Background of the Invention It is generally accepted that the control of blood glucose levels for the treatment of patients diagnosed with type II diabetes will have a beneficial effect. Established oral therapies for treating type II diabetes either improve insulin action or cause enhanced insulin secretion. The agents currently approved as therapies for type II diabetes patients that cause an enhanced insulin secretion contain a sulphonlyurea moiety. These compounds act by depolarising the beta cell by modulating closure of the K-ATP channel.

Additional compounds that act at the K-ATP channel are under consideration for treatment of type II treatment and that are not sulphonylurea compounds have a fast onset of activity and short duration of action such as (-)-N- (trans- 4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166) (Brit. J. Pharm. 1997,120,137-145).

All agents that function at the molecular level by modulating the K-ATP channel have the potential for inducing hypoglycemia. Hypoglycemia is the major cause of adverse reactions in patients receiving sulphonylurea therapy and the prevalence of hypoglycemic episodes can be as high as 20% of patients. Compounds that potentiate insulin secretion under high glucose conditions and have little or no effect at low blood glucose levels would offer a distinct advantage in the treatment of type II diabetes.

Summary of the Invention We have discovered compounds that potentiate the secretion of insulin from beta cells under high glucose conditions and have minimal effect under low glucose conditions.

The compounds are also operable in additional disease states where impaired glucose disposal is present. For example these include cardiovascular disease where above normal glucose levels are present or initial insulin resistance has occurred. The compounds can also be used to treat post operative insulin resistance induced by anaesthesia.

The present invention provides compounds of the following formula (I), and the use of said compounds in the treatment of diabetes, especially Type II diabetes, diabetic complications, and metabolic disorders or related diseases in particular where impaired glucose disposal is present. in which X is-0-,-S-, or-NR5- ;

R5 is hydrogen, C1_g alkyl, or an amino protecting group ; R1, R1', R2, and R3 are independently hydrogen or C1_g alkyl; R1 and R2 together form a bond and R1 and R3 are independently hydrogen or C1_g alkyl; R1 and R2 can combine together with the carbon atoms to <BR> <BR> <BR> <BR> which they are attached form a C3_7 carbocyclic ring and R1' and R3 are independently hydrogen or C1_g alkyl; R1 and R1 together with the carbon atom to which they are attached combine to form a C3_7 spirocarbocyclic ring and R2 and R3 are independently hydrogen or C1_8 alkyl; R2 and R3 together with the carbon atom to which they are attached combine to form a C3_7 spirocarbocyclic andR1 and R1'are independently hydrogen or C1-8 alkyl ; n is 0,1, or 2; R4 is Y is-0-,-S-, or-NR8- ; -O-or-S-;Y'is

R6 and R7 are independently hydrogen, C1_8 alkyl, C3_7 cycloalkyl, C1_g alkoxy, C1_g alkylthio, halo Cl-8 alkylthio, C1_g alkylsulfinyl, C1_g alkylsulfonyl, C3_7 cycloalkoxy, aryl-C1_g alkoxy, halo, halo-Cl-8 alkyl, halo- C1_g alkoxy, nitro, -NR10R11, -CONR10R11, aryl C1_g alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally halo substituted acylamino, cyano, hydroxy, COR12, halo C1_g alkylsulfinyl, or halo C1_g alkylsulfonyl, or alkoxyalkyl of the formula CH3 (CH2) p-O- (CH2) q-0- ; where p is 0,1,2,3, or 4; and q is 4, or 5; R12 is C1_g alkyl or optionally substituted phenyl ; R8 is hydrogen, C1_g alkyl, halo-C1-8 alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO C1-8 alkyl, optionally substituted COaryl, COC1_g alkyl, SO2C1-8 alkyl, optionally substituted S02 aryl, optionally substituted phenyl-C1_g alkyl, CH3 (CH2) p-0- (CH2) q-0- ; R9 is hydrogen, halo, C1_g alkyl, halo C1_g alkyl, C1_g alkylthio, halo C1_g alkylthio, C3_7 cycloalkylthio, optionally substituted arylthio or heteroarylthio, C1_g alkoxy, C3_7 cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, C3_7 cycloalkyl, halo C3_7 cycloalkyl, C3_7 cycloalkenyl, cyano, COOR10, CONR10R11 or NR10R11, C2-6 alkenyl, optionally substituted heterocyclyl,

optionally substituted aryl C1_g alkyl, optionally substituted heteroaryl C1_g alkyl in which the alkyl group can be substituted by hydroxy, R10 and Rll are independently hydrogen, C1-8 alkyl, optionally substituted aryl C1_g alkyl, optionally substituted phenyl, or R10 and Rll together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two C1_g alkyl groups or one carbon atom may be replaced by oxygen or sulfur; R14 and R16 are independently hydrogen, halo, C1_g alkyl, C3_7 cycloalkyl, C3_7 cycloalkoxy, halo-Cl-8 alkyl, halo-Cl-8 alkoxy, C1_g alkoxy, optionally substituted aryl, or optionally substituted heteroaryl; R15 and R17 are independently hydrogen, halo, C1_g alkoxy, C3_7-cycloalkyl, C1_g alkyl, C3_7 cycloalkoxy, hydroxy, halo C1_g alkoxy, optionally substituted phenyl, optionally substituted phenyl-Cl_g alkyl, optionally substituted phenyloxy, optionally substituted phenyl-C1-8 alkoxy, tetrahydropyran-2-ylmethoxy, C1_g alkyl-S (O) n-, optionally substituted aryl-C1-8 alkyl-S (O) n-, CH3 (CH2) p-Zl- (CH2) q_22-, or Z3- (CH2) q-z2- ; Zl and Z2 are independently a bond, 0, S, SO, SO2, sulphoximino, or NR10; Z3 is hydroxy, protected hydroxy, NRLO Roll, or protected amino ; and pharmaceutically acceptable salts and esters thereof.

One embodiment of the present invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for treating diabetes or a related disorder.

Another embodiment of the present invention is a method of treating diabetes or a related disorder, which comprises administering to a patient a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention In the above formulae, a"C1_g alkyl"group can be any alkyl group, branched or unbranched, containing up to eight carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. Preferred values of C1_g alkyl are C1_6 alkyl, and most preferably methyl and ethyl.

A"C3_7 cycloalkyl"group is cyclopropyl, cyclobutyl, cyclohexyl or cyclopentyl.

A"C3_7 cycoalkyl-C1_g alkyl"group is one such cycloalkyl group attached through a C1_g alkyl group (an alkylene group) to the ring.

A"Cl_g alkoxy"group is one of the above-mentioned Cl_ g alkyl groups attached through oxygen to the ring, and preferred examples are methoxy and ethoxy.

A"C3_7 cycloalkoxy"group is a C3_7 cycloalkyl group as mentioned above linked through an oxygen atom to the ring as, for example, cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.

An"aryl-C1_g alkyl"group can be, for example, optionally substituted phenyl-C1_g alkyl or optionally substituted naphthyl-Cl_g alkyl, such optionally substituted groups being optionally substituted with one or more, preferably one to three, substituents selected from, for

example, C1_g alkyl, C1_g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino. A preferred aryl-C1_g alkyl group is optionally substituted phenyl- (CH2) X-where x is 1 or 2, most preferably optionally substituted benzyl.

A halo group is preferably chloro, bromo or fluoro.

A halo C1_g alkyl or halo C1_g alkoxy group is a substituent in which one or more, preferably one to three, hydrogen atoms on the C1_g alkyl moiety is replaced by a halo atom, preferably chloro, bromo or fluoro.

An"alkoxyalkoxy"group is of the formula CH3 (CH2) p-O- (CH2) q-O-, where p is 0-4 and q is 1-5, preferred examples being those in which p is 0 or 1 and q is 1-3, especially methoxyethoxy, ethoxyethoxy, ethoxypropoxy, or methoxypropoxy.

A"C1_g acylamino"substituent is preferably of the formula RCONH-where RCO is any appropriate acid residue, RCO containing from 1-8 carbon atoms, Examples of R include C1_8 alkyl, in particular methyl or ethyl, acetyl being the most preferred acyl group. R can also be aryl C1_g alkyl, especially benzyl, or R can be halo-C1_g alkyl, especially trifluoromethyl.

The"acyl"moiety, alone or in combination, is derived from an alkanoic acid containing from one to eight carbon atoms. The term"acyl"also includes moieties derived from an aryl carboxylic acid.

The term"treating,"as used herein, describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of present invention to prevent the onset of the symptoms or complications, to

alleviate the symptoms or complications, or to eliminate the disease, condition, or disorder.

In the above formula (I), the moiety X is preferably -NR5-, where R5 is hydrogen or an amino protecting group, and is most preferably hydrogen, the protected derivatives being mainly useful as intermediates. Protecting groups can be any of the conventional amino protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 7, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective Groups in Organic Chemistry, chapter 2, J. F. W. McOmie, ed., Plenum Press, New York, 1973. Examples of such groups include but are not intended to be limited to benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl ; those of the formula-COOR where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl ; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p-methoxybenzoyl ; and other groups such as methanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrophenylethyl, p-toluenesulfonylaminocarbonyl, and the like. Preferred nitrogen protecting groups are benzyl, acyl, or silyl.

In addition, it is preferred that R1, R1, R2, and R3 are hydrogen, and that this component of the compounds of the invention is an imidazolinyl group.

Preferred compounds of formula (I) are those which have one or more of the following features:

r<BR> (i) R1 and R1 are hydrogen and R and R are hydrogen or methyl, more preferably R2andR3R'1, are hydrogen; (ii) X is-NH- ; (iii) n is 0 ; (iv) R4 is in which R14 and R16 is selected from hydrogen, halo, or optionally substituted phenyl, naphthyl or thienyl, more preferred phenyl, 4-methylphenyl, 2,4-dichlorophenyl, 5- chloro-2-thienyl, 3-thienyl, 4-methoxyphenyl, 4- (trifluoromethyl) phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3-fluorophenyl, 3- (trifluoromethyl) phenyl, 4-fluorophenyl, R is selected from hydrogen or halo, more preferred hydrogen, R17 is selected from benzyloxy, propoxy, butoxy, H3C (CH2) p-O- (CH2) q-O-, tetrahydropyran-2-ylmethoxy, more preferred H3C-O- (CH2) 2-0-, H3CCH2-0- (CH2) 2-0-, H3C-O- (CH2) 3- 0-, H3CCH2-0- (CH2) 3-0-, mostly preferred H3C-O-(CH2) 2-O-, (v) R4 is an indol-3-yl group of the formula

in which R is selected from hydrogen, halo, nitro, cyano, Ci-6 alkyl, halo C1-6 alkyl, halo C1-6 alkoxy, halo C1-6 alkylthio, more preferred chloro, fluoro, methyl, or trifluoromethyl which are in position 5 of the indole nucleus, R is hydrogen, halo, or methyl, more preferred hydrogen, R8 is hydrogen or methyl, more preferred hydrogen, R9 is C1-6 alkyl, optionally substituted benzyl, optionally substituted phenyl, or optionally substituted thienyl, more preferred methyl, phenyl, 4-methylphenyl, 2,4- dichlorophenyl, 3-methyl-2-thienyl, 2,5-dimethyl-3-thienyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3- chlorophenyl, 2-chlorophenyl, 2-methylphenyl, 3- methylphenyl, 3-thienyl, 2-bromophenyl, 4-chloro-3- methylphenyl, 2,4-dimethylphenyl, (vi) R4 is a benzofuran-3-yl (Y=O) or benzothien-3-yl (Y=S) group

in which R is selected from hydrogen, halo, C1-6 alkyl, halo C1-6 alkyl, more preferred chloro, fluoro, methyl, or trifluoromethyl which are in position 5 of the bicyclic nucleus, R9 is C1-6 alkyl, optionally substituted phenyl, or optionally substituted thienyl, more preferred methyl, 4- methylphenyl, 4-methoxyphenyl, 2-methoxyphenyl, 4- chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, (vii) R is a benzofuran-2-yl group in which R is selected from hydrogen, halo, C1-6 alkyl, or optionally substituted phenyl, naphthyl, or thienyl, more preferred 4-methylphenyl, 5-chloro-2-thienyl, 2-thienyl, 3- thienyl, 3- (trifluoromethyl) phenyl, 3-methoxyphenyl, 3- (trifluoromethyl)phenyl, 4-fluorophenyl, (viii) R4 is a benzothien-2-yl group

in which R is selected from hydrogen, halo, Cl-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, more preferred hydrogen, chloro, bromo, methoxy, methyl, or trifluoromethyl, R9 is hydrogen, halo, C1-4 alkoxy, C1-4 alkyl, optionally substituted phenyl, naphthyl, or thienyl, or an optionally substituted phenylmethyl, optionally substituted naphthylmethyl, optionally substituted thienylmethyl, or optionally pyridylmethyl group in which the methyl group is substituted by hydroxy.

Preferred compounds are listed below:

Most preferred compounds of the formula I include the following:

Particularly preferred compounds are those exemplified in the Examples.

By virtue of their acidic moieties, some of the compounds of Formula I include the pharmaceutically acceptable base addition salts thereof. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.

Because of a basic moiety, some of the compounds of Formula I can also exist as pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric,

benzoic, acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate,P- hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts.

In addition, it is recognised that compounds of the present invention may form a variety of solvates with a number of different solvents. Representative solvates can be useful as final embodiments of the present invention or as intermediates in the isolation or preparation of the final embodiments of this invention. For example solvates can be prepared with lower alcohols such as ethanol and with alkyl esters such ethylacetate.

It is recognised that various stereoisomeric forms of the compounds of Formula I may exist. The compounds may be prepared as racemates and can be conveniently used as such.

Therefore, the racemates, individual enantiomers, diastereomers, or mixtures thereof form part of the present invention. Unless otherwise specified, whenever a compound is described or referenced in this specification all the racemates, individual enantiomers, diastereomers, or mixtures thereof are included in said reference or description.

In addition to the pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.

General methods of synthesis for the compounds of the present invention are described in Schemes I-V below.

GENERAL SCHEME FOR THE SYNTHESIS OF INDOLYL-IMIDAZOLINES <BR> <BR> <BR> <BR> <BR> 1 in 2 3<BR> Compounds of formula I wherein X is NH; R1, R1', R2, R3 are hydrogen; n is 1 or 2; R4 is R, R, R have the definitions given above can be prepared according to scheme I.

Scheme I J is C1-C4 alkyl n = 1 or 2

The transformation described in Scheme I is novel and represents an additional embodiment of the present invention and is described in Scheme Ia.

Scheme Ia 0 RiAN NH2 H A) TMS-X/triethylamine B) Exc. HMDS (neat) C TMS-X/diethylaminomethyl- 60 tu 100 oc polystyrene 1 N- X=Clorl H The process described in Scheme Ia affords numerous advantages over similar methods known in the art. The transformation can be achieved in high yield and under mild conditions, whereas, methods known in the art require the use of extreme conditions or reagents.

Cyclisation is induced by a silylating agent or a mixture of silylating agents, optionally in the presence of an soluble or insoluble base, e. g. triethyl amine or dimethylaminomethyl polystyrene and a solvent. Useful reagents are e. g. described in FLUKA Chemika,"Silylating Agents" (1995) ISBN 3-905617-08-0 and the literature cited therein. In a more prefered embodiment, these silylating agents are trimethyl silyl halogenides, TMS-X (e. g. trimethyl silyl chloride or trimethyl silyl iodide) or hexamethyl disilazane, HMDS or trimethyl silyl diethylamine, TMS-DEA or mixtures of them. In the most prefered embodiment the reactions are carried out either in methylene chloride with excess TMS-C1 or, more prefered, TMS-I in presence of triethyl amine or dimethylaminomethyl polystyrene at ambient temperature, or in neat HMDS or HMDS/TMS-Cl 100/1, without

additional base and solvent at 50°C to reflux, preferably at 70°C to 90°C. In some cases, using TMS-X as cyclizing reagent, excessive reagent has to be added in several portions within a period of time (up to about a week) to ensure complete conversion. The process described herein is compatible to many functionalities present in an organic molecule, e. g. unprotected hydroxy, unprotected amino, olefinic double bond, cyano, nitro, aromatic halogen, amide and is sucessful in some cases, when conventional methods failed (Chem. Pharm. Bull. 1980,28,1394-1402). <BR> <BR> <BR> <BR> <P> 1 1"2 3<BR> <BR> Compounds of formula I wherein X is NH; R1, R1', R2, R3 are hydrogen; n is 0; R4 is R6, R, R have the definitions given above can be prepared according to scheme II.

Scheme II J1 is COR2 or CO2R2 and R2 is C1-C8 alkyl, aryl, or aryl C1-C8 alkyl.

The process described in Scheme II is novel and represents another embodiment of the present invention. The process describes the preparation of imidazolines of formula I in which X is NH and R4 is an indole nucleus. The process is affected by treating a compound of formula (IV)

with a compound of formula (III) in the presence of a dehydration agent between room temperature and 140°C; followed by treatment with an alcohol or water between room temperature and the boiling point of the reaction. The preferred compound of formula II is 1-acetyl-imidazoline-2- one or l (phenyloxycarbonyl)-imidazoline-2-one. The preferred dehydration agent is phosphorus oxychloride or thionylchloride. The preferred reagent for the deprotection of the N-substituted-imidazoline or the N-substituted- imidazole is ethanol or water.

The indole nuclei of formulas (II and IV) utilized in Schemes I and II are known in the art and can be prepared as shown in the Schemes IIIa-IIIf below.

Scheme IIIa Scheme IIIb Scheme IIIc

R6 R6 CH3COR9 1. reflux EtOH t1. reflux EtOH| | |\»RgNHN-H2 2. PPA 80C N 2 Separationby + chromotography RU Rg R6 N 6 Scheme IIId CH3COR9 1. reflux in ETOH (pN -NH2 H 2. PPA80°C. R6 R6 Scheme IIIe R6 R6 \ BrCH2COR9 I \ //N'R9 Nu2 H NHsH Scheme IIIf

Literature References- a) Schemes IIIa-IIId; Bull. Soc. Chim. Fr. 1969 (4), 1227-34 with the modifications shown. b) Scheme IIIf; J. Org. Chem. (1994) 59,6372 with the modifications shown.

Compounds of formula I, wherein X is NH; R2,R1', are R3 are hydrogen; n is 0; R4 is R14, R15, R16, and R have the definitions given above can be prepared as described herein. A skilled artisan would appreciate that the such compounds of formula I could be be prepared from the appropriate halo and hydroxy substituted naphthalenes. Such syntheses are demonstrated by the preparation of specific compound illustrates in Schemes IV and V.

For example, the synthesis of 2,3,4-tri-substituted naphthyl-compounds is shown in the following scheme IV.

Scheme IV

Cet COOH EtOH, HzS04, 80° C., 72 h (2-Bromethyl)-methylether OH OH DMF, K2CH3,80° C. Lit. Chem. Ber. 2621,1894 CONHCH2CH2NH2 Co2Et POCI3, 80° C. 8 h 0 H3 0 Br Br ber B (OH) 2 Pd [P (Ph) 3] 4 l 80° C., Dioxan Na2CO3 (aqu) ll|18h18 h N CI H N-'N , I H 90 ~ CH3 hzCI 3 ci Cl 2,3,7-tri-substituted naphthyl-compounds are demonstrated in the following scheme V.

Scheme V

Br< ETOH/H2SO4 mCOOC2H5 //16 h reflux I// Oh oh Lit. J. Med. Chem. 1990,176 Br COOC2H5 BrCH2CH20CH3 H2NCH2CH2NH2 z DMF/K2CO3,6h 60° C. OCH2CH2OCH3 6 h 100° C. Nez Br CONHCHpCH2NH2 I H H OCH2CH20CH3 4 h, 80-90° C. OCH2CH20CH3 H3C /\ N H3C e B (OH) 2/Pd (PPh3) 4/Dioxan/Na2C03/H20 w \ \ (i i 20 h 80° C. OCH2CH20CH3 In another process of the present invention, compounds of formula (I) in which R4 is a substituted benzofuran or benzothiophene are prepared by the imidazoline being introduced into position 3 by acylating the 3-unsubstituted benzofuran or benzothiophene with a chloroformate involving CS2 in the first stage followed by cyclisation with ethylene diamine in the second.

Compounds of formula (I) have primary action during hyperglycaemia in that they improve glucose tolerance

without producing marked reduction in basal plasma glucose levels.

Compounds of the invention were active in a screen for activity using assays based on the use of BTC6 cells [Poitout, V et al. Diabetes 44: 306-313 (1995) and D'Ambra, R et al Endocrinology, 126: 2815-2822 (1990)] and rat Langerhans islets [ (Lacy, P. E and Kostianovsky, M. Diabetes (1967)] as described in more detail in the examples below.

The invention further includes a method of treating diabetes in which an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof is administered to a patient requiring such treatment.

Preparations and Examples The following examples and preparations are provided merely to further illustrate the invention. The scope of the invention is not construed as merely consisting of the following examples. In the following examples and preparations, melting point, nuclear magnetic resonance spectra, mass spectra, high pressure liquid chromatography over silica gel, gas chromatography, N, N-dimethylformamide, palladium on charcoal, tetrahydrofuran, ethyl acetate, thin layer chromatography and elemental analysis are abbreviated M. Pt., NMR, MS, HPLC, GC, DMF, Pd/C, THF, EtOAc, TLC and EA respectively. The terms"EA","TLC","NMR", and"MS", when being utilised in the preparations, indicate that the data indicated was consistent with the desired structure.

Reported melting points are uncorrected and yields are unoptimized.

Preparation 1 Ethyl (2,5-dimethylindol-3-yl) acetate (X=Me, n=1)

A suspension of 1.6 g (0.01 mol) of p-tolylhydrazine hydrochloride salt in 50 mL of EtOH was treated with ethanolic NH3 to basify, heated on the water bath for 2 minutes, and then the NH4Cl salt formed was filtered off.

The filtrate was concentrated to dryness and treated with 1.4 g (0.01 mol) of ethyl levulinate and 0.92 mL of PC13 (0.01 mol) in 25 mL of toluene at 130°C. for 4 hours. The reaction mixture was poured into an ice-water and extracted with ethyl acetate which was washed three times with brine to neutral. The extract was dried over MgSO4, concentrated, and chromatographed with CH2Cl2 as an eluent to yield 1.2 g (48%) of the desired indolylacetate as an oil.

1H NMR (CDC13) d 7.75 (br. s, 1H), 7.31 (s, 1H), 6.9 (d, J=0.016 Hz, 1H), 6.76 (d, J=0.016 Hz, 1H), 4.12 (q, J=0.014 Hz, 2H), 3.63 (s, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 1.24 (t, J=0.014 Hz, 3H).

The following compounds were prepared from the appropriately substituted hydrazines essentially by the same procedure as described in Preparation 1.

Preparation 2 Ethyl (5-fluoro-2-methylindol-3-yl) acetate (X=F, n=1). 21% NMR Preparation 3 Ethyl (5-chloro-2-methylindol-3-yl) acetate (X=C1, n=1). 40% NMR

Preparation 4 Ethyl (5-bromo-2-methylindol-3-yl) acetate (X=Br, n=1). 23% NMR The following intermediates were prepared substantially in accordance with Preparation 1 from the corresponding hydrazine hydrochloride or hydrazine and ethyl 4-acetylbutyrate heated at 80°C. for 4 hours. The crude indolylpropionate esters obtained in high yields were used in the subsequent reaction without further purification.

Preparation 5 Ethyl 3- (2,5-dimethylindol-3-yl) propionate (X=Me, n=2) Yield: 96%; 1H NMR (CDC13) d 7.66 (br. s, 1H), 7.25 (s, 1H), 7.17 (d, J=0.016 Hz, 1H), 6.92 (d, J=0.016 Hz, 1H), 4.11 (q, J=0.014 Hz, 2H), 2.99 (t, J=0.015 Hz, 2H), 2.60 (t, J=0.016 Hz, 2H), 2.44 (s, 3H), 2.36 (s, 3H), 1.24 (t, J=0.014 Hz, 3H).

Preparation 6 Ethyl 3- (5-fluoro-2-methylindol-3-yl) proprionate (X=F, n=2).

Yield: 92% NMR Preparation 7 Ethyl 3- (5-chloro-2-methylindol-3-yl) propionate (X=Cl, n=2).

Yield: 96% NMR Preparation 8 Ethyl 3- (5-bromo-2-methylindol-3-yl) propionate (X=Br, n=2).

Yield: 62% NMR Preparation 9 Ethyl 3- (5-trifluoromethyl-2-methylindol-3-yl) propionate (X=CF3, n=2). Yield: 90% NMR Example 1

2-12- [l- (2, 4-Dichlorobenzyl)-lH-indol-3-yl]-ethyll-4,5-<BR> dihydro-lH-imidazole To a solution of 3- (lH-indol-3-yl)-propionic acid ethyl ester (1.6 g, 7.3 mMol) in dry acetonitrile (25 ml) was added successively cesium carbonate (2.35 g, 7.3 mMol) and 2,4-dichlorobenzyl chloride (1.0 ml, 7.3 mMol). The mixture was heated to 70°C. for 15 hours and, after cooling, poured into water (250 ml) and extracted with methylene chloride.

The combined organic solutions were dried over sodium sulphate and evaporated. The remaining brown oil was used in the next step without further purification.

A 2M solution of trimethyl aluminium in toluene (3.32 ml) was diluted with dry toluene (30 ml), cooled to 0°C. and 1,2-diaminoethane (0.43 ml) was added. The mixture was brought to ambient temperature and a solution of 2.5 g of 3- [l- (2, 4-Dichlorobenzyl)-lH-indol-3-yl]-propionic acid ethyl ester in dry toluene (20 ml) was added slowly. The reaction mixture was refluxed for 15 hours, cooled and carefully hydrolysed with water (20 ml). The organic phase was separated, dried over sodium sulphate and evaporated.

The crude product was purified by column chromatography using successively methylene chloride/ethanol/aqueous ammonium hydroxide 50: 49: 1 and 50: 43: 7 respectively to yield the titled product.

Example 2 2-methyl-3- (1-imidazol)-5-chlorobenzothiophene:

CI cl CI CI diethylaniline 210 C, 24 hr SH acetone, KzC03 S CI 94% yield 64% yield 0 O CI O O S CH AICI3, CS2 3 33% yield ethylene diamine N 120 C, 1 hr, CS2 (cat) Cl ~ N 57%yield H S CH3 To a dry acetone (50 mL) solution of 4-chlorothiophenol (14.6 g, 0.1 mol) and 2,3-dichloro-1-propene (10 g, 0.9 mol) was added K2CO3 (16.6 g, 0.12 mol) and the reaction mixture was refluxed. After 12 hr the reaction mixture was filtered and concentrated. The concentrate was dissolved in t-butyl methyl ether (250 mL), washed with 1 N NaOH (100 mL), water (100 mL), dried over Na2SO4 and concentrated to give a yellow oil (20.5 g, 94% yield).

The above oil (20.5g 94 mmol) was mixed in N, N- diethylaniline (100 mL) and heated to 210°C. After 24 hr the reaction was cooled, diluted with t-butylmethyl ether (300 mL), washed with 1.5N HC1 (3x200 mL), dried over Na2CO3, and concentrated to give a residue. The residue was eluted through a silica gel column with hexane. The eluant containing the product was concentrated to give 2-methyl-5- chlorobenzothiophene as a colorless solid, 11 g, 64% yield.

To a CS2 (20 mL) solution at 0°C containing AlCl3 (1.33 g, 10 mmol) and ethylchloroformate (0.54 g, 5 mmol) was added portionwise 2-methyl-5-chlorobenzothiophene (0.91 g, 5

mmol). After 1 hr the cooling bath was removed and the reaction came to room temperature. After 2 hr reaction was quenched with ice, extracted with CH2C12, dried over Na2SO4, and concentrated. The concentrate was eluted through a column of silica gel with hexane. The eluant containing the product was concentrated to give the 2-methyl-3-carboethoxy- 5-chlorobenzothiophene (420 mg, 33% yield) as a red oil.

Ethylenediamine (5 mL) was added to 2-methyl-3- carboethoxy-5-chlorobenzothiophene (200 mg) and heated to 120°C. After 1 hr the reaction was cooled and water (30 mL) was added. The resulting solid was filtered off, washed with water, and dried. The solid was recrystalized from acetonitrile to give 2-methyl-3- (l-imidazol)-5- chlorobenzothiophene 100 mg, 57% yield as a solid. MP 190- 192 C, MS 250 M+ Example 3 2- (4-Methyphenyl)-3- (1-imidazol)-5-chlorobenzothiophene: H3C CL Br CH3 SH 0 Cl p PPA acetone, K2CO3 13 29% yield 82%yield S O O ci ci)10-- ci s AIC13, CS2 !! J A) C) 3, CS2 t' CH3 33% yield CH3 NEZ ethylene diamine CI / 120 C, 1 hr, CS 2(cat) sJA H 51 % yield CH3

To an anhydrous DMF (100 mL) solution containing 4- chlorothiophenol (6.8 g, 47 mmol) and a-bromo-4- methylacetophenone was added K2CO3 and the reaction mixture was heated at 80°C. After 3 hr the reaction mixture was filtered and the filtrate was concentrated. The concentrate was stirred in water, the resulting solid was filtered off, and the solid was washed with water. The solid was recrystalized from ethanol to give a solid (10.7 g, 82% yield).

The above solid (9.7 g, 35 mmol) was dissolved in polyphosphoric acid (125 mL) and heated at 120°C. After 24 hr the reaction mixture was cooled and quenched with ice (125 g) with cooling. Ethyl acetate (100 mL) was added and the reaction mixture stirred for 30 min. The resulting solid was filtered off and washed with water, ethyl acetate, and dried to give 2- (4-methylphenyl)-5-chlorobenzothiophene (2,6 g, 29%).

To a CS2 (10 mL) solution at 0°C containing AlC13 (1.33 g, 10 mmol) and ethylchloroformate (0.54 g, 5 mmol) was added portionwise 2- (4-methylphenyl)-5-chlorobenzothiophene (1.29 g, 5 mmol). After 1 hr the cooling bath was removed and the reaction came to room temperature. After 4 hr reaction was quenched with ice, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The concentrate was eluted through a column of silica gel with hexane. The eluent containing the product was concentrated to give the ester (225 mg, 14% yield) as a red oil.

Starting material 250 mg, 20% was also recovered.

Ethylenediamine (2 mL) was added to the above ester (110 mg, 0.33 mmol) and heated to 120°C. After 2 hr the reaction was cooled and water (30 mL) was added. The resulting solid was filtered off, washed with water, and dried. The solid was eluted through a column of silica gel

with toluene (60%)/ethanol (40%) and the eluent was concentrated to give 2- (4-methylphenyl)-3- (1-imidazol)-5- chlorobenzothiophene 55 mg, 51% yield as a solid. MP 217- 220°C, MS 325 M-H.

Example 4 2- (n-Heptanyl)-3- (l-imidazolyl)-5-chloro-benzothiophene NBS, CCI4,70 C CI cat. benzoyIperoxide CI Ph3P, cylene S CH3 (97% yield) S6j 67% yield S~j Br PPh3Br n-H13C6CHO, t-BuOK.,, 1,2-epoxybutane cl BH3, amberlyst, C, Ni (ace) 2, MEOH CIC02Et, AIC13 72% yield vS+C5H11 47% yield uStC H 71% yield 0 N-- ci Ethylenediamine I 65% yield C7 S C7Hl5 H15 A solution of CC14 (100 mL) containing n- bromosuccinamide (2.7 g, 15 mmol), dibenzoylperoxide (100 mg) and 2-methyl-5-chloro-benzothiophene (2.7 g, 15 mmol) was heated to 70°C. The reaction mixture was refluxed for 0.5 hr, cooled to room temperature, filtered, and the filtrate concentrated. The concentrate was heated with i- hexane, filtered, and the filtrate was evaporated to dryness to give the bromide (3.8 g, 97% yield) as a colorless solid.

The bromide 2.5 g, 9.6 mmol) was mixed with triphenylphosphine (2.51 g, 9.6 mmol) in xylene (50 mL) at 140°C. After 3 hr the reaction mixture was cooled to room temperature filtered off and washed with xylene, t-butyl methyl ether, and dried to give the phosphonium salt (2.7 g, 54% yield).

The phosphonium salt (1.0 g, 1.9 mmol), hexenal (0.19 g, 1.9 mmol) was mixed in 1,2-epoxybutane (20 mL) containing potassium t-butoxide (100 mg) under argon at 70°C. The reaction mixture was cooled to room temperature, evaporated, dissolved in diisopropyl ether, filtered, and the filtrate was concentrated. The concentrate was eluted through a column of silica gel with i-hexane and the eluant was concentrated to give the olefin (0.36g, 72%) as a colorless foam.

To a methanol (50 mL) solution containing the olefin (0.36g, 1.4 mmol) and borohydride exchange resin (3 mmol) was added nickel (II) acetate (0.38 g, 1.5 mmol) and reaction mixture was refluxed. After 1 hr the reaction mixture was cooled to room temperature, filtered, and the filtrate concentrated. The concentrate was eluted through a column of silica gel with i-hexane and the eluant was evaporated to give the alkane (175 mg, 47% yield) as a colorless oil.

To a CS2 (10 mL) solution at 0°C containing AlCl3 (176 mg, 1.3 mmol) and ethylchloroformate (145 mg, 1.3 mmol) was added dropwise to the alkane (175 mg, 0.66 mmol). After 1 hr the cooling bath was removed and the reaction brought to room temperature. After 2 hr reaction was quenched with ice, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The concentrate was eluted through a column of silica gel with hexane. The eluent containing the product was concentrated to give the ester (160 mg, 71% yield) as a red oil.

Ethylenediamine (1 mL) was added to the above ester (75 mg, 0.22 mmol) and heated to 120°C. After 1 hr the reaction was cooled, water (30 mL) was added to the reaction mixture and then extracted with ethyl acetate (3x30 mL). The extract was dried, filtered, and concentrated. The concentrate was eluted through a column of silica gel with

CH2Cl2 (95%)/ethanol (4%)/10% NH3 (0.1%) and the eluent was concentrated to give the title compound 2- (n-heptanyl)-3- (l- imidazolyl)-5-chloro-benzothiophene 48 mg, 65% yield as a solid. MP 126-128°C, M 334 M+.

Example 5 2-Methyl-3- (1-imidazol)-5-chlorobenzofuran: cl ci Cl' K2C03 Cl N-dieth laniline C! \ acetone C! N. N-d! ethy! an!!! ne ,, 0 CI acetone y y con HCI o C/ C ! cri cl O N CI CICO2Et, AICI3 CI CS2, 0-5 c 0'-"-Ethylenediamine N I I-H O CH3 30% yield CH3 29% yield O CH3 To an acetone (50 mL) solution of 4-chloro-phenol (12.9 g, 100 mmol) was added K2CO3 (16.6 g, 120 mmol) and 2,3- dichloro-1-propene (10.0 g, 100 mmol). After refluxing 12 hr the reaction mixture was cooled, filtered, and concentrated. The concentrate was dissolved in t-butyl methyl ether (200 mL), washed with 5% NaOH (100 mL), water (100 mL), dried over Na2SO4, filtered and concentrated to give the ether (13.4 g, 66% yield) as a yellow oil.

The ether (13.4 g, 66 mmol) was dissolved in N, N- diethylaniline (75 mL) and heated to 210°C. After 12 hr the reaction mixture was cooled, dissolved in t-butyl methyl ether (400 mL), washed with 10% HC1 (3x250 mL), dried over Na2SO4, and concentrated to give a brown oil (13 g, 97%).

Concentrated HC1 (65 mL) was added to the above oil and the mixture was heated at 85°C. After 8 hr the reaction mixture was cooled, diluted with water (100 mL) and t-butyl methyl ether (200 mL). The mixture made basic with 30% NaOH, extracted with t-butyl methyl ether (100 mL), dried over

Na2SO4, filtered, and concentrated. The concentrate was eluted through a column of silica gel with i-hexane and the eluent evaporated to give the benzofuran (5.5 g, 52%) as a colorless oil.

To a CS2 (5 mL) solution at 0°C containing AlC13 (1.60 g, 120 mmol) and ethylchloroformate (1.3 g, 12 mmol) was added dropwise the benzofuran (1.0 g, 6 mmol). After 0.25 hr the cooling bath was removed and the reaction brought to room temperature. After 1 hr reaction was quenched with ice, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The concentrate was eluted through a column of silica gel with hexane. The eluent containing the product was concentrated to give the ester (420 mg, 29% yield) as a solid.

Ethylenediamine (0.1 mL) was added to the above ester (150 mg, 0.63 mmol) and heated to 120°C. After 0.75 hr the reaction was cooled, water (20 mL) was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate (3x30 mL). The extract was dried Na2SO4, filtered, and concentrated. The concentrate was eluted through a column of silica gel with CH2Cl2 (96%)/ethanol (3%)/10% NH3 (1%) and the eluant was concentrated to give the title compound 2-methyl-3- (l-imidazol)-5-chlorobenzofuran (43 mg, 29% yield as a solid. MP 187-190°C, MS 234 M+.

Example 6 5-Chloro-2-methyl-3- (4, 5-dihydro-l-H-imidazol-2-yl)-lH- indole

A mixture of 5-chloro-2-methylindole (30.1 g; 0.18 mole) and 1-acetyl-imidazolidine-2-one (24 g; 0.18 mole) was added to phosphorous oxychloride (178 ml) and heated to 50°C. After 5 hours, phosphorous oxychloride was evaporated. The residue was treated with ethanol (250 ml) cautiously and maintained at reflux for 3.5 hours. The mixture was concentrated under reduced pressure to half of the orignal volume to obtain a precipitate, which was collected on a filter. The crystalline residue was treated with water, washed with ethylacetate, treated with 2N sodium hydroxide to pH 11 and stirred overnight. The precipitate was filtered, washed with water and t-butylmethylether and dried to give product (10.9 g, 26%), m. p. 213°C.

1H-NMR (DMSO): d 2.5 (s, 3H, CH_31), 3.55 (s, 4H, 2xCH_2), 6.30 (b, 1H, imidazolin), 7.04 (d, 1H 8.00 (s, 1H, H-4), 11.57 (b, 1H, NH-indol); MS (Ei 70eV) m/Z 233M+.

The following examples were prepared in substantial accordance with Example 6 and the procedures and methods disclose herein. Ex. # MolStructure yield mp. MS 6a 2-Methyl-3- (4, 5- 50% 301-303 OC 199 M+ dihydro-lH- N imidazol-2-yl)- 1H-indole a F CH3 Hydrochloride N CIL CIH 6b, 3- (4, 5-dihydro-51. 302 > 290 °C 278 M+ NS lH-imidazol-2- N yl)-2, 5- /dimethyl-lH- H3C indole | | | \ » CH3HydrochlorideZon N CIH 6c 5-Methoxy-3-14. 60% 214 C 229 M+ (4, 5-dihydro-lH- N imidazol-2-yl)- 1H-indole ZON HsCi I C N 6d 3- (4, 5-Dihydro- 46% amorph 217 M+ 1H-imidazol-2- N N yl)-5-fluoro-2- methyl-lH-indole F Hydrochloride CH, N CIH 6e 2-Phenyl-3-(4, 5-63. 908 > 300 C 261 M+ dihydro-lH- N imidazol-2-yl)- 1H-indole Hydrochloride N CIH 6f (4, 5-23%> 350°C244 M+ dihydro-lH- N imidazol-2-yl)- 2-methyl-lH- N indole | || \ » CH3Hydrochloridezon CIL OH 6g 3- (4,5-Dihydro- 25% 350 °C 267 M+ 1H-imidazol-2- F N yl)-2-methyl-5- F trifluoromethyl- /1H-indole Hydrochloride N N CIH 6h 5-Bromo-3-(4, 5-808 > 350°C 277 M+ dihydro-lH- N imidazol-2-yl)- 2-methyl-lH- Bru indole Hydrochloride N CIH 6i 5-Chloro-3-(4, 5-9. 608 189 C 247(4, 5-9. 608 189 C 247 M+ N dihydro-lH- imidazol-2-yl)- 1,2-dimethyl-lH- ci indole N\ N CH3 6j/__ 5-Chloro-3-(4, 5-60. 202 > 300 °C 294 M+ dihydro-lH- N imidazol-2-yl)- Cl/2-phenyl-lH- indole Hydrochloride N CIH 6k 4-Chloro-3-(4, 5-66. 008 > 250 °C 233 M+ N dihydro-lH- imidazol-2-yl)- 2-methyl-lH- indole a FCH3 Hydrochloride L. iL/s N CIH 61 6-Chloro-3-(4, 5-608 > 300 °C 233 M+ dihydro-1H- \ N imidazol-2-yl)- 2-methyl-lH- indole Hydrochloride CI \ N CIH 6m 3- (4,5-Dihydro- 63% > 300 °C 325 M+ lH-imidazol-2- yl)-5-iodo-2- methyl-lH-indole Hydrochloride TfCH, N CIH 6n 5-Chloro-2-(4-40. 908 > 320 °C 330 M+ N chlorophenyl)-3- ( (4, 5-dihydro-lH- imidazol-2-yl)- 1H-indole CI Hydrochloride CH CIH 6o 5-Chloro-3-(4,5-7. 108 176 C 247 M+ N dihydro-lH- N imidazol-2-yl)- 2-ethyl-lH- ci indole NU 3 6p 5-Chloro-3-(4, 5-17. 408 > 300 °C 308 M+ N) dihydro-lH- imidazol-2-yl)- cri 2- (4- Cs CH3 methylphenyl)- N 1H-indole Hydrochloride CIH 6q 5-Chloro-3-(4, 5-64. 808 347 °C 326 dihydro-lH- [M+H] + imidazol-2-yl)- Ci 2- (4- o methoxyphenyl)- 1H-indole Hydrochloride CH 6r v 5-Chloro-3-(4, 5-15. 808 245 °C 309(4, 5-15. 808 245 °C 309 M+ dihydro-lH- N \ N imidazol-2-yl)- Cl/2-(2- methylphenyl)- 1H-indole N H3C 6s 5-Chloro-2-(2-68 257 C 330 M+ chlorophenyl)-3- tN (4, 5-dihydro-lH- imidazol-2-yl)- cl 1H-indole N Ci 6t 3-(4, 5-Dihydro-198 > 310 C 293 M+ 1H-imidazol-2- yl)-5-fluoro-2- \Ni \ methylphenyl)- /N 1H-indole N Hydrochloride Hui 6u 7-Dichloro-3-12%> 330 °C 330 M+ NH (4,5-dihydro-lH- imidazol-2-yl)- 2-phenyl-lH- indole Hydrochloride HCI 6v/i 5-Chloro-3-(4, 5-16. 50% > 310 °C 299 M+ dihydro-lH- imidazol-2-yl)- 2- (5- o methylfuran-2- yl)-lH-indole Hydrochloride 6w m 5-Chloro-3-(4, 5-62. 802 > 310 OC 301 M+ giH dihydro-lH- imidazol-2-yl)- 2- (2-thienyl)- R 1H-indole Hydrochloride CH 6x 2- (2- 2. 30% 201-202 °C 374 M+ Bromophenyl)-5- chloro-3- (4, 5- dihydro-lH- imidazol-2-yl)- 1H-indole Br 6y 5-Chloro-3- (4,5- 34. 30% 251 °C 314 M+ dihydro-lH- imidazol-2-yl)- cl 2- (3-methyl-2- thienyl)-lH- indole H

For reasons of purification the base was transformed in several cases to the HCl-salt in a known manner.

Example 7 2- (2,5-Dimethylindol-3-yl) methyl-4,5-dihydroimidazole hydrochloride (X=CH3, n=1) A mixture of 1.18 g (4.8 mmol) of ethyl (2,5-dimethylindol-3-yl) acetate and 7.5 mL of ethylenediamine was heated at 115°C overnight. The excess ethylenediamine was removed under reduced pressure and the residue was chromatographed with 1: 1 CH2Cl2- (EtOH + 10% ethanolic NH3). The pure fraction of N- (2-aminoethyl)- (2,5- dimethylindol-3-yl) acetamide obtained (1.2 g) was treated with 15 mL of hexamethyldisilazine (HMDS) at gentle reflux (130°C.) overnight. The mixture was concentrated to dryness, dissolved in EtOH and treated with etheric HC1 to acidic. Addition of ether in 3 portions induced light brown crystals. Yield: 39%; m. p. 245-7°C; 1H NMR (DMSO-d6) d 11.02 (br. s, 1H), 9.94 (br. s, 2H), 7.23 (s, 1H), 7.16 (d,

J=0.016 Hz, 1H), 6.85 (d, J=0.016 Hz, 1H), 3.90 (s, 2H), 3.79 (s, 4H), 2.36 (s, 6H).

The following examples 8-10 were performed substantially in accordance with Example 7.

Example 8 2- (5-Fluoro-2-methylindol-3-yl)methyl-4,5-dihydroimidazole hydrochloride (X=F; n=1) Yield: 21%, m. p. 274-5°C.

Example 9 2- (5-Chloro-2-methylindole-3-yl) methyl-4,5-dihydroimidazole hydrochloride (X=Cl; n=1) Yield: 4.8%, m. p. 279-281°C.

Example 10 2- (5-Bromo-2-methylindol-3-yl)methyl-4,5-dihydroimidazole hydrochloride (X=Br; n=1) Yield: 23%, m. p. 287-9°C.

The following examples 11-15 were performed substantially in accordance with Example 7 with the exception that 1 drop of TMSC1 was added to HMDS and heated at 120°C. in the imidazoline formation reaction.

Example 11 2- [2- (2,5-Dimethylindol-3-yl) ethyl]-4,5-dihydroimidazole hydrochloride (X=CH3, n=2) Yield: 46%, m. p. 292-4°C; 1H NMR (DMSO-d6) d 10.73 (br. s, 1H), 10.30 (br. s, 2H), 7.24 (s, 1H), 7.11 (d, J=0.016 Hz, 1H), 6.81 (d, J=0.016 Hz, 1H), 3.77 (s, 4H), 2.99 (t, J=0.015 Hz, 2H), 2.68 (t, J=0.015 Hz, 2H), 2.36 (s, 3H), 2.32 (s, 3H).

Example 12 2- [2- (5-Fluoro-2-methylindol-3-yl) ethyl]-4,5- dihydroimidazole hydrochloride (X=F, n=2) Yield: 48%; m. p. 323-5°C.

Example 13 2- [2- (5-Chloro-2-methylindol-3-yl) ethyl]-4,5- dihydroimidazole hydrochloride (X=C1, n=2) Yield: 69%; m. p. >330°C.

Example 14 <BR> <BR> <BR> <BR> 2- [2- (5-Bromo-2-methylindol-3-yl) ethyl]-4,5-dihydroimidazole hydrochloride (X=Br, n=2) Yield: 37%; m. p. >325°C.

Example 15 2- [2- (5-Trifluoromethyl-2-methylindol-3-yl) ethyl]-4,5- dihydroimidazole hydrochloride (X=CF3, n=2) Yield: m. p. >310°C.

Example 16 <BR> <BR> <BR> <BR> 2- (7-Bromo-3- [2-methoxyethoxy]-naphthalen-2-yl)-4,5-dihydro-<BR> <BR> <BR> <BR> <BR> 1H-imidazole Ethyl-7-bromo-3-hydroxy-2-naphthoate A solution of 81 g (0.3 mol) of 7-bromo-3-hydroxy-2- naphthoic acid in 600 ml dried EtOH and 60 ml conc. sulfuric acid was heated at reflux for 16 hours. The mixture was cooled to room temperature and treated with water (4000 ml) and neutralised with NaHCO3. The solid was separated by filtration and dried in a drying chamber afforded 75.3 g (85%) of the titled compound.

Ethyl-7-bromo-3- [2-methoxyethoxy]-2-naphthoate To a solution of 59 g (0.2 mol) of the above-mentioned compound in 400 ml dimethylformamide was added 27.6 g (0.2 mol) potassium carbonate and 34.8 g (0.25 mol) 2-methoxyethoxybromide. The mixture was heated for 6 hours at 60° C. under stirring. After cooling to room temperature, the mixture was added to water (2000 ml). The solid was separated and dried. Yield: 67.7 g (95%) {2-Aminoethyl}-7-bromo-3-[2-methoxyethoxy]-2- naphthoamide A mixture of 67.7 g (0.19 mol) of the above-mentioned compound and 114.2 g (0.19 mol) ethylenediamine was heated for 6 hours at 100° C. After cooling to room temperature, water (1500 ml) was added. The induced solid was separated, washed with water and dried. Yield: 59.9 g (85%). <BR> <BR> <P> 2- (7-Bromo-3- [2-methoxyethoxy]-naphthalen-2-yl)-4,5-<BR> dihydro-lH-imidazole To 48 g (0.13 mol) of the above-mentioned compound was added cautiously phosphorousoxy-trichloride. The mixture was heated for 4 hours at 80-90°C. After evaporation, the mixture was added to ice-water and was made basic with 5 N NaOH and extracted with dichloromethane. The extract was washed with water, dried and evaporated in vacuo and chromatographed with ethylacetate/isopropanole/methanole/ ammonia 10% in ethanole 45/45/5/5 on silica gel. Yield: 30 g (66%).

Example 17

2- (7- (4-Methyl-phenyl)-2- [2-methoxyethoxy]-naphthalen-2-yl)- 4,5-dihydro-1-H-imidazole To a solution of 1.4 g (4 mmol) of 2- (7-Bromo-3- [2- methoxyethoxy]-naphthalen-2-yl)-4,5-dihydro-lH-imidazole in 80 ml 1,4-dioxane was added under argon 0.46 g (0.4 mmol) of Pd (PPh3) 4 and 8 ml of 2M Na2CO3. After stirring at room temperature for 20 minutes 0.816 g 4-methylbenzeneboronic acid was added and the mixture was heated for 20 hours at 80°C. The mixture was cooled to room temperature and filtered to remove the solid. The solution was acidified with 2N HC1 and chromatographed on silica gel with dichloromethane/methanole 90/10 and gave 0.52 g (32%) of an amorphus product.

MS (Ei 70 eV) m/Z M+ 360.

1H-NMR (DMSO): d 2.43 (s, 3H, CH3), 3.39 (s, 3H, OCH3) 3.83 (bs, 2H, CH2), 4.05 (s, 4H, 2xCH2), 4.36 (bs, 2H, CH2), 7.56 (d, 2H, Ar-H), 7.71 (d, 2H, Ar-H), 7.73 (s, 1H, Ar-H), 7.96 (s, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 8.50 (s, 1H, Ar-H), 10.18 (bs, 2H, NH. HC1).

The following examples were prepared in substantial accordance with Examples 16,17, and the procedures and methods disclose herein. MolStructure Ex. # Name yield mp. MS (M+) H, C 17a 2- [3- 33% amorph 360 Methoxyethoxy)- N 7- (4- methylphenyl) nap htalen-2-yl]- 4, 5-dihydro-lH- imidazole CH3 Hydrochloride OH, 17b 2- [3- (2- 41% amorph 376 o ws Methoxyethoxy)- 7_ (4_ N methoxyphenyl) na phthalen-2-yl]- 4, 5-dihydro-lH- imidazole C ! H ! Hydrochloride o CH3 F 17c 2- [7- (4- 27% amorph 364 Fluorophenyl)-3- N (2- methoxyethoxy) na phthalen-2-yl]- 4,5-dihydro-lH- CIH imidazole Hydrochloride F F 17d 2- [3- (2- 46% amorph 414 Methoxyethoxy)- trifluoromethylp N henyl) naphthalen -2-yl]-4,5- dihydro-lH- imidazole C ! H 1Hydrochloride °c H3 17e 2- [3- (2- 30. 70% amorph 352 Methoxyethoxy)- thienyl) naphthal en-2-yl]-4,5- dihydro-lH- CIH imidazole CH3 Hydrochloride 17f 17f 2- [3- (2- 40% amorph 376 Methoxyethoxy)- won 7-(2- methoxyphenyl) na phthalen-2-yl]- 4, 5-dihydro-lH- CH imidazole p Hydrochloride CH3 17g 2- [3- (2- 26. 90% amorph 352 Methoxyethoxy)- N 7- (3- thienyl) naphthal en-2-yl]-4,5- dihydro-lH- HCI imidazole sCH, Hydrochloride 17h 2- [7- (3- 37% 240-364 Fluorophenyl)-3-242 C methoxyethoxy) na phthalen-2-yl]- 4,5-dihydro-lH- imidazole Hydrochloride 0 CH3 H, C 171 2- [3- (2- 42% 230-232 374 Ethoxyethoxy)-7-°C W \ Nq_ methylphenyl) nap HCI hthalen-2-yl]- Ha-Y 4, 5-dihydro-lH- imidazole o Hydrochloride CH,

Example 18 2- (4-Bromo-3- [2-methoxyethoxy]-naphthalen-2-yl)-4,5-dihydro-<BR> 1H-imidazole Ethyl-4-bromo-3-hydroxy-2-naphthoate A solution of 41.5 g (0.156 mol) 4-bromo-3-hydroxy- naphthoic acid in 300 ml ethanol and 15 ml conc. Sulfuric acid was heated as reflux for 24 hours. The mixture was cooled to room temperature. The formed crystals were filtered off, washed with ethanol and dried. Yield: 38.05 g (83%).<BR> <BR> <P> Ethyl-4-bromo-3- [2-methoxyethoxy]-2-naphthoate To a solution of 35.14 g (0.119 mol) of the above- mentioned compound in 200 ml dimethylformamide was added 16.46 g (0.119 mol) potassium carbonate and 24.9 g (0.179 g) 2-methoxyethoxybromide. The mixture was heated for 8 hours at 80°C. After cooling to room temperature, the mixture was given in water (300 ml) and extracted with ethylacetate.

The extract was washed with water, dried and evaporated in vacuo giving a brown oil. Yield: 36.27 g (86.2%).

{2-Aminoethyl}-4-bromo-3- [2-methoxyethoxy]-2- naphthoamide A mixture of 50.73 g, (0.144 mol) of the above- mentioned compound and 96 ml (0.144 mol) ethylenediamine was heated for 8 hours at 80°C. After cooling to room temperature, the mixture was evaporated in vacuo and without further purification used for the next step. Yield: 52.56 g (99.6%). <BR> <BR> <BR> <BR> <BR> <BR> <P>2- (4-Bromo-3- [2-methoxyethoxy]-naphthalen-2-yl)-4,5-dihydro-<BR> <BR> <BR> <BR> <BR> 1H-imidazole To 52.56 g (0.143 mol) of the above-mentioned compound was added cautiously 127 ml phosphorous-oxytrichloride. The mixture was heated for 8 hours at 80°C. After evaporation, the mixture was added to ice-water, extracted with dichloromethane, dried and evaporated in vacuo. Addition of isopropanol induced hygroscopic crystals. Yield: 23.1 g (41.9%) Example 19 <BR> <BR> <BR> 2- (4- (2, 4-dichloro-phenyl)-3- [2-methoxyethoxy]-naphthalen-2- yl)-4,5-dihydro-lH-imidazole To a solution of 25 g (0.0065 mol) of the above- mentioned compound in 100 ml 1,4-dioxan was added under argon 1.4 g (0.0012 mol) of Pd (PPh3) 4 and 15 ml 2M Na2CO3.

After addition of 2.47 g of 2,4-dichlorobenzeneboronic acid the mixture was heated to 18 hours at 80°C. After cooling to room temperature, the solid was filtered off, the solution was acidified with 2N HC1 and after evaporation

in vacuo chromatographed on silica gel with dichloromethane/ethanol 90/10 giving 860 mg (29.3%) of a crystalline product.

MS (Ei 70 eV) m/Z 414 M+, m. p. 153°C.

1H-NMR (DMSO) d 3.31 (s, 3H, Ome), 3.37 (bs, 2H, CH2), 3.72 (bs, 2H, CH2), 4.05 (s, 4H, 2xCH2), 7.25 (bs, 1H, Ar-H), 7.50 (bs, 1H, Ar-H), 7.66 (bs, 3H, Ar-H), 7.90 (s, 1H, Ar- H), 8.12 (bs, 1H, Ar-H), 8.54 (s, 1H, Ar-H).

The following examples were prepared in substantial accordance with Examples 18,19, and the procedures and methods disclose herein. MolStructure BL Name yield mp MS (M) 19a 2- [3- (2- 4. 16% 147 °C 361 Methoxyethoxy)-4- N (4- methylphenyl) naphth O CH alen-2-yl]-4,5- dihydro-lH- imidazole CH3 N- 19b 2- [4- (5-Chloro-2- 13. 60% 1800C 386 thienyl)-3- (2- N methoxyethoxy) napht halen-2-yl]-4,5- O CH dihydro-lH- imidazoline 4 S Hydrochloride CIH Cl 19c 2- [4- (2, 4- 21. 95% 153-155 414 Dichlorophenyl)-3-°C N (2- methoxyethoxy) napht halen-2-yl]-4,5- dihydro-lH- ci imidazole Hydrochloride Y CIH C ! 19d 2- [3- (2- 18. 50% 209-211 352 Methoxyethoxy)-4-°C MN (3- thienyl) naphthalen- 0"-"."0"CH3 2-yl]-4,5-dihydro- 1H-imidazole Hydrochloride CIH S 19e 2- [3- (2- 5. 80% 184-186 380 Methoxyethoxy)-4-°C N (4- chlorophenyl) naphth 0 CH3 alen-2-yl]-4,5- dihydro-lH- imidazole Hydrochlorid Cl Ci 19f 2- (3- (2- 18. 73% 81 °C 376 Methoxyethoxy)-4- wN (3- methoxyphenyl) napht 9k"9 halen-2-yl]-4,5- dihydro-lH- imidazole H i C : ! H Hydrochloride \ 19g 2- [4- (2- 49. 60% 126 °C 364 Fluorophenyl)-3- (2- N methoxyethoxy) napht halen-2-yl]-4,5- O CH dihydro-lH- irrlidazole Hydrochloride F 19h 2- [3- (2- 24. 29% 176-178 360 Methoxyethoxy)-4-°C N (4- methylphenyl) naphth OCH alen-2-yl]-4, alen-2-yl]-4, dihydro-lH- imidazole Hydrochloride oC CIH CH3

The pharmacological activity of the compounds of the present invention may be determined by methods well known in the art as well as by the assay disclosed herein.

ASSAY BTC6, F7 insulinoma cell screening models BTC6, F7 were cultured in DMEM 4,5g/l glucose with following supplements: * 15% (v/v) equine serum * 2.5% (v/v) FCS * 50 U/ml Penicillin/50 ug/ml Streptomycin A) adherent BTC6, F7 cells BTC6, F7 are seeded after trypsinization to 30.000 cells/well in a 96 well multiplate. The cells grow to 50 % confluence and at day 2 or 3 after seeding, the insulin secretion experiments were performed as follow: Discard the supernatante of the 96 well plates cells have been seeded, wash 3 times with EBSS (0 mM glucose)/0.1 <BR> <BR> <BR> % BSA and incubate in the EBSS solution 30 min at 5% CO2,<BR> <BR> <BR> <BR> 37°C.

The experiments with the compounds were run in the presence of 10 mM glucose and also in the absence of glucose in different concentrations. Incubation time is 1 hour. The supernatante is filtered and the insulin amounts measured by radioimmunoassay using an antibody directed against rat insulin. <BR> <BR> <BR> <BR> <BR> <P>B) dissociated BTC6, F7 cells<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> BTC6, F7 cells at 50 % confluence were dislodged using enzyme free cell dissociation solution. Dislodged cells were

dissociated by pressing the cell suspension through a needle (25 gauche). Cells were washed three times in EBSS (0 mM glucose)/0,1% BSA and insulin secretion experiments are performed as mentioned above.

Dose response titrations on the agonists described revealed ECso values of < 10 mM, preferably < lmmol.

The compounds of Formula I are preferably formulated prior to administration. Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of Formula I and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.

Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral

oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.

The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to about 500 mg, more usually about. 5 to about 200 mg, of the active ingredient. However, it will be understood that the therapeutic dosage administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.

The compounds can be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, topical, intravenous, intramuscular or intranasal routes.

For all indications, a typical daily dose will contain from about 0.05 mg/kg to about 20 mg/kg of the active compound of this invention. Preferred daily doses will be about 0.1 to about 10 mg/kg, ideally about 0.1 to about 5 mg/kg.

However, for topical administration a typical dosage is about 1 to about 500 mg compound per cm2 of an affected tissue. Preferably, the applied amount of compound will range from about 30 to about 300 mg/cm2, more preferably, from about 50 to about 200 mg/cm2, and, most preferably, from about 60 to about 100 mg/cm2.

The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.

Formulation 1 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) Active ingredient 25 starch, dried 425 magnesium stearate 10 Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

Formulation 2 Tablets each containing 10 mg of active ingredient are made up as follows: Active ingredient 10 mg Starch 160 mg Microcrystalline cellulose 100 mg Polyvinylpyrrolidone (as 10% solution in water) 13 mg Sodium carboxymethyl starch 14 mg Magnesium stearate 3 mg Total 300 mg The active ingredient, starch and cellulose are mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders and passed through a sieve. The granules so produced are dried and re-passed through a sieve. The sodium carboxymethyl starch and magnesium stearate are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 300 mg.

The principles, preferred embodiments and modes of operation of the present invention have been described in

the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed as limited to the particular forms disclosed, since they are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art without departing from the spirit of the invention.