CZ20014099A3 - Heterocyclic compounds containing imidazole ring and pharmaceutical preparation in which the compounds are comprised - Google Patents

Abstract

The subject invention involves compounds having structure (I), wherein each R1 is independently alkyl, aryl, or heterocycle; each R2 - R7 is independently hydrogen or other substituent; B is nil and n is 0-3, or B is ethenyl and n is 0-1; and pharmaceutically acceptable forms thereof. The subject invention also involves pharmaceutical compositions containing such compounds, and methods for treating or preventing diseases or disorders using such compounds.

Description

Technical field

The present invention relates to novel heterocyclic compounds containing an imidazole ring, to pharmaceutical compositions containing them and to their therapeutic or preventive use in the field of cardiovascular, oncological, infectious and inflammatory diseases.

BACKGROUND OF THE INVENTION

Certain imidazoisoquinoline compounds are disclosed in U.S. Patent No. 3,917,610, issued November 4, 1975; they are reported to exhibit certain cardiovascular activities. One such compound is further reported by Borchard, Fox and Greeff in "The Positive Inotropic, Antiarrhythic and N ⁺ , K ⁺ -ATPase Inhibitors of the Effects of the Isoquinoline Derivative, BIIA", Achives of Pharmacology, Volume 312 (1980), pp. 187- 192

SUMMARY OF THE INVENTION

The present invention provides compounds having the general formula:

where:

(a) each R 1 is independently selected from the group consisting of alkyl, aryl and heterocycle;

(b) R 2 is selected from the group consisting of hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl, and arylsulfonyl;

(c) each R 3 is independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl, aryl, or heterocycle substituted hydroxy, thio, amino, amide, formyl (acyl), carboxy and carboxamide; and two R 3 on adjacent carbon atoms may optionally form together an alkylene or heteroalkylene group to form a fused ring with the phenyl to which they are attached;

(d) R 4 is selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycle and carboxy and its alkyl and aryl esters and amides;

(e) each R 5 is independently selected from the group consisting of hydrogen, alkyl and aryl;

(f) each R 6 is independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl or aryl or heterockyl substituted hydroxy, thio, amino, amide, formyl (acyl), carboxy and carboxamide; and two R 6 on adjacent carbon atoms may optionally form together an alkylene or heteroalkylene group to form a fused ring with the phenyl to which they are attached;

(g) B is zero or -C (R 7) = C (R 7) -;

(h) if B is zero, then n is an integer from 0 to 3, otherwise n is from zero to 1;

(i) each R 7 is independently selected from the group consisting of hydrogen, alkyl and aryl; and an optical isomer, diastereomer or enantiomer thereof; and a pharmaceutically acceptable salt, hydrate or biohydrolyzable ester, amide or imide thereof.

The invention also includes compositions comprising a compound of the invention and a pharmaceutically acceptable excipient; and a method of treating or preventing a disease or disorder, comprising:. lodges. to a human or lower animal in need thereof a safe and effective amount of a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, the term "alkyl" as used herein means a hydrocarbon chain that is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted. The term "alkyl" may be used alone or as part of another word where it may be abbreviated to "alk" (for example, in alkoxy, alkylacyl). Preferred linear alkyl contains from one to twenty carbon atoms, more preferably from one to ten carbon atoms, even more preferably from one to six carbon atoms, even more preferably from one to four carbon atoms; most preferably methyl or ethyl. Preferred cyclic and branched alkyl

Obsahuje ···· © ·········· contains from three to twenty carbon atoms, more preferably from three to ten carbon atoms, even more preferably from three to seven carbon atoms, even more preferably from three to five carbon atoms. Preferably, the cyclic alkyl has one hydrocarbon ring, but may have two, three or more fused hydrocarbon rings. Preferably, the alkyl is unsaturated and contains one to three double or triple bonds, preferably double bonds; preferably, they are mono-unsaturated with one double bond. Even more preferably, the alkyls are saturated. Saturated alkyls are referred to herein as "alkanyl". Alkyls which are unsaturated and which contain only one or more double bonds (but not triple bonds) are referred to herein as "alkenyl". Preferred alkyl substituents include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy, and its allyl and aryl esters and amides , nitro and cyano. Preferred alkyls are unsubstituted.

The term "heteroatom" as used herein means a nitrogen, oxygen or sulfur atom. *

The term "alkylene" as used herein means an alkyl that connects two other moieties, "heteroalkylene" means an alkylene having one or more heteroatoms in the linking chain.

Unless otherwise indicated, the term "aryl" as used herein means an aromatic hydrocarbon ring (or fused rings) that is substituted or unsubstituted. The term "aryl" may be used alone or as part of another word (for example, in aryloxy or arylacyl). Preferably, aryl contains from six to fourteen carbon atoms, more preferably up to ten carbon atoms in the aromatic ring (s), and has a total of from six to twenty carbon atoms, more preferably up to twelve carbon atoms. Preferred aryl is phenyl or naphthyl; most preferably is phenyl. Preferred aryl substituents include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy, and its allylic and aryl esters and amides, nitro and cyano. Also preferred aryls are unsubstituted.

Unless otherwise indicated, the term "heterocycle" as used herein means a saturated, unsaturated or aromatic hydrocarbon ring (or fused rings) with one or more heteroatoms in the hydrocarbon ring (s). Preferred heterocycles contain from one to six heteroatoms in the ring (s), more preferably one or two heteroatoms in the ring (s). Preferred heterocycles contain from three to fourteen, more preferably up to ten, carbon atoms plus heteroatoms in the ring (s). . ·.? / 5 * - ~ ** Λ'βίΛί-. · Ίί <ίί '' *: • i ·? '' * * '' /? '· «£ -ί ·. · - -' jv · ; More preferably from three to seven, even more preferably five or six, carbon atoms plus ring heteroatoms; and a total of from three to twenty carbon atoms plus heteroatoms, more preferably from three to ten, even more preferably five or six, carbon atoms plus heteroatoms. Preferably, the heterocycles have one ring, but may have two, three or more fused heterocycles. Preferred heterocycles include those heterocycles that contain one ring of five or six carbon atoms plus ring heteroatoms, with a maximum of three heteroatoms, with a maximum of two being O and S. More preferably, the 5- or 6-membered heterocycles are one or two a ring atom which is O or S and the other are C; or with one, two or three ring heteroatoms which are N and the remaining atoms are C. Such preferred 5 or 6-membered heteroaromatic rings are preferably saturated, unsaturated with one or two double bonds or aromatic. Such preferred 5- or 6-alkyl

6-membered heterocycles are preferably single ring; or fused to a 3- to 6-membered hydrocarbon ring which is saturated, unsaturated with one double bond or aromatic (phenyl); or fused to another such 5- or 6-membered heterocyclic ring. Heterocycles are unsubstituted or substituted. Preferred substituents for heterocycle are the same as for alkyl. Compounds of the invention

The present invention includes compounds having the following general formula:

In Formula 1, each R 1 is independently selected from the group consisting of alkyl, aryl and heterocycle. Preferably R 1 comprises linear alkanyl having 1 to 6 carbon atoms, linear alkenyl having 2 to 6 carbon atoms and branched and cyclic alkanyl and alkenyl having from three to six carbon atoms, such as alkenyl preferably having 1 double bond. Such preferred alkanyls or alkenyls are preferably unsubstituted or substituted by phenyl, heterocycle containing 5 or 6 carbon atoms, carboxy and its C1-C6 alkyl or phenyl esters or cyano. More preferably, such alkanyl and alkenyl have up to 5 carbon atoms, more preferably up to 4 carbon atoms. More preferred R 1 is methyl, ethyl and isopropyl. Most preferably, R 1 is unsubstituted methyl. It is also preferred that both R1 be the same moiety.

In Formula 1, R 2 is selected from the group consisting of hydrogen, alkyl, alkylacyl, arylacyl, allylsulfonyl, and arylsulfonyl. Preferably R2 is selected from hydrogen; C 1 -C 6 alkyl, such as alkyl which is saturated or unsaturated with one double bond and unsubstituted or substituted by phenyl; C 1 -C 6 allylaclacyl, wherein the alkyl is saturated or unsaturated with one double bond; and phenylacyl. More preferably, the alkyl moiety is the above-mentioned C 1 -C 4 moieties and is saturated. Even more preferably R 2 is methyl. Most preferably, R 2 is hydrogen.

In Formula 1, each R 3 is independently selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, nitro and cyano; and also from the group consisting of hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide, which is unsubstituted or substituted, preferably with alkyl or aryl or hetreocycle; or two R 3 together are alkylene or heteroalkylene bonded to adjacent phenyl ring atoms to form a cycloalkyl, aryl or heterocyclic ring that is fused to the phenyl ring. Preferably R 3 is independently selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and alkyl or aryl esters and amides derived therefrom; more preferably, it is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, thio, C 1 -C 4 alkylthio, C 1 -C 4 mono- or dialkylamino and C 1 -C 4 alkylacyl. More preferably, one to three R 3 is halogen and the remaining are hydrogen. Also more preferably, one to three R 3 is methyl or ethyl and the remaining are hydrogen. Also preferably, one of R 3 is dialkylamino, wherein the alkyls contain 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and the others are hydrogen, wherein R 3 is preferably attached to a 4 'carbon atom. Even more preferably, one to three R 3 is independently selected from the group consisting of F, Cl and Br and the others are hydrogen; even more preferably, two or three R 3 are F, Cl or Br, and are the same. Also more preferably, one to three R 3 is unsubstituted methyl and the others are hydrogen. Also more preferably, one or two R 3 is trifluoromethyl, the others being hydrogen.

Also preferably, two R 3 are bonded to adjacent carbon atoms of the phenyl ring and together are saturated or unsaturated alkylene or heteroalkylene having from 1 to 6 carbon atoms and 0 to 3 heteroatoms to form a ring which is fused to phenyl, such a ring having 5 to 6 carbon atoms. 8 atoms in the ring. Such a ring, condensed

• · · · • · «« • · · • · · β ·· ·· «· · · • · · · · · • · · · · • · · · · ·

to the phenyl ring preferably has 5 to 6 ring atoms, of which 0 to 2, preferably 0 to 1 are heteroatoms. Preferably the fused rings (including the phenyl to which R 3 are attached) include naphthyl, indolyl, benzimidazolyl, benzofuranyl, benzopyranyl. If two R 3 form a ring fused to the phenyl ring, the other R 3 are preferably H.

In Formula 1, R 4 is selected from the group consisting of hydrogen, halo, alkyl, aryl, aryl, heterocycle, carboxy, or alkyl esters and amides thereof. Preferably, R 4 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl and phenyl. More preferably, R 4 is selected from the group consisting of hydrogen and unsubstituted or substituted phenyl; substituents on such phenyl are preferably selected from the group consisting of hydroxy, alkoxy, thio and alkylthio. Most preferably, R 4 is hydrogen.

In Formula 1, each R 5 is independently selected from the group consisting of hydrogen, alkyl and aryl. Preferably, R 5 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, especially unsubstituted methyl or ethyl. Most preferably, both R5 are hydrogen.

In Formula 1, each R 6 is independently selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, cyano, and nitro; also from the group consisting of hydroxy, thio, amino, amide, formyl (acyl), carboxy, carboxamide and sulfonamide, which are unsubstituted or substituted, preferably with an aryl or a heterocycle. Preferably, R 6 is selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, sulfonamide, alkylsulfonamide, arylsulfonamide, formyl , alkylacyl, arylacyl, carboxy and the alkyl or aryl esters and amides derived therefrom; more preferably from the group consisting of hydrogen, halo, hydroxy, C 1 -C 4 alkoxy, thio, C 1 -C 4 alkylthio, C 1 -C 4 alkyl esters and amides derived from carboxy and a heterocycle containing 5 or 6 ring atoms. More preferably, one or both of R 6 is selected such that at least one heteroatom directly binds to the phenyl ring. If both R 3 have a heteroatom attached directly to adjacent atoms of the phenyl ring, then both R 6 may together form an alkylene moiety joining the two heteroatoms, the alkylene moiety preferably containing 1 to 4, more preferably one or two carbon atoms. Preferably, one or both of R 6 is a non-hydrogen moiety; more preferably, both are non-hydrogen moieties. More preferably, both R 6 are alkoxy or both are alkylthio; preferably both are identical. Preferred alkyl moieties of R 6 contain 1 to 5

Carbon atoms, more preferably one or two carbon atoms; most preferably methyl. Such alkyl moieties are preferably unsubstituted. Such alkyl moieties are preferably saturated. Most preferably, both R 6 are methoxy or ethoxy, especially methoxy.

Also preferred are R 5 and R 6, which are bonded to adjacent carbon atoms together to form a saturated or unsaturated heteroalkylene containing from 1 to 6 carbon atoms and from 0 to 3 heteroatoms to form a ring that is fused to the phenyl ring, such a ring having from 5 to 8 ring atoms. Such a ring fused to phenyl preferably contains from 5 to 6 ring atoms, of which 0 to 2, preferably 0 or 1 heteroatoms. Preferred rings formed by such R 5 and R 6 include phenyl, furyl, pyrrolyl, dioxanyl, imidazolyl, pyridinyl, pyrrolidinyl, piperidinyl. If such R 5 and R 6 form a fused ring, the other R 5 and R 6 are both preferably hydrogen.

In formula 1, B is zero or -C (R 7) = C (R 7) -. If B is zero, n is an integer from 0 to 3, preferably 1 or 2. If B is C (R 7) = C (R 7) -, then n is an integer from 0 to 1, preferably 0. Preferably B is zero.

In formula 1 and B, each R 7 is independently selected from the group consisting of hydrogen, alkyl and aryl. The non-hydrogen substituent R 7 is preferably phenyl or alkyl of 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms. Such a non-hydrogen substituent R7 is preferably unsubstituted. Alkyl R7 is preferably saturated. Preferably, no more than one of all R7 is other than hydrogen. More preferably, all R 7 is hydrogen

The present invention encompasses optical isomers, diastereomers, and enantiomers of the compounds of Formula 1. The invention encompasses pharmaceutically acceptable salts, hydrates and biohydrolyzable esters, amides, and imides of such compounds.

A "pharmaceutically acceptable salt" is a cationic salt formed on any acidic moiety (e.g., carboxy) or an anionic salt formed on any basic moiety (e.g., amino) on a compound of formula (1). Many pharmaceutically acceptable salts are known. Preferred cationic salts include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, and organic salts such as ammonium salts. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates and the like. Addition salts can provide an optical center where none previously existed.

The compounds of the present invention and salts thereof may have one or more chiral centers. The invention includes all optical isomers of the compounds of Formula 1 and salts thereof, including diastereomers and enantiomers. The present invention encompasses all optical isomers, diastereomers or enantiomers, in pure form, substantially pure form, and mixtures thereof, including racemic mixtures.

Preferred compounds of the present invention include compounds having the general formula 2.

In the general formula 2, R 1, R 3 and R 6 are as defined above and x is 0 or 1.

In Formula 2, each R 1 is preferably non-binding selected from the group consisting of linear alkanyl containing one to four carbon atoms, linear alkenyl having one double bond and two to four carbon atoms, branched and cyclic alkanyl having from three to five carbon atoms, and branched and cyclic alkenyl having one double bond and three to five carbon atoms. Such R 1 are unsubstituted or substituted with one phenyl or are preferably unsubstituted. More preferably, R 1 is selected from the group consisting of methyl, ethyl, ethenyl, n-propyl, isopropyl, npropenyl, isopropenyl, sec-butyl, cyclopropyl, cyclobutyl and cyclopentyl. More preferably, R 1 is selected from the group consisting of methyl, ethyl, ethenyl, isopropyl and n-propenyl. Most preferably, R 1 is methyl. It is also preferred that both R1 be the same.

In formula 2, one or both of R 6 is preferably both preferably alkylthio or more preferably alkoxy, wherein the alkanyl contains from one to four carbon atoms. If R6 is not alkylthio or alkoxy, it is preferably hydrogen. Preferably both R6 are methoxy or ethoxy; most preferably both R 6 are methoxy.

In Formula 2, R 3 is preferably selected from hydrogen; mono-, di- or trihalo, preferably selected from fluorine, chlorine and bromine, preferably at one or more of the 2 ', 3', 4 'and 5' positions; mono-, di- and trimethyl, preferably at one or more positions 2 ', 3', 4 'and 6' 'and mono- or di-trifluoromethyl, preferably at one or both of the 3' and 5 'positions. Also preferably, one of R 3 is dialkylamino, preferably in the 4 'position, wherein the two alkyls are preferably the same or different and preferably contain from 1 to 4 carbon atoms and the other R 3 is hydrogen. More preferred R 3 combinations are selected from the group consisting of 4'-fluoro, 4'-chloro, 4'-bromo, 2 ', 4'-difluoro, 2', 4'-dichloro, 2 ', 4'dibromo, 2' 4 ', 5'-trifluoro, 2', 4 ', 5'-trichloro, 3', 4'-difluoro, 3 ', 4'-dichloro, 3', 4'-dibromo, 4'methyl, 2 ' 4'-dimethyl, 2 ', 4', 6'-trimethyl, 3'-trifluoromethyl, 3 ', 5'-ditrifluoromethyl and 4'-dibutylamino; in all cases, the other R 3 is hydrogen. Also preferred combinations are selected from the group consisting of 2 ', 4'-dihalo or 3', 4'-dihalo, wherein one of the halogens is selected from the group consisting of fluorine, chlorine and bromine and the remaining halogen is another halogen of these three; more preferably one of such halo is fluorine, all other R 3 are hydrogen. Most preferred combinations of R 3 are selected from 4'-chloro, 4'-bromo and 2 ', 4'-dichloro, the others being hydrogen.

Non-limiting examples of compounds of the present invention include compounds wherein both R 6 are methoxy and R 1 and R 3 are as defined in the following table (unspecified R 3 are all hydrogen).

Example x RI R3 1 0 methyl, methyl hydrogen 2 0 methyl, methyl 4'-fluoro 3 1 methyl, methyl 4'-chloro 4 0 methyl, methyl . 4'-bromo 5 0 methyl, methyl 2 ', 4'-difluoro 6 1 methyl, methyl 2 ', 4'-dichloro 7 , 0 methyl, methyl 2'-fluoro, 4'-chloro 8 - - 2 ··· · methyl, methyl 2'-fluoro, 4'-bromo 9 0 methyl, methyl 2'-chloro, 4'-fluoro 10 1 methyl, methyl 2'-bromo, 4'-fluoro 11 1 methyl, methyl 3 ', 4'-difluoro 12 0 methyl, methyl 3 ', 4'-dichloro 13 0 methyl, methyl 3'-fluoro, 4'-chloro 14 1 methyl, methyl 3'-fluoro, 4'-bromo 15 Dec 0 methyl, methyl 3'-chloro, 4'-fluoro 16 1 methyl, methyl 3'-bromo, 4'-fluoro 17 0 methyl, methyl 2 ', 4', 5'-trifluoro 18 0 methyl, methyl 4'-methyl 19 Dec 1 methyl, methyl 2 ', 4'-dimethyl 20 May 0 methyl, methyl 3 ', 4'-dimethyl 21 1 methyl, methyl 2 ', 4', 6'-trimethyl

22nd 1 methyl, methyl 3'-trifluoromethyl 23 0 methyl, methyl i O 'C' - j; Ut _Λ + Tu / 1 O -ui ii uu iuui 11 icu ly i 24 0 methyl, methyl 4'-fluoro, 3'-trifluoromethyl 25 1 ethyl, ethyl 4'-fluoro 26 0 ethyl, methyl 4'-chloro 27 Mar: 0 ethyl, ethyl 4'-bromo 28 1 ethyl, methyl 2 ', 4'-dichloro 29 1 ethyl, ethyl 3'-fluoro, 4'-chloro 30 1 ethenyl, ethenyl 4'-chloro 31 0 ethenyl, methyl 2 ', 4'-dichloro 32 0 isopropyl, isopropyl 4'-fluoro 33 0 isopropyl, methyl 4'-chloro 34 1 isopropyl, isopropyl 4'-bromo 35 1 isopropyl, methyl 2 ', 4'-dichloro 36 0 isopropyl, isopropyl 3'-flur, 4'-chloro 37 0 -CH 2 -CH ₂ = CH 2, methyl 4'-fluoro 38 1 -CH ₂ -CH ₂ = CH ₂ , -ch ₂ -ch = ch ₂ , 4'-chloro 39 1 -CH ₂ -CH = CH _2; ethyl 2 ', 4'-dichloro 40 0 sec-butyl, sec-butyl 4'-chloro .41 1 cyclopentyl, methyl 4'-chloro 42 1 methyl, methyl 2 ', 4', 5'-trifluoro 43 0 methyl, methyl 2 ', 3', 4'-trifluoro 44 0 ethyl, ethyl 2 ', 4', 5'-trifluoro 45 1 ethyl, ethyl 2 ', 3', 4'-trifluoro 46 1 isopropyl, isopropyl 2 ', 4', 5'-trifluoro 47 0 isopropyl, isopropyl 2 ', 3', 4'-trifluoro 48 0 methyl, methyl 4'-Dibutylamino 49 1 ethyl, ethyl 4'-dimethylamino 50 0 isopropyl, isopropyl 4'-diethylamino

Further, it has been found that salts and other derivatives of the above compounds may be used for purification, administration and the like. Thus, pharmaceutically acceptable salts, hydrates or biohydrolyzable esters, amides, or imides thereof are contemplated as being part of the present invention.

Methods for preparing compounds of the invention

In the preparation of the compounds of the present invention, the order of the synthetic steps may be varied to increase the yield of the desired product. One skilled in the art will recognize that the choice of reactants, solvents, and temperatures is important for successful synthesis. The starting materials used to prepare the compounds of the invention are known, are prepared by known methods or are commercially available.

It is believed that one skilled in the art can readily carry out standard manipulations of organic compounds without further guidance. These include, but are not limited to, reduction, oxidation, acylation, substitution, etherification, esterification, sulfonation, and the like. Examples of such manipulations are described in the standard literature.

Methods for preparing certain imidazo-isoquinoline compounds are described in U.S. Patent No. 3,917,610, issued November 4, 1975; No. 4,143,143, issued March 6, 1979, both incorporated herein by reference.

The following schemes may be used to prepare compounds of the present invention. In these schemes, R 1, R 2, R 3, R 4, R 5, R 6, R 7, B and n have the meanings given above. Unconventional symbols and abbreviations for other parts and chemicals that are not clear to the chemist are defined in the examples below.

General scheme

I.NaH / SEMCI

SEM O 'ΌΟ

2. nBuLi / PhSSPh

3. MCPBA / CH ₂ Cl ₂

nBuLVBu3SnCI

> ·

Pd (PPh _{3) 4}

Dioxane

nBuLi / THF

(R2) 1

NaH / THF

General scheme II

Br

Pd (PPh _{3) 4}

Toluene

R4-SnMe ₃ or R4-B (OH) ₂

• • • • 4 «· ·· • · AND A A AND A A AA AND AND AND • AND • « AND »» A A • · ·· AND A A AND • AAA AND AND A A AND AAA

R4

The following examples provide further information regarding the synthesis of compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Precursor Example 1

H

AND

N.

PULL

I hr

SEM = _o x _X ^ _S iMe ₃

-of

• » 9 · • * · • · • · · « « • · • • ft • ft ft ft • ft • • • • • • • • • · ft • • • • ft • ·· · ·· ·· • ftft • ft • ftftft

A suspended solution of NaH (6.5 g, 0.162 mol, washed twice with hexane) in anhydrous DMF (300 mL) was cooled in an ice / acetone bath (bath temperature -15 ° C). Solid imidazole (10 g, 0.145 mol) was added in small portions and the mixture was stirred at room temperature for 0.5 h; the solution becomes clear. SEM-CI (25 g, 0.150 mol) was added dropwise at room temperature and over one hour via syringe pump; sodium chloride precipitates during the addition. The mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC (CH ₂ Cl ₂ / MeOH, 9: 1). Water (10 mL) was carefully added to quench the reaction. The solvent was evaporated in vacuo. The residue was dissolved in Et ₂ O (200 mL) and washed with H ₂ O (4 x 50 mL), brine (50 mL), dried (MgSO ₄ ) filtered and evaporated in vacuo to give compound A as an orange liquid.

Precursor Example 2

A B

To a solution of SEM A protected imidazole (1.48 g, 7.50 mmol) in dry THF (75 mL) under argon at -78 ° C was added dropwise n-BuLi (1.6 M in hexane) (6 mL, 9.60 mmol) and the mixture was stirred at -78 ° C for 30 minutes. Phenyldisulfide (2.1 g, 9.60 mmol) in THF (2 mL) was then added dropwise. After addition, the dry ice / acetone bath is replaced with an ice bath. The mixture was stirred at 0 ° C for 1 hour and then at room temperature for 1 hour. The progress of the reaction was monitored by TLC (CH ₂ Cl ₂ / MeOH, 9: 1). Water (5 mL) was carefully added to quench the reaction. The solvent was evaporated in vacuo. The residue was dissolved in Et ₂ O (200 mL) and washed with 5% NaHCO 3 (3 x 20 mL), brine (20 mL), dried (MgSO ₄ ), evaporated in vacuo and purified by chromatography (silica gel, hexane / EtOAc 3: 1) to give Compound B as a yellow oil.

Precursor Example 3

3-Chloroperoxybenzoic acid (MCPBA, 80-85%) (17.03 g, 78.9 mol) was added to a solution of SEM B-protected 2-phenylsulfide-imidazole (9.71 g, 31.6 mmol) in anhydrous CH ₂ Cl ₂ (160 mL) and the reaction mixture was stirred under argon at room temperature for 15 hours. Progress was monitored by TLC (hexane / EtOAc, 3: 1). Sodium thiosulfate (3.9 g) was added to remove excess MCBA. The mixture was filtered. The filtrate was washed with 5% Na ₂ CO ₃ (3 x 150 mL), brine (150 mL), dried (MgSO ₄ ), filtered, evaporated in vacuo and purified by chromatography (silica gel, hexane / EtOAc 3: 1) and Compound C was obtained as a pale yellow oil.

Precursor Example 4

nBu3Sn

To a solution of SEM C-protected 2-phenylsulfonimidazole (8.61 g, 25.4 mmol) in anhydrous THF (250 mL) was added dropwise n-BuLi (1.6 M in hexane) dropwise under argon at -78 ° C. (19.0 mL, 30.0 mmol); the solution was stirred at -78 ° C for 30 minutes. Tributylstannane chloride (6.9 mL, 25.4 mmol) was then added dropwise via syringe pump. The mixture was stirred at room temperature for one hour. Progress was monitored by TLC (hexane / EtOAc, 9: 1). Water was added to stop the reaction. The solvent was evaporated in vacuo. The residue was dissolved in ether (550 mL) and washed with saturated NH ₄ Cl (3 x 50 150 mL), brine (150 mL), dried (MgSO ₄ ), filtered, evaporated in vacuo and purified by chromatography (silica gel) gradient: hexane (500 mL), hexane / EtOAc, 50: 1; hexane / EtOAc, 12: 1) to give D as a clear oil.

í • b

• 9 * 9 99 O • 9 99 * · (4 9 9 9 • 9 • 9 * 9 • 99 • · 9 9 9 9 • • 9 • · 9 9 9 9 · ♦ ·· • 9 • 9 999 99 999 9

Precursor Example 5

PULL

Pd (PPh ₃ ) ₄ (0.0177 g, 0.015 mmol) was added to the solution at room temperature. stannylimidazole D (0.51 g, 0.80 mmol), 4,5-dimethoxy-2- (2-hydroxyethyl) phenylbromide E (0.33 g, 1.1 mmol) and LiCl (0.087 g, 2.1 mmol) in anhydrous dioxane (4.0 mL). A few crystals (about 2 mg) of the radical scavenger, 2,6-di-tert-butyl-4-methylphenol were added and the reaction mixture was refluxed under argon for 5 hours. The reaction was cooled to room temperature and further treated with a 1: 1 mixture of ether and saturated aqueous KF (10 mL) for 15 hours. Progress was monitored by TLC (hexane / EtOAc, 3: 1). The mixture was filtered through a pad of celite with rinsing with ether. The filtrate was washed with water (3 x 12 mL), brine (3 x 12 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo and purified by column chromatography (silica gel, hexane / EtOAc, 2: 3) to give F as orange oil.

Precursor Example 6

To a solution of F (2.2 g, 4.24 mmol) and Et ₃ N (886 μΙ) in dichloromethane (200 mL) was added methylsulfonyl chloride (MsCl, 492 μΙ) under argon at 0 ° C over 0.5 h. . The reaction mixture was then warmed to room temperature and stirred for 1 hour. TLC (EtOAc: Hexane, 1: 1) was used to monitor the reaction; indicates that MsO-ester formation and SEM cleavage followed by ring closure occurs in a single vessel. The mixture was diluted with CH 2 Cl 2 (25 mL) and washed with aqueous HCl (0.5 N), aqueous NaHCO 3, water, brine, and dried over MgSO 4. Filtration by evaporation of the solvent gave a yellow solid. Purification by preparative HPLC (EtOAc: hexane, gradient from 1: 1 to 1: 0) gave product G (1.3 g).

Example I - Compound of the Invention Network

1-methyl-1-phenylethylamine H (164 mg, 1.2 mmol) in anhydrous THF under argon was cooled to 0 ° C in a 25 mL one-neck flask equipped with a magnetic stir bar, argon inlet, and a rubber septum. NBuLi in hexane (0.5 mL, 2.4 M) was slowly added to the solution. The reaction mixture turned to a light yellow color. The mixture was stirred for 45 minutes and compound G (150 mg, 0.405 mmol) in THF (1 mL) was added. The solution was warmed to room temperature and further refluxed for 12 hours. TLC (CH ₂ Cl ₂ : CH ₃ OH, 99.Ί) indicates complete reaction. The reaction was quenched with MeOH and evaporated to give a residue which was redissolved in CH ₂ Cl ₂ , washed with aqueous NaHCO 3 (5%), water, brine and dried over Na ₂ SO 4. The crude product, after filtration and evaporation in vacuo to remove excess amine H, is purified by chromatography (CH ₂ Cl ₂ : CH 3 OH, 99: 1) to give the compound of the invention J.

Example II - Compound of the Invention

In a 25 mL one-neck flask, Compound J (181 mg, 0.5 mmol) in anhydrous THF (10 mL) was cooled to 0 ° C under argon, and then NaH (18 mg), prewashed in hexane, was added to the solution. as a suspension in hexane. After stirring for 15 minutes, methyl iodide (71 mg, 0.5 mmol) in THF (0.5 mL) was added. The solution was warmed to room temperature and further refluxed for 2 hours to complete the reaction. The reaction is quenched with MeOH and evaporated to give a residue which is redissolved in CH 2 Cl 2, washed with aqueous NaHCO ₃ (5%), H 2 O, brine and dried over Na 2 SO 4 The crude product is purified by chromatography (CH 2 Cl 2 CH ₃ OH from 99: 1 to 95): 5) to obtain compound P. ........ ......_________ ..

Precursor Example 7

κ • to to β · to to · to · to · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Solid N-bromosuccinimide (NBS) (98 mg, 0.26 mmol) was added to a solution of compound G (0.5 mmol) in 15 mL of CCl ₄ . Then the free radical initiator benzoyl peroxide (2 mol%) was added gradually. The vessel was placed in a 90 ° C oil bath. After stirring for 10 minutes, the reaction was complete. Filtration of the mixture through a pad of celite and evaporation of the filtrate gave a residue. Purification by chromatography (EtOAc: hexane, 1: 3 to 1: 1) afforded the compound

TO.

Precursor Example 8

To a solution of K (0.22 mmol) and Pd (PPh ₃ ) ₄ (13 mg, 0.056 mmol) in 7 mL of anhydrous toluene was added phenyltributyltin (0.26 mmol) and several crystals (about 2 mg) of 2,6-di-tert-butyl ester. -butyl-4-methylphenol. The reaction mixture was refluxed under argon for 6 hours at which time the reaction was complete. The reaction mixture was cooled and then diluted with 1-2 mL of ethyl acetate (EtOAc). The resulting mixture was washed with water, brine, extracted with CH 2 Cl 2, dried over Na ₂ SO ₄ and filtered. The filtrate was treated with 3 ml of 30% aqueous KF at room temperature for 2 hours. The solid was filtered off. The filtrate was diluted with CH ₂ Cl ₂ and washed with water, 30% aqueous NH ₄ OH (3x), brine, extracted with EtOAc, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a yellow crude product. Purification by chromatography (silica gel, EtOA: hexane, 1: 1 to 1: 0) gave Compound L.

EXAMPLE III Compound of the Invention

1-methyl-1-phenylethylamine M (1.2 mmol) in anhydrous THF under argon atmosphere was cooled to 0 ° C in a 25 mL one-neck flask equipped with a magnetic stir bar, argon inlet, and a rubber septum. NBuLi in hexane (0.5 mL, 2.4 M) was slowly added to the solution. The reaction mixture turned pale yellow in color. The mixture was stirred for 45 minutes and compound L (150 mg, 0.405 mmol) in THF (1 mL) was added. The solution was warmed to room temperature and further heated at reflux for 12 hours to complete the reaction. The reaction is quenched with MeOH and evaporated to give a residue,

- which is redissolved in CH ₂ Cl ₂ , washed with aqueous NaHCO ₃ (5%), water, .................

brine and dried over Na ₂ SO ₄ . The crude product, after filtration and evaporation in vacuo to remove excess amine M, is purified by chromatography (to give the compound of the invention N.

Compositions of the invention

The composition of the invention comprises:

(a) a safe and effective amount of a compound of the invention; and

b) a pharmaceutically acceptable excipient

Typically, such a composition comprises several excipients. It may also contain optionally other active compounds which do not substantially interfere with the activity of the compound of the invention.

• · · · · ·

The compositions of the invention may be in any form suitable (for example) for oral, rectal, topical or parenteral administration. The compositions of the present invention are usually provided in unit dosage form. The term "unit dosage form as used herein" is a composition comprising an amount of a compound of the invention suitable for administration to a human patient or lower animal in a unit dose according to current medical practice.

The term "safe and effective amount" of a compound of the invention as used herein means an amount that is large enough to substantially induce a positive modification of the symptoms and / or condition to be treated in the host, but small enough to avoid serious side effects. effects in the host (such as toxicity, irritation or allergic reaction) at a reasonable benefit / risk ratio. The safe and effective amount will vary depending on such factors as the condition to be treated, the age and physical condition of the patient, the duration of treatment, the nature of the competitive therapy (if any), the specific dosage form to be used and the dosage regimen used. .

The term "pharmaceutically acceptable excipient" as used herein includes physiologically inert, pharmacologically inactive substances that are compatible with the physical and chemical characteristics of the compound of the invention and of sufficiently high purity and sufficiently low toxicity to be suitable for administration to a human or lower animal . The term "compatible" as used herein means the excipients of the present composition which are capable of being mixed with the compound of the invention and with each other in such a way that there is no interaction that could substantially reduce the pharmaceutical efficacy of the compound in conventional situations.

A variety of pharmaceutically acceptable excipients are known to be used with respect to a specific route of administration. Excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, cosolvents, buffer systems, surfactants, preservatives, sweeteners, flavors, dyes, and pigments. The amount of excipients used in conjunction with the compound of the invention should be sufficient to provide a practical amount of material for administration per dosage unit of the compound of the invention. Some examples of substances that can serve as pharmaceutically acceptable excipients are sugars such as lactose, dextrose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxypropylcellulose and cellulose acetate; polymers such as povidone and carbomers; powdered tragacanth, gums such as xanthan gum, guar gum and acacia; malt; solid lubricants such as stearic acid, magnesium stearate and talc; inorganic binders such as calcium phosphate and calcium sulfate; disintegrating agents such as sodium starch glycolate, crospovidone, sodium croscarmellose and microcrystalline cellulose; encapsulating and coating materials such as gelatin, waxes and cellulose derivatives, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and giant oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid, surfactants such as Tweens®, alkyl sulfate salts, fatty acid salts, sucrose esters, ethyl oleate; coloring agents; tableting agents; stabilizers; antioxidants; preservatives; solvents such as ethanol, pyrogen-free water, isotonic saline and buffer solutions such as phosphoric acid, tartaric acid, citric acid and acetic acid and their sodium, potassium and ammonium salts.

Preferred compositions of the present invention are oral dosage forms. The term "oral dosage form" as used herein means any pharmaceutical composition intended to be systemically administered to an individual so that the composition extends through the mouth into the gastrointestinal tract. Preferred oral unit dosage forms are tablets, which may be coated or uncoated, and capsules, gelatin or soft gel. The oral unit dosage form of the composition of the invention preferably contains at least 4 mg, more preferably at least 20 mg, even more preferably at least 100 mg and preferably at most 1000 mg, more preferably at most 500 mg, even more preferably at most 250 mg of a compound of the present invention. The oral dosage form of the composition of the invention preferably comprises at least 1%, more preferably at least 10% and preferably at most 70%, more preferably at most 40% of the compound of the invention; and preferably comprises at least 30%, more preferably at least 60% and preferably at most 99%, more preferably at most 90% of pharmaceutically acceptable excipients.

Parenteral dosage forms are also preferred compositions of the invention. The term "parenteral dosage form" as used herein means any pharmaceutical composition which is intended to be systemically administered to a human or lower animal to be disseminated by means of a solution or emulsion containing the active ingredient, by piercing the skin of the individual to extend the solution or emulsion into of the individual circulatory system, either by intravenous, intramuscular, intraperitoneal or subcutaneous injection. The parenteral unit dosage form of the present invention preferably comprises at least 1 mg, more preferably at least 6 mg, even more preferably at least 30 mg and preferably at most 400 mg, more preferably at most 100 mg, even more preferably at most 40 mg of a compound of the invention. The parenteral dosage form of the invention preferably comprises at least 1%, more preferably at least 5% and preferably at most 20%, more preferably at most 10% of a compound of the invention; and preferably contains at least 80%, more preferably at least 90% and preferably at most 99%, more preferably at most 95% of pharmaceutically acceptable excipients. Further, dosages for injection may be prepared in dried or lyophilized form. Such forms may be diluted with water, saline or buffer solution, depending on the preparation of the dosage form. Such forms may be packaged as single or multiple doses for ease of handling. When lyophilized or dried dosage forms are used, the diluted dosage form is preferably isotonic and at physiologically compatible pH and comprises the compound of the invention and excipients in the amounts and percentages indicated above in this paragraph.

Methods of treatment using the compounds of the invention.

The compounds of the invention demonstrate pharmaceutical activity in processes known to be associated with one or more cardiovascular activities, inflammatory mechanisms, oncology, and regulation of protein transport from cells. The present invention encompasses methods of using the above compounds of the invention for the therapeutic or prophylactic treatment of one or more of the following diseases or diseases: congestive heart failure, arrhythmia, hypotension, cardiac reperfusion injury, arteriosclerosis, restenosis, vascular tone, bacterial infection, cancer, Kaposi's sarcoma, psoriasis, migraine, nasal congestion, allergic reaction, rheumatoid arthritis and osteoporosis. Such methods include administering to a human or lower animal in need of such treatment or prevention a safe and effective amount of a compound of the present invention.

For oral administration of the compounds and / or compositions of the invention, preferably at least 0.1 mg / kg, more preferably at least 0.5 mg / kg, even more preferably at least 2 mg / kg and preferably at most 20 mg / kg are administered to a human or lower animal,

more preferably at most 5 mg / kg and even more preferably at most 2 mg / kg of a compound of the invention, preferably at least once a day, more preferably at least twice a day and preferably at most four times a day, more preferably at most twice a day. The duration of treatment at oral daily doses depends on the disease or disease to be treated; preferably is at least 1 day, more preferably at least 3 days, even more preferably at least 7 days and preferably at most 5 years, more preferably at most 60 days, even more preferably at most 15 days.

For parenteral administration of the compounds and / or compositions of the invention, preferably at least 0.04 mg / kg, more preferably at least 0.2 mg / kg, even more preferably at least 1 mg / kg and preferably at most 10 mg / kg, more preferably at least 0.04 mg / kg, at most 4 mg / kg and even more preferably at most 1 mg / kg of a compound of the invention, preferably at least once a day, more preferably at least twice a day and preferably at most four times a day, more preferably at most twice a day. The duration of treatment at oral daily doses depends on the disease or disease to be treated; preferably is at least 1 day, more preferably at least 3 days, even more preferably at least 7 days, and preferably at most 60 days, more preferably at most 20 days, even more preferably at most 5 days.

While particular embodiments of the present invention have been described herein, it will be apparent to those skilled in the art that many modifications of the present invention may be made without departing from the spirit and scope of the present invention. This scope is included in the appended claims and all such modifications are within the scope of the present invention.

Claims (10)

PATENT CLAIMS A heterocyclic compound comprising an imidazole ring of the general formula wherein: a) each R 1 is independently selected from the group consisting of hydrogen, alkyl, aryl and heterocycle; preferably each R 1 is independently selected from the group consisting of hydrogen; linear, branched and cyclic alkanyl, alkenyl; and phenyl; b) R 2 is selected from the group consisting of hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl and arylsulfonyl; preferably each R 2 is selected from the group consisting of hydrogen; linear, branched and cyclic alkanyl and alkenyl; alkylacyl and phenylacyl; c) each R 3 is independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycle, nitro, cyano and unsubstituted or alkyl or aryl or heterocycle substituted hydroxy, thio, amino, amide, formyl (acyl), carboxy and carboxamide ; or two R 3 together are alkylene or heteroalkylene, attached to adjacent carbon atoms of the phenyl to which R 3 are attached; preferably each R 3 is independently selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl , a carboxyl group, and alkyl and aryl esters and amides thereof; or preferably two R 3 together are alkylene or heteroalkylene and, with the carbon atoms to which they are attached, form a cycloalkyl, aryl or heterocyclic ring; d) R 4 is selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycle and carboxy and its alkyl and aryl esters and amides; e) each R 5 is independently selected from the group consisting of hydrogen, alkyl and aryl; 00 00 00 f) each R 6 is independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl, aryl, or heterocycle substituted hydroxy, thio, amino, amide, sulfonamide, formyl, carboxy, and carboxamide; or two R 6 are together alkylene or heteroalkylene, or R 5 and R 6, which are bonded to adjacent carbon atoms together to form alkylene or heteroalkylene; preferably each R 6 is independently selected from the group consisting of hydrogen, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, allyklamino, arylamino, amide, alkylamide, arylamide, sulfonamide, alkylsulfonamide, arylsulfonamide, formyl , alkylacyl, arylacyl, carboxy and its alkyl, and aryl esters and amides; or preferably two R 3 together are alkylene or heteroalkylene and, with the carbon atoms to which they are attached, form a cycloalkyl, aryl or heterocyclic ring; g) B is zero or -C (R 7) = C (R 7) -; h) if B is zero, then n is an integer from 0 to 3, otherwise n is from zero to 1; i) each R 7 is independently selected from the group consisting of hydrogen, alkyl and aryl; preferably, each R 7 is hydrogen or C 1 -C 4 alkyl; and an optical isomer, diastereomer or enantiomer thereof; and a pharmaceutically acceptable salt, hydrate or biohydrolyzable ester, amide or imide thereof. The imidazole ring-containing heterocyclic compound of claim 1, wherein a) each R 1 is independently selected from the group consisting of unsubstituted C 1 -C 5 linear or C 3 -C 5 branched or cyclic alkanyl; or unsubstituted C 2 -C 5 linear or C 3 -C 5 branched or cyclic alkenyl having one double bond; b) R2 is selected from the group consisting of hydrogen; unsubstituted C1-C5 linear or C3-C5 branched or cyclic alkanyl; or unsubstituted C 2 -C 5 linear or C 3 -C 5 branched or cyclic alkenyl having one double bond; c) each R 3 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, thio, C 1 -C ₄ alkylthio, C 1 -C 4 mono- or dialkylamino, C 1 -C 4 alkylacyl; d) R 4 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl and phenyl; e) both R5 are hydrogen; • 99 99 99 99 • 9 9 • • • 9 • • 9 • 99 • • 9 9 • 9 9 · • · 9 • 9 • «·· 9 9 9 9 f) one R 6 is selected from the group consisting of alkoxy, alkylthio, monoalkylamino, dialkylamino, wherein the alkyl moiety is saturated and unsubstituted and contains 1 to 4 carbon atoms; and the second R 6 is selected from the group consisting of hydrogen, alkoxy, alkylthio, monoalkylamino, dialkylamino, wherein the alkyl moiety is saturated and unsubstituted and contains 1 to 4 carbon atoms; or the alkyl moieties of the two R 6 are joined to form an alkylene moiety having 1 to 4 carbon atoms, preferably both R 6 moieties being C 1 -C 4 alkoxy or C 1 -C 4 alkylthio; and g) no more than one R 7 is other than hydrogen; preferably all R7 are hydrogen. An imidazole ring-containing heterocyclic compound according to claim 1 or 2, wherein both R 6 are methoxy. The imidazole ring-containing heterocyclic compound of claim 2, wherein B is zero and n is 1 or 2. An imidazole ring-containing heterocyclic compound according to claim 2, wherein B is -C (R 7) = C (R 7) - and n is 0. The imidazole-containing heterocyclic compound of claim 1 or 2, wherein one to three R 3 is independently selected from the group consisting of F, Cl, Br and the others being hydrogen; or one to three R 3 is unsubstituted methyl and the others are hydrogen; or one or two R 3 is trifluoromethyl and the others are hydrogen. The imidazole ring-containing heterocyclic compound of claim 2, wherein both R 1 are methyl. 8. A pharmaceutical composition comprising: a) a safe and effective amount of an imidazole ring containing heterocyclic compound according to claim 1 or 2; and b) a pharmaceutically acceptable carrier. The use of an imidazole ring-containing heterocyclic compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of nasal congestion, migraine, migraine, migraine. Cardiac arrhythmia, cardiac reperfusion injury, or hypotension in a human or lower animal subject in need thereof, wherein the treatment or prevention comprises administering to the subject a safe and effective amount of a heterocyclic compound containing an imidazole ring according to claim 1 or 2. Use of an imidazole ring-containing heterocyclic compound according to claim 1 or 2 for the treatment or prevention of a disease caused by cellular protein transport, including, but not limited to, osteoporosis, rheumatoid arthritis, allergic reactions, restenosis, vascular tone, cancer, Kaposi's sarcoma, psoriasis and a bacterial infection in a human or lower animal subject in need thereof, wherein the treatment or prevention comprises administering to the subject a safe and effective amount of a heterocyclic compound containing an imidazole ring according to claim 1, or