Tricyclic triazolobenzazepine derivatives, process for...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S081000, C540S487000, C540S521000

Reexamination Certificate

active

06372735

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a tricyclic triazolobenzazepine derivative having antiallergic activity as a prodrug, an intermediate for synthesizing the same, a process for producing the same, and an antiallergic agent.
2. Background Art
In recent years, it has been revealed that allergic reactions induced by various stimuli such as immunoreactions can be divided into two reactions, i.e., an immediate reaction which occurs immediately after the stimulation and a delayed reaction which occurs several hours after the stimulation (see, for example, “Laie Asthmatic Responses”, P. M. O'byrne, J. Dolovich and F. E. Hargreave, Am. Rev. Respir. Dis., 1987; 136: 740-751). Especially, the control of the latter reaction has become important.
Clinical studies show that there are few drugs which are significantly effective in inhibiting the delayed allergic reaction. Thus, the development of drugs therapeutically effective in treating both the immediate reaction and the delayed reaction has been expected in the art.
Sodium cromoglicate has been known as a representative drug for inhibiting the immediate and delayed allergic reactions. This drug is clinically administered by inhalation because it is not useful when orally administered.
The administration by inhalation, however, is disadvantageous in that it is difficult to properly administer the drug to babies, infants, and children and that it is difficult to continuously administer the drug to patients who are highly sensitive to inhalation stimuli.
Thus the development of oral drugs which can inhibit both the immediate and delayed allergic reactions and have excellent efficacy have been expected in the art.
In recent years, many studies on antiallergic agents and therapeutic agents for asthma have been conducted in the art. Tricyclic compounds containing seven membered ring which have been studied include dibenzoxepine derivatives (Japanese Patent Laid-Open Nos. 10784/1988 and 78292/1993 and Journal of Chemical & Pharmaceutical Bulletin, vol. 39, No. 10, p. 2724 and p. 2729 (1991)), dibenzoxazepine derivatives (Japanese Patent Laid-Open Nos. 184963/1991, 211071/1992, and 65257/1993 and EP 5180720), and dibenzocycloheptene derivatives (WO 93/13068). Further, tricyclic benzazepine derivatives and tricyclic benzothiazepine derivatives are disclosed in EP 0686636, WO 95/18130, and WO 97/00258.
Meanwhile, a prodrug technique has been known as one means for improving the bioavailability of a drug (Keiko Toyo Seizai No Sekkei To Hyoka (Design and Assay of Oral Preparation): edited by Mitsuru Hashida, Yakugyo Jiho Co., Ltd., pp. 216-231 (1995)). Chemical modification of a carboxyl, hydroxyl, amino or other group of the drug through an ester, amido, acetal or other bond can improve the bioavailability of the drug. However, any 1,2,3-triazole-modified prodrug has not been reported in the art.
SUMMARY OF THE INVENTION
The present inventors have synthesized a tricyclic triazolobenzazepine derivative having a chemically modified triazole ring and have found that the derivative has superior. bioavailability compared with the corresponding triazolobenzazepine.
In one aspect of the present invention, there are provided tricyclic triazolobenzazepine derivatives as a prodrug represented by formula (I) and pharmacologically acceptable salts and solvates thereof:
wherein
R
1
represents a hydrogen atom, a hydroxyl group, C
1-4
alkyl, or phenyl C
1-4
alkyl;
R
2
, R
3
, R
4
, and R
5
, which may be the same or different, represent any one of the following (a) to (n):
(a) a hydrogen atom;
(b) a halogen atom;
(c) an optionally protected hydroxyl group;
(d) formyl;
(e) C
1-12
alkyl which may be substituted by a halogen atom;
(f) C
2-12
alkenyl which has one or more carbon—carbon double bonds and may be substituted by
(1) a halogen atom,
(2) cyano,
(3) —COR
9
wherein R
9
represents a hydrogen atom or C
1-6
alkyl,
(4) —COOR
10
wherein R
10
represents a hydrogen atom or C
1-6
alkyl,
(5) —CONR
11
R
12
wherein R
11
and R
12
, which may be the same or different, represent
(i) a hydrogen atom,
(ii) C
1-6
alkyl which may be substituted by amino optionally substituted by C
10-4
alkyl, phenyl optionally substituted by C
1-4
alkyl which may be substituted by a saturated five- to seven-membered heterocyclic ring containing one or two nitrogen atoms (the nitrogen atoms may be substituted by C
1-4
alkyl), or a saturated or unsaturated five- to seven-membered heterocyclic ring,
(iii) phenyl which may be substituted by carboxyl, or
(iv) a saturated or unsaturated five to seven-membered heterocyclic ring,
(6) a saturated or unsaturated five- to seven-membered heterocyclic ring which may be substituted by C
1-4
alkyl or may form a bicyclic ring fused with another ring;
(g) C
1-12
alkoxy which may be substituted by
(1) a halogen atom,
(2) a hydroxyl group,
(3) cyano,
(4) C
3-7
cycloalkyl,
(5) phenyl,
(6) C
1-4
alkoxy,
(7) phenoxy,
(8) amino which may be substituted by C
1-4
alkyl,
(9) —COR
13
wherein R
13
represents a hydrogen atom, C
1-6
alkyl, phenyl optionally substituted by a halogen atom or C
1-4
alkoxy, or phenyl C
1-4
alkyl,
(10) —COOR
14
wherein R
14
represents a hydrogen atom or C
1-6
alkyl,
(11) —CONR
15
R
16
wherein R
15
and R
16
, which may be the same or different, represent a hydrogen atom or C
1-6
alkyl which may be substituted by a saturated or unsaturated five- to seven-membered heterocyclic ring, or
(12) a saturated or unsaturated five- to seven-membered heterocyclic ring which may be substituted by C
1-4
alkyl or phenyl C
1-4
alkyl;
(h) —C═N—OR
16
wherein R
16
represents a hydrogen atom, C
1-6
alkyl, phenyl C
1-4
alkyl, or phenyl;
(i) —(CH
2
)mOR
17
wherein m is an integer of 1 to 4, and R
17
represents a hydrogen atom, C
1-6
alkyl, or phenyl C
1-4
alkyl of which one or more hydrogen atoms on the benzene ring may be substituted by C
1-4
alkyl;
(j) —(CH
2
)k—COR
18
wherein k is an integer of 1 to 4, and R
18
represents a hydrogen atom or C
1-4
alkyl;
(k) —(CH
2
)j—COOR
19
wherein j is an integer of 0 to 4, and R
19
represents a hydrogen atom or C
1-6
alkyl;
(l) —(CH
2
)p—NR
20
R
21
wherein p is an integer of 1 to 4, and R
20
and R
21
, which may be the same or different, represent
(1) a hydrogen atom,
(2) C
1-6
alkyl which may be substituted by amino optionally substituted by C
1-4
alkyl,
(3) phenyl C
1-4
alkyl,
(4) —COR
22
wherein R
22
represents a hydrogen atom or C
1-4
alkyl which may be substituted by carboxyl, or
(5) —SO
2
R
23
wherein R
23
represents C
1-4
alkyl or phenyl which may be substituted by a halogen atom;
(m) —(CH
2
)q—CONR
24
R
25
wherein q is an integer of 0 to 4, and R
24
and R
25
, which may be the same or different, represent a hydrogen atom, a saturated or unsaturated five- to seven-membered heterocyclic ring, or C
1-6
alkyl which may be substituted by a saturated or unsaturated five- to seven-membered heterocyclic ring, or alternatively R
24
and R
25
may form a saturated or unsaturated five- to seven-membered heterocyclic ring together with a nitrogen atom to which they are attached (the heterocyclic ring may further contain at least one oxygen, nitrogen, or sulfur atom, may form a bicyclic ring fused with another ring, or may be substituted by C
1-4
alkyl); and
(n) —NR
26
R
27
wherein R
26
and R
27
, which may be the same or different, represent a hydrogen atom or —COR
28
wherein R
28
represents a hydrogen atom, C
1-6
alkyl, or phenyl which may be substituted by C
1-4
alkyl or C
1-6
alkoxy optionally substituted by phenyl;
R
31
and R
32
, which may be the same or different, represent a hydrogen atom or C
1-6
alkyl which may be substituted by a halogen atom; and
Q represents a group selected from the following groups (i) to (iv) or a halogen atom or C
1-6
alkoxy:
 wherein
R
33
represents
C
1-6
alkyl which may be substituted by C
1-6
alkoxy optionally substituted by C
1-6
alkoxy, phenyl optionally substituted by C
1-6
alkoxy, amino, or nitro, or a saturated or unsaturated five- to seven-

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