Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D.sub.4 antagonists Number:7,125,903 from the United States Patent and Trademark Office (PTO) owispatent The compounds are of the class thienoisoxazolyl- and thienylpyrrazolyl-phenoxy substituted propyl derivatives, useful as D.sub.4 antagonists. Said compounds are useful for the treatment of medical conditions mediated by inhibition of D.sub.4 receptor. These conditions comprise, for example, Attention Deficit Hyperactivity Disorder, Obsessive-Compulsive Disorder, Psychoses, Substance Abuse, Substance Dependence, Parkinson's Disease, Parkinsonism, Tardive Diskinesia, Gilles de la Tourette Syndrome, Conduct Disorder, and Oppositional Defiant Disorder. A further aspect of the invention is to provide a pharmaceutical composition, intermediates, and a method of making said class of compounds.<H thienylpyrrazolyl, Thienoisoxazolyl, Thienoisoxazoly, 7125903.html, Patent, pto, 7125903

Title: Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D.sub.4 antagonists

Abstract: The compounds are of the class thienoisoxazolyl- and thienylpyrrazolyl-phenoxy substituted propyl derivatives, useful as D.sub.4 antagonists. Said compounds are useful for the treatment of medical conditions mediated by inhibition of D.sub.4 receptor. These conditions comprise, for example, Attention Deficit Hyperactivity Disorder, Obsessive-Compulsive Disorder, Psychoses, Substance Abuse, Substance Dependence, Parkinson's Disease, Parkinsonism, Tardive Diskinesia, Gilles de la Tourette Syndrome, Conduct Disorder, and Oppositional Defiant Disorder. A further aspect of the invention is to provide a pharmaceutical composition, intermediates, and a method of making said class of compounds.

Patent Number: 7,125,903 Issued on 10/24/2006 to Fink, et al.

Inventors: Fink; David M. (Lebanon, NJ), Freed; Brian S. (Phillipsburg, NJ), Hrib; Nicholas J. (Hillsborough, NJ), Kosley, Jr.; Raymond W. (Bridgewater, NJ), Lee; George E. (Somerville, NJ), Merriman; Gregory H. (Phillipsburg, NJ), Rauckman; Barbara S. (Flemington, NJ)
Assignee: Aventis Pharmaceuticals Inc. (Bridgewater, NJ)

Appl. No.: 10/088,250

Filed: September 13, 2000

PCT Filed: September 13, 2000

PCT No.: PCT/US00/24962

371(c)(1),(2),(4) Date: December 23, 2002

PCT Pub. No.: WO01/19833

PCT Pub. Date: March 22, 2001

Current U.S. Class: 514/379 ; 514/406; 514/444; 548/241; 548/360.1; 549/59

Current International Class: A61K 31/42 (20060101); A61K 31/415 (20060101); C07D 231/00 (20060101); C07D 261/00 (20060101)

Field of Search: 548/241,360.1 549/59 514/379,406,444

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Primary Examiner: Shameem; Golam M. M.
Attorney, Agent or Firm: Kurys; Barbara E.

Parent Case Text

This application is a 371 of PCT/US00/24962, Filed Sep. 13, 2000, and claims the benefit of U.S. Provisional No. 60/229,355, Filed Sep. 14, 1999.

Claims

What is claimed is:

1. A compound of Formula I: ##STR00356## a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N(CH.sub.3) or O; R.sub.1 is OH or C.sub.1-6 alkoxy; R.sub.2 is H or C.sub.1-6 alkyl; R.sub.3 is (CH.sub.2).sub.n Q, CH.sub.2CH(OH)Q, CH(CH.sub.3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein Q is thienyl or furanyl and Q is optionally substituted with one or two moieties independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, S(O)H.sub.2NH.sub.2, trifluormethyl, or cyano, and n is 1 or 2; and R.sub.4 is H or C.sub.1-6 alkyl.

2. A compound according to claim 1 wherein Q is thienyl.

3. The compound according to claim 2 which is (2R)-2-methyl-1-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[thienophen-2-yl- methyl)-amino-propan-2-ol.

4. The compound according to claim 2 which is (2S)-1-(2-thienylmethylamino)-2-methyl-3-[3-thieno[2,3-d]isoxazol-3-yl-ph- enoxy]propan-2-ol.

5. The compound according to claim 2 which is (2S)-1-(3-thienylmethylamino)-2-methyl-3-[3-thieno[2,3-d]isoxazol-3-yl-ph- enoxy]propan-2-ol.

6. A compound according to claim 2 wherein R.sub.1 is OH; R.sub.2 is H; R.sub.3 is (CH.sub.2).sub.n Q; and n is 1.

7. A compound according to claim 6 wherein Q is thienyl.

8. The compound according to claim 7 which is (2R)-1-(4-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[(thiophen-3-ylmethyl)-am- ino]-propan-2-ol.

9. The compound of claim 7 which is (2R)-1-(4-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[(thiophen-2-ylmethyl)-am- ino]-propan-2-ol.

10. The compound of claim 7 which is (2R)-1-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[(thiophen-2-ylmethyl)ami- no]propan-2-ol.

11. The compound of claim 7 which is (2R)-1-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[(thiophen-3-ylmethyl)ami- no]propan-2-ol.

12. A compound according to claim 1 wherein Q is furanyl.

13. The compound of claim 12 which is (2R)-1-[(furan-2-ylmethyl)-amino]-2-methyl-3-(3-thieno[2,3-d]isoxazol-3-y- l-phenoxy)-propan-2-ol.

14. The compound of claim 12 which is (2R)-1-[(furan-2-ylmethyl)amino]-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)- -propan-2-ol.

15. The compound of claim 12 which is (2R)-1-[(furan-2-ylmethyl)-amino]-3-(4-thieno[2,3-d]isoxazol-3-yl-phenoxy- )propan-2-ol.

16. The compound of claim 12 which is (2S)-1-[(furan-2-ylmethyl)amino]-2-methyl-3-(3-thieno[2,3-d]isoxazol-3-yl- -phenoxy)propan-2-ol.

17. A compound according to claim 1 wherein R.sub.3 is indanyl.

18. The compound of claim 17 which is (2R)-1-(indan-1-ylamino)-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propan-- 2-ol.

19. The compound of claim 17 which is (2R)-1-(indan-2-ylamino)-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propan-- 2-ol.

20. A compound according to claim 1, wherein R.sub.3 is adamantyl.

21. The compound of claim 20 which is (2R)-1-(adamantan-1-ylamino)-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-pro- pan-2-ol.

22. A compound according to claim 1, wherein R.sub.3 is 1,2,3,4-tetrahydronaphthyl.

23. The compound of claim 22 which is (2R)-1-(1,2,3,4-tetrahydronaphthalen-1-ylamino)-3-[3-thieno[2,3-d]isoxazo- l-3-yl)phenoxy]propan-2-ol.

24. A composition comprising a compound according to claim 1 in admixture with an inert carrier.

25. The composition according to claim 24 wherein said inert carrier is a pharmaceutical carrier.

26. A method of making a compound of formula I ##STR00357## a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N(CH.sub.3) or O; R.sub.1 is OH or C.sub.1-6 alkoxy; R.sub.2 is H or C.sub.1-6 alkyl; R.sub.3 is (CH.sub.2).sub.n Q, CH.sub.2CH(OH)Q, CH(CH.sub.3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein Q is thienyl or furanyl, and Q is optionally substituted with one or two moieties independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, S(O).sub.2NH.sub.2, trifluoromethyl, or cyano, and n is 1 or 2; and R.sub.4 is H or C.sub.1-6 alkyl; comprising the step of coupling a reagent of formula II ##STR00358## wherein X and R.sub.2 are as defined in formula I; with a reagent of formula III ##STR00359## wherein R.sub.3 and R.sub.4 are as defined in formula I; to provide the compound of formula I.

27. A method of making a compound of formula I ##STR00360## a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N(CH.sub.3) or O; R.sub.1 is OH or C.sub.1-6 alkoxy; R.sub.2 is H or C.sub.1-6 alkyl; R.sub.3 is (CH.sub.2).sub.n Q, CH.sub.2CH(OH)Q, CH(CH.sub.3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein Q is thienyl or furanyl, and Q is optionally substituted with one or two moieties independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, S(O).sub.2NH.sub.2, trifluoromethyl, or cyano, and n is 1 or 2; and R.sub.4 is H or C.sub.1-6 alkyl; comprising the step of coupling a compound of formula II ##STR00361## wherein X and R.sub.2 are as defined in formula I; and R.sub.5 is CH.sub.3, CF.sub.3, F, p-bromobenzene, p-nitrobenzene, or p-methylbenzene; with a reagent of formula m ##STR00362## wherein R.sub.3 and R.sub.4 are as defined in formula I; to provide the compound of formula I.

28. A method of making a compound of formula I ##STR00363## a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N(CH.sub.3) or O; R.sub.1 is OH or C.sub.1-6 alkoxy; R.sub.2 is H or C.sub.1-6 alkyl; R.sub.3 is (CH.sub.2).sub.n Q, CH.sub.2CH(OH)Q, CH(CH.sub.3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein Q is thienyl or furanyl, and Q is optionally substituted with one or two moieties independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, S(O).sub.2NH.sub.2, trifluoromethyl, or cyano, and n is 1 or 2; and R.sub.4 is H or C.sub.1-6 alkyl; comprising the step of coupling a reagent of formula II ##STR00364## wherein X is as defined in formula I; with a reagent of formula III ##STR00365## wherein R.sub.2, R.sub.3, and R.sub.4 are as defined in formula I; to provide the compound of formula I.

Description

FIELD OF THE INVENTION

The present invention comprises compounds of Formula I useful as therapeutic agents for conditions treated by antagonizing D.sub.4 receptor stimulation, e.g., Attention Deficit Hyperactivity Disorder, Obsessive Compulsive Disorder and Psychoses. Intermediates, method of making the compounds and methods of using the compounds are also claimed.

BACKGROUND OF THE INVENTION

The relatively new science of molecular biology has allowed new insights into the mechanisms of CNS diseases via the isolation and cloning of receptor subtypes. Thus, while earlier functional studies had distinguished only two subtypes of dopamine receptor, to date five distinct subtypes have been identified. The dopamine D.sub.4 receptor was first cloned in 1991 by Van Tol, Seeman, Civelli, et al. and shown to be localized in the limbic regions of the brain, areas associated with cognitive and emotional behaviors (Van Tol, H. H. M.; Bunzow, J. R.; Guan, H-C.; Sunahara, R. K.; P. Seeman, Niznik, H. B.; Civelli, O.; Cloning of the gene for a human dopamine D.sub.4 receptor with high affinity for the antipsychotic clozapine. Nature 1991, 350, 610.)

The D.sub.4 receptor was also localized to the frontal cortex implying a role in cognition and executive function. Furthermore, it has been reported that the selective D.sub.4 antagonist NGD-94-1 caused improvement in performance retention in a passive avoidance test in rodents and improved performance in a spatial water maze task. (Tallman, J. NGD-94-1; A Specific Dopamine D.sub.4 Antagonist. Catecholamines-Bridging Basic Science with Clinical Medicine. Goldstein, D. S.; Eisenhofer, G.; McCarty, R., Eds.; Academic Press: New York, 1997). The effects of this compound in these assays are consistent with the anatomical localization of the D.sub.4 receptor in the cortex, hippocampus and thalamus.

Genetic linkage and association studies using polymorphism have been carried out to obtain insights into the possible roles for this receptor in disease. It has been reported that there is a positive association between the repeat polymorphism of seven repeat units and a number of clinical conditions which have a high degree of comorbidity such as Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder-tics (Cruz, C. et al., Increased prevalence of the seven-repeat variant of the dopamine D.sub.4 receptor gene in patients with obsessive-compulsive disorder with tics. Neurosci. Lett. 1997, 231, 1. Van Tol, H. H. M. (1995) Clin Neuropharmacol. 18: S143 153).

One of the most remarkable polymorphisms in the human dopamine D.sub.4 receptor is a variable number of 48 bp tandem repeats in the third cytoplasmic loop. Individuals with 2 10 tandem repeat units have been identified. Interestingly, this polymorphism appears to be primate-specific and has not been observed in rodents suggesting that these polymorphisms are evolutionarily recent events (Asghari, V. et al., Dopamine D.sub.4 receptor repeat: analysis of different native and mutant forms of the human and rat genes (1994) Mol. Pharm. 46: 364 373).

The human D.sub.4 receptor with seven repeat units has a number of unique characteristics which distinguish it from the other D.sub.4 polymorphisms. This D4.7 variant has displayed a two- to threefold lower potency for the endogenous ligand dopamine than did the D4.2 variant (EC.sub.50.ident.40 nM vs 15 nM) however, the functional implications of this lower affinity are not yet resolved.

Attention Deficit Hyperactivity Disorder (hereinafter ADHD)

Attention deficit hyperactivity disorder (ADHD) is a disease which affects 3 5% of school age children. It is highly prevalent, making up to 50% of child psychiatry populations. The disease can also persist into adulthood, affecting 1-3% of adults. The diagnosis of ADHD revolve around three basic criteria: inattention, hyperactivity, and impulsivity. Approximately 50 70% of school-age children with the diagnosis of ADHD continue to manifest symptoms through middle adolescence, and almost one third will show some signs of the disorder in adulthood.

It has been shown that dopamine D.sub.4 receptor gene polymorphism is associated with ADHD. Patients suffering from ADHD had a significant increase in the prevalence of 7-fold repeat form of the D.sub.4 receptor, a variant which is unique for primates (LaHoste, G. J.; Swanson, J. M.; Wigal, S. B.; Glabe, C.; Wigal, T.; King, N.; Kennedy, J. L.; Dopamine D.sub.4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol. Psychiatry 1996, 1, 121). Interestingly, an excess of the D4.7 allele has also been associated with the personality trait of "novelty-seeking"; individuals scoring higher than average on this scale are characterized as impulsive, exploratory, fickle, excitable, quick-tempered and extravagant (Ebstein, R. P. et al.; Dopamine D.sub.4 receptor (D.sub.4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nature Genetics. 1996, 12, 78 and Benjamin, J. et al.; Population and familial association between the D.sub.4 dopamine receptor gene and measures of Novelty Seeking. Nature Genetics. 1996, 12, 81).

This variant of the D.sub.4 receptor may have a dysregulated response to dopamine, perhaps suggesting a gain of function for this receptor (Van Tol, H. H. M.; Wu, C. M.; Guan, H-C.; Ohara, K.; Bunzow, J. R.; Civelli, O.; Kennedy, J.; Seeman, P.; Niznik, H. B.; Jovanovic, V.; Multiple dopamine D.sub.4 receptor variants in the human population. Nature 1992, 352, 149. b) Van Tol, H. H. M.; Structural and Functional characteristics of the Dopamine D.sub.4 Receptor. In Catecholamines Bridging Basic Science with Clinical Medicine. Goldstein, D. S.; Eisenhofer, G.; McCarty, R., Eds.; Academic Press: New York, 1997). Therefore, these data suggest that a D.sub.4 antagonist may be efficacious in the treatment of ADHD without the side effect liability seen with current drug therapies.

Patients with ADHD also have markedly increased incidence of Conduct Disorder and Oppositional Defiant Disorder. Conduct Disorder is a disorder wherein the patient exhibits a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated. These behaviors fall into four main groupings: aggressive conduct that causes or threatens physical harm to other people or animals, nonaggressive conduct that causes property loss or damage, deceitfulness or theft, and serious violations of rules. Oppositional Defiant Disorder is a disorder wherein the patient exhibits some of the patterns of behavior observed in Conduct Disorder (e.g., disobedience and opposition to authority figures), however it does not include the persistent pattern of the more serious forms of behavior in which either the basic rights of others or age-appropriate societal norms or rules are violated. Although children with ADHD often exhibit hyperactive and impulsive behavior that may be disruptive, this behavior does not by itself violate age-appropriate societal norms and therefore does not usually meet criteria for Conduct Disorder. No specific data regarding gene frequency is available for these conditions, which are relatively refractory to available pharmacotherapy. If abnormalities of the D.sub.4 neurotransmission involved in the pathogenesis of ADHD, it would be likely that D.sub.4 abnormalities would also play a role in these conditions.

Obsessive-Compulsive Disorder (hereinafter OCD)

Obsessive-compulsive disorder is a neurosis characterized by the presence of recurrent ideas and fantasies (obsessions) and repetitive impulses or actions (compulsions) that patients recognize as morbid and toward which they feel a strong inner resistance. In the US it is estimated that approximately four million patients are afflicted with OCD; however, fewer than half are diagnosed and treated.

The same seven-repeat variant of the dopamine D.sub.4 receptor gene has been found to show increased prevalence in patients suffering from obsessive-compulsive disorder with tics (Cruz, C. et al., Increased prevalence of the seven-repeat variant of the dopamine D.sub.4 receptor gene in patients with obsessive-compulsive disorder with tics. Neurosci. Lett. 1997, 231, 1. Van Tol, H. H. M. (1995) Clin Neuropharmacol. 18: S143 153). It has also been reported that adolescents with OCD plus tics are more prone to show violent and aggressive obsessions than those without tics (Cruz, C. et al., Increased prevalence of the seven-repeat variant of the dopamine D.sub.4 receptor gene in patients with obsessive-compulsive disorder with tics. Neurosci. Lett. 1997, 231, 1. Van Tol, H. H. M. (1995) Clin Neuropharmacol. 18: S143 153). As mentioned before, this D.sub.4 variant has been shown to have a dysregulated response to dopamine. Thus OCD may also be a disorder associated with a gain of function at the D.sub.4 receptor, which would respond to treatment with selective D.sub.4 antagonists.

Schizophrenia

Schizophrenia is a severe mental illness affecting an estimated 1% of the world's population. The disease has an uncertain pathophysiology possibly leading to disruption of dopaminergic neural systems through poorly understood interactions of atomic, metabolic and genetic abnormalities. The schizophrenic patient suffers from psychotic symptoms broadly categorized as positive, negative or cognitive. The positive symptoms include delusions, hallucinations, irrational fears, and disorganization of thought. Negative or deficit symptoms include social withdrawal, impairment in role functioning, diminished or inappropriate affect, poverty of speech, marked lack of initiative or energy and the inability to experience pleasure. Cognitive symptoms comprise impairment of attention, verbal fluency, recall memory or executive function. Since the discovery of the clinical antipsychotic activity of chlorpromazine in the 1950s, the pharmacological antagonism of central dopamine receptors remains the only proven means for treating schizophrenia. This is evidenced by the number of agents with varied chemical structures that have been found to share the property of dopamine D.sub.2 receptor antagonism and to have clinical benefit.

Recently using molecular biological techniques two families of dopamine receptors have been discovered namely the dopamine D.sub.1 family (D.sub.1 and D.sub.5 receptor subtype) and the dopamine D.sub.2 family (D.sub.2, D.sub.3, and D.sub.4 receptor subtype). All clinically effective antipsychotic agents have been shown to bind to these receptor subtypes with varying affinities (Corbett, R. et al., 1997; Iloperidone: Preclinical Profile and early clinical evaluation. CNS Drugs Reviews 3(2): 120 147). A number of the recently introduced antipsychotic drugs with a profile for reduced extrapyramidal side effect liability have been shown to have greater affinity for the dopamine D.sub.4 receptor subtype when compared to the dopamine D.sub.2 receptor subtype. This greater affinity for the D.sub.4 receptor compared to the D.sub.2 receptor may contribute to these drugs having greater efficacy and less side effect liability than the traditional typical antipsychotic drugs (Seeman, P., Corbett, R. and Van Tol H. H. M. (1997) Atypical neuroleptics have low affinity for dopamine D.sub.2 receptors or are selective for D.sub.4 receptors. Neuropsychopharmacology 16 (2): 93 135.). Therefore, compounds with selective D.sub.4 affinity may have efficacy against schizophrenia without causing the side effects associated with D.sub.2 receptor blockade.

Substance Abuse/Substance Dependence

Repeated administration of psychostimulants such as d-amphetamine to rodents produces a progressive and long-lasting increase in behaviors such as locomotor activity, a phenomenon known as "behavioral sensitization" or "reverse tolerance". This enduring hypersensitivity to psychostimulants is also observed in humans and is thought to underlie drug addiction (Robinson, T. E. and Berridge, K. C. 1993 The neural basis of drug craving: an incentive sensitization theory of addiction Brain Research Reviews 18: 247 291). The mesolimbic dopamine system plays a critical role in the development of drug addiction. The development of behavioral sensitization to amphetamine is thought to reflect neuroadaptive biochemical and genomic responses triggered by the first exposure to the psychostimulant. Postsynaptic neuroplasticity results in alterations in dopamine receptor number and sensitivity. The function of the dopamine D.sub.2 receptor family (D.sub.2, D.sub.3, and D.sub.4 receptor subtypes) are all altered by the administration of amphetamine. The chronic administration of a selective dopamine D.sub.4 receptor antagonist to rodents has been demonstrated to stop the development of behavioral sensitization to the administration of d-amphetamine indicating that selective dopamine D.sub.4 antagonists may have efficacy for the treatment of drug abuse (Feldpausch D. L et al., 1998 The role of Dopamine D.sub.4 receptor in the induction of behavioral sensitization to amphetamine and accompanying biochemical and molecular adaptations. Journal of Pharmacology and Experimental Therapeutics 266: 497 508).

A role for the D.sub.4 receptor in substance abuse and substance dependence is supported by reports of an excess of long alleles (chiefly 7-repeat) of the D.sub.4 exon 3 polymorphism in opiate and possibly alcohol abusers (Ebstein R P, Belmaker R H. 1997 Saga of an adventure gene: novelty seeking, substance abuse and the dopamine D.sub.4 receptor (D.sub.4DR) exon III repeat polymorphism. Mol Psychiatr 2:381 4; Kotler M, Cohen H, Segman R, et al. 1997 Excess dopamine D.sub.4 receptor (D.sub.4DR) exon III seven repeat allele in opioid-dependent subjects. Mol Psychiatr 2:251 4; Mel H, Horowitz R, Ohel N, et al. 1998 Additional evidence for an association between the dopamine D.sub.4 receptor (D.sub.4DR) exon III seven-repeat allele and substance abuse in opioid dependent subjects: Relationship of treatment retention to genotype and personality. Addiction Biology 3:473 81). Long alleles of the D.sub.4 exon 3 polymorphism may also be associated with increased difficulty in quitting smoking, which may be related to nicotine addiction (Shields P G, Lerman C, Audrain J, et al. 1998 Dopamine D.sub.4 receptors and the risk of cigarette smoking in African-Americans and Caucasians. Cancer Epidemiology, Biomarkers & Prevention 7:453 8).

Parkinson's Disease/Parkinsonism

Parkinson's disease is a progressive disorder of movement, characterized by tremor, rigidity, and bradykinesia. Other manifestations include depression, dementia (especially in advanced disease), and psychosis (especially as a complication of dopaminergic therapy). Parkinson's disease affects approximately 0.1% of the population, usually beginning after age 50. The major pathology is loss of dopaminergic neurons of the zona compacta in the substantia nigra. The major treatment is administration of dopamine precursors or agonists, but these are incompletely effective and are associated with side effects including dyskinesias, psychosis, and hypotension. Anticholinergic drugs are occasionally used, but are of limited efficacy and poorly tolerated.

Traditional antipsychotic drugs (neuroleptics) block the dopamine D.sub.2 receptor and commonly produce symptoms of Parkinson's disease "Parkinsonism" in a dose-dependent manner corresponding to the potency of their D.sub.2-blockade.

Dopamine synthesis in mouse dorsal striatum is increased in D.sub.4 knockout mice (Rubinstein M, Phillips T J, Bunzow J R, et al. 1997 Mice lacking dopamine D.sub.4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90:991 1001.). This suggests that a D.sub.4 antagonist might have efficacy in treating Parkinson's disease, both in the treatment of the primary symptoms and in the treatment of both psychiatric and movement side-effects of standard dopaminergic therapies.

Several studies have suggested benefit of the atypical antipsychotic clozapine not only for treatment levodopa induced psychosis, but also for treatment of Parkinsonian symptoms themselves, especially tremor. These findings were reviewed by Factor and Friedman (Factor S A, Friedman J H. 1997 The emerging role of clozapine in the treatment of movement disorders. Movement Disorders 12:483 96). Clozapine, in addition to prominent D.sub.4 blockade, has activity at multiple other receptors, notably serotonin 5-HT.sub.2 and acetylcholine muscarinic. It is unlikely that anticholinergic effects account for clozapine's efficacy, as anticholinergic non-responders have responded dramatically to clozapine. While this may be due in part to 5-HT.sub.2 antagonism; replacement of clozapine by olanzapine, a potent antagonist of 5-HT.sub.2 (albeit with greater dopamine D.sub.2 affinity than clozapine), was associated with increased Parkinsonian symptoms in a study of patients with Parkinson's disease (Friedman J H, Goldstein S, Jacques C. 1998 Substituting clozapine for olanzapine in psychiatrically stable parkinson's disease patients: Results of an open label pilot study. Clin Neuropharmacol 21:285 8). Dyskinesias and dystonia, associated with the use of levodopa, have also been reported to improve with clozapine (Factor S A, Friedman J H. 1997 The emerging role of clozapine in the treatment of movement disorders. Movement Disorders 12:483 96).

Further support for the potential role of the D.sub.4 receptor in Parkinson's disease comes from a report of increased incidence of long (.gtoreq.6 repeats) alleles of the D.sub.4 exon 3 polymorphism in Parkinson's disease (Ricketts M H, Hamer R M, Manowitz P, et al. 1998 Association of long variants of the dopamine D.sub.4 receptor exon 3 repeat polymorphism with Parkinsons-disease. Clinical Genetics 54:33 8).

Tardive Dyskinesia (hereinafter TD)

Tardive dyskinesia is a movement disorder, consisting of involuntary choreiform, athetoid, or rhythmic movements of the tongue, jaw or extremities which develops as a result of (usually chronic) administration of neuroleptics and typically persists even after these drugs are discontinued. The overall prevalence of Neuroleptic-Induced Tardive Dyskinesia in patients who have received long-term neuroleptic treatment is estimated at 20 30% (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth edition. Washington, D.C., American Psychiatric Association, 1994).

Increased concentrations of D.sub.4 receptor have been reported in some postmortem studies of schizophrenics (usually treated for extended periods with traditional neuroleptics) (Lahti R A, Roberts R C, Cochrane E V, et al. 1998 Direct determination of dopamine D.sub.4 receptors in normal and schizophrenic postmortem brain tissue: A (.sup.3H)NGD-94-1 study. Mol Psychiatr 3:528 33; Seeman P, Guan H C, Van Tol H H. 1995 Schizophrenia: elevation of dopamine D.sub.4-like sites, using [.sup.3H]nemonapride and [.sup.125I]epidepride. Eur J Pharmacol 286:R3 5). An up-regulation of the D.sub.2 receptor has been seen with chronic administration of the neuroleptic haloperidol in both animal and human studies (Schroder J, Silvestri S, Bubeck B, et al. 1998 D.sub.2 dopamine receptor up-regulation, treatment response, neurological soft signs, and extrapyramidal side effects in schizophrenia: a follow-up study with .sup.123I-iodobenzamide single photon emission computed tomography in the drug-naive state and after neuroleptic treatment. Biol Psychiatry 43:660 5). Use of these drugs might also be responsible for up-regulation of the D.sub.4 receptor.

Improvement in TD has been seen with clozapine (Bassift D P, Louza-Neto M R. 1998 Clozapine efficacy in tardive dyskinesia in schizophrenic patients. European Archives of Psychiatry & Clinical Neuroscience 248:209 11) a drug with prominent D.sub.4 antagonism. While clozapine has other pharmacologic actions, notably 5HT.sub.2 receptor blockade, an effect on T.D. has not to date been established for 5HT.sub.2/D.sub.2 receptor antagonists such as risperidone or olanzapine. The concern might be raised that chronic D.sub.4 blockade might also cause tardive dyskinesia, however this complication has been exceedingly rare in patients treated with clozapine.

Gilles de la Tourette Syndrome (hereinafter TS)

Gilles de la Tourette syndrome, a condition manifest by motor and vocal tics, with a prevalence of approximately 0.5% (most common in adolescents), is seen with increased frequency in patients with ADHD and/or OCD, and in family members of patients with those conditions. Use of stimulant drugs (which increase synaptic dopamine concentrations) in patients with ADHD has been associated with an increased incidence of tics and possibly TS (Erenberg G, Cruse R P, Rothner A D. 1985 Gille de la Tourette's syndrome: Effects of stimulant drugs. Neurology 35:1346 8). An increased incidence of the D4.7 allele has been reported in TS (Grice D E, Leckman J F, Pauls D L, et al. 1996 Linkage disequilibrium between an allele at the dopamine D.sub.4 receptor locus and Tourette syndrome, by the transmission-disequilibrium test. American Journal of Human Genetics 59:644 52), and haloperidol (a D.sub.2/D.sub.4 dopamine antagonist) is effective at controlling tics.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided a compound of formula I:

##STR00001## a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N(CH.sub.3) or O; R.sub.1 is OH or C.sub.1-6 alkoxy; R.sub.2 is H or C.sub.1-6 alkyl; R.sub.3 is (CH.sub.2).sub.n Q, CH.sub.2CH(OH)Q, CH(CH.sub.3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein Q is thienyl, phenyl, furanyl, naphthyl, pyridyl, indolyl, indazolyl, cyclohexyl, 1,2-methylenedioxyphenyl, cyclohexenyl, 1H-pyrazolo[4,3-c]pyridyl; and Q is optionally substituted with one or two moieties independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, S(O).sub.2NH.sub.2, trifluoromethyl, or cyano, and n is 1 or 2; R.sub.4 is H or C.sub.1-6 alkyl; or R.sub.3 and R.sub.4, together with the nitrogen atom to which R.sub.3 and R.sub.4 are attached, form 1,4-dioxa-8-azo-spiro[4.5]decanyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azocanyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-.beta.-carbolinyl, 4,5,6,7-tetrahydrothienyl[3,2-c]pyridyl, or 8-aza-bicyclo[3.2.1.]octane, each of which may be mono- or independently di-substituted with halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C(O)phenyl, OH, CN, O-phenyl or (CH.sub.2).sub.mZ, Z is benzisoxazolyl, indazolyl, benzisothiazolyl, benzothienyl, pyrimidinyl, pyridyl, 1,2-methylenedioxyphenyl, or phenyl, and Z, CH(OH)phenyl or O-phenyl are optionally substituted with one or two moieties independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, trifluoromethyl, S(O).sub.2NH.sub.2, or cyano, and m is 0 or 1; provided that when R.sub.1 is OH, R.sub.2 is H: (1) R.sub.4 is H, and R.sub.3 is (CH.sub.2).sub.nQ, where n is 1 or 2, then Q cannot be indolyl or phenyl; or (2) R.sub.3 and R.sub.4 form piperazinyl substituted with (CH.sub.2).sub.mZ, when m is 1, then Z cannot be phenyl.

Another aspect of the invention is to provide a pharmaceutical composition comprising a compound of formula I in an amount effective to antagonize D.sub.4 receptor stimulation and a pharmaceutically acceptable carrier.

In yet another of its aspects, the invention provides the use of compounds of Formula I as D.sub.4 receptor antagonists for the treatment of medical conditions mediated by inhibition of D.sub.4 receptor. These conditions comprise, for example, Attention Deficit Hyperactivity Disorder, Obsessive-Compulsive Disorder, Psychoses, Substance Abuse, Substance Dependence, Parkinson's Disease, Parkinsonism, Tardive Diskinesia, Gilles de la Tourette Syndrome, Conduct Disorder, and Oppositional Defiant Disorder.

A further aspect of the invention is to provide intermediates and a method of making compounds of the formula II:

##STR00002## a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N(CH.sub.3) or O; R.sub.1 is OH or C.sub.1-6 alkoxy; R.sub.2 is H or C.sub.1-6 alkyl; R.sub.3 is (CH.sub.2).sub.n Q, CH.sub.2CH(OH)Q, CH(CH.sub.3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein Q is thienyl, phenyl, furanyl, naphthyl, pyridyl, indolyl, indazolyl, cyclohexyl, 1,2-methylenedioxyphenyl, cyclohexenyl, 1H-pyrazolo[4,3-c]pyridyl; and Q is optionally substituted with one or two moieties independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, S(O).sub.2NH.sub.2, trifluoromethyl, or cyano, and n is 1 or 2; R.sub.4 is H or C.sub.1-6 alkyl; or R.sub.3 and R.sub.4, together with the nitrogen atom to which R.sub.3 and R.sub.4 are attached, form 1,4-dioxa-8-azo-spiro[4.5]decanyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azocanyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-.beta.-carbolinyl, 4,5,6,7-tetrahydrothienyl[3,2-c]pyridyl, or 8-aza-bicyclo[3.2.1.]octane, each of which may be mono- or independently di-substituted with halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C(O)phenyl, OH, CN, O-phenyl or (CH.sub.2).sub.mZ, Z is benzisoxazolyl, indazolyl, benzisothiazolyl, benzothienyl, pyrimidinyl, pyridyl, 1,2-methylenedioxyphenyl, or phenyl, and Z, CH(OH)phenyl or O-phenyl are optionally substituted with one or two moieties independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, trifluoromethyl, S(O).sub.2NH.sub.2, or cyano, and m is 0 or 1.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Terms used herein have the following meanings:

a) "Pharmaceutically acceptable salts" means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients for the intended use.

"Pharmaceutically acceptable acid addition salt" is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methanesulfonic acid, naphthalene sulfonic acid, and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated. solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents. Furthermore, in comparison to their free base forms, the acid addition salts generally demonstrate higher melting points.

"Pharmaceutically acceptable basic addition salts" means non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of its intermediates. Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline. The selection criteria for the appropriate salt will be known to one skilled in the art.

b) "Stereoisomers" is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). c) "Alkyl" as used herein means a branched or straight chain alkyl (monovalent) or alkylene (divalent) hydrocarbon radical, as is appropriate to the formula, specified by the amount of carbons in the alkyl, e.g., C.sub.1-6 alkyl means a one, two, three, four, five or six carbon branched or straight chain alkyl or alkylene, as the case may be, or any ranges thereof, for example, but not limited to C.sub.1-2, C.sub.1-3, C.sub.1-4, C.sub.1-5, C.sub.2-3, C.sub.2-4, C.sub.2-5, C.sub.2-6, C.sub.3-4, C.sub.3-5, C.sub.3-6, C.sub.4-5, C.sub.4-6, C.sub.5-6, etc. d) "Patient" means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans. e) "Treat" or "treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition. f) "Therapeutically effective amount" means a quantity of the compound which is effective in treating the named disorder or condition. g) "Pharmaceutically acceptable carrier" is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration. h) "Psychoses" means conditions wherein the patient experiences a major mental disorder of organic and/or emotional origin characterized by derangement of the personality and loss of contact with reality, often with delusions, hallucinations or illusions. Representative examples of psychotic illnesses include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder not otherwise specified, and substance-induced psychotic disorder. See Diagnostic and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Association, incorporated herein by reference. i) "Attention-Deficit/Hyperactivity Disorder" or "ADHD" means a condition wherein the patient exhibits a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. It includes ADHD Combined Type, ADHD Predominantly Inattentive Type, and ADHD Predominantly hyperactive-impulsive Type. j) "Conduct Disorder" means a disorder wherein the patient exhibits a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated. These behaviors fall into four main groupings: aggressive conduct that causes or threatens physical harm to other people or animals, nonaggressive conduct that causes property loss or damage, deceitfulness or theft, and serious violations of rules. k) "Oppositional Defiant Disorder" means a disorder wherein the patient exhibits some of the patterns of behavior observed in Conduct Disorder (e.g., disobedience and opposition to authority figures), however it does not include the persistent pattern of the more serious forms of behavior in which either the basic rights of others or age-appropriate societal norms or rules are violated. l) "Obsessive-Compulsive Disorder" or "OCD" means a condition wherein the patient exhibits recurrent obsessions or compulsions that are severe enough to be time consuming (i.e., take more than an hour a day) or cause marked distress or significant impairment. Obsessions are persistent ideas, thoughts, impulses, or images that are experienced as intrusive and inappropriate and that cause marked anxiety or distress. Compulsions are repetitive behaviors (e.g, hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) the goal of which is to prevent or reduce anxiety or distress, not to provide pleasure or gratification. m) "Substance Dependence" means a condition wherein the patient exhibits a maladaptive pattern of substance use, leading to clinically significant impairment or distress. There is a pattern of repeated self-administration that usually results in tolerance, withdrawal, and compulsive drug-taking. n) "Substance Abuse" means a condition wherein the patient exhibits a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to the repeated use of substances. There may be repeated failure to fulfill major role obligations, repeated use in situations in which it is physically hazardous, multiple legal problems, and recurrent social and interpersonal problems. Unlike the criteria for Substance Dependence, the criteria for Substance Abuse do not include tolerance, withdrawal, or a pattern of compulsive use and instead only include the harmful consequences of repeated use. o) "Parkinson's Disease" means a slowly progressive neurological condition, characterized by tremor, rigidity, bradykinesia, and postural instability. Other manifestations include depression and dementia. p) "Parkinsonism" means a condition where the patient exhibits parkinsonian signs or symptoms (i.e. tremor, muscular rigidity, or akinesia) that develop in association with the use of neuroleptic medication. q) "Neuroleptic-Induced Tardive Dyskinesia" means a disorder characterized by involuntary movements of the tongue, jaw, trunk, or extremities which have developed in association with the use of neuroleptic medication. The involuntary movements may be choreiform, athetoid or rhythmic. r) "Gilles de la Tourette Syndrome" means a condition manifested by motor and vocal tics. (A tic is a sudden, rapid, recurrent, non-rhythmic, stereotyped motor movement or vocalization.) The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning. The onset is before age eighteen years and the disturbance is not due to the physiological effects of a substance or general medical condition. s) Unless otherwise specified, "halo" or "halogen" means Cl, Br, F and I. t) "Aryl sulfonyl" means the radical:

##STR00003## wherein Ar is phenyl optionally substituted one or more moieties from the group consisting of halogen, nitro, or C.sub.1 C.sub.6alkyl. "Brosyl" means the radical wherein Ar is p-bromobenzene. "Nosyl" means the radical wherein Ar is p-nitrobenzene. "Tosyl" means the radical wherein Ar is p-toluene. "Alkyl sulfonyl" means the radical:

##STR00004## wherein R is C.sub.1 C.sub.6alkyl. "Mesyl" means the radical wherein R is CH.sub.3. u) "Sulfonic ester" means the radical:

##STR00005## wherein R is C.sub.1 C.sub.6alkyl or phenyl optionally substituted with one or more moieties from the group consisting of halogen, nitro, or C.sub.1 C.sub.6alkyl. "Sulfonic esters" are, for example, brosylate, nosylate, tosylate, and mesylate. v) "Parallel Synthesis" is a term used to describe the simultaneous synthesis of tens to millions of compounds in solution or on a solid phase. The key characteristic that distinguishes this approach from serial techniques is that it does not utilize mixtures.

As used herein, the terms used to describe specific chemical moieties are defined by the corresponding chemical drawings which are set forth on the following page:

##STR00006##

Specific embodiments of the invention are those compounds of Formula I set forth in Table 1.

A preferred embodiment of the invention is the compound according to Formula I wherein R.sub.3 is (CH.sub.2).sub.nQ, CH.sub.2CH(OH)Q, CH(CH.sub.3)Q, indanyl, adamantyl, or 1,2,3,4-tetrahydronaphthyl, wherein Q is thienyl, pyridyl, phenyl, furanyl, naphthyl, cyclohexyl, or benzimidazolyl; or wherein R.sub.3 and R.sub.4, together with the nitrogen atom to which R.sub.3 and R.sub.4 are attached, form piperidinyl, piperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-.beta.-carbolinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, and 8-aza-bicyclo[3.2.1.]octane.

A more preferred embodiment of the invention is a compound according to Formula I wherein R.sub.1 is OH; R.sub.2 is H; R.sub.3 is (CH.sub.2).sub.nQ, wherein n is 1 and Q is thienyl or pyridyl; or R.sub.3 and R.sub.4, together with the nitrogen atom to which R.sub.3 and R.sub.4 are attached, form piperidinyl.

Most preferred embodiments of the invention are those compounds of Formula I set forth in Table 1 that exhibit enhanced D.sub.4 potency.

Acid addition salts of the compound of Formula I and II are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids, e.g. hydrochloric, sulphuric, or phosphoric acids, and organic acids, e.g. succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts, e.g. oxalates, may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are solvates and hydrates of the invention.

The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, in which an aqueous solution of the given salt is treated with a solution of base, e.g. sodium carbonate or potassium hydroxide, to liberate the free base which is then extracted into an appropriate solvent, such as ether. The free base is then separated from the aqueous portion, dried, and treated with the requisite acid to give the desired salt.

The compounds of the present invention can be prepared by processes analogous to those known in the art. Schemes I, II, and III illustrate methods for the synthesis of compounds of Formula I.

##STR00007##

##STR00008##

##STR00009##

In Scheme I, step A, diarylketone (5) is prepared by reacting an appropriate alkoxy-substituted benzoyl halide (4) with the anion of a 3-halothiophene (3) using techniques and procedures well known to one or ordinary skill in the art.

For example, a solution of phenyllithium in cyclohexane-ether can be reacted with the halothiophene of structure 2 such as 3-bromothiophene, at 5.degree. C., to form a lithiated intermediate (3). The lithiated intermediate may then be added dropwise over a period of time of about 3 hours to a solution of an alkoxy-substituted benzoyl halide of structure (4) such as 3-methoxybenzoyl chloride and a suitable aprotic anhydrous solvent such as tetrahydrofuran at about -70.degree. C. The resulting ketone of structure (5) may be recovered from the reaction mixture by extractive methods as is well known in the art. Purification of the ketone of structure (5) may be done by alumina column chromatography eluting with a suitable solvent, such as hexane, or a mixture of solvents, such as a mixture of ether and hexane. Further purification may be done by vacuum distillation and/or recrystallization.

In step E, an appropriately substituted diarylketone (5) may be also prepared by treating a solution of a 3-halothiophene (2) such as 3-bromothiophene in a suitable solvent such as dichloromethane with a solution of titanium tetrachloride in a suitable solvent such as dichloromethane at about 5.degree. C. A solution of an appropriately substituted alkoxybenzoyl halide (4) such as 4-methoxybenzoylchloride in a suitable solvent such a dichloromethane is added at such a rate as to maintain the temperature at about or below 5.degree. C. The reaction is quenched with an aqueous acid such as hydrochloric acid and the diarylketone (5) may be recovered by extractive methods and purified by methods well known in the art.

In step B, the oxime derivative (7) (X.dbd.O) of diarylketone (5) is prepared by reacting diarylketone (5) and hydroxylamine hydrochloride (6) (X is O).

For example, a diarylketone (5) such as (3-bromothiophen-2-yl)-(3-methoxyphenyl)methanone and hydroxylamine hydrochloride can be reacted in a suitable solvent aprotic solvent, such as pyridine. The reactants are typically stirred together at room temperature for a period of time, typically overnight, followed by heating at a temperature of from about 100.degree. C. to about 105.degree. C. for about 4 hours. The resulting oxime of structure (7) may be recovered from the reaction mixture by extractive methods as is known in the art. The crude oxime of structure (7) may then be purified by recrystallization.

In step C, the oxime of structure (7) (X.dbd.O) is cyclized with the appropriate reagents to give the corresponding thieno[2,3-d]isoxazole of structure (8) (X.dbd.O).

For example, an oxime of structure (7) such as (3-bromothiophen-2-yl)-(3-methoxyphenyl)methanone oxime can be treated with a suitable base, such as potassium hydroxide in a protic solvent, such as 2-methoxyethanol. The reactants are typically stirred and heated together at a temperature of from about 105.degree. C. to about 110.degree. C., under a nitrogen atmosphere, for a period of time of ab