Benzenesulfonamide derivatives as bradykinin antagonists

The present invention relates to novel compounds of the formula in which: PA0 X is a halogen atom, PA0 R.sub.1 and R.sub.2, which are identical or different, are each --H or --A--B--R.sub.3, PA0 A is a linear or branched C.sub.1 -C.sub.12 -alkylene chain, PA0 B is a single bond, a divalent phenylene group or a divalent indolyl group of the structure ##STR1## R.sub.3 is --H, --OH, --NR.sub.4 R.sub.5 or --COR.sub.6, R.sub.6 is --OH, --OCH.sub.3, --OC.sub.2 H.sub.5 or --NR.sub.4 R.sub.5, PA0 R.sub.4 and R.sub.5, which are identical or different, are each H, a C.sub.1 -C.sub.4 -alkyl group, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --N(CH.sub.3).sub.2 or --CO--CH.sub.3, and n is an integer with a value of 2, 3 or 4; and their addition salts. It further relates to their preparation and to their use in therapeutics, especially for the treatment of pathological conditions involving bradykinin.

This application is the national phase of PCT/FR96/00845, filed Jun. 6, 
1996, published as WO 96/40639 on Dec. 19, 1996. 
FIELD OF THE INVENTION 
The present invention relates to novel benzenesulfonamide compounds, to the 
process for their preparation and to their use in therapeutics. 
These novel compounds have especially an antagonistic action towards 
bradykinin and are useful in therapeutics, particularly for the treatment 
of pain and inflammation and especially in the treatment of asthma and 
allergic rhinitis. 
PRIOR ART 
It is known that one of the possible ways of treating certain pathological 
conditions of a painful and/or inflammatory nature (such as asthma, 
rhinitis, septic shock, toothache, etc.) is to antagonize the action of 
certain hormones such as bradykinin or kallidin. These peptide hormones 
are in fact involved in a large number of physiological processes, some of 
which are closely associated with these pathological conditions. 
Although no products possessing this mode of action have yet been marketed, 
numerous studies have been undertaken to create compounds capable of being 
bradykinin receptor antagonists. Bradykinin is a peptide hormone 
consisting of 9 amino acids (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) and 
kallidin is a peptide hormone (Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) 
which has an additional amino acid (Lys) compared with bradykinin. Earlier 
studies are known to have produced peptides which react with the 
bradykinin receptors: some, such as bradycor (CP.0127 from Cortech), 
icatibant (HOE 140 from Hoechst) ["bradycor" and "icatibant" are 
international non-proprietary names (INN)] or NPC 17761 (from Scios-Nova), 
have an inhibitory action on the binding of bradykinin to the bradykinin 
B.sub.2 receptor. More recently, non-peptide compounds have been proposed 
as bradykinin antagonists in respect of binding to the bradykinin B.sub.2 
receptor, especially in EP-A-0596406 and EP-A-0622361. It is also known 
that certain compounds structurally related to those described in the two 
patent applications cited above have already been described as possibly 
having antithrombotic properties, especially in DE-A-3617183 and 
EP-A-0261539. 
OBJECT OF THE INVENTION 
There is a need for ways to reduce or eliminate pain and inflammation in 
mammals and particularly in man. 
To meet this need, a novel technical solution has been sought which is 
effective on the one hand in the treatment of pain, irrespective of its 
origin, especially that associated with inflammatory phenomena, and on the 
other hand in the treatment of inflammation. 
According to the invention, it is proposed to provide a novel technical 
solution which uses competitive binding, at the bradykinin B.sub.2 
receptor, between (i) bradykinin and related or analogous hormones, and 
(ii) an antagonistic substance, and utilizes benzenesulfonamide compounds 
which are structurally different from the known products mentioned above 
and which limit or substantially inhibit the binding of bradykinin and 
analogous hormones to said bradykinin B.sub.2 receptor. 
In accordance with this novel technical solution, it is proposed according 
to a first feature of the invention to provide benzenesulfonamide 
compounds as novel industrial products, according to a second feature of 
the invention to provide a process for the preparation of these compounds, 
and according to a third feature of the invention to provide the use of 
these compounds, especially in therapeutics, as analgesic and/or 
anti-inflammatory active ingredients. 
SUBJECT OF THE INVENTION 
In accordance with the novel technical solution of the invention, a 
benzenesulfonamide compound is recommended as a novel industrial product, 
said compound being characterized in that it is selected from the group 
consisting of: 
(i) the compounds of the formula 
##STR2## 
in which: X is a halogen atom, 
R.sub.1 and R.sub.2, which are identical or different, are each a hydrogen 
atom or a group --A--B--R.sub.3, 
A is a linear or branched C.sub.1 -C.sub.12 -alkylene chain, 
B is 
a single bond, 
a phenylene group of the structure 
##STR3## 
relative to which the substituents A and R.sub.3 are in the ortho, meta or 
para position, or 
a divalent indolyl group of the structure 
##STR4## 
R.sub.3 is --H, --OH, --NR.sub.4 R.sub.5 or --COR.sub.6, R.sub.6 is a 
group --OH, --OCH.sub.3, --OC.sub.2 H.sub.5 or --NR.sub.4 R.sub.5, 
R.sub.4 and R.sub.5, which are identical or different, are each a hydrogen 
atom, a C.sub.1 -C.sub.4 -alkyl group with a linear or branched 
hydrocarbon chain, a group --(CH.sub.2).sub.n --OH, a group 
--(CH.sub.2).sub.n --N(CH.sub.3).sub.2 or a group --CO--CH.sub.3, and 
n is an integer with a value of 2, 3 or 4; and 
(ii) their addition salts. 
The benzenesulfonamides according to the invention can be prepared by a 
method known per se by the application of conventional reaction 
mechanisms. Nevertheless, the process recommended according to the 
invention for the preparation of the benzenesulfonamide compounds of 
formula I and their addition salts is characterized in that it comprises a 
condensation reaction of 8-hydroxy-2-methylquinoline in the form of a 
phenate of the formula 
##STR5## 
in which Z is an alkali metal atom, with a halogenated toluenesulfonamide 
of the formula 
##STR6## 
in which Hal is a halogen atom and X, R.sub.1 and R.sub.2 are defined as 
indicated above, the functional groups (especially alcohol --OH, primary 
amine --NH.sub.2 and secondary amine --NH--) which may be contained in 
R.sub.1 and/or R.sub.2 and may take part in the reaction VIII+IX.fwdarw.I 
being protected. 
The use of a substance selected from the compounds of formula I and their 
non-toxic addition salts is also recommended for obtaining a drug intended 
for use in therapeutics to combat pathological conditions involving 
bradykinin or its analogs, in particular to combat pain, and especially in 
the treatment or prevention of pathological conditions associated with 
inflammatory or painful states. 
DETAILED DESCRIPTION OF THE INVENTION 
In general formula I of the compounds of the invention, the halogen atom is 
the fluorine, chlorine, bromine or iodine atom, the preferred halogen 
being the chlorine atom. 
C.sub.1 -C.sub.4 -Alkyl group is understood as meaning the methyl, ethyl, 
propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methylpropyl or 
2-methylpropyl group. 
"Addition salts" are understood as meaning the acid addition salts obtained 
by reacting a compound of formula I with a mineral acid or an organic 
acid. The preferred mineral acids for salifying a basic compound of 
formula I are hydrochloric, hydrobromic, phosphoric and sulfuric acids. 
The preferred organic acids for salifying a basic compound of formula I 
are methanesulfonic, maleic, fumaric, oxalic, citric and trifluoroacetic 
acids. 
For the sake of convenience, the benzenesulfonamide compounds which act as 
antagonists are arbitrarily mentioned as being either bradykinin 
antagonists or bradykinin B.sub.2 receptor antagonists. 
From the point of view of pharmacological activity, the preferred compounds 
of formula I according to the invention are those belonging to the group 
consisting of the compounds of the formula 
##STR7## 
in which the amide group can be in the ortho, meta or para position and 
R.sub.4 and R.sub.5, which are identical or different, are each: 
a hydrogen atom, 
a linear or branched C.sub.1 -C.sub.4 -alkyl group, 
a group --(CH.sub.2).sub.n --OH, or 
a group --(CH.sub.2).sub.n --N(CH.sub.3).sub.2, 
where n is an integer with a value of 2, 3 or 4; and their non-toxic acid 
addition salts. 
The general process for the preparation of the benzenesulfonamide compounds 
according to reaction (1): 
EQU VIII+IX.fwdarw.I (1) 
is carried out in an aprotic solvent [such as, in particular, 
dimethylformamide (DMF) or tetrahydrofuran (THF)], at a temperature 
between 0 and 50.degree. C., the alkali metal Z being Li, K or, 
preferably, Na. 
The phenate VIII can be prepared in situ for carrying out the reaction 
VIII+IX.fwdarw.I. In this reaction it can be advantageous for the 
electronegativity of the halogen atom Hal of the compound IX to be less 
than or equal to that of the halogen atom X; from a practical point of 
view, if X is Cl then Hal will advantageously be Br. 
Finally, the reaction VIII+IX.fwdarw.I entails the protection of the 
reactive functional groups which may be present in the groups R.sub.1 
and/or R.sub.2. These reactive functional groups include the groups --OH, 
--NH.sub.2 and --NH--, which contain a reactive hydrogen atom capable of 
disturbing the course of the desired reaction (1). 
By way of illustration, practical modalities of the reaction 
VIII+IX.fwdarw.I are given in Preparation III below. 
All the compounds of formula I are prepared in accordance with the 
following reaction scheme: 
(.alpha.) a compound of the formula 
##STR8## 
[which is a compound of formula I in which R.sub.2 is H and R.sub.1 is 
C(CH.sub.3).sub.3 ] is synthesized according to reaction (1) given above, 
(.beta.) if necessary, the compound of formula V is treated in order to 
replace the group R.sub.2 =H with a group R.sub.2 other than H to give a 
compound of the formula 
##STR9## 
(.gamma.) if necessary, the resulting compound of formula Va is treated in 
order to replace the group R.sub.1 =C(CH.sub.3).sub.3 with the hydrogen 
atom to give a compound of the formula 
##STR10## 
then (.delta.) if necessary, the resulting compound of formula Vb is 
treated in order to replace the group R.sub.1 =H with a group R.sub.1 
other than H to give a compound of formula I in which both R.sub.1 and 
R.sub.2 are other than H, 
and 
(.epsilon.) if necessary, the acid addition salt of the free base resulting 
from stage (.beta.). (.gamma.) or (.delta.) is obtained [by reacting said 
free base with the acid chosen for salification]. 
Stages (.beta.), (.gamma.) and (.delta.) entail the protection and then 
deprotection of any reactive group which may be contained in R.sub.1 
and/or R.sub.2. 
From a practical point of view, the reaction scheme given above will be 
applied in a variant selected from the group consisting of variant A, 
which comprises the steps consisting in: 
1) reacting a compound of the formula 
##STR11## 
in which X is a halogen atom, with excess tert-butylatine (alternative 
nomenclature: 1,1-dimethylethanamine), in a solvent such as, for example, 
dichloromethane, at room temperature, for 1 to 3 hours, to give a compound 
of the formula 
##STR12## 
in which X is a halogen atom, 2) halogenating the compound III obtained 
above with an N-halogenosuccinimide (preferably N-bromosuccinimide), in a 
halogenated solvent, especially carbon tetrachloride, and preferably in 
the presence of a free radical initiator, especially AIBN [alternative 
nomenclature: 2,2'-azobis(2-methylpropionitrile) or 
2,2'-azobis-(isobutyronitrile)], and/or in the presence of ultraviolet 
radiation, for 2 to 24 hours, at a temperature between 30.degree. C. and 
100.degree. C., to give a compound of the formula 
##STR13## 
in which X and Hal are each a halogen atom, 3) condensing the resulting 
compound IV with 8-hydroxy-2-methylquinoline, the latter first being 
reacted with sodium hydride, in the presence of a solvent (especially 
DMF), at a temperature between 0.degree. C. and 50.degree. C., to give the 
compound of the formula 
##STR14## 
in which X is a halogen atom, and 4) reacting the resulting compound of 
formula V with sodium hydride, in an anhydrous organic solvent (especially 
DMF), at a temperature between 0.degree. C. and 30.degree. C., and then 
reacting the resulting sodium derivative with a compound of the formula 
Y--R.sub.2, in which: 
Y is a halogen atom (especially an iodine atom, a bromine atom or a 
chlorine atom), a methanesulfonyl group or a toluenesulfonyl group, and 
R.sub.2 is a C.sub.1 -C.sub.12 -alkyl group or an arylalkyl group, these 
two groups optionally being substituted by one or more protected 
functional groups so as not to react with the sodium sulfonamide, 
to give a compound of the formula 
##STR15## 
in which: X is a halogen atom, 
R.sub.1 is the 1,1-dimethylethyl group, and 
R.sub.2 is as defined above; and 
variant B, which comprises the steps consisting in: 
1) treating a compound of formula I obtained in step 4) of variant A, in 
which R.sub.2 is the methyl group or the phenylmethyl group and R.sub.1 is 
the 1,1 -dimethylethyl group, with an excess of acid (especially 
trifluoroacetic acid), in the presence of a cation scavenger (especially 
anisole), at a temperature between 20.degree. C. and 60.degree. C., for 4 
to 24 hours, to give a compound of the formula 
##STR16## 
in which: X is a halogen atom, 
R.sub.1 is a methyl group or a phenylmethyl group, and 
R.sub.2 is a hydrogen atom, 
2) treating the compound of formula I obtained in stage B 1) above with a 
compound of the formula YR.sub.2, under conditions identical to those 
recommended in stage 4) of variant A, to give a compound of the formula 
##STR17## 
in which: X is a halogen atom, 
R.sub.1 is a methyl group or a phenylmethyl group, and 
R.sub.2 is a C.sub.1 -C.sub.12 -alkyl group or an arylalkyl group, these 
two groups optionally being substituted by protected functional groups so 
as not to react with the sodium sulfonamide group, 
3) if necessary, deprotecting the functional group or groups carried by the 
group R.sub.2 of the compound of formula I obtained in one of stages A 4) 
or B 2) above (especially by hydrolysis of an ester or deprotection of an 
amine) to give a compound of formula I in which the group R.sub.2 carries 
a free functional group, for example a free carboxylic acid group or 
primary amine group, 
4) if necessary, reacting the functional group freed in the previous stage 
to give a derivative, for example an amide by reacting a carboxylic acid 
group with a compound carrying a primary or secondary amine group, and 
5) if necessary, obtaining an addition salt of a compound of formula I 
initially obtained in the form of the free base, by reacting said free 
base with the acid chosen for salification. 
Protected functional group is understood here as meaning especially: 
a group NH or NH.sub.2 protected by one or two amino-protecting groups, 
an ester group, 
an N-monosubstituted or N-disubstituted carboxamide group, or 
a group OH protected by a hydroxyl-protecting group. 
The amino-protecting groups suitable here are those which are customarily 
employed in the field of peptide synthesis, in particular alkoxycarbonyl 
groups and especially the group Boc (t-butoxycarbonyl). Examples of the 
hydroxyl-protecting groups are silyl groups (especially trimethylsilyl or 
dimethyl-t-butylsilyl) or groups of the benzyl type. 
To illustrate step 3) of variant B, the procedure is as follows: A compound 
of the formula 
##STR18## 
in which: X is a halogen atom, 
R.sub.1 is a C.sub.1 -C.sub.4 -alkyl or arylalkyl group, and 
R' is a methyl or ethyl group, 
is reacted with sodium hydroxide solution, in the presence of a solvent 
such as, for example, methanol, at a temperature between 40.degree. C. and 
80.degree. C., for 0.5 to 5 hours, to give a compound of formula VI in 
which X and R.sub.1 are as defined above and R' is a hydrogen atom. 
To illustrate step 4) of variant B, the procedure is as follows: A 
resulting compound of formula VI in which R' is a hydrogen atom is reacted 
with an amine of the formula H--NR.sub.4 R.sub.5, in which: 
R.sub.4 and R.sub.5, which are identical or different, are each a hydrogen 
atom, a C.sub.1 -C.sub.4 -alkyl group (linear or branched), a group 
(CH.sub.2).sub.n --OH or a group (CH.sub.2).sub.n N(CH.sub.3).sub.2, where 
n is an integer with a value of 2, 3 or 4, 
in a solvent such as, for example, dichloromethane, in the presence of 
coupling agents such as, for example, N,N'-dicyclohexylcarbodiimide and 
1-hydroxybenzo-triazole, at a temperature close to room temperature, for 
10 to 48 hours, to give a compound of the formula 
##STR19## 
in which X, R.sub.4 and R.sub.5 are as defined above. 
The compound of formula IV in which X is a chlorine atom and Hal is the 
bromine atom is novel and forms one of the subjects of the invention. 
The invention will be understood more clearly from the following 
Preparatory Examples and the results of pharmacological tests obtained 
with some of the compounds according to the invention. The nomenclature 
used in these Examples is that which is recommended in Chemical Abstracts. 
In the experimental section the "Preparations" relate to the intermediates 
and the "Examples" relate to the products according to the invention. 
Some of the compounds are characterized by the spectral data obtained by 
nuclear magnetic resonance (NMR); in this case the spectral 
characteristics are given for the proton (.sup.1 H) and the chemical shift 
of the protons relative to the proton signal of tetramethylsilane is 
indicated with, in brackets, the shape of the signal (s for singlet, d for 
doublet, t for triplet, q for quadruplet, m for multiplet, bs for broad 
signal) and the number of protons corresponding to the signal. By way of 
indication, the .sup.1 H NMR spectra were run at 250 MHz. 
The melting points (m.p.) indicated below are generally measured using a 
Koffler bench and are not corrected, so they represent instantaneous 
melting points. 
PREATION I 
2,4-Dichloro-N-(1,1-dimethylethyl)-3-methylbenzenesulfonamide 
A solution of 100 g (0.385 mol) of 2,4-dichloro-3-methylbenzenesulfonyl 
chloride in 1 liter of dichloromethane is prepared and 112.5 g (1.54 mol) 
of 1,1-dimethylethanamine are added slowly at room temperature 
(20-25.degree. C.). The reaction medium is stirred for 2 hours after the 
addition has ended and is then hydrolyzed with water. After extraction 
with dichloromethane, the combined organic phases are washed with water 
until the pH of the washings is neutral, and are then dried over sodium 
sulfate and concentrated under reduced pressure. The solid residue is 
recrystallized from methylcyclohexane to give 80 g of the expected product 
in the form of a white solid (yield=70%). 
M.p.=148-150.degree. C. 
PREATION II 
2,4Dichloro-N-(1,1-dimethylethyl)-3-(bromomethyl)benzenesulfonamide 
2.1 g (0.012 mol) of AIBN and 55.6 g (0.312 mol) of N-bromosuccinimide are 
added to a solution of 77 g (0.26 mol) of the compound obtained according 
to Preparation I in 1.2 liters of carbon tetrachloride. The reaction 
mixture is then stirred under ultraviolet irradiation and heated at the 
reflux point of the solvent for 4 hours. After cooling, the mixture is 
hydrolyzed with water and then extracted with dichloromethane. The 
combined organic phases are washed with water, dried over sodium sulfate 
and concentrated under reduced pressure. The residue is recrystallized 
from isopropanol to give 91 g of the expected product in the form of a 
white crystalline solid (yield=94%). 
M.p.=157.degree. C. 
PREATION III 
2,4-Dichloro-N-(1,1-dimethylethyl)3-[(2-methylquinolin-8-yl)oxymethyl]-benz 
enesulfonamide (Example 29) 
A solution of 39.8 g (0.25 mol) of 2-methyl-8-hydroxyquinoline in 400 ml of 
dimethylformamide (DMF) is prepared and 7.5 g (0.25 mol) of an 80% 
suspension of sodium hydride in oil are added in small portions at room 
temperature. The mixture is stirred for 30 min and then cooled to 
0.degree. C. and a solution of 103.15 g (0.275 mol) of the compound 
obtained according to Preparation II in 120 ml of DMF is added dropwise. 
The mixture is subsequently stirred at room temperature for one hour and 
then hydrolyzed with water and extracted with dichloromethane. The organic 
phases are washed with water, dried over sodium sulfate and concentrated 
under reduced pressure to give 111.2 g of the expected product in the form 
of a beige pulverulent solid (yield=98%). 
M.p.=191.degree. C.

EXAMPLE 1 
2,4-Dichloro-N-(1,1-dimethylethyl)-N-methyl-3-[(2-methylquinolin-8-yl)-oxym 
ethyl]benzenesulfonamide 
6.3 g (0.21 mol) of an 80% suspension of sodium hydride in oil are added in 
small portions at room temperature (20-25.degree. C.) to a solution of 
90.68 g (0.2 mol) of the compound obtained according to Preparation III in 
650 ml of DMF. The mixture is stirred for 45 min and a solution of 31.22 g 
(0.22 mol) of methyl iodide in 10 ml of DMF is then added dropwise. After 
stirring for one hour, the reaction medium is poured into iced water. The 
precipitate formed is filtered off, washed with water on the filter and 
dried under vacuum at 70.degree. C. to give 89.9 g of the expected product 
in the form of a light beige powder (yield=96%). 
M.p.=160-162.degree. C. 
EXAMPLE 2 
2,4-Dichloro-N-methyl-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamid 
e 
A mixture of 88.8 g (0.19 mol) of the compound obtained according to 
Example 1 and 250 ml of 10 N hydrochloric acid is prepared and this 
mixture is stirred for one hour at room temperature. The reaction medium 
is subsequently poured into iced water and the suspended solid is then 
filtered off The resulting crude product is taken up with 2 N sodium 
hydroxide solution and extracted with dichloromethane. The organic phase 
is washed with water, dried over sodium sulfate and concentrated under 
reduced pressure to give 74.5 g of the expected product in the form of a 
white solid (yield=95%). 
M.p.=174-176.degree. C. 
EXAMPLE 3 
2,4-Dichloro-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamide 
A mixture of 2.26 g (5.10.sup.-3 mol) of the compound obtained according to 
Preparation III and 0.59 g (5.10.sup.-3 mol) of anisole is prepared and 20 
ml of trifluoroacetic acid are then added. The solution obtained is 
stirred for 12 hours at room temperature and then for 5 hours at 
40.degree. C. The trifluoroacetic acid is then driven off under reduced 
pressure. The residue obtained is rendered neutral with 1 N sodium 
hydroxide solution. The product is extracted with ethyl acetate. The 
organic phase is washed with water, dried and then concentrated under 
reduced pressure. The solid obtained is purified by recrystallization from 
toluene to give 1.4 g of the expected product in the form of an off-white 
crystalline solid (yield=70%). 
M.p.=206-208.degree. C. 
EXAMPLE 4 
2,4-Dichloro-N-methyl-N-(phenylmethyl)-3-[(2-methylquinolin-8-yl)oxymethyl] 
benzenesulfonamide 
60 mg (2.10.sup.-3 mol) of a suspension of sodium hydride in oil are added 
to a solution of 822 mg (2.10.sup.-3 mol) of the compound obtained 
according to Example 2 in 5 ml of DMF. After stirring for 30 minutes at 
room temperature, 376 mg (2.2.10.sup.-3 mol) of benzyl bromide are added 
and the reaction mixture is stirred for one hour at 40.degree. C. After 
cooling, it is poured into water and extracted with ethyl acetate. The 
organic phases are washed with water, dried over sodium sulfate and 
concentrated under reduced pressure. The solid obtained is recrystallized 
from ethyl acetate to give 750 mg of the expected product in the form of a 
white powder (yield=75%). 
M.p.=154.degree. C. 
EXAMPLE 5 
2,4-Dichloro-N-(1,1-dimethylethyl)-N-(phenylmethyl)-3-[(2-methylquinolin-8- 
yl)oxymethyl]benzenesulfonamide 
The expected product is obtained with a yield of 83% by following a 
procedure analogous to the process of Example 4, starting from the 
compound obtained according to Preparation III and benzyl bromide. 
M.p.=167-168.degree. C. 
EXAMPLE 6 
2,4-Dichloro-N-(phenylmethyl)-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesu 
lfonamide 
The expected product is obtained with a yield of 77% by following a 
procedure analogous to the process of Example 3, starting from the 
compound obtained according to Example 5. 
M.p.=140-142.degree. C. 
EXAMPLE 7 
2,4-Dichloro-N-methyl-N-[(indol-3-yl)methyl]-3-[(2-methylquinolin-8yl)oxyme 
thyl]benzenesulfonamide 
The expected product is obtained in the form of a white solid with a yield 
of 72% by following a procedure analogous to the process of Example 1, 
starting from the compound obtained according to Example 2 and 
trimethylgramine methosulfate (N,N,N-trimethylindol-3-ylmethanaminium 
methanesulfonate) and purifying the crude product by chromatography on 
silica gel using a dichloromethane/ethyl acetate mixture (9/1, v/v) as the 
eluent. 
M.p.=218.degree. C. 
PREATION IV 
2,4-Dichloro-N-methyl-N-[(4-nitrophenyl)methyl]-3-[(2-methylquinolin-8-yl)- 
oxymethyl]benzenesulfonamide 
The expected product is obtained with a yield of 61% by following a 
procedure analogous to the process of Example 4, starting from the 
compound obtained according to Example 2 and 4-nitro-.alpha.-bromotoluene 
(i.e. 4-nitrobenzyl bromide) and recrystallizing the crude product from 
ethyl acetate. 
M.p.=185.degree. C. 
EXAMPLE 8 
2,4-Dichloro-N-methyl-N-[(4-aminophenyl)methyl]-3-[(2-methylquinolin-8-yl)o 
xymethyl]benzenesulfonamide dihydrochloride 
A solution of 0.56 g (1.03.10.sup.-3 mol) of the compound obtained 
according to Preparation IV in 4 ml of methanol is prepared and 4 ml of 
concentrated hydrochloric acid are added, followed by 0.173 g 
(3.1.10.sup.-3 mol) of iron powder. The reaction mixture is refluxed for 3 
hours, with stirring, and then cooled and poured into iced water. The 
mixture is brought to pH 8 with 1 N sodium hydroxide solution and the 
precipitate formed is filtered off and then purified by chromatography on 
silica gel using a dichloromethane/ethyl acetate mixture (98/2, v/v) as 
the eluent. The solid obtained is recrystallized from a toluene/isopropyl 
ether mixture. The resulting compound is dissolved in ethanol and a 
saturated solution of hydrogen chloride in ethanol is added. The crystals 
formed are filtered off and dried under reduced pressure to give 0.3 g of 
the expected product in the form of white, slightly hygroscopic crystals 
(yield=50%). 
M.p.=190.degree. C. 
PREATION V 
2,4-Dichloro-N-methyl-N-[[4-[(1,1-dimethylethyl)(dimethyl)silyloxy]phenyl]m 
ethyl]-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of a creamy white solid with a 
yield of 78% by following a procedure analogous to the process of Example 
4, starting from the compound obtained according to Example 2 and 
.alpha.-bromo-4-[(1,1-dimethylethyl)(dimethyl)silyloxy]toluene and 
purifying the crude product by chromatography on silica gel using a 
toluene/ethyl acetate mixture (8/2, v/v) as the eluent. 
M.p.=95.degree. C. 
EXAMPLE 9 
2,4-Dichloro-N-methyl-N-[(4-hydroxyphenyl)methyl]-3-[(2-methylquinolin-8-yl 
)oxymethyl]benzenesulfonamide 
10 ml of 5 N hydrochloric acid solution are added to a suspension of 1.7 g 
(2.69.10.sup.-3 mol) of the compound obtained according to Preparation V 
in 50 ml of methanol and the resulting mixture is then stirred for 30 
minutes at room temperature. After evaporation of the methanol under 
reduced pressure, the residue obtained is taken up with water and the 
mixture is neutralized with aqueous ammonia solution. The precipitate 
formed is filtered off, washed with water, dried and then recrystallized 
from methanol to give 1.18 g of the expected product in the form of a 
white crystalline solid (yield=85%). 
M.p.=241.degree. C. 
PREATION VI 
2,4-Dichloro-N-methyl-N-[[3-(methoxycarbonyl)phenyl]methyl]-3-[(2-methylqui 
nolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of a white solid with a yield 
of 58% by following a procedure analogous to the process of Example 4, 
starting from the compound obtained according to Example 2 and methyl 
3-(bromomethyl)-benzoate and purifying the crude product by chromatography 
on silica gel using a dichloromethane/ethyl acetate mixture (98/2, v/v) as 
the eluent. 
M.p.=180.degree. C. 
PREATION VII 
2,4-Dichloro-N-methyl-N-[(3carboxyphenyl)methyl]-3-[(2-methylquinolin-8-yl) 
oxymethyl]benzenesulfonamide 
13 ml (13.10.sup.-3 mol) of N aqueous sodium hydroxide solution are added 
to a suspension of 3.6 g (6.4.10.sup.-3 mol) of the compound obtained 
according to Preparation VI in 50 ml of methanol. The reaction mixture is 
refluxed for 4 hours and then concentrated under reduced pressure. The 
residue is taken up with water and then acidified to pH 2 with 1 N 
hydrochloric acid solution. The precipitate formed is filtered off and 
dried to give 2.3 g of the expected product in the form of a white 
pulverulent solid (yield=66%). 
M.p.=204.degree. C. 
EXAMPLE 10 
2,4-Dichloro-N-methyl-N-[[3-(aminocarbonyl)phenyl]methyl]-3[(2-methylquinol 
in-8-yl)oxymethyl]benzenesulfonamide 
A solution of 0.5 g (0.92.10.sup.-3 mol) of the acid obtained according to 
Preparation VII in 10 ml of dichloromethane and 2 ml of methanol is 
prepared and 0.264 g (1.38.10.sup.-3 mol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.187 g 
(1.38.10.sup.-3 mol) of 1-hydroxy-7-azabenzotriazole are added, followed 
by 1.5 ml of a saturated solution of ammonia in ethanol. The reaction 
mixture is stirred at room temperature for 20 hours. Dichloromethane is 
added and the organic phase is subsequently washed with sodium bicarbonate 
solution and then with water until the washings are neutral. The organic 
phase is then dried and concentrated under reduced pressure. The solid 
residue is recrystallized from a toluene/isopropyl ether mixture to give 
0.3 g of the expected product in the form of a white solid (yield=60%). 
M.p.=208.degree. C. 
EXAMPLE 11 
2,4-Dichloro-N-methyl-N-[[3-(methylaminocarbonyl)phenyl]methyl]-3-[(2-methy 
lquinolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of a white solid with a yield 
of 55% by following a procedure analogous to the process of Example 10, 
but using a solution of methylamine in ethanol and purifying the crude 
product by chromatography on silica gel using a dichloromethane/ethyl 
acetate mixture (7/3, v/v) as the eluent, followed by recrystallization 
from ethyl acetate. 
M.p.=195.degree. C. 
EXAMPLE 12 
2,4-Dichloro-N-methyl-N-[[3-[(dimethylamino)carbonyl]phenyl]methyl]-3-[(2-m 
ethylquinolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of a white powder with a yield 
of 76% by following a procedure analogous to the process of Example 10, 
starting from a solution of dimethylamine in ethanol and purifying the 
crude product by chromatography on silica gel using a 
dichloromethane/ethyl acetate mixture (75/25, v/v) as the eluent, followed 
by recrystallization from a toluene/isopropyl ether mixture. 
M.p.=194.degree. C. 
EXAMPLE 13 
2,4-Dichloro-N-methyl-N-[[3-[(3-hydroxypropyl)aminocarbonyl]phenyl]-methyl] 
-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of a white pulverulent solid 
with a yield of 78% by following a procedure analogous to the process of 
Example 10, starting from 3-aminopropanol and purifying the crude product 
by chromatography on silica gel using a toluene/isopropyl ether mixture as 
the eluent. 
M.p.=98.degree. C. 
EXAMPLE 14 
2,4-Dichloro-N-methyl-N-[[3-[[2-(dimethylamino)ethyl]aminocarbonyl]-phenyl] 
-methyl]-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of a white crystalline solid 
with a yield of 60% by following a procedure analogous to the process of 
Example 10, starting from N,N-dimethylethylenediamine and purifying the 
crude product by chromatography on silica gel using a 
dichloromethane/methanol mixture (9/1, v/v) as the eluent, followed by 
recrystallization from an ethyl acetate/isopropyl ether mixture. 
M.p.=142.degree. C. 
EXAMPLE 15 
2,4Dichloro-N-methyl-N-(2-phenylethyl)-3-[(2-methylquinolin-8-yl)oxymethyl] 
benzenesulfonamide 
The expected product is obtained with a yield of 15% by following a 
procedure analogous to the process of Example 4, starting from 
(2-iodoethyl)-benzene and purifying the crude product by chromatography on 
silica gel using a toluene/ethyl acetate mixture (95/5, v/v) as the 
eluent. 
M.p.=156-160.degree. C. 
PREATION VIII 
(7-Bromoheptyl)(1,1-dimethylethoxycarbonyl)carbamic acid 1,1-dimethylethyl 
ester 
##STR20## 
A solution of 1.15 g (5.3.10.sup.-3 mol) of iminodicarboxylic acid bis(1,1 
-dimethylethyl) ester in 40 ml of DMF is prepared and 0.175 g 
(5.8.10.sup.-3 mol)of an 80% suspension of sodium hydride in oil is added. 
After stirring for 3 hours at room temperature, 6 g (23.25.10.sup.-3 mol) 
of 1,7-dibromoheptane are added and stirring is continued for 20 hours at 
60.degree. C. The reaction medium is then poured into saturated sodium 
chloride solution and extracted with pentane. The organic phase is washed 
with water, dried over sodium sulfate and concentrated under reduced 
pressure. The crude product is purified by chromatography on silica gel 
using a toluene/ethyl acetate mixture (9/1, v/v) as the eluent to give 
0.43 g of the expected product in the form of a colorless oil 
(yield=20.7%). 
.sup.1 H NMR (CDCl.sub.3): 1.50 (m,26H); 1.85 (q, 2H); 3.40 (t, 2H); 3.55 
(t, 2H). 
PREATION IX 
2,4-Dichloro-N-methyl-N-[7-[bis(1,1-dimethylethoxycarbonyl)amino]heptyl]-3- 
[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of white crystals with a yield 
of 74% by following a procedure analogous to the process of Example 4, 
starting from the compound obtained according to Preparation VIII and 
purifying the crude product by chromatography on silica gel using a 
toluene/ethyl acetate mixture (9/1, v/v) as the eluent. 
M.p.=96-99.degree. C. 
EXAMPLE 16 
2,4-Dichloro-N-methyl-N-(7-aminoheptyl)-3-[(2-methylquinolin-8-yl)oxymethyl 
]benzenesulfonamide bis(trifluoroacetate) 
A solution of 2.5 g (3.45.10.sup.-3 mol) of the compound obtained according 
to Preparation IX in 42 ml of dichloromethane is prepared and 42 ml of 
trifluoroacetic acid are added slowly, the temperature being kept at about 
10.degree. C. The mixture is subsequently stirred for 45 min at room 
temperature (20-25.degree. C.) and then concentrated under reduced 
pressure. The residue is taken up with dichloromethane and then with 
toluene and concentrated to dryness to give 2.57 g of the expected product 
in the form of beige crystals (yield=98.8%). 
M.p.=66-68.degree. C. 
EXAMPLE 17 
2,4-Dichloro-N-methyl-N-(6-ethoxy-6-oxohexyl)-3-[(2-methylquinolin-8-yl)-oy 
methyl]benzenesulfonamide 
The expected product is obtained with a yield of 54% by following a 
procedure analogous to the process of Example 4, starting from ethyl 
6-bromohexanoate and purifying the crude product by recrystallization from 
isopropyl alcohol. 
M.p.=84-86.degree. C. 
EXAMPLE 18 
2,4-Dichloro-N-methyl-N-(5-carboxypentyl)-3-[(2-methylquinolin-8-yl)oxymeth 
yl]benzenesulfonamide 
A solution of 1.4 g (2.53.10.sup.-3 mol) of the compound obtained according 
to Example 17 in 14 ml of ethanol is heated at 40-45.degree. C. for 3 
hours in the presence of 5 ml of 1 N sodium hydroxide solution. The 
reaction mixture is subsequently concentrated and then taken up with water 
and washed with ethyl ether. The aqueous phase is acidified to pH 4 with 1 
N hydrochloric acid and extracted with ethyl acetate. The resulting 
organic phase is washed with water, dried over sodium sulfate and 
concentrated under reduced pressure to give 1 g of the expected product in 
the form of a creamy white solid (yield=76%). 
M.p.=98-102.degree. C. 
EXAMPLE 19 
2,4-Dichloro-N-methyl-N-[6-(methylamino)-6-oxohexyl]-3-[(2-methylquinolin-8 
-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained with a yield of 58% by following a 
procedure analogous to the process of Example 11, starting from the acid 
obtained according to Example 18 and recrystallizing the crude product 
from methylcyclohexane. 
M.p.=110-112.degree. C. 
PREATION X 
2,4-Dichloro-N-methyl-N-[8-[(tetrahydropyran-2-yl)oxy]octy]-3-[(2-methylqui 
nolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of a yellow oil with a yield 
of 52% by following a procedure analogous to the process of Example 4, 
starting from 2-(8-iodooctyl)tetrahydropyran and purifying the crude 
product by chromatography on silica gel using a cyclohexane/ethyl acetate 
mixture (8/2, v/v) as the eluent. 
.sup.1 H NMR (CDCl.sub.3): 1.20-1.90 (m, 18H); 2.74 (s, 3H); 3.08 (s, 3H); 
3.22 (t, 2H); 3.37 (m, 1H); 3.50 (m, 1H); 3.72 (m, 1H); 3.86 (m, 1H); 4.56 
(m, 1H); 5.67 (s, 2H); 7.23-7.50 (m, 5H); 8.02 (d, 1H); 8.07 (d, 1H). 
PREATION XI 
2,4-Dichloro-N-methyl-N-[12-[(tetrahydropyran-2-yl)oxy]dodecyl]-3-[(2methyl 
quinolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained in the form of a yellow oil by following a 
procedure analogous to the process of Preparation X, starting from 
2-(12-iodododecyl)tetrahydropyran. 
.sup.1 H NMR (CDCl.sub.3): 1.10-1.90 (m, 26H); 2.74 (s, 3H); 2.86 (s, 3H); 
3.22 (t, 2H); 3.37 (m, 1H); 3.48 (m, 1H); 3.75 (m, 1H); 3.88 (m, 1H); 4.57 
(m, 1H); 5.67 (s, 2H); 7.23-7.50 (m, 5H); 8.03 (d, 1H); 8.08 (d, 1H). 
EXAMPLE 20 
2,4-Dichloro-N-methyl-N-(8-hydroxyoctyl)-3-[(2-methylquinolin-8-yl)oxymethy 
l]benzenesulfonamide 
A solution of 0.365 g (0.58.10.sup.-3 mol) of the compound obtained 
according to Preparation X in 4 ml of methanol is prepared and 89 mg 
(0.47.10.sup.-3 mol) of p-toluenesulfonic acid are added. The reaction 
mixture is stirred for 2 hours at room temperature and the methanol is 
then driven off under reduced pressure. The residue is taken up with water 
and extracted with dichloromethane and the combined organic phases are 
washed with water, dried over sodium sulfate and concentrated under 
reduced pressure. After purification by chromatography on silica gel using 
a cyclohexane/ethyl acetate mixture (6/4, v/v) as the eluent, 250 mg of 
the expected product are obtained in the form of a white solid 
(yield=66%). 
M.p.=50.degree. C. 
EXAMPLE 21 
2,4-Dichloro-N-methyl-N-(12-hydroxydodecyl)-3-[(2-methylquinolin-8-yl)oxyme 
thyl]benzenesulfonamide 
The expected product is obtained in the form of a white pulverulent solid 
by following a procedure analogous to the process of Example 20, starting 
from the compound obtained according to Preparation XI. 
M.p.=155.degree. C. 
PREATION XII 
N-[4-[Bis(1,1-dimethylethoxycarbonyl)amino]butyl]-N-(1,1-dimethylethyl) 
-2,4dichloro-3[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamide 
A solution of 1.55 g (3.42.10.sup.-3 mol) of the compound obtained 
according to Preparation III in 45 ml of acetonitrile is prepared and 1.41 
g (10.2.10.sup.-3 mol) of potassium carbonate and 1.50 g (3.76.10.sup.-3 
mol) of (4-iodobutyl)(1,1-dimethylethoxycarbonyl)carbamic acid 
1,1-dimethylethyl ester are added. The reaction mixture is heated at the 
reflux point of the solvent for 25 hours, with stirring. After cooling and 
filtration of the mineral salts, the filtrate is concentrated to dryness. 
The residue is taken up with water and extracted with dichloromethane. The 
organic phase is washed with water until the washings are neutral, dried 
over sodium sulfate and concentrated under reduced pressure. The crude 
product is purified by chromatography on silica gel using a 
cyclohexane/ethyl ether mixture (3/2, v/v) as the eluent to give 0.635 g 
of the expected product in the form of a white solid (yield=25.6%). 
M.p.=172-175.degree. C. 
EXAMPLE 22 
N-(4-Aminobutyl)N-(1,1-dimethylethyl 
)2,4-dichloro-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamide 
dihydrochloride 
A suspension of 1.21 g (1.67.10.sup.-3 mol) of the compound obtained 
according to Preparation XI in 8.35 ml (8.35.10.sup.-3 mol) of a 1 N 
solution of hydrogen chloride in ethyl acetate is prepared and the mixture 
is stirred for 15 min at room temperature. The residual precipitate is 
filtered off and washed on the filter with ethyl ether to give 6.58 g of 
the expected product in the form of a white solid (yield=58%). 
M.p.=172-174.degree. C. 
EXAMPLE 23 
N-(4-Aminobutyl)-N-(1,1-dimethylethyl)-2,4-dichloro-3-[(2-methylquinolin-8- 
yl)oxymethyl]benzenesulfonamide 
5 ml of aqueous ammonia (30% solution) are added to a solution of 0.563 g 
(0.94.10.sup.-3 mol) of the compound obtained according to Example 22 in 
70 ml of water and the mixture is stirred for 30 min at room temperature. 
After extraction of the reaction medium with ethyl ether, the organic 
phase obtained is washed with water, dried over sodium sulfate and 
concentrated under reduced pressure to give 0.20 g of the expected product 
in the form of beige crystals (yield=40.4%). 
M.p.=142-144.degree. C. 
EXAMPLE 24 
N-[4-[(1-Oxoethyl)aminolbutyl]-N-(1,1-dimethylethyl)2,4-dichloro 
-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesulfonamide 
0.109 ml (1.145.10.sup.-3 mol) of acetic anhydride is added to a solution 
of 0.120 g (0.229.10.sup.-3 mol) of the compound obtained according to 
Example 23 in 1 ml of acetic acid and the reaction medium is stirred for 
24 hours at room temperature. It is then concentrated under reduced 
pressure and the residue is taken up with ethyl ether to form a 
suspension. The precipitate obtained is filtered off and dried. 0.272 g of 
the expected product is thus isolated in the form of a white solid 
(yield=21%). 
M.p.=100-102.degree. C. (decomposition) 
EXAMPLE 25 
2,4-Dichloro-N-(phenylmethyl)-N-(7-hydroxyheptyl)-3-[(2-methylquinolin-8-yl 
]oxymethyl]benzenesulfonamide 
A solution of 0.5 g (0.83.10.sup.-3 mol) of the compound obtained according 
to Example 6 in 10 ml of dimethylformamide is prepared and 61.5 mg 
(2.10.sup.-3 mol) of an 80% suspension of sodium hydride in oil are added. 
After the mixture has been stirred for 30 min at room temperature, 220 mg 
(1.12.10.sup.-3 mol) of 7-bromoheptanol are added. The reaction mixture is 
stirred for 15 hours at 40.degree. C. and then cooled, hydrolyzed with 
water and extracted with ethyl acetate. The combined organic phases are 
washed with water until the washings are neutral, dried over sodium 
sulfate and concentrated under reduced pressure. After purification of the 
residue by chromatography on silica gel using a cyclohexane/ethyl acetate 
mixture (7/3, v/v) as the eluent, 150 mg of the expected product are 
obtained in the form of a white solid (yield=24%). 
.sup.1 H NMR (CDCl.sub.3): 0.90-1.60 (m, 10H); 2.75 (s, 3H); 3.20 (m, 2H); 
3.56 (m, 2H); 4.53 (m, 2H); 5.68 (m, 2H); 7.26-7.47 (m, 10H); 8.03 (d, 
1H); 8.09 (d, 1H). 
EXAMPLE 26 
2,4-Dichloro-N-(phenylmethyl 
)-N-(8-ethoxy-8-oxooctyl)-3-[(2-methylquinolin-8-yl)oxymethyl]benzenesulfo 
namide 
The expected product is obtained with a yield of 37% by following a 
procedure analogous to the process of Example 4, starting from the 
compound obtained according to Example 6 and ethyl 8-bromooctanoate and 
purifying the crude product by recrystallization from isopropyl alcohol. 
M.p.=117.degree. C. 
EXAMPLE 27 
2,4-Dichloro-N-(phenylmethyl)-N-(7-carboxyhepty l)-3-[(2-methylquinolin-8 
-yl)oxymethyl]benzenesulfonamide 
A suspension of 1.1 g (1.67.10.sup.-3 mol) of the compound obtained 
according to Example 26 in 100 ml of ethanol is prepared and a solution of 
0.1 g (2.5.10.sup.-3 mol) of sodium hydroxide in 10 ml of water is added. 
The reaction mixture is refluxed for 3 hours, the solvent is then 
evaporated off under reduced pressure and the residue is taken up with 
water. The resulting aqueous phase is acidified to pH 5 with 1 N 
hydrochloric acid. The precipitate formed is filtered off, washed with 
water, dried under vacuum at 60.degree. C. and then purified by 
chromatography on silica gel using a dichloromethane/methanol mixture 
(9/1, v/v) as the eluent. After recrystallization from a toluene/isopropyl 
ether mixture, 0.8 g of the expected product is obtained in the form of a 
creamy white solid (yield=76%). 
M.p.=100.degree. C. 
EXAMPLE 28 
2,4-Dichloro-N-(phenylmethyl)-N-[8-(methylamino)-8-oxooctyl]-3-[(2-methylqu 
inolin-8-yl)oxymethyl]benzenesulfonamide 
The expected product is obtained with a yield of 98% by following a 
procedure analogous to the process of Example 10, starting from the acid 
obtained according to Example 27 and a solution of methylamine in ethanol 
and purifying the crude product by chromatography on silica gel using a 
dichloromethane/methanol mixture (98/2, v/v) as the eluent, followed by 
crystallization from isopropyl ether. 
M.p.=120.degree. C. 
The activity of some of the products according to the invention was 
evaluated in respect of their ability to bind to the bradykinin receptors. 
Kinins, of which bradykinin is the main representative, actually form a 
group of small peptides which make a substantial contribution to the 
inflammatory response and therefore appear to be involved in the 
pathophysiology of inflammatory diseases. Furthermore, bradykinin is among 
the most potent analgesics known. Kinins activate two types of receptor, 
called B.sub.1 and B.sub.2. The B.sub.2 receptor belongs to the large 
family of receptors with seven transmembrane domains coupled to the G 
proteins. In the present invention we describe compounds which bind to the 
B.sub.2 receptor and therefore block the binding of bradykinin. 
We used the following pharmacological test: Ileum segments are isolated 
from male guinea-pigs of the Dunkin-Hartley strain (Iffa Credo, 
l'Arbresle, France) and ground in the following TES buffer: TES 25 mM, 
1,10-phenanthroline 1 mM (pH 6.8), bacitracin 140 .mu.g/ml, BSA 1 g/l. The 
membranes are then isolated by centrifugation (18,000 rpm; 20 min; 
4.degree. C.). The binding studies are carried out in the TES buffer using 
[.sup.3 H]-bradykinin (120 pM) and 50 .mu.g of membrane protein per test 
(final volume 500 .mu.l) with an equilibrium time of 90 min at 20.degree. 
C. The percentage inhibition of the binding of [.sup.3 H]-bradykinin is 
then determined in the presence of one of the test compounds according to 
the invention at a concentration of 10.sup.-6 M. 
The results obtained (indicated as "activity") from these tests are 
collated in Table I below with reference to the Examples given in the 
description. 
The compounds of the present invention which inhibit the binding of [.sup.3 
H]-bradykinin to the guinea-pig B.sub.2 receptor (see Table I) also bind 
to the human B.sub.2 receptor cloned and transfected in a stable manner 
into CHO cells (Chinese Hamster Ovary Cells). Thus, in this test, some 
compounds inhibit the binding of [.sup.3 H]bradykinin to the B.sub.2 
receptor by at least 95% at a concentration of 10 .mu.W. 
The compounds of the present invention can be useful in the treatment of 
numerous pathological conditions involving bradykinin or its homologs. 
These pathological conditions include septic and hemorrhagic shock, 
anaphylactic reactions, arthrosis, rheumatoid polyarthritis, rhinitis, 
asthma, inflammatory diseases of the gastrointestinal tract (for example 
colitis, rectitis, Crohn's disease), pancreatitis, certain carcinomas, 
hereditary angioedema, migraine, cerebrovascular complications, certain 
neurological disorders, vascular inflammatory states (for example 
atherosclerosis and arteritis of the lower limbs), painful states (for 
example toothache, menstrual pain), premature uterine contractions, 
cystitis and burns. 
The compounds of the present invention, which can be used in the form of 
the free base or in the form of their non-toxic addition salts in 
association with a physiologically acceptable excipient, will generally be 
prescribed in therapy at doses of about 1 to 1000 mg/day in a form which 
can be administered orally, by intravenous injection, intramuscularly or 
subcutaneously, transdermally, by means of aerosols or by means of 
suppositories. 
The compounds may also be administered topically, for example in the form 
of gels or ointments. 
The compounds of the present invention are also useful as pharmacological 
reagents, especially for the study of hormone-receptor interactions. Use 
as a pharmacological reagent may require a radiolabeled derivative of one 
of the compounds according to the invention (for example with tritium 
[.sup.3 H] or sulfur [.sup.35 S]) in order to obtain a radioligand 
intended for conformational studies of the bradykinin B.sub.2 receptor or 
for binding tests involving this type of receptor, for example for the 
evaluation of novel compounds which are capable of showing an affinity for 
the bradykinin B.sub.2 receptor. 
TABLE I 
__________________________________________________________________________ 
1 #STR21## 
Example Activity 
no. R.sub.1 R.sub.2 % 
__________________________________________________________________________ 
1 --CH.sub.3 --C(CH.sub.3).sub.3 -- 
2 --CH.sub.3 --H -- 
3 --H --H -- 
4 --CH.sub.3 
2 #STR22## -- 
5 --C(CH.sub.3).sub.3 
2 #STR23## -- 
6 --H 
2 #STR24## -- 
7 --CH.sub.3 
3 #STR25## 97.6 
8* --CH.sub.3 
4 #STR26## 99.5 
9 --CH.sub.3 
5 #STR27## 99.5 
10 --CH.sub.3 
6 #STR28## 99.8 
11 --CH.sub.3 
7 #STR29## 100 
12 --CH.sub.3 
8 #STR30## 96.9 
13 --CH.sub.3 
9 #STR31## 99.3 
14 --CH.sub.3 
0 #STR32## 100 
15 --CH.sub.3 
1 #STR33## 97.9 
16** 
--CH.sub.3 --(CH.sub.2).sub.7 --NH.sub.2 
100 
17 --CH.sub.3 --(CH.sub.2).sub.5 --COOC.sub.2 H.sub.5 
-- 
18 --CH.sub.3 --(CH.sub.2).sub.5 --COOH -- 
19 --CH.sub.3 --(CH.sub.2).sub.5 --CONHCH.sub.3 
99.0 
20 --CH.sub.3 --(CH.sub.2).sub.8 --OH 95.7 
21 --CH.sub.3 --(CH.sub.2).sub.12 --OH 94.3 
22* --C(CH.sub.3).sub.3 
--(CH.sub.2).sub.4 --NH.sub.2 
-- 
23 --C(CH.sub.3).sub.3 
--(CH.sub.2).sub.4 --NH.sub.2 
92.8 
24 --C(CH.sub.3).sub.3 
--(CH.sub.2).sub.4 --NH--CO--CH.sub.3 
90.5 
25 
2 #STR34## --(CH.sub.2).sub.7 --OH 95.1 
26 
2 #STR35## --(CH.sub.2).sub.7 --COOC.sub.2 H.sub.5 
-- 
27 
2 #STR36## --(CH.sub.2).sub.7 --COOH -- 
28 
2 #STR37## --(CH.sub.2).sub.7 CONHCH.sub.3 
98.0 
29 --H --C(CH.sub.3).sub.3 -- 
__________________________________________________________________________ 
Notes: 
*dihydrochloride, 
**bis(trifluoracetate)