CZ474699A3 - Certain diarylimidazole derivatives and compositions containing such derivatives being characterized by selective bond to human NPY receptors - Google Patents

Abstract

Pharmaceutical Compositions Containing Diarylimidazoles which act as partial agonists or antagonists on NPY receptors, especially NPY 5 receptors of formula (I) carry aryl groups in the 2-position. Advice compounds is new. They are used in the treatment of eating disorders and cardiovascular diseases.

Description

The present invention relates to pharmaceutical compositions comprising certain diarylimidazole derivatives that selectively bind to human NPY receptors. Some of these diarylimidazoles are believed to be novel. The invention further relates to the use of these compounds in the treatment of eating disorders such as obesity and bulimia as well as certain cardiovascular diseases such as hypertension.

BACKGROUND OF THE INVENTION

Neuropeptides, known as neuropeptide Y, play a role in various functions of the body and are particularly associated with taste stimulation, but also cause anxiety and coronary tone regulation.

Such compounds bind to a number of different receptor sites. U.S. Pat. U.S. Patent 5,571,695 to Selbie et al. discloses genomic DNA sequences that encode the Y-1 receptor. U.S. Pat. U.S. Patent 5,554,621 to Poindexter et al. discloses certain 4-phenyldihydropyridines that are NPY antagonists and discloses the existence of at least five NPY receptor subtypes. U.S. Pat. U.S. Patent 5,545,549 to Gerald et al. discloses a human Y2 receptor and the DNA encoding it. U.S. Pat. U.S. Patent 5,516,653 to Bard et al. discloses a human Y4 receptor and the DNA encoding it. U.S. Pat. U.S. Patent 5,602,024 to Gerald et al. discloses a human Y5 receptor and the DNA encoding it. This receptor appears to be very important in stimulating appetite.

A large number of diarylimidazoles are known for various uses. For example, European Patent Publication 627499 (Shikoku Chemicals Corporation) and its US equivalent, U.S. Pat. Patent 5 • · • ·

No. 498,301 (Hirao) discloses the use of 2,4-diphenylimidazole a

2,4-Diphenyl-5-methylimidazoles as an agent for use on copper surfaces and compares their activity with 2,4,5-triphenylimidazole. The phenyl group may be substituted with alkyl or halogen groups and the 4-phenyl group with alkyl, halogen, alkoxy, di-lower alkylamino, cyano or nitro groups. Specific compounds disclosed in the US patent include 2-phenyl-4- (4-chlorophenyl) imidazole,

2-phenyl-4- (2,4-dichlorophenyl) imidazole,

2-phenyl-4- (4-bromophenyl) imidazole

2-phenyl-4- (2-tolyl) imidazole, 2-phenyl-4-xylylimidazole,

2- (4-chlorophenyl) -4-phenylimidazole,

2- (4-bromophenyl) -4-phenylimidazole,

2- (2,4-dichlorophenyl) -4-phenylimidazole,

2- (4-tolyl) -4-phenylimidazole,

2- (4-methoxyphenyl) -4-phenylimidazole,

2- (4-dimethylaminophenyl) -4-phenylimidazole

2- (4-cyanophenyl) -4-phenylimidazole,

2- (3-nitrophenyl) -4-phenylimidazole,

2- (2,4-xylyl) -4-phenylimidazole

2- (4-chlorophenyl) -4- (chlorophenyl) imidazole,

2- (2,4-dichlorophenyl) -4- (2-tolyl) imidazole,

2- (2-bromophenyl) -4- (2,3-xylyl) imidazole,

2- (4-ethylphenyl) -4- (2-chlorophenyl) imidazole,

2- (2-ethoxyphenyl) -4- (4-bromophenyl) imidazole,

2- (2-cyanophenyl) -4- (4-tolyl) imidazole,

2- (3-nitrophenyl) -4- (2,3-dichlorophenyl) imidazole,

2- (4-diethylaminophenyl) -4- (4-fluorophenyl) imidazole,

2- (4-chlorophenyl) -4-phenyl-5-methylimidazole

2- (4-tolyl) -4-phenyl-5-methylimidazole

2- (2,4-dichlorophenyl) -4-phenyl-5-methylimidazole

2- (2,3-xylyl) -4-phenyl-5-methylimidazole

2- (4-Methoxyphenyl) -4-phenyl-5-methylimidazole

2- (4-dimethylaminophenyl) -4-phenyl-5-methylimidazole

2- (2-nitrophenyl) -4-phenyl-5-methylimidazole

2- (3-cyanophenyl) -4- (4-chlorophenyl) -5-methylimidazole,

2- (2-nitrophenyl) -4-phenyl-5-methylimidazole

2- (3-cyanophenyl) -4- (4-chlorophenyl) -5-methylimidazole.

PCT publication WO 95/04274 (Nippon Soda Co. Ltd.) discloses the use of a wide range of imidazoles for controlling insects, including 2- (optionally halogenated) phenyl-4- (optionally halogenated) phenylimidazoles.

Suzuki et al. in Chem. Pharm. Bull (1986) 34, 3111-20 describes the preparation of 2-aryl-4- (3-thienyl) imidazole derivatives used as anti-inflammatory agents.

U.S. Pat. U.S. Patent 5,017,467 discloses 2,4-di (substituted aminophenyl) imidazoles wherein the 5-position is optionally substituted by a group capable of cleavage by reaction with an oxidized dye product for use as a cyano coupling agent in a photograph.

NDR 299059 (Chemical Abstracts 117: 131199) discloses 2- (2-hydroxyphenyl) -4-substituted imidazoles wherein the substituent at the 4-position may be optionally substituted by a phenyl group and the 5-position may be substituted by a phenyl or alkyl group.

NDR 297816 (Chemical Abstracts 116: 214504) discloses 2-aryllimidazole compounds wherein the 4 or 5 position may have aryl substituents that are used as lipoxygenase inhibitors.

German Patent Publication 3917677 (Chemical Abstracts 115: 24542) discloses 2- (4-hydroxy-3,5-di-tert-butyl) phenyl-4- (4-dialkylamino) phenylimidazoles for use as chromogenic substrates in analytical redox reactions. The 4-phenyl group at the 5-position of the imidazole ring may be further substituted with alkyl groups.

• · · · · · · · · · · · · · · · · · · ·

German Patent Publication 3411997 (Chemical Abstracts 104: 145136) discloses compounds used as redox indicators including 2- (substituted phenyl) -4- (substituted phenyl) imidazoles.

Soviet Patent Publication 1051076 (Chemical Abstracts 101: 90924) discloses 2-phenyl-4- (phenyl or p-tolyl) imidazoles which may be methyl or phenyl substituted at the 5-position.

European Patent Publication 0131973 (Instituto de Angeli S.P.A) describes the use of certain imidazoles, including 2-phenyl-4- (4-nitrophenyl) -1H-imidazole and 2-phenyl-4- (4-aminophenyl) -1H -imidazoles as intermediates in the preparation of amidines used as H ₂ receptor blocking agents.

U.S. Pat. U.S. Pat. Nos. 4,757,124 and 4,758,639 to Koyangi et al. disclose the use of, inter alia, 2,4-diphenylimidazole for preventing the formation of wall coatings in polymerization equipment used in the production of vinyl polymers.

Other compounds found during database searches include: 4- (2,4-dichlorophenyl) -2-phenyl-5-methylimidazole;

2,4-bis- (2,4-dichlorophenyl) imidazole (C.A. 197514-18-4); 2- (4-methoxyphenyl) -2- (2-aminophenyl) imidazole (C.A. 197011-25-9); 2- (4-methoxyphenyl) -2- (2-trifluoromethylphenyl) imidazole (C.A. 174356-09-3); 4- (2-ethylaminophenyl) -2-phenylimidazole (C.A. 170448-20-1); N- [2- (2-phenyl-1H-imidazol-4-yl) phenyl] acetamide (C.A.

162706-94-7); 2- (4-chlorophenyl) -2- (3-trifluoromethylphenyl) imidazole (C.A. 162701-76-0); N- [4- [2- (2-hydroxyphenyl) -1H-imidazol-4-yl] phenyl] acetamide (C.A. 138500-29-5) and its methoxy homologue (C.A. 138500-28-4); a few 2-phenylimidazoles, where 4 is φ · φ · φ φ φ ·········· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · φφφ φφφφ • ΦΦΦ φ φφ φφφ φφ φφ

- 5 position substituted with 3,3-dimethyl-2H-indol-2-one (C.A. registration numbers 135466-37-4; 135466-36-3;

135437-73-9; 135437-72-8; 135437-71-7; 135437-68-2;

135437-66-0; 135437-65-9; 135437-64-8; 135437-63-7;

135437-62-6; 135437-61-5; 135437-60-4 and 135437-59-1); 2 (IH) -3,4-dihydroquinolone analogs (C.A.

135437-70-6 and 135437-67-1), 2,4-bis- (2-aminophenyl) imidazole (C.A. 131623-81-9); 4- (4-hydroxyphenyl) -2-phenylimidazole (C.A. 111273-30-4);

2,4-bis (4-phenoxyphenyl) imidazole (C.A. 107783-02-08); 2,4-bis (bi-phenyl-4-yl) imidazole (C.A. 106304-01-2); 4- (2-phenyl-1H-imidazol-4-yl) benzenamine (C.A. 96139-68-3); various 2- (2-hydroxyphenyl) 4- (optionally substituted) phenylimidazoles having a methyl, ethyl, butyl or phenyl substituent at the 5-position; and many other more complicated structures.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising compounds of formula I that interact with neuropeptide Y receptors and in particular with NPY5 receptors and methods of treating conditions susceptible to such interactions. The invention further relates to the use of these compounds in the treatment of eating disorders such as obesity and bulimia as well as certain cardiovascular diseases such as hypertension. Suitable compounds are those of formula I:

wherein R1 is an unsubstituted or mono, di or trisubstituted aryl group, wherein the aryl group is monocyclic or bicyclic, in which case only the ring attached to the imidazole ring must be aromatic, and said aryl group is carbocyclic or The 2 heteroatoms, which may be nitrogen, oxygen or sulfur, and said substituents are individually selected from the group consisting of halogen, trihalomethyl, cyano, hydroxy, straight or branched lower alkyl of 1 to 6 carbon atoms, straight or branched lower alkoxy (C 1 -C 6) chain (wherein the alkyl or alkoxy groups may be substituted by an amino or mono- or dialkylamino or acyl group); disubstituted with a straight-chain alkyl group; a branched chain having 1 to 6 carbon atoms, wherein said alkyl groups are optionally substituted by a hydroxy or amino group, a mono or disubstituted carbamoyl group, wherein the CO group is attached to an aryl ring and each substituent is a lower alkyl or aryl lower alkyl, mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group or mono or diarylcarbamates or any adjacent substituents on the aryl ring may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, wherein X, Y and Z is either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl; and n is 1, 2 or 3.

One of R ₂ and R ₂ is selected from the group consisting of hydrogen, hydroxymethyl, alkoxymethyl having up to 6 carbon atoms in each alkoxy group, straight or branched chain lower alkyl of 1 to 6 carbon atoms, cyano or a carboxyl or carboxylate ester group wherein the esterifying the group typically contains up to 6 carbon atoms.

The other of R ₂ and R ₃ is an aryl group which is an unsubstituted or mono, di or trisubstituted aryl group, wherein the aryl group is monocyclic or bicyclic (in which case only the ring which is bound to the imidazole ring must be aromatic), and it may be carbocyclic or contain up to 2 heteroatoms and said substituents are individually selected from the group consisting of halogen; trihalomethyl; cyano; hydroxy; straight or branched chain lower alkyl having 1 to 6 carbon atoms; straight or branched chain lower alkoxy having 1 to 6 carbon atoms (wherein the alkyl or alkoxy groups may be substituted by an amino or mono- or dialkylamino group, or an acyl group); straight or branched chain lower thioalkoxy of 1 to 6 carbon atoms; acyloxy groups; amino; amino groups mono or disubstituted with a straight or branched chain alkyl group having 1 to 6 carbon atoms (wherein said alkyl groups are optionally substituted with a hydroxy or amino group); a mono or disubstituted carbamoyl group wherein the CO group is bonded to an aryl group and the substituents are a lower alkyl or aryl lower alkyl group; mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group; or mono or diarylcarbamates; or any two adjacent substituents on the aryl ring may be represented as -X- (CH _{2) n} -Y- (CH _{2) m} -Z wherein X, Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl and is 1, 2 or 3.

These compounds are selective partial agonists or antagonists of human NPY5 receptors and are useful in the diagnosis and treatment of mammalian eating disorders such as obesity and bulimia, as well as certain cardiovascular diseases such as hypertension and congestive heart failure.

The compounds of the invention may be described by the general formula:

Ri

N

r ₃ • ·· ·

Wherein R 1 is an unsubstituted or mono, di or trisubstituted aryl group. The aryl groups from which R 1 is selected are typically mono or bicyclic groups where only the ring that is bound to the imidazole ring must be aromatic, and said aryl group is carbocyclic or contains up to 4 heteroatoms, with no more than one ring two heteroatoms. Typically, each ring of an aryl group is five or six members. Suitable aryl groups include phenyl, naphthyl, indanyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl, benzofuranyl, thianaphthyl, isoindolyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, quinoxalinyl, cinnolinyl,

1,2,3,4-tetrahydroquinolinyl, 2,3-dihydroindolyl, phenomorpholinyl, benzodioxazinyl, phenothiomorpholinyl and methylenedioxyphenyl groups. Suitable substituents include: halogen, trihalomethyl, cyano, hydroxy, straight chained or branched lower alkyl of 1 to 6 carbon atoms, straight chained or branched lower alkoxy of 1 to 6 carbon atoms (wherein the alkyl or alkoxy groups may be substituted with amino or mono- or dialkylamino or mono or di-alkarylamino (such as benzyl or acyl), straight-chain or branched lower thioalkoxy of 1 to 6 carbon atoms, acyloxy groups such as alkanoyloxy groups having 2 to 7 carbon atoms such as acetoxy, aroyloxy groups such as benzoyloxy, amino, amino mono or disubstituted with straight or branched chain alkyl of 1 to 6 carbon atoms, wherein said alkyl groups are optionally substituted with hydroxy or amino, mono or disubstituted carbamoyl groups wherein the substituent is lower alkyl or aryl lower alkyl, wherein CO the moiety is bonded to the aryl ring and the substituents are lower alkyl or aryl lower alkyl, mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group or mono or diarylcarbamates such as methylphenylcarbamate and diphenylcarbamate. Furthermore, any 2 adjacent substituents • 4 4 ·

4 4 4

4 4 4

4 4 4

44

4 ··

4 4 · 4 4

4 4 · · 444444 4 • 4 · ·

Can be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, where X,

Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl and n and m are 1, 2 or 3.

One of R _2a is selected from the group consisting of hydrogen, hydroxymethyl, alkoxymethyl having 1 to 6 carbon atoms in each alkoxy group, straight or branched chain lower alkyl of 1 to 6 carbon atoms, a cyano or carboxyl or carboxylate ester group wherein the esterifying group typically contains up to 6 carbon atoms.

The other of R ₂ and R ₃ is an aryl group which is unsubstituted or mono-, di- or tri-substituted aryl group. Suitable aryl groups are monocyclic or bicyclic and may be carbocyclic or contain up to 2 heteroatoms. They include phenyl, naphthyl, indanyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl, benzofuranyl, thianaphthyl, isoindolyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, quinoxalinyl, cinnolinyl, 1,2inol, 4-tetrahydro,

2,3-dihydroindolyl, phenomorpholinyl, benzodioxazinyl, phenothiomorpholinyl and methylenedioxyphenyl groups. Suitable substituents include: halogen, trihalomethyl, cyano, hydroxy, and said substituents are individually selected from the group consisting of halogen; trihalomethyl; cyano; hydroxy; straight or branched chain lower alkyl having 1 to 6 carbon atoms; straight or branched chain lower alkoxy of 1 to 6 carbon atoms (wherein the alkyl or alkoxy groups may be substituted by an amino or mono- or dialkylamino group, or an acyl group or a carbamate); straight or branched chain lower thioalkoxy of 1 to 6 carbon atoms; acyl groups such as acetyl, acyloxy groups such as C 2 -C 7 alkanoyloxy groups such as acetoxy and aryloxy groups such as benzyloxy; amino; amino groups mono- or disubstituted with a straight or branched chain alkyl group having 1 to 6 carbon atoms (wherein said alkyl groups are optionally substituted with hydroxy or a hydroxy group); * · · € € € € € € € € € € € € € € € € € € € € € €

- 10 amino group); a mono or disubstituted carbamoyl group wherein the CO group is bonded to an aryl group and the substituents are a lower alkyl or aryl lower alkyl group; mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group; or mono or diarylcarbamates, such as methylphenylcarbamate and diphenylcarbamate; Further, any adjacent substituents may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, where X, Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl and amam are 1, 2 or 3.

The term alkyl as used herein includes straight or branched chain alkyl groups and cycloalkyl groups.

Such alkyl groups may be interrupted by an oxygen or sulfur atom. Alkyl further includes groups containing both cyclic and acyclic moieties. Unless otherwise indicated, the alkyl groups mentioned in this application contain 1 to 8 carbon atoms and the cycloalkyl group or part thereof has three to six carbon atoms in the ring and may optionally be unsaturated.

A lower alkyl group is an alkyl group as defined above with up to six carbon atoms. Acyl groups may contain alkyl, aryl or aralkyl groups, but not as more with 8 carbon atoms. The term aralkyl is used for groups such as benzyl and phenylethyl groups. One skilled in the art will appreciate that some of the compounds of the invention may exist in tautomeric form. In such cases both tautomeric forms are included.

Particularly useful classes of compounds of the invention include those wherein the aryl group R 1 is selected from aryl monocyclic groups which may be carbocyclic or contain up to two heteroatoms (N, O, S) and which are unsubstituted or substituted in three groups such as halogen, trihalomethyl, cyano, hydroxy, straight or branched lower alkyl of 1 to 6 carbon atoms, straight or branched lower alkoxy of 1 to 6 carbon atoms,

44 * 4 4

4

444 «• 444 4 5

4 • 4 • 4

4 4 4

4 4 ·

4 < 44 lower or straight chained or branched chain thioalkoxy of 1 to 6 carbon atoms, acyloxy, amino, amino mono or disubstituted with straight or branched chain alkyl of 1 to 6 carbon atoms, said alkyl groups being optionally substituted by hydroxy or amino groups, dialkyl carbamates having up to 6 carbon atoms in each alkyl group, or mono or diarylcarbamates. Further, two adjacent substituents on the aryl ring may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, where X, Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is is hydrogen or lower alkyl; and n is 1, 2 or 3. For example, it may preferably be phenyl, 4-fluorophenyl, pyridin-2-yl or a thiophene group.

Similarly, particularly useful non-aryl groups R ₂ and R ₃ include hydrogen, alkyl (as defined above).

Particularly useful aryl groups include phenyl, thienyl, pyridyl, and naphthyl, for example bearing up to three substituents selected from the group consisting of halo (especially chlorine or fluorine), alkoxy (such as methoxy) and alkyl (such as methyl, ethyl groups). Particularly preferred groups include 4-methylphenyl,

3-methoxyphenyl, 4-methoxyphenyl, 3-bromophenyl, 4-bromophenyl,

4-chlorophenyl, 4-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl,

4-methoxy-2-fluorophenyl, 4-ethoxy-2-fluorophenyl,

3-fluoro-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl,

3-acetylphenyl, naphthyl, 1,4-benzodioxan-6-yl benzo [b] morpholinyl,

4-alkyl (e.g. methyl, ethyl or n-propyl) benzo [b] morpholinyl, 4-alkyl-2H, 3H, 4H-benzo [e] 1,4-thiazinyl, 3-methylaminophenyl,

4-dimethylaminophenyl, 3-ethylaminophenyl,

3- (2-methylbutylaminomethyl) phenyl,

3- (ethylbutylaminomethyl) phenyl, 3- (1,2-dimethylpropylaminomethyl) phenyl, 3 - [(3-cyclohexyl-1-phenylpropyl) methylaminomethyl] phenyl, 3 - [(2-cyclohex-1-enylethyl) aminomethyl] phenyl,

3 - [(3-methylethoxy) propylaminomethyl] phenyl, 3- (tert-butylaminomethyl) phenyl, 3- [methyl- (1-phenylpropyl) aminomethyl] •, phenyl, 3- (methylethylaminomethyl) phenyl and 3 - [(4 (methylphenyl) methylaminomethyl] phenyl.

Nontoxic pharmaceutical salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, toluenesulfonic acid, hydroiodic acid, mesylates and the like. A variety of non-toxic pharmaceutically acceptable addition salts can be found.

Many of the compounds of the invention are believed to be novel. We are aware that compounds have been described in the prior art where

1) R 1 and any of R ₂ and R 8 is aryl and are both phenyl, bromophenyl, chlorophenyl,

2,4-dichlorophenyl, cyanophenyl,

2-methoxyphenyl, 3-aminophenyl, 4-aminophenyl,

4-trifluoromethylphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,

3-acetylaminophenyl, 4-phenoxyphenyl or biphenyl;

2) when R 1 is phenyl, any of R 1 and R 1 is aryl and is 2-acetylaminophenyl, chlorophenyl, biphenyl, 4-aminophenyl, p-tolyl, xylyl, 4-methoxyphenyl, 4-dimethylaminophenyl,

4-bromophenyl or 4-hydroxy-2,5-di-tert-butylphenyl,

3) when one of R ₂ or R 8 is phenyl, R 1 is 2-hydroxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 4-chlorophenyl, biphenyl, 2,4-dichlorophenyl, 2,4-xylyl, 4- cyanophenyl or 6-quinolyl; and

4) R 1 is 2-hydroxyphenyl when R ₂ or R 8 is p-tolyl, R 6 is

4-hydroxy-3-methoxyphenyl when when R ₂ or R 8 is 4-dimethylaminophenyl; R 1 is 4-hydroxy-3,5-dimethoxyphenyl when R ₂ or R ₃ is 4-aminophenyl; R1 is 4-hydroxy-3,5-di-tert. butyl phenyl when R ₂ or R 8 is 4-hydroxyphenyl; R 4 is 4-chlorophenyl when R ₂ or R ₃ is 3-trifluorophenyl; R ¹ is • · · · · · · ···

2-hydroxyphenyl when R ₂ or R ₃ is 2- or 4-acetamidophenyl;

R is 2-methoxyphenyl, when R ₂ or R ₃ is 4-acetamidophenyl;

R 2 is 2-ethoxyphenyl when R ₂ or R ₃ is 2-acetamidophenyl;

R ₁ is 4-methoxyphenyl when R ₂ or R ₃ is 2-aminophenyl or 2-trifluoromethylphenyl; Rj. is 2-aminophenyl when R ₂ or R ₃ is 2-isopropylcarbamoylphenyl or 5-acetamido-2-hydroxyphenyl;

is 2-cyanophenyl when R ₂ or R ₃ is 4-tolyl, R 6 is

2-bromophenyl when R ₂ or R ₃ is 2,3-xylyl is

3- cyanophenyl, when R ₂ or R ₃ is 4-chlorophenyl and

R ₁ is 4-dimethylamino when R ₂ or R ₃ is an ester

3-methoxy-4-hydroxyphenyl or 3,5-dimethoxy-4-acetoxyphenyl.

Compounds believed to be novel include the diarylimidazoles of the above formula wherein R is 4-fluorophenyl, those wherein R ₂ or R ₃ is an N-substituted aminomethylphenyl group, or is selected from naphthyl, cyanophenyl N-substituted benzo [b] morpholine, 2H, 3H-benzo [e] 1,4-dioxin and N-substituted 2H, 3H, 4H-benzo [e] 1,4-thiazine.

Compounds of the invention include: 2- (4-fluorophenyl) -4- (4-methoxyphenyl) imidazole hydrochloride, 2- (thienyl-2-yl) -4- (4-chlorophenyl) imidazole, 2- (4-fluorophenyl) hydrochloride -4- (4-chlorophenyl) imidazole, 2-phenyl-4- (3-fluoro-4-methoxyphenyl) imidazole hydrochloride.

The pharmaceutical utility of the compounds of the invention is demonstrated by the following assay for human NPY receptor activity.

Assay for human NPY receptor binding activity.

SKNMC Coupling Test

A similar procedure to that described by Gordon et al. (J. Neurochem. 55: 506-513, 1990). Cells ·" ·

SK-M-MCs purchased from the ATCC Collection (Rockville, MD, USA) are maintained at 37 ° C in an atmosphere of 5% carbon dioxide in Dulbecco's Modified Base Medium (DMEM) with L-glutamine and 110 mg / ml sodium pyruvate supplemented with 10% fetal bovine serum and 25 mM HEPES (pH 7.3). The binding activity assay is performed in 24-well plates (Falcon) when the cells reach confluency. Carefully, to avoid cell disruption at the bottom of the wells, aspirate the medium and add 0.5 ml of Dulbecco's phosphate buffered saline (DPBS) with calcium and magnesium to each well. The DBS is aspirated and another DPBS aliquot is added, which is also aspirated. The assay is initiated by adding to each well a binding buffer consisting of serum-free DMEM containing 0.5% bovine serum albumin, 0.1% bacitracin and 0.1 mM phenylmethylsulfonyl fluoride. Cells and binding buffer are preincubated for 30 minutes at room temperature and then diluted drug and [ ¹² %] - PYY (MEM-DuPont: 50,000-75,000 cpm, 50pM) are added to a final volume of 250 μΐ. Non-specific binding is determined using ΙμΜ NPY (porcine or human, Bachem, California, USA). After incubating at room temperature for 2 hours, the plates are placed on ice and the wells are aspirated. The cells were washed with 2 x 0.5 ml ice-cold DPBS and diluted Triton X-100 (1%) was added to each well. After approximately 20 minutes at room temperature, an aliquot from each well is transferred to a 12 x 75 mm tube and quantitated [ ¹²⁵ L] with an efficiency of 80-85% using a gamma counter (Genesys 5000, Laboratory Technologies). IC ₅₀ values are calculated using the RS / 1 program for non-linear curves (SigmaPlott, Jandel).

[ ¹²⁵ I] binding at human NPY receptors expressed in Sf9 cells

Baculovirus-infected Sf9 cells expressing recombinant human NPY 5 receptors are harvested after 48 hours. At harvest time, cell pellets are resuspended in lysis buffer (20 * · ·· ··)

15 mM Tris-HCl pH 7.4, 5 mM EDTA, 0.5 gg / ml leupeptin, 2 µg / ml Aprotonin and 200 PMSF) and homogenized using Polytron (solidification 3.25-30 seconds). The homogenates are centrifuged at 4 ° C for 5 minutes at 200 xg (ca. 1.5 rpm) to pellet the embryo. The supernatant is transferred to a clean tube and centrifuged at 48,000 xg for 10 minutes. The pellets are washed once in lysis buffer and centrifuged. The final pellet is resuspended in PBS and stored in aliquots at -80 ° C. The purified membranes were washed with PBS and resuspended in binding buffer (50 mM Tris (HCl), pH 7.4, 5 mM KCl, 120 mM NaCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 0.1% bovine serum albumin (BSA)). Membranes (20 µg / reaction tube) are placed in polypropylene tubes containing 0.050 nM PYY (porcin), displacement ^10-12 M to 10 ^-5 M, and buffer to give a final volume of 0.250 mL. Non-specific binding is determined in the presence of 1 μΜ NPY (human) and is 10% of total binding. Following incubation at room temperature for 2 hours, the reaction was terminated by rapid vacuum filtration. The samples were filtered through a soaked GF / C Whatman filter (1.0% polyethyleneimine) and washed twice with 5 ml cold BSA-free binding buffer. A gamma counter with an efficiency of 85% is used to determine the radioactivity of the filters. IC ₅₀ values are calculated by a non-linear RS / 1 curve fitting program (Sigma Plot Jandel).

The compounds of formula (I) may be administered in unit dosage form for oral, topical, parenteral, inhalation spray, or rectal administration, the unit dosage forms containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration is intended to include administration by subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. Accordingly, the present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

One or more of these compositions may be present

444 4444 4444

444 44 4 4445

4444 44 4 44 44 4

4,444,444

4444 4,444 444 * 44

16 compounds of formula I in association with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and optionally other active ingredients. The pharmaceutical compositions containing the compounds of formula (I) may take a form suitable for oral administration and may, for example, be in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups and elixirs.

Compositions intended for oral administration may be manufactured by any method known in the art for the manufacture of pharmaceutical compositions and the resulting compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to render them pharmaceutically and elegant. patient acceptable character. Tablets contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricating agents such as 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 to provide a longer-lasting effect. For example, disintegration and absorption time delay materials such as glyceryl monostearate or glyceryl distearate may be used.

Hard capsules for oral administration may be made of hard gelatin and may contain the active ingredient in admixture with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin. In soft capsules of

In gelatin, the active ingredient may be admixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia, dispersing and wetting agents, for example natural phosphatides such as lecithin, or condensation products of alkylene oxide with fatty acids such as fatty acids polyoxyethylene stearate, ethylene oxide condensation products with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, ethylene oxide condensation products with partial fatty acid esters and hexitol, such as polyoxyethylene sorbitol monooleate, or ethylene oxide condensation products with partial fatty acid esters of fatty acid esters such as polyesters of fatty acid esters. Aqueous suspensions may also contain one or more preservatives, such as 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 prepared 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. The oily suspensions may contain thickeners such as beeswax, hard paraffin or cetanol. Sweetening agents, such as those mentioned above, and flavoring agents may be added to these suspensions to provide an oral composition with a better taste. They may also be preserved by the addition of antioxidants such as ascorbic acid.

ΦΦ ♦ ΦΦ ·

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water contain the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Compositions of this type may also contain additional excipients, for example sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the invention may also take the form of oil-in-water emulsions. The oily phase may consist of a vegetable oil, for example olive oil or arachis oil, a mineral oil, such as liquid paraffin or mixtures thereof. Suitable emulsifying agents include natural resins such as acacia or tragacanth, natural phosphatides such as soya lecithin and esters or partial esters of fatty acids with hexitol anhydrides such as sorbitan monooleate and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate . The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formed with a sweetening agent, for example glycerol, propylene glycol, sorbitol or sucrose.

In addition, these compositions may contain soothing agents, stabilizing agents, flavoring and coloring agents. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using suitable dispersing wetting agents and suspending agents as set forth above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, in a solution of 1,3-butanediol. Among acceptable carriers and diluents,

0 0 · • 0 · 0 which can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed oils are commonly used as solvents or suspending agents. A non-irritating fixed oil including synthetic mono- or diglycerides may be used for this purpose. Furthermore, they have found use in the preparation of injections of fatty acids such as oleic acid.

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

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

Dosage amounts in the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are preferred in the treatment of the above conditions (about 0.5 mg to about 7 g per patient per day). The content of the active ingredient to be combined with the carrier to produce a single dosage form will vary depending upon the host processing and the particular mode of administration. Unit dosage forms usually contain between about 1 mg to about 500 mg of the active ingredient.

However, it is understood that specific dosage levels for each patient depend on various factors including the efficacy of the particular compound used, age, body weight, overall health, sex, diet, time of administration, route of administration, and elimination rate, combination of drugs and severity.

Scheme I illustrates the preparation of compounds of the present invention. One of ordinary skill in the art will recognize that the starting materials may be varied, and other steps used in the manufacture of the compounds are carried out by the present invention.

• • • • • • • • • • • • • · · · · · · · · · · · · · ·

Scheme 1

RjCN

LiN (SiMe) 2

wherein R] _, R ₂ and R ₂ are as defined above.

The invention is further illustrated by the following examples, which are illustrative only and in no way limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 • 9 ·· t 9 9 4 ► 9 9 I »9 9 4

9 • ·

9 9 »

Nbfe '

K ₂ CO ₃

9

To a biphasic mixture of a solution of 30% K ₂ CO ₃ (5 mL) and chloroform (5 mL) containing 276 mg of 4-fluorobenzamidine was added a solution of 468 mg of 2-bromo-4 -chloracetofenonu ¹ in chloroform (3 mL) After stirring for 1 hour the reaction mixture was filtered.

The white crystalline solid was washed with distilled water and dried in a vacuum oven overnight to give 2- (4-fluorophenyl) -4- (4-chlorophenyl) imidazole (compound 1).

Example 2

9 9 9 9 9

9 9 9 9 9

9999 9 9 9 9 9 9 9 9 9

9 9 9 9 9

9900 9 99 999 99 99

To a solution of 2-cyanothiophene (10.9 g) in anhydrous diethyl ether (200 mL) was added solid lithium bis (trimethylsilyl) amide (24 g). After stirring for 30 minutes, the reaction mixture was cooled in ice, and a 2N HCl solution was added dropwise until the mixture was acidic to litmus paper. The reaction mixture was stirred for an additional 30 minutes and transferred to a separatory funnel. The acid extract was separated and the ether layer was removed. The acidic aqueous layer was returned to a separatory funnel, basified with 10 N NaOH solution and extracted with chloroform (2 x 150 mL). The organic extracts were dried over potassium carbonate, filtered and concentrated to give the desired product

2-thienylcarboxamidine (8 g) as an orange solid.

To a biphasic mixture of 30% K ₂ CO ₂ (5 mL) and chloroform (5 mL) containing 126 mg of thiophen-2-yl carboxamidine was added a solution of 233 mg of 2-bromo-4'-chloroacetophenone in 3 mL of chloroform. After stirring for 1 hour, the organic layer was dried (Na ₂ SO ₄ ) and concentrated. Purification by preparative TLC (5% MeOH / CH ₂ Cl ₂ ) afforded 2- (2-thienyl) -4- (4-chlorophenyl) imidazole (compound 2).

Example 3

Preparation of biarylimidazole acids

To a mixture of bromoacid (2.00 g, 8.20 mmol, 1.0 eq) in THF (200 mL) was added benzamidine free base (4.92 g, 41.0 mmol, 5.0 eq) as solids. After stirring at room temperature for 15 minutes, the mixture was evaporated and the crude product was purified by flash chromatography (95% EtOAc, 5% MeOH) to give biphenylimidazole acid as a colorless solid.

«4 44

4 4 4 •

4 4 4

4 4 4

44

4 ♦ ·· 4

To 0.1 ml of a 0.2Μ acid solution in 95% toluene / 5%

N-morpholine was added 0.1 ml of a solution of 0.2M methylamine in 95% toluene / 5% N-methylmorpholine, followed by 0.15 ml of a 0.2M solution of benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate ( BOP) in dichloromethane and stirred at room temperature for 2 hours. Chromatography (1 g silica gel, EtOAc) gave the amide as a yellow oil, which was immediately reduced by adding 0.4 mL of 0.5 M alan dimethylethylamine complex in toluene. The mixture was stirred at room temperature for 2 hours and then dissolved in ethyl acetate and washed with 1M NaOH and evaporated to give the amine.

Particularly preferred compounds include:

4- (4-fluorophenyl) -2-phenylimidazole

2-fluoro-4- [2- (4-fluorophenyl) imidazol-4-yl] -1-methoxybenzene 4-ethoxy-2-fluoro-1- (2-phenylimidazol-4-yl) benzene

4-Methoxy-3-fluoro-1- (2-phenylimidazol-4-yl) benzene

3-Fluoro-4- [2- (4-fluorophenyl) imidazol-4-yl] -1-methoxybenzene

3-Methoxy-1- (2-phenylimidazol-4-yl) benzene

2-methyl-1- (2-phenylimidazol-4-yl) benzene

4- [2- (4-methoxyphenyl) imidazol-4-yl] -1-chlorobenzene

4-Methoxy-2-fluoro-1- (2-phenylimidazol-4-yl) benzene

4- (4-chlorophenyl) -2-phenylimidazole

4- (4-methylphenyl) -2-phenylimidazole

4- (4-methoxyphenyl) -2-phenylimidazole

4- (3-bromophenyl) -2-phenylimidazole

1- [3- (2-Phenylimidazol-4-yl) phenyl] ethan-1-one.

4- (4-bromophenyl) -2-phenylimidazole

4- (3-cyanophenyl) -2-phenylimidazole

4- (3-cyanophenyl) -2- (4-fluorophenyl) imidazole

4- (4-cyanophenyl) -2-phenylimidazole

N- [3- (2-Phenylimidazol-4-yl) phenyl] acetamide ethyl 2,4-diphenylimidazole-5-carboxylate (2,4-diphenylimidazol-5-yl) methan-1-ol

2- (4-fluorophenyl) -5-methyl-4-phenylimidazole

4- [2- (2-Fluorophenyl) imidazol-4-yl] -1-chlorobenzene

ΦΦ φ φ φ φ φ · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

4- (2-naphthyl) -2-imidazole

6- (2-Phenylimidazol-4-yl) -2,3,3H-benzo [e] 1,4-dioxin

6 - [(2- (4-fluorophenyl) imidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6- {2- [4-trifluoromethyl) phenyl] imidazol-4-yl} -2H, 3H-benzo [e] 1,4-dioxin

6 - [(2- (4-fluorophenyl) -5-methylimidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin

6- (2,2-pyridyl) imidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6- (2-phenylimidazol-4-yl) benzo [b] morpholine 4-methyl-6- { 2-phenylimidazol-4-yl) benzo [b] morpholine 4-propyl-7- (2-phenylimidazol-4-yl) benzo [b] morpholine 6- [2- (4-fluorophenylimidazol-4-yl) benzo [b] Morpholine 6- [2- (4-fluorophenylimidazol-4-yl) -4-methylbenzo [b] morpholine 4-ethyl-6- [2- (4-fluorophenyl) imidazol-4-yl) benzo [b] morpholine 6 - [2- (4-fluorophenylimidazol-4-yl) -2H, 3H, 4H-benzo [e] 1,4-thiazine 4-methyl-6- [2- (4-fluorophenylimidazol-4-yl) -2H, 3H, 4H-benzo [e] 1,4-thiazine

4- (4-Chlorophenyl-2- (2-pyridyl) imidazole)

2- [4- (4-chlorophenyl) imidazol-2-yl] pyrazine

4- [2- (4-Fluorophenyl) imidazol-4-yl-chlorobenzene

-indol-3-yl-5-methyl-4-phenylimidazole

2- [4- (4-chlorophenyl) imidazol-2-yl] thiophene

4- (6-chloro (2-pyridyl) -2-phenylimidazol dimethyl [2- (2-phenylimidazol-4-yl) (4-pyridyl)] amine [3- (2-phenylimidazol-4-yl) phenyl] methylamine {3- [2- (4-Fluorophenyl) imidazol-4-yl] phenyl} methylamine methyl [3- (2-phenylimidazol-4-yl) phenyl] methyl} amino dimethyl [3- (2-phenylimidazol-4-) yl) phenyl] methyl} amine methyl [4- (2-phenylimidazol-4-yl) phenyl] methyl} amine dimethyl [4- (2-phenylimidazol-4-yl) phenyl] methyl} amine ethyl [3- (2- phenylimidazol-4-yl) phenyl] amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) (2-methylbutyl) amine (ethylbutyl) ({3- [2- (4-fluorophenyl)) imidazol-5-yl] phenyl} methyl) amine (1,2-dimethylpropyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl}) φφ φ φφφφφφφφφφφφ φφ φφ φ φ

- 25 φφφ φφφφ methyl methyl))))))))))))))))))))))))))))))))))))))))))) methyl))))) methyl) methyl)))))))))))))))))))))))))))))))))))))))) [2- (4-Fluorophenyl) imidazol-5-yl] phenyl} methyl) methylbutyl) amine (2-methylbutyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (2-cyclohex-1) -enylethyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine (cyclohexylphenylmethyl) methyl {[3- [2-phenylimidazol-5-yl) phenyl] methyl} amino ethyl ( 1- {3- [2- (4-Fluorophenyl) imidazol-5-yl} -isopropyl) amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) [3-methylethoxy) propyl] amine (tert-butyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine methyl {phenyl [3- (2-phenylimidazol-5-yl) phenyl] methyl} propylamine ( tert-butyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (methylethyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4-Fluorophenyl) imidazol-5-yl] phenyl} methyl) [(4-methylphenyl) methyl] amine (cyclohexylphenylmethyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) methylamine cyclopentyl {[3- (2-phenylimid azol-5-yl) phenyl] methyl} amine (methylpropyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl]) phenyl} methyl) (2-methylpropyl) amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl] methyl) pentylamine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl) methyl (methylethyl) amine cyclopropyl ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine cyclobutyl ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl] methyl) [2- (4-methylphenyl) ethyl] amine hexyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (methylbutyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine 9

9999 8 • ·

9

9

99

9 9 9

9 9 9

9 9 9

9 9 9

99 ({3- [2- (4-Fluorophenyl) imidazol-5-yl] phenyl} methyl) hexylamine (1,1-dimethylpropyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({ 3- [2- (4-fluorophenyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (2-cyclohexyl-1-phenylethyl) methyl {[3- (2-phenylimidazol-5-yl) Phenyl] methyl} amine {[3- (2-phenylimidazol-5-yl) phenyl] methyl} propylamine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) (2-phenylethyl) (2-Cyclopentyl-1-phenylethyl) methyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (2-cyclohex-1-enylethyl) {[3- (2-phenylimidazol-5-)] yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) benzylamine (ethylpropyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine cyclobutyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (3-methylbutyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine [2- (4 -methylphenyl) ethyl] {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (3-cyclohexyl-1-phenylpropyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl]) phenylmethyl) methylamine cyclopropyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (1,2-dimethylpropyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ethyl ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine ( {3- [2- (4-Fluorophenyl) imidazol-5-yl] phenyl} methyl) (3-methylbutyl) amine ethyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine cyclohexyl ({ 3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine methyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine pentyl 1 - {[3- (2-phenylimidazole- 5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) dipropylamine dibutyl {3- [2-phenylimidazol-5-yl) phenyl] methyl} amine .

Food denial protocol

00 00

0 0 0 • 0 0 ··

0 0 0 0 0 • 0 0 0 0

000 00 00

0 00 0 0 0 · · · · · · · ·

000000 0

0 0 0

0000 0 00

Subjects. Experimentally naive and experienced male Sprague dawley rats (Sasco, St. Louis, MO) weighing between 210 and 310 g were used at the start of the experiment. Animals are maintained at a controlled temperature (22 ° C) and a controlled humidity (40 to 70%)

RH) and lighting for 12 hours. They are kept in the dark for 12 hours. Lighting is provided daily from 5.30 to 17.30. If no measurement is performed, animals are allowed free access to food (Standard Rat Chow, PMI feeds Inc., # 5012) and water. Animals are placed in suspended stainless steel cages in groups of two if no measurement is performed. For data collection, animals are transferred to individual plastic metabolic cages housed in the same room.

Equipment. Consumption and elimination data are collected when animals are housed in Nalgen metabolic cages (model # 650-010). Each cage consists of clear polymethylpentene (PMP), polycarbonate (PC) and stainless steel (SS). All these parts can be easily disassembled for fast and accurate data collection and cleaning.

Cylindrical plastic and stainless steel cages are placed on a stainless steel pedestal with one animal per cage. The animal is located in a circular top chamber (PC) (12 cm high and 20 cm diameter) and is placed on a stainless steel floor (20 cm diameter). Two parts are connected to the upper chamber. The first part contains a feeding chamber (10 cm long, 5 cm wide and 5 cm high) with a PC feeding drawer attached to the bottom. This feeding drawer has two compartments. A food storage department with a capacity of approximately 50 g of feed and a food distribution department. The food storage compartment is distal to the upper chamber, while the food distribution compartment is proximal to the upper chamber. The animal has access to food after opening the floor of the feeding chamber. The floor of this chamber does not allow access to the chamber where the feed is spilled.

The second part connected to the top chamber comprises a water container holder, P.C. a water tank (100 mL capacity) and a calibrated spill collection tube. The water tank holder collects ··· ··· ············

9 9 «· · ····

9999 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 ·

9999 9 99 999 99 ··

- 28 spilled water into a spillage collection tube.

The lower chamber consists of a PMP separation cone, a PMP collection funnel, a PMP collection tube (urine, 70 ml capacity) and a faeces collection tube. The separation cone is connected to the top of the collecting funnel, which is connected to the bottom of the upper chamber. Urine flows from the separation cone to the walls of the collection funnel and to the urine collection tube. The separation cone also separates the feces and transfers them to the feces collection tube.

Ohaus weights (accuracy 0.1 g) are used to determine the weight of rats, food and water, urine and feces content in the collection tubes.

Method. The efficacy of test compounds on body weight, water and food consumption, urine and faecal excretion was determined using metabolic cages. Rats are weighed prior to inclusion in the experimental groups. Classification is performed using the yeast random method using a predetermined body weight to ensure that the treated groups have an average body weight.

All food is removed from the cage the night before the test. On the day of the test, approximately 1 hour before dosing, the animals are weighed to the nearest 0.5 g. For oral drug dosing, animals are given either methylcellulose (MC) or a single dose of the test compound and returned to the cage. When administered intravenously (iv), animals are administered either PEG-400 or a single dose of the test compound. After a suitable time, the animals are placed in a metabolic cage for 1 hour. Before testing, the feed receptacle is filled with bottle water and weighed. Next, empty urine and faeces collection tubes are weighed. Subsequently, the rats are removed from the metabolic cages, weighed and returned to their original cages. Water and food containers as well as faecal and urine collection tubes are then weighed.

Medicines. In oral dosing experiments, investigations are carried out.

• «• · • ♦. The test volume was 10 and the compound was suspended in 0.5% methylcellulose (MC) compound or MC was administered orally (PO) at a dose of ml / kg. The drug is made into a homogeneous suspension by stirring and ultrasound. The drug or suspension is administered 45 to 60 minutes prior to the test using a 6 cm polyethylene (PE 90) tube, connected via a Leuer clamp, to a 5 ml Becton Dickson syringe. For intravenous (iv) administration, the test compound is dissolved in a solution of 50% polyethylene glycol (PEG) -400 and 50% distilled mode. Animals were administered 5 minutes prior to the test with either PEG-400 (1-4 ml / kg) or a single dose of the test compound (1-4 ml / kg).

Statistical analysis. Average and standard areas of average (SEM) for body weight, food consumption, water consumption, faecal excretion and urine excretion are reported.

Deviation analysis (ANOVA) is performed using the Macintosh version of Systat (version 5.2.1). Analysis was then performed using the Fischer LSD test. A significant effect is defined when p has a value < 0.05.

The following parameters are defined as follows: Weight gain is the difference between the body weight of the animal at the time of dosing and the body weight of the animal after dosing. Food consumption is the difference in weight of the food drawer between dosing and after dosing. Water consumption is the difference in weight of the water tank between dosing and after dosing.

Faecal excretion is the difference in weight of the empty faeces collection tube and the weight of the tube after the test. Urinary excretion is the difference between the weight of the empty urine collection tube and the weight of the tube after the test.

Claims (4)

A pharmaceutical composition for interacting with the NPY5 receptor comprising an amount of a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1 is unsubstituted or mono, di or trisubstituted aryl, wherein the aryl group is monocyclic or bicyclic, in which case it must be only the ring that is attached to the imidazole ring is aromatic, and said aryl group is carbocyclic or contains up to 2 heteroatoms which may be nitrogen, oxygen or sulfur and said substituents are individually selected from halogen, trihalomethyl, cyano, hydroxy, straight chained or branched lower alkyl having 1 to 6 carbon atoms, straight chained or branched lower alkoxy having 1 to 6 carbon atoms (wherein the alkyl or alkoxy groups may be substituted by an amino or mono- or dialkylamino group or a mono or di-alkarylamino group or acyl sku lower) thioalkoxy of straight or branched chain of 1 to 6 carbon atoms, acyloxy, amino, amino mono or disubstituted with straight or branched chain of 1 to 6 carbon atoms, said alkyl groups being optionally substituted by hydroxy or an amino group, an alkyl, aryl or alkarylamide group whose nitrogen atom is attached to an aryl group, a mono or disubstituted carbamoyl group wherein the CO group is attached to an aryl ring and each substituent is a lower alkyl or aryl lower alkyl group; 4 4 · A group, mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group, or mono or diarylcarbamates or any 2 adjacent substituents on the aryl ring may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m - Z-, wherein X, Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl and amam are 1, 2 or 3; one of R ₂ and R 1 is selected from the group consisting of hydrogen, hydroxymethyl, alkoxymethyl having up to 6 carbon atoms in each alkoxy group, straight or branched lower alkyl of 1 to 6 carbon atoms, cyano or a carboxyl or carboxylate ester group wherein the esterifying group typically contains up to 6 carbon atoms; the other of R ₂ and R ₃ is an aryl group which is an unsubstituted or mono, di or trisubstituted aryl group, wherein the aryl group is monocyclic or bicyclic (in which case only the ring bound to the imidazole ring must be aromatic), and it may be carbocyclic or contain up to 2 heteroatoms and said substituents are individually selected from the group consisting of halogen; trihalomethyl; cyano; hydroxy; straight or branched chain lower alkyl having 1 to 6 carbon atoms; straight or branched chain lower alkoxy having 1 to 6 carbon atoms (wherein the alkyl or alkoxy groups may be substituted by an amino or mono- or dialkylamino group, and their alkyl groups may form a ring or mono- or di-group with the nitrogen atom to which they are attached -alkaryl or acyl or carbamate); straight or branched chain lower thioalkoxy of 1 to 6 carbon atoms; acyloxy groups; amino; amino groups mono or disubstituted with a straight or branched chain alkyl group having 1 to 6 carbon atoms (wherein said alkyl groups are optionally substituted with a hydroxy or amino group); an alkyl, aryl or alkarylamide group whose nitrogen atom is bonded to an aryl group, a mono or disubstituted carbamoyl group, wherein the CO group is bonded to an aryl group and the substituents are a lower alkyl or aryl lower alkyl group; mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group; or mono or diarylcarbamates; or any 2 adjacent substituents on the aryl ring may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, wherein X, Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl and am 1, 2 or 3; and a pharmaceutically acceptable diluent, carrier or solvent. The composition as claimed in claim 1, wherein each aryl group is independently selected from the group consisting of unsubstituted or substituted phenyl, naphthyl, indanyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl, benzofuranyl, thianaphthyl, isoindolyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, cinnolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydroindolyl, phenomorpholine, benzodioxazinyl, phenothiomorpholinyl and methylenedioxyphenyl. The composition as claimed in claim 2, wherein the substituted or unsubstituted phenyl or naphthyl group is. The composition of claim 2, wherein R 1 is phenyl, 4-fluorophenyl, pyridin-2-yl or 2- or 3-thienyl. The composition of claim 1, wherein the non-aryl R ₂ or is selected from hydrogen and alkyl. The composition of claim 1, wherein any of R ₂ and R ₂ is aryl and is selected from the group consisting of phenyl, 2- or 3-thienyl, 1,4-benzodioxan-6-yl, benzo [b] morpholinyl and naphthyl, optionally bearing up to three substituents selected from halo, cyano, alkoxy and alkyl groups. • · 0 »0 0 0 0 0 The composition of claim 6, wherein said aryl group carries one or two substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, fluoro, chloro, bromo, cyano and alkoxy of 1 to 6 carbon atoms. The composition of claim 6, wherein said aryl group carries an N-substituted aminomethyl substituent. The composition of claim 3, wherein either R ₂ and R ₃ is aryl and is selected from the group consisting of phenyl, 2- or 3-thienyl, 1,4-benzodioxan-6-yl, benzo [b] morpholinyl and naphthyl, optionally bearing up to three substituents selected from halo, cyano, alkoxy and alkyl groups. The composition of claim 9, wherein said aryl group carries one or two substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, fluorine, chlorine, bromine, cyano and alkoxy of 1 to 6 carbon atoms. The composition of claim 9, wherein said aryl group carries an N-substituted aminomethyl substituent. The composition of claim 6, wherein R ₂ or R ₃ is selected from the group consisting of 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-methoxy-2-fluorophenyl, 4-ethoxy-2-fluorophenyl, 3-fluoro-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 3-acetylphenyl, naphthyl, 1,4-benzodioxan-6-yl and benzo [b] morpholinyl, 4-alkyl benzo [b] morpholinyl and 4-alkyl-2H, 3H, 4H-benzo [e] 1,4-thiazinyl. The composition of claim 6, wherein R ₂ or is selected from the group consisting of 3-methylaminophenyl, 4-dimethylaminophenyl, 3-ethylaminophenyl, 3- (2-methylbutylaminomethyl) phenyl, 3- (ethylbutylaminomethyl) phenyl, 3- (1,2-dimethylpropylaminomethyl) phenyl, 3 - [(3-cyclohexyl-1-phenylpropyl) methylamino-34 methyl] phenyl, 3 - [(2-cyclohex-1-enylethyl) aminomethyl ] phenyl, 3 - [(3-methylethoxy) propylaminomethyl] phenyl, 3- (tert-butylaminomethyl) phenyl, 3- [methyl- (1-phenylpropyl) aminomethyl] phenyl, 3- (methylethylaminomethyl) phenyl and 3 - [(4-methylphenyl) methylaminomethyl] phenyl. The composition of claim 9, wherein R ₂ or R ₂ is selected from the group consisting of 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-methoxy-2-fluorophenyl, 4-ethoxy-2-fluorophenyl, 3-fluoro-4- methoxyphenyl, 2-fluoro-4-methoxyphenyl, 3-acetylphenyl, naphthyl, 1,4-benzodioxan-6-yl and benzo [b] morpholinyl, 4-alkyl benzo [b] morpholinyl and 4-alkyl-2H, 3H, 4H-benzo [e] 1,4-thiazinyl. The composition of claim 9, wherein R ₂ or R ₂ is selected from the group consisting of 3-methylaminophenyl, 4-dimethylaminophenyl, 3-ethylaminophenyl, 3- (2-methylbutylaminomethyl) phenyl, 3- (ethylbutylaminomethyl) phenyl, 3- (1,2-dimethylpropylaminomethyl) phenyl, 3 - [(3-cyclohexyl-1-phenylpropyl) methylaminomethyl] phenyl, 3 - [(2-cyclohex-1-enylethyl) aminomethyl] phenyl, 3 - [(3-methylethoxy) propylaminomethyl] phenyl, 3- (tert-butylaminomethyl) phenyl, 3- [methyl- (1-phenylpropyl) aminomethyl] phenyl, 3- (methylethylaminomethyl) phenyl and 3 - [(4-methylphenyl) methylaminomethyl] phenyl. The composition of claim 1, wherein R 1 is 4-fluorophenyl. 17. The composition of claim 1 wherein the diarylimidazole is selected from the group consisting of 4- (4-fluorophenyl) -2-phenylimidazole 2-Fluoro-4- [2- (4-fluorophenyl) imidazol-4-yl] -1-methoxybenzene 4-ethoxy-2-fluoro-1- (2-phenylimidazol-4-yl) benzene 4-Methoxy-3-fluoro-1- (2-phenylimidazol-4-yl) benzene 3-Fluoro-4- [2- (4-fluorophenyl) imidazol-4-yl] -1-methoxybenzene 35-Methoxy-1- (2-phenylimidazol-4-yl) benzene 4- [2- (4-methoxyphenyl) imidazol-4-yl] -1-chlorobenzene 4-Methoxy-2-fluoro-1- (2-phenylimidazol-4-yl) benzene 4- (4-chlorophenyl) -2-phenylimidazole 4- (4-methylphenyl) -2-phenylimidazole 4- (4-methoxyphenyl) -2-phenylimidazole 4- (3-bromophenyl) -2-phenylimidazole 1- [3- (2-Phenylimidazol-4-yl) phenyl] ethan-1-one 4- (4-bromophenyl) -2-phenylimidazole 4- (3-cyanophenyl) -2-phenylimidazole 4- (3-cyanophenyl) -2- (4-fluorophenyl) imidazole 4- (4-cyanophenyl) -2-phenylimidazole N- [3- (2-phenylimidazol-4-yl) phenyl] acetamide 2- (4-fluorophenyl) -5-methyl-4-phenylimidazole 4- [2- (2-Fluorophenyl) imidazol-4-yl] -1-chlorobenzene 4- (2-naphthyl) -2-imidazole 6- (2-Phenylimidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6 - [(2- (4-fluorophenyl) imidazol-4-yl)] - 2H, 3H-benzo [e] 1,4-dioxin 6 - [(2- (4-fluorophenyl) -5-methylimidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6- (2-Phenylimidazol-4-yl) benzo [b] morpholine 4-Methyl-6- (2-phenylimidazol-4-yl) benzo [b] morpholine 4-Propyl-7- (2-phenylimidazol-4-yl) benzo [b] morpholine 6- [2- (4-Fluorophenylimidazol-4-yl) benzo [b] morpholine 6- [2- (4-Fluorophenylimidazol-4-yl) -4-methylbenzo [b] morpholine 4-ethyl-6- [2- (4-fluorophenyl) imidazol-4-yl) benzo [b] morpholine 4-methyl -6- [2- (4-fluorophenylimidazol-4-yl) -2H, 3H, 4H-benzo [e] 1,4-thiazine 4- (4-Chlorophenyl-2- (2-pyridyl) imidazole) 4- [2- (4-Fluorophenyl) imidazol-4-yl-chlorobenzene 2-indol-3-yl-5-methyl-4-phenylimidazole 2- [4- (4-chlorophenyl) imidazol-2-yl] thiophene [3- (2-phenylimidazol-4-yl) phenyl] methylamine dimethyl [3- (2-phenylimidazol-4-yl) phenyl] methyl} amine dimethyl [4- (2-phenylimidazol-4-yl) phenyl] methyl} amine ethyl [3- (2-phenylimidazol-4-yl) phenyl] amine 9 9 ··· 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9,999 99 9 · 99,99 9 9 9 9 9 9 9999 9 99 999 99 99 ({3- [2- (4-Fluorophenyl) imidazol-5-yl] phenyl} methyl) (2-methylbutyl) amine (ethylbutyl) ({3- [2- (4-fluorophenyl) imidazol-5]) -yl] phenyl} methyl) amine (1,2-dimethylpropyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl} methyl) amine (3-cyclohexyl-1-phenylpropyl) methyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl] methyl) methylbutyl) amine (2-methylbutyl) {[3- (2-phenylimidazol) -5-yl) phenyl] methyl} amine (2-cyclohex-1-enylethyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine (cyclohexylphenylmethyl) methyl {[3- [2-phenylimidazol-5-yl) phenyl] methyl} amine ethyl (1- {3- [2- (4-fluorophenyl) imidazol-5-yl} -isopropyl) amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) [3-methylethoxy) propyl] amine (tert-butyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine methyl {phenyl [3] - (2-phenylimidazol-5-yl) phenyl] methyl} propylamine (tert-butyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (methylethyl) {[3- (2-phenylimidazol- 5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) [(4- methylphenyl) methyl] amine. 18. The composition of claim 1 comprising 2- (4-fluorophenyl) -4- (4-methoxyphenyl) imidazole hydrochloride. 19. The composition of claim 1 comprising 2- (2-thien-2-yl) -4- (4-chlorophenyl) imidazole. 20. The composition of claim 1 comprising 2- (4-fluorophenyl) -4- (4-chlorophenyl) imidazole hydrochloride. • 4 4 4 4 4 4444 4 21. The composition of claim 1 comprising 2-phenyl-4- (3-fluoro-4-methoxyphenyl) imidazole hydrochloride. 22. A method of treating conditions susceptible to modulation of NPY receptors, comprising administering to a patient suffering from such conditions an effective dose of a compound of formula: or a pharmaceutically acceptable salt thereof wherein R1 is an unsubstituted or mono, di or trisubstituted aryl group, wherein the aryl group is monocyclic or bicyclic, in which case only the ring that is bound to the imidazole ring must be aromatic, and said aryl group is carbocyclic or contains up to 2 heteroatoms, which may be nitrogen, oxygen or sulfur, and said substituents are individually selected from the group consisting of halogen, trihalomethyl, cyano, hydroxy, straight or branched lower alkyl of 1 to 6 carbon atoms, lower alkoxy with straight or branched chain; branched chain having 1 to 6 carbon atoms (wherein the alkyl or alkoxy groups may be substituted by an amino or mono- or dialkylamino group or a mono or di-alkarylamino group or acyl group), a straight or branched lower chain thioalkoxy group having 1 to 6 carbon atoms, acyloxy groups, amino groups, amino groups mono or disubstituted with a straight or branched chain alkyl group having 1 to 6 carbon atoms, said alkyl groups being optionally substituted by a hydroxy or amino group, an alkyl, aryl or alkarylamide group whose nitrogen atom is bonded to 9 9 9 99 9 9999 • 999999 9 9 9 9 99 9 • 9 9 9 9 9 9 9 9999 9 99 999 99 99 aryl group, mono or disubstituted carbamoyl group, wherein the CO group is attached to the aryl ring and each substituent is a lower alkyl or aryl lower alkyl group, mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group or mono or diarylcarbamates or any 2 adjacent substituents on the aryl ring may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, wherein X, Y and Z are either a direct bond, oxygen, sulfur or NR wherein R is hydrogen or lower alkyl and amam are 1, 2 or 3; one of R ₂ and R 8 is selected from the group consisting of hydrogen, hydroxymethyl, alkoxymethyl having up to 6 carbon atoms in each alkoxy group, straight or branched lower alkyl of 1 to 6 carbon atoms, cyano or a carboxyl or carboxylate ester group wherein the esterifying group typically contains up to 6 carbon atoms; the other of R ₂ and R 8 is an aryl group which is an unsubstituted or mono, di or trisubstituted aryl group, wherein the aryl group is monocyclic or bicyclic (in which case only the ring bound to the imidazole ring must be aromatic), and may be carbocyclic or contain up to 2 heteroatoms and said substituents are individually selected from halogen; trihalomethyl; cyano; hydroxy; straight or branched chain lower alkyl having 1 to 6 carbon atoms; straight or branched chain lower alkoxy having 1 to 6 carbon atoms (wherein the alkyl or alkoxy groups may be substituted by an amino or mono- or dialkylamino group, and their alkyl groups may form a ring or mono- or di-group with the nitrogen atom to which they are attached -alkaryl or acyl or carbamate); straight or branched chain lower thioalkoxy of 1 to 6 carbon atoms; acyloxy groups; amino; amino groups mono or disubstituted with a straight or branched chain alkyl group having 1 to 6 carbon atoms (wherein said alkyl groups are optionally substituted with a hydroxy or amino group); alkyl, aryl or alkarylamide, 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9,999 9 9 9 9 9 9 99 9 9 9 9 9 9 9900 9 99 999 99 99 Wherein the nitrogen atom is attached to the aryl group, a mono or disubstituted carbamoyl group, wherein the CO group is attached to the aryl group and the substituents are a lower alkyl or aryl lower alkyl group; mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group; or mono or diarylcarbamates; or any 2 adjacent substituents on the aryl ring may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, wherein X, Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl; and n is 1, 2 or 3; A method as claimed in claim 22, wherein said compound is a compound wherein each aryl group is independently selected from unsubstituted or substituted phenyl, naphthyl, indanyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl, benzofuranyl, thianaphthyl, isoindolyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, cinnolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydroindolyl, phenomorpholine, benzodioxazinyl, phenothiomorpholinyl and methylenediomorpholinyl; 24. The method as claimed in claim 22, wherein said compound is a compound wherein R1 is a substituted or unsubstituted phenyl or naphthyl group. 25. The method of claim 22, wherein the compound is a compound wherein R1 is phenyl or 4-fluorophenyl. 26. The method according to claim 22, characterized in that one of R ₂ and R ₃ is hydrogen or methyl and the other is selected from the group consisting of 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-methoxy-2 ·· 0 • · 0 • 00 • 0 0 · • 0 • 0 0 0 0 • · 0 0 0 0 0 · 0 0 0 · 0 0 0 0 • 0 0 0 -fluorophenyl, 4-ethoxy-2-fluorophenyl, 3-fluoro-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 3-acetylphenyl, naphthyl, 1,4-benzodioxan-6-yl and benzo [b] morpholinyl, 4-alkyl benzo [b] morpholinyl and 4-alkyl-2H, 3H, 4H-benzo [e] 1,4-thiazinyl. The method of claim 22, wherein one of R ₂ or R ₃ is hydrogen and the other is selected from the group consisting of 3-methylaminophenyl, 4-dimethylaminophenyl, 3-ethylaminophenyl, 3- (2-methylbutylaminomethyl) phenyl, 3- (ethylbutylaminomethyl) phenyl, 3- (1,2-dimethylpropylaminomethyl) phenyl, 3 - [(3-cyclohexyl-1-phenylpropyl) methylaminomethyl] phenyl, 3 - [(2-cyclohex-1-enylethyl) aminomethyl] phenyl, 3 - [(3-methylethoxy) propylaminomethyl] phenyl, 3- (tert-butylaminomethyl) phenyl, 3- [methyl- (1-phenylpropyl) aminomethyl] phenyl, 3- (methylethylaminomethyl) phenyl and 3 - [(4-methylphenyl) methylaminomethyl] phenyl. 28. The method of claim 22, wherein the administered compound is selected from the group consisting of 4- (4-fluorophenyl) -2-phenylimidazole 2-fluoro-4- [2- (4-fluorophenyl) imidazol-4-yl] -1-methoxybenzene 4-ethoxy-2-fluoro-1- (2-phenylimidazol-4-yl) benzene 4-Methoxy-3-fluoro-1- (2-phenylimidazol-4-yl) benzene 3-Fluoro-4- [2- (4-fluorophenyl) imidazol-4-yl] -1-methoxybenzene 3-Methoxy-1- (2-phenylimidazol-4-yl) benzene 4- [2- (4-methoxyphenyl) imidazol-4-yl] -1-chlorobenzene 4-Methoxy-2-fluoro-1- (2-phenylimidazol-4-yl) benzene 4- (4-chlorophenyl) -2-phenylimidazole 4- (4-methylphenyl) -2-phenylimidazole 4- (4-methoxyphenyl) -2-phenylimidazole 4- (3-bromophenyl) -2-phenylimidazole 1- [3- (2-Phenylimidazol-4-yl) phenyl] ethan-1-one 4- (4-bromophenyl) -2-phenylimidazole 4- (3-cyanophenyl) -2-phenylimidazole 4- (3-cyanophenyl) -2- (4-fluorophenyl) imidazole 9 9999 · 99 99 99 9 9 9 9 · · · · · · · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 4- (4-cyanophenyl) -2-phenylimidazole N- [3- (2-phenylimidazol-4-yl) phenyl] acetamide 2- (4-fluorophenyl) -5-methyl-4-phenylimidazole 4- [2- (2-Fluorophenyl) imidazol-4-yl] -1-chlorobenzene 4- (2-naphthyl) -2-imidazole 6- (2-Phenylimidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6 - [(2- (4-fluorophenyl) imidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6 - [(2- (4-fluorophenyl) -5-methylimidazol-4-yl) - 2H, 3H-benzo [e] 1,4-dioxin 6- (2-Phenylimidazol-4-yl) benzo [b] morpholine 4-Methyl-6- (2-phenylimidazol-4-yl) benzo [b] morpholine 4-Propyl-7- (2-phenylimidazol-4-yl) benzo [b] morpholine 6- [2- (4-Fluorophenylimidazol-4-yl) benzo [b] morpholine 6- [2- (4-Fluorophenylimidazol-4-yl) -4-methylbenzo [b] morpholine 4-ethyl-6- [2- (4-fluorophenyl) imidazol-4-yl) benzo [b] morpholine 4-methyl -6- [2- (4-fluorophenylimidazol-4-yl) -2H, 3H, 4H-benzo [e] 1,4-thiazine 4- (4-Chlorophenyl-2- (2-pyridyl) imidazole) 4- [2- (4-Fluorophenyl) imidazol-4-yl-chlorobenzene 2-indol-3-yl-5-methyl-4-phenylimidazole 2- [4- (4-chlorophenyl) imidazol-2-yl] thiophene [3- (2-phenylimidazol-4-yl) phenyl] methylamine dimethyl [3- (2-phenylimidazol-4-yl) phenyl] methyl} amine dimethyl [4- (2-phenylimidazol-4-yl) phenyl] methyl} amine ethyl [3- (2-phenylimidazol-4-yl) phenyl] amine ({3- [2- (4-fluorophenyl) imidazole-5- yl] phenyl} methyl) (2-methylbutyl) amine (ethylbutyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine (1,2-dimethylpropyl) ({3- [2- (4-Fluorophenyl) imidazol-5-yl} methyl) amine (3-cyclohexyl-1-phenylpropyl) methyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- ( 4-Fluorophenyl) imidazol-5-yl] phenyl} methyl) methylbutyl) amine (2-methylbutyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (2-cyclohex-1-enylethyl) ( {3- [2- (4-Fluorophenyl) imidazol-5-yl] phenyl} methyl) amine (cyclohexylphenylmethyl) methyl {[3- [2-phenylimidazol-5-yl) phenyl] methyl} amine ethyl (1- {3 - [2- (4-fluorophenyl) imidazol-5-yl} -isopropyl) amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) [3-methylethoxy) propyl] amine (tert. butyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl] methyl) amine methyl {phenyl [3- (2-phenylimidazol-5-yl) phenyl] methyl} propylamine (tert-butyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (methylethyl) {[3- (2-phenylimidazol-5) -yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) [(4-methylphenyl) methyl] amine. 29. The method as claimed in claim 22, wherein the receptor is an NPY5 receptor. 30. Diarylimidazole of the general formula: , r ₂ H, or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or mono, di or trisubstituted aryl group, wherein the aryl group is monocyclic or bicyclic, in which case only the ring bound to the imidazole ring must be aromatic, and said aryl group is carbocyclic or contains up to 2 heteroatoms which may be nitrogen, oxygen or sulfur and said substituents are individually selected from the group consisting of halogen, trihalomethyl, cyano, hydroxy, straight or branched lower alkyl having 1 to 6 carbon atoms, lower alkoxy having straight or branched chain with 1 44 4 4 4 4 4 4 4 4,444 • 4 4 4 4444 4 44 44 • 4 4 4 4 4 4 4 4 4 4 4 4 to 6 carbon atoms (where alkyl or alkoxy groups may be substituted by amino or mono- or dialkylamino or mono or di-alkarylamino or acyl or carbamate), straight or branched lower thioalkoxy having 1 to 6 atoms carbon, acyloxy, amino, mono or disubstituted amino with a straight or branched chain alkyl group having 1 to 6 carbon atoms, said alkyl groups being optionally substituted by a hydroxy or amino group, an alkyl, aryl or alkarylamide group whose nitrogen atom is bound to an aryl group, a mono or disubstituted carbamoyl group, wherein the CO group is attached to the aryl ring and each substituent is a lower alkyl or aryl lower alkyl group, mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group or mono or diarylcarbamates or any 2 neighboring substi the substituents on the aryl ring may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, wherein X, Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl and n and m are 1, 2 or 3; one of R ₂ and R ₃ is selected from the group consisting of hydrogen, hydroxymethyl, alkoxymethyl having up to 6 carbon atoms in each alkoxy group, straight or branched lower alkyl chain having 1 to 6 carbon atoms, cyano or a carboxyl or carboxylate ester group wherein the esterifying the group typically contains up to 6 carbon atoms; the other of R ₂ and R ₃ is an aryl group which is an unsubstituted or mono, di or trisubstituted aryl group wherein the aryl group is monocyclic or bicyclic (in which case only the ring which is bound to the imidazole ring must be aromatic), and it may be carbocyclic or contain up to 2 heteroatoms, wherein said substituents are individually selected from the group consisting of halogen; trihalomethyl; cyano; hydroxy; straight or branched chain lower alkyl having 1 to 6 carbon atoms; straight or branched chain lower alkoxy having 1 to 6 carbon atoms (where the alkyl or alkoxy groups may be substituted) 9 9 9,999 9 9 9 9 9900 9 99 9 99 99 9 9 9 9 9 9 9 9 An amino or mono- or dialkylamino group, wherein their alkyl groups may form with the nitrogen atom to which they are attached a ring or a mono- or di-alkaryl group or an acyl group or a carbamate); straight or branched chain lower thioalkoxy of 1 to 6 carbon atoms; acyloxy groups; amino; amino groups mono or disubstituted with a straight or branched chain alkyl group having 1 to 6 carbon atoms (wherein said alkyl groups are optionally substituted with a hydroxy or amino group); an alkyl, aryl or alkarylamide group whose nitrogen atom is bonded to an aryl group, a mono or disubstituted carbamoyl group, wherein the CO group is bonded to an aryl group and the substituents are a lower alkyl or aryl lower alkyl group; mono or dialkyl carbamates having up to 6 carbon atoms in each alkyl group; or mono or diarylcarbamates; or any adjacent substituents on the aryl ring may be represented as -X- (CH ₂ ) _n -Y- (CH ₂ ) _m -Z-, wherein X, Y and Z are either a direct bond, oxygen, sulfur or NR, wherein R is hydrogen or lower alkyl and am 1, 2 or 3; with that 1) R 1 and any of R ₂ and R ₃ is aryl, both of which are not phenyl, bromophenyl, chlorophenyl, 2,4-dichlorophenyl, cyanophenyl, 2-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-acetylaminophenyl, 4-phenoxyphenyl or biphenyl 2) when R ₄ is phenyl, any one of R ₂ and R 1 is aryl, and is not 2-acetylaminophenyl, chlorophenyl, biphenyl, 4-aminophenyl, p-tolyl, xylyl, 4-methoxyphenyl, 4-dimethylaminophenyl, 4-bromophenyl or 4-hydroxy-2,5-di-tert-butylphenyl. 3) when one of R ₂ or R ₃ is phenyl, R 6 is not 2-hydroxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 4-chlorophenyl, 4-cyanophenyl, 2,4-xylylphenyl, 9 9 9 4 4 4 9 999 9 9 9 98 9 9 999 9 · 9 9 9 9 9 9 4 9 9 99 99 biphenyl, 2,4-dichlorophenyl or 6-quinolyl; and further that: 4) R is not hydroxy when R ₂ or R ₃ is p-tolyl, R ₁ is not 4-hydroxy-3-methoxyphenyl when R ₂ or R ₃ is 4-dimethylaminophenyl; R is not 4-hydroxy-3,5-dimethoxyphenyl, when R ₂ or R ₃ is 4-aminophenyl; R 1 is not 4-hydroxy-3,5-di-tert-butylphenyl when R ₂ or R ₃ is 4-hydroxyphenyl; R 1 is not 4-chlorophenyl when R ₂ or R ₃ is 3-trifluorophenyl; R ¹ is not 2-hydroxyphenyl when R ₂ or R ₃ is 2- or 4-acetamidophenyl; R ₁ is not 2-methoxyphenyl when R ₂ or R ₃ is 4-acetamidophenyl; R 1 is not 2-ethoxyphenyl when R ₂ or R ₃ is 2-acetamidophenyl; R 1 is not 4-methoxyphenyl when R ₂ or R ₃ is 2-aminophenyl or 2-trifluoromethylphenyl; R ₁ is not 2-aminophenyl when R ₃ or R ₃ is 2-isopropylcarbamoylphenyl or 5-acetamido-2-hydroxyphenyl; R ₁ is not 4-dimethylamino when R ₂ or R ₃ is an ester 3-methoxy-4-hydroxyphenyl or 3,5-dimethoxy-4-acetoxyphenyl; is not 2-bromophenyl when R ₂ or R ₃ is 2,3-xylyl; R 1 is not 2-cyanophenyl when R ₂ or R ₃ is 4-tolyl; and R 1 is not 3- cyanophenyl, when R ₂ or R ₂ is 4-chlorophenyl. The diarylimidazole of claim 30, wherein each aryl group is independently selected from the group consisting of unsubstituted or substituted phenyl, naphthyl, indanyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl, benzofuranyl, thianaphthyl, isoindolyl, isobenzofuranyl, quinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl quinazolinyl, indazolyl, cinnolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydroindolyl, phenomorpholine, benzodioxazinyl, phenothiomorpholinyl and methylenedioxyphenyl. The diarylimidazole of claim 30, wherein R 1 is 4-fluorophenyl. The piarylimidazole of claim 30, wherein R ₂ or R ₃ is an N-substituted aminomethyl group. 34. diaryl according to claim 28, wherein R ₂ or R ₃ is selected from the group consisting of naphthyl, cyanophenyl, N-substituted 4 9 • 9 9 4 4 4 4 444 4 4 4444 4 - 47 4 4 9 4 4 4 4 4 4 Benzo [b] morpholine, 2H, 3H-benzo [e] 1,4-dioxin and N-substituted 2H, 3H, 4H-benzo [e] 1,4-thiazine. 35. Diarylimidazole selected from the group consisting of: 4- (4-fluorophenyl) -2-phenylimidazole 2-Fluoro-4- [2- (4-fluorophenyl) imidazol-4-yl] -1-methoxybenzene 4-Ethoxy-2-fluoro-1- (2-phenylimidazol-4-yl) benzene 4-Methoxy-3-fluoro-1- (2-phenylimidazol-4-yl) benzene 3-Fluoro-4- [2- (4-fluorophenyl) imidazol-4-yl] -1-methoxybenzene 3-Methoxy-1- (2-phenylimidazol-4-yl) benzene 4- [2- (4-methoxyphenyl) imidazol-4-yl] -1-chlorobenzene 4-Methoxy-2-fluoro-1- (2-phenylimidazol-4-yl) benzene 4- (4-methoxyphenyl) -2-phenylimidazole 4- (3-bromophenyl) -2-phenylimidazole 1- [3- (2-Phenylimidazol-4-yl) phenyl] ethan-1-one 4- (4-bromophenyl) -2-phenylimidazole 4- (3-cyanophenyl) -2-phenylimidazole 4- (3-cyanophenyl) -2- (4-fluorophenyl) imidazole 4- (4-cyanophenyl) -2-phenylimidazole N- [3- (2-phenylimidazol-4-yl) phenyl] acetamide ethyl 2,4-diphenylimidazole-5-carboxylate (2,4-diphenylimidazol-5-yl) methan-1-ol 2- (4-fluorophenyl) -5-methyl-4-phenylimidazole 4- [2- (2-Fluorophenyl) imidazol-4-yl] -1-chlorobenzene 4- (2-naphthyl) -2-imidazole 6- (2-Phenylimidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6 - [(2- (4-fluorophenyl) imidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6- {2- [4-trifluoromethyl) phenyl] imidazol-4-yl} -2H, 3H-benzo [e] 1,4-dioxin 6 - [(2- (4-fluorophenyl) -5-methylimidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6- (2,2-pyridyl) imidazol-4-yl) -2H, 3H-benzo [e] 1,4-dioxin 6- (2-phenylimidazol-4-yl) benzo [b] morpholine 4-methyl-6- { 2-phenylimidazol-4-yl) benzo [b] morpholine 4-propyl-7- (2-phenylimidazol-4-yl) benzo [b] morpholine 6- [2- (4-Fluorophenylimidazol-4-yl) benzo [b] morpholine 6- [2- (4-fluorophenylimidazol-4-yl) -4-methylbenzo [b] morpholine 4-ethyl-6- [2- (4-fluorophenyl) imidazol-4-yl] benzo [b] morpholine 6- [2- (4-fluorophenylimidazol-4-yl) -2H, 3H, 4H-benzo [e] 1,4-thiazine 4-methyl-6- [2- (4-fluorophenylimidazol-4-yl) -2H, 3H, 4H- benzo [e] 1,4-thiazine 4- (4-Chlorophenyl-2- (2-pyridyl) imidazole) 2- [4- (4-chlorophenyl) imidazol-2-yl] pyrazine 4- [2- (4-Fluorophenyl) imidazol-4-yl-chlorobenzene 2-indol-3-yl-5-methyl-4-phenylimidazole 2- [4- (4-chlorophenyl) imidazol-2-yl] thiophene 4- (6-chloro (2-pyridyl) -2-phenylimidazol dimethyl [2- (2-phenylimidazol-4-yl) (4-pyridyl)] amine [3- (2-phenylimidazol-4-yl) phenyl] methylamine {3- [2- (4-Fluorophenyl) imidazol-4-yl] phenyl} methylamine methyl [3- (2-phenylimidazol-4-yl) phenyl] methyl} amine dimethyl [3- (2-phenylimidazol-4-yl) phenyl] methyl} amine methyl [4- (2-phenylimidazol-4-yl) phenyl] methyl} amine dimethyl [4- (2-phenylimidazol-4-yl) phenyl] methyl} amine ethyl [3- (2-phenylimidazole) -4-yl) phenyl] amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) (2-methylbutyl) amine (ethylbutyl) ({3- [2- (4-fluorophenyl) imidazole) -5-yl] phenyl} methyl) amine (1,2-dimethylpropyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl} methyl) amine (3-cyclohexyl-1-phenylpropyl) methyl {[ 3- (2-Phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) methylbutyl) amine (2-methylbutyl) {[3- (2-Phenylimidazol-5-yl) phenyl] methyl} amine (2-cyclohex-1-enylethyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine (cyclohexylphenylmethyl) methyl {[3- [2-phenylimidazol-5-yl) phenyl] methyl} amino ethyl (1- {3- [2- (4-fluorophenyl) l) imidazol-5-yl} -isopropyl) amine 4 4 4 4 9499 4 44 44 9 4 4 4 4 1 2 3 4 « 4 4 4 4 ({3- [2- (4-Fluorophenyl) imidazol-5-yl] phenyl} methyl) [3-methylethoxy) propyl] amine (tert-butyl) ({3- [2- (4-fluorophenyl) imidazole) -5-yl] phenyl} methyl) amine methyl {phenyl [3- (2-phenylimidazol-5-yl) phenyl] methyl} propylamine (tert-butyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (methylethyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) [(4-methylphenyl) methyl] amine (cyclohexylphenylmethyl) ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) methylamine cyclopentyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (methylpropyl) {{3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) (2-methylpropyl) amine ({3 - [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) pentylamine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) (methylethyl) amine cyclopropyl ({ 3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl] methyl) amine cyclobutyl ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl] methyl) amine ({3- [2- (4 (Fluorophenyl) imidazol-5-yl] phenyl} methyl) [2- (4-methylphenyl) ethyl] amino n hexyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (methylbutyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4 (Fluorophenyl) imidazol-5-yl] phenyl} methyl) hexylamine (1,1-dimethylpropyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (2-cyclohexyl-1-phenylethyl) methyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine {[3 - (2-Phenylimidazol-5-yl) phenyl] methyl} propylamine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl] methyl) (2-phenylethyl) amine (2-cyclopentyl-1-phenylethyl) methyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (2-cyclohex-1-enylethyl) {[3- (2-phenylimidazol-5-yl) phenyl] 0 » 0 0 0 0 0 0 0 0 « 0 0 » 0 0 · 0 0 0 0 000 0 0 0000 0 00 00 0 0 0 0 0 · 0 0 0 · «0 0 0 0 0 »0 00 methyl} amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) benzylamine (ethylpropyl) {[3- (2-phenylimidazol-5-yl) phenyl] ] methyl} amine cyclobutyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (3-methylbutyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine [2-, (4-Methylphenyl) ethyl] {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (3-cyclohexyl-1-phenylpropyl) ({3- [2- (4-fluorophenyl) imidazole-5- yl] phenyl} methyl) methylamine cyclopropyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine (1,2-dimethylpropyl) {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ethyl ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) (3- methylbutyl) amine ethyl {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine cyclohexyl ({3- [2- (4-fluorophenyl) imidazol-5-yl] phenyl} methyl) amine methyl {[3 - (2-phenylimidazol-5-yl) phenyl] methyl} amine pentyl 1 {[3- (2-phenylimidazol-5-yl) phenyl] methyl} amine ({3- [2- (4-fluorophenyl) imidazole-5- yl] phenyl} methyl) dipropylamine dibutyl {3- [2-phenylimidazol-5-yl) phenyl] methyl} amine.