Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-30
2002-03-26
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S192000, C546S217000, C514S317000
Reexamination Certificate
active
06362203
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 4-hydroxy-4-phenylpiperidine derivatives excellent in peripheral analgesic action or salts thereof; and pharmaceuticals containing the same.
BACKGROUND ART
As an analgesic, known are central opioid analgesics typified by morphine, non-steroidal anti-inflammatory drugs (NSAIDS) typified by indomethacin and local anesthetics typified by lidocaine [The Journal of Medicinal Chemistry, 42(9), 1481(1999) and cited references described therein].
Morphine however cannot be used freely because of its undesirable central side effects. In addition, there are pains against which neither non-steroidal anti-inflammatory drugs nor local anesthetics have sufficient analgesic effects. There is accordingly a demand for the development of a medicament which is safer and has higher analgesic effects than them.
In recent years, existence of a &mgr;-receptor at the periphery has been revealed and analgesic action via this receptor has come to be elucidated [The Journal of Pharmacology and Experimental Therapeutics, 248(3), 1269(1989); The Journal of Investigative Dermatology, 111, 297(1988); and Drug Therapy, 323, 1685(1995)].
In Japanese Patent Application Laid-Open No. Sho 47-173, described are diarylpiperidinobutylamide compounds and among them, loperamide developed as a stegnotic is under development as a peripheral analgesic [Anesthesiology, 90, 225(1999); The Journal of Pharmacology and Experimental Therapeutics, 289, 494(1999)].
The peripheral analgesic action of loperamide is however not always satisfactory.
An object of the present invention is therefore to provide a compound excellent in peripheral analgesic action.
DISCLOSURE OF THE INVENTION
With the foregoing in view, the present inventors have carried out an extensive investigation to obtain a compound having excellent peripheral analgesic action. As a result, it has been found that a 4-hydroxy-4-phenylpiperidine derivative represented by the below-described formula (1) is markedly superior to the above-described loperamide in peripheral analgesic action and is therefore useful as a medicament, leading to the completion of the present invention.
In one aspect of the present invention, there is thus provided a 4-hydroxy-4-phenylpiperidine derivative
represented by the following formula (1):
[wherein, R
1
and R
2
are the same or different and each independently represents a hydrogen atom, a lower alkyl group or a cycloalkyl group, or R
1
and R
2
may form a heterocyclic group together with the adjacent nitrogen atom, R
3
represents a hydrogen atom or a group —(CR
4
R
5
)
n
—Y (in which, R
4
and R
5
each represents a hydrogen atom or a lower alkyl group, Y represents a group —COOR
6
, —CONR
7
R
8
, —OR
9
or —OCOR
10
(in which R
6
, R
9
and R
10
each independently represents a hydrogen atom, a lower alkyl group or a cycloalkyl group, R
7
and R
8
are the same or different and each independently represents a hydrogen atom, a lower alkyl group or a cycloalkyl group or R
7
and R
8
may form a heterocyclic ring together with the adjacent nitrogen atom), and n stands for 1 to 6)], or salt thereof; and a medicament containing it or its salt as an effective ingredient.
In another aspect of the present invention, there is also provided a pharmaceutical composition containing the above-described 4-hydroxy-4-phenylpiperidine derivative or salt thereof and a pharmaceutically acceptable carrier.
In a further aspect of the present invention, there is also provided use of the above-described 4-hydroxy-4-phenylpiperidine derivative or salt thereof as a medicament.
In a still further aspect of the present invention, there is also provided a paint treating method, which comprises administering the above-described 4-hydroxy-4-phenylpiperidine derivative or salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
Examples of the lower alkyl group as R
1
or R
2
in the formula (1) of the invention compound (1) include linear or branched C
1-6
alkyl groups, more specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl groups. As the cycloalkyl group, C
3-8
ones are preferred. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. Among them, hydrogen atom and C
1-6
alkyl groups are particularly preferred as each of R
1
and R
2
.
The number of the member of the heterocyclic ring formed by R
1
and R
2
together with the adjacent nitrogen atom is preferably 5 to 8. Examples of such a ring include pyrrolidine, piperidine, piperazine and morpholine rings, of which the pyrrolidine ring is particularly preferred.
Examples of the lower alkyl group as R
4
or R
5
include linear or branched C
1-6
alkyl groups, more specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl groups. As R
4
or R
5
, a hydrogen atom is preferred.
Examples of the lower alkyl group as R
6
, R
7
, R
8
, R
9
or R
10
include linear or branched C
1-6
alkyl groups, more specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl groups. As the cycloalkyl group, C
3-8
ones are preferred. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
The number of the member of the heterocyclic ring formed by R
7
and R
8
together with the adjacent nitrogen atom is 5 to 8. Examples of such a ring include pyrrolidine, piperidine, piperazine and morpholine rings. As R
6
, hydrogen atom and C
1-6
alkyl groups (particularly, ethyl) are preferred, while as R
9
, hydrogen atom and C
1-6
alkyl groups (particularly, methyl) are preferred. As R
10
, C
1-6
alkyl groups, particularly, methyl group is preferred. n stands for 1 to 6, of which 1 to 3 is preferred.
No particular limitation is imposed on the salt of the invention compound (1) insofar as it is a pharmaceutically acceptable salt thereof. Examples include addition salts of an inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid and addition salts of an organic acid such as formic acid, acetic acid, fumaric acid, maleic acid or tartaric acid. The invention compounds also embrace solvates such as hydrates.
Each of the 4-hydroxy-4-phenylpiperidine derivatives and salts thereof according to the present invention can be prepared, for example, by any one of the following (Process A) to (Process C).
(Process A)
[wherein, X represents a halogen atom, and R
1
and R
2
have the same meanings as described above].
Described specifically, Invention compound (1a) is available by reacting Compound (1) with Compound (2). This reaction is usually conducted in the presence of 2 to 5 equivalents, preferably 3 equivalents of a base at 40 to 100° C., preferably 50 to 60° C. for 1 to 3 hours. This reaction can be conducted in an anhydrous solvent such as benzene, toluene, tetrahydrofuran or dimethylformamide. Examples of the base include inorganic bases such as sodium carbonate and sodium hydroxide and organic bases such as triethylamine.
Each of Compound (1) and Compound (2) can be synthesized in a known manner.
(Process B)
[wherein, n stands for 1 to 6, and R
1
, R
2
, R
4
, R
5
, X and Y have the same meanings as described above].
Described specifically, Invention compound (1b) is available by reacting Compound (1a) with Compound (3). This reaction is usually conducted in the presence of 1 to 3 equivalents, preferably 1 to 1.5 equivalents of a base at 20 to 100° C., preferably 20 to 60° C. for 2 to 36 hours. This reaction can be conducted in an anhydrous solvent such as acetone, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. Examples of the base include inorganic bases such as sodium carbonate, sodium hydroxide and sodium hydride and organic bases such as triethylamine. The base may be added together with potassium iodide.
Compound (3) is commercially available as a reagent easily or can be synthesized in a known manner.
(Pro
Kanamaru Yoshihiko
Kawamoto Noriyuki
Komoto Teruo
Mogi Kinichi
Oka Tetsuo
Davis Zinna Northington
SSP Co., LTD
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