Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-24
1999-08-17
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142325, 5142352, 514253, 514254, 540575, 544121, 544357, 544364, 544373, A61K 3155, A61K 31495, C07D40306, C07D40314
Patent
active
059394137
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to new piperazine derivatives and a pharmaceutically acceptable salt thereof.
More particularly, it relates to new piperazine derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament.
Accordingly, one object of the present invention is to provide new and useful piperazine derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like.
Another object of the present invention is to provide a process for the preparation of said piperazine derivatives and a salt thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said piperazine derivatives and a pharmaceutically acceptable salt thereof.
Still further object of the present invention is to provide a use of said piperazine derivatives or a pharmaceutically acceptable salt thereof as Tachykinin antagonist, especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g., migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals.
DISCLOSURE OF INVENTION
The object compound of the present invention can be represented by the following general formula (I): ##STR1## wherein
Y is bond or lower alkylene;
R.sup.1 is halo(lower)alkyl;
R.sup.2 is indolyl which may have 1, 2 or 3 suitable substituent s);
A is bond or lower alkylene;
Z is hydrogen, carboxy, protected carboxy or a group of the formula: ##STR2## in which R.sup.3 and R.sup.4 are independently hydrogen or a N containing saturated heterocyclic group which may be substituted by 1 to 3 and same or different suitable substituent(s), or
R.sup.3 and R.sup.4 together with the adjacent nitrogen atom form a N containing saturated heterocyclic group which may be substituted by 1 to 3 and same or different suitable substituent(s); and same or different group; or its pharmaceutically acceptable salt.
According to the present invention, the object compound (I) or a salt thereof can be prepared by processes which are illustrated in the following schemes.
Process 1
##STR3##
Process 2
##STR4##
Process 3
##STR5##
Process 4
##STR6## wherein
A, Y, Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are each as defined above;
X.sup.1 is a leaving group;
Za is carboxy, protected carboxy or a group of the formula: ##STR7## in which R.sup.3 and R.sup.4 are the same as above;
Zb is protected carboxy;
A.sub.1 is lower alkylene; and
W is a leaving group.
As to the starting compounds (II) and (III), some of them are novel and can be prepared by the procedures described in the Preparations and Examples or an equivalent procedures thereof, or a conventional manner.
Suitable salts and pharmaceutically acceptable salts of the starting and object compounds are conventional non-toxic salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g. a
REFERENCES:
patent: 4598079 (1986-07-01), Beyerle et al.
patent: 5670505 (1997-09-01), Matsuo et al.
Frossard et al, Life Sciences vol. 49, pp. 1941-1953 (1991).
Hagiwara Daijiro
Konishi Nobukiyo
Manabe Takashi
Matsuda Hiroshi
Matsuo Masaaki
Bernhardt Emily
Fujisawa Pharmaceutical Co. Ltd.
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