Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-27
2001-04-03
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S314000, C544S363000, C546S166000
Reexamination Certificate
active
06211181
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds belonging to the benzenesulfonamide family and more particularly to 1-benzenesulfonylpyrrolidine compounds, to the process for their preparation and to their use in therapeutics.
In particular, these novel compounds have an antagonistic action on the bradykinin B
2
receptor and are useful in therapeutics, especially for the treatment of pain, inflammation, asthma and allergic rhinitis.
PRIOR ART
It is known that one of the possible treatments for certain pathological conditions of a painful and/or inflammatory nature (such as asthma, rhinitis, septic shock, toothache, etc.) is to inhibit 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 product possessing this mode of action has yet been marketed, numerous studies have been undertaken in order to create compounds capable of antagonizing the bradykinin receptors. 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 contains an additional amino acid (Lys) compared with bradykinin. It is known that earlier studies made it possible to obtain peptides which interact with the bradykinin receptors: some of them, like 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
2
receptor. More recently, non-peptide compounds have been proposed as antagonists towards the binding of bradykinin to its B
2
receptor, especially in published patent applications EP-A-0596406 and EP-A-0622361. It is also known that certain compounds which are structurally related to the compounds referred to in the two patent applications cited above have already been described for their possible antithrombotic properties, especially in DE-A-3617183 and EP-A-0261539.
OBJECT OF THE INVENTION
There is a need for reducing or eliminating 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 pain 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 involves competitive binding, at the bradykinin B
2
receptor, between (i) bradykinin and related or analogous hormones such as kallidin, and (ii) an antagonist, 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 said analogous hormones to said bradykinin B
2
receptor.
In accordance with this novel technical solution, it is proposed according to a first aspect of the invention to provide benzenesulfonamide compounds as novel industrial products, according to a second aspect of the invention to provide a process for the preparation of these compounds, and according to a third aspect 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 benzenesulfonylpyrrolidine 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
in which:
X is a halogen atom,
R
1
is a hydrogen atom or a linear or branched C
1
-C
3
alkyl group,
R
2
is a hydrogen atom or an OH group,
R
3
is a group
A is a single bond or a group —CO—(CH
2
)
p
—NH—,
R
4
is a hydrogen atom or a group
R
5
and R′
5
, which are identical or different, are each a hydrogen atom or a linear, branched or cyclized C
1
-C
6
alkyl group,
R
6
is a hydrogen atom or a linear or branched C
1
-C
3
alkyl group,
m is a number with a value of 0, 1 or 2,
n is a number with a value of 2, 3 or 4, and
p is a number with a value of 1, 2 or 3; and
(ii) their addition salts.
According to the invention, a process for the preparation of the compounds of formula I and their addition salts is also recommended.
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, halogen atom is understood as meaning a fluorine, chlorine, bromine or iodine atom, the preferred halogen being the chlorine atom.
C
1
-C
3
alkyl group with a linear or branched hydrocarbon chain is understood here as meaning the methyl, ethyl, propyl and 1-methylethyl groups. Linear, branched or cyclized C
1
-C
6
alkyl groups are understood as meaning especially the methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 1-methylpropyl, cyclopentyl and cyclohexyl groups.
In the compound of formula I, the nitrogen heterocycle of the pyrrolidine type carrying the groups COR
3
and R
2
can comprise 1 or 2 asymmetric carbon atoms. According to the invention, these carbon atoms can have the (R,S), R or S configuration; the carbon carrying the group COR
3
will preferably have the S configuration.
“Addition salts” are understood here as meaning the acid addition salts obtained by reacting a compound of formula I with a mineral or 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.
Room temperature (RT) is understood here as meaning a temperature of between 15 and 25° C., and temperature close to RT is understood here as meaning a temperature of between 5 and 35° C.
The process recommended according to the invention for the preparation of the compounds of formula I and their addition salts comprises the steps which consist in:
1) reacting a compound of the formula
in which X and X
1
are each a halogen,
R
2
is a hydrogen atom or an OH group, and
the carbon carrying the group COOCH
3
and the carbon carrying the group R
2
, when the latter is not the hydrogen atom, independently of one another have the (R,S), (R) or (S) configuration,
with a compound of the formula
in which:
R
1
is a hydrogen atom or a C
1
-C
3
alkyl group, and
Y is an alkali metal such as sodium or potassium,
in an anhydrous solvent, for example dimethylformamide, at a temperature of between 0 and 50° C., for 0.5 to 5 hours, to give a compound of the formula
in which X, R
1
and R
2
are as defined in the starting compounds and the carbon atoms carrying the substituents COOCH
3
and R
2
retain the same configuration as in the compound II above;
2) subjecting the resulting compound IV to alkaline hydrolysis of the ester linkage by reaction with an aqueous solution of a metal hydroxide (especially NaOH) in an inert solvent, especially dimethoxyethane, at a temperature of between 10 and 50° C., for 1 to 30 hours, to give, after acidification, the acid compound of the formula
in which X, R
1
and R
2
are as defined in the compound IV above;
3) reacting the resulting acid V with an alcohol or an amine of the formula
in which:
m is 0, 1 or 2,
n is 2, 3 or 4,
R
6
is a hydrogen atom or a C
1
-C
3
alkyl group, and
R
7
is an amino-protecting group, for example a Boc [(1,1-dimethylet
Barth Martine
Bondoux Michel
Dodey Pierre
Houziaux Patrick
Ou Khan
Evenson, McKeown, Edwards & Lenahan P.L.L.C.
Fournier Industrie et Sante
McKane Joseph K.
Solola Taofiq A.
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