Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-14
2002-08-27
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C514S327000, C514S432000, C514S451000, C514S462000, C514S469000
Reexamination Certificate
active
06440999
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to an intimal thickening inhibitory agent and more particularly an intimal thickening inhibitory agent comprising a 2,6-di-t-butylphenol derivative as an active ingredient.
BACKGROUND OF THE INVENTION
It is known that coronary sclerosis is a primary cause of ischemic heart diseases such as angina pectoris and cardiac infarction. Narrowing of the vascular lumen resulting from arteriosclerotic thickening of the intima brings about nutrition and oxygen deficiencies in the myocardial tissues to induce the above diseases. Percutaneous transluminal coronary angioplasty (hereinafter abbreviated as “PTCA”) that has recently been developed as a treatment for the ischemic heart diseases such as angina pectoris and cardiac infarction is to physically dilate a blood vessel by inflating a balloon at the stenosis region of the coronary artery. However, the problem which has been recognized from the beginning of development of this treatment is that restenosis appears at the treated region within 3 to 6 months after the angioplasty at a frequency of about 40% (see
Circulation
, 77, pp. 361-371 (1988)).
Up to the present time, use of anticoagulants, antiplatelet agents or drugs having an inhibitory effect on proliferation of vascular smooth muscle cells has been attempted to prevent stenosis due to arteriosclerotic intimal thickening or restenosis after PTCA. Thus, an extensive research for such drug has been conducted (see, for example, JP 2-121922 A/90, JP 3-83923 A/91, JP 3-118383 A/91, JP 4-99775 A/92, JP 4-154720 A/92, JP 6-135829 A/94, JP 6-206842 A/94, JP 7-25768 A/95, JP 7-149641 A/95 and JP 7-223958 A/95). However, there has been found no drug having clinically sufficient inhibitory effect on vascular stenosis due to arteriosclerotic intimal thickening or restenosis due to intimal thickening after PTCA (see,
Nihon Rinsvo
, 52 (extra ed.), pp. 869-872 (1994)).
DISCLOSURE OF THE INVENTION
As a result of an extensive research in an attempt to solve the foregoing problem, it has been found that a compound represented by formula (1):
wherein X represents an oxygen atom or a group of formula (2);
—S—(O)
n
(2)
wherein n represents an integer of from 0 to 2;
R
1
represents a hydrogen atom or an acyl group;
R
2
represents a hydrogen atom, a lower alkyl group or a lower alkenyl group;
R
3
represents a lower alkyl group; and
R
4
, R
5
, and R
6
, which may be the same or different, each represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted aryl group; or
R
3
and R
4
may be taken together to form a 5-membered ring; or
R
5
and R
6
may be taken together to form a cycloalkyl group or a heterocyclic ring derived from a cycloalkyl group by substituting any one or more methylene groups on the ring with oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms;
provided that R
6
is nil when R
3
and R
4
are taken together to form a benzofuran ring, a benzo[b]thiophene ring, a benzo[b]thiophene-1-oxide ring or a benzo[b]thiophene-1,1-dioxide ring,
exhibits an excellent inhibitory effect on proliferation of vascular smooth muscle cells as well as on intimal thickening in balloon injury models.
The fact that the compound represented by formula (1) is effective in the treatment and prevention of ischemic organopathy such as arteriosclerosis, cardiac infarction and apoplexy has already been revealed (see JP 6-206842 A/94, WO 94-08930, and WO 95-27710).
BEST MODE FOR CARRYING OUT THE INVENTION
In the above formula (1), the acyl groups include an acetyl group, a formyl group, a propionyl group, a benzoyl group, a benzyloxycarbonyl group, an aminoacetyl group, an N-methylaminoacetyl group, and an N,N-dimethylaminoacetyl group. The term “lower alkyl group” means a straight- or branched-chain alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a sec-butyl group, and a tert-butyl group. The term “lower alkenyl group” means a straight- or branched-chain alkenyl group having 2 to 6 carbon atoms, for example, a vinyl group, an allyl group, a butenyl group, and a pentenyl group.
The alkyl group represented by R
4
, R
5
, or R
6
is a straight- or branched-chain alkyl group having 1 to 20 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. The alkenyl group is a straight- or branched-chain alkenyl group having 2 to 20 carbon atoms, for example, a vinyl group, an allyl group, a butenyl group, a pentenyl group, a geranyl group, and a farnesyl group. The alkynyl group is a straight- or branched-chain alkynyl group having 2 to 20 carbon atoms, for example, an ethynyl group, a propynyl group, and a butynyl group. The aryl group is a monovalent substituent derived from an aromatic hydrocarbon by removing one hydrogen atom, for example, a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Substituents in the substituted alkyl, alkenyl, alkynyl or aryl group include a halogen atom, a lower alkyl group, a hydroxyl group, an amino group, an alkoxy group, an aryloxy group, a nitro group, and a trifluoromethyl group.
The 5-membered rings formed by R
3
and R
4
include a furan ring, a dihydrofuran ring, a thiophene ring, and a dihydrothiophene ring, which are taken together with the benzene ring to form a benzofuran ring, a dihydrobenzofuran ring, a benzo[b]thiophene ring, and a dihydrobenzothiophene ring, respectively.
The cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. The heterocyclic rings derived from the cycloalkyl group by substituting any one or more methylene groups on the ring with oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms include, for example, a tetrahydropyranyl group.
Where X in formula (1) is an oxygen atom,
R
1
is preferably a hydrogen atom, an acetyl group, a benzyloxycarbonyl group, an aminoacetyl group, an N-methylaminoacetyl group or an N,N-dimethylaminoacetyl group, particularly a hydrogen atom, an acetyl group or an N,N-dimethylaminoacetyl group;
R
2
is preferably a hydrogen atom, a methyl group or a n-propyl group, particularly a hydrogen atom;
R
3
and R
4
are preferably taken together to form a furan ring or a dihydrofuran ring, particularly a dihydrofuran ring;
R
5
is preferably a hydrogen atom, a methyl group, a n-butyl group, a n-pentyl group, a n-hexyl group or an i-amyl group, particularly a n-pentyl group; and
R
6
is preferably a hydrogen atom, a methyl group, a n-butyl group, a n-pentyl group, a n-hexyl group or an i-amyl group, particularly a n-pentyl group; or
R
5
and R
6
are preferably taken together to form a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, or a tetrahydropyranyl group, particularly a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group.
Where X in formula (1) is a group represented by formula (2):
—S—(O)
n
(2)
wherein n is an integer of from 0 to 2,
R
1
is preferably a hydrogen atom, an acetyl group, a benzyloxycarbonyl group, an aminoacetyl group, an N-methylaminoacetyl group or an N,N-dimethylaminoacetyl group, particularly a hydrogen atom, an acetyl group or an N,N-dimethylaminoacetyl group;
R
2
is preferably a hydrogen atom, a methyl group or an n-propyl group, particularly a hydrogen atom;
R
3
and R
4
are preferably taken together to form a thiophene ring or a dihydrothiophene ring, particularly a dihydrothiophene ring;
R
5
is preferably a hydrogen atom, a methyl group, a n-butyl group, a n-pentyl group, a n-hexyl group or an i-amy
Cynshi Osamu
Kato Yoshiaki
Sekimori Reiko
Browdy and Neimark
Chugai Seiyaku Kabushiki Kaisha
Krass Frederick
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