Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-22
2002-09-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S233500, C514S231200, C514S233800, C514S234200, C544S106000, C544S107000, C544S111000, C544S124000
Reexamination Certificate
active
06448247
ABSTRACT:
BACKGROUND TO THE INVENTION
The present invention relates to a series of new heterocyclic compounds having tachykinin receptor antagonist activity. It also provides methods and compositions using them for therapeutic and prophylactic purposes, as well as processes for their preparation and intermediates used in their preparation.
The presence in the mammalian body of the various forms of tachykinin is associated with a variety of diseases and disorders, including respiratory diseases, such as asthma, bronchitis, rhinitis and coughs; allergies; ophthalmic inflammatory diseases, such as conjunctivitis and spring catarrh; dermal diseases, such as contact dermatitis, atopic dermatosis and urticaria; inflammatory diseases, such as rheumatism and arthrosis deformans; pain, such as migraine, headache and toothache; central nervous system diseases, such as anxiety and Alzheimer's disease; and gastrointestinal diseases, such as colitis; and cystitis; and many others. Inhibition of the activity of these forms of tachykinin will, therefore, result in a new therapy and/or prophylaxis for these diseases and disorders.
The compounds of the present invention exhibit antagonism generally to tachykinin receptors, but especially to the receptors for substance P (which receptors are generally referred to as “neurokinin 1 receptors” —NK
1
) and the receptors for neurokinin A (which receptors are generally referred to as “neurokinin 2 receptors” —NK
2
). It is a particular advantage of the compounds of the present invention that they exhibit antagonism to both of these receptors, a so-called “dual effect”.
Compounds which are structurally close to those of the present invention are disclosed in FR 2729952, FR 2729953 and FR 2729954. However, these are selective for the NK
1
receptors and none of these compounds exhibits the dual effects of the compounds of the present invention.
A few low molecular weight non-peptide compounds are known to exhibit antagonism to both of these receptors, for example some of the compounds disclosed in WO 9429309 (1994), WO 9417045 (1994), WO 9426735 (1994) and WO 9528389 (1995) exhibit such an effect. Typical examples of compounds which are disclosed in these documents are:
However, oral absorption of these compounds is poor. As a result, these prior art compounds cannot be administered by mouth and must be administered parenterally, for example by injection. It is well known in the medical field that administration of any drug by injection is undesirable, as either the patient must be trained (and some patients are inherently untrainable) or the drug must be administered by experienced staff, which is expensive and inconvenient both for the patient and the staff.
There is, therefore, a need for a new tachykinin receptor antagonist which exhibits the aforementioned dual effects, and which has good oral absorption and a low toxicity.
We have now discovered a series of new compounds which exhibit an activity against the NK
1
receptors which is at least equal to that of the prior art compounds showing a dual effect and which unexpectedly exhibit a much stronger activity against the NK
2
receptors.
BRIEF SUMMARY OF INVENTION
It is, therefore, an object of the present invention to provide a series of new heterocyclic compounds.
It is a further, and more specific, object of the present invention to provide such compounds which exhibit antagonism to tachykinin receptors.
It is a still further, and more specific, object of the present invention to provide such compounds which exhibit antagonism to those tachykinin receptors known as NK
1
and NK
2
.
It is a still further, and more specific, object of the present invention to provide certain of such compounds which exhibit greatly improved activity.
Other objects and advantages of the present invention will become apparent as the description proceeds.
The compounds of the present invention are those compounds of formula (I):
and the quaternary ammonium derivative thereof of formula (Ia):
wherein:
R
1
and R
2
are the same as or different from each other, and each represents a carbocyclic aryl group or an aromatic heterocyclic group, said aryl group and said heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents &agr;, defined below;
A represents a methylene group, a carbonyl group or a sulfonyl group;
B represents a single bond between the groups represented by A and R
1
, an alkylene group having from 1 to 4 carbon atoms or an alkenylene group having from 2 to 4 carbon atoms;
D represents an oxygen or sulfur atom;
E represents an alkylene group having from 1 to 6 carbon atoms, a haloalkylene group having from 1 to 6 carbon atoms, a cycloalkane-1,1-diyl group having from 3 to 6 carbon atoms, a cycloalkane-1,1-diylmethyl group having from 3 to 6 carbon atoms in the cycloalkane part, or a cycloalkane-1,1-di(ylmethyl) group having from 3 to 6 carbon atoms in the cycloalkane part;
G represents an alkylene group having from 1 to 4 carbon atoms or an alkenylene group having from 2 to 4 carbon atoms;
L represents a group of formula —N(R
3
)— or a group of formula —C(R
4
)(R
5
)—
wherein R
3
represents a carbocyclic aryl group or an aromatic heterocyclic group, said aryl group and said aromatic heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents &agr;, defined below,
R
4
represents a hydrogen atom, a carbocyclic aryl group or an aromatic heterocyclic group, said aryl group and said aromatic heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents &agr;, defined below, and
R
5
represents a group of formula —CO—R
6
, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an amino group, an acylamino group, an alkyl group which has from 1 to 6 carbon atoms and which is substituted by an acylamino group, an acylamino group whose nitrogen atom is substituted with an alkyl group having from 1 to 6 carbon atoms, a hydroxy group, a hydroxyalkyl group having from 1 to 6 carbon atoms, an alkoxyalkyl group in which the alkoxy and alkyl parts each has from 1 to 6 carbon atoms, or an aralkyloxyalkyl group having from 1 to 6 carbon atoms in the oxyalkyl part, and in which the aralkyl part is an alkyl group which has from 1 to 4 carbon atoms and which is substituted by from 1 to 3 carbocyclic aryl groups which are unsubstituted or which are substituted by at least one substituent preferably selected from the group consisting of substituents &agr;, defined below,
wherein R
6
represents an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, a group of formula —NR
a
R
b
, a carbocyclic aryl group or a heterocyclic group, said aryl group and said heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents &agr;, defined below
wherein R
a
represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an aliphatic carboxylic acyl group having from 1 to 6 carbon atoms, an alkanesulfonyl group having from 1 to 6 carbon atoms, a haloalkanesulfonyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, a carbocyclic aryl group which is unsubstituted or which is substituted by at least one substituent preferably selected from the group consisting of substituents &agr;, defined below, or an aralkyl group in which an alkyl group having from 1 to 4 carbon atoms is substituted by from 1 to 3 carbocyclic aryl groups as defined above, and
R
b
represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an aliphatic carboxylic acyl group having from 1 to 6 carbon atoms, an alkanesulfonyl group having from 1 to 6 carbon atoms, a haloalkan
Fukazawa Tetsuya
Ishibashi Koki
Ito Kazuhiro
Kurata Hitoshi
Nakajima Katsuyoshi
Patel Sudhaker B.
Sankyo Company Limited
Shah Mukund J.
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