Note: Descriptions are shown in the official language in which they were submitted.
2~329V
Merck Patent Gesellschaft
mit be~chrankter Haftung
6100 D a r m 9 t a d t
Imidazopyridine~
The invention relates to novel imidazopyridine
derivatives of formula I:
R~
N
~NR3
N ll
Rl I Y f= R2
CH2~3
wherein
Rl i9 H or A,
10 R2 is H, Hal, OH, OA, COOH, COOA, CONH2, CN, NOz,
NH2, NHA, N(A)2, NHCoR5, NHSO2Rs or lH-5-tetra-
~olyl,
R3 i~ H, cyanoalkyl, ~r-alkyl, cycloalkylalkyl
having 3-8 C atom~ in the cycloalkyl group,
Het-al~yl, Ar'-alkyl, R6-CO-alkyl~ Ar-CO-alkyl
or Het-CO-alkyl having, in each casa, 1-6 C
atom~ in the 'alkyl' moiety, it being pos~ible
for an H atom in the 'alkyl' moiety to be
replaced by a COOH or a COOA group,
20 R4 i~ H or Hal,
Rs and R6 are ln each case alkyl having 1-6 C atoms,
wherein one or more H atom~) can also be
replaced by F,
Y i9 O or S,
25 A is alkyl, alkenyl or alkynyl in each case
having up to 6 C atom~,
Ar i9 a phenyl group which i~ un~ub~tituted or
mono~ubRtituted by ~al, R~, OH, OA, COO~, COOA,
CN, NO2, NH2, NHA, N(A)2, NHCOR5, NHSo2R5 or 1~-5-
20~2~a
-- 2 --
tetrazolyl,
Ar' is a phenyl group su~stituted by Ar,
Het is a five or six membered heteroaxomatic
radical having 1 to 3 N , 0 and/or S atoms,
S which can also be conden~ed with a benzene or
pyridine ring, and
Hal is F, Cl, Br or I,
and their salts.
The object of the invention was to find novel
compounds with valuable properties, especially compounda
which can be used for the preparation of ~ruga.
It has been found that the compounds of fo~nula
I and their 3alts possess ~ery valuable pharmacological
properties coupled with a good tolerance. In particular,
they exhibit antagonistic properties towards angiotensin
II and can therefore be used as
pharmaceutical active ingredient~ in human and veterinary
medicine, especially for the prophylaxis and/or therapy
of cardiac, circulatory and vascular diseases and in
particular for the txeatment of
angiotensin II-dependent hyperten~ion, aldosteronism and
cardiac insufficiency, as well as disorders of the
central nervous system, furthermore of hypertrophy andhyperælasY
of the blood vessels and the heart, angina pectoris, cardiac
infarction, haemorrhagic stroke, restenosis after angio-
plasty or by-pass surgery, arteriosclerosis, ocular hyper-
tension, glaucoma, macular degeneration, hyperuricaernia,
disturbances of the renal functions such as renal failure,
diabetic complications such as nephropathia diabetica or ~o retinopathia diabetica, psoriasis, angiotensinII-induces
disturbances in female sexual organs, cognitive disorders,
f.e. dementia, amnesia, disturbances of the functions of
memory, states of fear, depressions and/or epilepsy.
2~32~
The~e effect~ can be determined
by conventional in vitro or in vivo method~ such as those
deqcribed for example in US Patent 4 880 804 and in W0
91/14367, a~ well a~ thos2 de~cribed by A.T. Chiu et al.,
S J. Pharmacol. Exp. Therap. 250~, 867-874 (1989), and by
P.C. Wong et al., ibid. 252, 719-725 (1990j in vivo, on
rat~).
The invention relates to the compounda of formula
I, their ~alts and to a process for the preparation of
these compounds and their salts, characterised in that a
compound of formula II:
~2
E-CH ~ II
2~32~
-- 3 --
wherein
E is Cl, Br, I, a free O~ group or an OH group
which has been functionally modified to ~cquire
reactivity, and
5 R2 has the meaning stated in Claim 1,
is reacted with a compound of fon~ula III
III
~1 H
wherein
Rl, R3, R~ and Y have the meanings ~tated in Clalm 1,
or in that a compound of formula I iB liberated ~rom one
of its functional derivatives by treatment with a
solvolysing or hydrogenolysiny agent,
and/or in that one or more radical(~) Rl, R2, R3, R~ and/or
Y in a compound of formula I are converted to one or more
other radicals R1, R2, R3, R4 andtor Y, and/or a base or
acid of formula I is converted to one of its salt~.
Hereinabove and hereinafter, the radicals or
parameters Rl to Ra, y, A, Ar, Ar', Het, ~al and E have
the~ meanings stated in formulae I and II, unle~s
expres~ly indicated otherwise.
In the above formulae, A i9 particularly alkyl
having 1-6, preferably 1, 2, 3 or 4 C atom~, preferably
methyl, or el~e ethyl, propyl, i~opropyl, butyl,
isobutyl, sec-butyl or tert-butyl, or else pentyl, 1-, 2-
or 3-methylbutyl, 1,1-, 1,2- or 2,2-dim~thylpropyl,
1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,
1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-
ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-
methylpropyl or 1~1,2- or 1~2~2-trLmethylpropyl. However,
A can al~o be alkenyl or alkynyl in each ca~e having 2-6,
preferably 2, 3 or 4 C atoms, in particular vinyl, 1- or
2-propenyl lallyl), 1-propen-2-yl, 1-/ 2- or 3-butenyl,
- 4
ethynyl, 1- or 2-propynyl (propargyl), 1-, 2- or
3-butynyl.
Accordingly, the radical OA i9 preferably
methoxy, or else ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, ~ec-butoxy, tert-butoxy, vinyloxy, allyloxy,
ethynyloxy or propargyloxy. The ~roup COOA i8 preferably
methoxycarbonyl or ethoxycarbonyl, or el~e propyloxy-
carbonyl, isopropyloxycarbonyl, butyloxycarbonyl,
isobutyloxycarbonyl, allyloxycarbonyl, propargyloxy-
carbonyl. The group NHA i~ preferably methylamino orethylamino. The group N(A)z i~ preferably dimethylamino or
diethylamino.
Hal iB prefe~ably F, Cl or Br, or else I.
The radical Ar is preferably an un~ubstituted
phenyl group, or else preferably a phenyl group ~ub-
stituted in the p-po~ition or substituted in the o- or
m-po~ition. Preferred ~ubstituents are COO~, COOA, NO2
lH-5-tetrazolyl. Accordingly, Ar is preferably phenyl,
o-, m- or (e~pecially) p-carboxyphenyl, o, m- or
(especially) p-methoxycarbonylphenyl, o-, m- or
(especially) p-ethoxycarbonylphenyl, o-, m- or
(especially) p-nitrophenyl, o-, m- or (e~pecially) p-(1~-
5-tetrazolyl)-phenyl furthermore preferably, o-, m- or
(especially) p-aminophenyl, o-, m- or (especially)
p-climethylamino-phenyl, o-, m- or (especially) p-
diethylaminophenyl, o-, m- or p-tolyl, o , m or p-
trifluoromethylphenyl, o-, m- or p-hydroxyphenyl, o-, m
or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or
p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-
iodophenyl, o-, m- or p-cyanophenyl, o-, m- or p-
methylaminophenyl, o-, m- or p-acetamidophenyl, o-, m- or
p-trifluoroacetamidophenyl, o-, m- or p-
methylsulfonamidophenyl, o-, m- or p-tri-
fluoromethylsulfonamidophenyl.
The radical Ar' i~ preferably 4-biphenylyl,
2'-carboxy-4-biphenylyl, 2'-methoxycarbonyl-4-biphenylyl,
2'-cyano-4-biphenylyl or 2' (1~-5-tetrazolyl)-4-
biphenylyl.
2~3,5
-- 5
Het i~ preferably 2- or 3-ruryl, 2- or 3-thienyl,
1 , 2- or 3-pyrrolyl, 1-~, 2-, 4- or 5-imidazolyl, 1-, 3-,
4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or
5-i~oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or
5-i~othiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or
6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-,
-4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl,
1,2,3-oxadlazol-4- or -5-yl, 1,2,~-oxadiazol-3- or -5-yl,
1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or
-5-yl, 2,1,5-thiadiazol-3- or -4-yl, 3- or 4-pyridazinyl,
pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-,
4-, 5-, 6- or 7-benzothienyl, l-, 2-, 3-, 4-, 5-, 6- or
7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-,
2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or
7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-,
4-, 5-~ 6 or 7-benzi~oxazolyl, 2-, 4-, 5-, 6- or
7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzi~othiazolyl,
4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-,
6-, 7- or 8-quinolyl, 1~, 3-, 4-, 5-, 6-, 7- or
8-i~oquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl/ 2-, 4-,
5-, 6-, 7- or 8-quinazolyl, lH-1-, -2-, -5-, -6- or
-7-imidazo[4,5-b]pyridyl, 3~-2 , -3-, -5-, -6- or
-7-im.idazo[4,5-b]pyridyl, 1~-1-, -2-, -4-, -6- or
-7-imidazo[4,5-c]pyridyl, 3H-2-, -3-, -4-, -6- or
-7-imidazo[4,5-c]pyridyl.
The ter~ "~et" also include~ the homologous
radical~ in which the heteroaromatic ring i9 substituted
by one or more, prefera~ly 1 or 2, A groups, preferably
methyl and/or ethyl groups, for example 3-, 4- or
5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-di-
methyl-3-furyl, 3-, 4~ or 5-methyl-2-thienyl, 3-methyl-
S-tert.-b~tyl-2-thienyl, 2~, 4- or 5-methyl-3-thienyl, 2-
or 3-methyl-1-pyrrolyl, 1-, 3-, 4- or 5-methyl-2-
pyrrolyl, 3,5-dimethyl-4-ethyl-2-pyrrolyl, 2-, 4- or
5-methyl-1-imidazolyl, 4-methyl-5-pyrazolyl, 4- or
5-methyl-3-i~oxazolyl, 3- or 5-methyl-4-i~oxazolyl, 3- or
4-methyl-5-isoxazolyl, 3,4-dimethyl-5-i~oxazolyl, 4-,or
5-methyl-2-thiazolyl, 4- or 5-ethyl-2-thiazolyl, 2- or
~ t3~ ~ ~
5-methyl-4-thiazolyl, 2- or 1-methyl-5-khiazolyl,
2,4-dimethyl-5-thiazolyl, 3~, 4-, 5- or 6-methyl-2-
pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or
3-methyl-4-pyridyl,4-methyl-2-pyrimidinyl,4,6-dimethyl-
2-pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimidinyl,
2,6-dimethyl-4-pyrimidinyl, 3-, 4-, 5-, 6 or 7-methyl-
2-benzofuryl, 2-ethyl-3-benzofuryl, 3-, 4-, 5-, 6~ or
7-methyl-2-benzothienyl, 3-ethyl-2-benzothienyl, 1-, 2~,
4-, 5-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or
6-benzimidazolyl, l-ethyl-5- or 6-benzimidazolyl.
The radical Y i9 preferably 0.
The radical Rl i9 preferably A, in particular
butyl, furthermore preferably propyl, pentyl or hexyl.
The radical R2 i8 preferably COOH, f~rthermore
preferably 1~-5-tetrazolyl, COOCH3, COOC2Hs, CON~2, CN or
NO2 .
Th~ "alkyl" moiety in the radical R3 is in the
individual groups preferably -C~2~ or -CH2C~2-,
furthermore preferably -CH(CH3)-, -(C~2)3-, -(CH2) 4- ~
-(CH2)5- or -(C~2)B-' Specifically, R3 i9 preferably ~;
Ar-alkyl such as benzyl, 1- or 2-phenylethyl, o~, m- or
(especially) p-carboxybenzyl, o-, m- or (eqpecially)
p-methoxycarbonylbenzyl, o-, m- or (especially)
p-ethoxycarbonylbenzyl, o-, m- or (especially) p nitro-
benzyl, o-, m- or ~especially) p~aminobenzyl, o-, m- or
(especially) p-cyanobenzyl; cycloalkylalkyl such a~
cyclopropylmethyl, cyclobutyl-methyl, cyclopentylmethyl,
cyclohexylmethyl, 1- or 2-cyclohexylethyl, cycloheptyl-
methyl, cyclooctylmethyl; ~et-alkyl such a~
(especially) 2- or 3-thienylmethyl, 1~ or 2-(2-thienyl)-
ethyl; Ar'-alkyl such a~ 4-biphenylyl-methyl, 2'-carboxy-
4-biphenylylmethyl, 2'-methoxy~arbonyl-4-biphenylyl~
methyl, 2'-ethoxycarbonyl-4-biphenylylmethyl, 2'-cyano-
4-biphenylylmethyl, 2'-(lH-5-tetrazolyl)-4-biphenylyl-
methyl; RB-CO-alkyl such as 2-oxopropyl, 2-oxobutyl,
3-methyl-2-oxobutyl,3,3-dimethyl-2-oxobutyl;Ar-CO-alkyl
such as benzoyl-methyl, o-, m- or p-carboxybenzoylmethyl,
o-, m- or p-methoxycarbonylbenzoylmethyl, o-, m- or
2 0 ~
p-ethoxy carbonylbenzoylmethyl, o-, m~ or p-cyanobenzoyl-
methyl, o-, m- or p-nitrobenzoylmethyl, o-, m- or
p-aminobenzoylmethyl; Het-CO-alkyl such a~ 2-thlenyl-
carbonyl-methyl. If an H atom in the "alkyl" moiety of
5 the radical R3 i~ replaced by COO~ or COOA, the ~aid
radical i9 preferably, for example,
c~-ethoxycarbonylbenzyll ~-cyclo-hexyl-~-ethoxycarbonyl-
methyl, 1-ethoxycarbonyl-2-phenyl-ethyl.
The radical R4 i~ preferably E3.
10 The radicals R5 and R6 are each preferably A such
as methyl or ethyl, and trifluoromethyl, furthennore
preferably fluoromethyl, difluoromethyl, pentafluoroethyl
or haptafluoropropyl.
The compoundR of formula I can posses~3 one or
15 more chiral centres and can therefore exi~t in different
form~ (optically active or optically inactive). Formula
I includes all these forms.
Accordingly, the invention relates e~pecially to
those compound~3 of formula I in which at least one of
20 said radicals has one of the preferred meanings indicated
above. Some preferred groups of compounds can be
expressed by the following partial formulae Ia to Id
which correspond to the formula ï and wherein the
radical4 not described more precis~ly have the meaning~
25 stated for forrnula I but wherein:
in Ia Rl i9 alkyl ha~ring 1-6 C atoms;
in Ib R2 is COOI~, COOCE13, COOC2E~5, CN, CON~2, NO2 or
lH-5-tetrazolyl;
in Ic R2 COOH, COOCH3, COOC2Hs, CN, CONE~2, NO2 or
lH-5-tetrazolyl and i~ in the p position;
in Id R2 is alkyl having 1-6 C a~om~ and
R2 i4 COOH, COOCH3, (~OOC2H5, CN, CON~12, N02 or
lH-S-tetrazolyl.
Compounds which are furthermore preferred are
35 those of the formulae:
Ie and Iae, Ibe, Ice and Ide, ~hich corre~pond to the
formulae I and Ia, Ib, Ic and Id but wherein additionally
R3 is H;
~3~
-- 8 --
If and Iaf, Ibf, Icf and Idf, which corre~pond to the
formulae I and Ia, Ib, Ic and Id but wherein additionally
R3 is Ar-alkyl;
Ig and Iag, Ibg, Icg and Idg which correspond to the
formulae I and Ia, Ib, Ic and Id but wherein additionally
R3 is benzyl, carboxybenzyl, methoxycarbonylbenzyl,
cyanobenzyl, nitrobenzyl or aminobenzyl;
Ih and Iah, Ibh, Ich and Idh which correspond to the
formulae I and Ia, Ib, Ic and Id, but wherein
additionally
R3 i~ cycloalkylalkyl having 3-8 C atoms in the cycloakyl
group;
Ii and Iai, Ihi, Ici and Idi which correspond to the
formulae I and Ia, Ib, Ic and Id but wherein additionally
R3 is ~et-alkyl;
Ij and Iaj, Ibj, Icj and ~dj which corre~pond to the
formulae I and Ia, Ib, Ic and Id but wherein additionally
R3 is Ar'-alkyl;
Ik and Iak, Ibk, Ick and Idk which correspond to the
formulae I and Ia, Ib, Ic and Id but wherein additionally
R3 i9 R6-CO-alkyl;
Il and Ial, Ibl, Icl and Idl which correspond to the
formulae I and Ia, Ib, Ic ~nd Id b~t wherein additionally
R~ is Ar-CO-alkyl;
Im and Iam, Ibm, Icm and Idm which correspond to the
formulae I and Ia, Ib, Ic and Id but wherein additionally
~3 i~ ~et-C~-alkyl;
In and Ian, Ibn, Icn and Idn which correspond to the
formulae I and Ia, Ib, Ic and Id, but wherein
additionally
R3 is ~, benzyl, carboxybenzyl, methoxycarbonylbenzyl,
cyanobenzyl, nitrobenzyl, aminobenzyl/ -carboxy-~-
cyclohexylmethyl, ~-cyclohexyl-~-methoxycarbonylmethyl,
thienylmethyl, carboxy-4-blphenylylmethyl, methoxy-
carbonyl-4-biphenylylmethyl, (lH-S-tetrazolyl)-4-bi-
phenylylmethyl or 3,3-dimethyl-2-oxobutyl;
Io and Iao, Ibo, Ico and Ido which correspond to the
formulae I and Ia, Ib, Ic and Id but wherein additionally
2 ~
_ 9
R3 is H, benzyl, p-carboxybenzyl, ~-carboxybenzyl,
p-methoxycarbonylbenzyl, ~-methoxycarbonylbenzyl,
p-cyanobenzyl, p-nitrobenzyl, p-aminobenzyl, ~-carboxy-
~-cyclohexylmethyl, u-cyclohexy~ methoxycarbollymethylr
2-thienylmethyl, 2'-carboxy-4-biphenylylmethyl,
2'-methoxycarbonyl-4-biphenylylmethyl, 2' l1~-5-
tetrazolyl)-4-biphenylylmethyl or 3,3-dimethyl-2-oxo-
butyl.
Particularly preferred cornpounds are all tho~e of
the abovementioned formulae in which additionally Y i~ O
and/or R~ is H.
The compounds of formula I and also the ~tarting
materials for their preparation ara moreover prepared by
methods known per se, such a~ those de~cribed in the
literature (for example in the standard work~ like
Houben-Weyl, Methoden der organischen Chemie ~Method~ of
Organic Chemistry~, Georg-Thieme-Verlag, Stuttgart, but
especially in European Patent Application A2-0 430 709
and US Patent 4 880 804), under reaction condition~ which
are known and suitable for ~aid reactions, it also being
possible to make use of variants known per ~e, which are
not mentioned in greater detail here.
If desired, the starting materials can al80 be
formed in situ, so that they are not isolated from the
reaction mixture but in~ediately reacted further to give
the compound~ of formula I.
The compounds of for~ula I can preferably be
obtained by reacting compounds of formula II with
compounds of formula III.
In the compound~ of formula II, ~ i8 preferably
Cl, ~r, I or an 0~ group which ha~ been functionally
modified to acquire reactivity, such a~ alkyl~ulfonyloxy
having 1-6 C atoms (preferably methyl~ulfonyloxy) or
arylsulfonyloxy having 6-10 C atom~ (prefera~ly phenyl-
or p-tolyl-sulfonyloxy).
The reaction of II with III i~ convenlently
carried out by f irst converting III to a ~alt by
treatment with a base, for example with an alkali metal
-- 10 --
alcoholate such a~ CH~ONa or potassium tert-butylat2 in
an alcohol such as CH30H or in an amide such a~ dimethyl-
formamide (DMF), or with an alkali metal hydride such a~
NaH or an alkali metal alcoholate in DMF, and then
reacting said salt with II in an inert solvent, for
example an amide such as DMF or dlmethylacetamide, or a
sulfoxide such as dimethyl sulfoxlde (DMSO), conveniently
at temperatures of between -20 and 100, preferably of
between 10 and 30. Other suitable bases are alkali metal
carbonate~ such as Na2CO3 or K2CO3, or alkali metal hydro-
gen carbonates ~uch a~ NaHCO3 or KHCO3.
Some of the starting material~, especially those
of formula II, are known. If they are not known, they can
be prepared by known method~ in analogy to known
substances. Compounds of the formula III (R3 ~ ~) can be
obtained for example by condensation of 3,4-diamino-6--R~-
1,2-dihydro-2-oxo- (or -2-thioxo-)-pyridine~ or of 3,4-
diamino-2-chloro-6-R4-pyridines with carboxylic acid~ of
the formula Rl-COOH in the presence of polyphosphoric
acid.
A compound of formula I can also be liberated
from one of its functional derivatives by treatment with
a solvolysing (for example hydroly~ing) or
hydrogenolyYing agent.
Thus it i~ possible, using one of the methods
indicated, to prepare a compound which has formula I but
in which a 5 tetrazolyl ~roup is replaced with a 5-
tetrazolyl group functionally modified in the 1- position
(protected by a protecting group)~ Examples of ~uitable
protecting groups are triphenylmethyl, which can be
eliminated with HCl or formic acid in an inert solvent or
solvent mixture, for exampl~ methanol or
ether/dichloromethane/methanol; 2-cyanoethyl, which can
be eliminated with NaO~ in water/THF; and p-nitro-benzyl,
which can be eliminated with H2/Raney nickel in ethanol
(compare European Patent Application A2-0 291 969).
It is also possihle to convert one compound of
formula I to another compound of formula I by converting
~3~
one or more of the radical~ Rl, R2, R3, R4 and/or Y to
other radicals Rlt R2, R3, R4 and/or Y, for ex~nple by
reducing nitro groups to amino groups (for example by
hydrogenation on Raney nickel or Pd/charcoal in an inert
~olvent ~uch a3 methanol or ethanol), and/or functionally
modifying free amino and/or hydroxyl group~, and/or
freeing functionally modified amino and/or hydroxyl
groups by ~olvolysis or hydrogenoly~ia, and/or replacing
halogen atoms with CN groups (for example by reaction
with copper(I) cyanide), and/or hydrolysing nitrile
groups to cooa group~ or to CON~2 groups, or converting
nitrile groups to tetrazolyl groups w1th hydrazoic acid
derivatives, for example 30dium azide in N-methyl-
pyrrolidone or trimethyltin azide in toluene.
Thu~, for ex~nple, free amino groups can be
acylated in conventional manner with an acid chloride or
anhydride, or free hydroxyl and/or NR groups can be
alkylated with an unsubstituted or substituted alkyl or
Ar-alkyl halide or with aldehyde~ ~uch a~ formaldehyde,
in the presence of a reducing agent ~uch a~ NaBH~ or
formic acid, conveniently in an inert solvent such as
methylene chloride or THF, and/or in the presence of a
base such as triethylamine or pyridina, at temperatures
of between -60 and +30.
If desired, a functionally modified ~nino and/ or
hyclroxyl group in a compound of forlnula I can be freed by
~olvolysis or hydrogenolysis u~ing conventional methods.
Thus, for example, a compound of formula I containing an
NHCoR5 or COOA qroup can be converted to the corre~ponding
compound of formula I containing an NM2 or COOH group
insteadO E~ter group~ can be hydroly~ed for example with
NaOH or KO~ in water, water/THF or water/dioxane, at
temperature~ of between Q and 100.
The reaction of nitriles of formula I (R2 = CN or
R3 = cyanoalkyl) with hydrazoic acid deri~ative~ lead~ to
tetrazole~ of formula I (R2 ~ lH-5-tetrazolyl and/or
R3 = 1H-5-tetrazolylalkyl~. It i~ pra~era~le to use
trialkyltin azides such a~ trimethyltin azide, in an
~3~
- 12 -
inert ~olvent, for example an aromatic hydrocarbon such
a~ toluene, at temperatures of betw~en 20 and 150,
preferably of between 80 and 140, or sodium azide in N-
methylpyrrolidone at temperature~ of between about 100
and 200.
A base of formula I can be converted with an acid
to the corresponding acid addition salt. Possible acida
for this reaction are e~pecially those which yield
physiologically acceptable salts. Thus it is pos3ible to
u~e inorganic acids, for example sulfuric acid, nitric
acid, hydrohalic acids such as hydrochloric acid or
hydrobromic acid, phosphoric . acid~ such a~
orthophosphoric acid, and ~ulfamic acid, a~ well a~
organic acids, especially aliphatic, alicyclic,
~raliphatic, aromatic or heterocyclic monobasic or
polybasic carboxylic, sulfonic or sulfuric acids, for
example formic acid, acetic acid, propionic acid, pivalic
acid, diethylacetic acid, malonic acid, Rucclnic acid,
pimelic acid, fumaric acid, maleic acid, lactic acid,
tartaric acid, malic acid, citric acid, gluconic acid,
ascorbic acid, nicotinic acid, isonicotinic acid,
methane- or ethane-sulfonic acid, ethanedisulfonic acid,
2-hydroxyethane~ulfonic acid, benzenesulfonic acid, p-
toluenesulfonic acid, naphthalene-mono~ulfonic and
-disulfonic acids and lauryl sul~Euric acid. Salts with
physiologically unacceptable acids, for example picrates,
: can be used for i301ating and/or purifying the compounds
of f ormula I.
On the other hand, compounds of formula
containing COO~ or tetrazolyl groups can be converted
with bases lfor example sodiu~ or pota~sium hydroxide or
carbonate) to the corresponding metal salt~, especially
alkali metal or alkaline earth metal salt~, or to the
corre~ponding ammonium salt3. The potassium ~alts are
particularly preferred.
The novel compounds of formula I and their
physiologically acceptable salts can be used for the
preparation of pharmaceutical formulation~ by
2~!932~
- 13 -
incorporation into a suitable do~age form together with
at least one excipient or adjunct and, if desired,
together with one or more other active ingredients. The
resulting formulations can be used as drug~ in human or
veterinary medicine. Possible excipient~ are organic or
inorganic substance~ which are ~uitable for enteral (for
example oral or rectal) or parenteral admini~tration or
for administration in the form of an inhalation spray,
and which do not react with tlle novel compound~, example~
being water, vegetable oils, benzyl alcohol~,
polyethylene glycols, glycerol triacetate and other fatty
acid glycerides, gelatin, soya lecithin, carbohydrates
such a3 lactose or starch, magnesium stearate, talc and
cellulose. Tablets, coated tablets, capsules, ~yrups,
juices or drops, in particular, are used for oral
administration; lacquered tablets and capsules with
coatings or shells resistant to gastric juice~ are of
special intere~t. Suppo~itories are used for rectal
administration, and Dlutions, preferably oily or aqueous
solutions, as well as suspensions, emulsions or implants,
are used for parenteral administration. For
administration aa inhalation spray~, it is possible to
use ~pray~ containing the active ingredient either
di~solved or suspended in a propellant or propellant
mixture (for example hydrocarbons such as propane or
butane, or fluorocarbons such as heptafluoropropane). It
is convenient here to u~e the active ingredient in
micronised form, it being possible for one or more
additional physloloqically compatible ~olvents r for
example ethanol, to be pre~ent. Inhalation solutions can
be administered with the aid of conventional inhaler~.
The novel compounds can al~o be lyophili~ed and the
resulting lyophilisates used for example for the
manufacture of injectable preparations. The indicated
formulations can be starilised and/or can contain
adjuncts such as preservatives, stabilisera and/or
wetting agents, emulsifiers, salt~ for influencing the
osmotic pressure, buffer substances and colours and/or
2~32~
- 14 -
flavourings. If de~ired, they can al80 contain one or
more other active ingxedient~, for example one or more
vitamins, diureticq or antiinflammatory agent~.
The sub~tance~ according to the invention are
normally administered in analogy to other known,
commercially a~ailahle preparations, but in paxticular
in analogy to the compollnd~ de~cribed in US Patent
4 880 804, preferably in dose~ of between about 1 mg and
1 g, especially of between 50 and 500 mg per dQsage unit.
The daily dose i5 preferably between about 0.1 and
100 mg/kg, especially between 1 and 50 mg/kg of body
weight. However, the particular dose for each individual
patient depend~ on a very wide variety of factor , for
example on the efficacy of the particular compound u~ed,
age, body weight, general ~tate of health, ~ex, diet,
time and mode of admini~qtration, rate of excretion, drug
combination and severity of the particular di~ea~e to
which the therapy is applied. Oral admini~tration i8
preferred.
~ereinbefore and hereinafter, all temperature~
are given in C. In the following Examples, "conventional
working-up" mean~: Water i5 added if nece~sary, the pH i~
adjuated to between 2 and 10 if neces~ary, depending on
the con~titution of the end product, extractlon i~
carried out with ethyl acetate or methylene chloride, and
the organic pha~e i~ ~eparated off, dried over aodium
~ulfate, evaporated and purified by chromatography on
silica gel and/or by cry~tallisation. Rf = Rf on ~ilica
gel (by thin layer chromatography; eluent: ethyl
30 ac0tate/methanol 9:1). DOI - -4,5-dihydro-4-oxo-3~-
imidazo[4,5-c]pyridine.
~a~3~
- 15 -
Example l
19.1 g of 2-butyl-4,5-dihydro-4-oxo-l(or 3)H-
imidazo~4,5-c]pyridine (mOp. 285-290; obtainable by
heating 3,4-diamino-2-chloropyridine and valeric acid in
polypho~phoric acid at 1~0-140, then 170-180) ~re
di~solved in 500 ml of DMF, 16.6 g of K2CO3 are added, the
mixture is stirred for 45 min, a solution of 27.45 g of
methyl p-bromomethylbenzoate i8 added dropwi~e, the
mixture i9 stirred at 20 for 16 h, and water iR added.
The precipitate which ha~ ~eparated out i8 filtered off,
wa~hed with water, dried and chromatographed on ~ilica
gel. Uqing ethyl acetate and then ethyl acetate/methanol,
first 2-butyl-3,5 bi~-p-methoxycarbonylbenzyl-DOI ~m.p.
124) i~ obtained, and then 2-butyl-3-p-methoxycarbonyl-
benzyl-DOI Im.p. 219).
Obtained analogously ~ing p-bromomethylbenzo-
nitrile are 2-butyl-3,5-biq-p-cyanobenzyl-DOI (m.p.
12~.5~ and 2-butyl-3-p-cyanobenzyl-DOI (m.p. 201).
Obtained analogou~ly from 4,5-dihydro-4-oxo-
20 2-propyl-l(or 3)H-imidazo[4,5-c]pyridine (m.p. 258;
obtainable from 3,4-diamino-2-chloropyridine and butyric
acid in polyphosphorlc acid) are 3,5-bis-p-methoxy-
carbonylbenzyl-2-propyl DOI (oily; Rf 0.51 in ethyl
acetate) and 3-p-methoxycarbonylbenzyl-2-propyl-DOI, m.p.
25 235.
Example 2
Obtained in analogy to Example 1 from 2-butyl-5-
(~-cyclohexyl-~-methoxycarbonylmethyl)-DOI(obtainableby
benzylation of 2-butyl~4,5-dihydro-4-oxo-l(or 3)~-
imidazo[4,5-c~pyridine to give the 3-benzyl-3~-compound,
reaction with methyl ~-bromo-~-cyclohexylacetate to give
2-butyl-3-benzyl 5-l~-cyclohexyl-~-methoxycarbonyl-
methyl)-DOI and elimination of the benzyl group by
hydrogenolysis) and methyl p-bromomethylbenzoate i~
2-butyl-5-(~-cyclohexyl-~-methoxycarbonylmethyl)-3-p-
methoxycarbonylbenzyl-DOI, Rf 0.63.
2~32~
Example 3
1.34 g of K tert.-butylata are added under N2 to
a solution of 3.39 g of 2-butyl-3-p-methoxyca~bonyl-
benzyl-DOI (m.p. 218-219) in 85 ml of DMF, the mixture
i8 stirred at 20 for 10 min, a solution of 2.16 g o
p-nitrobenzyl bromide in 35 ml of DMF i8 added, and the
mixture is stirred at 20 for 2.5 h. Conventional
working-up (chromatography on ~ilica gel, ethyl acetate)
results in 2-butyl-3-p-methoxycarbonylben7yl-5-p-nitro-
benzyl-DOI, m.p. 142.
Obtained analogou~ly uaing 2-thlenylmethyl
chloride is 2-butyl-3-p-methoxycarbonylbenzyl-5-(2-
thienylmethyl)-DOI.
Obtained analogously using methyl ~-bromo-~-
lS cyclohexylacetate i9 2-butyl-5-(~-cyclohexyl-~-methoxy-
carbonylmethyl)-3-p-methoxycarbonylbenzyl-DOI, ~f. 063.
Obtained analogously u~ing methyl ~-bromo-~-
phenylacetate iB 2-butyl-3-p-methoxycarbonylbenzyl-5-~-
methoxycarbonylbenzyl-DOI, ~f 0.47 (ethyl acetate/hexane
9~
Obtained analogously u~ing methyl 2-bromo-3-
phenylpropionate i9 2-butyl-3-p-methoxycarbonylbenzyl 5-
(1-methoxycarbonyl-2-phenylethyl)-DOI, Rf 0~64.
Obtained analogously from 3-p-methoxycarbonyl-
benzyl-2-propyl-DOI are the following 3-p-methoxycar-
bonylbenzyl-2-propyl-DOI;
5-Benzyl-
S-p-Nitrobenzyl-
5-(3!3-Dimethyl-2-oxo~butyl)-.
Obtained analogou~ly from 2-butyl-3-p-cyano-
benzyl-DOI u~ing methyl 4'-bromomethylbiphenyl-2-car-
boxylate i9 2-butyl-3-p-cyanobenzyl-5-(2'-methoxy-
carbonylbiphenylyl-4-methyl)-DOI, m.p. 65.
Obtained analogously from 2-butyl-3-p-cyano-
benzyl-DOI u~ing chloroacetonitrile i~ 2-butyl-3-p-
cyanobenzyl-5-cyanomethyl-DOI, m.p. 197.
~32~
- 17 -
Example 4
3 g of 2-butyl-4,5-dihydro-4-oxo-l(or 3)H-
imidazo[4,5-c~pyridine are di~olved in 75 ml of ~ethanol
and, while stirring at 20, a solution of 0.4 g of Na in
10 ml of methanol i8 added dropwise. The mixture i8
~tirred for 45 min and then evaporated, the residue i~
di~olved in 30 ml of DMF and cooled to 0, and, at thi~
temperature, a solution of 3.7 g of p-nitrobenzyl bromide
i~ added, and the mixture is ~tirred at 20 for 16 h.
Evaporation and conventional working-up re~ult~, after
chromatography (silica gel; ethyl acetate/toluene 7:3),
first in 2-butyl-3,5-bi~-p-nitrobenzyl-DOI (m.p~ 142-
143) and then 2-butyl-3-p nitrobenzyl-DOI (m.p. 193-
194)
Example 5
1 g of 2-butyl-3-p-methoxycarbonylbenzyl-5-p-
nitrobenzyl-DOI iq di~olved in 50 ml of methanol and
hydrogenated on 0.5 g of Pd-c (5~) at 20 and under 1 bar
until the H2 uptake cea~e~, and the mixture i~ filt~red
and, after evaporation and chromatography on silica gel
(ethyl acetate/methanol 9:1), re~ults in 5-p-aminobenzyl-
2-butyl-3-p-methoxycarbonylbenzyl-DOI, m.p. 59-60.
Example 6
A mixture of 1 g of 2~utyl-3-p-methoxycarbonyl-
benzyl-5-p-nitrobenzyl DOI, 20 ml of 1 N ~odium hydroxide
solution, 6 ml of methanol and 18 ml of T~F i8 ~tirred ~t
20 for 16 h and is acidified with hydrochlori~ acid, and
con~entlonal workîng-up result~ in 2-butyl-3-p-carboxy-
benzyl-5-p-nitrobenzyl-DOI, m.p. 170.
The follo~ing DOI are obtained analogously by
hydroly~is of the corre~ponding methyl e~ters-
5-p-~ninobenzyl-2-butyl-3-p-carboxybenzyl-, m.p. 130
2-Butyl-3-p-carboxybenzyl-, m.p. 249
2-Butyl-3,5-bi~-p-carboxybenzyl, m.p. 150
3-p-Carboxybenzyl-2-propyl-, m.p. 2~9
3,5-Bis-p-c~rboxybenzyl-2-propyl-, m.,p. 209
5-Benzyl-3-p-carboxybenzyl-2-butyl-, m.p. 212, K salt,
m.p. ~ 300
- 18 -
3-p-Carboxybenzyl~5-p-nitrobenzyl-2-propyl-, m.p. 300
2-~utyl-3-p-carboxybenzyl-5-t2-thienylmethyl)-,m.p.201
3-p-Carboxybenzyl-5-(3,3-dimethyl-2-oxo-butyl)-2-propyl-,
m.p. 195
2-Butyl-3-p-carboxybenzyl~5-~-carboxy-u-cyclohexyl-
methyl-, m.p. 195
2-Butyl-3-p-carboxybenzyl-5-~-carboxybenzyl-,
se~quihydrate, m.p. 234
2-Butyl-3-p-carboxybenzyl-5-(1-carboxy-2-phenyl-ethyl)-,
10 m.p. 253.
Example 7
~eaction of 2-butyl-3-p-cyanobenzyl-5-(2'-
methoxycarbonylbiphenyl-4-methyl)-DOI in analogy to
Example 6 with ~odiu~ hydro~ide ~olution/methanol/T~F
15 re3ult~ in 2-butyl-3-p-carbamoylbenzyl-5-(2'-carboxy-
biphenylyl-4-methyl)-DOI~ m.p. 241, a~ main product.
Example 8
a) A mixture of 4.21 g of 2-butyl-3,5-bis-p-cyano-
benzyl-DOI, 41.2 g of trimethyltin azide and 300 ml
of toluene ~ 8 boiled for 72 h and evaporated. The
residue i~ ~tirred with 100 ml o~ methanolic
hydrochloric acid at 20 for 2 h, and conventional
working-up ~aturated NaCl solution/dichloromethane)
re~ult~ in 2-butyl-3,5-bii-~p~ 5-tetrazolyl)-
benzyl]-DOI, m.p. 272.
Obtained analogouily from 2-butyl-3-p-cyanobenzyl-
DOI i~ 2-butyl-3-[p~ 5-tetrazolyl)b~nzyl]-DOI.
Obtained analogously fro~ 2-butyl-3-p-cyanobenzyl-
5-(2'-methoxycarbonylbiphenylyl-4-methyl)-DQI i~
2-butyl-5-(2'-methoxycarbonylbiphenylyl-4-methyl)-
3-[p-(1~-5-tetrazolyl)benzyl]-DOI, m.p. 154.
Obtained analogou~ly from 2-~utyl-3-p-cyanobenzyl-
5-cyanomethyl-DOI i3 2-butyl-~-[p-(1~-5-tetrazolyl)-
benzyl]-5-(1~-5-tetra201yl~ethyl)-DOI, m.p. 276
(decompo~ition~.
2~3~
- 19
The following Examples relate to pharmaceutical
formulations containi.ng active ingredient~ of formula I
or their salts.
E mple A: TabletR and coated kablet~
Tablet~ of the following composition are produced
by compres~ion in conventional manner and, where
required~ are provided with a conventional 3ucro~e-based
coating:
Active ingredient o~ formula I 100 mg
10 Microcrystalline cellulose278.8 mg
Lactose 110 mg
Maize ~tarch 11 mg
Magne~ium ~tearate 5 mg
Finely divided silicon dioxide 0.2 mg
Example B: Hard gelatin capsules
Conven-tional two-piece haxd gelatin capsules are
each filled with
Active ingredient of formula I 100 mg
Lactose 150 mg
20 Cellulose 50 mg
Magnes1um stearate 6 mg
Example C: Soft gelatin cap~ules
Conventional soft gelatin cap~ule~ are filled
with a mixture of 50 mg of active ingredient and 250 mg
of olive oil in each case.
Example D: Ampoules
A solution of 200 g of active ingredient in 2 kg
of 1,2-propanediol is made up to 10 1 with water and
filled into ampoule~ so that each ampoule contains 20 mg
of active ingredient.
~ ~9 3 2 e63i 0
~ ~0 ~
~alllpl.Q_~: Aqlleoul luF~p~ll310n for oral a~miniatratiQn
An aqu~ou~ Huspen~lon i8 prepared in conventional
manner. The Ull.i.t dose (5 ml) cQntains 100 m~ c~f active
i.n~r~cli.~nt, 1001llg o~ aodium ca~boxylnethylcellulos~, 5 I~J
S o~ 1od.~m b~nzoat~ and 100 mg of aorbitol.
