Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-07
2001-05-08
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S486000
Reexamination Certificate
active
06228880
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a series of 4-amino-(ethylamino)-oxindoles having dopaminergic properties. The compounds of the present invention are useful in treating various conditions affected by dopamine agonists, such as Parkinson's disease, Tourette's syndrome, schizophrenia, and alcohol and drug addiction.
BACKGROUND OF THE INVENTION
Efforts to induce antipsychotic activity with dopamine autoreceptor agonists have been successful (e.g., see Dorsini et al.,
Adv. Biochem. Psychopharmacol.,
16:645-648 (1977); Tamminga et al.,
Science,
200:567-568 (1975); and Tamminga et al.,
Psychiatry
398-402 (1986). A method for determining intrinsic activity at the dopamine D
2
receptor was recently reported by Lahti et al.,
Mol. Pharm.
42:432-438 (1993). Intrinsic activity is predicted using the ratio of the “low-affinity agonist” (i.e., LowAg) state of the receptor and the “high-affinity agonist” (i.e., HighAg) state of the receptor, i.e. LowAg/HighAg. These ratios correlate with the agonist, partial agonist, and antagonist activities of a given compound. Such activities characterize the ability of a compound to elicit an antipsychotic effect.
WO 9109849 broadly discloses a series of indole-amine compounds, such as, compounds A and B below, that are disclosed as being useful as reverse transcriptase inhibitors for the treatment of AIDS.
However, there is no disclosure or suggestion in this reference that such compounds have D
2
receptor agonist activity or act to relieve the symptoms of Parkinson's disease, schizophrenia, or other conditions affected by dopamine.
SUMMARY OF THE INVENTION
The compounds of this invention are 4-amino-(ethylamino)-oxindoles represented by Formula I:
wherein R
1
and R
2
are each, independently, hydrogen, C
1-10
alkyl, or (CH
2
)
m
R
4
, wherein R
4
is phenyl or naphthyl which may be substituted by one or two substituents selected from the group consisting of C
1-6
alkyl, halogen, C
1-6
alkoxide and trifluoromethyl and m is 1 to 5; and
R
3
is hydrogen or C
1-6
alkyl; or
pharmaceutically acceptable salts thereof.
The compounds of this invention are dopamine agonists having various degrees of intrinsic dopaminergic activity. Some of these compounds are selective autoreceptor agonists, (i.e., partial agonists which activate only autoreceptors versus postsynaptic D
2
dopamine receptors). As such, the present compounds provide functional modulation of the dopamine systems of the brain without causing an excessive blockade of the postsynaptic dopamine receptors. Such excessive blockades have been observed to be responsible for the serious side effects frequently exhibited by agents known to be clinically effective for the treatment of schizophrenia. Moreover, the compounds of this invention have a high degree of intrinsic activity and, therefore, they can behave as the natural neurotransmitter, i.e., as a full agonist. As such, they are useful in the treatment of diseases caused by abnormal concentrations of dopamine, such as Parkinson's disease.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the compounds of the present invention are those of Formula I, wherein:
R
1
and R
2
are each, independently, C
1-10
alkyl or (CH
2
)
m
R
4
, wherein R
4
is phenyl and m is 1; and
R
3
is hydrogen or C
1-6
alkyl; or
pharmaceutically acceptable salts thereof.
Most preferably, the compounds of the present invention may be selected from the group consisting of:
4-(2-Benzylamino-ethylamino)-1,3-dihydro-indol-2-one dihydrochloride; and
4-[2-(Benzyl-methylamino)-ethylamino]-1,3-dihydro-indol-2-one dihydrochloride.
As used herein, the terms “alkyl” and “alkoxy” refer to either straight or branched chain alllyl and alkoxy groups, respectively. The term “halogen” refers to chlorine, bromine, fluorine and iodine.
The compounds of the present invention may be used in the form of their pharmaceutically acceptable acid addition salts having the utility of the free base. Such salts, preparable by methods well known to those skilled in the art, are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
The compounds of the present invention are dopamine autoreceptor agonists which modulate the synthesis and release of the neurotranmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schzophrenia, Parkinson's disease and Tourette's syndrome. The present compounds are also partial agonists at the postsynaptic dopamine D
2
receptor and are thus useful in the treatment of other conditions affected by such agonists, such as alcohol and drug addiction.
The compounds of the present invention may be prepared by any suitable, conventional method which will be recognized by one skilled in the art. However, it is preferred that the present compounds be prepared by the overall sequences depicted in Schemes I and II.
REFERENCES:
patent: 4835166 (1989-05-01), Kitamura et al.
patent: WO9109849 (1991-07-01), None
Corsini et al.,Adv. Biochem. Psychopharmacol., 16:645-648 (1977).
Tamminga et al.,Science, 200:567-568 (1978).
Tamminga et al.,Psychiatry, 43:398-402 (1986).
Lahti et al.,Mol. Pharm., 42:432-438 (1993).
Kanzelberger Mira A.
Mewshaw Richard E.
Nelson James A.
American Home Products Corp
Mazzarese Joseph M.
Morris Patricia L.
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