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C-linked pyrazole biaryl tetrazoles as antagonists of angiotensin II
0960-8941092 $5.00 + .OO @ 1992 Pergamon Press Ltd
Bimrganic & Medicinaf Chemistry Lef~ers,Vol2. No.10. pp. 1243-1246. 1992 Printedin Great Britain
C-LINKED PYRAZOLE BIARYL TETRAZOLES AS ANTAGONISTS OF ANGIOTENSIN II D. Middlemiss’, B.C. Ross, C. Eldred, J.G. Montana, P. Shah, G.C. Hirst, S.P. Watson, T.A. Panchal, J.M.S. Paton, T. Hubbard, G.M. Drew, M.J. Robertson, A Hilditch, K.L. Clark Glaxo Group Research, Park Road, Ware, Hertfondshire SG12 ODP, U.K.
(Received 30 June 1992)
Abstract: The identification of a novel series of C-linked pyrazole biaryl tetrazole antagonists of angiotensin II is described. These compounds are highl;y potent in vitro @Ku e 10) and some examples cause significant reductions in blood pressure at lmgkg‘ p.o. in renal hypertenstve rats. Introduction The biaryl tetrazole DuP-753l can be regarded as the prototype non-peptide angiotensin II (Ang Il) antagonist. In the wake of its discovery a host of analagous compounds, in which an alternative “northern” heterocycle is linked through nitrogen to the “southern” biaryl tetrazole, has been reported.
Cl
Cl
DuP 753
N-N’
CR 117289
R
Bu
Bu
(1) In our efforts to identify a structurally dissimilar follow-up to our Ang II antagonist, GR 11728g2, we explored the possibility of linking a northern heterocyclic unit to a biaryl tetrazole through carbon. This novel approach led to the identification of a series of C-linked pyrazoles3 (1) which are potent orally active Ang lI antagonists selective for the AT, receptor. 1243
D. MIDDLEMISS~~ al.
1244
Structure-Activity Our initial efforts pyrazole mgioisomers leading
to C-link a northern
methoxymethyl
of GR
to a southern
with a carboxylic
that replacement
but only a moderate enhancement
of a hydroxymethyl
or
(2) the carboxylic
acids (3) were prepared.
@. 1000 fold) increase in potency in the l%zgioisorneI-6 (3b)
in potency in the a-isomefi
potency may be due to either introduction
led to the two
acid led to a marked increase in potency. Thus
the modest potency of the pyrazoles
resulted in a substantial
biaryl tetrazole
potent antagonists of Ang II (both pKB ~a. 74). In the work
117289* we found
imidazole-5-substituent
in an effort to enhance This modification
heterocycle
(2) which are moderately
to the identification
Relationships
(3a) (Table 1). These observed increases in
of a new coulombic
interaction
between the y-carboxylic
acid
and the receptor, or simply modulation of a hydrogen bonding interaction.
Table 1: In Vitro Potencies4 of Pyrazoles (3) Compound
R
PKB
3a
a-CH,CF,
7.7
3b
P-CH2cF3
9.g5
3c
H
8.8
The much greater increase in potency in the P-regioisomer terms of a favourable receptor.
interaction
between
In the y-methoxymethyl
compounds
and may allow either an a or b-subsdtuent of the two isomers. However align these
molecules
the intermediate
destabilizing
interaction
rigidly
pyrazole
(4) left potency
pocket
of the
will be less tightly bound to the receptor
into the pocket, hence the similar potencies
interactions
a b-substituent
in the y-carboxylic can gain access
acids (3) may to the pocket.
potency of the des-alkyl pyrazole (3~) suggests that the a-substituent of the N-P-trifluoroethyl
unchanged
on functional
potency
functional
substituent
has a
were performed
of moderate
compounds
more potent than the y-carboxylic
potency,
4
CO,H
9.g5
5
CH,OH
8.0
6
CO,Et
8.0
7
CONHMe
7.5
Although
variation of the pyrazole y-substituent acid (4) (Table 2).
Et N-N'
PKB
the effects of other structural
with this N-substituent.
Table 2: In Vitro Potencies of Pyrazoles (4-7) R
of (3b) with an ethyl group to give
(Table 2); further work to investigate
compounds
Compound
for as follows in
and a lipophilic
with the receptor.
We found that replacement
modifications
to be incorporated
such that only
(3b) can be accounted
N-substituent
(2) the molecules
the enhanced receptor-ligand
more
Furthermore,
the pyrazole
Bu
affording
some
failed to reveal any
1245
C-Linked pyrazole biaryl tetrazoles
The nature of the acidic group of the southern biaryl region was also investigated. the C-linked
tetrazole
sulphonamide
(9) led to a ~a. 100 fold potency decrease
replacement
group of pyrazole
(4) with either
a carboxylic
(Table 3). This effect mirrors that observed
of the tetrazole of DuP-753 with either of these other acidic functions’,
findings for GR 117289 where replacement increase2v7. This suggests, not suprisingly,
Replacement
of
acid (8) or a trifluoromethyl-
of the tetrazole with a carboxylic
on
but is in contrast with
acid causes a slight potency
that the pyrazole (4) binds to the AT, receptor in a manner akin
to DuP-753, rather than GR 117289.
Table 3:
In Vitro Potencies of Pyrazhs
Compound
X
PRB
4
Tet
9.g5
8
C02H
8.0
9
NHso$F,
8.0
Once the optimum tetrazole
combination
had been established
potency
seemed
potencies
of the
(4,8 and 9) Et
N-N’
of a P-N-substituent,
a y-carboxylic
the nature of the alkyl p-substituent
largely insensitive
to changes
a and fi-substituted
pyrazoles
in the p-substituent
acid and a southern
was examined.
(Table 4). Furthermore
(la and b) confirm
the earlier finding
superior potency in y-acid P-mgioisomers.
Table 4: In Vitro Potencid Compound
of Pyrazoles (1)
R
PKB a
B
R N-N’
la
“Bu
8.0
10.0
lb
‘Fr
8.0
10.0
lc
Me
9.8
Id
“pr
10.5
le
CH&l
10.6
If
cycle-Bu
10.9
lg
‘Bu
11.0
lh
CPM9
10.5
However,
BU
(1)
biaryl in vitro
the relative
(see above ) of
1246
D. MIDDLEMISSet al.
In contrast pyrazoles (1) cyclopropylmethyl hypertensive
to their in virro activity, is
very
sensitive
pyrazole
in animal models
to the
nature
(Ih) is very effective
of
the
of hypertension, nitrogen
at lowering
rats8 (Figl) whereas the closely related cyclobutyl
the oral activity of the
substituent.
blood pressure
For
example,
the
in renal artery ligated
analogue (If) is ineffective
despite having
superior activity in vitro. Figure 1: The Effect of Pyrazole (lh) (lmgkg” of Renal Artery Ligated Hypertensive G 3:
170
g
160
z
150
a 2
140
B 5
130
g & P
120
2
110
;: $ 4
100
5
90
p.0.) on the Diastolic Blood Pressure
Rats*
80 I
0
1
3
/
6
I
9
I
12
I
15
t
I
18
21
/
24
1
27
1
1
30
33
1
36
1
39
1
42
I
45
I
48
TIME(h)
Conclusion We have identified AT,
selective
Ang
a series of C-linked pyrazole
II antagonists.
Their
therapeutic potential for these compounds,
excellent
biaryl tetrazoles pharmacological
which are potent, orally active, profile
suggests
considerable
particularly in the area of essential hypertension. References and Notes
1. 2.
3. 4. 5. 6. 7. 8. 9.
Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Price, W.A.; Santella J.B., III; Wells, G.J.; Wexler, R.R.; Wang, P.C.; Yoo, S.; and Timmermans, P.B.M.W.M. J. Med. Chem., 1991,34,2525, and references therein. Middlemiss, D.; Drew, G.M.; Ross, B.C.; Robertson, M.J.; Scopes, D.I.C.; Dowle, M.D.; Akers, J.; Cardwell, K.: Clark, K.L.; Coote, S.; Eldred, C.D.; Hamblett, J.; Hilditch, A.; Hirst, G.C.; Jack, T.I.; Montana, J.; Panchal, T.A.; Paton, J.M.S.; Shah, P.; Stuart, G.; and Travers, A. Biorg. Med. Chem. Lerr., 1991,1,711. The compounds described herein were prepared via a non regiospecific synthesis affording mixtures of pyrazole a and a regioisomers which were separated chromatographically. This synthesis, and the development of a regioselective synthesis of pyrazoles (1) will be published subsequently. For in virro test method see Ref. 2 In common with some other di-acidic Ang II antagonists (e.g. GR 117289*) pyrazoles (1, 3d and 4) display insurmountable antagonism. For a description of the determination of pK, under these conditions see Ref.2 The pyrazole ring positional nomenclature is shown on structure (3). Middlemiss D.; et. al. forthcoming publication Cagiano, J.;Rodriguez-Sargent, C.;Martinez-Maldonado, M. J.Pharmacol. Exp Ther ,1979,208, 3 10. CPM - Cyclopropylmethyl
Bimrganic & Medicinaf Chemistry Lef~ers,Vol2. No.10. pp. 1243-1246. 1992 Printedin Great Britain
C-LINKED PYRAZOLE BIARYL TETRAZOLES AS ANTAGONISTS OF ANGIOTENSIN II D. Middlemiss’, B.C. Ross, C. Eldred, J.G. Montana, P. Shah, G.C. Hirst, S.P. Watson, T.A. Panchal, J.M.S. Paton, T. Hubbard, G.M. Drew, M.J. Robertson, A Hilditch, K.L. Clark Glaxo Group Research, Park Road, Ware, Hertfondshire SG12 ODP, U.K.
(Received 30 June 1992)
Abstract: The identification of a novel series of C-linked pyrazole biaryl tetrazole antagonists of angiotensin II is described. These compounds are highl;y potent in vitro @Ku e 10) and some examples cause significant reductions in blood pressure at lmgkg‘ p.o. in renal hypertenstve rats. Introduction The biaryl tetrazole DuP-753l can be regarded as the prototype non-peptide angiotensin II (Ang Il) antagonist. In the wake of its discovery a host of analagous compounds, in which an alternative “northern” heterocycle is linked through nitrogen to the “southern” biaryl tetrazole, has been reported.
Cl
Cl
DuP 753
N-N’
CR 117289
R
Bu
Bu
(1) In our efforts to identify a structurally dissimilar follow-up to our Ang II antagonist, GR 11728g2, we explored the possibility of linking a northern heterocyclic unit to a biaryl tetrazole through carbon. This novel approach led to the identification of a series of C-linked pyrazoles3 (1) which are potent orally active Ang lI antagonists selective for the AT, receptor. 1243
D. MIDDLEMISS~~ al.
1244
Structure-Activity Our initial efforts pyrazole mgioisomers leading
to C-link a northern
methoxymethyl
of GR
to a southern
with a carboxylic
that replacement
but only a moderate enhancement
of a hydroxymethyl
or
(2) the carboxylic
acids (3) were prepared.
@. 1000 fold) increase in potency in the l%zgioisorneI-6 (3b)
in potency in the a-isomefi
potency may be due to either introduction
led to the two
acid led to a marked increase in potency. Thus
the modest potency of the pyrazoles
resulted in a substantial
biaryl tetrazole
potent antagonists of Ang II (both pKB ~a. 74). In the work
117289* we found
imidazole-5-substituent
in an effort to enhance This modification
heterocycle
(2) which are moderately
to the identification
Relationships
(3a) (Table 1). These observed increases in
of a new coulombic
interaction
between the y-carboxylic
acid
and the receptor, or simply modulation of a hydrogen bonding interaction.
Table 1: In Vitro Potencies4 of Pyrazoles (3) Compound
R
PKB
3a
a-CH,CF,
7.7
3b
P-CH2cF3
9.g5
3c
H
8.8
The much greater increase in potency in the P-regioisomer terms of a favourable receptor.
interaction
between
In the y-methoxymethyl
compounds
and may allow either an a or b-subsdtuent of the two isomers. However align these
molecules
the intermediate
destabilizing
interaction
rigidly
pyrazole
(4) left potency
of the
will be less tightly bound to the receptor
into the pocket, hence the similar potencies
interactions
a b-substituent
in the y-carboxylic can gain access
acids (3) may to the pocket.
potency of the des-alkyl pyrazole (3~) suggests that the a-substituent of the N-P-trifluoroethyl
unchanged
on functional
potency
functional
substituent
has a
were performed
of moderate
compounds
more potent than the y-carboxylic
potency,
4
CO,H
9.g5
5
CH,OH
8.0
6
CO,Et
8.0
7
CONHMe
7.5
Although
variation of the pyrazole y-substituent acid (4) (Table 2).
Et N-N'
PKB
the effects of other structural
with this N-substituent.
Table 2: In Vitro Potencies of Pyrazoles (4-7) R
of (3b) with an ethyl group to give
(Table 2); further work to investigate
compounds
Compound
for as follows in
and a lipophilic
with the receptor.
We found that replacement
modifications
to be incorporated
such that only
(3b) can be accounted
N-substituent
(2) the molecules
the enhanced receptor-ligand
more
Furthermore,
the pyrazole
Bu
affording
some
failed to reveal any
1245
C-Linked pyrazole biaryl tetrazoles
The nature of the acidic group of the southern biaryl region was also investigated. the C-linked
tetrazole
sulphonamide
(9) led to a ~a. 100 fold potency decrease
replacement
group of pyrazole
(4) with either
a carboxylic
(Table 3). This effect mirrors that observed
of the tetrazole of DuP-753 with either of these other acidic functions’,
findings for GR 117289 where replacement increase2v7. This suggests, not suprisingly,
Replacement
of
acid (8) or a trifluoromethyl-
of the tetrazole with a carboxylic
on
but is in contrast with
acid causes a slight potency
that the pyrazole (4) binds to the AT, receptor in a manner akin
to DuP-753, rather than GR 117289.
Table 3:
In Vitro Potencies of Pyrazhs
Compound
X
PRB
4
Tet
9.g5
8
C02H
8.0
9
NHso$F,
8.0
Once the optimum tetrazole
combination
had been established
potency
seemed
potencies
of the
(4,8 and 9) Et
N-N’
of a P-N-substituent,
a y-carboxylic
the nature of the alkyl p-substituent
largely insensitive
to changes
a and fi-substituted
pyrazoles
in the p-substituent
acid and a southern
was examined.
(Table 4). Furthermore
(la and b) confirm
the earlier finding
superior potency in y-acid P-mgioisomers.
Table 4: In Vitro Potencid Compound
of Pyrazoles (1)
R
PKB a
B
R N-N’
la
“Bu
8.0
10.0
lb
‘Fr
8.0
10.0
lc
Me
9.8
Id
“pr
10.5
le
CH&l
10.6
If
cycle-Bu
10.9
lg
‘Bu
11.0
lh
CPM9
10.5
However,
BU
(1)
biaryl in vitro
the relative
(see above ) of
1246
D. MIDDLEMISSet al.
In contrast pyrazoles (1) cyclopropylmethyl hypertensive
to their in virro activity, is
very
sensitive
pyrazole
in animal models
to the
nature
(Ih) is very effective
of
the
of hypertension, nitrogen
at lowering
rats8 (Figl) whereas the closely related cyclobutyl
the oral activity of the
substituent.
blood pressure
For
example,
the
in renal artery ligated
analogue (If) is ineffective
despite having
superior activity in vitro. Figure 1: The Effect of Pyrazole (lh) (lmgkg” of Renal Artery Ligated Hypertensive G 3:
170
g
160
z
150
a 2
140
B 5
130
g & P
120
2
110
;: $ 4
100
5
90
p.0.) on the Diastolic Blood Pressure
Rats*
80 I
0
1
3
/
6
I
9
I
12
I
15
t
I
18
21
/
24
1
27
1
1
30
33
1
36
1
39
1
42
I
45
I
48
TIME(h)
Conclusion We have identified AT,
selective
Ang
a series of C-linked pyrazole
II antagonists.
Their
therapeutic potential for these compounds,
excellent
biaryl tetrazoles pharmacological
which are potent, orally active, profile
suggests
considerable
particularly in the area of essential hypertension. References and Notes
1. 2.
3. 4. 5. 6. 7. 8. 9.
Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Price, W.A.; Santella J.B., III; Wells, G.J.; Wexler, R.R.; Wang, P.C.; Yoo, S.; and Timmermans, P.B.M.W.M. J. Med. Chem., 1991,34,2525, and references therein. Middlemiss, D.; Drew, G.M.; Ross, B.C.; Robertson, M.J.; Scopes, D.I.C.; Dowle, M.D.; Akers, J.; Cardwell, K.: Clark, K.L.; Coote, S.; Eldred, C.D.; Hamblett, J.; Hilditch, A.; Hirst, G.C.; Jack, T.I.; Montana, J.; Panchal, T.A.; Paton, J.M.S.; Shah, P.; Stuart, G.; and Travers, A. Biorg. Med. Chem. Lerr., 1991,1,711. The compounds described herein were prepared via a non regiospecific synthesis affording mixtures of pyrazole a and a regioisomers which were separated chromatographically. This synthesis, and the development of a regioselective synthesis of pyrazoles (1) will be published subsequently. For in virro test method see Ref. 2 In common with some other di-acidic Ang II antagonists (e.g. GR 117289*) pyrazoles (1, 3d and 4) display insurmountable antagonism. For a description of the determination of pK, under these conditions see Ref.2 The pyrazole ring positional nomenclature is shown on structure (3). Middlemiss D.; et. al. forthcoming publication Cagiano, J.;Rodriguez-Sargent, C.;Martinez-Maldonado, M. J.Pharmacol. Exp Ther ,1979,208, 3 10. CPM - Cyclopropylmethyl