Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-12
2001-04-10
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S443000, C514S465000, C548S484000, C548S503000, C549S049000, C549S051000, C549S441000, C549S454000, C564S454000
Reexamination Certificate
active
06214859
ABSTRACT:
This application is a 371 of PCT/JP98/03468 Aug. 3, 1998.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel ethylamine derivatives which are promising as psychotropic drugs, antidepressants, drugs for Parkinson's disease and/or drugs for Alzimer's disease.
2. Description of the Related Art
A great many ethylamine derivatives have already been described in several publications. For example, 6-(2minoethyl)benzoxazolinone derivatives are described as antianxiety drugs and drugs for heart failure in EP 110, 781 and aminoalkylbenzoxazinone derivatives are described as useful remedies for damage of central nervous system in FR 2, 035,749. Moreover, the alkylamines which are structurally similar to the compounds of this invention are described as psychotropic drugs in JP examined publication 06-99, 420. However, as they have the releasing effects to displace catecholamines from their storage place on the central nervous system, they easily cause to release excess catecholamines from storage place such as synaptic vesicle and so on. Consequently, it is indicated that they have side effects as neurotoxicity similar to the effects of stimulants, abnormal behavior (excitation shown in high dose and the increase of intersignal reaction on conditioned avoidance task) or the like. The continuous administration of the drugs which enhance to release excess catecholamines cause decrease of catecholaminergic receptor. Consequently, the response of patients to drugs is reduced gradually and no sufficient therapeutic effect can be obtained as the result. Thus, they are inadequate as drugs for Parkinson's disease and Alzheimer's disease for which a long continuous treatment is required.
On the other hand, phenethylamine derivatives are disclosed in WO 88/2254 as psychotropic drugs and so on. These phenethylamine derivatives have the catecholaminergic activity enhancing effect (CAE effect: the enhancing effect on catecholamine release through amplification of the membrane potential dependent exocytosis) which is based on the new mechanism different from the above releasing effect to displace catecholamine from their storage [Life Sci., 58, 945-952 (1996)]. However, their compounds are not settled the effect which increase intersignal reaction on the conditioned avoidance task which is indicator of abnormal behavior. Therefore, the development of drugs which have high selectivity to CAE effect have been required.
The development of the compounds which have little side effects and are promising medicines as psychotropic drugs, antidepressant drugs, drugs for Parkinson's disease, drugs for Alzheimer's disease or the like has been longed for and an purpose of this invention is to comply with the said longing.
SUMMARY OF THE INVENTION
We, this inventors, judged that the neurotoxicity on central nervous system and abnormal behavior of said phenethylamine derivative are caused by or related to structural similarity with those of stimulants such as amphetamine and methamphetamine and bad examined diligently to achieve the purpose of this invention. As the result, we found out that certain kinds of specific novel ethylamine derivatives different from stimulants in structure and their acid addition salts had high selectivity to catecholaminergic activity enhancing effect (CAE effect), and completed this invention which was purposed to present psychotropic drugs, antidepressant drugs, drugs for Parkinson's disease and/or drugs for Alzheimer's disease which bad little side effects as neurotoxicity on central nervous system, abnormal behavior or the like.
This invention concerns with novel ethylamine derivatives of formula (I):
(wherein R
1
is hydrogen, hydroxyl, lower alkoxy or halogen; R
2
is alkyl having 2 to 5 carbon atoms; R
3
is hydrogen, alkyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 11 carbon atoms; the ring is a bicyclic compound which comprises of at least one benzene ring and may comprise a saturated or unsaturated five- or six-membered ring which may or may not have heteroatoms, providing that when the ring is indole or 1,3-benzodioxole, R
2
and R
3
do not constitute, at the same time, two carbon atoms members, and when R
3
is hydrogen, the ring is a bicyclic compound which is not indole, benzothiophene or benzodioxole and R
2
is alkyl having 3 to 5 carbon atoms) and pharmaceutically acceptable acid addition salts thereof. And this invention concerns with medicines as psychotropic drugs, antidepressants, drugs for Parkinson's disease, drugs for Alzheimer's disease or the like, wherein the active components are these compounds.
As the acid addition salts, they should preferably be pharmaceutically acceptable salts. Examples are salts with such inorganic acids as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, methanesulfonic acid or the like and salts with such organic acids as gluconic acid, tartaric acid, maleic acid, fumaric acid, succinic acid, malic acid, citric acid, mandelic acid or the like.
Lower alkoxy in formula (I) means the alkoxy having 1 to 4 carbon atoms. For example, it includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or the like.
Concrete examples of A ring are naphthalene, indole, 1,3-benzodioxole, 1,4-benzodioxane, indan, indene, benzofuran, benzothiophene, 2,3-dihydrobenzofuran, dihydronaphthalene, tetralin or the like. The substituents may be present in any positions in A ring.
REFERENCES:
patent: 3296072 (1967-01-01), Szmuszkovicz et al.
patent: 3883560 (1975-05-01), Colgate et al.
patent: 5494928 (1996-02-01), Bos
patent: 5627200 (1997-05-01), Pfizer et al.
patent: 1198128 (1970-07-01), None
patent: 7-149723 (1995-06-01), None
patent: 98-34646 (1998-08-01), None
Chemical Abstract, vol. 125, 1996, Abstract No. 125:265667, Moreau, J.L. et al., “5HT2C Receptor Agonists Exhibit Antidepressant-like Properties in the Anhedonia Model of Depression in Rats”, Eur. Neuropsychopharmacol., 1996, vol. 6, No. 3, pp. 169-175.
Simantov, Rabi, “Neurotransporters at the Jucture of Drug Action: Role in Programmed Cell Death, and Toxicity of Abused MDMA”, Nato ASI Ser., Ser. H, 1997, vol. 100, pp. 237-248.
McGrath, C. et al., “Effect of Acute Administration of 3,4-methylenedioxymethamphetamine (MDMA) on Temperature and Locomotor Activity in the olfactory Bulbectomized Rate Model of Depression”, Med. Sci. Res., 1995, vol. 23, No. 3, pp. 199-201.
White, S.R. et al., “Methylenedioxymethamphetamine Depresses Glutamate-evoked Neuronal Firing and Increases Extra-cellular Levels of Dopamine and Serotonin in the Nucleus Accumbens in vivo”, Neuroscience, Oxford, 1994, vol. 62, No. 1, pp. 41-50.
Piercey, M.F. et al., “Effects of MDMA (“Extacy”) on Firing Rates of Serotonergic, Dopaminergic, and Noradrenergic Neurons in the Rat”, Brain Res., 1990, vol. 526, No. 2, pp. 203-206.
Ricaurte, G.A. et al., “3,4-Methylenedioxymethamphetamine, Serotonin and Memory”, J. Pharmacol. Exp. Ther., 1993, vol. 226, No. 2, pp. 1097-1106.
Lehman, J. et al., “Regional Distribution to Recovery of 5-HT Levels after Administration of ‘Atrophins’ MDMA and D,L-Fenfluramine. Stereospecificity and Comparison with 5,7-Dihydroxytryptamine”, Ann, N.Y. Acad. Sci., 1992, vol. 648, pp. 291-295.
Chemical Abstract, vol. 64, No. 12, 1966, Abstract No. 64:17522d, “Synthesis and Pharmacological Activity of Alkylated Tryptamines”, J. Med. Chem., 1966, vol. 9, No. 3, pp. 341-344.
Chemical Abstract, vol. 64, No. 4, 1966, Abstract No. 64:5032f, “The Indole Series. I. Indolyl-alkylamines”, J. Chem. Soc., 1965, pp. 7165-7178.
Chemical Abstract, vol. 63, No. 8, 1965, Abstract No. 63:9840e, “Synthesis of New Compounds in the Amphetamine Group, ”, Acta Polon. Pharm., 1865, vol. 22, No. 2, pp. 103-109.
Chemical Abstract, vol 60, No. 10, 1964, Abstract No. 60:11989d, “4 (or 5 or 6)-(2-Aminoalkyl) indols”, FR, 1344579, Al.
Chemical Abstract, vol. 57, No. 10, 1962, Abstract No. 57:12438g, “Tryptamine Derivatives”, GB
Ando Takashi
Fujimoto Michitaro
Katurada Masanori
Knoll Joseph
Moto Toshiaki
Fujimoto Brothers Co., Ltd.
McKane Joseph K.
Wenderoth , Lind & Ponack, L.L.P.
LandOfFree
Ethylamine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Ethylamine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Ethylamine derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2513976