Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-06
2001-12-04
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S157000, C546S158000, C546S189000, C546S191000, C546S301000, C548S260000, C548S310100, C548S478000, C549S437000, C552S298000, C560S028000, C560S053000, C560S056000, C560S119000, C560S121000, C560S160000, C560S256000, C562S466000, C562S501000, C562S503000, C564S158000, C564S172000, C564S217000, C564S360000, C568S033000, C568S327000, C568S379000, C568S441000, C568S633000
Reexamination Certificate
active
06326369
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a bicyclic or tricyclic quinone compound having an excellent mitochondrial function activating effect, to a production thereof and to a use thereof, for example, a pharmaceutical composition effective in treating Alzheimer's disease, etc.
BACKGROUND ART
Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are becoming popular with the recent increase in the old-age population, and there is an increasing demand for medicines for preventing and/or treating such neurodegenerative diseases.
Recently, it is said that one factor causing those diseases is the hypofunction of mitochondrial complexes. Mitochondria exist in all animal cells, while participating in the production of energy necessary for cell activities via electron-transfer system. However, mitochondria and mitochondrial genes are easily damaged by oxidative stress deriving from dysfunction of the electron-transport system (for example, radical attack of reactive oxygen species, etc.), resulting in energetic hypometabolism and cell degeneration. In particular, brain cells require high energy consumption, in which, therefore, mitochondria existing are more easily degenerated, thereby resulting in so-called brain electron-transport mitochondrial disorders to be caused by anomalous mitochondrial transmission with aging [e.g., Proceeding of National Academy of Sciences, USA, 91, 8731-8738 (1994), etc.].
Ubiquinone, which is a particular quinone compound, is indispensable as the coenzyme for oxidation-reduction in electron-transport systems. Derivatives having the quinone skeleton of ubiquinone have been produced.
As a compound having a mitochondrial function activating effect and a nerve growth factor production enhancing effect, known is idebenone; 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone [e.g., JP-A-56-97223, U.S. Pat. No. 4,436,753, JP-A-3-81218, U.S. Pat. No. 5,059,627, Biochemical and Biophysical Research Communications, 125, 1046-1052 (1984), etc.].
On the other hand, the following bicyclic or tricyclic quinone compounds are known.
1) JP-A-59-128348 discloses a compound of the formula:
which has a prostaglandin biosynthesis inhibiting effect and is useful as a non-steroidal, anti-inflammatory analgesic.
2) Journal of the American Chemical Society, 112, 1987-1905 (1990) discloses a compound of the formula:
3) Chemical Society Perkin Transactions, 1, 2979-2988 (1990) discloses compounds of formulae:
which have an anti-tumoral activity.
4) Australian Journal of Chemistry, 29, 179-190 (1976) discloses a compound of the formula:
R
1
R
2
R
3
H
OMe
H
H
H
OMe
OMe
H
H
H
OMe
OMe
H
Me
H
H
H
Me
Studies of medicines for inhibiting mitochondrial dysfunctions, which are for treatment of Alzheimer's disease, etc., are being made, while being essentially directed to antioxidants. It is now desired to develop compounds which are different from the above-mentioned known compounds in their chemical structures but which have an excellent mitochondrial function activating effect and are satisfactory as active ingredients in medicines.
DISCLOSURE OF INVENTION
We, the inventors of the present invention have studied various compounds having a mitochondrial function activating effect, a result, have synthesized, for the first time, a compound being characterized by its chemical structure in that the ring A of the bi- or tri-cyclic quinone skeleton of the formula:
wherein each symbol is as defined below, is substituted by the group of the formula: —X—Y wherein each symbol is as defined below, which is represented by the formula:
wherein R
1
and R
2
each represents a lower alkyl, or
R
1
and R
2
may be bonded together to form a ring;
X represents a spacer of which the number of atoms constituting the principal chain is 1 to 15;
Y represents an acyl, a hydroxy which may be substituted, an amino which may be substituted or an aromatic group which may be substituted; and
ring A represents a 5- to 8-membered ring which may be further substituted apart from the group of the formula: —X—Y wherein each symbol is as defined above, or a salt thereof [hereinafter referred to as compound (I)].
We have further found for the first time that the compound (I), being based on its specific chemical structure, has an unexpected, excellent mitochondrial function activating effect along with good metabolism resistance, and is satisfactory as active ingredients in medicines. On the basis of these findings, the inventors have completed the present invention.
Specifically, the invention relates to:
1) Compound (I);
2) a compound of the above 1), wherein R
1
and R
2
each is a C
1-6
alkyl, or R
1
and R
2
form a 5- to 7-membered ring of the formula:
X is (1) a C
1-15
alkylene, C
2-15
alkenylene or C
2-15
alkynylene group, each of which group may be substituted by 1 to 3 substituents selected from the group consisting of oxo and optionally halogenated C
1-6
alkyl, or (2) a group of the formula: —(CH
2
)m—X
1
—, —(CH
2
)m—X
2
—X
1
—, —X
1
—X
2
—(CH
2
)n-, —X
2
—X
1
—(CH
2
)n-, —(CH
2
)m—X
1
—(CH
2
)n-, —(CH
2
)m—X
2
—(CH
2
)n-, —(CH
2
)m—X
1
—X
2
—(CH
2
)n-, —(CH
2
)m—X
2
—X
1
—(CH
2
)n- or —X
2
—X
1
—X
2
—(CH
2
)n- wherein X
1
is a (i) divalent C
1-8
monocyclic non-aromatic hydrocarbon group, (ii) divalent C
1-14
aromatic hydrocarbon group or (iii) divalent 5- to 14-membered heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, each of which group may be substituted by 1 to 3 substituents selected from the group consisting of oxo and optionally halogenated C
1-6
alkyl; X
2
is O, S, SO or SO
2
; m and n each is an integer of 0 to 10; and m+n is an integer of 1 to 13;
Y is (1) an acyl of the formula:
—CO—R
3
, —CO—OR
3
, —CO—NR
3
R
4
, —CS—NHR
3
, —SO
2
—R
3a
or —SO—R
3a
wherein R
3
is
(a) hydrogen,
(b) a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, C
1-14
aryl or C
7-16
aralkyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of (i) halogen, (ii) C
1-3
alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C
1-6
alkyl, (vi) optionally halogenated C
3-6
cycloalkyl, (vii) optionally halogenated C
1-6
alkoxy, (viii) optionally halogenated C
1-6
alkylthio, (ix) hydroxy, (x) amino, (xi) mono-C
1-6
alkylamino, (xii) di-C
1-6
alkylamino, (xiii) acyl selected from the group consisting of formyl, carboxy, C
1-6
alkyl-carbonyl, C
1-6
alkoxy-carbonyl, C
6-10
aryl-carbonyl, C
6-10
aryloxy-carbonyl, C
7-16
aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, carbamoyl, mono-C
1-6
alkyl-carbamoyl, di-C
1-6
alkyl-carbamoyl, C
6-10
aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C
1-6
alkylsulfonyl and C
6-10
arylsulfonyl, (xiv) acylamino selected from the group consisting of formylamino, C
1-6
alkyl-carboxamido, C
6-10
aryl-carboxamido, C
1-6
alkoxy-carboxamido and C
1-6
alkylsulfonylamino, (xv) acyloxy selected from the group consisting of C
1-6
alkyl-carbonyloxy, C
6-10
aryl-carbonyloxy, C
1-6
alkoxy-carbonyloxy, mono-C
1-6
alkyl-carbamoyloxy, di-C
1-6
alkyl-carbamoyloxy, C
6-10
aryl-carbamoyloxy and nicotinoyloxy, (xvi) 5- to 7-membered saturated cyclic amino which may be substituted by 1 or 2 substituents selected from the group consisting of (xvi-1) a C
1-6
alkyl, (xvi-2) a C
6-14
aryl, C
7-16
aralkyl, 5- to 7-membered saturated cyclic amino or 5- or 6-membered aromatic heterocyclic group, each of which group may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C
1-3
alkylenedioxy, nitro, cyano, optionally halogenated C
1-6
alkyl, optionally halogenated C
3-6
cycloalkyl, optionally halogenated C
1-6
alkoxy, optionally halogenated C
1-6
alkylthio, hydroxy, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, C
6-10
aryl, carboxy, formyl, C
1-6
alkyl-carbonyl, C
1-6
alkoxy-carbonyl, C
6-10
aryl-carbonyl, carbamoyl, mono-C
1-6
alkyl-carbamoyl, di-
Kato Kaneyoshi
Miyamoto Masaomi
Ohra Taiichi
Chao Mark
Davis Brian J.
Ramesh Elaine M.
Richter Johann
Takeda Chemicals Industries, Ltd.
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