Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-09-15
2004-05-18
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S222000, C560S027000, C560S028000, C514S480000, C514S481000, C514S625000, C514S629000
Reexamination Certificate
active
06737547
ABSTRACT:
Throughout this application, various references are identified by authors and full citation. Disclosure of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
The present invention relates to novel aminoindene derivatives, their preparation and their use to treat neurodegenerative conditions such as Alzheimer's disease, idiopathic-, accident-, and drug-induced seizures, and to treat acute neurological traumatic disorders such as head trauma, stroke, hypoxia/anoxia. More specifically, the invention describes aminoindene derivatives of structure 1, wherein n is 1 or 2, R
1
is hydrogen or lower alkyl or lower alkoxy and R
2
is hydrogen or a halogen, having useful neuroprotective and anti-convulsant properties. These compounds will also be useful as adjunct therapy in the above conditions.
The relevant art reveals several aminoindans. See for example, Youdim, et al., (U.S. Pat. No. 5,599,991), Guillaumet et al., (U.S. Pat. No. 5,569,669), and Oshiro et al., (U.S. Pat. No. 4,788,130). Cohen, et al., International Application published under PCT, Publication No. WO 95/18617, disclosed that 1-aminoindan derivatives have anticonvulsant and other activity in the central nervous system.
One such 1-aminoindan derivative, N-acetyl-1-aminoindan (structure 2), has strong anticonvulsant activity with the R-enantiomer (structure 2a) showing somewhat greater activity than the S-isomer. This result was observed in the Maximal Electroshock Model (MES) representing general and partial seizures, and in the subcutaneous pentylenetetrazol seizure threshold test (scMET) model (mice only) representing absence seizures. However, these stereoisomers afforded only modest protection against hypobaric hypoxia in mice.
While 1-aminoindan derivatives have been well-studied, the structure and pharmacologic activity of aminoindenes remain practically unexplored. Brettle and Mosedale (J. Chem. Soc., Perkin Trans. I, 1988, 2187-95) have noted that some highly complex secondary enamides occur in nature but have not disclosed any uses of enamides.
Barton et al., Tetrahedron Letters (1988) 29: 3343-3346, prepared an analog of structure 1 where n is 2, and R
1
and R
2
are hydrogen, but solely as an intermediate in a synthesis leading to vinyl isonitriles, with no disclosure of any pharmacological studies.
Similarly, Zheng et al., Tetrahedron Letters, (1997) 38: 2817-2820, prepared an analog of structure 1 where n is 1, R
1
is isobutyl and R
2
is hydrogen. Zheng et al., obtained that compound as a minor by-product and have not explored its pharmacological activity.
In contrast to the above-described work by other investigators, the present invention discloses not only novel N-acylaminoindenes (also known as indenamides) and their synthesis, but also methods of using the N-acylaminoindenes as neuroprotectants and anticonvulsants.
As a class, the present compounds are novel, achiral with respect to the species having a five-membered ring and a more planar configuration than structure 2. One would expect that the presently disclosed aminoindene derivatives, which are achiral, would be less active than compound 2a as anticonvulsants and neuroprotectants because normally the hypothetical enzymatic or cellular active site interacting with these compounds prefers a chiral molecule. Surprisingly, the presently disclosed aminoindenes which are achiral, have shown significant anticonvulsant and neuroprotectant properties. In particular, they are anticonvulsant to about the same degree as compound 2 in the MES and scMET models described above. More significantly, they display very pronounced neuroprotective action in the hypobaric hypoxia model. They are also more effective than compound 2 in depressing response to both electrical and chemical stimulation in a guinea pig ileal preparation, and in potentiating the effect of exogenous adenosine. All this activity indicates unexpected but significant neuroprotection.
The present compounds which have been found to have neuroprotective properties are useful in neuroprotection after deprivation impact events such as trauma, stroke, and hypoxia/anoxia. The present compounds have also been found to have anticonvulsant properties which are useful in the treatment of idiopathic accident and drug-induced seizures. These compounds are also useful as adjunct therapy in the above conditions.
SUMMARY OF THE INVENTION
This invention provides compounds having the following structure:
wherein n is 1 or 2, R
1
is hydrogen, a linear or branched chain C
1
-C
8
alkyl or a linear or branched chain C
1
-C
8
alkoxy and R
2
is hydrogen or a halogen and a pharmaceutically acceptable carrier.
This invention also provides a compound selected from the group consisting of N-acetyl-3-amino-1H-indene; N-acetyl-4-amino-1,2-dihydronaphthalene; N-formyl-3-amino-1H-indene; N-acetyl-3-amino-6-chloro-1H-indene; N-formyl-6-chloro-3-amino-1H-indene; and N-methoxycarbonyl-3-amino-1H-indene.
This invention also provides a method for treating injury or neurodamage caused by trauma, nutritive deprivation or deficiency, neurodegenerative pathology, or convulsant activity (idiopathic, drug-induced, etc.). This invention further provides a method for treating head trauma, stroke, hypoxia, anoxia, epilepsy, convulsions, seizures, or Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of a compound having the structural formula:
wherein n is 1 or 2, R
1
is hydrogen, lower alkyl or lower alkoxy and R
2
is hydrogen or halogen provided that where n is 1, and R
1
is isobutyl, R
2
cannot be H; and where n is 2, both R
1
and R
2
cannot be hydrogen.
This invention also provides a method of treating head trauma, stroke, hypoxia, anoxia, epilepsy, convulsions, seizures, or Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: N-acetyl-3-amino-1H-indene; N-acetyl-3-amino-6-chloro-1H-indene; N-formyl-3-amino-1H-indene; N-formyl-6-chloro-3-amino-1H-indene; N-methoxycarbonyl-3-amino-1H-indene; and N-acetyl-4-amino-1,2-dihydronaphthalene.
Further, this invention provides a process for preparing a composition of claim 1, comprising detailed steps A-D:
A. reacting an oxime with a 5- or 6-membered heterocyclic amine such as pyridine or imidazole, and acetic anhydride to produce a residue;
B. agitating the residue of step (a) with sodium carbonate;
C. extracting the residue of step (b) with a suitable solvent such as an ether or an ester; and
D. drying the residue of step (c) with a drying agent such as magnesium sulfate.
REFERENCES:
patent: 2573645 (1951-10-01), Kerwin et al.
patent: 2916490 (1959-12-01), Schenck et al.
patent: 2982783 (1961-05-01), Schenck et al.
patent: 3060091 (1962-10-01), Witkin
patent: 3123642 (1964-03-01), Temple et al.
patent: 3178478 (1965-04-01), Huebner et al.
patent: 3201470 (1965-08-01), Huebner et al.
patent: 3253037 (1966-05-01), Huebner et al.
patent: 3308157 (1967-03-01), Robertson et al.
patent: 3513244 (1970-05-01), Gittos et al.
patent: 3637740 (1972-01-01), Sarges
patent: 3704323 (1972-11-01), Krapcho
patent: 3709996 (1973-01-01), Gittos et al.
patent: 3751420 (1973-08-01), Hauck et al.
patent: 3804898 (1974-04-01), Panneman
patent: 3886168 (1975-05-01), Himmele et al.
patent: 3991207 (1976-11-01), Sarges et al.
patent: 4029731 (1977-06-01), Sarges
patent: 4096173 (1978-06-01), Molloy
patent: 4128666 (1978-12-01), Bondinell et al.
patent: 4132737 (1979-01-01), Molloy
patent: 4134997 (1979-01-01), Cannon et al.
patent: 4172093 (1979-10-01), Göransson-Dahlander et al.
patent: 4632939 (1986-12-01), Beedle et al.
patent: 4638001 (1987-01-01), Kuhla et al.
patent: 4788130 (1988-11-01), Oshiro et al.
patent: 4792628 (1988-12-01), Oshiro et al.
patent: 4826875 (1989-05-01), Chiesi
patent: 4833273 (1989-05-01), Goel et al.
patent: 4873241 (1989-10-01), Napier et
Cohen Sasson
Nachman Rachel
Sklarz Benjamin
Speiser Tzipora
Cooper & Dunham LLP
Kumar Shailendra
Teva Pharmaceutical Industries Ltd.
White John P.
LandOfFree
Compositions containing and methods of using... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compositions containing and methods of using..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compositions containing and methods of using... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3187326