Note: Descriptions are shown in the official language in which they were submitted.
`~
~ 2~82~
-- 1
I~ETEROCYCLIC DERIVATIVI~S
This invention concerns novel heterocyclic d~rivatives and,
more particularly, novel pyrimidine derivatives which possess
pharmacologically useful properties in antagonising at least in part
one or more of the actions of the substances known as angiotensins,
and in particular of that known as angiotensin II (hereinafter
re~erred to as "AII"). The invention also concerns pharmaceutical
compositions of the novel compounds for use in treating diseases or
medical conditions such as hypertension, congestive heart failure
and/or hyperaldosteronism in warm-blooded animals (including man), as
well as in other diseases or medical conditions in which the
renin-angiotensin-aldosterone system plays a significant causative
role. The invention also includes processes for the manufacture of
the novel compounds and their use in treating one of the
afore-mentioned diseases or medical conditions and for ~he production
of novel pharmaceuticals for use in such medical treatments.
The angiotensins are key mediators of the renin-angiotensin-
aldosterone system, which is involved in the control of homeostasis
and fluid/electrolyte balance in many warm-blooded animals, including
man. The angiotensin known as AII is produced by the action of
angiotensin converting enzyme (ACE) on angiotensin I, itself produced
by tbe action of the enzyme renin on the blood plasma protein
angiotensinogen. AII is a potent spasmogen especially in ~he
vasculature and is kno~n to increase vascular resistance and blood
pressure. In addition, the angiotensins are known to stimulate the
release of aldosterone and hence result in vascular congestion and
hypertension vla sodium and fluid retention mechanisms. Hitherto
there have been a number of different approaches to pharmacological
intervention in the renin-angiotensin-aldosterone system for
therapeutic control of blood pressure andJor fluid/electrolyte
balance, including, for example, inhibiting the actions of renin or
ACE. Ho~ever, there remains a continuing need for an alternative
approach because of the side-effects and/or idiosyncratic reactions
associated with any particular therapeutic approach.
. .
2~82~
-- 2 --
Certain pyrimidines having ~II antagonist activity are
disclosed in European patent application, publication no. (EPA)
424317, EPA 465323 and International Patent Application, Publication
No. W0 ~1/15209. EPA 475206 and US patent 5149699 (both published
after the priority date of the present invention) disclose
respectively certain pyrimidines and pyridopyrimidines having AII
antagonist activity. In EPA 475206 there is disclosed the compound
4-[N-butyl-N-(2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl)amino]-2,6-
dimethylpyrimidine.
We have now discovered that the compounds of the invention
(set out below) surprisingly antagonise one or more of the actions of
the substances known as angiotensins (and in particular of AII) and
thus minimise the physiological effects associated with their presence
in warm-blooded animals (including man) and this is the basis of the
invention.
According to the invention there is provided a pyrimidine
deivative of the formula I ~set out hereinafter, together with the
other chemical formulae identified by Roman numerals) wherein
R1 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted
(1-4C)alkyl, the latter containing one or more fluoro substituents or
bearing a t3-8C)cycloalkyl, (1-4C)alkoxy or phenyl substituent;
R is selected fro~ (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or
substituted (1-4C)alkyl, the latter containing one or more fluoro
substituents or bearing a (3-8C)cycloalkyl, (1-4C)alkoxy or phenyl
substituent, halogeno, (1-4C)alkoxy, amino and alkylamino and
dialkylamino of up to 6 carbon atoms;
R3 i8 selected from hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl,
substituted (1-4C)alkyl bearing a (3-8C)cycloalkyl, amino, hydroxy,
(1-4C)alkoxy, carboxy or (1-4C)alkoxycarbonyl substituent or
containing one or more fluoro substituents, hydroxy(1-4C)alkoxy,
carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro,
carbamoyl, (1-4C)alkannyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl
of up to 7 carbon atoms, halogeno, amino, alkylamino and dialkylamino
of up to 6 carbon ato~s, (1-4C)alkanoylamino, phenyl,
phenyl(1-4C)alkyl and benzoyl, the benzene ring of which last three
20~2&~'
groups optionally bearing one or two substituents selected from
(L-4C)alkyl, (1-4C)alkoxy, halogeno, cyano, trifluoromethyl, nitro,
hydroxy, carboxy, (1-4C)alkanoylamino, (1-4C)alkanoyl,
~:Luoro(1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
carbamoyl, alkyl or dialkylcarbamoyl of up to 7 carbon atoms,
sulphamoyl, N-alkyl or di-(N-alkyl)sulphamoyl of up to 6 carbon atoms,
(1-4C)alkoxycarbonyl, (1-4C)alkanesulphonamido, (1-4C)alkyl.S(O)n- lin
which n is zero, 1 or 2l, lH-tetrazol-5-yl, phenyl, phenoxy,
benzyloxy, benzyloxycarbonyl, benzamido and benzenesulphonamido, the
benzene moiety of the last six groups optionally bearing a halogeno,
(1-4C)alkyl or (1-4C)alkoxy substituent;
R4 is hydrogen or (1-4C)alkyl;
or R2 and R3 together complete a benzene ring, said benzene ring
optionally bearing one or two substituents independently selected from
any of the previous values defined for R3;
or R2 and R3 together form an (3-6C)alkenylene group, an
(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene
is replaced by carbonyl;
or R3 and R4 together form a l~nking group A which is selected from
-CH2-CH2-~ -CH2-cH2-cH2-~ -CO-CH2_, CH2 CO , 2 2
-CH2-CH2-CO-, -CO-CH=CH- and -CH=CH-CO-, and wherein said linking
group A optionally bears one or two substituents independently
selected from (1-4C)alkyl, substituted (1-4C)alkyl containing one or
more fluoro substituents or bearing a (3-8C)cycloalkyl, (1-4C)alkoxy
or phenyl substituent, (3-8C)cycloalkyl, (1-4C)alkoxy, halogeno,
carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro,
(1-4C)alkanoyl, (1-4C)alkyl.S(O)m- [in which m is zero, 1 or 23 and
phenylsulphonyl;
A1 is a group of the partial formula IIa, IIb or IIc wherein
(1) in partial formula IIa, B1 is a dlrect bond or is phenylene
optionally bearlng a substituent selected from (1-4C)alkyl,
(1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano and
nitro; Ra is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano,
trifluoromethyl or nitro; and Za is lH-tetrazol-5-yl, a carboxy group
or in vivo hydrolysable ester thereof, -CO.NH.(lH-tetrazol-5-yl), or a
group of the formula -CO.NH.C02R8 in which R8 is (1-6C)alkyl,
`''' ' :
2~82~
(3-8C)cycloalkyl, trifluoromethyl or phenyl;
(2) in partial formula IIb, B2 is oxygen, sulphur or a group of the
formula -NR5- in which R5 is hydrogen or (1-4C)alkyl; Zb has any of
the values defined above for Za; B3 is phenyl optionally bearing one
or two substi~uents independently selected from (1-4C)alkyl,
(1-4C)alkoxy and halogeno; and Rb and Rc are independently selected
from hydrogen, (1-4C)alkyl, (1-4C)alkoxy and halogeno; and
(3) in partial formula IIc, Zc is lH-tetrazol-5-yl, carboxy or in vivo
hydrolysable ester thereof or a group of the formula CF3S02NH-; Rd is
selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno,
trifluoromethyl, cyano and nitro; X1 is oxygen, sulphur or a group of
the formula _NR6_ in which R6 is hydrogen or (1-4C)alkyl; and x2 is
nitrogen or is a group of the formula -C(R7)= wherein R7 is hydrogen,
(1-4C)alkyl optionally containing one or more fluoro substituents,
carbamoyl or N-alkyl or di-(N-alkyl)carbamoyl of up to 7 carbon atoms,
halogeno, cyano, (1-4C)alkoxycarbonyl or (1-4C)alkanoyl;
and wherein any of said phenyl moieties of R1, R2 or R8, or of an
optional substituent on linking group A, may be unsubstituted or bear
one or two substituents independently selected from (1-4C)alkyl,
(1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt
thereof; but excluding the compound 4-lN-butyl-N-(2'-(1H-tetrazol-5-
yl)biphenyl-4-ylmethyl)aminol-2,6-dimethylpyrimidine.
It will be appreciated that, depending on the nature of the
substituents, certain of the formula I compounds may possess one or
more chiral centres and may be isolated in one or more racemic or
optically active forms. It is to be understood that this lnvention
concerns any form of such a compound of formula I which possesses the
afore-mentioned useful pharmacological properties, it bein8 well known
how to make optically active forms, for example by synthesis from
suitable chiral intermediates, and how to determine their
pharmacological properties, for example by use of the standard tests
described hereinafter.
It is to be understood that generic terms such as "alkyl"
include both straight and branched chain variants when the carbon
2082~
-- 5 --
numbers permit. However, when a particular radical such as "propyl~
is given, it is specific to the straight chain variant, branched chain
variants such as "isopropyl" being specifically named where intended.
The same convention applies to other radicals.
A particular value for R1 or R2 when it is alkyl is, for
example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or
hexyl; when it is cycloalkyl is, for example, cyclopropyl, cyclopentyl
or cyclohexyl; when it is alkyl containing one or more fluoro
substitutents is, for example, fluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl or pentafluoroethyl; and when it is alkyl bearing
a cycloalkyl, (1-4C)alkoxy or phenyl substituent is, for example,
cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,
cyclopentylethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, l-phenylethyl
or 2-phenylethyl.
A particular value for R2 when it is halogeno is, for
example, fluoro, chloro, bromo or iodo; when it is alkoxy is, for
example, methoxy, ethoxy; when it is alkylamino or dialkylamino of up
to 6 carbon atoms is, for example, methylamino, ethylamino,
butylamino, dimethylamino, diethylamino or dipropylamino.
Particular values for R3 are, by ~ay of example,
for alkyl: methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl
or hexyl;
for cycloalkyl: cyclopropyl, cyclopentyl or cyclohexyl;
for alkyl bearing a cycloalkyl, amino, hydroxy, alkoxy, carboxy or
alkoxycarbonyl substituent~ cyclopropylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclopentylethyl, hydroxymethyl, l-hydroxyethyl,
2-hydroxyethyl, aminomethyl, 2-amlnoethyl, methoxymethyl,
2-methoxyethyl, 2-ethoxyethyl, carboxymethyl, l-carboxyethyl,
2-carboxyethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,
2-~ethoxycarbonylethyl or 2-ethoxycarbonylethyl;
for alkyl contalnlng one or more fluoro substituents: fluoromethyl,
trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl;
for hydroxyalkoxy: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or
3-hydroxypropyl;
,.
20g2~
for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl or
propoxycarbonyl;
for alkenyloxycarbonyl: allyloxycarbonyl,
2-methyl-2-propenyloxycarbonyl or 3-methyl-3-butenyloxycarbonyl;
for alkanoyl: formyl, acetyl or butyryl;
for N-alkylcarbamoyl: N-methyl or N-ethylcarbamoyl;
for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl or
N,N-diethylcarbamoyl;
for halogeno: fluoro, chloro, bromo or iodo;
for alkylamino: methylamino, ethylamino or butylamino;
for dialkylamino: dimethylamino, diethylamino or dipropylamino;
for alkanoylamino: formamido, acetamido or propanamido; and
for phenylalkyl: benzyl, 1-phenylethyl or 2-phenylethyl.
A particular value for R4, R5 or R6 when it is alkyl is, for
example, methyl, ethyl or propyl.
Particular values for an optional substituent on R3 when it
is phenyl, phenyl(1-4C)alkyl or benzoyl, or for optional substituents
on R2 and R3 when together they complete a benzene ring, include, by
way of example, for alkyl: methyl and ethyl; for alkoxy: methoxy and
ethoxy; and for halogeno: chloro, bromo and iodo; for alkanoylamino:
formamido, acetamido and propanamido; for alkanoyl: formyl, acetyl and
butyryl; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy,
2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for hydroxyalkyl:
hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; for alkoxyalkyl:
2-methoxyethyl and 2-ethoxyethyl; for N-alkylcarbamoyl: N-methyl and
N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and
N,N-diethylcarbamoyl; for N-alkylsulphamoyls N-methyl and
Nethylsulphamoyl; for dl(N-alkyl)sulphamoyl: N,N-dimethylsulphamoyl
and N,N-diethylsulphamoyl; for alkoxycarbonyl: methoxycarbonyl,
ethoxycarbonyl and propoxycarbonyl; for alkanesulphonamido:
metanesulphonamido and ethanesulphonamido; for alkylthio: methylthio
an~s ethylthio; for alkylsulphinyl; methylsulphinyl and ethylsulphinyl;
for alkylsulphonyl: methylsulphonyl and ethylsulphonyl; and for
phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and
benzenesulphonamido optionally bearing a substituent: phenyl, phenoxy,
.
2~2~8
-- 7 --
benzyloxy, benzyloxycarbonyl, benzamido and ben7enesulphonamido
optionally bearing a fluoro, chloro, bromo, methyl, ethyl, methoxy or
ethoxy substituent.
A particular value for R2 and R3 when together they form
(3-6C)alkylene is, for example, trimethylene, tetramethylene or
pentamethylene; when together they form (3-6C)alkenylene is, for
example, 1-propenylene, 2-propenylene, l-butenylene, 2-butenylene or
3-butenylene; and when together they form (3-6C)alkylene wherein one
of the methylene groups is replaced by a carbonyl group is, for
example, 1-oxopropylidene, 3-oxopropylidene, l-oxobutylidene or
4-oxobutylidene.
Particular values for optional substituents on R3 and R4
when together they form linking group A is, include, by way of
example, for alkyl: methyl and ethyl; for alkyl containing one or more
fluoro substitutents: fluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl and pentafluoroethyl; for alkyl bearing a
cycloalkyl, (1-4C)alkoxy or phenyl substituent: cyclopropylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, 2-methoxyethyl,
2-ethoxyethyl, benzyl, l-phenylethyl and 2-phenylethyl; for
cycloalkyl: cyclopropyl, cyclopentyl and cyclohexyl; for alkoxy:
methoxy, ethoxy and propoxy; for halogeno: fluoro, chloro, bromo and
iodo; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and
propoxycarbonyl; for alkenyloxycarbonyl: allyloxycarbonyl,
2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl;
for alkanoyl: formyl, acetyl and butyryl; for alkylthio: methylthio
and ethylthio; for alkylsulphinyl; methylsulphlnyl and ethylsulphinyl;
and for alkylsulphonyl: methylsulphonyl and ethylsulphonyl.
A particular value for Ra, Rb, Rc, Rd or an optional
substituent on B1 when it is phenylene, or an optional substituent or
substituents on B3, when it is alkyl is, for example, methyl or ethyl;
when it i8 alkoxy iB, for example, methoxy or ethoxy; and when it is
halogeno is, for example, fluoro, chloro or bromo.
A particular value for an alkanoyl substituent on Bl when it
2082~
-- 8 --
is phenylene is, for example, formyl, acetyl or propionyl.
A particular value for ~a, Zb, or Zc when it is an in vivo
hydrolysable ester is, for example an ester derived from a
(1-6C)alkanol such as methanol or ethanol, or phenol, glycerol or the
like.
A particular value for R8 when it is alkyl is, for example,
methyl, ethyl, propyl, isopropyl, butyl or pentyl; and when it is
cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.
A particular value for R7 includes, by way of example,
fo~ alkyl: methyl and ethyl;
for alkyl containing one or more fluoro substitutents: fluoromethyl,
trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl;
for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl;
for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and
N,N-diethylcarbamoyl;
for halogeno: fluoro, chloro, bromo or iodo;
for alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl; and
for alkanoyl: formyl, acetyl or propionyl.
Particular values for optional substituents which may be
present on phenyl moieties of R1, R2 or R8, or on linking group A
include, by way of example, for halogeno: fluoro, chloro and bromo;
for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.
A preferred value for Rl or R2 is, for example, methyl,
ethyl or propyl.
A preferred value for R3 is, for example, hydrogen, halogeno
(especially iodo) or phenyl(1-4C)alkyl.
A preferred value for R4 is, for example, hydrogen or
methyl.
A preferred value for R2 and R3 when together they form
~''''' , , :
2082~
g
alkylene is, for example, trimethylene or tetramethylene.
A preferred value for R3 and R4 when together they form
linking group A is, for example, -CH=CH-CO-, -CH2-CH2-CH2- or
CH2 CH2 CO
A preferred value for A is, for example, a group of the
partial formula IIa.
A preferred value for B1 is, for example, a p-phenylene
group.
A preferred value for Za, Zb or Zc is, for example, carboxy
or lH-tetrazol-5-yl.
An especially preferred value for Za is when it is attached
at the ortho position relative to Bl. Za is lH-tetrazol-5-yl is
particularly preferred.
A preferred value for B2 is, for example, oxygen.
A particularly preferred combination of values is, for
example, R1 and R2 are both alkyl.
A preferred group of compounds of the formula I comprises
those compounds of the formula I wherein Al is a group of the partial
formula IIa in which Za is lH-tetrazol-5-yl or carboxy and Rl, R2, R3,
R4, Ra and Bl have any of the values defined above; and the non-toxic
salts thereof. Particularly preferred withln this group are those
compounds whereln Za ls a lH-~etrazol-5-yl group and especlally when
it ls attached at the ortho posltlon relatlve to Bl.
Particular groups of novel compounds of the lnvention are,
for example, compounds of the formula I wherein:
~1) R3 is halogeno and Rl, R2, R4 and Al have any of the values
defined above;
(2) R3 is (1-4C)alkoxycarbonyl and Rl, R2, R4 and Al have any of the
values defined above;
2 0 ~
-- 10 --
(3) R3 is benzoyl optionally bearing one or two substituents
independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno,
cyano, trifluoromethyl, nitro, hydroxy, carboxy, (1-4C)alkanoylamino,
(1-4C)alkanoyl, fluoro(1-4C)alkoxy, hydroxy(1-4C)alkyl,
(1-4C)alkoxy(1-4C)alkyl, carbamoyl, alkyl or dialkylcarbamoyl of up to
7 carbon atoms, sulphamoyl, alkyl or dialkylsulphamoyl of up to 6
carbon atoms, (1-4C)alkoxycarbonyl, (1-4C)alkanesulphonamido,
(1-4C)alkyl.S(O)n- [in which n is zero, 1 or 21, lH-tetrazol-5-yl,
phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and
benzenesulphonamido, the benzene moiety of the last six groups
optionally bearing a halogeno, (1-4C)alkyl or (1-4C)alkoxy
substituent; and R1, R2, R4 and A1 have any of the values defined
above;
(4) R3 is phenyl optionally bearing one or two substituents
independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno,
cyano, trifluoromethyl, nitro, hydroxy, carboxy, (1-4C)alkanoylamino,
(1-4C)alkanoyl, fluoro(1-4C)alkoxy, hydroxy(1-4C)alkyl,
(1-4C)alkoxy~1-4C)alkyl, carbamoyl, alkyl or dialkylcarbamoyl of up to
7 carbon atoms, sulphamoyl, alkyl or dialkylsulphamoyl of up to 6
carbon atoms, (1-4C)alkoxycarbonyl, (1-4C)alkanesulphonamido,
(1-4C)alkyl.S(O)n- [in which n is zero, 1 or 2], lH-tetrazol-5-yl,
phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and
benzenesulphonamido, the benzene moiety of the last six groups
optionally bearing a halogeno, (1-4C)alkyl or (1-4C)alkoxy
substituent; and Rl, R2, R4 and A1 have any of the values defined
above;
(5) R2 and R3 together form an (3-6C)alkylene group; and Rl, R4 and
have any of the values defined above; or
(6) R3 and R4 together form a linking group A as defined above; and
R1, R2 and Al have any of the values defined above.
Further particular groups of novel compounds of the
invention are, for example, compounds of the formula I wherein;
(7) R3 is phenyl(1-4C)alkyl optionally bearing one or two substituents
independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno,
cyano, trifluoromethyl, nitro, hydroxy, carboxy, (1-4C)alkanoylamino,
(1-4C)alkanoyl, fluoro(l-4C)alkoxy, hydroxy(1-4C)alkyl,
2082~
11
(1-4C)alkoxy(1-4C)alkyl, carbamoyl, alkyl or dialkylcarbamoyl of up to
7 carbon atoms, sulphamoyl, alkyl or dialkylsulphamoyl of up to 6
carbon atoms, (1-4C)alkoxycarbonyl, (1-4C)alkanesulphonamido,
(l-4C)alkyl.S(O)n- [in which n is zero, 1 or 2], lH-tetrazol-5-yl,
phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and
benzenesulphonamido, the benzene moiety of the last six groups
optionally bearing a halogeno, (1-4C)alkyl or (1-4C)alkoxy
substituent; and R1, R2, R4 and A1 have any of the values defined
above; or
(8) R3 and R4 together form a linking group -CH2-CH2- or -CH2-CH2-CH2-
(of which the latter is of particular interest); and R1, R2 and
have any of the values defined above.
Compounds of the invention which are of particu~ar interest
include, for example, the specific embodiments set out hereinafter in
the accompanying Examples, in particular the compounds of examples 1,
3, 4, 6, 7, 8, 9 and 10. These compounds, or a non-toxic salt
thereof, are provided as a further feature of the invention.
Although all of the formula I compounds can form salts with
suitable acids, it will be appreciated that those compounds of formula
I wherein Za, Zb or Zc is other than an ester group or in which R3 or
linking group A bears a carboxy group can form salts with bases as
well as with acids. Particularly suitable non-toxic salts for such
compounds therefore also include, for example, salts with bases
affording physiologically acceptable cations, for example, alkali
metal (such as sodium and potassium), alkaline earth metal (such as
magneslum and calcium), aluminium and ammonium salts, as well as salts
wlth suitable organic bases, such as with ethanolamine, methylamine,
diethylamine or triethylamine, as well as salts with acids forming
physiologically acceptable anions, such as salts with mineral acids,
for example ~ith hydrogen halides (such as hydrogen chloride and
hydrogen bromide), sulphuric and phosphoric acid, and with strong
organic acids, for example with p-toluenesulphonic and
methanesulphonic acids.
The compounds of formula I may be obtained by standard
.
.
-` 20~2~6~
- 12 -
procedures of organic chemistry well known in the art for the
production of structurally analogous compounds. Such procedures are
provided as a further feature of the invention and include, by way of
example, the following procedures in which the generic radicals have
any of the values given above, unless stated otherwise:
a) For those compounds in uhich A1 is a group of the partial
formula IIa, IIb or IIc in which Za, Zb and Zc respectively are
carboxy, a carboxylic acid derivative of the formula IIIa, IIIb or
IIIc in which Qa, Qb and Qc respectively are protected carboxy groups
selected from (1-6C)alkoxycarbonyl (especially methoxy-, ethoxy-,
propoxy- or t-butoxy-carbonyl), phenoxycarbonyl, benzyloxycarbonyl and
carbamoyl, is converted to carboxy.
The conversion may be carried out, for example by
hydrolysis, conveniently in the presence of a suitable base such as an
alkali metal hydroxide, for example, lithium, sodium or potassium
hydroxide. The hydrolysis is generally carried out in the presence of
a suitable aqueous solvent or diluent, for example in an aqueous
(1-4C)alkanol, such as aqueous methanol or ethanol. However, it may
also be performed in a mixture of an aqueous and non-aqueous solvent
such as water and toluene using a conventional qua~ernary ammonium
phase transfer catalyst. The hydrolysis is generally performed at a
temperature in the range, for example, 0 - 120C, depending on the
reactivity of the group Qa, Qb or Qc. In general, when Qa, Qb or Qc
is carbamoyl, temperatures in the range, for example, 40 - 120C are
required to effect the hydrolysis.
Alternatively, when Qa, Qb or Qc is benzyloxycarbonyl the
conversion may also be performed by hydro~enolysis, for example using
hydrogen at 1-3 bar in the presence of a suitable catalyst, such as
palladium on charcoal or on calcium sulphate, in a suitable solvent or
diluent such as a (1-4C)alkanol (typically ethanol or 2-propanol) and
at a temperature in the range, for example, 0 - 40C.
Further, when Qa9 Qb or Qc is t-butoxycarbonyl, the
conversion may also be carried out by hydrolysis at a temperature in
208~
- 13 -
the range, for example, 0 - 100C, in the presence of a strong acid
catalyst, such as trifluoroacetic acid. The hydrolysis may either be
plerformed in an excess of the acid or in the presence of a suitable
diluent such as tetrahydrofuran, t-butyl methyl ether or
1,2-dimethoxyethane.
b) For those compou~ds of formula I in which A1 is a group of
the partial formula IIa, IIb or IIc in which Za, Zb and Zc
respectively are tetrazolyl, a compound of the formula IVa, IVb or IVc
in which La, Lb and Lc respectively are suitable protecting groups,
such as trityl, benzhydryl, trialkyltin (for example trimethyltin or
tributyltin) or triphenyltin affixed to a nitrogen of the tetrazolyl
moiety, is deprotected.
The reaction conditions used to carry out the deprotection
necessarily depend on the nature of the group La, Lb or Lc. As an
illustration, ~hen it is trityl, benzhydryl, trialkyltin or
triphenyltin, the decomposition conditions include, for example, acid
catalysed hydrolysis in a mineral acid (such as aqueous hydrochloric
acid), conveniently in an aqueous solvent ~such as aqueous dioxan or
2-propanol). Alternatively, a trityl or benzhydryl group may be
removed by hydrogenolysis, for example as described in (a) above for
conversion of a benzyloxycarbonyl to a carboxy.
Compounds of the formula IVa, IVb or IVc wherein La, Lb and
Lc respectively are trialkyltin or triphenyltin may be obtained, for
exa~ple, by reaction of a nitrile of the formula I~a, IXb or IXc
respectively with a trialkyltin azide, such as tributyltin azide, or
triphenyltin azide respectively. The reactlon is conveniently carried
out in a suitable solvent or diluent, such as toluene or xylene, and
at a temperature in the range, for example, 50-150C. Nitriles of the
formula I~a, IXb or IXc may be obtained, for example, by alkylation of
a 4-amlnopyrimidine of the formula V wherein R1 and R2 are other than
hydrogen with a nitrile of the formula Xa, ~b or Xc respectively
wherein ~al. stands for a suitable leaving group such as chloro,
bromo, iodo, methanesulphonyloxy or ~-toluenesulphonyloxy, using
similar conditions to those used in process (c) described hereinafter.
: '
20~26~
- 14 -
The necessary compounds of formula Xa, Xb or Xc, as well as those of
formula VIIa, VIIb, VIIc, VIIIa, VIIIb or VIIIc described herein, may
be obtained, for example, as described in European patent application,
publication nos. 253310, 291969, 453210, 434249, 430709, 429257 and
International patent application no. W0 91/11999.
The nitriles of the formula IXa, IXb or IXc may also be
obtained, for example, by reaction of a pyrimidine of the formula VI
wherein yl is a suitable leaving group (such as chloro, bromo, iodo,
methanesulphonyl, methanesulphonyloxy, p-toluenesulphonyloxy or
trifluoromethanesulphonyloxy) with an amine of the formula XIa, XIb or
XIc respectively, using similar conditions to those used in process
(d? described hereinafter.
The amines of the formula XIa, XIb or XIc may be obtained,
for example, by standard procedures such as from the corresponding
compounds of formula Xa, Xb or Xc by reaction with the appropriate
amine of formula R4NH2 using conventional conditions.
Alternatively, compounds of the formula IVa, IVb or IVc may
be obtained, for example, by reaction of a pyrimidine of the formula
VI wherein y1 is as defined above with an amine of the formula XIIa,
XIIb or XIIc respectively under similar conditions to those described
in process (d) hereinafter. The amines of formula XIIa, XIIb or XIIc
may be obtained, for example, from the corresponding compound of
formula VIIIa, VIIIb or VIIIc respectively by reaction with the
approprlate amine of formula R4NH2 using standard conditions.
c) For compounds of the formula I, an aminopyrimidine of the
formula V is alkylated with a compound of the formula VIIa, VIIb or
VIIc wherein Hal. stands for a suitable leaving group such as chloro,
bromo, iodo, methanesulphonyloxy or ~-toluenesulphonyloxy.
The reaction is preferably carried out in the presence of a
suitable non-nucleophillic base, for example, an alkali metal
tert-butoxide such as sodium or potassium tert-butoxide, an alkali
metal hydride such as sodium hydride, or an alkali metal carbonate
'
.. . .
2082~
- 15 -
such as sodium or potassium carbonate, or an organic base such as
d:lisopropylethylamine or 4-dimethylaminopyridine. The reaction is
conveniently carried out in a suitable solvent or diluent, for
e~ample, a (l-4C)alkanol such as methanol or ethanol, or in a polar
solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a
temperature in the range, for example, 10 - 100C. In carrying out
process (c), ~hen in the starting material Za, Zb or Zc is an acidic
group about two molecular equivalents of a suitable base is generally
required, whereas when Za, Zb or Zc does not bear an acidic group the
presence of one molecular equivalent of a suitable base is generally
sufficient.
Procedure (c) is particularly suitable for the production of
those compounds of the formula I in which Za, Zb or Zc is an ester
group, for example wherein Za, Zb or Zc is an (1-6C)alkyl, benzyl or
phenyl ester, which compounds are also starting materials of formula
IIIa, IIIb and IIIc respectively for the reactions described in (a)
above. Similarly, using an analogous procedure, but starting with
the appropriate compound of the formula VIIIa, VIIIb or VIIIc, the
starting materials of formula IVa, IVb or IVc respectively may be
obtained for procedure (b).
Hany of the aminopyrimidines of formula V are already known
and the remainder can be made by analogy therewith using standard
procedures of organic chemistry well known in the art, for example as
described in standard works of heterocyclic chemistry such as
"Chemistry of Heterocyclic Compounds" edited by Welssberger, or as
illustrated in Scheme 1.
(d) For compounds of formula I, a heterocyclic derivative of the
formula VI wherein yl is a suitable leaving group (such as chloro,
bromo, iodo, methanesulphonyl, methanesulphonyloxy,
~-toluenesulphonyloxy or trifluoromethanesulphonyloxy) is reacted with
an amine of the formula XIIIa, XIIIb or XIIIc.
The reaction is optionally carried out in the presence of a
suitable base, for example an alkali metal carbonate or bicarbonate
2~2~s~
- 16 -
such as sodium or potassium carbonate or bicarbonate, or an organic
base for example a tertiary amine such as triethylamine. The reaction
is conveniently carried out in a suitable solvent or diluent, for
example a (1-4C)alkanol such as methanol, ethanol or butanol, a
non-polar solvent such as dioxane or diphenyl ether, or a polar
solvent such as N,N-dimethylformamide or N-methylpyrrolidone, and
usually at a temperature in the range of 40 to 180C.
Heterocyclic derivatives of the formula VI wherein yl is
halogeno may be obtained, for example, by halogenation of the
corresponding 4-pyrimidones, themselves already known or which can be
made by analogy therewith using procedures well known in the art and
described in standard works of organic chemistry such as "Chemistry of
Heterocyclic Compounds" edited by Weissberger. For example, the
formula VI compounds may be obtained by reaction of the corresponding
4-pyrimidone with phosphorus oxychloride in the absence of a solvent,
or in the presence of an inert solvent or diluent such as toluene or
dioxane, and at a temperature in the range 60 - 110C. Compounds of
the formula VII wherein y1 is methanesulphonyloxy,
~-toluenesulphonyloxy or trifluoromethanesulphonyloxy and R1 and R3
are other than hydrogen may be obtained, for example, by acylation of
the corresponding 4-pyrimidone with the corresponding sulphonyl
chloride under standard conditions. Compounds of the formula VI
wherein y1 is methanesulphonyl may be obtained from alkylation of the
corresponding mercaptopyrimidine, themselves known or obtained by
analogy therewith, followed by oxidation under standard conditions.
The amines of formula XIIIa, XIIIb and XIIIc may be obtained, for
example, from the corresponding compound of formula VIIa, VIIb and
VIIc respectively by reaction with the approprlate amine of formula
R4NH2 using standard conditions
(e~ For those compounds of formula I wherein A1 is a group of
partial structure IIc in which Zc is a group of the formula CF3S02NH-,
a compound of formula XIV is reacted with trifluoromethanesulphonic
acid anhydride.
The reaction is preferably carried out in the presence of a
2082~
- 17 -
base, such as triethylamine, and conveniently in a suitable solvent or
diluent, for example dichloromethane, and at a temperature in the
range of -78C to ambient temperature. The compounds of the formula
XIV may be obtained by alkylation of a compound of formula V with a
compound of the formula XV (itself obtained using analogous procedures
to those described in EPA 429257 and 430709) using similar conditions
to those of process (c) above, followed by reduction of the nitro
group in the intermediate obtained, for example by conventional
catalytic hydrogenation.
Whereafter, those compounds of formula I wherein Za, Zb or
Zc is lH-tetrazol-5-yl may be obtained by stepwise conversion of a
compound of the formula I wherein Za, Zb or Zc is a carboxylic acid or
ester group respectively into the corresponding nitrile under standard
conditions, followed by reac~ion of the nitrile uith an azide such as
an alkali metal azide, preferably in the presence of an ammonium
halide, and preferably in the presence of a suitable polar solvent
such as N,N-dimethylformamide and at a temperature in the range, for
example, 50 to 160~.
Whereafter, those compounds of the formula I wherein Za, Zb
or Zc is -CO.NH.(lH-tetrazol-5-yl), a group of the formula
-CO.NH.S02R8 or an ester group, may be obtained, for example, by
reacting a carboxylic acid of the formula I in which Za, Zb and Zc is
carboxy (or a reactive derivative of said acid) with 5-aminotetrazole,
a sulphonamide of the formula NH2.S02R8 or a salt thereof (for
example, an alkali metal salt), or an appropr~ate alcohol or with a
salt thereof (for example, an alkali metal thereof). Suitable
reactive derivatlves include, for example the chloride, bromide,
azide, anhydrlde and mixed anhydride with formic or acetic acid of the
carboxylic acid of formula I as defined above. When the free acid
form is used, the reaction is generally carried out in the presence of
a suitable dehydrating agent such as dicyclohexycarbodiimide or
3-(3-dimethylaminopro wl)-l-ethylcarbodiimide in the presence of a
base such as triethylamine or pyridine. When a reactive derivative is
used, either the reaction is carried out in the presence of a base
such as mentioned above, or, for the preparation of a compound of the
.
2!0~2~
- 18 -
formula I wherein Za, Zb or Zc is a group of the formula -Co.N~.S02R3
or an ester group, the sulphonamide or hydroxy compound is used in the
form of a salt, such as its alkali metal salt (in particular the
lithium, sodium or potassium salt thereof). The reaction is generally
performed in the presence of a suitable diluent or solvent such as
dioxan, t-butyl methyl ether or tetrahydrofuran and at a temperature
in the range, for example, ~ - 60C.
Whereafter, when a non-toxic salt of a compound of formula I
is required, it may be obtained, for example, by reaction with the
appropriate base affording a physiologically acceptable cation, or
with the appropriate acid affording a physiologically acceptable
anion, or by any other conventional salt formation procedure.
Further, when an optically active form of a compound of
formula I is required, one of the aforesaid processes may be carried
out using an optically active starting material. Alternatively, the
racemic form of a compound of formula I in which Za, Zb or Zc is an
acidic group may be resolved, for example by reaction with an
optically active form of a suitable organic base, for example,
ephedrine, N,N,N-trimethyl(1-phenylethyl)ammonium hydroxide or
l-phenylethylamine, followed by conventional separation of the
diastereoisomeric mixture of salts thus obtained, for example by
fractional crystallisation from a suitable solvent, for example a
(1-4C)alkanol, whereafter the optically active form of said compound
of formula I may be liberated by treatment with acid using a
conventional procedure, for example using an aqueous mineral acid such
as dilute hydrochloric acid.
According to a further aspect of the invention, there is
provided a process for the manufacture of a compound of the formula I
wherein A1 is a group of partial structure IIa in which Za is
tetrazolyl, B1 is p-phenylene optionally bearing a substituent
selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl,
trifluoromethyl, cyano and nitro and Rl, R2, R3, R4, and Ra have any
of the meanings defined hereinbefore; which comprises reaction of a
compound of the formula XVI wherein pl is an electron-deficient phenyl
20~2~
-- 19 --
group or a pyrimidyl or pyridyl group; Re is hydrogen, (1-4C)alkyl,
(L-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano or
n:itro; and R1, R2, R3, R4 and Ra have any of the values defined above;
w:ith a base selected from an alkali metal hydroxide,
(I-12C)alkanolate, (1-12C)alkanethiolate, phenolate, thiophenolate or
diphenylphosphide, wherein any phenyl ring of the latter three groups
may optionally bear a (1-4C)alkyl, (1-4C)alkoxy or halogeno group.
A particular value for p1 includes, for example, a phenyl
group bearing 1, 2 or ~ electron-withdrawing groups independently
selected from nitro, cyano and trifluoromethyl.
A particular value for Re when it is alkyl is, for example,
methyl or ethyl; when it is alkoxy is, for example, methoxy or ethoxy;
and when it is halogeno is, for example, fluoro, chloro, bromo or
iodo.
A particular value for a base includes the following by way
of example:-
for an alkali metal hydroxide: sodium or potassium hydroxide;
for an alkali metal-alkanolate: an alkali metal (1-8C)alkanolate, for
example an alkali metal (1-4C)alkoxide, such as sodium or potassium
methoxide9 ethoxide, propoxide or butoxide;
for an alkali metal alkanethiolate: an alkali metal
(1-8C)alkanethiolate, for example an alkali metal (1-4C)alkanethiolate
such as sodium or potassium methanethiolate, ethanethiolate,
propanethiolate or butanethiolate.
A particular value for an optlonal substituent on a phenyl
group of an alkali metal phenolate, thiophenolate or
diphenylphosphide, when it is alkyl is, for example, methyl or ethyl;
when it is alkoxy is, for example, methoxy or ethoxy; and ~hen it is
halogeno is, for example, fluoro, chloro or bromo.
A preferred value for pl is, for example, a nitrophenyl
group, especially 4-nitrophenyl.
' `
6 ~ ~
- 20 -
A prefer}ed value for X is, ~or exa~ple, when it is
~msubstituted ~-phenylene.
A particularly preferred base is an alkali metal
alkanethiolate such as sodiun. or potassium propanethiolate, an alkali
metal alkanolate such as sodium or potassiun ethoxide, or an alkali
metal thiophenolate such as sodium or potassium 4-fluorothiophenolate.
It will be appreciated that when the base is an alkali metal
alkanolate, alkanethiolate, phenolate, thiophenolate or
diphenylphosphide, it may be generated in situ from the corresponding
alkanol, alkanethiol, phenol, thiophenol or diphenylphosphine with a
suitable alkali metal base such as an alkali metal hydride, for
exan.ple, lithiun., potassium or sodium hydride.
The process of the invention is particularly useful for the
preparation of compounds of the formula I wherein the tetrazolyl group
is at the ortho position relative to the ad~2acent phenyl group.
The reaction is conveniently carried out in a suitable inert
organic solvent or diluent, for example, a polar solvent such as
N,N-dimethylformamide or N-methylpyrrolidone. Alternatively, an
alkanol such as methanol or ethanol may be used, for example, when an
alkali metal hydroxide or alkoxide such as sodium or potassium
hydroxide, methoxide or ethoxide is employed. The reaction is
generally carried out at a temperature in the range, for example,
-30C to 50C~ It ~ill be appreciated that the choice of temperature
will depend on the nature of the base employed. For example, when an
alkali metal alkanethlolate or alkanolate is used, a temperature in
the range of 0C to ambient temperature is preferred.
Compounds of the formula XVI may be obtained by reaction of
a boronic acid of the formula XVII ~ith a compound of the formula
XVIII wherein pl is an electron-deficient phenyl group or a W rimidyl
or pyridyl group having any of the meanings defined above and V is a
bromo, iodo or ~rifluoromethanesulphonyloxy group, in the presence of
a palladium(0) or palladium (II) catalyst, such as
20~2&~Y
- 21 -
tetrakis(triphenylphosphine)palladium (0) or palladium (II)chloride.
The reaction is preferably carried out in the presence of a base, such
as sodium or potassium carbonate, in an inert solvent or diluent, for
example, a hydrocarbon such as toluene or xylene, an ether, such as
dioxan or tetrahydrofuran, an (1-4C)alkanol such as methanol or
ethanol, water, or mixture thereof, for example a mixture of water,
methanol and toluene, and at a temperature in the range of, for
example, 50C to 150C., and conveniently at or about the reflux
temperature of the solvent or mixture of solvents used.
Compounds of the formula XVII may be obtained, for example,
by heating at reflux a 4-methylphenylboronic acid in a solvent such as
methyl chloroform with azeotropic removal of water, followed by
radical bromination of the product which may be carried out in situ,
for example with bromine or N-bromosuccinimide in the presence of
azo(bisisobutyronitrile). The resultant 4-bromomethylphenylboronic
acid anhydride may then be used to alkylate a compound of the formula
V (using similar alkylation conditions to those used in process (c)
described above), followed by subsequent acidic hydrolysis, to give a
formula XVII compound. Alternatively the product from the alkylation
step prior to hydrolysis may be isolated and reacted directly with a
compound of the formula XVIII under similar conditions to those
described above to obtain a formula ~VI compound directly. In a yet
further alternative procedure, a 4-methylphenylboronic acid and an
appropriate alkanediol, for example 2,2-dimethylpropan-1,3-diol, may
be heated at reflux in a solvent (such as cyclohexane) with azeotropic
removal of water followed by free radical bromination of the product,
which may be carried out in situ. The resultant bromomethyl compound
may then be reacted using analogous procedures to those described
above for the 4-bromomethylphenylboronic acid anhydride to obtain a
formula XVII compound or a compound of the formula XVI directly.
Compounds of the formula XVIII may be obtained, for example, by
reaction of an appropriately substituted benzoyl chloride with an
amine of formula Pl.NH2 under standard conditions. The resultant
amide ls then, for example, reacted with thionyl chloride in the
presence of triethylamine and N,N-dimethylformamide in acetonitrile at
ambient temperature to form ~he corresponding imidoyl chloride, which
,
- 22 _ 2~2~
is reacted in situ with triethylamine, sodium azide and
tetrabutylammonium bromide at 10-30C to give the formula XVIII
compound.
Whereafter, the optional subsequent steps of non-toxic salt
formation and/or formation of an optically active form of a compound
of the formula I, may be carried out as described above for procedures
(a) to (e).
Certain of the intermediates defined herein are novel, for
example the compounds of the formula IIIa, IIIb, IIIc, IVa, IVb, IVc,
IXa, IXb and IXc, and are provided as a further feature of the
invention.
As stated above, the compounds of formula I will have
beneficial pharmacological effects in warm-blooded animals (including
man) in diseases and medical conditions where amelioration of the
vasoconstrictor and fluid retaining properties of the renin-
angiotensin-aldosterone system is desirable, at least in part by
antagonism of one or more of the physiological actions of AII. The
compounds of the invention will thus be useful in the treatment of
diseases or medical conditions such as hypertension, congestive heart
failure and/or hyperaldosteronism in warm-blooded animals (including
man), as well as in other diseases or medical conditions in which the
renin-angiotensin-aldosterone syste~ plays a significant causative
role. The compounds of the invention may also be useful for the
treatment of ocular hypertension, glaucoma, cognitive disorders ~such
as Alzheimer's disease, amnesia, senile dementia and learning
disorders), as well as other diseases such as renal failure, cardiac
insufflciency, post-myocardial infarction, cerebrovascular disorders,
anxiety, depression and certain mental illnesses such as
schizophrenia.
The antagonism of one or more of the physiological actions
of AII and, in particular, the antagonism of the interaction of AII
with the receptors which mediate its effects on a target tissue, may
be assessed using one or more of the following, routine laboratory
.,
'
2~2~&~
_ 23 -
procedures:
_est A: This in vitro procedure involves the incubation of the
test compound initially at a concentration of 100 micromolar (or less)
in a buffered mixture containing fixed concentrations of radiolabelled
AII and a cell surface membrane fraction prepared from a suitable
angiotensin target tissue. In this test, the source of cell surface
membranes is the guinea pig adrenal gland which is well known to
respond to AII. Interaction of the radiolabelled AII with its
receptors (assessed as radiolabel bound to the particulate membrane
fraction following removal of unbound radiolabel by a rapid filtration
procedure such as is standard in such studies) is antagonized by
compounds which also bind to the membranP receptor sites and the
degree of antagonism (observed in the test as displacement of
membrane-bound radioactivity) is determined readily by comparing the
receptor-bound radioactivity in the presence of the test compound at
the specified test concentration with a control value determined in
the absence of the test compound. Using this procedure compounds
showing at least 50% displacement of radiolabelled AII binding at a
concentration of 10 4 h are retested at lower concentrations to
determine their potency. Por determination of the IC50 (concentration
for 50X displacement of radiolabelled AII binding1, concentrations of
the test compound are ordinarily chosen to allow testing over at least
four orders of magnitude centred about the predicted approximate IC50,
which latter is subsequently determined from a plot of percentage
displacement against concentration of the test compound.
In general, acidic compounds of formula I as defined above
show slgnlflcant inhlbition in Test ~ at a concentratlon of 50
micromolar or much less.
Test B: This in vitro test involves the measurement of the
antagonistic effects of the test compound against AII-induced
contractions of isolated rabbit aorta, maintained in a physiological
salt solution at 37C. In order to ensure that the effect of the
compound is specific to antagonism of AII, the effect of the test
compound on noradrenaline-induced contractions may also be determined
, ' - ", ~ ' -
- 24 _ 2 ~ ~ 2
in the same preparation.
In general, acidic compounds of formula I as defined above
show significant inhibition in Test B at a final concentration of 50
micromolar or much less. [Note: Compounds of formula I wherein Za, Zb
or Zc is an ester group in general show only weak activity in the in
vitro Tests A or B-l
Test C: This in vivo test involves using terminally-anaesthetised or
conscious rats in which an arterial catheter has been implanted under
anaesthesia for the measurement of changes in blood pressure. The AII
antagonistic effects of the test compound following oral or parenteral
administration, are assessed against angiotensin II-induced pressor
responses. To ensure that the effect is specific, the effect of the
test compound on vasopressin-induced pressor responses may also be
determined in the same preparation.
The compounds of formula I generally show specific
AII-antagonist properties in Test C at a dose of 50 mg/kg body weight
or much less, without any overt toxicological or other untoward
pharmacological effect.
Test D: This in vivo test involves the stimulation of endogenous AII
biosynthesis in a variety of species including rat, marmoset and dog
by introducing a diet of low sodium content and giving appropriate
daily doses of a saluretic known as frusemide. The test compound is
then administered orally or parenterally to the animal in which an
arterial catheter has been implanted under anaesthesia for the
measurement of changes in blood pressure.
In general compounds of formula I will show AII-antagonist
properties in Test D as demonstrated by a significant reduction in
blood pressure at a dose of SO mg/kg body weight or much less, without
any overt toxicological or other untoward pharmacological effect.
The compounds of formula I will generally be administered
for therapeutic or prophylactic purposes to warm-blooded animals
' ~ '
- 25 - 2~2~
(including man) requiring such treatment in the form of a
pharmaceutical composition, as is well known in the pharmaceutical
art. According to a further feature of the invention there is
provided a pharmaceutical composition comprising a compound of formula
I, or a salt as defined above, together with a pharmaceutically
acceptable diluent or carrier. Such compositions will conveniently be
in a form suitable for oral administration (e.g. as a tablet, capsule,
solution, suspension or emulsion) or parenteral administration (e.g.
as an injectable aqueous or oily solution, or injectable emulsion).
The compounds of formula I, or a non-toxic salt thereof, may
also be advantageously administered for therapeutic or prophylactic
purposes together with another pharmacological agent known in the
general art to be of value in treating one or more of the diseases or
medical conditions referred to hereinabove, such as a beta-adrenergic
blocker (for example atenolol), a calcium channel blocker (for example
nifedipine), an angiotensin converting enzyme (ACE~ inhibitor (for
example lisinopril) or a diuretic (for example furosemide or
hydrochlorothiazide). It is to be understood that such combination
therapy constitutes a further aspect of the present invention.
In general a compound of formula I (or a pharmaceutically
acceptable salt thereof as appropriate) will generally be administered
to man so that, for example, a daily oral dose of up to 50 mg/kg body
weight (and preferably of up to 10 mg/kg) or a daily parenteral dose
of up to 5 mgJkg body weight (and preferably of up to 1 mg/kg) is
received, given in dlvided doses as necessary, the precise amount of
compound (or salt) administered and the route and form of
admlnlstratlon depending on size, age and sex of the person being
treated and on the particular disease or medical condition being
treated according to principles well known in the medical arts.
In addition to their aforesaid use in therapeutic medicine
in humans, the compounds of formula I are also useful in the
veterinary treatment of similar conditions affecting commercially
valuable warm-blooded animals, such as dogs, cats, horses and cattle.
In general for such treatment, the compounds of the formula I will
`''` ~ -
208~6~
- 26 -
generally be administered in an analogous amount and manner to those
described above for administration to humans. The compounds of
formula I are also of value as pharmacological tools in the
development and standardisation of test systems for the evaluation of
the effects of AII in laboratory animals such as cats, dogs, rabbits,
monkeys, rats and mice, as part of the continuing search for new and
improved therapeutic agents.
The invention will now be illustrated by the following non-
limiting ~xamples in which, unless otherwise stated:-
(i) concentrations and evaporations were carried out by ro~ary
evaporation _ vacuo;
(ii) operations wsre carried out at room temperature, that is in
the range 18-26C;
(iii) flash column chromatography was performed on Nerck Kieselgel
60 (Art. no. 9385) obtained from E Merck, Darmstadt, Germany;
(iv) yields, where given, are intended for the assistance of the
reader only and are not necessarily the maximum attainable by diligent
process development;
(v) 1H NNR spectra were normally determined at 200 NHz in CDCl3
using tetramethylsilane (TNS) as an internal standard, and are
expressed as chemical shifts ~delta values) in parts per million
relative to TMS using conventional abbreviations for designation of
ma~or peaks: s, singlet; m, multiplet; t, triplet; br, broad;
d,doublet;
(vi) 13C NHR spectra were normally determined at 100 MHz in CDCl3
or d6-dimethylsulphoxide (d6-DMS0) using the solvent signal as
internal standard, and are expressed as chemical shifts (delta values)
ln parts per million relat~ve to TNS; and
(vii) all end-products had satisfactory microanalyses.
20~2~
- 27 -
~LE 1
Concentrated hydrochloric acid (0~5 ml) was added to a
solution of 2,6-dimethyl-4-[N-(2'-(2-triphenylmethyl-2H-tetrazol-5-
yl)biphenyl-4-ylmethyl)amino]pyrimidine (A) (0.5 g) in methanol and
the mixture was stirred for 10 minutes. Volatile material was removed
by evaporation and the residue was purified by crystallisation from
iso-propanol~ethanol to give 2,6-dimethyl-4-lN-(2'-(lH-tetrazol-5-yl)-
biphenyl-4-ylmethyl)amino~pyrimidine hydrochloride (138 mg), as an off
white solid, m.p. 248-252C (decomposition); NMR (d6-DMSO): 2.37(s,
3H), 2.52(s, 3H), 4.63(d, 2H), 6.54(s, lH), 7.11(d, 2H), 7.25(d, 2H),
7.43-7.66(m, 4H), 9.29(broad s, lH); mass spectrum (positive fast atom
bombardment (+ve FAB), DMS0/methanol/nitrobenzyl alcohol): 358(~+H)+;
microanalysis, found: C, 60.1; H, 5.3; N, 23.4X;
C2oHlgN7~HCl~0~25C2H50H~0~25H20 requires: C, 60.0; H, 5.4; N, 23.2~.
The starting material A was prepared as follows:
(i) 4-Amino-2,6-dimethylpyrimidine (B) (2.5 g) was added to a
suspension of sodium hydride (60% dispersion in mineral oil; 1.11 g)
in N,N-dimethylformamide (DNF) (180 ml) and the mixture was stirred
for 6 hours. 5-12-(4'-Bromomethylbiphenyl)]-2-triphenylmethyl-2H-
tetrazole (14.8 g) (obtained as described in European patent
application, publication no. 291969) was added and the mixture was
stirred for 16 hours. Solvent was removed by evaporation and the
residue was partitioned between ethyl acetate and water. The organic
layer was separated, washed with saturated sodium chloride solution
and dried. Solvent was removed by evaporation and the residue was
pllrified by flash chromatography eluting with ethyl acetate/methanol
(49:1 v/v). Fractions containing the desired compound were combined
and solvent was removed by evaporation. The residue was further
purified by flash chromatography eluting with dichloromethane/methanol
(19:1 v/v) to give 2,6-dimethyl-4-lN-(2'-(lH-triphenylmethyl-2H-
tetrazol-5-yl)biphenyl-4-ylmethyl)aminolpyrimidine (A) (1.52 g), as a
white foam; NMR (CDCl3): 2.26(s, 3H), 2.50(s, 3H), 4.41(d, 2H),
4.88(broad s, lH), 5.90(s, lH), 6.86-S.97(m, 6H), 7.02-7.17(m, 4H),
7.19-7.55(complex m, 12H), 7.96(m, lH); mass spectru~ (+ve FAB,
methanol/nitrobenzyl alcohol): 600(M+H)+.
'
,
2 0 ~ 8
- 28 -
~LLHPLES 2-7
Using an analogous procedure to that described in Example 1,
but starting from the appropriate compound of formula IVa wherein La
is triphenylmethyl, the following compounds of formula I (in which
is a group of partial structure IIa) were obtained in yields of
52-92%.
(~xample 2): 2,6-dimethyl-4-lN-methyl-N-(2'-(lH-tetrazol-5-yl)-
biphenyl-4-ylmethyl)amino]pyrimidine hydrochloride as a solid, m.p.
222-226C; NMR (d6-DMS0/d4-acetic acid): 2.41,2.46(d of s, 3H),
2.56,2.58(d of s, 3H), 3.17,3.32(d of s, 3H), 4.85,5.05(d of s, 2H),
6.75,6.9(d of s, lH), 7.05-7.4(complex m, 4H), 7.45-7.8(complex m,
4H); mass spectrum (+ve FAB, glycerol/methanol): 372(M+H)+;
microanalysis, found: C, 61.3; H, 5.2; N, 26.6X; C21H21N7.HCl requires
C, 61.8; H, 5.44; N, 24.0%.
(ex ~ple 3): 2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl)-
arino]-5,6,7,8-tetrahydroquinazoline hydrochloride as a solid, m.p.
277-278C; NMR (d6-DNSO): l.l9(t, 3H), 1.78(m, 4H), 2.38(m, 2H),
2.67(m, 2H), 2.74(q, 2H), 4.70(d, 2H), 7.06(d, 2H), 7.27(d, 2H),
7.56(m, 4H), 9.05(t, lH); mass spectrum (+ve FAB methanol/nitrobenzyl
alcohol): 412(M+H)+; microanalysis, found: C, 64.1; H, 5.9; N, 21.8%;
C24H25N7.HCl requires: C, 64.3; H, 5.8; N, 21.9-~.
(EYarple 4): 2,6-di~ethyl-5-iodo-4-l~2'-(lH-tetrazol-5-yl)biphenyl-4-
ylmethyl)a~dno]pyrioidine hydrochloride as a solid, m.p. 221-223C;
NMR (d6-DNS0): 2.40(s, 3H), 2.50(s, 3H), 4.72(d, 2H), 7.06(d, 2H),
7.25(d, 2H), 7.64(m, 4H), 8.92(broad t, lH); mass spectrum (+ve FAB,
DMS0/glycerol): 484(~+H)+; microanalysis, found: C, 45.8; H, 3.7; N,
18.6X; C20H18IN7.HCl requires: C, 46.2; H, 3.7; NJ 18.9X.
(~xample 5): 2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl~-
a~inolquinazoline hydrochloride as a solid, m.p. 256-257C;
NNR (d6-DMSO): 1.31(t, 3H), 2.93(q, 2H), 4.95(d, 2H), 7.07(d, 2H),
7.37(d, 2H), 7.60(m, 5H), 7.88(d, lH), 8.00(m, lH), 8.59(d, lH),
10.83(t, lH); mass spectrum (+ve FAB, DHS0/methanol/Ditrobenzyl
: ` :
2 ~
- 29 -
alcohol): 408(H+H)+; microanalysis, found: C, 64.3; H, 5.0; N, 21.6%;
C~4H21N7.HClØ25CH30H requires: C, 64.4; H, 5.1; N, 21.7%.
(F.xample 6): 2,6-diethyl-5-iodo-4-l(2'-(lH-tetrazol-5-yl~biphenyl-4-
ylmethyl)amino]pyrimidine hydrochloride as a solid m.p. 226-229C; NMR
(d6-DNS0): 1.18(d of t, 6H), 2.80(d of q, 4H), 4.7(d, 2H), 7.05(d,
2H), 7.27(d, 2H), 7.85(m, 4H), 8.9(broad s, lH); mass spectrum (+ve
FAB, D~S0/nitrobenzyl alcohol): 512(~+H)+; microanalysis, found: C,
48-6; N, 4-2; N, 17.8%; C22H22IN7.HCl requires: C, 48.2; H, 4.2; N,
17.9%.
(Example 7): 2,4-diethyl-8-1(2'-(lH-tetrazol-5-yl)biphenyl-4-
ylmethyl)]pyridol2,3-dlpyrimidin-7(8H)-one as a solid, m.p.
214-215C; NMR (d6-DMS0): 1.26(d of t, 6H), 2.89(q, 2H), 3.05(q, 2H),
5.53(s, 2H), 6.72(d, lH), 7.01(d, 2H), 7.26(d, 2H), 7.56(m, 4H),
8.21(d, lH); mass spectrum (+ve FAB, methanol/nitrobenzyl alcohol):
438(~+H)+; microanalysis, found: C, 67.1; H, 5.4; N, 21.5X;
C25H23N70Ø5H20 requires: C, 67.2; H, 5.4; N, 21.9%.
The necessary starting materials of formula IVa used in
Examples 2-7, corresponding to starting material A in Example 1, were
obtained in yields of 30-75X using a similar procedure to that
described in Example 1, part (i) as follows:-
(Example 2A): 2,6-dimethyl-4-IN-methyl-N-(2'-(2-triphenylmethyl-2H-
tetrazol-5-yl)biphenyl-4-ylmethyl)aminolpyrimidine as a solid, m.p.
155C (decomposition); NMR (CDCl3): 2.31(s, 3H), 2.51(s, 3H), 2.65(s,
3H), 4.72(s, 2H), 6.07(s, lH), 6.6-6.92(m, 6H), 6.93(d, 2H), 7.09(d,
2H), 7.15-7.4(complex m, lOH), 7.45(m, 2H), 7.95(m, lH); mass spectrum
(+ve PAB, DHS0/methanol/nitrobenzyl alcohol): 614(H+H)+.
(Example 3AL: 2-ethyl-4-1(2'-(2 triphenylmethyl-2H-tetrazol-5-yl)-
biphenyl-4-ylmethyl)amino]-5,6,7,8-tetrahydroquinazoline as a solid,
m.p. 190-192C; NNR (CDCl3): 1.32(t, 3H), 1.75(m, 4H), 2.08(m, 2H),
2.69(m, 2H), 2.74(q, 2~), 4.5(broad t, lH), 4.64(d, 2H), 6 91(m, 6H),
7.10(s, 4H), 7.25(complex m, lOH), 7.48(m, 2H), 7.95(m, lH).
. ~ . . . .
2 0 ~
- 30 -
(Example 4A): 2,6-dimethyl-5-iodo-4-~(2'-(2-triphenylmethyl-2H-
tetrazol-5-yl)biphenyl-4-ylmethyl)amino]pyrimidine as a solid; NMR
(CDCl3): 2.48(s, 3H), 2.57(s, 3H), 4.62(d, 2H), 5.55(broad t, lH),
6.92(m, 6H), 7.10(m, 4H), 7.26(complex m, lOH), 7.48(m, 2H), 7.95(m,
lH).
(Example 5A): 2-ethyl-4-l(2'-(2-triphenylmethyl-2H-tetrazol-5-
yl)biphenyl-4-ylmethyl)amino]quinazoline as a foam; NMR (CDCl3):
1.39(t, 3H), 2.92(q, 2H), 4.79(d, 2H), 5.55(broad t, lH), 6.90(m, 6H),
7.26(complex m, 15H), 7.41(m, lH), 7.48(m, 2H), 7.67(m, lH), 7.80(d,
lH), 7.98(m, lH)-
(Example 6A): 4-amino-2,6-diethyl-5-iodopyrimidine (320 mg) was added
to a mixture of potassium t-butoxide (130 mg) and
1,4,7,10,13,16-hexaoxacyclooctadecane (20 mg) in THF (25 ml) and the
mixture was stirred for 5 minutes. A solution of
5-[2-(4'-bromomethylbiphenyl)]-2-triphenylmethyl-2H-tetrazole (111 mg)
in tetrahydrofuran (THF) (2 ml) was added and the mixture was stirred
for 4 hours. Solvent was removed by evaporation and the residue was
partitioned between ethyl acetate and saturated sodium chloride
solution. The aqueous layer was separated, extracted with ethyl
acetate and the combined organic extracts dried. Solvent was removed
by evaporation and the residue was purified by flash chromatography
eluting with diethyl ether/hexane (2:3 vtv) to give 2,6-diethyl-5-
iodo-4-l(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-ylmethyl)-
aminolpyrimidine as a foam; NHR (CDCl3): 1.25(double t, 6H), 2.82(d of
q, 4H), 4.36(d, 2H), 5.68(broad s, lH), 6.92(m, 6H), 7.09(s, 4H),
7.26(complex m, 8H), 7.38(m, 2H)~ 7.47(m, 2H~, 7.95(m, lH).
(Example 7A): 2,4-diethyl-8-l(2'-(2-triphenylmethyl)-2H-tetrazol-5-
yl)biphenyl-4-ylmethyl)lpyridol2,3-d]pyrimidin-7(8H)-one, was obtained
using an analogous procedure to that described in Example 6A, as a
solid; NMR (CDCl3): 1.35(t, 6H~, 3.0(d of q, 4H), 5.60(s, 2H), 6.69(d,
lH), 6.93(m, 6H), 7.04(d, 2H), 7.35(complex m, 14H), 7.83(d, lH),
7.89(m, lH).
The necessary starting materials of formula V used in
2~82~
- 31 -
Examples 2-4, corresponding to compound B in Example 1, were obtained
as follows:
(Example 2B): An 8M solution of methylamine in ethanol (6.2 ml) was
added to a solution of 6-chloro-2,4-dimethyl pyrimidine (1.42 g)
(obtained as described in Chem. Ber., 1902, 35, 1576) in ethanol (5
ml) and the mixture was stirred for 16 hours. Solvent was removed by
evaporation and the residue was partitioned between 0.25M sodium
carbonate solution (50 ml) and ethyl acetate (25 ml). The aqueous
phase was separated and extracted with ethyl acetate (2 x 25 ml). The
combined organic extracts were washed with saturated sodium chloride
solution and dried. Solvent was removed by evaporation and the
residue was triturated with ethyl acetate to give 2,6-dimethyl-4- -
(N-methylamino)pyrimidine (1.07 g), as a pale yellow solid; NMR
(CDCl3): 2.33(s, 3H), 2.47(s, 3H), 2.09 and 2.92(two s, 3H), 5.2(broad
s, lH), 6.00(s, lH); mass spectrum (CI, ammonia): 138(M+H)+.
(Exam~le 3B): (i) A solution of propionamidine hydrochloride (2.7 g)
in ethanol (25 ml) was added to a solution of sodium (600 mg) in
ethanol (25 ml) and the mixture was stirred for 10 minutes. Ethyl
cyclohexanone-2-carboxylate ~4.25 g) was added and the mixture was
stirred for two days and then heated at reflux for 1 hour. Solvent
was removed by evaporation and ice was added to the residue. The
mixture was then extracted with ethyl acetate (2 x 50 ml). The
combined extracts were washed with water, saturated sodium chloride
solution and then dried (MgS04). Solvent was removed by evaporation
and the residue was triturated with hexane. The resultant solid was
collected by filtratlon to give 4-hydroxy-2-ethyl-5,~,7,8-
tetrahydroquinazol~ne (C) (1.1 g), as a solld, m.p. 199-200C; NMR
(CDC13): 1.33(t, 3H), 1.77(m, 4H), 2.5(m, 2H), 2.66(m, 4H), 12.5(broad
s, lH); mass spectrum (CIJ ammonia): 179(~+H)+.
(ii) A solution of compound C (100 mg) in phosphorous oxychloride
(2 ml) was heated at reflux for 45 minutes. The mixture was cooled to
ambient temperature and volatile material was removed by evaporation.
Ice was added to the residue and the mixture was basified with sodium
bicarbonate. The mixture was extracted with ethyl acetate and the
2~82~
- 32 -
extract dried (HgS04). Solvent was removed by evaporation to give
4-chloro-2-ethyl-5,6,7,8-tetrahydroquinazoline (D) (92 mg), as a low
melting solid; NMR (CDC13): 1.33(t, 3H), 1.66(m, 4H), 2.69(m, 2H),
2.85(m, 4H); mass spectrum (CI, ammonia): 196,198(N+H)+.
(iii) Compound D (4.7 g) was added to a saturated solution of
ammonia in ethanol (50 ml) and the mixture was heated at 135C in a
sealed tube for 12 hours. Volatile materi-al was removed by
evaporation and the residue was partitioned between ethyl acetate and
water. The organic layer was separated and solvent was removed by
evaporation. The residue was purified by flash chromatography eluting
with ethyl acetate/methanol (9:1 v/v) to give 4-amino-2-ethyl-5,6,7,8-
tetrahydroquinazoline (2.1 g), as a solid, m.p. 184C; NNR (d6-DMS0):
1.15(t, 3H), 1.7(m, 4H), 2.25(broad s, 2H), 2.5(m, 4H), 6.25(broad s,
2H); mass spectrum (CI, ammonia): 178(M+H)+.
(Example 4Bl: Bis(trifluoroacetoxy)iodobenzene (4.3 g) and iodine
(1.27 g) were added to a solution of 4-amino-2,6-dimethylpyrimidine
(1.23 g) in dichloromethane (30 ml) and methanol (70 ml) and the
mixture was stirred for 16 hours. Solvent was removed by evaporation
and 5% sodium metabisulphite solution (50 ml) was added to the
residue. The mixture was basified with sodium bicarbonate and the
resultant solid was collected by filtration to give 6-iodo-2,4-
dimethylpyrimidine (1.5 g), as a yellow solid, m.p. 133-134C; NMR
(d6-DMS0): 2.26(s, 3H), 2.40(s, 3H), 6.73(broad s, 2H); mass spectrum
(CI, ammonia): 250(N+H)+.
(Example 5B): (i) A mixture of 2-aminobenzamide (13.6 g), methyl
propionylacetate (26.6 ml) and p-toluenesulphonic acid (150 mg) in
benzene (200 ml) was heated at reflux for 6 hours with azeotropic
removal of wate~. The mixture was cooled to ambient temperature and
solvent was removed by evaporation. The residue was dissolved in a
eutectic mixture of diphenyl/diphenyl ether (1:2.77 v/v) (10 ml) and
the solution was added to a refluxing eutectic mixture of
diphenyl/diphenyl ether (1:2.77 v/v) (40 ml). The mixture was heated
at reflux for 20 minutes and then cooled to ambient temperature.
Hexane (200 ml) was added and the mixture was then decanted to leave a
.
`" 20~2~8
- 33 -
solid residue. The residue was washed with hexane (2 x 200 ml) and
collected by filtration to give 2-ethyl-4-hydroxyquinazoline (C) (16.9
g), as a brown solid, m.p. 199-201C; NMR (d6-DMS0): 1.25(t, 3H),
2.64(q, 2H), 7.4(m, lH), 7.6(d, lH), 7.78(m, lH), 8.06(dd, lH),
12.12(broad s, lH).
(ii) A solution of compound C (1 g) in phosphorous oxychloride
(12 ml) was heated at reflux for 1 hour. The mixture was cooled to
ambient temperature and volatile material was removed by evaporation.
Ice was added to the residue and the mixture was basified with
potassium carbonate. The mixture was extracted with ether (2 x 10 ml)
and the combined extracts dried (NgS04). Decolourising activated
carbon was added to the ethereal solution and the carbon was then
removed by filtration. Solvent was removed by evaporation to give
4-chloro-2-ethylquinazoline (D) (500 mg), as a yellow solid; NMR
(CDCl3): 1.4(t, 3H), 3.10(q, 2H), 7.64(mt lH), 7.98(m, 2H), 8.23(dd,
lH); mass spectrum (CI, ammonia): 192,194(N+H)+.
(iii) Compound D (600 mg) was added to a saturated solùtion of
ammonia in ethanol (25 ml) and the mixture was heated at 180C for 18
hours. Volatile material was removed by evaporation and saturated
sodium bicarbonate solution (25 ml) was added to the residue. The
resultant solid was collected by filtration to give 4-amino-2-ethyl-
quinazoline (B) (250 mg), as an off white solid, m.p. 214-216C
(decomposition); NMR (CDCl3): 1.39(t, 3H), 2.87(q, 2H), 5.58(broad s,
2H), 7.44(m, lH), 7.75(m, 3H); mass spectrum (CI, ammonia): 174(M+H)+.
(Example 6B): (i) 4-chloro-2,6-diethylpyrimidlne (0.86 g) (obtalned as
descrlbed ln J. Chem. Soc., 1963, 5642) was added to a saturated
solution of ammonia in ethanol (50 ml) and the mixture was heated at
135C in a sealed tube for 16 hours. The mixture was cooled to
ambient temperature and solvent was removed by evaporation. The
residue was trlturated with diethyl ether (3 x 2.5 ml) to give
4-amino-2,6-diethylpyrimidine hydrochloride (C) (0.57 g), as an off
white solid; N~R (d6-DNSO): 1.18(d of t, 6H), 2.55(q, 2H), 2.66(q,
2H), 7.6(broad s, lH); mass spectrum (CI, ammonia): 152(M+H)+.
'" ' `'""' " '''''~ ~''`' ''' ' ` '`'' -- - .
: .
2 ~
- 34 -
(ii) Using an analo~ous procedure to that described in Example
4B, but starting from compound (C), there was obtained in 38% yield
4-amino-2,6-diethyl-5-iodopyrimidine as a solidj NMR (CDC13):
1.28(d of t, 6H), 2.71(q, 2H), 2.85(q, 2H), 5.42(broad s, 2H); mass
spectrum (CI, a~monia): 278(M+H)+.
(Example 7B): (i) Iodine (20.3 g) was added to a solution of 2,6-
diethyl-4-hydroxypyrimidine (15.2 g) (obtained as described in J.
Chem. Soc., 1963, 5642) in lN sodium hydroxide solution (105 ml) and
the mixture stirred for 2 hours. The product was collected by
filtration, washed with water and dried to give 2,6-diethyl-4-hydroxy-
5-iodopyrimidine (C) (14.6 g) as an off white solid, m.p. 166-168C;
NMR (d6-DNS0): 1.13(d of t, 6H), 2.51(q, 2H), 2.70(q, 2H), 12.53(broad
s, lH); mass spectrum (CI, ammonia): 279(~+H)+.
(ii) A mixture of compound C (556 mg), ethyl acrylate (0.33 ml),
palladium (II) acetate (50 mg) and triethylamine (1 ml) in DMF (3 ml)
was heated at 120C for 6 hours. The mixture was cooled to ambient
temperature and triturated with saturated sodium carbonate solution.
The product was collected by filtration and re-crystallised from ethyl
acetate to give ethyl 3-[(2,6-diethyl-4-hydroxy)pyrimidin-5-yl]-
acrylate (D) (200 mg) as an off white solid, m.p. 171-174C; NHR
(CDC13): 1.33(t of t, 9H), 2.80~d of q, 4H), 4.26(q, 2H), 7.30(d, lH),
7.70(d, lH); mass spectrum (CI, ammonia): 268(M+NH4)+, 251(H+H)+.
(iii) A solution of compound D (1 g~ in phosphorous oxychloride
(10 ml) was heated at reflux for 1 hour. The mixture was cooled to
ambient temperature and volatlle materlal was removed by evaporation.
Ice was added to the residue and the mixture was then basified with
potassiu~ carbonate. The mixture was extracted with ether (3 x 50 ml)
and the combined extracts dried (~gS04). Solvent was removed by
evaporation and the residue purified by flash chromatography eluting
with ethyl acetate~hexane (1:9 v/v) to give ethyl 3-1(4-chloro-2,6-
diethyl)pyrimldin-3-yl]acrylate (E) (720 mg) as an oil; NMR (CDC13):
1.32(t of t, 9H), 2.89(d of q, 4H), 4.30(q, 2H), 6.35(d, lH), 7.71(d,
lH); mass spectrum (CI, ammonia): 268,270(M+H)+.
~', ,
20~2~ 3~
(:iv) Compound E (700 mg) was added to a saturated solution of
ammonia in ethanol (50 ml) and the mixture was heated at 120C for 12
hours in a sealed tube. The mixture was cooled to ambient temperature
and solvent was removed by evaporation. The residue was triturated
with acetone and the solid ~as removed by filtration and discarded.
The filtrate was concentrated by evaporation and the residue was
purified by flash chromatography to give ethyl 3-l(4-amino-2,6-
diethyl)pyrimidin-5-yl]acrylate (F) (220 mg) as an oil; NM~ (CDC13):
1.30(t of t, 9H), 2.73(d of q, 4H), 4.28(q, 2H), 5.07(broad s, 2H),
6.29(d, lH), 7.73(d, lH); mass spectrum (CI, ammonia): 250(M+H)+.
(v) Compound F (50 mg) was added to a solution of sodium (18 mg)
in ethanol (10 ml) and the mixture heated at reflux for 2 hours. The
mixture was cooled to ambient temperature and solvent was removed by
evaporation. Saturated sodium chloride solution (10 ml) was added to
the residue and the mixture was acidified to pH 4 with lM citric acid
solution. The mixture was then extracted with dichloromethane (2 x
10 ml) and the combined extracts dried (MgS04). Solvent was removed
by evaporation ~o give 2,4-diethylpyridol2,3-d]pyrimidin-7(8H)-one (B)
(22 mg), as a foam; NNR (CDC13): 1.37(t, 6H), 3.01(d of q, 4H),
6.66(d, lH), 7.89(d, lH), 9.57(broad s, lH); mass spectrum (CI,
ammonia): 204(M+H)+.
EXA~PLES 8-11
Using an analogous procedure to that described in Example 1,
but star~ing from the appropriate compound corresponding to startin~
material A in Example 1, the following compounds were obtained in
yields of 53-85X:
( _arple 8): 2,4-diethyl-8-l(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)-
methyl]-5,6,7,8-tetrahydropyridol2,3-dlpyri~idin-7-o~e hydrochloride
as a solid, m.p. 240-241C; NHR (d6-DNS0): 1.2(dt, 6H), 2.85(m, 6H),
2.99(q, 2H), 5.22~s, 2H), 7.01(d, 2H), 7.24(d, 2H), 7.60(m, 4H); mass
spectrum (+ve ~AB, methanol/nitrobenzyl alcohol): 462(N+Na)+,
440(H+H)+; microanalysis, found: C, 62.4; H, 5.5; N, 19.7%;
C25H27N70.1.0HCl.O.l(C2H5)20 requires: C, 62.1; H, 5.5; N, 19.9%-
2082~
- 36 -
(Example 9): 2,6-diethyl-5-(4-methylphenyl)-4-1(2'-(lH-tetrazol-5-
yl)methylamino]pyrimidine hydrochloride as a solid m.p. 246C; NHR
(d6-DMS0): 1.05(t, 3H), 1.24(t, 3H), 2.39(q, 2H), 2.40(s, 3H), 2.86(q,
2H), 4.60(d, 2H), 7.03(d, 2H), 7.20(d, 4H), 7.39(d, 2H), 7.48(m, 4H),
8.30(t, lH); mass spectrum (+ve FAB, methanol/nitrobenzyl alcohol):
476 (N+H)+; microanalysis, found: C, 67.9; H, 6.0; N, 19.3%;
C29H29N7.1.0HCl requires: C, 68.0; H, 5.9; N, 19.1%.
(Example 10): 2,6-diethyl-5-(phenylmethyl)-4-1(2'-(lH-tetrazol-5-
yl)methylamino]pyrimidine hydrochloride as a solid, m.p. 202-203C;
NNR (d6-DMS0): 1.02(t, 3H), 1.15(t, 3H), 2.5(q, 2H), 2.55(q, 2H),
3.93(s, 2H), 4.58(d, 2H), 6.95(d, 2H), 7.07(d, 4H), 7.21m, 3H),
7.55(m, 5H); mass spectrum (+ve FAB, methanol/nitrobenzyl alcohol):
476 (M+H)+; microanalysis, found: C, 70.4; H, 6.4; N, 19.6%;
C29H29N7.1.0HCl.1.0H20 requires: C, 70.5; H, 6.3; N, 19.8%.
( ample 11): 2,4-diethyl-8-1(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)-
methyll-5,6,7,8-tetrahydropyridol2,3-dlpyT$nidine hydrochloride as a
solid, m.p. 255-256C; NMR (d6-DNSO): 1.20(dt, 6H), 1.88(m, 2H),
2.70(m, 6H), 3.55(m, 2H), 4.98(s, 2H), 7.08(d, 2H), 7.27(d, 2H),
7.60(m, 4H); mass spectrum (~ve FAB, methanol/nitrobenzyl alcohol):
426 (M~H)+; microanalysis, found: C, 64.1; H, 5.9; N, 20.1%;
C25N27N5.1ØHC1Ø15(C2H5)20 requires: C, 64.3; H, 6.0; N, 20.5%.
The necessary starting materials of formula IVa used in
Examples 8-11, corresponding to starting material A in Example 1, were
obtained in yields of 28-75X as follows:
(Example 8A): Using an analogous procedure to that described in
Example 6~ there was thus obtained 2,4-dlethyl-8-1(2'-(2-
triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyll-5,6,7,8-
tetrahydropyridol2,3-dlpyrlmldin-7-one as a foam; NHR (CDC13): 1.24(t,
3H), 1.32(t, 3H), 2.8(m, 8H), 5.26(s, 2H), 6.9(m, 6H), 7.03(d, 2H),
7.28(complex m, 12H), 7.45(m, 2H), 7.89(m, lH).
(Example 9A~: Uslng an analogous procedure to that described in
Example 6A there was thus obta$ned 2,6-diethyl-5-(4-methylphenyl)-4-
~.
~.
,
20~2~
- 37 -
~(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyla~ino]-
pyrimidine as a foam; NMR (CDC13): l.lO(t, 3H), 1.35(t, 3H), 2.36(s,
3H), 2.40(q, 2H), 2.83(q, 2H), 4.95(d, 2H), 4.6(bs, H), 6.90(complex
m, 8H), 7.05(complex m, 7H), 7.25(complex m, 9H), 7.45(m, 2H), 7.90(m,
lH).
(Example lOA): Using an analogous procedure to that described in
Example 6A there was thus obtained 2,6-diethyl-5-(phenylmethyl)-4-
[2-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methylamino]-
pyrimidine as a foam; NNR (CDC13): 1.31(dt, 6H), 3.0(broad s, 4H),
3.81(s, lH), 4.57(d, 2H), 6.73(d, 2H), 6.90(complex m, 6H),
7.00(complex m, 4H), 7.10(s, lH), 7.26(complex m, llH), 7.50(m, 3H),
7.91(m, lH); mass spectrum (+ve FAB, DMS0/nitro benzyl alcohol): 718
(~+H)+.
(Example llA): Using an analogous procedure to that described in
Example 1, par~ (i), 2,4-diethyl-8-l2'-~2-triphenylmethyl-2H-
tetrazol-5-yl)biphenyl-4-yl)methyll-5,6,7,8-tetrahydrow ridol2,3-d]-
pyrimidine as a foam; NMR (CDC13): 1.25(dt, 6H), 1.8(m, 2H), 2.59(m,
4H), 2.72(q, 2H), 3.13(m, 2H), 4.82(s, 2H), 6.9(m, 6H), 7.07~s, 3H),
7.15-7.5(complex m, 14H), 7.92(m, lH); mass spectrum (+ve FAB,
methanol/nitrobenzyl alcohol): 66~ (H+H)+.
The necessary starting materials of formula V used in
Examples 8-11 corresponding to B in Example 1 were prepared as
follows:-
(Example 8B)s (i) A solutlon of ethyl 3-l(4-amlno-2,6-diethyl)-
pyrlmldin-5-yllacrylate (100 mg) ln ethanol (6 ml) was catalytically
hydrogenated over 30X palladlum on carbon. When hydrogen uptake
ceased the catalyst was removed by flltration through diatomaceous
earth. Solvent was removed from the filtrate by evaporation to give
ethyl 3-l(4-amino-2,6-diethyl)wrimidin-5-yl]proplonate (B) (88 mg) as
an oil; NMR (CDC13): 1.18(m, 9N), 2.6(m, 8H), 4.09(q, 2H), 5.09(broad
s, 2H); mass spectrum (chemical ionisation, ammonia): 252 ~N+N)+,
(ii) Sodium metal (27 mg) was added to a solution of compound B
2082~-;3~
- 38 -
(290 mg) in ethanol ~15 ml) and the mixture was stirred at ambient
temperature for 2 hours. Solvent was removed by evaporation and the
residue was partitioned between water (5 ml) and ethyl acetate (20
ml). The aqueous layer was separated and extracted with ethyl acetate
(20 ml). The combined organic solutions were dried (HgS04) and
solvent removed by evaporation to give 2,4-diethyl-5,6,7,8-
tetrahydropyridol2,3-d]pyrimidin-7-one (C) (205 mg) as a pale pink
solid, m.p. 93-96C; NMR (CDC13): 1.30(dt, 6H), 2.86(m, 8H),
8.02(broad s, 2H); mass spectrum (chemical ionisation, ammonia): 206
(M+H)+.
(Example 9B): (i) A solution of 2,6-diethyl-4-hydroxy-5-iodopyrimidine
(1.0 g) in phosphorus oxychloride (10 ml) was heated at reflux for 2
hours. The solution was cooled to ambient temperature and volatile
material was removed by evaporation. The residue was treated with
water (100 ml) and the mixture basified with solid potassium
carbonate. The mixture was extraoted with ether (2 x 50ml) and the
combined organic extracts dried (NgS04). Solvent was removed by
evaporation to give 4-chloro-2,6-diethyl-5-iodopyrimidine (C) (1.01
g); NMR (CDC13): 1.31 (dt, 6H), 2.94(dq, 4H); mass spectrum (chemical
ionisation, ammonia): 296, 298 (M+H)+.
(ii) A mixture of compound C (0.72 g), 4-methylphenyl boronic
acid (0.35 g), tetrakis(triphenylphosphine)palladium (86 mg),
saturated sodiu~ bicarbonate solution (12 ml) and toluene (40 ml) was
heated under reflux for 6 hours. The mixture was cooled to ambient
temperature and the organic phase was separated. me aqueous layer
was extracted with ethyl acetate and the comblned organlc phases were
dried (NgS04) and solvent was removed by evaporatlon. The resldue was
purlfled by flash chromatography elutlng wlth ethyl acetate/hexane
(1:9 v/v) to give 4-chloro-2,6-diethyl-5-(4-methylphenyl)pyrimidine
(D) (0.42 g) as a solid; NHR (CDCl3): 1.13(t, 3H), 1.39(t, 3H),
2.56(q, 2H), 2.97(q, 2H), 7.10(d, 2H), 7.27(d, 2H); mass spectrum
(chemical ionisation, ammonia): 261 (N+~)+.
(iii) Compound D (0.40 g) was added to a saturated solution of
ammonia in ethanol (10 ml) and the mixture was heated at 150C for 12
2082~
- 39 -
hours. Volatile material was removed by evaporation and the residue
was partitioned between saturated sodium bicarbonate solution (5 ml)
and ethyl acetate (20 ml). The aqueous layer was separated, extracted
with ethyl acetate (20 ml) and the combined organic extracts dried
(NgS04). Solvent was removed by evaporation and the residue was
purified by flash chromatography eluting with ethyl acetate to give
4-amino-2,6-diethyl-5-(4-methylphenyl)pyrimidine (E) (0.2 g) as a
solid, m.p. 110-114C; N~R (CDC13): 1.10(t, 3H), 1.35(t, 3H), 2.41(s,
3H), 2.42(q, 2H), 2.78(q, 2H), 4.62(broad s, 2H), 7.12(d, 2H), 7.27(d,
2H); mass spectrum (chemical ionisation, ammonia): 242 (H+H)+.
(Example lOB): (i) Benzyl bromide (1.18 ml) was added to a suspension
of zinc dust ~1.0 g) in THF (25 ml) containing dibromoethane (20 mg)
and the mixture was stirred at ambient temperature for 1 hour.
4-Chloro-2,6-diethyl-5-iodopyrimidine (0.9 g) and
tetrakis(triphenylphosphine) palladium (0.1 g) were added and the
mixture was heated at reflux for 4 hours under an argon atmosphere.
The mixture was cooled to ambient temperature and insoluble material
was removed by filtration. The filtrate was extracted with saturated
ethylenediamine tetracetic acid solution and the organic phase
separated and dried (HgS04). Volatile material was removed by
evaporation and the residue was purified by flash chromatography
eluting with ethyl acetate/hexane (1:9 v/v) to give
4-chloro-2,6-diethyl-5-(phenylmethyl) pyrimidine (C) (0.5 g) as an
oil; NMR (CDC13): l.l9(t, 3H), 1.38(t, 3H), 2.74(q, 2H), 2-93(q, 2H),
4.18(s, 2H), 7.08(d, 2H), 7.27(m, 3H).
(ii) Compound C (0.5 g) was added to a saturated solutlon of
ammonia in ethanol (15 ml) and the mixture was heated at 150C for 18
hours. Volatile material was removed by evaporation and the residue
was purified by flash chromatography eluting with ethyl acetate to
give 4-amino-2,6-diethyl-5-(phenylmethyl)pyrimidine) (0.15 g) as an
oil; NMR (CDC13) 1.28(dt, 6H), 2.77(dq, 4H), 3.91(s, 2H), 4.67(broad
s, 2H), 7.13(m, 2H), 7.28(m, 3H); mass spectrum (chemical ionisation,
ammonia): 242 (H+H)+.
(Example llB): A solution of 2,4-diethyl-5,6,7,8-tetrahydro-
.... .. . . . . .. . . . . .. ... .. . . . . . .. ..
2082~
- 40 -
p~rido[2,3-d]pyrimidin-7-one (205 mg) in THF (5 ml) was added dropwise
to a suspension of lithium aluminium hydride (40 mg) in THF (10 ml).
The mixture was heated at reflux for 1 hour under an atmcsphere of
argon. The mixture was cooled to ambient temperature and lM sodium
hydroxide solution (1 ml) was added. Volatile material was removed by
evaporation and the residue was partitioned between ethyl acetate (20
ml) and water (5 ml). The organic layer was separated and dried
(NgS04). Solvent was removed by evaporation to give 2,4-diethyl-
5,6,7,8-tetrahydropyridol2,3-d] wrimidine as a solid; N~R (CDC13):
1.23(dt, 6H), 1.94(m, 2H), 2.62(m, 6H), 3.40(m, 2H), 5.22(broad s,
lH); mass spectrum (chemical ionisation, ammonia): 192 (H+H)+.
EXAXPLE 12
(Note: all parts by weight)
The compounds of the invention may be administered for
therapeutic or prophylactic use to warm-blooded animals such as man in
the form of conventional pharmaceutical compositions, typical examples
of which include the following:-
a) Capsule (for oral administration)
Active ingredient * 20
Lactose powder 578.5
Magnesium stearate 1.5
b) Tablet ~for oral administration)
Active ingredient * 50
Hicrocrystalline cellulose 400
Starch (pregelatinised) 47.5
Magnesium stearate 2.5
c) ID~ectable Solution (for intravenous administration)
Active ingredient * 0.05 - 1.0
Propylene glycol 5.0
Polyethylene glycol (300) 3.0 - 5.0
Purified water to 100%
d) In~ectable Suspension (for intramuscular administration)
'
. .
20g2~S~
- 41 -
Active ingredient * 0.05 - 1.0
Methylcellulose 0-5
lween 80 0-05
Benzyl alcohol 0.9
Benzalkonium chloride 0.1
Purified water to 100%
Note: the active ingredient * may typically be an Example described
hereinbefore and will conveniently be present as a pharmaceutically
acceptable acid-addition salt, such as the hydrochloride salt.
Tablets and capsules formulations may be coated in conventional manner
in order to modify or sustain dissolution of the active ingredient.
Thus, for example, they may be coated with a conventional enterically
digestible coating.
HS36669
JJH: 210CT92
2082668
R ~ N ~ R 1 Chemical Formulae
N~R
N--R
~ A
Za~ CH--133 Zc
--B ~ 3
~ Rb Rc
II~ IIb . IIc
~R~ m ~-CU~ 4 1 Qc
~x~ }R
R~ Rb Rc
~II~ IIIb IlIc
~--r3
I R~ ~ P~ ~ Plm I ~L~
@cX~3
Rb RC IYc .
R~ R~
.
~0~2~6~
4~3 _
Chemical Formulae
( con t i nued )
R 1~ ~N R
R
NUR y
Zb
ZC~ B- CH-g
--6 ~3 ~ ~Qd
Rb Rc
~llb ~lllc
H~
~lIlo~ Rb RC ~llllb ~c
~H-6 ~j, ~R,
R<~ ' Ri Rc
lXo~ IXb ~XC
2 0 ~ 8
44 -
Chemical Formulae
( continued )
C~ C~
p, CH-B H~Xl ~3
Xo~ Rb Rc ~b Xc
c~
a Rb Rc X~ c
Lb
~ ~L~ 3 / ~L~'
4 ~ -6 H~ 4 ~ N
N;~ }
-Xl~ X~ c
z6
~R4 1_~3 N~
X~ b X~c
_ ~5 2 0 8 2
Chemical Formulae
(continued)
Prr~ Pn~
~tX~ Rc~ X
X~- ` X~
N~pl ~p~
X~ll R Ro~ X~tl
R~ ~ N
',
:` ` ` .' , . ' ` '
`:
.
~' ,
- 46 - 208~
Scheme 1
~,C~ ~Y`2
~1 ~ RC~,CC~,Q
R2 I R3 \ (b)
c ~
b~2er~c ~ R~ 1 R~ ~IR~
'J ~ R~ ~ =~ R~
)3 ~RIt
H (et I R3- H
R CLR R ~ R R
(9~ )2
R~ tR~
~co~ R R
R~t_H/ H
... .. ... _ _
Note: R' = lower alkyl; Rx and Ry are optional substituents
Reagents: a) sodium ethoxide, ethanol, ambient te~perature
b) p-Toluenesulphonic acid, benzene, reflux with azeotropic
removal of uater; heat .-
~
- c) P~Cl3, reflux
d) R N~ , EtO~, ambient to 180C
e) bis(~rifluoroacetoxy)iodobenzene, I , C~ Cl /MeOR
f) tetrakis(triphenylphosphine)palladium, trie~hylamine,
dimethoxyethane
g) ethyI acrylate, Pd(II)acetate, ~t ~, 120C, DHF
h) sodium ethoxide, ethanol, reflux 3
i) hydrogenation, palladium on carbon
.
,:, . . . .
'' ~ . ' : ` ` ' . :
,: :
'
