N-benzenesulphonyl-L-proline derivatives as bradykinin B.sub.2 a

Details N-benzenesulphonyl-L-proline derivatives as bradykinin B.sub.2 a N-benzenesulphonyl-L-proline derivatives as bradykinin B.sub.2 a

1999-01-25

2000-06-06

Huang, Evelyn Mei

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514218, 514314, 540575, 544363, 546172, A61K 3147, A61K 31495, C07D40112, C07D40114, C07D40314

Patent

active

060719176

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to novel compounds derived from N-benzenesulfonyl-L-proline, to the process for their preparation and to their use in therapeutics.
These novel compounds have an inhibitory action on bradykinin and are useful in therapeutics, particularly for the treatment of pain and inflammation and especially for the treatment of asthma, cerebral traumatic shock 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 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 (SEQ ID NO:1)) and kallidin is a peptide hormone (Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (SEQ ID NO:2)) 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 (FHOE 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 its B.sub.2 receptor. More recently, non-peptide compounds have been proposed as antagonists towards the binding of bradykinin to its B.sub.2 receptor, especially in EP-A-0596406 and EP-A-0622361. It is also known that certain compounds whose structure is related to those of 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 in the treatment of inflammation and pain, irrespective of their origin, and especially in the treatment of pain associated with inflammatory phenomena.
According to the invention, it is proposed to provide a novel technical solution which involves competitive binding, at the bradykinin B.sub.2 receptor, between (i) bradykinin and related or analogous hormones, 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 analogous hormones to said bradykinin B.sub.2 receptor.
In accordance with this novel technical solution, it is proposed according to a first aspect of the invention to provide compounds derived from N-benzenesulfonyl-L-proline 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 analgesics and/or anti-inflammatories.


SUBJECT OF THE INVENTION

In accordance with the novel technical solution of the invention, a compound derived from N-benzenesulfonyl-L-proline is recommended as a novel industrial product, said compound being characterized in that it is selected from the group consisting of: ##STR2## in which: X.sub.1 and X.sub.2 are each independently a halogen atom or a C.sub.1 -C.sub.3 -alkoxy group, C.sub.1 -C.sub.3 -alkyl group with a linear or branched hydrocarbon chain, ##STR3## B is a single bond, --CO--, --CO--CH.sub.2 --, --CO--CH.sub.2 --O--, --CO--CH.dbd.CH-- or --SO.sub.2 --, a pyridyl group), and 4-position on the aro

REFERENCES:
Stewart JM. Biopolymers (Peptide Science). 37, 143-155 1995.
Stewart JM. Recent Progress on Kinins. Birkhauser Verlag Basel. pp.546-550 1992.

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