Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-24
2003-12-16
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254080, C514S254110, C514S255030, C544S230000
Reexamination Certificate
active
06664258
ABSTRACT:
BACKGROUND TO THE INVENTION
The present invention pertains to novel pharmacologically active trans-piperazin-1-yl-spiro[cyclohexane-1,1′-isobenzofuran] derivatives that are dopamine receptor subtype ligands having a preference for the D4-dopamine receptor. These compounds exhibit central dopaminergic activity, as defined below, and are useful in the treatment and/or prevention of disorders of the dopamine system, including schizophrenic and schizoaffective disorders, akinesia, dementia, Parkinson's disease, nausea, bipolar disorders, emesis, tardive dyskinesia, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, hyperprolactemia and amenorrhoea.
The biological activity of only a few spirocyclic cylcohexane systems has been described. For example, in U.S. Pat. No. 3,932,425, U.S. Pat. No. 4,025,558 and U.S. Pat. No. 4,010,201, D. Lednicer refers to a series of spirocyclic cyclohexylamine derivatives that possess tranquilizing activity and are consequently useful in anxiety and schizophrenia and can be administered to reduce aggressive behavior and lower blood pressure. In U.S. Pat. No. 5,403,846, John J. Baldwin et al. refer to a series of spirocyclic benzopyrano cyclohexylamine derivatives that were studied for potassium channel blocking activity and found to exhibit type III antiarrythmic activity. In World Patent Application PCT/US95/05940, the same inventor, John J. Baldwin, refers to a series of spirocyclic dihydrobenzopyrano derivatives as constituting part of a combinatorial chemical library that contains ligands for potassium channels, adrenergic receptors, dopamine receptors and sigma-opioid receptors, and also refers to the use of this library for identifying biologically active agents such as, for example, inhibitors for carbonic acid anhydrase useful for treatment of glaucoma. Lawrence L. Martin describes, in
J. Med. Chem
., 24, pg. 617-621, 1981, the synthesis of a series of spiro isobenzofuran derivatives containing dialkylamino substituents and refers to the activity of these agents as centrally acting serotinergic agents. Similarly, William E. Parham describes, in
J. Org. Chem
., 41, pg. 2628-2633, 1976, the synthesis of a series of spiro[isobenzofuran-(3H),4′piperidine derivatives and biological activities that suggest their utility as antidepressant and antipsychotic agents. U.S. Pat. No. 5.352,678 refers to a series of dopaminergic cyclohexane derivatives and their use as antiischemic and antipsychotic agents.
U.S. Pat. No. 5,352,678, which issued on Oct. 4, 1994, refers to dopaminergic cyclohexane derivatives and to their utility as antiischemic and antipsychotic agents.
International Patent Application WO 94/19367, which was published on Sep. 1, 1994, refers to spiropiperidine derivatives and to their ability to increase endogenous hormone levels.
Thus, it is generally known that dopamine receptors are important for many functions in the animal body. For example, altered functions of these receptors are thought to participate in the genesis of psychosis, drug addiction, compulsive disorders, bipolar disorders, vision, emesis, sleep, feeding, learning, memory, sexual behavior, regulation of immunological responses and blood pressure. Since these receptors control a great number of pharmacological events and, on the other hand, not all of them are presently known, it is possible that compounds acting preferentially on dopamine receptor subtypes, for example, on the D4 dopamine receptor, will exert a wide range of therapeutic effects in humans.
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula
wherein a is oxygen, CH
2
, C(CH
3
)
2
, NR
10
, sulfur, SO or SO
2
;
b is oxygen, CH
2
, C═O, C═NR
11
, C═NOH, SO
2
, sulfur, SO, C═NO(C
1
-C
5
)alkyl or CR
7
R
8
;
each of R
1
through R
8
is selected, independently, from hydrogen, halogen (e.q., chloro, fluoro, bromo or iodo), trifluoromethyl, cyano and hydroxy, or R
7
and R
8
together can be C(═O)NH
2
or C(═O)N(C
1
-C
4
)alkyl, with the proviso that neither R
7
nor R
8
can be halo when a is oxygen, NR
11
, sulfur, SO or SO
2
; and
each of R
10
and R
11
is selected, independently, from hydrogen, benzyl and (C
1
-C
6
)alkyl;
and the pharmaceutically acceptable salts of such compounds.
Preferred compounds of the formula I are those wherein a is oxygen, b is CH
2
, each of R
1
, R
4
and R
5
is hydrogen, and each of R
2
, R
3
and R
6
is selected, independently from hydrogen, cyano, chloro and fluoro.
Other more specific embodiments of this invention include:
(a) compounds of the formula I wherein a is oxygen;
(b) compounds of the formula I wherein a is oxygen and b is CH
2
;
(c) compounds of th formula I wherein a is oxygen, b is CH
2
and each of R
1
, R
4
and R
5
is hydrogen;
(d) compounds of the formula I wherein a is oxygen, b is CH
2
, each of R
1
, R
4
and R
5
is hydrogen and R
3
is fluoro, cyano or chloro;
(e) compounds of the formula I wherein a is oxygen, b is CH
2
, each of R
1
, R
4
and R
5
is hydrogen and each of R
2
, R
3
and R
6
is selected, independently, from hydrogen, fluoro, cyano and chloro; and
(f) compounds of the formula I wherein a is oxygen, b is CH
2
, each of R
1
, R
4
and R
5
is hydrogen, and R
2
and R
3
are selected, independently, from fluoro, cyano and chloro.
The compounds of formula I above may contain chiral centers and therefore may exist in different enantiomeric forms. This invention relates to all optical isomers and all other stereoisomers of compounds of the formula I and mixtures thereof.
This invention also relates to a pharmaceutical composition for treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson's disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising an amount of a compound of the formula I, or pharmaceutically acceptable salt thereof, that is effective in treating or preventing such condition, and a pharmaceutical acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson's disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or pharmaceutically acceptable salt thereof, that is effective in treating or preventing such condition.
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson's disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising a dopaminergic effective amount of a compound of the formula I, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson's disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, and nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising an administering to said mammal a dopami
Butler Todd W.
Fliri Anton F. J.
Bernhardt Emily
Ginsburg P. H.
Joran A. D.
Pfizer Inc
Richardson P. C.
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