Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-18
2003-04-01
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S302100
Reexamination Certificate
active
06541501
ABSTRACT:
BACKGROUND OF THE INVENTION
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). A method for determining intrinsic activity at the dopamine D2 receptor was recently published [Lahti et al., Mol. Pharm. 42, 432-438, (1993)]. As reported, intrinsic activity is predicted using the ratio of the “low-affinity agonist” (LowAg) state of the receptor and the “high-affinity agonist” (HighAg) state of the receptor, i.e. LowAg/HighAg. These ratios correlate with agonist, partial agonist, and antagonist activities for a given compound, which activities characterize a compound's ability to elicite an antipsychotic effect.
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.
SUMMARY OF THE INVENTION
The present invention discloses compounds represented by Formula (I) which are useful antipsychotic agents:
wherein:
X is O or S;
Y is H or alkyl of 1 to 10 carbon atoms;
R
1
is H, alkyl of 1 to 10 carbon atoms, —CH
2
-cycloalkyl of 3 to 10 carbon atoms,
—CH
2
-bicycloalkyl of 7 to 10 carbon atoms,
m is an integer of 0 to 4;
R
2
is H or alkyl of 1 to 10 carbon atoms;
R
3
is H, halogen, alkyl of 1 to 10 carbon atoms, —O-alkyl of 1 to 10 carbon atoms or hydroxy;
Z is O, S, or —CH
2
—;
or R
1
and R
2
when taken together with the nitrogen atom to which they are attached form a moiety of the formula:
n is an integer of 1 or 2;
R
7
and R
8
are independently selected from H, halogen, alkyl of 1 to 10 carbon atoms, -0-alkyl of 1 to 10 carbon atoms or hydroxy;
R
4
and R
5
are independently hydrogen, alkyl of 1 to 10 carbon atoms, —O-alkyl of 1 to 10 carbon atoms, —S-alkyl of 1 to 10 carbon atoms, —CN, —NO
2
, or halogen; or a pharmaceutically acceptable salt thereof.
Preferred are compounds of Formula (I) wherein R
1
is —(CH2)
m
Z—R where m is 0, Z is —CH
2
— and R is selected from the group consisting of:
and R
1
, R
2
, R
3
, R
7
, X, Y and n are hereinbefore defined.
A particularly preferred compound of this invention according to general Formula (I) is 8-(benzylamino-methyl)-3,5,7,8-tetrahydro-9-oxa-1,3-diazacyclo-penta[a]naphthalen-2-one, and pharmaceutical salts thereof.
The present invention provides methods of treating diseases of brain dopamine dysregulation such as schizophrenia, Parkinson's disease, hyperprolactinemia, depression. Because compounds of the present invention are partial agonists at the postsynaptic dopamine D
2
receptor they are also useful in the treatment of alcohol and drug addiction in warm-blooded animals in need thereof. Thus, an effective amount of compound of the present invention is administered to a warm-blooded animal, preferably mammal, most preferably human.
For the compounds defined above and referred to herein, unless otherwise noted; halogen, or halo as used herein means chloro, fluoro, bromo and iodo.
Alkyl as used herein means a branched or straight chain having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
Cycloalkyl as used herein means a saturated ring having 3 to 10 carbon atoms and more preferably from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term bicycloalkyl means fused saturated bicyclic rings of 7-15 carbon atoms. Exemplary bicycloalkyl rings include bicyclo[3.3.1]nonane, bicyclo[3.3.0]octane, bicycloheptane[2.2.1], bicyclooctane[3.2.1], bicyclononane [4.3.0], and bicyclodecane[4.4.0].
Phenyl as used herein refers to a 6-membered aromatic ring.
The range of carbon atoms defines the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituent groups.
It is understood by those practicing the art that the definition of compounds of Formula (I) when R
1
, R
2
, and R
3
contain asymmetric carbons, encompass all possible stereoisomers, mixtures and regioisomers thereof which possess the activity discussed below. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art. In particular, the definition encompasses any optical isomers and diastereomers as well as the racemic and resolved enantiomercially pure R and S stereoisomers as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the activity discussed below. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formula (I). The pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids.
The present invention further provides a pharmaceutical composition which comprises a compound of Formula (I) of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and one or more pharmaceutically acceptable carriers.
DESCRIPTION OF THE INVENTION
Compounds of Formula I are synthesized as described in Scheme I from substituted ethyl 7-hydroxy-8-nitro4-oxochromen-2-carboxylate 1 where R
3
is hereinbefore defined by reaction with p-toluenesulfonyl chloride to give tosylate 2. Reaction of tosylate 2 with substituted benzylamine 3 where R
6
is hydrogen, alkyl of 1 to 10 carbon atoms, —O-alkyl of 1 to 10 carbon atoms, halogen or —NO
2
at 100 to 180° C. in o-dichlorobenzene affords ethyl-7-substituted benzylamino-8-nitro-4-oxo-4H-chromene-2-carboxylate 4 where R
3
and R
6
are hereinbefore defined, followed by hydrogenation in the presence of palladium-on-carbon to give ethyl substituted-7,8-diamino-chroman-2-carboxylate 5.
The carboxylate 5 is reduced with lithium borohydride in tetrahydrofuran to give alcohol 6 where R
3
is hereinbefore defined. Alcohol 6 is reacted with 1,1′-carbonyidiimidazole in tetrahydrofur
Mewshaw Richard E.
Zhao Rulin
Barrett Rebecca R.
Stockton Laura L.
Wyeth
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