GB2351081A

GB2351081A - Pharmaceutically active imidazoline compounds and analogues thereof

Info

Publication number: GB2351081A
Application number: GB9914222A
Authority: GB
Inventors: Michael Paal; Gerd Ruehter; Theo Schotten; Wolfgang Stenzel
Original assignee: Lilly Forschung GmbH
Current assignee: Lilly Forschung GmbH
Priority date: 1999-06-18
Filing date: 1999-06-18
Publication date: 2000-12-20
Also published as: GB9914222D0; AU5722800A; WO2000078726A1

Abstract

Certain novel imidazoline compounds and analogues thereof are useful for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present.

Description

2351081 PHARMACEUTICAL COMPOUNDS This invention relates to certain novel

imidazoline-type compounds and analogues thereof, to their use for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present, to pharmaceutical compositions comprising them, and to processes for their preparation.

It is generally accepted that the control of blood glucose levels for the treatment of patients diagnosed with type H diabetes will have a beneficial effect.

Established oral therapies for treating type H diabetes either improve insulin action or cause enhanced insulin secretion. 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, which are not sulphonylureas compounds and which have a fast onset of activity and a short duration of action, are under consideration for treatment of type II diabetes. One such compound is (-)-N-(trans4-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.

Compounds of the present invention 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 (1), and the use of said compounds in the treatment of diabetes, especially Type H diabetes, diabetic complications, and metabolic disorders or related diseases in particular where impaired glucose disposal is present.

The present invention provides compounds of the following Formula (I): 10 2 R, 3 N 9 -X H2 n R4 1 wherein 15 R', R 2, R3, and R9 are each independently hydrogen or C 1-8 alkyl; or R 1 and R3, together with the carbon atoms to which they are attached, combine to form a C3-7 carbocyclic ring and R 2 and R9 are each independently hydrogen or Cl -8 alkyl; or 20 RI and R 3, together optionally form a bond and R 2 and R9 are each independently hydrogen or C 1-8 alkyl; or 2 R' and R, together with the carbon atom to which they are attached combine to form a C3-7 spirocarbocyclic ring and R 3 and R9 are each independently hydrogen or C 1-8 alkyl; or R3 and R9, together with the carbon atom to which they are attached, combine to form a C3-7 spirocarbocyclic ring and R' and R2 are each independently hydrogen or C 1-8 alkyl; X is -0-, -S-, or -NR-5-; R5 is selected from the group consisting of hydrogen, Cl -8 alkyl, optionally substituted aryl, and an amino protecting group; n is 0, 1, or 2; R4 is a group of the formula:

R8 YR6 q R7 Y is selected from the group consisting of a bond, -O(CHA-, -(CH2)kO-9 - CO- -CHOH-,-CONR-,-NRCO-,-NR'CONR'5-. -(CH2)kW(CH2)R"' - 0 -C-C(CH2)1- 5 -(CH2)kC-C- -CH-CH(CH2)k -(CH2) k -CH - 0 9 NR S02, SO2W', and NR... S02; wherein -(CH2)kW(CH2)b - is optionally substituted with C alkyl or hydroxy; k is independently 0, 1, 2, 3, or 4; b is independently 0, 1, 2, 3, or 4; provided that the sum of k and b together is not more than 4; - 4 W is selected from the group consisting of a bond, 0, S S02, SO, S02NW', W' S02, NR", CONW, WCO, -C=C-, -C=C-, C=Q and NR.... CONR....; R, R', W' and R... are each independently selected from the group consisting of hydrogen, C] -4 alkyl, and benzyl; R.... is selected from the group consisting of of hydrogen, C 1-8 alkyl, benzyl, and an an-lino protecting group; R8 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C3-7 cycloalkyl, C3-7 CYCIO C 1-8 alkoxy, hydroxy, halo, carbo Cl-8 alkoxy, halo Cl-6 alkyl, halo-Cl-8 alkoxy, optionally substituted phenyl Cl-8 alkyl; R7 is selected from the group consisting of hydrogen, Cl-8 alkyl, Cl-8 alkoxy, C3-7 cycloalkyl, C3-7 cYclO C1-8 alkoxy, hydroxy, halo, carbo Cl- 8 alkoxy, halo Cl-6 alkyl, halo-Cl-8 alkoxy, optionally substituted phenyl 1.5 C 1-8 alkyl, optionally substituted phenyloxy, optionally substituted phenyl C 1-8 alkoxy, optionally substituted naphthyl, optionally substituted heteroaryl, (tetrahydropyran-2-yl)methoxy, Cl -8 alkyPS(O),,,, optionally substituted aryl-Cl-8 alkyl-S(O),,,,, CH3(CH2)p-ZL(CH2)q -Z2-, and Z3(CH2)q'-Z1; where 11 ZI and Z2 are each independently a bond, -0-, -S-, 0 S02, sulphoximino, or NR 13 Z3 is hydroxy, protected hydroxy, NW4R15, protected amino, SH, or protected SH; R 6 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, and optionally substituted 4,5dihydroisoxazolinyl; R 13, R 14 and R15 are each independently selected from the group consisting of hydrogen, C 1 -g alkyl, optionally substituted aryl C 1 -g alkyl, and optionally substituted phenyl; or R 14 and R15 together with the nitrogen atom to which they are attached may combine to form a heterocyclic ring comprising the nitrogen and C2-6 alkyl, wherein C2-6alkyl is optionally substituted with one or two C 1-8 alkyl groups or one carbon atom of the heterocyclic ring is optionally replaced by oxygen or sulfur; p is 0, 1, 2, 3, or 4; q and q' are each independently selected from the group consisting of 1, 2, 3, 4, and 5; m and m' are each independently selected from the group consisting of 0, 1 and 2; and pharmaceutically acceptable salts and esters thereof.

One embodiment of the present application is the use of a compound of the 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 1, or a pharmaceutically acceptable salt thereof In the above formulae, a "C 1 -8 alkyl" group can be any alkyl group, branched or unbranched, containing up to eight carbon atoms, likewise, C I -n, alkyl is a branched or unbranched alkyl containing up to n' carbon atoms whereing n' is an integer. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl. and hexyl. Preferred values Of C 1-8 alkyl. are C 1-6 alkyl, and most preferably methyl and ethyl.

The term "C 1-8 alkylthio" has the meaning known to the artisan. That is that one of the carbon atoms is replaced with a sulfur atom.

A "C3-7 cycloalkyF' group is a saturated carbon ring having from 3 to 7 carbon atoms. Such groups include, but are not limited to, as cyclopropyl, cyclobutyl, 5 cycloheptyl, cyclohexyl or cyclopentyl.

A "C3-7 cycloalkyl-C 1-8 alkyl" group is one such cycloalkyl group attached through a C 1-8 alkyl group to the cycloalkyl group. It is especially preferred that the alkyl group is C1-6 alkyl.

A "C 1-8 alkoxy" group is one of the above-mentioned Cl -8 alkyl groups attached through oxygen to the base molecule, 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 cycloalkyl as, for example, cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.

A "C3-7 cycloalkylCI-8 alkoxy" group is a C3-7 cycoalkyl-CP8 alkyl as mentioned above linked through an oxygen atom to the base molecule as, for example, cyclohexylmethoxy.

0 11 A "carbo(C1-8)alkoxy" group is a -C-OC,-8alkyl group, for example a carbomethoxy or carboethoxy group.

An "optionally substituted aryl" group is a mononuclear or polynuclear aromatic hydrocarbon group, for example phenyl or naphthyl, which is optionally substituted with from one to three substituents, each independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, anfino, and phenyl which is optionally substituted by from one to three substituents independently selected from the group consisting Of Cl-8 alkyl, C2-8 alkenyl, C1-8 alkoxy, alkoxyhydroxymethyl, alkoxy hydroxyformyl, C 1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and anfino., carboxy, hydroxy, An "optionally substituted 4,5-dihydroisoxazolinyl" means a dihydroisoxazolinyl group which is optionally substituted with from one to three substituents selected from the group consisting Of C 1-8 alkyl, C2-8 alkenyl, C 1-8 alkoxy, alkoxyhydroxymethyl, alkoxy hydroxyformyI, C 1-8 alkoxy, carboxy, hydroxy, 5 cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.

An "optionally substituted phenyF' group is a phenyl which is optionally substituted with from one to three substituents independently selected from the group consisting Of C 1-8 alkyl, Cl -g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, andno, and phenyl which is optionally substituted by from one to three substituents independently selected from the group consisting of C 1-8 alkyl, C2-8 alkenyl, Cl -8 alkoxy, alkoxyhydroxymethyl, alkoxy hydroxyforTnyl, C 1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4- methylenedioxy, and amino.

An "optionally substituted naphthyl" group is a naphthyl which is optionally substituted with from one to three substituents independently selected from, the group consisting Of C 1-8 alkyl, Cl -8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three independently selected from the group consisting of C 1-8 alkyl, Cl -g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.

An "optionally substituted COaryl" group is an optionally substituted aryl 0 which is bound to the base molecule through a group of the formula:,"-. The optionally substituted aryl group is defined herein above.

A "optionally substituted arYI-CI-8 alkyPS(O)m- " group is an optionally substituted aryl which is bound to the base molecule through an alkylS(O),,,,, group, wherein the S- bonds to the base molecule. The optionally substituted aryl group is as defined herein above.

"Heteroaryl" means a four to a ten membered aromatic mononuclear, binuclear or trinuclear ring system in which from one to three atoms of the ring system are each 8 - independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, naphthofuran, imidazo [ 1,2-al pyridyl, imidazo [ 1,2-al pyrimidyl, imidazo [ 1,2-bl pyrazinyl, imidazo [ 1,2-bl pyrazinyl, imidazo [2, 1 -bl thiazolinyl, imidazo [ 1,2-bl benzothiazolinyl, in-lidazo [ 1,2- bl benzoxazolinyl, M- imidazo [1,2-al benzimidazolinyl, indolyl, imidazolyl, furanyl, thienyl, isoquinolinyl, benzofuranyl, benzothienyl, pyridyl, quinolinyl, oxazolyl, pyrrolyl, isoxazolyl, pyrimidyl, thiazolyl, and benzimidazolyl. An "optionally substituted heteroaryl" group is a heteroaryl group which is optionally substituted with from one to three substituents each independently selected from the group consisting 10 of C 1-8 alkyl, C 1-8 alkoxy, carboxy, alkoxy carbonyl, formyl, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting Of Cl -8 alkyl, C 1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.

"Optionally substituted heterocyclyP' means a four to 10 membered mononuclear or binuclear saturated or partially unsaturated ring system in which from one to three atoms of the ring system are each independently selected from the group consisting of nitrogen, oxygen, and sulfur, and which ring system is optionally substituted with from one to three substituents each independently selected from the 20 group consisting Of C 1-8 alkyl, C 1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, an-lino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting Of C 1-8 alkyl, C 1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, morpholinyl, hornopiperidinyl, tetrahydroquinolinyl, dioxanyl, and tetrahydropyranyl.

An "aryl-C 1-8 alkyl" group can be, for example, optionally substituted phenyl- Cl -8 alkyl or optionally substituted naphthyl-Cl-8 alkyl, such optionally substituted phenyl or naphthyl groups being optionally substituted with one or more, preferably one to three, substituents selected from, Cl -8 alkyl, C 1-8 alkOxY, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino. A preferred aryl-Cl- 8 alkyl group is optionally substituted phenyl-(CH2)x- where x is 1 or 2, most preferably optionally substituted benzyl. Thus, the alkyl group serves as the link between the phenyl or naphtyl and the base molecule.

An "optionally substituted phenyloxy" is a group wherein the phenyl group is attached to the base molecule through an oxygen, and such phenyl group is optionally substituted with one or more, preferably one to three, substituents selected from, C 1-8 alkyl, C 1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino.

An "optionally substituted pheny1C1-8 alkoxy" is a group wherein the phenyl group is attached to the base molecule through an alkoxy group, and such phenyl group is optionally substituted with one or more, preferably one to three, substituents selected from, C 1-8 alkyl, C 1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino.

Of course, it will be understood that "optionally substituted" means that there may be zero non-hydrogen substituents.

An "aryl-C 1-8 alkoxy" group can be, for example, optionally substituted phenyl-C 1 -8 alkoxy or optionally substituted naphthyl-C 1 -8 alkoxy, such optionally substituted groups being optionally substituted with one or more, preferably one to three, substituents selected from, for example, C 1-8 alkyl, C 1-8 alkOXY, carboxY, hydroxy, cyano, halo, trifluorornethyl, SCH3, nitro and amino. A preferred aryl-Cl-8 alkyl group is optionally substituted phenyl-(CH2)x- where x- is 1 or 2. Thus, the aryl is linked to the base molecule through the alkoxy group.

A halo group is preferably chloro, bromo or fluoro.

A "halo C 1-8 alkyl" or "halo C 1-8 alkoxy" or "halo C 1-8 alkylthio" is a substituent in which one or more, preferably one to three, hydrogen atoms on the C 1-8 alkyl moiety is replaced by a halo atom, preferably chloro, bromo or fluoro.

Trifluoromethyl is one preferred haloalkyl group.

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 I and q is 1-3, especially methoxyethoxy, ethoxyethoxy, ethoxypropoxy, or methoxypropoxy.

The term "spirocarbocyclic" means a ring which is fused to the base molecule through one shared tetravalent carbon atom to form two rings which are annelated by a single carbon atom.

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 or heteroaryl.

As used herein, the term "aryl coupling" shall mean any appropriate method for coupling two aromatic or heteroaromatic rings known to the artisan. Such methods may include, but are not limited to Ullmann, Stille coupling or Suzuki coupling methods. The Suzuki coupling is an especially preferred coupling method.

The Suzuki method using aryl boronic acid derivatives, e.g. Ar-B(OH)2 and Pd catalyst is particularly preferred for use in the synthesis methods described herein.

The artisan will appreciate that there are a variety of available Pd catalysts which are acceptable for the Suzuki coupling. One such Pd catalyst which is preferred for the methods described herein is Pd(PPh3)4.

The artisan will also appreciate that there are a variety of available metal catalysts other than Pd which are acceptable for aryl coupling reactions.

The term "base molecule" means the ring system to which the named substituent is bound.

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.

As used herein the term "amino protecting group" means 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, 198 1, and by J. W. Barton, Protective GrolAps in Organic Chen-dstry, 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-dimethoxybenzyI, o-nitrobenzyI, and triphenyImethyl; those of the formula 5 -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-nitrobenzyI, o-nitrobenzyI, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyI, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and j2-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, like benzyloxycarbonyl or tbutyloxycarbonyl, or silyl or acetyl phenyloxycarbonyl.

The term "protected amino" means that the amino group is substituted with an amino protecting group, as defined herein.

As used herein the term "protected hydroxy" means that the hydroxyl group is substituted with any of the conventional hydroxyl protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 2, John Wiley and Sons, New York, 198 1, and by J. W. Barton, Protective Groups in Organic Chemisliy, J. F. W. McOrnie, ed., Plenum Press, New York, 1973. Examples of such groups include but are not intended to be limited to acetals, ethers such as silyl ethers and the like; esters such as formate, benzoylformate, acetate, phenoxyacetate and the like; carbonates such as methyl carbonate, ethyl carbonate, isobutylcarbonate, benzyl, nitrobenzyI, and the like; and others such as nitrate, borate, phenylcarbamate, tetrahydropyrinyl (THP), trityloxypyrinyl and the like. The artisan will recognise that the art includes other acceptable protecting groups as provided by the cited references.

As used herein the term "protected SIT' means that the thiol group is substituted with any of the conventional thiol protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 6, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective GroLips in Organic Chernistly, J. F. W. McOmie, ed., Plenum Press, New York, 1973. Examples of such groups include but are not intended to be limited to thioethers like benzylthioether, 4- methylbenzyIthioether, p-nitrobenzyIthioether, diphenylmethylthioether, substituted methyl derivatives such as methoxymethyl (MOM), isobutoxymethyl, 2tetrahydropyranyl, thioesters like, acetyl, benzoyl, thiocarbonates like t- butoxycarbonyl, and the like.

The compounds of the present invention can be useful for modulating insulin secretion and as research tools. Certain compounds and conditions within the scope of this invention are preferred. The following conditions, invention embodiments, and compound characteristics listed in tabular form may be independently combined to produce a variety of preferred compounds and process conditions. The following list of embodiments of this invention is not intended to limit the scope of this invention in any way. Some prefered characteristics of compounds of Formula I are:

(i) R' and R 2 are hydrogen and R 3 and R9 are each hydrogen or methyl; is (ii) R', R 2, R 3 and R9 are each hydrogen; (iii) X is NH; Y is selected from the group consisting of -O(CH2)k-, -(CHAO-v -CO-s (vi) -CHOH-, -CONR-, -NRCO-, -NR'CONR"-, -(CH2)kW(CH2)R"" - -C-C(CH2)k - (CH2) kC-C p 5 1 CH--CH(CH 2)- -(CH 2) CCH - k k W' ", S02. SO2W', and NR'S02; -(CH2)kW(CH2)R"" (vii) Y is -c-C(CH2)k"- (viii) Y is selected from the group consisting of -C=C-, -(CH2)kC-C- ( -CH2C=C(CH2)-, and (CH2)kC==CCH2 (ix) Y is a bond; R7 (x) R6 is heteroaryl wherein heteroaryl is 0 R 17 is substituted phenyl, halo, naphthyl, or a group of R the formula. S where R18 is halo, hydrogen, -Cl-3alkoxy; R (xi) R(' is heteroaryl wherein heteroaryl is S where R18 is halo, hydrogen, -Cl-3alkoxy; (xii) n is 1; (xiii) R 6 is substituted phenyl where the phenyl ring is substituted with up to three substituents selected from the group consisting of halo, naphthyl, halo Cl-6 alkyl, Cl-6 alkoxy, N02, and Cl-6 alkyl; (xiv) R 7 is selected from the group consisting of halo, nitro, cyano, C2- 6 alkyl, halo Cl-6 alkyl, halo Cl-6 alkoxy, or halo Cl-6 alkylthio; (xv) n is 0; (xvi) X is 0 or S; (xvii) R7 is selected from the group consisting of halo, C2-6 alkyl, and halo C 1-6 alkyl; (xviii) R6 is 3chlorobenzyI, 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, 2-(trifluoromethyl)phenyl, and 3 fluorophenyl; (xix) Y is not a bond; (xx) R 6 is optionally substituted naphthyl; (xxi) R' and R 3 together form a bond; (xxii) Preferred compounds of this invention include any one of the following compounds:

14 N CM CH3 N l 1 CH NU CH N/') N CH NJ ":1 0 N UN N 0:

H31 N N N14. %..

N OH CH N 9 N CN4, N N CHCH N 7 H3c---c::\ N CH CN 12 N N 13 N CH 0 14 CM CN N N N 16 N - 16 OH N N 17 N CH 18 HC-0 N PH3 0 19 -N N CH N c 1 / \ \1 / CH cl cl-d 21 N 22 N NyN 23 7 NJ N 24 / 0::0NJ 17 N GDN -7N CN5 0 N C5 26 0_\ CH CH3 N 27 OH CH N 28 H -N HNj N 29 CN 0 1H HC CN N H3C-0 1H CN S \ 31 CH3 1H CN 32 N 1H 18 - CN 33 N 1H 7 ---Q 1 -c 11 34 N Scl 1H F F F CN - NI -G- F 1H F F CN 36 0 N- 1H CH, CN 37 N NH 2 1H N 38 CN -0 NO2 CN 39 N4 1H _ F F F CN F N cl 1H 1 1 19 CN 41 N 1H F CN 42 N cl 55ll 1 \, \1 43 CN 44 N 1H cl N Br 0 46 "N N CH3 47 CN N CH 48 CN N CN 49 CH3 CN N s 51 CN N N -N 52 CH 0 53 CH, CN N% F F F F F 54 F N CN NJ N T.

0 56 )::: w 0 - p (N cl 1 " 57 0 l, 1 111 \1 58 H,C Zll -U - 1 \ 59 %0 0 N N N Z: PM, F-\ N,, N 61 N N 62 N.,, N 63 6.&Cl r-\ N., N 64 cl - 22 F_\ N,,, N CC 0 H F-\ N,, N 66 "' 1 0 'CH N N 67 N N 68 F-\ N 'I N 69 N 15: N Yb 0 r-\ N N 71 F 72 23 F F F 73 NN N 0 c 74 N N-F CAH CIH 0 Cl.

N 0 N 76 0 CH C CH, CN 0 77 N 0H CH.

N N\\- \\-/", 0 N 78 H N N 79 N CN CNI, to 81 N O-CH CH 82 83 1 N,; N cl 84 N N 86 N,,, N 1 cl "I cl 87 F F f F F F N N F 88 89 N N 01 CH3 NN 91 N N 92 S N N 93 1 \,--ci :-" 1 S 0 94 H3C, 0 CH F F 0 OH N 96 N W-T S \,N: N 26 c CN N 97 N 98 1 CN yCH3 99 N \1 Br F FF:

F 101 F N- Cl 5'' cl 102 0 NN 103 N- CN 104 N N CH3 CN N_ -S NJ cl S 3 106 107 F F F 108 7N F F 109 0, CH 0 0 -"N ,0 l H,C N CH3 N N 112 H 3 C NR 28 CH 1 S, 113 0 F F N-) F N 114 F NH 0 NN S ll 0 116 O"N 0 C3 S 117 0 O"N 0 F 118 0 Zt, 0 N CN N, 0 0 119 c; \--/ N 1 -,o C-11 N 0 0 CH H, H3 3C ' 3 "0 N1 121 CH 3 -U - 0 N- CA N- 3 N 122 CM OCH, 123 0H 0, CH.

124 CH 01 CH.

ICH, CH, 126 0 127 CH 128 z, "0_ N - 129 cl ci-'6 N CIH 0 'CH, 01 N-O CN \x 131 C1H CN 132 N CH 0:

CN 133 N -N 134 0 H, 0 CH, 00 136 0 31 N 137 138 CN 139 el- Br :1111 1 \11 \ Zll 0 141 0 N- 0 11.

lo- 142 N 143 144 1 cl ' 1 32 N N 0 CH, cN k - N 146 0 147 c, Ci m 1 ' N 10 -k" %No 148 cl a F F F 149 N) CF F N 3 N GH 0, CH3 HU 0 N 1 151 0 CM 01 CH.

cl N-) 152 0 CH 33 1 6k 153 O'cFS N 154 0 CH O'CH., S N 0 CH O-ICH H3CC, N 156 0 aH 0 'CH, 0 'CH, 157 0 NN 158 \l A p jjN 159 -P 0 F 0 rAH N 34 CN \1 CH3 161 N CM CN 162 N CH cl, N N 163 1 0, cl cc, N H N, 164 C %H cl, 0 0 \-, HC CN 166 N H,C (AH 167 cl, CN 168 N N 169 0 cl cl S 0 N- CH N 171 CNN CH C NW, F F 172 N F CH CN - S cl \1 1 173 N - CAH cl N4 c _ 174 NJ cl CH CH3 N N N N-:"rN 176 N C 36 CN Nz:z 177 N 0 CH3 CN 178 N N5_ N 179CN cl S 0 I- CH N cl 1 1 I Cl 181 1 -- \\ \1 - CH 182 CH F F F 183 0 N- CH Cl 0 N 3 N 184 CM 0, 37 - CH, Q 185 CH O'CH PH, 0 186 N N CH F FN 187 CH 0, 0.6 N N 188 CH 0, CH,, Br 5;>, 1 \, / \1 189 0 B "rN 0 CIH 191 cl S 1 1 N S CH N 192 F F CH 0.1 CH3 38 N- N 193 0 F F F CH 0, 194 0 B "rN, N 0 CAH 0 CH3 F N 196 CH -1 01 Ch 3 N 197 CH 01 CF 0 CH3 198 ?-,1 0 0 N CN 199 \\ __N N 0 Br T 200 H,C 39 C H 201 1 0 CH 0 202 N- CN Ccl H N 203 CH CH, 1 HIC CH.

204 1 0 N- CH F F F F F F 205 0 N- CH N cl 1 206,7 \1 i - \ - 1 em CN N 207 cl N N 208 CH, S-CA, 209 ewl N CNN 210 cl N N--:

CN > 211 CH N 212 F' CH O CH, N- Ll N 213 0 HC, CH CH N 214 CH 0, CH3 N- N 215;1-1 1 1, 0 H 3C c CHCH N N 216 0,51)t CH 0, 1 217 cl 1 1 0 N cl CH O-CH 3 lp-- CF, 218 aH N F 219 CH N 220 CN -0 221 0 Ch N 9,( ' 222 0 223 1 F -N N H 224 N F F 42 0 225 0 CF H 0 226 0 CH, 227 0 N v- P-\ CH N 228 o'-,-A 'CH3 S CH 229 CH H,c 10 N 230 OH N 231 0 "'oCH, S CH cl <:, 1 1 0 232 - (M 43 N 233 0H N 234 CN N:

:Is 235 N? \ c CN N- 236 N5 237 N 238 0,,,,0, CH, F CN4 239 N > Ci-6 N N 240 - 44 N N 0 241 al Br N N 0C 0;N 242 Cl Cl Br 1 \ \, 243 0 o N H 3C N C11-1 N 244 o'-,-'o' CH, CH Cl N- -N 245 0 ^,-'o' CH3 CH Cl,":_" Cl N-, ", N 0 246 0 ' CH OH N 247 0,^,-'o' CH, CH Br Cl 248 1 0 NN 1 F 249 \l A CH N- H3C N 250 Ch li,c CN N 251 Br CN N _,N 252 Z N P4 I N 253 N 0 CH3 CN, N N 254 0 C'H3 CN N \,N 255 A CH N N CN 256 A 46 N \ CN 257 CH CN N N 258 -cl 1 1\ A cl CN4 N N Nf 259 CN N N - 260 61s\ i 261 1 0 c -- 262.% CH N 0;'N 263 CH N 264 ' N CC.

H cl C"-,0 N) 265 N N 1 C 266 CIH -N N 267 0 F F N IN 0 0 268 :CH N 0 269 0 CH O-CH.

S 270 "N CH 271 aH 272 48 N 273 Yy',' N 1H GN 0 N 274 OCH 275 CH 3 CH S N276 CH3 CH F N- 3 277 N CH3 CH cl 278 CH, CH so N 279 CH3 CH N 280 0,-,-"o' CH, CM 49 H3C, 281 CH 3 CH -N N 1 NI 0 282 F -0 N N N, 0 283 CH3 284 NJ CH 0 N 285 286 Nj CH N- N 287 CH CH,O, OCki H 288 i_ 0, o,C- OCH CH,0 HN- 289 N O'"'-'O'CH Hcl cl cl HN-- 290 -- N 0" -"O-CH HCA A 291 HN F-\ N NH 1H 292 293 FC.C N 0,o Q - - - o\ - % N 294 H N-N 295 H 0 F S------- CH, 0 j, 296 6N N ' -N H H r H 51 H,C H HN 297 0 -CH H,C laN s 298 0 0, CH, 0 299 0 N 5--- NH 1 CH, --J 0 300 1 0' NH OCH, 301 H3COúr Np' NH 302 0 N N a0CH.3 H 303 so 304 CHo"ao N NH - 52 0 0 -CH 305 11-, "' N y NH CH \-i F-\ H 306 CH CH 0 3 307 N':kNH CH F_\ N N H 308 & CH o.,,,,,,,,a0CH3 309 N NH \-i cl 0 310 1 1 Cl^H N cl 0 311 1 1 Cl^H N HO N 312 dN HO N cl 313 N CH3 cl CH HO N Cl ' \ m 3 - m 1 314 - 0 F r, cl +k OH F CN 0 N 315 H CH 3169,-pyo F HN,,,,, -. UJ N- N H 317 a0CH, 318 &0 :1Y H CH301.,ao",.

319 UN 320H 54 -N N H 321 CH HC N - IL,', cl N 322 H 1 % 1H H3C 3C 1 51l NH 323 CM 11- N 324 0 H N N H 325 H 0 F -P- OH F 0 CN N 326 N 0 H H F OH F H3C \ N No 327 N H 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 5 basic organic amines such as aliphatic and aromatic arnines, 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, parabromophenylsulfonic, 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, 0-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-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 racernates and can be conveniently used as such. Therefore, the racemates, individual enantiomers; (including, but in no way limited to atropisomers), 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 below.

A general scheme for the synthesis of 3-, 4-, and 5-arylic substituted 2(2methoxyethoxy)phenyl-4,5-dihydro-IH-imidazoles is generally illustrated by Scheme 1.

The artisan will appreciate that the methods indicated in Scheme I are standard procedures which are well known in the art. The artisan can select appropriate intermediates and process conditions using the description set forth in Scheme I. The artisan will recognize that the process set forth in Scheme I is more generally applicable to allow preparation of compounds of this invention, provided that the corresponding starting materials are utilized.

Scheme I COOH CO0C2H5 BA OH E0H1HS04 BrOCOH CO0C2H5 BrCH2CH20Me CO0C2H5 0 CCOH K2CO3IDMF ao"", "CH Br r 3 CO0C2H5 H2NCH2CH2NH2 CONHCH2CH2NH2 0 eO"-'o"CH3 'CH3 Br Br HN CONHCH2CH2NH2 N 0 CH3 POCI, 0.10, CH3 Br r Cl n, HN,-- arylic boronic acid N Sunkicoupling Ar 0"',011 CH3 General scheme for the synthesis of 4-, 5- or 7-arylic substituted 2-(2phenyl-4,5-dihydro-1H-imidazole) benzofuranes Scheme II CHO 2 NaOMe \ "70 OH Br 0 0 Br M Br CN EDAOTs Br K_. 0 1\ // 0 r "N NH arylic boronic acid 0 1\ // Suzukicoupling Ar N- NH - 59 Compounds of Formula I wherein X is NH; wherein X is as defined above and the other Formula I substituents have the definitions setforth above, can be prepared according to scheme III.

Scheme III silylating agent no ND R4-(CH2)nCOOJ R4(CH2)n---(/.

ethylene diamine N wherein R4 and n are as defined herein for Formula 1, and J is CI-8alkyl, aryl, or aryl 1-0 C1-8alkyl.

The transformation is further described by Scheme EEla.

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 dimethylaminornethyl 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-Cl 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 900C. 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, an-tide and is successful in some cases, when conventional methods failed (Chem. Pharm. Bull. 1980, 28, 1394-1402).

Scheme Ma 0 R4 k N -- NH 2 H A) TMS-X/triethylami GeB) Exc. HIADS (neat) C) TM -X / diethylaminomethyi to 100 OC polystyrene N R4 --/ N X = Cl or 1 H The process described in Scheme ffia 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 The artisan will recognise that there are other processes which could be used to prepare desired compounds. See for example, LMed.Chern. 1990, 33, 2501-8 (uses (CH2NH2)2); LChem.Soc. 1947,497(uses (CH2NH2)2 and TsOI-F200-2200c); LArn.Chern.Soc. 1953, 75, 2986-8497(uses (CH2NH2)2 and W0-2200Q LMed.Chern. 1987, 30, 1482-9 (uses AI(CH3b and (CH2NH2)2); Tetrahedron Lett.

1990, 31, 1771-74(uses (CH2NH2)2); J.Org.Chem. 1987, 52, 1017-21 (La(OS02CF3)3 and (CH2NH2)2); Zh.Prikl.Khim. 1970,43,1641 (CA:73:77138r) (uses (CH2NH2)2 and strongly acidic cation exchanger); Arch.Pharm. 1986, 319, 830-34 (uses (CH2NH2)2); J.Heterocycl.Chem. 1990, 27, 803 -5 (uses (CH2NH2)2); Tetrahedron Lett. 1995, 51, 6315-36 (uses two step process with 1) H2S and MI then 2)(CH2NH2)2).

The skilled artisan will also appreciate that a hydroxy substituted group can be used to prepare desired compounds claimed by this invention. Such process is illustrated by Scheme IV below.

Scheme IV COOH 0i ROH, H2SO4 7 --------- N.

R8' 7 Heat R8' B CONHCH2CH2NH2 ethylenediarnine 7 heat R ' POC13, heat N N N RT H ON N H aryl coupling 7 Y-1; 6' R8' R8' R Y is a bond 7 8 wherein R, R7'and R8' are R6, R and R, respectively, protected derivatives thereof, or precursor moieties thereto. 15 The artisan appreciates that, in some instances, desired isomeric forms may be obtained using separation methods which are generally known.

Compounds of Formula (1) have primary action during hyperglycemia in that they improve glucose tolerance without producing marked reduction in basal plasma glucose levels.

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

Diabetes (1967),and as described in more detail in hereinbelow, and in an Intravenous Glucose Tolerance Test as described hereinbelow.

The invention further includes a method of treating diabetes in which an effective amount of a compound of formula (1) 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 in any way limited or to be 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,Ndimethylformamide, palladium on charcoal, tetrahydrofuran, ethyl acetate, thin layer chromatography and elemental analysis are abbreviated M.Pt. or m.p., NMR, MS, HPLC, GC, DMF, Pd/C, TBF, 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 not optimised.

Ethyl-5-bromo-2-hydroxy-benzoate A solution of 50 g (230 mmol) 5-bromosalicylic acid in 300 ml dried EtOH and 20 n-d cone. H2S04 was heated at reflux for 8 h. The mixture was cooled to room temperature and treated with water and neutralised with Na11C03. The aqueous phase was extracted with ethylacetate. The extract was dried and concentrated to give 46 g (8 1 %) of a solid product. (m.p. 5 1 'C) Ethyl-5-bromo-2-(2-methoxyethoxy)-benzoate To a solution of 20 g (81,6 mmol) of the above-mentioned compound in 200 M1 dimethylforman-fide was added 11,28 g (81,6 mmol) potassium carbonate and 13,9 g (100 mmol) (2-bromoethyl)methylether. The n-iixture was heated at 80 'C for 48 hours. After cooling to room temperature the mixture was added to water and extracted with ethylacetate. The organic phase was dried and concentrated to give 22,8 g (89%) of a syrup.

Aminoethyl-5-bromo-2-(2-methoxyethoxy)-benzoamide A mixture of 22,6 g (74,5 mmol) of the above-mentioned compound and 44 g (745 mmol) ethylenediamine was heated for 8 h at 1OWC. After cooling to room temperature water (500 ml) was added. The induced solid was separated, washed with water and dried to give 19 g (80%) of an amorphous product.

5-Bromo-2-(2-methoxyethoxy)-phenyl-4,5-dihydro-1H-Iniidazole To 18,8 g (59,2 mmol) of the above-mentioned compound was added cautiously phosphorousoxy-trichloride. The mixture was heated for 8 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 dichloromethane/ethanole 70130 on silicagel to give after concentration 10 g (56 %) of a solid product. (mp 182 OC dec.) 5-(3-Chloro-4-fluoro-phenyl)-2-(2-methoxyethoxy)-phenyl-4,5-dihydro1Himidazole To a solution of 0,4 g (I mmol) of the above-mentioned compound in 20 M1 1,4dioxan was added under argon 0, 115 g (0, 1 mmol) Pd(PPh3)4 and 2 mI 2M Na2C03. 10 After addition of 0,244 g (1,5mmol) 5chloro-2-thiophenboronic 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 HO and after evaporation in vacuo chromatographed on silica gel with dichloromethanelethanol 90/10 giving 0, 16 g (36%) of a crystalline product. (mp 15 204-206 'C) The following examples were prepared in substantial accordance with the abovementioned examples and the procedures and methods disclose herein.

The Examples set forth herein by Table 1 were prepared using the general synthesis methods illustrated by Scheme I, herein. The corresponding starting materials were used to prepare the compounds set forth below M+ mp (OC) yield(%) N 0 296 amorphous 24 01. CH3 F F F NF 432 amorphous 23 -F F 0 0.1 N 330 amorphous 28 CH 0-'CH3 N N 0 346 amorphous 18 CM CH3 F F NN 0 364 amorphous 24 GH 0, CH3 66 a N 3 1 365 amorphous 18 0 CH o', Q F F F N- 364 171-173 21 0 CA H 01 CH 3 F,N 3 N 0 314 234-235 38 C1H 01 C1t Hj 0 N N 0 326 208-209 33 CM 0, CH, cl N N 0 336 amorphous 13 CA H CF 67 O,W-0 341 184-186 20 CH 011 CH3 N' N 0 302 226 30 CH O'CH 3 S N 0 302 amorphous 50 CH CH3 H,C N 0 310 amorphous 26 aH 0.'CH3 ci",a a N- N 0 364 amorphous 37 CH 01.1 68 CH3 1 0 N N 0 326 amorphous 30 CH 0.1 CH 3 0 326 amorphous 14 0 CH o, CH3 F F F N N 364 amorphous 22 0 CA H CH3 CH 3 3 N 0 310 amorphous 13 CH 0 69 N 314 amorphous 23 0 CA H N o',0-, 302 189 10 S SS CH NI I- N 0"o''CH3 326 162-164 9 CM N 0,-"""0" CF 310 206-207 15 aH N 336 185-187 22 S S CH cl 3 N 314 213-215 24 CH F N 0"-",o"CH3 330 236-238(dec.) 46 CH cl N F N 0"'o"CH3 364 174 (dec.) 25 C12 CH cl 71 N 0 011 CH, 346 124-126 22 aH N' I- , N 0"-'o'CH3 346 67-69 22 CW N H 0 341 amorphous 26 c- rAH CH3 cl S 1 0 IHI aH 336 amorphous 7 N H 0 364 amorphous 37 F CW O-CI.6 N- N H 0 364 amorphous 25 F F OH 0 'Cl.

1 9 1 1 72 1 1 IN 0 314 190-192 68 CM Cf- 326 202-204 62 CM 01 Cl 1 N H 0 296 202-204 50 aH N H H3C'.( Z:Y 310 198-200 42 aH CH 1 S 0 302 210-212 57 aH 01 CF 1 N 1 H cl 0 364 210-212 8 1 a OH o., 73 A General scheme for the synthesis of 4-, 5- or 7-arylic substituted 2-(2-phenyl-4,5-dihydro-lH-imidazole) benzofuranes is provided herein above by Scheme H. Examples prepared following the method set forth in Scheme H are set forth herein. 5-Bromo-2-(2-cyanophenyl) benzofurane To a solution of 6.47 g (3.2 mmol) 5-bromosalicylic aldehyde in dimethylformaniide (28 ml) was given at room temperature 1.88 g ( 3.47 mmol) sodium methoxide in 6 ml ethanol. After stirring at room temperature for 8 hours 1.88 g (3.47 mmol) sodium methoxide in 6 ml ethanol was added and the mixture was heated (70'C) and stirred for 3 hours. After cooling to room temperature the solvents were evaporated, water and dichloromethane was added and the organic phase was dried and concentrated.

After additon of ethanol the induced crystalls were filtered and dried. Yield: 2.3 g (25 mp 140'C.

5-Bromo-2-(2-(4,5-dihydro-1H-imidazolo) phenyl) benzofurane A mixture of lg (0.33 nimol) of the above-mentioned compound and 0.9 g (0. 38 mmol) of ethylenediamine monotosylate was heated at 21WC for 5 hours. After cooling to room temperature water (30 ml) and 2N NaOH (30 M1) was added and the mixture was extracted with dichloromethane. The organic phase was dried with Na2S04 and evaporated giving an oil 10 Yield: 0.3 g (26 %).

5-(4-Metboxy-phenyl)-2-(2-(4,5-dihydro-1H-imidazolo) phenyl) benzofurane To a solution of 0.322 g (0.94 mmol) of the above-mentioned compound in 1, 4- dioxan (15 ml) was added under argon 0. 109 g (0.94 mmol) Pd(PPh3)4 and 2 rnl 2 M Na2C03. After addition of 0.172 g (1.1 mmol) 4-methoxyphenylboronic acid the mixture was heated 16 hours at WC. After cooling to room temperature, the solid was filtered off, the solution was acidified with 2N HQ and after evaporation in vacuo chromatographed on silicagel with isopropanoYethylacetatelmethanoYammonia in ethanol 40/40/5/ 10 to give after concentration an amorphous product. Yield: 0.27 g (78%).

The following examples set forth in Table II were prepared in substantial accordance with the above-mentionedexamples and the procedures and methods disclose herein.

is MS+ mp Yield (%) cl NI 0, p 372 amorphous 69 N a 1, 51,11 \N / \ 1 \ "IOC, 338 oil 70 --- 0 - - F .1 "0' 356 amorphous 54 F F F 1 442 > 280 'C 35 N CH N a Cl 407 273 - 274 OC 81 N N F F F F 474 > 280 'C 59 F 1 F - 0 N a cl 0 407 amorphous 58 76 395 amorphous 38 cl 378 amorphous 71 O"N-0 383 amorphous 45 S 384 180 - 182 OC 34 N NI 353 amorphous 55 N S 0 344 amorphous 52 0 N S 0 344 290 OC (Z) 52 N F 356 298 - 299 OC 46 0 N 77 hc c' 1 1 a 380 amorphous 19 Z_., -U N ,C-.

" 1 368 amorphous 49 01 0 368 amorphous 40 388 amorphous 88 388 amorphous 75 0 Br 00 341 155-156 OC 30 N S 0 344 amorphous 79 78 0 0 383 amorphous 78 0 N "rN, 0 341 amorphous 24 B 404 266 - 267 'C 30 ot aH 0 N- 392 215 216 'C 19 C N cl CH 79, The pharmacological activity of compounds of the present invention may be determined by methods well known in the art and by the assays disclosed herein.

ASSAYS BTC6, F7 Insulinoma Cell Screening Models BW6,F7 are cultured in DMEM 4.5g/1 glucose with the following supplements:

15%(v/v) equine serum; 2.5% (v/v) FCS; and 50 UlmI Penicillin/ 50 ggln-il Streptomycin.

A) Adherent BW6,F7 cells BW6,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 follows:

Discard the supernatant of the 96 well plates after the cells have been seeded, wash 3 times with EBSS (Earl's balanced salt solution) (0 MM glucose)/ 0. 1 % BSA and incubate in the EBSS solution 30 rain at 5% C02, 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.

B) Dissociated BW6,F7 cells BW6,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 gauge). Cells were washed three times in EBSS (0 niM glucose)/O. 1 % BSA and insulin secretion experiments are performed as described above.

Dose response titrations on the agonists described revealed EC50 values of < mM, preferably < lmmol.

Rat Islet Ass4y The number of islets of three rats is usually sufficient to test 8 compounds including standards.

Solutions 1. 100 ml EBSS (Earl's balanced salt solution): For example, as commercially available Cat. No. BSS-008-B (Specialty Media) without Glucose & Phenol Red, with 0. 1% BSA, other comparable commercially available media are acceptable.

2. 100 ml EBSS/BSA buffer + 130.8 ing D(+)-Glucose monohydrate (MW:

198.17) (=3.3 mM final concentration).

3. 100 ml EBSS/BSA buffer + 661.8 ing D(+)-Glucose monohydrate (MW:

198.17) (=16.7 mM final concentration).

4. 100 ml EBSS (Earl's balanced salt solution). For example, as commercially available,Cat. No. BSS-008-B (Specialty Media) without Glucose & Phenol Red, with 0. 1% BSA, with 0.6 % DMSO; other comparable solutions may be used as well; Dilution of compounds:

Each dilution of compound has to be double concentrated as it will be diluted 1 + 1 by EBSS/BSA + Glucose (either high Glucose, 16.7 mM final cone. or low Glucose, 3.3 mM final cone.) in a 24 -well tissue culture plate (or other appropriate tissue culture receptacle, if desired).

A stock solution of the compound to be tested of 10 mM in 13MS0 is made, and the following solutions made for the compounds to be tested, and for standards.

Tube Concentration final Dilution No. (pm) Concentration (0) 1 200 100 40 gI of stock + 2000 Vtl EWS/BSA 2 60 30 900 gI of tube 1 + 2100 W EBSS/BSA 3 20 10 300 gI of tube 1 + 2700 d EMS/BSA/ 0.6 % DMSO 4 6 3 300 d of tube 2 + 2700 0 EMS/BSA1 0.6 % DMSO 2 1 300 W of tube 3 + 2700 pI EBSS/BSA/ 0.6 % DMSO 6 0.6 0.3 300 gI of tube 4 + 2700 gI EBSS/BSAI 0.6 % 13MS0 7 0.2 0.1 300 gI of tube 5 + 2700 gI EBSS/BSAI 0.6 % 13MS0 8 0.06 0.03 300 W of tube 6 + 2700 pI EBSS/BSA/ 0.6 % 13MS0 - -:82 - Culture dishes are prepared (untreated, 100 x 20 mm, one per two compounds) with 10 mI EMS/BSA and 10 mI low glucose EMS/BSA or similar preparative solution and place in an incubator at 37'C, 5 % C02. for at least 15 min.

Preparation of Rat islets in culture dishes:

Approximately half of an islet is selected with a 100 W pipette and transfered to a prepared culture dishe with EBSS/BSA/low Glucose by using binoculars (magnification about 30 x.

The dish is put back into the incubator (37'C, 5 % C02) for preincubation (30 min) If a 24 well plate is used for the assay, the dilutions are distributed (500 each) as shown in the scheme below.

500 MI of EMS/BSA + 0.6 % DMSO (0 = Control).

is 0 0 0.03 0.03 0.1 0.1 1 2 3 4 5 6 0.3 0.3 1 1 3 3 7 8 9 10 11 12 10 30 30 0 0 13 14 15 16 17 18 0.1 0.1 1 1 10 10 19 20 21 22 23 24 - 83. EBSS/BSA/ high Glucose, 500 VI is added to wells 1-16, and EBSS/BSA/ low Glucose, 500 W is added to wells 17-24.

This scheme is repeated with the other compounds in tissue culture plates and the plates are placed into the incubator (37'C, 5 % C02) for at least 15 min.

The culture dish with the second half of the islets is taken out of the incubator.

The rest of the islet is picked up with a 100 W pipette and placed into the second of the prepared culture dishes with EBSS/BSA/low Glucose using binoculars, and placed back into the incubator (37"C, 5 % C02) for preincubation (30 min).

Take out the tissue culture plates I and 2 and the first preincubated islets.

Place 8 islets into each well by using a 10 pl pipette and binoculars (general guideline magnification about 40 x), generally trying to select islets of similar size which are not 1-5 digested. The plates are placed back in the incubator (37'C, 5 % COD for 90 min.

Remove the second of the overnight cultured culture dishes with islets from incubator. Approximately half of the islets are placed into the 3rd of the prepared culture dishes with EBSS/BSA/low Glucose with a 100 pl pipette and using binoculars (general guideline-magnification about 30 x), then placed back into the incubator (37'C, 5 % COD for preincubation (30 min).

-.84 - The 24 -well tissue culture plates 3 and 4 and the second preincubated islets culture dish are removed from the incubator and 8 islets placed into each well by using a 10 pI pipette and binoculars (magnification about 40 x), again selecting islets of similar size which are not digested. Put the plates back to the incubator (37'C, 5 %.5 C02) for 90 min.

Take the culture dish with the second half of the islets out of the incubator. with a 100 V1 pipette into the 4th of the prepared culture dishes with EBSS/BSAllow Glucose by using binoculars (magnification about 30 x) and put them back into the incubator (37'C, 5 % C02) for preincubation (30 min) Take out the 24 -well tissue culture plates 5 and 6 and the 3rd preincubated islets culture dish. Place 8 islets into each well with a 10 0 pipette by using binoculars (magnification about 40 x). Put the plates back into the incubator (37'C, 5 15 % C02) for 90 min.

Take out the 24 -well tissue culture plates 7 and 8 and the last preincubated islets culture dish. Place 8 islets into each well with a 10 W pipette by using binoculars (magnification about 40 x). Put the plates back to the incubator (37'C, 5 % C02) for 20 90 min.

When 90 minutes of incubation are over, transfer approximately 300 gI of each well into one well of the 96 well filter plate and by using a vacuum pump filter it into a 96 well Microplate. 4 of the 24 -well tissue culture plates cover one filterplate and 96-well-Microplate.

The insulin secreted by the islets is measured in a RIA after dilution (1:5).

Intravenous Glucose Tolerance Test This test is used to examine in vivo efficacy of compounds of the present invention on insulin secretion and blood glucose at hyperglycemia.

The intravenous glucose tolerance test (IVGTT) is performed in overnight fasted anesthetized male wistar rats weighing 280-350g. Under pentobarbitone anesthesia (50 mg/kg ip) polyethylene catheters are placed in the left jugular vein and in the left common carotid artery. Glucose (10% solution) is administered intravenously at a dose of 0.5 g/kg, followed directly by an iv injection of the compound to be tested.

Blood samples are drawn before and 3, 6, 10, 15, 30 and 45 min after glucose administration, centrifuged and the obtained serum is stored at 20'C for analytics.

Test compounds are examined along with a reference (positive control) and a vehicle control with n=8 animals per group. Glucose is determined by the hexokinase method, and insulin via radioimmunoassay (RIA) from serum.

In order to examine the effects of test compounds on insulin and blood glucose at euglycemia in vivo, the protocol of the IVGTT as described above is used except for the administration of intravenous glucose.

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 mglkg to about mglkg 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 mglcm2, more preferably, from about 50 to about 200 mg/cm2, and,most preferably, from about 60 to about 100 mglcm2.

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 (mglcapsule) 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 88 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.

i

Claims

We claim

1. A compound of Formula (I):

2 R, 3 N 9 -X H2 R4 wherein R', R2, R 3, and R9 are each independently hydrogen or Cl -8 alkyl; or 3 R' and R, together with the carbon atoms to which they are attached, combine to form a C3-7 carbocyclic ring and R 2 and R9 are each independently hydrogen or C 1-8 alkyl; or R 1 and R 3, together optionally form a bond and R2 and R9 are each independently 15 hydrogen or C 1-8 alkyl; or R' and R2, together with the carbon atom to which they are attached combine to form a C3-7 spirocarbocyclic ring and R3 and R? are each independently hydrogen or C 1-8 alkyl; or R 3 and R9, together with the carbon atom to which they are attached, combine to form a C3-7 spirocarbocyclic ring and R' and R 2 are each independently hydrogen or C 1-8 alkyl; X is -0-, -S-, or -NR5-; G-1341 - 90 R 5 is selected from the group consisting of hydrogen, Cl -8 alkyl, optionally substituted aryl, and an amino protecting group; n is 0, 1, or 2; R 4 is a group of the formula:

Rq YR6 R7 Y is selected from the group consisting of a bond, -O(CHA-, -(C112)k0-3 - CO-Y -CHOW, -CONR-, -NRCO-, -NR'CONR"-, -(CH2)kW(CH2)R"" - i -C:::::::C(CH2)k- (CH2) kc-C -CH--CH(CH 2) k -(CH2) k CCH NR S025 SO2W', and NR... S02; wherein -(CH2)kW(CH2)b - is optionally substituted with C alkyl or hydroxy; k is independently 0, 1, 2, 3. or 4; b is independently 0, 1, 2, 3, or 4; provided that the sum of k and b together is not more than 4; W is selected from the group consisting of a bond, 0, S, S02, SO, S02W', W' S02, NR", CONW, WCO, -C=C-, -C=C-, C=O, and NR.... CONR....; R, R', W' and R are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, and benzyl; R.... is selected from the group consisting of of hydrogen, Cl -8 alkyl, benzyl, and an amino protecting group; R 8 is selected from the group consisting of hydrogen, G-1341 C1-8 alkyl, Cl-8 alkoxy, C3-7 cycloalkyl, C3-7 cYclO Cl-8 alkoxy, hydroxy, halo, carbo C 1 -8 alkoxy, halo C 1 -6 alkyl, halo-C 1-8 alkoxy, optionally substituted phenyl C 1-8 alkyl; R7 is selected from the group consisting of hydrogen, C 1 -8 alkyl, C 1-8 alkoxy, C3 -7 cycloalkyl, C3 -7 cYCIO C 1-8 alkoxy, hydroxy, halo, carbo C 1-8 alkoxy, halo Cl -6 alkyl, halo-C 1-8 alkoxy, optionally substituted phenyl C 1-8 alkyl, optionally substituted phenyloxy, optionally substituted phenyl C 1-8 alkoxy, optionally substituted naphthyl, optionally substituted heteroaryl, (tetrahydropyran-2-yl)methoxy, CI-S alkyPS(O).',, optionally substituted aryl-Cl-8 alkyPS(O),,,, CE13(CH2)p-ZL(CH2)q-Z2-, and Z3-(CH2)q'-Z2-; where ZI and Z2 are each independently a bond, -0-, -S-, 0, S02. sulphoximino, or NR 13; 14 15 Z3 is hydroxy, protected hydroxy, NR R ' protected amino, SH, or protected SH; R 6 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, and optionally substituted 4,5dihydroisoxazolinyl; R 13, R 14 and R 1-5 are each independently selected from the group consisting of 25 hydrogen, C 1-8 alkyl, optionally substituted aryl C 1-8 alkyl, and optionally substituted phenyl; or R 14 and R's together with the nitrogen atom to which they are attached may combine to form a heterocyclic ring comprising the nitrogen and C2-6 alkyl, wherein C2-6alkyl is optionally substituted with one or two C 1-8 alkyl groups G-1341 or one carbon atom of the heterocyclic ring is optionally replaced by oxygen or sulfur; p is 0, 1, 2, 3, or 4; q and q' are each independently selected from the group consisting of 1, 2, 3, 4, and 5; m and m' are each independently selected from the group consisting of 0, 1 and 2; and provided that when X is NH and Y is a bond, then R is not unsubstituted phenyl or, 1 -phenyl- 1 -cyclohexylmethyl or phenyl substituted by halo, C 1-6 alkYlthiO, C 1 -6 alkyl, -CF3, phenyl, acylan-iino, aminosulfonyl, methoxy, indol-5-yl, 1-phenyl-lcyclohexylmethyl, phenyl, or CI-6 alkyl subsituted aminosulfonyl; pharmaceutically acceptable salts and esters thereof.

2. A compound of claim I wherein R' and R 2 are each hydrogen and R 3 and W are each hydrogen or methyl.

3. R6 is aryl-CI-8 alkyl, unsubstituted naphthyl, optionally substituted heteroaryl.

4. A pharmaceutical formulation comprising a compound according to any one of the preceding Claims or a pharmaceutically acceptable salt or ester thereof, together with a pharmaceutically acceptable carrier or diluent therefor.

5. A compound according to Claim I or a pharmaceutically acceptable salt or ester thereof, for use as a pharmaceutical.

6. A compound according to Claim I or a pharmaceutically acceptable salt or ester thereof, for use in the manufacture of a medicament for the treatment of a mammal for diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present.

G-1341