Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-23
2004-10-12
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252150, C514S252190, C514S254060, C514S256000, C514S277000, C514S278000, C514S318000, C514S319000, C514S322000, C514S394000, C544S295000, C544S357000, C544S370000, C546S019000, C546S199000, C546S273100, C548S300400, C548S300700, C548S302100
Reexamination Certificate
active
06803368
ABSTRACT:
BACKGROUND OF THE INVENTION
The application claims priority from co-pending provisional application serial No. 60/286,229, filed on Apr. 25, 2001, the entire disclosure of which is hereby incorporated by reference.
The clinical treatment of schizophrenia has long been defined by the dopamine hypothesis of schizophrenia, which holds that schizophrenia is a result of hyperactivity of dopaminergic neurotransmission, particularly in limbic brain structures such as nucleus accumbens (the mesolimbic dopamine system). Indeed, the positive symptoms of schizophrenia (hallucinations, delusions, thought disorder) are successfully treated with neuroleptics, which block dopamine receptors. However, such treatment is accompanied by the production of movement disorders or dyskinesias (extrapyramidal side effects), due to the blockade of nigrostriatal dopamine receptors. In addition, neuroleptics do not treat the negative symptoms of schizophrenia (social withdrawal, anhedonia, poverty of speech) which are related to a relative hypoactivity of neurotransmission in the mesocortical dopamine system and which respond to treatment by dopamine agonists.
Efforts to induce antipsychotic activity with dopamine autoreceptor agonists have been successful (Corsini et al., Adv. Biochem. Psychopharmacol. 16, 645-648, 1977; Tamminga et al., Psychiatry 398-402, 1986). Dopamine autoreceptor agonists produce a functional antagonism of dopaminergic neurotransmission by the reduction of neuronal firing and the inhibition of dopamine synthesis and release. Since dopamine autoreceptor agonists are partial agonists at postsynaptic dopamine receptors, they provide a residual level of stimulation sufficient to prevent the production of dyskinesias. Indeed, partial agonists are capable of functioning as either agonists or antagonists depending on the level of dopaminergic stimulation in a given tissue or brain region, and would therefore be expected to have efficacy versus both positive and negative symptoms of schizophrenia. Thus, novel dopamine partial agonists are of great interest for the treatment of schizophrenia and related disorders.
DESCRIPTION OF THE INVENTION
In accordance with this invention, there is provided a group of novel compounds of the formula:
wherein
R
1
and R
2
are, independently, hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
Z is NR
3
—(CH
2
)
n
—Y,
Y is hydrogen, hydroxy, cycloalkyl of 3 to 15 carbon atoms, or phenyl, substituted phenyl, phenoxy, substituted phenoxy, naphthyl, substituted naphthyl, naphthyloxy, substituted naphthyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy or substituted heteroaryloxy, wherein the heteroaryl or the heteroaryl group of heteroaryloxy is selected from thiophene, furan, pyridine, indole, chroman, coumarin, carbostyril, and quinoline;
R
3
is hydrogen or alkyl of 1 to 6 carbon atoms;
n is an integer from 0 to 6;
R
4
is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, substituted phenyl, &ohgr;-phenylalkyl, substituted &ohgr;-phenylalkyl, &ohgr;-diphenylalkyl, substituted &ohgr;-diphenylalkyl, wherein the alkyl chain contains 1 to 4 carbon atoms, indole, substituted indole, indazole, substituted indazole, pyridine, substituted pyridine, pyrimidine, substituted pyrimidine, quinoline, substituted quinoline, benzoisothiazole, substituted benzoisothiazole, benzisoxazole, or substituted benzisoxazole;
R
5
is hydrogen, hydroxy, cyano or carboxamido;
R
6
is hydrogen, 1-benzimidazol-2-one, benzoisothiazole, or benzisoxazole, each optionally substituted, or —Q—Ar;
Q is C═O, CHOH, or (CH
2
)
m
,
m is an integer from 0 to 4;
Ar is phenyl optionally substituted; or
R
5
and R
6
, taken together with the carbon atom to which they are attached, form
R
7
is hydrogen;
R
8
is phenyl, naphthyl, thiophene, benzoisothiazole, or benzisoxazole, each optionally substituted; or
R
7
and R
8
, taken together with the carbon atoms to which they are attached, form phenyl or substituted phenyl;
R
9
is hydrogen or alkyl of 1 to 6 carbon atoms; and
R
10
, R
11
and R
12
are, independently hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.
In some preferred embodiments of the invention R
1
is hydrogen, methoxy or halogen.
In other preferred embodiments of the invention, R
2
is hydrogen, alkyl of one to six carbon atoms, or trifluoromethyl.
In other preferred embodiments of the invention Z is NR
3
—(CH
2
)
n
—Y.
Y is preferably phenyl or substituted phenyl.
R
3
is, in some aspects of the invention, preferably, hydrogen.
R
4
is preferably phenyl, indole, indazole, pyridine, pyrimidine, quinoline, benzoisothiazole, or benzisoxazole.
In certain preferred embodiments of the invention R
5
is hydrogen or hydroxy.
In other preferred embodiments of the invention R
6
is 1-benzimidazol-2-one, benzoisothiazole, benzisoxazole or Q—Ar.
Q is preferably C═O.
Preferably R
7
is hydrogen.
In other preferred embodiments of the invention R
8
is phenyl, benzoisothiazole, or benzisoxazole.
When taken together, R
7
and R
8
preferably form phenyl.
In certain preferred embodiments of the invention R
1
is hydrogen, methoxy or halo, R
2
is hydrogen, trifluoromethyl or alkyl of one to six carbon atoms, Z is NR
3
—(CH
2
)
n
—Y and R
3
is hydrogen.
In some preferred embodiments of the invention , R
2
is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
and R
4
is phenyl, indole, indazole, pyridine, pyrimidine, quinoline, benzoisothiazole, or benzisoxazole, each optionally substituted. In more preferred embodiments of this invention R
1
is hydrogen, methoxy or halo, R
2
is hydrogen, trifluoromethyl or alkyl of one to six carbon atoms, Z is
and R
4
is phenyl, indole, indazole, pyridine, pyrimidine, quinoline, benzoisothiazole, or benzisoxazole, each optionally substituted.
In other preferred embodiments of the invention R
2
is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
R
5
is hydrogen or hydroxy and R
6
is 1-benzimidazol-2-one, benzoisothiazole, or benzisoxazole, each optionally substituted. More preferably, R
1
is hydrogen, methoxy or halo, R
2
is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
R
5
is hydrogen and R
6
is 1-benzimidazol-2-one, benzoisothiazole, or benzisoxazole, each optionally substituted.
In still other preferred embodiments of the invention R
2
is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
R
5
is hydrogen or hydroxy, R
6
is —Q—Ar, Q is C═O, and Ar is phenyl or substituted phenyl. More preferably, R
1
is hydrogen, methoxy or halo, R
2
is hydrogen, trifluoromethyl or alkyl of one to six carbon atoms, Z is
R
5
is hydrogen, R
6
is —Q—Ar, Q is C═O, and Ar is phenyl or substituted phenyl.
In yet other preferred embodiments of the invention R
2
is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
R
7
is hydrogen and R
8
is phenyl, benzoisothiazole, or benzisoxazole, each optionally substituted. More preferably R
1
is hydrogen, methoxy or halo, R
2
is hydrogen, trifluoromethyl or alkyl of one to six carbon atoms, Z is
R
7
is hydrogen and R
8
is phenyl, benzoisothiazole, or benzisoxazole, each optionally substituted.
In other preferred embodiments of the invention, R
2
is hydrogen, alkyl of one to six carbon atoms or trifluoromethyl, Z is
and R
7
and R
8
, taken together with the carbon atoms to which they are attached form phenyl or substituted phenyl. Still more preferably R
1
i
Nelson James A.
Stack Gary P.
Kifle Bruck
Woodcock & Washburn LLP
Wyeth
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