Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-28
2002-03-12
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S626000, C540S467000
Reexamination Certificate
active
06355637
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to novel quinazolinone compounds which are useful as local anesthetics. This invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds as, for example, local anesthetics; and processes and intermediates for preparing such compounds.
2. State of the Art
Local anesthetics are widely used for preventing and treating various types of pain. However, currently available local anesthetics have a relatively short duration of action and must be repeatedly or continuously administered to provide prolonged pain relief. As a result, such agents are generally unsatisfactory for treating post-surgical or chronic pain. See, for example, Paul J. Kuzma et al., “Progress in the Development of Ultra-Long-Acting Local Anesthetics”
Regional Anesthesia
1997, 22(6), 543-551. Accordingly, a significant need exists for long-acting local anesthetics to provide effective post-operative analgesia and treatment for chronic pain.
SUMMARY OF THE INVENTION
The present invention provides novel quinazolinone compounds which are useful as local anesthetics. Among other properties, compounds of this invention have been found to provide a longer duration of analgesia compared to currently available local anesthetics.
Accordingly, in one of its composition aspects, this invention provides a compound of formula I:
wherein
R
1
is selected from the group consisting of hydrogen, C
1-6
alkyl and C
1-6
alkoxy;
R
2
is selected from the group consisting of hydrogen, C
1-6
alkyl and C
1-6
alkoxy;
R
3
is hydrogen or C
1-6
alkyl;
R
4
is hydrogen or C
1-6
alkyl;
R
5
is hydrogen or C
1-6
alkyl;
each R
6
is independently selected from the group consisting of C
1-6
alkyl and C
1-6
alkoxy;
n is an integer from 0 to 3;
and pharmaceutically acceptable salts and stereoisomers thereof.
This invention is also directed to intermediates useful for preparing compounds of formula I. Accordingly, in another of its composition aspects, this invention provides a compound of formula II:
wherein R
4
, R
5
, R
6
and n are as defined herein, or a salt thereof, which compounds are useful as intermediates for preparing compounds of formula I.
Additionally, in still another of its composition aspects, this invention provides a compound of formula III:
wherein R
1
, R
2
and R
3
are as defined herein, or a salt thereof, which compounds are also useful as intermediates for preparing compounds of formula I.
In yet another of its composition aspects, this invention provides a pharmaceutical composition comprising a pharamaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The compounds of formula I have been discovered to inhibit or modulate voltage-gated sodium channels associated with nerve conduction. Additionally, the compounds of this invention produce local anesthesia or analgesia when administered to a mammal. Therefore, among other properties, the compounds of formula I are useful as local anesthetics.
Accordingly, in one of its method aspects, this invention is directed to a method for producing local anesthesia or analgesia in a mammal, the method comprising administering to a mammal a pharmaceutical composition comprising a pharamaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
Additionally, in another of its method aspects, this invention provides a method for treating a disease or medical condition associated with or modulated by a volatge-gated sodium channel, the method comprising administering to a patient in need of treatment a pharmaceutical composition comprising a pharamaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
This invention is also directed to processes for preparing compounds of formula I. Accordingly, in another of its method aspects, this invention is directed to a process for preparing a compound of formula I, the process comprising contacting a compound of formula II above with a compound of formula IV:
wherein R
1
, R
2
and R
3
are as defined herein; and X is a leaving group; to provide a compound of formula I. Additionally, in another of its composition aspects, this invention is directed to a compound of formula I prepared by this process.
In still another of its method aspects, this invention is directed to another process for preparing a compound of formula I, the process comprising contacting a compound of formula III with a compound of formula V:
wherein R
4
, R
5
, R
6
and n are as defined herein, and X is a leaving group; to provide a compound of formula I. This invention is also directed to a compound of formula I prepared by this process.
In yet another of its method aspects, this invention is directed to the use of a compound of formula I for the manufacture of a medicament. Preferably, the medicament is used to produce local anesthesia or analgesia in a mammal.
REFERENCES:
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patent: 5389630 (1995-02-01), Sato et al.
patent: 5405975 (1995-04-01), Kuhn et al.
patent: 5948906 (1999-09-01), Tsien et al.
Ager, I.R., et al. “Synthesis and Central Nervous System Activity of Quinazolones Related to 2-Methyl-3-(o-tolyl)-4(3H)-quinazoline (Methaqualone).”J. Med. Chem.20(3): 379-386 (1977).
Debnath, A.K., et al. “Structure-Based Identification of Small Molecule Antiviral Compounds Targeted to the gp41 Core Structure of the Human Immunodeficiency Virus Type I.”J. Med. Chem.42: 3203-3209 (1999).
Gatto, et al. “Synthesis and Binding Properties of Bibracchial Lariat Ethers (BiBBLEs): Surveys of Synthetic Methods and Cation Selectivities.”J. Org. Chem.51: 5373-5384 (1986).
Gupta, C.M., et al. “Drugs Acting on the Central Nervous System. Syntheses of Substituted Quinazolones and Quinazolines and Triazepino-and Traizocinoquinazolones.”J. Med. Chem.11(2): 392-395 (1968).
Hollowood, J., et al. “Local Anesthetics with Enhanced Affinity for Proteins.”J. Med. Chem.10(5): 863-867 (1967).
Kuzma, P.J., et al. “Progress in the Development of Ultra-Long-Acting Local Anesthetics.”Regionals Anesthesia. 22(6): 543-551 (1997).
Padia, J.K., et al. “Design and Synthesis of Novel Nonpeptide CCK-B Receptor Antagonists.”Bioorg.&Med. Chem. Letts.7(7): 805-810 (1997).
Vogtle, F., et al. “Kronenether mit haptophoren bzw. pharmakophoren Gruppen.”Chem. Ber.111: 1434-1439 (1978). (summary in English).
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Database Chemcats Online! Chemical Abstracts, Columbus, Ohio, US. AN 2000: 927662, Aug. 23, 1999.
Axt Sabine M.
Church Timothy J.
Jacobsen John R.
Jenkins Thomas E.
Ji Yu-Hua
Advanced Medicine, Inc.
Boone David E.
Hagenah Jeffrey A.
Kifle Bruck
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