Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-22
2004-08-03
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254020, C514S326000, C514S575000, C544S137000, C544S168000, C544S367000, C544S393000, C546S209000, C546S234000, C562S621000
Reexamination Certificate
active
06770644
ABSTRACT:
TECHNICAL FIELD
The present invention relates to hydroxamic acid derivatives, the methods for preparation thereof and inhibitors of interleukin-6 production comprising thereof, as an active ingredient.
More particularly, it relates to (1) inhibitors of IL-6 production comprising hydroxamic acid derivatives of the formula (I)
(wherein all the symbols have the same meaning as defined hereinafter), non-toxic salts thereof and prodrugs thereof, as an active ingredient,
(2) novel hydroxamic acid derivatives of the above formula (I), non-toxic salts thereof and prodrugs thereof and
(3) the methods for preparation of hydroxamic acid derivatives of the above formula (I), non-toxic salts thereof and prodrugs thereof.
BACKGROUND
Cytokine is a multifunctional factor which plays an important role in the host defense system of living body and it relates to various life phenomena. However, there are many diseases which may be caused by overproduction thereof or overresponse thereto.
IL-6 is a cytokine produced from various cells, e.g. T cells, B cells, macrophages, kidney mesangial cells, fibroblasts, and its various physiological effects are known e.g. induction of B cells differentiation to antibody-producing cells, activation of T cells, increase of platelets, and production of acute phase protein from liver cells. But an abnormal production of IL-6 has been observed in various inflammations, autoimmune diseases and neoplastic diseases and it is suggested that IL-6 plays a certain role in the causes of such pathophysiological situations. In the experiment using an animal model in which IL-6 was forcibly expressed, various types of diseases could be observed and such results strongly suggest the existence of relationship between the abnormal production of IL-6 and the cause of certain diseases (Biochem. J., 265, 621 (1990), Immunol. Today, 11, 443 (1990), J. Autoimmun., 5 Suppl A, 123 (1992), Clin. Immunol. Immunopathol., 62, S60 (1992)).
Therefore inhibition of IL-6 production is expected to improve various kinds of diseases such as inflammatory diseases as a representative. The present invention is targeted for the cytokine and provides novel medicines through inhibiting the production thereof.
Clinical application of the compounds of the present invention involves those diseases which may be caused and be changed to worse by abnormal production of IL-6 or by overresponse to them. Inhibitors of IL-6 production may be used for the prevention and/or treatment of various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis, hypergammaglobulinemia, Castleman's disease, atrial myxoma, diabetes mellitus, autoimmne diseases, hepatitis, colitis, graft versus host disease, infectious diseases and endometriosis (J. Immunol., 145, 4185 (1990), J. Exp. Med., 172, 1505 (1990), J. Clin. Invest., 87, 739 (1991), J. Clin. Invest., 89, 1681 (1992), EMBO J., 13, 1189 (1994), Hematol. Oncol. Clin. North Am., 11, 159 (1997), Cytokines Cell Mol. Ther., 4(3), 161 (1998), Folia Med. (Plovdiv), 41(1), 78 (1999), JPEN J. Parenter Enteral Nutr., 23(5), S20 (1999), J. Infect. Dis., 180(1), 10 (1999), Am. J. Obstet. Gynecol., 176(3), 593 (1997)).
For example, in the specification of Japanese Patent Application Kokai S59-46244, it is described that hydroxamic acid derivatives of the formula (X)
A
X
—B
X
—(CH
2
)
nX
—CONHOH (X)
[wherein A
X
is R
X
X
X
m
X
(R
X
is phenyl, pyrrolyl, thienyl, imidazolyl or thiazolyl, X
X
is halogen, lower alkyl, lower alkoxy or nitro, m
X
is 0 or an integer of 1-2 and each X
X
is the same or different optionally.), B
X
is —CHOH—, —CH—, —O— or —CO, nX is an integer of 2-10.]
is useful as anti-parasite agent.
And in the U.S. Pat. No. 4,769,461, it is described that hydroxamic acid derivatives of the formula (Y)
[wherein W
Y
is a bond, —O—, —S—, —NR
2Y
—, —CH(OH)—or —NR
2Y
—CO—, X
Y
is N or CR
2Y
,
when nY=0, Y
Y
is O, S, NR
2Y
or C(R
2Y
)
2
when nY=1, Y
Y
is N or CR
2Y
,
Z
Y
is —CH
2
O—, —CH
2
S—, —CH
2
NR
2y
—, —O—, —S—, —NR
2
—, —CO—, —CONR
2Y—, —CHR
2Y
CHR
2Y
—, —C(R
2Y
)═C(R
2Y
)— or —C≡C—,
R
1Y
is hydrogen, lower alkyl, trifluoromethyl, nitro, hydroxy, lower alkoxy, mercapto, lower alkylthio or halogen,
R
2Y
is hydrogen or lower alkyl,
nY is 0 or 1,
mY is 1-6.
With the proviso that when W
Y
is a bond, then mY is 0-5.]
is useful as antiinflammatory or anti-allergy agent by inhibition of cyclooxygenase and lipoxygenase.
DISCLOSURE OF THE INVENTION
Energetic investigations have been carried out to discover a compound possessing an inhibitory activity of IL-6 production. As a results, the present inventors have found that the purpose has been achieved by hydroxamic acid derivatives of the formula (I) or non-toxic salts thereof.
Hydroxamic acid derivatives of the formula (I) of the present invention have not been known as inhibitors of IL-6 production at all. Further, almost hydroxamic acid derivatives of the formula (I), non-toxic salts thereof and prodrugs thereof are novel compounds which are not known at all.
The present invention relates to
1) an inhibitor of IL-6 production comprising hydroxamic acid derivatives of the formula (I),
[wherein, R
1
is
(a) C1-8 alkyl,
(b) C2-8 alkenyl,
(c) C2-8 alkynyl,
(d) halogen,
(e) nitro,
(f) nitrile,
(g) trifluoromethyl,
(h) trifluoromethoxy,
(i) —OR
2
,
(j) —SR
2
,
(k) —NR
3
R
4
,
(l) —COR
5
,
(m) keto,
(n) Cyc1,
(o) C1-8 alkyl substituted by —OR
2
, —SR
2
, —NR
3
R
4
, —COR
5
or Cyc1,
(p) —SO
2
R
10
,
(q) (C1-8 alkylene)—OR
11
,
(r) C1-8 alkyl substituted by nitrile, —SO
2
R
10
or —O—(C1-8 alkylene)—OR
11
,
(s) —O—(C1-8 alkylene)—NR
12
R
13
,
(t) —S—(C1-8 alkylene)—NR
12
R
13
,
(u) C
1-8
alkyl substituted by —O—(C1-8 alkylene)—NR
12
R
13
— or —S—(C1-8 alkylene)—NR
12
R
13
,
(v) C2-8 alkenyl substituted by —OR
2
, —SR
2
, —NR
3
R
4
, —COR
5
, Cyc1, nitrile, —SO
2
R
10
, —O—(C1-8 alkylene)—OR
11
, —O—(C1-8 alkylene)—NR
12
R
13
or —S—(C1-8 alkylene)—NR
12
R
13
or
(w) C2-8 alkynyl substituted by —OR
2
, —SR
2
, —NR
3
R
4
, —COR
5
, Cyc1, nitrile, —SO
2
R
10
, —O—(C1-8 alkylene)—OR
11
, —O—(C1-8 alkylene)—NR
12
R
13
or —S—(C1-8 alkylene)—NR
12
R
13
,
R
2
is hydrogen, C1-8alkyl, C2-9 acyl or Cyc1,
R
3
and R
4
are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
R
5
is hydroxy, C1-8 alkyl, C1-8 alkoxy, —NR
6
R
7
or Cyc1,
R
6
and R
7
are each independently hydrogen, C1-8 alkyl or Cyc1,
R
10
is C1-8 alkyl or Cyc1,
Cyc1 is C3-7 monocarbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom,
R
11
is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
R
12
and R
13
are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
m is 0 or an integer of 1-5,
ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 membered mono-, bi- or tri-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
E is a bond, —CH═CH— or —C≡C—,
R
8
is
(a) C1-8 alkyl,
(b) C1-8 alkoxy,
(c) halogen,
(d) nitro,
(e) nitrile,
(f) trifluoromethyl or
(g) trifluoromethoxy.
With the proviso that when E is a bond, then R
1
and R
8
, taken together, may be optionally C1-4 alkylene.
n is 0 or an integer of 1-5,
R
9
is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl.],
nontoxic salts thereof or prodrugs thereof, as an active ingredient,
2) Hydroxamic acid derivatives of the formula (I)
[wherein, R
1
is
(a) C1-8 alkyl,
(b) C2-8 alkenyl,
(c) C2-8 alkynyl,
(d) halogen,
(e) nitro,
(f) nitrile,
(g) trifluoromethyl,
(h) trifluoromethoxy,
(i) —OR
2
,
(j) —SR
2
,
(k) —NR
3
R
4
,
(l) —COR
5
,
(m) keto,
(n) Cyc1,
(o) C1-8 alkyl substituted by —OR
2
, —SR
2
, —NR
3
R
4
, —COR
5
or Cyc1,
(p) —SO
2
R
10
,
(q) —O—(C1-8 alkylene)—OR
11
,
(r) C1-8 alkyl
Kishimoto Tadamitsu
Konishi Mikio
Konno Mitoshi
Naka Masao
Sakaki Katsuhito
McKane Joseph K.
Ono Pharmaceuticals Co. Ltd.
Saeed Kamal
Sughrue & Mion, PLLC
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