Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-25
2004-01-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S228200, C514S234800, C514S248000, C540S575000, C544S062000, C544S119000, C544S237000
Reexamination Certificate
active
06677333
ABSTRACT:
TECHNICAL FIELD
This invention relates to 2H-phthalazin-1-one derivatives and poly (ADP-ribose) polymerase inhibitors containing 2H-phthalazin-1-one derivatives as active ingredient.
More particularly, this invention relates to poly (ADP-ribose) polymerase inhibitors containing 2H-phthalazin-1-one derivatives of the formula (I)
(wherein all symbols are as hereinafter defined) and non-toxic salts thereof as active ingredient, novel 2H-phthalazin-1-one derivatives of the formula (Ia) as hereinafter defined and non-toxic salts thereof, and processes for the preparation thereof.
BACKGROUND
Poly(ADP-ribose)polymerase (abbreviated as PARP hereinafter) is a nuclear enzyme activated by DNA strand breaks, which play an important role the reaction that transfer of the ADP-ribose moiety from nicotinamide adenine dinucleotide (abbreviated as AND
+
hereinafter) to various proteins such as histones, DNA-polymerases and DNA-topoisomerases, etc. DNA strand breaks is caused by Peroxynitrite (ONOO
−
) and oxygen radicals that leads to overactivation of PARP. (PARP on Zn finger domain binds to DNA with nicks and then PARP is activated up to 100 times.) Overactivation of PARP elicits depletion of AND
+
which essential of electron transport and then ATP depletion leads to disturbance of energy production system, consequently cause to cell death. (The suicide theory of PARP activation: Free Radic. Biol. Med., 21, 855 (1996); TIPS., 19, 287 (1998)). Therefore, it is considered that PARP inhibitor may be useful as inhibition of cell death. Since caspase-3, one of interleukin-1&bgr;-converting enzyme family, specifically cleaves PARP as the substrate, it is suggested PARP is associated with apoptosis. (Cell., 81, 801 (1995).
It is reported that 3-aminobenzamide and nicotinamide generally known as inhibitors of PARP are useful for inhibition of cell death and improvement of diseases on various models of ischemic diseases (cerebral, myocardial, intestinal, skeletal muscular or retinal ischemia etc.), inflammatory diseases (inflammatory bowel disease, multiple sclerosis or arthritis etc.), diabetes, shock, extrapyramidal disease (TIPS., 19, 287 (1998); Eur. J. Pharmacol., 350, 1 (1998)) and hyperalgesia (Pain, 72, 355 (1997)) in vitro, in vivo and in the knockout mouse. And it is known they are increased the effects of antiretroviral (HIV etc.) (Biochem. Biophys. Res. Commum., 180, 504 (1991)) or anticancer drugs. (Radiat. Res., 126, 367 (1991); Br. J. Cancer., 72, 849 (1995)).
PARP inhibitor may be useful for prevention and/or treatment of various diseases, for example, ischemic diseases (cerebral, myocardial, intestinal, skeletal muscular or retinal ischemia etc.), inflammatory diseases (inflammatory bowel disease, multiple sclerosis or arthritis etc.), neurodegenerative disorders (extrapyramidal disease, Alzheimer's disease or muscular dystrophy etc.), diabetes, shock, head trauma, renal insufficiency or hyperalgesia etc. And it may be increased the effects of antiretroviral (HIV etc.) or anticancer drugs.
For example, it is disclosed in JP kokai hei 2-124874 that the compound of formula (A)
(wherein R
A
is OR
1A
, lower alkyl, NR
1A
R
2
A, a halogen, trifluoromethyl, C(O)X
2A
, CN, COX
2A
(wherein X
2A is
lower alkyl, aryl, or aralkyl), R
1A
is a hydrogen, lower alkyl, benzyl, etc., R
2A
is a hydrogen, lower alkyl, phenyl or benzyl, Z
A
is (i) —CHR
2A
CHR
3A
— (wherein R
3A
is a hydrogen, alkyl, phenyl or benzyl), (ii) —CR
5A
═CR
3A
, or (iii) —CR
3A
═N— (when Z
A
is (iii), then N of Z
A
binds to N of ring), R
3A
is a hydrogen, lower alkyl, phenyl or benzyl, R
5A
is a hydrogen, lower alkyl, phenyl, benzyl, chlorine, bromine or NR
7A
R
8A
(wherein R
7A
and R
8A
each, independently, is a hydrogen or lower alkyl)) have an inhibitory activity on PARP (with the proviso that, definitions not related are omitted).
It is disclosed in SU 1378303 that the compound of formula (B)
and it is not disclosed about the biological activity.
It is disclosed in JP kokai sho 57-167974 that the compound of formula (C)
(wherein R
2c
and R
3c
each, independently, is C1-5 alkyl, C1-5 alkoxy, a halogen, C2-6 alkoxycarbonyl, carboxy, cyano, C2-4 alkylcarbonyl, hydroxy or trifluoromethyl, mC and nC is 0-3) is an intermediate of platelet aggregate inhibitor.
It is disclosed in JP kokai sho 54-032489 that the compound of formula (D)
(wherein R
D
is hydroxy, methoxy or protected hydroxy) is an intermediate of antihypertensive.
It is disclosed in EP 534443 that the compound of formula (E)
(wherein A
E
is C3-6 alkyl, C5-7 cycloalkyl, phenyl, thienyl, furyl, thiazolyl, phenoxy, C7-9 phenylalkyl, phenylthio, azacycloalkyl, pyridyl or imidazolyl, all of which may be substituted by C1-4 alkyl, C1-4 alkoxy and/or halogen; ring C
E
is benzene, furan or thiophene, all of which may be subsituted by C1-4 alkyl)
is an intermediate of platelet aggregate inhibitor.
It is disclosed in WO 9911624 that the compound of formula (F)
(wherein X
F
is double-bonded oxygen or OH; R
7F
when present, is hydrogen or lower alkyl; Y
F
represents the atoms necessary to form a fused mono-, bi- or tricyclic, carbocyclic or heterocyclic ring, wherein each individual ring has 5-6 ring member atoms; Z
F
is (i) —CHR
2F
CHR
3F
— (R
2F
and R
3F
are independently hydrogen, alkyl, aryl, aralkyl); (ii) —R
6F
FC═CR
3F
— (R
3F
and R
6F
are independently hydrogen, lower alkyl, aryl, aralkyl, halo, nitro, —COOR
7F
, —NR
7F
R
8F
where R
8F
is independently hydrogen or C1-9 alkyl, or R
6F
and R
3F
, taken together, form a fused aromatic ring, wherein each individual ring has 5-6 ring members); (iii) —R
2F
C═N—; (iv) —CR
2F
(OH)—NR
7F
—, (v) —(C(O)NR
7F
— or (vi) —NR
9F
—C(O)—CHR
10F
— (R
9F
and R
10F
are independently hydrogen or lower alkyl, etc.),wherein said alkyl,aryl and aralkyl , are substituted at one or more positions with hydrogen, hydroxy, halo, haloalkyl, alkoxy, alkenyloxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imino, sulfhydryl, thioalkyl, carboxy, carbocycle, heterocycle, lower alkyl, lower alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitroso, dimethylamino) have an inhibitory activity on PARP. the following compound is known.
compound (1): 4-(2-acetyloxyphenyl)-2H-phthalazin-1-one (CAS Registry No. 71271-37-9).
DISCLOSURE OF THE INVENTION
Energetic investigations have been carried out to find a compound having poly(ADP-ribose)polymerase inhibitory activity. As a result, the present inventor have found that these aims may be accomplished by a 2H-phthalazin-1-one derivatives of the formula (I).
The 2H-phthalazin-1-one derivatives of the formula (I) have not been known as poly(ADP-ribose)polymerase inhibitor at all. The 2H-phthalazin-1-one derivatives of the formula (Ia) are novel compounds, which have been unknown so far.
The present invention relates to
(1) Poly(ADP-ribose)polymerase inhibitors containing a 2H-phthalazin-1-one derivatives of the formula (I)
wherein R
1
is
(i) C1-4 alkyl substituted by hydroxy or amino, or
(ii) —A
1
—A
2
—A
3
,
in which A
1
is
(i) —NR
3
C(O)—,
(ii) —NR
4
C(S)—,
(iii) —NR
5
SO
2
—,
(iv) —CH
2
—NR
6
—,
(v) —CH
2
—O—,
(vi) —OC(O)—,
(vii) —CH
2
—NR
7
C(O)—,
(viii) —NR
8
C(O)NR
9
—,
(ix) —NR
10
C(O)O—,
(x) —NR
11
C(S)NR
12
—,
(xi) —NR
13
—, or
with the proviso that the linkage of the right side of each group represented by A
1
binds to A
2
,
wherein R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
and R
15
each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl,
A
2
is
(i) C1-8 alkylene,
(ii) C2-8 alkenylene,
(iii) Cyc
1
,
(iv) —(C1-4 alkylene)—O—(C1-4 alkylene)—,
(v) —(C1-4 alkylene)—S—(C1-4 alkylene)—,
(vi) —(C1-4 alkylene)—NR
16
—(C1-4 alkylene)—,
(vii) —(Cyc
1
)—(C1-8 alkylene)—,
(viii) —(C1-8 alkylene)—(Cyc
1
)—, or
(ix) —(C1-4 alkylene)—(Cyc
1
)—(C1-4 alkylene),
R
16
is a hydrogen atom, C1-8 alkyl, C1-8 alkoxycarbonyl, phenyl or C1-8 alkyl substituted by phenyl,
Cyc
1
is
(i) a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring, or
(ii) a 3-10
Naka Masao
Seko Takuya
Takahashi Shinya
Takeuchi Jun
Ono Pharmaceutical Co. Ltd.
Raymond Richard L.
Sughrue & Mion, PLLC
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