Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-24
2002-11-12
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S172000, C546S159000, C544S128000, C544S363000, C514S235500, C514S253030
Reexamination Certificate
active
06479515
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel benzenesulphonamide compounds, their method of preparation and their therapeutic use.
These novel compounds have an antagonist action towards bradykinin and are useful in therapeutics, particularly for the treatment of pain and inflammation, and especially in the treatment of asthma, cerebral traumatic shock and allergic rhinitis.
PRIOR ART
It is known that one of the possibilities for treatment of certain pathologies of painful and/or inflammatory character (such as asthma, rhinitis, septic shock, dental pain, etc.) is to inhibit the action of certain hormones such as bradykinin or kallidin. In reality, these peptide hormones are involved in a large number of physiological processes, some of which are closely associated with these pathologies.
Although at present no product having this mode of action is commercially available yet, many studies have been undertaken in order to understand the mode of action of kinins and in particular of bradykinin and its homologues, then to create compounds capable of being bradykinin-receptor antagonists. Among the numerous publications relating to these studies, mention may be made of Pharmacological Reviews Vol. 44 no. 1, pages 1-80 (1992) and Biopolymers (Peptide Science) vol. 37 pages 143-155 (1995).
Bradykinin is a peptide hormone formed 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 a supplementary amino acid (Lys) with respect to bradykinin. It is known that prior studies have made it possible to obtain peptides which interact with the bradykinin receptors: some such as bradycor (CP.0127 from the company Cortech), icatibant (HOE 140 from the company Hoechst) [“bradycor” and “icatibant” are international non-proprietary names (INN)] or alternatively NPC 17761 (from the company Scios-Nova) have an inhibitory action on the binding of bradykinin to its B
2
receptor. Recent publications cite other peptides capable of having a bradykinin-antagonist action towards its B
2
receptor; among these it is possible to mention, for example, WO-A-97/09347, WO-A-97/09346, U.S. Pat. Nos. 5,610,140, 5,620,958, 5,610,142 and 5,597,803. In addition, non-peptide compounds have been proposed as antagonists towards the binding of bradykinin to its B
2
receptor, especially in EP-A-0596406, EP-A-0622361, U.S. Pat. Nos. 5,578,601, 5,510,380, FR-A-2735128, JP-A-09/040662, FR-A-2737892, WO-A-97/11069, WO-A-97/41104, WO-A-96/13485 and FR-A-2765222. It is additionally known that certain compounds of structure which is more or less related to those of the compounds aimed at in the present application have already been described, especially in DE-A-3617183 and EP-A-0261539, with regard to their possible antithrombotic properties.
AIM OF THE INVENTION
There is a need to attenuate or to suppress pain and inflammation in mammals and especially in man.
To satisfy this need, a novel technical solution has been sought which is effective in the treatment of pain irrespective of its origin, especially in the treatment of pain associated with inflammatory or traumatic phenomena.
According to the invention, it is proposed to provide a novel technical solution, which employs, at the level of the bradykinin B
2
receptor, competitive binding between (i) bradykinin and related or analogous hormones, and (ii) an antagonist substance, and which requires compounds of benzenesulphonamide type, which are structurally different from the abovementioned known products, and are capable of limiting or substantially inhibiting the binding of bradykinin and analogous hormones to the said bradykinin B
2
receptor.
According to this technical solution, the novel compounds bind competitively to the bradykinin B
2
receptor without causing the effects of bradykinin on this receptor (these novel compounds are so-called antagonist substances). This results in the appearance of a state analogous to that observed in the absence of bradykinin, namely a decrease in pain, inflammatory reactions and other harmful effects caused by the receptors activated by bradykinin.
In accordance with this novel technical solution, according to a first aspect of the invention, compounds derived from benzenesulphonamide are proposed as novel industrial products; according to a second aspect of the invention, a method of preparation of these compounds is proposed; and according to a third aspect of the invention, a use of these compounds, especially a therapeutic use, as active principles of specialities or medicinal compositions is proposed.
SUBJECT OF THE INVENTION
According to the novel technical solution of the invention, a benzenesulphonamide compound is recommended as novel industrial product, which is characterized in that it is chosen from the group formed by:
(i) the compounds of formula I:
in which:
Het
1
represents a 5-membered nitrogen-containing heterocycle, especially imidazole, pyrazole or triazole,
Het
2
represents a 4-, 5- or 6-membered nitrogen-containing heterocycle of structure:
in which
R
1
represents a hydrogen atom or a hydroxyl, C
1
-C
4
alkoxy, phenoxy, phenylmethoxy, —CH
2
OH, cycloalkyloxy, cycloalkylalkoxy (where each cycloalkyl fragment is C
3
-C
8
and the alkoxy fragment is C
1
-C
4
), —NH—CO—CH
3
, —CO—NH
2
or —CO—NH—CH
3
group,
R
2
represents a hydrogen atom or a —CH
2
OH, —CH
2
—O—CH
3
, —CONR
3
R
4
,
R
3
represents a hydrogen atom, a C
1
-C
3
alkyl group, a C
3
-C
8
cycloalkyl group, a (C
3
-C
8
) cycloalkyl (C
1
—C
3
) alkyl group, a phenyl group, or a phenylmethyl group,
R
4
represents a hydrogen atom, a C
1
-C
3
alkyl, —(CH
2
)n—CH
2
OH, —(CH
2
)n—COOH, —(CH
2
)n—CH
2
—NR
5
R
6
,
R
5
represents a hydrogen atom, a C
1
-C
3
alkyl, phenyl, phenylmethyl, pyridinyl, pyridinylmethyl, pyridinylethyl, benzoyl, 4-(amino-iminomethyl)benzoyl, —(CH
2
)
m
—CH
2
OH, —(CH
2
)
m
—COOH, —(CH
2
)
m
CH
2
—O—(CH
2
)
m
—CH
2
OH, —CO—(CH
2
)
m
—COOH, or
R
6
represents a hydrogen atom or a C
1
-C
3
alkyl group, or, R
5
and R
6
considered together form, with the nitrogen atom to which they are attached, a 5- to 6-membered N heterocycle,
n=1, 2, 3 or 4,
m=1, 2 or 3; and
(ii) their addition salts.
According to the invention, a method of preparation of the compounds of formula I and their addition salts is also recommended.
The use of a bradykinin B
2
receptor antagonist substance, chosen from the compounds of formula I of the present invention and their non-toxic addition salts, is likewise recommended for obtaining a medicament intended for human or animal therapeutic use, against pathologies involving bradykinin or its homologues, in particular against pain, especially in the treatment or prevention of pathologies associated with inflammatory or painful states, and against severe traumatic shock, in particular cerebral traumatic shock.
DETAILED DESCRIPTION OF THE INVENTION
In the general formula I of the compounds of the invention, C
1
-C
3
alkyl group is understood as meaning a methyl, ethyl, propyl or 1-methylethyl group.
C
1
-C
4
alkoxy group is preferentially understood here as meaning the methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy and 1,1-dimethylethoxy groups. C
3
-C
8
cycloalkyl group is understood as meaning the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, and (cycloalkyl)alkyl groups are understood as meaning especially the cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl groups.
When a group such as R
5
comprises a heterocycle, for example pyridine, and the position of substitution is not specified, it must be understood that the bond with the heterocycle can be made with any of the substitutable members.
5- to 6-membered NR
5
R
6
heterocycle is understood as meaning a pyrrolidine, piperidine, piperazine or morpholine ring, and more particularly a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or 1-morpholinyl group.
The heterocycle Het
1
, which has five members, comprises one or more heteroatoms. Advantageously, it comprises 1
Barth Martine
Bondoux Michel
Dodey Pierre
Aulakh C. S.
Fournier Industrie et Sante
Merchant & Gould P.C.
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