Triazolo and derivatives as chemokine inhibitors

Details Triazolo and derivatives as chemokine inhibitors Triazolo and derivatives as chemokine inhibitors

2000-09-22

2002-12-10

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S250000, C514S252160, C514S267000, C514S293000, C544S183000, C544S184000, C544S251000, C544S252000, C544S346000, C544S361000, C546S082000, C546S084000, C546S085000, C546S086000

Reexamination Certificate

active

06492364

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel triazolo derivatives, pharmaceutically acceptable salts thereof, chemokine inhibitors, particularly CC chemokine inhibitors, containing the same as effective components.
BACKGROUND ART
It is well-known that in many inflammatory diseases, infiltration of leukocytes such as macrophages, neutrophils, eosinophils and lymphocytes into the inflammatory site is observed. It is thought that a physiologically active substance called chemotactic factor plays a role in the tissue accumulation of leukocytes. In particular, it has been reported that chemokines known as chemotactic cytokines induce not only infiltration of leukocytes, but also degranulation of leukocytes, production of active oxygen and adhesion reaction, and play central roles in the chemotaxis and activation of leukocytes (e.g., The New England Journal of Medicine, Vol. 338, pp. 436-445, 1998).
Chemokines are classified into 4 subgroups, i.e., C chemokines, CC chemokines, CXC chemokines and CXXXC chemokines, depending on the characteristics of the amino acid sequences (e.g., Blood, Vol. 90, pp. 909-928, 1997).
It is known that lymphotactins, to which C chemokines belong have chemotactic activities to T lymphocytes, while CC chemokines induce chemotactic activities to leukocytes other than nuetrophils, such as monocytes, lymphocytes, eosinophils, basophils and NK cells. CXC chemokines have chemotactic activities mainly to neutrophils and CXXC chemokines have chemotactic activities mainly to NK cells (e.g., The New England Journal of Medicine, Vol. 338, pp. 436-445, 1998). Such a cell specificity suggests that among these subgroups of chemokines, CC chemokines play important roles in the diseases including allergic diseases such as bronchial asthma and atopic dermatitis, chronic rheumatoid arthritis, sarcoidosis, pulmonary fibrosis, bacterial pneumonia, nephritis, atherosclerosis, ulcerative colitis, psoriasis, viral meningitis and AIDS. For example, in mice in which MIP-1&agr;, one of the CC chemokines, is knocked out, the pneumonia induced by infection with influenza virus is reduced (Science, Vol. 269, pp. 1583-1585, 1995). In addition, it is known that in mice in which CCR1, one of the receptors of CC chemokines, is knocked out, the response by helper T cells type 2 which give important contribute to onset of atopic diseases is reduced (The Journal of Experimental Medicine, Vol. 185, pp. 1959-1968, 1997), and that in mice in which CCR2 is knocked out, delayed hypersensitivity reaction and response by helper T cells type 1 is reduced (The Journal of Clinical Investigation, Vol. 100, pp. 2552-2561, 1997). Further, it is known that in mice in which eotaxin, one of CC chemokines, is knocked out, tissue accumulation of eosinophils, which play important roles as effector cells in allergic diseases, occurs (The Journal of Experimental Medicine, Vol. 185, pp. 785-790, 1997). Further, it has been reported that CCR5 and CCR3, which are CC chemokine receptors, are cofactors in infection of AIDS virus, and that RANTES, MIP-1&agr; and MIP-1&bgr;, which are CC chemokines prevent infection of AIDS virus (e.g., Annual Review of Immunology, Vol. 15, pp. 675-705, 1997).
Thus, drugs which inhibit activities of such chemokines are expected to be useful as prophylactic or therapeutic agents against these diseases. So far, 10 types of CC chemokine receptors (CCR), i.e., CCR1 to CCR10 are known (e.g., The New England Journal of Medicine, Vol. 338, pp. 436-445, 1998; and DNA and Cell Biology, Vol. 10, pp. 1249-1256, 1997). As for low molecular weight compounds which act on these receptors, although an inhibitor against CCR1 has been reported (e.g., Japanese Laid-open Patent Application (Kokai) No. 9-249566), low molecular weight compounds against other receptors as well as application thereof to therapeutic agents have not been reported.
DISCLOSURE OF THE INVENTION
An object of the present invention is to discover a substance which inhibits the actions of CC chemokines, thereby enabling prophylaxis and therapy of inflammatory diseases caused by infiltration by leukocytes such as monocytes, lymphocytes, acidophils, basophils and NK cells.
The present inventors intensively studied to discover that specific novel triazolo derivatives and pharmaceutically acceptable salts thereof have activities to inhibit actions of CC chemokines, thereby completing the present invention.
That is, the present invention provides a triazolo derivative of the Formula I:
(wherein W represents a carbon atom or a nitrogen atom, X represents a C
2
-C
6
straight chain alkyl group, a C
3
-C
8
branched alkyl group, a C
2
-C
6
fluoroalkyl group,
Formula II:
(wherein m and n represent integers of 0 to 6, and —(CH
2
)
n
— is bound to the position of any one of 2-, 3- and 4-position in the cyclohexane ring)
or Formula III:
(wherein m and n represent integers of 0 to 6, and —(CH
2
)
n
— is bound to the position of any one of 2-, 3- and 4-position in the benzene ring);
Y represents a carbon atom or a nitrogen atom;
...
represents a single bond or a double bond; Z
1
and Z
2
, which may or may not simultaneously exist, each represents C
6
-C
18
substituted or non-substituted cyclohexyl group, indole-3-yl group, imidazoyl group, furyl group, thienyl group, pyrrolyl group, pyridyl group or QCR
6
R
7
R
8
, with the proviso that in cases where Z
1
and Z
2
represent QCR
6
R
7
R
8
, Q and R
6
may or may not exist, and when Q exists, Q is selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom; and when R
6
exists, R
6
represents hydrogen or hydroxyl group; R
7
and R
8
, which may be the sane or different, represent hydrogen, C
1
-C
6
straight alkyl group, C
3
-C
8
branched alkyl group, or one selected from the group consisting of C
6
-C
16
substituted or non-substituted phenyl group, C
10
-C
16
substituted or non-substituted naphthyl group and C
6
-C
16
substituted or non-substituted cycloalkyl group, which phenyl group, naphthyl group or cycloalkyl group is bound through C
0
-C
6
methylene chain; V represents a carbon atom or a nitrogen atom; R
1
represents C
1
-C
6
straight alkyl group or aryl group; R
2
and R
3
, which may or may not exist and which may be the same or different, each is selected from the group consisting of C
1
-C
6
straight alkyl group, C
1
-C
6
straight alkoxyl group, C
3
-C
8
branched alkyl group, C
3
-C
8
branched alkoxyl group, hydroxyl group; chloro, bromo, fluoro, amino group, monoalkylamino group in which the alkyl group has 1 to 6 carbon atoms, diaikylamino group in which each alkyl group has 2 to 6 carbon atoms, trifluoromethyl group, and nitro group; in cases where V and W are carbon atoms and where V and W are bound through double bond, R
4
does not exist, and R
5
represents hydrogen, C
1
-C
6
straight alkyl group, C
1
-C
6
straight alkoxyl group, C
3
-C
8
branched alkyl group, C
3
-C
8
branched alkoxyl group, or represents one selected from the group consisting of C
6
-C
16
substituted or non-substituted phenyl group, C
10
-C
16
substituted or non-substituted naphthyl group and C
6
-C
16
substituted or non-substituted cycloalkyl group, which phenyl group, naphthyl group or cycloalkyl group is bound through C
0
-C
6
methylene chain; in cases where V is nitrogen atom and W is carbon atom and where V and W are bound through double bond, both R
4
and R
5
do not exist; in cases where V is carbon atom, W is nitrogen atom or carbon atom, and V and W are bound through single bond, R
4
and R
5
cooperatively represent oxo group; wherein the substituent(s) in said substituted phenyl group, substituted naphthyl group and substituted cycloalkyl group is(are) 1 to 5 C
1
-C
6
straight alkyl group(s), C
3
-C
6
branched alkyl group(s), phenyl group(s), phenoxy group(s), naphthyl group(s), cyclopentyl group(s) or cyclohexyl group(s)) or a pharmaceutically acceptable salt thereof. The present invention also provides a chemokine inhibitor comprising the above-described triazolo derivative of the present invention or a pharmaceutically acceptab

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