JP2002544279A - Imidazo-containing heterocyclic compounds, compositions and uses thereof - Google Patents

Abstract

  (57) [Summary] The invention is a compound having structural formula (I), wherein each R 1 is independently an alkyl, aryl, or heterocycle, each R 2 -R 7 is independently hydrogen or another substituent, and B is Absent, n is 0-3, or B is ethenyl and n is 0-1 and to compounds and pharmaceutically acceptable forms thereof. The invention also relates to pharmaceutical compositions containing such compounds, and methods for treating or preventing a disease or disorder using such compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to novel imidazo-containing heterocyclic compounds, pharmaceutical compositions containing them, and their therapeutic or prevention in the fields of cardiovascular, oncology, infectious and inflammatory diseases. Related to use.

BACKGROUND Certain imidazo-isoquinoline compounds are disclosed in US Pat. No. 3,917,610, issued Nov. 4, 1975, and are reported to have certain cardiovascular activities. ing. One such compound is also Borc
Hard, Fox and Greeff, The Positive In
otropic, Antiarrhythmic and Na ⁺ , K ⁺ -ATP
case Inhibitory Effects of the Isoqui
noline Derivative BIIA ", Achives of P
pharmacology, vol. 312 (1980); 187-192
Has been reported to.

(Summary of the Invention) The present invention relates to a compound having a structure represented by the following formula:

[0004]

Embedded image

Wherein: (a) each R1 is independently selected from alkyl, aryl, and heterocycle; (b) R2 is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl, and arylsulfonyl; (C) each R3 is independently hydrogen, halo, alkyl, aryl, heterocycle, nitro,
Selected from cyano, and unsubstituted or alkyl-substituted or aryl-substituted or heterocyclic-substituted hydroxyl, thio, amino, amide, formyl (acyl), carboxy, and carboxamide, wherein the two R3s on adjacent carbons are optionally (D) R4 is hydrogen, halo, alkyl, aryl, heterocycle, and carboxy and its alkyl and aryl, which can be taken together to form an alkylene or heteroalkylene, thereby forming a fused ring with the attached phenyl. (E) each R5 is independently selected from hydrogen, alkyl and aryl; (f) each R6 is independently hydrogen, halo, alkyl, aryl, heterocycle, nitro,
Selected from cyano and unsubstituted or alkyl-substituted or aryl-substituted or heterocyclic-substituted hydroxyl, thio, amino, amide, sulfonamide, formyl (acyl), carboxy, and carboxamide, or two R6 are optional To form an alkylene or heteroalkylene, thereby forming a fused ring with the attached phenyl; (g) B is absent or -C (R7) = C (R7)- (H) n is an integer from 0 to about 3 if B is absent; 0 otherwise.
And (j) each R7 is independently a compound selected from hydrogen, alkyl and aryl;
And their optical isomers, diastereomers or enantiomers, their pharmaceutically acceptable salts, hydrates, or biohydrolysable esters, amides or imides.

The present invention also provides a composition comprising the compound and a pharmaceutically acceptable pharmaceutical excipient,
And methods of treating or preventing a disease or disorder by administering a safe and effective amount of the compounds to a human or lower animal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION Unless otherwise specified, “alkyl” as used herein refers to a branched, straight or cyclic, saturated or unsaturated (not aromatic), substituted or Means an unsubstituted hydrocarbon chain. The term “alkyl” can be used alone or “alk” (eg,
(In alkoxy, alkylacyl) can be used as part of another term that can be shortened to: Preferred straight chain 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. It has carbon atoms and is most preferably methyl or ethyl. Preferred cyclic and branched alkyls are
It has 3 to about 20 carbon atoms, more preferably 3 to about 10 carbon atoms, even more preferably 3 to about 7 carbon atoms, and even more preferably 3 to about 5 carbon atoms. Preferred cyclic alkyls have one hydrocarbon ring, but 2
It is possible to have three or more fused hydrocarbon rings. Preferred alkyls are unsaturated with one to about three double or triple bonds, preferably with double bonds, and more preferably with one double bond. Even more preferred alkyls are saturated. Saturated alkyl is referred to herein as "alkanyl." Alkyls unsaturated with only one or more double bonds (no triple bonds) are referred to herein as "alkenyl". Preferred alkyl substituents include halo, alkyl, aryl, heterocyclic, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl , Arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted alkyl is preferred.

[0008] As used herein, "heteroatom" means a nitrogen, oxygen, or sulfur atom.

[0009] As used herein, "alkylene" refers to an alkyl bonded to two other moieties, and "heteroalkylene" refers to an alkylene having one or more heteroatoms in the bond. I do.

In the present specification, unless otherwise specified, “aryl” means a substituted or unsubstituted aromatic hydrocarbon ring (or fused ring). The term “aryl”
It can be used alone or as part of another word (eg, aryloxy, arylacyl). Preferred aryls have from 6 to about 1 in the aromatic ring.
It has 4, preferably up to about 10 carbon atoms, for a total of from about 6 to about 20, preferably up to about 12 carbon atoms. Preferred aryls are phenyl or naphthyl, most preferred 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 alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted aryl is preferred.

In the present specification, unless otherwise specified, “heterocycle” refers to a saturated, unsaturated or aromatic cyclic hydrocarbon having one or more heteroatoms in a hydrocarbon ring (including a plurality of rings). It means a hydrogen ring (or fused ring). Preferred heterocycles are from 1 to about 6 rings (including multiple rings), more preferably 1 or 2 rings (including multiple rings).
Or it has three heteroatoms. Preferred heterocycles are rings (including multiple rings).
From 3 to about 14, preferably up to about 10 carbon and heteroatoms, more preferably from 3 to about 7 and even more preferably 5 or 6 carbon and heteroatoms. Having from 3 to about 20 carbon plus heteroatoms, more preferably from 3 to about 10, even more preferably 5 or 6 carbon plus heteroatoms.
Have carbon plus heteroatoms. Preferred heterocycles are one ring,
It can be two, three, or more fused rings. More preferred heterocycles include one ring having up to 3 ring heteroatoms, of which up to 2 are O and S, having 5 or 6 carbons plus heteroatoms in the ring. Even more preferably, one or two ring atoms are O or S and the other is C, or one, two or three ring atoms are N and the other is C It is a heterocycle of 5 or 6 ring atoms. Such preferred 5 or 6 ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic. Such preferred 5 or 6 ring atom heterocycles are
Monocyclic, saturated, unsaturated with one double bond, or fused with an aromatic (phenyl) hydrocarbon ring of 3 to 6 ring atoms Or another such heterocycle of 5 or 6 ring atoms. Heterocycles are unsaturated or saturated. Preferred heterocyclic substituents are the same as those for alkyl.

Compounds of the Present Invention The compounds of the present invention include compounds having the following structures.

[0013]

Embedded image

In Structure 1 , each R 1 is independently selected from alkyl, aryl, and heterocycle. Preferred R1 include straight-chain alkanyl having 1 to about 6 carbon atoms, straight-chain alkenyl having 2 to about 6 carbon atoms, and branched and cyclic alkanyl having 3 to about 6 carbon atoms and Alkenyl is included, and such alkenyl preferably has one double bond. Such preferred alkanyls and alkenyls are preferably unsubstituted or substituted with phenyl, heterocycles having 5 or 6 ring atoms, carboxy and C ₁ -C ₆ alkyl and phenyl esters or cyano. More preferably, such alkanyls and alkenyls have up to about 5 carbon atoms, even more preferably, up to 4 carbon atoms. More preferred R1 is methyl, ethyl and isopropyl. Most preferred R1 is unsubstituted methyl. Further, it is preferable that both R1s are the same part.

In Structure 1 , R2 is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl, and arylsulfonyl. Preferred R2 is
Hydrogen, C ₁ -C ₆ alkyl (alkyl is 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 preferred are alkyl moieties wherein said moieties are saturated with C ₁ -C ₄ . Even more preferred R2 is methyl.
Most preferred R2 is hydrogen.

In Structure 1 , each R 3 is independently hydrogen, halo, alkyl, aryl, heterocycle, nitro and cyano, and is unsubstituted or preferably substituted with alkyl or aryl or heterocycle. Selected from hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide, or two R3 together form an alkylene or heteroalkylene attached to an adjacent carbon atom of the phenyl ring; Form a cycloalkyl or aryl or heterocycle fused to the phenyl ring. Preferred R3s are independently hydrogen, halo, alkyl, aryl, heterocyclic, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkyl Acyl,
Arylacyl, carboxy and its alkyl or aryl esters and amides, 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 Selected from ＣC ₄ alkylacyl. More preferably, one to three R3 are halo and the others are hydrogen. More preferred are those in which one to three R3 are methyl or ethyl and the others are hydrogen. One R3 is dialkylamino, which alkyl has 1 to about 6 carbon atoms, preferably about 1 to about 4 carbon atoms, and the other is hydrogen, and such R3 is preferably 4 Those attached to the 'carbon atom are also preferred. Even more preferably, one to three R3 are independently selected from F, Cl and Br, and the others are hydrogen, wherein two or three R3 are F,
It is even more preferred that Cl or Br be the same. Even more preferred are those in which one to three R3 are unsubstituted methyl and the others are hydrogen. Even more preferred are those in which one or two R3 are trifluoromethyl and the others are hydrogen.

A saturated or unsaturated alkylene or heteroalkylene having two to three R3 attached to adjacent carbon atoms of the phenyl ring together having 1 to about 6 carbon atoms and 0 to about 3 heteroatoms; Also preferred are those which form a ring fused to phenyl, such rings having from about 5 to about 8 ring atoms. Such rings fused to phenyl preferably have about 0 to 2, more preferably about 5 to about 6 ring atoms, where 0 or 1 is a heteroatom. Preferred fused rings (including phenyl with R3 attached) include naphthyl, indolyl, benzimidazoyl, benzofuryl, benzopyranyl. When two R3s form a ring fused with phenyl, the other R3 is preferably H.

In Structure 1 , R4 is selected from hydrogen, halo, alkyl, aryl, heterocycle, carboxy and its alkyl esters or amides. Preferred R4 is hydrogen,
Halo, C ₁ -C ₄ alkyl is selected from phenyl. More preferred R4 is selected from hydrogen and unsubstituted and substituted phenyl, and the substituents on such phenyl are preferably selected from hydroxy, alkoxy, thio and alkylthio. Most preferred R4 is hydrogen.

In Structure 1 , each R5 is independently selected from hydrogen, alkyl, and aryl. Preferred R5 is selected from hydrogen and alkyl having 1 to about 4 carbon atoms, especially unsubstituted methyl or ethyl. Most preferably, both R5 are hydrogen.

In structure 1 , each R 6 is independently hydrogen, halo, alkyl, aryl, heterocycle, cyano and nitro, and is unsubstituted or preferably substituted with alkyl or aryl or heterocycle, hydroxy, thio, amino. , Amide, formyl (acyl), carboxy, carboxamide, and sulfonamide. Preferred R6 is hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, sulfonamide, alkylsulfonamide , aryl sulfonamide, formyl, alkyl acyl, aryl acyl, carboxy and from its alkyl and aryl esters and amides, more preferably hydrogen, halo, hydroxyl, C ₁ -C ₄ alkoxy, thio, C ₁ -C ₄ alkylthio, carboxy C ₁ -C ₄ alkyl esters and amides, and heterocycles having 5 or 6 ring atoms. More preferably, one or both R6 are selected such that at least one heteroatom is directly attached to the phenyl ring. When both R6s have a heteroatom directly attached to the adjacent carbon of the phenyl ring, the two R6s can together form an alkylene moiety attached to the two heteroatoms, The moiety preferably has 1 to about 4, more preferably 1 or 2 carbon atoms. R6
Preferably, one or both are non-hydrogen moieties, more preferably both are non-hydrogen moieties. Even more preferably, both R6 are alkoxy, or both are alkylthio, and preferably both are the same.
Preferred alkyl moieties for R6 are 1 to about 4 carbon atoms, more preferably 1 or 2 carbon atoms, and most preferably methyl. Preferably, such alkyl moieties are unsubstituted. Preferably, such alkyl moieties are saturated. Most preferably, both R6 are methoxy or ethoxy, especially methoxy.

R5 and R6 attached to adjacent carbon atoms of the phenyl ring are both saturated or unsaturated alkylene or heteroalkylene having 1 to about 6 carbon atoms and 0 to about 3 heteroatoms. It is therefore also preferred that they form a fused ring with phenyl, and that such rings have about 5 to about 8 ring atoms. Such rings fused to phenyl preferably have about 5 to about 6 ring atoms, where 0 to 2, preferably 0 to 1, are heteroatoms. Such R
Preferred rings formed by 5 and R6 include phenyl, furyl, pyrrolyl, dioxanyl, imidazolyl, pyridinyl, pyrrolidinyl, piperidinyl. When such R5 and R6 form a condensed ring, the other R5 and R6 are preferably both hydrogen.

In Structure 1 , B is absent or -C (R7) = C (R7)-.
When B is absent, n is an integer from 0 to about 3, preferably 1 or 2.
When B is -C (R7) = C (R7)-, n is an integer of 0 to about 1, preferably 0. Preferably, B is not present.

In structures 1 and B, each R7 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 or 2 carbon atoms. Such non-hydrogen R7 is preferably unsubstituted. Preferably, the alkyl R7 is saturated. It is preferable that one of all R7 other than hydrogen is one or less. More preferably, all R7 are hydrogen.

The present invention includes the optical isomers, diastereomers, and enantiomers of the compound of structure 1 . The invention includes pharmaceutically acceptable salts, hydrates, and biohydrolysable esters, amides, and imides of such compounds.

A “pharmaceutically acceptable salt” is a cationic salt formed at an acidic group (eg, a carboxy group) or an anionic salt formed at a base (eg, an amino group) of a compound of structure 1 . 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 organic salts such as ammonium. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates and the like. The addition of a salt can provide an optical center where nothing was.

The compounds of the present invention and their salts can have one or more chiral centers. The present invention includes all optical isomers of compounds of structure 1, including diastereomers and enantiomers, and salts thereof. The present invention contemplates each of these optical isomers, diastereomers and enantiomers as being included in purified form, substantially purified form, and as mixtures, including racemic mixtures.

Preferred compounds of the present invention include those having structure 2:

[0028]

Embedded image

In Structure 2 , R 1, R 3 and R 6 are as described above, and x is 0 or 1.

In Structure 2 , R 1 is independently linear alkanyl having 1 to 4 carbon atoms, linear alkenyl having 1 double bond and 2 to 4 carbon atoms, 3
It is preferably selected from branched or cyclic alkanyls having from 5 to 5 carbon atoms, and branched and cyclic alkenyls having one double bond and 3 to 5 carbon atoms. Such preferred R1s are unsubstituted or substituted with one phenyl, more preferably unsubstituted. More preferred R1 is
Methyl, ethyl, ethenyl, n-propyl, i-propyl, n-propenyl, i
Selected from -propenyl, sec-butyl, cyclopropyl, cyclobutyl, and cyclopentyl. Even more preferably, R1 is selected from methyl, ethyl, ethenyl, i-propyl, and n-propenyl. Most preferred R1
Is methyl. It is also preferred that both R1 are the same.

In Structure 2 , one or both, preferably both, of R 6 are preferably alkylthio, more preferably alkoxy with alkanyl having 1 to 4 carbon atoms. If one R6 is not alkylthio or alkoxy, it is preferably hydrogen. More preferably, both R6 are methoxy or ethoxy, most preferably both R6 are methoxy.

In structure 2 , all R3 are hydrogen, preferably mono, di, or (in one or more of the 2 ′, 3 ′, 4 ′ and 5 ′ positions, preferably selected from fluoro, chloro and bromo) Trihalo, mono, di or trifluoromethyl (preferably at one or more of the 2 ', 3', 4 'and 6' positions) and (3 '
And (in one or both of the 5'-positions) mono- or di-trifluoromethyl. It is also preferred that one of R3, preferably R3 at the 4'-position, is dialkylamino and that the two alkyls are identical and preferably have 1 to 4 carbon atoms and the other R3 is hydrogen. preferable. 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 ',
It is selected from 5'-ditrifluoromethyl and 4'-dibutylamino, in each case all other R3 are hydrogen. Preferred R3 combinations also include 2 ',
Selected from 4'-dihalo and 3 ', 4'-dihalo, wherein one halo is fluoro,
When selected from chloro and bromo, the other halo is a different one of the three, more preferably one such halo is fluoro and all other R3 have hydrogen. The most preferred R3 combinations are 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 those of Structure 2 where both R6 are methoxy and R1 and R3 are as shown in the table below (all R3s not specified are hydrogen) is there).

[0034]

[Table 1]

[0035]

[Table 2]

[0036]

[Table 3]

It has further been determined that salts and other derivatives of the above compounds can be used for purification, administration and the like. Thus, their pharmaceutically acceptable salts, hydrates, or biohydrolysable esters, amides or imides are:
It is considered part of the present invention.

Methods for Preparing Compounds 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 careful choice of reactants, solvents, and temperatures is important for successful synthesis.
Starting materials used to prepare compounds of the present invention are known, made by known methods, or are commercially available.

It is recognized that one of ordinary skill in the art can readily perform standard manipulations of organic compounds without further instructions. These include, but are not limited to, reduction, oxidation, acylation, substitution, etherification, esterification, sulfonation, and the like. Examples of these operations are discussed in standard reference books.

A method for preparing some imidazo-isoquinoline compounds is described in
No. 3,917,610 issued on Mar. 4, and U.S. Pat. No. 4,143,143 issued on Mar. 6, 1979, both of which are incorporated herein by reference.

The following general scheme can be used to synthesize the compounds of the present invention. In these schemes, R1, R2, R3, R4, R5, R6, R7,
B and n are as defined above. Unusual marks and abbreviations for other parts and chemicals are defined in the examples below, as they may not be obvious to the skilled chemist.

[0042]

Embedded image

[0043]

Embedded image

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

[0045]

Embedded image

A suspension of NaH (6.5 g, 0.162 mol, washed twice with hexane) in anhydrous DMF (300 ml) is cooled in an ice / acetone bath (bath temperature −15 ° C.). Solid imidazole (10 g, 0.145 mol) is added in small portions and the mixture is stirred at room temperature for 0.5 h, when the solution becomes clear. SEM-Cl (25 g, 0.15
0 mol) with a syringe pump over 1 hour at room temperature.
l precipitate. The mixture is stirred at room temperature for about 1 hour. The progress of the reaction was monitored by TLC (C
Monitor with H ₂ Cl ₂ / MeOH, 9: 1). The reaction is stopped by careful addition of H ₂ O (10 ml). The solvent is distilled off in vacuo. The residue was washed with Et ₂ O (200 ml)
And washed with H ₂ O (4 × 50 ml), brine (50 ml) and dried (M
gSO ₄ ), filter and evaporate in vacuo to give compound A as an orange liquid.

[0047]

Embedded image

SEM protected imidazole A (1.48 g, dissolved in dry THF (75 ml)
7.50 mmol) in n-BuLi (1
. 6M hexane solution) (6 ml, 9.60 mmol) was added dropwise, and the mixture was added to -78.
Stir at 30 ° C. for 30 minutes. The phenyl disulfide (2 in THF (2 ml) was then
. 1 g, 9.60 mmol) are added dropwise. After the addition, replace the dry ice / acetone bath with an ice bath. The mixture is stirred at 0 ° C. for 1 hour and then at room temperature for 1 hour. The progress is monitored by TLC (CH ₂ Cl ₂ / MeOH, 9: 1). H ₂ O (5 ml
) Is added to stop the reaction. The solvent is distilled off in vacuo, the residue is dissolved in Et ₂ O,
Wash with 5% NaHCO ₃ (3 × 20 ml), brine (20 ml), dry (M
gSO ₄ ), evaporate in vacuo and chromatograph (silica gel, hexane / EtO
Purify Ac3: 1) to give B as a yellow oil.

[0049]

Embedded image

3-Chloroperoxybenzoic acid (MCPBA, 80-85%) (17.03 g)
Was added 78.9Mol) to a solution of anhydrous CH ₂ Cl ₂ (160mL) solution of SEM- protected 2-phenyl sulfide imidazole B (9.71g, 31.6mmol), 15 the reaction at room temperature under argon Stir for hours. Progress to TLC (
Monitor with hexane / EtOAc, 3: 1). Sodium thiosulfate (3.9
g) is added to remove excess MCPBA. The mixture is filtered. 5 filtrates
% Na ₂ CO ₃ ( ₃ × 150 mL), brine (150 mL) and dried (
MgSO ₄ ), filter, evaporate in vacuo and purify by chromatography (silica gel, hexane / EtOAc 3: 1) to give C as a pale yellow oil.

[0051]

Embedded image

SEM protected 2-phenylsulfonimidazole in anhydrous THF (250 mL) C (8.61 g, 25.4 mmol) at −78 ° C. under argon.
n-BuLi (1.6 M hexane solution) (19.0 ml, 30.0 mmol)
Add dropwise with a syringe pump and stir the solution at -78 ° C for 30 minutes. Tributyl chloride
Tin (6.9 mL, 25.4 mmol) is added dropwise with a syringe pump. This mixture
Stir at room temperature for 1 hour. Progress by TLC (Hexane / EtOAc, 9: 1)
Monitor. H_TwoThe reaction is stopped by adding O (30 mL). This solution
Distill off in the sky. The residue was dissolved in ether (550 mL) and saturated NH_FourCl (3x
150 mL), washed with brine (150 mL), dried (MgSO_Four),vacuum
And chromatography (silica gel, gradient: hexane (500 mL),
Purified with hexane / EtOAc 50: 1; Hexane / EtOAc 12: 1) and clear
As an oily substanceDGet.

[0053]

Embedded image

Pd (PPh_Three)_Four(0.0177 g, 0.015 mmol) in anhydrous dioxane
Stanyl imidazole in (4.0 mL)D(0.51 g, 0.80 mmol)
, 4,5-Dimethoxy-2- (2-hydroxyethyl) phenyl bromideE(
0.33 g, 1.1 mmol) and LiCl (0.087 g, 2.1 mmol)
) At room temperature. Radical scavenger, 2,6-di-tert-butyl-4-me
A little (about 2 mg) of tyl phenol crystals was added and the reaction was allowed to run under argon for 5 hours.
Heat to reflux for a while. The reaction was cooled to room temperature and ether and saturated aqueous KF
(10 mL) with a 1: 1 mixture for 15 hours. Check the progress by TLC (Hexane / E
Monitor with tOAc, 3: 1). The mixture was filtered through a pad of Celite,
Rinse with ether. Wash the filtrate with water (3 × 12 mL), brine (3 × 12 mL)
, Dried (MgSO_Four), Filter, evaporate in vacuo and chromatograph
Lycagel, purified by hexane / EtOAc 2: 3) as an orange oil F Get.

[0055]

Embedded image

To a solution of F (2.2 g, 4.24 mmol) and Et ₃ N (886 μL) in dichloromethane (200 mL) at 0 ° C. under argon atmosphere was added methylsulfonyl chloride (MsCl, 492 μL) for 0.5 h. Add over time. The reaction is then warmed to room temperature and stirred for 1 hour. Use TLC (EtOA) to monitor the reaction.
Using c: hexane, 1: 1), shows that ring closure occurs in one vessel following MsO-ester formation and SEM cleavage. This mixture is treated with CH ₂ Cl ₂ (25
mL), cold aqueous HCl (0.5 N), aqueous NaHCO ₃ , H ₂ O,
Wash with brine and dry over MgSO ₄ . Filtration and evaporation of the solvent gives a yellow solid. Purification using preparative HPLC (EtOAc: hexane,
Gradients 1: 1 to 1: 0) give product G (1.3 g).

[0057]

Embedded image

In a 25 mL one 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 anhydrous THF. Is cooled to 0 ° C. under an argon atmosphere. Slowly add nBuLi in hexane (0.5 mL, 2.4 M) to this solution. The reaction turns pale yellow. After stirring for 45 minutes, compound G (150 mg, 0.405 mmol) in THF (1 mL) is added. The solution is warmed to room temperature and further heated at reflux for 12 hours. TLC (CH ₂ Cl ₂ : CH ₃ OH, 99:
1) indicates the completion of the reaction. The solution was quenched with MeOH and evaporated to give a residue, which was re-dissolved in CH ₂ Cl ₂ , aqueous NaHCO ₃ (5%), H ₂ O,
Wash with brine and dry over Na ₂ SO ₄ . The crude product was filtered off under high vacuum to remove excess amine H and then chromatographed (CH ₂ Cl ₂ : CH ₃
OH, 99: 1) to give compound J of the invention.

[0059]

Embedded image

In a 25 mL one neck round bottom flask, compound J (18) in anhydrous THF (10 mL)
(1 mg, 0.5 mmol) is cooled to 0 ° C. under an argon atmosphere, then NaH (18 mg), prewashed with hexane, is added to the solution as a suspension in hexane. After stirring for 15 minutes, methyl iodide (71 mg, 0.5 mg) in THF (0.5 mL) was used.
mmol). The solution was allowed to warm to room temperature and additional 2
Heat to reflux for hours. The solution was quenched with MeOH and evaporated to give a residue, redissolved in CH ₂ Cl ₂ , washed with aqueous NaHCO ₃ (5%), H ₂ O, brine, and Na ₂ SO ₄ Dry with. The crude product is chromatographed (CH ₂ Cl ₂ : CH ₃
OH, 99: 1 to 95: 5) to give compounds P of the invention.

[0061]

Embedded image

N-bromosuccinimide (NBS) solid (98 mg, 0.26 mmol)
To a solution of compound G (0.5 mmol) in 15 mL of CCl ₄ . The radical initiator benzoyl peroxide (2 mol%) is then added. Put this flask in 9
Place in 0 ° C. oil bath. After stirring for 10 minutes, the reaction is complete. The mixture is filtered through a pad of celite and the filtrate is evaporated to give a residue. Chromatography (EtOAc:
Purification by hexane, 1: 3 to 1: 1) gives compound K.

[0063]

Embedded image

K (0.22 mmol) and Pd (PPh ₃ ) ₄ (1
3 mg, 0.056 mmol) in a solution of phenyltributyltin (0.26 m
mol) and some crystals (about 2 mg) of 2,6-di-tert-butyl-4-methylphenol. The reaction mixture is refluxed at 110 ° C. for 6 hours under nitrogen to complete the reaction. The reaction mixture was cooled and then ethyl acetate (EtO
Ac) Dilute with 1-2 mL. The resulting mixture is washed with water and then with brine,
Extract with H ₂ Cl ₂ , dry over Na ₂ SO ₄ and filter. The filtrate is treated with 3 mL of a 30% aqueous KF solution at room temperature for 2 hours. The solid is filtered off. The filtrate was diluted with CH ₂ Cl ₂ , washed with water, 30% aq. NH ₄ OH (3 ×), brine, extracted with EtOAc, dried (Na ₂ SO ₄ ) and concentrated in vacuo To give a crude product. Purification by chromatography (silica gel, EtOAc: hexane, 1: 1 to 1: 0) gives compound L.

[0065]

Embedded image

In a 25 ml one neck round bottom flask equipped with a magnetic stir bar, an argon inlet, and a rubber septum, (1-methyl-1-phenyl-ethylamine) ( M ) (1.2 mmol) in anhydrous THF was added. Cool to 0 ° C. under an argon atmosphere. Slowly add nBuLi in hexane (0.5 mL, 2.4 M) to this solution. The reaction turns pale yellow. After stirring for 45 minutes, compound G (18) in THF (1 mL)
(0 mg, 0.405 mmol). The solution was warmed to room temperature and
Heat to reflux for 2 hours to complete the reaction. The solution was quenched with MeOH and evaporated to give a residue, which was re-dissolved in CH ₂ Cl ₂ , aqueous NaHCO ₃ (5%), H ₂ O,
Wash with brine and dry over Na ₂ SO ₄ . The crude product is filtered off under high vacuum to remove excess amine M and purified by chromatography to give compound N of the invention.

Compositions of the Invention The compositions of the invention comprise a) a safe and effective amount of a compound of the invention, and b) a pharmaceutically acceptable excipient.

Generally, such compositions will include several excipients. Other active compounds that do not substantially interfere with the activity of the compounds of the present invention can also optionally be included.

The compositions of the present invention can take any of a variety of forms suitable for (for example) oral, rectal, topical or parenteral administration. Preferably, the compositions of the present invention are provided in unit dosage form. As used herein, "unit dosage form" refers to a composition comprising a compound of the present invention in an amount suitable for administration to a human or lower animal subject in a single dose according to the Code of Practice. .

As used herein, a “safe and effective amount” of a compound of the present invention is large enough to cause a significant change in the condition and / or condition to be treated by the host, but at a reasonable profit or loss ratio. In short, an amount small enough to avoid serious adverse side effects of the host (such as a toxic, inflammatory, or allergic response). This safe and effective amount is
It will vary with factors such as the particular condition being treated, the age and physical condition of the patient, the duration of the treatment, the nature of the combination therapy (if any), the particular dosage form used, and the dosage regimen used.

As used herein, the term “pharmaceutically acceptable excipient” refers to the physical and chemical properties of the compound of the invention used that are suitable for administration to a human or lower animal. Physiologically inert, pharmacologically inert substances with sufficiently high purity and sufficiently low toxicity are included. As used herein, the term "compatible" refers to the mutual relationship between the excipients of the composition and the compound of the present invention that, under normal use, substantially reduce the pharmacological effect of the compound of the present invention. It means that it is possible to mix in such a way that no reaction occurs.

[0072] Depending on the particular route of administration desired, various pharmaceutically acceptable excipients well known in the art can be used. Excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents,
Co-solvents, buffer systems, surfactants, preservatives, sweeteners, flavors, and dyes or pigments are included. The amount of excipient used in combination with a compound of the present invention is sufficient to provide a practical amount of the substance when the present invention is administered per unit dose.

Some examples of substances that can serve as pharmaceutically acceptable excipients include:
Sugars such as lactose, dextrose, glucose and sucrose, starches such as corn starch and potato starch, celluloses and derivatives thereof such as methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylcellulose and cellulose acetate, polymers such as povidone and carbomer, tragacanth powder , Gums such as xanthan, guar and acacia, solid lubricants such as malt, stearic acid, magnesium stearate, and talc; inorganic fillers such as calcium phosphate and calcium sulfate; sodium starch glycolate, crospovidone, croscarmellose sodium Disintegrants such as microcrystalline cellulose and capsule bases such as gelatin, wax and cellulose derivatives And coating agents, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter, polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol, alginic acid, Tweens®, alkyl sulfates, fatty acid salts , Sucrose ester and other surfactants, ethyl oleate, coloring agents, flavoring agents,
Tableting agents, stabilizers, antioxidants, preservatives, solvents such as ethanol, pyrogen-free water, saline, phosphoric acid, tartaric acid, citric acid, and acetic acid and their sodium, potassium, and ammonium salts and the like There is a buffer solution.

Preferred compositions of the present invention are in oral dosage form. As used herein, "oral dosage form"
The term means a pharmaceutical composition intended for systemic administration to a patient by delivering the composition through the gastrointestinal tract from the patient's mouth. Preferred oral dosage forms include coated or uncoated tablets, and hard or soft gel capsules. Preferably, the oral dosage form composition of the present invention contains at least about 4 mg, more preferably at least about 20 mg, and even more preferably at least about 100 mg.
And preferably at most about 1000 mg, more preferably at most about 500 mg
mg, even more preferably at most 250 mg of a compound of the invention.
Preferably, the oral dosage form composition of the present invention contains at least about 1%, more preferably at least about 10%, and preferably at most about 70%, more preferably at most about 40% of the present invention. The compound is included, preferably at least about 30%, more preferably at least 60%, and preferably at most about 99%, more preferably at most about 90% of a pharmaceutically acceptable excipient. .

Parenteral dosage forms are also preferred compositions of the present invention. As used herein, the term "parenteral dosage form" pierces a patient's skin to deliver a solution or emulsion to the patient's circulatory system by either intravenous, intramuscular, intraperitoneal or subcutaneous injection. A pharmaceutical composition intended for systemic administration to a human or lower animal by delivering a solution or emulsion containing the active ingredient. The parenteral dosage unit compositions of the present invention preferably contain at least about 1 mg, more preferably at least about 6 mg, even more preferably at least about 30 mg, and preferably at most about 400 mg, more preferably at most About 100 mg, even more preferably at most about 40 mg, of a compound of the present invention is included. The parenteral dosage form compositions of the present invention preferably contain at least about 1%, more preferably at least about 5%, and preferably at most about 20%, more preferably at most about 10% of the present invention. And preferably comprises at least about 80%, more preferably at least about 90% and preferably at most about 99%, more preferably at most about 95% of a pharmaceutically acceptable excipient. It is. In addition, preparations for injection can be prepared in dried or lyophilized form. Such a form can be reconstituted with water, saline, or a buffered solution, depending on the preparation of the dosage form. Such forms are capable of packaging individual doses or multiple doses for easy handling. If a lyophilized or dried preparation is used, the reconstituted dosage form will contain the compounds and excipients of the invention in isotonic, physiologically compatible pH and in the amounts and percentages already given in this section. Is preferred.

Methods of Treatment Using the Compounds The compounds of the present invention are known to be involved in the control of one or more cardiovascular activities, inflammatory mechanisms, oncology, and transport of proteins from cells. Showed pharmacological activity. The present invention provides one or more of the following diseases or disorders:
: Congestive heart failure, arrhythmia, hypotension, reperfusion heart injury, atherosclerosis,
Methods of using the compounds for the treatment or prevention of restenosis, vascular tone, bacterial infection, cancer, Kaposi's sarcoma, psoriasis, migraine, nasal congestion, allergic response, rheumatoid arthritis, and osteoporosis are included. Such methods include administering a safe and effective amount of a compound of the present invention to a human or lower animal in need of such treatment or prevention.

For preferred oral administration of a compound and / or composition of the invention, 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, and preferably at most about 20 mg / kg, more preferably at most about 5 mg / kg, and even more preferably at most about 2 mg / kg of a compound of the invention Alternatively, the lower animal is preferably administered daily at least about once, more preferably at least twice, and preferably at most four times, more preferably at most about twice. The duration of treatment for such daily oral administration depends on the disease or disorder to be treated, but is preferably at least about 1 day, more preferably at least about 3 days, even more preferably at least 7 days, and preferably At most about 5 years, more preferably at most about 60
Days, even more preferably at most about 15 days.

For preferred parenteral administration of a compound and / or composition of the invention, preferably at least about 0.04 mg / kg, more preferably at least about 0.2 mg / k
g, even more preferably at least about 1 mg / kg, and preferably at most about 10 mg / kg, more preferably at most about 4 mg / kg, and more preferably at most about 1 mg / kg of a compound of the invention Alternatively, the lower animal is preferably administered daily at least about once, more preferably at least twice, and preferably at most four times, more preferably at most about twice. The duration of treatment for such daily oral administration depends on the disease or disorder to be treated, but is preferably at least about 1 day, more preferably at least about 3 days, even more preferably at least 7 days, and preferably At most about 60 days, more preferably at most about 20 days
Days, even more preferably at most about 5 days.

While particular embodiments of the present invention have been described, it will be apparent to those skilled in the art that various changes and modifications of the present invention can be made without departing from the spirit and scope of the invention. It is intended that the appended claims cover all such modifications as fall within the scope of the invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/06 A61P 9/06 17/06 17/06 19/02 19/02 19/10 19/10 29 / 00 101 29/00 101 31/04 31/04 35/00 35/00 37/08 37/08 C07D 487/04 150 C07D 487/04 150 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AE, A , AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK , MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor David Edward Portlock United States 45039 Mainville Chestnut Landing Drive, Ohio 3237 (72) Inventor Schwe van Pom United States 45069 West Chester, Ohioー Tylers Way 8005 F term (reference) 4C050 AA01 BB09 CC05 EE02 FF02 GG04 4C065 AA03 BB06 CC09 DD02 EE02 HH02 JJ01 KK02 LL07 PP02 4C086 AA01 AA03 CB05 CB11 MA04 MA52 MA55 NA14 ZA89 ZAB ZAA

Claims (10)

[Claims] 1. A compound having the structure of the following formula: Wherein (a) each R1 is independently selected from the group consisting of hydrogen, alkyl, aryl, and heterocycle; preferably, each R1 is independently hydrogen, linear, branched and cyclic alkanyl and alkenyl, and phenyl (B) R2 is selected from the group consisting of hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl and arylsulfonyl, preferably each R2
Is hydrogen, linear, branched and cyclic alkanyl and alkenyl, alkylacyl,
And (c) each R3 is independently hydrogen, halo, alkyl, aryl, heterocycle, nitro,
Selected from the group consisting of cyano, and unsubstituted or alkyl-substituted or aryl-substituted or heterocyclic-substituted hydroxyl, thio, amino, amide, formyl (acyl), carboxy, and carboxamide, or two R3s are taken together. To become an alkylene or heteroalkylene attached to the adjacent carbon of the phenyl to which R3 is attached, preferably each R3 is independently hydrogen, halo, alkyl, aryl, heterocycle, hydroxyl, alkoxy, aryloxy, thio, Alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide,
Selected from the group consisting of arylamides, formyl, alkylacyl, arylacyl, carboxy and their alkyl and aryl esters and amides, or preferably the two R3s are taken together to form an alkylene or a heteroalkylene; (D) R4 is selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, and carboxy and its alkyl and aryl esters and amides; R5 is independently selected from the group consisting of hydrogen, alkyl and aryl; (f) each R6 is independently hydrogen, halo, alkyl, aryl, heterocycle, nitro,
Cyano and unsubstituted or alkyl-substituted or aryl-substituted or heterocyclic-substituted hydroxyl, thio, amino, amide, sulfonamide, formyl, carboxy,
Or two R6 are taken together to form an alkylene or heteroalkylene, or R5 and R6 attached to adjacent carbons are taken together to form an alkylene or heteroalkylene, preferably Each R6 is independently hydrogen, halo, alkyl, aryl, heterocycle, hydroxyl, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, sulfonamide, alkyl Selected from the group consisting of sulfonamides, arylsulfonamides, formyl, alkylacyl, arylacyl, carboxy and their alkyl and aryl esters and amides, or preferably two R
6 together form an alkylene or heteroalkylene, and together with the carbon to which they are attached, a cycloalkyl, aryl or heterocycle; (g) B is absent or -C (R7) = C (R7)- (H) n is an integer from 0 to about 3 if B is absent; 0 otherwise.
(J) each R7 is independently selected from the group consisting of hydrogen, alkyl and aryl, preferably each R7 is hydrogen or alkyl having 1 to about 4 carbon atoms, preferably R2 , R4 and both R5 are hydrogen, and their optical isomers, diastereomers or enantiomers, their pharmaceutically acceptable salts, hydrates, or biohydrolyzable Esters, amides or imides. 2. (a) Each R1 is independently unsubstituted C ₁ -C ₅ linear, or C ₃ -C
C ₅ branched or cyclic, alkanyl or unsubstituted C ₂ -C ₅ straight chain or C ₃ ~,
Of C ₅ branched or cyclic, one alkenyl having a double bond, (b) R2 is hydrogen, C ₁ -C ₅ linear unsubstituted or C ₃ -C ₅ branched or cyclic alkanyl, or unsubstituted C ₂ -C ₅ linear or C ₃ -C ₅ branched or cyclic, 1
It is selected from the group consisting of alkenyl having number of double bonds, (c) each R3 is independently hydrogen, halo, C ₁ -C ₄ alkyl, thio, C ₁ -C ₄ alkylthio, C ₁ -C ₄ mono- or dialkylamino is selected from the group consisting of C ₁ -C ₄ alkyl acyl, the (d) R4 hydrogen, halo, C ₁ -C ₄ alkyl, and is selected from the group consisting of phenyl, with (e) both R5 is hydrogen (F) one R6 is selected from the group consisting of alkoxy, alkylthio, monoalkylamino, dialkylamino, wherein these alkyl moieties are saturated and unsubstituted and have from 1 to about 4 carbon atoms. And the other R6 is selected from the group consisting of hydrogen, alkoxy, alkylthio, monoalkylamino, dialkylamino, wherein those alkyl moieties are saturated and unsubstituted and have 1 to about Or having carbon atoms, or two attached alkyl moiety of R6, forms an alkylene moiety of from 1 to about 4 carbon atoms, preferably both R6 is C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylthio, and (g) 1 or less R7 is other than hydrogen, preferably a compound according to claim 1, characterized in that all of R7 are hydrogen. 3. The method of claim 1, wherein both R6 are methoxy.
The compound according to the above. 4. The compound according to claim 2, wherein B is absent and n is 1 or 2. 5. The compound according to claim 2, wherein B is -C (R7) = C (R7)-and n is 0. 6. One to three R3 are independently selected from F, Cl and Br and the others are hydrogen, or one to three R3 are unsubstituted methyl and the others are hydrogen Or one or two R3 is trifluoromethyl;
The compound according to claim 1, wherein the other is hydrogen. 7. The compound according to claim 2, wherein both R1 are methyl. 8. A composition comprising (a) a safe and effective amount of the compound of claim 1 or (b), and (b) a pharmaceutically acceptable excipient. 9. A method for the manufacture of a medicament for the treatment or prevention of nasal congestion, migraine, cardiac arrhythmia, reperfusion heart damage, congestive heart failure or hypotension in a human or lower animal subject in need of treatment or prevention. 3. Use of a compound of claim 1 or 2, wherein treating or preventing comprises administering to the subject a safe and effective amount of the compound of claim 1 or 2. 10. Including, but not limited to, osteoporosis, rheumatoid arthritis, allergic response, restenosis, vascular tone, cancer, Kaposi's sarcoma, psoriasis and bacterial infection in a human or lower animal subject in need of treatment or prevention. Use of the compound of claim 1 or 2 for the manufacture of a medicament for the treatment or prevention of a disease or disorder caused by unselected cellular protein transport, wherein the treatment or prevention is a safe and effective amount. Use comprising administering the compound to a subject.