Note: Descriptions are shown in the official language in which they were submitted.
~15~729
Boehringer Mannheim GmbH
3790/OA/
New 4-aminopyridines, processe~ for their production as
well as pharmaceutical agents containing these compounds
The invention concerns new 4-aminopyridines of the
general formula I
R2
Rl ~ R3 (I),
X--C~H2 ~
N -~ N
R4 1 ~
R5
in which
R1 denotes a R6-So-NR7-, R6-So2-NR7-, R6-NR7-So-,
R6-NR7-So2-, R6-SO-O-, R6-SO2-O-, R6-O-SO- or
R6-O-SO2- group,
R2 denotes a hydrogen or halogen atom, a cyano, alkyl,
alkoxy or haloalkyl group,
X denotes an oxygen atom, a sulphur atom or a NH
group,
3 and R4 are the same or different and denote hydrogen
atoms or alkyl groups,
- 2156729
-
-- 2
R5 denotes a hydrogen atom, an alkyl group or an
aralkyl group,
R6 denotes an alkyl, cycloalkyl, aryl, heteroaryl,
aralkyl or heteroarylalkyl group in which the aryl
or heteroaryl residues can be substituted once or
several times by nitro, halogen, nitrile, hydroxy,
carboxy, alkoxycarbonyl, alkenyloxycarbonyl,
alkinyloxycarbonyl, aralkoxycarbonyl, alkyl,
cycloalkyl, alkenyl, alkinyl, cyanoalkyl, alkoxy,
alkenyloxy, alkinyloxy, aralkyloxy, cyanoalkyloxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, amino,
alkylamino, dialkylamino, aralkylamino, di-aralkyl-
amino, alkylsulfonylamino, alkylcarbonylamino,
formylamino, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl or by one or several of the
groups -Y-C02R8, -S-Y-C02R8, -0-Y-C02R8,
-NH-Y-C02R8, -S-Y-CONR8R9, -O-Y-CO-NRaR9 or
-NH-Y-CONR8R9 in which the alkyl, alkenyl or
alkinyl fragments can be substituted once or
several times by halogen, hydroxy, alkoxy, alkyl-
carbonyloxy, amino or carboxy groups,
R7 denotes a hydrogen atom, an alkyl, cycloalkyl,
alkenyl or alkinyl residue wherein these residues
can be substituted once or several times by
halogen, hydroxy, alkoxy, amino, alkylamino,
dialkylamino, carboxy, alkylcarbonyl or alkoxy-
carbonyl, or denote an alkoxycarbonyl, cyanoalkyl,
heteroaryl, aryl, aralkyl or heteroarylalkyl group
in which case the aryl or heteroaryl residue can be
substituted once or several times by halogen,
nitrile, alkyl, alkenyl, alkinyl, trifluoromethyl,
alkoxy, alkenyloxy, alkinyloxy, alkylthio, alkyl-
sulfinyl, alkylsulfonyl, haloalkoxy, trifluoro-
- ~156729
-- 3
methoxy, hydroxy, carboxy, hydroxyalkyl, carboxy-
alkyl, alkoxycarbonyl, amino, alkylamino, dialkyl-
amino, alkylsulfonylamino, alkylcarbonylamino,
formylamino, aminocarbonyl or phenyl, or denotes a
-Y-C02R8 or -Y-CONR8R9 group,
Y denotes a linear or branched alkylene chain,
R8 and R9 are the same or different and denote hydrogen
atoms, aralkyl, cycloalkyl or alkyl groups, which
can be substituted once or several times by
halogen, hydroxy, alkoxy, alkylcarbonyloxy, amine
or carboxy, or R8 and R9 together with the N atom
to which they are bound, form a saturated ring
which can contain an additional oxygen, sulphur or
nitrogen atom,
as well as hydrates, solvates and physiologically
tolerated salts thereof. The invention also concerns the
optically active forms, racemates and mixtures of
diastereomers of these compounds.
In addition the invention also concerns processes for
the production of the above-mentioned compounds,
pharmaceutical agents that contain such compounds as
well as the use of these compounds in the production of
pharmaceutical agents.
The aminopyridines of the general formula I, their
solvates and their salts inhibit thrombin-induced
coagulation of fibrinogen in blood as well as thrombin-
induced aggregation of blood platelets. Thus they
prevent formation of hyaline thrombi and platelet-rich
thrombi and can be used to combat and prevent diseases
-- 21~6729
such as thrombosis, apoplexy, coronary infarction,
inflammations and arteriosclerosis. Furthermore, these
compounds have an effect on tumour cells and prevent
formation of metastases. As a result they can be used as
anti-tumour agents.
Thrombin, the last enzyme of the coagulation cascade,
cleaves fibrinogen to form fibrin which is cross-linked
by factor XIIIa and becomes an insoluble gel which forms
the matrix for a thrombus. Thrombin activates platelet
aggregation by proteolysis of its receptor on the blood
platelets and in this way also contributes to thrombus
formation. When a blood vessel is damaged these
processes are necessary in order to stop bleeding. No
measurable thrombin concentrations are present in blood
plasma under normal circumstances. Increases in the
thrombin concentration can lead to the formation of
thrombi and hence to thromboembolic diseases which occur
very frequently and above all in industrial countries.
Thrombin in plasma is kept ready in the form of
prothrombin and is released from it by factor Xa.
Thrombin activates factors V, VIII and XI by which means
factor X is then converted into factor Xa. By this means
thrombin catalyzes its own release which is why very
rapid increases in thrombin concentrations can occur.
Thrombin inhibitors can therefore inhibit the release of
thrombin, the platelet-induced and plasmatic blood
coagulation.
There is a whole series of serine proteases apart from
thrombin that cleave peptide substrates next to a basic
amino acid. In order to limit side-effects, the thrombin
- 21S6729
inhibitors should be selective i.e. they should inhibit
other serine proteases only slightly or not at all.
Trypsin in particular being the least specific serine
protease, can be easily inhibited by the various
inhibitors. Trypsin inhibition can lead to pancreatic
stimulation and to pancreatic hypertrophy (J.D. Geratz,
Am. J. Physiol. 216, (1969) p.~812).
Plasma contains the protein plasminogen which is
converted into plasmin by activators. Plasmin is a
proteolytic enzyme whose activity is similar to that of
trypsin. It serves to dissolve thrombi by degrading
fibrin. Inhibition of plasmin would thus have the
opposite effect to that which one would like to achieve
by inhibiting thrombin.
/
Synthetic thrombin inhibitors have already been known
for a long time. Substances of the (D)-Phe-Pro-Arg type
were synthesized from fibrinogen the natural substrate
of thrombin. Such tripeptides imitate the amino acid
sequence before the cleavage site on fibrinogen. In
order to obtain good inhibitors the carboxylate group of
the arginine was changed in such a way that the hydroxy
group of serine 195 in the active site of thrombin can
react with it. This can for example be achieved by
replacing the carboxylate group by an aldehyde group.
Corresponding (D)-Phe-Pro-arginals are described in the
Patent Application EP-A 185390.
Benzamidine, a known trypsin inhibitor, was used as the
basis for a second type of thrombin inhibitor. The
inhibitors obtained in this way do not only differ from
the (D)-Phe-Pro-Arg types in their chemical structure
but also in the way they inhibit: serine 195 of thrombin
2156729
does not bind to these inhibitors. This clearly follows
from X-ray examinations of the structure (W. Bode, D.
Turk, J. Sturzebecher, Eur. J. Biochem. 193, 175-182
(1990)). Na-(2-naphthylsulfonylglycyl)-4-amidino-(R,S)-
phenylalanine-piperidide ("NAPAP", DD 235866) belongs to
this second class of thrombin inhibitors.
It was now surprisingly found that compounds of the
general formula I which do not have any structural
features in common with known thrombin inhibitors, are
selective thrombin inhibitors.
The alkyl or alkoxy fragments mentioned in the
definitions of R1 - R9 contain 1-6 carbon atoms wherein
these fragments can be straight-chained or branched. The
same applies to the corresponding alkenyl or alkinyl
fragments. Cycloalkyl groups are rings with three to
seven carbon atoms. In the case of a haloalkyl or
haloalkoxy group, the alkyl or alkoxy group can be
substituted once, twice or three times by halogen. A
trifluoromethyl or trifluoromethoxy group preferably
comes into consideration in the case of groups
substituted three times by halogen. In all cases halogen
denotes fluorine, chlorine, bromine or iodine. Aralkyl
and aralkoxy groups are preferably understood as a
benzyl or benzyloxy group. In those cases in which the
stated groups can be substituted once or several times,
a single, double or triple substitution comes into
particular consideration. In the case of the six-
membered rings in aryl or heteroaryl groups, the
substituents can independently be in the ortho, meta or
para position.
If one of the substituents R2 - R9 in the general
- ~lS6729
formula I denotes an alkyl group, or R6 denotes an aryl
or heteroaryl group substituted by one or several alkyl
groups, then the alkyl groups are to be understood as
straight-chained or branched alkyl groups with 1 to 6
carbon atoms and preferably a methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert.butyl, pentyl and hexyl
group. The halogen atoms as substituents on the alkyl
groups are understood as fluorine, chlorine, bromine or
iodine and preferably fluorine and chlorine. The
trifluoromethyl, chloromethyl, 2-chloroethyl and
3-chloropropyl group are preferred. If the alkyl groups
are substituted by hydroxy groups, then the hydroxy-
methyl, 2-hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxy-
ethyl and 2,3-dihydroxypropyl group are preferred. If
the alkyl groups are substituted by alkoxy groups, then
the methoxymethyl, ethoxymethyl, methoxyethyl and
ethoxyethyl group are preferred. If the alkyl groups are
substituted by amino groups, then the aminomethyl,
2-aminoethyl, 3-aminopropyl, 4-aminobutyl and 5-amino-
pentyl group are preferred. If the alkyl groups are
substituted by carboxy groups, then the carboxymethyl,
l-carboxyethyl, 2-carboxyethyl and 2-methyl-1-carboxy-
ethyl group are particularly preferred.
If R6, R7, R8 or R9 in the general formula I denote a
cycloalkyl group or if R6 denotes an aryl or heteroaryl
group substituted with a cycloalkyl group, then the
cycloalkyl groups are to be understood as rings with 3
to 7 members and preferably a cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl group. In all
cases the cycloalkyl group can also be linked via an
alkyl group so that a cycloalkyl-alkyl group results as
a substituent. In this case a cyclopropylmethyl or
cyclohexylmethyl group are particularly preferred.
- ~156729
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkenyl residue or
if R7 denotes an alkenyl residue, then these are to be
understood as straight-chained or branched residues with
3 to 6 members and preferably an allyl, butenyl or
isobutenyl residue.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkinyl residue or
if R7 denotes an alkinyl residue, then these are to be
understood as straight-chained or branched residues with
3 to 6 members and preferably a propargyl residue.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkoxycarbonyl,
alkenyloxycarbonyl or alkinyloxycarbonyl residue, then
these are to be understood as straight-chained or
branched residues with 2 to 6 carbon atoms and
preferably a methoxycarbonyl, ethoxycarbonyl or
allyloxycarbonyl group.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkoxy residue,
then this is to be understood as a straight-chained or
branched residue with 1 to 6 carbon atoms and preferably
a methoxy, ethoxy, propyloxy, butyloxy or pentyloxy
group. If the alkoxy groups are substituted by hydroxy
groups, then a 2-hydroxyethoxy, 3-hydroxypropyloxy and
2,3-dihydroxypropyloxy group are preferred. If the
alkoxy groups are substituted by alkoxy groups, then a
methoxyethoxy or ethoxyethoxy group is preferred. If the
alkoxy groups are substituted by amino groups, then a
2-aminoethoxy and 3-aminopropyloxy group are preferred.
- 2156729
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkenyloxy residue,
then this is to be understood as a straight-chained or
branched residue with 3 to 6 carbon atoms and preferably
an allyloxy group.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkinyloxy residue,
then this is to be understood as a straight-chained or
branched residue with 1 to 6 carbon atoms and preferably
a propargyloxy group.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted by an alkylthio, alkyl-
sulfinyl or alkylsulfonyl residue, then these are to be
understood as straight-chained or branched residues with
1 to 6 carbon atoms and preferably a methylthio, methyl-
sulfinyl or methylsulfonyl group.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkylamino or
dialkylamino residue, then these are to be understood as
straight-chained or branched residues with 1 to 6 carbon
atoms and preferably a methylamino, dimethylamino or
diethylamino group.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkylsulfonylamino
residue, then this is to be understood as a straight-
chained or branched residue with 1 to 6 carbon atoms and
preferably a methylsulfonylamino group.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkylcarbonylamino
2156729
-- 10 --
residue, then this is to be understood as a straight-
chained or branched residue with 1 to 6 carbon atoms
and preferably an acetylamino group.
If R6 in the general formula I denotes an aryl or
heteroaryl group substituted with an alkylaminocarbonyl
or dialkylaminocarbonyl residue, then these are to be
understood as straight-chained or branched residues
with 1 to 6 carbon atoms and preferably a
methylaminocarbonyl, dimethylaminocarbonyl or
diethylaminocarbonyl group.
The benzyl group is particularly preferred among the
aralkyl groups for R6 and R7.
The aryl residues R6 or R7, either alone or linked to
an alkyl chain, are to be understood as aromatic hydro-
carbons with 6-14 C atoms, in particular a phenyl,
biphenyl, naphthyl, tetrahydronaphthyl, indanyl or
fluorenyl residue.
As heteroaryl radical for R6 are to be understood mono,
bi- and tricyclic aromatics with heteroatoms, such as
nitrogen, oxygen and sulphur, for example furan,
thiophene, pyrrole, oxazole, isoxazole, thiazole,
isothiazole, imidazole, pyrazole, triazole, tetrazole,
pyridine, pyrazine, pyrimidine, pyridazine, triazine,
tetrazine, benzothiophene, dibenzothiophene,
benzimidazole, carbazole, benzofuran, benzofurazane,
benzo-2.1.3-thiadiazole, quinoline, isoquinoline,
quinazoline.
By the alkylene group Y in the general formula I one
understands linear or branched hydrocarbon chains with
1 to 6 carbon atoms, preferably methylene, ethylene or
propylene group.
- ~156729
-- 11 --
If the substituents R8 and R9, together with the
nitrogen atom to which they are attached, form a ring,
then there are to be understood thereunder rings with 4
to 7 members, especially the pyrrolidine, the
piperidine and the homopiperidine ring. If this cycle
contains additional heteroatoms, then thereunder are
preferred the morpholine, thiomorpholine and the
piperazine ring.
The radical R2 on the phenyl ring of the general
formula I can stand in any desired positions to the
fragment X (oxygen atom or NH group). However,
especially preferred is an arrangement in which all
three substituents of the phenyl ring of the general
formula I stand in meta-position to one another.
Rl signifies especially the groups R6-So2-NR7-, R6-NR7-
S02-, R6-S02-0- or R6-0-S02-.
R2 signifies especially a hydrogen, chlorine or bromine
atom or a Cl-C6-alkyl group, such as e.g. a methyl or
ethyl group, or a Cl-C6-alkoxy group, such as e.g. the
methoxy group, or the trifluoromethyl group.
X is especially an oxygen atom or the NH group.
R3 and R4 can be the same or different and preferably
represent hydrogen atoms or Cl-C6-alkyl group,
especially hydrogen atoms or the methyl group.
.,
'~lS6729 -
- 12 -
R5 is in particular a hydrogen atom, a C1-C6 alkyl group
(such as a methyl group) or a benzyl group.
R6 is in particular a C1-C6 alkyl group (such as an
isopropyl group), a C3-C7 cycloalkyl group (such as a
cyclopentyl or cyclohexyl group), a phenyl group
substituted once or several times by fluorine, chlorine,
C1-C6 alkyl (such as e.g. methyl, ethyl, tert.butyl),
C1-C6 alkoxy (such as methoxy), nitro, amino, hydroxy,
carboxy, benzyloxycarbonyl, Cl-C6-alkoxycarbonyl (such
as e.g. methoxycarbonyl), trifluoromethyl or the group
-O-Y-C02R8; a naphthyl, tetrahydronaphthyl, biphenyl or
indanyl group, a thienyl, pyrazolyl or pyridyl group, a
benzthienyl or benzothiadiazinyl group or a benzyl
group.
R7 is in particular a hydrogen atom, a C1-C6 alkyl or
C2-C6 alkenyl group (such as e.g. a methyl, ethyl,
n-propyl, allyl, i-propyl group) or an aralkyl group
(such as e.g. a benzyl group), a C1-C6 alkoxycarbonyl
group (such as e.g. an ethoxycarbonyl group), a
cyanoalkyl group (such as e.g. a cyanomethyl group), a
hydroxyalkyl group (such as e.g. a hydroxyethyl or
dihydroxypropyl group), or an aminoalkyl group (such as
e.g. an aminoethyl group), a -Y-COR8 group or a
-Y-CONR8R9 group.
Y is in particular a methylene, propylene, butylene or
pentylene group.
R8 is in particular a hydrogen atom or an alkyl group
(such as e.g. a methyl or ethyl group), a hydroxyalkyl
group (such as e.g. a hydroxyethyl, hydroxypropyl or
dihydroxypropyl group) or an aminoalkyl group (such as
- 21S6729
- 13 -
e.g. an aminoethyl group).
R9 is in particular a hydrogen atom or an alkyl group
(such as e.g. a methyl group).
Preferred are compounds of the general formula I,
R2
Rl ~ R3
X--C~2 ~=~
(I) 4 N ~ N
R5
in which Rl signifies the groups R6-So2-NR7-, R6-NR7-
S02-, R6-S02-0- or R6-0-S02-, R2 signifies a hydrogen,
chlorine or bromine atom, a methyl, ethyl, methoxy or
the trifluoromethyl group, X signifies an oxygen atom
or the NH group, R3 and R4 are the same or different
and signify hydrogen atoms or methyl groups, R5
signifies a hydrogen atom, a methyl or benzyl group, R6
signifies an isopropyl, cyclopentyl or cyclohexyl
group, phenyl group unsubstituted or substituted one or
more times by fluorine, chlorine, methyl, ethyl, tert.-
butyl, methoxy, nitro, amino hydroxyl, carboxyl
benzyloxycarbonyl, methoxycarbonyl, trifluoromethyl or
the group -O-Y-C02R8, a naphthyl, tetrahydronaphthyl,
biphenyl or indanyl group, a thienyl, pyrazolyl or
pyridyl group, a benzthienyl-or benzothiadiazinyl group
or the benzyl group, R7 signifies a hydrogen atom, a
methyl, ethyl, n-propyl, allyl, i-propyl or a benzyl
group, an ethoxy carbonyl, hydroxyethyl,
dihydroxypropyl, cyanomethyl or aminoethyl group, a
group -Y-COR8 or a group -Y-CONR8R9, Y signifies a
21~6729
_
- 14 -
methylene, propylene, butylene or pentylene group, R8
signifies a hydrogen atom or a methyl, ethyl,
hydroxyethyl, hydroxypropyl, dihydroxypropyl or
aminoethyl group, R9 signifies a hydrogen atom or a
methyl group.
The preparation of compounds of the general formula I
takes place according to per se known processes.
One starts from the compounds of the general formula II,
R2
~ R3
(II) Rl X ~
N ~ N
~4 1 ~
Rs
which one reduces according to conventional processes.
As reducing agent, there come into consideration
complex boron and aluminium hydrides, boron hydride
complexes, aluminium hydride, which one prepares in
situ by reaction of LiAlH4 with AlC13 or H2SO4, or a
mixture of AlC13 and NaBH4.
One prepares compounds of the general formula II by
reaction of compounds of the general formula III
R2
(III) Rl ~
X COOI-I
R4
~1~6729
- 15 -
with 4-aminopyridine, the amino N-atom of which carries
the radical R5. This reaction takes place by reaction of
equimolar amounts of the 4-aminopyridine and of the
carboxylic acid of the general formula III in the
presence of a water-removing agent, such as
polyphosphoric acid, an acidic cation exchanger,
sulphuric acid halide, 2-halopyridinium salt,
dicyclohexylcarbodi-imide or N,N'-carbonyldiimidazole.
One can also allow this reaction to take place in two
steps, whereby one first converts the carboxylic acid
into a reactive derivative, e.g. an acid chloride, an
acid azide or imidazolide, and then brings to reaction
with the 4-aminopyridine.
One prepares the carboxylic acids of the general formula
III from the esters of the general formula IV
R2
(IV) ~ R3
Rl ~ COOR
~4
in which R10 signifies an alkyl or benzyl group.
Depending upon the nature of this group, the reaction
takes place either with the help of bases or acids or
hydrogenolytically. If Rl0 is a methyl or ethyl group,
then the reaction preferably takes place with caustic
soda solution, caustic potash solution in methanol,
ethanol or in water. If Rl0 is a tert.-butyl group, then
the reaction takes place with an acid, preferably
hydrochloric acid, formic acid or trifluoroacetic acid.
If Rl0 is a benzyl group, then the reaction preferably
takes place hydrogenolytically in the presence of a
catalyst, such as palladium on carbon, or with platinum.
2156729
-
- 16 -
From compounds of the general formula IV, in which Rl
signifies the group R6-NH-SO-, R6-NH-SO2_, R6-SO-NH- or
R6-SO2-NH-, one can prepare by alkylation another
compound of the general formula IV in which Rl signifies
the group R6-NR7 -SO-, R6-NR7 -SO2-, R6-So-NR7 or
R6-So2-NR7 -. As alkylation agents, one uses compounds
of the general formula R7 -Z, whereby R7 has the same
meaning as R7 with the exception of the hydrogen atom,
the phenyl and heteroaryl group and Z signifies a
reactive group, such as halogen, preferably bromine,
chlorine, or a sulphate. These reactions are preferably
carried out in a solvent, such as acetone, ether, toluene
or dimethylformamide, at temperature between -30C and
100C, preferably at room temperatures, in the presence
of a base, such as sodium hydride or calcium carbonate.
One prepares the compounds of the general formula IV from
the compounds of the general formula V
R2
(V) ,~
which one reacts with a-haloesters of the general formula
Hal-CR3R4-CO2R10. By Hal is to be understood a halogen
atom, preferably chlorine and bromine. These reactions
are preferably carried out in a solvent, such as acetone,
ether, toluene or dimethylformamide, at temperatures
between -30C and 100C, preferably at room temperature,
in the presence of a base, such as sodium hydride or
calcium carbonate.
One prepares the compounds of the general formula IV, in
which Rl signifies the group R6-SO-O-, R6-SO2-O-, R6-
21afi729
- 17 -
SO-NH- or R6-S02-NH-, from the compounds of the general
formula VI
R2
(VI) A ~ R3
X COORI
R4
in that one reacts them with a sulphinyl chloride R6-SOCl
or sulphonyl chloride R6-S02Cl. A thereby signifies a
hydroxyl or amino group NHR7. The reaction expediently
takes place with addition of an acid-binding agent, such
as e.g. alkali metal acetate, alkali metal hydroxide,
calcium oxide, calcium carbonate, magnesium carbonate or
with organic bases, such as pyridine, triethylamine, N-
methylmorpholine or diisopropylmethylamine, whereby as
inert solvent, there serve e.g. ether, methylene
chloride, dioxane, toluene or an excess of the tertiary
amine. In the case of the use of inorganic acid binders,
as reaction medium one uses e.g. water, aqueous ethanol
or aqueous dioxane.
One can prepare the compounds of the general formula IV,
in which Rl signifies the group R6-O-SO-, R6-0-S02-,
R6-NR7-So- or R6-NR7-So2-, from the compounds of the
general formula VII,
R2
(VII) CIOnS ~ R3
X COORI'
R4
2156729
.
- 18 -
in which n is equal to one (sulphinyl chloride) or equal
to 2 (sulphonyl chloride). One reacts with compounds of
the general formula R6-OH or R6-NH-R7, respectively. The
reaction expediently takes place with the addition of an
acid-binding agent, such as e.g. alkali metal acetate,
alkali metal hydroxide, calcium oxide, calcium carbonate,
magnesium carbonate or with organic bases, such as
pyridine, triethylamine, N-methylmorpholine or
diisopropylmethylamine, whereby, as inert solvent, there
serve e.g. ether, methylene chloride, dioxane, toluene or
an excess of the tertiary amine. In the case of the use
of inorganic acid binders, as reaction medium one uses
e.g. water, aqueous ethanol or aqueous dioxane.
The compounds of the general formulae V and VII are known
from the literature (Methoden der Organischen Chemie
(Houben-Weyl), Thieme Verlag, Stuttgart 1955: p. 285: M.
Quaedvlieg, Aliphatische Sulfinsauren; p. 299: F. Muth,
Aromatische Sulfinsaureni p. 343: M. Quaedvlieg,
Aliphatische Sulfonsaure; p. 429: F. Muth, Aromatische
Sulfonsaure: p. 599: F. Muth, Funktionelle N-Derivate der
Arylsulphonsaure; p. 659: F. Muth, Aromatische
Sulfonsaureester) or can be prepared according to the
there-described methods. The compounds of the general
formula VI are known from the literature (Sobotka,
Austin, J. Am. Chem. Soc. 74, 3813 (1952)) or can be
prepared by the there-described methods.
A further method for the preparation of compounds of the
general formula I consists in the reaction of compounds
of the general formula VIII
R~
(VIII) Rl ~ R3
X Cl-~2
4 N~
~5
21S672!~
`_
-- 19 --
with a pyridine derivative which has a nucleofugic group
which can be removed in position 4. As such groups which
can be removed, there come into question halogens,
preferably bromine, chloride and fluorine, as well as
nitro, alkoxy and phenoxy groups. For the simplification
of the reaction, the 4-aminopyridine derivative can
contain further halogen atoms, preferably chlorine.
Preferred derivatives are pentachloropyridine and 4-
nitrotetrachloropyridine. One preferably carries out
this reaction in an inert solvent, such as e.g. toluene,
dioxane, dimethylformamide, dimethylacetamide, methylene
chloride or ethanol, at temperatures between room
temperature and the boiling temperature of the solvent,
preferably between 20 and 40C. If the pyridine
derivative contains further chlorine atoms, then the
nucleophilic reaction is followed by a dehalogenation
reaction, e.g. by catalytic hydrogenation.
One prepares the compounds of the general formula VIII by
reduction of the compounds of the general formula IX
R2
( IX) Rl ~ R3
X--R
R4
in which Rll signifies a nitrile group or an amide group
CoNHR5. As reducing agents, there come into
consideration complex boron and aluminium hydrides, boron
21a6729
- 20 -
hydride complexes, aluminium hydride, which one prepares
in situ by reaction of LiAlH4 with AlC13 or sulphuric
acid, or a mixture of AlC13 and NaBH4.
One prepares the compounds of the general formula IX from
the compounds of the general formula III. The reaction
takes place by reaction of equimolar amounts of an amine
H2NR5 and of the carboxylic acid of the general formula
III in the presence of a water-removing agent, such as
polyphosphoric acid, an acidic cation exchanger,
sulphuric acid halide, 2-halopyridinium salt,
dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole.
One can also allow this reaction to run in two steps,
whereby one first converts the carboxylic acid into a
reactive derivative, e.g. an acid chloride or an acid
azide, and then brings to reaction with ammonia.
A further process for the preparation of
compounds of the general formula I starts from the
compounds of the general formula X
R3
Cl Cl
(X) HO \ ~
N -~ N
R4 / ~
Rs
Cl Cl
2156729
which are obtained according to methods known from the
literature (M.M. Boudakian, in Heterocyclic Compounds,
Vol. 14, Suppl. Part. 2, (R.A. Abramovitch, Ed.), Wiley,
New York 1974, page 407) by reacting the commercially
available aminoethanols Ho-CR3R4-CH2-NHR5 with
pentachloropyridine or 4-nitrotetrachloropyridine in an
inert solvent such as dioxane, tetrahydrofuran,
methylene chloride or ethanol at temperatures between
-10C and the boiling temperature of the solvent. The
hydroxy group of compounds of the general formula X is
converted into a leaving group W and by this means
compounds of the general formula XI are obtained
I
R3
Cl Cl
(XI) W \ ~
N -~ N
R4 / ~
R5 Cl Cl
2156S29
- 22 -
in which W denotes a halogen atom such as chlorine or
bromine or a sulfonic acid ester such as tosyloxy. The
conversion of the hydroxy group into a halogen atom is
carried out with a halogenation agent such as thionyl
chloride or phosphoryl chloride, conversion into a
sulfonic acid ester is carried out by reaction with a
sulfonyl chloride such as tosyl chloride.
The compounds of the general formula XI are then reacted
with compounds of the general formula V'
R2
(v ~ ) R~
XH
in which Rl has the same meaning as Rl but additionally
can also be a protected hydroxyl group or amino group.
By a protected hydroxyl group, one understands the
benzyloxy group or the acetyloxy group. By the protected
- 21567~
_ ~3 ~
amino group one preferably understands the tert.-butyl-
oxy-carbamoyl group, the benzyloxycarbamoyl group, the
dibenzylamino group or the phthalimido group. The
compounds of the general formula XII thereby result. The
reaction of compounds of the general formula V' with
compounds of the general formula X instead of XI accord-
ing to Mitsunobu in the presence of triphenylphosphine
and diazodicarboxylic acid diethyl ester or piperidide
also leads to compounds of the general formula XII,
R2
~ Cl Cl
(XII) R X ----~ ~
N ~\ N
R4 / ~
R Cl Cl
If Rl in the compounds of the general formula XII is a
protected hydroxyl group or a protected amino group, then
now, in the next step, the protective group is removed.
This takes place for the benzyl protective group by
hydrogenolysis in the presence of a catalyst, such as
palladium on carbon, for the tert.-butylcarbamoyl group
by a strong acid, such as trifluoroacetic acid, and for
the acetyl group by a base, such as caustic soda
solution. Compounds of the general formula XIII thereby
result,
R2
(XIII) A /~ ~ Cl Cl
N YN
R5 ~
- cl cl
~la6729
- 24 -
which, by reaction with sulphinyl chloride or sulphonyl
chloride, one converts into compounds of the general
formula XIV,
R2
(XIV) ~ R3
R6--SOn--X Cl Cl
X~ ~
N -~ N
R4 /
R5 Cl
in which n = 1 or 2 and X' signifies the oxygen atom or
the imino group NH. If X' signifies an imino group, then
compounds of the general formula XIV are now converted
into the compounds of the general formula XV
(XV) R6-Son-NR7 ~ ____~ Cl Cl
N ~ N
R4 / ~ //
R5 /---\
Cl Cl
in which R7 has the same meaning as R7 with the
exception of the hydrogen atom. This takes place by
reaction with the alkylation agents R7 -Y as is described
in the case of the alkylations of the general formula IV.
215672.q
-
- 25 -
One finally obtains the compounds of the general formula
I from the compounds of the general formula XII, in which
Rl has the same meaning as Rl, from the compounds of the
general formula XIV, or from the compounds of the general
formula XV by removal of the chlorine atoms of the
pyridine ring. This takes place by catalytic
hydrogenation in the presence of a catalyst, such as
Raney nickel or palladium on carbon, in the presence of a
base, such as potassium carbonate, sodium hydrogen
carbonate or sodium methylate.
For the preparation of compounds of general formula I, in
which Rl signifies the group R6-So-NR7-, R6-So2-NR7-,
R6-SO-O- or R6-S02-0-, there exists a further synthesis
route in the reaction of compounds of the general formula
XVI
R2
(XVI) A ~ R3 ~
X \ /~\
R4 / ~ N
R5
with a sulphinyl chloride R6-SOCl or a sulphonyl chloride
R6-S02-Cl, respectively. The reaction takes place as
described for the reaction with compounds of the general
formula VI. A thereby signifies the hydroxyl group or an
amino group NHR7.
One prepares compounds of the general formula XVI from
the compounds of the general formula XVII
21~672q
- Z6 -
R2
i
(XVII) B-A ~ R3
X~ ~
N -~, N
R4 / ~
R5
in which B signifies a protective group which is split
off for the preparation of compounds of the general
formula XVI. As protective groups B, there come into
question the benzyl group, which one removes hydro-
genolytically in the presence of a catalyst, such as
palladium on charcoal, the tert.-butyloxycarbonyl group,
which one removes by the action of acids, such as
trifluoroacetic acid, formic acid or hydrochloric acid,
or an aromatic sulphonyl group, such as the benzene-
sulphonyl or tosyl group, which one removes by the action
of alkali, such as caustic soda solution or caustic
potash solution.
One prepares compounds of the general formula XVII
according to the same principles as compounds of the
general formula I. Preferably one starts from compounds
of the general formula XVIII
..
R2
(XVIII) B-A ~
XH
- ~7 -
which one reacts with haloesters of the general formula
Hal-CR3R4-CO2R10 as is described for the reactions with
compounds of the general formula V. Compounds of the
general formula XIX thereby result
R2
(XIX) B-A ~
X COORIu
R4
which, after saponification of the ester and activation
of the acid function, one reacts, as described in the
case of the compounds of the general formula III, with
4-aminopyridine or N-R5-4-aminopyridine to give compounds
of the general formula XVI.
Certain compounds of the general formula I can
subsequently be converted into other compounds of the
general formula I.
This concerns compounds of the general formula I, in
which the groups R5, R6 or R7 signify the benzyl group,
or in which R6 signifies an aryl or heteroaryl group
which, as substituents, carry one or more benzyloxy,
benzylamino or bentyloxycarbonyl groups. By catalytic
hydrogenation in the presence of a catalyst, preferably
palladium on carbon, the benzyl group is thereby replaced
2156729
- Z8 -
by the hydrogen atom. The removal of the benzyl group
also takes place by reaction with a strong acid, such as
trifluoroacetic acid, in the presence of mesitylene,
anisole or thioanisole.
This also concerns compounds of the general formula I, in
which R6 signifies an aryl or heteroaryl group, which as
substituents, carry one or more chlorine atoms. By
catalytic hydrogenation in the presence of a catalyst,
preferably palladium on carbon, the chlorine atom is
thereby replaced by the hydrogen atom.
This also concerns compounds of the general formula I, in
which R6 signifies an aryl or heteroaryl group, which, as
substituents, carry one or more nitro groups. By
catalytic hydrogenation in the presence of a catalyst,
preferably palladium on carbon.
This also applies to compounds of the general formula I
in which R6 denotes an aryl or heteroaryl group which
carry an alkyloxycarbonyl, alkyloxycarbonylalkyl or
alkyloxycarbonylalkyloxy group as substituents or the
group R7 denotes an alkoxycarbonylalkyl group. In this
case the free carboxylic acids can be produced from the
alkoxycarbonyl groups by reaction with acids such as
hydrochloric acid, or bases such as sodium hydroxide. If
these alkoxycarbonyl groups are reacted with an amine of
the general formula NHR8R9~ then a CONR8R9 group is
formed from the alkoxycarbonyl group. If these
alkoxycarbonyl groups are treated with a reducing agent
such as LiAlH4 then the corresponding hydroxymethyl
groups are formed from this.
~la6729
.
- 29 -
This also applies to compounds of the general formula I
in which R6 denotes an aryl or heteroaryl group which
carry one or several nitriles, cyanoalkyl, cyano-
alkyloxy, formylamino, alkylcarbonylamino, amino-
carbonyl, alkylaminocarbonyl groups or a -S-Y-CONHR8,
-O-Y-CONHR8, -NH-Y-CONHR8 group as substituents or in
which R7 denotes a cyanoalkyl, aminocarbonylalkyl or the
group -Y-CONHR8. These groups can be reduced preferably
with LiAlH4 to form the corresponding aminomethyl
compounds.
Examples of salts of compounds of formula I which can be
used physiologically are salts with physiologically
tolerated mineral acids such as hydrochloric acid,
sulphuric acid, sulphurous acid or phosphoric acid; or
with organic acids such as methanesulfonic acid,
p-toluenesulfonic acid, acetic acid, trifluoroacetic
acid, citric acid, fumaric acid, maleic acid, tartaric
acid, succinic acid or salicylic acid. The compounds of
formula I with a free carboxy group can also form salts
with physiologically tolerated bases. Examples of such
salts are alkaline metal, alkaline-earth metal, ammonium
and alkylammonium salts such as a sodium, potassium,
calcium or tetramethylammonium salt.
The compounds of formula I can be solvated and in
particular hydrated. The hydration can be achieved in
the course of the production process or gradually occur
as a result of hygroscopic properties of a compound of
formula I which is firstly anhydrous.
Pure enantiomers of compounds of formula I can either be
obtained by racemate resolution (by formation of salts
~156729
- 30 -
with optically active bases) or by using optically
active starting materials in the synthesis.
For the production of pharmaceutical agents, the
substances of the general formula I are mixed with
suitable pharmaceutical carrier substances, aromatics,
flavourings and dyes and are for example formed into
tablets or coated tablets or are suspended or dissolved
in water or oil e.g. olive oil with the addition of
appropriate auxiliary substances.
The substances of the general formula I and their salts
can be administered enterally or parenterally in a
liquid or solid form. Water is preferably used as an
injection medium which contains the usual additives in
injection solutions such as stabilizers, solubilizers or
buffers. Such additives are e.g. tartrate and citrate
buffer, complexing agents (such as ethylenediaminetetra-
acetic acid and their non-toxic salts) and high
molecular polymers such as liquid polyethyloxide in
order to regulate viscosity. Solid carrier materials are
for example starch, lactose, mannitol, methylcellulose,
talcum, highly dispersed silicic acids, high molecular
fatty acids (such as stearic acid), animal and vegetable
fats and solid high molecular polymers (such as
polyethylene glycols). Preparations suitable for oral
administration can, if desired, contain flavourings and
sweeteners.
The compounds are usually administered in amounts of 10-
1500 mg per day in relation to 75 kg body weight. It is
preferable to administer 1-2 tablets with a content of
active substance of 5-500 mg, 2-3 times per day. The
tablets can also be retarded as a result of which only
2156729
- 31 -
1-2 tablets have to be administered per day with 20-
700 mg active substance. The active substance can also
be administered by injection 1-8 times per day or by
continuous infusion in which case 50-2000 mg per day are
usually sufficient.
The following compounds are preferred within the sense
of the invention in addition to those mentioned in the
examples:
1. Benzenesulfinic acid-3-methyl-5-[2-(pyridin-4-
ylamino)-ethoxy~-phenyl ester
2. N-{3-[2-(Pyridin-4-ylamino)-ethoxy]-phenyl~-
benzenesulfinamide
3. 3-{3-Methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-
phenylaminosulfonyl}-phenoxy-acetic acid
4. 2-{3-Methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-
phenylaminosulfonyl~-phenoxy-acetic acid
5. 3-{3-Methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-
phenylaminosulfonyl}-phenoxy-acetamide
6. N-(2-Hydroxyethyl)-3-{3-methyl-5-[2-(pyridin-4-
ylamino)-ethoxy]-phenylaminosulfonyl}-phenoxy-
acetamide
7. N-(2,3-Dihydroxypropyl)-3-{3-methyl-5-[2-(pyridin-
4-ylamino)-ethoxy]-phenylaminosulfonyl~-phenoxy-
acetamide
21~6729
8. N-(2-Hydroxyethyl)-3-{3-methyl-5-[2-(pyridin-4-
ylamino)-ethoxy]-phenyloxysulfonyl}-phenoxy-
acetamide
9. 3-{3-Methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-
phenylaminosulfonyl}-phenoxy-acetic acid-morpholide
10. Acetic acid 2-[2-(benzenesulfonyl-{3-methyl-5-[2-
pyridin-4-ylamino)-ethoxy]-phenyl}-
aminoacetylamino]-ethyl ester
11. Acetic acid 3-[2-(benzenesulfonyl-{3-methyl-5-[2-
(pyridin-4-ylamino)-ethoxy]-phenyl}-amino-
acetylamino]-propyl ester
12. Acetic acid 2-[2-(2-methoxybenzenesulfonyl-{3-
methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-phenyl}-
amino-acetylamino]-ethyl ester
13. N-{3-Cyano-5-[2-(pyridin-4-ylamino)-ethoxy]-
phenyl}-benzenesulfonamide
2156729
,.
Example
N-~3- r 2-fPyridin-4-ylamino)-ethoxy~-phenyl~-2-
naphthalene-sulfonamide
a) 6.3 g (28 mmol) naphthalene-2-sulfonyl chloride in
30 ml methylene chloride was added dropwise at 10C
to 5.9 g (25 mmol) 3-aminophenoxyacetic acid ethyl
ester and 6.9 ml triethylamine in 100 ml methylene
chloride while cooling on ice. It was stirred for
1 hour at room temperature, extracted with water
and the organic phase was dried over sodium
sulfate. The solvent was removed in a vacuum and
9.6 g N-{3-[(ethoxycarbonyl)-methoxy]-phenyl}-2-
naphthalene-sulfonamide was obtained as an oil.
MS m/e = 385.
b) 4.2 g (75 mmol) potassium hydroxide was added to
9.6 g (25 mmol) of this compound in 100 ml ethanol
and it was stirred for 1 hour at 70C. It was
filtered, the precipitate was dissolved in water,
acidified with concentrated hydrochloric acid and
extracted with ethyl acetate. The solvent was
removed in a vacuum, the residue was dissolved in
2 N sodium hydroxide solution, acidified with
concentrated hydrochloric acid and extracted with
ethyl acetate. The organic phase was dried over
sodium sulfate, filtered and the solvent was
removed in a vacuum. The oily residue crystallizes
on standing. 7.6 g (85 %) N-{3-[(carboxy)-methoxy]-
phenyl}-2-naphthalene-sulfonamide was obtained. Fp.
153 - 155C. FAB-MS: M+H = 358.
21~6729
-
c) 2.7 g (16.8 mmol) 1,1-carbonyldiimidazole was added
to 3 g (8.4 mmol) of this compound in 30 ml
tetrahydrofuran at 45C and it was stirred for
20 minutes. 0.8 g (8.4 mmol) 4-aminopyridine was
added to this and stirred for 6 hours at 60C. Then
2.7 g (16.8 mmol) l,1-carbonyldiimidazole and 0.8 g
(8.4 mmol) 4-aminopyridine was again added and it
was stirred for a further 6 hours at 60C. The
solvent was removed in a vacuum, the residue was
taken up in ethyl acetate and extracted with
aqueous sodium bicarbonate and with phosphate
buffer, pH = 7Ø The organic phase was dried over
sodium sulfate, filtered and the solvent was
removed in a vacuum. 2.5 g (69 %) N-~3-[(pyridin-4-
ylaminocarbonyl)-methoxy]-phenyl}-2-naphthalene-
sulfonamide was obtained. Fp. 204 - 207C.
MS m/e = 433.
d) 2.0 g (4.6 mmol) of this compound was added under
nitrogen to 1.0 g (20.4 mmol) lithium aluminium
hydride in 20 ml tetrahydrofuran and it was boiled
for 1 hour under reflux. Excess LiAlH4 was
decomposed with water, filtered and the filtrate
was concentrated by evaporation in a vacuum. The
residue was taken up in ethyl acetate, extracted
with water, the organic phase was dried with sodium
sulfate, filtered and the solvent was removed in a
vacuum. The oily residue was separated on a
reverse-phase column (RP-18; mobile solvent:
methanol/water pH = 6.8, 7:3). The desired fraction
was evaporated to dryness in a vacuum and extracted
with ethyl acetate. The organic phase was dried
over sodium sulfate, filtered and the solvent was
removed in a vacuum. 0.3 g (16 %) of the title
21S6729
compound was obtained of Fp. 90 - 91C.
MS m/e = 419.
ExamPle 2
N-~3-~2-rPyridin-4-ylamino)-ethoxyl-phen
naphthalene-sulfonamide
The production was carried out analogously to
example 1 except that in step a) 1-naphthalene-
sulfonyl chloride was used instead of
2-naphthalenesulfonyl chloride.
Intermediate steps:
a) N-{3-[(Ethoxycarbonyl)-methoxy]-phenyl}-l-
naphthalenesulfonamide as an oil. MS m/e = 385.
b) N-{3-[(Carboxy)-methoxy]-phenyl}-1-naphthalene-
sulfonamide. Fp. 147 - 149C. FAB-MS: M+H = 358.
c) N-{3-[(Pyridin-4-ylaminocarbonyl)-methoxy]-phenyl}-
1-naphthalenesulfonamide. Fp. 210 - 211C
(decomp.). MS m/e = 433.
d) Title compound. Yield 38 %. Fp. 239 - 241C
(decomp.). MS: pos. LSIMS m/e = 419
2156729
- 36 -
Example 3
4-Methyl-N-r3- r 2-(pyridin-4-Ylamino)-ethoxy~-phen
benzenesulfonamide
The production was carried out analogously to
example 1 except that in step a) 4-toluenesulfonyl
chloride was used instead of 2-naphthalenesulfonyl
chloride.
Intermediate steps:
a) 4-Methyl-N-{3-[(ethoxycarbonyl)-methoxy]-phenyl}-
benzenesulfonamide. Fp. 100 - 102C. MS m/e = 349.
b) 4-Methyl-N-{3-[(carboxy)-methoxy]-phenyl}-benzene-
sulfonamide. Fp. 170 - 173C. FAB-MS: M+H = 322.
c) 4-Methyl-N-{3-[(pyridin-4-ylaminocarbonyl)-
methoxy]-phenyl}-benzenesulfonamide as an oil.
MS m/e = 397.
d) Title compound. Yield 26 %. Fp. 165 - 167C.
MS m/e = 383.
Example 4
4-Fluoro-N-~3-~2-(pyridin-4-ylamino)-ethoxy]-phenyl~-
benzenesulfonamide-hydrochloride
The production was carried out analogously to
example 1 except that in step a) 4-fluoro-
2156729
benzenesulfonyl chloride was used instead of2-naphthalenesulfonyl chloride.
Intermediate steps:
a) 4-Fluoro-N-{3-[(ethoxycarbonyl)-methoxy]-phenyl~-
benzenesulfonamide Fp. 94 - 96C. MS m/e = 353.
b) 4-Fluoro-N-{3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. Fp. 154 - 156C. FAB-MS: M+H =
326.
c) 4-Fluoro-N-{3-[(pyridin-4-ylaminocarbonyl)-
methoxy]-phenyl~-benzenesulfonamide. MS m/e = 401.
d) Title compound. The base was ground with
hydrochloric acid in ether: Yield 21 %. Fp. 203 -
205C. MS m/e = 387.
Example 5
4-Chloro-N-~3-~2-(Pyridin-4-ylamino)-ethoxyl-phenyl~-
benzenesulfonamide hYdrochloride
The production was carried out analogously to
example 1 except that in step a) 4-chloro-
benzenesulfonyl chloride was used instead of
2-naphthalenesulfonyl chloride.
Intermediate steps:
21a6729
- 38 -
a) 4-Chloro-N-{3-~(ethoxycarbonyl)-methoxy]-phenyl}-
benzenesulfonamide. MS m/e = 369.
b) 4-Chloro-N-{3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. Fp. 190 - 192C. FAB-MS: M+H =
342.
c) 4-Chloro-N-{3-[(pyridin-4-ylaminocarbonyl)-
methoxy]-phenyl}-benzenesulfonamide. Fp. 168 -
171C. MS m/e = 417.
d) 1.79 ml (3.58 mmol) 2 M borane dimethylsulfide in
tetrahydrofuran was added to 0.65 g (1.55 mmol)
from step c) in 15 ml dry tetrahydrofuran. It was
stirred for 3 hours at 60C and 10 ml methanol was
then added in an ice bath. 5 ml hydrogen chloride
in ether was added. The solvent was removed in a
vacuum and the residue was ground with warm water.
0.13 g of the title compound was obtained of Fp.
241 - 243C. MS m/e = 403.
Example 6
4-Trifluoromethyl-N-~3-~2-(pyridin-4-Ylamino)-ethoxy~-
phenYl~-benzenesulfonamide
It was produced analogously to example 1 except
that in step a) 4-trifluoromethyl-benzenesulfonyl
chloride was used instead of 2-naphthalenesulfonyl
chloride.
Intermediate steps:
`_ 21~6729
- 39 -
a) 4-Trifluoromethyl-N-{3-[(ethoxycarbonyl)-methoxy]-
phenyl}-benzenesulfonamide. MS m/e = 403.
b) 4-Trifluoromethyl-N-{3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. Fp. 155 - 158C. FAB-MS: M+H =
375.
c) 4-Trifluoromethyl-N-~3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl}-benzenesulfonamide.
Fp. 66 - 68C. MS m/e = 451.
d) Title compound Fp. 145 - 148C. MS m/e = 437.
Example 7
3-Trifluoromethyl-N-~3-[2-(pyridin-4-ylamino)-ethoxy]-
phenyl~-benzenesulfonamide
It was produced analogously to example 1 except
that 3-trifluoromethyl-benzenesulfonyl chloride was
used instead of 2-naphthalenesulfonyl chloride.
Intermediate steps:
a) 3-Trifluoromethyl-N-{3-[(ethoxycarbonyl)-methoxy]-
phenyl}-benzenesulfonamide. MS m/e = 403.
b) 3-Trifluoromethyl-N-{3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. Fp. 147 - 149C. FAB-MS: M+H =
375.
~- 215~729
- 40 -
c) 3-Trifluoromethyl-N-{3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl}-benzenesulfonamide as an
oil. MS m/e = 451.
d) Title compound. Fp. 185 - 187C. MS m/e = 437.
Example 8
N-~3-r2-(Pyridin-4-Ylamino)-ethoxy~-phenyl~-cYclohexane-
sulfonamide
It was produced analogously to example 1 except
that in step a) cyclohexyl-sulfonyl chloride was
used instead of 2-naphthalenesulfonyl chloride.
Intermediate steps:
a) N-{3-[(Ethoxycarbonyl)-methoxy]-phenyl}-
cyclohexanesulfonamide. MS m/e = 341.
b) N-{3-[(Carboxy)-methoxy]-phenyl}-cyclohexane-
sulfonamide. Fp. 132C. FAB-MS: M+H = 313.
c) N-{3-[(Pyridin-4-ylaminocarbonyl)-methoxy]-phenyl}-
cyclohexanesulfonamide as an oil. MS m/e = 389.
d) Title compound. MS m/e = 375.
`_ 21S6729
- 41 -
Example 9
N-~3-[2-(PYridin-4-ylamino)-ethoxy]-phen
benzenesulfonamide
It was produced analogously to example 1 except
that in step a) benzenesulfonyl chloride was used
instead of 2-naphthalenesulfonyl chloride.
Intermediate steps:
a) N-{3-[(Ethoxycarbonyl)-methoxy]-phenyl}-
benzenesulfonamide as an oil. MS m/e = 335.
b) N-{3-[(Carboxy)-methoxy]-phenyl~-benzene-
sulfonamide. Fp. 160 - 161C. FAB-MS: M+H = 307
c) N-{3-[(Pyridin-4-ylaminocarbonyl)-methoxy]-phenyl}-
benzenesulfonamide. Fp. 151 - 156C. MS m/e = 383.
d) Title compound. Yield 26 %. Fp. 182 - 184C.
MS m/e = 369.
Example 10
N-~3- r 1-Methyl-2-(Pyridin-4-ylamino~-ethoxy~-phen
benzenesulfonamide
a) 5.6 ml (44 mmol) benzenesulfonyl chloride was added
dropwise at 10C to 8.4 g t40 mmol) 2-(3-amino-
phenoxy)-propionic acid ethyl ester and 6.1 ml
(44 mmol) triethylamine in 50 ml methylene chloride
~ 213 6 729
- 42 -
while cooling on ice. It was stirred for 1 hour at
room temperature, extracted with water, the organic
phase was dried with sodium sulfate, filtered and
the solvent was removed in a vacuum. 14 g N-{3-[1-
(ethoxycarbonyl)-ethoxy]-phenyl}-benzenesulfonamide
was obtained as an oil. MS m/e = 349.
b) 14 g (40 mmol) of this compound and 6.7 g
(120 mmol) potassium hydroxide in 100 ml ethanol
were stirred for 1 hour at 70C. It was extracted
twice with ethyl acetate, acidified with half-
concentrated hydrochloric acid and again extracted
with ethyl acetate. The combined organic phases
were dried over sodium sulfate, filtered and the
solvent was removed in a vacuum. 9.2 g (72 %) N-{3-
- [1-(carboxy)-ethoxy]-phenyl}-benzenesulfonamide was
obtained an oil. MS m/e = 321.
c) 3.4 g (57 %) N-{3-[1-(pyridin-4-ylaminocarbonyl)-
ethoxy]-phenyl}-benzenesulfonamide (Fp. 142 -
144C. MS m/e = 397) was produced as in example 1,
step c) from 4.8 g (15 mmol) of this compound,
2.1 g (22.5 mmol) 4-aminopyridine and 3.2 g
(19.5 mmol) 1,1-carbonyl-diimidazole in 40 ml
tetrahydrofuran.
d) 0.6 g (37 %) of the title compound (Fp. 162 -
163C. MS m/e = 383) was produced from 1.7 g
(4.3 mmol) of this compound and 0.65 g (17.2 mmol)
lithium aluminium hydride in 20 ml tetrahydrofuran
as in example 1, step d).
2156729
- 43 -
Example 11
N- r 3- r 1,1-Dimethyl-2-(pyridin-4-Ylamino)-ethoxy~-
phenyl~-benzenesulfonamide
The compound was produced analogously to example
10. 2-methyl-2-(3-aminophenoxy)-propionic acid
ethyl ester was used in step a) instead of 2-(3-
aminophenoxy)-propionic acid ethyl ester.
a) N-{3-[1-Methyl-1-(ethoxycarbonyl)-ethoxy]-phenyl}-
benzenesulfonamide as an oil. MS m/e = 363.
b) N-{3-[1-Methyl-(carboxy)-ethoxy]-phenyl}-
benzenesulfonamide as an oil. MS m/e = 335.
c) N-{3-[1-Methyl-(pyridin-4-ylaminocarbonyl)-ethoxy]-
phenyl}-benzenesulfonamide. Fp. 141 - 143C.
MS m/e = 411.
d) Title compound as an oll. MS m/e = 397.
ExamPle 12
N-Methyl-N-~3- r 2-(pyridin-4-ylamino)-ethoxY~-phenyl~-
benzenesulfonamide hydrochloride
a) A solution of 1.6 ml (25 mmol) iodomethane in 10 ml
dimethylformamide was added dropwise at 80 - 90C
to 8.4 g (25 mmol) N-{3-[(ethoxycarbonyl)-methoxy]-
phenyl}-benzenesulfonamide (example 9, step a) and
3.5 g potassium carbonate in 10 ml dimethyl-
~ 2156729
- 44 -
formamide. It was stirred for a further 2 h at this
temperature, allowed to cool to room temperature,
filtered and the filtrate was concentrated in a
vacuum. The residue was taken up in ethyl acetate
- and extracted with water. It was dried over sodium
- sulfate, filtered and the solvent was removed in a
vacuum. 8.6 g N-methyl-N-{3-[(ethoxycarbonyl)-
methoxy]-phenyl}-benzenesulfonamide was obtained as
an oil. MS m/e = 349.
b) The further reaction was carried out as in example
1; step b. N-methyl-N-{3-[(carboxy)-methoxy]-
phenyl}-benzenesulfonamide was obtained. Fp.: 110 -
111C. MS m/e = 321.
c) N-Methyl-N-{3-[(pyridin-4-ylaminocarbonyl)-
methoxy]-phenyl}-benzenesulfonamide. Fp.: 76 -
78C. MS m/e = 397.
d) Title compound. 2 N hydrochloric acid was added to
the free base, it was extracted with ethyl acetate
and the aqueous phase was evaporated to dryness. An
oil was obtained which crystallized after grinding
with isopropanol. Yield 46 %. Fp.: 174 - 176C.
Example 13
N-Ethyl-N-~3-~2-(pyridin-4-ylamino)-ethoxyl-phenyl~-
benzenesulfonamide
It was produced analogously to example 12 except
that iodoethane was used instead of iodomethane in
step a).
~- 2156729
- 45 -
a) N-Ethyl-N-{3-[(ethoxycarbonyl)-methoxy]-phenyl}-
benzenesulfonamide as an oil. MS m/e = 363.
b) N-Ethyl-N-{3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. Fp.: 122C. MS m/e = 335.
c) N-Ethyl-N-{3-[(pyridin-4-ylaminocarbonyl)-methoxy]-
phenyl}-benzenesulfonamide. MS m/e = 411.
d) Title compound as an oil. MS m/e = 397.
Example 14
N-Propyl-N-~3-~2-(pyridin-4-ylamino)-ethoxy]-phenyl~-
benzenesulfonamide
It was produced analogously to example 12 except
that iodopropane was used instead of iodomethane in
step a).
a) N-Propyl-N-{3-[(ethoxycarbonyl)-methoxy]-phenyl}-
benzenesulfonamide as an oil. MS m/e = 377.
b) N-Propyl-N-{3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. Fp.: 147C. MS m/e = 349.
c) N-Propyl-N-{3-[(pyridin-4-ylaminocarbonyl)-
methoxy]-phenyl}-benzenesulfonamide. Fp. 105C.
MS m/e = 425.
d) Title compound as an oil. MS m/e = 411.
- 21~6729
- 46 -
Example 15
N-Benzyl-N-~3-~2-(pyridin-4-ylamino)-ethoxy]-Phenyl~-
benzenesulfonamide
It was produced analogously to example I2 except
that benzyl bromide was used instead of iodomethane
in step a).
a) N-Benzyl-N-{3-[(ethoxycarbonyl)-methoxy]-phenyl}-
benzenesulfonamide as an oil. MS m/e = 425.
b) N-Benzyl-N-{3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. Fp.: 190C. MS m/e = 397.
c) N-Benzyl-N-{3-[(pyridin-4-ylaminocarbonyl)-
methoxy]-phenyl}-benzenesulfonamide. Fp. 140C.
MS mte = 473.
d) Title compound. Fp.: 128C. MS m/e = 459.
Example 16
N-Allyl-N-~3-~2-(pyridin-4-ylamino)-ethoxy~-phenyl~-
benzenesulfonamide
It was produced analogously to example 12 except
that allyl bromide was used instead of iodomethane
in step a).
a) N-Allyl-N-{3-[(ethoxycarbonyl)-methoxy]-phenyl}-
benzenesulfonamide as an oil. MS m/e = 375.
21a6729
.
- 47 -
b) N-Allyl-N-{3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. MS m/e = 347.
c) N-Allyl-N-{3-[(pyridin-4-ylaminocarbonyl)-methoxy]-
phenyl}-benzenesulfonamide. MS m/e = 423.
d) Title compound as an oil. MS m/e = 409.
Example 17
N-~5-Methyl-3-r2-(pyridin-4-ylamino)-ethoxy]-Phenyl~-
benzenesulfonamide hYdrochloride
It was produced analogously to example 12 except that in
step a) benzenesulfonyl chloride was used instead of
2-naphthalenesulfonyl chloride and 3-amino-5-methyl-
phenoxyacetic acid ethyl ester instead of 3-amino-
phenoxyacetic acid ethyl ester.
Intermediate steps:
a) N-{5-Methyl-3-[(ethoxycarbonyl)-methoxy]-phenyl}-
benzenesulfonamide as an oil. MS m/e = 349.
b) N-{5-Methyl-3-[(carboxy)-methoxy]-phenyl}-
benzenesulfonamide. Fp.: 156 - 159C. FAB-MS: M+H =
322.
c) N-{5-Methyl-3-[(pyridin-4-ylaminocarbonyl)-
methoxy]-phenyl}-benzenesulfonamide. Fp.: 193 -
196C. MS m/e = 397.
2156729
- 48 -
d) Title compound. Yield 56 %. Fp. 170C.
MS m/e = 383.
Exàmple 18
Benzenesulfonic acid-3-~2-(pYridin-4-ylamino)-ethoxyl-
phenyl ester
a) 0 44 g (0.011 mol) sodium hydride (60 % in white
oil) is added to 2.5 g (0.01 mol) benzenesulfonic
acid-3-hydroxyphenyl ester in 30 ml acetonitrile
while cooling at 10C and it is stirred for 1 hour
at this temperature. 2.2 ml (0.02 mol) ethyl
bromoacetate in 10 ml acetonitrile is added
dropwise within 30 minutes and it is stirred for
3 hours at room temperature. After addition of 5 ml
isopropanol, the solvent is removed in a vacuum.
30 ml ethanol, 50 ml water and 0.8 g (0.015 mol)
potassium hydroxide are added to the residue. After
16 hours at room temperature, the ethanol is
removed in a vacuum and the aqueous solution is
extracted three times with ether. The aqueous phase
is acidified with hydrochloric acid and extracted
with ether. The ether is removed in a vacuum and
1.5 g (48 %) 2-[3-(phenylsulfonyloxy)-phenyloxy]-
acetic acid with a Fp. of 152 - 155C is obtained.
b) 1.4 g (4.5 mmol) of this compound and 958 mg
(5.9 mmol) carbonyldiimidazole are stirred for
30 minutes at 45C. 0.64 g (6.8 mmol) 4-amino-
pyridine is added and it is stirred for two days at
60C. The solvent is removed in a vacuum and the
residue is dissolved in ethyl acetate which
contained 0.5 % acetic acid. The organic phase is
21~6729
- 49 -
dried, filtered and the solvent is removed in a
vacuum. The residue is ground with ether, filtered
and 1.8 g (94 %) N-(4-pyridinyl)-2-[3-(phenyl-
sulfonyloxy)-phenyloxy]-acetamide of'Fp. 127 -
130C is obtained.
c) 2.23 ml (18 mmol) chlorotrimethylsilane is added at
5C to 192 mg (8.8 mmol) lithium borohydride in
5 ml dry tetrahydrofuran while cooling in an ice
bath. After 30 minutes 1.7 g (4.4 mmol) of the
compound from step b) is slowly added at 5C. After
i6 hours at room temperature it is decomposed with
3 ml methanol and the solvent is removed in a
vacuum. The residue is taken up in ethyl acetate
and bicarbonate solution. The ethyl acetate phase
is purified on a silica gel column (ethyl acetate
/methanol = 9:1). The solvent is removed in a
vacuum and 1.3 g of the title compound (80 %) is
obtained as a viscous oil. FAB-MS: M+H 371.
ExamPle 19
N-Methyl-N-phenyl-3-~2-(pyridin-4-ylamino)-ethoxy]-
benzenesulfonamide
a) 3-Nitrobenzenesulfonic acid-N-methYl-anilide
5 g 3-nitrobenzenesulfonic acid-chloride is
dissolved in 20 ml absolute pyridine and 2.7 ml
N-methylaniline is added while cooling on ice and
stirring. It is stirred for a further 2 hours at
room temperature, the reaction mixture is poured
onto ice water and acidified with dilute
hydrochloric acid. The aqueous phase is extracted
with ethyl acetate, the ethyl acetate phase,is
- 2156729
- 50 -
dried over sodium sulfate and evaporated. The
residue is recrystallized from alcohol. Yield:
6.3 g. Fp. 90C.
b) 3-Aminobenzenesulfonic acid-N-methyl-anilide
6 g 3-nitrobenzenesulfonic acid-N-methylanilide is
dissolved in 100 ml absolute tetrahydrofuran and
hydrogenated after addition of 0.5 g Pd/C (10 %)
catalyst. After the calculated amount of hydrogen
has been taken up, it is filtered from the catalyst
and the filtrate is concentrated by evaporation.
Yield: 5.5 g. Fp. 104C.
c) 3-Hydroxybenzenesulfonic acid-N-methyl-anilide
5 g 3-aminobenzenesulfonic acid-N-methylanilide is
dissolved in 20 ml 50 % sulphuric acid. A solution
of 1.75 g sodium nitrite in 5 ml water is added
dropwise to this while cooling on ice and stirring.
When the diazotization is completed, the reaction
mixture is heated for 20 minutes to 100C, it is
allowed to cool and extracted with ethyl acetate.
The ethyl acetate phase is dried over sodium
sulfate and evaporated. The residue is suff~ciently
~pure for further processing.
d) r 3-(Methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid
ethyl ester
3.5 g 3-hydroxybenzenesulfonic acid-N-methylanilide
is dissolved in 20 ml absolute dimethylformamide.
2 g potassium carbonate and 1.9 ml ethyl
bromoacetate are added to this and the mixture is
heated for 3 hours to 100C. It is cooled and the
solvent is removed by distillation in a vacuum. The
21a~729
; - 51 -
residue obtained (4.3 g) is sufficiently pure for
further processing.
e) r 3-rMethyl-phenyl-sulfamoyl)-Phenoxy~-acetic acid
4.2 g [3-[methyl-phenyl-sulfamoyl)-phenoxy]-acetic
acid ethyl ester is dissolved in 40 ml ethanol. 1 g
potassium hydroxide is added to this and the
mixture is stirred for one hour at 90C. It is
cooled to room temperature, acidified with dilute
hydrochloric acid and extracted with methylene
chloride. The methylene chloride phase is dried
over sodium sulfate and evaporated. 4 g [3-[methyl-
phenyl-sulfamoyl)-phenoxy]-acetic acid is obtained
as an amorphous solid.
f) 2- r 3-(Methyl-phenyl-sulfamoYl)-phenoxy~-N-pyridin-
4-yl-acetamide
2 g [3-(methyl-phenyl-sulfamoyl)-phenoxy]-acetic
acid is dissolved in 20 ml absolute tetrahydro-
furan. 1.35 g carbonyldiimidazole is added to this
and the mixture is heated for 20 minutes to 45C.
It is cooled to room temperature, 900 mg 4-amino-
pyridine is added and it is stirred for a further
3 hours at 60C. The solvent is removed by
distillation, the residue is dissolved in ethyl
acetate and extracted by shaking with water. The
ethyl acetate phase is dried over sodium sulfate
and evaporated. The residue is chromatographed on a
silica gel column for purification (eluting agent:
methylene chloride/ methanol 9:5). After
evaporating the column fractions, 1.5 g of the
title compound is obtained as an amorphous solid.
FAB-MS: M+H 398.
- 215~72~
g) N-Methyl-N-phenyl-3-~2-(pyridin-4-ylamino-ethoxy~-
benzenesulfonamide
800 mg 2-[3-(methyl-phenyl-sulfamoyl)-phenoxy]-N-
pyridin-4-yl-acetamide is dissolved in 15 ml
absolute tetrahydrofuran. 320 mg lithium aluminium
hydride is added under nitrogen and the mixture is
subsequently heated for one hour to reflux
temperature. It is cooled and saturated ammonium
sulfate solution is added to the reaction mixture.
Insoluble material is removed by suction
filtration, the filter residue is washed with
ether, the filtrate is dried over sodium sulfate
and evaporated. The residue is chromatographed on a
silica gel column for purification (eluting agent:
methylene chloride/methanol 8:2). After evaporating
the column fractions, 420 mg of the title compound
is obtained as an amorphous substance. FAB-MS: M+H
384.
Bxample 20
N-BenzYl-N-phenyl-3-~2-(Pyridin-4-ylamino)-ethoxY]-
benzenesulfonamide
The title compound was prepared analogously to
example 19 except that N-benzylaniline was used in
step a) instead of N-methylaniline. Amorphous
substance. FAB-MS: M+H 460.
21~672Cl~
- 53 -
Example 21
.
N-Phenyl-3- r 2-(pyridin-4-ylaminol-ethoxy~-
benzenesulfonamide
300 mg N-benzyl-N-phenyl-3-[2-(pyridin-4-ylamino)-
ethoxy]-benzenesulfonamide texample 20) is
dissolved in 20 ml methanol and hydrogenated after
addition of 100 mg Pd/C (10 %) catalyst. After the
uptake of hydrogen has ceased, the catalyst is
removed by fiitration and it is evaporated. 240 mg
of the title compound is obtained as an amorphous
substance. FAB-MS: M+H 370.
Example 22
N-Methyl-N-pYridin-2-yl-3-[2-(pyridin-4-ylamino)-
ethoxy]-benzenesulfonamide
The title compound was prepared analogously to
example 19 except that N-methyl-2-aminopyridine was
used in step a) instead of N-methylaniline.
Amorphous substance. FAB-MS: M+H 385.
Example 23
N-~3-r2-(Pyridin-4-Ylamino)-ethoxy~-phenyl~-2-
propanesulfonamide hydrochloride
2.88 ml (22.9 mmol) chlorotrimethylsilane was added
dropwise to 0.26 g (11.4 mmol) LiBH4 in 50 ml
tetrahydrofuran, it was stirred for 5 minutes at
room temperature and 2.00 g (5.72 mmol) N-{3-
215~729
[(pyridin-4-ylaminocarbonyl)-methoxy]-phenyl}-2-
propanesulfonamide was added in portions which had
been prepared analogously to example 1. It was
boiled for 30 minutes under reflux, 20 ml methanol
is carefully added dropwise after cooling followed
by 30 ml 2 N sodium hydroxide solution. The solvent
was mostly removed in a vacuum and it was extracted
with methylene chloride. It was dried, the solvent
was removed in a vacuum and ethereal hydrochloric
acid was added to the residue. The solvent was
removed in a vacuum, the residue was ground with
tert.butylmethyl ether and 1.5 g (70 %) of the
title compound was obtained of Fp. 204 - 207C.
Example 24
N-~3-[2-(Pyridin-4-ylamino)-ethoxy~-Phenyl~-
cyclopentanesulfonamide hydrochloride
was produced analogously to example 23. Fp. 129 -
134C.
Example 25
N-MethYl-N-~3-~2-(pyridin-4-ylamino)-ethoxy]-phenyl~-4
fluoroPhenYlsulfonamide hydrochloride
was produced analogously to example 23. Fp. 140 - 143C.
21~6729
Example 26
N-~3-[2-(Pyridin-4-ylamino)-ethoxy]-Phenyl~-
benzenesulfonamide
was produced analogously to example 1. Oil.
MS: [EI] = 383.
Example 27
N-~3-~2-(Pyridin-4-ylamino)-ethoxy~-phenyl~-4-
tert~butylbenzenesulfonamide
was produced analogously to example 1. Oil.
MS: [EI] = 425.
Example 28
N-~3-~2-(Pyridin-4-ylamino)-ethoxy~-phenyl~-1,2,3,4-
tetrahydronaphthalene-6-sulfonamide hydrochloride
was produced analogously to example 23. Fp. 235 - 237C.
Example 29
N-~3-~2-(Pyridin-4-ylamino)-ethoxy]-phenyl~-indane-5-
sulfonamide
was produced analogously to example 23 as a free base.
Fp. 140C (decomp.).
21~6729
Example 30
N-~3- r 2-(PYridin-4-ylamino)-ethoxy~-phenyl~-2-
biphenylsulfonamide
was produced analogously to example 23 as a free base.
Fp. 214 - 216C.
Example 31
N-Methyl-N-~5-methyl-3- r 2-(pyridin-4-ylamino)-ethoxy~-
phenyl~-4-fluorobenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 122 - 129C.
The starting material N-{5-methyl-3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl}-4-fluorobenzene-sulfonamide
(MS m/e = 429) was produced analogously to example 17.
Example 32
N-~5-Methyl-3- r 2-(pYridin-4-ylamino)-ethoxy~-phenyl~-2-
chloro-4-fluorobenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 198 - 200C.
The starting material N-{5-methyl-3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl~-2-chloro-4-fluorobenzene-
sulfonamide (MS m/e = 449) was produced analogously to
example 17.
- 21S6729
- 57 -
Example 33
,
N-Methyl-N-~5-methyl-3-~2-(pyridin-4-Ylamino)-ethoxy]-
phenyl~-2-trifluorobenzenesulfonamide hYdrochloride
was produced analogously to example 23. Fp. 203 - 207C.
,The starting material N-{5-methyl-3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl}-2-chloro-4-fluorobenzene-
sulfonamide (MS m/e = 479) was produced analogously to
example 17.
Example 34
N-~5-Methyl-3-~2-(pyridin-4-ylamino)-ethoxy~-phenyl~-2-
methylbenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 135C
(decomp.). The starting material N-{5-methyl-3-
[(pyridin-4-ylaminocarbonyl)-methoxy]-phenyl}-2-
methylbenzene-sulfonamide (MS m/e = 411) was produced
analogously to example 17.
Example 35
N-Methyl-N-~5-methyl-3-~2-(pyridin-4-ylamino)-ethoxy~-
phenyl~-2-methyl-4-fluorobenzenesulfonamide
hydrochloride
was produced analogously to example 23. Fp. 146C. The
starting material N-methyl-N-{5-methyl-3-[(pyridin-4-
ylaminocarbonyl)-methoxy]-phenyl~-2-methyl-4-fluoro-
benzenesulfonamide (MS m/e = 443) was produced
analogously to example 17.
21~6729
- 58 -
Example 36
N-~5-Methyl-3-[2-rPyridin-4-ylamino)-ethoxy~-phenYl~-2-
methyl-4-fluorobenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 193C. The
starting material N-{5-methyl-3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl~-2-methyl-4-fluorobenzene-
sulfonamide (MS m/e = 429) was produced analogously to
example 17.
Example 37
N-~5-MethYl-3-r2-(Pyridin-4-ylamino)-ethoxy~-phenyl~-2
methyl-5-fluorobenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 246 - 247C.
The starting material N-{5-methyl-3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl}-2-methyl-5-fluorobenzene-
sulfonamide (MS m/e = 429; Fp. 211 - 213C) was produced
analogously to example 17.
Example 38
N-Methyl-N-~5-methyl-3-~2-(pyridin-4-Ylamino)-ethoxy]
phenyl~-2-methyl-5-fluorobenzenesulfonamide
hydrochloride
.
was produced analogously to example 23. Fp. 165 - 166C.
The starting material N-methyl-N-{5-methyl-3-[(pyridin-
4-ylaminocarbonyl)-methoxy]-phenyl}-2-methyl-5-fluoro-
benzenesulfonamide (MS m/e = 443) was produced
analogously to example 17.
21~6729
-
- 59 -
Example 39
N-~5-Methyl-3-~2-(pyridin-4-ylamino)-ethoxy]-Phen
2,4-difluorobenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 227 - 228C.
The starting material N-{5-methyl-3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl}-2l4-difluorobenzene-
sulfonamide (MS m/e = 433; Fp. 194C) was produced
analogously to example 17.
Example 40
N-r5-Methyl-3-~2-(pyridin-4-ylamino)-ethoxyl-phenyl~-
3,5-dimethyl-4-pyrazolesulfonamide
was produced analogously to example 23 as a free base.
Fp. 121C. The starting material N-{5-methyl-3-
[(pyridin-4-ylaminocarbonyl)-methoxy]-phenyl}-3,5-
dimethyl-4-pyrazolesulfonamide (MS m/e = 415) was
produced analogously to example 17.
Example 41
N-~5-Methyl-3-[2-(pyridin-4-ylamino)-ethoxYl-phenyl~-4-
fluorobenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 232C. The
starting material N-{5-methyl-3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl}-4-fluorobenzenesulfonamide
(MS m/e = 415; Fp. 156 - 159C was produced analogously
to example 17.
21~6729
- 60 -
Example 42
N- r 5-MethYl-3- r 2-(pyridin-4-ylamino)-ethoxY~-phenyl~-2-
fluorobenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 263C. The
starting material N-{5-methyl-3-[(pyridin-4-ylamino-
ca~bonyl)-methoxy]-phenyl}-2-fluorobenzenesulfonamide
(MS m/e = 415) was produced analogously to example 17.
Example 43
N-~5-Methyl-3-r2-(pyridin-4-ylamino)-ethoxy~-phenyl~-2
trifluoromethylbenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 217 - 222C.
The starting material N-{5-methyl-3-[(pyridin-4-ylamino-
carbo~yl)-methoxy]-phenyl}-2-trifluoromethylbenzene-
sulfonamide (MS m/e = 465) was produced analogously to
example 17.
Example 44
N-Methyl-N-~5-methYl-3-~2-(pYridin-4-ylamino)-ethoxyl-
phenyl~-4-methylbenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 180C. The
starting material N-methyl-N-{5-methyl-3-[(pyridin-4-
ylaminocarbonyl)-methoxy]-phenyl}-4-methylbenzene-
sulfonamide (MS m/e = 425) was produced analogously to
example 17.
- 21~6729
- 61 -
Example 45
N- r 5-Methyl-3- r 2-(pyridin-4-ylamino)-ethoxYl-Phen
2,6-difluorobenzenesulfonamide hydrochloride
was produced analogously to example 23. Fp. 263C. The
starting material N-~5-methyl-3-[(pyridin-4-ylamino-
carbonyl)-methoxy]-phenyl}-2,6-difluorobenzene-
sulfonamide (MS m/e = 433; Fp. 234 - 242C) was produced
analogously to example 17.
Exam~le 46
N-r5-Methyl-3-~2-(pyridin-4-ylamino)-ethoxy]-Phenyl~-2-
hydroxy-3-tert.butyl-5-methylbenzenesulfonamide
hYdrochloride
a) 50 ml (100 mmol) 2 N sodium hydroxide solution was
added to 27.2 g (87.0 mmol) (3-tert.butyloxy-
carbonylamino-5-methylphenoxy)-acetic acid ethyl
ester (example 57b) in 300 ml methanol and stirred
for 3 days at room temperature. The solvent was
partially removed in a vacuum, it was extracted
with ethyl acetate, the aqueous phase was acidified
with hydrochloric acid and extracted with ether. It
was dried and the solvent was removed in a vacuum.
15.6 g (3-tert.butyloxycarbonylamino-5-methyl-
phenoxy)-acetic acid is obtained of Fp. 120 -
122C.
b) This compound was reacted with 4-aminopyridine as
described in example lc) and one obtained N-(4-
~ ~156729
- 62 -
pyridinyl)-(3-tert.butyloxycarbonylamino-5-methyl-
phenoxy)-acetamide of Fp. 204 - 205C.
c) 25 ml trifluoroacetic acid was added to 5.00 g
(14.0 mmol) of this compound, stirred for
30 minutes at room temperature, it was made
alkaline with sodium hydroxide solution and the
precipitate was filtered by suction. 2.93 g (78 %)
N-(4-pyridinyl)-3-(amino-5-methylphenoxy)-acetamide
of Fp. 163C was obtained.
d) This compound was reduced as described in example
23 and 3-[2-(pyridin-4-ylamino)-ethoxy]-5-methyl-
aniline was obtained in a 50 % yield of Fp. 208C.
e) This compound was reacted with 2-hydroxy-3-
tert.butyl-5-methylbenzenesulfonyl chloride as
described in example la) and the title compound was
obtained. Amorphous. MS + FAB: 470.
Example 47
N-~5-Methyl-3-~2-(pyridin-4-Ylamino)-ethoxy]-Phenyl~-3-
benzothiophene-sulfonamide hydrochloride
was produced analogously to example 46. For this the
compound obtained in example 46d) was reacted with
benzothiophene-3-sulfonyl chloride. Fp. 130C (decomp.).
21~6729
- 63 -
Example 48
N-~5-Methyl-3- r 2-lpyridin-4-Ylamino)-ethoxy~-phenyl~-
benzo-2,3,1-thiadiazole-4-sulfonamide hydrochloride
was produced analogously to example 46. For this the
compound obtained in example 46d) was reacted with
benzo-2,3,1-thiadiazole-4-sulfonyl chloride. Fp. 110C.
Example 49
N-~5-Methoxy-3-[2-(pyridin-4-ylamino)-ethoxyl-phenyl~-4
fluorobenzenesulfonamide hydrochloride
a) 16.0 g (115 mmol) 3-hydroxy-5-methoxyphenol (G.
Rodighiero, C. Antonello, Il Farmaco, Ed. Sci. 10,
889 - 896, (1955)), 3.7 g ammonium chloride,
13.8 ml water and 24 ml concentrated ammonia were
heated in a 100 ml autoclave for 12 hours to 130C.
After cooling, the contents of the autoclave were
rinsed out with methanol, the solvent was removed
in a vacuum, the residue was triturated with -ethyl
acetate, insoluble material (6.5 g) was removed by
filtration, the solvent was removed in a vacuum,
the oily residue was applied to a nutsch filter
with silica gel and rewashed with heptane/ethyl
acetate 1:1. The solvent of the filtrate was
removed and 10.4 g 3-hydroxy-5-methoxyaniline was
obtained as a red oil.
b) This compound (10.4 g, 75.0 mmol) was acetylated in
100 ml methylene chloride in the presence of 0.1 g
4-dimethylaminopyridine with 100 ml acetic
_ 21~729
- 64 -
anhydride for 12 hours at room temperature. The
solvent was removed in a vacuum, 200 ml methanol
and 20 ml saturated sodium carbonate solution was
added to the residue (mainly diacetyl compound) and
it was stirred for 3 hours at room temperature. The
solvent was removed in a vacuum, 250 ml water was
added, it was acidified with concentrated
hydrochloric acid and extracted with ethyl acetate.
Removal of the solvent yielded 11 g (81 %) N-(3-
hydroxy-5-methoxy-phenyl)-acetamide of Fp. 126C.
c) This compound (11.0 g, 61.0 mmol) was alkylated in
100 ml dry dimethylformamide in the presence of
9.1 g (65 mmol) potassium carbonate with 6.9 ml
(65 mmol) ethyl chloroacetate for 8 hours at 60C.
It was diluted with water, acidified with
hydrochloric acid and extracted with ethyl acetate.
The organic phase was extracted with water, the
organic phase was dried over magnesium sulfate,
filtered and the solvent was removed in a vacuum.
10.8 g (66 %) 2-(3-acetamido-5-methoxy-phenoxy)-
acetic acid ethyl ester was obtained as an oil.
d) This compound (10.8 g, 40 mmol) in 70 ml ethanol
was stirred for 4 hours with 30 ml 2 N sodium
hydroxide solution, the solvent was removed in a
vacuum, water was added and it was acidified. The
precipitate (5.5 g carboxylic acid) was filtered by
- suction, dissolved in 50 ml ethanol, 50 ml 10 N
sodium hydroxide solution was added and boiled for
8 hours under reflux. It was acidified with
- concentrated hydrochloric acid, the solvent was
removed in a vacuum, 100 ml methanol was added and
it was stirred for 12 hours at room temperature.
The solvent was removed in a vacuum, it was
~ 2156729
- 65 -
digested with ethyl acetate, filtered by suction
and 5.6 g 2-(3-amino-5-methoxy-phenoxy)-acetic acid
methyl ester was obtained (MS, m/e = 211).
e) 2-[3-(4-Fluorobenzenesulfonylamino)-5-methoxy-
phenoxy?-acetic acid methyl ester (MS m/e = 369)
was obtained from this as an oil by reaction with
4-fluorobenzenesulfonyl chloride as described in
example la).
f) 2-[3-(4-Fluorobenzenesulfonylamino)-5-methoxy-
phenoxy)-acetic acid of Fp. 161C was obtained from
this in a yield of 95 % as described in example
lb).
g) N-(4-Pyridinyl)-2-[3-(4-fluorobenzenesulfonyl-
amino)-5-methoxy-phenoxy)-acetamide of Fp. 161C
was obtained from this in a yield of 58 % as
described in example lc).
h) The title compound of Fp. 62C was obtained from
this in a yield of 76 % as described in example 23.
Example 50
N-~3-[2-(PYridin-4-ylamino)-ethoxy~-phenyl~-2-
chlorobenzenesulfonamide
was produced analogously to example 1 in a yield of
58 %. Melting point 221 - 223C.
~ 21a6729
- 66 -
Example 51
N-Methyl-N-~3-~2-(pyridin-4-ylamino)-ethoxY]-phenyl~-2-
chlorobenzenesulfonamide
was produced analogously to example 12 in a yield of
22 %. Melting point 188 - 190C.
Example 52
N-2-Propyl-N-~3-~2-tpyridin-4-ylamino)-ethoxy]-phenyl~-
benzenesulfonamide
was produced analogously to example 12 in a yield of
47 %. Oil. MS (m/e) = 411.
Example 53
N-Methyl-N-~3- r 2-(pyridin-4-ylamino)-ethoxy]-phenyl~-2-
thiophenesulfonamide
was produced analogously to example 12 in a yield of
12 %. Melting point 179 - 181C.
Example 54
N-~5-MethYl-3-[2-(pyridin-4-ylamino)-ethoxYl-phenyl~-1-
naphthalenesulfonamide hydrochloride
was produced analogously to example 17 in a yield of
14 %. Melting point 215 - 218C.
~156729
- 67 -
Example 5S
N-~5-Methyl-3-~2-(pyridin-4-ylamino)-ethoxyl-Phenyl~-2-
thiophenesulfonamide hYdrochloride
was produced analogously to example 17 in a yield of
24 %. Melting point 252 - 254C.
Example 56
N-~5-Methyl-3-[2-(pyridin-4-ylamino)-ethoxy~-phenyl~-2-
chlorobenzenesulfonamide hydrochloride
was produced analogously to example 17 in a yield of
42 %. Melting point 254 - 258~C.
Example 57
N-Methyl-N-~5-methyl-3-[2-(pyridin-4-ylamino)-ethoxyl-
phenyl~-1-chlorobenzenesulfonamide hydrochloride
a) 96 g (0.78 mol) 3-hydroxy-5-methyl-aniline (F.
Wessely, H. Eibel, G. Friedrich, "Monatshefte Chem.
83, 24 - 30, (1952)) in 1.2 l dioxane and 840 ml
water was admixed with 420 ml 2 N sodium hydroxide
solution and with 171 g (0.78 mol) ditert.butyl-
dicarbonate while cooling on ice. It was stirred
for 12 hours at room temperature, the solvent was
removed in a vacuum, it was acidified to pH 2 - 3
while cooling on ice and extracted with ethyl
acetatè. The organic phase was dried over sodium
sulfate, filtered and the solvent was removed in a
vacuum. 174 g (quantitative) N-(tert.butyloxy-
`~ s 21~6729
- 68 -
carbonyl)-3-hydroxy-5-methyl-aniline was obtained
as an oil. MS (m/e) = 223.
b) 132 g (0.59 mol) of this compound in 400 ml dry
dimethylformamide, 90 g (0.65 mol) potassium
carbonate and 69 ml (0.65 mol) ethyl chloroacetate
were heated for 3 hours to 70C. It was poured into
1 l ice water, extracted with ethyl acetate, the
organic phase was dried over sodium sulfate,
filtered and the solvent was removed in a vacuum.
174 g (95 %) 2-(3-tert.butyloxycarbonyl-amino-5-
methyl-phenoxy)-acetic acid ethyl ester was
obtained as an oil. MS (m/e) = 309.
c) 174 g (0.562 mol) of this compound was admixed with
200 ml trifluoroacetic acid while cooling on ice,
it was stirred for 2 hours at room temperature and
the solvent was removed in a vacuum. 2 N
hydrochloric acid was added to the residue, it was
extracted with ethyl acetate, the aqueous phase was
made alkaline with sodium hydroxide solution and it
was extracted with ethyl acetate. The organic phase
was dried with sodium sulfate, filtered and the
solvent was removed in a vacuum. 87.5 g (74 %)
2-(3-amino-5-methyl-phenyloxy)-acetic acid ethyl
ester was obtained as an oil. MS (m/e) = 209.
d) As described in example 17a), this compound was
reacted with 2-chlorobenzenesulfonyl chloride and
2-[3-(2-chlorobenzenesulfonylamino)-5-methyl-
phenoxy]-acetic acid ethyl ester of Fp. 133 - 137C
was obtained in a yield of 56 %.
P 2156729
- 69 -
e) This compound was methylated as described in
example 12a) and N-methyl-2-[3-(2-chlorobenzene-
sulfonylamino)-5-methyl-phenoxy]-acetic acid ethyl
ester was obtained in a quantitative yield. Oil.
MS (m/e) = 398.
f) This compound was saponified as described in
example lb) and N-methyl-2-[3-(2-chlorobenzene-
sulfonylamino)-5-methyl-phenoxy]-acetic acid was
obtained in a quantitative yield. Fp. 113 - 115C.
g) This compound was reacted with 4-aminopyridine as
described in example lc) and 2-{3-[(2-chloro-
benzenesulfonyl)-methyl-amino]-5-methyl-phenoxy}-N-
pyridin-4-yl-acetamide was obtained as an oil in a
yield of 68 %.
h) This compound was reduced as described in example
ld) and the title compound was obtained in a yield
of 41 %. Fp. 213 - 215C.
Example 5-8
N-MethYl-N-~5-methyl-3-[2-(pyridin-4-ylamino)-ethoxy~-
phenyl~-benzenesulfonamide hydrochloride
The compound from example 57 (0.86 g, 2 mmol) was
hydrogenated in 30 ml ethanol in the presence of 0.3 g
10 % palladium on carbon at room temperature and normal
pressure. Hydrogen uptake 55 ml. It was filtered and the
solvent was removed in a vacuum. It was digested with
ether and 0.75 g (86 %) of the title compound was
obtained of Fp. 182 - 184C.
`-- P 21S~ 729
- 70 -
Example 59
N- r 2-MethoxY-5- r 2-(PYridin-4-ylamino)-ethoxyl-phen
benzenesulfonamide
a) 8.4 g (50 mmol) ethyl bromoacetate was added
dropwise in an ice bath to 8.5 g (50 mmol)
2-hydroxy-4-nitroanisole and 13.8 g (100 mmol)
potassium carbonate in 120 ml acetonitrile. It was
stirred for 12 hours at room temperature, the
solvent was removed in a vacuum, water was added to
the residue and it was extracted with ethyl
acetate. The organic phase was dried with sodium
sulfate, filtered and the solvent was removed in a
vacuum. 12.7 g (quantitative) 2-(2-methoxy-5-nitro-
phenoxy)-acetic acid ethyl ester was obtained as an
oil. MS (m/e) = 255.
b) This compound (12.1 g, 47 mmol) was hydrogenated in
300 ml methanol in the presence of 5 g Raney nickel
at normal pressure and room temperature. When 3.4 l
hydrogen had been taken up, it was filtered and the
solvent was removed in a vacuum. 10.7 g
(quantitative) 2-(2-methoxy-5-amino-phenoxy)-acetic
acid ethyl ester was obtained as an oil. MS (m/e) =
225.
c) This compound (10.7 g, 47 mmol) was reacted with
benzenesulfonyl chloride as described in example
la) and 17.2 g (quantitative) 2-(2-methoxy-5-
benzenesulfonylamino-phenoxy)-acetic acid ethyl
ester was obtained. MS (m/e) = 413.
~1 56729
- 71 -
d) Following the instructions of example lb), 11.8 g
(74 %) 2-(2-methoxy-5-benzenesulfonylamino-
phenoxy)-acetic acid was obtained from this
compound. MS (m/e) = 337.
e) Following the instructions of example lc), S g (35
%) N-(4-pyridinyl)-2-(2-methoxy-5-
benzenesulfonylamino-phenoxy)-acetamide of
Fp. 179C was obtained from this compound.
f) Following the instructions of example 23, the title
compound of Fp. 188 - 189C was obtained from this
compound.
Example 60
N-~2-Methyl-5-[2-(pyridin-4-ylamino)-ethoxyl-phenyl~-
benzenesulfonamide
was produced analogously to example 59 except that in
step a) 2-hydroxy-4-nitrotoluene was used instead of
2-hydroxy-4-nitroanisole. This precursor was prepared as
follows: 100 g 2-amino-4-nitrotoluene was stirred into
300 ml concentrated sulphuric acid at 50C, until it was
all dissolved (30 min), 2.5 kg ice was added, it was
cooled to -15C and a solution of 50 g sodium nitrite in
200 ml water was added dropwise in such a way that the
temperature did not exceed 0C. This solution was added
to a mixture of 500 ml concentrated sulphuric acid and
1 1 water which was boiling under reflux. It was boiled
for 1 hour under reflux, allowed to stand for 12 hours
and the precipitate was filtered by suction. 87.1 g
(87 %) 2-hydroxy-4-nitrotoluene of Fp. 117-120C was
obtained.
-- ~ 2156729
- 72 -
a) 2-(2-MethyI-5-nitro-phenoxy)-acetic acid ethyl
ester as an oil. MS (m/e) = 239.
b) 2-(2-Methyl-5-amino-phenoxy)-acetic acid ethyl
ester as an oil. MS (m/e) = 209.
c) 2-(2-Methyl-5-benzenesulfonylamino-phenoxy)-acetic
acid ethyl ester. Fp. 78 - 83C.
d) 2-(2-Methyl-5-benzenesulfonylamino-phenoxy)-acetic
acid. Fp. 157 - 160C.
e) N-(4-Pyridinyl)-2-(2-methyl-5-benzenesulfonylamino-
phenoxy)-acetamide of Fp. 157 - 161C.
f) Title compound of Fp. 179 - 180C.
Example 61 -
Benzenesulfonic acid-5-methYl-3- r 2-(pyridin-4-ylamino)-
ethoxy~-phenyl ester
a) 7.1 g (50 mmol) 5-methyl-resorcinol, 10 g
(100 mmol) potassium bicarbonate and 12.6 g
(55 mmol) benzyl bromoacetate were boiled in 70 ml
acetonitrile for 24 hours under reflux. The solvent
was removed in a vacuum, water was added to the
residue and it was extracted with ether, the ether
phase was extracted three times with 0.1 N sodium
hydroxide solution, the ether phase was dried over
sodium sulfate, filtered and the solvent was
removed in a vacuum. The residue (7.75 g) was
separated on silica gel with isohexane/ethyl
21~729
- 73 -
acetate (9:1) and 4.0 g (29 %) 2-(3-hydroxy-5-
methyl-phenoxy)-acetic acid benzyl ester was
obtained as an oil. MS (m/e) = 272.
b) 2.0 g (7.5 mmol) of this compound was reacted with
benzenesulfonyl chloride analogously to example la)
and 2.1 g (68 %) 2-(3-benzenesulfonyloxy-5-methyl-
phenoxy)-acetic acid benzyl ester was obtained as
an oil. MS (m/e) = 412.
c) 2.0 g (5 mmol) of this compound in 150 ml methanol
was hydrogenated in the presence of 0.5 g 10 %
palladium on carbon for 1 hour at room temperature
and normal pressure until 140 ml hydrogen had been
taken up. It was filtered, ether was added and
extracted three times with a sodium bicarbonate
solution. The sodium bicarbonate solution was
acidified with 2 N sulphuric acid, extracted with
ether, dried, the solvent was removed in a vacuum
and 600 mg (38 %) 2-(3-benzenesulfonyloxy-5-methyl-
phenoxy)-acetic acid was obtained. MS (m/e) = 322.
d) 0.6 g (2 mmol) of this compound was reacted with
4-aminopyridine analogously to example lc) and
N-(pyridin-4-yl)-2-(3-benzenesulfonyloxy-5-methyl-
phenoxy)-acetamide was obtained (16 %).
MS (m/e) = 392.
e) The title compound was obtained from this
analogously to example 23. Fp. 144 - 146C.
~ - - 21~729
- 74 -
Example 62
2-Chlorobenzenesulfonic acid-5-methyl-3- r 2-(pyridin-4-
Ylamino)-ethoxy~-phenyl ester
was produced analogously to example 61. Fp. 156 - 158C.
Intermediate steps: 2-[3-(2-Chlorobenzenesulfonyloxy)-5-
methyl-phenoxy]-acetic acid: Fp. 157 - 161C.
N-(Pyridin-4-yl)-2-[3-[2-chlorobenzenesulfonyloxy)-5-
methyl-phenoxy]-acetamide. MS (m/e) = 432.
Example 63
4-Fluorobenzenesulfonic acid-5-methyl-3- r 2-(pyridin-4-
Ylamino)-ethoxy~-phenYl ester
was produced analogously to example 61 except that in
step b) 4-fluorobenzenesulfonyl chloride was used.
Fp. 161 - 163C.
ExamPle 64
1-NaPhthalenesulfonic acid-5-methyl-3-~2-(pyridin-4-
Ylamino)-ethoxy~-phenyl ester
was produced analogously to example 61 except that in
step b) 1-naphthalenesulfonyl chloride was used.
Fp. 95 - 99C.
~ 21~6729
- 75 -
Example 65
2-Thiophenesulfonic acid-5-meth~1-3-[2-fPyridin-4-
ylamino)-ethoxy~-phenyl ester
a) 24.8 g (200 mmol) 5-methylresorcinol, 43.8 g
(240 mmol) 2-thiophenesulfonyl chloride and 1.5 g
solid sodium bicarbonate in 200 ml water were
covered with a layer of 100 ml ether and the pH was
kept constant at 7.2 with a dosing apparatus using
saturated sodium bicarbonate solution. It was
stirred for 12 hours at room temperature at
pH = 7.2, the water phase was separated, the ether
phase was dried with sodium sulfate, it was
filtered and the solvent was removed in a vacuum.
Thiophenesulfonic acid-3-hydroxy-5-methyl-phenyl
ester was obtained in a quantitative yield as an
oil. MS (m/e) = 270.
b) This compound was reacted with ethyl bromoacetate
analogously to example 18a and 2-[3-(2-thiophene-
sulfonyloxy)-5-methyl-phenoxy]-acetic acid ethyl
ester was obtained. MS (m/e) = 356.
c) 2-t3-(2-Thiophenesulfonyloxy)-5-methyl-phenoxy]-
acetic acid was obtained from this compound
analogously to example lb) of Fp. 142 - 143C.
d) N-(Pyridin-4-yl)-2-[3-(2-thiophenesulfonyloxy)-5-
methyl-phenoxy]-acetamide was obtained from this
compound analogously to example lc). Fp. 136 -
138C.
- ! 2 1 5 6 7 2 9
- 76 -
e) The title compound of Fp. 176C was obtained from
this compound.
ExamPle 66
(2-Benzyloxycarbonyl-benzenesulfonic acid)-5-methyl-3-
r 2-(pyridin-4-ylamino)-ethoxyl-Phenyl ester
a) 5-Methylresorcinol was reacted analogously to
example 6la) with ethyl bromoacetate and 2-(3-
hydroxy-5-methyl-phenoxy)-acetic acid ethyl ester
was obtained as an oil. MS (m/e) = 210.
b) Analogously to example 61b), 2-[3-(2-benzyloxy-
carbonyl)-benzenesulfonyloxy-5-methyl-phenoxy]-
acetic acid ethyl ester (MS (m/e) = 484) was
obtained from this as an oil by reaction with
2-benzyloxy-carbonyl-benzenesulfonyl chloride.
c) This compound was saponified for 4 h at room
temperature analogously to example lb) and 63 %
2-[3-(2-benzyloxycarbonyl-benzenesulfonyloxy)-5-
methyl-phenoxy]-acetic acid was obtained.
MS (m/e) = 456.
d) N-(Pyridin-4-yl)-2-[3-(2-benzyloxycarbonyl-
benzenesulfonyloxy)-5-methyl-phenoxy]-acetamide was
obtained from this. MS (m/e) = 532.
e) The title compound was obtained from this
analogously to example 23. MS (m/e) = 518.
2156729
- 77 -
Example 67
(2-Carboxy-benzenesulfonic acid)-5-methyl-3-~2-(pyridin-
4-ylamino)-ethoxYl-phenyl ester
2.5 g (1 mmol) of the compound from example 66 was
hydrogenated in 100 ml methanolic ammonia solution in
the presence of 1 g 10 % palladium on carbon at normal
pressure and room temperature. It was filtered, the
solvent was removed in a vacuum, the residue was
triturated with isopropanol, it was filtered by suction
and recrystal~ized from ethanol. 0.4 g (14 %) of the
title compound of Fp. 189C was obtained.
Example 68
(2-Methyl-benzenesulfonic acid)-5-methyl-3-~2-(pyridin-
4-ylamino)-ethoxy]-phenYl ester
was produced analogously to example 61. Fp. 152 - 154C.
Precursor: N-(pyridin-4-yl)-2-[3-(2-methyl-benzene-
sulfonyloxy)-5-methyl-phenoxy]-acetamide. Fp. 158 -
160C.
Example 69
(2-Methoxy-benzenesulfonic acid)-5-methyl-3-~2-(pyridin-
4-ylamino)-ethoxy]-phenyl ester
was produced analogously to example 61. Fp. 116 - 119C.
Precursor: N-(pyridin-4-yl)-2-[3-(2-methoxy-benzene-
sulfonyloxy)-5-methyl-phenoxy]-acetamide. Fp. 156 -
159C
~ 2156729
-- 78 --
Example 70
(2-Nitro-benzenesulfonic acid)-5-methYl-3- r 2-(PYridin-4-
ylamino)-ethoxyl-phenyl ester
was produced analogously to example 61. Fp. 137 - 140C.
Precursor: N-(pyridin-4-yl)-2-[3-(2-nitrobenzene-
sulfonyloxy)-5-methyl-phenoxy]-acetamide.
MS (m/e) = 453.
Example 71
(2-Amino-benzenesulfonic acid~-5-methyl-3-~2-(Pyridin-4-
ylamino)-ethoxyl-phenyl ester
1.0 g (2.33 mmol) of the compound from example 70 was
hydrogenated in 40 ml methanol in the presence of 1 g
Raney nickel for 1.5 hours at room temperature and
normal pressure. It was filtered, the solvent was
removed in a vacuum, the residue was admixed with 25 ml
tetrahydrofuran and 25 ml ether, extracted with 0.05 M
sodium hydroxide solution, the organic phase was dried,
filtered and the solvent was removed in a vacuum. 0.5 g
(54 g6) of the title compound of Fp. 168 - 171C was
obtained.
Example 72
2-Chlorobenzenesulfonic acid-5-methyl-3-~2-(N-methyl-
pyridin-4-ylamino)-ethoxyl-phenyl ester
a) N-Methyl-N-(pyridin-4-yl)-2-[3-(2-chlorobenzene-
sulfonyloxy)-5-methyl-phenoxy]-acetamide (MS (m/e)
2156729
- 79 -
= 447) was obtained by reacting 2-[3-(2-
chlorobenzene-sulfonyloxy)-5-methyl-phenoxy]-acetic
acid with 4-methylamino-pyridine according to
example 62.
:
b) The title compound of Fp. 152 - 161C was obtained
from this analogously to example 23.
ExamPle 73
Benzenesulfonic acid-5-chloro-3-~2-(pyridin-4-Ylamino)
ethoxyl-Phenyl ester
a) 98.8 g (0.57 mol) 5-chlororesorcinol dimethyl ether
and 108 ml (1.14 mol) boron tribromide in 400 ml
methylene chloride were stirred for 72 hours at
room temperature. It was extracted with water, the
aqueous phase was extracted with n-butanol, most of
the n-butanol was removed in a vacuum and it was
allowed to crystallize for 12 hours at 4C. 19.5 g
(24 %) 5-chlororesorcinol of Fp. 70 - 71C was
obtained.
b) 3 0 g (21 mmol) of this compound in 50 ml water was
covered with a layer of 20 ml ether, saturated
sodium bicarbonate solution was added until a pH of
5.2 was reached. 8.6 ml (21 mmol) benzenesulfonyl
chloride was slowly added while keeping the pH
constant, the pH was increased to 7.0 and it was
stirred for 48 hours at room temperature while
keeping the pH value constant. It was extracted
with ether, the ether phase was extracted with
0.1 N sodium hydroxide solution, the sodium
hydroxide solution was acidified with 2 N sulphuric
2156729
- 80 -
acid and extracted three times with ether. The
solvent was removed in a vacuum and 1.7 g (28 %)
benzene-sulfonic acid-3-chloro-5-hydroxy-phenyl
ester was obtained. MS (m/e) = 284.
c) This compound was reacted with ethyl bromoacetate
analogously to example 18a) and 2-[3-chloro-5-
(phenylsulfonyloxy)-phenoxy]-acetic acid ethyl
ester was obtained in a yield of 95 %. MS (m/e) =
370.
d) This compound was saponified analogously to example
lb) to obtain 2-[3-chloro-5-(phenylsulfonyloxy)-
phenoxy]-acetic acid of Fp. 136 - 138C in a yield
of 80 %.
e) This compound was reacted with 4-aminopyridine
analogously to example lc) and N-(pyridin-4-yl)-2-
[3-chloro-5-(phenylsulfonyloxy)-phenoxy]-acetamide
of Fp. 173 - 176C was obtained in a yield of 70 %.
f) This compound was reduced analogously to example
23) and the title compound of Fp. 144 - 146C was
obtained. Hydrochloride: Fp. 173 - 176C.
Example 74
2-Chlorobenzenesulfonic acid-5-chloro-3- r 2-(Pyridin-4-
ylamino)-ethoxYl-phenYl ester
was produced analogously to example 73. Intermediate
steps:
-- 215G729
- 81 -
b) 2-Chlorobenzenesulfonic acid-3-chloro-5-hydroxy-
phenyl ester. Fp. 99 - 105C.
c) 2-[3-Chloro-5-(2-chloro-phenylsulfonyloxy)-
phenoxy]-acetic acid ethyl ester as an oil.
MS (m/e) = 405.
d) 2-[3-Chloro-5-(2-chloro-phenylsulfonyloxy)-
phenoxy]-acetic acid. Fp. 140 - 142C.
e) N-(Pyridin-4-yl)-2-[3-chloro-5-(2-chlorophenyl-
sulfonyloxy)-phenoxy]-acetamide. Fp. 158 - 160C.
f) Title compound. Fp. 149 - 150C.
Example 75
Benzenesulfonic acid-3-~2-(pyridin-4-ylamino)-
ethylaminol-phenyl ester
a) 15 g (54 mmol) benzenesulfonic acid-(3-nitro-phenyl
ester) in 200 ml methanol was hydrogenated in the
presence of 2.5 g 10 % palladium on carbon at
normal pressure and room temperature. It was
filtered and the solvent was removed in a vacuum.
The residue (13 g benzenesulfonic acid-(3-amino-
phenyl ester)), 4.3 g sodium acetate and 8.7 g
ethyl bromoacetate in 10 ml ethanol were boiled for
12 hours under reflux. Water was added and it was
extracted with ether. The ether was removed in a
vacuum and 17.3 g (99 %) 2-[3-(phenyl-sulfonyloxy)-
phenylamino]-acetic acid ethyl ester was obtained
as an oil. MS (m/e) = 335.
- 2156729
- 82 -
b) This compound was saponified analogously to example
lb) to form 2-[3-(phenylsulfonyloxy)-phenylamino]-
acetic acid. Yield 65 %. MS (m/e) = 307.
c) This compound was reacted with 4-aminopyridine
analogously to example lc) to form N-(pyridin-4-
yl)-2-t3-tphenylsulfonyloxy)-phenylamino]-
; acetamide. Oil. MS (m/e) = 383.
d) The title compound was obtained from this
analogously to example 23. 0.6 g of the compound
which formed as an oil was dissolved in 10 ml ethyl
acetate and a solution of 220 mg cyclohexane-
sulfamic acid in 10 ml ethyl acetate was added. A
few drops of isopropanol were added and it was
allowed to crystallize. 0.3 g of the cyclaminate of
the title compound of Fp. 106 - 111C was obtained.
Example 76
Benzenesulfonic acid-3-methyl-5- r 2-tpyridin-4-ylamino)-
ethylamino~-phenyl ester
a) 12.3 g (100 mmol) 3-hydroxy-5-methylaniline (see
example 57) and 25.1 g (170 mmol) phthalic acid
anhydride in 250 ml acetic acid were boiled for
1 hour under reflux. 250 ml water was added, it was
filtered while hot, 250 ml water was added to the
filtrate and it was allowed to crystallize. It was
filtered, the precipitate was dissolved in 400 ml
hot methanol, admixed with active charcoal, the
-water was removed in a vacuum and 21.7 g (86 %)
3-phthalimido-5-methyl-phenol of Fp. 170 - 175C
was obtained.
-- 2156729
- 83 -
b) Benzenesulfonic acid-3-methyl-5-phthalimido-phenyl
ester was obtained from this analogously to example
la). MS (m/e) = 393.
c) 3.9 g (10 mmol) of this compound and 0.7 ml
(15 mmol) hydrazine hydrate in 10 ml ethanol and
30 ml methylene chloride were stirred for 12 hours
at room temperature, 4 ml concentrated hydrochloric
acid was added, stirred for 2 hours at room
temperature, filtered, the solvent was removed in a
vacuum, 2 N sodium hydroxide solution was added to
the residue and it was extracted with ether, the
ether phase was washed with water and with
saturated saline solution, the ether was removed in
a vacuum and 2.5 g (96 %) benzenesulfonic acid-3-
methyl-5-amino-phenyl ester was obtained.
MS (m/e) = 263.
d) 2.5 g (9.5 mmol) of this compound was reacted with
tosyl chloride analogously to example la) and
benzenesulfonic acid-3-methyl-5-(4-methylphenyl-
sulfonylamino)-phenyl ester was obtained in a
quantitative yield. MS (m/e) = 417.
e) This compound was alkylated with ethyl bromoacetate
analogously to example 18a) and 5 g (quantitative
yield) [4-methylbenzenesulfonyl-(3-benzene-
sulfonyloxy-5-methyl-phenyl)-amino]-acetic acid
ethyl ester was obtained. MS (m/e) = 503.
f) 5 g (10 mmol) of this compound in 60 ml 6 N
hydrochloric acid was boiled for 6 hours under
reflux. The solvent was removed in a vacuum, water
was added, it was neutralized with sodium
P 2156729
- 84 -
bicarbonate, extracted with ethyl acetate, the
aqueous phase was adjusted to pH 3 with 2 N
hydrochloric acid and extracted with ethyl acetate.
The ethyl acetate was removed in a vacuum and 2 g
(62 %) (3-benzenesulfonyloxy-5-methyl-phenyl)-
amino-acetic acid was obtained. MS (m/e) = 321.
g) This compound was reacted analogously to example
lc) and N-(pyridin-4-yl)-benzenesulfonyloxy-5-
methyl-phenyl)-amino-acetamide was obtained in a
yield of 12 %. MS (m/e) = 397.
h) The title compound was obtained from this compound
analogously to example 23) as an oil.
MS (m/e) = 383.
Example 77
N-~3-~2-(Pyridin-4-ylamino)-ethylamino~-Phen
benzenesulfonamide
a) 13.8 g (100 mmol) 3-nitroaniline, 12.3 g sodium
acetate (150 mmol) and 25 g (150 mmol) ethyl
bromoacetate in 5 ml dimethylsulfoxide were heated
for 48 hours to 80C. It was poured onto 400 ml
0.5 N hydrochloric acid, 15 ml isohexane and 10 ml
ether were added and it was allowed to crystallize.
It was filtered and 18.7 g (84 %) 3-nitro-phenyl-
amino-acetic acid ethyl ester was obtained.
Fp. 92C.
2156729
- 85 -
b) 3-Nitro-phenylamino-acetic acid was obtained from
this analogously to example lb) in a yield of 90 %.
Fp. 159 - 162C.
c) N-(Pyridin-4-yl)-3-nitro-phenylamino-acetamide was
obtained from this analogously to example lc) in a
yield of 89 %. Fp. 196 - 198C.
d) 10.4 g (38 mmol) of this compound was hydrogenated
in 200 ml methanol and 100 ml ethyl acetate in the
presence of 10 g Raney nickel at normal pressure
and at room temperature. It was filtered, the
solvent was removed in a vacuum and 7.7 g (82 %)
N-(pyridin-4-yl)-(3-aminophenylamino)-acetamide was
obtained. MS (m/e) = 292.
e) N-(Pyridin-4-yl)-(3-phenylsulfonylamino-
phenylamino)-acetamide was obtained from this
compound analogously to example la).
MS (mte) = 382.
f) The title compound was obtained from this
analogously to example 23) in a yield of 40 %.
MS (m/e) = 368.
ExamPle 78
N-~3-~2-(Pyridin-4-ylamino)-ethylaminol-Phenyl~- -
thioPhene-2-sulfonamide
a) N-(Pyridin-4-yl)-[3-(thiophene-2-ylsulfonylamino)-
phenylamino]-acetamide (MS (m/e) = 388) was
obtained in a yield of 59 ~ by reaction of the
-- 2156729
- 86 -
compound from example 77d) with 2-thiophene-
sulfonyl chloride analogously to example la).
b) The title compound was obtained from this
analogously to example 23) in a yield of 24 %.
Fp. 196 - 198C.
Example 79
N-~3-~2-(Pyridin-4-~lamino)-ethylamino~-5-trifluoro-
methyl-phenyl~-benzenesulfonamide
a) 15 g (270 mmol) iron powder was added in portions
to 24.5 g (100 mmol) 3,5-dinitrobenzenetrifluoride
in 180 ml boiling glacial acetic acid. It was
poured onto water, extracted with ethyl-acetate and
the ethyl acetate phase was neutralized with solid
sodium bicarbonate. It was filtered, the solvent
was removed in a vacuum, the residue (26.3 g) was
applied to silica gel and eluted with
isohexane/ethyl acetate (8:2). 13.0 g (63 ~)
3-nitro-5-trifluoromethylaniline of Fp. 80 - 84C
was obtained.
b) 5 0 g (24 mmol) of this compound was dissolved in
20 ml sulphuric acid and 17 ml water, it was cooled
to 0C and a solution of 1.9 g (27 mmol) sodium
nitrite in 10 ml water was added. The cold solution
was added to 250 ml boiling, concentrated copper
sulphate solution. When the formation of nitrogen
had ceased, it was extracted with ether. The ether
phase was extracted with O.OS N sodium hydroxide
solution, the aqueous phase was acidified with
dilute sulphuric acid and it was extracted with
`-- ~ 2156729
- 87 -
ether. The ether was removed in a vacuum and 3.4 g
(68 %) 3-nitro-5-trifluoromethyl-phenol of Fp. 82 -
84C was obtained.
c) 36.7 g (600 mmol) ethanolamine and 80.7 g
(550 mmol) phthalic acid anhydride in 290 ml
toluene were heated for 2 hours under reflux on a
water separator. After separating 9.3 ml water it
was allowed to cool, filtered and 95.1 g (90 %)
N-(2-hydroxyethyl)-phthalimide of Fp. 128 - 132C
was obtained.
d) 28.8 g (150 mmol) of this compound and 42.9 g
(225 mmol) tosyl chloride in 200 ml pyridine were
stirred for 3 hours at room temperature, acidified
with 2 N hydrochloric acid and extracted with ethyl
acetate. The ethyl acetate was removed in a vacuum
and 48.3 g (85 %) 4-toluenesulfonic acid-(2-
phthalimidoethyl)-ester of Fp. 144 - 148C was
obtained.
e) 1.7 g (12.5 mmol) of this compound, 2.6 g
(12.5 mmol) of compound 79c) and 4.1 g potassium
carbonate in 80 ml dimethylsulfoxide were stirred
for 12 hours at 50C. It was poured onto ice,
extracted with ethyl acetate, the ethyl acetate was
washed with 0.01 N sodium hydroxide and saturated
saline solution, the ethyl acetate was removed in a
vacuum and 1.9 g (40 %) N-{2-[2-(3-nitro-5-
trifluoromethylphenoxy)-ethyl]}-phthalimide of
Fp. 146 - 148C was obtained.
`-- 21SG729
- 88 -
f) 2-(3-Nitro-5-trifluoromethyl-phenoxy)-ethylamine
was obtained quantitatively from this analogously
to example 76c). MS (m/e) = 250.
g) 1.0 g (4 mmol) of this compound, 1.15 g (4.4 mmol)
4-nitro-tetrachloropyridine`(M. Roberts, H.
Suschitzky, J. Chem. Soc. C 1968, 2844 - 2848) and
0.48 ml (4.4 mmol) N-methylmorpholine in 20 ml
dioxane were stirred for 3 hours at room
temperature. Water was added, it was extracted with
ethyl acetate, the ethyl acetate was washed with
water and saturated saline solution, the ethyl
acetate was removed in a vacuum and 1.4 g (75 %)
N-(tetrachloropyridin-4-yl)-2-(3-nitro-5-trifluoro-
methylphenoxy)-ethylamine of Fp. 126 - 129C was
obtained.
.
h) This compound was reduced analogously to step a)
and N-(tetrachloropyridin-4-yl)-2-(3-amino-5-
trifluoromethylphenoxy)-ethylamine of Fp. 144 -
146C was obtained.
i) 0.4 g (0.92 mmol) of this compound and 0.12 ml
(0.92 mmol) benzenesulfonyl chloride in 5 ml
pyridine were stirred for 3 hours at room
temperature, acidified with 2 N hydrochloric acid,
extracted with ethyl acetate, washed with saturated
saline solution, the ethyl acetate was removed in a
vacuum and 0.4 g N-{3-[2-(tetrachloro-pyridin-4-
ylamino)-ethoxy]-5-trifluoromethyl-phenyl}-
benzenesulfonamide of Fp. 139-- 143C was obtained.
j) 0.4 g (0.7 mmol) of this compound was hydrogenated
in 50 ml methanol in the presence of 3.5 mmol
-- ~ 2156729
- 89 -
sodium methylate and 0.5 g 10 % palladium on carbon
at room temperature and normal pressure. It was
filtered, water was added and it was extracted with
ethyl acetate. The ethyl acetate was removed in a
vacuum and 0.2 g of the title compound of Fp. 140 -
144C was obtained.
ExamPle 80
3-MethoxY-N-methYl-N-PhenYl-5- r 2-tpyridin-4-ylamino)-
ethoxyl-benzenesulfonamide
a) 92 g (0.4 mmol) 3,5-dinitrobenzoyl chloride and
28.4 g (0.44 mol) sodium azide in 240 ml glacial
acetic acid were stirred for 8 hours at room
temperature, 400 ml water was added, the
precipitate was filtered and 80.8 g (85 %)
3,5-dinitrobenzoyl azide of Fp. 105C (decomp.) was
obtained.
b) 80.8 g (0.34 mol) of this compound in 500 ml acetic
anhydride was carefully heated until generation of
gas starts (90 - 100C) and it was kept at this
temperature for 4 hours. The solvent was removed in
a vacuum, the residue was digested with water and
136 g (quantitative) N-(3,5-dinitrophenyl)-
acetamide of Fp. 163C was obtained.
c) 136 g (0.34 mol) of this compound was boiled for
3 h under reflux in 500 ml ethanol and 500 ml
concentrated hydrochloric acid, undissolved
material was removed by filtration, the filtrate
was poured into 2 l water, the yellow precipitate
was filtered by suction and 41.4 g (66 %)
21a6729
-- 90 --
3,5-dinitroaniline was obtained. Fp. 140C
(decomp.).
d) 25 g (137 mmol) of this compound was dissolved in
50 ml glacial acetic acid and 100 ml concentrated
hydrochloric acid, 10.4 g (155 mmol) sodium nitrite
in 20 ml water was added dropwise within 5 minutes,
it was stirred for a further 15 minutes at this
temperature, the brown suspension was cooled to
-20C and it was added within 15 minutes to a
solution of 2.7 g copper dichloride dihydrate in
200 ml glacial acetic acid which was saturated with
sulphur dioxide and cooled to 0C. It was extracted
with ethyl acetate, the ethyl acetate was removed
in a vacuum and dried at 10-2 torr. 35.4 g (97 %)
dinitro-benzenesulfonyl chloride was obtained as a
brown solid which was used without further
purification.
e) 4 9 g (38 %) N-methyl-N-phenyl-3,5-dinitrobenzene-
sulfonamide (Fp. 175 - 178C) was obtained
analogously to example 79i) from 10.2 g (38.2 mmol)
of this compound and 4.5 ml (42 mmol) N-methyl-
anillne.
f) 3.5 g (10.4 mmol) of this compound in 31 ml
0.4 molar methanolic sodium methylate solution was
boiled for 1 hour under reflux. The solvent was
removed in a vacuum, the residue was digested with
ethyl acetate and it was purified over a silica gel
column (100 g silica gel). It was eluted with
isohexane/ethyl acetate 2:1 and 2.5 g (75 %)
N-methyl-N-phenyl-3-methoxy-5-nitrobenzene-
sulfonamide of Fp. 112C was obtained~
2156729
,
-- 91 --
g) This compound was hydrogenated analogously to
example 58) and 2.3 g N-methyl-N-phenyl-3-methoxy-
5-aminobenzenesulfonamide was obtained as an oil.
MS (m/e) = 292.
h) A solution of 630 mg (9 mmol) sodium nitrite in
2 ml water was added dropwise to a suspension of
2.3 g (7.8 mmol) of this compound in 10 ml water
and 5 ml concentrated sulphuric acid which had been
cooled to 0C, it was stirred for 2 hours at this
temperature, urea was added, it was heated for
15 minutes to 110C, extracted with ethyl acetate,
the ethyl acetate was washed with 2 N sodium
hydroxide solution, the solvent was removed in a
vacuum and 300 mg (13 %) N-methyl-N-phenyl-3-
methoxy-5-hydroxy-benzenesulfonamide was obtained
as an oil. MS (m/e) = 293.
i) 250 mg (0.85 mmol) of this compound was alkylated
with 0.14 ml ethyl bromoacetate analogously to
example 18a) and 360 mg (quantitative) [3-methoxy-
5-(methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid
ethyl ester was obtained as an oil. MS (m/e) = 379.
j) This compound was saponified analogously to example
lb) and 300 mg [3-methoxy-5-(methyl-phenyl-
sulfamoyl)-phenoxy]-acetic acid was obtained as a
viscous substance. MS (m/e) = 351.
k) 120 mg (33 %) N-(pyridin-4-yl)-[3-methoxy-5-
(methyl-phenyl-sulfamoyl)-phenoxy]-acetamide was
obtained from this compound analogously to example
lc). Fp. 105C.
- 21S6729
- 92 -
l) 45 mg (46 ~) of the title compound was obtained
from 100 mg of this compound analogously to example
ld). MS (m/e) = 413.
Example 81
3-Methoxy-N-benzyl-N-phenyl-5- r 2-(Pyridin-4-ylamino)-
ethoxy1-benzenesulfonamide
a) N-Benzyl-N-phenyl-3,5-dinitrobenzenesulfonamide was
obtained from compound 80c) and N-benzylaniline in
a yield of 65 % analogously to example 80d).
Fp. 200C.
b) N-Benzyl-N-phenyl-3-methoxy-5-nitrobenzene-
sulfonamide was obtained from this in a
quantitative yield analogously to example 80e).
Fp. 142C.
c) N-Benzyl-N-phenyl-3-methoxy-5-aminobenzene-
sulfonamide was obtained from this analogously to
79a) in a 56 % yield as a viscous substance.
MS (m/e) = 368.
d) N-Benzyl-N-phenyl-3-methoxy-5-hydroxy-benzene-
sulfonamide was obtained from this analogously to
example 80g). MS (m/e) = 369.
e) [3-Methoxy-5-(benzyl-phenyl-sulfamoyl)-phenoxy]-
acetic acid ethyl ester was obtained from this
analogously to example 18a) in a yield of 30 %.
MS (m/e) = 455.
`- 2156729
- 93 -
f) [3-Methoxy-5-(methyl-phenyl-sulfamoyl)-phenoxy]-
acetic acid was obtained quantitatively from this
analogously to example lb). MS (m/e) - 427.
g) N-(Pyridin-4-yl)-[3-methoxy-5-(methyl-phenyl-
sulfamoyl)-phenoxy]-acetamide was obtained from
this analogously to example lc) in a yield of 42 %.
Fp. 175C.
h) The title compound was obtained from this
analogously to example ld) in a 50 % yield as an
amorphous powder. MS (m/e) = 489.
ExamPle 82
3-Methoxy-N-phenYl-5-~2-(Pyridin-4-YlaminO)-ethOX
benzenesulfonamide
60 mg (0.12 mmol) of the compound from example 81) was
hydrogenated analogously to example 58) and 20 mg (40 %)
of the title compound was obtained as an amorphous
powder. MS (m/e) = 399.
Example 83
N-MethYl-N-~3-r2-(Pyridin-4-Ylamino)-ethoxyl-5-meth
phenYl~-benzenesulfonamide
a) 18.3 g (100 mmol) of the compound from 80c) was
reacted with 14.3 g (110 mmol) benzenesulfonyl
chloride analogously to example 79i) and 32.5 g
(quant.) N-(3,5-dinitrophenyl)-benzenesulfonamide
was obtained. Fp. 165C.
2156729
- 94 -
b) 44 g (136 mmol) of this compound was methylated
analogously to example 12a) and 25.1 g (54 %)
N-methyl-N-(3,5-dinitrophenyl)-benzenesulfonamide
was obtained. Fp. 125C.
c) 6.8 g (20 mmol) of this compound was reduced
analogously to 79a) and 6.1 g (quant.) N-methyl-N-
(3-amino-5-nitro-phenyl)-benzenesulfonamide was
obtained as an amorphous powder. MS (m/e) = 307.
d) 1.8 g (30 %) N-methyl-N-(3-hydroxy-5-nitro-phenyl)-
benzenesulfonamide was obtained from 6.1 g
(20 mmol) of this compound as an amorphous powder
analogously to example 80g). MS (m/e) = 308.
(380 after silylation).
e) 1.2 g (4 mmol) of this compound, 6 ml 1 N sodium
hydroxide solution, 1.3 g tetrabutylammonium
bromide, 6 ml dichloromethane and 0.4 ml
iodomethane were stirred for 12 hours at room
temperature. The organic phase was separated, the
solvent was removed in a vacuum and the residue was
purified on silica gel (150 g). It was eluted with
isohexane/ethyl acetate = 2:1 and 240 mg (18 %)
N-methyl-N-(3-methoxy-5-nitrophenyl)-benzene-
sulfonamide was obtained. Fp. 136C.
f) This compound was hydrogenated analogously to
example 58 and N-methyl-N-(3-methoxy-5-
aminophenyl)-benzenesulfonamide was obtained
quantitatively as an amorphous powder.
MS (m/e) = 292.
- 2156729
g) N-Methyl-N-(3-methoxy-5-hydroxyphenyl)-benzene-
sulfonamide was obtained from this analogously to
example 80g) in a 74 % yield as an amorphous
powder. MS (m/e) = 293.
h) [3-Methoxy-5-(N-methyl-phenylsulfonyl-amino)-
phenoxy]-acetic acid ethyl ester was obtained from
this in a yield of 89 % as an amorphous powder
analogously to example 18a). MS (m/e) = 379.
i) [3-Methoxy-5-(N-methyl-phenylsulfonyl-amino)-
phenoxy]-acetic acid (74 %; MS = 351), N-(pyridin-
4-yl)-[3-methoxy-5-(N-methyl-phenylsulfonyl-amino)-
phenoxy]-acetamide (34 %; MS = 427) and the title
compound (MS (m/e) = 413) as an amorphous powder
were obtained from this analogously to examples
81f) to 81h).
Example 84
3-Chloro-N-methyl-N-phenyl-5-~2-(Pyridin-4-ylamino)-
ethoxyl-benzenesulfonamide
a) The compound 80e) was reduced analogously to
example 79a) and N-methyl-N-phenyl-3-amino-5-nitro-
benzenesulfonamide was obtained in a 50 % yield.
Fp. 175C.
b) A solution of 760 mg (11 mmol) sodium nitrite in
2 ml water was added dropwise to 3.5 g (10 mmol) of
this compound in 40 ml 6 N hydrochloric acid at 0C
and then the suspension obtained was poured into a
solution which had been prepared as follows: 3.75 g
~ 2156729
96 -
copper sulfate pentahydrate and 1.35 g sodium
chloride were dissolved in 12 ml warm water, a
solution of 950 mg (7.5 mmol) sodium sulfite in
3 ml water was added dropwise, the precipitate was
rapidly filtered and it was dissolved in 6 ml
concentrated hydrochloric acid. It was slowly
heated to 100C, cooled, extracted with ethyl
acetate and filtered over a silicic acid gel (100 g
silica gel). It was eluted with isohexanetethyl
acetate and 1.45 g (43 %) N-methyl-N-phenyl-3-
chloro-5-nitrobenzenesulfonamide was obtained.
Fp. 143C.
c) This compound was reduced quantitatively
analogously to example 79a) to form N-methyl-N-
phenyl-3-chloro-5-aminobenzenesulfonamide.
Amorphous powder. MS (m/e) = 296.
d) The f-ollowing were produced from this analogously
to examples 83g) to 83i): N-methyl-N-phenyl-3-
chloro-5-hydroxybenzenesulfonamide (69 %,
amorphous, MS = 297); [3-chloro-5-(methyl-phenyl-
sulfamoyl)-phenoxy]-acetic acid ethyl ester (92 %,
amorphous, MS = 383); [3-chloro-5-(methyl-phenyl-
sulfamoyl)-phenoxy]-acetic acid (quant., amorphous,
MS = 355); N-(pyridin-4-yl)-[3-chloro-5-(methyl-
phenyl-sulfamoyl)-phenoxy]-acetamide (32 %,
amorphous, MS = 431); title compound (40 %;
amorphous MS = 417).
-- 2156729
- 97 -
ExamPle 85
3-Chloro-N-benzyl-N-phenyl-5- r 2-(pYridin-4-ylamino)-
ethoxy~-benzenesulfonamide
a) 12.3 g (46 mmol) of compound 80d) was reacted with
9.2 g (50 mmol) benzylamine analogously to example
79i) and 31.3 g (83 %) N-benzyl-N-phenyl-3,5-
dinitrobenzenesulfonamide was obtained. Fp. 205C.
b) This compound was reduced analogously to example
79a) and N-benzyl-N-phenyl-3-amino-5-nitrobenzene-
sulfonamide was obtained quantitatively. Fp. 170C.
c) N-Benzyl-N-phenyl-3-chloro-5-nitrobenzene-
sulfonamide was obtained from this analogously to
example 84b). Fp. 160C.
d) The following compounds were produced analogously
to examples 84c) to 84d): N-benzyl-N-phenyl-3-
chloro-5-aminobenzenesulfonamide (quant.,
amorphous, MS = 372); N-benzyl-N-phenyl-3-chloro-5-
hydroxy-benzenesulfonamide (quant., amorphous,
MS = 373); [3-chloro-5-(benzyl-phenyl-sulfamoyl)-
phenoxy]-acetic acid ethyl ester (15 %j oil,
MS = 459; [3-chloro-5-(benzyl-phenyl-sulfamoyl)-
phenoxy]-acetic acid (50 % amorphous, MS = 431);
N-(pyridin-4-yl)-[3-chloro-5-(benzyl-phenyl-
sulfamoyl)-phenoxy]-acetamide (44 %, amorphous,
MS = 507); title compound (40 %, amorphous,
MS = 493).
- 2156729
- 98 -
Example 86
3-Chloro-N-benzyl-N-phenyl-5- r 2-(pyridin-4.-ylamino)-
ethylaminol-benzenesulfonamide
The following compounds were produced from
N-benzyl-N-phenyl-3-chloro-5-aminobenzene-
sulfonamide (example 85d) analogously to examples
83h) to 83i): [3-chloro-5-(benzyl-phenyl-
sulfamoyl)-phenylamino]-acetic acid ethyl ester
(18 %, oil, MS = 458); [3-chloro-5-(benzyl-phenyl-
sulfamoyl)-phenylamino]-acetic acid (quant.,
amorphous, MS = 430); N-(pyridin-4-yl)-[3-chloro-5-
(benzyl-phenyl-sulfamoyl)-phenylamino]-acetamide
(25 %, amorphous, MS = 506); title compound (50 %,
amorphous, MS = 492).
ExamPle 87
N-MethYl-N-~3- r 2-(Pvridin-4-ylamino)-ethox~l-phenyl~-
benzenesulfonamide
a) N-Methyl-N-(3-amino-5-nitro-phenyl)-benzene-
sulfonamide (example 83c) was reacted analogously
to example 84b) to form N-methyl-N-(3-chloro-5-
nitrophenyl)-benzenesulfonamide (52 %, amorphous,
MS ~m/e) = 326).
b) This compound was reduced analogously to example
79a) to form N-methyl-N-(3-chloro-5-aminophenyl)-
benzenesulfonamide (42 %, oil, MS = 296);
[3-chloro-5-(N-methyl-phenylsulfonylamino)-
phenoxy]-acetic acid ethyl ester (89 %, amorphous,
~ 21S6~29
99
MS (m/e) = 383); [3-chloro-5-(N-methyl-phenyl-
sulfonyl-amino)-phenoxy]-acetic acid (88 %;
MS = 355); N-(pyridin-4-yl)-[3-chloro-5-(N-methyl-
phenylsulfonyl-amino)-phenoxy]-acetamide (28 %;
MS = 431) and the title compound (56 %) as an
amorphous powder. MS (m/e) = 417.
Example 88
N-Benzyl-N- r 3- r 2-(pyridin-4-Ylamino)-ethoxyl-5-chlor
phenyl~-benzenesulfonamide
a) The compound of example 83a) was benzylated with
benzyl bromide analogously to example 92c) and
N-benzyl-N-(3,5-dinitrophenyl)-benzenesulfonamide
was obtained (quant.). Fp. 170C.
b) This compound was reduced analogously to 79a) and
27 % N-benzyl-N-(3-amino-5-nitrophenyl)-benzene-
sulfonamide was obtained as an amorphous powder.
MS (m/e) = 383.
c) N-Benzyl-N-(3-chloro-5-nitrophenyl)-benzene-
sulfonamide was obtained from this compound
analogously to example 84b) in a 45 % yield.
Fp. 148C.
d) This compound was reduced analogously to example
79a) and 34 % N-benzyl-N-(3-chloro-5-aminophenyl)-
benzenesulfonamide was obtained. Fp. 145C.
e) The following compounds were obtained from this
analogously to examples 83g) to 83i): N-benzyl-N-
2156729
-- 100 --
(3-chloro-5-hydroxyphenyl)-benzenesulfonamide
(quant., amorphous, MS (m/e) = 373); [3-chloro-5-
(N-benzyl-phenylsulfonyl-amino)-phenoxy]-acetic
acid ethyl ester (quant., amorphous, MS (m/e) =
459); [3-chloro-5-(N-benzyl-phenylsulfonyl-amino)-
phenoxy]-acetic acid (82 %, Fp. 180C (decomp.));
N-(pyridin-4-yl)-[3-chloro-5-(N-benzyl-phenyl-
sulfonyl-amino)-phenoxy]-acetamide (54 %; Fp.
178C) and the title compound as an amorphous
powder. MS (m/e) = 493.
Example 89
N-~3-~2-Pyridin-4-ylamino)-eth~lamino~-5-bromoPhenyl~-
benzenesulfonamide
a) A solution of 7.6 g (110 mmol) sodium nitrite in
15 ml water was added dropwise within 15 minutes to
18.3 g (100 mmol) 3,5-dinitroaniline (example 80c)
in 100 ml glacial acetic acid and 100 ml 47 %
aqueous hydrobromic acid at 0C and the further
- procedure was as described in example 84b). 21.7 g
(88 %) 3,5-dinitrobromobenzene was obtained.
Fp. 65C.
b) This compound was reduced analogously to example
79a) and 17.4 g (91 %) 3-bromo-5-nitroaniline was
obtained. Fp. 105C.
c) This compound was alkylated analogously to example
18a) and 3-bromo-5-nitrophenylamino-acetic acid
ethyl ester was obtained quantitatively. Amorphous
MS (m/e) = 303.
21~6729
-- 101 --
d) This compound was saponified analogously to example
lb) and bromo-5-nitro-phenylamino acetic acid was
obtained (22 %, amorphous, MS (m/e) = 274).
e) This compound was reacted analogously to example
lc) and N-(pyridin-4-yl)-(3-bromo-5-nitro-phenyl-
amino)-acetamide was obtained in a 29 % yield.
Fp. 240C.
-f) This compound was hydrogenated analogously to
example 58) and N-(pyridin-4-yl)-(3-bromo-5-amino-
phenyl-amino)-acetamide was obtained
quantitatively. Amorphous. MS (m/e) = 321.
g) N-(Pyridin-4-yl)-[3-bromo-5-benzenesulfonylamino-
phenyl-amino)-acetamide was obtained from this.
Amorphous. MS (m/e) = 460.
h) The title compound was obtained from this
analogously to example ld). Amorphous.
MS (m/e) = 446.
ExamPle 9O
Benzenesulfonic acid-3-ethyl-5- r 2-(Pyridin-4-Ylamino)
ethoxy~-phenyl ester
a) 20 g 3,5-dimethoxybenzoic acid (110 mmol) in 80 ml
thionyl chloride was boiled for 1 hour under
reflux. The solvent was removed in a vacuum, the
residue was taken up in 500 ml dry methylene
chloride and dry ammonia was passed for 90 min over
the ice-cooled solution. It was stirred for a
21~672~
- 102 -
further 2 hours at room temperature, the solvent
was removed in a vacuum, the residue was stirred
for 12 hours in 200 ml water and 50 ml saturated
sodium bicarbonate solution, filtered, the
precipitate was dissolved in ethyl acetate,
filtered over active charcoal and the ethyl acetate
was removed until crystallization begun. 10.8 g
3,5-dimethoxybenzamide was obtained. Fp. 145C.
b) 19.5 ml (310 mmol) iodomethane in 30 ml ether was
added dropwise to 7.6 g (310 mmol) magnesium in
10 ml dry ether, it was boiled for 30 min under
reflux and then 11.6 g (63 mmol) 3,5-dimethoxy-
benzamide was added in portions. It was boiled for
22 h under reflux, 125 ml 6 N hydrochloric acid was
added dropwise while cooling on ice, it was stirred
for 16 hours at room temperature, the organic phase
was washed with water, the solvent was removed in a
vacuum and 9.4 g 3,5-dimethoxyacetophenone was
obtained as an oil. MS (m/e) = 180.
c) 9.4 g (52 mmol) of this compound in 150 ml ethanol
and 2 ml concentrated hydrochloric acid was
hydrogenated in the presence of 1 g palladium at
50C and 5 bar pressure. It was filtered, the
solvent was removed in a vacuum and 6.8 g (78 %)
3,5-dimethoxy-ethylbenzene was obtained as an oil.
MS (m/e) = 166.
d) 6.8 g (41 mmol) of this compound in 65 ml glacial
acetic acid and 25 ml concentrated 47 ~ hydrobromic
acid were boiled for 4 hours under reflux. The
solvent was removed in a vacuum, water was added to
the residue, it was extracted with ethyl acetate,
`~ 21~729
- 103 -
the ethyl acetate was washed with water, the
solvent was removed in a vacuum and the residue was
filtered over silica gel (isohexane/ethyl acetate =
3:1). 3.9 g (69 %) 5-ethyl-resorcinol was obtained
as an oil. MS (m/e) = 138.
e) 3 9 g (28 mmol) of this compound and 4.3 ml
(33 mmol) benzenesulfonyl chloride in 30 ml ether
and 60 ml saturated sodium bicarbonate solution
were stirred for 48 hours at room temperature. The
ether phase was separated, the solvent was removed
in a vacuum, the residue was filtered over silica
gel (isohexane/ethyl acetate 3:1) and 5.4 g (69 %)
benzenesulfonic acid-3-hydroxy-5-ethyl-phenyl ester
was obtained as an oil. MS (m/e) = 278.
f) The following compounds were obtained from this
analogously to examples 81e) to 81h): (3-benzene-
sulfonyloxy-5-ethyl-phenyloxy)-acetic acid ethyl
ester (77 %, oil, MS (m/e) = 364); (3-benzene-
sulfonyloxy-5-ethyl-phenyloxy)-acetic acid (59 %,
amorphous, MS (m/e) = 336); N-(pyridin-4-yl)-(3-
benzenesulfonyloxy-5-ethyl-phenyloxy)-acetamide
(70 %, amorphous, MS (m/e) = 412); title compound
(10 %, Fp. 136C).
Example 91
N-Benzyl-N-~3- r 2-(P~ridin-4-ylamino)-ethoxy~-5-methyl-
phenyl~-benzenesulfonamide
a) 107 g (1 mol) para-toluidine was reacted with
p-tosyl chloride analogously to example 79i) and
280 g (quant.) N-(4-methylphenyl)-4-methyl-benzene-
-
21S6729
-- 104 --
sulfonamide was obtained as an oil which was
reacted without further purification. Crystals from
ether of Fp. 105C.
b) 21 g (80 mmol) of this compound was added to 56 ml
fuming nitric acid, 32 ml concentrated sulphuric
acid was slowly added dropwise, it was poured onto
ice, the precipitate was washed with water and
46.6 g (73 %) yellow solid of Fp. 170C was
obtained which was heated for 10 minutes to 100C
in 80 ml concentrated sulphuric acid, it was poured
onto ice water and extracted with ethyl acetate.
The solvent was removed in a vacuum and 20 g (88 %)
2,6-dinitro-4-methylaniline of Fp. 171C was
obtained.
c) 800 ml glacial acetic acid was added to 20.5 g
(300 mmol) sodium nitrite in 220 ml sulphuric acid
and 53.5 g (270 mmol) 2,6-dinitro-4-methylaniline
was added in portions, it was stirred for 3 hours
at 40C until all had dissolved and this solution
was added dropwise to an ice-cooled suspension of
20 g copper oxide in ethanol, the solvent was
removed in a vacuum, water was added and it was
extracted with ethyl acetate. This preparation was
carried out again for a second time and a total of
88 g (88 %) 3,5-dinitrotoluene was obtained as an
amorphous powder.
d) 88 g (480 mmol) of this compound in 520 ml methanol
was saturated with 53 g ammonia and hydrogen
sulphide was passed in for 15 minutes during which
the temperature increased to 52C. It was boiled
for 30 minutes under reflux, 1 l water was added
- 21~6729
- 105 -
and 60.5 g (82 %) 3-methyl-5-nitroaniline was
obtained. Fp. 97C.
e) N-(3-Methyl-5-nitrophenyl)-benzenesulfonamide
(quantitative) was obtained from this analogously
to example 79i). Fp. 165C.
f) N-Benzyl-N-(3-methyl-5-nitrophenyl)-benzene-
sulfonamide (83 %) Fp. 154C and N-benzyl-N-(3-
methyl-5-aminophenyl)-benzenesulfonamide (34 %,
amorphous, MS (m/e) = 352) were obtained from this
analogously to examples 88a) to 88b).
g) The following compounds were obtained from this
analogously to examples 81e) to 81h): [3-(benzene-
sulfonyl-benzyl-amino)-5-methyl-phenylamino]-acetic
acid ethyl ester (quant., oil, MS (m/e) = 438);
[3-(benzenesulfonyl-benzyl-amino)-5-methyl-phenyl-
amino)-acetic acid (90 %, amorphous, MS (m/e) =
410); N-(pyridin-4-yl)-[3-(benzenesulfonyl-benzyl-
amino)-5-methyl-phenylamino)-acetamide (10 %,
amorphous, MS (m/e) = 486); title compound (47 %,
amorphous, MS (m/e) = 472).
Example 92
(BenzenesulfonYl-~3-methyl-5-~2-(Pyridin-4-ylamino)-
ethoxy~-phenyl~-amino)-acetic acid ethyl ester
a) 100 g 4-nitrotetrachloropyridine and 50.6 ml
ethanolamine in 1.2 l dioxane were stirred for
90 minutes at room temperature, the solvent was
removed ln a vacuum, water was added to the
~- 215672~
-- 106 --
residue, it was extracted with ethyl acetate, the
ethyl acetate was washed with water, the solvent
was removed in a vacuum and 105 g (72 %) 4-(2-
hydroxyethylamino)-tetrachloropyridine was
obtained. Fp. 131 - 133C.
b) 36.3 g (130 mmol) of this compound and 12.1 ml
(170 mmol) acetyl chloride in 450 ml glacial acetic
acid were stirred for 12 hours at room temperature,
poured onto ice, neutralized with concentrated
ammonia, extracted with ethyl acetate, the ethyl
acetate was washed with water, the solvent was
removed in a vacuum and 41.6 g (99 %) acetic acid-
2-(tetrachloropyridin-4-ylamino)-ethyl ester was
obtained. Fp. 72 - 75C.
c) A suspension of 10.8 g sodium hydride in 150 ml
dimethylformamide was added to 109 g (340 mmol) of
this compound in 700 ml dry dimethylformamide and
subsequently a solution of 54 ml benzyl bromide in
350 ml dimethylformamide was added dropwise at
10C. It was stirred for 2 hours at room
temperature, poured onto 7 l ice water, filtered,
the precipitate was washed with water, dissolved in
800 ml methanol and 200 ml dichloromethane, it was
concentrated until crystallization began and
allowed to crystallize. 120 g acetic acid-2-
(benzyl-tetrachloropyridin-4-ylamino)-ethyl ester
was obtained. Fp. 97 - 100C.
d) Enough dimethylformamide was added to 108 g
(260 mmol) of this compound in 1.2 l ethanol and
390 ml 2 N sodium hydroxide solution to dissolve it
all (ca. 0.5 l). It was stirred for 12 hours at
21~6729 -
- 107 -
room temperature, the solvent was removed in a
vacuum (finally at 1o-2 torr), 3 l water was added
to the residue and it was extracted with 1 l ethyl
acetate, the ethyl acetate was washed with 3 l
water, the solvent was removed in a vacuum and 99 g
(quant.) N-benzyl-N-(2-hydroxyethyl)-N-(tetra-
chloropyridin-4-yl)-amine was obtained as an oil.
MS (m/e) = 366.
e) 73 ml (520 mmol) triethylamine was added to 107 g
(290 mmol) of this compound in 800 ml dichloro-
methane, it was cooled to 0C and a solution of
67.1 g (350 mmol) 4-toluenesulfonyl chloride in
500 ml dichloromethane was added dropwise. The
solution was stored for 16 hours at 4C, water was
added, the organic phase was separated and the
solvent was removed in a vacuum. 90.6 g (64 %)
4-toluenesulfonic acid-2-(benzyl-tetrachloro-
pyridin-4-ylamino)-ethyl ester was obtained.
Fp. 114 - 116C.
f) 57.2 g (240 mmol) of this compound, 64.8 g
(260 mmol) 3-phthalimido-5-methylphenol (example
76a) and 66.2 g (480 mmol) potassium carbonate in
1.15 l dimethylsulfoxide were stirred for 72 hours
at room temperature, poured onto 3 l water,
filtered, the residue was digested with diiso-
propyl ether and 63 g (38 %) N-benzyl-N-(tetra-
chloropyridin-4-yl)-N-[2-(3-phthalimido-5-methyl-
phenoxy)-ethyl]-amine was obtained. Fp. 142 -
144C.
g) 19.1 g (31.8 mmol) of this compound, 2.3 ml
(47.6 mmol) hydrazine hydrate and 50 ml ethanol in
21S6729
- 108 -
100 ml dichloromethane were stirred for 12 hours at
room temperature, the solvent was removed in a
vacuum, the residue was suspended in 150 ml 2 N
sodium hydroxide solution, extracted with dichloro-
methane, the organic phase was washed with water,
the solvent was removed in a vacuum, the residue
was digested with methanol and ll.S g (77 %)
N-benzyl-N-(tetrachloropyridin-4-yl)-N-[2-(3-amino-
5-methyl-phenoxy)-ethyl]-amine was obtained.
Fp. 91 - 93C.
h) 11.5 g (25.5 mmol) of this compound was reacted
analogously to example 79i) with 3.51 ml
(27.0 mmol) benzenesulfonyl chloride and 13.7 g
(91 %) N-{3-[2-(benzyl-tetrachloropyridin-4-
ylamino)-ethoxy]-5-methyl-phenyl}-benzene-
sulfonamide was obtained. Fp. 147 - 149C.
i) 3.0 g (4.00 mmol) of this compound in 15 ml dry
dimethylformamide was added to 147 mg (6.38 mmol)
sodium hydride in 2 ml dimethylformamide and 0.6 ml
(5.4 mmol) ethyl bromoacetate was added dropwise.
It was poured onto 300 ml water, extracted with
ethyl acetate, the organic phase was washed with
water, the solvent was removed in a vacuum and
3.15 g (91 %) (benzenesulfonyl-{3-methyl-5-[2-
(benzyl-tetrachloropyridin-4-ylamino)-ethoxy]-
phenyl}-amino)-acetic acid ethyl ester was
obtained. Fp. 141 - 142C.
j) 3.15 g (4.5 mmol) of this compound, 50 ml
trifluoroacetic acid and 6.8 ml 1,2,3-trimethyl-
benzene were stirred for 12 hours at room
temperature, poured onto ice water, neutralized
21a6 729
-- 109 --
,
with concentrated ammonia, extracted with ether,
the ether phase was washed with water, the solvent
was removed in a vacuum, the residue was filtered
over silica gel (ethyl acetate/isohexane 1:2.5) and
2.50 g (91 %) (benzenesulfonyl-{3-methyl-5-[2-
(tetrachloropyridin-4-ylamino)-ethoxy]-phenyl}-
amino)-acetic acid ethyl ester was obtained as an
oil. MS (m/e) = 605.
.
k) 3.5 g (5.76 mmol) of this compound and 4.0 g
potassium carbonate in 40 ml tetrahydrofuran and
40 ml methanol were hydrogenated in the presence of
1.0 g 10 % palladium on carbon at 4 bar pressure.
It was filtered after 48 hours, the solvent was
removed in a vacuum, it was filtered over silica
gel (methylene chloride/methanol = 4:1) and 2.1 g
(78 %) of the title compound was obtained.
Amorphous. MS (m/e) = 469.
Example 93
(Benzenesulfonyl-~3-methyl-5-~2-(pyridin-4-ylamino)-
ethoxy~-phenYl~-amino)-acetic acid
1.20 g (2.55 mmol) of the compound of example 92) was
saponified in 20 ml ethanol with 5.1 ml 1 N sodium
hydroxide solution for 2 hours at 45C. It was
neutralized with 1 N hydrochloric acid, the solvent was
removed in a vacuum, the residue was taken up in 20 ml
water and it was allowed to crystallize. 0.97 g (86 %)
of the title compound was obtained. Fp. 100 - 102C
(decomp.)
~1~6729
-
-- 110 --
Example 94
tBenzenesulfonyl-~3-methyl-5-~2-(pyridin-4-ylamino)-
ethoxYl-phenyl~-amino)-acetamide
1.5 g (3.2 mmol) of the compound of example 92) was
dissolved in 12 ml concentrated ammonia and 30 ml
methanol. After 12 hours at room temperature, it was
filtered and 0.99 g (70 %) of the title compound was
obtained. Fp. 163 - 165C.
ExamPle 95
N-(2-Hydroxyethyl)-(benzenesulfonyl-~3-methyl-5-~2-
(pyridin-4-ylamino)-ethoxy~-phenyl~-amino)-acetamide
was obtained in a yield of 60 % analogously to example
94 using ethanolamine instead of ammonia. Fp. 169 -
170C.
Example 96
N-(3-Hydroxyethyl)-(benzenesulfonyl-~3-methyl-5- r 2-
(pyridin-4-ylamino)-ethoxYl-phenyl}-amino~-acetamide
was obtained in a yield of 70 % analogously to example
94 using 3-propanolamine instead of ammonia. Fp. 148 -
152C.
21S6729
-- 111 -- .
Example 97
N-Methyl-(benzenesulfonyl-~3-methYl-5-~2-(pyridin-4-
ylamino)-ethoxyl-phenyl~-amino~-acetamide
was obtained in a yield of 58 % analogously to example
94 using a 25 % ethanolic methylamine solution instead
of ammonia. Fp. 136 - 140C.
Example 98
N~N-Dimethyl-(benzenesulfonyl-r3-methyl-5-~2-(pYridin-4
ylamino)-ethoxyl-Phenyl~-amino)-acetamide
was obtained in a yield of 38 % analogously to example
94 using a 41 % ethanolic dimethylamine solution instead
of ammonia. Amorphous. MS (m/e) = 468.
Example 99
N-(2-Aminoethyl)-(benzenesulfonyl-r3-methyl-5-~2-
(pyridin-4-Ylamino)-ethoxy~-phenyl~-amino~-acetamide
was obtained in a yield of 45 % analogously to example
94 using ethylenediamine instead of ammonia. Amorphous.
MS (m/e) = 483.
-- ~ 2156729
- 112 -
ExamPle 100
N-(2-Aminoethyl)-N-~3-[2-(pyridin-4-ylamino)-ethoxy~-5-
methyl-phenyl~-amino)-benzenesulfonamide
The compound of example 94) was reduced analogously to
example 18c) and the title compound was obtained in a
yield of 34 %. Amorphous MS (m/e) = 426.
Example 101
N-(2,3-DihYdroxYPropyl)-(benzenesulfonyl-~3-methYl-5-[2-
(pYridin-4-ylamino)-ethoxY~-Phenyl~-amino)-acetamide
was obtained in a yield of 40 % analogously to example
94 using 2,3-dihydroxypropylamine instead of ammonia.
Fp. 148 - 151C.
Example 102
N-(2,3-DihydroxYpropyl)-N-~3- r 2-pYridin-4-Ylamino)
ethoxyl-5-methyl-phenYl~-benzenesulfonamide
a) 10.0 g (75.7 mmol) 2,2-dimethyl-4-hydroxymethyl-
1,3-dioxolane and 14.3 g (75 mmol) 4-toluene-
sulfonic acid chloride in 7 ml pyridine were
stirred for 16 hours at room temperature, poured
onto 200 ml water, extracted with ethyl acetate and
the solvent was removed in a vacuum. It was
crystallized from isohexane and 10.3 g (48 %)
4-methylbenzenesulfonic acid-(2,2-dimethyl-1,3-
dioxolan-4-yl-methyl) ester was obtained. Fp. 45 -
47C.
21~6729
- 113 -
b) 0.24 g (0.83 mmol) of this compound was added to a
solution of 23 mg sodium hydride and 0.46 g
(0.75 mmol) of the compound of example 92h) in 3 ml
dimethylformamide, it was stirred for 8 hours at
110C, poured onto water, extracted with ethyl
acetate, the solvent was removed in a vacuum and
300 mg (55 %) N-(2,2-dimethyl-1,3-dioxolan-4-yl-
methyl)-N-{3-[2-(benzyl-tetrachloropyridin-4-
ylamino)-ethoxy]-5-methyl-phenyl}-benzene-
sulfonamide was obtained as an oil. MS (m/e) = 725.
c) N-(2-,3-Dihydroxypropyl)-N-{3-[2-(benzyl-
tetrachloropyridin-4-ylamino)-ethoxy]-5-methyl-
phenyl}-benzene-sulfonamide (38 %, Fp. 133 - 136C)
was obtained from this compound analogously to
example 92j).
d) The title compound (66 %, amorphous, MS (m/e) =
457) was obtained from this compound analogously to
example 96k).
Example 103
4-(Benzenesulfonyl-~3-methYl-5-~2-(pyridin-4-ylamino)
ethoxy~-Phenyl~-amino)-butyric acid ethYl ester
The following compounds were obtained analogously to
examples 92i) to 92k) by using ethyl 4-bromobutyrate in
example 92i) instead of ethyl bromoacetate: 4-(benzene-
sulfonyl-{3-methyl-5-[2-(benzyl-tetrachloropyridin-4-
ylamino)-ethoxy]-phenyl}-amino-butyric acid ethyl ester
(78 %, Fp. 106 - 108C); 4-(benzenesulfonyl)-{3-methyl-
5-[2-(tetrachloropyridin-4-ylamino)-ethoxy]-phenyl}-
amino)-butyric acid ethyl ester (oil, MS (m/e) = 633);
21S6729
- 114 -
title compound (75 %, amorphous, MS (m/e) = 497).
Example 104
5-(Benzenesulfonyl-~3-methyl-5- r 2-(pyridin-4-ylamino)-
ethoxyl-phenyl~-amino)-pentanoic acid ethYl ester
The following compounds were obtained analogously to
examples 92i) to 92k) by using ethyl 5-bromopentanoate
in example 92i) instead of ethyl bromoacetate:
5-(benzenesulfonyl-{3-methyl-5-[2-(benzyl-tetrachloro-
pyridin-4-ylamino)-ethoxy]-phenyl}-amino)-pentanoic acid
ethyl ester (72 %, Fp. 90 - 91C); 5-(benzenesulfonyl-
{3-methyl-5-[2-(tetrachloropyridin-4-ylamino)-ethoxy]-
phenyl}-amino)-pentanoic acid ethyl ester (86 %, oil,
MS (m/e) = 647); title compound (78 %), amorphous,
MS (m/e) = 511).
Example 105
6-(Benzenesulfonyl-~3-methyl-5-~2-(pyridin-4-ylamino)-
ethoxY~-phenyl~-amino)-hexanoic acid ethyl ester
The following compounds were obtained analogously to
examples 92i) to 92k) by using ethyl 6-bromohexanoate in
example 92i) instead of ethyl bromoacetate: 6-(benzene-
suIfonyl-{3-methyl-5-[2-(benzyl-tetrachloro-pyridin-4-
ylamino)-ethoxy]-phenyl}-amino)-hexanoic acid ethyl
ester (75 %, oil, MS (m/e) = 751); 6-(benzene-sulfonyl-
{3-methyl-5-[2-(tetrachloro-pyridin-4-ylamino)-ethoxy]-
phenyl}-amino)-hexanoic acid ethyl ester (49 ~, oil,
MS (m/e) = 661); title compound (56 %, amorphous,
MS (m/e) = 525).
2156729
- 115 -
Example 106
4-(Benzenesulfonyl-~3-methYl-5-[2-(PYridin-4-ylamino)-
ethoxy]-phenYl~-amino)-butYric acid
was obtained analogously to example 93) from the
compound of example 103). 65 % yield, amorphous,
MS (m/e) = 469-
Example 107
5-tBenzenesulfonyl-{3-methyl-5-[2-(pyridin-4-ylamino)-
ethoxy~-phenyl~-amino)-pentanoic acid
was obtained analogously to example 93) from the
compound of example 10-4). 53 ~ yield, Fp. 117 - 120C.
Example 108
6-(Benzenesulfonyl-~3-methyl-5-r2-(pyridin-4-ylamino)-
ethoxYl-phenyl~-amino)-hexanoic acid
was obtained analogously to example 93) from the
compound of example 105). 53 ~ yield, amorphous,
MS (m/e) = 498.
Example 109
2-Methoxy-benzenesulfonyl-~3-methyl-5- r 2-(Pyridin-4-
ylamino)-ethoxyl-phenyl~-amino)-acetic acid ethyl ester
The following compounds were obtained analogously to
21S6729
.
- 116 -
examples 92hj to 92k) by using 2-methoxybenzenesulfonyl
chloride in step 92h) instead of benzenesulfonyl
chloride: 2-methoxy-N-~3-[2-benzyl-tetrachloropyridin-4-
ylamino)-ethoxy]-5-methyl-phenyl}-benzene sulfonamide
(65 %, Fp. 175C); (2-methoxy-benzene-sulfonyl-{3-
methyl-5-[2-(benzyl-tetrachloropyridin-4-ylamino)-
ethoxy]-phenyl}-amino]-acetic acid ethyl ester (91 %,
Fp. 1~28 - 130C); (2-methoxybenzenesulfonyl-{3-methyl-5-
[2-(t!etrachloropyridin-4-ylamino)-ethoxy]-phenyl}-
amino)-acetic acid ethyl ester (89 %, Fp. 126C); title
compound (81 %, Fp. 58 - 63C).
Example 110
2-Methoxy-benzenesulfonyl- r 3-methYl-5-[2-(PYridin-4-
ylamino)-ethoxy]-phenyl~-amino)-acetic acid
was obtained from the compound of example 109)
analogously to example 93). 82 %, Fp. 218 - 222C.
Example 111
(2-Methoxy-benzenesulfonyl-~3-methyl-5-~2-(pyridin-4-
ylamino)-ethoxyl-phenYl~-amino)-acetamide
was obtained analogously to example 94) from the
compound of example 109. (63 %, Fp. 205C).
21567~9
- 117 -
Example 112
N-(2-HYdroxyethyl)-(2-methoxy-benzenesulfonyl-r3-methYl-
5~ r 2-(pyridin-4-ylamino)-ethoxy~-phenyl~-amino)-
acetamide
was obtained in a yield of 93 % analogously to example
95) from the compound of example 109. Fp. 175C.
Example 113
N-(3-Hydroxypropyl)-(2-methoxy-benzenesulfonyl-~3-
methyl-5-r2-(pyridin-4-ylamino)-ethoxYl-phenyl~-amino)-
acetamide
was obtained in a yield of 95 % analogously to example
96 from the compound of example 109. Fp. 165 - 167C.
Example 114
N-Methyl-(2-methoxy-benzenesulfonyl-~3-methyl-5- r 2-
(pyridin-4-ylamino)-ethoxy]-phenyl~-amino)-acetamide
was obtained in a yield of 96 % analogously to example
97 from the compound of example 109. Amorphous.
MS (m/e) = 484.
`_ 21S672~
- 118 -
ExamPle 115
N,N-Dimethyl-(2-methoxy-benzenesulfonyl-~3-methyl-5- r 2-
(pyridin-4-ylamino~-ethoxy~-phenyl~-amino)-acetamide
was obtained in a yield of 73 % analogously to example
98 from the compound of example 109. Amorphous,
MS (m/e) = 498.
Example 116
N-(2-Aminoethyl)-(2-methoxy-benzenesulfonYl-~3-methyl-5-
~2-(pyridin-4-ylamino)-ethoxy~-phenyl~-amino)-acetamide
was obtained in a yield of 93 % analogously to example
99 from the compound of example 109. Amorphous,
MS (m/e) = 513.
Example 117
N-(2,3-Dihydroxypropyl)-(2-methoxy-benzenesulfonyl-~3-
methyl-5- r 2-(pyridin-4-ylamino)-ethoxy~-phenyl~-amino)-
acetamide
was obtained in a yield of 75 % analogously to example
101 from the compound of example 109. Amorphous,
MS (m/e) = 544.
~1~6729
- -- 119 --
Example 118
(2-MethoxY-benzenesulfonyl-~3-methyl-5-r2-(pYridin-4-
ylamino)-ethoxyl-Phenyl~-amino)-acetonitrile
250 ~l trichloroacetyl chloride in 0.5 ml dichloro-
methane was added at 0C to 94 mg (0.2 mmol) of the
compound of example 111) in 0.5 ml dichloromethane and
60 ~l triethylamine. After 5 minutes it was neutralized
with triethylamine, the solvent was removed in a vacuum,
and the residue was filtered over silica gel (ethyl
acetate/ methanol ammonia = 4:1). 60 mg of the title
compound was obtained as an amorphous substance.
MS (m/e) = 452.
ExamPle 119
N-(2-Aminoethyl)-N-~3-~2-(pyridin-4-Ylamino)-ethoxy]-5-
methyl-phenyl~-2-methoxy-benzenesulfonamide
(2-Methoxy-benzenesulfonyl-{3-methyl-5-[2-(benzyl-
tetrachloropyridin-4-ylamino)-ethoxy]-phenyl}-amino)-
acetonitrile (92 %, Fp. 154C) was obtained by reacting
2-methoxy-N-{3-[2-(benzyl-tetrachloropyridin-4-ylamino)-
ethoxy]-5-methyl-phenyl}-benzenesulfonamide (example
109) with chloroacetonitrile analogously to example
92i), from which (2-methoxy-benzenesulfonyl-{3-methyl-5-
[2-(tetrachloropyridin-4-ylamino)-ethoxy]-phenyl}-
amino)-acetonitrile was obtained analogously to example
92j) (85 %, amorphous, MS (m/e) = 588) which was reacted
to form the title compound analogously to example 92k)
(10 %, amorphous, MS (m/e) = 456).
21~6729
- 120 -
Example 120
2-~3-~2-(Benzyl-pyridin-4-ylamino)-ethoxyl-5-meth
Phenyl-sulfamoyl~-benzoic acid methYl ester
a) 4-Toluenesulfonic acid-2-(benzyl-tetrachloro-
pyridin-4-ylamino)-ethyl ester (example 92e) was
reacted with 3-nitrophenol analogously to example
92f) and N-benzyl-N-(tetrachloropyridin-4-yl)-N-[2-
(3-nitro-phenoxy)-ethyl]-amine was obtained. (61 %,
Fp. 120 - 122C).
b) This compound was reduced analogously to example
79a) and N-benzyl-N-(tetrachloropyridin-4-yl)-N-[2-
(3-aminophenoxy)-ethyl]-amine was obtained (41 %,
Fp. 105 - 107C).
c) This compound was reacted analogously to example
92h) to form N-{3-[2-(benzyl-tetrachloropyridin-4-
- ylamino)-ethoxy]-phenyl}-benzenesulfonamide. (78 %,
Fp. 120 - 122C).
d) This compound was hydrogenated analogously to
example 92k) and the title compound was obtained
(63 %, amorphous, MS (m/e) = 517).
ExamPle 121
r 2-(Methyl-~3-methyl-5-~2-fpyridin-4-ylamino)-ethoxy-
phenYl~-sulfamoyl)-phenoxy~-acetic acid ethyl ester
a) N-Benzyl-N-(tetrachloropyridin-4-yl)-N-[2-(3-amino-
5-methyl-phenoxy)-ethyl]-amine (example 92g) was
- 2156~2~
- 121 -
reacted analogously to example 92h) with 2-benzyl-
oxy-benzenesulfonyl chloride to obtain N-{3-[2-
(benzyl-tetrachloropyridin-4-ylamino)-ethoxy]-5-
methyl-phenyl}-2-benzyloxy-benzenesulfonamide.
(55 %, Fp. 176C).
b) This compound was methylated analogously to example
12) and N-methyl-N-{3-[2-(benzyl-tetrachloro-
pyridin-4-ylamino?-ethoxy]-5-methyl-phenyl}-2-
benzyloxy-benzenesulfonamide was obtained (78 ~,
amorphous, MS (m/e) = 729).
c) N-Methyl-N-{3-[2-(tetrachloropyridin-4-ylamino)-
ethoxy]-5-methyl-phenyl}-2-hydroxy-benzene-
sulfonamide was obtained from this compound
analogously to example 92j) (87 ~, amorphous,
MS (m/e) = 549).
d) This compound was reacted analogously to example
18) to form [2-(methyl-{3-methyl-5-[2-(tetrachloro-
pyridin-4-ylamino)-ethoxy-phenyl}-sulfamoyl)-
phenoxy]-acetic acid ethyl ester (~uant. oil,
MS (m/e) = 635).
e) This compound was hydrogenated analogously to
example 92k) and the title compound was obtained
(50 ~, amorphous, MS (m/e) = 499).
21a672~
_
-- 122 --
Example 122
N-~3-Methyl-5-r2-(pyridin-4-ylamino)-ethoxYl-phenYl~-2-
hYdroxy-benzenesulfonamide
a) N-{3-[2-(Benzyl-tetrachloropyridin-4-ylamino)-
ethoxy]-5-methyl-phenyl}-2-benzyloxybenzene-
sulfonamide (example 121a) was reacted analogously
to example g2j) to form N-{3-[2-(tetrachloro-
pyridin-4-ylamino)-ethoxy]-5-methyl-phenyl}-2-
hydroxy-benzenesulfonamide (70 %, amorphous,
MS (m/e) = 535).
b) The title compound was obtained from this
analogously to example 92k). (81 %, amorphous,
MS (m/e) = 399).
Example 123
N-Methyl-N-~3-methyl-5-~2-(pyridin-4-ylamino)-ethoxy
phenYl~-2-hYdroxy-benzenesulfonamide
N-Methyl-N-{3-[2-(benzyl-tetrachloropyridin-4-ylamino)-
ethoxy]-5-methyl-phenyl}-2-benzyloxy-benzenesulfonamide
(example 121b) was reacted analogously to example 122)
to obtain N-methyl-N-{3-[2-(tetrachloropyridin-4-
ylamino)-ethoxy]-5-methyl-phenyl}-2-hydroxy-benzene-
sulfonamide (65 %, amorphous, MS (m/e) = 549) and the
title compound (27 %, amorphous, MS (m/e) = 413).
21567~
- 123 -
Example 124
[2-(MethYl-~3-methyl-5-r2-(pyridin-4-ylamino)-ethoxy]-
phenyl~-sulfamoyl~-phenoxY]-acetic acid
a) [2-(Methyl-{3-methyl-5-[2-~tetrachloropyridin-4-
ylamino)-ethoxy-phenyl}-sulfamoyl)-phenoxy]-acetic
acid ethyl ester (example 121d) was saponified
analogously to example 93) to obtain (2-(methyl-{3-
methyl-5-[2-(tetrachloropyridin-4-ylamino)-ethoxy-
phenyl}-sulfamoyl)-phenoxy]-acetic acid (94 %,
amorphous, MS (m/e) = 607).
b) The title compound was obtained from this
analogously to example 92k) (75 %, amorphous,
MS (m/e) = 471).
Example 125
N-Ethoxycarbonyl-N-~3-methyl-5-~2-(pyridin-4-ylamino)-
ethoxY]-phenYl~-2-methoxy-benzenesulfonamide
a) 2-Methoxy-N-{3-[2-(benzyl-tetrachloropyridin-4-
ylamino)-ethoxy]-5-methyl-phenyl}-benzene-
sulfonamide (example 109) was reacted analogously
to example 92i) with ethyl chloroformate to obtain
N-ethoxycarbonyl-N-{3-[2-(benzyl-tetrachloro-
pyridin-4-ylamino)-ethoxy]-5-methyl-phenyl}-2-
methoxy-benzenesulfonamide was obtained (quant.
amorphous, MS (m/e) = 711).
b) N-Ethoxycarbonyl-N-{3-[2-(tetrachloro-pyridin-4-
ylamino)-ethoxy]-5-methyl-phenyl}-2-methoxy-
215672~
- 124 -
benzenesulfonamide was obtained from this
analogously to example 92j) (80 %, Fp. 156C).
c) The title compound was obtained from this
analogously to example 92k) (66 %, amorphous,
MS (m/e) = 485).
Example 126
N-(2-Hydroyethyl~-N-~3-methyl-5-~2-(pyridin-4-Ylamino)-
ethoxyl-Phenyl~-2-methoxY-benzenesulfonamide
24 mg (0.6 mmol) lithium aluminium hydride was added to
150 mg (0.3 mmol) (2-methoxy-benzenesulfonyl-{3-methyl-
5-[2-(pyridin-4-ylamino)-ethoxy]-phenyl}-amino)-acetic
acid ethyl ester (example 109) in 5 ml dry tetrahydro-
furan and it was boiled for 2 hours under reflux. 1 drop
of water and 3 drops of 2 N hydrochloric acid were
added, it was filtered and the solvent was removed in a
vacuum. The residue was filtered over 50 g silica gel
(methylene chloride/methanol = 4:1) and 50 mg (36 ~) of
the title compound was obtained as an amorphous solid.
MS (m/e) = 457.
ExamPle 127
N-~3-Methyl-5-~2-(pyridin-4-ylamino)-ethoxYl-phenYl~-
pyridin-3-sulfonamide
was obtained analogously to example 57) by using
3-pyridinesulfonyl chloride in step 57d). Amorphous.
MS (m/e) = 385.
2156729
- 125 -
Example 128
Descriptio~ of pharmacolo~ical experiments
Thrombin time
The thrombin time is a conventional test in clinical
coagulation diagnostics. This parameter measures the
action of thrombin on fibrinogen and the formation of
clots. Inhibitors of thrombin result in an extended
thrombin time.
In order to obtain plasma, 9 parts of fresh blood from
healthy donors was mixed with one part of sodium citrate
solution (0.11 mol/l) and centrifuged for 10 minutes at
room temperature-at ca.i~3000 r.p.m.. The plasma was
pipetted off and can be stored at room temperature for
ca. 8 hours.
200 ~l citrate plasma was incubated for 2 minutes at
37C in a ball coagulometer (KC10 from the Amelung
Company). 10 ~l dimethylsulfoxide (DMSO) or a solution
of the active substance in DMSO was added to 190 ~l pre-
heated thrombin reagent (Boehringer Mannheim GmbH;
contains ca. 3 U/ml horse thrombin and 0.0125 M Ca++).
On addition of 200 ~l of this solution to the plasma a
stopwatch was started and the time at which coagulation
starts was determined. The thrombin time was ca. 24 sec.
in control measurements and was substantially increased
by the active substances.
The measured thrombin times in seconds are given in the
following table as a difference to the control. The
21561~g
-
- 126 -
concentrations of the active substances in the final
volume were 250 ~M (TT250), 25 ~M (TT25) and 2.5 ~M
(TT2.5).
Thrombin inhibition
The kinetic measurements were carried out in 0.1 M
phosphate buffer that contained 0.2 M sodium chloride
and 0.5 % polyethylene glycol 6000 at a pH = 7.5 and
25C with the substrate H-(D)-Phe-Pro-Arg-pNA (S-2238
Kabi) and human a thrombin (Sigma, specific activity =
2150 NIH units/mg) in polystyrene semi-microcuvettes in
a total volume of 1 ml.
In a preliminary test each active substance was tested
whether it inhibits thrombin rapidly or slowly. For this
the reaction was firstly started by adding 0.03 NIH
- units thrombin to a 100 ~M solution of the substrate and
the active substance. In a second experiment, substrate
was added to a solution of thrombin and the active
substance which had b~een incubated for 5 minutes. The
increase in the concentration of p-nitroaniline with
time was monitored spectroscopically (W -VIS
spectrophotometer Lambda-2 from the Perkin-Elmer
Company) at 405 nm for 12 min. Since the measured curves
obtained in both experiments were linear and parallel,
the active substances of the following table are rapid
thrombin inhibitors. The inhibition constants Ki were
then determined as follows. The substrate was used at
concentrations of 100 ~M, 50 ~M, 30 ~M, 20 ~M and at
each substrate concentration a measurement was carried
out without inhibitor and three measurements were
carried out in the presence of various concentrations of
the inhibitors listed in the following table. The
~1~6729
-
- 127 -
reactions were started by addition of thrombin. The
increase in absorbance at 405 nm due to the formation of
p-nitroaniline was monitored over a time period of
12 minutes. Measurement points (time versus absorbance)
were transferred to a PC at intervals of 20 seconds. The
rates VO (change in absorbance per second; measurements
without inhibitor) and Vi (measurements with inhibitor)
were determined by linear regression. Only that part of
the measurement was used in which the substrate
concentration had decreased by less than 15 %. Km and
Vmax were determined from a measurement series (constant
inhibitor concentration, variable substrate
concentrations) by a non-linear fit to the equation
Vmax* [S]
V ________
[S] + Km
Finally Ki was calculated from the entire series of
measurements by non-linear fitting to the equation
Vmax* [S]
V _____ ______
Km* (1 + [S] /Ki) + [S]
The Michaelis constant Km was 3.8 + 2 ~M in all
measurements.
The inhibition constants Ki f the active substances are
stated in the following table in units of ~M.
21a6729
- 128 -
Inhibition of tr~Psin and plasmin
10 mg bovine pancreatic trypsin (Sigma) was dissolved in
100 ml 1 mM hydrochloric acid and stored in a
refrigerator. 20 ~l of this was admixed with 980 ~1 1 mM
hydrochloric acid. 25 ~1 thereof was used for each
measurement. The measurement was carried out as
described for thrombin. Km = 45 ~M. The substances
listed in the following table do not inhibit trypsin
(Ki > 400 ~M).
The measurements with human plasmin (Sigma, 10 units)
were carried out as described for thrombin using the
substrate S-2251 (H-(D)-Val-Leu-Lys-pNA, Kabi). 0.01
units plasmin were used for each measurement. Km =
250 ~M. The substances listed in the following table do
not inhibit plasmin (Ki > 400 ~M).
~ 2156729
- 129 -
Example RiTT250 TT25 TT2.
No. thrombin
2 0.300 150 40 6
8 1.000 288 58 13
3.000 157 43 7
0.130 270 144 15
48 0.600 300 238 46
59 6.000 53 8 0
0.600 137 62 13
72 0.024 300 300 159
79 5.000 30 8 0
0.150 300 213 44
83 0.100 300 192 48
86 0.040 300 167 11
89 1.000 132 38 6
0.024 300 300 125
100 0.083 300 300 186
108 0.055 300 300 62
124 0.250 300 300 104
125 0.150 300 273 73