JP2941950B2 - Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives; a novel class of dopamine receptor subtype specific ligands - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Background of the Invention This application is a US patent application Ser.
N. 08-344,154; U.S. Patent Application SN 08 / 401,201 filed March 9, 1995; and U.S. Patent Application SN 08 / 344,552 filed November 23, 1994;
Each of which is a US patent application filed September 27, 1994.
A continuation-in-part of SN08 / 313,435, which was filed in 1993
This is a continuation-in-part of U.S. Patent Application SN08 / 081,317, filed November 8, which is incorporated by reference in U.S. Patent Application SN07 / 635,256, filed December 28, 1990 (now U.S. Patent No. 5,159,08).
3) is a continuation-in-part application.

FIELD OF THE INVENTION The present invention relates to certain 4-aminomethyl-2-substituted imidazole and 2-aminomethyl-4-substituted imidazole derivatives that selectively bind to brain dopamine, receptor subtypes. The invention further relates to pharmaceutical compositions comprising such compounds. In addition, the present invention is directed to the treatment of emotional disorders such as schizophrenia and depression, as well as certain movement disorders such as Parkinson's disease, as well as the extrapyramidal side effects associated with the use of conventional neuroleptics. It also relates to the use of said compounds in treatment.

2. Description of the Related Art Schizophrenia or psychosis is a term used to describe a group of diseases of unknown cause affecting about 2.5 million people in the United States. These impaired abilities are characterized by various signs classified as positive signs (disordered thinking, hallucinations and delusions) and negative signs (social autism and nonresponsiveness). These disorders have an onset of adolescence or early adulthood and persist for many years. These disorders tend to be more severe over the life of the patient and can result in long hospital stays. Currently, in the United States, about 40% of all hospitalized mentally ill patients have schizophrenia.

In the 1950s, doctors showed successful treatment of psychiatric patients with drugs called neuroleptics. This classification of antipsychotics is based primarily on the activating (nerve relaxing) properties of the nervous system by these drugs. Subsequently, neuroleptics were shown to increase the concentration of dopamine metabolites in the brain, suggesting altered dopaminergic neurological effects. Other evidence also shows that dopamine increases the activity of adenylate cyclase in the striatum, and this effect is reversed by neuroleptics. Thus, the accumulated evidence from these and subsequent experiments strongly suggested that neurotransmitter dopamine is involved in schizophrenia.

One of the main actions of antipsychotics is the blockade of dopamine receptors in the brain. Several dopamine systems appear to be present in the brain, and at least five dopamine receptors appear to mediate the effects of this mediator. These dopamine receptors differed in their pharmacological specificity and were initially classified based on differences in the pharmacology of different chemicals. Butyrophenone, which contains many potential antipsychotics, was extremely weak at dopamine receptors (now known as D1 dopamine receptors) that activate adenylate cyclase.
In contrast, they label other dopamine receptors in the subnanomolar range (referred to as D2 receptors),
In addition, a third type of D3 in the nanomolar range was labeled. Two other receptor subtypes have also been identified, D5, which is slightly similar to the D1 receptor type, and D4, which is closely related to the D3 and D2 receptor types. Phenothiazine has nanomolar affinity for all three dopamine receptors. Other drugs with great specificity for D1 and D2 subtype receptors have also been developed.

Certain classes of drugs (eg, sulpiride and clozapine) have also been developed and have a lower incidence of extrapyramidal side effects than conventional neuroleptics. In addition, there are certain indications that may be more beneficial in treating negative symptoms in certain patients. This class of drugs is often referred to as atypical antipsychotics. Since all D2 sequestrants do not have similar profiles, the hypothesis underlying these differences has been examined. The main difference is the anticholinergic effects of neuroleptic drugs, as well as the possibility that dopamine receptors may differ in the motor area from those in the peri-cerebral area where they seem to mediate antipsychotic responses. D3,
The presence of undiscovered dopamine receptors such as D4 and D5 may be involved in this profile. Certain atypical compounds show similar activity at the D2, D3 and D4 receptors. The examples of this application fall into this general class of molecules.

Using molecular biology techniques, cDNAs encoding each of the pharmacologically defined receptors can be cloned. At least two types of D1 classified as D1 and D5
There are two types of receptors, type D receptors, and now classified as D2 and D4 dopamine receptors. In addition, there is at least one D3 dopamine receptor. Examples of the substituted aminomethylimidazole series of the present application have different affinities for each receptor subtype.

Schizophrenia is characterized by various cognitive dysfunctions. Schizophrenics perform less than other groups for most cognitive or intensive tasks. The extent of positive and negative signs of schizophrenia are also associated with various cognitive deficits. In general, positive signs (impaired thought processes, hallucinations and delusions) are associated with auditory processing disorders, including deficits in verbal memory and verbal understanding. Negative signs (social autism and unresponsiveness) are more associated with gross / motor dysfunction, including poorer behavior to gross memory, motor speed and agility.

These disorders have an onset of early adolescence or early adulthood and persist for many years. Interactions between the forebrain and the septo-hippocampal system, as well as deficits in information processing and self-monitoring, have been theorized as the basis for positive symptoms. Negative signs may result from abnormalities in the interaction between the forebrain and striatum. Since cognitive impairment is present in most patients diagnosed as having schizophrenia, it has been theorized that understanding the etiology and etiology of schizophrenia requires understanding the underlying dysfunction of cognitive impairment. ing.

The cognitive deficits found in schizophrenia include, but are not limited to, various language and visual memory deficits. There are various neurocognitive tasks for both animals and humans that are being developed to assess memory deficits and the memory enhancement of various treatments. Many neural cognitive behavioral tasks are modulated or mediated by eural activity in the hippocampal system described above.

Drugs that interact with the hippocampus can modulate memory in animals. Certain memory paradigms used in animals also have a constructive and predictive truth about memory evaluation in humans. In animals (rodents), for example, the Step-Down Passive Avoidance Task analysis or the Spatial Water Maze Task
Paradigms such as the Water Maze Task analysis reliably detect defects caused by certain drugs in humans. For example, the commonly prescribed benzodiazepines, anxiolytics and sedating ophthalmic drugs, can cause memory impairment in humans, such as memory impairment, including varying degrees of aversion amnesia (which is truly drug dependent). Are known. In the step-down passive avoidance paradigm, these identical drugs destroy an animal's memory if given the compound during information acquisition or processing. Similarly, benzodiazepines disrupt information processing and memory in the Spatial Water Maze task in rodents. That is, these animal models can be used to predict the memory impairment effect of certain compounds in humans. Conversely, these same animal models can predict the memory enhancing or enhancing effects of compounds in humans. To a lesser extent, drugs that enhance memory in humans (eg Nutroprice, β-carboline) produce memory enhancing effects in rats in these models. Thus, the spatial water maize and step-down passive avoidance paradigms in rodents are useful in predicting the memory impairment and memory enhancing effects of test compounds in humans.

SUMMARY OF THE INVENTION The present invention provides novel compounds of Formula I that interact with dopamine receptor subtypes.

The present invention provides a pharmaceutical composition comprising a compound of Formula I. The invention further provides compounds useful in the treatment of emotional disorders, such as, for example, schizophrenia and depression, and certain movement disorders, such as, for example, Parkinson's disease. In addition, the compounds of the invention are useful in treating extrapyramidal side effects associated with the use of conventional neuroleptics.

Because dopamine D3 and D4 receptor subtypes are particularly focused on the pericerebral system that regulates cognition and emotion (Taubes,
Science (1994), 265, 1034], and compounds that interact with these receptors have use in treating cognitive disorders. This type of disorder is a cognitive deficit that is a prominent component of the negative signs of schizophrenia (social autism and nonresponsiveness). Other disorders, including memory disorders or intensive deficits disorders, can also be treated with certain compounds of the invention that interact specifically with dopamine D3 and / or D4 receptor subtypes.

Thus, the present invention provides a compound of formula I: Wherein R ₁ is aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl, each of which may be the same or different, hydrogen, halogen, trifluoromethyl, cyano, hydroxy, 1-6 carbon atoms Linear or branched lower alkyl having an atom, 1
Linear or branched lower alkoxy having from 6 to 6 carbon atoms, or SO ₂ R _9, wherein R ₉ is NH ₂ , NHCH ₃ or linear or branched having from 1 to 6 carbon atoms X is N or NR ₂ , wherein R ₂ is hydrogen or 1 to
Straight-chain or branched lower alkyl having 6 carbon atoms; Y is N or CR ₃ ; Z is CR ₃ or N; however, Y and Z are not both CR ₃ ; Further, Y and Z are both N
R ₃ is hydrogen, lower alkyl, halogen, hydroxy lower alkyl, or hydrogen, halogen, trifluoromethyl, cyano, sulfonamide, hydroxy, which may be the same or different, straight chain having 1 to 6 carbon atoms or R ₄ is hydrogen or 1-C-substituted lower alkyl, or phenyl, optionally substituted by up to three substituents representing straight-chain or branched lower alkoxy having 1 to 6 carbon atoms; R ₃ and R ₄ together when Z is CR _{3 represent} — (CH ₂ ) _n1 —, wherein n 1 is straight or branched lower alkyl having 6 carbon atoms. Is 2, 3 or 4; or R ₂ and R ₄ together represent — (CH ₂ ) _n2 —, wherein n 2 is 2, 3 or 4; m is 0, 1 or 2 There; R ₅ and R ₆ are same or lay It is different from hydrogen, 1
Denotes straight or branched lower alkyl having from 6 to 6 carbon atoms, straight or branched lower alkoxy or aryl having from 1 to 6 carbon atoms; or R ₄ and R ₅ together or NR ₅ R ₆ together 2- (1,2,3,4-tetrahydroisoquinolinyl); made by - are shown, where n3 is 2 or 3 - (CH _{2) n3} Which is unsubstituted or halogen, hydroxy, straight or branched lower alkyl having 1 to 6 carbon atoms, or straight or branched lower alkoxy having 1 to 6 carbon atoms. Mono- or disubstituted; or NR ₅ R ₆ is: Wherein R ₇ is phenyl, benzyl or phenethyl, and each phenyl ring may be the same or different as required, and may be hydrogen, halogen, trifluoromethyl, hydroxy, a straight chain having 1 to 6 carbon atoms A chain or branched lower alkyl, or a straight or branched lower alkoxy having 1 to 6 carbon atoms 3
Or NR ₅ R ₆ is: Wherein p is 1, 2 or 3; W is N or CH; W is N and R ₈ is hydrogen, trifluoromethyl, phenyl, pyridyl or pyrimidinyl, each of which is Optionally mono- or di-substituted or substituted by halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms, or linear or branched lower alkoxy having 1 to 6 carbon atoms. Or W is CH and R ₈ is an optionally substituted phenyl or arylalkyl group, for example, wherein the phenyl ring is independently hydrogen, halogen, trifluoromethyl, hydroxy, 1-6 carbon atoms. Selected from straight or branched lower alkyl having 1 to 6 carbon atoms or straight or branched lower alkoxy having 1 to 6 carbon atoms Phenylalkyl which can be substituted with up to three substituents].

These compounds are highly selective partial agonists or antagonists at the brain dopamine receptor subtype or its prodrugs, and include emotional disorders such as schizophrenia and depression, as well as certain disorders such as Parkinson's disease. Useful for the diagnosis and treatment of certain movement disorders. In addition, the compounds of the invention are useful in treating extrapyramidal side effects associated with the use of conventional neuroleptics. Furthermore, the compounds of the invention have use in the treatment of cognitive disorders. Disorders of this type include the negative manifestations of schizophrenia (social autism and other disorders including cognitive deficits or memory deficits or intensive deficits, which are prominent components of nonresponsiveness.

Compounds of the invention, for example 2-phenyl-4 (5)-
[(4- (2-pyridinyl) -piperazin-1-yl) -methyl] -imidazole dihydrochloride (Compound 23),
2-phenyl-4 (5)-[(4- (2-pyridyl)-
Piperazin-1-yl) -methyl] -imidazole dihydrochloride (compound 24) and 2-phenyl-4 (5)-
[(4-phenyl-piperazin-1-yl) -methyl]
-Imidazole dihydrochloride (compound 45) is an antagonist that binds to dopamine D4 receptors in both rat and human hippocampus.

As noted above, the hippocampus is associated with schizophrenia and with general memory processes in humans. In rodents, compound 23 has a memory enhancing effect in both step-down passive avoidance analysis and spatial water maize analysis. Without being bound by a particular theory, it is believed that the D4 receptor present in the hippocampus mediates the memory enhancing effects of the compounds according to the present invention.
Thus, (1) compound 23 is active in animal models that predict cognitive enhancement and specific enhancement of memory and learning, and (2) compound 23 binds to D4 receptors in the hippocampus, The D4 dopamine antagonists, including compounds, are useful for enhancing memory in humans.

Accordingly, the present invention further provides a method for improving cognition, particularly learning and memory, in mammals. These methods comprise administering to a mammal, such as a human, a compound of the present invention in an amount effective to enhance cognition.

DETAILED DESCRIPTION OF THE INVENTION In addition to the compounds of general formula I above, the present invention further provides compounds of formula II: Wherein R ₁ , X, Y, Z and m have the meanings given above for formula I; R ₃ is hydrogen, halogen, straight-chain or branched lower alkyl having 1 to 6 carbon atoms. R ₄ is hydrogen or straight-chain or branched lower alkyl having 1 to 6 carbon atoms, or if Z is CR ₃ , R ₃ and R ₄ together are — (CH _{2) n1} - indicates, where n1 is 2, 3 or 4; or R ₂ and R ₄ together - (CH _{2) n2} - are shown, where n2 is 2, 3 or 4 R ₂ and R ₅ together represent — (CH ₂ ) _n3 —, where n
3 is 2 or 3; R ₆ is hydrogen, straight or branched lower alkyl, phenyl or arylalkyl; or NR ₅ R ₆ is: Wherein R ₇ has the meaning given above for formula I;
₅ R ₆ is: Wherein p is 1, 2 or 3; W is N and R8 is unsubstituted or halogen, hydroxy, straight or branched lower alkyl having 1-6 carbon atoms, or W is CH and R ₈ is phenyl, optionally substituted phenyl, pyridyl or pyrimidinyl mono- or disubstituted by straight-chain or branched lower alkoxy having 1 to 6 carbon atoms; Alternatively, an arylalkyl group such as a phenyl ring is independently hydrogen, halogen, trifluoromethyl, hydroxy,
Substitute up to three substituents selected from straight or branched lower alkyl having 1 to 6 carbon atoms, or straight or branched lower alkoxy having 1 to 6 carbon atoms Phenylalkyl].

Preferred compounds according to formula I are those wherein Z is CR ₃ and R ₃ and R ₄
Together form a 5- or 6-membered ring; R ₁ is substituted or unsubstituted phenyl; X is N; Y is N; R ₅ and R ₆ are: Wherein W is N and R ₈ is phenyl, pyridyl or pyrimidinyl, each of which is optionally halogen, hydroxy, straight chain having 1 to 6 carbon atoms or Phenyl or W-CH optionally substituted with R ₈ optionally substituted with branched lower alkyl, or straight or branched lower alkoxy having 1 to 6 carbon atoms; Arylalkyl groups such as phenyl rings independently represent hydrogen, halogen, trifluoromethyl, hydroxy,
Substituted by up to 3 substituents selected from straight or branched lower alkyl having from 6 to 6 carbon atoms, or straight or branched lower alkoxy having from 1 to 6 carbon atoms. And phenylalkyl.

A preferred compound according to formula II is phenyl, wherein R ₁ is optionally substituted at the 4-position by halogen or alkyl;
Y and X are nitrogen, Z is CH, R ₄ is hydrogen, m is 0, and NR ₅ R ₆ is a 4-substituted piperazine-1-
Compounds that represent yl or 4-substituted piperidin-1-yl. The pyrazinyl or piperidinyl group is substituted at the 4-position by pyridyl or pyrimidinyl or phenyl or benzyl, each of which is preferably substituted at the 4-position by halogen, alkyl or alkoxy as required. Preferred pyridinyl groups are optionally substituted at the 3-position by alkyl, more preferably by methyl. Particularly preferred R ₁ groups are 4-
Methylphenyl and 4-halophenyl groups.

The present invention further provides a compound of formula IIA: Wherein R ₁ is unsubstituted or may be the same or different, hydrogen, halogen, trifluoromethyl, cyano, linear or branched lower alkyl having 1 to 6 carbon atoms, hydroxy, 1 to 6 Linear or branched lower alkoxy having 5 carbon atoms, or SO ₂ R _9, where R ₉
Is NH ₂ or NHCH ₃ ), aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl substituted by up to 3 substituents, wherein R ₂ is hydrogen or alkyl; R ₃ is hydrogen; Lower alkyl, halogen, hydroxy lower alkyl or unsubstituted or independently hydrogen, halogen, trifluoromethyl, cyano, sulfonamide, hydroxy, straight-chain or branched lower alkyl having 1 to 6 carbon atoms, or 1 R ₄ is hydrogen or a straight chain having 1 to 6 carbon atoms, substituted by up to 3 substituents selected from straight or branched lower alkoxy having from 6 to 6 carbon atoms; a lower alkyl or branched chain, or R ₃ and R ₄ together - (CH _{2) n1} - indicates, where n1 is two or three Teeth 4; or R ₂ and R ₄ together - (C
H _{2) n2} - indicates, this in n2 is 2, 3 or 4; m is 0, 1 or 2; R ₅ and R ₆ are hydrogen the same or different and may be 1
R ₄ and R ₅ together represent straight-chain or branched lower alkyl, aryl having -6 carbon atoms, aryl, straight-chain or branched lower alkoxy having 1-6 carbon atoms; -(CH ₂ ) _n3- , where n
3 is 2 or 3; or NR ₅ R _{6 taken} together are unsubstituted or halogen, hydroxy, straight or branched lower alkyl having 1 to 6 carbon atoms, or 1 to 6 NR ₅ R ₆ represents 2- (1,2,3,4-tetrahydroisoquinolinyl) mono- or di-substituted by straight-chain or branched lower alkoxy having carbon atoms; Wherein R ₇ is phenyl, benzyl or phenethyl, wherein the phenyl ring is unsubstituted or may be the same or different, hydrogen, halogen, trifluoromethyl, hydroxy, straight chain having 1 to 6 carbon atoms. Or NR ₅ R ₆ is substituted by up to three substituents, or branched lower alkyl, or straight or branched lower alkoxy having 1 to 6 carbon atoms; Wherein p is 1, 2 or 3; W is N and R ₈ is hydrogen, unsubstituted or halogen,
Phenyl mono- or disubstituted by hydroxy, straight-chain or branched lower alkyl having 1 to 6 carbon atoms, or straight-chain or branched lower alkoxy having 1 to 6 carbon atoms, Or W is CH and R ₈ is an optionally substituted phenyl, an optionally substituted benzoyl or arylalkyl group, for example, wherein the phenyl ring is independently hydrogen, halogen, trifluoromethyl, hydroxy, Substituted with up to three substituents selected from linear or branched lower alkyl having from 6 to 6 carbon atoms, or linear or branched lower alkoxy having from 1 to 6 carbon atoms. Phenylalkyl].

Preferred compounds of formula IIA are those wherein R ₁ is optionally substituted phenyl; R ₂ and R ₄ are hydrogen; R ₅ is alkyl; R ₆ is preferably optionally substituted arylalkyl;
More preferably unsubstituted benzyl; or NR ₅ R ₆
But: Wherein p, W and R ₈ have the meanings given above in formula I.

Particularly preferred compounds of formula IIA are those in which R ₁ is optionally substituted phenyl; R ₂ and R ₄ are hydrogen; R ₅ is alkyl; R ₆ is preferably optionally substituted arylalkyl, Preferably unsubstituted benzyl; or NR
₅ R ₆ is; Wherein p is 2; W is N and R ₈ is unsubstituted or halogen or 1
Phenyl mono- or di-substituted by straight-chain or branched lower alkoxy having from 6 to 6 carbon atoms,
Such compounds are pyridyl or pyrimidinyl.

Particularly preferred compounds of formula IIA are those wherein R ₁ is optionally substituted phenyl; R ₂ and R ₄ are hydrogen; R ₃ is hydrogen; R ₅ is alkyl; R ₆ is preferably A substituted arylalkyl, more preferably unsubstituted benzyl; or NR ₅ R ₆ is: Wherein p is 2; W is N and R ₈ is unsubstituted or halogen or 1
Phenyl mono- or di-substituted by straight-chain or branched lower alkoxy having from 6 to 6 carbon atoms,
Such compounds are pyridyl or pyrimidinyl.

Other particularly preferred compounds of formula IIA are: R ₁ is phenyl; R ₂ and R ₄ are hydrogen; R ₃ is hydrogen; NR ₅ R ₆
But: Wherein p is 2; W is CH and R ₈ is optionally halogenated or alkoxylated phenyl or an arylalkyl group;
For example, if the phenyl ring is independently hydrogen, halogen or 1
Phenylalkyl substituted with up to three substituents selected from straight-chain or branched lower alkoxy having up to 6 carbon atoms.

Such a compound.

Further, the present invention provides a compound of formula III: Wherein R ₁ is aryl, heteroaryl or naphthyl, each of which is the same or different as required and is hydrogen, halogen, trifluoromethyl, cyano, straight chain having 1 to 6 carbon atoms. Or branched lower alkyl, hydroxy, straight or branched lower alkyl having 1-6 carbon atoms, straight or branched lower alkoxy having 1-6 carbon atoms,
Or substituted by up to three substituents indicating SO ₂ R _9, wherein R ₉ is NH ₂ or NHCH ₃ ; X, Y, Z and m have the meanings given above in formula I; ₃ is hydrogen, halogen, or straight or branched lower alkyl having 1 to 6 carbon atoms; R ₄ is hydrogen or straight or branched lower having 1 to 6 carbon atoms. alkyl, or if Z is a CR ₃ R ₃ and R ₄ together - (CH _{2) n1} - indicates, where n1 is 2, 3 or 4; or NR ₅ R ₆ is Together: Wherein R ₇ has the meaning given above for formula I; or NR ₅ R ₆ is: Wherein p is 1, 2 or 3; W is N and R ₈ is phenyl, pyridyl or pyrimidinyl, each of which is halogen, hydroxy, a straight chain having 1 to 6 carbon atoms. W is CH and R ₈ is optionally substituted by a chain or branched lower alkyl, or a straight or branched lower alkoxy having 1 to 6 carbon atoms; or A phenyl or arylalkyl group wherein the phenyl ring is independently hydrogen, halogen, trifluoromethyl, hydroxy, 1-
It may be substituted with up to three substituents selected from straight or branched lower alkyl having 6 carbon atoms, or straight or branched lower alkoxy having 1 to 6 carbon atoms. Phenylalkyl].

Further, the present invention provides a compound of formula IV: Wherein R ₁ is phenyl or naphthyl, each of which is independently hydrogen, halogen, trifluoromethyl, cyano, linear or branched lower alkyl having 1 to 6 carbon atoms, hydroxy, Linear or branched lower alkyl having 1 to 6 carbon atoms, 1 to 6
Substituted with up to three substituents selected from linear or branched lower alkoxy having 6 carbon atoms, or SO ₂ R _9, wherein R ₉ is NH ₂ or NHCH _3. can; X, Y, Z have the meaning given above for formula I; R ₃ is hydrogen, halogen, straight-chain or lower alkyl branched chain having 1 to 6 carbon atoms; R ₄ is hydrogen or a straight-chain or lower alkyl branched chain having 1 to 6 carbon atoms; m is 0; NR ₅ R ₆ is: Wherein R ₇ has the meaning given above for formula I; or NR ₅ R ₆ is: Wherein p is 1, 2 or 3; W is N and R ₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted or halogen, hydroxy, straight-chain having 1 to 6 carbon atoms. W is CH and R ₈ is optionally substituted by a chain or branched lower alkyl, or a straight or branched lower alkoxy having 1 to 6 carbon atoms; or A phenyl or arylalkyl group wherein the phenyl ring is independently hydrogen, halogen, trifluoromethyl, hydroxy, 1-
It may be substituted by up to three substituents selected from straight or branched lower alkyl having 6 carbon atoms, or straight or branched lower alkoxy having 1 to 6 carbon atoms. Phenylalkyl].

Further, the invention provides a compound of formula V: Wherein R ₁ and T are the same or different and are hydrogen, halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms, or 1 to 6
Represents a straight or branched lower alkoxy having 5 carbon atoms; Wherein R ₂ is hydrogen or straight-chain or branched lower alkyl having 1 to 6 carbon atoms, or
R ₁ and R ₂ together - (CH _{2) n1} - indicates, where n
X and Z are the same or different and are hydrogen, halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms, 1 to 6 Linear or branched lower alkoxy having at least one carbon atom, or SO
₂ R ₆ wherein R ₆ is straight or branched lower alkyl having 1 to 6 carbon atoms; Y is hydrogen, halogen, amino or has 1 to 6 carbon atoms R ₃ is hydrogen or straight or branched lower alkyl having 1 to 6 carbon atoms; or R ₃ and R ₄ together − (CH ₂ ) _n2 −, where n
2 is 3 or 4; R ₄ and R ₅ are the same or different and are hydrogen, 1
Denotes straight or branched lower alkyl having from 6 to 6 carbon atoms, or phenylalkyl or pyridylalkyl, wherein each alkyl is a straight or branched alkyl having from 1 to 6 carbon atoms. Yes; or R ₂
And R ₅ together - (CH _{2) n3} - indicates, where n3
Is 2 or 3; or NR ₅ R ₅ is 2- (1,2,3,4-tetrahydroisoquinolinyl)
Or halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms, or 1 to 6
2- (1,2,3,4) mono- or disubstituted by straight-chain or branched lower alkoxy having 5 carbon atoms
-Tetrahydroisoquinolinyl); or NR ₅ R ₆ is: Wherein W is N or CH; R ₇ is hydrogen, phenyl, pyridyl or pyrimidinyl,
Or mono- or disubstituted by halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms, respectively, or linear or branched lower alkoxy having 1 to 6 carbon atoms, respectively. Or phenyl, pyridyl or pyrimidinyl, which is
R ₇ is oxygen or sulfur; n is 1, 2 or 3] and the non-toxic pharmaceutically acceptable salts thereof.

Further, the present invention provides a compound of formula VI: Wherein R ₁ is hydrogen, halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms,
Or is linear or branched lower alkoxy having 1 to 6 carbon atoms; Wherein R ₂ is hydrogen or straight-chain or branched lower alkyl having 1 to 6 carbon atoms, or
R ₁ and R ₂ together - (CH _{2) n1} - indicates, where n
1 is 1, 2 or 3; X is hydrogen, halogen, hydroxy, straight or branched lower alkyl having 1 to 6 carbon atoms, straight or branched lower alkyl having 1 to 6 carbon atoms. R ₃ is hydrogen, or a branched lower alkoxy, or SO ₂ R _6, wherein R ₆ is a straight or branched lower alkyl having 1 to 6 carbon atoms. lower alkyl straight or branched chain having carbon atoms, or R ₃ and R ₄ together - (CH _{2) n2} - indicates, where n
2 is 3 or 4; R ₄ and R ₅ are the same or different and are hydrogen, 1
Denotes straight or branched lower alkyl having from 6 to 6 carbon atoms, phenylalkyl or pyridylalkyl, wherein each alkyl is a straight or branched lower alkyl having from 1 to 6 carbon atoms. Or R ₂ and R ₅ together represent — (CH ₂ ) _n3 —, wherein n3 is 2 or 3; or NR ₄ R ₅ is 2- (1,2,3,4- Tetrahydroisoquinolinyl)
Or halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms, or 1 to 6
2- (1,2,3,4) mono- or disubstituted by straight-chain or branched lower alkoxy having 5 carbon atoms
-Tetrahydroisoquinolinyl); or Wherein W is N or CH; R ₇ is hydrogen, phenyl, pyridyl or pyrimidinyl or each halogen, hydroxy, straight or branched lower alkyl having 1 to 6 carbon atoms, or 1 Phenyl, pyridyl or pyrimidinyl, mono- or disubstituted by straight-chain or branched lower alkoxy having from 6 to 6 carbon atoms;
R ₇ is oxygen or sulfur; and n is 1, 2 or 3].

Further, the present invention provides a compound of formula VII: Wherein R ₁ is hydrogen, halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms,
Or linear or branched lower alkyl having 1 to 6 carbon atoms, or linear or branched lower alkoxy having 1 to 6 carbon atoms; Wherein R ₂ is hydrogen or straight-chain or branched lower alkyl having 1 to 6 carbon atoms, or
R ₁ and R ₂ together - shows the (CH _{2) n1,} where n1
Is 1, 2 or 3; R ₃ is hydrogen, or linear or branched lower alkyl having 1 to 6 carbon atoms; or R ₃ and R ₄ together are — (CH ₂ ) _n2- , where n2 is 3
Or R ₄ and R ₅ are the same or different and are hydrogen, 1
Straight-chain or branched lower alkyl having 1 to 6 carbon atoms, aryl represents straight-chain or branched lower alkyl having 1 to 6 carbon atoms, or R ₂ and R ₅ together Te - (CH _{2) n3} - indicates, where n3 is 2 visually is 3; or NR ₄ R ₅ is 2- (1,2,3,4-tetrahydroisoquinolinyl)
Or halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms, or 1 to 6
2- (1,2,3,4) mono- or disubstituted by straight-chain or branched lower alkoxy having 5 carbon atoms
-Tetrahydroisoquinolinyl); or Wherein W is N or CH; R ₇ is hydrogen, phenyl, pyridyl or pyrimidinyl or halogen, hydroxy, straight or branched lower alkyl having 1 to 6 carbon atoms, or 1 to Phenyl, pyridyl or pyrimidinyl mono- or disubstituted by straight-chain or branched lower alkoxy having 6 carbon atoms; or W—R ₇ is oxygen or sulfur; n is 1, 2 or 3] is also included.

Further, the present invention provides a compound of formula VIII: [Where M is: Wherein R ₂ is hydrogen or straight-chain or branched lower alkyl having 1 to 6 carbon atoms, or
R ₁ and R ₂ together - (CH _{2) n1} - indicates, where n
1 is 1, 2 or 3; X is hydrogen, halogen, hydroxy, straight or branched lower alkyl having 1 to 6 carbon atoms, straight or branched lower alkyl having 1 to 6 carbon atoms. R ₃ is hydrogen, or a branched lower alkoxy, or SO ₂ R _6, wherein R ₆ is a straight or branched lower alkyl having 1 to 6 carbon atoms. be a number of lower straight or branched chain alkyl group having carbon atoms; or R ₃ and R ₄ together - (CH _{2) n2} - indicates, n2 is 3
Or R ₄ and R ₅ are the same or different and are hydrogen, 1
Denotes straight-chain or branched lower alkyl having -6 carbon atoms, phenylalkyl or pyridylalkyl, each alkyl being a straight-chain or branched lower alkyl having 1-6 carbon atoms; or R ₂ and R ₅ together - (CH _{2) n3} - indicates, where n
3 is 2 or 3; or NR ₄ R ₅ is 2- (1,2,3,4-tetrahydroisoquinolinyl)
Or halogen, hydroxy, linear or branched lower alkyl having 1 to 6 carbon atoms, or 1 to 6
2- (1,2,3,4) mono- or disubstituted by straight-chain or branched lower alkoxy having 5 carbon atoms
-Tetrahydroisoquinolinyl); or Wherein W is N or CH; R ₇ is hydrogen, phenyl, pyridyl or pyrimidinyl or hydrogen, phenyl, pyridyl or pyrimidinyl, halogen, hydroxy, straight chain having 1 to 6 carbon atoms. Or a branched lower alkyl, or 1 to
Wherein R ₇ is oxygen or sulfur; n is 1, 2 or 3] mono- or disubstituted by straight-chain or branched lower alkoxy having 6 carbon atoms. Include.

Further, the present invention provides a compound of formula IX: Wherein X represents hydrogen or halogen; R _a and R _b are the same or different and represent hydrogen or alkoxy; NR ₄ R ₅ is 4-phenylpiperazin-1-yl or 4
-Phenylpiperidin-1-yl, wherein each phenyl group can be replaced by hydrogen, halogen, alkyl or alkoxy].

Further, the present invention provides a compound of formula X: Wherein X represents hydrogen or halogen; R represents hydrogen or alkyl; R _a and R _b are the same or different and represent hydrogen or alkoxy; A and B are the same or different Independently represents hydrogen or (4- (2-optionally substituted pyrimidinyl) piperazin-1-yl) methyl.

Preferred compounds of formula X are those where R is hydrogen or methyl and X, _Ra and _Rb are hydrogen. Particularly preferred compounds of formula X are those wherein R is hydrogen or methyl, X, _Ra and _Rb are hydrogen, A and B are different and hydrogen or (4- (2-pyrimidinyl) piperazine- 1-yl) methyl, wherein the pyrimidinyl group is a compound which is optionally substituted by hydrogen, hydroxy or alkoxy. A preferred alkoxy group is methoxy.

Further within the scope of the present invention are formulas XI: [Wherein, X represents a hydrogen or halogen; R represents hydrogen or alkyl; R _a and R _b are the same or different and represents hydrogen, halogen or alkyl; R _c is the formula: Wherein W is N or CH; R represents alkyl; R _d represents pyridyl, pyrimidinyl, phenylalkyl or phenyl optionally substituted by halogen, alkyl or alkoxy; R _e is alkyl Is present.

Preferred compounds of the formula XI X, R _a, R _b and R _e are hydrogen, a compound such as R _c is a 4-substituted piperazin-1-yl or piperidin-1-yl group. Particularly preferred compounds of formula XI are those wherein the 4-substituted piperazin-1-yl or piperidin-1-yl group is substituted with an appropriately substituted phenyl, phenylalkyl, 2-pyridinyl or 2-pyrimidinyl group. Other preferred compounds of formula XI X, R _a, R _b and R _e are hydrogen, R _e is methyl, R _c is a piperazin-1-yl or piperidin-1-yl group, each of Is substituted at the 4-position by benzyl, pyridyl or pyrimidinyl.

Further, the present invention provides a compound of formula XII: Wherein W is N or CH; R _f is halogen or alkyl; R _d is pyridyl, pyrimidinyl, phenylalkyl or phenyl, each of which is optionally substituted by halogen, alkyl or alkoxy as required. Is provided.

Preferred compounds of formula XII are those wherein R _f is halogen or methyl, W is nitrogen and R _d is pyridyl, pyrimidinyl or benzyl. Particularly preferred compounds of formula XII are those wherein R _f is halogen or methyl, W is nitrogen and R _d is pyrimidinyl.

Further, the present invention provides a compound of formula XIII: Wherein W is N or CH; R _a and R _b independently represent hydrogen, halogen, or alkoxy; R _f is alkyl; R _d is pyridyl, pyrimidinyl, phenylalkyl or phenyl. And optionally substituted by halogen, alkyl or alkoxy].

Preferred compounds of formula XIII are those wherein R _f is methyl, W is nitrogen and R _d is pyridyl, pyrimidinyl or benzyl. A particularly preferred compound of formula XIII is where R _f is methyl, W is nitrogen, R _d is pyrimidinyl optionally substituted by halogen, hydroxy or alkoxy, and at least one of R _a and R _b is Such compounds are halogens.

Further, the present invention provides a compound of formula XIV: Wherein Ar is 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-thienyl or 2-quinolinyl; W is N or CH; R _d is pyridyl, Pyrimidinyl, phenylalkyl or phenyl, optionally substituted by halogen, alkyl or alkoxy].

Preferred compounds of formula XIV are those wherein W is CH and R _d is pyridyl, pyrimidinyl or benzyl.

Further, the present invention provides a compound of formula XV: Wherein Ar is 1- or 2-naphthyl, phenyl or phenyl mono-, di- or trisubstituted by alkyl, alkoxy or halogen; W is N or CH; R _d is pyridyl, pyrimidinyl, Phenylalkyl or phenyl, optionally substituted by halogen, alkyl or alkoxy].

Preferred compounds of formula XV are those wherein Ar is phenyl, W is CH and R _d is pyridyl, pyrimidinyl or benzyl.

Further, the present invention provides a compound of formula XVI: Wherein X represents hydrogen or halogen; R _a and R _b are the same or different and represent hydrogen, halogen or alkoxy; W is N or CH; R _d is pyridyl, pyrimidinyl, phenylalkyl Or phenyl, each of which is optionally substituted by halogen, hydroxy, alkyl or alkoxy].

Preferred compounds of formula XVI are those wherein X, _Ra and _Rb are hydrogen;
Compounds wherein W is CH and R _d is optionally substituted pyridyl, pyrimidinyl or benzyl.

The invention further provides XVII: Wherein X represents hydrogen or halogen; R _a and R _b are the same or different and represent hydrogen, halogen or alkoxy; W is N or CH; R _d 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 wherein X, _Ra and _Rb are hydrogen;
W is N and R _d is pyridyl, pyrimidinyl or benzyl, each of which is optionally halogen,
Such compounds are substituted by hydroxy or alkoxy.

Further, the present invention provides a compound of formula XVIII: Wherein m is 0, 1 or 2; X represents hydrogen or halogen; R _a and R _b are the same or different and represent hydrogen, halogen or alkoxy; W is N or CH R _d is pyridyl, pyrimidinyl, phenylalkyl or phenyl, each of which is optionally substituted by halogen, hydroxy, alkyl or alkoxy].

Preferred compounds of formula XVIII are X, R _a and R _b are hydrogen, W is N, a R _d is pyridyl, pyrimidinyl or benzyl, optionally substituted by their respective halogen necessary, hydroxy or alkoxy Such a compound.

Further, the present invention provides a compound of formula XIX: Wherein m is 0, 1 or 2; X represents hydrogen or halogen; R _a and R _b are the same or different and represent hydrogen, halogen or alkoxy; W is N or CH R _d is pyridyl, pyrimidinyl, phenylalkyl or phenyl, each of which is optionally substituted by halogen, hydroxy, alkyl or alkoxy].

Preferred compounds of formula XIX are those wherein X, _Ra and _Rb are hydrogen,
Compounds wherein W is N and R _d is pyridyl, pyrimidinyl or benzyl. Other preferred compounds of formula XIX are those wherein X, _Ra and _Rb are hydrogen, W is CH and _Rd
Is phenyl or pyrimidinyl, optionally substituted by halogen / and / or hydroxy.

Further, the present invention provides a compound of formula XX: Wherein R _a is hydrogen or alkyl; W is N or CH; R _d is pyridyl, pyrimidinyl, phenylalkyl or phenyl, each of which is optionally substituted by halogen, alkyl or alkoxy. ] Is also provided.

Preferred compounds of formula XX are those wherein W is nitrogen, R _a is hydrogen or methyl, R _d is pyridyl, pyrimidinyl or benzyl, each of which is optionally substituted by halogen, hydroxy, alkyl or alkoxy. Such a compound. Other preferred compounds of formula XX are those wherein W is CH, _Ra is hydrogen or methyl, and R _d
Is a substituted pyridyl, pyrimidinyl or benzyl, each of which is optionally substituted by halogen, hydroxy or alkoxy.

The present invention further provides compounds of formula XXI: Wherein, W is is N or CH; R _g and R _h are independently represents hydrogen, lower alkyl, or together represent an alkylene bridge to form a ring; R _d
Is pyridyl, pyrimidinyl, phenylalkyl or phenyl, optionally substituted by halogen, alkyl or alkoxy.]

Preferred compounds of formula XXI are W or nitrogen, R _g and R _h
Is hydrogen, and R _d is optionally substituted pyridyl, pyrimidinyl or benzyl. Formula XX
Other preferred compounds of I are, W is CH, R _g and R _h are hydrogen, pyridyl R _d is optionally substituted, a compound such that pyrimidinyl or benzyl.

Further, the present invention provides a compound of formula XXII: Wherein R _a represents hydrogen or lower alkyl; R ₁ and Y independently represent hydrogen, lower alkyl or halogen; R ₁₀ represents hydrogen, hydroxy, lower alkoxy or halogen; E is CH or nitrogen The compound of the formula is also provided.

Preferred compounds of formula XXII are those wherein E is nitrogen, R ₁ and Y are independently hydrogen or halogen, and R ₁₀ is halogen, hydroxy or lower alkoxy. Particularly preferred compounds of formula XXII are those wherein E is nitrogen, R ₁ and Y are hydrogen or fluorine (but not both) and R ₁₀ is fluorine.

Further, the present invention provides a compound of formula XXIII: Wherein R ₁ and Y independently represent hydrogen, lower alkyl or halogen; R ₁₀ represents hydrogen, hydroxy, lower alkoxy or halogen; E represents CH or nitrogen.

Preferred compounds of formula XXIII are those wherein E is nitrogen, R ₁ and Y
Is independently hydrogen or halogen, and R ₁₀ is halogen, hydroxy or lower alkoxy. Particularly preferred compounds of formula XXIII are those wherein R _a is hydrogen or methyl, E is nitrogen, R ₁ is hydrogen or fluorine, R ₁₀ is fluorine, and Y is hydrogen. .

Further, the present invention provides a compound of formula XXIV: Wherein R ₁ and T independently represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy;
Y and Z are independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, or -SO ₂ R ₆ (wherein R ₆
Is lower alkyl); E is CH or nitrogen.]

Further, the present invention provides a compound of formula XXV: Wherein R ₁ represents hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; R ₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; E is CH or nitrogen.

The present invention provides a compound of formula XXVI: Wherein R ₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; E is CH or nitrogen.

Further, the present invention provides a compound of formula XXVII: Wherein R ₁ and T independently represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy;
Y and Z are independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, or -SO ₂ R ₆ (wherein R ₆
Is lower alkyl); n is 0 or 1; R ₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; A and Q are the same or different and represent CH or nitrogen. Also provide.

Further, the present invention provides a compound of formula XXVIII: Wherein n is 0 or 1; R ₁ and T independently represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; R ₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; Q is the same or different and represents CH or nitrogen.]

Further, the present invention provides a compound of formula XXIX: Wherein R ₁ and T independently represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy;
₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; E is CH or nitrogen.]

The present invention further provides a compound of formula XXX: Wherein R ₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; R ₁ , T, X, Y and Z independently represent hydrogen or lower alkyl; E represents CH or nitrogen. Also provide.

Further, the present invention provides a compound of formula XXXI: Wherein R ₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; R ₁ , T, X, Y and Z independently represent hydrogen or lower alkyl; E represents CH or nitrogen. Also provide.

Further, the present invention provides a compound of formula XXXII: Wherein R ₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; R ₁ and T independently represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; X, Y and Z are independently hydrogen , Halogen, hydroxy, lower alkyl, lower alkoxy or —SO ₂ R _6, wherein R ₆ is lower alkyl; and n is 0 or 1.].

Further, the present invention provides a compound of formula XXXIII: Wherein R ₁₀ is hydrogen, hydroxy, halogen or lower alkoxy; R ₁ and T independently represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; X, Y and Z are independently hydrogen , Halogen, hydroxy, lower alkyl, lower alkoxy or —SO ₂ R _6, wherein R ₆ is lower alkyl.

Further, the present invention provides a compound of formula XXXIV: Wherein R is halogen, alkoxy having 1 to 6 carbon atoms or hydroxy; R ₁ and T independently represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; X, Y and Z Independently represents hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy or —SO ₂ R _6, wherein R ₆ is lower alkyl; and E is CH or nitrogen.

Preferred compounds of formula XV are those wherein R ₁ , T, X, Y and Z are hydrogen. Particularly preferred compounds of formula XV are
Compounds wherein R ₁ , T, X, Y and Z are hydrogen, E is nitrogen and R is hydroxy, fluorine or methoxy.

Further, the present invention provides a compound of formula XXXV: Wherein R is halogen, alkoxy or hydroxy having 1 to 6 carbon atoms; E is CH or nitrogen.

Preferred compounds of formula XVI are those wherein E is nitrogen. Particularly preferred compounds of formula XVI are those wherein E is nitrogen;
Compounds wherein R is hydroxy, fluorine or methoxy.

Further, the present invention provides a compound of formula XXXVI: Wherein R is halogen, alkoxy or hydroxy having 1 to 6 carbon atoms.

Preferred compounds of formula XVII are those wherein R is hydroxy, fluorine or methoxy.

Further, the present invention provides a compound of formula XXXVII: Wherein R ₁ and Y independently represent hydrogen, lower alkyl or halogen; R ₁₀ represents hydrogen, hydroxy, lower alkoxy or halogen; E represents CH or nitrogen.

Preferred compounds of formula XVIII are those wherein E is nitrogen, R ₁ and Y are hydrogen or halogen and R ₁₀ is halogen, hydroxy or lower alkoxy. Particularly preferred compounds of formula XV are those wherein E is nitrogen and R ₁
And Y is hydrogen or fluorine (both are not fluorine) and R ₁₀ is fluorine.

Particularly preferred NR ₅ R ₆ and NR ₄ R _{5 of the} formulas I and V, respectively
The radical has the formula: Wherein W is CH or N; Z represents phenyl, pyridyl or pyrimidinyl;
Each of which is optionally mono- or disubstituted by halogen, hydroxy or lower alkoxy].

This formula means a saturated heterocyclic ring system such as, for example, piperidinyl or piperazinyl, and also an unsaturated heterocyclic ring system such as, for example, 1,2,3,6-tetrahydropyridine. These groups include: Wherein Z has the above meaning.

The most preferred NR ₅ R ₆ and NR ₄ R ₅ groups include those described below.

Representative examples of compounds according to the present invention are shown in Table A below. These compounds are shown in Table A as free base compounds and are not shown as salts described in the examples.

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

The invention further includes the acylated prodrugs of the compound of formula I. One skilled in the art will recognize the various non-toxic pharmaceutically acceptable addition salts of the compounds encompassed by Formula I and the various synthetic methods that can be used to make the acylated prodrugs.

The terms "aryl" and "Ar" can be a single ring (eg, phenyl), multiple rings (eg, biphenyl) or multiple condensed rings wherein at least one is aromatic (eg, 1,
(2,3,4-tetrahydronaphthyl, naphthyl, anthryl or phenanthryl) means an aromatic carbocyclic group which is unsubstituted or optionally substituted, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl , Lower acyloxy, aryl, heteroaryl and hydroxy.

The terms “alkyl” and “lower alkyl” are 1
A straight or branched alkyl group having up to 6 carbon atoms is meant.

The terms "lower alkoxy" and "alkoxy" mean a straight or branched alkoxy group having 1 to 6 carbon atoms.

The term "hydroxy lower alkyl" or "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxy group. Preferred hydroxyalkyl groups are straight-chain alkyl groups in which the terminal carbon atom has been replaced by one hydroxy group.

The term "heteroaryl" means a 5-, 6- or 7-membered aromatic ring system having at least one heteroatom 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 are optionally unsubstituted or for example halogen, lower alkyl, lower alkoxy,
It can be substituted by lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

"Arylalkyl" means a group -R-Ar where Ar is an aryl group and R is a straight or branched chain aliphatic group. The arylalkyl group can be substituted as needed with, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy and hydroxy. A preferred arylalkyl group in the above formula wherein W is CH and R ₈ is arylalkyl is a phenylalkyl group wherein the alkyl portion is lower alkyl. Particularly preferred phenylalkyl groups are those wherein the phenyl ring is independently hydrogen, halogen, trifluoromethyl, hydroxy, straight or branched lower alkyl having 1 to 6 carbon atoms or 1 to 6 carbon atoms. Is benzyl which can be substituted with up to three substituents selected from linear or branched lower alkoxy having

The term "cycloalkyl" means a cyclic hydrocarbon having 3 to 8 carbon atoms. These cyclic hydrocarbon groups are independently hydrogen, halogen, trifluoromethyl, cyano, linear or branched lower alkyl having 1 to 6 carbon atoms, hydroxy, having 1 to 6 carbon atoms. Straight-chain or branched lower alkyl, straight-chain or branched lower alkoxy having 1 to 6 carbon atoms,
Alternatively, it can be substituted with up to three substituents selected from SO ₂ R _9, where R ₉ is NH ₂ or NHCH ₃ .

The numbering system used here to identify the position of the imidazole ring is as follows: The pharmaceutical use of the compounds according to the invention is demonstrated by the following analysis for dopamine receptor subtype affinity.

Analysis of D2 and D3 receptor binding activity Striatal tissue was excised from adult male Sprague-Dawley rats, or BHK 293 cells containing recombinantly produced D2 or D3 receptors were collected. This sample was homogenized in 100 volumes (w / v) of 0.05M Tris HCl buffer at 4 ° C and pH 7.4. The sample was then centrifuged at 30,000 xg, resuspended and rehomogenized. The sample was then centrifuged as above and frozen until the final tissue sample was used. The tissue was resuspended 1:20 (w / v) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Cultures were performed at 48 ° C., which consisted of 0.5 mL tissue sample and 0.5 nM
Of ³ H- raclopride and the compound of interest contained in the entire culture volume of 1.0 mL. Nonspecific binding is defined as binding as seen in the presence of 10 ^-4 M dopamine, with no additional nonspecific binding being less than 20% of the total binding. Table 1 shows the binding characteristics in the examples of the present invention for rat striatal homogenized products.

Table I Compound No. ¹ IC ₅₀ (mM) 1 0.900 8 0.011 16 0.014 19 0.100 21 0.018 24 0.620 26 0.200 Note 1: Compound No. refers to the compounds described in the Examples below and / or the compounds shown in Table A above. Things.

Analysis of D4 receptor binding activity Clonal cell lines expressing human dopamine receptor subtype were collected in PBS, cells were centrifuged and the pellet was stored at -80 ° C until used for binding analysis. Resuspend the pellet and remove cells from 120 mM NaC
It was dissolved at 4 ° C. at 50mM Tris (pH 7.4) buffer containing the MgCl ₂ of l and 1mM of EDTA and 5 mM. The homogenate was centrifuged at 48,000 xg for 10 minutes at 4 ° C. The resulting pellet was resuspended in fresh buffer and centrifuged again. After resuspending the pellet in fresh buffer, 100 mL was removed for protein determination. The remaining homogenate was centrifuged as above, the supernatant was removed, and the pellet was stored at 4 ° C. until needed, at which point 50 mM was reached to a final concentration of 625 mg / mL (250 mg per sample).
Resuspended immediately before use with M Tris buffer (pH 7.4) and 120 mM NaCl. The culture was incubated with 0.1 nM [ ³ H] YM-09151-
2 at 25 ° C. for 60 minutes. The culture was stopped by rapid filtration through Whatman GF / C filters,
× 4 mL of chilled 50 mM Tris (pH 7.4) and 120 mM NaC
Washed from l. Non-specific binding was determined with 1 mM spiperone and radioactivity was determined by counting on an LKBβ counter. The binding parameters were determined by non-linear least squares regression analysis, from which the inhibition constants (Ki) could be calculated for each test compound. The binding properties of the examples of the present invention are shown in Table 2 for dopamine D4 binding assay. In general, the compounds of the attached examples were tested in the above analysis, and all
From the dopamine D4 receptors subtypes ^[3 H] YM-09151
-2 was found to have a Ki value of less than 500 nM for substitution. Some specific data is shown in Table 2.

Table 2 Compound ^No.1 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 Note 1: Compound No. Refers to the compounds described in the Examples below and / or the compounds shown in Table A above.

The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally as a unit dosage formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Can be.
The term parenteral as used herein refers to subcutaneous injection, intravenous,
Includes intramuscular, intrasternal injection or perfusion techniques. Also provided is a reagent formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and optionally other active ingredients. it can. Pharmaceutical compositions containing a compound of general formula I may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or It can be elixir.

Compositions intended for oral use can be prepared by any of the methods known in the art of making pharmaceutical compositions, which compositions include sweetening, flavoring, coloring and preserving amounts. A pharmaceutically elegant and comfortable formulation can be provided containing one or more substances selected from the group consisting of: Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or gum acacia; 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 provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or provided as soft gelatin capsules. Wherein the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents are naturally occurring phosphatides, such as lecithin or alkylene oxide. Of polyoxyethylene stearate or ethylene oxide with long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol or ethylene oxide with partial esters obtained from aliphatic and hexitol Condensation products,
For example, polyoxyethylene sorbitol monooleate or a condensation product of ethylene oxide with a partial ester obtained from a fatty acid and hexitol anhydride, for example, polyethylene sorbitan monooleate. Further aqueous suspensions may contain one or more preservatives, for example ethyl p-hydroxybenzoate or n-hydroxybenzoate.
Propyl, 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 ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions are thickeners, for example, beeswax,
Hard paraffin or cetyl alcohol can be included. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a comfortable oral formulation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

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

The pharmaceutical composition of the present invention can further be an oil-in-water emulsion. The oily phase can be a vegetable oil (eg, olive oil or peanut oil) or a mineral oil (eg, liquid paraffin) or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia or tragacanth gum, naturally occurring phosphatides such as soy,
Lecithin and esters or partial esters obtained from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate, can be used. Emulsions may also contain sweetening and coloring agents.

Syrups and elixirs can be formulated with sweetening agents, for example glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, 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 a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the 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 this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. 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 as suppositories for intra-anal administration of the drug. These compositions can be made by mixing the drug with a suitable nonirritating excipient that is solid at room temperature but liquid at intra-anal temperature and thus melts in the anus to release the drug. Such substances are cocoa butter and polyethylene glycols.

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

Dosage levels on the order of about 0.1 to about 140 mg / kg body weight daily are useful in treating the above conditions (about 0.5 mg to about 7 g daily per patient). The amount of active ingredient that can 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 about 1 to about 500 mg of an active ingredient.

However, the particular dosage level for any particular patient will depend on the activity of the particular compound used, the age, weight, general health, gender, diet, time of administration, route of administration and excretion rate of the particular compound used, drug combination, and treatment. It depends on a variety of factors, including the degree of the particular illness that is being experienced.

An example of the preparation of a representative 2-phenyl-4-aminomethyl-imidazole according to the present invention is shown in Scheme I. Those skilled in the art
It will be appreciated that the starting materials can be varied and additional steps can be used to prepare compounds encompassed by the present invention.

Wherein S ₁ , S ₂ , S ₃ , S ₄ and S ₅ are the same or different and are hydrogen, halogen, trifluoromethyl, cyano, linear or branched having 1 to 6 carbon atoms. Lower alkyl of a chain, hydroxy, straight-chain or branched lower alkyl having 1 to 6 carbon atoms, straight-chain or branched lower alkoxy having 1 to 6 carbon atoms,
Or SO ₂ R _9, wherein R ₉ is NH ₂ or NHCH ₃ ; R ₅ and R ₆ have the meanings given above for formula I; or NR ₅ R ₆ together form formula I Represents a cyclic group as described above.

Alternatively, the compounds of the present invention can be made by the reaction shown in Scheme 2.

Wherein R ₁ , T, M, X, Y, Z, R ₄ and R ₅ have the meanings defined for formula V above.

Another alternative route for making compounds according to the present invention is shown in Schemes 3 and 4 below. Substituents in the starting materials and reagents have the same meanings as in Formula I above.

Another example of a synthetic route for producing a compound according to the present invention is the following reaction scheme 5a to 5
c. The starting materials can be varied to make other compounds according to the invention having different groups instead of pyrimidinyl. Substituents in the starting materials and reagents have the same definitions as in Formula I above.

Without limiting the invention to the specific methods and compounds described herein in their scope or spirit,
This will be further described with reference to the following examples.

Example 1 6.45 g of 5-bromo-o-anisaldehyde, 2.2 g of hydroxylamine hydrochloride, 4.1 g of sodium formate and 20 g
The mixture with mL of formic acid was heated at 100 ° C. with stirring for 1 hour. Pour the reaction mixture onto ice-water and pour the mixture.
It was made basic by careful addition of 50% sodium hydroxide. The product was extracted with ether, the ether extract was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from ether / hexane to give 5-bromo-2-methoxybenzonitrile.

Example 2 4.0 g of 5-bromo-2-methoxybenzonitrile and 5 g
A mixture of 3A molecular sieve and 60 mL of anhydrous methanol was saturated with HCl gas at 0 ° C. and left at 0 ° C. for 24 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 75 mL of anhydrous methanol, then saturated with ammonia gas at room temperature. The reaction mixture is then placed in a sealed tube at 80 ° C.
For 4 hours. The solvent was removed under reduced pressure and the reaction mixture was
Diluted with 3N HCl and washed with ethyl acetate to remove unreacted nitrile. The aqueous layer was 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 solvent was removed in vacuo to give 5-bromo-2-methoxybenzamidine as a glassy solid.

Example 3 A solution of 20 g of 1,1,1,3,3,3-hexamethyldisilazane in 150 mL of dry ether in 5 mL of hexane
2.4M n-butyllithium was added. After 10 minutes at room temperature, 16.3 g of 2,3-dimethoxybenzonitrile was added in one portion and the mixture was kept at room temperature for 16 hours. The reaction mixture was then poured into excess 3N HCl. Separate the aqueous layer and add 50% NaO
Basified with H, product is 10% in methylene chloride
Extracted three times with methanol. The combined organic extracts were dried over calcium carbonate and the solvent was removed under reduced pressure to give 2,3-dimethoxy-benzamidine as a glassy solid.

Example 4 1.5 g of 5-bromo-2-methoxybenzamidine and 1.
A mixture of 0 g of 1,3-dihydroxyacetone dimer, 1.3 g of ammonium chloride, 3 mL of tetrahydrofuran and 10 mL of a concentrated aqueous solution of ammonium hydroxide was heated at 90 ° C. for 3 hours. The reaction mixture was cooled on ice and the precipitated product was collected and recrystallized from methanol to give 2- (5-bromo-
2-methoxyphenyl) -4-hydroxymethylimidazole was obtained as a yellow solid.

Example 5 500 mg of 2- (5-bromo-2-methoxyphenyl)
A mixture of -4-hydroxymethylimidazole and 1.5 mL of thionyl chloride was heated at 80 ° C for 15 minutes, then concentrated under reduced pressure. Diethyl ether (15 mL) was added and the resulting solid was collected and washed with ether. 3m of this solid
To a mixture of L dimethylamine, 15 mL of isopropanol and 30 mL of methylene chloride was added in one portion and the mixture was stirred for 20 minutes. The solvent was removed under reduced pressure and the residue was dissolved in 2N HCl and washed twice with ethyl acetate. The aqueous layer was basified with 50% NaOH and the product was extracted with methylene chloride. The organic extract was dried over magnesium sulfate, the solvent was removed under reduced pressure, and the residue was treated with ethanolic HCl / ether to give 2-
(5-bromo-2-methoxyphenyl) -4 (5)-
[(N, N-dimethyl) aminomethyl] -imidazole dihydrochloride (Compound 1) was obtained. mp 242-243 ° C.

Example 6 The following compounds were made essentially according to the procedure described in Examples IV: (a) 2-phenyl-4 (5)-[(N, N-dimethyl)
Aminomethyl] -imidazole dihydrochloride (Compound 2),
mp 259-260 ° C.

(B) 2-phenyl-4 (5)-(piperidinomethyl))-imidazole dihydrochloride (compound 3), mp245
~ 247 ° C.

(C) 2-phenyl-4 (5)-[(N-methyl-N-
[Benzyl] aminomethyl] -imidazole dihydrochloride (compound 4), mp 239-240 ° C.

(D) 2- (2-methoxyphenyl) -4 (5)-
[(N, N-dimethyl) aminomethyl] -imidazole dihydrochloride (compound 5), melting point at X <0> C.

(E) 2- (3-methoxyphenyl) -4 (5)-
[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 6), mp 115-117 ° C.

(F) 2- (2,3-dimethoxyphenyl) -4 (5)-
[(N, N-dimethyl) aminomethyl] -imidazole dihydrochloride (compound 7), mp 220-221 ° C.

(G) 2- (2,3-dimethoxyphenyl) -4 (5)-
[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 8), mp 200-202 ° C.

(H) 2- (3-methoxyphenyl) -4 (5)-
[(N, N-diethyl) aminomethyl] -imidazole dihydrochloride (compound 9), mp 213-214 ° C.

(I) 2- (3-fluorophenyl) -4 (5)-
[(N, N-dimethyl) aminomethyl] -imidazole dihydrochloride (compound 10), mp 211-214 ° C.

(J) -2- (2-fluorophenyl) -4 (5)-
[(N-Methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (Compound 11), mp 241-244 ° C.

(K) 2- (3-methylphenyl) -4 (5)-[(N,
[N-dimethyl) aminomethyl] -imidazole dihydrochloride (compound 12), mp 231-234 ° C.

(L) 2- (2-fluorophenyl) -4 (5)-
[(N, N-dimethyl) aminomethyl] -imidazole dihydrochloride (compound 13), mp 246-247 ° C.

(M) 2- (4-fluorophenyl) -4 (5)-
[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 14), mp 237-239 ° C.

(N) 2- (2-methoxyphenyl) -4 (5)-
[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 15), mp 239-241 ° C.

(O) 2- (5-bromo-2,3-dimethoxyphenyl)
-4 (5)-[(N, N-dimethyl) aminomethyl] -imidazole dihydrochloride (compound 16), mp 194-194 ° C.

(P) 2- (5-bromo-2-methoxyphenyl) -4
(5)-[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 17), mp 242-2
43 ° C.

(Q) 2- (5-bromo-2,3-dimethoxyphenyl)
-4 (5)-[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (Compound 18).

Example 7 A mixture of 350 mg of 2-phenyl-4-hydroxymethylimidazole and 3 mL of thionyl chloride was heated at 80 ° C. for 15 minutes. Excess thionyl chloride was removed under reduced pressure, and the residue was dissolved in 20 mL of methylene chloride. This solution was added to a mixture of 410 mg of 1- (2-methoxyphenyl) piperazine in 1 mL of triethylamine and 20 mL of methylene chloride and the mixture was stirred for 20 minutes. Remove the solvent under reduced pressure,
The residue was dissolved in 2N HCl and washed twice with ethyl acetate.
The aqueous layer was basified with 50% NaOH and the product was extracted with methylene chloride. Dehydrate the organic extract with magnesium sulfate,
The solvent was removed under reduced pressure, and the residue was crystallized from ethyl acetate to give 2-phenyl-4 (5)-[(4- (2-methoxyphenyl) -piperazin-1-yl) -methyl] imidazole (compound 19). ) Got. mp 105-107 ° C.

Example 8 The following compound was made essentially according to the procedure described in Example VII: (a) 2- (4-fluorophenyl) -4 (5)-
[(4- (2-methoxyphenyl) -piperazine-1-
Yl) -methyl] -imidazole (compound 20), mp95
~ 97 ° C.

(B) 2- (2,3-dimethoxyphenyl) -4 (5)-
[(4- (2-methoxyphenyl) -piperazine-1-
Yl) -methyl] -imidazole dihydrochloride (compound 2
1), mp 217-218 ° C.

(C) 2- (3-chlorophenyl) -4 (5)-[(4
-(2-methoxyphenyl) -piperazin-1-yl)
-Methyl] -imidazole dihydrochloride (compound 22), mp
198-199 ° C.

(D) 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole dihydrochloride (compound 23), mp 246-248 ° C.

(D ') 2-Phenyl-4 (5)-[(4- (2-pyrimidinyl) piperazin-1-yl) methyl] -imidazole (Compound 23A).

(D ″) 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) piperazin-1-yl) -methyl] -imidazole dimaleate (compound 23B), mp 176-178.
° C.

(E) 2-phenyl-4 (5)-[(4- (2-pyridyl) -piperazin-1-yl) -methyl] -imidazole dihydrochloride (compound 24), mp 176-177 ° C.

(F) 2-phenyl-4 (5)-[(4-benzyl-piperidin-1-yl) -methyl] -imidazole dihydrochloride (compound 25), mp 234-236 ° C.

(G) 2-phenyl-4 (5)-[(4-phenyl-piperidin-1-yl) -methyl] -imidazole dihydrochloride (compound 26), mp 238-240 ° C.

(H) 2-phenyl-4 (5)-[(1,2,3,4-tetrahydroisoquinoline) -2-yl-methyl] -imidazole dihydrochloride (Compound 27).

(I) 2-phenyl-4 (5) -2-phenyl-5,6,7,
8-Tetrahydrobenzimidazole imidazole dihydrochloride (Compound 76).

Example 9 The following compound was made essentially according to the procedure described in Examples I-VII: (a) 2- (2,3-dimethoxyphenyl) -4 (5)-
[(1,2,3,4-tetrahydroisoquinoline) -2-yl-methyl] -imidazole dihydrochloride (compound 28), mp
205-207 ° C.

(B) 2- (4-methoxyphenyl) -4 (5)-
[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (Compound 29).

(C) 2- (3,4-dimethoxyphenyl) -4 (5)-
[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (Compound 30).

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

(E) 2- (5-chloro-2-methoxyphenyl) -4
(5)-[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (Compound 32), mp 88-89
° C.

(F) 2- (5-chloro-2-methoxyphenyl) -4
(5)-[(N, N-dimethyl) aminomethyl] -imidazole dihydrochloride (Compound 33), mp 231-233 ° C.

(G) 2- (5-chloro-2-methoxyphenyl) -4
(5)-[(N-methyl) aminomethyl] -imidazole dihydrochloride (compound 34), mp 225-227 ° C.

(H) 2- (5-chloro-2-methoxyphenyl) -4
(5)-[(N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 35), mp 184-186 ° C.

(I) 2- (5-chloro-2-benzyloxyphenyl) -4 (5)-[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (Compound 36), mp
118-123 ° C.

(J) 2- (2-benzyloxyphenyl) -4 (5)
-[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 37), mp 199-200 <0> C.

(L) 2- (3-ethylphenyl) -4 (5)-[(N
-Methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 38), mp 234-235 ° C.

(M) 2- (5-chloro-2-methoxyphenyl) -4
(5)-[(N-methyl-N- (4-chlorobenzyl)
Aminomethyl] -imidazole dihydrochloride (Compound 39),
mp 186-188 ° C.

(N) 2- (5-chloro-2-hydroxyphenyl)-
4 (5)-[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 40), mp 227-2
28 ° C.

(O) 2- (5-Bromo-2-benzyloxyphenyl) -4 (5)-[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (Compound 41).

(P) 2- (5-ethyl-2-methoxyphenyl) -4
(5)-[(N-methyl-N-benzyl) aminomethyl] -imidazole dihydrochloride (compound 42), mp 114-1
15 ° C.

(Q) 2- (5-chloro-2-methoxyphenyl) -4
(5)-[(4- (2-Methoxyphenyl) -piperazin-1-yl) -methyl] -imidazole dihydrochloride (compound 43), mp 138-143 ° C.

(R) 2- (5-chloro-2-methoxyphenyl) -4
(5)-[(4-phenyl-piperidin-1-yl)-
Methyl] -imidazole dihydrochloride (compound 44), mp13
8-143 ° C.

(S) 2-phenyl-4 (5)-[(4-phenyl-piperazin-1-yl) methyl] imidazole (compound 4
5), mp 189-191 ° C.

(T) 2- (4-fluorophenyl) -4 (5)-
[(4-phenyl-piperidin-1-yl) -methyl]
-Imidazole dihydrochloride (compound 46), mp 260-264 ° C
(Disassembly).

(U) 2- (4-methoxyphenyl) -4 (5)-
[(4-phenyl-piperidin-1-yl) -methyl]
-Imidazole dihydrochloride (compound 47), mp 196-19
° C.

(V) 2-phenyl-4 (5)-[(4- (3-trifluoromethylphenyl) -piperazin-1-yl) methyl] imidazole (compound 48), mp 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-1-yl) -methyl]
-Imidazole dihydrochloride (compound 50), mp 114-117
° C.

(Y) 2- (3-fluorophenyl) -4 (5)-
[(4-phenyl-piperidin-1-yl) -methyl]
-Imidazole (compound 51), mp 110-112 ° C.

(Z) 2- (2-fluorophenyl) -4 (5)-
[(4-phenyl-piperidin-1-yl) -methyl]
-Imidazole dimaleate (compound 52), mp142
~ 144 ° C.

(Aa) 2- (2-methylphenyl) -4 (5)-[(4
-Benzyl-piperidin-1-yl) -methyl] -imidazole dihydrochloride (compound 53), mp 242-244 ° C.

(Ab) 2- (5-ethyl-2-methoxyphenyl) -4
(5)-[(4-phenyl-piperidin-1-yl)-
Methyl] -imidazole dihydrochloride (compound 54), mp76
~ 78 ° C.

(Ac) 2- (5-ethyl-2-methoxyphenyl) -4
(5)-[(4- (2-Methoxyphenyl) -piperazin-1-yl) -methyl] -imidazole dihydrochloride (compound 55), mp 61-64 ° C.

(Ad) 2-Phenyl-4 (5)-[(4- (4-fluorophenyl) -piperazin-l-yl) methyl] imidazole dihydrochloride (compound 56), mp 64-68 ° C.

(Ae) 2- (5-ethyl-2-methoxyphenyl) -4
(5)-[(4- (2-pyrimidinyl) -piperazine-
1-yl) -methyl] -imidazole dihydrochloride (compound
57), mp 75-78 ° C.

(Af) 2-Phenyl-4 (5)-[(4- (5-fluoro-2-pyrimidinyl) -piperazin-1-yl) -methyl] imidazole dihydrochloride (compound 58), mp 188-1
90 ° C.

(Ag) 2- (4-fluorophenyl) -4 (5)-
[(4- (2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole dihydrochloride (Compound 59),
mp 181-184 ° C.

(Ah) 2-phenyl-4 (5)-[(4- (5-chloro-2-methylphenyl) -piperazin-1-yl) -methyl] -imidazole dihydrochloride (compound 60), mp142.
~ 145 ° C.

(Ai) 2-phenyl-4 (5)-[(4- (3,4-dichlorophenyl) -piperazin-1-yl) methyl] imidazole (compound 61), mp 179-181 ° C.

(Aj) 2-phenyl-4 (5)-[(4- (4-fluorophenyl) -piperidin-1-yl) methyl] imidazole dimaleate (compound 62), mp 148-149 ° C.

(Ak) 2- (3-fluorophenyl) -4 (5)-
[(4-benzyl-piperidin-1-yl) -methyl]
-Imidazole dimaleate (compound 63), mp148
~ 149 ° C.

(Al) 2- (4-fluorophenyl) -4 (5)-
[(4-benzyl-piperidin-1-yl) -methyl]
-Imidazole dihydrochloride (compound 64), mp 254-256
° C.

(Am) 2-Phenyl-4 (5)-[(4- (4-fluorobenzyl) -piperidin-1-yl) -methyl] -imidazole dihydrochloride (Compound 65).

(An) 2- (2-fluorophenyl) -4 (5)-
[(4- (2-Pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole (compound 66), mp159
~ 161 ° C.

(Ao) 2- (4-methylphenyl) -4 (5)-[(4
-(2-Pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole (compound 67), mp 176-179 ° C.

(Ap) 2- (2-Fluorophenyl) -4 (5)-
[(4-benzyl-piperidin-1-yl) -methyl]
-Imidazole dimaleate (compound 68), mp113
~ 115 ° C.

(Aq) 2- (4-chlorophenyl) -4 (5)-[(4
-(2-pyridyl) -piperazin-2-yl) -methyl] -imidazole (compound 69), mp 176-177 ° C.

(Ar) 2-phenyl-4 (5)-[(4-fluoro-2
-Pyrimidinyl) -piperazin-1-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-fluorophenyl) -4 (5)-
[(4- (4-Fluoro-2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole dimaleate (Compound 72).

(Au) 2- (2-Fluorophenyl) -4 (5)-
[(4- (5-Fluoro-2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole dimaleate (Compound 72A), mp 170-171 ° C.

(Av) 2- (4-fluorophenyl) -4 (5)-
[(4- (5-Fluoro-2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole dimaleate (Compound 72B), mp 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 72
E), mp 185-1186 ° C.

Example 10 Cool a solution of 40 mL of tetrahydrofuran containing 1.0 g of 2-phenylimidazole to 0 ° C. and then add 4 mL
Of 2M lithium diisopropylamide was added dropwise to form a white suspension. The mixture was stirred at 0 ° C. for 10 minutes,
Then 0.7 mL of dimethyl sulfate was added. The reaction was stirred at room temperature for an additional 30 minutes, during which time the solution became homogeneous. An aqueous ammonium chloride solution was added and tetrahydrofuran was removed by evaporation under reduced pressure. The aqueous phase was extracted with 2 x 100 mL portions of dichloromethane. The combined organic extracts were washed with dilute ammonium hydroxide and brine. The combined organic extracts are dried over anhydrous sodium sulfate,
Concentration under reduced pressure gave 1 g of 1-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 of acetic acid was 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, then the acetic acid was removed by evaporation under reduced pressure. Dissolve the residue in water,
Made alkaline with 5% sodium hydroxide, 2 x 100mL
Extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and then concentrated to a small volume under reduced pressure to give 1-methyl-2-phenyl-4-[(4-benzylpiperidin-1-yl) methyl] -imidazole. Was.

2-phenyl-4 (5)-[(4-
(2-Pyrimidinyl) piperazin-1-yl) methyl]
The following compounds were made using imidazole (Compound 22) and essentially following the procedure described in Example X. The isomers obtained were separated by chromatography on silica gel using ethyl acetate as eluent.

(A) 1-methyl-2-phenyl-4-[(4- (2-
Pyrimidinyl) piperazin-1-yl) methyl] -imidazole (Compound 74).

(B) 1-methyl-2-phenyl-5-[(4- (2-
Pyrimidinyl) piperazin-1-yl) methyl] -imidazole (Compound 75).

Example 11 A mixture of 3 g 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 to reflux for 3 hours. The reaction mixture was cooled to room temperature and the acetic acid was removed by evaporation under reduced pressure. The residue was basified with aqueous sodium carbonate and extracted with 2 × 100 mL of ethyl acetate.
The combined extracts were washed with 2.times.100 mL of brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
2.8 g of ethyl 4-phenylimidazole-2-carboxylate were obtained as a solid, which was used in the next step without further purification or characterization.

To a solution of 2.75 g of ethyl 4-phenylimidazole-2-carboxylate in 20 mL of tetrahydrofuran was added 30
A suspension of 0.5 g lithium aluminum hydride in mL tetrahydrofuran was added. The reaction mixture is stirred overnight at room temperature, poured into 100 mL of ice water and 2 × 100 mL
Extracted with ethyl acetate. The combined extracts were washed with 2 × 100 mL of brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 2 g of 2-hydroxymethyl-4-phenylimidazole, which was further purified in the next step Or used without characterization.

A solution of 1 g of 2-hydroxymethyl-4-phenylimidazole in 10 mL of thionyl chloride was heated at 60 ° C. for 1 hour. After removal of excess thionyl chloride by evaporation under reduced pressure, the residue was treated with a solution of 1 g of 4-benzylpiperidine and 2 g of N, N-diisopropylethylamine in 50 mL of chloroform. The reaction mixture is
Stir at room temperature for 1 hour, cool to room temperature, and add 50 mL of 1N
Washed with sodium hydroxide solution and 50 mL of water. The organic phase was then dried over anhydrous sodium oxide and the solvent was evaporated under reduced pressure to give 850 mg of 4-phenyl-2 (5)-[(4-
Benzylpiperidin-11-yl) -methyl] imidazole was obtained, which was converted to its monofumarate salt (compound 77). mp 155-157 ° C.

Example 12 The following compound was made essentially according to the procedure described in Example XI: (a) 4-phenyl-2 (5)-[(N-methyl-N-
[Benzyl] aminomethyl] -imidazole dihydrochloride (compound 78), mp 229-231 ° C.

(B) 4-phenyl-2 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole dihydrochloride (Compound 79), mp 178-180 ° C.

(C) 4-phenyl-2 (5)-[(4- (4-fluoro-benzyl-piperidin-1-yl) -methyl] -imidazole dihydrochloride (compound 80), mp 216-218 ° C.

(D) 4-phenyl-2 (5)-[(4- (4-phenyl-piperidin-1-yl) -methyl] -imidazole dihydrochloride (compound 81), mp 182-184 ° C.

(E) 4-phenyl-2 (5)-[(4- (4-fluorophenyl) piperazin-1-yl) methyl] -imidazole dihydrochloride (compound 82), mp 161-163 ° C.

(F) 4-phenyl-2 (5)-[(4- (2-methoxyphenyl) piperazin-1-yl) -methyl] -imidazole dihydrochloride (compound 83), mp 229-231 ° C.

(G) 4-phenyl-2 (5)-[(4- (2-pyridyl) -piperazin-1-yl) -methyl] -imidazole trihydrochloride (compound 84), mp 165-167C.

(H) 4-phenyl-2 (5)-[(4-phenyl-piperazin-1-yl) methyl] imidazole dihydrochloride (compound 85), mp 182-184 ° C.

(I) 4-phenyl-2 (5)-[(4-benzoyl-
Piperidin-1-yl) -methyl] -imidazole dihydrochloride (Compound 86), mp 200-202 ° C.

(J) 4-phenyl-2 (5)-[(4- (4-fluoro-benzoyl-piperidin-1-yl) -methyl]-
Imidazole dihydrochloride (Compound 87), mp 173-175 ° C.

Example 13 A solution of 10 g of 2-bromopropiophenone in 50 mL of formamide was heated at 180 C overnight. The reaction was then cooled to room temperature and poured into 250 mL of ice water. The mixture was adjusted to pH 9 with 1N sodium hydroxide and the resulting precipitate was collected by filtration, washed with water, and then dried to give 6.0 g of 4-methyl-5-phenylimidazole as a solid, which was used in the next step. Used without further purification.

128 mg of 4-methyl-5-phenylimidazole and 180
A mixture of mg 4-benzylpiperidine and 85 mg 37% formamide in 10 mL acetic acid was heated at reflux for 8 hours. The acetic acid is then removed by evaporation under reduced pressure,
The residue was dissolved in 50 mL of ethyl acetate. The ethyl acetate solution was washed successively with 50 mL of dilute sodium hydroxide solution and water. The ethyl acetate extract was then dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give 5-methyl-4-phenyl-2 (5)-[(4-benzyl-piperidin-1-yl)-. Methyl] imidazole is obtained as an oil, which is eluted with 5
Purified by chromatography on silica gel using% methanol. The purified free base is treated with ethanolic HCl to give 5-methyl-4-phenyl-2 (5)
-[(4-Benzyl-piperidin-1-yl) -methyl] imidazole dihydrochloride (Compound 88) was obtained.

14.3 g of 2-phenyl-4 in 50 mL of ethanol
To a solution of (5) -methylimidazole and 13.8 g of 1- (2-pyrimidyl) piperazine was added 7.1 mL of an aqueous formamide solution. The resulting mixture was heated at reflux for 2 hours and cooled to room temperature. The solid was collected by filtration and then dried to give 20 g of 2-phenyl-5-methyl-4.
(5)-[(4- (2-pyrimidinyl) piperazine-1
-Yl) methyl] imidazole, which is treated with 2 equivalents of maleic acid in isopropanol to give 2-phenyl-5-methyl-4 (5)-[(4- (2-pyrimidinyl) piperazin-1-yl). Methyl] -imidazole dimaleic acetic acid (Compound 89) was obtained. mp 172-174 ° C.

Example 14A The following compound was made essentially according to the procedure described in Example 14.

(A) 2-phenyl-5 (4) -methyl-4 (5)-
[(4- (4-Fluoropyrimidin-2-yl) piperazin-1-yl) methyl] -imidazole (Compound 89
A).

(B) 2- (2-fluorophenyl) -5 (4) -methyl-4 (5)-[(4- (4-fluoropyrimidine-2
-Yl) piperazin-l-yl) methyl] -imidazole (Compound 89B).

Example 14B 2-phenyl-5 (4) -methyl-4 (5)-[(4-
(4- (5-Fluoropyrimidin-2-yl) piperazin-1-yl) methyl] -imidazole (Compound 89
C).

1- (5-Fluoropyrimidin-2-yl) piperazine (1.44 g, 7.9 mmol) in ethanol (15 mL)
To a solution of and formaldehyde (0.7 mL, 37%) was added solid 2-phenyl-4-methylimidazole (1.25 g) and the resulting mixture was stirred for about 2 hours.
The mixture was cooled, upon which a white solid formed. This solid was collected by filtration and washed with a small amount of cold ethanol (1.0 g). Dissolve the solid in isopropanol (20 mL) and maleic acid (0.66 g) in isopropanol (10 mL)
Solution. The resulting solution was concentrated to a total volume of 15 mL and allowed to stand. The crystalline dimaleate was collected by filtration (1.4 g). mp 178-179 ° C.

Example 14C 2- (2-fluorophenyl) -5 (4) -methyl-4
(5)-[(4- (5-Fluoropyrimidin-2-yl) -piperazin-1-yl) methyl] -imidazole (Compound 89D) Methyl-2-fluorobenzimidate (26.9 mmol) in 6N HCl (50 mL) ) And 2-aminopropionaldehyde dimethyl acetal (20.8 g)
Heated to about 2 hours and then cooled. The cooled mixture was poured on ice, basified with 50% NaOH and extracted with chloroform. The extracts were combined, dried and then concentrated. The resulting oxalate salt of 2- (2-fluorophenyl) -4-methylimidazole was made in isopropanol.

Solid 2- (2-fluorophenyl) -4 in a solution of 1- (5-fluoropyrimidin-2-yl) piperazine (0.53 g, 2.87 mmol) and formaldehyde (0.5 mL, 37%) in ethanol (10 mL) -Methylimidazole (1.25 g) was added and the resulting mixture was stirred for about 12 hours. The mixture was cooled and then concentrated to a solid. This solid was collected by filtration and washed with a small amount of cold ethanol (1.0 g). The solid was dissolved in isopropanol (15 mL) and combined with a solution of maleic acid (0.645 g) in isopropanol (5 mL). The resulting solution
Concentrated to a total volume of 7 mL and allowed to stand overnight. The crystalline dimaleate was collected by filtration (0.8 g). mp13
8-139 ° C.

Example 15 100 mg of 2-phenyl- in 10 mL of chloroform
4 (5)-[(4- (2-pyrimidinyl) piperazine-
1-yl) methyl] imidazole in a solution of 1 equivalent (80 mg) of iodine in 5 mL of chloroform, then 0.5 mL
Of triethylamine was added. The reaction mixture was stirred at room temperature for 30 minutes, during which time a solid crystallized from solution. The solid was collected by filtration to give 52 mg of 2-phenyl-5-
There was obtained iodo-4 (5)-[(4- (2-pyrimidinyl) piperazin-1-yl) methyl] -imidazole hydroiodide (Compound 90), which had a melting point of 196-199 ° C.

Example 16 To a solution of 220 mg of 2-phenyl-4-imidazolecarboxaldehyde in 5 mL of tetrahydrofuran,
A 1 L solution of methyllithium in 6.4 mL of tetrahydrofuran was added. The reaction mixture was quenched with 50 mL of water, and the mixture was extracted with 2 x 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to 250 mg.
2-phenyl-4 (5)-(1-hydroxyethyl)
Imidazole was obtained and used in the next step without further purification or characterization. 2-phenyl-4
(5) Dissolve the residue of-(1-hydroxyethyl) imidazole in 8 mL of thionyl chloride and heat at reflux for 30 minutes, then remove the thionyl chloride by distillation under reduced pressure to give 250 mg of 2-phenyl -4 (5)-(1-Chloroethyl) imidazole was obtained as an oil which was used in the next step without further purification or characterization.
Dissolve the oil in 10 mL of chloroform and add
224 mg of 4-benzylpiperidine and 2 mL of triethylamine were added. The reaction was left at room temperature for 10 minutes, then washed with 50 mL of 1N sodium hydroxide. The chloroform extract was then separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure to give 2-phenyl-4 (5)-[1-((4-benzyl-piperidine- 1-yl) -ethyl)] imidazole was obtained and purified by chromatography on silica gel using 10% methanol / dichloromethane as eluent. Treatment with ethanolic HCl gave 2-phenyl-4 (5)-[1-((4-benzyl-piperidine-
1-yl) -ethane-1-yl)] imidazole dihydrochloride (Compound 91). mp 169-171 ° C.

Example 17 A solution of 5.5 g of 1-cyanonaphthalene in 150 mL of dry ether was cooled to 0 ° C. To this solution 12.1 g of lithium bis (trimethylsilyl) amide was added in one portion. The mixture was stirred for 12 hours and then warmed to room temperature. The reaction mixture was cooled to 0 ° C. and then 200 mL of 3N HC
The reaction was stopped by the addition of l. After stirring at 0 ° C. for 20 minutes, the mixture was transferred to a separatory funnel and washed with 3 × 100 mL of ether. The aqueous layer was cooled in an ice bath and adjusted to pH 14 with solid sodium hydroxide. This solution was extracted with 4 × 100 mL of dichloromethane. The combined organic extracts were washed with 2 × 100 mL of water and 1 × 100 mL of brine, dried over potassium carbonate, filtered, and 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 purified amidine, 2.5 g of dihydroxyacetone dimer and 2.5 g of ammonium chloride was suspended in 35 mL of concentrated 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. The reaction mixture was cooled to room temperature and the product was collected by filtration, washed with cold water, and dried under reduced pressure to give 3 g of 2- (1-naphthyl) -4.
(5)-(Hydroxymethyl) imidazole was obtained as off-white crystals. mp 155-158 ° C.

A solution of 62 mg of 2- (1-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 of chloroform and 53 mg of 4-
Benzylpepyridine was added, followed by 47 mg of diisopropylethylamine. The reaction mixture was stirred at room temperature for 1 hour, diluted with 3 volumes of chloroform and then washed with 3 × 3 mL of 10% sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 5% methanol in dichloromethane, to give 62 mg of 2- (1-naphthyl) -4.
(5)-[(4-benzyl-piperidin-1-yl)-
Methyl] imidazole (compound 92) was obtained, mp 81-83.
° C.

Example 18 The following compound was made from the corresponding nitrile substantially according to the procedure described in Example XVII.

(A) 2- (1-naphthyl) -4 (5)-[(4- (2
-Pyrimidinyl) -pyrrazin-1-yl) -methyl]
-Imidazole (compound 93), mp 187-188 ° C.

(B) 2- (1-naphthyl) -4 (5)-[(4- (2
-Pyridyl) -pyrrazin-1-yl) -methyl] -imidazole (compound 94), mp 182-183 ° C.

(C) 2- (1-naphthyl) -4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound
95), mp 74-76 ° C.

(D) 2- (2-Naphthyl) -4 (5)-[(4-benzyl-piperidin-1-yl) -methyl] -imidazole (compound 96), mp 92-94 ° C.

(E) 2- (2-naphthyl) -4 (5)-[(4- (2
-Pyrimidinyl) -piperazin-1-yl) -methyl]
-Imidazole (compound 97), mp 218-219 ° C.

(F) 2- (2-naphthyl) -4 (5)-[(4- (2
-Pyridyl) -piperazin-1-yl) -methyl] -imidazole (compound 98), mp 199-201 ° C.

(G) 2- (2-naphthyl) -4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound
99), mp 86-87 ° C.

(H) 2- (2-pyridyl) -4 (5)-[(4-benzyl-piperidin-1-yl) -methyl] -imidazole (compound 100), mp 96-98 ° C.

(I) 2- (2-pyridyl) -4 (5)-[(4- (2
-Pyrimidinyl) -piperazin-1-yl) -methyl]
-Imidazole (compound 101), mp 134-135 ° C.

(J) 2- (2-pyridyl) -4 (5)-[(4- (2
-Pyridyl) -piperazin-1-yl) -methyl] -imidazole (compound 102), mp 135-137 ° C.

(K) 2- (2-pyridyl) -4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound
103), mp 61-63 ° C.

(L) 2- (3-pyridyl) -4 (5)-[(4- (2
-Pyrimidinyl) -piperazin-1-yl) -methyl]
-Imidazole (compound 104), mp 155-157 ° C.

(M) 2- (3-pyridyl) -4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound
105), mp 141-142 ° C.

(N) 2- (4-pyridyl) -4 (5)-[(4- (2
-Pyrimidinyl) -piperazin-1-yl) -methyl]
-Imidazole (compound 106), mp 154-156 ° C.

(O) 2- (2-pyrazinyl) -4 (5)-[(4-
(4-benzyl-piperidin-1-yl) -methyl]-
Imidazole (Compound 107), mp 80-81 ° C.

(P) 2- (2-pyrazinyl) -4 (5)-[(4-
(2-Pyrimidinyl) -piperidin-1-yl) -methyl] -imidazole (Compound 108), mp 164-165 ° C.

(Q) 2- (2-pyrazinyl) -4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound 109), mp 93-94 ° C.

(R) 2- (2-thienyl) -4 (5)-[(4- (2
-Benzyl-piperidin-1-yl) -methyl] -imidazole (Compound 110), mp 77-79 ° C.

(S) 2- (2-thienyl) -4 (5)-[(4- (2
-Pyrimidinyl) -piperazin-1-yl) -methyl]
-Imidazole (compound 111), mp 204-205 ° C.

(T) 2- (2-thienyl) -4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound
112), mp 132-134 ° C.

(U) 2- (2-thienyl) -4 (5)-[(4- (2
-Pyridyl-piperazin-1-yl) -methyl] -imidazole (compound 113), mp 179-181 ° C.

(V) 2- (2-quinolinyl) -4 (5)-[(4-
(2-Pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole (Compound 114), mp 263 DEG C. (decomposition).

(W) 2- (2-quinolinyl) -4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound 115), mp 247 ° C (decomposition).

Example 19 193 mg of 2-benzoylimidazole and 330 mg of 1-
A solution was made by dissolving (2-pyrimidyl) -piperazine and 165 mg 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 with 3N hydrochloric acid and extracted with 5 × 10 mL of ethyl acetate. 2x organic extraction
Washed with 10 mL water and 1 × 10 mL brine, 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 for 43 mg of 2- (benzoyl) -4 (5)-[(4-
(2-Pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole (compound 116), mp 177-179 ° C.

Example 20 The following compounds were made essentially according to the procedure described in Example XVII.

(A) 2-benzyl-4 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole (compound 117), mp 160-161 ° C.

(B) 2- (5-methoxy-3,4-dihydro-naphtho-
1-yl) -4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound 118), mp133
~ 134 ° C.

Example 21 A solution of 1.25 g of 2-phenyl-4 (5) -imidazolepropenoic acid was dissolved in 20 mL of thionyl chloride and then heated at reflux for 2 hours. The solvent was removed and the residue was suspended in 20 mL of chloroform. 1.
7 g of 1- (2-pyrimidinyl) -piperazine dihydrogen chloride was added, followed by 3.5 mL of diisopropylethylamine. The reaction mixture is stirred at room temperature for 6 hours, then 50 mL
And washed with 3 × 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, 554 mg of 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -propene-propene-. 1-yl-oil] -imidazole (compound 119) was obtained, mp 235-236 ° C.

Example 22 The following compound was made essentially according to the procedure described in Example XXI.

(A) 2-phenyl-4 (5)-[(4-phenyl-piperazin-1-yl) -propen-1-oil] -imidazole (compound 120), mp 151-152 ° C.

(B) 2-phenyl-4 (5)-[(4-hydroxy-
4- (4-chlorophenyl) -piperidin-1-yl)
-Propene-1-oil] -imidazole (compound 12
1), mp 236-240 ° C.

Example 23 68 mg of 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -propen-1-
Oil] -Imidazole solution in 2 mL of ethyl acetate and 0.2 mL
was dissolved in a mixture of mL of ethanol, the suspension was stirred for 2 days under an atmosphere of H ₂ using Pt on carbon that time 20mg as a catalyst. The mixture was filtered through celite to remove the solvent. The residue was chromatographed on silica gel using 5% methanol / dichloromethane as eluent.
37 mg of 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -propen-1-oil] -imidazole (compound 122) were obtained, mp143-
148 ° C.

Example 24 The following compounds were made essentially according to the procedure described in Example XXIII.

(A) 2-phenyl-4 (5)-[(4-phenyl-piperazin-1-yl) -propen-1-oil] -imidazole (compound 123), mp 180-183 ° C.

(B) 2-phenyl-4 (5)-[(4- (2- (3,4,
5,6-Tetrahydroxy) -pyrimidinyl) -piperazin-1-yl) -propen-1-oil] -imidazole (compound 124), mp 210-211 ° C.

Example 25 A solution of 84 mg of 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -propane-1-oil] -imidazole in 5 mL of dry tetrahydrofuran at room temperature with 18 mg of hydrogen Lithium aluminum bromide was added and the mixture was heated at reflux and refluxed for 2 hours. After quenching with ethyl acetate, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using 10% methanol in dichloromethane as eluent to give 20 mg of 2-phenyl-
There was obtained 4 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -propan-1-yl] -imidazole (compound 125), mp 133-135 ° C.

Example 26 The following compound was made essentially according to the procedure described in Example XXV.

(A) 2-Phenyl-4 (5)-[(4-phenyl-piperazin-1-yl) -propan-1-yl] -imidazole (Compound 126), mp 50-54 ° C.

(B) 2-phenyl-4 (5)-[(4-hydroxy-
4- (4-chlorophenyl) -piperidin-1-yl]
-Propan-1-yl] -imidazole (compound 12
7), mp 122-124 ° C.

Example 27 A solution of 6.8 g of 2-phenylimidazole in 200 mL of 3N hydrochloric acid was added to 5% rhodium on carbon (Degussa type
G10 NB / w) was added. The mixture was hydrogenated at 100 psi for 24 hours and then filtered over celite. The solution
Neutralized with 25% sodium hydroxide and extracted with 2 × 100 mL of ethyl acetate. The combined extracts were washed with 200 mL of brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give 2-cyclohexylimidazole as a feathery white solid which was used in the next step without further purification or characterization.

To a solution of 251 mg of 2-cyclohexylimidazole in 8 mL of acetic acid was added 274 mg of 1- (2-pyrimidyl) piperazine and 88 μL of 37% formaldehyde. The solution was heated at 100 ° C. for 12 hours, then the solvent was removed under reduced pressure and the residue was diluted with water. The mixture was made slightly alkaline with 5% sodium hydroxide and then extracted with 2.times.25 mL of ethyl acetate. The combined extracts were washed with 25 mL of brine, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The product was separated on reverse phase silica gel (Whatman PLKC18F) using a 0.2 M aqueous sodium chloride solution containing 80% methanol. The fractions are evaporated and 2-cyclohexyl-4 (5) -hydroxymethylimidazole and 50 mg of the desired 2-cyclohexyl-4 (5)-[(4- (2-pyrimidinyl)-
Piperazin-1-yl) -methyl] -imidazole (Compound 128) was obtained, mp 210-235 ° C.

Example 28 The following compound was made essentially according to the procedure described in Example XXVII.

(A) 2-cyclohexyl-4 (5)-[(4-benzyl-piperidin-1-yl) -methyl] -imidazole (compound 129), mp 185-188 ° C.

(B) 2-cyclohexyl-4 (5)-[(N-methyl-N-benzyl) -methyl] -imidazole (compound
130), mp 235-238 ° C.

(C) 2- (4-methylcyclohexyl) -4 (5)-
[(4- (2-Pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole (Compound 131).

Example 29 30 mL of a solution of 790 mg iodine in 5 mL chloroform
1.0 g of 2-phenyl-4 dissolved in chloroform
(5)-[(4- (2-pyrimidinyl) piperazine-1
-Yl) methyl] imidazole at room temperature. After stirring the solution for 10 minutes, 1 mL of triethylamine was added and stirring was continued until no more solids were formed. The solid was collected by filtration and, after drying, 700 mg of 2-
Phenyl-5-iodo-4 (5)-[(4- (2-pyrimidinyl) piperazin-1-yl) methyl] -imidazole was obtained and used in the next step without further purification or characterization.

To a solution of 53 mg of 2-phenyl-5-iodo-4 (5)-[(4- (2-pyrimidinyl) piperazin-1-yl) methyl] -imidazole in 1 mL of dimethylformamide was added 130 μL of phenyltrimethyl spanate and 3 mg.
Bis (triphenylphosphine) -palladium (II)
And chloride were added. The reaction mixture was heated at 100 ° C. for 4 hours, then poured into water, extracted with 2 × 10 mL of ethyl acetate, and washed with 10 mL of 10% aqueous ammonium chloride. The combined organic extracts are dried over anhydrous sodium sulfate,
The solvent was removed by evaporation under reduced pressure. The resulting material was chromatographed on silica gel using 5% methanol in dichloromethane as eluent to give 15 mg of
2,5-Diphenyl-4 (5)-[(4- (2-pyrimidinyl) piperazin-1-yl) methyl] -imidazole (compound 132) was obtained, mp 221-225 ° C.

Example 30 To a solution of 12.4 g of p-tolunitrile in 500 mL of diethyl ether was added 23 g of solid lithium bis (trimethylsilyl) amide at room temperature. The mixture was stirred for 2 hours and then hydrolyzed at 0 ° C. with 10% HCl. The mixture was stirred for a further 30 minutes and then concentrated to dryness to give 6 g of 4-methylbenzamidine hydrochloride, which was used without further purification in the next step.

A solution of 4 g of 4-methylbenzamide hydrochloride in 60 mL of ammonium hydroxide was treated with 4.0 g of dihydroxyacetone and 4.8 g of ammonium chloride. The reaction mixture was heated to 90 ° C. for 4 hours in a sealed tube.
After cooling to room temperature, the resulting solid was collected by filtration.
3.0 g of 2- (4-methylphenyl-5-hydroxymethyl-imidazole are obtained, which is converted according to the procedure described in Example VII to give 2- (4-methylphenyl-4
(5)-[(4- (2-pyrimidinyl) -piperazine-
1-yl) -methyl] -imidazole (compound 133) was obtained, mp 178-180 ° C.

Example 31 The following compounds were made essentially according to the procedure described in Example XXX.

(A) 2- (4-iodophenyl-4 (5)-[(4-
(2-Pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole (compound 134), mp 218-220 ° C.

(B) 2-phenyl-4 (5)-[(4- (4-chlorophenyl) -3-methylpiperazin-1-yl) methyl] imidazole (compound 135), mp 137-139 ° C.

(C) 2-phenyl-4 (5)-[(4-methylphenyl) -3-methylpiperazin-l-yl) methyl] imidazole (compound 136), mp 172-174 ° C.

(D) 2-phenyl-4 (5)-[(4-methoxyphenyl) -3-methylpiperazin-1-yl) methyl] imidazole (compound 135), mp 188-190 ° C.

Example 32 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. After cooling to room temperature,
The crystals formed are collected by filtration and, after drying, 3.0 g of 2
-Phenyl-4,5,6,7-tetrahydrobenzimidazole (compound 136) was obtained, mp 300-301 ° C.

50 mg of 2-phenyl-5,6, in 5 mL of carbon tetrachloride
40 mg in a solution of 7,8-tetrahydrobenzimidazole
1,3-Dibromo-5,5-dimethylhydantoin was added. The mixture was heated to reflux and irradiated with a 500 watt tungsten lamp for 30 minutes. The temperature was lowered temporarily and a solution of 41 mg of 1- (2-pyrimidyl) piperazine was added to the reaction. The mixture is again heated at reflux temperature for 30 minutes.
Heated for minutes. Then 0.5 mL of triethylamine was added to the reaction and the solution was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and the product was purified on silica gel using 10% methanol in dichloromethane to give 28 mg of 2-phenyl-7-[(4- (2-pyrimidinyl) -piperazin-1-yl)-. Methyl] -4,5,
6,7-Tetrahydrobenzimidazole (compound 137) was obtained, mp 200-202 ° C.

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

(A) 2-phenyl-7-[(4-benzyl-piperazin-1-yl) -methyl] -4,5,6,7-tetrahydrobenzimidazole (compound 138), mp 189-191 ° C.

(B) 2-Phenyl-7-[(N-methyl-N-benzyl) aminomethyl] -4,5,6,7-tetrahydrobenzimidazole (Compound 139), mp 181-183 ° C.

Example 34 A solution of 820 mg of 2-chloropyrimidine and 1.6 g of cis-2,6-dimethylpiperazine in 25 mL of toluene was heated at reflux for 12 hours. Evaporate the solvent,
The residue was made basic with 5% sodium hydroxide and 2 × 10
Extracted with 0 mL of dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated to give cis-2,6.
-Dimethyl-1- (2-pyrimidyl) -piperazine was obtained. This amine is then used according to the procedure described in Example VIII for 2-phenyl-4 (5)-[(4- (2-
Pyrimidinyl) -cis-2,6-dimethylpiperazine-1-
Yl) -methyl] -imidazole (compound 140) was obtained, mp 130-135 ° C.

Example 35 The following compounds were made according to the procedure described in Example XXXIV.

(A) 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) -trans-2,5-dimethylpiperazin-1-yl) -methyl] -imidazole (compound 141), mp175
~ 178 ° C.

(B) 2-phenyl-4 (5)-[(8- (2-pyrimidinyl) -3,8-diazabicyclo (3,2,1) octane-3
-Yl) -methyl] -imidazole (compound 142), m.p.
p. 190-194 ° C.

Example 36 A mixture of 5.0 g of 1,4-dihydroxy-2-butanone and 7.5 g of benzamide dihydrochloride in 70 mL of ammonium hydroxide was heated in a sealed tube to 90 ° C. for 5 hours. The reaction mixture was diluted with 100 mL of water and 2 × 5
Extracted with 0 mL of chloroform, dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was chromatographed on silica gel using 10% methanol in dichloromethane as eluent to give 1.0 g of 2-phenyl-4 (5) -hydroxyethylimidazole, which was prepared according to the procedure of Example 8 1-
Reaction with (2-pyrimidyl) piperazine to give 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) -piperazin-1-yl) -ethane-1-yl] -imidazole (compound 143). Mp 142-144 ° C.

Example 37 A mixture of 77 mg of 2-phenylimidazole-4 (5) -carboxylic acid and 5 mL of thionyl chloride was heated at reflux temperature for 1 hour.
Heated for hours. Thionyl chloride was removed under reduced pressure to give 75 mL of 2-phenylimidazole-4-carboxylic acid chloride, which was then dissolved in 5 mL of chloroform and treated with 67 mg of 1- (2-pyrimidyl) piperazine. The solution was heated at reflux for 1 hour, then 0.5 mL of triethylamine was added. The solution was stirred for an additional hour, concentrated under reduced pressure and the residue was chromatographed on silica gel using 10% methanol in dichloromethane as eluent for 50 mg of 2-phenyl-4.
(5) -N-[(4- (2-Pyrimidinyl) -piperazin-1-yl) -carboxamide] -imidazole (compound 144) was obtained, mp 231-232 ° C.

Example 38 The following compounds were made according to the procedure described in Example XXXVII.

(A) 2-phenyl-4 (5) -N-[(N-methyl-
N-benzyl) -carboxamide] -imidazole (compound 145), (characterized as oxalate), mp 198-199
° C.

(B) 2-phenyl-4 (5) -N-[(4-benzyl-piperidin-1-yl) -carboxamide] -imidazole (compound 146), (characterized as hydrochloride), mp1
79-181 ° C.

Example 39 Part A In a suitable container, add ammonium hydroxide (90.4 g) to benzamidine hydrochloride hydrate (19.6 g, 125 mmol), 1,3
-Dihydroxyacetone dimer (19.85 g, 110.06 mmol) and ammonium chloride (19.98 g, 373.8 mmol) were added. The mixture is heated to 55 ° C. over 2 hours and 2-phenyl-4 (5)-(hydroxymethyl)
Imidazole (50 mg) was added to the reactor to initiate crystallization. The mixture was heated to 55 ° C. for an additional 1.5 hours and then cooled to 5 ° C. for 4 hours. After cooling overnight, the solid was collected on a Buchner funnel and washed with water. This material is dried on a tray under reduced pressure at 55-60 ° C for about 2 days to give 2-phenyl-4 (5)-(hydroxymethyl)
Imidazole (10.7 g, 64.66 mmol) was obtained as a dark blue solid. This material had a proton nuclear magnetic resonance (NMR) spectrum consistent with the structure. C18 reverse layer plate and 6
Thin layer chromatography using 5:35 methanol: 0.5M NaCl-1% acetic acid gave a single spot (Rf = 0.64).

Part B 2-phenyl-4 (5) in a suitable reaction vessel equipped with mixing, heating and cooling means and purged with nitrogen
-(Hydroxymethyl) imidazole (10.38 g, 59.6 mmol) and 1- (2-pyrimidinyl) piperazine (17
g, 130.6 mmol). Piperazine was warmed to 50 ° C. and added as a liquid. Then the mixture is 130-1
Heated at 40 ° C. for about 2 hours, at which point the mixture had solidified. Stirring was stopped and heating was continued for an additional hour after which the reaction was cooled to about 120 ° C. Toluene (42 g) was added and the mixture was stirred at 50 ° C. for about 30 minutes. Toluene was removed by filtration through a 30 μM wrap filter. Additional toluene (42 g) was added to the solid and the resulting mixture was slurried under reflux for 1 hour, cooled to room temperature and finally allowed to stand overnight. The mixture was filtered through a Buchner funnel and the solid was washed with toluene (10g). This material was dried in a vacuum tray dryer at about 60 ° C. for 18 hours to give crude compound 23A as a free base.

Part C 2-phenyl-4 (5)-[(4- (2-pyrimidinyl) piperazin-1-yl) methyl] -imidazole dimaleate 1. In a suitable container 2-propanol (95.5 g) and compound 23A
With the crude free base (15.28 g, 47.69 mmol). The mixture was then heated to 70 ° C and the 2-
Maleic acid (11.4 g) dissolved in propanol (51.27 g)
(6 g, 98.8 mmol) was added over 2 hours with cooling, keeping the temperature below 80 ° C. The reaction was then cooled and maintained at 23 ° C. for 5 hours, then the solid was collected by filtration on a Buchner funnel to give dimaleate (30.4 k
g) was obtained. The dimaleate was then purified as described below without prior drying.

2. In a suitable container, water (73g) and 2-propanol (228g)
And 30.4 g of the material made in Part 1 of Part C in this example. The mixture was then heated at 70 ° C. for 1 hour and filtered hot through a 3 μM filter. The filtrate was cooled to about 3 ° C. and the crystals were collected by filtration through a polyethylene cloth. The crystals were then washed with 2-propanol (11.8 g) and dried at 41 ° C. under reduced pressure (28 inches Hg) for 3 days to give the title compound, 2-phenyl-4 (5).
-[(4- (2-pyrimidinyl) piperazin-1-yl) methyl] -imidazole dimaleate (19.95 g, 3
6.1 mmol). This material was subsequently milled in a Pitz mill with a 0.0027 inch screen to give the final product.

Example 40 2-Phenyl-4 (5) -hydroxymethylimidazole (300 g, 0.17 mmol) was dissolved in 5 mL of thionyl chloride and the mixture was heated slightly to reflux. After concentration on a rotary evaporator, chloroform was added and the resulting solution was re-concentrated. Dissolve the residue in 5 mL of chloroform, 335 mg
Of 1- (5-methoxy-2-pyrimidinyl) piperazine [prepared by the procedure described in Journal Chemical Society, 4590 (1960)], followed by 2 mL of triethylamine. After 20 minutes, the reaction mixture is washed with 1N NaOH
Washed with the solution, dried and then concentrated. The resulting material was dissolved in a solution of 2 equivalents of macreinic acid in 2 mL of isopropanol, and then 3 mL of isopropanol was added. The obtained solid was filtered to obtain 870 mg of 2-phenyl-4 (5)-[(4- (2- {5-methoxypyrimidinyl}) piperazinyl-1) methyl] imidazole dimaleate (86%). Was.

Example 41 2-Phenyl-4 (5) -hydroxymethylimidazole (200 g) was dissolved in 5 mL of thionyl chloride and the mixture was heated slightly to reflux. After concentration on a rotary evaporator, chloroform was added and the resulting solution was re-concentrated. The residue was dissolved in 5 mL of chloroform, and 210 mg of 1- (5-fluoro-2-pyrimidinyl) piperazine [Chemical Pharmaceutical Bretin, vol. 39, p. 2298 (1991)]
And 1 mL of triethylamine were added. After 20 minutes, the reaction mixture was washed with a 1N NaOH solution, dried and concentrated. Silica chromatography eluting with 10% methanol in chloroform gave 175 mg of 2-phenyl-4 (5)-
This gave [(4-((2- {5-fluoropyrimidinyl}) piperazin-1-yl) methyl] imidazole, which was crystallized from isopropyl alcohol, mp 185-186 ° C.

Example 42 2-Phenyl-4 in dry chloroform (8 mL)
(5) A solution of-[(4-((2- {methoxypyrimidinyl) piperazin-1-yl) methyl] -imidazole (Example X) (0.37 g) was added to a solution of boron tribromide (1.0 N BBR in methylene chloride). ₃ 11.5 mL) "was added. the resulting mixture was refluxed for 4 hours, poured into ice and ammonium hydroxide, dried and extracted with chloroform. the organic extracts (Na ₂ SO _4), then concentrated The product was purified by preparative thin layer chromatography eluting with 10% methanol in chloroform to give 75 mg of 2-phenyl-4 (5)-[(4-((5-hydroxypyrimidin-2-yl) piperazine- 1-yl) methyl] imidazole was obtained, the dioxalate salt of which was prepared in ethyl alcohol (mp 214-216 ° C.).

 Further dihydrochloride was prepared, m.p.

Example 43 The following compounds were analyzed for D2, D3 and D4 receptor binding activity using the assay described above.

Example 44 Summary The effects of 2-phenyl-4 (5)-[(4- (2-pyrimidyl) -piperazin-l-yl) methyl] -imidazole dihydrochloride (Compound 23) and clozapine were studied following learning and memory. Were evaluated using the following models: Step-Down Passive, Avoidance Task Analysis and Modified Morris Water Maze Analysis. Separate groups of male Sprague-Dawley rats were pretreated with either compound 23 or clozapine prior to acclimatization to these tests. The comparative compound, clozapine, was administered at the two highest doses tested (1.0 and 2.0 mg / kg) by passive avidance.
This resulted in learning flaws in task work. Clozapine did not show any defects in the Water Maze task at the doses tested. Animals receiving a 0.25 mg / kg dose of Compound 23 showed a marked improvement in memory in the step-down passive avoidance task analysis compared to the vehicle group. Similarly 0.03 mg / kg, 0.25 mg / kg and 1.0 m in modified Morris Water Maze analysis
Animals that received the g / kg amount of compound 23 showed significantly improved work retention compared to the vehicle group. These data indicate that compound 23 does not inhibit learning but enhances learning in animals.

Methods Non-naive male Sprague-Dawley rats (SASCO Setlouis) weighing 2000-300 g were housed in groups of three in a temperature and humidity controlled housing with a 12 hour light / dark cycle. These animals had free 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 0.25-2 mg / kg. Both drugs train in both learning tasks 5
Minutes before intravenous administration.

Equipment: Step-Down Passive Avoidance Task: Step-Down Passive Avoidance Task Platform 4cm x 7cm installed on a powered GRIS floor, large (45 x 45) with lid capable of sealing this floor × 50c
m) in a white translucent flexiglass enclosure. Each bar of the grip was 1.5 cm apart and connected to a BRS-LVE shock generator / scrambler designed to deliver a 2 mA 6 second shock. 4 Passive Avoidance Task Tests with Conventional Software (Labview)
And a commercially available interface module (National Instruments) connected to a computer. The timing and delivery of shock, as well as the ability to step-down and the number of tests required to reach a baseline in training, were under computer control. All tests were performed in the presence of 62 db white noise.

Modified Morris Water Maze: The Water Maze device consisted of a circular tank (120 cm in diameter and 56 cm in height) with a black interior. The tank was surrounded by an external visible cue consisting of black and white check walls, black and white striped walls, white walls and blue panels. Fill the tank with water (18-20 ° C)
Filled to a height of 52 cm and divided into quadrants (North, South, East and West). A black circular plexiglass platform (with a black rubber top) was placed in the northeast quadrant about 1 cm below the right surface. The dipped platform was 51 cm high and had a diameter of 9 cm. 6 training and exams
Performed in the presence of a 2db white noise source and under low light conditions.

Procedure: 1. Passive Avoidance Task Acquisition Training: After treatment with clozapine compound 23 or a comparison (vehicle), the animal was placed on the platform and the timer was started automatically. The animal automatically received a limb shock as the animal descended from the platform. After each shock, the animals were removed from the box, placed in their cages for 1 minute intervals, and then returned to the platform. Training was terminated when the animal remained on the platform for 120 seconds. Immediately after training, the animals were returned to their cages in the breeding box.

Retention test: The test was performed approximately 24 hours after training, drug-free animals were placed on platforms in the box where they were trained, and the tendency of step-down to the unshocked floor was recorded per test. . Animals were subjected to a 120 second step-down.

2. Modified Morris Water Maze: Acquisition training: The acquisition training in this work analysis consisted of 4 or 6 training tests. Four test procedures detect the cognitive-enhancing effects of the drug, while six test procedures detect the drug that results in learning deficits in this work analysis. Compound 23 was tested in a water maize with four test procedures, and six test training procedures were used for clozapine. Each animal was placed on the platform in the tank for 20 tests separated at 2 minute intervals. The starting position was varied randomly but to the same extent for each animal. Animals were dried during ITI (test interval) and placed near a heat source (heat lamp). The ability to reach the immersion platform during each test was measured and the animals were left on the platform for 10 seconds after they reached the platform. Since the platform was submerged just below the surface of the water, the animals needed to locate the platform using an external visible cue (distal cue) surrounding the tank.

Retention training: The following day, each animal was tested individually for retention in one test. Each animal was placed in the "south" starting position and the ability to find the immersion platform was recorded.

Results Passive Avoidance Task: There were no significant differences in learning between the vehicle group and animals tested with Compound 23. Animals receiving the 0.25 mg / kg dose of compound 23 remained on the platform for significantly longer periods of time than vehicle comparison animals. Animals receiving the 1.0 mg / kg and 2.0 mg / kg doses of clozapine showed significant acquisition deficits compared to the vehicle group. There was no significant residence time difference between the clozapine treated animals and the vehicle group.

Water Maze: The difference between the first test and the retest (ability to find the platform the next day) is 0.03 mg / kg, 0.25 mg / kg and 1.0 mg / kg
A dose of kg of compound 23 showed a significant retention improvement over the comparison. However, for animals receiving clozapine, the differences between the scales of Test I and Retest did not show a significant difference.

These results indicate that compound 23 improved memory in mammals. Furthermore, these results also indicate that compound 23 enhances learning in mammals. That is, the compounds of the present invention are important in improving cognition in mammals and can be used in methods for improving cognition, particularly learning and memory in mammals.

All publications and publications cited herein are hereby incorporated by reference.

While the present invention has been described in sufficient detail to enable it to be practiced by those skilled in the art, the description is for the description of a preferred embodiment of the invention, and various modifications may be made without departing from the spirit and scope of the invention. It will be appreciated by those skilled in the art that

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 487/08 C07D 487/08 // A61K 31/00 626 A61K 31/00 626F 626G 626L 31/415 612 31/415 612 31 / 445 610 31/445 610 31/505 601 31/505 601 (31) Priority claim number 401, 201 (32) Priority date March 9, 1995 (33) Priority claim country United States (US) (72) Invention Yuan, Jun United States 06413 Cheddar Road, Clinton, Connecticut 26 (72) Inventor Peterson, John M. United States 06511 New Haven Lawrence Street, Connecticut 193 (56) References Table 6-6-504054 (JP, A ) (58) investigated the field (Int.Cl. ^6, DB name) CAPL S (STN) REGISTRY (STN)

Claims (15)

(57) [Claims] 1. The formula: Wherein W is nitrogen or CH; R _a is hydrogen or lower alkyl; R _d is pyridinyl, pyrimidinyl, phenylalkyl or phenyl, each of which is optionally halogen, hydroxy, lower alkyl or Substituted by lower alkoxy], or a pharmaceutically acceptable salt thereof. 2. The formula: Wherein W is nitrogen; R _a is hydrogen or lower alkyl; R _d is pyridyl, pyrimidinyl, phenylalkyl or phenyl, each of which is optionally halogen, hydroxy, lower alkyl or lower alkoxy. Or a pharmaceutically acceptable salt thereof. 3. The formula: Wherein W is CH; R _a is hydrogen or lower alkyl; R _d is pyridinyl, pyrimidinyl, phenylalkyl or phenyl, each of which is optionally halogen, hydroxy, lower alkyl or lower alkoxy. Or a pharmaceutically acceptable salt thereof. 4. The formula: Wherein W is nitrogen or CH; R _g and R _h are methyl; or R _g and R _h form an ethylene group, and together with the ring system to which they are attached, azabicyclo (3.2 .1) forming an octane group; R _d is pyridinyl, pyrimidinyl, phenylalkyl or phenyl, each of which is optionally substituted by halogen, hydroxy, lower alkyl or lower alkoxy]. Acceptable salts. 5. The formula: Wherein R is fluorine, or a pharmaceutically acceptable salt thereof. 6. The formula: Wherein R is halogen, alkoxy or hydroxy having 1 to 6 carbon atoms; R ₁ and T independently represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; X, Y and Z Independently represents hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy.] 7. The formula: Wherein R is fluorine, methoxy or hydroxy, or a pharmaceutically acceptable salt thereof. (8) 2- (2-fluorophenyl) -4 (5)
-[(4- (5-fluoro-2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole; 2- (4-fluorophenyl) -4 (5)-[(4-
(5-Fluoro-2-pyrimidinyl) -piperazine-1
A compound according to claim 5 selected from the group consisting of -yl) -methyl] -imidazole, or a non-toxic pharmaceutically acceptable salt thereof. (9) 2-phenyl-5-methyl-4 (5)-
[(4- (2-pyrimidinyl) piperazin-1-yl)
Methyl] -imidazole; and 2-phenyl-5-iodo-4 (5)-[(4- (2-
Pyrimidinyl) piperazin-1-yl) methyl] -imidazole; 2-phenyl-5-methyl-4 (5)-[(4- (5-
Fluoropyrimidin-2-yl) piperazin-1-yl) methyl] -imidazole; and 2- (2-fluorophenyl) -5-methyl-4 (5)
-[(4- (5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl] -imidazole; 2-phenyl-5-methyl-4 (5)-[(4- (4-
Fluoropyrimidin-2-yl) piperazin-1-yl) methyl] -imidazole; 2- (2-fluorophenyl) -5-methyl-4 (5)
A compound selected from the group consisting of-[(4- (4-fluoropyrimidin-2-yl) piperazin-1-yl) methyl] -imidazole, or a non-toxic pharmaceutically acceptable salt thereof. (10) 2-phenyl-4 (5)-[1-((4
-Benzyl-piperidin-1-yl) -ethane-1-yl)] imidazole, or a non-toxic pharmaceutically acceptable salt thereof. (11) 2-cyclohexyl-4 (5)-[(4
-(2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole; 2-cyclohexyl-4 (5)-[(4- (2-benzyl-piperidin-1-yl) -methyl] -imidazole; -Cyclohexyl-4 (5)-[(N-methyl-N-
Benzyl) -aminomethyl] -imidazole; 2- (4-methylcyclohexyl) -4 (5)-[(4
-(2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole, or a non-toxic pharmaceutically acceptable salt thereof. (12) 2-phenyl-4 (5)-[(4- (2
-Pyrimidinyl) -cis-2,6-dimethylpiperazine-1
-Yl) -methyl] -imidazole; from 2-phenyl-4 (5)-[(8- (2-pyrimidinyl) -3,8-diazabicyclo (3.2.1) octan-3-yl) -methyl] -imidazole A compound according to claim 4 selected from the group consisting of: or a non-toxic pharmaceutically acceptable salt thereof. (13) 2-phenyl-4 (5)-[(4- (2
-Pyrimidinyl) -piperazin-1-yl) -ethane-
1-yl] -imidazole, or a non-toxic pharmaceutically acceptable salt thereof. (14) 2-phenyl-4 (5)-[(4- (2
-Pyrimidinyl) -trans-2,5-dimethylpiperazine-
1-yl) -methyl] -imidazole, or a non-toxic pharmaceutically acceptable salt thereof. (15) 2-phenyl-4 (5)-[(4- (5
-Fluoro-2-pyrimidinyl) -piperazin-1-yl) -methyl] -imidazole.