Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-13
2004-09-14
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S018000, C546S020000, C546S199000, C546S201000, C546S247000, C514S322000, C514S323000, C514S331000
Reexamination Certificate
active
06790854
ABSTRACT:
TECHNICAL FIELD
The present invention relates to diphenylalkylamine derivatives, which have affinity for the opioid &dgr; receptor and are useful in the medicinal field, and relates to medicaments comprising said compounds as an active ingredient.
BACKGROUND ART
Opioid receptors are mainly classified into three types, i.e., &mgr;, &dgr; and &kgr; from a viewpoint of differences in pharmacological actions. On the basis of the discovery of an endogenous opioid peptide in 1970's, some progresses were made in studies about their mechanism of action. In 1990's, studies about opioid receptor structures advanced based on genetic analysis, and their mechanism of action has been being elucidated by the molecular biology. As also for the &dgr; receptor, based on the success of cloning of &dgr; receptor by Evans, Kieffer et al. in 1992, many studies have been vigorously performed in the medicinal and pharmaceutical fields by the molecular biology.
Although higher order functions of the opioid &dgr; receptors have not yet been successfully elucidated, those already reported include that an opioid &dgr; receptor agonist exhibits analgesic activity (D. E. Moulin et al., Pain, 1985, 23, 213), and that the opioid &dgr; receptor agonist has a reducing effect on adverse reactions induced by an opioid &mgr; receptor agonist and an opioid &kgr; receptor agonist (Gallingan et. al., J. Pharm. Exp. Ther. 1984, 229, 641). Since the opioid &dgr; receptor is known to be present widely in the central and peripheral nerve systems and considered to have a wide variety of functions, discovery of an effective and selective opioid &dgr; receptor ligands can greatly contribute to therapeutic treatments of central nerve system diseases including schizophrenia, depression, cerebral apoplexy, epilepsy, Alzheimer's disease, and Parkinson's disease, and peripheral nerve system diseases including pains (Exp. Opin. ther. Patents, 1999, 9, 353).
Compounds related to the general formula (I) of the present invention are reported in J. Med. Chem. 1994, 37, 2125, WO93/15062, WO96/36620, WO97/10230, WO98/28270, WO98/28275 and the like. The compounds described in J. Med. Chem. 1994, 37, 2125 and WO93/15062 have very high affinity for &dgr; receptors. However, these compounds have not been used clinically, because their productions are difficult due to three asymmetric centers, which are apparent from their chemical formulas, and they have poor pharmacokinetics. Derivatives having a structure with no asymmetric center are reported in WO96/36620, WO97/10230, WO98/28270, WO98/28275 and the like. However, their affinities for the &dgr; receptor are undesirably lowered compared to the compounds described above. Thus, no compound has been reported which has a structure with no asymmetric center and high affinity for the &dgr; receptor.
Further, among the compounds relevant to the compounds of the general formula (I) of the present invention, derivatives that do not have a partial structure represented by X have been reported in WO94/11337, WO97/44329, WO98/43942 and the like. However, as for these compounds, affinity for &dgr; receptor has not been reported.
DISCLOSURE OF THE INVENTION
An aim of the present invention is to provide a substance having affinity for the opioid &dgr; receptor, in particular, to provide an effective and selective opioid &dgr; receptor ligand. A further aim is to provide a medicament useful for preventive and/or therapeutic treatment of central nerve system diseases and peripheral nerve system diseases on the basis of the features.
In the specification, the term “opioid &dgr; receptor ligand” means a compound having an ability to bind to an opioid &dgr; receptor, and comprehensively includes an agonist, antagonist, partial agonist, and inverse agonist for an opioid &dgr; receptor.
In order to achieve the aim described above, the inventors of the present invention studied variety of compounds. As a result, they found that compounds represented by the following general formula (I) had high affinity for the opioid &dgr; receptor, and achieved the present invention.
The present invention thus provides compounds represented by the following general formula (I):
[in the formula, X represents the following group (II), (III), (IV), (V), or (VI),
n represents 1, 2 or 3,
R
1
and R
2
each independently represent a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkoxy group which may be substituted, or a hydroxy group, or represent —O—CH
2
—O— as —R
1
—R
2
—,
R
3
represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkoxy group which may be substituted, a hydroxy group, a cyano group, an amino group which may be substituted, a carbamoyl group which may be substituted, a carboxyl group, a (substituted or unsubstituted lower alkoxy)carbonyl group, or a (substituted or unsubstituted lower alkyl)carbonyl group,
R
4
represents a saturated or unsaturated monocyclic or bicyclic carbocyclic group or a monocyclic or bicyclic heterocyclic group containing one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom,
R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
and R
12
each independently represent a hydrogen atom, a lower alkyl group which may be substituted, or a lower alkenyl group which may be substituted, and R
3
and R
4
, R
5
and R
6
, R
7
and R
8
, and R
9
and R
10
may bind to each other to form a cyclic structure] or salts thereof.
The present invention further provides medicaments comprising a substance selected from the group consisting of the compounds represented by the general formula (I) and pharmacologically acceptable salts thereof as an active ingredient. The preferred medicaments consist of a pharmaceutical composition comprising the substance described above and an additive for pharmaceutical preparations. These medicaments are useful for preventive treatment and/or therapeutic treatment of central nerve system diseases or peripheral nerve system diseases.
The present invention further provides an opioid &dgr; receptor ligand comprising a substance selected from the group consisting of the compounds represented by the general formula (I) and pharmacologically acceptable salts thereof.
The present invention still further provides use of substances selected from the group consisting of the compounds represented by the general formula (I) and pharmacologically acceptable salts thereof for manufacture of the medicaments and methods for preventive treatment and/or therapeutic treatment of central nerve system diseases or peripheral nerve system diseases, which comprises the step of administering a preventively and/or therapeutically effective amount of a substance selected from the group consisting of the compounds represented by the general formula (I) and pharmacologically acceptable salts thereof to a mammal including human.
BEST MODE FOR CARRYING OUT THE INVENTION
The entire disclosures of Japanese Patent Application No. 2000-085202 are incorporated by reference in the disclosures of the specification.
Novel compounds of the present invention will be explained in more detail.
In the specification, a “lower alkyl group” or a “lower alkoxy group” as a substituent, or a “lower alkyl group” or “lower alkoxy group” constituting a part of a substituent means an alkyl or alkoxy group in a straight or branched chain, cyclic form, or any combination thereof having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and the like. Similarly, a “lower alkenyl group” as a substituent means a straight, branched, or cyclic alkenyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and examples th
Asai Kenji
Kudo Toshiaki
Miike Naoko
Tadauchi Kaori
Tsushima Masaki
Aulakh Charanjit S.
Greenblum & Bernstein P.L.C.
Meiji Seika Kaisha Ltd.
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