(e)
there was prepared
N-(3,5-dichloro-4-pyridyl)-1-4-methoxybenzyl-3-methyl-1H-indazol-
e-6-carboxamide as a white solid, m.p. 213-214.degree. C.
[Elemental analysis: C,59.47; H,4.21; N,12.24%. Calculated for
C.sub.22H.sub.18Cl.sub.2N.sub.4O.sub.2.0.25H.sub.2O: C,59.25;
H,4.18; N,12.57%]. NMR (CDCl.sub.3): .delta.2.60(s,3H); 3.70(s,3H);
5.50(s,2H); 6.70-6.80 and 7.10-7.20(m,4H); 7.60-7.65, 7.70-7.75 and
8.00-8.05(m,3H); 8.50(bs,2H).
EXAMPLE 27
[1010] (a)
N-(3,5-Dichloro-1-oxido-4-pyridinio)-4-methoxy-2-methoxymethyl--
benzoxazole-6-carboxamide
[1011] A stirred solution of 4-acetylamino-3,5-dichloro-pyridine
N-oxide (0.64 g) in dry dimethylformamide (40 ml), under nitrogen
and at room temperature, was treated portionwise with sodium
hydride (2.15 g, 60% dispersion in mineral oil). After stirring for
1.5 hours the pale yellow solution was treated with a solution of
4-methoxy-2-methoxymethyl-benzoxa- zole-6-carbonyl chloride
[Reference Example 42(c), prepared from 0.68 g of
4-methoxy-2-methoxymethyl-benzoxazole-6-carboxylic acid] in dry
dimethylformamide (15 ml) whilst maintaining the reaction
temperature at about 10.degree. C. The reaction mixture was allowed
to warm to room temperature, then stood at room temperature for 18
hours, then treated with piperidine (1 ml), then stood at room
temperature for 24 hours. The mixture was evaporated and the
residual dark brown oil was treated with ethyl acetate, then
filtered. The filtrate was treated with silica (Ig) then
evaporated. The residue was subjected to flash chromatography on
silica eluting initially with dichloromethane then with a mixture
of dichloromethane and methanol (49:1 ,v/v) and then with a mixture
of dichloromethane and methanol (25:1 ,v/v). Fractions containing
the required product were combined and evaporated and the resulting
white solid was washed with diethyl ether to give the title
compound (0.44 g) as a white powder, m.p. 199-202.degree. C.
[Elemental analysis: C,48.26;H,3.43; N,10.83%. Calculated:
C,48.22;H,3.29; N,10.55%].
[1012] (b) By proceeding in a similar manner to Example 27(a) but
using 4-amino-3,5-dichloropyridine and Reference Example 42(d),
there was prepared
N-(3,5-dichloro-4-pyridyl)-3-isopropyl-1-methyl-1H-indole-5-carb-
oxamide which was recrystallised form toluene as a colourless
solid, m.p. 186-189.degree. C.
Reference Example 1
[1013] (a) 1'-Benzotriazolyl
7-methoxy-2-methoxymethyl-3H-benzimidazole-4-- carboxylate
[1014] A stirred solution of
7-methoxy-2-methoxymethyl-3H-benzimidazole-4-- carboxylic acid
[10.6 g, Reference Example 2(a)] in a mixture of dichloromethane
(120 ml) and diisopropylethylamine (12.5 ml) was treated with
O-benzotriazol-1-yl-N,N,N',N'-bis(tetramethylene)uronium
tetrafluoroborate (15.4 g). After stirring for 2 hours the reaction
mixture was evaporated. The residue was treated with toluene and
concentrated under vacuum affording the title compound which was
used without further purification.
[1015] (b) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(b), there was prepared
1'-benzotriazolyl
7-methoxy-2-phenyl-3H-benzimidazole-4-carboxylate.
[1016] (c) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(c), there was prepared
1'-benzotriazolyl
7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxylate.
[1017] (d) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(d), there was prepared
1'-benzotriazolyl
2-benzyl-7-methoxy-3H-benzimidazole-4-carboxylate.
[1018] (e) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(e), there was prepared
(RS)-1'-benzotriazolyl
7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxylate.
[1019] (f) By proceeding in a similar manner to Reference Example 1
(a) but using Reference Example 2(f), there was prepared
1'-benzotriazolyl
7-methoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-carboxylate
[1020] (g) By proceeding in a similar manner to Reference Example 1
(a) but using Reference Example 2(g), there was prepared
(RS)-1'-benzotriazolyl
2-(cyclohexyl-phenyl-methyl)-7-methoxy-3H-benzimid-
azole-4-carboxylate.
[1021] (h) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(h), there was prepared
(RS)-1'-benzotriazolyl
2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxylate
[1022] (i) By proceeding in a similar manner to Reference Example 1
(a) but using Reference Example 2(i), there was prepared
(RS)-1'-benzotriazolyl
7-methoxy2-(2-phenylpropyl)-3H-benzimidazole-4-car- boxylate.
[1023] (j) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(j), there was prepared
1'-benzotriazolyl
7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxylate
[1024] (k) By proceeding in a similar manner to Reference Example 1
(a) but using Reference Example 2(k), there was prepared
(RS)-1'-benzotriazolyl
7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-car- boxylate.
[1025] (l) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(1), there was prepared
1'-benzotriazolyl
2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate.
[1026] (m) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(m), there was prepared
(RS)-1'-benzotriazolyl
7-methoxy-2-(3-methoxy-1-phenyl-propyl)-3H-benzimidazole-4-carboxylate
[1027] (n) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(n), there was prepared
1'-benzotriazolyl 2-(4-cyanobenzyl
-7-methoxy-3H-benzimidazole-4-carboxylate.
[1028] (o) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(o), there was prepared
1'-benzotriazolyl
7-methoxy-2-(4-{3-pyridyl}benzyl)-3H-benzimidazole-4-carboxylate.
[1029] (p) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(p), there was prepared
1'-benzotriazolyl
7-methoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-carboxylate .
[1030] (q) By proceeding in a similar manner to Reference Example 1
(a) but using Reference Example 2(q), there was prepared
(RS)-1'-benzotriazolyl
7-methoxy-2-(methoxy-phenyl-methyl)-3H-benzimidazo-
le-4-carboxylate.
[1031] (r) By proceeding in a similar manner to Reference Example 1
(a) but using Reference Example 2(r), there was prepared
1'-benzotriazolyl
7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxylate.
[1032] (s) By proceeding in a similar manner to Reference Example 1
(a) but using Reference Example 2(s), there was prepared
1'-benzotriazolyl
7-methoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxylate.
[1033] (t) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(t), there was prepared
1'-benzotriazolyl
2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxylate.
[1034] (u) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(u), there was prepared
1'-benzotriazolyl
7-methoxy-2-methyl-3H-benzimidazole-4-carboxylate.
[1035] (v) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(v), there was prepared
1'-benzotriazolyl
7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxylate.
[1036] (w) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(w), there was prepared
1'-benzotriazolyl
2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate.
[1037] (x) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(x), there was prepared
1'-benzotriazolyl 2-benzyl-3H-benzimidazole-4-carboxylate.
[1038] (y) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(y), there was prepared
1'-benzotriazolyl
2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate.
[1039] (z) By proceeding in a similar manner to Reference Example 1
(a) but using Reference Example 2(z), there was prepared
1'-benzotriazolyl
2-cyclopentyl-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate.
[1040] (aa) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(aa), there was prepared
1'-benzotriazolyl 2,7-dimethoxy-3H-benzimidazole-4-carboxylate.
[1041] (ab) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(ab), there was prepared
1'-benzotriazolyl
2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carboxylate.
[1042] (ac) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(a), there was prepared
1-benzotriazolyl
1-cyclohexylmethyl-3-methyl-1H-indole-6-carboxylate.
[1043] (ad) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 31(b), there was prepared
1'-benzotriazolyl
1-cyclohexyl-3-methyl-1H-indole-6-carboxylate.
[1044] (ae) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(c), there was prepared
1'-benzotriazolyl
1-(2-cyclohexyl)ethyl-3-methyl-1H-indole-6-carboxylate.
[1045] (af) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(d), there was prepared
1-benzotriazolyl
1-(3-cyclohexyl)propyl-3-methyl-1H-indole-6-carboxylate.
[1046] (ag) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(e), there was prepared
1'-benzotriazolyl 1-heptyl-3-methyl-1H-indole-6-carboxylate.
[1047] (ah) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 31(d), there was prepared
1'-benzotriazolyl
1-cycloheptylmethyl-3-methyl-1H-indole-6-carboxylate.
[1048] (ai) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 31(a), there was prepared
1'-benzotriazolyl
1-(6,6-dimethyl-bicyclo[3.1.1.]hept-3-ylmethyl)-3-methyl-1H-indole-6-carb-
oxylate.
[1049] (aj) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(f), there was prepared
1-benzotriazolyl
1-(3-phenyl)butyl-3-methyl-1H-indole-6-carboxylate.
[1050] (ak) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(g), there was prepared
1'-benzotriazolyl
1-(4-trifluoromethylbenzyl)-3-methyl-1H-indole-6-carboxylate.
[1051] (al) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(h), there was prepared
1'-benzotriazol
1-(4-methylsulphonylbenzyl)-3-methyl-1H-indole-6-carboxylate.
[1052] (am) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(i), there was prepared
1'-benzotriazolyl
1-(1,3-benzodioxol-5-yl)methyl-3-methyl-1H-indole-6-carboxylate.
[1053] (an) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(j), there was prepared
1'-benzotriazolyl
3-methyl-1-(naphthalen-2-yl)methyl-1H-indole-6-carboxylate.
[1054] (ao) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(k), there was prepared
1'-benzotriazolyl
3-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl-1H-indole-6-carboxylate.
[1055] (ap) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(1), there was prepared
1'-benzotriazolyl
3-methyl-1-(tetrahydrofuryl)methyl-1H-indole-6-carboxylate.
[1056] (aq) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(m), there was prepared
1'-benzotriazolyl
3-methyl-1-(4-toluenesulphonyl)-1H-indole-6-carboxylate.
[1057] (ar) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(n), there was prepared
1'-benzotriazolyl
3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6-carboxylate.
[1058] (as) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 26(a), there was prepared
1'-benzotriazolyl-8-methoxy-2-n-propylquinoline-5-carboxylate.
[1059] (at) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 28(b), there was prepared
1-benzotriazolyl 3-methyl-1H-indole-6-carboxylate.
[1060] (au) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 32, there was prepared 1
'-benzotriazolyl l-butyloxycarbonyl-3-methyl-indole
6-carboxylate.
[1061] (av) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 37, there was prepared
1'-benzotriazolyl 1-benzyl-3-methyl1H-indoline-6-carboxylate.
[1062] (aw) By proceeding in a similar manner to Reference Example
1(a) but using 1H-indole-6-carboxylic acid, there was prepared
1'-benzotriazolyl 1H-indole-6carboxylate.
[1063] (ax) By proceeding in a similar manner to Reference Example
1(a) but using Reference Example 2(ac), there was prepared
1'-benzotriazolyl
7-methoxy-2-n-propyl-3H-benzimidazole-4-carboxylate.
Reference Example 2
[1064] a) 7-Methoxy-2-methoxymethyl-3H-benzimidazole-4- carboxylic
acid
[1065] A solution of methyl
7-methoxy-2-methoxymethyl-3H-benzimidazole-4-c- arboxylate [12.12
g, Reference Example 3(a)] in methanol (100 ml) was treated with 2M
sodium hydroxide (48 ml). The resulting mixture was heated to
50.degree. C. then stirred at this temperature for 6 hours. The
reaction mixture was concentrated to half its original volume then
treated with 1M hydrochloric acid (98 ml). The solution was cooled
in an icebath and the resulting solid filtered then dried under
high vacuum overnight to give the title compound (11.0 g) as a
solid. M.sup.+236. This material was used without further
purification.
[1066] (b) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(b), there was prepared
7-methoxy-2-phenyl-3H-be- nzimidazole-4-carboxylic acid as a white
solid. M.sup.+268.
[1067] (c) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(c), there was prepared
7-methoxy-2-phenethyl-3H- -benzimidazole-4-carboxylic acid as a
white solid. NMR {(CD.sub.3).sub.2SO}: .delta.3.10(m,2H),
3.25(m,2H), 4.05(s,3H), 6.90(d,J=8 Hz,1H), 7.25(m,5H), 7.83(d,J=8
Hz,1H).
[1068] (d) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(d), there was prepared
2-benzyl-7-methoxy-3H-be- nzimidazole-4-carboxylic acid as a solid.
NMR {(CD.sub.3).sub.2SO}: .delta.4.00(s,3H), 4.28(s,2H), 6.92(d,J=8
Hz,1H), 7.30(m,5H), 7.78(d,J=8 Hz,1H).
[1069] (e) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(e), there was prepared
(RS)-7-methoxy-2-(1-phen- ylethyl)-3H-benzimidazole-4-carboxylic
acid. M.sup.+296.
[1070] (f) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(f), there was prepared
7-methoxy-2-(4-methoxybe- nzyl)-3H-benzimidazole-4-carboxylic acid.
M.sup.+312.
[1071] (g) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(g), there was prepared
(RS)-2-(cyclohexyl-pheny- l-meth
)-7-methoxy-3H-benzimidazole-4-carboxylic acid as a tan coloured
solid.
[1072] (h) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(h), there was prepared
(RS)-2-(1,2-diphenylethy- l-7-methoxy-3H-benzimidazole-4-carboxylic
acid. M.sup.+372.
[1073] (i) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(i), there was prepared
(RS)-7-methoxy-2-(2-phen- ylpropyl)-3H-benzimidazole-4-carboxylic
acid. NMR {(CD.sub.3).sub.2SO}: .delta.1.20(d,3H), 3.50(m,3H),
3.95(s,3H), 7.15(m,1H), 7.15-7.20(m,1H), 7.23-7.36(m,4H),
7.69(d,1H), 12.10(bs,1H).
[1074] (j) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(j), there was prepared
7-methoxy-2-(4-methoxyph-
enoxymethyl)-3H-benzimidazole-4-carboxylic acid. M.sup.+328.
[1075] (k) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(k), there was prepared
(RS)-7-methoxy-2-(1-phen- ylbutyl).-3H-benzimidazole-4-carboxylic
acid. M.sup.+324.
[1076] (l) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(k), there was prepared
2-(4-bromobenzyl)-7-meth- oxy-3H-benzimidazole-4-carboxylic acid.
NMR {(CD.sub.3).sub.2SO}: .delta.3.90(s,3H), 4.30(s,2H),
6.80(d,1H), 7.20(d,2H), 7.40(d,2H), 7.75(d,l1H).
[1077] (m) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(m), there was prepared
(RS)-7-methoxy-2-(3-meth-
oxy-1-phenyl-propyl)-3H-benzimidazole-4-carboxylic acid.
M.sup.+340.
[1078] (n) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 14, there was prepared
2-(4-cyanobenzyl)-7-methox- y-3H-benzimidazole-4-carboxylic acid.
NMR {(CD.sub.3).sub.2SO}: .delta.4.00(s,3H), 4.35(s,2H),
6.80(d,1H), 7.35(d,2H), 7.50(d,2H), 7.75(d,1H).
[1079] (o) By proceeding in a similar manner to Reference Example
2(a) but Reference Example 15, there was prepared
7-methoxy-2-(4-{3-pyridyl}benzyl- )-3H-benzimidazole-4-carboxylic
acid. NMR {(CD.sub.3).sub.2SO}: .delta.3.95(s,3H), 4.30(s,2H),
6.75(d,1H), 7.45(d,3H), 7.70(d,3H), 8.05(dd,1H), 8.55(d,1H),
8.85(d,1H).
[1080] (p) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(n)], there was prepared
7-methoxy-2-(2-methoxyb- enzyl)-3H-benzimidazole-4-carboxylic acid.
M.sup.+312.
[1081] (q) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(o) or Reference Example 12,
there was prepared
(RS)-7-methoxy-2-(methoxy-phenyl-methyl)-3H-benzimidazole-4-carboxylic
acid. M.sup.+312.
[1082] (r) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(p), there was prepared
7-methoxy-2-(2-methoxyph-
enoxy)methyl-3H-benzimidazole-4-carboxylic acid.
[1083] (s) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 13, there was prepared
7-methoxy-2-(3-pyridyl)-3H- -benzimidazole-4-carboxylic acid.
[1084] (t) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(q), there was prepared
2-isopropyl-7-methoxy-3H- -benzimidazole-4-carboxylic acid as a
solid. NMR {(CD.sub.3).sub.2SO}: .delta.1.36(d,J=6 Hz,6H),
3.50(m1H), 4.05(s,3H), 6.95(d,J=8 Hz,1H), 7.85(d,J=8 Hz,1H).
[1085] (u) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(r), there was prepared
7-methoxy-2-methyl-3H-be- nzimidazole-4-carboxylic acid as a white
solid. M.sup.+206.
[1086] (v) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(s), there was prepared
7-methoxy-2-phenoxymethy- l-3H-benzimidazole-4-carboxylic acid as a
solid. M.sup.+298.
[1087] (w) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(t), there was prepared
2-cyclopentyl-7-methoxy-- 3H-benzimidazole-4-carboxylic acid as a
solid. NMR {(CD.sub.3).sub.2SO}: .delta.1.68(m,2H), 1.82(m,2H),
1.94(m,2H), 2.09(m,2H), 3.56(m,1H), 4.04(s,3H), 7.00(d,J=8 Hz,1H),
7.86(d,J=8 Hz,1H).
[1088] (x) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(u), there was prepared
2-benzyl-3H-benzimidazol- e-4-carboxylic acid. M.sup.+252.
[1089] (y) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 5, there was prepared
2-cyclopentyl-7-methoxy-1-m- ethyl-1H-benzimidazole-4-carboxylic
acid. M.sup.+274.
[1090] (z) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 6, there was prepared
2-cyclopentyl-7-methoxy-3-m- ethyl-3H-benzimidazole-4-carboxylic
acid.
[1091] (aa) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 7, there was prepared
2,7-dimethoxy-3H-benzim- idazole-4-carboxylic acid. M.sup.+222.
[1092] (ab) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(v), there was prepared
2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carboxylic acid.
[Elemental analysis: C,62.06;H,5.21; N,12.05%. Calculated:
C,62.07;H,5.17; N,12.07%].
[1093] (ac) By proceeding in a similar manner to Reference Example
2(a) but using Reference Example 3(x), there was prepared
7-methoxy-2-n-propyl-3H-benzimidazole-4-carboxylic acid.
Reference Example 3
[1094] (a) Methyl
7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate
[1095] A solution of methyl
3-(1-imino-2-methoxy-ethylamino)-4-methoxybenz- oate [15.7 g,
Reference Example 4(a)] in methanol (150 ml) was treated with 1M
hydrochloric acid (62.6 ml) then with sodium hypochlorite solution
(32.3 ml, 13%). Further aliquots of sodium hypochlorite solution
were added until all the starting material was consumed. The
solution containing methyl
3-(1-chloroimino-2-methoxy-ethylamino)-4-methoxybenzoat- e was
treated with a saturated solution of sodium carbonate (8.62 g) in
water. The mixture was then refluxed for 1 hour, then cooled to
room temperature, then diluted with water and then extracted with
chloroform. The chloroform extract was washed with brine, dried
over magnesium sulphate and then evaporated. The residue was
subjected to flash chromatography on silica eluting with a mixture
of ethyl acetate and hexane (1:1, v/v) then with a mixture of ethyl
acetate and hexane (6:1, v/v) to give the title compound (13.0 g)
as a solid. M.sup.+250.NMR (CDCl.sub.3): .delta.3.48(s,3H),
3.98(s,3H), 4.10(s,3H), 4.78(s,2H), 6.70(d,J=8 Hz,1H), 7.87(d,J=8
Hz,1H).
[1096] (b) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(b), there was prepared methyl
7-methoxy-2-phenyl-3H-benzimidazole-4-carboxylate as a solid. NMR
(CDCl.sub.3): .delta.4.00(s,3H), 4.11(s,3H), 6.74(d,J=8 Hz,1H),
7.5(m,3H), 7.88(d,J=8 Hz,1H), 8.12(m,2H), 10.69(bs,1H).
[1097] (c) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(c), there was prepared methyl
7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxylate as a white
solid. NMR (CDCl.sub.3): .delta.3.20(m, 4H), 3.90(s,3H),
4.08(s,3H), 6.70(d,J=8 Hz,1H), 7.25(m,5H), 7.83(d,J=8 Hz,1H),
9.95(bs,1H).
[1098] (d) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(d), there was prepared methyl
2-benzyl-7-methoxy-3H-benzimidazole-4-carboxylate. NMR
(CDCl.sub.3): .delta.3.90(s,3H), 4.10(s,3H), 4.35(s,2H), 6.70(d,J=8
Hz,1H), 7.30(m,5H), 7.80(d,J=8 Hz,1H), 9.97(bs,1H).
[1099] (e) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(e), there was prepared
(RS)-methyl
7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxylate. NMR
(CDCl.sub.3): .delta.1.88(d,J=7.5 Hz,3H), 3.90(s,3H), 4.10(s,3H),
4.44(q,J7=7.5Hz,1H), 6.70(d,J=8 Hz,1H), 7.30(m,5H), 7.82(d,J=8
Hz,1H).
[1100] (f) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(f), there was prepared methyl
7-methoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-carboxylate. NMR
(CDCl.sub.3): .delta.3.80(s,3H), 3.90(s,3H), 4.08(s,3H),
4.27(s,2H), 6.69(d,J=8 Hz,1H), 6.88(m,2H), 7.25(m,2H), 7.90(d,J=8
Hz,1H), 9.90(bs,1H).
[1101] (g) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(g), there was prepared
(RS)-methyl
2-(cyclohexyl-phenyl-methyl)-7-methoxy-3H-benzimidazole-4-carboxylate.
NMR (CDCl.sub.3): .delta.0.80-1.40(m,5H), 1.6(m,5H), 2.4(m,1H),
3.86(d,1H), 3.90(s,3H), 4.07(s,3H), 6.65(d,J=8 Hz,1H), 7.20(m,1H),
7.3(m,2H), 7.45(m,2H), 7.78(d,J=8Hz,1H), 10.1(bs,1H).
[1102] (h) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(h), there was prepared
(RS)-methyl
2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxylate as a
solid. NMR (CDCl.sub.3): .delta.3.40(dd,J=15 and 8.5 Hz,3H),
3.87(s,3H), 3.94(dd, J=15 and 7 Hz,1H), 4.10(s,3H), 4.43(dd, J=8.5
and 7 Hz,1H), 6.70(d,J=8Hz,1H), 7.00-7.30 (m,10H), 7.33(d,J=8
Hz,1H), 9.93(bs,1H).
[1103] (i) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(i), there was prepared
(RS)-methyl
7-methoxy-2-(2-phenylpropyl)-3-benzimidazole-4-carboxylate. NMR
(CDCl.sub.3): .delta.1.38(d,3H). 3.22(d,2H), 3.36-3.49(m,1H),
3.90(s,3H), 4.08(s,3H), 6.70(d,1H), 7.22-7.39(m,5H), 7.81(d,1H),
9.65(s,1H).
[1104] (j) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(j), there was prepared methyl
7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxylate.
NMR (CDCl.sub.3): .delta.3.79(s,3H), 3.94(s,3H), 4.10(s,3H),
5.32(s,2H), 6.71(d,J=8 Hz,1H), 6.84(m,2H), 6.97(m,2H), 7.90(d,J=8
Hz,1H).
[1105] (k) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(k), there was prepared
(RS)-methyl
7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxylate. NMR
(CDCl.sub.3): .delta.0.93(t,J=7.5 Hz,3H), 1.3(m,2H), 2.06(m,3H),
2.46(m,1H), 3.90(bs,3H), 4.10(s,3H), 4.23(dd, J=9 and 7 Hz,1H),
6.69(d,J=8Hz,1H), 7.30(m,5H), 7.79(d,J=8 Hz,1H), 9.90(bs,1H).
[1106] (l) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(1), there was prepared methyl
2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate as a
solid. NMR (CDCl.sub.3): .delta.3.90(s,3H), 4.06(s,3H), 4.25(s,2H),
6.70(d,J=8 Hz,1H), 7.19(d,J=8 Hz,1H), 7.45(d,J=8 Hz,2H), 7.83(d,J=8
Hz,1H), 10.04(bs,1H).
[1107] (m) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(m), there was prepared
(RS)-methyl
7-methoxy-2-(3-methoxy-1-phenyl-propyl)-3H-benzimidazole-4-carboxylate.
NMR (CDCl.sub.3): .delta.2.39(m,1H), 2.73(m,1H), 3.31(s,3H),
3.39(s,2H), 3.91(s,3H), 4.10(s,3H), 4.50(t,J=8 Hz,1H), 6.70(d,J=8
Hz,1H), 7.30(m,5H), 7.84(d,J=8 Hz,1H).
[1108] (n) By proceeding in a similar. manner to Reference Example
3(a) but using Reference Example 4(n), there was prepared. methyl
7-methoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-carboxylate. NMR
(CDCl.sub.3): .delta.3.92(s,3H), 4.02(s,3H), 4.03(s,3H),
4.79(s,2H), 6.62(d,J=9 Hz,1H), 6.92(m,2H), 7.24(m,1H), 7.30(m,1H),
7.78(d,J=9 Hz,1H), 10.58(bs,1H).
[1109] (o) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(o), there was prepared
(RS)-methyl
7-methoxy-2-(methoxy-phenyl-methyl)-3H-benzimidazole-4-carboxylate.
[1110] (p) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(p), there was prepared methyl
7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxylate.
NMR (CDCl.sub.3): .delta.3.95 (s,3H), 3.96(s,3H), 4.07(s,3H),
5.47(s,2H), 6.71(d,J=8Hz,1H), 6.82-7.05(m,3H), 7.10(m,1H),
7.90(d,J=8 Hz,1H).
[1111] (q) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(q), there was prepared methyl
2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxylate as a tan
coloured solid.
[1112] (r) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(r), there was prepared methyl
7-methoxy-2-methyl-3H-benzimidazole-4-carboxylate. NMR
(CDCl.sub.3): .delta.2.65(s,3H), 3.96(s,3H), 4.07(s,3H), 6.68(d,J=8
Hz, 1H), 7.80(d,J=8 Hz, 1H).
[1113] (s) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(s), there was prepared methyl
7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxylate. NMR
(CDCl.sub.3): .delta.3.95(s,3H), 4.10(s,3H), 5.40(s,2H), 6.73(d,J=8
Hz,1H), 7.05(m, 3H), 7.73(m,2H), 7.90(d,J=8 Hz,1H).
[1114] (t) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(t), there was prepared methyl
2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate, as a solid.
NMR (CDCl.sub.3): .delta.1.73(m,2H), 1.85(m,2H), 2.00(m,2H),
2,16(m,2H), 3.31(m,1H), 3.98(s,3H), 4.08(s,3H), 6.70(d,J=8 Hz,1H),
7.80(d,J=8 Hz,1H), 10.10(bs,1H).
[1115] (u) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(u), there was prepared methyl
2-benzyl-3H-benzimidazole-4-carboxylate. NMR (CDCl.sub.3):
.delta.3.90(s,3H), 4.33(s,2H), 7.20-7.40(m,5H), 7.82(d,J=7.6
Hz,1H), 7.93(d,J=7.6 Hz,1H), 10.02(bs,1H).
[1116] (v) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(v), there was prepared methyl
2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carboxylate, m.p.
124-126.degree. C. [Elemental analysis: C,53.89;H,5.11; N,9.62%.
Calculated: C,55.21;H,5.35; N,9.90%].
[1117] (w) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(w) and isolating the
intermediate
1-bromo-3-(cyclopropyl-chloroimino-methylamino)-4-methoxybenzene
then treating with potassium carbonate there was prepared
4-bromo-2-cyclopropyl-7-methoxy-3H-benzimidazole as a pale brown
solid, m.p. 185.degree. C.
[1118] (x) By proceeding in a similar manner to Reference Example
3(a) but using Reference Example 4(x), there was prepared methyl
7-methoxyl-2-n-propyl-3H-benzimidazole-4-carboxylate.
Reference Example 4
[1119] (a) Methyl
3-(1-imino-2-methoxy-ethylamino)-4-methoxybenzoate Method A:
4-Toluenesulphonic acid monohydrate (17.8 g) was heated under
vacuum at 100.degree. C. for 4 hours then allowed to cool to room
temperature and then treated with methoxy-acetonitrile (7.4 g) and
methyl 3-amino-4-methoxybenzoate (17.5 g). The resulting mixture
was heated to 180.degree. C. and then stirred at this temperature
for 4 hours. The reaction mixture was allowed to cool to room
temperature then diluted with chloroform and then washed
sequentially with 1M sodium hydroxide solution, saturated sodium
bicarbonate and brine. The organic phase was dried over magnesium
sulphate then evaporated. The residue was subjected to flash
chromatography on silica eluting initially with a mixture of hexane
and ethyl acetate (4:1, v/v) then with a mixture of hexane and
ethyl acetate (1:1, v/v) and finally with a mixture of ethyl
acetate and triethylamine (50:1, v/v) to give the title compound
(15.79 g) as a solid. M.sup.+252.NMR (CDCl.sub.3):
.delta.3.48(bs,3H), 3.90(bs,6H), 4.20(bs,2H), 4.95(bs,1H),
6.92(d,J=8 Hz,1H), 7.60(bs,1H), 7.77(d,J=8 Hz,1H).
[1120] Method B: A solution of methyl 2-methoxyacetimidate (36.5 g,
prepared by treating the corresponding hydrochloride [prepared
according to the procedure of C. G.Bakker et. al.,
Rec.Trav.Chim.Pays-Bas, 1981,100, page 13] with aqueous sodium
hydroxide) and methyl 3-amino-4-methoxybenzoate (64.1 g) in
butan-2-one (256 ml) was heated at reflux with stirring under a
nitrogen atmosphere for 3.5 hours then a further quantity of methyl
2-methoxyacetimidate (36.5 g) was added. After heating at reflux
for a further 4 hours the reaction mixture was left at ambient
temperature for 18 hours and then concentrated under reduced
pressure. The residual brown oil was treated with cyclohexane (100
ml) and then evaporated. The residual oil was dissolved in a
mixture of cyclohexane and ethyl acetate (150 ml, 7:3, v/v) and
heated to 50.degree. C. Some seed crystals of methyl
3-(1-imino-2-methoxy-ethylamino)-4-methox- ybenzoate were added and
then mixture was allowed to cool to ambient temperature with
stirring. The resulting solid was collected by filtration, then
washed with a small amount of a mixture of cyclohexane and ethyl
acetate (7:3, v/v), and then dried to give the title compound
(62.72 g).
[1121] (b) By proceeding in a similar manner to Reference Example
4(a), method A, but using benzonitrile, there was prepared methyl
3-(imino-phenyl-methylamino)-4-methoxybenzoate as a tan coloured
solid. NMR (CDCl.sub.3): .delta.3.85(s,3H), 3.86(s,3H),
6.94(bd,J=8.8 Hz,1H), 7.45(m,3H), 7.65(s,1H), 7.75(m,2H),
7.90(bs,1H)]
[1122] (c) By proceeding in a similar manner to Reference Example
4(a), method A, but using hydrocinnamonitrile, there was prepared
methyl 3-(1-imino -3-phenyl-propylamino)-4-methoxybenzoate as a tan
coloured solid. NMR (CDCl.sub.3) .delta.2.65(bt,2H), 3.10(bt,2H),
3.90(s,6H), 4.34(bs,1H), 6.90(d,J=8 Hz,1H), 7.30(m,5H),
7.52(bs,1H), 7.74(dd,J=8 and 1 Hz,1H)]
[1123] (d) By proceeding in a similar manner to Reference Example
4(a), method A, but using phenylacetonitrile, there was prepared
methyl 3-(1-imino-2-phenyl-ethylamino)-4-methoxybenzoate as a
solid. M.sup.+298.
[1124] (e) By proceeding in a similar manner to Reference Example
4(a), method A, but using (.alpha.-methylbenzyl cyanide, there was
prepared (RS)-methyl
3-(1-imino-2-phenyl-propylamino)-4-methoxybenzoate. M.sup.+312.
[1125] (f) By proceeding in a similar manner to Reference Example
4(a), method A, but using 4-methoxyphenylacetonitrile, there was
prepared methyl
3-(1-imino-2-{4-methoxyphenyl}-ethylamino)-4-methoxybenzoate.
M.sup.+328.
[1126] (g) By proceeding in a similar manner to Reference Example
4(a), method A, but using .alpha.-cyclohexylbenzyl cyanide, there
was prepared (RS)-methyl
3-(2-cyclohexyl-1-imino-2-phenyl-ethylamino)-4-methoxybenzoat- e as
an orange solid. M+H 381.
[1127] (h) By proceeding in a similar manner to Reference Example
4(a), method A, but using 2,3-diphenylpropionitrile, there was
prepared (RS)-methyl
3-(2,3-diphenyl-1-imino-propylamino)-4-methoxybenzoate as a
solid.
[1128] (i) By proceeding in a similar manner to Reference Example
4(a), method A, but using 3-phenylbutyronitrile, there was prepared
(RS)-methyl 3-(1-imino-3-phenyl-butylamino)-4-methoxybenzoate. NMR
(CDCl.sub.3): .delta.1.43(d,3H), 2.60(d,2H), 3.26-3.39(m,1H),
3.85(s,3H), 3.87(s,3H), 4.20(bs,2H), 6.89(d,1H), 7.25-7.35(m,5H),
7.42(bs,1H), 7.75(dd,1H).
[1129] (j) By proceeding in a similar manner to Reference Example
4(a), method A, but using 4-methoxyphenoxy-acetonitrile, there was
prepared methyl
3-(1-imino-2-{4-methoxyphenoxy}-ethylamino)-4-methoxybenzoate. NMR
(CDCl.sub.3): .delta.63.79 (s,3H), 3.88(s,3H), 3.99(s,3H),
4.74(bs,2H), 5.00(bs,1H), 6.80-7.00(m,5H), 7.60(bs,1H), 7.78(dd,J=8
and 1 Hz,1H).
[1130] (k) By proceeding in a similar manner to Reference Example
4(a), method A, but using .alpha.-propylphenylacetonitrile, there
was prepared (RS)-methyl
3-(1-imino-2-phenyl-pentylamino)-4-methoxybenzoate. M+H 341.
[1131] (l) By proceeding in a similar manner to Reference Example
4(a), method A, but using 4-bromophenylacetonitrile, there was
prepared methyl
3-(2-{4-bromophenyl}-1-imino-ethylamino)-4-methoxybenzoate as a tan
coloured solid. M.sup.+H 378. NMR (CDCl.sub.3): .delta.3.70(s,2H),
3.90(d,6H), 4.35(s,1H), 6.90(d,1H), 7.30(d,2H), 7.50(m,3H),
7.75(d,1H).
[1132] (m) By proceeding in a similar manner to Reference Example
4(a), method A, but using 4-methoxy-2-phenylbutyronitrile, there
was prepared (RS)-methyl
3-(1-imino-4-methoxy-2-phenyl-butylamino)-4-methoxybenzoate. NMR
(CDCl.sub.3): .delta.2.10(m,1H), 2.54(m,1H), 3.35(bs,3H),
3.40(m,1H), 3.60(m,1H), 3.74(m,1H), 3.85(bs,6H), 4.25(bs,2H),
6.90(bd,J=8 Hz,1H), 7.30(m,1H), 7.38(m,2H), 7.50(m,2H), 7.75(m,
1H).
[1133] (n) By proceeding in a similar manner to Reference Example
4(a), method A, but using 2-methoxyphenyl-acetonitrile, there was
prepared methyl
3-(1-imino-2-{2-methoxyphenyl}-ethylamino)-4-methoxybenzoate.
[1134] (o) By proceeding in a similar manner to Reference Example
4(a), method A, but using methoxy-phenylacetonitrile, there was
prepared methyl 3-(
1-imino-2-methoxy-2-phenyl-ethylamino)-4-methoxybenzoate.
[1135] (p) By proceeding in a similar manner to Reference Example
4(a), method A, but using (2-methoxyphenoxy)acetonitrile, there was
prepared methyl
3-(1-imino-2-{2-methoxyphenoxy}-ethylamino)-4-methoxybenzoate.
M.sup.+344.
[1136] (q) By proceeding in a similar manner to Reference Example
4(a), method A, but using iso-butyronitrile, there was prepared
methyl 3-(1-imino-2-methyl-propylamino)-4-methoxybenzoate. NMR
(CDCl.sub.3): .delta.1.29(d,J=6 Hz,6H), 2.60(m,1H), 3.88(bs,6H),
4.33(bs,1H), 6.89(d,J=8 Hz,1H), 7.50(bs,1H), 7.72(dd,J=8
Hz,1H).
[1137] (r) By proceeding in a similar manner to Reference Example
4(a), method A, but using acetonitrile, there was prepared methyl
3-(1-imino-ethylamino)-4-methoxybenzoate. M.sup.+222.
[1138] (s) By proceeding in a similar manner to Reference Example
4(a), method A, but using phenoxy-acetonitrile, there was prepared
methyl 3-(1-imino-2-phenoxy-ethylamino)-4-methoxybenzoate.
M.sup.+314.
[1139] (t) By proceeding in a similar manner to Reference Example
4(a), method A, but using cyclopentanecarbonitrile, there was
prepared methyl 3-(cyclopentyl-imino-methylamino)-4-methoxybenzoate
as a solid. NMR (CDCl.sub.3): .delta.1.54-2.10(m,8H), 2.75(m,1H),
3.86(bs,6H), 4.30(bs,1H), 6.88(bd,J=8 Hz,1H), 7.53(bs,1H),
7.73(d,J=8 Hz,1H).
[1140] (u) By proceeding in a similar manner to Reference Example
4(a), method A, but using phenylacetonitrile and methyl
3-aminobenzoate, there was prepared methyl
3-(2-phenyl-1-imino-ethylamino)benzoate as a tan coloured solid.
M.sup.+312.
[1141] (v) By proceeding in a similar manner to Reference Example
4(a), method A, but using cyclopropyl cyanide and methyl
3-amino-4-methoxybenzoate, there was prepared methyl
3-(cyclopropyl-imino-methylamino)benzoate as a colourless
solid.
[1142] (w) By proceeding in a similar manner to Reference Example
4(a), method A, but using cyclopropyl cyanide and
5-bromo-2-methoxyaniline (Reference Example 50), there was prepared
1-bromo-3-(cyclopropyl-imino-m- ethylamino)-4-methoxybenzene.
[1143] (x) By proceeding in a similar manner to Reference Example
4(a), method A, but using propyl cyanide there was prepared methyl
3-(propyl-imino-methylamino)-4-methoxybenzoate.
[1144] (y) By proceeding in a similar manner to Reference Example
4(a), method A, but using 3-amino-4-methoxysalicylate (Reference
Example 8(b)), there was prepared methyl
4-methoxy-2-methoxymethyl-benzoxazole-7-carboxy- late as a white
solid, m.p. 104-106.degree. C.
Reference Examples 5(a) and 6(a)
Methyl
2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate and
methyl
2-cyclopentyl-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate
[1145] A suspension of sodium hydride (0.55 g, 60% dispersion in
mineral oil) in dimethylformamide (1 ml), cooled to 0.degree. C.,
was treated with a solution of methyl
2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carb- oxylate [3.61 g,
Reference Example 3(t)]) in dimethylformamide (34 ml). The
resulting mixture was stirred for 40 minutes then treated with
iodomethane (0.82 ml). The reaction mixture was allowed to stand at
4.degree. C. for 2 days then diluted with diethyl ether, then
washed with brine, then dried over magnesium sulphate and then
evaporated. The residue was subjected to flash chromatography on
silica to give methyl
2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate
(3.18 g), [NMR (CDCl.sub.3): .delta.1.70 (m,2H), 1.90(m,2H),
2,16(m,4H), 3.25(m1H), 3.95(s,6H), 4.00(s,3H), 6.64(d,J=8 Hz,1H),
7.89(d,J=8 Hz,1H)]; and methyl
2-(cyclopentyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate
(0.37 g), [M.sup.+288, NMR (CDCl.sub.3): .delta.1.70(m,2H),
1.90(m,2H), 2,14(m,4H), 3.25(m,1H), 3.92(s,6H), 4.02(s,3H),
6.64(d,J=8 Hz,1H), 7.75(d,J=8 Hz,1H)].
[1146] (5b) By proceeding in a similar manner but using methyl
3-isopropyl-1H-indole-5-carboxylate (Reference Example 52) with
tetrahydrofuran as the solvent, there was prepared methyl
3-isopropyl-1-methyl-1H-indole-5-carboxylate as an orange-brown
coloured solid.
Reference Example 7
Methyl 2,7-dimethoxy-3H-benzimidazole-4-carboxylate
[1147] A mixture of methyl 2,3-diamino-4-methoxybenzoate [0.5 g,
Reference Example 8(a)] acetic acid (0.15 ml) and
tetramethoxymethane (0.53 ml) was stirred at 80.degree. C. for 40
minutes. After cooling to room temperature the reaction mixture was
diluted with a mixture of methanol (3.6 ml), 1N sodium hydroxide
(2.55 ml) and water (8 ml). The resulting precipitate was filtered
and then passed through a short filtration silica gel column to
give the title compound (0.49 g) as a tan coloured solid.
M.sup.+236.NMR (CDCl.sub.3): .delta.3.93(s,3H), 4.05(s,3H),
4.23(s,3H), 6.69(d,J=8 Hz,1H), 7.74(d,J=8 Hz,1H). 9.48(bs,1H)]
Reference Example 8
[1148] (a) Methyl 2,3-diamino-4-methoxybenzoate
[1149] A solution of methyl 2-amino-4-methoxy-3-nitrobenzoate (1.84
g, Reference Example 9) in ethanol (100 ml) was treated with 10%
palladium on carbon (0.2 g). The resulting suspension was stirred
under 3 atmospheres of hydrogen for 3 hours. The catalyst was then
removed by filtration and the filtrate evaporated to give the title
compound (1.6 g) as a black solid which was used without further
purification. M.sup.+196.
[1150] (b) By proceeding in a similar manner to Reference Example
8(a) but using methyl 2-hydroxy-4-methoxy-3-nitrobenzoate
(Reference Example 51) and ethyl acetate as the solvent, there was
prepared methyl 3-amino-2-hydroxy-4-methoxybenzoate as a white
solid, m.p. 72-74.degree. C.
Reference Example 9
Methyl 2-amino-4-methoxy-3-nitrobenzoate
[1151] A solution of methyl 2-carboxy-4-methoxy-3-nitrobenzoate
(3.43 g, Reference Example 10) was dissolved in toluene (20 ml) was
treated with thionyl chloride (1.5 ml) then with dimethylformamide
(0.015 ml). The resulting solution was stirred at reflux for 1 hour
then cooled to room temperature and then evaporated. The residue
was dissolved in acetone (20 ml) and added to a solution of sodium
azide (1.3 g) in water (20 mi) cooled in an ice bath. The mixture
was stirred for 1 hour then diluted with water. The resulting
precipitate was collected by filtration. This solid was dissolved
in a mixture of t-butanol and water (20 ml, 9:1) and gradually
warmed to reflux and held at this temperature for 1 hour. The
solution was cooled to room temperature and then evaporated. The
residue was subjected to flash chromatography on silica to give the
title compound (1.8 g). M.sup.+H 227. NMR ((CD.sub.3).sub.2SO):
.delta.3.82 (s,3H), 3.90(s,3H), 6.53(d,J=8 Hz,1H), 7.1(bs,2H),
7.96(d,J=8 Hz,1H).
Reference Example 10
Methyl 2-carboxy-4-methoxy-3-nitrobenzoate
[1152] A solution of 3-nitro-4-methoxyphthallic acid (25.1 g,
Reference Example 11) in methanol (160 ml), cooled to 0.degree. C.,
was saturated with hydrogen chloride gas then allowed to stand at
4.degree. C. for 2 days. The reaction mixture was then diluted with
water and then extracted with ether. The ether extract was washed
with saturated sodium bicarbonate solution. The bicarbonate
washings were acidified and then extracted with ether. These ether
extracts were dried over magnesium sulphate and then evaporated.
The residue was recrystallised from a mixture of chloroform and
methanol to give the title compound (3.42 g). M.sup.+255. NMR
{(CD.sub.3).sub.2SO} .delta.3.85(s,3H), 4.00(s,3H), 7.55(d,J=8.5
Hz,1H), 8.07(d,J=8.5 Hz,1H). A further quantity of the title
compound (3.54 g) was obtained after subjecting the mother liquors
from the recrystallisation to flash chromatography on silica.
Reference Example 11
3-Nitro-4-methoxyphthallic Acid
[1153] 4-Methoxyphthallic acid (21.5 g) was treated dropwise with
fuming nitric acid (75 ml). The resulting mixture was heated to
60.degree. C. and stirred for 15 minutes whereupon the reaction
mixture became homogenous. This solution was then cooled to room
temperature and then diluted with water. The mixture was extracted
with diethyl ether. The combined extracts were washed with brine
then dried over magnesium sulphate and then evaporated to give the
title compound (25.1 g) as a tan coloured solid. M.sup.+241.
Reference Example 12
Methyl
7-methoxy-2-(.alpha.-methoxybenzyl)-3H-benzimidazole-4-carboxylate
[1154] A solution of a-methoxy-phenylacetic acid (0.596 g) in
chloroform (10 ml) was treated with dimethylformamide (10 .mu.l)
then with thionyl chloride (0.52 ml). The reaction mixture was
stirred at ambient temperature for 2 hours then evaporated. The
residue was dissolved in chloroform (4 ml) and the solution added
to a stirred solution of methyl 2,3-diamino-4-methoxybenzoate
[0.352 g, Reference Example 8(a)] in a mixture of chloroform (6 ml)
and triethylamine (1 ml). After stirring for 1 hour the mixture was
treated with ether and then with water. The organic phase was
washed with sodium bicarbonate solution, then with brine, then
dried over magnesium sulphate and then evaporated. The residue was
dissolved in acetic acid (8 ml) and the solution heated at
80.degree. C. for 1.5 hours. The solution was cooled to ambient
temperature then diluted with ether. The mixture was washed with
water, then with sodium bicarbonate solution, then with brine and
then dried over magnesium sulphate. The ethereal solution was
evaporated and the residue subjected to flash chromatography on
silica eluting with a mixture of ethyl acetate and hexane (1:1,
v/v) to give the title compound (0.36 g). NMR (CDCl.sub.3):
.delta.3.50(s,3H), 3.96(s,3H), 4.05(s,3H), 5.17(s,1H), 6.70(d,J=8
Hz,1H), 7.24-7.40(m,3H), 7.46(m,2H), 7.85(d,J=8 Hz,1H)].
Reference Example 13
Methyl 7-methoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxylate
[1155] A solution of methyl 2,3-diamino-4-methoxybenzoate [0.73 g,
Reference Example 8(a)] and triethylamine (0.94 g) in dry
dichloromethane (20 ml), at 0.degree. C., was treated with
nicotinyl chloride (0.53 g). The reaction mixture was stirred at
ambient temperature for 2 hours and then evaporated. The residue
was dissolved in acetic acid (8 ml) and the solution heated at
80.degree. C. for 2 hours. After cooling to room temperature the
reaction mixture was treated with water. The insoluble material was
subjected to flash chromatography on silica to give the title
compound (0.46 g). NMR (CDCl.sub.3): .delta.4.00(s,3H), 4.15(s,3H),
6.70(d,1H), 7.40(m,1H), 7.90(d,1H), 8.45(m,1H), 8.75(d,1H),
9.30(d,1H), 10.80(s,1H)].
Reference Example 14
Methyl
2-(4-cyanobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate
[1156] A solution of methyl
2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4- -carboxylate [1.4
g, Reference Example 3(1)] in dry dimethylformamide was treated
with tetrakis(triphenylphosphine) palladium (0) (0.266 g) and zinc
cyanide (0.275 g). The reaction mixture was heated at 100.degree.
C. for 12 hours then cooled to room temperature. The mixture was
diluted with ethyl acetate and then washed with ammonium hydroxide
(2N), then with water and then with brine. The organic solution was
dried over magnesium sulphate then evaporated. The residue was
subjected to flash chromatography on silica to give the title
compound (0.88 g). NMR (CDCl.sub.3): .delta.3.85(s,3H), 4.00(s,3H),
4.40(s,2H), 6.70(d,1H), 7.40(d,2H), 7.65(d,2H), 7.85(d,1H).
Reference Example 15
Methyl
7-methoxy-2-(4-1{pyrid-3-yl}benzyl)-3H-benzimidazole-4-carboxylate
[1157] A solution of methyl
2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4- -carboxylate [0.268
g, Reference Example 3(1)] in toluene (8 ml) was treated with
tetrakis(triphenylphosphine) palladium (0) (0.266 g), aqueous
sodium carbonate solution (0.5 ml, 2M) and diethyl
(3-pyridyl)borane (0.085 g). The mixture was heated at reflux for
12 hours then cooled to room temperature. Aqueous work-up and
subjected to flash chromatography on silica to give the title
compound (0.128 g). NMR {(CD.sub.3).sub.2SO}: .delta.3.90(s,3H),
4.10(s,3H), 4.40(s,2H), 6.70(d,1H), 7.45(d,3H), 7.60(d,3H), 7.90
(dd,1H), 8.60(d,!H), 8.85(d,1H), 10.10(s,1H).
Reference Example 16
3-Bromo-2-(3-chlorophenoxy)pyridine
[1158] A solution of 3-chlorophenol (5.34 g) in tetrahydrofuran (50
ml) was added dropwise to a suspension of sodium hydride (1.66 g,
60% dispersion in mineral oil) in tetrahydrofuran (50 ml). The
solvent was evaporated and the residue was treated with
3-bromo-2-chloropyridine (6.15 g) and the mixture heated at
180.degree. C. for 6 hours. The reaction mixture was cooled to
100.degree. C., then poured into water. The mixture was extracted
with dichloromethane. The combined organic extracts were washed
with 1N sodium hydroxide, then with brine, then dried over
magnesium sulphate and then evaporated. The residual brown solid
was subjected to flash column chromatography eluting with a mixture
of ethyl acetate and pentane (2:98, v/v) to give the title compound
as white solid, m.p. 88-90.degree. C.
[1159] NMR (CDCl.sub.3): .delta.6.94(dd,J=7 Hz and 4 Hz,1H),
7.07(m,1H), 7.19(t,J=2 Hz, 1H), 7.22(m,1H), 7.35(t,J=8 Hz,1H),
7.95(dd,J=6 Hz and 1 Hz,1H), 8.09(dd, J=4 Hz and 1 Hz,1H).
Reference Example 17
2-Cyclopropyl-7-(3,5-dimethyl-4-pyridylmethoxy)-4-methoxy-1 (or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole
[1160]
[1161] A stirred solution of 2-cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or
3H)-benzimidazol-4-ol[0.69 g, Reference Example 19(a)],
triphenylphosphine (0.12 g) and (3,5-dimethyl-4-pyridyl)methanol
(0.31 g, Reference Example 23) in tetrahydrofuran (15 ml) was
treated with diisopropyl azodicarboxylate (0.48 g). After stirring
at room temperature. for 4 hours the resulting homogeneous solution
was allowed to stand for a further 12 hours then evaporated. The
residue was subjected to column chromatography on neutral alumina
eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to
give a mixture of the title compound and triphenylphosphine oxide
which was used without further purification.
Reference Example 18
[1162] By proceeding in a similar manner to Reference Example 17,
but using
7-methoxy-2-methoxymethyl-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H-
(3H)-benzimidazol-4-ol [mixture of isomers, Reference Example
19(b)], there was prepared a mixture of
7-(3,5-dimethyl-4-pyridylmethoxy)-4-metho-
xy-2-methoxymethyl-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-benzimida-
zole and triphenylphosphine oxide which was used without further
purification.
Reference Example 19
[1163] (a) 2-Cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethy- l)-1H(or 3H)-benzimidazol4-ol
isomer A
[1164] A cooled solution of 2-cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or
3H)-benzimidazole-4-carbaldehy- de [2.00 g, isomer A, Reference
Example 20(a)] in dichloromethane (40 ml) was treated with
m-chloroperbenzoic acid (3.66 g). The mixture was allowed to warm
to room temperature then allowed to stand at room temperature for a
further 12 hours. The reaction mixture was diluted with
dichloromethane (40 ml), then washed twice with a saturated aqueous
solution of sodium metabisulphite (100 ml), then washed twice with
a saturated aqueous solution of sodium hydrogen carbonate (100 ml),
then washed with brine (100 ml), then dried over magnesium sulphate
and then evaporated to yield the title compound as a colourless
oil.
[1165] (b) By proceeding in a similar manner to Reference Example
19(a), but using Reference Example 20(b), there was prepared
7-methoxy-2-methoxymethyl-1(or
3)-(2-trimethylsilanyl-ethoxyethyl)-1H(or
3H)-benzimidazol-4-ol.
Reference Example 20
[1166] (a) 2-Cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethy- l)-1H(or
3H)-benzimidazole-4-carbaldehyde, isomer A
[1167] A stirred solution of
2-cyclopropyl-7-methoxy-3H-benzimidazole-4-ca- rbaldehyde [7.23 g,
Reference Example 21(a)] in dry dimethylformamide (115 ml), at room
temperature and under nitrogen, was treated portionwise with sodium
hydride (1.60 g, 60% dispersion in mineral oil,). After stirring
for a further 40 minutes the orange-brown suspension was treated
dropwise with 2-(trimethylsilyl)ethoxymethyl chloride (7.15 ml),
over 30 minutes. The resulting yellow-orange suspension was allowed
to stand at room temperature for 12 hours then treated carefully
with a little water. The mixture was evaporated to yield a yellow
oil which was dissolved in ethyl acetate (400 ml). The solution was
washed twice with water (100 ml), then dried over magnesium
sulphate and then evaporated to yield a yellow oil (10.5 g) which
was subjected to flash chromatography on silica, eluting with a
mixture of dichloromethane and methanol (99:1, v/v) to give
2-cyclopropyl-7-methoxy-1
(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-be-
nzimidazole-4-carbaldehyde (mixture of isomers), as a yellow oil
(7.00 g). The mixture of isomers was further subjected to flash
chromatography on silica, eluting with a mixture of dichloromethane
and methanol (99:1, v/v) to give 2-cyclopropyl-7-methoxy-1 (or
3)-(2-trimethylsilanyl-ethoxym- ethyl)-1H(or
3H)-benzimidazole-4-carbaldehyde (isomer A).
[1168] (b) By proceeding in a similar manner to Reference Example
20(a), but using Reference Example 21(b), there was prepared
7-methoxy-2-methox
methyl-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-benzimidazole-4-carb-
aldehyde, (mixture of isomers), as a pale yellow oil.
[1169] (c)) By proceeding in a similar manner to Reference Example
20(a), but Reference Example 3(w) there was prepared
4-bromo-2-cyclopropyl-7-met-
hoxy-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-benzimidazole,
(mixture of isomers), as a yellow oil. The mixture of isomers was
subjected to flash chromatography on silica, eluting with a mixture
of dichloromethane and methanol (99:1, v/v) to give
4-bromo-2-cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole,
(isomer A).
Reference Example 21
[1170] (a)
2-Cyclopropyl-7-methoxy-3H-benzimidazole-4-carbaldehyde
[1171] A stirred suspension of
2-cyclopropyl-7-methoxy-3H-benzimidazole-4-- methanol [7.73 g,
Reference Example 22(a)] in a mixture of toluene (250 ml) and
dichloromethane (150 ml), at room temperature and under nitrogen,
was treated portionwise with activated manganese dioxide (11 g).
The resulting suspension was stirred under nitrogen at 85.degree.
C. for 3 hours. The suspension was allowed to cool slightly and was
then filtered through hyflosupercel washing the filter pad six
times with hot ethyl acetate (50 ml). The combined filtrate and
washings were dried over magnesium sulphate and then evaporated to
yield the title compound as a cream coloured powder (7.26 g).
[1172] (b) By proceeding in a similar manner to Reference Example
22(a), but using Reference Example 22(b), there was prepared
7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carbaldehyde as a pale
yellow solid.
Reference Example 22
[1173] (a) 2-Cyclopropyl-7-methoxy-3H-benzimidazole-4-methanol A
stirred solution of methyl
2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carboxylate [15.5 g,
Reference Example 3(v)], in dry tetrahydrofuran (220 ml), at
-78.degree. C. and under nitrogen, was treated dropwise over 3
hours with a solution of diisobutylaluminium hydride in
dichloromethane (270 ml, 1.0M). The reaction mixture was allowed to
warm to room temperature over 30 minutes, then cooled to
-78.degree. C., then treated dropwise with water (27m1), then
allowed to warm to room temperature. The reaction mixture was
diluted with ice-water (500 ml) and the pH of the mixture was
adjusted to above 12 by the addition of aqueous sodium hydroxide
(750 ml, 1M). The resulting white suspension was filtered to yield
a clear filtrate which was extracted seven times with ethyl acetate
(500 ml). The combined extracts were dried over magnesium sulphate
and then evaporated to yield the title compound as a cream coloured
powder (10.13 g).
[1174] b) By proceeding in a similar manner to Reference Example
22(a), but using Reference Example 3(a), there was prepared
7-methoxy-2-methoxymethyl-3H-benzimidazole-4-methanol as a cream
coloured solid.
[1175] c) By proceeding in a similar manner to Reference Example
22(a), but using Reference Example 41 there was prepared
3-methyl-1-{3-(phenyl)p- ropyl}-1H-indole-6-methanol.
Reference Example 23
(3,5-Dimethyl-4-pyridyl)methanol
[1176] A stirred solution of 3,5-dimethyl-pyridyl-4-carbaldehyde
(2.3 g, Reference Example 24) in methylated spirit (50 ml), at room
temperature and under nitrogen, was treated with powdered sodium
borohydride (1.28 g). After stirring for 6 hours the resulting
homogeneous solution was allowed to stand at room temperature for a
further 12 hours then treated with water (10 ml). The reaction
mixture was evaporated, then azeotroped with toluene. The residue
was extracted three times with hot dichloromethane (100 ml). The
combined extracts were evaporated to afford a white solid which was
subjected to flash chromatography on silica, eluting with a mixture
of ethyl acetate and pentane (1:1, v/v) to afford the title
compound (1.2 g) as a white solid, m.p. 93-95.degree. C.
Reference Example 24
3,5-Dimethyl-pyridine-4-carbaldehyde
[1177] A stirred solution of 4-bromo-3,5-dimethylpyridine (3.72 g,
Reference Example 25) in diethyl ether (50 ml), at -78.degree. C.
and under nitrogen, was treated dropwise with n-butyl lithium
(0.025 ml, 1.6M). After stirring at -78.degree. C. for 1 hour the
resulting homogeneous solution was treated with dry
dimethylformamide (6 ml) whilst maintaining the temperature below
-65.degree. C. The reaction mixture was allowed to warm to room
temperature over 1 hour, then treated with a saturated aqueous
solution of ammonium chloride (10 ml), and then extracted twice
with ethyl acetate (100 ml). The combined extracts were evaporated
to yield an orange oil which was subjected to flash chromatography
on silica, eluting with a mixture of ethyl acetate and pentane
(1:4, v/v) to afford the title compound (2.3 g) as a
semi-solid.
Reference Example 25
4-Bromo-3,5-dimethylpyridine
[1178] By proceeding in a similar manner to the procedure contained
in J.Chem.Soc., 1956, page 771 but using
4-nitro-3,5-dimethylpyridine-N-oxid- e (23.06 g), phosphorous
tribromide (111.47 g) in toluene (50 ml) there was prepared the
title compound (8 g) as a yellow oil.
Reference Example 26
[1179] (a) 8-Methoxy-2-n-propylquinoline-5-carboxylic acid
[1180] A mixture of methyl
8-methoxy-2-n-propylquinoline-5-carboxylate (1.0 g, Reference
Example 27), potassium carbonate (0.8 g), methanol (30 ml), and
water (2 ml) was refluxed for 5 hours. The solution was
concentrated, then diluted with water and then washed with diethyl
ether. The pH of the aqueous phase was adjusted to 6 by addition of
hydrochloric acid (6M). The resulting cream precipitate was washed
with water and then dried at 60.degree. C. to give the title
compound (0.43 g) as a cream coloured solid, m.p. 214-217.degree.
C. [Elemental analysis: C,67.00;H,6.32; N,5.53%. Calculated for
C.sub.14H.sub.15NO.sub.3.0.25H.su- b.2O: C,67.30;H,6.06;
N,5.61%].
[1181] b) By proceeding in a. similar manner to Reference Example
26(a), but using Reference Example 4(y), there was prepared
4-methoxy-2-methoxyethyl-benzoxazole-7-carboxylic acid as a cream
coloured solid.
[1182] c) By proceeding in a similar manner to Reference Example
26(a), but using Reference Example 5(b), there was prepared
3-isopropyl-1-methyl-1H-indole-5-carboxylic acid as a cream
coloured solid.
Reference Example 27
[1183] Methyl-8-methoxy-2-n-propylquinoline-5-carboxylate
[1184] Methyl-3-amino-4-methoxybenzoate (10.0 g) was treated with
concentrated hydrochloric acid (14 ml) and n-butanol (10 ml), under
nitrogen, with stirring. The stirred mixture was treated with
p-chloranil (13.65 g) and then heated at reflux whilst a mixture of
trans-2-hexanal (8 ml) and n-butanol (5 ml) was added dropwise over
2 hours using a syringe pump. After heating at reflux for a further
30 minutes the mixture was treated with a solution of anhydrous
zinc chloride (7.52 g) in tetrahydrofuran (60 ml), then allowed to
cool slowly to room temperature and then cooled to 0.degree. C. for
18 hours. The reaction mixture was evaporated, then diluted with
hydrochloric acid (1M) and then washed with diethyl ether. The pH
of the solution was adjusted to 6 and the resulting emulsion was
treated with ammonium hydroxide and the solution extracted with
diethyl ether. The combined dark green extracts were dried over
magnesium sulphate then evaporated. The resulting dark green oil
was subjected to flash chromatography on silica eluting with a
mixture of ethyl acetate and pentane (3:7, v/v) to give the title
compound (1.5 g) as an orange oil. NMR(CDCl.sub.3):
.delta.9.36(d,J=8.9 Hz,1H), 8.26(d,J=8.4 Hz,1H),
7.47(d,J=8.9Hz,1H), 7.03(d,J=8.4 Hz,1H), 4.14(s,3H), 3.97(s,3H),
3.02(m,2H), 1.86(m,2H), 1.03(t,J=7.3 Hz,3H).
Reference Example 28
[1185] (a) 1-Cyclohexylmethyl-3-methyl-1H-indole-6-carboxylic
acid
[1186] A mixture of methyl
1-cyclohexylmethyl-3-methyl-1H-indole-6-carboxy- late [9.0 g,
Reference Example 29(a)] and lithium hydroxide (8.0 g) in aqueous
methanol (300 ml, 1:2, v/v) was heated at 70.degree. C. for 4
hours. The reaction mixture was cooled to room temperature, then
acidified by addition of dilute hydrochloric acid and then
extracted three times with ethyl acetate (150 ml). The combined
extracts were dried over sodium sulphate then evaporated to give
the title compound as a white solid (7.3 g). M.sup.+271.
[1187] (b) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 30, there was prepared
3-methyl-1H-indole-6-carboxylic acid as a white solid. NMR
(CD.sub.3OD): .delta.2.10(s), 7.10(s), 7.30-7.40(m), 7.50-7.60(m),
8.00(s).
[1188] (c) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(b), there was prepared
1-(2-cyclohexyl)ethyl-3-methyl-1H-indole-6-carboxylic acid as a
white solid.
[1189] (d) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(c), there was prepared
1-(3-cyclohexyl)propyl-3-methyl-1H-indole-6-carboxylic acid as a
white solid. NMR (CDCl.sub.3): .delta.0.80-0.90, 1.00-1.30,
1.60-1.70 and 1.79-1.80(m,15H); 2.30(s,3H); 4.00-4.10(m,2H);
7.00(s,1H); 7.50-7.60(m,1H); 7.80-7.90(m,1H); 8.20(s,1H).
[1190] (e) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(d), there was prepared
1-heptyl-3-methyl-1H-indole-6-carboxylic acid.
[1191] (f) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(e), there was. prepared
1-3-phenyl)butyl-3-methyl1H indole-6-carboxylic acid as a white
solid. NMR (CDCl.sub.3): .delta.1.60-1.70(m,2H): 1.80-1,90(m,2H);
2.30(s,3H); 2.60-2.70(m,2H); 4.10-4.20(m,2H); 7.00(s, 1H);
7.10-7.30(m,5H); 7.50-7.60(m1H); 7.80-7.90(m,1H); 8.20(s,1H).
[1192] (g) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(f), there was prepared
1-(4-trifluoromethylbenzyl)-3-methyl-1H-indole-6-carboxylic acid as
a white solid. NMR {(CD.sub.3).sub.2SO}: .delta.2.30(s), 5.50(s),
7.20-7.30(m), 7.30-7.40(m), 7.60-7.70(m), 7.90(s).
[1193] (h) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(g), there was prepared
1-(4-methylsulphonylbenzyl)-3-methyl-1H-indole-6-carboxylic acid as
a white solid.
[1194] (i) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(h), there was prepared
1-(1,3-benzodioxol-5-yl)methyl-3-methyl-1H-indole-6-carboxylic
acid.
[1195] (j) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(i), there was prepared
1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-carboxylic acid as a
white solid. NMR {(CD.sub.3).sub.2SO}: .delta.2.30(s), 5.60(s),
7.30-8.10(m).
[1196] (k) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(j), there was prepared
1-(tetrahydro-2H-pyran-2-yl)methyl-3-methyl-1H-indole-6-carboxylic
acid.
[1197] (l) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(k), there was prepared
3-methyl-1-(tetrahydrofurfuryl)-1H-indole-6-carboxylic acid, as a
white solid, m.p 217-219.degree. C. [Elemental analysis:
C,69.3;H,6.6; N,5.2%. Calculated for C.sub.15H.sub.7NO.sub.3:
C,69.48;H,6.61; N,5.40%].
[1198] (m) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(l), there was prepared
3-methyl-1-(4-toluenesulphonyl)-1H-indole-6-carboxylic acid. NMR
(CD.sub.3OD): .delta.2.1(s,3H), 2.3(s,3H), 4.8(s,2H),
7.1-7.2(m,2H), 7.4-7.5(m,2H), 7.6-7.7(m,2H), 7.75-7.80(m,1H),
8.5(s,1H). (n) By proceeding in a similar manner to Reference
Example 28(a) but using Reference Example 29(m), there was prepared
3-methyl-1-(tetrahydrofuran-3- -yl)-1H-indole-6-carboxylic acid as
a white solid, m.p. 211-213.degree. C. [Elemental analysis:
C,68.00;H,6.20; N,5.60%. Calculated for C.sub.14H.sub.15NO.sub.3:
C,68.56;H,6.16; N,5.71%].
[1199] (o) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 43(a), there was prepared
1-benzyl-3-methyl-indazole-6-carboxylic acid.
[1200] (p) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 29(o), there was prepared
1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carboxylic acid as a white
solid. NMR (CD.sub.3OD): .delta.2.2(s,3H), 3.6(s,3H), 5.2(s,2H),
6.6-6.7(m,2H), 6.95-7.0(m,2H), 7.1(s,1H), 7.4-7.45,
7.55-8.0(s,1H).
[1201] (o) By proceeding in a similar manner to Reference Example
28(a) but using Reference Example 43(b), there was prepared
1-(4-methoxybenzyl)-3-methyl-indazole-6-carboxylic acid.
Reference Example 29
[1202] (a) Methyl
1-cyclohexylmethyl-3-methyl-1H-indole-6-carboxylate
[1203] A mixture of methyl 3-methyl-1H-indole-6-carboxylate(10 g,
Reference Example 30), cyclohexylmethylbromide (19 g), potassium
hydroxide (12 g) and sodium iodide (0.1 g) in acetone (200 ml) was
stirred at room temperature for 6 hours. The reaction mixture was
evaporated. The residue was partitioned between ethyl acetate (250
ml) and water (250 ml). The aqueous layer was extracted three times
with ethyl acetate (250 ml). The total combined organic phases were
dried over sodium sulphate then evaporated.
[1204] The residue was subjected to flash column chromatography on
silica eluting with a mixture of ethyl acetate and hexane (gradient
elution, 0:10 to 1:9, v/v)to yield the title compound (9.5 g). NMR
(CDCl.sub.3): .delta.0.90-1.10(m), 1. 10-1.40(m), 1.60-1.90(m),
2.30(s), 3.90-4.00(m), 3.90(s), 7.00(s), 7.50-7.60(m),
7.70-7.80(m), 8.00(s). MH.sup.+271.
[1205] (b) By proceeding in a similar manner to Reference Example
29(a) but using (2-cyclohexyl)ethyl bromide there was prepared
methyl 1-(2-cyclohexyl)ethyl-3-methyl-1H-indole-6-carboxylate. NMR
(CDCl.sub.3): .delta.0.80-1.00(m), 1.10-1.30(m), 1.60-1.80(m),
2.30(s), 3.90(s), 4.10-4.20(t), 7.00(s), 7.60(d), 7.80(d),
8.10(s).
[1206] (c) By proceeding in a similar manner to Reference Example
29(a) but using (3-cyclohexyl)propyl bromide there was prepared
methyl 1-(3-cyclohexyl)propyl-3-methyl-1H-indole-6-carboxylate.
[1207] (d) By proceeding in a similar manner to Reference Example
29(a) but using heptyl bromide there was prepared methyl
1-heptyl-3-methyl-1H-indole-6-carboxylate.
[1208] (e) By proceeding in a similar manner to Reference Example
29(a) but using (3phenyl)butyl bromide there was prepared methyl
1-(3-phenylbutyl-3-methyl1H indole-6-carboxylate.
[1209] (f) By proceeding in a similar manner to Reference Example
29(a) but using 4-trifluoromethylbenzyl bromide there was prepared
methyl 1-(4-trifluoromethylbenzyl-3-methyl-1H-indole-6-carboxylate
as a white solid. NMR (CDCl.sub.3): .delta.2.30(s); 3.90(s);
5.40(s); 7.00(s); 7.10-7.20(m); 7.50-7.60(m); 7.80-7.90(m);
8.00(s).
[1210] (g) By proceeding in a similar manner to Reference Example
29(a) but using 4-methylsulphonylbenzyl bromide there was prepared
methyl 1-(4-methylsulphonylbenzyl)-3-methyl-1H-indole-6-carboxylate
as a white solid. NMR (CDCl.sub.3): .delta.2.40(s); 3.00(s);
3.90(s); 5.40(s); 7.00(s); 7.20-7.30(m); 7.50-7.70(m)
[1211] 7.80-7.90(m); 8.00(s).
[1212] (h) By proceeding in a similar manner to Reference Example
29(a) but using piperonyl chloride there was prepared methyl
1-(1,3-benzodioxol-5-yl)methyl-3-methyl-1H-indole-6-carboxylate.
[1213] (i) By proceeding in a similar manner to Reference Example
29(a) but using (naphthalen-2-yl)methyl chloride there was prepared
methyl
1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-carboxylate.
[1214] (j) By proceeding in a similar manner to Reference Example
29(a) but using (tetrahydro-2H-pyran-2-yl)methyl chloride there was
prepared methyl
1-(tetrahydro-2H-pyran-2-yl)methyl-3-methyl-1H-indole-6-carboxylat-
e.
[1215] (k) By proceeding in a similar manner to Reference Example
29(a) but using tetrahydrofurfuryl chloride there was prepared
methyl 3-methyl-1-(tetrahydrofurfuryl)-1H-indole-6-carboxylate. (1)
By proceeding in a similar manner to Reference Example 29(a) but
using toluene-4-sulphonyl chloride there was prepared methyl
3-methyl-.alpha.-(toluene-4-sulphonyl)-1H-indole-6-carboxylate. NMR
(CDCl.sub.3): .delta.2.2(s,3H), 2.3 (s,3H), 4.0(s,3H,
7.15-7.2(m,2H), 7.4-7.5(m,2H), 7.7-7.8(m,2H),
7.9-8.0(m,1H),8.7(s,1H),
[1216] (m) By proceeding in a similar manner to Reference Example
29(a) but using tetrahydrofuran-3-yl chloride there was prepared
methyl
3-methyl-1-(tetrahydofuran-3-yl)-1H-indole-6-carboxylate.
[1217] (n) By proceeding in a similar manner to Reference Example
29(a) but using benzyl bromide there was prepared methyl
1-benzyl-3-methyl-1H-indole-6-carboxylate as a white solid. NMR
(CDCl.sub.3): .delta.2.30(s), 3.80(s), 5.20(s), 7.00(s),
7.00-7.10(m), 7.10-7.20(m), 7.50-7.60(m), 7.70-7.80(m),
8.00(s).
[1218] (o) By proceeding in a similar manner to Reference Example
29(a) but using 4-methoxybenzyl bromide there was prepared methyl
1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carboxylate as a white
solid, m.p. 116-118C. [Elemental analysis: C,73.48;H,6.27; N,4.36%.
Calculated for C.sub.19H.sub.19NO.sub.3: C,73.77;H,6.19;
N,4.53%].
Reference Example 30
Methyl 3-methyl-1H-indole-6-carboxylate
[1219] A mixture of methyl 3-formyl-1H-indole-6-carboxylate (12.0
g), p-toluenesulphonic acid (2.0 g) and p-toluenesulphonylhydrazide
(13.0 g) in a mixture of formamide (100 ml) and sulpholane (50 ml)
was heated at 100.degree. C. for 15 minutes and then cooled to room
temperature. The mixture was treated with sodium cyanoborohydride
(15.0 g, 5 g portions after 10 minute intervals), then heated at
100.degree. C. for 2 hours. After cooling to ambient temperature
the reaction mixture was treated with ice water (500 ml) giving a
white precipitate. Water (1000 ml) was added and the mixture
stirred for 30 minutes then filtered. The off-white solid was
washed with warm water then azeotroped with toluene to yield the
title compound (10.2 g) as a white solid.
Reference Example 31
[1220] (a)
1-(6,6-Dimethyl-bicyclo[3.1.1.]hept-3-ylmethyl)-3-methyl-1H-ind-
ole-6-carboxylic acid
[1221] A mixture of 3-methyl-indole-6-carboxylic acid [1.8 g,
Reference Example 28(b)], (1S,2S,5S)-(-)-myrtanol tosylate and
potassium hydroxide (3.17 g) in dimethyl sulphoxide (35 ml) was
stirred at room temperature for 18 hours. The reaction mixture was
partitioned twice between ethyl acetate (25 ml) and dilute
hydrochloric acid (25 ml, 1N). The combined organic layers were
dried over sodium sulphate then evaporated. The residue was
subjected to flash chromatography on silica to give the title
compound (2.45 g) as a white solid. M.sup.+325.
[1222] (b) By proceeding in a similar manner to Reference Example
31 (a) but using cyclohexanol tosylate there was prepared
1-cyclohexyl-3-methyl-1H-indole-6-carboxylic acid as a white
solid.
[1223] (c) By proceeding in a similar manner to Reference Example
31(a) but using cyclopentanol tosylate there was prepared
1-cyclopentyl-3-methyl-1-indole-6-carboxylic acid as a white solid.
NMR {(CD.sub.3).sub.2CO}: .delta.0.80-0.90(m), 1.20-1.30(m),
1.70-1.90(m), 2.10-2.30(m), 2.30(s), 4.90-5.00(m), 7.30(s),
7.50(d), 7.70(d), 8.20(s).
[1224] (d) By proceeding in a similar manner to Reference Example
31 (a) but using cycloheptyl methanol tosylate there was prepared
1-cycloheptylmethyl-3-methyl1H indole-6-carboxylic acid as a white
solid. NMR {(CD.sub.3).sub.2CO}: .delta.1.10-1.80(m), 2.30(s),
3.30-3.40(m), 4.00-4.10(m), 7.30(s), 7.50-7.60(m), 7.70-7.80(m),
8.10(s).
Reference Example 32
1-Butyloxycarbonyl-3-methyl-indole-6-carboxylic acid
[1225] A stirred solution of 3-methyl-indole-6-carboxylic acid [2.0
g, Reference Example 28(b)]) in dichloromethane (10 ml) was treated
with di-tert-butyl dicarbonate (5.4 g). triethylamine (3.5 ml) and
4-dimethylaminopyridine (0.1 g). After stirring at room temperature
for 4 hours the reaction mixture was evaporated. The residue was
partitioned three times between dichloromethane (100 ml) and water
(100 ml). The combined organic layers were washed with ice-cold
dilute hydrochloric acid (200 ml, 0.1N), then with brine (150 ml),
then dried over sodium sulphate and then evaporated. The residue
was subjected to flash chromatography to yield the title compound
(2.5 g) as a white solid. NMR {(CD.sub.3).sub.2SO}: .delta.2.30(s),
7.50-7.60(m), 7.80-7.90(s), 8.70(s).
Reference Example 33
2-Cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole-4-yl
tributyl tin
[1226] A solution of 4-bromo-2-cyclopropyl-7-methoxy-1 (or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole [3.6
g, Reference Example 20(c)] in dry tetrahydrofuran at -70.degree.
C. was treated with a solution of butyl lithium in hexane (6.8 ml,
1.6M). After stirring for 1 hour the mixture was treated with
tributyltin chloride (3.07 ml) whilst maintaining the temperature
below -70.degree. C., and the reaction mixture was stirred for 1
hour, then allowed to warm to room temperature and then left
overnight at room temperature. The reaction mixture was quenched
with water and then extracted twice with diethyl ether (100 ml).
The combined extracts were dried over magnesium sulphate then
evaporated. The residual yellow oil was subjected to flash column
chromatography on silica eluting with a mixture of ether and
pentane (1:1, v/v) to give the title compound as colourless thick
oil (3.83 g).
Reference Example 34
2-Cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-4-(4-mor-
pholinosulphonyl)-1H(or 3H)-benzimidazole
[1227] A solution of 2-cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-e- thoxymethyl)-1H(or
3H)-benzimidazol-4-ylsulphonyl chloride (0.67 g, Reference example
35) in dichloromethane (16 ml) was treated with pyridine (0.56 ml)
and morpholine (0.5 ml). After stirring at room temperature for 1
hour then standing overnight at room temperature the reaction
mixture was evaporated. The residue was azeotroped with toluene to
give the title compound which was used without further
purification.
Reference Example 35
2-Cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or
3H)-benzimidazole-4-yl-sulphonyl chloride
[1228] A solution of 4-bromo-2-cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole (5.96
g, Reference Example 20(c)]) in dry tetrahydrofuran (80 ml) at
-70.degree. C. was treated dropwise with a solution of butyllithium
in hexane (11 ml, 1.6 M) whilst maintaining the reaction
temperature below -60.degree. C.
[1229] After stirring at this temperature for 1 hour the solution
was then transferred under nitrogen via a cannula to a cooled
solution of excess sulphur dioxide in tetrahydrofuran (80 ml) below
-60.degree. C. and stirred for a further 30 minutes at -60.degree.
C. The reaction mixture was then allowed to warm to room
temperature over 1 hour and then evaporated to dryness under
reduced pressure. The residue was triturated with ether to give
lithium 2-cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl)-4-1H(or-3H)-benzimidazolyl
sulphinate as cream solid (4.82 g). A mixture of this solid and
dichloromethane (80 ml), cooled to 0.degree. C. was treated
dropwise with a solution of sulphuryl chloride (2 ml) in
dichloromethane (20 ml). After allowing to warm to room temperature
the reaction mixture was evaporated and the residue was azeotroped
with toluene and then triturated with toluene. The mixture was
filtered, the solid was washed with ether. The combined filtrate
plus washings were evaporated to give the title compound as yellow
gum (2.2 g).
Reference Example 36
[1230] 5-[2-Cyclopropyl-7-methoxy-1(or
3)-(2-trimethylsilanyl-ethoxymethyl- )-1H(or
3H)-benzimidazole-4-yl]pyridine-2-carboxamide
[1231] A solution of
2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-et-
hoxymethyl)-1H(or 3H)-benzimidazole-4-yl tributyl tin (1g,
Reference Example 33) in dimethylformamide (10 ml) was treated with
a mixture of 5-bromo-pyridine-2-carboxamide (0.275 g),
bis(dibenzylidene)acetone palladium(0) (39.45 mg) and
triphenylphosphine (36 mg) in dimethylformamide (1 ml). The mixture
was heated at 120.degree. C. under an atmosphere of N.sub.2 for 5
hours then diluted with methanol and then filtered through a pad of
hyflosupercel. The filtrate was evaporated and the residue was
subjected to flash column chromatography on silica eluting with a
mixture of ethyl acetate and pentane (2:8 to 1:0, v/v) to give the
title compound as cream solid (0.4 g).
Reference Example 37
Methyl 1-benzyl-3-methyl-1H-indoline-6-carboxylate
[1232] A solution of methyl
1-benzyl-3-methyl-1H-indole-6-carboxylate [0.8 g, Reference Example
29(n)] in trifluoroacetic acid at 0.degree. C. was treated with a
solution of borane-tetrahydrofuran complex in tetrahydrofuran (9
ml, 1M). The solution was kept at 0.degree. C. for 24 hours, then
quenched with methanol, then evaporated. The residual solid was
dried under high vacuum and used without purification.
Reference Example 38
[1233] Methyl
3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-3-nitromethy-
l-propionate
[1234] A stirred solution of methyl
3-(3-methyl-1-{3-(phenyl)propyl}-1H-in- dol-6-yl)-propenoate (0.263
g, Reference Example 39) in nitromethane (5 ml) was treated with
tetramethylguanidine (0.091 g). The mixture was heated to
65.degree. C. for 2 hours then treated with a further aliquot of
tetramethylguanidine (0.091 g). After heating at 65.degree. C. for
a further hour the reaction mixture was cooled to room temperature
then poured into hydrochloric acid (20 ml, 1N) then extracted three
times with ethyl acetate (25 ml).
[1235] The combined extracts were dried over magnesium sulphate
then evaporated. The residue was subjected to preparative layer
chromatography on silica using a mixture of ethyl acetate and
hexane (1:2, v/v) as eluent to yield the title compound (0.296
g).
Reference Example 39
Methyl 3-(3-methyl-1-{3-(phenyl
propyl}-1H-indol-6-yl)-propenoate
[1236] A stirred
3-methyl-1-{3-(phenyl)propyl}-1H-indole-6-carboxaldehyde (0.283 g,
Reference Example 40) in dry toluene (20 ml), under argon, was
treated with carbomethoxymethylene triphenylphosphorane (0.409 g).
The mixture was heated at 80.degree. C. for 4 hours then cooled to
room temperature and then poured into water (20 ml). The organic
phase was separated and the aqueous phase was extracted three times
with ethyl acetate (30 ml). The combined organic phases were dried
over magnesium sulphate then evaporated. The residue was subjected
to flash chromatography on silica eluting with a mixture of diethyl
ether and hexane (10:1, v/v) to yield the title compound (0.263
g).
Reference Example 40
[1237] 3-methyl-1-{3-(phenyl)propyl}-1H-indole-6-carboxaldehyde
[1238] Dimethylsulphoxide (0.311 g) was added to a stirring
solution of oxalyl chloride in dichloromethane (1 ml, 2M) in
dichloromethane (25 ml) at -60.degree. C. under argon and the
mixture was stirred for 2 minutes. A solution of
3-methyl-1-{3-(phenyl)propyl}1H indole-6-methanol [0.501 g,
Reference Example 22(c)] in dichloromethane (10 ml) was then added
dropwise and the mixture stirred for 15 minutes at -60.degree. C.
Triethylamine (0.956 g) was then added and the solution warmed to
room temperature and stirred for 1 hour. The mixture was poured
into water (20 ml) and then extracted three times with
dichloromethane (25 ml). The combined extracts were washed with
brine (30 ml), then dried over sodium sulphate and then evaporated.
The residue was subjected to flash chromatography on silica eluting
with a mixture of ethyl acetate and hexane (1:1, v/v) to yield the
title compound (0.283 g).
Reference Example 41
Methyl 3-methyl-1-{3-(phenyl)propyl}-1H-indole-6-carboxylate
[1239] A stirred solution of methyl
3-methyl-1H-indole-6-carboxylate (0.5 g; Reference Example 30) in
acetone (35 ml) was treated with 1-bromo-3-phenylpropane (0.577 g)
and sodium hydroxide (0.116 g). The mixture was stirred at room
temperature for 12 hours then poured into water (35 ml) and then
extracted three times with ethyl acetate (50 ml). The combined
extracts were washed with dilute hydrochloric acid (50 ml, 1N) then
with saturated sodium bicarbonate solution (50 ml), then dried over
magnesium sulphate and then evaporated. The residue was subjected
to flash column chromatography on silica eluting with a mixture of
ethyl acetate and hexane (50: 1, v/v) to yield the title compound
(0.58 g).
Reference Example 42
[1240] (a) 1-Benzyl-3-methyl-1H-indazole carbonyl chloride
[1241] A solution of 1-benzyl-3-methyl-indazole-6-carboxylic acid
[0.15 g, Reference Example 28(o)] in dichloromethane (20 ml) was
treated with dimethylformamide (2 drops) then with oxalyl chloride
(1.69 ml). After stirring for 2 hours the reaction mixture was
evaporated and the residue was dried under high vacuum to give the
title compound (0.16 g) which was used without further
purification.
[1242] (b) By proceeding in a similar manner to Reference Example
42(a) but using Reference Example 28(p) there was prepared
1-(4-methoxybenzyl)-3-methyl1H indole-6-carbonyl chloride.
[1243] (c) By proceeding in a similar manner to Reference Example
42(a) but using Reference Example 26(b) there was prepared
4-methoxy-2-methoxymethyl-benzoxazole-6-carbonyl chloride as a pale
orange-brown coloured solid.
[1244] (d) By proceeding in a similar manner to Reference Example
42(a) but using Reference Example 26(c) there was prepared
3-isopropyl-1-methyl-1H indole-5-carbonyl chloride.
[1245] (e) By proceeding in a similar manner to Reference Example
42(a) but using Reference Example 28(q) there was prepared
1-(4-methoxybenzyl)-3-methyl1H indazole-6-carbonyl chloride.
Reference Example 43
[1246] (a) Methyl 1-benzyl-3-methyl-1H-indazole-6-carboxylate A
solution of methyl 3-methyl-indazole-6-carboxylate (0.2 g,
Reference Example 44) in acetone (15 ml) was treated with benzyl
bromide (0.898 g) then with potassium carbonate (0.290 g) and a
catalytic amount of 18-crown-6.The mixture was stirred for hours at
room temperature then poured into water (30 ml) and then extracted
three times with ethyl acetate (30 ml). The combined extracts were
dried over sodium sulphate then evaporated. The residue was
subjected to flash chromatography on silica eluting with a mixture
of ethyl acetate and hexane (7:1, v/v) to yield the title compound
(0.161 g) and methyl 2-benzyl-3-methyl-indazole-6-carboxylate
(0.069 g).
[1247] (b) By proceeding in a similar manner to Reference Example
43(a) but using 4-methoxybenzyl bromide there was prepared methyl
1-(4-methoxybenzyl)-3-methyl-indazole-6-carboxylate.
Reference Example 44
Methyl 3-methyl-H-indazole-6-carboxylate
[1248] A solution of 3-methyl-indazole-6-carboxylic acid (1.57 g,
Reference Example 45) in methanol (75 ml) was treated with hydrogen
chloride gas for 10 minutes. The reaction mixture was stirred for
12 hours at room temperature then evaporated. The residue was
partitioned between ethyl acetate (50 ml) and saturated sodium
bicarbonate solution (50 ml). The combined extracts were dried over
sodium sulphate then evaporated. The residue was washed with hexane
to give the title compound (1.56 g) which was used without further
purification.
Reference Example 45
3-methyl-1H-indazole-6-carboxylic acid
[1249] A solution of methyl
1-triflyl-3-methyl-indazole-6-carboxylate(0.66- 8 g, Reference
Example 46) in a mixture of methanol and water (3:1, 80 ml) was
treated with potassium carbonate (1.15 g). The mixture was heated
at reflux for 5 hours then cooled to room temperature then poured
into 1N'hydrochloric acid (50 ml). The mixture was extracted three
times with ethyl acetate (50 ml). The combined extracts were dried
over sodium sulphate then evaporated. The residue was washed with a
mixture of hexane and ether to give the title compound (0.360
g).
Reference Example 46
Methyl 1-triflyl-3-methyl-1H-indazole-6-carboxylate
[1250] The 6-triflyloxy-1-triflyl-3-methyl-indazole (1.0 g,
Reference Example 47) was dissolved in dimethylformamide under
argon and the solution was flushed with carbon monoxide for 5
minutes. The solution was treated with palladium acetate (0.11 g),
diphenylphosphine ferrocene (0.272 g), triethylamine (0.491 g) and
methanol (1.56 g) then stirred at room temperature for 12 hours
under an atmosphere of carbon monoxide. The reaction mixture was
poured into water (150 ml) and the aqueous layer was extracted
three times with ethyl acetate (35 ml). The combined extracts were
dried over sodium sulphate then evaporated. The residue was
subjected to flash chromatography on silica eluting with a mixture
of ethyl acetate and hexane (1:7, v/v) to yield the title
compound.
Reference Example 47
6-triflyloxy-1-triflyl-3-methyl-1H-indazole
[1251] A solution of 6-hydroxy-3-methyl-1H-indazole (0.45 g,
Reference Example 48) in tetrahydrofuran (30 ml) under argon was
treated with sodium hydride (0.198 g). After the initial
effervescence had subsided the solution was warmed to 50.degree. C.
for 1 hour.
[1252] The reaction mixture was cooled to room temperature and
N-phenyltrifluoromethane sulphonimide (2.48 g) was added. The
mixture was stirred for 2 hours then poured into water (50 ml) then
extracted three times with ethyl acetate (50 ml). The combined
extracts were dried over sodium sulphate then evaporated. The
residue was subjected to flash chromatography on silica eluting
with a mixture of ethyl acetate and hexane (1:7, v/v) to yield the
title compound (1.10 g).
Reference Example 48
6-hydroxy-3-methyl-1H-indazole
[1253] A solution of 6-methoxy-3-methyl-1H-indazole(2.0 g,
Reference Example 49) in dichloromethane (75 ml) was cooled to
0.degree. C. then treated with a solution of boron tribromide in
dichloromethane (54 ml, 1M). The mixture was allowed to warm to
room temperature and then stirred for 12 hours. The solution was
poured into an ice-saturated sodium bicarbonate mixture and the
aqueous layer was extracted three times with ethyl acetate (50 ml).
The combined extracts were dried over sodium sulphate then
evaporated. The residue was subjected to flash chromatography on
silica eluting with a mixture of ethyl acetate and hexane (2:1,
v/v) to yield the title compound (1.7 g).
Reference Example 49
6-methoxy-3-methyl-1H-indazole
[1254] 2-fluoro-4-methoxyacetophenone (5.0 g) was treated with
hydrazine (75 ml) under argon and the mixture was heated to reflux
for 12 hours. After cooling to room temperature, the reaction
mixture was poured into water (200 ml) then extracted three times
with ethyl acetate (50 ml). The combined extracts were dried over
sodium sulphate then evaporated. The residue was subjected to flash
chromatography on silica eluting with a mixture of ethyl acetate
and hexane (1:3, v/v) to yield the title compound (4.05 g).
Reference Example 50
5-bromo-2-methoxyaniline
[1255] A stirred mixture of 4-bromo-2-nitroanisole (98.56 g) and
iron powder (113.7 g) in ethanol (1.51) was heated to reflux and
treated dropwise with hydrochloric acid (350 ml, 0.5N) over 1 hour.
After refluxing for a further 3 hours the reaction mixture was
cooled to room temperature then filtered through hyflosupercel. The
filtrate was evaporated and the residue was treated with saturated
sodium bicarbonate solution (21) then filtered. The solid was
washed with water then recrystallised from cyclohexane to give the
title compound (61.98 g) as a pale brown solid, m.p. 93-93.degree.
C.
Reference Example 51
Methyl 2-hydroxy-4-methoxy-3-nitrobenzoate
[1256] A solution of methyl 4-methoxysalicylate (50 g) in glacial
acetic acid (700 ml) was treated dropwise with concentrated nitric
acid (50 ml) over 15 minutes. After stirring for 2 hours, then
standing at room temperature for 18 hours, the mixture was treated
with a further aliquot of concentrated nitric acid (10 ml) then
stirred for 6 hours. The reaction mixture was diluted with ice then
poured into water (1000 ml), then filtered. The solid was dried
then subjected to flash chromatography on silica eluting with a
mixture of toluene and dichloromethane (2:1, v/v) to give the title
compound as a white solid, m.p. 185-187.degree. C.
Reference Example 52
Methyl 3-isopropyl-1H-indole-5-carboxylate
[1257] A solution of methyl
3-iodo-4-(3-methyl-but-2-enylamino)-benzoate (2.0 g, Reference
Example 53) in triethylamine (1.6 ml) and acetonitrile (35 ml) was
treated with palladium acetate (0.05 g). The mixture was sealed in
a bomb and heated at 110.degree. C. for hours. After cooling the
reaction mixture was filtered and the filtrate was evaporated. The
residue was subjected to flash chromatography on silica eluting
with a mixture of ethyl acetate and petroleum ether (1:4, v/v) to
give the title compound (1.0 g).
Reference Example 53
Methyl 3-iodo-4-(3-methyl-but-2-enylamino)-benzoate
[1258] A solution of diisopropylamine (2.8 ml) in tetrahydrofuran
(25 ml), under nitrogen, cooled to -10.degree. C. was treated with
butyl lithium in hexane (12.4 ml, 1.6M). The solution was-added
slowly via a syringe to a cooled to solution of methyl
4-amino-3-iodobenzoate (5 g, prepared according to the procedure of
M. L. Hill, Tetrahedron, 1990, 46, page 4587) in tetrahydrofuran
(100 ml), under nitrogen and at -78.degree. C. The mixture was
allowed to warm to 0.degree. C. and after stirring for a further 10
minutes the mixture was cooled to -78.degree. C. and then treated
with 4-bromo-2-methyl-2-butene (2.49 ml). The reaction mixture was
allowed to warm to room temperature over 1.5 hours then poured into
saturated brine (100 ml). The organic layer was separated and the
aqueous phase was extracted with ethyl acetate (100 ml). the
combined organic phases were evaporated and the residue was
subjected to flash chromatography on silica eluting with a mixture
of ethyl acetate and petroleum ether (1:9, v/v) to give the title
compound (5 g).
In vitro and in vivo Test Procedures
[1259] 1(a) Inhibitory Effects of Compounds on PDE IV Activity
[1260] 1.1 Preparation of PDE from Guinea Pig Macrophages
[1261] The method is described by Turner et al., Br. J. Pharmacol,
1993, 108, pages 876-883.Briefly, cells are harvested from the
peritoneal cavity of horse-serum treated (0.5 ml i.p.) Dunkin
Hartley guinea pigs (250-400 g) and the macrophages purified by
discontinuous (55%, 65%, 70% v/v) gradient (Percoll)
centrifugation. Washed macrophages are plated out in cell culture
flasks and allowed to adhere. The cells are washed with Hank's
balanced salt solution, scraped from the flasks and centrifuged
(1000 g). The supernatant is removed and the pellets stored at
-80.degree. C. until use. The pellet is homogenised in 20 mM
tris(hydroxymethyl)aminomethane HCl, pH7.5, 2 mM magnesium
chloride, 1 mM dithiothreitol, 5 mM ethylenediaminetetraacetic
acid, 0.25 mM sucrose, 20 mM p-tosyl-L-lycine chloromethyl ketone,
10 mg/ml leupeptin and 2000 U/ml aprotinin.
[1262] 1.2 Measurement of PDE Activity
[1263] PDE activity is determined in macrophage homogenates by the
two-step radioisotopic method of Thompson et al., Adv. Cyclic Nucl.
Res., 1979, 10, pages 69-92.The reaction mixture contains 20 mM
tris(hydroxymethyl)-aminomethane HCl (pH8.0), 10 mM magnesium
chloride, 4 mM 2-mercaptoethanol, 0.2 mM
ethylenebis(oxyethylenenitrilo)-tetraacetic acid and 0.05 mg of
bovine serum albumin/mL. The concentration of substrate is 1 ,M.
The IC.sub.50 values (i.e. concentrations which produce 50%
inhibition of substrate hydrolysis) for the compounds examined are
determined from concentration-response curves in which
concentrations range from 0.03 nM to 10 .mu.M.
[1264] 1.3 Results
[1265] Compounds within the scope of the invention exhibit
IC.sub.50 values against guinea pig macrophage cyclic AMP-specific
phosphodiesterase (PDE IV) of between 10.sup.-10M to about
10.sup.-5M, preferably from about 10.sup.-10M up to about
10.sup.-6M. The compounds of the invention are from about
10,000-fold to about 50-fold more selective for cyclic AMP
phosphodiesterase IV than cyclic nucleotide phosphodiesterase types
I, II, III or V.
[1266] (b) Inhibitory Effects of Compounds on PDE V Activity
[1267] 1.4 Preparation of PDE From Human Platelets
[1268] The method is described by R. E. Weishaar et al.,
Biochem.Pharmacol., 1986, 35, pages 787-800.
[1269] 1.5 Measurement of PDE Activity
[1270] PDE activity is determined by the radioisotopic method of
Thompson et al., Adv. Cyclic Nucl. Res., 1979, 10, pages
69-92.Following incubation for 30 minutes at 30.degree. C.,
[.sup.3H]-guanosine 5'-monophosphate is separated from the
substrate, guanosine [.sup.3H]-guanosine 3':5'-cyclic
monophosphate, by elution on cation-exchange columns, and
radioactivity is determined using a liquid scintillation counter
(LS 1701, Beckman) using a liquid scintillation cocktail (Flow
Scint II, Packard). The concentration of substrate is. 1 .mu.M. The
IC50 values for the compounds examined are determined from
concentration-response curves in which concentrations range from
10.sup.-9M to 10.sup.-5M.
[1271] 2. In vivo Bronchodilator Actions of Compounds
[1272] 2.1 Measurement of Bronchodilatation
[1273] Bronchorelaxant activity is measured in in vivo tests in the
anaesthetized guinea-pig or rat according to the method described
by Underwood et al., Pulm.
[1274] Pharmacol., 1992, 5, pages 203-212, in which the effects on
bronchospasm induced by histamine (or other spasmogens such as
methacholine or leukotriene D4) is determined. Compounds are
administered orally 1 hour prior to administration of
spasmogen.
[1275] 3. In vivo Actions of Compounds on Antigen
(Ovalbamin)-induced Eosinophilia in Guinea-Pigs
[1276] 3.1 Treatment of Animals and Measurement of Eosinophil
Numbers
[1277] Male Dunkin-Hartley guinea-pigs weighing 200-250 g are
sensitized using 10 g ovalbumin in 1 mL of a 100 mg/mL suspension
of aluminium hydroxide, i.p.
[1278] 28 days after sensitization guinea-pigs are dosed orally. 23
Hours later this procedure is repeated and 60 minutes later the
guinea-pigs are challenged with nebulised saline or ovalbumin (1%
in saline) for 15 seconds. 24 Hours after challenge the guinea-pigs
are killed and the lungs are lavaged with warm saline. Total and
differential cell counts are made.
[1279] 4. Inhibitory Effects of Compounds Against Antigen-induced
Eosinophilia in the Rat in vivo
[1280] 4.1. Treatment of Rats and Measurement of Eosinophil
Numbers
[1281] Male Brown Norway rats weighing 150-250 g are sensitized on
days 0, 12 and 21 with ovalbumin (100 g, i.p.). Rats are challenged
on any one day between days 27-32. 24 hours and 1 hour before
antigen challenge the test compound is orally dosed. Rats are
challenged by exposure for 30 minutes to nebulized saline or
ovalbumin (1% in saline). 24 hours after challenge, rats are killed
and the airways are lavaged with RPMI and 10% foetal calf serum.
Total and differential cell counts are made.
[1282] 5.In vitro inhibitory Effects on TNF-alpha Release by Human
Monocytes
[1283] The effects of compounds on TNF-alpha production by human
peripheral blood monocytes (PBMs) are examined as follows.
[1284] 5.1.Preparation of Blood Monocytes
[1285] Blood is drawn from normal donors into sodium citrate (3.8%)
as an anticoagulant. Mononuclear cells are fractionated by
centrifugation through a histopaque gradient system (Accuspin,
Sigma, U.K.). The monouclear cell fraction comprising 90%
mononuclear cells (contaminating cells being neutrophils), is
suspended in Hanks balanced salt solution (HBSS), (Life
Technologies Ltd U.K.) containing 1% v/v Human serum albumin (HSA)
(Sigma U.K.). The cells are washed, counted and resuspended at 106
cells /ml in RPMI 1640 tissue culture medium containing 1% v/v
foetal calf serum (FCS), 50 U/ml penicillin, 50 mg/ml streptomycin
(Life Technologies Ltd), then plated out in 96 well plates at
2.times.10.sup.6 cells / well.
[1286] 5.2. TNF-alpha Release
[1287] Following 2 hours incubation (37.degree. C., 5% CO.sub.2)
medium and non adherent cells are removed leaving pure adherent
monocytes. RPMI (200.mu.l ) medium is replaced with that containing
compounds for evaluation, or vehicle. Control treatments and
compounds for test are assayed in quadruplicate wells. Compounds
are tested within the concentration range 10.sup.-10-10.sup.-5 M,
and allowed to incubate with the cells for 1 hour. LPS (E.coli
055:B5 Sigma, U.K.) is added in RPMI to give a final concentration
of 1.0 ng/ml and the incubation is continued for a further 18
hours.
[1288] 5.3. TNF-alpha Measurement
[1289] Cell supernatants are removed and assayed for TNF-alpha by
sandwich ELISA as follows.
[1290] ELISA plates (Costar, U.K.) are coated overnight at
4.degree. C. with 2.5tg/ml polyclonal goat anti-human TNF-alpha
antibody (R&D Systems, U.K.) in pH 9.9 bicarbonate buffer.
Polyclonal rabbit anti-human TNF-alpha antibody (Endogen, U.S.A.)
is used as the second antibody (2.5 .mu.g/ml) and polyclonal goat
anti-rabbit IgG-horseradish peroxidase (Calbiochem, U.K.) is used
as the detection antibody (1:8000 dilution).
[1291] Colour development following addition of the substrate
tetramethybenzidine (TMB) solution (Sigma,U.K.) is measured by
absorbance at 450 um using a Titertek plate reader (ICN, U.K.). 2 5
TNF-alpha levels are calculated by interpolation from a standard
curve using recombinant human TNF-alpha (R&D Systems)
(0.125-16ng/ml). Data are fitted by linear regression using
GraphPad PRIZM v 2.01 software. Basal TNF-alpha levels are less
than 100 pg/ml whilst LPS stimulation of monocytes increases
TNF-alpha levels to 5-10 ng/ml.
[1292] 5.4. Results
[1293] Compounds within the scope of the invention produce 50%
inhibition of LPS induced TNF-alpha release from human monocytes at
concentrations within the range of about 10.sup.-9M -10.sup.-6M,
preferably about 10.sup.-9M -10.sup.-7M.
[1294] 6. Inhibitory effects of compounds on Antigen-induced
Bronchoconstriction in the Conscious Guinea-pig
[1295] 6.1 Sensitisation of Guinea-pigs and Measurement of
Antigen-induced Bronchoconstriction
[1296] Male Dunkin-Hartley guinea-pigs (550-700 g) are sensitized
as above. Specific airways resistance (SRaw) is measured in
conscious animals by whole body plethysmography using a variation
of the method of Peimock et. al. J. Appl. Physiol., 1979, 46, 399).
Test compounds or vehicle are administered orally 24 hours and 1
hour before antigen challenge. 30 Minutes before challenge the
animals are injected with mepyramine (30 mg/kg i.p.) to prevent
anaphyl-actic collapse and placed into the plethysmography chambers
where SRaw is determined at 1 minute intervals. Resting SRaw is
then determined. Animals are challenged with an aerosol of
ovalbumin and SRaw is determined every 5 minutes for 15
minutes.
[1297] 7.Inhibitory Effects of Compounds Against Antigen-induced
Bronchoconstriction in the Anaesthetized Rat in vivo
[1298] 7.1. Treatment of rats and measurement of antigen-induced
bronchoconstriction
[1299] Male Brown Norway rats weighing 150-250 g are sensitized on
days 0, 12 and 21 with ovalbumin (100 tg, i.p.). Rats are
challenged on any one day between days 27-32.24 hours and 1 hour
before antigen challenge the test compounds are orally dosed. Rats
are anaesthetized to allow recording of lung function (airway
resistance and lung compliance) using respiratory mechanics
software. Rats are challenged with ovalbumin i.v. and the peak
changes in airway resistance and lung compliance are determined.
7.2 Results
[1300] Compounds within the scope of the invention inhibit
antigen-induced bronchoconstriction by up to 89% at doses of 10
mg/kg. 8.Inhibitory effects of compounds on serum TNF-alpha levels
in LPS-challenged mice 8.1. Treatment of Animals and Measurement of
Murine TNF-alpha
[1301] Female Balb/c mice (age 6-8 weeks, weight 20-22 g) are
orally dosed with the test compound. After a minimum of 30 minutes
they are challenged i.p. with 30[tg of LPS per mouse. After 90
minutes the animals are killed by carbon dioxide asphyxiation and
bled by cardiac puncture. Blood is allowed to clot at 4.degree. C.,
centrifuged (385 g for 5 minutes) and serum taken for TNF-alpha
analysis. TNF-alpha levels are measured using a commercially
available murine TNF-alpha ELISA kit, purchased from Genzyme (Cat.
no. 1509.00), as recommended by the manufacturer. Values for
TNF-alpha are calculated from a recombinant murine TNF-alpha
standard curve.
[1302] 9. Systemic Bioavailability in Female Balb/c Mouse
Intravenous Administration
[1303] Following surgery to expose the jugular vein for dosing, a
solution of test compound in dimethylsulphoxide is added at a dose
of 1 mg/kg body weight.
[1304] Oral Administration
[1305] A suspension of test compound in 1.5% aqueous
carboxymethylcellulose is introduced into the stomach by gavage at
a dose of 1 mg/kg body weight. Following either i.v. or oral
dosing, blood is obtained by cardiac puncture following carbon
dioxide asphyxiation and is obtained at a single time post-dose for
each animal. Three animals are sacrificed at each time point. Blood
samples are obtained at the following times after dosing by both
the i.v. and oral routes; 5 minutes (i.v. only), 0.25, 0.5, 1, 2,
3, 4, 5.5, 7 and 24 hours. Corresponding plasma is obtained by
centrifugation of each blood sample. The drug content in the plasma
samples is then determined using conventional methods.
[1306] 9.1 Metabolism
[1307] (i)Preparation of Mouse Liver Homogenate
[1308] Fresh mouse liver is homogenised in sucrose-phosphate
buffer. Following centrifugation the resulting supernatant (liver
homogenate) is used fresh or frozen in liquid nitrogen for one
minute and stored at -30.degree. C. to -40.degree. C. prior to
use.
[1309] (ii) Incubation of Compounds with Mouse Liver Homogenate
[1310] To 0.5 ml of mouse liver homogenate is added 0.5 ml taken
from a vortexed mixture of 8 mg NADPH added to a mixture of a
queous magnesium chloride (1 ml, 0.15M) nicotinamide (1 ml, 0.5M)
and pH 7.4 tis buffer (8.5 ml, 0.1M). The compound is added at a
concentration of 1 .mu.g/ml in 10 .mu.l of solvent. Incubates are
maintained at 37.degree. C. Samples are taken at 0 minutes, 5
minutes, 10 minutes, 20 minutes and 30 minutes and the incubation
stopped by the addition of 100 .mu.l acetonitrile. The drug content
in the incubation samples is determined using conventional
methods.
[1311] 10. Streptococcal Cell Wall-Induced Arthritis in Rats
[1312] 10.1. Preparation of S. pyogenes Purified Cell Wall
[1313] Purified S. pyogenes cell wall is prepared from the cell
pellet of a log-phase culture of S. pyogenes, group A, strain D-58.
The whole bacteria are homogenized by grinding with glass beads and
the crude cell wall collected by centrifugation and subsequently
washed with 2% sodium dodecyl sulphate in phosphate buffered saline
followed by phosphate buffered saline to remove contaminating
proteins and nucleic acids. The cell wall is further purified by
sonication and differential centrifugation to obtain a purified
preparation which pelleted at 100,000 g. This material is suspended
in sterile phosphate buffered saline and the quantity of cell wall
determined by measuring the rhamnose content of the preparation
(purified cell wall contains 28% rhamnose by weight). The material
is filtered through a 0.2211 .mu.M filter and stored at 4.degree.
C. until used for arthritis induction.
[1314] 10.2 Arthritis Induction and Measurement of Joint
Diameters
[1315] Female Lewis rats weighing 140-160 g are injected
intra-articularly into the left or right tibio-tarsal joint of one
hind leg on day 0 with purified S. pyogenes cell wall extract (10
mg in 10 ml sterile saline). On day 20, rats received an
intravenous injection of purified cell wall (100 .mu.g in 100 .mu.l
sterile saline) via the lateral vein of the tail. Joint diameters
are measured with calipers across the lateral and medial malleoli
of the previously intra-articularly injected joint immediately
prior to the i.v. injection and then daily through day 24. The net
joint diameter is determined by subtracting the value for the
contralateral joint. Body weights are also measured daily.
Compounds or vehicle are administered by oral gavage on days 20-23.
Typically, 8-10 animals are used per group. For each dose, the
total daily dose is divided into two equal aliquots which are given
at approximately 9 a.m. and 3 p.m.
* * * * *