Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1993-11-18
2001-01-30
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S416000
Reexamination Certificate
active
06180657
ABSTRACT:
BACKGROUND OF THE INVENTION
Melatonin, represented by the structure below:
is named systematically as N-[2-(5-methoxy-3-indolyl)ethyl]-acetamide. Trivial names for the compound include N-acetyl-5-methoxytryptamine and N-acetyl-O-methylserotonin. Melatonin is a pineal gland hormone which has ovulation inhibitory activity, Chu et al.,
Endocrinology,
75, 238 (1964), as well as some activity against MCF-7 human breast cancer cells, Blask et al.
J. Neural. Transm.
[Supp.], 21, 433 (1986) and for the treatment of mammalian breast carcinoma, Blask et al.,
Neuroendocrinol. Lett.,
9(2), 63 (1987). Furthermore, melatonin has been known to expedite recovery from “jet lag syndrome”, Arendt et al.,
Ergonomics,
30, 1379 (1987), to cause sleep, Waldhauser et al.,
Psychopharmacology,
100, 222 (1990) and to minimize disturbances in circadian rhythms of bodily performance and function, U.S. Pat. Nos. 4,600,723 and 5,242,941.
Several melatonin analogues of the formula
wherein
R
1
is hydrogen, C
1
-C
4
alkyl or C
1
-C
4
alkoxy;
R
2
is hydrogen or C
1
-C
4
alkyl;
R
3
is hydrogen or methyl;
R
4
is hydrogen, haloacetyl, C
1
-C
5
alkanoyl, benzoyl or benzoyl substituted with halo or methyl;
R
5
and R
6
are individually hydrogen or halo; and
R
7
is hydrogen or C
1
-C
4
alkyl;
provided that when R
2
is hydrogen, at least one of R
5
and R
6
is halo, have also been prepared and shown to possess ovulation inhibition activity (see U.S. Pat. Nos. 4,997,845 and 4,614,807). Such analogues are also stated to be active in treating hormonally dependent breast carcinomas in U.S. Pat. No. 5,196,435. However, none of these analogues were previously shown to possess activity in treating desynchronization disorders.
Finally, European Patent Application 513,702 discloses that melatonin and its analogues of the formula
wherein R
1
and R
2
are the same or different and are hydrogen or halogen can be used in treating sleep disorders and in pre-anesthetic medication. Again, such disclosure does not teach or suggest the use of melatonin analogues for treating desychronization disorders.
It is an object of this invention to provide a method for treating desynchronization disorders by employing certain melatonin analogues. The instant method is believed to provide a more efficacious (in terms of activity, side effect profile and duration of action) means for treating such disorders than previously known. Further, the melatonin analogues used in the instant method are believed to be completely devoid of toxicity at the dosages required for treatment and, as such, a further object of the present invention is to provide a safe, efficacious, method of treating desynchronization disorders. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
SUMMARY OF THE INVENTION
This invention provides a method of treating desynchronization disorders in a mammal suffering from or susceptible to such disorders which comprises administering to said mammal an effective amount of a compound of Formula (I)
wherein
R
1
is hydrogen, C
1
-C
4
alkyl or C
1
-C
4
alkoxy;
R
2
is hydrogen or C
1
-C
4
alkyl;
R
3
is hydrogen, C
1
-C
4
alkyl, phenyl or substituted phenyl;
R
4
is hydrogen, haloacetyl, C
1
-C
5
alkanoyl, benzoyl or benzoyl substituted with halo or methyl;
R
5
and R
6
are each individually hydrogen or halo; and
R
7
is hydrogen or C
1
-C
4
alkyl;
provided that when R
2
is hydrogen then at least one of R
5
and R
6
is halo.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions refer to the various terms used above and throughout the disclosure.
The term “halo” refers to fluoro, chloro, bromo and iodo.
The term “C
1
-C
4
alkyl” refers to the straight and branched aliphatic radicals of 1-4 carbon atoms including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
The term “C
1
-C
4
alkoxy” includes the straight and branched aliphatic ether radicals of 1-4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
The term “halocetyl” refers to chloroacetyl, bromoacetyl, fluoroacetyl and iodoacetyl.
The term “C
1
-C
5
” alkanoyl” includes formyl, acetyl, propionyl, butyryl, &agr;-methylpropionyl, valeryl, &agr;-methylbutyryl, &bgr;-methylbutyryl and pivaloyl.
The term “benzoyl substituted with halo” defines mono- and di-halo benzoyl groups. Specific mono-halo benzoyl groups are chlorobenzoyl, bromobenzoyl, fluorobenzoyl and iodobenzoyl.
Di-halo benzoyl groups include those in which both halo substituents are the same. Typical di-halo benzoyl groups include 2,4-dichlorobenzoyl, 2,4-dibromobenzoyl, 2,4-diflluorobenzoyl and 2,4-diiodobenzoyl.
The term “benzoyl substituted with methyl” contemplates methylbenzoyl, dimethylbenzoyl and trimethylbenzoyl.
The term “substituted phenyl” refers to a phenyl ring which is substituted with one or two substituents selected from the group consisting of halo, C
1
-C
4
alkyl or C
1
-C
4
alkoxy. Examples of such term, therefore, include 4-chlorophenyl, 2-fluorophenyl, 3-iodophenyl, 4-bromophenyl, 3,4-dibromophenyl, 4-methylphenyl, 2-ethylphenyl, 3-n-propylphenyl, 4-isopropyl-phenyl, 4-n-butylphenyl, 3-t-butylphenyl, 4-sec-butylphenyl, 3,4-dimethylphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-n-propylphenyl, 4-isopropoxyphenyl, 3-isobutoxyphenyl, 4-t-butoxyphenyl, 3-ethoxy-4-methoxyphenyl and the like.
While all of the compounds of Formula I are believed to be useful for the method of treating desynchronization disorders presented herein, certain of such compounds are preferred for such use. Preferred compounds of Formula I for use in the instantly claimed method include those compounds wherein R
1
is C
1
-C
4
alkyl (especially methyl), R
3
is hydrogen or C
1
-C
4
alkyl (especially methyl) and R
4
is hydrogen.
Of such preferred compounds, particularly preferred compounds include those wherein R
2
and R
7
are each independently C
1
-C
4
alkyl (preferably methyl). The most preferred compounds for use in the method of the present invention include N-[2-methyl-2-(5-methoxy-6-fluoroindol-3-yl)ethyl]acetamide, N-[2-ethyl-2-(5-methoxy-6-chloroindol-3-yl)ethyl]acetamide, N-[2-methyl-2-(5-methoxy-6,7-dichloroindol-3-yl)ethyl]acetamide and N-[2-methyl-2-(5-methoxy-6-chloroindol-3-yl)ethyl]acetamide. The later compound is especially preferred for purposes of the present invention.
Those compounds employed in the method of the present invention wherein R
2
is C
1
-C
4
alkyl have an asymmetric center at the carbon atom to which such R
2
substituent is attached (i.e., the &bgr;-carbon atom). As such, such R
2
substituted compounds can exist as either a racemic mixture or as individual stereoisomers. All such types of compounds are contemplated for use in the method of the present invention.
The following list illustrates representative compounds suitable for use in the present invention.
N-[2-methyl-2-(5-methoxy-6-chloroindol-3-yl)ethyl]-acetamide
N-[2-methyl-2-(5-methoxy-6-fluoroindol-3-yl)ethyl]-acetamide
N-[2-ethyl-2-(5-methoxy-6-fluoroindol-3-yl)ethyl]-acetamide
N-[2-ethyl-2-(5-methoxy-6-chloroindol-3-yl)ethyl]-acetamide
N-[2-isopropyl-2-(5-methoxy-6-chloroindol-3-yl)ethyl]-acetamide
N-[2-isopropyl-2-(5-methoxy-6-fluoroindol-3-yl)ethyl]-acetamide
N-[2-methyl-2-(5-methoxy-6-bromoindol-3-yl)ethyl]-formamide
N-[2-butyl-2-(5-methoxy-6-bromoindol-3-yl)ethyl]-formamide
N-[2-ethyl-2-(5-propoxy-6-chloroindol-3-yl)ethyl]-formamide
N-[2-propyl-2-(5-isopropoxy-6-iodoindol-3-yl)ethyl]-formamide
N-[2-methyl-2-(5-methoxy-6-chloroindol-3-yl)ethyl]-propionamide
N-[2-ethyl-2-(5-methoxy-6-fluoroindol-3-yl)ethyl]-propionamide
N-[2-methyl-2-(5-ethoxy-6-bromoindol-3-yl)ethyl]-propionamide
N-[2-methyl-2-(5-ethoxy-6-fluoroindol-3-yl)ethyl]-butyramide
N-[2-propyl-2-(5-butoxy-6-chloroindol-3-yl)ethyl]-butyramide
N-&ls
Eli Lilly and Company
Titus Robert D.
Weddington Kevin E.
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