Note: Descriptions are shown in the official language in which they were submitted.
CA 02357771 2001-07-06
Imidazo[4,5-c]pyridin-4-one derivatives
The invention relates to compounds of the formula I
R3
..N
E~''H2)n-R~
0
in which
R is H or unbranched or branched alkyl having 1-6
C atoms or cycloalkyl having 3-6 C atoms,
R1 is Ar,
R2 is Ar' ,
R3 is H, R, R~, H<~l, CN, COOH, CODA or CONH2,
Ar, Ar' are phenyl, naphthyl or biphenyl, in each case
independently or one another unsubstituted or
mono-, di- or trisubstituted by R, OH, Hal, CN,
N02, CF3, NfI2, NHR, NRz, pyrrclidin-1-yl,
piperidin-1-yl, benzyloxy, SOzNH2, SOzNHR,
SO~NRz, -CONHR, -COIJRZ, - ( CHZ ) n-NHz, - ( CH2 ) n-NHR,
- (CHz) n-NR2, -0- (CHZ) n-NH2, -O- (CHz) n-NHR,
-0- (CHz) n-NRz, R° or together by -0- (CHZ) m-0-,
or are NH2-substituted isoquinolinyl,
R9 is -C (=NH) -Nfi~ which is unsubstituted or
monosubstituted by -COR, -COOR, -OH or by a
conventional amino protective group or
-NH-C {=NH) -NH2, -C (=0) -N=C (NHZ) 2,
{'~..~~N' 0 {~ N~O
HN---,~' or N
~CH
0
A is alkyl having 1-9 C atoms,
Hal is F, C1, Br cr I,
m is 1 or 2,
n is 0 or 1,
and their salts and sc>lvates.
CA 02357771 2001-07-06
2
The invention also relates to the optically active
forms, the racemate;s, the diastereomers and the
hydrates and solvates, e.g. a'~coholates, of these
compounds.
The invention is based on the object of finding novel
compounds having useful properties, in particular those
which can be used for the production of medicaments.
It has been found that the compounds of the formula I
and their salts have very useful pharmacological
properties together with good tolerability. In
particular, they show factor Xa-inhibiting properties
and can therefore be employed for the control and
prevention of thromboembolic disorders such as
thrombosis, myocardial infarct, arteriosclerosis,
inflammations, apoplexy, angina pectoris, restenosis
after angioplasty and intermittent. claudication.
The compounds of the formula I according to the
invention ~~an furtherrriare be inhibitors of the clotting
factors factor VIIa, factor IXa and thrombin of the
blood clotting cascade.
Aromatic amidine derivatives having antithrombotic
action are disclosed, for example, in ~P 0 540 051 BI.
Cyclic guanidines for the treatment o~ thromboembolic
disorders are described, for examp'ye, in WO 97/08165.
Aromatic heterocycles having factor Xa-inhibitory
activity are disclosed, for example, in WO 96/10022.
Substituted V-[(aminoiminomethyl)phenylalkyl]-
azaheterocyclylamides as factor' Xa inhibitors are
described in WO 96/40679.
The antithrombotic and anticoaguiating effect of the
compounds according to the invention is attributed to
the inhibiting action against the activated clotting
protease, known under the name factor Xa, or to the
CA 02357771 2001-07-06
- 3 -
inhibition of other activated serine proteases such as
factor VIIa, factor IXa or thrombin.
Factor Xa is one of the proteases which is involved in
the complex process of blood clotting. Factor Xa
catalyses the conversion of prothrombin into thrombin.
Thrombin cleaves fibrinogen into fibrin monomers which,
after crosslinking, contribute elementarily to thrombus
formation. Activation of thrombin can lead to the
occurrence of thromboembolic disorders. Inhibition of
thrombin, however, can ,inhibit the fibrin formation
involved in thrombus formation.
The inhibition of thrombin can be measured, for
example, by the method of G.F. Cousins et al. in
Circulation 199fr, 94, 1705-1712.
Inhibition of factor X:a can thus prevent thrombin being
formed.
The compounds of th;e formula I according to the
invention and their salts intervene in the blood
clotting process by inhibition of factor Xa and thus
inhibit the formation of thrombi.
The inhibition of faci~or Xa by the compounds according
to the invention and the anticoagulating and
antithrombotic activity can be determined by customary
in vitro or in vivo methods. A suitable procedure is
described, for example, by J. Hauptmann et al. in
Thrombosis and Haemostatis 1990, n3, 220-223.
The inhibition of factor Xa can be measured, for
example, by the method of T. Hara et al. in Thromb.
Haemostas. 1994, 71, 31.4-319.
After binding to ti~:sue factor, the clotting factor
VIIa initiates the extrinsic part of the clotting
cascade and contributes to the activation of factor X
to factor Xa. Inhibit.i.on of factor VIIa thus prevents
CA 02357771 2001-07-06
- 4 -
the formation of factor Xa and thus subsequent thrombin
formation.
The inhibition of factor VIIa by the compounds
according to the invention and the anticoagulating and
antithrombotic activity can be determined by customary
in vitro or in vivo ma_thods. A customary procedure for
the measurement of the inhibition of factor VIIa is
described, for examp:Le, by H.F. Ronning et al. in
Thrombosis Research 1996, 84, 73-81.
The clotting factor IXa is generated in the intrinsic
clotting cascade and is likewise involved in the
activation of factor X to factor Xa. Inhibition of
factor IXa can therefcre prevent factor Xa being formed
in another way.
The inhibition of factor IXa by the compounds according
to the invention .and the anticoagulating and
antithrombotic activity can be determined by customary
in vitro or in vivo methods. A suitable procedure is
described, for examplE~, by J. Chang et al. in Journal
of Biological Chemistry 1998, 273, 12089-12094.
The compounds of the: formula I can be employed as
pharmaceutical active compounds in human and veterinary
medicine, in particular for the control and prevention
of thromboembolic disorders ouch as thrombosis,
myocardial infarct, arteriosclerosis, inflammations,
apoplexy, angina pectoris, restenosis after angioplasty
and intermittent claud.ication.
35
The invention relates to the compounds of the formula I
and their salts, and to a process for the preparation
of compounds of the formula I according to Claim 1 and
their salts, characterized in that
a? they are set free from one of their functional
derivatives by treating with a solvolysing or
hydrogenolysing agent, by
CA 02357771 2001-07-06
- 5 -
i) liberating an amidino group from its
oxadiazole derivative or oxazolidinone
derivative by hydrogenol.ysis or solvolysis,
ii) replacing a conventional amino protective
group by hydrogen by treating with a
solvolysing or hydrogenolysing agent or
liberating an amino group protected by a
conventional protective group,
or
b) in a compound of the formula I, one or more
radicals R, R1, RZ and/or R3 are converted into one
or more radicals R, R1, RZ and/or R',
by, for example
i) hydrol_ysing an ester group to a carboxyl group
ii) reducing a vitro group
iii) acylating an amino group
iv) converting a cyano group into an amidino group
and/or
c) a base or acid of the formula I is converted into
one of its salts.
For all radicals which occur a number of times, it is a
condition that their meanings are independent of one
another.
Above and below, the radicals and parameters R, R1, Rz,
R3 and n have the meanings indicated in the formula I,
if not expressly stated otherwise.
CA 02357771 2001-07-06
_ 6 _
R is alkyl, is unbranched (linear) or branched, and has
1 to 6, preferably 1, 2, 3, 4, S or 6, C atoms . R is
preferably methyl, furthermore ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl or tert -butyl, in
addition also pentyl, 1-, 2- or 3-methylbutyl, 1,1-,
1,2- or 2,2-dimethy.lpropyl, 1-ethylpropyl, hexyl, 1-,
2-, 3- or 4-methylpent=yl, 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, 1,1,2- or 1,2,2-
trimethylpropyl. R is also cycloalkyl and is preferably
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl.
A is alkyl having :':, 2, 3 or 4 C atoms and is
preferably methyl, furthermore ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Hal is preferably F, C1 or Br, but also I.
Ar and Ar' are phenyl, benzodioxol-5-yl, naphthyl or
biphenyl, in each case independently of one another
unsubstituted or mono-, di- or trisubstituted by R, OH,
OR, Hal, CN, NOz, CF3, NH2, NHR, NR2, pyrrolidin-1-yl,
piperidin-1-yl, benzyloxy, SOzNHz, SOzNHA, SOZNR2,
phenylsulfonamido, - (C~HZ) ~-NHz, - (CHZ) n-NHR, - (CHZ) n-NR2,
-0- ( CHZ ) n-NH2, -O- ( CH2 ) n-NHR, -0- ( CHy ) n-NR2, -0- ( CHZ ) m-0-
or Rq, naphthyl or biphenyl monosubstituted by amidino
being preferred. Prej_erred substituents for biphenyl
are amidino, fluorine, SOZNHZ or SOzNHR.
Ar and Ar' are phenyl, naphthyl or biphenyl, in each
case independently of one another preferably
unsubstituted, phenyl, naphthyl or biphenyl,
furthermore preferab3_y, for example, mono-, di- or
trisubstituted by methyl, ethyl, propyl, isopropyl,
butyl, cyclopentyl, cyclohexyl, fluorine, chlorine,
bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy,
butoxy, pentyloxy, hexyloxy, cyano, nitro,
trifluoromethyl, amino, methylamino, ethylamino,
CA 02357771 2001-07-06
dimethylamino, di.ethylamino, pyrrolidin-1-yl,
piperidin-L-yl, benzyloxy, sulfonamido,
methylsulfonamido, ethylsulfonamido, propylsulfonamido,
butylsulfonamido, di:methylsulfonamido, phenylsulfon-
amido, aminomethyl, aminoethyl, N-methylaminomethyl, N-
ethylaminomethyl, N,N-dimethylaminomethyl, amino-
methyloxy, am.inoethyLoxy or Rq and in addition
benzodioxolyl.
Ar and Ar' are therefore, in each case independently of
one another, very particularly preferably, for example,
o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or
p-propylphenyl, o-, m~- or p-isopropylphenyl, o-, m- or
p-tert-butylphenyl, ow, m- or p-hydroxyphenyl, o-, m-
or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-
(N-methylamino)phenyl, o-, m- or p-(N-methylamino-
carbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- or
p-methoxyphenyl, o-, ~~- or p-ethoxyphenyl, o-, m- or p-
(N,N-dimethylamino)phenyl, o-, m- or p-(N,N-
dimethylaminocarbonyl)phenyl, o-, m- or p-(N-
ethylamino}phenyl, o-, m- or p-(N,N-
diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-
or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or
p-(methylsulfonamido)phenyl, o-, m- or p-amidinophenyl,
7-amidino-2-naphthyl, 2'-amidinobiphenyl-3-yl, 3-
fluoro-2'-sulfamoylbiphenyl-4-yl, 3-fluoro-2'-N-tert-
butylsulfamoylbiphenyl.-4-yl, 2'-sulfamoylbiphenyl-4-yl,
2'-N-tert-butylsulfamoylbiphenyl-4-yl, o-, m- or p-
(pyrrolidin-1-yl)phenyl, o-, m- or p-(piperidin-1-
yl)phenyl, o-, m- ~~r p-(5-methyl(1,2,4]axadiazol-3-
yl)}phenyl, 7-{5-methyl[1,2,9]oxadiazol-3-yl)}naphth-2-
yl, o-, m- or p-(5-oxo[1,2,4]oxadiazol-3-yl)}phenyl, 7-
(5-oxo[1,2,4]oxadiazol_-3-yl))naphth-2-yl, furthermore
preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-
difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-
dichlorophenyl, 2,3-, 2,4-, 2,5--, 2,6-, 3,4- or 3,5-
dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-
dimethoxyphenyl, 3-vitro-4-chlorophenyl, 3-amino-4-
chloro-, 2-amino-3-ch.loro-, 2-amino-4-chloro-, 2-amino-
CA 02357771 2001-07-06
-
5-chloro- or 2-amino-6-chlorophenyl, 2-vitro-4-N,N-
dimethylamino- or 3--vitro-4-N,N-dimethylaminophenyl,
2,3-diaminophenyl, 2,3,9-, 2,3,5-, 2,3,6-, 2,4,6- or
3,4,5-trichlorophenyl, 2,9,6-trimethoxyphenyl, 2-
hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-
4-aminophenyl, 4-flu.oro-3-chlorophenyl, 2-fluoro-4-
bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-
methoxyphenyl, 3-chlo:ro-6-methoxyphenyl, 3-chloro-4-
acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-
methylphenyl, 3-chloi:o-4-acetamidophenyl or 2,5-
dimethyl-4-chlorophenyl.
20
R3 is preferably, for example, H, Hal, COON, CODA or
CONHZ .
R4 is preferably, for example, unsubstituted
-C (=NH) -NH2, -NH-C (=NH) -NHZ, -C (=O) -N=C (NHZ) 2, which can
also be monosubstituted by OH,
i
1 \ N.O ~~N.O
HN--~ or N~'CH
O a
very particularly preferably unsubstituted or OH-
substituted -C(=NH)-NH2 or
{'~ N' O
N=
CHa
m is 1 or 2.
n is preferably 0 or 1.
R3 R5
N~n. R I N~R
R2~ N N (CH2)~ R' i s R2~ N
O O (CHz)~ R'
CA 02357771 2001-07-06
_ g _
(~ Hz~~ R,
N
or RZ~N N (IB).
0
The compounds of the formula I can have one or more
chiral centres and therefore occur in various
stereoisomeric forms. mhe formula I includes all these
forms.
Accordingly, the invention relates in particular
to
those compounds
of thE: formula
I in which at
least one
of the radicals mentioned has one of the preferred
meanings indicat ed above. Some preferred groups
of
10compounds can exprE:ssed by the following subformulae
be
Ia to Ii, which correspond to the formula I and
in
which the radicals
no,. designated
in greater detail
have the meaning indicated in the formula I, but
in
which
in Ia Ar is phenyl, naphthyl or biphenyl
which
is monosubstituted by R9;
in Ib Ar' is phenyl, napht=hyl or biphenyl
which
is monosubstituted by SO2NH2 or
R4;
20in Ic Ar, Ar' are phenyl, naphthyl or biphenyl,
in
each case independently of one another
monosubstituted by S02NH2 or R4;
in Id Ar, Ar' are phenyl, naphthyl or biphenyl,
in
each case independently of one another
monosubstituted by -CONR2, SOZNH2
or
R9;
in Ie R3 is H, R, Hal, COUH or COOA;
in If R4 is SOzNH2 or -C (=NH) -NHz or
~'~ N, O
N=
CH3
Y
CA 02357771 2001-07-06
in Ig R is unbranched or branched alkyl having
1-6 C atoms or cycloalkyl having 3-6 C
atoms,
R1 is A:r,
5 RZ is A:r'
R3 is H,, R, Hal, COOH or COOA,
Ar, Ar' are phenyl, naphthyl or biphenyl, in
each case independently of one another
monoaubstituted by -CONR2, SOzNH2 or
10 R4 ,
R4 is -C (=NH) -NHz or
~.~N,
O
N~ ,
GH3
A is a:Lkyl having 1-4 C atoms,
Ha1 is F, C1, Br or I,
m is 1 or 2,
n is 0 or
in Ih R is H or unbranched or branched alkyl
having 1-6 C atoms or cycloalkyl
having 3-6 C atoms,
R1 is A.r,
Rz i s A.r ' ,
R3 is H, R, Hal, COOH or CODA,
Ar, Ar' are phenyl, naphthyl or biphenyl, in
each case independently of one another
monosubstituted by SOZNHZ or R",
Rq is -~~ (=NH) -NHZ or
~.~N.o
N -=~ ,
CHI
A is alkyl having 1-4 C atoms,
Hal is F, C1, Br or I,
m is 1 or 2,
n is 0 or l;
in Ii R is Fi or unbranched or branched alkyl
having 1-6 C atoms or cycloalkyl
having 3-6 C atoms,
CA 02357771 2001-07-06
- 11 -
R1 is A:r,
Rz is A.r' ,
R3 is H, R, Hal, COOH or COOA,
Ar, Ar' are phenyl, naphthyl or biphenyl, in
each case independently of one another
monosubstituted by SOzNHR or R°,
or a.re NHZ-substituted isoquinolinyl,
R° is unsubstituted or OH-substituted
-C (=1VH) -NHZ or
~_~N.o
N -_~ ,
CH3
A is alkyl having 1-9 C atoms,
Hal is E, Cl, Br or I,
m is 1 or 2,
n is 0 or 1.
The compounds of the formula I and also the starting
substances for their preparation are otherwise prepared
by methods known per se, such as are described in the
literature (e. g. in the standard works such as Houben-
Weyl, Methoden der organischen Chemie [Methods of
Organic Chemistry], ~eorg-Thieme-Verlag, Stuttgart),
namely under reaction conditions which are known and
suitable for the reacaions mentioned. Use can also be
made in this case of variants which are known per se,
but not mentioned here in greater detail.
The starting substances can, if desired, also be formed
in situ, such that they are not isolated from the
reaction mixture, but immediately reacted further to
give the compounds of the formula I.
Compounds of the forrnula I can preferably be obtained
by setting compounds of the formula I free from one of
their functional dE:rivatives by treating with a
solvolysing or hydrogf~nolysing agent.
CA 02357771 2001-07-06
- 12 -
Preferred starting ~;ubstances for the solvolysis or
hydrogenolysis are those which otherwise correspond to
the formula I, but instead of one or more free amino
and/or hydroxyl groups contain corresponding protected
amino and/or hydroxy: groups, preferably those which,
instead of an H atom which is bonded to an N atom,
carry an amino protective group, in particular those
which, instead of an HN group, carry an R'-N group in
which R' is an amino protective group, and/or those
which, instead of the H atom of a hydroxyl group, carry
a hydroxyl protective group, e.g. those which
correspond to the formula I, but instead of a group
-COON carry a group --COOR", in which R" is a hydroxyl
protective group.
Preferred starting substances are also the oxadiazole
derivatives, which can be converted into the
corresponding amidino compounds.
The amidino group can be liberated from its oxadiazole
derivative, fo:r example, by treating with hydrogen in
the presence of a catalyst (e. g. Raney nickel).
Suitable solvents are those indicated below, in
particular alcohols such as methanol or ethanol,
organic acids such as acetic acid or propionic acid, or
mixtures thereof. As a rule, the hydrogenolysis is
carried out at temperatures between approximately 0 and
100° and pressures between approximately 1 and 200 bar,
preferably at 20-30° i;room temperature) and 1-10 bar.
The oxadiazole group is introduced, for example, by
reaction of the cyana compounds with hydroxylamine and
reaction with phosgene, dialkyl carbonate, chloroformic
acid esters, N,N'-carbonyldiimidazole or acetic
anhydride.
A number of - identical or different - protected amino
and/or hydroxyl groups can also be present in the
molecule of the start:::ng substance. If the protective
CA 02357771 2001-07-06
- 13 -
groups present are different from one another, in many
cases they can be removed selectively.
The expression "aminc> protective group" is generally
known and relates to groups which are suitable for
protecting (for blocking) an amino group from chemical
reactions, but which are easily removable after the
desired chemical react.i.on has been carried out at other
positions in the mole~z~ule. Typical groups of this type
are, in particular, unsubstituted or substituted acyl,
aryl, aralkoxymethyl or aralkyl groups. Since the amino
protective groups are removed after the desired
reaction (or reaction sequence), their nature and size
is otherwise not critical; however, those having 1-20,
in particular 1-8, C atoms are preferred. The
expression "acyl group" is to be interpreted in the
widest sense in conneca:ion with the present process. It
includes acyl groups derived from aliphatic,
araliphatic, aromatic or heterocyclic carboxylic acids
or sulphonic acids and, in particular, alkoxycarbonyl,
aryloxycarbonyl and especially aralkoxycarbonyl groups.
Examples of acyl groups of this type are alkanoyl such
as acetyl, propionyl_, butyryl; aralkanoyl such as
phenylacetyl; aroyl such as benzoyl or toluyl;
aryloxyalkanoyl such as POA; a.lkoxycarbonyl such as
methoxycarbonyl, ethoxycarbonyl, 2,2,2-
trichloroethoxycarbonyl., BOC (t.ert-butyloxycarbonyl),
2-iodoethoxycarbonyl; aralkyloxy<;arbonyl such as CBZ
("carbobenzoxy"). 4-methoxybenzyloxycarbonyl, FMOC;
arylsulfonyl such as Mtr. Preferred amino protective
groups are BOC and Mt:r, in addition CBZ, Fmoc, benzyl
and acetyl.
The liberation of the compounds of the formula I from
their functional deri~ratives is carried out - depending
on the protective group used - far example using strong
acids, expediently using TFA or perchloric acid, but
also using other strong inorganic acids such as
hydrochloric acid or sulphuric acid, strong organic
CA 02357771 2001-07-06
- 14 -
carboxylic acids such as trichloroacetic acid or
sulphonic acids such as benzene- or p-toluenesulphonic
acid. The presence o:f an additional inert solvent is
possible, but not always necessary. Suitable inert
solvents are preferabi~y organic, for example carboxylic
acids such as acetic acid, ethers such as
tetrahydrofuran or dioxane, amides such as DMF,
halogenated hydrocarbons such as dichloromethane, in
addition also alcoho:Ls such as methanol, ethanol or
isopropanol, and also water. Mixtures of the
abovementioned solvenvs are additionally suitable. TFA
is preferably used in an excess without addition of a
further solvent, perchloric acid in the form of a
mixture of acetic acid and 70~ perchloric acid in the
ratio 9:1. The reaction temperatures for the cleavage
are expediently between approximately 0 and
approximately 50°; tr.e reaction is preferably carried
out between 15 and 30'' (room temperature).
The groups BOC, OBut and Mtr can be removed, for
example, preferably using TFA in dichloromethane or
using approximately 3 to 5N HC1 in dioxane at 15-30°;
the FMOC group using a n approximately 5 to 50~ solution
of dimethylamine, diethylamine or piperidine in DMF at
15-30°.
Hydrogenolytically removable protective groups (e. g.
CB2, benzyl) can be removed or the amidino group can be
liberated from its o:xadiazole derivative, for example
by treating with hydrogen in the presence of a catalyst
(e. g. of a noble metal catalyst such as palladium,
expediently on a support such as carbon). Suitable
solvents here are those indicated above, in particular,
for example, alcohols such as methanol or ethanol or
amides such as DMF. As a rule, the hydrogenolysis takes
place at temperatures between approximately 0 and 100°
and pressures between approximately 1 and 200 bar,
preferably at 20-30° and i-10 bar. Hydrogenolysis of
the CBZ group takes place readily, for example, on 5 to
CA 02357771 2001-07-06
- 15 -
10$ Pd/C in methanol or using ammonium formate (instead
of hydrogen) on Pd/C in methanol/DMF at 20-30°.
Suitable inert solvent=s are, for example, hydrocarbons
such as hexane, petroleum ether, benzene, toluene or
xylene; chlorinated hydrocarbons such as trichloro-
ethylene, 1,2-dichloroethane, carbon tetrachloride,
trifluoromethylbenzene, chloroform or dichloromethane;
alcohols such as methanol, ethanol, isopropanol,
n-propanol, n-butanol or tert-butanol; ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran (THF)
or dioxane; glycol ethers such as ethylene glycol
monomethyl or monoethyl ether (methyl glycol or ethyl
glycol), ethylene glycol dimethyl ether (diglyme);
ketones such as acetone or butanone; amides such as
acetamide, dimethylace~t:amide, N-methylpyrrolidone (NMP)
or dimethylformamide (DMF); nitriles such as
acetonitrile; sulphox:ides such as dimethyl sulphoxide
(DMSO); carbon disul~~hide; carboxylic acids such as
formic acid or acetic acid; nitro compounds such as
nitromethane or nitrobenzene; esters such as ethyl
acetate or mixtures of the solvents mentioned.
The biphenyl-S02NHz group is preferably employed in the
form of its tert-buty__ derivative. The tert-butyl group
is removed, for example, using TFA with or without
addition of an inert solvent, preferably with addition
of a small amount of anisole (1~ by volume).
The cyano group is converted into an amidino group by
reaction with, fo=r example, hydroxylamine and
subsequent reduction of the N-hydroxyamidine with
hydrogen in the presence of a catalyst such as, for
example, Pd/C.
For the preparation of an amidine of the formula I
(e. g. Ar - phenyl monosubstituted by C(=NH)-NHZ),
ammonia can also be added to a nitrile. The addition is
preferably carried out in a number of stages in a
manner known per se ~~y a) converting the nitrite using
CA 02357771 2001-07-06
- 16 -
HZS into a thioamide, which is converted using an
alkylating agent, e.g. CH3I, into the corresponding
S-alkyl imidothioester, which for its part is reacted
with NH3 to give the amidine, b) converting the nitrite
into the corresponding imido ester using an alcohol,
e.g. ethanol in the presence
of HC1, and treating this
with ammonia, or c) reacting the nitrite with lithium
bis(trimethylsilyl)amide and then hydrolysing the
product.
The radical R1 (if n==U) or R Z is introduced into
the
dihydroimidazo(4,5-c]pyridin-4-one
system by N-
aryiation (Lit.: Chan et al., Tetrahedron Letters
1998,
39, 2933ff and 2941ff).
Thus it is possible, for example, for preparing
compounds of the formula (IA) to react a compound
of
the formula II
R3
N
HNr \
''N
li
(CHz)~ R,
in which R has the meaning indicated in Claim 1 and R1
and R3 are each a radical of the type which cannot be
alkylated, such as, for example, for R1 a phenyl,
benzyl or
~'''~N~O
naphthyl radical substituted by 1N~
CH3
,
with a compound of the formula II:L
.,,, B(Oli)x
tll
N
CA 02357771 2001-07-06
- 17 -
This gives compounds of the formula IV
\\
i~
_R1 w.
These are then reacted further to give the compounds
according to the invention.
Suitable solvents are those mentioned above. The
reaction is carried out in the presence of , for
example, Cu(II)(OAc)~. Depending on the conditions
used, the reaction tome is between a few minutes and
14 days, and the reaction temperature is between
approximately 0° and 150°, normally between 15° and
80°.
20
Analogously, Rz can also firstly be introduced into the
dihydroimidazole (4,5--c]pyridin-4-one system and then a
compound of the formula (V)
R3
N
.~ N N~ V
R2 ~ 1H
C)
in which R has the meaning indicated in Claim 1 and Rz
and R3 are each a radical of the type which cannot be
alkylated,
can be reacted with a compound of the formula VI
R1- (CHZ) n-L VI
In the compounds of the formula VI, n is 1, R1 is a
radical which cannot be alkylated, such as, for
CA 02357771 2001-07-06
- 18 -
example, a phenyl radical substituted by
5-methyl [ 1, 2, 4 ] oxadiacol-3-yl, and L is C1, Br, I or a
free or reactive functionally modified OH group.
L is preferably C1, Br, I or a reactive modified OH
group, such as, for example, an activated ester, an
imidazolide or alkylsulfonyloxy having 1-6 C atoms
(preferably methylsulfonyloxy) or arylsulfonyloxy
having 6-10 C atoms (preferably phenyl- or
p-tolylsulfonyloxy).
This process gives compounds of the formula (IA) and/or
(IB} .
If compounds cf the formula II in which n is 0 are
reacted with ccmpound~; of the formula VII
~ B(OH)z
VII
r~
Br
compounds of the formula VIII
R3
N
~ N ~ VIII
B / I O Rt
are obtained.
Subsequent reaction of the compounds of the formula
VIII with compounds of the formula IX
B~oH>z
' Ix
~~ SOZNHtBu
gives compounds of the formula X
CA 02357771 2001-07-06
- 19 -
Ra
N
_ v I \~---R
N
0 v
R
I ~ v
x
SOZNHtBu
The compounds of the formula I are subsequently
obtained by cleaving off the tert-butyl group and
conversion of the oxi.diazole radical into an amidino
group.
In addition, it is possible to convert a compound of
the formula I into another compound of the formula I by
converting one or more radicals R, R1, RZ and/or R3 into
one or more radicals R, R1, RZ and/or R3, e.g. by
acylating an amino group or reducing nitro groups (for
example by hydrogenat_Lon on Raney nickel or Pd-carbon
in an inert solvent such as methanol or ethanol) to
amino groups.
Esters can be hydrolysed, for example, using acetic
acid or us_~ng NaOH or KOH in water, water-THF or water-
dioxane at temperatures between 0 and 100°.
In addition, free amino groups can be acylated in a
customary manner using an acid chloride or anhydride or
alkylated using an unsubstituted or substituted alkyl
halide, expediently in an inert solvent such as
dichloromethane or THF and/or in the presence of a base
such as triethylamine or pyridine at temperatures
between -6U and +30°.
A base of the formu~_a I can be converted into the
associated acid addition salt using an acid, for
example by reaction of equivalent amounts of the base
and of the acid in an inert solvent such as ethanol and
subsequent evaporation. Acids suitable for this
CA 02357771 2001-07-06
- 20 -
reaction are in particular those which yield
physiologically acceptable salts. Thus, inorganic acids
can be used, e.g, sulphuric acid, nitric acid,
hydrohalic acids such as hydrochloric acid or
hydrobromic~ acid, phosphoric acids such as
orthophosphoric acid, sulphamic acid, in addition
organic acids, in particular aliphatic, alicyclic,
araliphatic, aromatic or heterocyclic mono- or
polybasic carboxylic, sulphonic or sulphuric acids,
e.g. formic ac;.d, acetic acid, propionic acid, pivalic
acid, diethylacetic acid, malonic acid, succinic acid,
pimelic acid, fumaric acid, malefic acid, lactic acid,
tartaric acid, malic acid, citric acid, gluconic acid,
ascorbic acid, nicot=inic acid, isonicotinic acid,
methane- or ethanesulphonic acid, ethanedisulphonic
acid, 2-hydroxyethanesulphonic acid, benzenesulphonic
acid, p-toluenesulphonic acid, naphthalenemono- and
-disulphon~c acids, and laurylsulphonic acid. Salts
with physiologically unacceptable <scids, e.g. picrates,
can be used for the isolation and/or purification of
the compounds of the formula I.
On the other hand, compounds of the formula I can be
converted into the corresponding metal salts, in
particular alkali metal. or alkaline earth metal salts,
or into the corresponding ammonium salts using bases
(e. g. sodium or potassium hydroxide or carbonate).
Physiologically acceptable organic bases, e.g.
ethanolamine can also ;oe used.
Compounds of the formula I according to the invention
can be chiral on account of their molecular structure
and can accordingly occur in various enantiomeric
forms. They car. there:Eore be present in racemic or in
optically active form.
Since the pharmaceutical activity of the racemates or
of the stereoisomers of the compounds according to the
invention can differ, it can be desirable to use the
CA 02357771 2001-07-06
- 21 -
enantiomers. In these cases, the final product or else
even the intermediates can be separated into
enantiomeric compounds by chemical or physical measures
known to the person skilled in the art, or even
employed as such in the synthesis.
In the case of racemic amines, diastereomers are formed
from the mixture by reaction with an optically active
resolving agent. Suitable resolving agents are, for
example, optically active acids, such as the R and S
forms of tartaric acid, diacetyltartaric acid,
dibenzoyltartaric acid, mandelic acid, malic acid,
lactic acid, suitably N-protected amino acids (e. g.
N-benzoylproline or N-benzenesulfonylproline) or the
various optically active camphorsulphonic acids.
Chromatographic resolution of enantiomers with the aid
of an optically <~ctive resolving agent (e. g.
dinitrobenzoylphenylgl:ycine, cellulose triacetate or
other derivatives of carbohydrates or chiral
derivatized methacrylate polymers attached to silica
gel? is also advantageous. Suitable eluents for this
are aqueous or alcoholic solvent mixtures such as, for
example, hexane/isopropanol/acetonitrile, e.g. in the
ratio 82:15:3.
The invention further relates to the use of the
compounds of the formula ~ and/or their physiologically
acceptable salts for the production of pharmaceutical
preparations, in particular in a non-chemica-.~ manner.
In this connection, they can be brought into a suitable
dose form together with at least one solid, liquid
and/or semi-liquid excipient or auxiliary and, if
appropriate, in combination with one or more other
active compounds.
The invention further relates to pharmaceutical
preparations comprising at least one compound of the
formula I and/or one of its physiologically acceptable
salts.
CA 02357771 2001-07-06
- 22 -
These preparations can be used as medicaments in human
or veterinary medicine. Possible excipients are organic
or inorganic substances which are suitable for enteral
(e. g. oral) or parenteral administration or topical
application and do not react with the novel compounds,
for example water, vegetable oils, benzyl alcohols,
alkylene glycols, polyethylene glycols, glycerol
triacetate, gelatin, carbohydrates such as lactose or
starch, magnesium stearate, talr_, petroleum jelly.
Tablets, pills, sugar-coated tablets, capsules,
powders, granules, syrups, juices or drops, in
particular, are used for oral administration,
suppositories are used for rectal administration,
solutions, preferably oily or aqueous solutions, in
addition to suspensions, emulsions or implants, are
used for parenteral administraticn, and ointments,
creams or powders are used for topical application. The
novel compounds can also be .Lyophilized and the
lyophilizates obtained used, for example, for the
production of injection preparations. The preparations
indicated can be sterilized and/or can contain
auxiliaries such as lubricants, preservatives,
stabilizers and/or wetting agents, emulsifiers, salts
for affecting the osmotic pressure, buffer substances,
colourants, flavourings and/or one or more further
active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physio-
logically acceptable salts can be used in the control
and prevention of thromboembolic disorders such as
thrombosis, myocardial infarcts, arteriosclerosis,
inflammations, apoplexy, angina pectoris, restenosis
after angioplasty and intermittent claudication.
In this connection, as a rule the substances according
to the invention are preferably administered in doses
of between approximately 1 and 500 mg, in particular
between 5 and 100 mg, per dose unit . The daily dose is
CA 02357771 2001-07-06
- 23 -
preferably between approximately 0.02 and 10 mg/kg of
bodyweight. The specific dose for each patient depends
on all sorts of factors, however, for example on the
efficacy of the specific compound employed, on the age,
bodyweight, general state of health, sex, on the diet,
on the time and route of administration, and on the
excretion rate, pharmaceutical combination and severity
of the particular disorder to which the therapy
applies. Oral administration is preferred.
Above and below, all temperatures are indicated in °C.
In the following examples, "customary working up"
means: water is added, if necessary, the mixture is
adjusted, if necessary, depending on the constitution
of the final product, to a pH of between 2 and 10 and
extracted with ethyl acetate or dichloromethane, the
extract is separated off, the organic phase is dried
over sodium sulfate ar;d evaporated, and c.he residue is
purified by chromatocxraphy on silica gel and/or by
crystallization. RE va:Lues on silica gel; eluent: ethyl
acetate/methanol 9:1.
Mass spectrometry (MS): EI (el.ectron impact
ionization) M+
FAB (fast atom bombardment)
(M+H);
Example 1
140 ml of isobutyrir_ acid and 250 ml of fuming
hydrochloric acid are added to 50.0 g of 3,4-diamino-2-
chloropyridine. The reaction mixture is heated under
reflux for 7 days. If. is poured into ice water, the
deposited precipitate is separated off and 2-isopropyl-
3,5-dihydroimidazo(4,5-c]pyridin-4-one ("AB"), m.p.
310-311° (decomposition), EI 177 i.s obtained
CA 02357771 2001-07-06
- 24 -
N
HN
H "AB" .
O
A mixture of "AB'° and 9-chloro-2-isopropyl-3H-
imidazo[4,5-c]pyridine is found in the mother liquor.
A solution of 0.877 g of "AB" and 0.691 g of potassium
carbonate in 30 ml of DMF is stirred at room
temperature for 30 minutes. 1.5 g of 3-(3-bromo-
methylphenyl)-5-methyl[1,2,4]oxadiazole are added and
the mixture is stirred for 16 hours and worked up in
the customary manner. After chromatography over silica
gel, in addition to the two regioisomeric dialkylation
products, the compound 2-isopropyl-3-[3-(5-
methyl[1,2,4]oxadiazol-3-yl)benzyl]-5H-imidazo[4,5-c]-
pyridin-4-one ("CA") is ob=ained
"CA" ,
H 0
An alternative process leads to "CA" as follows
(analogously to Mederski et al., J. Med. Chem. 1994,
1632 ff):
reaction of 3,4-diamino-2-chloropyridine with
isobutyric anhydride to give N-(4-amino-2-chloro-
pyridin-3-yl)isobutyrami<ie. The subsequent reaction
with 3-(3-bromomethy:1.phenyl)-5-methyl[1,2,4]oxadiazole
leads to a mixture of 9-chloro-2-isopropyl-
3-[3-(S-methyl[1,2,4]oxadiazol-3-yl)benzyl]-3H-
imidazo[9,5-c]pyridine and N-(4-amino-2-chloropyridin-
3-yl)-N -[3-(5-methyl[1,2,4]oxadiazol-3-yl)benzyl]-
isobutyramide. Both compounds are reacted to give "CA".
CA 02357771 2001-07-06
- 25 -
A solution of 0.4 g of "CA" in 10 ml of DMF is mixed
with 0.5 g of the compound of the formula III, 258 mg
of Cu(II)(OAc)2 in 5U ml of dichloromethane and 1 g of
molecular sieve (0.4 nm), and the mixture is stirred at
room temperature for 4 days.
The molecular sieve is removed, and customary work-up
gives the compound
2-isopropyl-3-((5-methyl[1,2,4]oxadiazol-3-yl)-
benzyl]-5-(3-cyanophenyl)-3,5-dihydroimidazo--
[4,5-c]pyridin-4-one ("'BC1"), 345 mg, m.p. 168°, EI 450
N
i
l ~ N ~ I
N
D N,~
N.
"8C 1 ".
330 mg of BC1 are suspended in 20 ml of ethanol, and
490 mg of sodium bicarbonate and 407 mg of
hydroxylammonium chloride are then added successively.
After further addition of 2 ml of water, the mixture is
boiled under reflux for 5 hours. 50 ml of ice-water are
added, and customary work-up gives 280 mg of
2-isopropyl-3-((5-methyl[1,2,4]oxadiazol-3-yl)benzyl]-
5-(3-N-hydroxyamidinophenyl)-3,5-dihydroimidazo-
[ 4, 5-c] pyridin-4-one (" BC2" ) , EI 4 B 3 .
Analogously, the compound 2-isopropyl-3-(7-cyanonaphth-
2-ylmethyl)-5H-imidazo[4,5-c]-pyridin-4-one is obtained
by reacting the compound "AB" with 2-bromomethyl-7-
cyanonaphthalene, followed by work-up. Analogous
reaction with the compound of the formula III as
described above gives the compound 2-isopropyl-3-(7-
cyanonaphth-2-ylmethy:L)-5-(3-cyanophenyl)-3,5-dihydro-
imidazo[4,5-c]pyridin-4-cne, EI: (M'] 443 (74~), 166
( 1000 .
CA 02357771 2001-07-06
- 26 -
Subsequent reaction with hydroxy:Lammonium chloride
gives 2-isopropyl-3-(7-N-hydroxyamidinonaphth-2-
ylmethy~)-5-(3-N-hydroxyamidinophenyl)-3,5-
dihydroimidazo[4,5-c]pyridin-9-one, EI: [M+] 509 (8$),
166 (1000 .
Example 2
A solution of 0.27 g of "BC2" in 2C ml of methanol is
admixed with 100 mg of Raney nickel and a drop of
acetic acid, and the mixture is hydrogenated at room
temperature for B hours. The catalyst is filtered off
and the solvent is removed, giving the compound
2-isopropyl-3-(3-amidinobenzyl)-
5-(3-amidinophenyl)-3,'.p-dihydroimidazo[9,5-c]pyridin-
4-one, FAB 428.
The compounds 2-65 o.f the formula IA listed in Table 1
are obtained analogously to Examples 1 and/or 2
R~
N
y ~ \~
IA
0 (CHZ)n'R1
Table 1
No. R R1 R' R3 :z m.p. EI (FAB)
2 H (1) (1) H 1 119-120
3 Me (1) (1) H 1
4 Et (1) (1) H 1
5 t-Bu (1) (1) F3 1 >300
6 H (1) (1) H 0
7 Me (1) (1) H 0
8 Et (1) (1) H 0
9 i-Pr (1) (1) H 0
10 t-Bu (1) (1) H 0
CA 02357771 2001-07-06
- 27 -
I
No. R R1 R' ~ R3 n m. ET (FAB)
11 H (1) (2) H 0
'
12 Me (1) (2) H 0
13 Et (1) (2) H 0
14 i-Pr (1) (2) H 0
15 t-Bu (1) (2) H 0
16 H {1) (2) H 1 149-150
i
17 Me (1~ (2) 1
H
18 Et (1) (2) H 1
19 i-Pr (1) ~ (2) H 1
~
20 t-Bu !1) (2) H 1
21 H (3) ~~, H 1 (M+H] 437 (2$)
(1) 131 (100$)
22 Me (3) (1) H 1
23 Et (3) (1) H 1 [M+H) 464 (8$)
91 ( 100
0
24 i-Pr (3) (1) H 1 _
[M+H] 478
131 (100$)
25 t-Bu (3) (i) H 1
m
26 H (1) {4) H 0
27 Me (1) (4) H 0
28 Et (1) {4) H 0
29 i-Pr (1) (4) H 0
30 t-Bu (1) (4) H 0 '
31 H (1) (4) H 1
32 Me (1) (4) H 1
33 Et (1) (4) H 1
39 i-Pr (1) (4) t! 1
35 t-Bu (1) (4) H 1
~
i a
36 H (1) (5) H 0
~
37 Me (1) (5) ~ 0
H
38 Et {1) (5) H 0
39 i-Pr (1) (5) H 0
CA 02357771 2001-07-06
- 28 -
No. R R1 R' R'' n m~-- EI (FAB)
40 t-Bu (1) (5) H D
41 H (1) (5) H 1
42 Me (1) (5) H 1
43 Et (1) (5) _H 1
44 i-Pr (1) (5) H 1
45 t-Bu (1) (5) H 1
46 H (3) (2) H 1
47 Me (3) (2) H 1
48 Et (3) (2) H 1
49 i-Pr (3) (2) H 1
50 t-Bu (3) (2) H 1
51a iso- (10) (9) H 1 [M+H) 514 (16$)
Bu 223 (1000
51b iso- (10) t16) H 1 [M+H] 548 (38$)
gu 166 (100$)
51c iso- (3) (1) H 1. 249
Bu
1
52 i-Pr (6) (7) 1 186' [M+H] 560 (52~)
'' 924 1100$)
H
53 Bu (1) (1) H 1 214-2;5
~
54 Bu (61 (8) H 1 220-221
55 Bu (9) (9) H 1 166-167 I
56 Bu (3) (1) H. 1 244-295
~
57 Bu (10) ~ 1 1 169-170
(8) H
58 Bu (1) H: 1 126 [M+H] 555 (94~)
(4) (decom 91 (100$)
.)
59 Bu (6) tll) ~H. 1 175
60 Pe (1) ~ 1 191
(1)
~~
61 Bu (12) t8) ~ 1 18'7;188
fi
62 Bu (13) (8) H 1 120-121
63 Bu (13) (1) H ~1 13'7-138
64 (14) (15) (1) H 1 88--89
65 Pe (15) (1) Fi ~ 145
CA 02357771 2001-07-06
- 29 -
(1) - 3-amidinophenyl; (2) - 2-aminosulfonylphenyl;
(3) = 7-amidinonaphth-2-yl;
(4) - ~ ~ ~ ~ /
842NH~
(5) _ ~ / ~ '~ /
(6) HN '
NHz
(6) - 3-[(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl;
(7) - 2-(N-tert-butylaminosulphonyl)phenyl;
(8) - 3-aminocarbonylphenyl;
(9) - 3-cyanophenyl;
(10) - 7-[(5-methyl-[1,2,4]-oxadiazol-3-yl)naphth-2-yl;
(11) - 4-bromophenyl;
(12) - 3-(N-tert-butylaminosulphonyl)phenyl;
(13) - 3-aminosulphonylphenyl;
(14) - cyclopentylmethyl;
(15) - 1-aminoisoquinolin-7-yl;
(16) - 3-N-hydroxyamidinophenyl;
Me - methyl; Et - ethyl; i-Pr - isopropyl; Bu
n-butyl; t-Bu - tert-butyl; iso-Bu - isobutyl; Pe
Pentyl
The examples be'~ow relate to pharmaceutical
preparations:
Example A: Injection vials
A solution of 100 g of an active compound of the
formula I and 5 g of disodium hydrogen phosphate is
adjusted to pH 6.5 in 3 1 of double-distilled water
CA 02357771 2001-07-06
- 30 -
using 2N hydrochloric acid, sterile-filtered, dispensed
into injection vials, lyophilized under sterile
conditions and aseptically sealed. Each injection vial
contains 5 mg of active compound.
Exampl~ B: Suppositories
A mixture of 20 g of an active compound of the formula
I is fused with 100 g of Soya lecithin and 1400 g of
cocoa butter, poured into moulds and allowed to cool.
Each suppository contains 20 mg of active compound.
Example C: Solution
A solution of 1 g of an active compound of the formula
I, 9. 38 g of NaHzPOa ~ 2 H20, 28 . 48 g of Na2HP0q ~ 12 HZO and
0.1 g of benzalconium chloride in 940 ml of double-
distilled water is prepared. It is adjusted to pH 6.8,
made up to 1 1 and sterilized by irradiation. This
solution can be used in the form of eye drops.
Example D: Ointment
500 mg of active compound of the formula I are mixed
with 99.5 g of petroleum jelly under aseptic
conditions.
Example E: Tablets
A mixture of 1 kg of active compound of the formula I,
4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of
talc and 0.1 kg of magnesium stearate is compressed in
a customary manner to give tablets, such that each
tablet contains 10 mg of active compound.
CA 02357771 2001-07-06
- 31 -
Example F: Sugar-coated tablets
Analogously to Example E, tablets are pressed and are
then coated in a cusr_omary manner using a coating of
sucrose, potato starch" talc, tragacanth and colorant.
Example G: Capaulea~
2 kg of active compound of the formula I are dispensed
into hard gelatin capsules in a customary manner such
that each capsule contains 20 mg of the active
compound.
Example H: Ampoules
A solution of 1 kg of active compound of the formula I
in 60 1 of double-distilled water is sterile-filtered,
dispensed into ampoules, lyopholized under sterile
conditions and aseptically sealed. Each ampoule
contains 10 mg of act.i~ae compound.
