Drugs containing phosphoric acid derivatives as the active...

Details Drugs containing phosphoric acid derivatives as the active... Drugs containing phosphoric acid derivatives as the active...

2001-08-22

2002-12-17

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S127000, C514S129000, C558S170000, C558S208000

Reexamination Certificate

active

06495533

ABSTRACT:

TECHNICAL FIELD
This invention relates to phosphoric acid derivatives. More particularly, this invention relates to
1) phosphoric acid derivatives of the formula (I)
wherein all symbols are the same meaning as hereinafter defined and non-toxic salts thereof,
2) processes for the preparation thereof, and
3) pharmaceutical compositions containing them as active ingredient.
BACKGROUND
Tumor necrosis factor a (TNF&agr;) was discovered found as a factor that induces tumor hemorrhagic necrosis. TNF&agr; is produced by macrophages as well as various other cells, including lymphocytes (CD4+ T cells, CD8+ T cells, B cells), neutrophils, stellate cells, endothelial cells and smooth muscle cells. TNF&agr; showed various physiological activities by affecting various cells. TNF&agr; is believed to play an important role especially in inflammatory reactions as a biophylactic response. Macrophages and neutrophils are deeply involved in development and progress of inflammatory reaction. TNF&agr; stimulates vulnerary activities of macrophages and increases release of inflammatory cytokines, including TNF&agr;, interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) etc. Also TNF&agr; is associated with activation of neutrophils such as phagocytosis, degranulation, chemotaxis and expression of adhesion molecules and enhances production of platelet activating factor and active oxygen by neutrophils. TNF&agr; stimulates growth, induction of interleukin-2 (IL-2) receptor and production of interferon &ggr; and colony-stimulating factor in T cells, which play an important role in immune response. Besides TNF&agr; provides help to B lymphocytes for antibody production and cell division.
It is reported below that TNF&agr; is involved in variety of diseases. p
0
(1) It may be a cause of fulminant hepatitis that TNF&agr; levels in serum of the patients with fulminant hepatitis were higher than that of the patients with the severe form of acute hepatitis [H. Iwai et. al., Crit. Care. Med., 26, 873 (1998)].
(2) TNF&agr; contents in intestinal mucosa from inflammatory bowel disease were markedly increased [Z. Kmiec, Arch. Immunol. Ther. Exp., 4, 143 (1998)].
(3) In the patients with Crohn's disease, anti TNF&agr; antibody was effective endoscopically [D. W. Hommes et. al., Haemostasis, 27, 269 (1997)].
(4) There was a correlation between TNF&agr; and glucose level in serum of the patients with insulin dependent diabetes [M. Muc-Wierzgon et. al., Pol. Arch. Med. Wewn., 97, 426 (1998)].
(5) In the patients with interstitial pneumonia, ability to produce TNF&agr; by alveolar macrophages are enhanced than in controls [J. Ancochea et. al., Arch. Bronconeumol., 33, 335 (1997)].
(6) Anti-TNF&agr; antibody was effective on experimental autoimmune uveitis in mice [G. Sartani et. al., Invest. Ophthalmol. Vis. Sci., 37, 2211 (1996)].
(7) Thalidomide, which is a TNF&agr; production inhibitor, diminished mechanical allodynia and thermal hyperalgesia in bennet model and improved the pathologic vascular injury [C. Sommer et. al., Pain, 74, 83 (1998)].
(8) Thalidomide was effective for diarrhea and weight loss in HIV patients [D. Sharpstone et. al., Gastroenterol, 112, 1823 (1997)].
(9) Anti-TNF&agr; antibody reduced infarct volume in middle cerebral artery ischemia-reperfusion model [G. Yang et. al., Neuroreport, 9, 2131 (1998)].
Therefore inhibitors of TNF&agr; production may be considered useful as preventives and/or remedies of various diseases induced by inflammatory cytokines including TNF&agr;. In view of physiological activity and involvement of TNF&agr; with diseases, these inhibitors may be useful for rheumatoid arthritis, ulcerative colitis, Crohn's disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen's disease, infection, etc.
RELATED ARTS
For example, it is disclosed in JP kokai 55-118494 that the phosphorylcholine type compound of the formula (A)
wherein R
1A
and R
2A
are the same or different to represent hydrogen atom, optionally substituted by alkyl, alkenyl, aralkyl, aryl, acyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, alkoxycarbonylaminoalkyl, carbamoyl, thiocarbamoyl, or heterocyclic ring, R
3A
and R
5A
are the same or different to represent hydrogen atom, carboxyl, optionally substituted by alkyl, alkenyl, aralkyl, aryl, alkoxycarbonyl, or heterocyclic ring, R
4A
represents hydrogen atom, alkyl, alkenyl, aralkyl, or aryl etc., A
A
represents oxygen atom, sulfur atom, or —NR
8A
— (wherein R
8A
repersents hydrogen atom, etc.), R
6A
is the same or different to represent hydrogen atom, or optionally substituted by alkyl, aralkyl, R
7A
represents alkyl, aralkyl, X
1A
and X
2A
represent oxygen atom or sulfur atom, I
A
and m
A
each, is 0, 1 or 2, and n
A
is 2 or 3 is useful as antitumor agent.
It is disclosed in WO 96/22966 that the compound of the formula (B)
wherein X
B
represents —COOH, —P
−
O
3
H, —SO
2
R
5B
, —SO
3
H, —OP
−
O
3
H, —COOR
4B
or —CON(R
4B
)
2
, Y
B
repersents —CO—, —SO
2
—, or —PO
2
—, R
1B
represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl etc., R
2B
represents hydrogen atom, aryl, alkyl, alkenyl, alkynyl, or cycloalkyl etc., R
3B
represents alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl etc., or R
2B
and R
3B
, taken together with the atom to which they are attached, represent heterocyclyl, R
4B
represents aryl, alkyl, or cycloalkyl etc., and n
B
is 0, 1 or 2 is useful as a cell adhesion inhibitor.
PURPOSE OF THE INVENTION
Energetic investigations have been carried out to find new compounds having TNF&agr; production inhibitory activity. As a result, the present inventor have found that these aims may be accomplished by a phosphoric acid derivatives of the formula (I).
The phosphoric acid derivatives of the formula (I) have not been known as TNF&agr; production inhibitor at all.
DISCLOSURE OF THE INVENTION
The present invention relates to
1) Phosphoric acid derivatives of the formula (I)
wherein R
1
is
(1) C1-20 alkyl,
(2) C1-20 alkyl which one carbon atom is replaced by an oxygen atom, a sulfur atom, —S(O)— or S(O)
2
— (with the proviso that, a carbon atom which attached with E is not replaced by these groups),
(3) C2-20 alkenyl,
(4) C2-20 alkynyl,
(5) Cyc
1
(wherein Cyc
1
is C5-15 membered mono-, bi- or tricarbocyclic ring or 5-15 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom),
(6) C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl substituted by Cyc
1
(wherein all symbols are the same meaning as hereinbefore defined), Cyc
1
may be substituted by one or more substituents selected from the following (a)-(r):
(a) C1-8 alkyl,
(b) C1-8 alkoxy,
(c) nitro,
(d) halogen atom,
(e) trifluoromethyl,
(f) trifluoromethyloxy,
(g) hydroxy,
(h) cyano,
(i) NR
10
R
11
(wherein R
10
and R
11
each, independently, is a hydrogen atom, C1-8 alkyl, C1-8 hydroxyalkyl, C2-5 acyl or C1-8 alkylsulfonyl),
(j) COOR
20
(wherein R
20
is a hydrogen atom or C1-4 alkyl),
(k) CONR
30
R
31
(wherein R
30
and R
31
each, independently, is a hydrogen atom or C1-4 alkyl),
(l) —S(O)
m
—R
32
(wherein m is 0, 1 or 2, R
32
is 1-8 alkyl or C1-8 alkyl substituted by C1-8 alkoxy, COOR
20
(wherein R
20
is the same meaning as hereinbefore defined) or CONR
30
R
31
(wherein R
30
and R
31
each, independently, is a hydrogen atom or C1-4 alkyl)),
(m) —O—Cyc
2
(wherein Cyc
2
is C3-8 cycloalkyl or phenyl),
(n) —S—Cyc
2
(wherein Cyc
2
is the same meaning as hereinbefore defined),
(o) C1-8alkyl substituted by one substituent selected from C1-8 alkoxy, COOR
20
(wherein R
20
is the same meaning as hereinbefore defined), CONR
30
R
31
(wherein R
30
and R
31
are the same meaning as hereinbefore defined), phenyl or hydroxy.
(p) C1-8alkoxy substituted by on

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