Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-25
2002-06-18
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S285000, C544S283000, C514S258100, C514S259500
Reexamination Certificate
active
06407116
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel nitrogen-containing condensed cyclic compounds (preferably quinazoline derivatives) which have a superior anti-allergic action, anti-histaminic action, anti-inflammatory action, eosinophil chemotaxis-inhibiting action and so on, and are useful as agents for preventing or treating allergic diseases, atopic dermatitis, allergic rhinitis, asthma (e.g., bronchial asthma), allergic conjunctivitis, urticaria (e.g., chronic urticaria), etc., a method for producing them, a composition and so on.
BACKGROUND
In these days, compounds having a nitrogen-containing condensed ring (e.g., quinazoline) backbone as a drug against various diseases have been extensively synthesized, including:
(1) a compound disclosed in JP-A-57-206665 represented by the formula:
[wherein each of R
1
and R
3
is a lower alkyl group, R
2
is a straight or branched alkoxycarbonyl group, R
1
, R
2
and R
3
are bound to 5-, 6- and 7-positions, or 6-, 7- and 8-position in a quinazoline ring, R
4
is a hydrogen atom, a halogen atom, an alkyl group, a trifluoromethyl group or a nitro group, X is an alkylene group optionally having an alkyl side chain, Y is a nitrogen atom or a CH moiety, each of R
5
, R
6
and R
7
is a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, each of R
8
and R
9
is a hydrogen atom or a lower alkyl group, m is an integer of 0 to 3 and n is 0 or 1], or a salt thereof which is purported to be useful as a vasodilator, a blood flow-improving agent, a hypotensive agent or an anti-arteriosclerotic agent;
(2) a compound disclosed in JP-A-60-152417 represented by the formula:
[wherein R is a hydrogen atom or a fluorine atom] or a salt thereof which is purported to be useful as an anti-cancer effect-promoting agent;
(3) a compound disclosed in EP-A-040793 represented by the formula:
[wherein each of R
1
and R
3
is an alkyl group, R
2
is an alkoxycarbonyl group, B is an alkyl group or a phenyl group optionally substituted with at least one halogen, alkyl, alkoxy, dialkylamino, O—CH
2
—O, CF
3
or NO
2
, A is a hydrogen atom, an alkyl group, a carboxy-alkyl group, an alkoxycarbonyl-alkyl group, a hydroxyalkyl group, a benzyl group optionally substituted with NO
2
or a lower alkoxy, an aminoalkyl group substituted with pentamethylene, hexamethylene, heptamethylene, methylene optionally substituted with pyridylmethyl, alkyl, alkoxy, benzyl, tetramethylene, alkyl, a lower alkyl group substituted with piperidine or pyrrolidine, R
4
R
5
N—CO—X, R
6
R
7
N—X
1
—O—CO—X, a group represented by the formula:
[wherein each of X and X
1
is a lower alkylene group, R
4
is a hydrogen atom or an alkyl group, R
5
is a hydrogen atom, an alkyl group, a dialkylamino-alkyl group, a benzyl group, piperidino-morpholino, 1-piperazinyl, a 4-(lower)acyl-1-piperazinyl, a 4-carbamoyl-1-piperazinyl-alkyl group whose carbamoyl group is optionally substituted with alkyl or phenyl, or NR
4
R
5
is piperidino or 4-alkylpiperazino, R
6
is an alkyl group, R
7
is an alkyl group, a benzyl group, a piperidino group-alkyl, morpholino-alkyl], or a salt thereof which is purported to be useful as an anti-arteriosclerotic agent;
(4) a compound disclosed in U.S. Pat. No. 3,274,194. represented by the formula:
[wherein R
1
is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group or an amino group, n is an integer of 0 to 6, R
2
is a di-lower alkylamino or a heterocyclic group], or a salt thereof which is purported to be useful as an anti-inflammatory agent or a sedative; or,
(5) a compound disclosed in JP-A-1-213284 represented by the formula:
[wherein one of X, Y and Z is a sulfur atom, and the others are carbon atoms, E and G are same or different and each is an oxygen atom or a sulfur atom, R
1
is a substituted piperidino group or a substituted 1-piperazinyl group (substituent is an aralkyl group, an aralkyloxy group, an aralkylcarbonyl group, an aromatic acyl group or an aralkylidene group), R
2
and R
3
are same or different and each is a hydrogen atom, a lower alkyl group, an aryl group or a halogen atom, R
4
is a hydrogen atom, a lower alkyl group or an acyl group, A is an alkylene group having 1 to 4 carbon atoms], or a salt thereof which is purported to have an anti-histaminic action, an anti-serotonin action, an anti-allergic action and an anti-asthmatic action.
On the other hand, examples of a compound having an anti-allergic action or an anti-histaminic action are Terfenadine (The Merck Index, 12th ed., 9307) and Ebastine (The Merck Index, 12th ed., 3534), which are used clinically.
DISCLOSURE OF INVENTION
A novel compound which is more satisfactory in terms of efficacy, duration of action, safety and the like when compared with conventional anti-allergic agents, anti-histaminic agents, anti-inflammatory agents and the like is still desired.
The inventors of this invention made an effort and finally synthesized for the first time a novel nitrogen-containing condensed ring compound (preferably a quinazoline derivative) represented by the formula:
[wherein ring A represents a cyclic hydrocarbon optionally having substituents or a nitrogen-containing heterocycle optionally having substituents; D and E are the same or different and represent, independently, an oxygen atom or a sulfur atom; one of R
1
and R
2
represents a group represented by the formula:
(wherein Ar
1
and Ar
2
represent, independently, an aromatic group optionally having substituents; Ar
1
and Ar
2
may form a condensed cyclic group optionally having substituents together with an adjacent carbon atom; ring B represents a nitrogen-containing heterocycle optionally having substituents; X and Y are the same or different and represent, independently, a bond, an oxygen atom, S(O)p (p represents an integer of 0 to 2), NR
4
(R
4
represents a hydrogen atom or a lower alkyl group) or a bivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atoms, optionally having substituents; and R
3
represents ahydrogen atom, a hydroxy group optionally having substituents or an optionally esterified carboxyl group); and the other is a hydrogen atom, a cyano group or a hydrocarbon group optionally having substituents], or its salt whose chemical structure is characterized substantially in that two substituents bound to one of two nitrogen atoms of the nitrogen-containing condensed ring (preferably a quinazoline) backbone via a spacer having a nitrogen-containing heterocycle such as piperidine or piperazine, and discovered that this compound has unexpectedly excellent anti-allergic action, anti-histaminic action, anti-inflammatory action, eosinophil chemotaxis-inhibiting action (especially as a combination of an anti-histaminic action with an eosinophil chemotaxis-inhibiting action) and excellent duration of the action and safety and undergoes an extremely low migration into the brain, based on which it is considered to be useful as a prophylactic and therapeutic agent against atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, chronic urticaria and the like, thereby establishing the present invention.
That is, the present invention relates to:
[1] A compound represented by the formula:
[wherein ring A represents a cyclic hydrocarbon optionally having substituents or a nitrogen-containing heterocycle optionally having substituents; D and E are the same or different and represent, independently, an oxygen atom or a sulfur atom; one of R
1
and R
2
represents a group represented by the formula:
(wherein Ar
1
and Ar
2
represent, independently, an aromatic group optionally having substituents; Ar
1
and Ar
2
may form a condensed cyclic group optionally having substituents together with an adjacent carbon atom; ring B represents a nitrogen-containing heterocycle optionally having substituents; X and Y are the same or different and represent, independently, a bond, an oxygen atom, S(O)p (p represents an integer of 0 to 2), NR
4
Inaba Atsuhiro
Kajino Masahiro
Morimoto Shinji
Nagaya Hideaki
Chao Mark
Liu Hong
Ramesh Elaine M.
Shah Mukund J.
Takeda Chemical Industries, Inc.
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