^**

BACKGROUND OF THF TNVFNTTQN

Field of the Tnventinn

This invention relates to certain aminomethyl biphenyl. phenylpyridines and phenylpyrimidine derivatives which selectively bind to brain dopamine receptor subtypes. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Par insonism.

Descrimioπ nf the Related Art

Schizophrenia or psychosis is a term used to describe a group of illnesses of unknown origin which affect approximately 2.5 million people in the United States. These disorders of the brain are characterized by a variety of symptoms which are classified as positive symptoms

(disordered thought, hallucinations and delusions) and negative symptoms (social withdrawal and uπresponsiveness). These disorders have an age of onset in adolescence or early adulthood and persist for many years. The disorders tend to become more severe during the patient's lifetime and can result in prolonged institutionalizarion. In the United States today, approximately 40% of all hospitalized psychiatric patients suffer from schizophrenia.

During the 1950's physicians demonstrated that they could successfully treat psychotic patients with medications called neuroleptics: this classification of antipsychoric medication was based largely on die activating ι,neuroleptic) properties of the nervous system by these drugs. Subsequently, neuroleptic agents were shown to increase the concentrations of dopamine metabolites in the brain suggesting altered neuronal firing of the dopamine system. Additional evidence indicated that dopamine could increase the activity of adenylate cyclase in the corpus

striatum, an effect reversed by neuroleptic agents. Thus, cumulative evidence from these and later experiments strongly suggested that the neurotransmiαer dopamine was involved in schizophrenia. One of the major actions of antipsychotic medication is the blockade of dopamine receptors in brain. Several dopamine systems appear to exist in the brain and at least five classes of dopamine receptors appear to mediate the actions of this transmitter. These dopamine receptors differ in their pharmacological specificity and were originally classified upon these differences in the pharmacology of different chemical series. The butyrophenones, a class of compounds containing many potent antipsychotic drugs, were quite weak at the dopamine receptor that activated adenylate cyclase (now known as a Dl dopamine receptor). In contrast, they labelled other dopamine receptors (called D2 receptors) in the subnanomolar range and a third type, D3, in the nanomolar range. Two additional receptor subtypes have also been identified. D5, which is somewhat similar to the Dl receptor subtype, and D4 which is closely related to D3 and D2 receptor types. The phenothiazines, which include chlorpromazine, possess nanomolar affinity for all three types of dopamine receptors. Other drugs have been developed with great specificity for the Dl receptor subtype and for the D2 receptor subtype.

A group of drugs (such as sulpiride and clozapine) have been developed which display a lesser incidence of extrapyramidal side effects than classical neuroleptics. In addition, there is some indication that these drugs may be more beneficial in treating negative symptoms in some patients. Since all D2 blockers do not possess a similar profile, certain hypotheses underlying the differences have been investigated. One of the major differences among these various classes of antipsychotics has been in the anticholinergic actions of these drugs. The possibility also exists that the various dopamine receptor subtypes may be differentially distributed between the limbic areas, thought to mediate antipsychotic responses, and the motor areas of the brain. The existence of the D3, D4 and D5 and other as yet undiscovered dopamine receptors may contribute to this profile. Atypical antipsychotics have loosely been defined as those compounds which impart antipsychotic action without the concurrent motor impairment. Some of the atypical compounds

G and K are the same or different and represent N or CR' where R' is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched lower alkoxy having 1-6 carbon atoms: R is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; Ri, X, Y. Z and T are the same or different and represent hydrogen, halogen, cyano. hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms or SO2R4 where R4 is straight or branched chain lower alkyl having 1-6 carbon atoms or where R4 is NH2 or NHCH3; R2 and R3 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl, arylalkyl; or

NR2R3 together represent 2-(l,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR2R3 represents:

where R5 is phenyl, either unsubstituted or mono or disubstituted by either halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

NR2 3 represents

where W is N or CH; and

R6 is phenyl, benzyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl

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SUMMARY OF THF INVFNTTON

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

The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism. Furthermore compounds of this invention may be useful in treating the extrapyramidyl side effects associated with the use of conventional neuroleptic agents. Since dopamine D3 and D4 receptor subtypes are concentrated in the limbic system (Taubes, Science (1994) 265. 1034) which controls cognition and emotion, compounds which interact with these receptors may have utility in the treatment of cognitive disorders. Such disorders may be the cognitive deficits which are a significant component of the negative symptoms (social withdrawal, and unresponsiveness) of schizophrenia.

Other disorders involving memory impairment or attention deficit disorders may also be treated with the compounds of this invention that interact specifically with dopamine D3 and/or D4 receptor subtypes. Accordingly, a broad embodiment of the invention is directed to a compound of

Formula I:

I where S and V are the same or different and represent hydrogen; halogen, hydroxy, phenyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1 -6 carbon atoms;

G and K are the same or different and represent N or CR' where R' is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched lower alkoxy having 1-6 carbon atoms; R is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; Rj, X. Y. Z and T are the same or different and represent hydrogen, halogen, cyano. hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms or SO2R4 where R4 is straight or branched chain lower alkyl having 1-6 carbon atoms or where R4 is NH2 or NHCH3; R2 and R3 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl, arylalkyl; or

NR2R3 together represent 2-(l,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR2R3 represents:

where R5 is phenyl, either unsubstituted or mono or disubstituted by either halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR2R3 represents

where W is N or CH; and

R6 is phenyl, benzyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl

having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; and n is 1, 2 or 3.

The interaction of the aminomethyl biphenyl, aminomethyl phenylpyridiπes and aminomethyl phenylpyrimidine derivatives of the invention with dopamine receptor subtypes results in the pharmacological activities of these compounds. These compounds are highly selective partial agonists or antagonists at brain dopamine receptor subtypes or prodrugs thereof and are useful in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism. Furthermore, compounds of this invention are useful in treating the extrapyramidyl side effects associated with the use of conventional neurolepπc agents.

Thus, the invention encompasses methods for the treatment of neuropsychological disorders comprising administering to a patient having a neuropsychological disorder an amount of a compound according to Formula I effective to treat the neuropsychological disorder.

m where Ri, X, Y. Z and T represent hydrogen or alkyl and R9 represents hydrogen or alkyl.

Preferred compounds according to Formula III are those where Ri, X, Y, Z and T are hydrogen; R9 represents hydrogen; and Ar represents benzyl or phenyl. Other preferred compounds of Formula III are those where Ri, X. Y, Z and T are hydrogen; Ro represents hydrogen; and Ar represents 2-pyridyl or pyrimidinyl.

The invention further encompasses compounds of Formula IV:

IV where Ri, X. Y. Z and T represent hydrogen or alkyl; and Rio and Rl 1 independently represent hydrogen or alkyl.

Preferred compounds according to Formula IV are those where Rl, X, Y, Z and T are hydrogen; Ar represents phenyl; and Rio and Ri 1 independendy represent alkyl. Other preferred compounds of Formula IV are those where Rl, X, Y, Z and T are hydrogen; Rio and Ri 1 independendy represent methyl; and Ar represents phenyl.

The invention further encompasses compounds of Formula V:

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DETA ILED DESCR.PTTQN OF THF INVFNTTQN

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

II where R 1 , X. Y. Z and T represent hydrogen or alkyl; R7 and Rg independently represent hydrogen or alkoxy; Rα is hydrogen or alkyl; and W represents nitrogen or CH.

Preferred compounds of Formula I include ti ose where W is N or CH; and R7 is phenyl, pyridyl or pyrimidinyl, each of which is optionally mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

Preferred compounds according to Formula II are those where Ri, X, Y, Z and T are hydrogen: R7 and Rg are different and represent hydrogen or alkoxy; W is CH: and Ar represents benzyl or phenyl. Other preferred compounds of Formula II are those where Rj, X, Y. Z and T are hydrogen; R7 and R% are different and represent hydrogen or alkoxy; W is nitrogen; and Ar represents 2-pyridyl or pyrimidinyl.

The invention further encompasses compounds of Formula IH:

where Ri, X, Y, Z and T represent hydrogen or alkyl; R9 is hydrogen or alkyl; Rifj represents hydrogen or alkyl: and R12 represents alkoxy.

Preferred compounds according to Formula V are those where Rl , X, Y, Z and.T are hydrogen; R9 is hydrogen; Rio represents alkyl and R 12 is an alkoxy group in die 2-position of die phenyl ring.

The invention further encompasses compounds of Formula VI:

' VI where Rl, X, Y, Z and T represent hydrogen or alkyl; and R is a group of the formula:

^■ 1 1-

where

W is N or CH; R represents alkyl; and R _< j represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionally substituted with halogen, alkyl or alkoxy.

Preferred compounds according to Formula VI are those where Ri, X. Y. Z and T are hydrogen; Ar is optionally substituted phenyl and Re is a 4-substituted pipcrazin- 1 -yl or piperidin-

1-yl group. Particularly preferred compounds of Formula VI are those where the 4-substituted piperazin- 1-yl or piperidin-1-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups.

The invention further provides compounds of Formula VII:

vπ where Ri , X, Y, Z and T represent hydrogen or alkyl; and R is a group of the formula:

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where

W is N or CH;

R represents alkyl: and R ι represents pyridyl, pyrimidinyl. phenylalkyl, or phenyl optionally substituted wirJi halogen, alkyl or alkoxy.

Preferred compounds according to Formula VII are those where Rl, X. Y. Z and T are hydrogen; and Re is a 4-substituted piperazin-1-yl or piperidin-l-yl group. Particularly preferred compounds of Formula VII are those where the 4-substituted piperazin- 1-yl or piperidin-l-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups.

The invention further provides compounds of Formula VIE:

vm where Ri, X, Y, Z and T represent hydrogen or alkyl; and Re is a group of the formula:

^■ 13-

where

W is N or CH: R represents alkyl; and R represents pyridyl. pyrimidinyl, phenylalkyl, or phenyl optionally substituted widi halogen. alkyl or alkoxy.

Preferred compounds according to Formula VIII are those where Ri, X, Y. Z and T are hydrogen: and Re is a 4-substituted piperazin-1-yl or piperidin-l-yl group. Particularly preferred compounds of Formula VIII are those where the 4-substituted piperazin-1-yl or piperidin-l-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups.

The invention further provides compounds of Formula DC:

IX where R i , X, Y, Z and T represent hydrogen or alkyl; and Re is a group of die formula:

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where

W is N or CH; R represents alkyl; and Rd represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionally substituted widi halogen, alkyl or alkoxy.

Preferred compounds according to Formula IX are those where Rj, X, Y. Z and T are hydrogen; and Re is a 4-substiruted piperazin- 1-yl or piperidin-l-yl group. Particularly preferred compounds of Formula IX are those where the 4-substituted piperazin- 1 -yl or piperidin-l-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups. Still other preferred compounds of Formula IX are those where Re is N-benzyl-N- methylamino.

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

Formula I. Those skilled in the an will recognize various synthetic methodologies which may be

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employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

By aryl or "Ar" is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2.3,4-tetrahydronaphthyl. naphthyl. anthryl. or phenanthryl), which can optionally be unsubstituted or substituted with e.g., halogen, lower alkyl. lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.

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

By heteroaryl is meant 5. 6. or 7 membered aromatic ring systems having at least one hetero atom selected from die group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which can optionally be unsubstituted or substituted widi e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio. trifluoromethyl, lower acyloxy. aryl, heteroaryl, and hydroxy.

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

By arylalkyl and aralkyl is meant the group -R-Ar where Ar is an aryl group and R is a straight or branched chain aliphatic group. Arylalkyl groups may optionally be substituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, and hydroxy. Preferred arylalkyl groups in the above formulas where W is CH and R8 represents arylalkyl are phenylalkyl groups where die alkyl portion is lower alkyl. A particularly preferred phenylalkyl group is benzyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

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By cycloalkyl is meant cyclic hydrocarbons having from 3-8 carbon atoms. These cyclic hydrocarbon groups may be substituted with up to three substituents independendy selected from hydrogen, halogen, trifluoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy. straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2R9 where R9 is H2 or

NΗCH3.

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

Assay for D2 and D3 receptor binding activity

Striatial tissue is dissected from adult male Sprague Dawley rats or BHK 293 cells are harvested containing recombinandy produced D2 or D3 receptors. The sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HC1 buffer at 4°C and pH 7.4. The sample is then centrifuged at 30,000 x g and resuspended and rehomogenized. The sample is then centrifuged as described and die final tissue sample is frozen until use. The tissue is resuspended 1:20 (wt vol) in 0.05 M Tris HC1 buffer containing 100 mM NaCl.

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

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TABLE I

D2 binding D3 binding

ComoQund Number ¹ ICgn uM) ICgn uM) l 0.175 0.329

3 0.012 0.012

4 0.005 0.061

5 ND 2.490

6 ND 6.120

7 ND 0.342

8 1.940 ND

9 0.290 ND

10 ND 1.140

11 ND 1.612

1 Compound numbers relate to compounds shown in Figure I. ND = Not Done

Assay for D4 receptor binding activity

Clonal cell lines expressing the human dopamine D4 receptor subtype were harvested in PBS and the cells centrifuged and the pellets stored at -80°C until used in the binding assay. The pellets were resuspended and the cells lysed at 4° C in 50 mM Tris pH 7.4 buffer containing 120 mM NaCl, 1 mM EDTA and 5 mM MgC-2- The homogenate is centrifuged at 48000 x g for 10 minutes at 4°C. The resulting pellet is resuspended in fresh buffer and centrifuged again. After resuspension of the pellet in fresh buffer a 100 ml aliquot is removed for protein determination. The remaining homogenate is centrifuged as above, d e supernatant removed and the pellet stored at 4°C until needed; at which time it is resuspended to a final concentration of 625 mg/ml (250 mg per sample) with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior to use. Incubations were carried out for 60 minutes at 25°C in die presence of 0.1 nM [ ³ H] YM-09151-2. The incubation was terminated by rapid filtration through Whatman GF/C filters and rinsed with 2x4 ml washes of chilled 50 mM Tris (pH 7.4) and 120 mM NaCl. Non-specific binding was determined

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with 1 mM spiperone and radioactivity determined by counting in an LKB beta counter. Binding parameters were determined by non-linear least squares regression analysis, from which the inhibition constant Ki could be calculated for each test compound. The binding characteristics of some examples of this patent are shown in Table 2 for the dopamine D4 binding assay. In general, compounds of die accompanying examples were tested in the above assay, and all were found to possess a Ki value for the displacement of [*- ^* H|YM -09151-2 from the human dopamine D4 receptor subtype of below 500 nM. Some specific data is indicated in Table 2.

Table 2

Compound Number- ¹ Ki(uM)

1 0.032

2 0.243

3 0.018

4 0.028

5 0.286

6 >0.075

7 >0.075

8 1.055

9 0.056

10 0.769

11 0.600

Compounds 1, 3, 4 and 9 are particularly preferred embodiments of die present invention because of their potency in binding to dopamine receptor subtypes.

The compounds of die invention including those represented by general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association

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with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use. for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the an for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from die group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture widi non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inen diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agents, for example, com starch, or alginic acid: binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed wid an inen solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein die active ingredient is mixed wid water or an oil medium, for example 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. polyvinylpynolidone. gum tragacandi and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene

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oxide widi fatty acids, for example polyoxyethylene stearate. or condensation products ot ^" ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol. or condensation products of ediylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide widi partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate. one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil. olive oil, sesame oil or coconut oil. or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as diose set fonh above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anri-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by die addition of water provide the active ingredient in admixture widi a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients. for example sweetening, flavoring and coloring agents, may also be present. Pharmaceutical compositions of the invention may also be in d e form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacantii. naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol ^, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters widi ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

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Syrups and elixirs may be formulated with sweetening agents, for example giycerol. propylene glycol. sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known an using tiiose suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1.3-butanediol. Among 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 syndietic mono or diglycerides. In addition, fatty acids such as oieic acid find use in die preparation of injectables.

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

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

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above- indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient diat may be combined with die carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient-

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It will be understood, however, diat the specific dose level for any panicular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and die severity of the particular disease undergoing therapy. An illustration of die preparation of representative aminomethyl biphenyls, aminomethyl phenyl pyridines and aminomethyl phenyl pyrimidines of the present invention is given in Scheme

I. Those having skill in the an will recognize that the staning materials may be varied and additional steps employed to produce compounds encompassed by the present invention. The substituents R'. R\ , R2, R3, S, T, V, X, Y, and Z carry the definitions set foπh above for Formula I.

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SCHEME 1

A. Representauve preparauons ot Aminomethyl Biphenyls

B. Representative preparation of Aminomeϋiyl Phenyl Pyridines

C. Representative preparation of Aminomethyl Phenyl Pyrimidines l. Pd/C. H ₂

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This invention is funher illustrated by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described therein.

A mixture of 1.1 g of 2-(chloromedιyl)-4-bromoanisole. 1 g of l-(2-pyrimidyl)piperazine dihydrochloride and 2.0 mL N,N-diisopropylethylamine in 10 mL chloroform was heated at reflux temperature for 2 hr, cooled to room temperature, washed widi IN NaOH and water. The solvent was removed by evaporation under reduced pressure to yield 3.6 g of 2-[(4-(2- pyrimidinyl)-piperazinyl)methyl]-4-bromoanisole as a white solid which was used in die next step without funher purification.

A solution of 182 mg 2-[(4-(2-pyrimidinyl)-piperazinyl)medιyl]-4- bromoanisole in 1 rnL of tetrahydrofuran heated to 60°C and 6 mg of Pd(PPh3)4 was added. To this mixture 0.5 mL of a 1 M solution of phenylmagnesium bromide in tetrahydrofuran was added dropwise. The reaction mixture was heated at rclux temperature under nitrogen for 1 hr, cooled to room temperature and the solvent removed by evaporation under reduced pressure to yield 4-phenyl-2-[(4-(2- pyriι dinyl)-piperazinyl)methyl]anisole which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded 140 mg of a solid which was treated widi ethyl acetate-HCl to give 50 mg of 4-phenyl-2-[(4-(2-pyrimidinyl)- piperazinyl)methyl]anisole dihydrochloride (Compound 1), mp 205-207°C.

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Example II

Compound 2

A mixture of 1.1 g of 4-(chloromethyl)-2-bromoanisole 1.0 g l-(2-pyrimidyl)piperazine dihydrochloride and 2.0 mL of N,N-diisopropylethylamine in 10 mL chloroform was heated at reflux temperature for 2 hr. cooled to room temperature, washed widi IN NaOH and water. The solvent was removed by evaporation under reduced pressure to give 3.4 g of 4-[(4-(2- p> ^* rimidinyl)-piperazinyl)methyl]-2-bromoanisole as a white solid which was used in the next step without funher purification or characterization.

To a solution of 181 mg 4-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-2- bromoanisole in 2 L of dimethylformamide was added phenylboric acid (91.5 mg), triediylamine (152 mg), palladium acetate (3.4 mg) and triphenylphosphine (8.1 mg). The reaction mixture was heated at 100°C under nitrogen for 4 hr, cooled to room temperature and partitioned between dilute ammonium hydroxide and dichloromethane. The organic layer was washed widi water and die solvent removed by evaporation under reduced pressure to 2-phenyl-4-[(4-(2-pyrimidinyl)- piperazinyOmethyl] anisole which was purified by reverse phase chromatography on C18 resin using a methanol- water mixture (4:1) as eluent.

Evaporation of the. solvent yielded 10 mg of a solid which was treated with etiiereal-HCl to give 10 mg of 2-phenyl-4-[(4-(2-pyrimidinyl)-piperazinyl)methyl] anisole dihydrochloride (Compound 2), mp 213-215°C.

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Example HI

Compound 3

To a suspension of 100 mg of lithium aluminum hydride in 20 mL of ether was added 500 mg 3-phenylbenzoic acid. The reaction mixture was stirred at room temperature overnight. After any excess lidiium aluminum hydride was destroyed widi water, the organic layer was washed successively widi 25 mL aliquots of dilute hydrochloric acid, dilute sodium hydroxide and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure to yield 360 mg of 3-hydroxymedιylbipheπyl as a crystalline solid. This material was used in he next step without further purification. A solution of 50 mg of 3-hydroxymethylbiphenyl in 1.5 mL diionyl chloride was heated at reflux temperature for 4 hr. cooled to room temperature and die solvent removed by evaporation under reduced pressure to yield 45 mg of 3-chloromethylbiphenyl which was used in the next step without further purification or characterization.

To a solution of 45 mg of 3-chloromedιylbiphenyl in 5 mL of chloroform was added 50 mg of 4-phenyl- 1 ,2,3,6-tetrahydropyridine hydrochloride and 0.5 mL triethylamine. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature, washed successively with 50 mL aliquots of dilute sodim hydroxide and brine. The chloroform was removed by evaporation under reduced pressure to yield 3-phenyl[(4-phenyl-1.2,3,6- tetrahydropyridin-l-yl)methyl] benzene which was purified by chromatography on silica gel using 5% medianol in dichloromed ane as eluent. Evaporation of die solvent yielded a solid which was treated widi etiiereal-HCl to give 15 mg of 3-[(4- l,2,3.6-tetrahydropyridin-l-yl)medιyl]biphenyl hydrochloride (Compound 3), mp 236-238°C.

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Example IV The following compounds were prepared essentially according to the procedure described in Example IH.

(a) 3-[(4-phenyl-piperidin-l-yl)methyl]biphenyl hydrochloride (Compound 4).

(b) 3-phenyl-6-[(4-benzyl-piperidin-l-yl)methyl]toluenehydrochlo ride (Compound 5), mp 215-217°C.

(c) 3-[(N-methyl-N-benzyl)aminomethyl]biphenyl hydrochloride, mp 184-187°C.

(d) N-(l-(3-biphenyl)ethyl-N-methylbenzylamine hydrochloride (Compound 6). mp 143- 145°C.

(e) l-(2-methoxyphenyl)-4-(l-(3-biphenyl)ethyl)piperazine dihydrochloride (Compound 7), mp 181-183°C.

(0 l-(2-pyrimidyl)-4-((3, 5-diphenylphenyl)methyl)piperazine dihydrochloride (Compound 8), mp 212-214°C.

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Compound 9

To a solution of 5.0 g of 2-hydroxy-4-methylpyridine in 70 mL of pyridine at 0°C was added 13.3 g triflic anhydride dropwise. The reaction was stirred at 0°C for 15 minutes and then allowed to warm to room temperature. After removal of the volatile reactants under reduced pressure, die residue was partitioned between 100 mL of ethyl acetate and 100 mL of 10% sodium carbonate solution. The organic layer was washed with 100 mL of brine and the solvent removed by evaporation under reduced pressure. The resulting oil was vacuum distilled at 150°C (25 mm Hg) to provide 10.5 g of 2-trifluoromethanesulfonyl-4-methylpyridine as a colorless oil. To a solution of 1.65 g 2-trifluoromethanesulfonyl-4-methylpyridine in 30 mL of dimediylformamide and 30 mL of dioxane was added PdCl2(PPh3)2 (400 mg), lithium chloride (873 mg) and tetraphenyltin (10.5 g). The reaction mixture was heated at reflux temperature for 3 hr, cooled to room temperature and filtered. The filtrate was diluted with IN hydrochloric acid, washed widi 250 mL ether, tiien basified with 2N sodium hydroxide and extracted with 2 x 250 mL of ethyl acetate. The combined extracts were washed widi 150 mL water, separated and die ethyl acetate removed by evaporation under reduced pressure to yield 900 mg of 2-phenyl-4- methylpyridine as an oil.

To a solution of 100 mg of 2-phenyl-4-metiτylpyridine in 2 mL of carbon tetrachloride was added 300 mg of sodium carbonate and 100 mg of bromine. The reaction mixture was stirred and irradiated with a 500W lamp for 1 h, filtered and the solvent removed by evaporation under reduced pressure to yield 2-phenyl-4-bromomethylpyridine which was used in the next step without further purification or characterization

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To a solution of 2-phenyl-4-bromomethylpyridine in 5 mL of chloroform was added 100 mg of 4-benzylpiperidine and 1 mL of N.N-diisopropylethylamine. The reaction mixture was heated at reflux temperature for 30 minutes, cooled to room temperature, washed with 5 mL of IN NaOH and the solvent removed by evaporation under reduced pressure. The product was purified by chromatography on silica gel using 5% methanol in dichloromediane as eluent. Evaporation of the solvent yielded a solid which was treated with ediereal-HCl to give 15 mg of 2-phenyl-4-[(4- benzyl-piperidin-l-yl)methyl]-pyridine dihydrochloride (Compound 9). mp 222-225°C.

Example VI The following compound was prepared essentially according to the procedure described in

Example V. (a) 2-Phenyl-6-[(4-benzyi-piperidin-l-yl)medιyl]-pyridine (Compound 10), mp 81-83°C.

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Compound 11

A solution of 500 mg 5-bromo-2-phenyl-4-pyrimidinecarboxylic acid and lmL N,N- diisopropylediylamine in 5 mL of ethanol was hydrogenated at 40 psi of H2 for 16 hr using 200 mg of 10% palladium-on-carbon as catalyst. The catalyst was filtered off and die edianol removed by evaporation under reduced pressure. The residue was dissolved in water, acidified widi 3N hydrochloric acid and the precipitate was collected by filtration. This material was air dried to yield

300 mg of 2-phenyl-4-pyrimidinecarboxylic acid as a white solid which was used in the next step without further purification or characterization. A solution of 150 mg of 2-phenyl-4- pyrimidinecarboxylic acid in 1 mL of thionyl chloride was heated at 70°C for 1 hr, cooled to room temperature and die excess diionyl chloride removed by evaporation under reduced pressure to yield 145 mg of 2-phenyl-4-pyrimidinecarboxylic acid chloride which was used in die next step without further purification or characterization.

To a solution of 145 mg of 2-phenyi-4-pyrimidinecarboxylic acid chloride in 5 mL tetrahydrofuran was added excess lidiium borohydride. The reaction mixture was stirred at room temperature for 10 minutes dien diluted widi 25 mL of ethyl acetate and filtered. The filtrate was washed successively widi 25 mL aliquots of IN sodium hydroxide and brine. The solvent was removed by evaporation under reduced pressure to yield 100 mg of 2-phenyl-4- hydroxymediylpyrimidine as a white solid. A solution of 55 mg 2-phenyl-4-hydroxymethylpyrimidine in 1 mL of thionyl chloride was heated at reflux temperature for 1 hr and the excess thionyl chloride removed by evaporation under

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reduced pressure to yield 50 mg of 2-phenyl-4-chloromethylpyπmιdine as an oil which was used in the next step without further purification or characterization.

To a solution of 50 mg of 2-phenyl-4-chloromethylpyrimidine in 5 mL chloroform was added 80 mg 4-benzylpiperidine and 1 mL of N.N-diisopropylethylamine. The reaction mixture was heated at reflux temperature for 4 hr. cooled to room temperature, washed with 5 mL IN sodium hydroxide solution and die solvent removed by evaporation under reduced pressure to yield 2-phenyl-4-[(4-benzyl-piperidin-l-yl)methyl]-pyrimidine. This material was purified by chromatography on silica gel using 5% methanol in dichloromediane as eluent. Evaporation of the solvent yielded a solid which was treated with ediereal-HCl to give 15 mg of 2-phenyl-4-[(4- benzyl-piperidin- l-yl)methyl]-pyrimidine dihydrochloride (Compound 11), mp 211-213°C.

Example VTH The following compound was prepared essentially according to die procedure described in Example VII. (a) 2-phenyl-4-[(N-methyl-N-benzyl)aminomedιyl]-pyrimidine dihydrochloride (Compound 12).

The disclosures in this application of all articles and references, including patents, are incorporated herein by reference. The invention and the manner and process of making and using it are now described in such full, clear, concise and exact terms as to enable any person skilled in die an to which it pertains, to make and use die same. It is to be understood that d e foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set foπh in the claims. To particularly point out and distincdy claim the subject matter regarded as invention, die following claims conclude die specification.

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