WO1996016040A1

WO1996016040A1 - Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives; new classes of dopamine receptor subtype specific ligands

Info

Publication number: WO1996016040A1
Application number: PCT/US1995/015262
Authority: WO
Inventors: Andrew Thurkauf; Raymond F. Horvath; Jun Yuan; John M. Peterson
Original assignee: Neurogen Corporation
Priority date: 1994-11-23
Filing date: 1995-11-22
Publication date: 1996-05-30
Also published as: CN1088062C; EP0793653A1; JP2941950B2; CA2205998A1; CA2205998C; CN1177349A; MX9703736A; AU4368996A; JPH10502670A; BR9509760A

Abstract

Disclosed are compounds of formula (III), wherein R1 represents optionally substituted aryl, heteroaryl, arylalkyl, or cycloalkyl groups; X, Z, and Y are optionally substituted nitrogen or carbon atoms; R3 and R4 are organic or inorganic substituents which may together form ring structures; m is zero, one or two; and R5 and R6 are organic or inorganic substituents; and the pharmaceutically acceptable addition salts thereof, which compounds are highly selective partial agonists or antagonists at brain dopamine receptor subtypes or prodrugs thereof and are useful in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism.

Description

Certain 4-Aminon-et--yl-2-Substituted Imidazole Derivatives and

2-Aminomethyl-4-Substituted Imidazole Derivatives; New Classes of

Dopamine Receptor Subtype Specific Ligands

BACKGROUND OF THE INVENTION

This application is a continuation-in-part of U.S. Patent Applications S.N.08 344,154 filed November 23, 1994; S.N. 08/401,201, filed March 9, 1995 and S.N. 08/344,552 filed November 23, 1994, each of which is a continuation-in-part of U.S. Patent Application S.N. 08/313,435, filed September 27, 1994, which is a continuation in part of U.S. Patent Application S.N. 08/081,317, filed November 8, 1993, which is a continuation-in-part of U.S. Patent Application S.N. 07/635,256, filed December 28, 1990, now U.S. Patent No. 5,159,083.

Field of the Invention This invention relates to certain 4-aminomethyl-2-substituted imidazole and 2- aminomethyl-4-substituted imidazole derivatives which selectively bind to brain dopamine receptor subtypes. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism, as well as in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.

Description of the Relate, Art

Schizophrenia or psychosis is a term used to describe a group of illnesses of unknown origin which affect approximately 2.5 million people in the United States. These disorders of the brain are characterized by a variety of symptoms which are classified as positive symptoms (disordered thought, hallucinations and delusions) and negative symptoms (social withdrawal and unresponsiveness). These disorders have an age of onset in adolescence or early adulthood and persist for many years. The disorders tend to become more severe during the patient's lifetime and can result in prolonged institutionalization. In the United States today, approximately 40% of all hospitalized psychiatric patents suffer from schizophrenia.

During the 1950's physicians demonstrated that they could sucessfully treat psychotic patients with medications called neuroleptics; this classification of antipsychotic medication was based largely on the activating (neuroleptic) properties of the nervous system by these drugs. Subsequently, neuroleptic agents were shown to increase the concentrations of dopamine metabolites in the brain suggesting altered neuronal firing of the dopamine system. Additional evidence indicated that dopamine could increase the activity of adenylate cyclase in the corpus striatum, an effect reversed by neuroleptic agents. Thus, cumulative evidence from these and later experiments strongly suggested that the neurotransmitter dopamine was involved in schizophrenia.

One of the major actions of antipsychotic medication is the blockade of dopamine receptors in brain. Several dopamine systems appear to exist in the brain and at least five classes of dopamine receptors appear to mediate the actions of this transmitter. These dopamine receptors differ in their pharmacological specificity and were originally classified upon these differences in the pharmacology of different chemical series. Butyrophenones, containing many potent antipsychotic drugs were quite weak at the dopamine receptor that activated adenylate cyclase (now known as a DI dopamine receptor). In contrast, they labelled other dopamine receptors (called D2 receptors) in the subnanomolar range and a third type D3 in the nanomolar range. Two additional receptor subtypes have also been identified. D5 which is somewhat similar to DI receptor type and D4 which is closely related to D3 and D2 receptor types. Phenothiazines possess nanomolar affinity for all three types of dopamine receptors. Other drugs have been developed with great specificity for the DI subtype receptor and for the D2 subtype receptor. A certain group of drugs (such as sulpiride and clozapine) have been developed with a lesser incidence of extrapyramidal side effects than classical neuroleptics. In addition, there is some indication that they may be more beneficial in treating negative symptoms in some patients. Drugs of this class are often referred to as atypical antipsychotic agents. Since all D2 Mockers do not possess a similar profile, hypotheses underlying the differences have been investigated. The major differences have been in the anticholinergic actions of the neuroleptics as well as the possibility that the dopamine receptors may differ in motor areas from those in the limbic areas thought to mediate the antipsychotic responses. The existence of the D3, D4 and D5 and other as yet undiscovered dopamine receptors may contribute to this profile. Some of the atypical compounds possess similar activity at D2, D3 and D4 receptors. The examples of this patent fall into this general class of molecules.

Using molecular biological techniques it has been possible to clone cDNAs coding for each of the pharmacologically defined receptors. There are at least two forms of Dl-type receptors which have been classiifed as DI and D5, and two forms of D2-type receptors, classified now as D2 and D4 dopamine receptors. In addition, there is at least one form of D3 dopamine receptor. Examples from the substituted aminomethylimidazole series of this patent possess differential affinities for each receptor subtype.

Schizophrenia is characterized by a variety of cognitive dysfunctions; schizophrenic patients perform less well than other groups on most cognitive or attentional tasks. The positive and negative symptom dimensions of schizophrenia are also associated with distinct cognitive deficits. In general, positive symptoms (disordered thought processes, hallucinations and decisions) are related to auditory processing imairments including deficits in verbal memory and language comprehenion. Negative symptoms (social withdrawal and unresponsiveness) are related more to visual/motor dysfunctions including poorer performance on visual memory, motor speed and dexterity tasks.

These disorders have an age of onset in adolescence or early adulthood and persist for many years. The interaction of frontal and septo-hippocampal brain systems, and failures of information processing and self monitoring have been theorized as the basis of positive symptoms. Negative symptoms are thought to arise from abnormalities in the interactions of frontal and striatal systems. Since cognitive disturbances are present in most of the patients diagnosed as having schizophrenia, it has been theorized that to understand die pathogenesis and etiology of schizophrenia one must understand the basic dysfunction of the cognitive disorder. The cognitive disturbances found in schizophrenia include, but are not limited to, various verbal and visual memory deficits. There are various neurocognitive tasks for both animals and humans that have been developed to assess memory deficits, as well as memory enhancements, of various treatments. Many of the neurocognitive behavioral tasks are modulated or mediated by eural activity within the hippocampal brain system noted above. Drug substances that interact with the hippocampus are capable of modulating memory in animals. Certain memory paradigms employed in animals have construct and predictive validity for memory assessment in humans. In animals (rodents), paradigms such as the Step-Down Passive Avoidance Task assay or the Spatial Water Maze Task assay reliably detect deficits produced by certain drugs in humans. For example, commonly prescribed benzodiazepine anxiolytics and sedative hypnotics are known to produce memory impairment in humans, including varying degrees of anterograde amnesia (depending on the exact drug). In the step- down passive avoidance paradigm, these very same drugs disrupt the memory of animals given the compounds during the information acquisition or processing period. Likewise, benzodiazepines disrupt information processing and memories in the spatial water maze task in rodents. Thus, these animal models can be used to predict the memory impairing effects of certain compounds in humans. Conversely, these same animal models can predict th memory improving or enhancing effects of compounds in humans. Although fewer in number, drugs that improve memory in humans (e.g., Nootroprice, Beta carbolines) produce memory enhancing effects in rats in these models. Therefore, the spatial water maze and step-down passive avoidance paradigms in rodents are useful in predicting memory impairing and memory enhancing effects of test compounds in humans. SIJMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes.

The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism.

Furthermore compounds of this invention are useful in treating the extrapyramidal side effects asssociated with the use of conventional neuroleptic agents.

Since dopamine D3 and D4 receptor subtypes are particularly concentrated in the limbic system (Taubes, Science (1994) 265 1034) which controls cognition and emotion, compounds which interract with these receptors may have utility in the treatment of cognitive disorders. Such disorders may be me cognitive deficits which are a significant component of the negative symptoms (social withdrawal, and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorders can also be treated with some of the compounds of this invention that interact specifically with dopamine D3 and or D4 receptor subtypes.

Accordingly, the invention is directed to a compound of Formula I:

I where

Rl is aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl, each of which is optionally substituted by up to 3 substituents which may be the same or different and represent hydrogen, halogen, trifiuoromethyl, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2 9 where Ro is NH2, NHCH3, or a straight or branched chain lower alkyl having 1-

6 carbon atoms; X is or NR2 where R2 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; Y is N or CR3; Z is CR3 or N; provided that Y and Z are not both CR3; and provided that Y and Z are not both N; R3 is hydrogen, lower alkyl, halogen, hydroxy lower alkyl or phenyl optionally substituted by up to three substituents which may be the same or different and represent hydrogen, halogen, trifiuoromethyl, cyano, sulfonamido, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms;

R4 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or, when Z is CR3, R3 and R4 together may represent -(CH2)ni" where ni is 2, 3 or 4; or R2 and R4 together may represent -(CH2)n2* where n2 is 2, 3 or 4. m is zero, one or two ; R5 and R are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, aryl; or R4 and R5 together may represent -(CH2)n3- where n3 is 2 or 3; or

NR5R6 together represent 2-(l,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR5R6 represents:

where R7 is phenyl, benzyl or phenethyl where the phenyl ring of each is optionally or substituted with up to three substituents which are the same or different and represent hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

NR5R6 represents:

where p is 1, 2, or 3;

W is N or CH; and

W is N and R8 is hydrogen, trifiuoromethyl, phenyl, pyridyl or pyrimidinyl, each of which is optionally or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or W is CH and R8 is optionally substituted phenyl or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

These compounds are highly selective partial agonists or antagonists at brain dopamine receptor subtypes or prodrugs thereof and are useful in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism. Furthermore, compounds of this invention are useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. Furthermore, compounds of this invention have utility in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal, and unresponsiveness) of schizophrenia or other disorders involving memory impairment or attention deficit disorders.

The compounds of the invention, such as, for example, 2-Phenyl-4(5)-[(4-(2- pyrimidinyl)-piperazin-l-yl)-methyl] -imidazole dihydrochloride (compound 23), 2-Pheny 1-4(5)- [(4-(2-pyridyl)-piperazin-l-yl)-methyl]-imidazole dihydrochloride (Compound 24), and 2- Phenyl-4(5)-[(4-phenyl-piperazin-l-yl)-methyl] -imidazole dihydrochloride (Compound 45), are antagonists binding to dopamine D4 receptors in both the rat and human hippocampus.

As noted above, the hippocampus is associated with both schizophrenia, and general memory processes in humans. In rodents, Compound 23 produces memory enhancing effects in both the step-down passive avoidance assay as well as in the spatial water maze assay. Without being bound by a particular theory, it is believed that the D4 receptors located in the hippocampus mediate the memory enhancing effects of the compounds of the invention. Therefore, since (1) Compound 23 is active in animal models that are predictive of cognition enhancement, and specifically enhancement of memory and learning, and (2) Compound 23 binds to D4 receptors in the hippocampus, the D4 class of dopamine antagonists, including the compounds of the invention, are useful for enhancing memory in humans. Thus, the invention further provides methods for enhancing cognition, and specifically learning and memory, in mammals. These methods comprise administering to a mammal such as a human a compound of die invention in an amount effective to enhance cognition . DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of general formula I described above, the present invention further encompasses compounds of Formula II:

π where

Rl, X, Y, Z, and m are as defined above for Formula I;

R3 is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms;

R4 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or, where Z is CR3, R3 and R4 together may represent -(CH2)n_j- where ni is 2, 3 or 4; or R2 and

R4 together may represent -(CH2)n2* where n2 is 2, 3 or 4;

R2 and R5 togedier may represent -(CH2)n3- where n3 is 2 or 3;

R6 is hydrogen, straight or branched chain lower alkyl, phenyl or arylalkyl; or NR5R6 represents:

where R7 is as defined for Formula I;

NR5R6 represents:

where p, and is 1, 2, or 3;

W is N and Rδ is phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W is CH and R8 is optionally substituted phenyl or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms. Preferred compounds according to Formula I include those where Z is CR3 and R3 and R4 together form a 5 or 6-membered ring; Ri is substituted or unsubstituted phenyl; X is N; Y is N; and R5 and R6 represents:

where p is 2; and

W is N and R8 is phenyl, pyridyl or pyrimidinyl, each of which is optionally mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W is CH and R8 is optionally substituted phenyl or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

Preferred compounds according to Formula II are those where Ri is phenyl optionally substituted in the 4-position with halogen or alkyl, Y and X are nitrogen, Z is CH, R4 is hydrogen, m is 0, and NR5R6 represents 4-substituted piperazin- 1-yl or 4-substituted piperidin- 1-yl. The piperazinyl or piperidinyl groups are substituted in the 4-position with pyridyl or pyrimidinyl, or phenyl or benzyl each of which is optionally substituted, preferably in the 4- position, with halogen, alkyl, or alkoxy. The preferred piperidinyl groups are optionally substituted in the 3-position with alkyl, and more preferably, methyl, groups. Particularly preferred Ri groups are 4-methylphenyl and 4-halophenyl groups.

The present invention also encompasses compounds of Formula IIA:

ΠA where Ri is aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl; unsubstituted or substituted by up to 3 substituents which may be the same or different and represent hydrogen, halogen, trifluoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2 9 where R9 is NH2 or NHCH3; R2 is hydrogen or alkyl; R3 is hydrogen, lower alkyl, halogen, hydroxy lower alkyl, or phenyl unsubstituted or substituted by up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, cyano, sulfonamido, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; R4 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or R3 and R4 together may represent -(CH2)n_j- where ni is 2, 3 or 4; or R2 and R4 together may represent -(CH2)n2^_ where n2 is 2, 3 or 4; m is zero, one or two;-

R5 and R6 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl, straight or branched chain lower alkyl having 1-6 carbon atoms; or R4 and R5 togetiier may represent -(CH2)n3- where n3 is 2 or 3; or

NR5R6 together represent 2-(l,2,3,4-tetrahydroisoquinolinyl), eidier unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

NR5R6 represents:

where R7 is phenyl, benzyl or phenethyl with d e phenyl ring unsubstituted or substituted with up to three substituents which may be the same or different and represent hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR5R6 represents:

where p is 1, 2, or 3; and W is N and R8 is hydrogen, phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W is CH and R8 is optionally substituted phenyl, optionally substituted benzoyl, or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

Preferred compounds of Formula HA are those where Ri is optionally substituted phenyl; R2 and R4 are hydrogen; and R5 is alkyl and R6 is arylalkyl, preferably optionally substituted, and more preferably unsubstituted, benzyl; or NR5R6 is:

where p, W, and R8 are as defined above for Formula I.

Particularly preferred compounds of Formula IIA are those where Ri is optionally substituted phenyl; R2 and R4 are hydrogen; R5 is alkyl and R6 is arylalkyl, preferably optionally substituted, and more preferably unsubstituted, benzyl; or NR5R6 is:

where p, is 2;

W is N and R8 is phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

Particularly preferred compounds of Formula IIA are those where Rl is optionally substituted phenyl; R2 and R4 are hydrogen; R3 is hydrogen; R5 is alkyl and R6 is arylalkyl, preferably optionally substituted, and more preferably unsubstituted, benzyl; or NR5R6 is:

where p, is 2; W is N and R8 is phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, or straight or branched chain lower alkoxy having 1-6 carbon atoms. Other particularly preferred compounds of Formula HA are those where Ri is phenyl; R2 and R4 are hydrogen; R3 is hydrogen; and NR5R6 is:

where p is 2; and

W is CH and Rs is optionally halogenated or alkoxylated phenyl or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring is optionally substituted with up to three substituents independently selected from hydrogen, halogen, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

The present invention also encompasses compounds of Formula ni:

m where

Rl is aryl, heteroaryl, or naphthyl each of which is optionally substituted by up to three substituents which are the same or different and represent hydrogen, halogen, trifiuoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2R9 where R9 is NH2 or NHCH3;

X, Y, Z, and m, are as defined above for Formula I;

R3 is hydrogen, halogen, or straight or branched chain lower alkyl having 1-6 carbon atoms; R4 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or, when Z is CR3, R3 and R4 together may represent -(CH2)n_]- where ni is 2, 3 or 4;

NR5R6 represents:

where R7 is as defined above for Formula I; or NR5R6 represents:

where p, and is 1, 2, or 3;

W is N and Rs is phenyl, pyridyl or pyrimidinyl, each of which is mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W is CH and Rs is optionally substituted phenyl or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1 -6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

In addition, die present invention encompasses compounds of Formula IV:

IV where Ri is phenyl or naphthyl, each of which may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2R9 where R9 is NH2 or NHCH3; X, Y, Z, are as defined above for Formula I;

R4 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; m is zero; NR5R6 represents:

where R7 is as defined above for Formula I; or NR5R6 represents:

where p, and is 1, 2, or 3;

W is N and Rg is phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W is CH and R8 is optionally substituted phenyl or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring may be substituted with up to tiiree substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

The invention further encompasses compounds of Formula V:

V and the pharmaceutically acceptable non-toxic salts thereof wherein

Rl and T are the same or different and represent hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; M is

where R2 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or Ri and R2 together may represent -(CH2)m where ni is 1, 2, or 3; X and Z are the same or different and represent hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms or SO2 6 where R6 is straight or branched chain lower alkyl having 1-6 carbon atoms; Y is hydrogen, halogen, amino, or straight or branched chain lower alkyl having 1-6 carbon atoms; R3 is hydrogen or.straight or branched chain lower alkyl having 1-6 carbon atoms, or R3 and R4 together may represent -(CH2)n₂ ^_ where n2 is 3 or 4; and R4 and R5 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain alkyl having 1-6 carbon atoms; or R2 and R5 together may represent -(CH2)n₃- where n₃ is 2 or 3; or

NR4R5 represents 2-(l,2,3,4-tetrahydroisoquinolinyl), or 2-(l,2,3,4-tetrahydroiso- quinolinyl) mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

F>7 where W is N or CH; and

R7 is hydrogen, phenyl, pyridyl or pyrimidinyl, or phenyl, pyridyl or pyrimidinyl, each of which is mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or W-R7 is oxygen or sulfur; and n is 1, 2, or 3.

The present invention further encompasses compounds of Formula VI:

VI wherein Rl is hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; M is

where R2 is hydrogen or,straight or branched chain lower alkyl having 1-6 carbon atoms, or Ri and R2 together may represent -(CH2)nι where ni is 1, 2, or 3;

X is hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms or SO2R6 where R6 is straight or branched chain lower alkyl having 1-6 carbon atoms; R3 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or R3 and R4 together may represent -(CH2)n₂" where n2 is 3 or 4; and R4 and R5 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or R2 and R5 togedier may represent -(CH2)n₃- where n3 is 2 or 3; or

NR4R5 represents 2-(l,2,3,4-tetrahydroisoquinolinyl) or 2-(l,2,3,4-tetrahydroiso- quinolinyl) mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

where W is N or CH; R7 is hydrogen, phenyl, pyridyl or pyrimidinyl, or phenyl, pyridyl or pyrimidinyl, each of which may be mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or W-R7 is oxygen or sulfur, and n is 1, 2, or 3.

The present invention also encompases compounds of Formula VH:

wherein

Rl is hydrogen, halogen.hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; M is

where R2 is hydrogen, or straight or branched chain lower alkyl having 1-6 carbon atoms, or Ri and R2 together may represent -(CH2)m where ni is 1, 2, or 3;

R3 is hydrogen, or straight or branched chain lower alkyl having 1-6 carbon atoms, or

R3 and R4 together may represent -(CH2)n₂" where n2 is 3 or 4; or R4 and R5 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl straight or branched chain lower alkyl having 1-6 carbon atoms or R2 and R5 together may represent -(CH2)n3* where n3 is 2 or 3; or NR4R5 represents 2-(l,2,3,4-tetrahydroisoquinolinyl), or 2-(l,2,3,4-tetrahydroiso- quinolinyl) mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or r ^(CH2^

— N ;

where

W is N or CH;

R7 is hydrogen, phenyl, pyridyl or pyrimidinyl; or phenyl, pyridyl or pyrimidinyl mono or disubstituted witii halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W-R7 is oxygen or sulfur, and n is 1 , 2, or 3.

In addition, the present invention encompasses compounds of Formula V-Η:

wherein M is

where R2 is hydrogen or,straight or branched chain lower alkyl having 1-6 carbon atoms, or Ri and R2 together may represent -(CH2)m where ni is 1, 2, or 3;

X is hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having

1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2 6 where R6 is straight or branched chain lower alkyl having 1-6 carbon atoms; R3 is hydrogen, or straight or branched chain lower alkyl having 1-6 carbon atoms, or

R3 and R4 together may represent -(CH2)n₂ ^_ where n2 is 3 or 4; and R4 and R5 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenylalkyl or pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or

R2 and R5 together may represent -(CH2)n₃" where n3 is 2 or 3; or NR4R5 represents 2-(l,2,3,4-tetrahydroisoquinolinyl), or 2-(l,2,3,4-tetrahydroiso- quinolinyl) mono or disubstituted witii halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

R. where W is N or CH; R7 is hydrogen, phenyl, pyridyl or pyrimidinyl, or hydrogen, phenyl, pyridyl or pyrimidinyl, mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or W-R7 is oxygen or sulfur, and n is 1, 2, or 3.

The invention also provides compounds of Formula IX:

IX where X represents hydrogen or halogen;

Ra and Rb are the same or different and represent hydrogen or alkoxy; and

NR4R5 represents 4-phenylpiperazin-l-yl or 4-phenyl-piperidin-l-yl, where each phenyl group may be substituted with hydrogen, halogen, alkyl, or alkoxy.

The invention also provides compounds of Formula X:

X where

X represents hydrogen or halogen; R represents hydrogen or alkyl;

Ra and Rb are the same or different and represent hydrogen or alkoxy; and

A and B are die same or different and independently represent hydrogen or (4-(2-optionally substituted pyrimidinyl)piperazin- 1 -yl)methyl.

Preferred compounds of Formula X are tiiose where R is hydrogen or methyl and X, Ra and Rb are hydrogen. Particularly preferred compounds of Formula X are those where R is hydrogen or methyl, X, R_a and Rb are hydrogen, and A and B are different and represent hydrogen or (4-(2-pyrimidinyl)piperazin-l-yl)methyl where the pyrimidinyl group is optionally substituted widi hydrogen, hydroxy or alkoxy. A preferred alkoxy group is methoxy.

Also widiin die scope of the invention are compounds of Formula XI:

XI where

X represents a hydrogen or halogen; R represents hydrogen or alkyl; R_a and Rb are the same or different and represent hydrogen, halogen, or alkoxy; and Re is a group of the formula:

where

W is N or CH; R represnts alkyl; R_d represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionally substituted with halogen, alkyl or alkoxy; and Re is alkyl.

Preferred compounds of Formula XI are those where X, R_a, Rb. and R_e are hydrogen and Rς is a 4-substituted piperazin- 1-yl or piperidin-1-yl group. Particularly preferred compounds of Formula XI are those where the 4-substituted piperazin- 1-yl or piperidin-1-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2- pyrimidinyl groups. Otiier preferred compounds of formula XI are those where X, Ra. Rb. and Re are hydrogen, Re is methyl and Re is piperazin- 1-yl or piperidin-1-yl each of which is substituted in the 4-position with benzyl, pyridyl or pyrimidinyl. The invention also provides compounds of Formula XII:

R d

XII where

W is N or CH; Rf is halogen or alkyl;

R is pyridyl, pyrimidinyl, phenylalkyl, or phenyl each of which is optionally substituted with halogen, alkyl or alkoxy. Preferred compounds of Formula XII are tiiose where Rf is halogen or methyl, W is nitrogen, and Rd is pyridyl, pyrimidinyl, or benzyl. Particularly preferred compounds of Formula XII are those where Rf is halogen or methyl, W is nitrogen, and Rd is pyrimidinyl. The invention further provides compounds of Formula XIII:

XIII where

W is N or CH;

Ra and Rb independendy represent hydrogen, halogen, or alkoxy; Rf is alkyl; and

Rd is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionally substituted with halogen, alkyl or alkoxy.

Preferred compounds of Formula XIII are those where Rf is methyl, W is nitrogen, and R is pyridyl, pyrimidinyl, or benzyl. Particularly preferred compounds of Formula XIII are those where Rf is methyl, W is nitrogen, and R is pyrimidinyl optionally substituted with halogen, hydroxy, or alkoxy; and at least one of R_a and R are halogen. The invention further provides compounds of Formula XIV:

XIV where

Ar is 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-thienyl, or 2-quinolinyl,

W is N or CH;

Rd is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionally substituted with halogen, alkyl or alkoxy. Preferred compounds of Formula XIV are those where W is CH, and Rd is pyridyl, pyrimidinyl, or benzyl.

The invention further provides compounds of Formula XV:

XV where Ar is 1- or 2-naphthyl, phenyl or phenyl mono-, di- or trisubstituted with alkyl, alkoxy or halogen, W is N or CH; Rd is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionally substituted witii halogen, alkyl or alkoxy.

Preferred compounds of Formula XV are those where Ar is phenyl, W is CH, and Rd is pyridyl, pyrimidinyl, or benzyl.

The invention further provides compounds of Formula XVI:

XVI where

X represents hydrogen or halogen;

Ra and Rb are the same or different and represent hydrogen, halogen or alkoxy; W is N or CH;

Rd is pyridyl, pyrimidinyl, phenylalkyl, or phenyl each of which is optionally substituted with halogen, hydroxy, alkyl or alkoxy.

Preferred compounds of Formula XVI are those where X, R_a and Rb are hydrogen, W is CH, and Rd is optionally substituted pyridyl, pyrimidinyl, or benzyl. The invention further provides compounds of Formula XVII :

xvπ where

X represents hydrogen or halogen; R_a and R are the same or different and represent hydrogen, halogen or alkoxy; W is N or CH; Rd is pyridyl, pyrimidinyl, phenylalkyl, or phenyl each of which is optionally substituted with halogen, hydroxy, alkyl or alkoxy.

Preferred compounds of Formula XVII are those where X, R_a and Rb are hydrogen, W is N, and Rd is pyridyl, pyrimidinyl, or benzyl each of which is optionally substituted with halogen, hydroxy, or alkoxy.

The invention further provides compounds of Formula XVIII:

xvm where m is 0, 1 or 2;

X represents hydrogen or halogen;

Ra and Rb are die same or different and represent hydrogen, halogen, or alkoxy;

W is N or CH; Rd is pyridyl, pyrimidinyl, phenylalkyl, or phenyl each of which is optionally substituted with halogen, hydroxy, alkyl or alkoxy.

Preferred compounds of Formula XVIII are those where X, R_a and Rb are hydrogen, W is N, and Rd is pyridyl, pyrimidinyl, or benzyl each of which is optionally substituted with halogen, hydroxy, or alkoxy. The invention further provides compounds of Formula XIX :

XIX where m is 0, 1 or 2; X represents hydrogen or halogen;

R_a and Rb are die same or different and represent hydrogen, halogen or alkoxy; W is N or CH;

Rd is pyridyl, pyrimidinyl, phenylalkyl, or phenyl each of which is optionally substituted with halogen, hydroxy, alkyl or alkoxy. Preferred compounds of Formula XIX are those where X, R_a and Rb are hydrogen, W is

N, and Rd is pyridyl, pyrimidinyl, or benzyl. Other preferred compounds of formula XIX are those where X, Ra and Rb are hydrogen, W is CH, and R is phenyl or pyrimidinyl optionally substituted with halogen and/or hydroxy.

The invention also provides compounds of Formula XX:

XX where

R_a is hydrogen or alkyl;

W is N or CH; Rd is pyridyl, pyrimidinyl, phenylalkyl, or phenyl each of which is optionally substituted with halogen, alkyl or alkoxy.

Prefened compounds of Formula XX are those where W is nitrogen, R_a is hydrogen or methyl, and R is pyridyl, pyrimidinyl, or benzyl each of which is optionally substituted with halogen, hydroxy, alkyl or alkoxy. Other preferred compounds according to Formula XX are those where W is CH, Ra is hydrogen or methyl, and Rd is substituted pyridyl, pyrimidinyl, or benzyl each of which is optionally substituted with halogen, hydroxy, or alkoxy. The invention also provides compounds of Formula XXI:

XXI where

W is N or CH;

Rg and Rh independenlty represent hydrogen, lower alkyl, or together represent an alkylene bridge forming a ring; and

Preferred compounds of Formula XXI are those where W is nitrogen, Rg and Rh are hydrogen, and R is optionally substituted pyridyl, pyrimidinyl, or benzyl. Other preferred compounds according to Formula XXI are those where W is CH, Rg and Rh are hydrogen, and Rd is optionally substituted pyridyl, pyrimidinyl, or benzyl.

The invention also provides compounds of formula XXII:

XXII wherein:

R_a represents hydrogen or lower alkyl;

Rl and Y independently represent hydrogen, lower alkyl or halogen, RlO represents hydrogen, hydroxy, lower alkoxy or halogen; and E represents CH or nitrogen. Pref erred compounds of formula XXII are those where E is nitrogen, Ri and Y are independently hydrogen or halogen, and Rio is halogen, hydroxy or lower alkoxy. Particularly preferred compounds of formula XXII are those where E is nitrogen, Ri and Y are hydrogen or fluorine provided diat not both are fluorine, and Rio is fluorine.

The invention also provides compounds of formula XXIII:

XXIII wherein:

Rl and Y independently represent hydrogen, lower alkyl or halogen, RlO represents hydrogen, hydroxy, lower alkoxy or halogen; and E represents CH or nitrogen.

Preferred compounds of formula XXIII are those where E is nitrogen, Ri and Y are independently hydrogen or halogen, and RlO is halogen, hydroxy or lower alkoxy. Particularly prefened compounds of formula XXIII are those where R_a is hydrogen or methyl, E is nitrogen, Rl is hydrogen or fluorine, RlO is fluorine and Y is hydrogen.

The invention also provides compounds of formula XXIV:

XXIV wherein: Rl and T independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; X, Y and Z independently represent hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, or

-SO2R6 where R6 is lower alkyl; and E is CH or nitrogen.

The invention also provides compounds of formula XXV

XXV wherein: Ri represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; RlO is hydrogen, hydroxy, halogen, or lower alkoxy; and E is CH or nitrogen.

The invention provides compounds of formula XXVI:

XXVI wherein:

RlO is hydrogen, hydroxy, halogen, or lower alkoxy; and E is CH or nitrogen.

The invention also provides compounds of formula XXVII:

xvπ wherein:

Rl and T independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; X, Y and Z independently represent hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, or -SO2 6 where R6 is lower alkyl; n is O or 1; RlO is hydrogen, hydroxy, halogen, or lower alkoxy; and A and Q are the same or different and represent CH or nitrogen.

The invention also provides compounds of formula XX VIII:

xxvπi wherein: n is O or l;

Rl and T independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;

RlO is hydrogen, hydroxy, halogen, or lower alkoxy; and

A and Q are the same or different and represent CH or nitrogen.

The invention also provides compounds of formula XXD :

XXIX wherein:

RlO is hydrogen, hydroxy, halogen, or lower alkoxy; and

E is CH or nitrogen.

The invention also provides compounds of formula XXX:

XXX wherein:

RlO is hydrogen, hydroxy, halogen, or lower alkoxy; Rl, T, X, Y and Z independently represent hydrogen or lower alkyl; and E represents CH or nitrogen.

The invention also provides compounds of formula XXXI:

XXXI wherein: RlO is hydrogen, hydroxy, halogen, or lower alkoxy; and Rl, T, X, Y and Z independently represent hydrogen or lower alkyl; and E represents CH or nitrogen.

The invention also provides compounds of formula XXXII:

XXXII wherein

RlO is hydrogen, hydroxy, halogen, or lower alkoxy; Ri and T independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and X, Y and Z independently represent hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, or -SO2 6 where R6 is lower alkyl. n is 0 or 1.

The invention also provides compounds of formula XXXIII:

XXXIII wherein: Rio is hydrogen, hydroxy, halogen, or lower alkoxy;

Rl and T independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and X, Y and Z independently represent hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, or -SO2R6 where R6 is lower alkyl. The invention further provides compounds of formula XXXIV:

XXXIV wherein:

R is halogen, alkoxy having 1-6 carbon atoms, or hydroxy;

Rl and T independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; X, Y and Z independently represent hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, or -SO2R6 where R6 is lower alkyl; and E is CH or nitrogen.

Preferred compounds of Formula XV are those where Rl, T, X, Y, and Z are hydrogen. Particularly preferred compounds of Formula XV are those where Ri , T, X, Y, and Z are hydrogen, E is nitrogen, and R is hydroxy, fluorine, or methoxy.

The invention provides compounds of formula XXXV:

XXXV wherein:

R is halogen, alkoxy having 1 -6 carbon atoms, or hydroxy; E is CH or nitrogen.

Preferred compounds of Formula XVI are those where E is nitrogen. Particularly preferred compounds of Formula XVI are those where E is nitrogen and R is hydroxy, fluorine, or methoxy.

The invention also provides compounds of formula XXXVI:

XXXVI wherein:

R is halogen, alkoxy having 1-6 carbon atoms, or hydroxy. Preferred compounds of Formula XVII are those where R is hydroxy, fluorine, or methoxy.

Further, the invention provides compounds of formula XXXVII:

XXXVI wherein:

Preferred compounds of formula XVIII are those where E is nitrogen, Ri and Y are hydrogen or halogen, and RlO is halogen, hydroxy or lower alkoxy. Particularly preferred compounds of formula XV are those where E is nitrogen, Ri and Y are hydrogen or fluorine provided that not both are fluorine, and RlO is fluorine.

Particularly preferred NR5R6 and NR4R5 groups of formulas I and V respectively are the following formula:

where W is CH or N; and

Z represents phenyl, pyridyl or pyrimidinyl, each of which is optionally mono- or disubstituted witii halogen, hydroxy, or lower alkoxy.

This formula designates saturated heterocyclic ring systems such as, for example, piperidinyl and piperazinyl, as well as unsaturated heterocyclic ring systems such as, for example, 1, 2, 3, 6-tetrahydropyrindine. These groups include the following:

where Z is defined above.

Most preferred NR5R6 and NR4R5 groups include die following:

a oxy

en

alkoxy

Representative examples of compounds of the invention are shown below in Table A. The compounds are shown in Table A as the free base compounds and not as the salts that are described in die examples.

Table A

Compound 1

Compound 8

Compound 16

Compound 19

Compound 20

Compound 21

Compound 22

Compound 23A

Compound 24

Compound 25

Compound 43

Compound 45

Compound 50 Compound 52

Compound 65

Compound 61

Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to die compounds in Figure I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic, hydroiodic, acetic and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses die acylated prodrugs of the compounds of Formula I. Those skilled in die art will recognize various synthetic mediodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

By "aryl" and "Ar" is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which can optionally be unsubstituted or substituted with e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifiuoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.

By "alkyl" and "lower alkyl" is meant straight and branched chain alkyl groups having from 1-6 carbon atoms. By "lower alkoxy" and "alkoxy" is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms.

By "hydroxy lower alkyl" or "hydroxy alkyl" is meant an alkyl group substituted by at least one hydroxy group. Preferred hydroxy alkyl groups are straight chain alkyl groups substituted with one hydroxy group at the terminal carbon atom. By "heteroaryl" is meant 5, 6, or 7 membered aromatic ring systems having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolo, pyrazolo, pyrazinyl, pyridazinyl, oxazolo, furanyl, quinoline, isoquinoline, thiazole, and thienyl, which can optionally be unsubstituted or substituted witii e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifiuoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.

By "halogen" is meant fluorine, chlorine, bromine and iodine.

By "arylalkyl" is meant the group -R-Ar where Ar is an aryl group and R is a straight or branched chain aliphatic group. Arylalkyl groups may optionally be substituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifiuoromethyl, lower acyloxy, and hydroxy. Preferred arylalkyl groups in the above formulas where W is CH and Rg represents arylalkyl are phenylalkyl groups where die alkyl portion is lower alkyl. A particularly preferred phenylalkyl group is benzyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

By "cycloalkyl" is meant cyclic hydrocarbons having from 3-8 carbon atoms. These cyclic hydrocarbon groups may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2R9 where R9 is NH2 or NHCH3.

The numbering system used herein to identify positions of the imidazole ring is as follows:

The pharmaceutical utility of compounds of this invention are indicated by die following assays for dopamine receptor subtype affinity.

Assay for D2 and D3 receptor binding activity

Striatial tissue is dissected from adult male Sprague Dawley rats or BHK 293 cells are harvested containing recombinantly produced D2 or D3 receptors. The sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4°C and pH 7.4. The sample is then centrifuged at 30,000 x g and resuspended and rehomogenized. The sample is then centrifuged as described and the final tissue sample is frozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48°C and contain 0.5 ml of tissue sample, 0.5 nM ^H- raclopride and the compound of interest in a total incubation volume of 1.0 ml. Nonspecific binding is defined as that binding found in the presence of 10^~4 M dopamine; without further additions, nonspecific binding is less than 20% of total binding. The binding characteristics of examples of tiiis patent are shown in Table 1 for rat striatal homogenates.

TABLE I

Com^pound Number 1 Il-≤fl mM)

1 0.900

8 0.011

16 0.014 19 0.100

21 0.018

24 0.620

26 0.200

1 Compound numbers relate to compounds described in the examples below and/or shown in Table A above.

Assay for D4 recentor binding activity

Clonal cell lines expressing the human dopamine D4 receptor subtype were harvested in PBS and the cells centrifuged and d e pellets stored at -80°C until used in die binding assay. The pellets were resuspended and the cells Iysed at 4°C in 50 mM Tris pH 7.4 buffer containing 120 mM NaCl, 1 mM EDTA and 5 mM MgCl2. The homogenate is centrifuged at 48000 x g for 10 minutes at 4°C. The resulting pellet is resuspended in fresh buffer and centrifuged again. After resuspension of die pellet in fresh buffer at 100 ml aliquot is removed for protein determination. The remaining homogenate is centrifuged as above, the supernatant removed and the pellet stored at 4°C until needed at which time it is resuspended to a final concentration of 625 mg ml (250 mg per sample) with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior to use. Incubations were carried out for 60 minutes at 25°C in the presence of 0.1 nM [³H] YM-09151-2. The incubation was terminated by rapid filtration through Whatman GF/C filters and rinsed with 2x4 ml washes of chilled 50 mM Tris (pH 7.4) and 120 mM NaCl. Non-specific binding was determined with 1 mM spiperone and radioactivity determined by coiunting in an LKB beta counter. Binding parameters were determined by non-linear least squares regression analysis, from which the inhibition constant (Ki) could be calculated for each test compound. The binding characteristics of some examples of tiiis patent are shown in Table 2 for the dopamine D4 binding assay. In general, compounds of the accompanying examples were tested in the above assay, and all were found to possess a Ki value for the displacement of [³H]YM-09151-2 from the human dopamine D4 receptor subtype of below 500 nM. Some specific data is indicated in Table 2.

able 2

Cnmnoiind Numherl Ki (mM)

19 0.001

20 0.014 22 0.048

23 0.003

24 0.001

25 0.002 43 0.014 45 0.005 47 0.053 50 0.005 52 0.002

55 0.500

56 0.450 58 0.003

60 0.015

61 0.013

65 0.013

1 Compound numbers relate to compounds described in d e examples below and/or shown in Table A above.

The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, tiiere is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to die art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from die group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and diereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed widi an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture widi excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecitiiin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of etiiylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of etiiylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among d e acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For tiiis purpose any bland fixed oil may be employed including syndietic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing die drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anaestiietics, preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, diat the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and die severity of die particular disease undergoing dierapy.

An illustration of die preparation of representative 2-phenyl-4-aminomethyl-imidazoles of the present invention is shown in Scheme I. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by die present invention.

Scheme I

where

S i , S2, S3, S4, and S5 are the same or different and represent hydrogen, halogen, trifiuoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2R9 where R9 is NH2 or

NHCH3; R5 and R6 are as defined as above for Formula I; or NR5R6 together represent cyclic groups as defined above for Fromula I.

Alternatively, compounds of the invention may be prepared according to the reactions shown in Scheme 2. Scheme 2

where Ri, T, M, X, Y, Z, R4, and R5 are as defined for Formula V above.

Other alternative routes for the preparation of compounds of the invention are depicted in

Schemes 3 and 4, below. The substituents on the starting materials and reagents carry die definitions as for formula I above.

Scheme 3

Scheme 4

An additional example of a synthetic route for the preparation of compounds of the invention is depicted in Schemes 5a-c shown below showing the prepartion of a pyrimidinyl derivative. Starting materials may be varied to prepare other inventive compounds having different groups in place of the pyrimidinyl. The substituents on the starting materials and reagents carry the definitions as for formula I above.

Scheme 5a

Scheme 5b

Scheme 5c

The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in diem. Exa-i-pl- 1

A mixture of 6.45 g 5-bromo-o-anisaldehyde, 2.2 g of hydroxylamine hydrochloride , 4.1 g of sodium formate and 20 mL formic acid were heated at 100°C with stirring for 1 h. The reaction mixture was poured onto ice water and d e mixture was made basic by the careful addition of 50% sodium hydroxide. The product was extracted with etiier, the ether extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was crystallized from ether hexane to afford 5-bromo-2-methoxybenzonitrile.

Example 2

A mixture of 4.0 g 5-bromo-2-methoxybenzonitrile, 5 g 3 A molecular sieves and 60 mL of anhydrous methanol was saturated with HCl gas at 0°C and allowed to stand at 0°C for 24 h. The solvent was removed in vacuo and the residue taken up in 75 mL of anhydrous methanol and saturated with ammonia gas at room temperature. The reaction mixture was tiien heated at 80°C for 4 h in a sealed tube. The sovent was removed in vacuo, the reaction mixture was diluted with 3N HCl and washed with ethyl acetate to remove unreacted nitrile. The aqueous layer was made basic with 50% NaOH and the product was extracted three times with 10% methanol in methylene chloride. The combined organic extracts were dried over potassium carbonate and the solvents removed in vacuo to afford 5-bromo-2-metiιoxybenzamidine as a glassy solid.

To a solution of 20 g 1,1,1,3,3,3-hexamethyldisilazane in 150 mL dry ether was added 5 mL 2.4 M n-butyllithium in hexane. After 10 min at room temperature, 16.3 g 2,3- dimethoxybenzonitrile was added in one portion and the mixture was kept at room temperature for 16 h. The reaction mixture was then poured onto excess 3N HCl. The aqueous layer was separated, basified with 50% NaOH and the product was extracted three times with 10% methanol in methylene chloride. The combined organic extracts were dried over potassium carbonate and the solvents removed in vacuo to afford 2,3-dimethoxy-benzamidine as a glassy solid.

Example 4

A mixture of 1.5 g of 5-bromo-2-medιoxybenzamidine, 1.0 g of 1,3-dihydroxyacetone dimer, 1.3 g of ammonium chloride, 3 mL of tetrahydrofuran and 10 mL concentrated aqueous ammonium hydroxide was heated at 90°C for 3 h. The reaction mixture was chilled on ice and the precipitated product was collected and recrystallized from methanol to afford 2-(5-bromo-2- methoxyphenyl)-4-hydroxymethylimidazole as a yellow solid.

Example -

(Compound 1)

A mixture of 500 mg 2-(5-bromo-2-methoxyphenyl)-4-hydroxymethylimidazole and 1.5 mL thionyl chloride was heated at 80°C for 15 min and then concentrated under reduced pressure. Diethyl ether (15 mL) was added and the resulting solid was collected and washed with ether.

This solid was added in one portion to a mixture of 3 mL of dimethylamine, 15 mL isopropanol and 30 mL of methylene chloride and the mixture was stirred for 20 min. The solvents were removed in vacuo and the residue was dissolved in 2N HCl and washed two times with ethyl acetate. The aqueous layer was made basic with 50% NaOH and the product was extracted with methylene chloride. The organic extracts were dried over magnesium sulfate, the solvents removed in vacuo, and die residue was treated widi ethanolic HCl/ether to afford 2-(5-bromo-2- methoxyphenyl)-4(5M(N,N-dimethyl)aminomethyl]-imidazole dihydrochloride (Compound 1) , m.p. 242-243°C. Example 6

The following compounds were prepared essentially according to die procedure described in Examples I-V:

(a) 2-Phenyl-4(5)-[(N,N-dimethyl)aminometiιyl]-imidazole dihydrochloride (Compound 2), m.p. 259-260°C.

(b) 2-Phenyl-4(5)-(piperidinomethyl)-imidazole dihydrochloride (Compound 3), m.p. 245- 247°C.

(c) 2-Phenyl-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole dihydrochloride (Compound 4), m.p. 239-240°C.

(d) 2-(2-Methoxyphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazole dihydrochloride (Compound 5), melting at X °C.

(e) 2-(3-Methoxyphenyl)-4(5)-[(N-medιyl-N-benzyl)aminomethyl]-imida-ole dihydrochloride (Compound 6), m.p. 115-117°C.

(f) 2-(2,3-Dimethoxyphenyl)-4(5)-[(N,N-dimedιyl)aminomethyl]-imidazole dihydrochloride (Compound 7), m.p. 220-221°C.

(g) 2-(2,3-Dimethoxyphenyl)-4(5)-[(N-methyl-N-benzyl)an- nomethyl]-imidazole dihydrochloride (Compound 8), m.p. 200-202°C.

(h) 2-(3-Methoxyphenyl)-4(5)-[(N,N-diethyl)aminomethyl]-imidazole dihydrochloride (Compound 9), m.p. 213-214°C.

(i) 2-(3-Fluorophenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazole dihydrochloride (Compound 10), m.p. 211-214°C.

(j) 2-(2-Fluorophenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole dihydrochloride (Compound 11), m.p. 241-244°C.

(k) 2-(3-Methylphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazole dihydrochloride (Compound 12), m.p. 231-234°C. G) 2-(2-Fluorophenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazole dihydrochloride (Compound 13), m.p. 246-247°C.

(m) 2-(4-Fluorophenyl)-4(5)-[(N-memyl-N-I--enzyl)aminomethyl]-imidazole dihydrochloride (Compound 14), m.p. 237-239°C.

(n) 2-(2-Memoxyphenyl)-4(5)-[(^-n-ιedιyl-N-benzyl)aminomethyl]-imida-ole dihydrochloride (Compound 15), m.p. 239-241 °C.

(o) 2-(5-Bromo-2,3-dimethoxyphenyl)-4(5)-[(N,N-dimeAyl)aminomemyl]-iιnidazole dihydrochloride (Compound 16), m.p. 194-194°C.

(p) 2-(5-Bromo-2-methoxyphenyl)-4(5)-[(N-memyl-N-ben-^l)---mmomethyl]-i-midazole dihydrochloride (Compound 17), m.p. 242-243°C.

(q) 2-(5-Bronrø-2,3-dime oxyphenyl)-4(5)-[(N-πιedιyl-N-benzyl)- ι-momeΛyl]-imidazole dihydrochloride (Compound 18).

(Compound 19) A mixture of 350 mg 2-phenyl-4-hydroxymethylimidazole and 3 mL thionyl chloride was heated at 80°C for 15 min. The excess thionyl chloride was removed in vacuo and the residue was dissolved in 20 mL of methylene chloride. This solution was added to a mixture of 1 mL triethylamine and 410 mg l-(2-methoxyphenyl)piperazine in 20 mL methylene chloride and the mixture was stirred for 20 min. The solvents were removed in vacuo and d e residue was dissolved in 2N HCl and washed two times with ediyl acetate. The aqueous layer was made basic with 50% NaOH and d e product was extracted with methylene chloride. The organic extracts were dried over magnesium sulfate, the solvents removed in vacuo, and die residue was crystallized from ediyl acetate to afford 2-phenyl-4(5)-[(4-(2-methoxyphenyl)-piperazin-l-yl)- methyljimidazole (Compound 19), m.p. 105-107°C.

Example 8 The following compounds were prepared essentially according to the procedure described in Example VII:

(a) 2-(4--- _uorophenyl)-4(5)-[(4-(2-methoxyphenyl)-pipera-tin-l-yl)-methyl]-imidazole (Compound 20), m.p. 95-97°C.

(b) 2-(2,3-Dimedιoxyphenyl)-4(5)-[(4-(2-methoxyphenyl)-piperazin- 1 -yl)-methyl]-imida--ole dihydrochloride (Compound 21), m.p. 217-218°C.

(c) 2-(3-Chlorophenyl)-4(5)-[(4-(2-methoxyphenyl)-piperazin- 1 -yl)-metfιyl]-imidazole dihydrochloride (Compound 22), m.p. 198-199°C.

(d) 2-Phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl] -imidazole dihydrochloride (compound 23), m.p. 246-248°C.

(d') 2-Phenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-l-yl)meu_yl]-imidazole (Compound 23 A), (d") 2-Phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole dimaleate (compound 23B), m.p. 176-178°C.

(e) 2-Phenyl-4(5)-[(4-(2-pyridyl)-piperazin- 1 -yl)-methyl]-imidazole dihydrochloride (Compound 24), m.p. 176-177°C.

(f) 2-Phenyl-4(5)-[(4-benzyl-piperidin-l-yl)-methyl]-imidazole dihydrochloride (Compound 25), m.p. 234-236°C.

(g) 2-Phenyl-4(5)-[(4-phenyl-piperidin-l-yl)-methyl]-imidazole dihydrochloride (Compound 26), m.p. 238-240°C.

(h) 2-Phenyl-4(5)-[(l,2,3,4-tetrahydroisoquinolin)-2-yl-methyl]-imidazole dihydrochloride (Compound 27).

(i) 2-Phenyl-4(5)-2-phenyl-5,6,7,8-tetrahydrobenzimidazole imidazole dihydrochloride (Compound 76). Examnle 9

The following compounds were prepared essentially according to the procedures described in Examples I- VII:

(a) 2-(2,3-Dimethoxyphenyl)-4(5)-[(l,2,3,4-tetrahydroisoquinolin)-2-yl-methyl]-imidazole dihydrochloride (Compound 28), m.p. 205-207°C.

(b) 2-(4-Methoxyphenyl)-4(5)-[( f-n-edιyl-N-benzyl)ammomeΛyl]-i--mdazole dihydrochloride (Compound 29).

(c) 2-(3,4-Dimeώoxyphenyl)-4(5)-[(N-medιyl-N-benzyl)aminomedιyl]-imidazole dihydrochloride (Compound 30).

(d) 2-(3-Methoxyphenyl)-4(5)-[(N-methyl)aminomethyl]-imidazole dihydrochloride (Compound 31).

(e) 2-(5-Chloro-2-medιoxyphenyl)-4(5)-[(N-me_ιyl-N-benzyl)aminomedιyl]-imidazole (Compound 32), m.p. 88-89°C.

(f) 2-(5-Chloro-2-methoxyphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazole dihydrochloride (Compound 33), m.p. 231-233°C.

(g) 2-(5-Chloro-2-methoxyphenyl)-4(5)-[(N-n-«thyl)a----nomethyl]-imidazole dihydrochloride (Compound 34), m.p. 225-227°C.

(h) 2-(5-CWoro-2-methoxyphenyl)-4(5)-[(N-benzyl)a--m_ιomethyl]-imidazole dihydrochloride (Compound 35), m.p. 184-186°C.

(i) 2-(5-CUoro-2-benzyloxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole dihydrochloride (Compound 36), m.p. 118-123°C.

(j) 2-(2-Benzyloxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole dihydrochloride (Compound 37), m.p. 199-200°C.

(1 ) 2-(3-Ethylphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole dihydrochloride (Compound 38), m.p. 234-235°C. (m) 2-(5-Chloro-2-meAoxyphenyl)-4(5)-[(N-memyl-N-(-4-chlorobenzyl))aminomemyl]- imidazole dihydrochloride (Compound 39), m.p. 186-188°C.

(n ) 2-(5-Chloro-2-hydroxyphenyl)-4(5)-[(N-memyl-N-benzyl)aminomethyl]-imidazole dihydrochloride (Compound 40), m.p. 227-228°C.

(o ) 2-(5-Bromo-2-ben2yloxyphenyl)-4(5)-[(N-meΛyl-N-benzyl)arm-ιomeώyl]-imidazole dihydrochloride (Compound 41).

(p ) 2-(5-Edιyl-2-me oxyphenyl)-4(5)-[(N-medιyl-N-benzyl)arm_ιomeΛyl]-imidazole dihydrochloride (Compound 42), m.p. 114-115°C.

(q) 2-(5-Chloro-2-methoxyphenyl)-4(5)-[(4-(2-methoxyphenyl)-piperazin- 1 -yl)-methyl]- imidazole dihydrochloride (Compound 43), m.p. 138- 143°C.

(r) 2-(5-Chloro-2-medιoxyphenyl)-4(5)-[(4-phenyl-piperidin- 1 -yl)-methyl] -imidazole dihydrochloride (Compound 44), m.p. 138-143°C.

(s) 2-Phenyl-4(5)-[(4-phenyl-piperazin-l-yl)methyl]imidazole (Compound 45), m.p. 189- 191°C.

(t) 2-(4-Fluorophenyl)-4(5)[(4-phenyl-piperidin- 1 -yl)-methyl]-imidazole dihydrochloride (Compound 46), m.p. 260-264°C (dec).

(u) 2-(4-Methoxyphenyl)-4(5)[(4-phenyl-piperidin- l-yl)-methyl]-imidazole dihydrochloride (Compound 47), m.p.l96-199°C.

(v) 2-Phenyl-4(5)-[(4-(3-trifluoromethylphenyl)-piperazin- 1 -yl-)medιyl]imidazole (Compound 48), m.p.182- 184°C.

(w) 2-(2-Methoxyphenyl)-4(5)[(4-phenyl-piperidin- 1 -yl)-methyl]-imidazole dihydrochloride (Compound 49).

(x) 2-(3-Methoxyphenyl)-4(5)[(4-phenyl-piperidin-l-yl)-methyl]-imidazole dihydrochloride (Compound 50), m.p.114-117°C. (y) 2-(3-Fluorophenyl)-4(5)[(4-phenyl-piperidin-l-yl)-methyl]-imidazole (Compound 51), m.p. 110-112°C

(z) 2-(2-Fluorophenyl)-4(5)[(4-phenyl-piperidin- 1 -yl)-methyl]-imidazole dimaleate (Compound 52), m.p. 142-144°C.

(aa) 2-(2-Methylphenyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imidazole dihydrochloride (Compound 53), m.p.242-244°C.

(ab) 2-(5-Ethyl-2-medιoxyphenyl-4(5)-[(4-phenyl-piperidin- 1 -yl)-methyl]-imidazole dihydrochloride (Compound 54), m.p.76-78°C.

(ac) 2-(5-Ethyl-2-medιoxyphenyl-4(5)-[(4-(2-methoxyphenyl)-piperazin- 1 -yl)-methyl]- imidazole dihydrochloride (Compound 55), m.p.61-64°C.

(ad) 2-Phenyl-4(5)-[(4(4-fluorophenyl)- piperazin- l-yl-)methyl]imidazole dihydrochloride (Compound 56), m.p.64-68°C.

(ae) 2-(5-E_ιyl-2-memoxyphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-medιyl] -imidazole dihydrochloride (Compound 57), m.p.75-78°C.

(af) 2-Phenyl-4(5)-[(4-(5-fluoro-2-pyrimidinyl)-piperazin- 1 -yl)-methyl]imi dazole dihydrochloride (Compound 58), m.p.l88-190°C.

(ag) 2-(4-Huorophenyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-methyl]-imidazole dihydrochloride (Compound 59), m.p.l81-184°C.

(ah) 2-Phenyl-4(5)-[(4(5-chloro-2-methylphenyl)- piperazin- l-yl-)-methyl]imidazole dihydrochloride (Compound 60), m.p.l42-145°C.

(ai) 2-Phenyl-4(5)-[(4(3,4-dichlorophenyl)- piperazin- l-yl-)methyl]imidazole (Compound 61), m.p.l79-181°C.

(aj) 2-Phenyl-4(5)-[(4(4-fluorophenyl)- piperidin- l -yl-)methyl]imidazole dimaleate(Compound 62), m.p.148-149°C. (ak) 2-(3-Fluorophenyl)-4(5)-[(4-benzyl-piperidin- l-yl)-methyl]-imidazole dimaleate (Compound 63), m.p.l48-149°C.

(al) 2-(4-Fluorophenyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imidazole dihydrochloride (Compound 64), m.p. 254-256°C.

(am) 2-Phenyl-4(5)-[(4-(4-fluorobenzyl)-piperidin- l-yl)-methyl] -imidazole dihydrochloride (Compound 65).

(an) 2-(2--- -uorophenyl-4(5)-[(4-(2-py- nidinyl)-piperazin-l-yl)-methyl]-imidazole (Compound 66), m.p.159-161 °C.

(ao) 2-(4-MeΛylphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole (Compound 67), m.p.l76-179°C.

(ap) 2-(2-Fluorophenyl)-4(5)-[(4-benzyl-piperidin- l-yl)-methyl]-imidazole dimaleate (Compound 68), m.p.H3-115°C

(aq) 2-(4-Chlorophenyl-4(5)-[(4-(2-pyridyl)-piperazin- 1 -yl)-methyl]-imidazole (Compound 69), m.p. 176-177°C.

(ar) 2-Phenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-piperazin-l-yl)-methyl]-imidazole dimaleate (Compound 70).

(as) 2-(2-Fluorophenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole dimaleate (Compound 71).

(at) 2-(4-Huorophenyl-4(5)-[(4-(4-fluc»ro-2-pyr--rι_dinyl)-piperazin-l-yl)-meuιyl]-imidazole dimaleate (Compound 72).

(au) 2-(2-Fluorophenyl-4(5)-[(4-(5-fluoro-2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole dimaleate (Compound 72A), m.p.l70-171°C.

(av) 2-(4-Huorophenyl-4(5)-[(4-(5-fluoro-2-pyriinidinyl)-piperazin-l-yl)-methyl]-imidazole dimaleate (Compound 72B), m.p.180- 181 °C.

(aw) 2-phenyl-4(5)-[(4-(2-pyridyl)-piperidin- 1 -yl)-methyl } -imidazole dihydrochloride (Compound 72B).

(ax) 2-Phenyl-4(5)-[(4-(5-fluoropyrimidin-2-yl)-piperazin- 1 -yl)-methyl]-imidazole dimaleate (Compound 72E) m.p.l85-186°C.

Example 10

A solution of 40 mL tetrahydrofuran containing 1.0 g of 2-phenylimidazole was cooled to

0°C and 4 mL of 2M litiiium diisopropylamide was added dropwise which resulted in die formation of a white suspension. The mixture was stirred for 10 min at 0°C and men 0.7 mL of dimethyl sulfate was added. The reaction was allowed to stir at room temperature for an additional 30 min during which time die solution became homogeneous. Aqueous ammonium chloride was added and die tetrahydrofuran was removed by evaporation under reduced pressure. The aqueous phase was extracted witii 2 x 100 mL aliquots of dichloromethane. The combined organic extracts were washed with dilute ammonium hydroxide and brine. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1 g of l-methyl-2-phenylimidazole which was used in the next step without further purification or characterization.

To a solution of 1 g of 1 methyl-2-phenylimidazole in 10 mL acetic acid were added 0.4 mL of 37% aqueous formaldehyde and 1.2 mL of 4-benzylpiperidine. The reaction mixture was heated at 100°C for 10 hours and die acetic acid then removed by evaporated under reduced pressure. The residue was dissolved in water and made alkaline with 5% sodium hydroxide and extracted with 2 x 100 mL of dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and concentrated to small volume under reduced pressure to give 1 methyl-2-phenyl-4-[(4-benzylpiperidin- 1 -yl)methyl]-imidazole.

The following compounds were prepared essentially according to the procedure described in Example X utilizing 2-phenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-l-yl)methylimidazole ( Compound 22) as starting material. The resulting isomers were separated by chromatography on silica gel using ethyl acetate as eluant

a) 1 -Methyl-2-phenyl-4-[(4-(2-pyrimidinyl)piperazin- 1 -yl)methyl]-imidazoIe (Compound 74).

b) 1 -Methyl-2-phenyl-5-[(4-(2-pyrimidinyl)piperazin- 1 -yl)methyl] -imidazole (Compound 75).

A mixture of 3g of ethylthiooxamate, 4.25 g of 2-aminoacetophenone hydrochloride and 3.69 g of sodium acetate was dissolved in 20 mL of acetic acid and heated under reflux for 3 hr. The reaction mixture was allowed to cool to room temperature and die acetic acid removed by evaporation under reduced pressure. The residue was basified widi aqueous sodium carbonate and extracted with 2 x 100 mL of ethyl acetate. The combined extracts were washed with 2 x 100 mL of brine, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to yield 2.8 g of ethyl 4-phenylimidazole-2-carboxylate as a solid which was used in the next step widiout further purification or characterization. To a solution of 2.75 g etiιyl-4-phenylimidazole-2-carboxylate in 20 mL tetrahydrofuran was added a suspension of 0.5 g lithium aluminum hydride in 30 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature overnight, poured into 100 mL of ice water and extracted with 2 x 100 mL of ediyl acetate. The combined extracts were washed widi 2 xlOO mL of brine, dried over anhydrous sodium sufate and the solvent removed under reduced pressure to yield 2 g of 2-hydroxymethyl-4-phenylimidazole which was used in die next step without further purification or characterization.

A solution of 1 g of 2-hydroxymethyl-4-phenylimidazole in 10 mL of thionyl chloride was heated at 60°C for 1 hr. After removal of excess thionyl chloride by evaporation under reduced pressure, the residue was treated with a solution of 1 g 4-benzylpiperidine and 2 g N,N,- dusopropylethylamine in 50 mL of chloroform. The reaction mixture was stirred at 60°C for 1 hr, allowed to cool to room temperature and washed successively widi 50 mL of IN sodium hydroxide solution and 50 mL of water. The organic phase was then dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 850 mg of 4-phenyl- 2(5)-[(4-benzylpiperidin-l-yl)-med yl]imidazole which was converted into its monofumarate salt (Compound 77), mp 155-157 °C.

Example 12

The following compounds were prepared essentially according to die procedure described in Example XI.

(a) 4-Phenyl-2(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole dihydrochloride (Compound 78), m.p. 229-231°C.

(b) 4-Phenyl-2(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl] -imidazole dihydrochloride (Compound 79), m.p.l78-180°C. (c) 4-Phenyl-2(5)-[4-(4-fluoro-benzyl-piperidin-l-yl)-methyl]-imidazole dihydrochloride (Compound 80), m.p. 216-218°C.

(d) 4-Phenyl-2(5)-[(4-phenyl-piperidin- 1 -yl)-methyl]-imidazole dihydrochloride (Compound 81), m.p.l82-184°C.

(e) 4-Phenyl-2(5)-[(4(4-fluorophenyl)- piperazin- l-yl-)methyl] imidazole dihydrochloride (Compound 82), m.p.161-163°C

(f) 4-Phenyl)-2(5)-[(4-(2-methoxyphenyl)-piperazin- 1 -yl)-methyl]-imidazole dihydrochloride (Compound 83), m.p. 229-231°C.

(g) 4-Phenyl-2(5)-[(4-(2-pyridyl)-piperazin-l-yl)-methyl]-imidazole trihydrochloride (Compound 84), m.p. 165-167°C. (h) 4-Phenyl-2(5)-[(4-phenyl-piperazin-l-yl-)methyl]imidazole dihydrochloride (Compound

85), m.p. 182-184°C.

(i) 4-Pheny 1-2(5)- [(4-benzoyl-piperidin- 1 -yl)-methyl] -imidazole dihydrochloride (Compound 86) m.p. 200-202°C

(j) 4-Phenyl-2(5)-[4-(4-fluoro-benzoyl-piperidin- l-yl)-methyl]-imidazole dihydrochloride (Compound 87), m.p.l73-175°C. Example 13

A solution of 10 g of 2-bromopropiophenone in 50 mL formamide was heated at 180°C overnight. The reaction was then allowed to cool to room temperature and poured into 250 mL ice water. The mixture was adjusted to pH 9 widi IN sodium hydroxide and the resulting precipitate was collected by filtration, washed with water and dried to yield 6.0 g of 4-medιyl-5- phenylimidazole as a solid which was used in the next step without further purification.

A mixture of 128 mg 4-methyl-5-phenylimidazole, 180 mg of 4-benzylpiperidine and 85 mg of 37% formaldehyde in 10 mL acetic acid was heated under reflux for 8 hr. The acetic acid was then removed by evaporation under reduced pressure and the residue was dissolved in 50 mL ethyl acetate. The ethyl acetate solution was washed successively widi 50 mL of dilute sodium hydroxide solution and water. The ethyl acetate extract was then dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure to yield 5-methyl- 4-phenyl-2(5)-[(4-benzyl-piperidin-l-yl)-med yl]imidazole as an oil which was purified by chromatography on silica gel using 5% methanol in methylene chloride as eluent. Treatment of the purified free base with ethanolic HCl yielded 5-methyl-4-phenyl-2(5)-[(4-benzyl-piperidin-l- yl)-methyl]imidazole dihydrochloride (Compound 88).

To a solution of 14.3 g 2-phenyl-4(5)-methylimidazole and 13.8 g of l-(2- pyrimidyl)piperazine in 50 mL of ethanol was added a solution of 7.1 mL of aqueous formaldehyde. The resulting mixture was heated at reflux temperature for 2 hr and allowed to cool to room temperature. The solid was collected by filtration and dried to yield 20 g of 2- phenyl-5-methyl-4(5)-[(4-(2-pyrimiώnyl)piperazin-l-yl)meΛyl]imidazole which was treated with 2 equivalents of maleic acid in isopropanol to yield 2-phenyl-5-methyl-4(5)-[(4-(2- pyrir-tidinyl)pipe-^n-l-yl)nιedιyl]-imidazole dimaleate (Compound 89), m.p. 172-174°C.

Example 14A The following compounds were prepared essentially according to the procedures described in Example 14.

(a) 2-phenyl-5(4)-methyl-4(5)-[(4-(4-fluoropyrimidin-2-yl)piperazin-l-yl)medιyl]- imidazole (Compound (89A).

(b) 2-(2-fluorophenyl)-5(4)-rnedιyl-4(5)-[(4-(4-fluoropyrimidi-n-2-yl)piperazin- 1 - yl)medιyl]-imidazole (Compound (89B).

Example 14B

2-phenyl-5(4)-memyl-4(5)-[(4-(5-fluoropyrirm-lin-2-yl)pipe--ι-άn-l-yl)memyl]-imidazole .Compound 89Q

To a solution of l-(5-fluoropyrimidine-2-yl)piperazine (1.44 g, 7.9 mmol) and formaldehyde (0.7ml, 37%) in ethanol (15 ml) is added solid 2-phenyl-4-methylimidazole (1.25 g) and the resulting mixture stirred for about 2 hours. The mixture is cooled upon which a white solid forms. The solid is collected by filtration and washed with a small amount of cold ethanol (1.0 g). The solid is dissolved in isopropanol (20 ml) and combined with a solution of maleic acid (0.66 g) in isopropanol (10 ml). The resulting solution is concentrated to a total volume of 15 ml and allowed to stand. The crystalline dimaleate is collected by filtration (1.4 g). mp 178- 179°C.

2-(2-fluorophenyl)-5(4)-memyl-4(5)-[(4-(5-fluoropyrimidin-2-yl)- piperazin-l-yl)me-hyll-imida-ole (Compound 89D)

A solution of methyl-2-fluorobenzimidate (26.9 mmol) and 2-aminopropionaldehyde dimethyl acetal (20.8 g) in 6 N HCl (50 ml) is heated to 100°C for about 12 hours and then cooled. The cooled mixture is poured onto ice, basified with 50% NaOH, and extracted with chloroform. The extracts are combined, dried and concentrated. The oxalate salt of die resulting 2-(2-fluorophenyl)-4-methylimidazole is prepared in isopropanol.

To a solution of l-(5-fluoropyrimidine-2-yl)piperazine (0.53 g, 2.87 mmol) and formaldehyde (0.5 ml, 37%) in ethanol (10 ml) is added solid 2(2-fluorophenyl)-4- methylimidazole (1.25 g) and the resulting mixture stined for about 12 hours. The mixture is cooled and concentrated to provide a solid. The solid is collected by filtration and washed with a small amount of cold ethanol (1.0 g). The solid is dissolved in isopropanol (15 ml) and combined widi a solution of maleic acid (0.645 g) in isopropanol (5 ml). The resulting solution is concentrated to a total volume of 7 ml and allowed to stand overnight. The crystalline dimaleate is collected by filtration (0.8 g). mp 138-139°C. Example 15

To a solution of 100 mg of 2-phenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-l- yl)methyl]imidazole in 10 mL of chloroform was added one equivalent (80 mg) of iodine in 5 mL of chloroform followed by 0.5 mL of triethylamine. The reaction mixture was stined at room temperature for 30 min during which time a solid crystallized from the solution. The solid was collected by filtration to yield 52 mg of 2-phenyl-5-iodo-4(5)-f(4-(2-pyrimidinyl)piperazin-l- yl)medιyl]-imidazole .hydroiodide salt (Compound 90) which had a m.p. of 196-199°C.

To a solution of 220 mg of 2-phenyl-4-imidazole carboxaldehyde in 5 mL of tetrahydrofuran was added 6.4mL of a 1L methyllidiium solution in tetrahydrofuran. The reaction mixture was quenched witii 50 mL of water and the mixture extracted widi 2x50 mL aliquots of etiiyl acetate. The combined ediyl acetate extracts were dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure to yield 250 mg of 2-phenyl-4(5)-(l- hydroxyethyl)imidazole which was used in the next step without further purification or characterization. The residue of 2-phenyl-4(5)-(l-hydroxyethyl)imidazole was dissolved in 8mL of thionyl chloride and heated at reflux temperature for 30 min after which the thionyl chloride was removed by distillation under reduced pressure to yield 250 mg of 2-phenyl-4(5)-(l- chloroedιyl)imidazole as an oil which was used in die next step widiout additional purification or characterisation. This oil was dissolved in 10 mL of chloroform and to this solution was added 224 mg of 4-benzylpiperidine and 2 mL of triethylamine. The reaction was allowed to stand at room temperature for 10 min and then washed with 50 mL IN sodium hydroxide. The chloroform extract was tiien separated and dried over anhydrous sodium sulfate, filtered and d e solvent removed by evaporation under reduced pressure to yield 2-phenyl-4(5)-[l-((4-benzyl- piperidin-l-yl)-edιyl)} imidazole which was purified by chromatography on silica gel using 10% methanol/dichloromethane as eluent. Treatment widi edianolic HQ yielded 2-phenyl-4(5)-[l-((4- benzyl-piperidin-l-yl)-ethan-l-yl)]imidazole dihydrochloride salt (Compound 91), m.p. 169- 171°C

Example 17

A solution of 5.5 g 1-cyanonaphthalene in 150 mL dry ether was cooled to 0°C. To tiiis solution 12.1 g lithium bis(trimethylsilyl)amide was added in one portion. The mixture was stined for 12 hours and allowed to warm to room temperature. The reaction mixture was cooled to 0°C then quenched by the addition of 200 mL 3N HCl. After stirring 20 minutes at 0°C, the mixture was transferred to a separatory funnel and washed 3 X 100 mL ether. The aqueous layer was cooled on an ice bath and adjusted to pH 14 with solid sodium hydroxide. This solution was extracted 4 X lOOmL dichloromethane. The combined organic extracts were washed 2 X lOOmL water, 1 X 100 mL brine, dried over potassium carbonate, filtered, then concentrated under reduced pressure to give 3.6 g of the desired amidine which was used without further purification.

A mixture of 3.6 g of the crude amidine, 2.5 g of dihydroxyacetone dimer, and 2.5 g of ammonium chloride were suspended in 35 mL cone, ammonium hydroxide in a pressure tube. The mixture was heated to 90°C for 3 hours during which time the amidine dissolved and the product precipitated out. The reaction mixture was cooled to room temperature and the product collected by filtration, washed with cold water, and dried in vacuo to give 3 g 2-(l-naphthyl)- 4(5)-(hydroxymethyl)imidazole as off-white crystals, m.p. 155-158°C.

A solution of 62 mg 2-(l-naphthyl)-4(5)-(hydroxymethyl)imidazole was dissolved in 3 mL of thionyl chloride and warmed to 60°C for 2 hours. The solvent was removed and the residue was dissolved in 3 mL chloroform and 53 mg 4-benzylpiperidine was added followed by 47 mg of diisopropyletliylamine. The reaction mixture was stirred at room temperature for 1 hour, diluted widi 3 volumes of chloroform, then washed 3 X 3 mL of 10% sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 5% methanol in dichloromethane to yield 62 mg of 2-(l-naphthyl)-4(5)-[(4-benzyl-piperidin-l-yl)- metiiyljimidazole (Compound 92), m.p. 81-83°C.

Example 18 The following compounds were prepared from die corresponding nitriles essentially according to the procedures described in Example XVII.

(a) 2-(l -Naphthyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl] -imidazole (Compound 93), m.p.l87-188°C.

(b) 2-(l-Naph_ιyl)-4(5)-r(4-(2-pyridyl)-piperazin-l-yl)-medιyl]-imidazole (Compound 94), m.p. 182-183°C.

(c) 2-( 1 -Naphthyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole (Compound 95), m.p. 74-76°C.

(d) 2-(2-Naphthyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imidazole (Compound 96), m.p. 92-94°C (e) 2-(2-Naphthyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-methyl]-imidazole (Compound 97), m.p.218-219°C.

(f) 2-(2-Naphthyl)-4(5)-[(4-(2-pyridyl)-piperazin- 1 -yl)-methyl]-imidazole(Compound 98), m.p. 199-201 °C.

(g) 2-(2-Naphthyl)-4(5)-[(N-medιyl-N-benzyl)-medιyl]-imidazole (Compound99), m.p. 86- 87°G

(h) 2-(2-Pyridyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-me thylj-imidazole

(Compound 100), m.p. 96-98°C.

(i) 2-(2-Pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-methyl]-imidazole (Compound

101), m.p. 134-135°C. (j) 2-(2-Pyridyl)-4(5)-[(4-(2-pyridyl)-piperazin-l-yl)-methyl]-imidazole (Compound 102), m.p. 135-137°C.

(k) 2-(2-Pyridyl)-4 (5)-[(N-methyl-N-benzyl)-methyl]-imidazole

(Compound 103), m.p. 61-63°C.

G) 2-(3-Pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-methyl]-imidazole (Compound 104), m.p. 155-157°C.

(m) 2-(3-Pyridyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole

(Compound 105), m.p. 141-142°C. (n) 2-(4-Pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-metiιyl]-imidazole (Compound

106), m.p. 154-156°C.

(o) 2-(2-Pyrazinyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl] -imidazole

(Compound 107), m.p. 80-81°C. (p) 2-(2-Pyrazinyl)-4(5)-[(4-(2-pyrimidinyl)-piperizin-l-yl)-metiιyl]-imidazole (Compound

108), m.p. 164-165°C.

(q) 2-(2-Pyrazinyl)-4 (5)-[(N-methyl-N-benzyl)-methyl]-imida_ole

(Compound 109),. m.p. 93-94°C.

(r) 2-(2-Thienyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl] -imidazole (Compound 110), m.p. 77-79°C.

(s) 2-(2-Thienyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-methyl]-imidazole (Compound l l l), m.p. 204-205°C.

(t) 2-(2-Thienyl)-4 (5)-[(N-methyl-N-benzyl)-methyl]-imidazole

(Compound 112), m.p. 132-134°C. (u) 2-(2-Thienyl)-4(5)-[(4-(2-pyridyl)-piperazin-l-yl)-methyl]-imidazole (Compound 113), m.p. 179-18 TC.

(v) 2-(2-Quinolinyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl] -imidazole (Compound

114), m.p. 263°C (dec).

(w) 2-(2-Quinolinyl)-4 (5)-[(N-methyl-N-benzyl)-methyl]-imidazole (Compound 115), m.p. 247°C (dec).

A solution was prepared by dissolving 193 mg of 2-benzoylimidazole, 330 mg of l-(2- pyrimidyl)-piperazine and 165 mL of a 37% solution of formaldehyde in 1 mL of acetic acid and the resulting mixture was heated to 100°C for 15 hours. The mixture was then cooled to 0°C, basified wid 3 N hydrochloric acid, then extracted widi 5 X 10 mL of ethyl acetate. The organic extracts were washed with 2 X 10 mL water, 1 X 10 mL of brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was chromatographed on silca gel using 5 % methanol in dichloromediane as eluent to yield 43 mg of 2-(benzoyl)-4(5)-[(4- (2-pyrirm nyl)-piρerazin-l-yl)-medιyl]-imidazole (Compound 116), m.p. 177-179°C.

Example 20 The following compounds were prepared essentially according to the procedures described in Example XVII. a) 2-Benzyl-4(5)-[(4-(2-pyrirmdinyl)-piperazin-l-yl)-methyl]-imidazole (Compound 117), m.p. 160- 161 °C.

(b) 2-(5-Metiιoxy-3,4-dihydro-naphth- 1 -yl)-4(5)-[(N-medιyl-N-benzyl)-methyl]-imidazole (Compound 118), m.p. 133-134°C

Example 21

A solution of 1.25 g of 2-phenyl-4(5)-imidazole propenoic acid was dissolved in 20 mL thionyl chloride and heated at reflux temperature for 2 hours. The solvent was removed and the residue suspended in 20 mL chloroform. To this solution was added 1.7 g of l-(2-pyrimidinyl)- piperazine dihydrogen chloride followed by 3.5 mL of dusopropylethylamine. The reaction mixture was stirred for 6 hours at room temperature then diluted widi 50 mL chloroform, washed with 3 X 20 mL of 10% sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using 5 % methanol in dichloromethane as eluent to yield 554 mg of 2-phenyl-4(5)-[(4(2- pyrimidinyl)-piperazin-l-yl)-propen-l-oyl]-imidazole (Compound 119), m.p. 235-236°C.

Example 22 The following compounds were prepared according to the procedure described in

Example XXI:

(a) 2-Phenyl-4(5)-[(4-phenyl-piperazin- 1 -yl)-propen- 1 -oyl]-imidazole (Compoundl20), m.p.l51-152°C.

(b) 2-Phenyl-4(5)-[(4-hydroxy-4-(4-chlorophenyl)-piperidin- 1 -yl)-propen- 1 -oyl] -imidazole (Compound 121), m.p. 236-240°C. Example 23

A solution of 68 mg 2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-propen-l-oyl]- imidazole was dissolved a mixture of in 2 mL ethyl acetate and 0.2 ml ethanol and die suspension was stirred for 2 days under a H2 atmosphere, using 20 mg Pt on carbon as catalyst. The mixture was filtered dirough Celite and die solvent removed. The residue was chromatographed on silca gel using 5 % methanol /dichloromediane as eluent to yield 37 mg 2-phenyl-4(5)-[(4-(2- pyri--ύdinyl)-piper--_--n-l-yl)-propan-l-oyl]-imidazole (Compound 122), m.p.l43-148°C.

Example 24

The following compounds were prepared according to the procedure described in Example XXIII

(a) 2-Phenyl-4(5)-[(4-phenyl-piperazin-l-yl)-propan-l-oyl]-imidazole (Compound 123), m.p. 180-183°C. (b) 2-Phenyl-4(5)-[(4-(2-(3,4,5,6-tetrahydro)-pyrimidinyl)-piperazin-l-yl)-propan- 1-oyl]- imidazole (Compound 124), m.p. 210-211°C.

Example 25

To a solution of 84 mg 2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-propan- 1 -oyl]- imidazole in 5 mL dry tetrahydrofuran at room temperature was added 18 mg of lithium aluminum hydride and the mixture was heated at reflux temperature refluxed for 2 hours. After quenching with ethyl acetate, die solvent was removed under reduced pressure. The residue was chromatographed on silca gel using 10 % methanol in dichloromethane as eluent to yield 20 mg of 2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-propan-l-yl]-imidazole (Compound 125), m.p.l33-135°C. Example 26

The following compounds were prepared according to the procedure described in Example XXV.

(a) 2-Phenyl-4(5)-[(4-phenyl-piperazin-l-yl)-propan-l-yl]-imidazole (Compound 126), m.p. 50-54°C.

(b) 2-Phenyl-4(5)-[(4-hydroxy-4-(4-chlorophenyl)-piperidin- 1 -yl)-prσpan- 1 -yl]-imidazole (Compound 127), m.p. 122-124°C.

Example 27

To a solution of 6.8 g of 2-phenylimidazole in 200 mL 3N hydrochloric acid was added 5% Rhodium on Carbon, Degussa type G10 NB/W. The mixture was hydrogenated at 100 psi for 24 hours then filtered through celite. The solution was neutralized with 25% sodium hydroxide and extracted with 2 x 100 mL ethyl acetate. The combined extract was washed widi 200 mL of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2- cyclohexylimidazole as a fluffy, white solid which was used in the next step without further purification or characterization.

To a solution of 251 mg 2-cyclohexylimidazole in 8 mL of acetic acid, 274 mg of l-(2- pyrimidyl)piperazine and 88 microliters of 37% formaldehyde were added. The solution was heated at 100°C for 12 hours then the solvent was removed under reduced pressure and die residue was diluted widi water. The mixture was made slightly alkaline with 5% sodium hydroxide and then extracted with 2 x 25 mL of ethyl acetate. The combined extracts were washed widi 25 mL of brine, dried over anhydrous sodium sulfate and die solvent removed by evaporation under reduced poressure. The products were separated on reverse phase silica gel (Whatman PLKC18F) using 0.2 M aqueous sodium chloride with 80% methanol. Evaporation of die individual fractions yielded 2-cyclohexyl-4(5)-hydroxymethyl imidazole and 50 mg of the desired 2-cyclohexyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- l-yl)-methyl] -imidazole (Compound 128), m.p.210-213°C. Example 28

The following compounds were prepared essentially according to die procedure described in Example XXVU.

(a) 2-cyclohexyl-4(5)-[(4-benzyl-piperidin-l-yl)-metiιyl]-imidazole (Compound 129), m.p. 185-188°C.

(b) 2-cyclohexyl-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole (Compound 130), m.p.235- 238°C.

(c) 2-(4-memylcyclohexyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole (Compound 131).

Example 29

A solution of 790 mg of iodine in 5 mL of chloroform was added to 1.0 g of 2-phenyl- 4(5)-[(4-(2-pyrimidinyl)pipera_άn-l-yl)methyl]imidazole dissolved in 30 mL of chloroform at ambient temperature. After the solution was stined for 10 minutes 1 mL of triethylamine was added and stirring was continued until no more solids formed. The solid was collected by filtration and after drying yielded 700 mg of 2-phenyl-5-iodo-4(5)-[(4-(2-pyrimidinyl)piperazin- l-yl)methyl] -imidazole which was used in the next step without further purification or characterization. To a solution of 53 mg 2-phenyl-5-iodo-4(5)-[(4-(2-pyriniidinyl)piperazin-l-yl)methyl]- imidazole in 1 mL of dimediylfoππamide was added 130 microliters of phenyltrimethylstannane and 3 mg of bis(triphenylphosphine)-palladium(II) chloride. The reaction mixture was heated at 100°C for 4 hours men poured into water and extracted with 2 x 10 mL of ethyl acetate and washed widi 10 mL of 10% ammonium hydroxide. The combined organic extracts were dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure. The resulting material was chromatographed on silica gel with 5% methanol in dichloromethane as eluant to yield 15 mg of 2,5-diphenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-l-yl)methyl]- imidazole (Compound 132), m.p. 221-225°C.

To a solution of 12.4 g p-tolunitrile in 500 mL of diethyl etiier was added 23 g of solid lithium bis(trimethylsilyl)amide at ambient temperature. The mixture was stirred for 2 hours then hydrolysed widi 10% HCl at 0°C. The mixture was stirred for an additional 30 minutes and dien concentrated to dryness to yield 6 g of 4-metiιylbenzamidine hydrochloride which was used in the next step widiout further purification

A solution of 4 g 4-methylbenzamidine hydrochloride in 60 mL ammonium hydroxide was treated with 4.0 g with dihydroxyacetone and 4.8 g ammonium chloride. The reaction mixture was heated to 90°C for 4 hours in a sealed tube. On cooling to room temperature a the solid formed was collected by filtration to yield 3.0 g 2-(4-methylphenyl)-5-hydroxymedιyl- imidazole which was converted according to the procedure described in Example VII to yield 2- (4-methylphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-methyl]-imidazole (Compound 133), m.p.l78-180°C.

Example 31 The following compounds were prepared according to the procedure described in

Example XXX.

(a) 2-(4-Iodophenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl] -imidazole (Compound 134), m.p.218-220°C.

(b) 2-Phenyl-4(5)-[(4-(4-chlorophenyl)-3-methylpiperazin- 1 -yl)methyl]imidazole (Compound 135), m.p. 137-139°C.

(c) 2-Phenyl-4(5)-[(4-(4-methylphenyl)-3-methylpiperazin- 1 -yl)methyl]imidazole (Compound 136), m.p. 172-174°C. (d) 2-Phenyl-4(5)-[(4-(4-medιoxyphenyl)-3-methylpiperazin- 1 -yl)methyl]imidazole (Compound 135), m.p. 188-190°C.

To a solution of 6.3 g benzamidine hydrochloride in 60 mL ammonium hydroxide was added 4.6 g 2-hydroxycyclohexanone. The reaction mixture was heated to 90°C for 7 hours in a sealed tube. On cooling to room temperature die crystals formed were collected by filtration and after drying yielded 3.0g 2-phenyl-4,5,6,7,-tetrahydrobenzimidazole (Compound 136), m.p. 300-301°C.

To a solution of 50 mg 2-phenyl-5,6,7,8-tetrahydrobenzimidazole in 5 mL carbon tetrachloride was added 40 mg l,3-dibromo-5,5-dimethylhydantoin. The mixture was heated to reflux and inadiated with a 500W Tungsten lamp for 30 min. The temperature was lowered momentarily and a solution of 41 mg l-(2-pyrimidyl)piperazine was added to the reaction. The mixture was again heated at reflux temperature for 30 min. Then 0.5 mL triethylamine was added to the reaction and the solution was stirred for 1 hour at room temperature. The volatiles were evaporated under reduced pressure and the product was purified on silica gel with 10% methanol in dichloromethane to yield 28 mg 2-phenyl-7-[(4-(2-pyrimidinyl)-piperazin-l-yl)- me-hyl]-4,5,6,7-tetrahydrobenzimidazole (Compound 137), m.p. 200-202°C.

Example 33 The following compounds were prepared according to the procedure described in Example XXXII.

(a) 2-phenyl-7-[(4-benzyl-piperidin-l-yl)-medιyl]-4,5,6,7-tetrahydrobenzimidazole (Compound 138), m.p. 189-191 °C.

(b) 2-phenyl-7-[(N-methyl-N-benzyl)aminomedιyl]-4,5,6,7-tetrahydrobenzimidazole (Compound 139), m.p. 181-183°C.

A solution of 820 mg 2-chloropyrimidine and 1.6 g c/_-2,6-c_metiιylpipera_ine in 25 mL toluene was heated at reflux temperature for 12 hours. The solvent was evaporated, die residue was basified witii 5% sodium hydroxide and extracted widi 2 x lOOmL of dichloromediane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give c _-2,6-dimediyl-l-(2-pyrimidyl)-piperazine. This amine was then used to prepare 2-phenyl- 4(5)-[(4-(2-pyrimidinyl)-cis-2,6-dimethylpiperazin- 1 -yl)-methyl]-imidazole (Compound 140), m.p.l30-135°C, according to die procedures described in Example Vm.

Example 35

The following compounds were prepared according to the procedure described in Example XXXTV.

(a) 2-phenyl-4(5)-[(4-(2-pyrimidinyl)-trans-2,5-dimedιylpiperazin- 1 -yl)-medιyl]- imidazole (Compound 141), m.p.l75-178°C.

(b) 2-phenyl-4(5)-[(8-(2-pyrimidinyl)-3-8-diazabicyclo(3.2.1 )octan-3-yl)-methyl]- imidazole (Compound 142), m.p.l90-194°C.

Example 36

A mixture of 5.0 g l,4-dihydroxy-2-butanone and 7.5 g benzamidine dihydrochloride in 70 mL ammonium hydroxide was heated to 90°C for 5 hours in a sealed tube. The reaction mixture was diluted witii 100 mL water, extracted with 2x50 mL chloroform, dried over anhydrous sodium sodium sulfate and the solvent removed by evaporation under reduced pressure. The residue was chromatographed on silica gel using 10% methanol in dichloromediane as eluent to yield 1.0 g 2-phenyl-4(5)-hydroxyethylimidazole which was reacted with l-(2-pyrimidyl)piperazine according to the procedure Example VIE to yield 2-phenyl-4(5)- [(4-(2-pyrimidinyl)-piperazin-l-yl)-edιan-l-yl]-imidazole (Compound 143), m.p. 142-144°C.

A mixture of 77 mg 2-phenylimidazole-4(5)-carboxylic acid and 5 mL of thionyl chloride was heated at reflux temperature for 1 hr. The thionyl chloride was removed under reduced pressure to yield 75 mg of 2-phenylimidazole-4-carboxylic acid chloride which was then dissolved in 5 mL chloroform and treated with 67 mg l-(2-pyrimidyl)piperazine. The solution was heated at reflux temperature for 1 hr and dien 0.5 mL triethylamine was added. The solution was stined for another hour, concentrated under reduced pressure and the residue chromatographed on silica gel using 10% methanol in dichloromethane as eluent to yield 50 mg 2-phenyl-4(5)-N-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-carboxamido] -imidazole (Compound 144), m.p. 231-232°C.

Example 38 The following compounds were prepared according to the procedure described in Example XXXVπ.

(a) 2-phenyl-4(5)-N-[(N-methyl-N-benzyl)-carboxamido]-imidazole (Compound 145), characterized as oxalate salt, m.p. 198-199°C.

(b) 2-phenyl-4(5)-N-[(4-benzyl-piperidin- 1 -yl)-carboxamido]-imidazole (Compound 146), characterized as die hydrochloride salt, m.p. 179-181 °C.

Part A

To a suitable bessel is charged ammonium hydroxide (90.4 g), benzamidine hydrochloride hydrate (19.6 g, 125 mmoles), 1,3-dihydroxyacetone dimer (19.85 g, 110.06 mmol) and ammounium chloride (19.98 g, 373.8 mmol). The mixture is heated to 55°C over a 2 hour period and 2-phenyl4(5)-(hydroxym ethyl)imidazole (50 mg) is added to die reactor to initiate crystalization. The mixture is heated to 55°C for an additional 1.5 hr and dien cooled to

5°C over a 4 hour period. After cooling overnight, the solids are collected on a Buchner funnel and washed widi water. The material is dried on trays under vacuum at 55 - 60°C for about 2 days to afford 2-phenyl-4(5)-(hydroxymethyl)imidazole (10.7 g, 64.66 mmol), as a tan sold.

This material has a proton nuclear magnetic resonance (NMR) spectrum consistent with die structure. Thin layer chromatography utilizing C18 reversed phases plates and a mobile phase of

65:35 metiianol: 0.5 M NaCl-1% acetic acid provides a single spot (Rf = .64).

Part B

Compound 23A

To a suitable reaction vessel equipped with mixing, heating, and cooling means and purged widi nitrogen is charged 2-phenyl-4(5)-(hydroxymethyl)imidazole (10.38 g, 59.6 mmol), and l-(2-pyrimidinyl)piperazine (17 g, 130.6 mmol). The piperazine is warmed to 50°C and added as a liquid. The mixture is then heated at 130-140°C for about 2 hours at which point the mixture solidifies. Agitation is stopped and heating continued for an additional hour after which the the reaction is cooled to about 120°C. Toluene (42 g) is added and the mixture stined at 50°C for about 30 minutes. Removal of die toluene is accomplished by filtration through a 30 micron wound filter. Additional toluene (42 g) is added to the solids, the resulting mixture slurried at reflux for one hour, allowed to cool to room temperature, and finally allowed to stand overnight. The mixture is filtered using a Buchner funnel and the solids washed with toluene (10 g). The material is dried at approximately 60°C in a vacuum tray drier for 18 hours to yield crude Compound 23A as a free base. Part C

2-Phenvl-4(5Vr(4-(2-pvri---idinvnpiper-zin-l-vnmemyl1-imidazole dimaleate salt

1. To a suitable vessel is charged 2-propanol (95.5 g) and crude free base of Compound 23A (15.28 g, 47.69 mmol). The mixture is then heated to 70°C and a solution containing maleic acid (11.46 g, 98.8 mmol) dissolved in 2-propanol (51.27 g) at 72°C is added over a 2 hour period with cooling to keep the temperature below 80°C. The reaction is subsequently cooled, maintained at 23°C for 5 hours, and die solid collected by filtration through a Buchner funnel to yield a dimaleate salt (30.4 kg). The dimaleate salt is dien purified as described below without prior drying.

2. To a suitable vessel is charged water (73 g), 2-propanol (228 g) and die 30.4 g of material prepared in part 1 of part C of this example. The mixture is then heated for 1 hour at 70°C and filtered hot dirough a 3 micron filter. The filtrate is cooled to about 3°C, and the crystals are collected by filtration through polyethylene cloth. The crystals are then washed with 2-propanol (11.8 g) and dried under vacuum (28 inch Hg) for 3 days at 41°C to yield the title compound, 2-phenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-l-yl)methyl]-imidazole dimaleate salt, (19.95 g, 36.1 mmol). This material may subsequently be milled on a Fitz mill using a 0.0027 inch screen to yield final product.

Example 40

2-Phenyl-4(5)-hydroxymethylimidazole (300 g, 0.17 mmol) was dissolved in 5 mL of thionyl chloride and die mixture was briefly heated to reflux. After concentration on a rotary evaporator, chloroform was added and the resulting solution reconcentrated. The residue was dissolved in 5 mL of chloroform and 335 mg of l-(5-methoxy-2-pyrimidinyl)piperazine (prepared essentially according to die procedure described in J. Chem. Soc., 4590, 1960) and 2 mL of triethylamine were added. After 20 min., the reaction mixture was washed widi IN NaOH solution, dried and concentrated. The resulting material was taken up in a solution of 2 equivalents of maleic acid in 2 mL of isopropanol after which 3 mL of isopropanol was added. Filtration of the resulting solid provided 870 mg of 2-phenyl-4(5)-[4((2-{ 5- π-ethoxypyri-mdinyl})piper-ι-inyl-l)meώyl]imidazole dimaleate (86%).

Example 41

2-Phenyl-4(5)-hydroxymethylimidazole (200 g) was dissolved in 5 mL of thionyl chloride and the mixture was briefly heated to reflux. After concentration on a rotary evaporator, chloroform was added and die resulting solution reconcentrated. The residue was dissolved in 5 mL of chloroform and 210 mg of l-(5-fluoro-2-pyrimidinyl)piperazine (prepared essentially according to the procedure described in Chem. Pharm. Bull., 2£: 2298, 1991) and 1 mL of triethylamine were added. After 20 min., the reaction mixture was washed with IN NaOH solution, dried and concentrated. Silica chromatography, eluting with 10% medianol in chloroform, provided 175 mg of 2-phenyl-4(5)-[4-((2-{5-fluoropyrimidinyl})piperazin-l- yl)medιyl]imidazole. The dimaleate salt was crystallized from isopropyl alcohol (m.p. 185- 186°C).

Example 42

To a solution of 2-phenyl-4(5)-[4-((2-{methoxypyrimidinyl})piperazin-l-yl)methyl]- imidazole (Example X) (0.37 g) in dry chloroform (8 mL) was added. boron tribromide solution 11.5 mL of 1.0 N BB13 in methylene chloride). The resulting mixture was refluxed for 4 hours, poured onto ice and ammonium hydroxide and extracted with chloroform. The organic extracts were dried (Na2SO4 ) and concentrated. The product was purified by preparative thin layer chromatography eluting widi 10% methanol in chloroform to provide 75 mg of 2-phenyl-4(5)-[4- ((5-hydroxypyriιmdin-2-yl)piperazin-l-yl)methyl]imidazole. The dioxalate salt was prepared in ethyl alcohol (m.p.214-216°C).

The dihydrochloride salt was also prepared, m.p.: 217-220°C.

Example 43

The following compounds were assayed for D2, D3, and D4 receptor binding activity using the assays described above.

Receptor Binding Activity (Ki. nM.

Dopamine Receptor

Compound No. D2 D3 D4

45 239 169 5

23 1033 8200 2.7

24 1029 123 0.85

Example 44 Summary

The effects of 2-phenyl-4(5)-[(4-(2-pyrimidyl)-piperazin-l-yl)methyl]-imidazole dihydrochloride (Compound 23) and clozapine were evaluated in tthe following models of learning and memory: a step-down passive avoidance task assay and a modified Morris water maze assay Separate groups of male Sprague Dawley rats were pretreated with eitiier Compound 23 or clozapine prior to training in these tasks. The control compound, clozapine, produced an acquisition deficit in the passive avoidance task at the two highest doses tested (1.0, 2.0 mg/kg) but produced no significant deficits in retention. Clozapine produced no deficits in the water maze task at the doses tested. In the step-down passive avoidance assay animals that received the 0.25 mg/kg dose of Compound 23 showed significant improvement in memory compared to the vehicle group. Likewise in the modified Morris water maze, animals that received the 0.03, 0.25 and die 1.0 mg/kg dose of Compound 23 showed significant improvement in task retention compared to the vehicle group. These data show that Compound 23 does not impair learning, but enhances learning in animals. Method

Non-naive male Sprague Dawley rats (SASCO St. Louis) weighing between 2000-300 grams, were housed in groups of three in a temperature and humidity controlled vivarium having a 12 hour light/dark cycle. Animals had ad lib access to food and water. Compound 23 was dissolved in 50% Polyethylene glycol (PEG) and administered in a dose range of 0.03-1.0 mg kg. Clozapine was dissolved in 50% PEG and administered in a dose range of from 0.25 to 2mg/kg. Both drugs were administered intravenously 5 minutes prior to training in both learning tasks.

Apparatus:

Step-Down Passive Avoidance: A step-down passive avoidance platform 4 (cm)x7(cm) was placed in the center of an electrified gris floor, which was contained within a large (45 x 45 x 50 cm) white translucent plexiglas enclosure.having a closable lid. The bars of the grip were spaced 1.5 cm apart and were wired to a BRS-LVE shock generator/scrambler which was set to deliver a 2mA 6 second shock. Four passive avoidance boxes were automated by customer software (Labview) and commercial interface modules (National Instruments) connected to a computer The timing and delivery of the shock as well as the latency to steo down and the number of trials taken to reach criterion during training was under die control of the computer. All testing was done in die presence of 62db white noise.

Modified Morris Water Maze: A water maze apparatus consisted of a circular tank (120 cm in diameter and 56 cm in height) having a black interior. The tank was sunounded by external visual cues which consisted of a black and white checkered wall, a black and white striped wall, a while wall and a blue panel. The tank was filled with water (18-20°C) to a height of 52 cm and was divided into four quadrants (North, South, East and West). A black circular plexiglas platform (with black rubber top) was placed in the northeast quadrant approximately 1 cm below the surface of the water. The submerged platform was 51 cm in height and had a diameter of 9 cm. Training and testing was conducted in the presence of a 62db white noise source and under dim light conditions.

Procedure:

1. Passive Avoidance:

Acquisition Training: After pretreatment with clozapine, Compound 23 or control (vehicle), the animal was placed on the platform which automatically started a timer. When the animal stepped off the platform it automatically received the footshock. Following each shock the animal was removed from the box and placed in its cage for a one minute intertrial interval and then returned to the platform. Training was terminted when the animal remained on the platform for 120 Seconds. Immediately after training die animal was returned to its home cage in a vivarium.

Retention Testing: Testing was conduced approximately 24 hours after training, Drug- free animals were placed on die platform in die box in which they were trained and die latency to step down onto the unshocked floor was recorded for one trial. The animal was allowed to a maximum of 120 seconds to step down.

2. Modified Morris Water Maze: Acquisition Training: Acquisition training in this task assay consisted of eidier four or six training trials. The four trial procedure detects cognitive enhancing effects of drugs while the six trial procedure detects drugs that produce learning deficits in this task.assay Compound 23 was tested in the water maze using a four trial procedure and clozapine using a six trial training procedure. Each animal was placed on the platform in the tank for 20 trials separated by an intertrial interval of 2 minutes. The starting position was pseudo-randomly varied but was the same order for each animal. During the ITI (intertrial interval) the animal was dried off and placed near a heat source (heat lamp). The latency to reach the submeged platform on each trial was measured and animals were allowed to remain on the platform for 10 seconds once they reach it. Since the platform was submerged just below the surface of the water, the animal was required to use die external visual cues sunounding the tank (distal cues) to locate die platform. Retention Training: On the following day, each animal was individually tested for retention in one trial. All animals were placed in die "SOUTH" starting position and latency to find die submerged platform was recorded.

Results

Passive Avoidance: There were no significant differences for acquisition between the vehicle grup and animals treated with Compound 23. Animals that received 0.25 mg kg dose of Compound 23 remained on the platform for a significantly longer time during retest than the vehicle animals. Animals that received die 1.0 mg/kg and 2.0 mg/kg doses of clozapine showed a significant deficit in acquisition compared to the vehicle group. There were no significant differences in retention between clozapine treated animals and the vehicle group.

Water Maze: The difference between the first trial and the retest trial (latency to locate the platform on die following day) revealed significant improvement in retention relative to controls at the 0.03 mg/kd, 0.25 mg/kg and the 1.0 mg/kg dose of Compound 23. However, the difference between the scores of trial 1 and the retest trial for animals that received clozapine revealed no significant differences. These results indicate that compound 23 improved memory in mammals. These results further show diat compound 23 also enhances learning in mammals. Thus, the compounds of die invention are useful for enhancing cognition in mammals and can be used in methods for enhancing cognition, specifically learning and memory, in mammals.

The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.

The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in die art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, die following claims conclude tiiis specification.

Claims

WHAT IS CLAIMED IS:

1. A compound of die formula:

or the pharmaceutically acceptable salts thereof wherein: Rl is aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl; unsubstituted or substituted by up to 3 substituents which may be the same or different and represent hydrogen, halogen, trifiuoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2R9 where R9 is NH2. NHCH3, or a straight or branched chain lower alkyl having 1-6 carbon atoms;

X is N or NR2 where R2 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; Y is N or CR3; Z is CR3 or N; provided that Y and Z are not bodi CR3; and provided that Y and Z are not both N; R3 is hydrogen, lower alkyl, halogen, hydroxy lower alkyl or phenyl unsubstituted or substituted by up to tiiree substituents which may be the same or different and represent hydrogen, halogen, trifiuoromethyl, cyano, sulfonamido, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; R4 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or, when Z is CR3, R3 and R4 together may represent -(CH2)n " where ni is 2, 3 or 4; or R2 and R4 togedier may represent -(CH2)n2" where n2 is 2, 3 or 4; m is zero, one or two;

R5 and R are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl, straight or branched chain lower alkoxy having 1-6 carbon atoms; or R4 and R5 together may represent -(CH2)n3- where n3 is 2 or 3; or NR5R6 together represent: 2-( 1 ,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR5R6 represents:

where R7 is phenyl, benzyl or phenethyl widi die phenyl ring unsubstituted or substituted with up to diree substituents which may be die same or different and represent hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

NR5R6 represents:

where p is 1, 2, or 3;

W is N or CH; and W is N and Rg is hydrogen, trifiuoromethyl, phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W is CH and Rg is optionally substituted phenyl or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

2. A compound of claim 1 which is:

where

Rl is aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl; unsubstituted or substituted by up to 3 substituents which may be the same or different and represent hydrogen, halogen, trifiuoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2R9 where R9 is NH2 or NHCH3;

R2 is hydrogen or alkyl; R3 is hydrogen, lower alkyl, halogen, hydroxy lower alkyl, or phenyl unsubstituted or substituted by up to diree substituents independently selected from hydrogen, halogen, trifiuoromethyl, Cyano, sulfonamido, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms;

R4 is: hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or R3 and R4 togedier may represent -(CH2)n " where ni is 2, 3 or 4; or R2 and R4 together may represent -(CH2)n2^_ where n2 is 2, 3 or 4. m is: zero, one or two R5 and R6 are die same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl, straight or branched chain lower alkyl having 1-6 carbon atoms; or R4 and R5 together may represent -(CH2)n3- where n3 is 2 or 3; or

NR5R6 togedier represent: 2-(l,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR5R6 represents:

where R7 is phenyl, benzyl or phenethyl with die phenyl ring unsubstituted or substituted with up to three substituents which may be die same or different and represent hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

NR5R6 represents:

where p is 1, 2, or 3; and

W is N and Rg is hydrogen, phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

W is CH and Rg is optionally substituted phenyl, optionally substituted benzoyl, or an arylalkyl group such as, for example, phenylalkyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifiuoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

3. A compound according to Claim 1, wherein Rl is phenyl or pyrimidinyl optionally substituted widi halogen or alkoxy; R2 and R4 are hydrogen; and NR5R6 is:

where p is 2;

W is N and Rg is phenyl, pyridyl or pyrimidinyl,each of which is optionally or disubstituted with halogen, hydroxy or straight or branched chain lower alkoxy having 1-6 carbon atoms.

4. A compound according to claim 1, wherein Rl is an aryl substituted with up to 3 fluorine atoms and NR5R6 is N,N,dimetiιyl.

5. A compound according to Claim 1 , which is selected from the group consisting of

2-phenylr4(5)-[(4-phenylpiperazin- 1 -yl)methyl]imidazole ; 2-(4-fluorophenyl)-4(5)[(4-phenyl-piperidin-l-yl)-methyl]-imidazole ;

2-(4-methoxyphenyl)-4(5)[(4-phenyl-piperidin- 1 -yl)-methyl] -imidazole ;

2-phenyl-4(5)-[(4-(3-trifluoromethylphenyl)piperazin-l-yl-)methyl]imidazole;

2- (2-methoxyphenyl )-4(5)[ (4-phenyl-piperidin- 1 -y l)-methy 1] -imidazole ;

2-(3-methoxyphenyl)-4(5)[(4-phenyl-piperidin- 1 -yl)-methyl] -imidazole ; 2-(3-fluorophenyl)-4(5)[(4-phenyl-piperidin- 1 -yl)-methyl]-imidazole;

2-(2-fluorophenyl)-4(5)[(4-phenyl-piperidin- 1 -yl)-methyl]-imidazole ;

2-(2-methylphenyl)-4(5)-[(4-benzyl-piperidin-l -yl)-methyl]-imidazole ;

2-(5-ethyl-2-methoxyphenyl-4(5)-[(4-phenyl-piperidin-l-yl)-methyl]-imidazole;

2-(5-ethyl-2-methoxyphenyl-4(5)-[(4-(2-medιoxyphenyl)-piperazin-l-yl)-methyl]-imidazole; 2-phenyl-4(5)-[(4(4-fluorophenyl)- piperazin- l-yl-)medιyl]imidazole;

2-(5-ethyl-2-meΛoxyphenyl-4(5)-[(4-(2-pyr--nrύdinyl)-piperazin-l-yl)-meώyl]-imidazole;

2-phenyl-4(5)-[(4(4-fluoro-2-pyrimidinyl)-piperazin-l-yl)-methyl]imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

6. A compound according to Claim 1 , which is selected from the group consisting of 2-(4-fluorophenyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-medιyl]-imidazole; 2-phenyl-4(5)-[(4(5-chloro-2-methylphenyl)piperazin-l-yl)-medιyl]imidazole; 2-phenyl-4(5)-[(4-(3,4-dichlorophenyl)piperazin- 1 -yl)-metiιyl]-imidazole; 2-phenyl-4(5)-[(4-(4-fluorophenyl)- piperidin-l-yl)-methyl]imidazole;

2-(3-fluorophenyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imidazole;

2-(4-fluorophenyl)-4(5)-[(4-benzyl-piperidin-l-yl)-methyl]-imidazole;

2-phenyl-4(5)-[(4-(4-fluorobenzyl)-piperidin- 1 -yl)-methyl] -imidazole ;

2-(2-fluorophenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole; 2-(4-memylphenyl-4(5)-[(4-(2-pyrir dmyl)-piper--z-Λ-l-yl)methyl]-imidazole;

2-(2-fluorophenyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-medιyl]imidazole ;

2-(4-chlorophenyl-4(5)-[(4-(2-pyridyl)-piperazin- 1 -yl)-methyl]-imidazole;

2-phenyl-4(5)-[(4-(5-fluoro-2-pyrimidinyl)-piperazin- 1 -yl)-medιyl]-imidazole;

2-phenyl -4(5)-{ l-[(4-benzyl-piperidin-l-yl)-edιyl)] imidazole; 2-(2-fluorophenyl-4(5)-[(4-(5-fluoro-2-pyrirnidinyl)-piperazin- 1 -yl)-methyl]-imidazole;

2-(4-fluorophenyl-4(5)-[(4-(5-fluoro-2-pyrir dinyl)-piperaan-l-yl)-methyl]-i-midazole

2-phenyl-4(5)-[(4-(4-fluoro-2-pyrin-idinyl)-pipera-tin-l-yl)-me-hyl]-iπ-ida--ole;

2-(2-fluorophenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-pipe-^n-l-yl)-meΛyl]--midazole;

2-(4-fluc>rophenyl-4(5)-[(4-(4-fluoro-2-pyrimiώnyl)-piperazin-l-yl)-methyl]-imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

7. A compound according to Claim 1 , which is selected from the group consisting of l-medιyl-2-phenyl -4-[(4-(2-pyrimidinyl)piperazin- l-yl)methyl]-imidazole;

1 -methyl-2-phenyl -5-[(4-benzyl-piperidin- 1 -yl)medιyl] -imidazole; 1-methyl - 2-phenyl -5-[(4-(2-pyrimidinyl)piperazin-l-yl)medιyl]-imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

8. A compound according to Claim 1 , which is selected from the group consisting of 4-phenyl-2(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imidazole; 4-phenyl-2(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole;

4-phenyl-2(5)- [(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole;

4-phenyl-2(5)-[4-(4-fluorobenzyl-piperidin-l-yl)-methyl]-iιnidazole;

4-phenyl-2(5)-[(4-phenylpiperidin- 1 -yl)-methyl]-imidazole;

4-phenyl-2(5)-[(4-(4-fluorophenyl)- piperazin- 1 -yl-)methyl]imidazole; 4-phenyl)-2(5)-[(4-(2-methoxyphenyl)-piperazin- 1 -yl)-methyl]imidazole;

4-phenyl-2(5)-[(4-(2-pyridyl)-piperazin-l-yl)-methyl]imidazole;

4-phenyl-2(5)-[(4-phenyl - piperazin- 1 -yl-)methyl]imidazole; 4-phenyl-2(5)-[(4-benzoyl-piperidin- 1 -yl)-methyl] -imidazole; 4-phenyl-2(5)-[4-(4-fluorobenzoyl-piperidin- 1 -yl)-me_ιyl]-imidazole; 5-methyl-4-phenyl-2(5)-[(4-benzy 1-piperidin- 1 -yl)-medιyl]imidazole, and die non-toxic pharmaceutically acceptable salts thereof.

9. A compound according to Claim 1 which is selected from the group consisting of 2-phenyl-5-memyl-4(5)-[(4-(2-pyriπήdinyl)piperazin-l-yl)meώyl]-im-dazole; and 2-phenyl-5-iodo-4(5)-[(4-(2-pvrimidinyl)piperazin- 1 -yl)methyl]-imidazole. 2-phenyl-5-meώyl-4(5)-[(4-(5-fluoropyrimidin-2-yl)piperazin- 1 -yl)methyl]-imidazole; and 2-(2-fluorophenyl)-5-memyl-4(5)-[(4-(5-fluoropyri-midin-2-yl)piperazin- 1 -yl)metiιyl]-imidazole; 2-phenyl-5-meΛyl-4(5)-[(4-(4-fluoropyjirmdin-2-yl)piperazin-l-yl)meώyl]-irmda_ole; 2-(2-fluorophenyl)-5-memyl-4(5)-[(4-(4-fluoropyrimidin-2-yl)piperazin-l-yl)medιyl]-imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

10. A compound according to Claim 1 which is 2-phenyl-4(5)-[l-((4-benzyl- piperidin-l-yl)-ethan-l-yl)]imidazole, or the non-toxic pharmaceutically acceptable salts thereof.

11. A compound according to Claim 1 which is selected from the group consisting of 2-(l-naphAyl)-4(5)-[(4-benzyl-piperidin-l-yl)-methyl]-irmdazole; 2-( 1 -naphdιyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole;

2-(l-naphthyl)-4(5)-[(4-(2-pyridyl)-piperazin-l-yl)-methyl]-imidazole;

2-(l-naphthyl)-4(5)-[(N-medιyl-N-benzyl)-methyl]-imidazole;

2-(2-naphthyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imidazole;

2-(2-naphdιyl)-4(5)-[(4-(2-pyri-mimnyl)-piperazin-l-yl)-methyl]-imidazole; 2-(2-naphthyl)-4(5)-[(4-(2-pyridyl)-piperazin- 1 -yl)-methyl]-imidazole;

2-(2-naphdιyl)-4(5)-[(N-medιyl-N-benzyl)-methyl]-imidazole, and the non-toxic pharmaceutically acceptable salts diereof.

12. A compound according to Claim 1 , which is selected from the group consisting of 2-(2-pyridyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imidazole;

2-(2-pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl] -imidazole; 2-(2-pyridyl)-4(5)-[(4-(2-pyridyl)-piperazin-l-yl)-methyl]-i--ιidazole; 2-(2-pyridyl)-4 (5)-[(N-methyl-N-benzyl)-methyl]-imidazole; 2-(3-pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-methyl]-imidazole; 2-(3-pyridyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole;

2-(4-pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-medιyl]-imidazole; 2-(2-quinohnyl)-4(5)-[(4-(2-pyrirmώnyl)-piperazin-l-yl)-methyl]-imidazole; 2-(2-quinolinyl)-4 (5)-[(N-medιyl-N-benzyl)-methyl]-imidazole; 2-(2-pyrazinyl)-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imida--ole; 2-(2-pyra-dnyl)-4(5)-[(4-(2-pyriιmdinyl)-piperi--in-l-yl)-methyl]-imidazole; 2-(2-pyrazinyl)-4 (5)-[(N-medιyl-N-benzyl)-methyl]-imidazole, and die non-toxic pharmaceutically acceptable salts thereof.

13. A compound according to Claim 1 , which is selected from the group consisting of 2-(2- _ιienyl)-4(5)-[(4.benzyl-piperidin- 1 -yl)-methyl]-imidazole; 2-(2-tltienyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-medιyl]-imidazole; 2-(2-thienyl)-4 (5)-[(N-methyl-N-benzyl)-methyl] -imidazole;

2-(2-thienyl)-4(5)-[(4-(2-pyridyl)-piperazin- 1 -yl)-methyl] -imidazole., and the non-toxic pharmaceutically acceptable salts thereof.

14. A compound according to Claim 1 , which is selected from the group consisting of 2-(benzoyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole;

2-(benzyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-medιyl]-imidazole; 2-(5-methoxy-3,4-dihydro-naphth-l-yl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

15. A compound according to Claim 1 , which is selected from the group consisting of

2-phenyl-4(5)-[(4(2-pyrimidinyl)-piperazin- 1 -yl)-propen- 1 -oyl]-imidazole;

2-phenyl-4(5)-[(4-phenyl-piperazin-l-yl)-propen-l-oyl]-imidazole;

2-phenyl-4(5)-[(4-hydroxy,4-(4-chlorophenyl)-piperidin-l-yl)-propen-l-oyl]-imidazole;

2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-propan-l-oyl]-imidazole; 2-phenyl-4(5)- [(4-phenyl-piperazin- 1 -yl)-propan- 1 -oylj-imidazole;

2-phenyl-4(5)-[(4-(2-(3,4,5,6-tetrahydro)-pyrimidinyl)-piperazin- 1 -yl)-propan- 1 -oylj-imidazole;

2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- l-yl)-propan- 1 -yl]-imidazole;

2-phenyl-4(5)-[(4-phenyl-piperazin- 1 -yl)-propan- 1 -yl] -imidazole;

2-phenyl-4(5)-[(4-hydroxy-4-(4-chlorophenyl)-piperidin- 1 -yl)-propan- 1 -yl ]-imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

16. A compound according to Claim 1, which is selected from the group consisting of 2-cyclohexyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-l-yl)-medιyl]-imidazole; 2-cyclohexyl-4(5)-[(4-benzyl-piperidin- 1 -yl)-methyl]-imidazole; 2-cyclohexyl-4(5)-[(N-medιyl-N-benzyl)-medιyl]-imidazole;

2-(4-n-«-;thylcyclohexyl)-4(5)-[(4-(2-pyrirnidinyl)-piperazin-l-yl)-methyl]-imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

17. A compound according to Claim 1, which is selected from the group consisting of 2,5-diphenyl-4(5)-[(4-(2-pyrimidinyl)pipera_in- 1 -yl)methyl] -imidazole; 2-( memylphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-methyl]-imidazole; 2-(4-iodophenyl-4(5)-[(4-(2-pyrimidinyl)-pipera2in-l-yl)-n-«myl]-imidazole; 2-phenyl-4(5)-[(4-(4-chlorophenyl)-3-methylpiperazin- 1 -yl)methyl]imidazole; 2-phenyl-4(5)-[( (4-me_ιylphenyl)-3-medιylpiperazin- 1 -yl)methyl]imidazole; 2-phenyl-4(5)-[(4-(4-methoxyphenyl)-3-methylpiperazin- 1 -yl)me-hyl]imidazole, and die non-toxic pharmaceutically acceptable salts thereof.

18. A compound according to Claim 1 , which is selected from the group consisting of 2-phenyl-7-[(4-(2-pyrimimnyl)-piperazk-l-yl)-meώyl]-4,5,6,7-tetrahydrobenzimidazole; 2-phenyl-7-[(4-benzyl-piperidin-l-yl)-memyl]-4,5,6,7-tetrahydrobenzimidazole; 2-phenyl-7-[(N-memyl-N-ben-tyl)-tminomethyl]-4,5,6,7-tetrahydrobenzimidazole, and die non-toxic pharmaceutically acceptable salts thereof.

19. A compound according to Claim 1 , which is selected from the group consisting of 2-phenyl-4(5)-[(4-(2-pyrirm^nyl)-ds-2,6-dimethylpiperazin-l-yl)-medιyl]-imidazole; 2-phenyl-4(5)-[(4-(2-pyrimidmyl)-trans-2,5-dime ylpiperazin-l-yl)-methyl]-imidazole; 2-phenyl-4(5)-[(8-(2-pyrimidinyl)-3-8-diazabicyclo(3.2.1)octan-3-yl)-medιyl]-imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

20. A compound according to Claim 1, which is 2-phenyl-4(5)-[(4-(2-pyrimidinyl)- pipera-dn-l-yl)-eth-m-l-yl]-imidazole or the non-toxic pharmaceutically acceptable salts thereof.

21. A compound according to Claim 1 , which is selected from the group consisting of 2-phenyl-4(5)-N-[(4-(2-pyrimidinyl)-piperazin- 1 -yl)-carboxamido]-imidazole; 2-phenyl-4(5)-N-[(N-methyl-N-benzyl)-carboxamido]-imidazole; 2-phenyl-4(5)-N-[(4-benzyl-piperidin- 1 -yl)-carboxamido]-imidazole, and the non-toxic pharmaceutically acceptable salts thereof.

22. A compound of die formula:

or die non-toxic pharmaceutically acceptable salts thereof wherein: R_a represents hydrogen or lower alkyl; Ri and Y independently represent hydrogen, lower alkyl or halogen,

RlO represents hydrogen, hydroxy, lower alkoxy or halogen; and E represents CH or nitrogen.

23. A compound according to Claim 22, wherein E is nitrogen, Ri and Y are hydrogen or halogen, and Rio is halogen, hydroxy or lower alkoxy.

24. A compound according to Claim 22, wherein E is nitrogen, Ri and Y are hydrogen or fluorine provided diat not bodi are fluorine, and Rio is fluorine.

25. A compound according to Claim 22 which is selected from the group consisting of

2-phenyl-4(5)-[4((5-meu-oxypyrimidin-2-yl)piperazinyl-l)methyl]imida-ole;

2-phenyl-4(5)-[4-((5-fluoropyrimidin-2-yl)piperazin-l-yl)medιyl]imida_ole;

2-phenyl-4(5)-[4-((5-hydroxypyrimidin-2-yl)piperazin- 1 -yl)methyl]imidazole; 2-Phenyl-4(5)-[( (2-pyrirmdinyl)piperazin- 1 -yl)methyl] -imidazole;

2-(2-fluorophenyl-4(5)-[(4-(5-fluoro-2-pyrimidinyl)-piperazin-l-yl)-medιyl]-imidazole;

2-(4-fluorophenyl-4(5)-[(4-(5-fluoro-2-pyrimimnyl)-piperazin-l-yl)-meΛyl]-imidazole;

2-phenyl-5-methyl-4(5)-[(4-(2-pyrimidinyl)piperazin-l-yl)me-hyl]imidazole;

2-phenyl-5(4)-medιyl-4(5)-[(4-(5-fluoropyrimidin-2-yl)piperazin-l-yl)medιyl]-imidazole; 2-(2-fluorophenyl)-5(4)-methyl-4(5)-[(4-(5-fluoropyrimidin-2-yl)-piperazin- 1 -yl)methyl]- imidazole, and the non-toxic pharmaceutically acceptable salts thereof.