KR20020002462A - Imidazo-containing heterocyclic compounds, their compositions and uses - Google Patents

Abstract

[Formula 1]

[Wherein each R 1 is independently alkyl, aryl or a heterocycle; Each R2-R7 is independently hydrogen or another substituent; Without B and n is 0-3, or B is ethenyl and n is 0-1

The present invention relates to a compound having the above formula (I) and a pharmaceutically acceptable form thereof. The present invention also relates to pharmaceutical compositions containing the compounds and methods of treating or preventing diseases or disorders using the compounds.

Description

Imidazo-containing heterocyclic compounds, compositions and uses thereof {IMIDAZO-CONTAINING HETEROCYCLIC COMPOUNDS, THEIR COMPOSITIONS AND USES}

Certain imidazo-isoquinoline compounds are disclosed in US Pat. No. 3,917,610, issued Nov. 4, 1975; They are known to have specific cardiovascular activity. One such compound is also described in Borchard, Fox and Greeff, "The Positive Inotropic, Antiarrhythmic and Na ⁺ , K ⁺ -ATPase Inhibitory Effects of the Isoquinoline Derivative, BIIA", Achives of Pharmacology , vol. 312 (1980), pp. 187-192.

The present invention relates to novel imidazo-containing heterocyclic compounds, pharmaceutical compositions containing them, and their therapeutic or prophylactic use in cardiovascular, tumor, infectious and inflammatory diseases.

The present invention provides a compound having the formula: an optical isomer, diastereomer or enantiomer thereof; Pharmaceutically acceptable salts, hydrates, or biohydrolyzable esters, amides or imides thereof.

[In the meal,

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

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

(c) each R 3 represents hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, formyl (acyl ), Carboxy, and carboxamide; Two R 3 on adjacent carbon may optionally be alkylene or heteroalkylene together to form a ring fused with the phenyl to which they are attached;

(d) R 4 is selected from hydrogen, halo, alkyl, aryl, heterocycle, and carboxy and alkyl and aryl esters and amides thereof;

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

(f) each R 6 represents hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, sulfonamide, fort Independently selected from wheat (acyl), carboxy, and carboxamide; Both R 6 may together optionally be alkylene or heteroalkylene, forming a fused ring with the phenyl to which they are attached;

(g) B is absent or -C (R7) = C (R7)-;

(h) if B is absent, n is an integer from 0 to about 3, else n is from 0 to about 1;

(i) each R 7 is independently selected from hydrogen, alkyl and aryl].

The invention also provides a composition comprising a subject compound and a pharmaceutically acceptable excipient; And a method for treating or preventing a disease or disorder by administering a safe effective amount of a subject compound to a human or lower animal in need thereof.

As used herein, unless specified otherwise, "alkyl" means branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted hydrocarbon chain. The term "alkyl" may be used alone or as part of another word that may be shortened to "alk" (eg, in alk oxy: alkoxy, alk ylacyl: alkylacyl). Preferred linear alkyls have 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms, even more preferably 1 to about 6 carbon atoms, even more preferably 1 to about 4 carbon atoms; Most preferred is methyl or ethyl. Preferred cyclic and branched alkyls have from 3 to about 20 carbon atoms, more preferably from 3 to about 10 carbon atoms, even more preferably from 3 to about 7 carbon atoms, even more preferably from 3 to about 5 carbon atoms. . Preferred cyclic alkyls have one hydrocarbon ring, but may have two, three or more fused hydrocarbon rings. Preferred alkyls are unsaturated with 1 to about 3 double or triple bonds, preferably double bonds; More preferably monounsaturated with one double bond. Even more preferred alkyl is saturated. Here, saturated alkyl is referred to as "alkanyl". Here, alkyl unsaturated with only one or more double bonds (no triple bonds are present) is referred to as "alkenyl". Preferred substituents of alkyl are halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkyl Acyl, arylacyl, carboxy and their alkyl and aryl esters and amides, nitro, and cyano. Also preferred is unsubstituted alkyl.

As used herein, "heteroatom" means a nitrogen, oxygen or sulfur atom.

As used herein, "alkylene" refers to alkyl connecting two different moieties, and "heteroalkylene" refers to alkylene having one or more heteroatoms in the linking chain.

Unless otherwise specified, "aryl" as used herein means a substituted or unsubstituted aromatic hydrocarbon ring (or fused ring). The term "aryl" may be used alone or as part of another word (eg, in aryloxy, arylacyl). Preferred aryls have 6 to about 14, preferably about 10 or less carbon atoms in the aromatic ring, and a total of 6 to 20, preferably about 12 or less carbon atoms. Preferred aryl is phenyl or naphthyl; Phenyl is most preferred. Preferred substituents of aryl are halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkyl Acyl, arylacyl, carboxy and their alkyl and aryl esters and amides, nitro, and cyano. Unsubstituted aryl is also preferred.

Unless otherwise specified, "heterocycle" as used herein means a saturated, unsaturated or aromatic ring hydrocarbon ring (or fused ring) having one or more hetero atoms in the hydrocarbon ring (s). Preferred heterocycles have from 1 to about 6 heteroatoms in the ring, more preferably 1 or 2 or 3 heteroatoms in the ring (s). Preferred heterocycles have from 3 to about 14, preferably up to about 10, carbon and heteroatoms in the ring (s), more preferably from 3 to about 7, even more preferably in the ring (s) Has 5 or 6 carbons and hetero atoms; The total in total has 3 to about 20 carbons and hetero atoms, more preferably 3 to about 10, even more preferably about 5 or 6 carbons and hetero atoms. Preferred heterocycles have one ring, but may also have two, three or more fused rings. More preferred heterocyclic rings include those having one ring having 5 or 6 carbons and hetero atoms, having up to 3 ring heteroatoms in the ring and up to 2 being O and S. One or two ring atoms are O or S and the rest are C; Even more preferred are 5- or 6-ring atom heterocycles in which one, two or three ring atoms are N and the rest are C. Said preferred 5- or 6-ring atom heterocycle is preferably saturated, unsaturated or aromatic with one or two double bonds. Said preferred 5- or 6-ring atom heterocycle is preferably a single ring; Saturated or fused with a 3- to 6-ring atom hydrocarbon ring which is unsaturated or aromatic (phenyl) with one or two double bonds; Another fused with said 5- or 6-ring atom heterocyclic ring. The heterocycle is substituted or unsubstituted. Preferred heterocyclic substituents are the same as for alkyl.

Compound of the Invention

The present invention includes compounds having the formula:

In formula (1), each R 1 is independently selected from alkyl, aryl and heterocycle. Preferred R1 comprises linear alkanyl having 1 to about 6 carbon atoms, linear alkenyl having 2 to about 6 carbon atoms, and branched and cyclic alkanyl and alkenyl having 3 to about 6 carbon atoms, wherein the alkenyl is preferably 1 Has double bonds. Said preferred alkanyls and alkenyls are preferably unsubstituted or substituted with phenyl, heterocycles having 5 to 6 ring atoms, carboxy and C ₁ -C ₆ alkyl and phenyl esters thereof, or cyano. More preferably such alkanyls and alkenyls have about 5 carbon atoms or less, even more preferably 4 carbon atoms or less. More preferred R1 is methyl, ethyl and isopropyl. Most preferred R 1 is unsubstituted methyl. It is also preferable that both R1 are the same moiety.

In formula (1), R 2 is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl, and arylsulfonyl. Preferred R2 is hydrogen; C ₁ -C ₆ alkyl (the alkyl being saturated or unsaturated with one double bond, unsubstituted or substituted with phenyl); C ₁ -C ₆ alkylacyl (alkyl is saturated or unsaturated with one double bond); And phenylacyl. More preferably, the alkyl addition of said moiety is C ₁ -C ₄ and is saturated. Even more preferred is that R2 is methyl. Most preferred R2 is hydrogen.

In Formula 1, each R 3 represents hydrogen, halo, alkyl, aryl, heterocycle, nitro and cyano; Or are each independently selected from hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide unsubstituted or preferably substituted with alkyl or aryl or heterocycle; Both R 3 together are alkylene or heteroalkylene bonded to adjacent carbon atoms of the phenyl ring, thereby forming a cycloalkyl or aryl or heterocyclic ring fused with the phenyl ring. Preferred R3 is hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkyl Acyl, arylacyl, carboxy and alkyl or aryl esters and amides thereof; More preferably 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 . It is more preferable that 1-3 R <3> is halo and the remainder is hydrogen. Furthermore, it is more preferable that 1-3 R <3> is methyl or ethyl and remainder is hydrogen. It is also preferred that one R 3 is dialkylamino (the alkyl has from 1 to about 6 carbon atoms, preferably from about 1 to about 4 carbon atoms), and the remainder is hydrogen, wherein R 3 is preferably carbon of 4 Is attached to. R 3 of 1 to 3 are independently selected from F, Cl and Br, more preferably the remainder is hydrogen; If two or three R 3 are F, Cl or Br, it is even more preferred that they are identical to each other. Furthermore, it is more preferable that 1-3 R <3> is unsubstituted methyl and the remainder is hydrogen. It is more preferable that one or two R 3 is trifluoromethyl, and the remainder is hydrogen.

Or two R 3 attached to adjacent carbon atoms of a phenyl ring together are saturated or unsaturated alkylenes having 1 to about 6 carbon atoms and 0 to about 3 hetero atoms, or heteroalkylenes and thus ring fused to phenyl And the ring preferably has about 5 to about 8 ring atoms. The ring fused to said phenyl preferably has 5 to about 6 ring atoms, of which 0 to 2, more preferably 0 or 1, are hetero atoms. Preferred fused rings (including phenyl bound to R3) include naphthyl, indolyl, benzimidazolyl, benzofuryl, benzopyranyl. When two R 3 form a fused ring with phenyl, the other R 3 is preferably H.

In formula (1), R 4 is selected from hydrogen, halo, alkyl, aryl, heterocycle, carboxy and alkyl esters and amides thereof. Preferred R 4 is selected from hydrogen, halo, C ₁ -C ₄ alkyl, phenyl, more preferred R 4 is selected from hydrogen and unsubstituted and substituted phenyl; Substituents on the phenyl are preferably selected from hydroxy, alkoxy, thio and alkylthio. Most preferred R4 is hydrogen.

In Formula 1, each R 5 is independently selected from hydrogen, alkyl and aryl. Preferred R5 is selected from hydrogen and alkyl of 1 to 4 carbon atoms, in particular unsubstituted methyl or ethyl. Most preferably both R 5 are hydrogen.

In Formula 1, each R 6 represents hydrogen, halo, alkyl, aryl, heterocycle, cyano and nitro; Or independently selected from hydroxy, thio, amino, amide, formyl (acyl), carboxy, carboxamide, and sulfonamide, unsubstituted or preferably substituted with alkyl or aryl or heterocycle. Preferred R6 is hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, sulfonamide, alkyl Sulfonamides, arylsulfonamides, formyl, alkylacyls, arylacyls, carboxys and their alkyl and aryl esters and amides; More preferably hydrogen, halo, hydroxy, C ₁ -C ₄ alkoxy, thio, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkyl esters and amides of carboxy, and a compound having 5 to 6 ring atoms It is chosen from summons. More preferably one or both R 6 are selected such that at least one hetero atom is directly bonded to the phenyl ring. When two R 6 have a hetero atom directly bonded to the adjacent carbon of the phenyl ring, the two R 6 together may form an alkylene moiety which connects two heteroatoms, the alkylene moiety being preferably 1 to about 4, more Preferably it has 1 or 2 carbon atoms. It is preferred that one or both R 6 are non-hydrogen moieties; It is preferred that both are non-hydrogen moieties. More preferably, both R 6 are alkoxy or both alkylthio, preferably both are the same. Preferred alkyl moieties of R 6 have 1 to about 4 carbon atoms, more preferably 1 or 2 carbon atoms; Methyl is most preferred. The alkyl moiety is preferably unsaturated. The alkyl moiety is preferably saturated. Most preferably both R 6 are methoxy or ethoxy, in particular methoxy.

And R 5 and R 6 bonded to adjacent carbon atoms of the phenyl ring together are saturated or unsaturated alkylene or heteroalkylene having from 1 to about 6 carbon atoms and 0 to about 3 heteroatoms, so that the ring fused to phenyl It is preferred that the ring has about 5 to about 8 ring atoms. The ring fused to phenyl preferably has about 5 or about 6 ring atoms, of which 0 to 2, more preferably 0 or 1, are heteroatoms. Preferred rings formed of R 5 and R 6 include phenyl, furyl, pyrrolyl, dioxanyl, imidazoyl, pyridinyl, pyrrolidinyl, piperidinyl. When R5 and R6 form a fused ring, the other R5 and R6 are both preferably hydrogen.

In Formula 1, B is absent or -C (R7) = C (R7)-. In the absence of B, n is an integer from 0 to about 3, preferably 1 or 2. When B is -C (R7) = C (R7)-, n is an integer from 0 to about 1, preferably 0. It is preferable that there is no B.

In formulas (1) and (B), each R 7 is independently selected from hydrogen, alkyl and aryl. Non-hydrogen R7 is preferably phenyl or alkyl having 1 to about 4 carbon atoms, preferably 1 to 2 carbon atoms. The non-hydrogen R7 is preferably unsubstituted. Alkyl R7 is preferably saturated. Preferably at least one of the total R 7 is other than hydrogen. More preferably all R 7 are hydrogen.

The present invention includes the optical isomers, diastereomers, and enantiomers of the compound of formula (I). The present invention includes pharmaceutically acceptable salts, hydrates and biohydrolyzable esters, amides and imides of such compounds.

A “pharmaceutically acceptable salt” is a cationic salt formed from any acidic group (eg carboxyl group) of a compound of Formula 1, or an anionic salt formed from any basic group (eg an amino group). Many pharmaceutically acceptable salts are known. Preferred cationic salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and inorganic salts such as ammonium. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates and the like. The addition salt may provide an optical center that did not exist.

The compounds of the present invention, and salts thereof, may have one or more chiral centers. The present invention includes all optical isomers of Formula 1 compounds and salts thereof, including diastereomers and enantiomers. The present invention includes and contemplates each optical isomer, diastereomer, or enantiomer thereof in a mixture comprising a purified form, a substantially purified form, and a racemic mixture.

Preferred compounds of the present invention include compounds having Formula 2:

In formula (2), R 1, R 3 and R 6 are as described above and X is 0 or 1.

In formula (2), each R 1 is preferably linear alkanyl having 1 to 4 carbon atoms, linear alkenyl having 1 double bond and having 2 to 4 carbon atoms, branched and cyclic alkanyl having 3 to 5 carbon atoms, and 1 double It is independently selected from branched and cyclic alkenyl having 3 to 5 carbon atoms with a bond. Said preferable R <1> is unsubstituted or substituted by 1 phenyl, More preferably, it is unsubstituted. More preferred R1 is selected from methyl, ethyl, ethenyl, n-propyl, i-propyl, n-propenyl, i-propenyl, s-butyl, cyclopropyl, cyclobutyl and cyclopentyl. Even more preferred R1 is selected from methyl, ethyl, ethenyl, i-propyl and n-propenyl. Most preferred R 1 is methyl. It is also preferred that both R1 are the same.

In formula (2), one or both R 6, preferably both R 6 are alkylthio or more preferably alkoxy having alkanyl having 1 to 4 carbon atoms. If one R 6 is not alkylthio or alkoxy, it is preferably hydrogen. More preferably both R6 is methoxy or ethoxy; Most preferably both R 6 are methoxy.

In formula (2), R 3 is preferably all hydrogen; Mono-, di-, or trihalo (preferably selected from fluoro, chloro and bromo and preferably present in one or more 2 ', 3', 4 'and 5' positions); Mono-, di- and trimethyl (preferably in one or more 2 ', 3', 4 'and 6' positions); And mono- or di-trifluoromethyl (preferably in the 3 'and 5' positions of one or both). It is also preferred that one R 3 is preferably dialkylamino in the 4 ′ position, the two alkyls are preferably identical and have from 1 to 4 carbon atoms and the other R 3 is hydrogen. More preferred combinations of R3 are 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 each case all other R 3 are hydrogen. Also preferred R3 combinations are selected from 2 ', 4'-dihalo and 3', 4'-dihalo, wherein one halo is selected from fluoro, chloro and bromo and the other halo is different from the three ; More preferably one of the halo is fluoro and all other R 3 have hydrogen. Most preferred R3 combination is selected from 4'-chloro, 4'-bromo, and 2 ', 4'-dichloro, all other R3 being hydrogen.

Non-limiting examples of compounds of the present invention include compounds of formula 2, wherein R6 is methoxy and R1 and R3 are all as specified in the following table (unspecific R3 is hydrogen):

Example x R1 R3 One 0 Methyl, methyl Hydrogen 2 0 Methyl, methyl 4'-fluoro 3 One Methyl, methyl 4'-chloro 4 0 Methyl, methyl 4'-Bromo 5 0 Methyl, methyl 2 ', 4'-difluoro 6 One Methyl, methyl 2 ', 4'-dichloro 7 0 Methyl, methyl 2'-fluoro, 4'-chloro 8 One Methyl, methyl 2'-fluoro, 4'-bromo

Example x R1 R3 9 0 Methyl, methyl 2'-chloro, 4'-fluoro 10 One Methyl, methyl 2'-bromo, 4'-fluoro 11 One Methyl, methyl 3 ', 4'-difluoro 12 0 Methyl, methyl 3 ', 4'-dichloro 13 0 Methyl, methyl 3'-fluoro, 4'-chloro 14 One Methyl, methyl 3'-fluoro, 4'-bromo 15 0 Methyl, methyl 3'-chloro, 4'-fluoro 16 One Methyl, methyl 3'-bromo, 4'-fluoro 17 0 Methyl, methyl 2 ', 4', 5'-trifluoro 18 0 Methyl, methyl 4'-methyl 19 One Methyl, methyl 2 ', 4'-dimethyl 20 0 Methyl, methyl 3 ', 4'-dimethyl 21 One Methyl, methyl 2 ', 4', 6'-trimethyl 22 One Methyl, methyl 3'-trifluoromethyl 23 0 Methyl, methyl 3 ', 5'-di-trifluoromethyl 24 0 Methyl, methyl 4'-fluoro, 3'-trifluoromethyl 25 One Ethyl, ethyl 4'-fluoro 26 0 Ethyl, methyl 4'-chloro 27 0 Ethyl, ethyl 4'-Bromo

28 One Ethyl, methyl 2 ', 4'-dichloro 29 One Ethyl, ethyl 3'-fluoro, 4'-chloro 30 One Ethenyl, ethenyl 4'-chloro 31 0 Ethenyl, methyl 2 ', 4'-dichloro 32 0 i-profiles, i-profiles 4'-fluoro 33 0 i-propyl, methyl 4'-chloro 34 One i-profiles, i-profiles 4'-Bromo 35 One i-propyl, methyl 2 ', 4'-dichloro 36 0 i-profiles, i-profiles 3'-fluoro, 4'-chloro 37 0 -CH ₂ -CH = CH ₂ , methyl 4'-fluoro 38 One -CH ₂ -CH = CH ₂ , -CH ₂ -CH = CH ₂ 4'-chloro

Example x R1 R3 39 One -CH ₂ -CH = CH ₂ , ethyl 2 ', 4'-dichloro 40 0 s-butyl, s-butyl 4'-chloro 41 One Cyclopentyl, methyl 4'-chloro 42 One Methyl, methyl 2 ', 4', 5'-trifluoro 43 0 Methyl, methyl 2 ', 3', 4'-trifluoro 44 0 Ethyl, ethyl 2 ', 4', 5'-trifluoro 45 One Ethyl, ethyl 2 ', 3', 4'-trifluoro 46 One Isopropyl, Isopropyl 2 ', 4', 5'-trifluoro 47 0 Isopropyl, Isopropyl 2 ', 3', 4'-trifluoro 48 0 Methyl, methyl 4'-dibutylamino 49 One Ethyl, ethyl 4'-dimethylamino 50 0 Isopropyl, Isopropyl 4'-diethylamino

It is also recognized that salts and other derivatives of these compounds can be used for tableting, administration and the like. Accordingly, pharmaceutically acceptable salts, hydrates or biohydrolyzable esters, amides or imides thereof are contemplated as part of the present invention.

Method of Preparation of the Compound

In preparing the compounds of the present invention, the order of the synthetic steps can be varied to increase the yield of the desired product. Those skilled in the art will recognize that in a successful synthesis, a sensible choice of reactants, solvents and temperatures is important. Starting materials used to prepare the subject compounds are known, prepared by known methods or commercially available.

It is recognized that one skilled in the art can easily perform standard manipulations of organic compounds without further instructions. This includes, but is not necessarily limited to, reduction, oxidation, acylation, substitution, etherification, esterification, sulfonation, and the like. Examples of such manipulations are discussed in the reference literature.

The process for preparing imidazo-isoquinoline compounds has been disclosed in US Pat. No. 3,917,610, issued November 4, 1975 and US Pat. No. 4,143,143, issued March 6, 1979, all of which are incorporated herein by reference. Is introduced.

The following schemes can be used to synthesize the compounds of the present invention. In this scheme, R1, R2, R3, R4, R5, R6, R7, B and n are as defined above. Unusual symbols and abbreviations for other parts are defined in the Examples below.

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

Precursor Example 1

A suspension solution of NaH (6.5 g, 0.162 mol, washed twice with hexanes) in anhydrous DMF (300 ml) was cooled in an ice / acetone bath (bath: bath temperature-15 ° C). Solid imidazole (10 g, 0.145 mol) was added in small amounts and the mixture was stirred at room temperature (rt) for 0.5 h; The solution became clear. SEM-Cl (25 g, 0.150 mol) was added dropwise over 1 hour at room temperature with a syringe pump; NaCl precipitated during the addition. The mixture was stirred at rt for about 1 h. Progress of the reaction was monitored by TLC (CH ₂ Cl ₂ / MeOH, 9: 1). The reaction was quenched by the careful addition of H ₂ O (10 ml). The solvent was evaporated in vacuo. The residue is dissolved in Et ₂ O (200 ml), washed with H ₂ O (4 × 50 ml), brine (50 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo to give compound A as an orange liquid. It was.

Precursor Example 2

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

Precursor Example 3

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

Precursor Example 4

To a solution of SEM-protected 2-phenylsulfon imidazole C (8.61 g, 25.4 mmol) in dry THF (250 mL), n-BuLi (1.6 M in hexane) (19.0 mL, 30.0 mmol) at -78 ° C. under argon. Drop wise with a syringe pump; The solution was stirred at -78 ° C for 30 minutes. Tributyltin chloride (6.9 mL, 25.4 mmol) was added dropwise by syringe pump. The mixture was stirred at rt for 1 h. Progress was monitored by TLC (hexane / EtOAc, 9: 1). H ₂ O (30 mL) was added to quench the reaction. The solvent was evaporated in vacuo. The residue is dissolved in ether (550 mL), washed with saturated NH ₄ Cl (3 × 150 mL), brine (150 mL), dried (MgSO ₄ ), filtered, evaporated in vacuo, chromatography (silica gel, gradient) : Purified with hexane (500 mL), hexane / EtOAc 50: 1; hexane / EtOAc 12: 1) to give D as clear oil.

Precursor Example 5

Pd (PPh ₃ ) ₄ (0.0177 g, 0.015 mmol) was added to stannylimidazole D (0.51 g, 0.80 mmol), 4,5-dimethoxy-2 in dioxane anhydride (4.0 mL) at room temperature. To a solution of-(2-hydroxyethyl) phenyl bromide E (0.33 g, 1.1 mmol) and LiCl (0.087 g, 2.1 mmol). A slight radical scavenger crystal (~ 2 mg), 2,6-di-tert-butyl-4-methylphenol, were added and heated to reflux for 5 hours under argon. The reaction was cooled to room temperature and treated with a 1: 1 mixture of ether and saturated aqueous KF solution (10 mL) for 15 hours. Progress was monitored by TLC (hexane / EtOAc, 3: 1). The mixture was filtered through a pad of celite and ether washed. The filtrate was washed with water (3 × 12 mL), brine (3 × 12 mL), dried (MgSO ₄ ), filtered, evaporated in vacuo and purified by chromatography (silica gel, hexane / EtOAc, 2: 3). F was obtained as an orange oil.

Precursor Example 6

To a solution of F (2.2 g, 4.24 mmol) and Et ₃ N (886 μl) in dichloromethane (200 mL) was added methylsulfonyl chloride (MsCl, 492 μl) over 0.5 h at 0 ° C. under a nitrogen atmosphere. . The reaction was then warmed to room temperature and stirred for 1 hour. The reaction was monitored using TLC (EtOAc: hexane, 1: 1); This indicated that MsO-ester formation and SEM-fracture followed by ring closure occurred in one reactor. The mixture was diluted with CH ₂ Cl ₂ (25 mL), washed with cold aqueous HCl (0.5N), aqueous NaHCO ₃ , H ₂ O, brine and dried over MgSO ₄ . Filtration and evaporation of the solvent gave a yellow solid. Purification using preparative HPLC (EtOAc: hexane, 1: 1 to 1: 0 gradient) gave the product G (1.3 g).

Compound Example I of the Invention

In a 25 mL 1 neck round bottom flask equipped with a magnetic stir bar, argon inlet and rubber septum, 1-methyl-1-phenyl-ethylamine (H) (164 mg, 1.2 mmol) in dry THF under argon atmosphere was zero. Cool to C. NBuLi (0.5 mL, 2.4 M) in hexane was added slowly to the solution. The reaction turned light yellow. After stirring for 45 minutes, compound G (150 mg, 0.405 mmol) in THF (1 mL) was added. The solution was allowed to warm to room temperature, further heated and stirred for 12 hours. TLC (CH ₂ Cl ₂ : CH ₃ OH, 99: 1) indicated completion of the reaction. The solution was quenched with MeOH and evaporated to give a residue, which was redissolved in CH ₂ Cl ₂ , washed with aqueous NaHCO ₃ (5%), H ₂ O, brine and dried over Na ₂ SO ₄ . After filtration and evaporation at high vacuum to remove any excess amine H, the crude product was purified by chromatography (CH ₂ Cl ₂ : CH ₃ OH, 99: 1) to afford compound J of the present invention.

Compound Example II of the Invention

In a 25 mL 1 neck round bottom flask, compound J (181 mg, 0.5 mmol) in dry THF (10 mL) under argon atmosphere was cooled to 0 ° C., and NaH (18 mg), which was prewashed with hexane, was added to the solution as a suspension in hexane. Added. After stirring for 15 minutes, methyl iodide (71 mg, 0.5 mmol) in THF (0.5 mL) was added. The solution was allowed to warm to room temperature, further heated to reflux for 2 hours to complete the reaction. The solution was quenched with MeOH and evaporated to give a residue, which was 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 was purified by chromatography (CH ₂ Cl ₂ : CH ₃ OH, 99: 1 to 95: 5) to give compound P of the present invention.

Precursor Example 7

N-bromosuccinimide (NBS) solid (98 mg, 0.26 mmol) was added to a solution of compound G (0.5 mmol) in 15 mL of CCl ₄ . The radical initiator benzoyl peroxide (2 mol%) was then added. The flask was placed in a 90 ° C. oil bath. After stirring for 10 minutes, the reaction was completed. The mixture was filtered through a pad of celite and the filtrate was evaporated to give a residue. Purification by chromatography (EtOAc: hexane, 1: 3 to 1: 1) yielded compound K.

Precursor Example 8

To a solution of K (0.22 mmol) and Pd (PPh ₃ ) ₄ (13 mg, 0.056 mmol) in 7 mL anhydrous toluene, phenyltributyltin (0.26 mmol) and some 2,6-di-tert-butyl-4-methylphenol Crystals (˜2 mg) were added. The reaction mixture was refluxed at 110 ° C. for 6 hours under nitrogen to complete the reaction. The reaction mixture was cooled and then diluted with 1-2 mL of ethyl acetate (EtOAc). The resulting mixture was washed with water, then 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 for 2 hours at room temperature. The solid was filtered off. The filtrate was diluted with CH ₂ Cl ₂ , washed with water, 30% aqueous NH ₄ OH (3 ×), brine, extracted with EtOAc, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the crude product. . Chromatographic purification (silica gel, EtOAc: hexane, 1: 1 to 1: 0) yielded compound L.

Example III of the present invention

In a 25 mL 1 neck round bottom flask equipped with a magnetic stir bar, argon inlet and rubber stopper, (1-methyl-1-phenyl-ethylamine) (M) (1.2 mmol) in dry THF under argon atmosphere was cooled to 0 ° C. Let's do it. NBuLi (0.5 mL, 2.4 M) in hexane is added slowly to the solution. The reaction turned light yellow. After stirring for 45 minutes, compound L (180 mg, 0.405 mmol) in THF (1 mL) was added. The solution is warmed to room temperature, further heated to reflux for 12 hours to complete the reaction. The solution was quenched with MeOH and evaporated to give a residue, which was redissolved in CH ₂ Cl ₂ , washed with aqueous NaHCO ₃ (5%), H ₂ O, brine and dried over Na ₂ SO ₄ . After filtration and evaporation at high vacuum to remove excess amine M, the crude product was purified by chromatography to give compound N of the present invention.

Compositions of the Invention

The composition of the present invention comprises the following a) and b):

a) a safe effective amount of a compound of the present invention; And

b) pharmaceutically acceptable excipients.

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

The compositions of the present invention may be in any of a variety of forms suitable for, for example, oral, rectal, micro or parenteral administration. The composition of the present invention is preferably provided in unit dosage form. As used herein, “unit dosage form” is a composition containing an amount of a subject compound suitable for administration to a human or lower animal subject in a single dose according to good treatment.

As used herein, a "safe effective amount" of a subject compound is large enough to induce significant positive modifications to the condition and / or condition being treated for the receptor, but can avoid serious side effects (toxic, irritant or allergic reactions) at the receptor. It is a balanced amount with a modest benefit / risk ratio that is small enough to be. The safe effective amount can vary depending on factors such as the particular condition being treated, the age and physical condition of the patient, the duration of treatment, the nature of the combination treatment (if any), the particular dosage form used, and the dosage regimen used.

As used herein, a “pharmaceutically acceptable excipient” is physiologically inert, compatible with the physical and chemical properties of the compounds of the invention used, sufficiently high purity and sufficiently low toxicity to be suitable for administration to humans or lower animals, Includes pharmacologically inactive ingredients. As used herein, the term "commercially available" is intended to be mixed with the excipients of the subject composition with each other and with the compounds of the present invention in such a way that, under normal conditions of use, there is no interaction that substantially reduces the pharmaceutical efficacy of the compound. That means you can.

Depending on the particular route of administration desired, various pharmaceutically acceptable excipients known in the art can be used. Excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, cosolvents, buffer systems, surfactants, preservatives, sweeteners, flavorings, and dyes or pigments It doesn't happen. The amount of excipient used with the subject compound is sufficient to provide the actual amount of the administered substance, per unit dose of the subject compound.

Some examples of materials that can be used as pharmaceutically acceptable excipients include sugars such as lactose, dextrose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and its derivatives such as methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose and cellulose acetate; Polymers such as povidone and carbomer; Powder tragacanth; Gums such as xanthan, guar and acacia; Malt; Solid lubricants such as stearic acid, magnesium stearate and talc; Inorganic fillers such as calcium phosphate and calcium sulfate; Disintegrants such as sodium starch glycolate, crospovidone, croscarmellose sodium, and microcrystalline cellulose; Encapsulation and coating materials such as gelatin, wax and cellulose derivatives; Vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and obroma oil; Polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; Alginic acid; Tweens Surfactants such as alkyl sulfate salts, fatty acid salts, sucrose esters; Ethyl oleate; coloring agent; Spice; Tableting agents; Stabilizer; Antioxidants; antiseptic; Solvents such as ethanol and pyrogen removal water; Isotonic salt solution; Buffer solutions such as phosphoric acid, tartaric acid, citric acid and acetic acid, and their sodium, potassium and ammonium salts.

Preferred compositions of the invention are in oral dosage form. As used herein, the term “oral dosage form” means any pharmaceutical composition intended for systemic administration to an individual by delivering the composition through the gastrointestinal tract in the mouth of the individual. Preferred are oral unit dosage forms such as coated or uncoated tablets, and hard or soft gel capsules. The topical oral unit dosage form composition is preferably about 4 mg or more, more preferably about 20 mg or more, even more preferably about 100 mg or more, preferably about 1000 mg or less, more preferably about 500 mg or less, even more preferably Contains up to about 250 mg of the subject compound. The topical oral dosage form composition preferably contains at least about 1%, more preferably at least about 10%, preferably up to about 70%, more preferably up to about 40% of the subject compound; Preferably at least about 30%, more preferably at least about 60%, preferably at most about 99%, more preferably at most about 90%.

Parenteral dosage forms are also preferred compositions of the present invention. As used herein, “parenteral dosage form” refers to a solution or emulsion containing an active ingredient by penetrating the skin of an individual to deliver the solution or emulsion to the individual's circulatory system by intravenous, intramuscular, peritoneal or transdermal injection. By any means is meant any pharmaceutical composition intended for systemic administration to a human or lower animal. The topical parenteral unit dosage form composition is preferably about 1 mg or more, more preferably about 6 mg or more, even more preferably about 30 mg or more, preferably about 400 mg or less, more preferably about 100 mg or less, even more preferred Preferably up to about 40 mg of the subject compound. The topical parenteral dosage form composition preferably comprises at least about 1%, more preferably at least about 5%, preferably up to 20%, more preferably up to 10% of the subject compound; Preferably at least about 80%, more preferably at least about 90%, and preferably at most about 99%, more preferably at most about 95%. Injectable dosages can also be prepared in dried or lyophilized form. The form may be reconstituted with water, saline solution or buffered solution depending on the preparation of the dosage form. The forms may be packaged in individual or multidose forms for easier handling. When lyophilized or dried preparations are used, the reconstituted dosage form is preferably isotonic and physiologically compatible pH and includes the subject compound and excipients in the amounts and percentages already indicated in this paragraph.

Treatment Methods Using Compound

Subject compounds have shown pharmacological activity in processes known to be involved in one or more cardiovascular activity, inflammatory mechanisms, oncology, and protein transport regulation from cells. The present invention encompasses methods of using said compounds of the invention for the therapeutic or prophylactic treatment of one or more of the following diseases or disorders: congestive heart failure, arrhythmia, hypotension, heart reperfusion injury, atherosclerosis, re Restenosis, vascular tone, bacterial infection, cancer, Kaposi's sarcoma, psoriasis, migraine, nasal congestion, allergic reactions, rheumatoid arthritis and osteoporosis. The method comprises administering a safe effective amount of a compound of the invention to a human or lower animal in need of said treatment or prevention.

For preferred oral administration of the compounds and / or compositions of the invention, it is preferably at least about 0.1 mg / kg, more preferably at least about 0.5 mg / kg, even more preferably at least about 2 mg / kg, preferably A subject compound of about 20 mg / kg or less, more preferably about 5 mg / kg or less, even more preferably about 2 mg / kg or less of the subject compound is to humans or lower animals, preferably about one or more times per day, more preferably About 2 or more times, preferably about 4 or less times, more preferably about 2 or less times. The duration of treatment using said daily oral administration depends on the disease or disorder being treated; Preferably at least 1 day, more preferably at least 3 days, even more preferably at least about 7 days, preferably at most 5 years, more preferably at most 60 days, even more preferably at most 15 days. .

For preferred parenteral administration of the compounds and / or compositions of the invention, it is preferably at least about 0.04 mg / kg, more preferably at least about 0.2 mg / kg, even more preferably at least about 1 mg / kg, preferably Is about 10 mg / kg or less, more preferably about 4 mg / kg or less, even more preferably about 1 mg / kg or less of the subject compound, preferably about one or more times per day, more preferably about two or more times , Preferably up to about 4 times, more preferably up to about 2 times, to a human or lower animal. The duration of treatment using said daily parenteral administration depends on the disease or disorder being treated; Preferably at least about 1 day, more preferably at least about 3 days, even more preferably at least about 7 days, preferably at least about 60 days, more preferably at least about 20 days, even more preferably About 5 days or less.

While specific embodiments of the invention have been described, it will be apparent to those skilled in the art that various modifications of the light modifications of the invention may be made without departing from the spirit and scope of the invention. In the appended claims, it is intended that all such modifications within the scope of the invention be included.

Claims (10)

Compounds having the formula and optical isomers, diastereomers or enantiomers thereof; Pharmaceutically acceptable salts, hydrates, or biohydrolyzable esters, amides or imides thereof: [In the meal, (a) each R 1 is independently selected from the group consisting of hydrogen, alkyl, aryl and a heterocycle; Preferably each R 1 is hydrogen; Linear, branched and cyclic alkanyls and alkenyls; And phenyl independently; (b) R 2 is selected from the group consisting of hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl and arylsulfonyl; Preferably each R 2 is hydrogen; Linear, branched and cyclic alkanyls and alkenyls; Alkylacyl, and phenylacyl; (c) each R 3 represents hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, formyl (acyl ), Carboxy, and carboxamide; Two R 3 together are alkylene or heteroalkylene attached to an adjacent carbon of phenyl to which R 3 is attached; Preferably each R3 is hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, fort Independently from the group consisting of wheat, alkylacyl, arylacyl, carboxy and alkyl and aryl esters and amides thereof; Preferably both R 3 together are alkylene or heteroalkylene, together with the carbon to which they are attached, a cycloalkyl, aryl or heterocyclic ring; (d) R 4 is selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, and carboxy and alkyl and aryl esters and amides thereof; (e) each R 5 is independently selected from the group consisting of hydrogen, alkyl and aryl; (f) each R 6 represents hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, sulfonamide, fort Independently from the group consisting of wheat, carboxy, and carboxamide; Two R 6 together are alkylene or heteroalkylene, or R 5 and R 6 bonded to adjacent carbon together are alkylene or heteroalkylene together; Preferably each R6 is hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, sulfone Amide, alkylsulfonamide, arylsulfonamide, formyl, alkylacyl, arylacyl, carboxy and alkyl and aryl esters and amides thereof; Preferably both R 6 together are alkylene or heteroalkylene, together with the carbon to which they are attached, a cycloalkyl, aryl or heterocyclic ring; (g) B is absent or -C (R7) = C (R7)-; (h) if B is absent, n is an integer from 0 to about 3, else n is from 0 to about 1; (i) each R 7 is independently selected from the group consisting of hydrogen, alkyl and aryl; Preferably each R 7 is hydrogen or alkyl of 1 to about 4 carbon atoms; Preferably R 2, R 4 and both R 5 are hydrogen. The method of claim 1, (a) each R 1 is independently 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) R 2 is hydrogen; Unsubstituted C ₁ -C ₅ linear, or C ₃ -C ₅ branched or cyclic alkanyl; Or selected from the group consisting of unsubstituted C ₂ -C ₅ linear, or C ₃ -C ₅ branched or cyclic alkenyl, having one double bond; (c) each R 3 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, C ₁ -C ₄ alkylacyl Independently selected; (d) R 4 is selected from the group consisting of hydrogen, halo, C ₁ -C ₄ alkyl, and phenyl; (e) both R 5 are hydrogen; (f) one R 6 is selected from the group consisting of alkoxy, alkylthio, monoalkylamino, dialkylamino, the alkyl moiety of which is saturated or unsaturated, having from 1 to about 4 carbon atoms; The other R 6 is selected from the group consisting of hydrogen, alkoxy, alkylthio, monoalkylamino, dialkylamino, the alkyl moiety of which is saturated or unsaturated, having 1 to about 4 carbon atoms; The alkyl moieties of the two R 6 are joined to form an alkylene moiety having 1 to about 4 carbon atoms, preferably both R 6 are C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylthio; (g) one or less R 7 is other than hydrogen; Preferably all R 7 are hydrogen. The compound of claim 1 or 2, wherein both R 6 are methoxy. 3. A compound according to claim 2, wherein B is absent and n is 1 or 2. The compound of claim 2, wherein B is —C (R 7) ═C (R 7) — and n is 0. 4. 3. The compound of claim 1, wherein one to three R 3 are independently selected from F, Cl, and Br, the remainder being hydrogen; 1 to 3 R 3 are unsubstituted methyl and the remainder are hydrogen; One or two R 3 is trifluoromethyl, the remainder is hydrogen. The compound of claim 2, wherein both R 1 are methyl. A composition comprising the following (a) and (b): (a) a safe effective amount of the compound of claim 1 or 2; And (b) pharmaceutically acceptable excipients. Nasal congestion, migraine, cardiac arrhythmia, cardiac reperfusion in a human or lower animal subject in need of treatment or prevention, comprising administering a safe effective amount of a compound of claim 1 or 2 to a subject ) Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment or prophylaxis of injury, congestive heart failure or hypotension. Osteoporosis, rheumatoid arthritis, allergic reactions, restenosis, blood vessels in human or lower animal subjects in need of treatment or prevention, comprising administering to a subject a safe effective amount of a compound of claim 1 or 2 Claim 1 for the manufacture of a medicament for the treatment or prevention of diseases or disorders caused by cellular protein transport, including, but not limited to, vascular tone, cancer, Kaposi's sarcoma, psoriasis, and bacterial infections. Or the use of the compound of claim 2.