Benzopiperidine derivatives

Details Benzopiperidine derivatives Benzopiperidine derivatives

1999-04-05

2003-02-11

Shah, Mukund J. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C544S058200, C544S058600, C544S345000, C546S199000, C546S236000, C546S238000

Reexamination Certificate

active

06518423

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to benzopiperidine derivatives, salts thereof or hydrates thereof, which are useful in the prevention and treatment of immunologic diseases, etc., drugs containing the same, processes for producing the same and intermediates thereof.
2. Prior Art
In recent years, the participation adhesion molecules such as ICAM-1, VCAM-1 and E-selectin participate in the processes of extravascular infiltration of leukocytes into inflammatory tissues, metastasis of cancer cells, recognition of antigens by immunocytes and proliferation of immunocytes has come to be regarded as highly important. For example, rheumatoid arthritis is actually associated with the promoted expression of adhesion molecules in joints, the infiltration of lymphocytes into joint synovial membranes and neutrophil infiltration into the synovial fluid. It has been also reported that adhesion molecules participate in asthma, nephritis, ischemic reflow disorders, psoriasis, atopic dermatitis, the rejection reaction accompanying organ transplantation, and cancer metastasis. Therefore, it is expected that the inflammatory immunologic diseases such as asthma, nephritis, psoriasis, atopic dermatitis, inflammation, ischemic reflow disorders and the rejection reaction accompanying organ transplantation, autoimmune diseases such as rheumatism and collagen disease, and cancer metastasis can be inhibited by regulating the adhesion of leukocytes, neutrophilis, cancer cells, etc. to intravascular endothelial cells and controlling the antigen recognition process.
When treating various inflammatory diseases and immune diseases such as rheumatoid arthritis, it has been a common practice to suppress the inflammation by the use of nonsteroidal antiinflammatory drugs (NSAID) such as indomethacin and ibuprofen, and steroids, i.e., “symptomatic treatments”.
Recently, attempts have been also made to use immunomodulators such as D-penicillamine which is a remedy for rheumatism and Wilson's disease, and levamisole which is an immunopotentiator activating T cells, in order to ameliorate immunopathy at the early stage, i.e., “causal treatments”.
However, NSAIDs such as indomethacin have serious side effects such as gastric ulceration. Moreover, it is considered that these drugs are not efficacious against tissue disorders or the pathological progression associated with chronic inflammation. With respect to steroids too, the problem of serious side effects frequently arises.
On the other hand, hitherto no immunomodulator has been known satisfactory both in its therapeutic effects and side effects. Accordingly, the development of excellent drugs suitable for both symptomatic and causal treatments has been urgently required.
As compounds having similar structures to those of the compounds of the present invention, it was disclosed in JP-A-60-115524 that 1,4-diazaphenothiazine derivatives have 5-lipoxygenase inhibitory effects. However, this patent provides few examples, despite its broad claims. That is to say, the claims thereof are not clearly supported by the description in the specification.
Furthermore, the above-mentioned patent neither states nor suggests that these compounds are efficacious in the prevention and treatment of various diseases owing to the cell adhesion inhibitory effects thereof, as clarified in the present invention.
On the other hand, compounds analogous to the compounds of the present invention are reported as nerve relaxants in J. Med. Chem., 16 (4), 564 (1983) and as antibacterial agents, insecticides and herbicides in U.S. Pat. Nos. 3,663,543, 3,746,707, 3,808,208, 3,821,213 and 3,845,044.
SUMMARY OF THE INVENTION
The present inventors have conducted extensive studies in order to provide drugs efficacious in the prevention and treatment of these various inflammatory diseases and immunologic diseases such as rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and the rejection reaction accompanying organ transplantation. As a result, they have succeeding in discovering that benzopiperidine derivatives with novel structures have excellent antiinflammatory and anti-immunologic disease effects, thus completing the present invention.
Accordingly, the present invention relates to benzopiperidine derivatives represented by the following formula (I), salts thereof or hydrates thereof, processes for producing the same and drugs comprising the same:
wherein R
1
to R
3
may be the same or different and each represents:
1) hydrogen,
2) optionally substituted lower alkyl;
3) optionally substituted lower alkenyl;
4) optionally substituted lower alkynyl;
5) optionally substituted lower cycloalkyl;
6) optionally substituted lower cycloalkenyl;
7) optionally substituted C
2-6
alkoxy;
8) a group represented by the following formula:
 wherein X and Y represent each optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom; l and m may be the same or different and each represents 0 or 1; the ring A represents an optionally substituted cycloalkyl ring optionally having one or more heteroatoms; the ring B represents a ring optionally having one or more double bonds in the ring which is selected from owing following:
a) an optionally substituted cycloalkyl ring optionally having a heteroatom;
b) an optionally substituted bicycloalkyl ring optionally having a heteroatom, wherein the different atoms (bridgehead atoms) in the ring B are bonded to each other via an optionally substituted C
1
or higher alkylene group optionally having a heteroatom; or
c) an optionally substituted spiro-hydrocarbon ring optionally having a heteroatom, wherein the both ends of an optionally substituted C
1
or higher alkylene group optionally having a heteroatom are bonded to a carbon atom (bridgehead carbon atom) in the ring B;
9) a group represented by the following formula:
 wherein
X
1
represents an optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom;
l
1
is 0 or 1;
the ring A
1
represents:
a) an optionally substituted cycloalkyl ring optionally having one or more heteroatoms;
b) an optionally substituted cycloalkenyl ring optionally having one or more heteroatoms; or
c) an optionally substituted spiro-hydrocarbon ring optionally having a heteroatom, wherein the both ends of an optionally substituted C
1
or higher alkylene group optionally having a heteroatom are bonded to a carbon atom (bridgehead carbon atom) in the ring A
1
; or
10) a group represented by the following formula:
 wherein
X
2
represents an optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom;
l
2
is 0 or 1;
Q represents:
a) heteroaryl consisting of one or more optionally substituted rings or aryl consisting of one or more optionally substituted rings;
b) optionally substituted quaternary ammonio;
c) a group represented by the following formula:
 wherein R
5
and R
6
may be the same or different and each represents hydrogen or lower alkyl;
d) lower acyl;
e) lower acyloxy;
f) carbamoyl;
g) a group represented by the following formula:
 wherein R
7
and R
8
may be the same or different and each represents hydrogen, lower alkyl, a group represented by the formula:
 wherein R
71
represents lower alkyl, trifluoromethyl, aryl or a group represented by the formula:
 wherein R
72
and R
73
may be the same or different and each represents hydrogen, lower alkyl, lower cycloalkyl or aryl;
a group represented by the following formula:
 wherein R
81
represents hydrogen, lower alkyl or aryl;
a group represented by the following formula:
 wherein R
74
and R
75
may be the same or different an

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