JP2007518787A - Imidazole-based HMG-CoA reductase inhibitors - Google Patents

Abstract

HMG-Co-A reductase inhibitory compounds useful as cholesterol lowering agents and antihyperlipidemic agents are provided. Also provided are pharmaceutical compositions of the compounds. Also provided are methods of making and using the compounds.
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[Chemical 1]

Description

  The present invention relates to compounds and pharmaceutical compositions useful as hypocholesterolemic agents and antihyperlipidemic agents. More specifically, the present invention relates to certain potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (“HMG-CoA reductase”).

  The present invention further provides such compounds for treating subjects (including humans) suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer's disease, BPH, diabetes and osteoporosis and It relates to a method of using the composition.

  High levels of blood cholesterol and blood lipids are conditions that are involved in the development of atherosclerosis. Conversion of HMG-CoA to mevalonic acid is an early rate-limiting step in the cholesterol biosynthesis pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. Thus, statin drugs are commonly powerful lipid lowering drugs. Statins are therefore first line drugs for the treatment of many lipid abnormalities. Exemplary statin drugs include atorvastatin, lovastatin, pravastatin and simvastatin.

Inhibitors of HMG-CoA reductase are known to have the effect of lowering plasma levels of low density lipoprotein cholesterol (LDL-C) in humans. (MS Brown and JL Goldstein, New England Journal of Medicine,
305, No. 9,515-517 (1981)). It has been shown that reducing LDL-C levels can prevent coronary artery disease (Journal
of the American Medical Association, 251, No. 3,351-374 (1984)). Furthermore, certain mevalonic acid derivatives (3,5-dihydroxy-3-methylpentanoic acid) and the corresponding ring-closing lactone mevalonolactone are known to inhibit cholesterol biosynthesis (F.
M. Singer et al., Proc. Soc. Exper. Biol. Med., 102: 370 (1959) and FH Hulcher,
Arch. Biochem. Biophys., 146: 422 (1971)). US Pat. Nos. 3,983,140; 4,049,495 and 4,137,322 describe the fermentative production of a natural product now called compactin, which has an inhibitory effect on cholesterol biosynthesis. Disclosure. Compactin has been shown to have a complex structure containing a mevalonolactone moiety (Brown
Et al., J. Chem. Soc. Perkin I (1976) 1165). U.S. Pat. No. 4,255,444 to Oka et al. Discloses a plurality of synthetic mevalonolactone derivatives having antilipidemic activity. US Pat. Nos. 4,198,425 and 4,262,013 to Mitsue et al. Disclose aralkyl derivatives of mevalonolactone useful for the treatment of hyperlipidemia.

  Atorvastatin and its pharmaceutically acceptable salts are selective and competitive inhibitors of HMG-CoA reductase. Thus, atorvastatin calcium is a potent lipid-lowering agent and is therefore not only useful as an antihyperlipidemic and / or hypocholesterolemic agent, but also useful in the treatment of osteoporosis and Alzheimer's disease. Many patents have been published that disclose atorvastatin. These include US Pat. Nos. 4,681,893; 5,273,995 and 5,969,156, which are incorporated herein by reference.

  All statin drugs inhibit the conversion of HMG-CoA to mevalonic acid, a cholesterol precursor by HMG-CoA reductase, to varying degrees. Although these drugs have many common features, they also show differences in pharmacological attributes that can contribute to differences in clinical utility and effectiveness in modifying lipid risk factors for coronary artery disease (Clin Cardiol. Bol. 26 (Suppl. III), III-32-III-38 (2003)). Desirable pharmacological features for statin therapy include potent reversible inhibition of HMG-CoA reductase, the ability to greatly reduce LDL-C and non-high density lipoprotein cholesterol (non-HDL-C), HDL cholesterol ( Including the ability to increase HDL-C), tissue selectivity, optimal pharmacokinetics, availability of once-daily administration and low potential for drug-drug interactions. Along with the ability to reduce circulating very low density lipoprotein (VLDL), the ability to reduce triglyceride levels is also desirable.

Currently, the most potent statin drugs exhibit in vitro IC ₅₀ values of about 5.4 to about 8.0 nM when using purified human HMG-CoA reductase catalytic domain samples (Am J. Cardiol 2001; 87 (suppl): 28B-32B; Atheroscer Suppl. 2002; 2:
33-37). In general, the most potent LDL-C-lowering statin drugs are also the most potent non-HDL-C-lowering statin drugs. Therefore, maximum inhibitory activity is desirable. With respect to HDL-C, known statin drugs generally only moderately increase HDL-C. Therefore, the ability to increase HDL-C more greatly is also advantageous.

With respect to tissue selectivity, differences between relative lipophilic or hydrophilic statin drugs can affect pharmacokinetics and tissue selectivity. Drugs that are relatively hydrophilic may show reduced access to non-hepatocytes as a result of weak passive diffusion and may show a relative increase in hepatocyte uptake by selective organic ion transport. Furthermore, the relative water solubility of the drug can reduce the need for extensive cytochrome P450 (CYP) enzyme metabolism. Many drugs, including known statin drugs, are metabolized by the CYP3A4 enzyme system (Arch Intern Med 2000; 160: 2273-2280; J Am Phann Assoc 2000; 40:
637-644). Therefore, relative hydrophilicity is desired for statin therapy.

Two important pharmacokinetic variables in statin drugs are bioavailability and elimination half-life. Statin with reduced systemic utilization to minimize any potential risk of systemic side effects, while having sufficient systemic utilization to show any multifaceted effects on the vasculature with statin treatment Taking statins has advantages. These pleiotropic effects include improved or repaired endothelial function, increased atherosclerotic plaque stability, decreased plasma levels of certain inflammatory markers such as C-reactive protein, reduced oxidative stress and reduced vascular inflammation (Arterioscler Thromb Vasc Biol 2001; 21: 1712-1719; Heart Dis 5 (1):
2-7, 2003). Furthermore, it would be advantageous to take a statin with a sufficiently long elimination half-life to maximize the effectiveness for reducing LDL-C.

  Finally, when statin drugs are administered in combination with other drugs, take statins that are metabolized or minimally metabolized by CYP3A4 to minimize any potential risk of drug-drug interactions Doing seems to have advantages.

  Therefore, high efficacy in inhibiting HMG-CoA reductase, ability to greatly reduce LDL-C and non-dense lipoprotein cholesterol, ability to increase HDL cholesterol, selectivity of effects or uptake in hepatocytes, optimal systemic It would be most beneficial to provide statins that have the desired combination of properties including bioavailability, long elimination half-life, and minimal or minimal metabolism by the CYP3A4 system.

（式中、
−−−−−−−−−−−は１本の結合または無結合であり；
Ｒ^１はＨ；Ｃ_１−Ｃ_６アルキルまたはＣ_３−Ｃ_８シクロアルキルであり；
Ｒ^２はＨ；ハロゲン；置換されていてもよいＣ_１−Ｃ_６アルキルもしくはＣ_３−Ｃ_８シクロアルキル；置換されていてもよいアリール、アラルキル、ヘテロアリールもしくはヘテロアラルキル；Ｒ^６Ｒ^７ＮＳ（Ｏ）_２−；
Ｒ^８Ｓ（Ｏ）_ｎ−；−（ＣＨ_２）_ｎＣＯＲ’；−（ＣＨ_２）_ｎＮＲ^６Ｒ^７；−（ＣＨ_２）_ｎＣＯＯＲ’；またはＲ^６Ｒ^７ＮＣ（Ｏ）−であり；
Ｒ^６およびＲ^７はそれぞれ独立してＨ；ハロゲン、ＯＲ’、（ＣＨ_２）_ｎＣＯＯＲ’、（ＣＨ_２）_ｎＣＯＮＲ’Ｒ”、（ＣＨ_２）_ｎＳＯ_２Ｒ’もしくはＣＮで置換されていてもよいアリール、アラルキル、ヘテロアリールもしくはヘテロアラルキル；
置換されていてもよいＣ_１−Ｃ_１０アルキル；（ＣＨ_２）_ｎＣＯＲ’；（ＣＨ_２）_ｎＣＯＯＲ’；（ＣＨ_２）ＣＯＮＲ’Ｒ”または（ＣＨ_２）_ｎＳＯ_２Ｒ’であり；あるいは
Ｎ、Ｒ^６およびＲ^７は共に、所望によりＯ、ＮおよびＳから選択される２個までのヘテロ原子を含有する、置換されていてもよい４〜１１員環を形成し；
Ｒ^４は置換されていてもよいＣ_１−Ｃ_６アルキルまたはＣ_３−Ｃ_８シクロアルキル；Ｈ；ハロ；置換されていてもよいアリールまたはヘテロアリールであり；
Ｒ^８は置換されていてもよいアリール、アラルキル、アルキル、ヘテロアリールまたはヘテロアラルキルであり；
Ｒ’およびＲ”はそれぞれ独立してＨ；置換されていてもよいＣ_１−Ｃ_１２アルキル、アリールまたはアラルキルであり；かつｎは０〜２である）。 The present invention provides a series of novel imidazoles as HMG-CoA reductase inhibitors. The compounds of the present invention are potent inhibitors of cholesterol biosynthesis. Therefore, this compound has utility as a therapeutic agent for treating hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer's disease, BPH, diabetes and osteoporosis. More specifically, the present invention provides a compound having Formula I, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of a prodrug.

(Where
----------- is a single bond or no bond;
R ¹ is H; C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl;
R ² is H; halogen; optionally substituted C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; optionally substituted aryl, aralkyl, heteroaryl or heteroaralkyl; R ⁶ R ⁷ NS ( O) ₂ −;
_{^{R 8 S (O) n -}} ;-( CH 2) n COR ';-( CH 2) n NR 6 R 7 ;-( CH 2) n COOR'; or ^{R 6 R 7 NC (O)} - and is ;
R ⁶ and R ⁷ are each independently H; substituted with halogen, OR ′, (CH ₂ ) _n COOR ′, (CH ₂ ) _n CONR′R ″, (CH ₂ ) _n SO ₂ R ′ or CN Optionally aryl, aralkyl, heteroaryl or heteroaralkyl;
Be (CH 2) CONR'R "or _{(CH 2) n SO 2 R} '; optionally substituted _C 1 _{-C 10 alkyl; (CH 2) n COR'} ; (CH 2) n COOR '; Or N, R ⁶ and R ⁷ together form an optionally substituted 4-11 membered ring containing up to two heteroatoms optionally selected from O, N and S;
R ⁴ is an optionally substituted C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; H; halo; optionally substituted aryl or heteroaryl;
R ⁸ is an optionally substituted aryl, aralkyl, alkyl, heteroaryl or heteroaralkyl;
R ′ and R ″ are each independently H; optionally substituted C ₁ -C ₁₂ alkyl, aryl or aralkyl; and n is 0-2.

（式中、
Ｒ^１はＨ；Ｃ_１−Ｃ_６アルキルまたはＣ_３−Ｃ_８シクロアルキルであり；
Ｒ^２はＨ；ハロゲン；置換されていてもよいＣ_１−Ｃ_６アルキルもしくはＣ_３−Ｃ_８シクロアルキル；
Ｒ^６Ｒ^７ＮＳ（Ｏ）_２−；Ｒ^８Ｓ（Ｏ）_ｎ−；−（ＣＨ_２）_ｎＣＯＲ’；−ＮＲ^６Ｒ^７；−（ＣＨ_２）_ｎＣＯＯＲ’；またはＲ^６Ｒ^７ＮＣ（Ｏ）−であり；
Ｒ^６およびＲ^７はそれぞれ独立してＨ；ハロゲン、ＯＲ’、（ＣＨ_２）_ｎＣＯＯＲ’、（ＣＨ_２）_ｎＣＯＮＲ’Ｒ”、（ＣＨ_２）_ｎＳＯ_２Ｒ’もしくはＣＮで置換されていてもよいアリール、アラルキル、ヘテロアリールもしくはヘテロアラルキル；
置換されていてもよいＣ_１−Ｃ_１０アルキル；（ＣＨ_２）_ｎＣＯＲ’；（ＣＨ_２）_ｎＣＯＯＲ’；（ＣＨ_２）ＣＯＮＲ’Ｒ”；または（ＣＨ_２）_ｎＳＯ_２Ｒ’であり；あるいは
Ｎ、Ｒ^６およびＲ^７は共に、所望によりＯ、ＮおよびＳから選択される２個までのヘテロ原子を含有する、置換されていてもよい４〜１１員環を形成し；
Ｒ^４は置換されていてもよいＣ_１−Ｃ_６アルキルまたはＣ_３−Ｃ_８シクロアルキル；Ｈ；ハロ；置換されていてもよいアリールまたはヘテロアリールであり；
Ｒ^８は置換されていてもよいアリール、アラルキル、アルキル、ヘテロアリールまたはヘテロアラルキルであり；
Ｒ’およびＲ”はそれぞれ独立してＨ、置換されていてもよいＣ_１−Ｃ_１２アルキル、アリールまたはアラルキルであり；かつｎは０〜２である）。
（発明の詳細な説明） Further provided is a compound having the formula: or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of a prodrug:

(Where
R ¹ is H; C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl;
R ² is H; halogen; optionally substituted C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl;
_{^{R 6 R 7 NS (O)}} 2 -; R 8 S (O) n - ;-( CH 2) n COR '; - NR 6 R 7 ;-( CH 2) n COOR'; or ^R 6 ^R 7 NC (O)-;
R ⁶ and R ⁷ are each independently H; substituted with halogen, OR ′, (CH ₂ ) _n COOR ′, (CH ₂ ) _n CONR′R ″, (CH ₂ ) _n SO ₂ R ′ or CN Optionally aryl, aralkyl, heteroaryl or heteroaralkyl;
Optionally substituted C ₁ -C ₁₀ alkyl; (CH ₂ ) _n COR ′; (CH ₂ ) _n COOR ′; (CH ₂ ) CONR′R ″; or (CH ₂ ) _n SO ₂ R ′. Or N, R ⁶ and R ⁷ together form an optionally substituted 4-11 membered ring containing up to two heteroatoms optionally selected from O, N and S;
R ⁴ is an optionally substituted C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; H; halo; optionally substituted aryl or heteroaryl;
R ⁸ is an optionally substituted aryl, aralkyl, alkyl, heteroaryl or heteroaralkyl;
R ′ and R ″ are each independently H, optionally substituted C ₁ -C ₁₂ alkyl, aryl or aralkyl; and n is 0-2.
(Detailed description of the invention)

（式中、
−−−−−−−−−−は１本の結合または無結合であり；
Ｒ^１はＨ；Ｃ_１−Ｃ_６アルキルまたはＣ_３−Ｃ_８シクロアルキルであり；
Ｒ^２はＨ；ハロゲン；置換されていてもよいＣ_１−Ｃ_６アルキルもしくはＣ_３−Ｃ_８シクロアルキル；置換されていてもよいアリール、アラルキル、ヘテロアリールもしくはヘテロアラルキル；Ｒ^６Ｒ^７ＮＳ（Ｏ）_２−；Ｒ^８Ｓ（Ｏ）_ｎ；−（ＣＨ_２）_ｎＣＯＲ’；−（ＣＨ_２）_ｎＮＲ^６Ｒ^７；−（ＣＨ_２）_ｎＣＯＯＲ’；またはＲ^６Ｒ^７ＮＣ（Ｏ）−であり；
Ｒ^６およびＲ^７はそれぞれ独立してＨ；ハロゲン、ＯＲ’、（ＣＨ_２）_ｎＣＯＯＲ’、（ＣＨ_２）_ｎＣＯＮＲ’Ｒ”、（ＣＨ_２）_ｎＳＯ_２Ｒ’もしくはＣＮで置換されていてもよいアリール、アラルキル、ヘテロアリールもしくはヘテロアラルキル；
置換されていてもよいＣ_１−Ｃ_１０アルキル；（ＣＨ_２）_ｎＣＯＲ’；（ＣＨ_２）_ｎＣＯＯＲ’；（ＣＨ_２）ＣＯＮＲ’Ｒ”または（ＣＨ_２）_ｎＳＯ_２Ｒ’であり；あるいは
Ｎ、Ｒ^６およびＲ^７は共に、所望によりＯ、ＮおよびＳから選択される２個までのヘテロ原子を含有する、置換されていてもよい４〜１１員環を形成し；
Ｒ^４は置換されていてもよいＣ_１−Ｃ_６アルキルまたはＣ_３−Ｃ_８シクロアルキル；Ｈ；ハロ；置換されていてもよいアリールまたはヘテロアリールであり；
Ｒ^８は置換されていてもよいアリール、アラルキル、アルキル、ヘテロアリールまたはヘテロアラルキルであり；
Ｒ’およびＲ”はそれぞれ独立して置換されていてもよいＨ；Ｃ_１−Ｃ_１２アルキル、アリールまたはアラルキルであり；かつｎは０〜２である）。 The present invention provides a compound having Formula I, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of a prodrug thereof.

(Where
---------- is one bond or no bond;
R ¹ is H; C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl;
R ² is H; halogen; optionally substituted C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; optionally substituted aryl, aralkyl, heteroaryl or heteroaralkyl; R ⁶ R ⁷ NS ( _{^{O) 2 -; R 8 S}} (O) n ;-( CH 2) n COR ';-( CH 2) n NR 6 R 7 ;-( CH 2) n COOR'; or ^R 6 ^R 7 NC (O )-;
R ⁶ and R ⁷ are each independently H; substituted with halogen, OR ′, (CH ₂ ) _n COOR ′, (CH ₂ ) _n CONR′R ″, (CH ₂ ) _n SO ₂ R ′ or CN Optionally aryl, aralkyl, heteroaryl or heteroaralkyl;
Be (CH 2) CONR'R "or _{(CH 2) n SO 2 R} '; optionally substituted _C 1 _{-C 10 alkyl; (CH 2) n COR'} ; (CH 2) n COOR '; Or N, R ⁶ and R ⁷ together form an optionally substituted 4-11 membered ring containing up to two heteroatoms optionally selected from O, N and S;
R ⁴ is an optionally substituted C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; H; halo; optionally substituted aryl or heteroaryl;
R ⁸ is an optionally substituted aryl, aralkyl, alkyl, heteroaryl or heteroaralkyl;
R ′ and R ″ are each independently substituted H; C ₁ -C ₁₂ alkyl, aryl or aralkyl; and n is 0-2.

Further provided is the above compound, wherein R ¹ is C _1-3 alkyl. Further provided are compounds wherein R ¹ is isopropyl or cyclopropyl. Further provided are compounds wherein R ¹ is ethyl. Further provided is the above compound, wherein R ² is R ⁶ R ⁷ NS (O) ₂ — or R ⁶ R ⁷ NC (O) —. Further provided is the above compound, or a pharmaceutically acceptable salt, solvate or composition thereof, wherein R ² is — (CH ₂ ) _n NR ⁶ R ⁷ . Further provided are compounds wherein R ⁶ and R ⁷ are each independently H; or an optionally substituted aralkyl.

Further, R ⁶ and R ⁷ are each independently H; halogen, CN, (CH ₂ ) _n CONR′R ″, (CH ₂ ) _n SO ₂ R ′, OR ′, or (CH ₂ ) _n COOR ′. Provided are compounds that are optionally substituted phenyl, pyridinyl, phenyl-ethyl or benzyl; R ″ and R ′ are each independently H or lower alkyl.

Further provided is the above compound, wherein R ⁴ is H; optionally substituted lower alkyl, phenyl or heteroaryl. Further provided are compounds wherein R ⁴ is phenyl substituted by one or more groups selected from halogen or —CH ₃ ; or pyridinyl. Further provided are compounds wherein R ⁴ is 4-fluorophenyl, methylfluoro-phenyl or difluorophenyl.

Further provided is the above compound, wherein R ⁶ and R ⁷ are each independently lower alkyl or phenyl; or pyridinyl. Furthermore one of R ⁶ and R ⁷ is a phenyl optionally substituted, one other of R ⁶ and R ⁷ are offered compounds is methyl.

Further provided is the above compound, wherein R ¹ is isopropyl.

  Further provided are pharmaceutically acceptable salts of the above compounds, wherein the salt is a sodium salt or a calcium salt.

  Further provided are stereoisomers of the above compounds, including the (3R, 5R) -isomer or a pharmaceutically acceptable salt, ester or amide thereof. Further provided are (3S, 5R) -isomers of the above compounds. Further provided is the (3S, 5S) -isomer of the above compound. Further provided is the (3R, 5S) -isomer of the above compound. Further provided is a racemic mixture comprising the above compound.

  Further provided are pharmaceutically acceptable esters of the above compounds wherein the ester is a methyl ester.

  The present invention particularly relates to the following compounds: (3R, 5R) -7- [2-benzylcarbamoyl-5- (3,4-difluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5 -Dihydroxy-heptanoic acid; (3R, 5R) -7- [2-benzylcarbamoyl-3-propyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptane Acid; (3R, 5R) -7- [2-benzylcarbamoyl-3-isobutyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; (3R , 5R) -7- [2-Benzylcarbamoyl-3-ethyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-he (3R, 5R) -7- [2-benzylcarbamoyl-3-isopropyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 3R, 5R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenethylcarbamoyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; (3R, 5R) -7- [2- (4-fluoro-benzylcarbamoyl) -3-propyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; (3R, 5R) -7- [2-Phenylcarbamoyl-3-propyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy- (3R, 5R) -7- [2- (4-Fluoro-benzylcarbamoyl) -5- (4-fluoro-3-methyl-phenyl) -3-isopropyl-3H-imidazol-4-yl]- 3,5-dihydroxy-heptanoic acid; (3R, 5R) -7- [5- (4-fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -3,5 Dihydroxy-heptanoic acid; (3R, 5R) -7- (2-benzylcarbamoyl-3-isopropyl-5-pyridin-3-yl-3H-imidazol-4-yl) -3,5-dihydroxy-heptanoic acid; (3R, 5S) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3,5-dihydroxy-hept -6-enoic acid; (3R, 5R) -3,5-dihydroxy-7- [3-isopropyl-5-phenyl-2-((R) -1-phenyl-ethylcarbamoyl) -3H-imidazole-4- Yl] -heptanoic acid; (3R, 5R) -3,5-dihydroxy-7- [3-isopropyl-5-phenyl-2-((S) -1-phenyl-ethylcarbamoyl) -3H-imidazole-4- Yl] -heptanoic acid; 7- [5- (4-fluoro-phenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxy-heptane Acid; 7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-methanesulfonylamino-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid 7- [5- (4-Fluoro-phenyl) -3-isopropyl-2- (methyl-phenylmethanesulfonyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [ 5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonylamino-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [2-benzenesulfonylamino-5- (4-Fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [2- (benzenesulfonyl-methyl-amino) -5- (4-fluoro -Phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid sodium salt; 7- 2- (acetyl-methyl-amino) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [2-acetylamino- 5- (4-Fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [2- (acetyl-benzyl-amino) -5- (4- Fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [2- (benzoyl-methyl-amino) -5- (4-fluoro-phenyl)- 3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [2-benzoylamino-5- (4-fluoro-phenyl) -3-Isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [5- (4-fluoro-phenyl) -3-isopropyl-2-phenylacetylamino-3H-imidazole- 4-yl] -3,5-dihydroxy-heptanoic acid; 7- [5- (4-fluoro-phenyl) -3-isopropyl-2- (methyl-phenylacetyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; 7- [2- (benzyl-methanesulfonyl-amino) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3.5 -Dihydroxy-heptanoic acid; 7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-methylsulfamoyl-3H-imidazole 4-yl] -3,5-dihydroxy-heptanoic acid; 7- [2-benzylsulfamoyl-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5 7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylsulfamoyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; (3R , 5R) -7- {5- (4-Fluoro-phenyl) -3-isopropyl-2-[(pyridin-3-ylmethyl) -carbamoyl] -3H-imidazol-4-yl} -3,5-dihydroxy- Heptanoic acid; and pharmaceutically acceptable salts, amides and esters thereof are provided.

  Further provided is the use of the above compounds for the manufacture of a medicament for the treatment of diseases for which an HMG Co-A reductase inhibitor is indicated. Further provided are combinations of the above compounds with other pharmaceutically active drugs. Furthermore, the other pharmaceutically active drugs are CTEP inhibitor, PPAR-activator, MTP / apo B secretion inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, fibrate, niacin, ion exchange resin, antioxidant Combinations that are agents, ACAT inhibitors, bile capture agents, antihypertensive agents, or acetylcholinesterase inhibitors are provided.

  Further provided is a pharmaceutical composition comprising the above compound or the above combination and a pharmaceutically acceptable carrier, diluent or vehicle. Further provided is the use of a compound, combination or composition as described above for the manufacture of a medicament for treating atherosclerosis.

  The following definitions are used unless otherwise noted. Halo is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, alkenyl, alkynyl and the like refer to both straight and branched chain groups.

As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbon of 1 to 11 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. Alkyl groups are also lower alkoxy, lower thioalkoxy, —O (CH ₂ ) _0-2 CF ₃ , halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF ₃ , —CO ₂ H , —CO ₂ C ₁ -C ₆ alkyl, —NR′R ″ or —CONR′R ″, which may be substituted (where R ′ and R ″ are independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or together form a 4-7 membered ring; or N, R ′ and R ″ are both 4-7 membered Forming a ring). Useful alkyl groups have 1 to 6 carbon atoms (C ₁ -C ₆ alkyl).

As used herein, the term “lower alkyl” refers to a subset of alkyl, meaning a straight or branched chain hydrocarbon radical having 1 to 6 carbon atoms, eg, methyl, ethyl, n-propyl, Including isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like. Optionally, lower alkyl is referred to as “C ₁ -C ₆ alkyl”.

  As used herein, the term “haloalkyl” is defined above having at least one halogen substituent, such as chloromethyl, fluoroethyl, trifluoromethyl, or 1,1,1-trifluoroethyl. Refers to a lower alkyl radical. Haloalkyl also includes perfluoroalkyl in which all hydrogens of the lower alkyl group are replaced with fluorine atoms.

  The term “alkenyl” refers to a straight or branched unsaturated hydrocarbon radical of 2 to 12 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1- Pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, etc. including.

  The term “alkynyl” means a straight or branched hydrocarbon radical of 2 to 12 carbon atoms having at least one triple bond, for example 3-propynyl, 1-butynyl, 3-butynyl, 1-pentynyl. 3-pentynyl, 3-methyl-3-butynyl, 1-hexynyl, 3-hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1-dodecynyl and the like Including.

As used herein, the term “alkylene” has 1 to 10 carbon atoms, such as methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like. Refers to a divalent group derived by removing two hydrogen atoms from a straight or branched chain saturated hydrocarbon. The alkylene group of the present invention includes lower alkyl, lower alkoxy, lower thioalkoxy, —O (CH ₂ ) _0-2 CF ₃ , halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF _3. , —CO ₂ H, —CO ₂ C ₁ -C ₆ alkyl, NR′R ″, or —CONR′R ″, optionally substituted (where R ′ and R ″ is independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or together form a 4- to 7-membered ring; or N, R ′, and R ″ together A 4-7 membered ring is formed). Useful alkylene groups have 1 to 6 carbon atoms (C ₁ -C ₆ alkylene).

As used herein, the term “heteroatom” refers to not only oxygen, nitrogen, or sulfur (O, N, or S), but also sulfoxyl or sulfonyl (SO or SO ₂ ), unless otherwise specified.

As used herein, the term “hydrocarbon chain” refers to a straight chain hydrocarbon of 2 to 6 carbon atoms. The hydrocarbon chain includes lower alkyl, lower alkoxy, lower thioalkoxy, —O (CH ₂ ) _0-2 CF ₃ , halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF ₃ , — Optionally substituted by one or more substituents selected from CO ₂ H, —CO ₂ C ₁ -C ₆ alkyl, NR′R ″ or —CONR′R ″, wherein R ′ and R ″ are Independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or together form a 4-7 membered ring; or N, R ′, and R ″ are 4-7 together. Forming a member ring).

As used herein, the term “hydrocarbon-heteroatom chain” refers to a hydrocarbon chain in which one or more carbon atoms have been replaced with a heteroatom. The hydrocarbon-heteroatom chain includes lower alkyl, lower alkoxy, lower thioalkoxy, —O (CH ₂ ) _{0 -2} CF ₃ , halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF. ₃ , —CO ₂ H, —CO ₂ C ₁ -C ₆ alkyl, NR′R ″ or —CONR′R ″, optionally substituted by one or more substituents (where R ′ and R ″ is independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or together form a 4-7 membered ring; or N, R ′, and R ″ together A 4-7 membered ring is formed).

  As used herein, the term “heteroalkylene” refers to one or more heterocycles such as oxygen, sulfur, or nitrogen (having a valence completed by hydrogen or oxygen) in or at the end of the carbon chain. Refers to an alkylene radical as defined above containing an atom.

  As used herein, the terms “lower alkoxy” and “lower thioalkoxy” refer to O-alkyl or S-alkyl of 1 to 6 carbon atoms as defined above for “lower alkyl”.

As used herein, the term “aryl” refers to an unsubstituted aromatic ring, or lower alkyl, lower alkoxy, lower thioalkoxy, —O (CH ₂ ) _0-2 CF ₃ , halogen, nitro, cyano-OH, _{-SH, -CF 3, -CO 2 H} , -CO 2 C 1 -C 6 alkyl, -NR'R ", - S (O ) 2 -alkyl, S _{(O) 2} aryl, S _(O) 2 NR ' R ″ or an aromatic ring optionally substituted by 1 to 4 substituents selected from —CONR′R ″ (wherein R ′ and R ″ are independently H, alkyl, cycloalkyl, alkenyl, Alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or together form a 4-7 membered ring; or N, R ′, and R ″ together form a 4-7 membered ring. Not something Is phenyl, biphenyl, naphthyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-2 -Methylphenyl, 4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 3,4 -Dimethylphenyl etc. Furthermore, the term “aryl” includes alkyl, a Kenyir, and unsubstituted or substituted with up to four substituent groups listed with respect to alkynyl means a monocyclic or polycyclic aromatic ring having 5 to 12 carbon atoms.

  As used herein, the term aralkyl means aryl as defined above attached to an alkyl group as defined above.

  The term “heteroaryl” refers to an aromatic ring containing one or more heteroatoms. Furthermore, the term “heteroaryl” refers to an aromatic monocyclic, bicyclic, or polycyclic ring containing one or more (ie, 1-4) heteroatoms selected from N, O, and S. Means. A heteroaryl may be substituted with one or more groups listed for aryl. Examples of heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, and the like. Examples are further 1-, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, Or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 1,3-, or 5-triazolyl, 1-, 2-, or 3-tetrazolyl, 2- Including pyrazinyl, 2-, 4-, or 5-pyrimidinyl. Specific examples of suitable bicyclic heteroaryl compounds include, but are not limited to, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 1-, 2-, 3- , 4-, 5-, 6-, or 7-indolyl, 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolidinyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzothienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl 1-, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, and 1-3 -, 4-, 5-, 6-, 7-, Others, including the 8-isoquinolinyl.

  As used herein, the term heteroaralkyl means heteroaryl as defined above attached to an alkyl group as defined above.

The term “heterocycle” means a saturated monocyclic or polycyclic (ie bicyclic) ring containing one or more (ie 1-4) heteroatoms selected from N, O and S To do. The heterocycle is lower alkoxy, lower thioalkoxy, —O (CH ₂ ) _0-2 CF ₃ , halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF ₃ , —CO ₂ H, It is understood that it may be substituted by one or more substituents selected from —CO ₂ C ₁ -C ₆ alkyl, —NR′R ″ or —CONR′R ″, where R ′ and R ″ Are independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or together form a 4- to 7-membered ring; or N, R ′, and R ″ are both 4- Forming a seven-membered ring). Useful alkyl groups have 1 to 6 carbon atoms (C ₁ -C ₆ alkyl). Examples of suitable monocyclic heterocycles include, but are not limited to, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl, oxetaryl.

The term “cycloalkyl” means a saturated hydrocarbon ring. Furthermore, the term “cycloalkyl” refers to a hydrocarbon ring containing from 3 to 12 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl, norpinanyl, or adamantyl. The cycloalkyl ring is lower alkoxy, lower thioalkoxy, — (CH ₂ ) _0-2 CF ₃ , halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF ₃ , —CO ₂ H, — Can be unsubstituted or substituted by 1-3 substituents selected from one or more of the substituents selected from CO ₂ C ₁ -C ₆ alkyl, —NR′R ″ or —CONR′R ″ Wherein R ′ and R ″ are independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or together form a 4-7 membered ring; or N, R 'And R "together form a 4-7 membered ring). Useful alkyl groups have 1 to 6 carbon atoms (C ₁ -C ₆ alkyl), where alkyl, aryl, and heteroaryl are as defined herein. Examples of substituted cycloalkyl groups include fluorocyclopropyl, 2-iodocyclobutyl, 2,3-dimethylcyclopentyl, 2,2-dimethoxycyclohexyl, and 3-phenylcyclopentyl.

  “Cycloalkenyl” means a cycloalkyl group having one or more carbon-carbon double bonds. Examples include cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, and the like.

  The term “isomer” means “stereoisomer” and “geometric isomer” as defined below.

  The term “stereoisomer” means compounds having one or more chiral centers, each center being capable of existing in the R or S configuration. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as their racemates and mixtures thereof.

  The term “geometric isomer” can exist not only in the cis, trans, syn, anti, entgegen (opposite) (E), and zusammen (same side) (Z) forms, but also as a mixture thereof.

  The symbol “=” means a double bond.

  The symbol “∩” means a bond to a group that forms a 4-8 membered ring. Generally this symbol appears in pairs.

  When a bond to a substituent is depicted as intersecting a bond connecting two atoms in the ring, such a substituent is present in the ring provided that the atom can bind to the substituent without compromising its valence. Can be bonded to any atom. When there are several atoms in a substituent that can be attached to a ring atom, the first atom of the described substituent is attached to the ring.

  Where a bond from a substituent is depicted as intersecting a bond connecting two atoms in the ring of the substituent, such substituent can be bonded to any bondable atom in the ring.

  When a bond is represented by a line such as "---", it is meant to indicate that the bond may or may not be present when the resulting compound is stable and satisfies the valence. When an asymmetric carbon is generated by such a bond, it does not mean a special stereochemical structure unless otherwise specified.

As used herein, the following terms have the meanings given: RT or rt means room temperature. MP means melting point. MS means mass spectrometry. TLC means thin layer chromatography. [S] at. Means saturation. [C] onc. Means high concentration. TBIA means tert-butylisopropylideneamine. DCM means dichloromethane and is used synonymously with methylene chloride. NBS means N-bromosuccinimide. “H” means time. “V / v” means capacity ratio or “capacity to capacity”. R _f means a retention coefficient. Tf ₂ O means “trifluoromethanesulfonic anhydride” or C (F) ₃ S (O) ₂ OS (O) ₂ C (F) ₃ or (CF ₃ SO ₂ ) O. Ac ₂ O means acetic anhydride. “[T] rifluorotol.” Or “TFT” means trifluorotoluene. “DMF” means dimethylformamide. “DCE” means dichloroethane. “Bu” means butyl. “Me” means methyl. “Et” means ethyl. “DBU” means 1,8-diazabicyclo- [5.4.0] undec-7-ene. “TBS” means “TBDMS” or tert-butyldimethylsilyl. “DMSO” means dimethyl sulfoxide. “TBAF” means tetrabutylammonium fluoride. THF means tetrahydrofuran. [N] -BuLi or BuLi means n-butyllithium. TFA means trifluoroacetic acid. i-Pr means isopropyl. [M] in. Means minutes. ml or mL means milliliters. “M” or “m” means moles.

The term “patient” means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits.
A “therapeutically effective amount” is an invention that improves symptoms of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, BPH, Alzheimer's disease, diabetes or osteoporosis when administered to a patient. The amount of the compound.

  As used herein, the term “pharmaceutically acceptable salt, ester, amide, or prodrug” is used within the scope of medically correct judgment for a patient without excessive toxicity, irritation, allergic reaction, etc. Not only carboxylates, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention that are suitable for use in contact with tissues, consistent with a reasonable benefit / risk ratio, and effective for the intended use Where possible, it also refers to the zwitterionic form of the compounds of the invention. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid or base addition salts of the compounds of the present invention. These salts can be obtained by reacting the free form of the compound with an appropriate organic or inorganic acid or base, either in situ or separately during final isolation and purification of the compound, and then isolating the resulting salt. Can be manufactured. Typical salts are hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate , Borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, And lauryl sulfonate.

Pharmaceutically acceptable salts also include, but are not limited to, cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methyl Non-toxic ammonium, quaternary ammonium, and amine cations, including amines, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like can also be included. (Eg, Berge SM, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:
See 1-19. This is incorporated herein by reference). The free base form can be regenerated by contacting the salt form with a base. Although the free base may differ from the salt form with respect to physical properties such as solubility, the salt is equivalent to the corresponding free base for purposes of the present invention.

Examples of pharmaceutically acceptable non-toxic esters of the compounds of the present invention include C ₁ -C ₆ alkyl esters in which the alkyl group is straight or branched. Acceptable esters also, C ₅ -C ₇ cycloalkyl esters as well, but are not limited like benzyl, including arylalkyl esters containing it. C ₁ -C ₄ alkyl esters are preferred. Esters of the compounds of the present invention can be prepared according to conventional methods.

Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention are derived from ammonia, primary C ₁ -C ₆ alkylamines and alkyls whose primary or branched alkyl groups are secondary C ₁ -C ₆ dialkylamines. Containing amides. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, primary C ₁ -C ₃ alkylamines and secondary C ₁ -C ₂ dialkylamines are preferred. Amides of the compounds of the present invention can be prepared according to conventional methods.

“Prodrug” is used to include all covalently bonded carriers that release the active parent drug according to Formula I in vivo. Furthermore, the term “prodrug” refers to a compound that has been converted to generate the parent compound of the above formula in vivo, for example by hydrolysis in blood. A thorough discussion by T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.
14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 (both incorporated herein by reference). Examples of prodrugs include acetates, formates, benzoate derivatives and amines of alcohols present in compounds of formula I.

  In some cases, compounds can exist as tautomers. All tautomers are included in Formula I and provided by the present invention.

  Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms and are used within the scope of the present invention.

  Certain compounds of the present invention have one or more chiral centers and each center can exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers can be obtained by methods known in the art, such as chiral chromatographic columns and separation of stereoisomers by chiral synthesis, if desired. Furthermore, the compounds of the invention can exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (opposite side) (E), and zusammen (same side) (Z) form isomers as well as their appropriate mixtures.

  The compounds of the present invention are administered to patients for the treatment, suppression or prevention of hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertriglyceridemia, BPH, Alzheimer's disease, diabetes and osteoporosis Is appropriate. The terms “treatment”, “treatment”, “suppression”, “prevention”, etc. refer to the disease or condition to which such term is applied, or one or more symptoms of such disease or condition to be stopped, alleviated, or progressed. It refers to inhibiting. As used herein, these terms also depend on the patient's condition, including alleviating the severity of the disease or condition or the symptoms associated therewith before the pain associated with the disease or condition. Including preventing the onset of symptoms associated with the disease or condition. Such prevention or alleviation prior to distress refers to administration of a compound of the present invention to a subject who is not suffering from the disease or condition at the time of administration. “Prophylaxis” also includes prevention of recurrence of the disease or condition or symptoms associated therewith. Thus, the compounds of the present invention may be administered to a patient alone or as part of a composition containing other ingredients such as excipients, diluents, and carriers (all known in the art). Can do. The composition can be oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intrasternal, intravaginal, intraperitoneal, intravenous, topical (powder, ointment, or drops), or cheek or It can be administered to humans and animals as a nasal spray.

  Compositions suitable for parenteral injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Can do. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles are water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol), suitable mixtures thereof, vegetable oils (such as olive oil), and oleic acid Contains injectable organic esters such as ethyl. For example, proper fluidity can be maintained by using a coating such as lecithin, maintaining the required particle size in the case of a dispersant, and using a surfactant.

  These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispensing agents. Prevention of the activity of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. For example, it may be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of injectable formulations can be brought about by the use of drugs that delay absorption, for example, aluminum monostearate and gelatin.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid formulations, sodium citrate or dicalcium phosphate, or (a) a filler or bulking agent such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) carboxymethylcellulose, alginate, gelatin, Binders such as polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerol; (d) such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate Disintegrants; (e) solution retarders such as paraffin; (f) absorption enhancers such as quaternary ammonium compounds; (g) humectants such as cetyl alcohol and glycerol monostearate; (h) kaolin and bentonite Adsorbents; and ( ) Talc, calcium stearate, magnesium stearate, solid polyethylene glycols, at least one inert conventional excipients, such as sodium lauryl sulfate, or combinations thereof lubricants (or carrier) and the active compound is mixed. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents.

  Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as high molecular weight polyethylene glycol as well as lactose or lactose.

  Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings known in the art. These can contain opacifiers and can also be compositions that release the active compound or compound by delayed release at a specific site in the intestine. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound can also be packed into microencapsulated formulations, if appropriate with one or more of the above-mentioned excipients.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -Butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil), fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan or mixtures of these substances Inert diluents commonly used in the art can be included.

  In addition to such inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and flavoring agents.

  In addition to the active compounds, suspensions are suspension agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances. Can be included.

  Compositions for rectal administration are preferably solids at room temperature but liquid at body temperature, such as cocoa butter, polyethylene glycols, or suppository waxes, and thus soluble in the rectum or vaginal cavity, such as cocoa butter. Suppositories that can be prepared by mixing with a suitable nonirritating excipient or carrier that releases the active compound.

  Dosage forms for topical administration of the compounds of this invention include ointments, powders, sprays, and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Intraocular formulations, eye ointments, powders, and solutions are also considered within the scope of this invention.

The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg / day. For normal human adults having a body weight of about 70 kilograms, dosages in the range of about 0.01 to about 100 mg / kg body weight / day are preferred. However, the specific dosage used can be varied. For example, dosage can be determined by a number of factors including patient requirements, the severity of the disease being treated, and the pharmacological activity of the compound used. Methods of determining optimal dosages for a particular patient are known to those skilled in the art.

Combination aspect of the present invention

  The compounds of the present invention have the following diseases / conditions: dyslipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, peripheral vascular disease, cardiovascular disorder, angina, ischemia, cardiac ischemia, Stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, diabetes and vascular complications of diabetes, obesity, unstable angina, Alzheimer's disease, BPH, osteoporosis, cerebrovascular disease, coronary artery disease, ventricular function Disorder, cardiac arrhythmia, pulmonary vascular disease, renovascular disease, renal disease, vascular hemostasis disorder, autoimmune disease, lung disease, sexual dysfunction, cognitive dysfunction, cancer, organ transplant rejection, psoriasis, endometriosis, and Can be used alone or in combination with other drugs described herein in the treatment of macular degeneration

  The compounds of the invention can also be used with other drugs (eg, HDL-cholesterol raising agents, triglyceride lowering agents) for the treatment of the diseases / conditions described herein. A combination aspect of the present invention includes a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one other compound. For example, the compounds of the present invention may be cholesterol absorption inhibitors, MTP / apo B secretion inhibitors, or fibrate, niacin, ion exchange resins, antioxidants, ACAT inhibitors, PPAR-activators, CETP inhibitors or bile acids It can be used in combination with other cholesterol modulators such as scavengers. In combination therapy treatment, the compounds of the present invention and other drug therapies are administered together to the mammal by conventional methods. Hereinafter, various combinations of the present invention will be described more specifically.

  Any cholesterol absorption inhibitor can be used in the combination aspect of this invention. The term cholesterol absorption inhibition refers to the ability of a compound to prevent cholesterol contained within the lumen of the intestine from being taken up into and / or released from the enterocyte into the bloodstream. One skilled in the art can readily determine such cholesterol absorption inhibitory activity according to standard assays (eg, J. Lipid Res. (1993) 34: 377-395). Cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT International Publication No. WO 94/00480. An example of a recently approved cholesterol absorption inhibitor is ZETIA ™.

  Any cholesterol ester transfer protein (“CETP”) inhibitor can be used in the combination aspect of this invention. The term CETP inhibitor inhibits transport between cholesteryl ester and triglyceride high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), and lipoprotein particles including chylomicrons. Refers to the compound to which The end result of CETP activity is a decrease in HDL cholesterol and an increase in LDL cholesterol, so such end effect is pro-atherogenic. Therefore, the effect of CETP inhibitors on the lipoprotein profile is thought to suppress atherogenesis. Those skilled in the art take this by measuring the amount of drug required to alter plasma lipid levels, such as HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides in the plasma of a particular mammal Inhibition can be readily measured (eg, Crook et al., Arteriosclerosis 10,625, 1990; US Pat. No. 6,140,343). A variety of these compounds are described and cited below, although other CETP inhibitors will be known to those skilled in the art. For example, US Pat. Nos. 6,197,786, 6,723,752 and 6,723,753, the disclosures of each of which are incorporated herein by reference, are specific containing high density lipoprotein-cholesterol. Low levels of HDL, such as atherosclerosis and cardiovascular disease in mammals, including humans, by increasing plasma lipid levels and lowering certain other plasma lipid levels such as LDL-cholesterol and triglycerides Disclosed are cholesteryl ester transfer protein inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors for the treatment of diseases exacerbated by cholesterol and / or high levels of LDL-cholesterol and triglycerides. Examples of useful CETP inhibitors include the following compounds: [2R, 4S] 4-[(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-tri Fluoromethyl-3,4-dihydroxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester (also known as torcetrapib ™) and 3-{[3- (4-Chloro-3-ethyl-phenoxy) -phenyl]-[3- (1,1,2,2-tetrafluoro-ethoxy) -benzyl] -amino} -1,1,1 -Trifluoro-propan-2-ol. Many of the CETP inhibitors of the present invention are poorly soluble, and dosage forms with enhanced solubility facilitate administration of such compounds. One such dosage form comprises (1) a solid amorphous dispersant comprising a cholesteryl ester transfer protein (CETP) inhibitor and an acidic concentration improving polymer; and (2) an acid sensitive HMG-CoA reductase inhibitor. It is a dosage form. This dosage form is described in more detail in US patent application Ser. No. 10 / 739,567, entitled “Dosage Form Comprising CETP Inhibitor and HMG-CoA Reductase Inhibitor”. Incorporated herein by reference).

  Any compound that activates or otherwise interacts with human peroxisome proliferator activated receptor (“PPAR”) can be used in the combination aspect of this invention. Three mammalian peroxisome proliferator-activated receptors have been isolated and named PPAR-alpha, PPAR-gamma, and PPAR-beta (also known as NUC1 or PPAR-delta). These PPARs regulate the expression of target genes by binding to DNA sequence elements called PPAR response elements. These elements have been identified in enhancers of many genes that encode proteins that regulate lipid metabolism, suggesting that PPAR plays a pivotal role in the lipid signaling cascade and lipid homeostasis. is doing. PPAR-gamma receptors are involved in the regulation of insulin sensitivity and blood glucose levels. PPAR-α activators are involved in lowering plasma triglycerides and LDL cholesterol. PPAR-β activators have been reported to increase HDL-C levels and reduce LDL-C levels. Thus, the combination of activating PPAR-β alone or simultaneously activating PPAR-α and / or PPAR-gamma may be useful for planning treatment of lipid metabolism disorders with increased HDL and decreased LDL. Can be desired. One skilled in the art can readily measure PPAR-activation using standard assays (eg, US 2003/0225158 and US 2004/0157885). A variety of these compounds are cited and described below, but other PPAR-activators will be known to those skilled in the art. Samples are provided in the following patents and published patent applications incorporated herein by reference. US 2003/0225158 describes compounds that alter PPAR activity and therapeutic agents for treating or preventing dyslipidemia, hypercholesterolemia, obesity, hyperglycemia, atherosclerosis and hypertriglyceridemia The method of use thereof is disclosed. US Pat. No. 6,710,063 discloses selective activators of PPARdelta. US 2003/0171377 discloses certain PPAR-activators useful as antidiabetic agents. US 2004/0157885 describes PPAR agonists (particularly certain PPARα agonists), pharmaceutical compositions containing such agonists, and atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity, It relates to the use of such agonists for the treatment of osteoporosis and syndrome X or metabolic syndrome. Examples of useful PPAR-activators are the following compounds: [5-methoxy-2-methyl-4- (4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl) -phenoxy] -acetic acid; [5- Methoxy-2-methyl-4- (3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl) -phenoxy] -acetic acid; [4- (4′fluoro-biphenyl-4-ylmethylsulfanyl) -5-methoxy -2methyl-phenoxy] -acetic acid; {5-methoxy-2-methyl-4- [4- (4-trifluoromethyl-benzyloxy) -benzylsulfanyl] -phenoxy} -acetic acid; {{5-methoxy-2- Methyl-4- [4- (5-trifluoromethyl-pyridin-2-yl) -benzylsulfanyl] -phenoxy} -acetic acid; (4- {4- [ -(3-Fluoro-phenyl) -vinyl] -benzylsulfanyl} -5-methoxy-2-methyl-phenoxy) -acetic acid; [5-methoxy-2-methyl-4- (3-methyl-4'-trifluoro) Methyl-biphenyl-4-ylmethylsulfanyl) -phenoxy] -acetic acid; [5-methoxy-2-methyl-4- (4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl) -phenoxy] -acetic acid; { 5-methoxy-2-methyl-4- [2- (4-trifluoromethyl-benzyloxy) -benzylsulfanyl] -phenoxy} acetic acid; 3- {5- [2-(-5-methyl-2-phenyl-oxazole) -4-yl-ethoxy] -indol-1-yl} -propionic acid; 3- {4 [2- (5-methyl-2-phenyl-1,3-oxa -4-yl) ethoxy-1H-indazol-1yl} propanoic acid; 2-methyl-2- {3-[({2- (5-methyl-2-phenyl-1,3-oxazole-4- Yl) ethoxy] carbonyl} amino) methyl] phenoxy} propionic acid; 1- {3 ′-[2-5-methyl-2-phenyl-1,3-oxazol-4-yl] -1,1′-biphenyl- 3-yl} oxy) cyclobutanecarboxylic acid; 3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl] -piperidine-1-carboxylic acid 3-trifluoromethyl-benzyl ester; 2- {2- Methyl-4-[({4-methyl-2- [4- (trifluoromethyl) phenyl] -1,3-thiazol-5-yl} methyl) sulfanyl] phenoxy} acetic acid; 2- {2-methyl -4-[({4-Methyl-2- [4- (trifluoromethyl) phenyl] -1,3-oxazol-5-yl} methyl) sulfanyl] phenoxy} acetic acid; 2- {4-[({4 -Methyl-2- [4- (trifluoromethyl) phenyl] -1,3-thiazol-5-yl} methyl) sulfanyl] phenoxy} acetic acid methyl; 2- {4-[({4-methyl-2- [ 4- (trifluoromethyl) phenyl] -1,3-thiazol-5-yl} methyl) sulfanyl] phenoxy} acetic acid; (E) -3- [2-methyl-4-({4-methyl-2- [ 4- (trifluoromethyl) phenyl] -1,3-thiazol-5-yl} methoxy) phenyl] -2-propenoic acid; 2- {3-chloro-4-[({4-methyl-2- [4 -(Trifluoromethyl) pheny ] -L, 3-thiazol-5-yl} methyl) sulfanyl] phenyl} acetic acid; 2- {2-methyl-4-[({4-methyl-2- [3-fluoro-4- (trifluoromethyl)] Phenyl] -1,3-thiazol-5-yl} methyl) sulfanyl] phenoxy} acetic acid; and pharmaceutically acceptable salts thereof.

  Any MTP / apo B secretion (microsomal triglyceride transfer protein and / or apolipoprotein B secretion) inhibitor can be used in the combination aspect of this invention. The term MTP / apo B secretion inhibitor refers to compounds that inhibit the secretion of triglycerides, cholesteryl esters and phospholipids. One skilled in the art can readily measure such inhibition according to standard assays (eg, Wetterau, J. R. 1992; Science 258: 999). A variety of these compounds are known to those skilled in the art, including Imputaprid (Bayer) and other compounds such as those disclosed in International Publication No. WO96 / 40640 and International Publication No. WO98 / 23593.

Any ACAT inhibitor can be used in the combination therapy aspect of the present invention. The term ACAT inhibitor refers to a compound that inhibits the intracellular esterification of dietary cholesterol by the enzyme acyl CoA (cholesterol acyltransferase). Those skilled in the art can readily determine such inhibition according to standard assays such as the method of Heider et al. (Journal of Lipid Research. 24: 1127 (1983)). A variety of these compounds are known to those skilled in the art, for example, US Pat. No. 5,510,379 discloses certain carboxysulfonates, including International Publication No. WO 96/26948 and International Publication No. WO 96/10559. Both numbers disclose urea derivatives having ACAT inhibitory activity. Examples of ACAT inhibitors are abashimib (Pfizer), CS-505 (Sankyo) and eflucimib (Eli
Including compounds such as Lilly and Pierre Fabre).

  Lipase inhibitors can be used in the combination therapy aspect of the present invention. Lipase inhibitors are compounds that inhibit the metabolic breakdown of dietary triglycerides into free fatty acids and monoglycerides. Under normal physiological conditions, lipolysis occurs in a two-step process involving acylation of the activated serine moiety of the lipase enzyme. This produces a fatty acid-lipase hemiacetal intermediate that is then decomposed to release diglycerides. After further deacylation, the lipase-fatty acid intermediate decomposes to produce free lipase, monoglycerides, and fatty acids. The resulting free fatty acids and monoglycerides are taken up by bile acid-phospholipid micelles which are then absorbed at the level of the small intestinal brush border. These micelles eventually enter the peripheral circulation as chylomicrons. One skilled in the art can readily determine such lipase inhibitory activity according to standard assays (eg, Methods Enzymol. 286: 190-231).

  Pancreatic lipase mediates the metabolic degradation of fatty acids from the C-1 and C-3 positions of triglycerides. The main sites of ingested fat metabolism are the duodenum and proximal jejunum due to pancreatic lipase, which is normally secreted in the large excess necessary for fat breakdown in the upper small intestine. Since pancreatic lipase is a major enzyme required for the absorption of dietary triglycerides, inhibitors have utility in the treatment of obesity and other related conditions. One skilled in the art can readily determine such pancreatic lipase inhibitory activity according to standard assays (eg, Methods Enzymol. 286: 190-231).

Gastric lipase is an immunologically distinguishable lipase responsible for approximately 10-40% of dietary fat digestion. Gastric lipase is secreted in response to mechanical stimulation, food intake, the presence of a high fat diet, or sympathomimetic drugs. Lipolysis in the stomach of ingested fat has a physiological significance in the supply of fatty acids necessary to induce pancreatic lipase activity in the intestine, and various physiological and pathologies associated with pancreatic dysfunction The absorption of fat in the target state is also important. See, for example, CK Abrams, et al., Gastroenterology, 92, 125 (1987). One skilled in the art can readily determine such gastric lipase inhibitory activity according to standard assays (eg, Methods
Enzymol. 286: 190-231).

  Various gastric and / or pancreatic lipase inhibitors are known to those skilled in the art. A preferred lipase inhibitor is an inhibitor selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), varilactone, estellatin, evelactone A, and evelactone B. A compound called tetrahydrolipstatin is particularly preferred. The lipase inhibitor N-3-trifluoromethylphenyl-N′-3-chloro-4′-trifluoromethylphenylurea and various related urea derivatives are described in US Pat. No. 4,405,644. It is disclosed. The lipase inhibitor elastacin is disclosed in US Pat. Nos. 4,189,438 and 4,242,453. The lipase inhibitor, cyclo-O, O ′-[(l, 6-hexanediyl) -bis- (iminocarbonyl)] dioxime, and the various bis (iminocarbonyl) dioximes associated therewith, are Petersen et al., Liebig's It can be prepared as described in Annalen, 562, 205-229 (1949).

Various pancreatic lipase inhibitors are described below. Pancreatic lipase inhibitor lipstatin (2S, 3S, 5S, 7Z, 10Z) -5-[(S) -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-7,10- Hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat), (2S, 3S, 5S) -5-[(S) -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-hexadecanoic acid 1, 3 lactones and various substituted N-formylleucine derivatives and stereoisomers thereof are disclosed in US Pat. No. 4,598,089. For example, tetrahydrolipstatin is as described, for example, in US Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. Manufactured. The pancreatic lipase inhibitor FL-386, 1- [4- (2-methylpropyl) cyclohexyl] -2-[-(phenylsulfonyl) oxy] -ethanone, and various substituted sulfonate derivatives related thereto are described in US Pat. No. 4,452,813. The pancreatic lipase inhibitor WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and various carbamate esters and pharmaceutically acceptable salts associated therewith are described in US Pat. No. 5,512. 565; No. 5,391,571 and 5,602,151. Pancreatic lipase inhibitor varilactone and its production method by microbial culture of Actinomycetes sp. Strain MG147-CF2 are disclosed in Kitahara et al., J. Antibiotics, 40 (11), 1647-1650 (1987). A method for producing pancreatic lipase inhibitors Evelactone A and Evelactone B and its Actinomycetes genus MG7-G1 by microbial culture is disclosed in Umezawa
Et al., J. Antibiotics, 33, 1594-1596 (1980). The use of Evelactone A and B in the inhibition of monoglyceride production is disclosed in JP 08-143457, published June 4, 1996.

  Other compounds that are marketed for hyperlipidemia, including hypercholesterolemia, and are used to help prevent or treat atherosclerosis include Welchol®, Colestid®, LoCholest. (Registered trademark), bile acid scavengers such as Questran (registered trademark) and fibric acid derivatives such as Atromid (registered trademark), Loopid (registered trademark) and Tricor (registered trademark).

  The compounds of the present invention can be used with antidiabetic agents. Other drugs that can be used to treat diabetes in patients with diabetes (especially type II), insulin resistance, impaired glucose tolerance, etc. or patients with diabetic complications such as neuropathy, nephropathy, retinopathy or cataract Diabetes can be treated by administering a therapeutically effective amount of a compound of formula I in combination with (eg, insulin). This includes the class of antidiabetic drugs (and certain drugs) described herein.

Any glycogen phosphorylase inhibitor can be used in combination with the Formula I compound of the present invention. The term glycogen phosphorylase inhibitor refers to compounds that inhibit the bioconversion of glycogen to glucose-1-phosphate, catalyzed by the enzyme glycogen phosphorylase. One skilled in the art can readily determine such glycogen phosphorylase inhibitory activity according to standard assays (eg, J. Med. Chem. 41 (1998) 2934-2938). Various glycogen phosphorylase inhibitors are known to those skilled in the art, including those described in International Publication No. WO 96/39384 and International Publication No. WO 96/39385. Any aldose reductase inhibitor can be used in combination with the Formula I compound of the present invention. The term aldose reductase inhibitor refers to compounds that inhibit the bioconversion of glucose to sorbitol catalyzed by the enzyme aldose reductase. One skilled in the art can readily measure aldose reductase inhibition according to standard assays (e.g., J.
Malone, Diabetes, 29: 861-864 (1980). ”Red Cell Sobitol, an Indicator of Diabetic
Control "). Various aldose reductase inhibitors are known to those skilled in the art.

  Any sorbitol dehydrogenase inhibitor can be used in combination with a compound of formula I of the present invention. The term sorbitol dehydrogenase inhibitor refers to compounds that inhibit the bioconversion of sorbitol to fructose catalyzed by the enzyme sorbitol dehydrogenase. One skilled in the art can readily determine such sorbitol dehydrogenase inhibitor activity according to standard assays (eg, Analyt. Biochem (2000) 280: 329-331). Various sorbitol dehydrogenase inhibitors are known, for example, US Pat. Nos. 5,728,704 and 5,866,578 treat diabetic complications by inhibiting the enzyme sorbitol dehydrogenase. Alternatively, compounds and methods for prevention are disclosed.

  Any glucosidase inhibitor may be used in combination with the Formula I compound of the present invention. Glucosidase inhibitors inhibit enzymatic hydrolysis of complex carbohydrates to bioavailable simple sugars (eg, glucose) by sugar hydrolases (eg, amylase or maltase). Among other things, the rapid metabolic action of glucosidase after ingestion of high levels of carbohydrates results in a state of dietary hyperglycemia, which increases insulin secretion and increases fat synthesis in patients with adiposity or diabetes And leads to reduced lipolysis. Such hyperglycemia is often followed by hypoglycemia due to the presence of excessive levels of insulin. In addition, the chyme remaining in the stomach promotes the production of gastric juice, which initiates or promotes the development of gastritis or duodenal ulcer. Thus, glucosidase inhibitors are known to have utility in promoting carbohydrate passage through the stomach and inhibiting absorption of glucose from the intestine. Furthermore, the conversion of carbohydrates into adipose tissue lipids and the subsequent uptake of dietary fat into the adipose tissue store has the advantage of being reduced or retarded accordingly, thereby mitigating or preventing the harmful abnormalities caused thereby. One skilled in the art can readily determine such glucosidase inhibitory activity according to standard assays (eg, Biochemistry (1969) 8: 4214).

  Generally preferred glucosidase inhibitors include amylase inhibitors. Amylase inhibitors are glucosidase inhibitors that inhibit the enzymatic degradation of starch or glycogen into maltose. One skilled in the art can readily determine such amylase inhibitory activity according to standard assays (eg, Methods Enzymol. (1955) 1: 149). Such inhibition of enzymatic degradation has the advantage of reducing the amount of bioavailable saccharides including glucose and maltose and reducing adverse diseases caused by bioavailable saccharides.

  Various glucosidase inhibitors are known to those skilled in the art and examples are given below. Preferred glucosidase inhibitors are inhibitors selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, camiglibose, tendamistat, trestatin, pradimicin-Q and sarvostatin. The glucosidase inhibitor acarbose, and various amino sugar derivatives related thereto, are disclosed in US Pat. Nos. 4,062,950 and 4,174,439, respectively. The glucosidase inhibitor adiposine is disclosed in US Pat. No. 4,254,256. 3,4-dideoxy-4-[[2-hydroxy-1- (hydroxymethyl) ethyl] amino] -2-C- (hydroxymethyl-1) -D-epi-inositol, which is the glucosidase inhibitor voglibose, and Various N-substituted pseudoamino sugars related thereto are disclosed in US Pat. No. 4,701,559. The glucosidase inhibitor miglitol (2R, 3R, 4R, 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3,4,5-piperidinetriol, and the various 3, 4,5-Trihydroxypiperidine is disclosed in US Pat. No. 4,639,436. Glucosidase inhibitor emigrate, p- [2-[(2R, 3R, 4R, 5S) -3,4,5-trihydroxy-2- (hydroxymethyl) piperidino] ethoxy] -ethyl benzoate, related thereto Various derivatives and their pharmaceutically acceptable acid addition salts are disclosed in US Pat. No. 5,192,772. Glucosidase inhibitor MDL-25637, 2,6-dideoxy-7-O-beta-D-glucopyranosyl-2,6-imino-D-glycero-L-gluco-heptitol, various homodisaccharides related thereto And their pharmaceutically acceptable acid addition salts are disclosed in US Pat. No. 4,634,765. Glucosidase inhibitor Camiglibose, methyl 6-deoxy-6-[(2R, 3R, 4R, 5S) -3,4,5-trihydroxy-2- (hydroxymethyl) piperidino] -alpha-D-glucopyranoside 3 / Dihydrates, related deoxynojirimycin derivatives, various pharmaceutically acceptable salts thereof, and methods of synthesis thereof are disclosed in US Pat. Nos. 5,157,116 and 5,504,078. The glycosidase inhibitor salvostatin and its various pseudo sugars are described in US Pat. No. 5,091,524.

  Various amylase inhibitors are known to those skilled in the art. The amylase inhibitor tendamistat and various cyclic peptides related thereto are disclosed in US Pat. No. 4,451,455. The amylase inhibitor AI-3688 and various cyclic polypeptides related thereto are disclosed in US Pat. No. 4,623,714. The amylase inhibitor trestatin, which consists of a mixture of trestatin A, trestatin B and trestatin C, and various trehalose-related amino sugars are disclosed in US Pat. No. 4,273,765.

  Additional anti-diabetic agents that can be used in combination with the Formula I compounds of the present invention include, for example, biguanides (eg, metformin), insulin secretagogues (eg, sulfonylureas and glinides), glitazones, non-glitazone PPARgamma Agonist, PPARbeta agonist, DPP-IV inhibitor, PDE5 inhibitor, GSK-3 inhibitor, glucagon antagonist, f-1 inhibitor, 6-BPase (Metabassis / Sankyo), GLP-1 / analog (AC2993, Exendin-4), insulin and insulin mimetics (Merck natural products). Other examples include PKC-beta inhibitors and AGE disrupters.

  The compounds of the present invention can be used in combination with anti-obesity agents. Any anti-obesity agent can be used in such combinations, and examples are provided herein. Those skilled in the art can readily determine such anti-obesity activity according to standard assays known in the art. Suitable anti-obesity agents are phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, beta 3 adrenoreceptor agonist, apolipoprotein-B secretion / microsomal triglyceride transport protein (apo B / MTP) inhibitor, MCR-4 agonist A cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor (eg, sibutramine), a sympathomimetic drug, a serotonin agonist, a cannabinoid receptor antagonist (eg, rimonabant (SR-141, 716A)), Dopamine agonist (eg, bromocriptine), melanocyte stimulating hormone receptor analog, 5HT2c agonist, melanin-concentrating hormone antagonist, leptin (OB protein), leptin analog, leptin Tin receptor agonists, galanin antagonists, lipase inhibitors (eg, tetrahydrolipstatin, ie orlistat), bombesin agonists, appetite suppressants (eg, bombesin agonists), neuropeptide-Y antagonists, thyroxine, thyromimetic drugs , Dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factor (eg, Axokin ™) ), Human agouti-related protein (AGRP), ghrelin receptor antagonist, histamine 3 receptor antagonist or inverse agonist, neuro Medin U receptor agonist and the like.

  Any tyromimetic drug can be used in combination with a compound of the present invention. One skilled in the art can readily measure such tyromimetic activity according to standard assays (eg, Atherosclerosis (1996) 126: 53-63). For example, U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; 5,061,798; 5,284,971; 5,401,772. Various thyrometic drugs are known to those skilled in the art, such as No. 5,654,468; and 5,569,674. Other anti-obesity agents are described in Sibutramine, which can be prepared as described in US Pat. No. 4,929,629, and in US Pat. Nos. 3,752,814 and 3,752,888. Bromocriptine, which can be produced as such.

  Osteoporosis is a systemic bone disease characterized by decreased bone mass and deterioration of bone tissue, resulting in increased bone fragility and fracture development. In the United States, more than 25 million people are affected by this disease and more than 1.3 million cases each year, including 500,000 vertebral fractures, 250,000 hip fractures and 240,000 wrist fractures each year Causes fractures. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year and over 50% of survivors being unable to work. Older people are most at risk for osteoporosis and therefore this problem is expected to increase significantly with the aging of the population. The incidence of global fractures is expected to increase three-fold over the next 60 years, and one study predicts 4.5 million hip fractures worldwide in 2050. Women are at higher risk of osteoporosis than men. Women experience a sharp decrease in bone loss during the five years after menopause. Other factors that increase the risk include smoking, alcohol abuse, sedentary lifestyle and lack of calcium intake.

  Those skilled in the art will be able to use bone resorption inhibitors (eg, progestins, polyphosphonates, biphosphonates, estrogen agonists / antagonists, estrogens, estrogen / progestin combinations, premarin RTM, estrone, estriol or It will be appreciated that 17 alpha- or 17 beta-ethynylestradiol) can be used. Typical progestins are available from commercial sources, including algestone acetophenide, altrenogest, amadinone acetate, ananagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, chromegestone acetate, dermadinone acetate, desogestrel, dimethisterone, dihydrogesterone, Ethinerone, etinodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, guestden, guestnolone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, linesterenol, medrgestone, medroxyprogesterone acetate, melengestrol acetate, Methinodiol diacetate, norethindrone, norethindrone acetate, norethinodrel, norgestimate, Guest Met, norgestrel, Fen acid Okisogesuton, progesterone, acetate Kin Guess pentanol, Kin guest Ron, and soup stall. Preferred progestins are medroxyprogesterone, norethindrone and norethinodrel. Exemplary bone resorption inhibiting polyphosphonates include polyphosphonates of the type disclosed in US Pat. No. 3,683,080, the disclosure of which is incorporated herein by reference. A preferred polyphosphonate is geminal diphosphonate (also called bisphosphonate). Tiludronate disodium is a particularly preferred polyphosphonate. Ibandronic acid is a particularly preferred polyphosphonate. Alendronate and resindronate are particularly preferred polyphosphonates. Zoledronic acid is a particularly preferred polyphosphonate. Other preferred polyphosphonates are 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and 1-hydroxy-3 (methylpentylamino) -propylidene-bisphosphonic acid. The polyphosphonate can be administered in the form of an acid or a soluble alkali metal salt or alkaline earth metal salt. Also included are hydrolysable esters of polyphosphonates. Specific examples are ethane-1-hydroxy 1,1-diphosphonic acid, methanediphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid, methanedichlorodiphosphonic acid, methanehydroxydiphosphonic acid, ethane-1- Amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonic acid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid, propane-N, N-dimethyl-3-amino -1-hydroxy-1,1-diphosphonic acid, propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylaminomethanediphosphonic acid, N, N-dimethylaminomethanedi Phosphonic acid, N (2-hydroxyethyl) aminomethane diphosphonic acid, butane-4-amino-1-hydroxy-1,1-diphosphonic acid, Pentane-5-amino-1-hydroxy --1,1- diphosphonic acid, hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceutically acceptable esters and salts thereof.

In particular, the compounds of the invention can be combined with a mammalian estrogen agonist / antagonist. Any estrogen agonist / antagonist can be used as the second compound of this invention. The term estrogen agonist / antagonist refers to a compound that binds to the estrogen receptor, inhibits bone metabolism, and / or suppresses bone loss. In particular, an estrogen agonist is defined herein as a chemical compound that binds to an estrogen receptor site in mammalian tissue and can mimic the action of estrogen in one or more tissues. As used herein, an estrogen antagonist is defined as a chemical compound that can bind to an estrogen receptor in mammalian tissue and block the action of estrogen in one or more tissues. Technicians in the field have demonstrated estrogen receptor binding assays, standard bone histomorphometry and densitometry methods, and Eriksen EF et al., Bone Histomorphometry, Raven Press, New York, 1994,
pages 1-74; Grier SJ et al., The Use of Dual-Energy X-Ray Absorptiometry In
Animals, Inv. Radiol., 1996, 31 (1): 50-62; Wahner HW and Fogelman I., The
Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical
Practice., Martin Dunitz Ltd., London 1994, pages 1-296) can easily measure such activity. In the following, a variety of these compounds are described and referenced.

  Another preferred estrogen agonist / antagonist is 3- (4- (1,2-diphenyl-but-1-enyl) -phenyl) -acrylic acid, which is Willson et al., Endocrinology, 1997, 138, 3901-3911. Is disclosed. Other preferred estrogen agonist / antagonists are tamoxifen: (2-(-4-((Z) -2-1,2-diphenyl-1-butenyl) phenoxy) -N, N-dimethylethanamine, 2-hydroxy-1 , 2,3-propanetricarboxylate (1: 1)) and related compounds (disclosed in US Pat. No. 4,536,516), the disclosure of which is incorporated herein by reference. Another related compound is 4-hydroxy tamoxifen (disclosed in US Pat. No. 4,623,660), the disclosure of which is incorporated herein by reference.

  A preferred estrogen agonist / antagonist is raloxifene: ((6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl) (4- (2- (1-piperidinyl) ethoxy) phenyl) -methanone hydrochloride Salt) and is disclosed in US Pat. No. 4,418,068 (the disclosure of which is incorporated herein by reference). Other preferred estrogen agonist / antagonists are toremifene: (2- (4-((Z) -4-chloro-1,2-diphenyl-1-butenyl) phenoxy) -N, N-dimethyl-ethanamine, 2-hydroxy- 1,2,3-propanetricarboxylate (1: 1)), which is disclosed in US Pat. No. 4,996,225, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist / antagonist is centchroman: 1- (2-((4-(-methoxy-2,2, dimethyl-3-phenyl-chroman-4-yl) -phenoxy) -ethyl) -p-pyrrolidine. Which is disclosed in U.S. Patent No. 3,822,287, the disclosure of which is incorporated herein by reference, also preferred is levormeloxifene. The antagonist is idoxifene: (E) -1- (2- (4- (1- (4-iodo-phenyl) -2-phenyl-but-1-enyl) -phenoxy) -ethyl) -pyrrolidinone, which is U.S. Patent No. 4,839,155, the disclosure of which is incorporated herein by reference. The antagonist is 2- (4-methoxy-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol, which is disclosed in US Pat. , 488,058 (the disclosure of which is incorporated herein by reference).

  Another preferred estrogen agonist / antagonist is 6- (4-hydroxy-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -benzyl) -naphthalen-2-ol, which is a US patent. No. 5,484,795, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist / antagonist is (4- (2- (2-azabicyclo [2.2.1] hept-2-yl) -ethoxy) -phenyl)-(6-hydroxy-2- (4-hydroxy- Phenyl) -benzo [b] thiophen-3-yl) -methanone, which is disclosed in PCT International Publication No. WO95 / 10513 assigned to Pfizer Inc., together with the production method (the disclosure of which is hereby incorporated by reference). Cited and incorporated).

  Other preferred estrogen agonist / antagonists include the compounds TSE-424 (Wyeth-Ayerst Laboratories) and Arazoxifene. Other preferred estrogen agonist / antagonists include the compounds described in US Pat. No. 5,552,412 assigned to the assignee of the present invention, the disclosure of which is incorporated herein by reference. Particularly preferred compounds disclosed therein are: cis-6- (4-Fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5,6, -7,8 -Tetrahydro-naphthalen-2-ol; (-)-cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene -2-ol (also known as lasofoxifene); cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro -Naphthalen-2-ol; cis-1- (6'-pyrrolidinoethoxy-3'-pyridyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene; 1- (4'- Pyrrolidinyl Toxiphenyl) -2- (4 ″ -fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline; is-6- (4-hydroxyphenyl) -5- (4- (2-piperidine) -1-yl-ethoxy) -phenyl) -5,6, -7,8-tetrahydro-naphthalen-2-ol; and 1- (4′-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1 Other estrogen agonists / antagonists are described in US Patent No. 4,133,814, the disclosure of which is incorporated herein by reference. , 133,814 are derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3-aroylbenzothiophene-1-oxide It discloses.

  Other osteoporosis agents that can be used in combination with the compounds of formula I of the present invention include, for example: parathyroid hormone (PTH) (bone anabolic agent); parathyroid hormone (PTH) secretion enhancer (eg, US Pat. No. 6, 132,774), among others, calcium receptor antagonists; calcitonin; and vitamin D and vitamin D analogs.

  Any compound that is an antihypertensive agent can be used in the combination aspect of this invention. Such compounds include amlodipine and related dihydropyridine compounds, calcium channel blockers, angiotensin converting enzyme inhibitors (“ACE-inhibitors”), angiotensin-II receptor antagonists, beta-adrenergic receptor blockers and alpha-adrenergic receptor blockers. including. One skilled in the art can measure such antihypertensive activity according to standard tests (eg, blood pressure measurement).

  Amlodipine and related dihydropyridine compounds are disclosed in US Pat. No. 4,572,909, which is incorporated herein by reference, as a potent anti-ischemic and antihypertensive agent. U.S. Pat. No. 4,879,303 (which is incorporated herein by reference) discloses amlodipine benzene sulfonate (also referred to as amlodipine besylate). Amlodipine and amlodipine besylate are potent long-acting calcium channel blockers. Thus, amlodipine, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensives and anti-ischemic agents. Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in US Pat. No. 5,155,120 as having utility in the treatment of congestive heart failure. Amlodipine besylate is currently marketed as Norvasc®.

  Calcium channel blockers within the scope of the present invention include, but are not limited to, bepridil (as disclosed in US Pat. No. 3,962,238 or US Reissue Pat. No. 30,577). Clentiazem (which can be prepared as disclosed in US Pat. No. 4,567,175); Diltiazem (which can be prepared as disclosed in US Pat. No. 3,562); Fendiline (US Galopamil (which can be prepared as disclosed in US Pat. No. 3,261,859); mibefradil, prenylamine, semothiazil, Terodiline, verapamil, alanipin, varnidipine, benidipine, cilnidipine, efonidipine, ergodipin Felodipine, including isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, Etafenon, and perhexiline. The entire disclosure of such US patents is incorporated herein by reference.

  Angiotensin converting enzyme inhibitors (ACE-inhibitors) within the scope of the present invention include, but are not limited to, alacepril (which can be prepared as disclosed in US Pat. No. 4,248,883); Benazepril (which can be prepared as disclosed in U.S. Pat. No. 4,410,520); captopril, celonapril, delapril, enalapril, fosinopril, imadapril, lisinopril, mobelpril, perindopril, quinapril, ramipril, spirapril, and temocapril Includes trandolapril. The disclosures of all such US patents are incorporated herein by reference.

  Angiotensin-II receptor antagonists (A-II antagonists) within the scope of the present invention include, but are not limited to, candesartan (which can be prepared as disclosed in US Pat. No. 5,196,444). Eprosartan (which can be prepared as disclosed in US Pat. No. 5,185,351); including irbesartan, losartan, and valsartan. The disclosures of all such US patents are incorporated herein by reference.

  Beta-adrenergic receptor blockers (beta- or beta blockers) that are within the scope of the present invention include, but are not limited to, acebutolol (as disclosed in US Pat. No. 3,857,952). Alprenolol, amosulalol (can be produced as disclosed in US Pat. No. 4,217,305); including arotinolol, atenolol, befnolol, betaxolol. The disclosures of all such US patents are incorporated herein by reference.

  Alpha-adrenergic receptor blockers (α- or alpha-blockers) that are within the scope of the present invention include, but are not limited to, amosulalol (as disclosed in US Pat. No. 4,217,307). Arotinolol (which can be prepared as disclosed in U.S. Pat. No. 3,932,400); dapiprazole, doxazosin, fence pyrido, indolamine, rabetrol, naphthopidyl, nicergoline, prazosin, tamsulosin, trazoline, trimazosin And yohimbine (which can be isolated from natural sources according to methods known to those skilled in the art). The disclosures of all such US patents are incorporated herein by reference.

Any compound known to be useful in the treatment of Alzheimer's disease can be used in the combination aspect of this invention. Such compounds include acetylcholinesterase inhibitors. Examples of known acetylcholinesterase inhibitors include donepezil (Aricept®), tacrine (Cognex®), rivastigmine (Exelon®) and galantamine (reminyl). Aricept® is available from the following US patents: 4,895,841, 5,985,864, 6,140,321, 6,245,911, and 6,372,760. (All of which are hereby fully incorporated by reference). Exelon® is disclosed in US Pat. Nos. 4,948,807 and 5,602,176, all of which are hereby fully incorporated by reference. Cognex® is disclosed in US Pat. Nos. 4,631,286 and 4,816,456, all of which are hereby fully incorporated by reference. Reminil® is disclosed in US Pat. Nos. 4,663,318 and 6,099,863, all of which are hereby fully incorporated by reference.
(Method for producing the compound of the present invention)

  The present invention includes compounds that can be prepared in a number of ways known to those skilled in the art of organic synthesis. The compounds outlined herein are in accordance with the methods commonly used by organic synthetic chemists and combinations or variations of those methods commonly known to those skilled in the art of synthetic chemistry, as well as the methods described below. Can be synthesized. The synthetic route of the compound in the present invention is not limited to the method outlined below. One skilled in the art would be able to synthesize the claimed compound in the present invention using the following scheme. Individual compounds may require skillful handling of conditions in order to adapt to various functional groups. Various protecting groups known to those skilled in the art may be required. If necessary, purification can be carried out on a silica gel column eluting with a suitable organic solvent system. Alternatively, reverse phase HPLC or recrystallization can be used. Although not limited, the synthesis | combining method of the compound of this invention is shown below.

Scheme 1 shows a process for the preparation of compounds of formula I wherein --------- is unbonded and R ² is R ⁶ R ⁷ NC (O) —.

Scheme 1a shows that ------- is unbonded, R ¹ is isopropyl, R ² is R ⁶ R ⁷ NC (O) —, and one of R ⁶ and R ⁷ is H. , R ⁶ and the other one of R ⁷ are benzyl and R ⁴ is 4-fluorophenyl.

In Scheme 1a, compound 1a comprises 1- (isocyano-4-fluorophenyl-methanesulfonyl) -4-methyl-benzene and imine (generated by condensing isopropylamine and dimethoxy-acetaldehyde in situ). Prepared by cycloaddition (J. Org. Chem. 1998, 63, 4529 and references cited therein). Compound 1a is treated with n-butyllithium and the resulting 2-lithiated imidazole is reacted with benzyl isocyanate to give compound 2a, which is deprotected under acidic conditions to give compound 3a. Compound 4a is obtained by condensation of compound 3a with optically active ylide (R) -3- (tert-butyl-dimethyl-silanyloxy) -5-oxo-6- (triphenyl-λ ⁵ -phosphanylidene) -hexanoic acid methyl ester. Get (Konoike,
T .; Araki, YJ Org. Chem. 1994, 59, 7849). Compound 5a is obtained by catalytic hydrogenation of compound 4a, which is deprotected with hydrogen fluoride to give compound 6a. Diastereoselective reduction of compound 6a with sodium borohydride in the presence of diethylmethoxyborane provides compound 7a. Finally, compound 7a is saponified with aqueous sodium hydroxide solution to obtain compound 8a. Alternatively, the reaction can be worked up under acidic conditions to give the corresponding lactone 9a or the corresponding free acid 10a.

Scheme 2 shows an alternative synthetic route for compound 3 of scheme 1 (compound 4, scheme 2).

A further example is shown in Scheme 2a.

  As shown in Scheme 2a, N-alkylimidazole 10a can be synthesized by alkylating tribromoimidazole 9a with isopropyl iodide. Tribromide 10a is treated with 1 equivalent of n-butyllithium to give the 2-lithio-imidazole intermediate, which is reacted with benzyl isocyanate. Without isolating the resulting lithioamide, one equivalent of n-butyllithium is further added to lithiate the 5-position. This dianion is treated with DMF, and after workup, aldehyde 11a is obtained. Bromide 11a is coupled with 3-pyridinylboronic acid with a Pd catalyst to give compound 12a.

スキーム３に概略を示すように、式１２のイソシアニドとＴＢＳＯＣＨ_２ＣＨＯおよび式Ｒ^１ＮＨ_２の一級アミンとを縮合させることにより、式１３のイミダゾールを得ることができる。ついで酢酸によるシリルエーテルの脱保護により式１４のアルコールを生成させ、次いでこれをトリフェニルホスフィンおよびＨＢｒで式１５のホスホニウム塩に変換することができる。式１５のホスホニウム塩を例えばｎ−ブチルリチウムなどの適切な塩基で脱プロトン化し、ついで適切なアルデヒドを添加することにより、式１６のオレフィンを得ることができ、これを接触水素化で還元して式１７のイミダゾールを得ることができる。ついでＮ−ブロモスクシンイミドで臭素化して式１８の臭化物を得ることができ、これを適切なパラジウム触媒の存在下でＲ^６Ｒ^７ＮＨと反応させて式１９のアミノイミダゾールを得ることができる。あるいはまた、化合物１８を一級アミンと反応させて式２０のアミノイミダゾールを得ることができる。さらに、Ｒ^７ＣＯＣｌ、Ｒ^７ＮＣＯ、Ｒ^７ＯＣＯＣｌまたはＲ^７ＳＯ_２Ｃｌなどのアシル化剤またはスルホニル化剤との反応により、アシル化アミンまたはスルホニル化アミンを生成させることができる。ついで、ケタールおよびｔｅｒｔ−ブチルエステル保護基を酸水溶液で切断することにより最終生成物２２を得ることができる。スキーム３ａに類似化合物の別法の経路を示す。

Scheme 3 shows a method for producing a compound of the present invention in which --------- is non-bonded, R ² is — (CH ₂ ) _n NR ⁶ R ⁷ , and n is 0.

As outlined in Scheme 3, the imidazole of formula 13 can be obtained by condensing the isocyanide of formula 12 with a primary amine of TBSOCH ₂ CHO and formula R ¹ NH ₂ . The deprotection of the silyl ether with acetic acid can then produce the alcohol of formula 14, which can then be converted to the phosphonium salt of formula 15 with triphenylphosphine and HBr. By deprotonating the phosphonium salt of formula 15 with a suitable base such as n-butyllithium and then adding the appropriate aldehyde, the olefin of formula 16 can be obtained, which is reduced by catalytic hydrogenation. The imidazole of formula 17 can be obtained. It can then be brominated with N-bromosuccinimide to give the bromide of formula 18, which can be reacted with R ⁶ R ⁷ NH in the presence of a suitable palladium catalyst to give the aminoimidazole of formula 19. Alternatively, compound 18 can be reacted with a primary amine to give an aminoimidazole of formula 20. Furthermore, acylated amines or sulfonylated amines can be generated by reaction with acylating or sulfonylating agents such as R ⁷ COCl, R ⁷ NCO, R ⁷ OCOCl or R ⁷ SO ₂ Cl. The final product 22 can then be obtained by cleaving the ketal and tert-butyl ester protecting groups with aqueous acid. Scheme 3a shows an alternative route for similar compounds.

As shown in Scheme 3a, for example, α-oximinoketone 23, which can be prepared from a substituted acetone precursor by nitrosation using alkyl nitrite, is converted to 1,3,5-trisubstituted hexahydro-1,3,5-triazine 24. Treatment with (commercially available or prepared from amine R ¹ NH ₂ and formaldehyde) converts to imidazole N-oxide 25 (Helv. Chim. Acta 1998, 81, 1585, and references cited therein). Then treated with isocyanate or isothiocyanate (R ⁶ NCO or R ⁶ NCS) to give 2-aminoimidazole 26 (Tetrahedron
2000, 56, 5405, and references cited therein, which are reacted with acylating or sulfonylating agents such as R′COCl, (R′CO) O or R′SO ₂ Cl to give imidazole 27. . The 5-methyl group is oxidized with cerium ammonium nitrate to introduce the aldehyde functional group, which is then reduced with, for example, lithium tri-tert-butoxyaluminum hydride to obtain the alcohol intermediate 29. Reaction with triphenylphosphine hydrobromide gives phosphonium salt 30 which is then deprotonated with a suitable base such as n-butyllithium or sodium bis (trimethylsilyl) amide to give 6-formyl-2,2 -Dimethyl- [1,3] dioxan-4-yl) acetic acid tert-butyl ester (or 6-oxo-3,5-O-isopropylidene-3,5-dihydroxyhexanoic acid tert-butyl) [optically active substance, (4R, 6S) -6-Formyl-2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid tert-butyl ester, Syn.
Conm. 2003, 33 (13), 2275-83)] to give Wittig product 31 as a cis / trans olefin isomer mixture. The acetonide protecting group is then cleaved in the presence of an aqueous acid solution to give diol 32, which is then reduced by catalytic hydrogenation with, for example, palladium / carbon to give intermediate 33. It is then saponified with aqueous sodium hydroxide to give the final product 34 in which ------- is unbound. Alternatively, the cis / trans olefin isomer 32 is chromatographically separated and saponified to give the final product 34 where ------- is a single bond. Alternatively, the aldehyde 28 may be converted to the final product 34 using the method described in Scheme 1.

Scheme 4 shows a process for preparing compounds of the invention starting from compound 17 where -------- is unbonded and R ² is SO ₂ NR ⁶ R ⁷ .

  As shown in Scheme 4, compound 17 can be deprotonated with n-butyllithium, quenched with sulfur dioxide gas, and then exposed to N-chlorosuccinimide to give the chlorosulfonylimidazole of formula 35. The sulfonamide of formula 36 can then be obtained by adding various amines. Cleavage of the ketal and tert-butyl ester protecting groups with aqueous acid can yield the final product 37.

スキーム５ステップ１に図示するように、適切な５−ホルミル−１，２，４−三置換イミダゾール３８をイリド（３Ｒ）−３−（ｔｅｒｔ−ブチルジメチルシロキシ）−５−オキソ−６−トリフェニルホスホラニリデンヘキサノエートと反応させてエノン３９を得ることができる。ステップ２において、エノン３９を水素化ホウ素ナトリウムまたはカリウムにより還元して分離可能なエピマーアルコール４０および４１の混合物を得る。この変換の溶媒には、−７８℃〜０℃の温度のメタノールおよびイソプロパノールなどが含まれる。ステップ３において、シリルエーテル４０または４１をフッ化テトラブチルアンモニウムで処理して、それぞれジオール４２または４３を得る。反応時間および温度に応じて、ステップ３において、メチルエステル４２または４６からラクトン４４または４５がさらに生じる可能性がある。メチルエステルおよびラクトンの混合物は分離でき、あるいは最終の鹸化に共に用いることができる。従って、ステップ４において、４２［および／または４４］または４６［および／または４５］を水酸化ナトリウム水溶液で処理して、ナトリウム塩４６または４７をそれぞれ得る。スキーム６に、Ｒ^２が−（ＣＨ_２）_ｎＮＲ^６Ｒ^７でありｎが１である本発明の化合物の製造方法を示す。

Scheme 5 shows a method for producing the compound of the present invention in which --------- is one bond.

As illustrated in Scheme 5, Step 1, the appropriate 5-formyl-1,2,4-trisubstituted imidazole 38 is converted to ylide (3R) -3- (tert-butyldimethylsiloxy) -5-oxo-6-triphenyl. Enone 39 can be obtained by reaction with phosphoranilidene hexanoate. In step 2, enone 39 is reduced with sodium or potassium borohydride to obtain a mixture of separable epimeric alcohols 40 and 41. Solvents for this conversion include methanol and isopropanol at temperatures between -78 ° C and 0 ° C. In step 3, silyl ether 40 or 41 is treated with tetrabutylammonium fluoride to give diol 42 or 43, respectively. Depending on the reaction time and temperature, further lactone 44 or 45 may be generated from methyl ester 42 or 46 in step 3. The mixture of methyl ester and lactone can be separated or used together for final saponification. Thus, in step 4, 42 [and / or 44] or 46 [and / or 45] is treated with aqueous sodium hydroxide to give the sodium salt 46 or 47, respectively. Scheme 6 shows a method for producing a compound of the present invention in which R ² is — (CH ₂ ) _n NR ⁶ R ⁷ and n is 1.

As outlined in Scheme 6, imidazole-2-carboxaldehyde 49 was prepared by treating imidazole 48 (prepared as in Scheme 1) with a base such as n-butyllithium or lithium diisopropylamide and the resulting 2-lithiol. It can be produced by reacting imidazole with N, N-dimethylformamide. Subsequent reductive amination with amine R ⁶ NH ₂ gives 2- (aminomethyl) imidazole 50 and acylation or sulfonylation as in Scheme 3a gives intermediate 51. Alternatively, imidazole-2-carboxaldehyde 49 is treated with hydroxylamine hydrochloride to convert it to an oxime derivative and then reduced under catalytic hydrogenation conditions, for example 2- (aminomethyl) where R ⁶ is H Imidazole 50 can be obtained. Deprotection of acetal 51 under acidic conditions affords 5-formylimidazole 52, which is converted to final product 53 using the method described in Scheme 3a for converting structure 28 to final compound 34. To do.

ステップＡ
５−ジメトキシメチル−４−（４−フルオロ−フェニル）−１−イソプロピル−１Ｈ−イミダゾール

The following non-limiting examples illustrate the practice of the present invention. The synthetic route of the compounds of the present invention is not limited to the methods outlined below. Those skilled in the art will be able to use the scheme outlined below to synthesize the compounds described in this invention. Example 1 illustrates a method for preparing a compound of formula I, wherein R ¹ is isopropyl, R ² is R ⁶ R ⁷ NC (O) —, and R ⁴ is 4-fluorophenyl. In Example 1, one of R ⁶ and R ⁷ is H and the other one of R ⁶ and R ⁷ is benzyl. Compounds with variations of R ⁶ and R ⁷ were prepared using a similar reaction scheme and are shown in Table I following Example 1 with characterization data.
Example 1
(3R, 5R) -7- [2-Benzylcarbamoyl-5- (4-fluorophenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid sodium salt

Step A
5-Dimethoxymethyl-4- (4-fluoro-phenyl) -1-isopropyl-1H-imidazole

A solution of dimethoxy-acetaldehyde (7.2 mL, 28 mmol, 45% in methyl-tertbutyl ether, Fluka Chem.) And isopropylamine (5.7 mL, 67 mmol, Aldrich Chemical Co.) in anhydrous tetrahydrofuran (90 mL) under a nitrogen atmosphere. Stir at ambient temperature for approximately 3 hours. To this solution was added 1- (isocyano-4-fluorophenyl-methanesulfonyl) -4-methylbenzene (6.44 g, 22 mmol). The resulting mixture was stirred at ambient temperature for 18 hours and then concentrated under vacuum to 30% of the original volume. The reaction mixture was diluted with water (20 mL) and extracted (2 ×) with ethyl acetate. The combined extracts were washed with sodium hydroxide solution (20 mL, 1M) and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo to give a yellow oil and subjected to silica chromatography (10-80% ethyl acetate / hexane) to give 4.88 g of a pale yellow amorphous powder. Low resolution mass spectrometry (APCI) m / z 279 [M + H] ⁺ .
Step B
5-Dimethoxymethyl-4- (4-fluoro-phenyl) -1-isopropyl-1H-imidazole-2-carboxylic acid benzylamide

To a stirred solution of 5-dimethoxymethyl-4- (4-fluoro-phenyl) -1-isopropyl-1H-imidazole (1.07 g, 3.8 mmol) in anhydrous tetrahydrofuran (15 mL) cooled to −78 ° C. was added −70 N-Butyllithium (2.9 mL, 2.0 M pentane solution) was added via syringe while maintaining the temperature below <0> C. The mixture was stirred for 30 minutes. 1-Fluoro-4-isocyanatomethyl-benzene (0.863 mL, 7.7 mmol) was added and the reaction mixture was allowed to warm to ambient temperature for 30 minutes. Saturated sodium bicarbonate solution (20 mL) was added and the mixture was extracted with ethyl acetate (2 × 15 mL). The combined extracts were concentrated under reduced pressure to obtain a yellow slurry. The slurry was triturated with 1-propanol and the solid precipitate was removed by vacuum filtration and washed with 1-propanol. The filtrate was concentrated in vacuo to give a yellow oil, which was purified by silica chromatography (10-60% ethyl acetate / hexane) and concentrated in vacuo to give 1.2 g of the desired product as a pale yellow color. Obtained as a powder. Low resolution mass spectrometry (APCI) m / z 412 [M + H] ⁺ .
Step C
4- (4-Fluoro-phenyl) -5-formyl-1-isopropyl-1H-imidazole-2-carboxylic acid benzylamide

5-Dimethoxymethyl-4- (4-fluoro-phenyl) -1-isopropyl-1-H-imidazole-2-carboxylic acid 4-fluoro-benzylamide (1.2 g, 2.9 mmol) was added to trifluoroacetic acid 10% Dissolved in a mixture of methylene chloride (10 mL) and stirred at room temperature for 2 hours. The solution was concentrated under vacuum to 10% of the original volume and sodium hydroxide (40 mL, 1M) was added. The mixture was extracted with methylene chloride (3 × 15 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.0 g of the desired product as an off-white amorphous powder. Low resolution mass spectrometry (APCI) m / z 366 [M + H] ⁺ .
Step D
(R) -7- [2-Benzylcarbamoyl-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3- (tert-butyl-dimethyl-silanyloxy) -5-oxo -Hept-6-enoic acid methyl ester

4- (4-Fluoro-phenyl) -5-formyl-1-isopropyl-1H-imidazole-2-carboxylic acid 4-fluoro-benzylamide (1.16 g, 3.2 mmol) and (R) -3- (tert -Butyldimethyl-silanyloxy) -5-oxo-6- (triphenyl-15-phosphanylidene) -hexanoic acid methyl ester (2.5 g, 4.8 mmol) in toluene (15 mL) was heated to reflux under a nitrogen atmosphere for 24 hours. did. The cooled mixture was concentrated in vacuo to give a crude oil, which was purified by silica chromatography (15-60% ethyl acetate / hexanes) to give the desired product as a colorless glass. Low resolution mass spectrometry (APCI) m / z 622 [M + H] ⁺ . ¹ H-NMR (400 MHz, chloroform-D) δ ppm 0.0 (d, J = 3.4 Hz, 2H), 0.1 (m, 4H), 0.8 (m, 10H), 1.7 (m, 8H), 2.5 (m, 2H), 2.6 (m, 2H), 3.1 (m, 1H), (d, J = 3.9 Hz, 3H), 3.7 (s, 1H) 4.6 (m3H), 7.1 (m, 2H), 7.3 (m, 2H), 7.3 (d, J = 5.9 Hz, 4H), 7.5 (m, 1H), 7.6 (d, J = 3.4 Hz, 1H).
Step E
(R) -7- [2-Benzylcarbamoyl-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3- (tert-butyl-dimethyl-silanyloxy) -5-oxo -Heptanoic acid methyl ester

The product from Step D was hydrogenated in tetrahydrofuran (0.2 g) with 10% Pd / C in a hydrogen atmosphere (4295 psi / mol) for 13.3 hours. The mixture was filtered through celite and concentrated in vacuo to give 0.862 g of the desired product as a pale yellow glass. Low resolution mass spectrometry (APCI) m / z 624 [M + H] ⁺ .
Step F
(R) -7- [2-Benzylcarbamoyl-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3-hydroxy-5-oxo-heptanoic acid methyl ester

(R) -7- [2-Benzylcarbamoyl-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3- (tert-butyl-dimethyl-) in a 50 mL polypropylene conical tube An ice-cold solution of silanyloxy) -5-oxo-heptanoic acid methyl ester (0.862 g, 1.4 mmol) in anhydrous THF (12 mL) was treated with hydrogen fluoride-pyridine (3 mL, 70% HF). The mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was adjusted to pH 11 with sodium carbonate solution (40 mL, 1M). The mixture was diluted with water and extracted with ethyl acetate (3 × 15 mL). The extracts were combined, washed sequentially with saturated sodium bicarbonate solution (15 mL) and brine (15 mL), and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo to give 757 mg of product as an amber glass. Low resolution mass spectrometry (APCI) m / z 510 [M + H] ⁺ . ¹ H-NMR (400 MHz, chloroform-D) δ ppm 1.4 (s, 1H), 1.7 (m, 7H), 2.5 (m, 2H), 2.6 (m, 1H), 2.7 (M, 1H), 3.1 (d, J = 8.3 Hz, 2H), 3.7 (m, 3H), 4.4 (s, 1H), 4.6 (d, J = 6.1 Hz) , 2H), 7.1 (t, J = 8.7 Hz, 2H), 7.3 (m, 6H), 7.5 (dd, J = 8.8 Hz, 5.4 Hz, 2H), 7.9 (S.1H)
Step G
(3R, 5R) -7- [2-Benzylcarbamoyl-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid methyl ester

(R) -7- [2- (Benzylcarbamoyl) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3-hydroxy-5-oxo-heptanoic acid methyl ester ( A solution of 643 mg, 1.3 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled to −74 ° C. under a nitrogen atmosphere. Diethylmethoxyborane (0.497 mL, 3.79 mmol, Aldrich
Chemical Co. ) Was added dropwise and the solution was stirred at -74 ° C for 60 minutes. Sodium borohydride (67 mg, 1.8 mmol) was added neat and stirring was continued at −75 ° C. for 1.5 hours. 6 drops of glacial acetic acid was added and the mixture was warmed to ambient temperature. Ethanolamine (0.457 mL, 7.6 mmol, Aldrich) was added to decomplex boron and stirred at RT for 18 hours. The reaction mixture was washed with saturated sodium bicarbonate solution (15 mL) and extracted three times with methylene chloride. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a crude oil. The product was purified by silica chromatography (10-60% ethyl acetate / hexane) to give 574 mg of the desired product as a colorless glass. Low resolution mass spectrometry (APCI) m / z 512 [M + H] ⁺ . ¹ H-NMR (400 MHz, chloroform-D) δ ppm 1.4 (m, 1 H), 1.6 (m, 1 H), 1.7 (d, J = 7.1 Hz, 6 H), 1.8 (m, 1H), 1.9 (m, 1H), 2.6 (m, 1H), 2.9 (m, 1H), 3.2 (m, 1H), 3.7 (s, 3H), 4. 0 (m, 1H), 4.4 (m, 1H), 4.6 (d, J = 6.1 Hz, 2H), 5.3 (m, 1H), 7.1 (m, 2H), 7 .3 (m, 1H), 7.3 (m, 4H), 7.6 (m, 2H), 8.0 (t, J = 6.0 Hz, 1H)
Step H
(3R, 5R) -7- [2-Benzylcarbamoyl-5- (4-fluorophenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid sodium salt

(3R, 5R) -7- [2- (Benzylcarbamoyl) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid methyl ester ( A stirred solution of 574 mg, 1.12 mmol) in THF (1 mL) and water (1 mL) was treated with sodium hydroxide (1.07 mL, 1M). The resulting solution was stirred at room temperature for 2 hours. Water (30 mL) was added and the mixture was lyophilized to give 496 mg of the desired final product as a fluffy white powder. Low resolution mass spectrometry (APCI) m / z 498 [M + H] ⁺ .
A compound having variations of R ⁶ and R ⁷ was prepared using the same reaction scheme as in Example 1. Representative compounds are shown in Table I along with property data.

ステップＡ
Ｎ−［（３，４−ジフルオロ−フェニル）−（トルエン−４−スルホニル）−メチル］−ホルムアミド

Example 2 illustrates a method for preparing a compound of formula I wherein R ¹ is isopropyl, R ² is benzylcarbamoyl, and R ⁴ is difluorophenyl. Compounds with varying R ⁴ were prepared with a similar reaction scheme. Along with the characteristic data, it is shown in Table II following Example 2.
(Example 2)
(3R, 5R) -7- [2-Benzylcarbamoyl-5- (3,4-difluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid sodium salt

Step A
N-[(3,4-Difluoro-phenyl)-(toluene-4-sulfonyl) -methyl] -formamide

（注意：この試薬は４０℃以上で不安定な場合がある。） Sulfinic acid sodium salt dihydrate (21.4 g, 95 mmol) and formamide (4.28 g, 95.0 mmol, Aldrich)
Chemical Co. ) To a 1 L 3 neck flask. A positive pressure of nitrogen gas was applied and 500 mL of dry acetonitrile was added. The mixture was stirred to form a slurry and neat 3,4-difluorobenzaldehyde (9.0 g, 63.33 mmol) was added in one portion. The flask was cooled to 12 ° C. with an ice-water bath and chlorotrimethylsilane (28.13 mL, 221.7 mmol) was added via a pressure equalizing dropping funnel while keeping the temperature below 25 ° C. during the addition (approximately 20 minutes). The mixture was slowly warmed to RT and stirred for 48 hours. The heterogeneous mixture was treated with water (1.2 L) and the resulting suspension was stirred for 30 minutes. The solid was isolated by filtration and the resulting filter cake was washed with water (500 mL). The solid was dried in a vacuum oven at 50 ° C., 27 inches Hg for 24 hours to give the product (18.2 g of a white solid). Low resolution mass spectrometry (APCI) m / z 326 [M + H] ⁺ .
Step B
1,2-difluoro-4- [isocyano- (toluene-4-sulfonyl) -methyl] -benzene

(Note: This reagent may be unstable above 40 ° C.)

A suspension of N-[(3,4-difluoro-phenyl)-(toluene-4-sulfonyl) -methyl] -formamide (18.2 g, 55.9 mmol) in anhydrous tetrahydrofuran (150 mL) was stirred with mechanical stirring. Treated with phosphorus chloride (8.2 mL, 89.5 mmol). The solution was stirred for 10-15 minutes and then cooled to -5 ° C to 0 ° C. To the slurry, triethylamine (37.4 mL, 268.5 mmol) was added dropwise over 45 minutes at such a rate that the reaction temperature was kept below 0 ° C. and above −5 ° C. After completion of the triethylamine addition, the tan slurry was stirred at 0 ° C. for 30 minutes. The reaction mixture was diluted with chilled ethyl acetate (100 mL) and water (50 mL), stirred at around 10 ° C. for 10 minutes and transferred to a separatory funnel. The aqueous layer was removed and the organic phase was washed with water (2 × 100 mL), saturated sodium bicarbonate solution (100 mL), and again with water (100 mL). The organic phase was concentrated under vacuum to 10-15% of the initial volume. 1-propanol (100 mL) was added and the solution was concentrated again under vacuum at 35 ° C. until 10% of the original volume. The solution was allowed to stand at 4-8 ° C. for 40 minutes, and the fine yellow precipitate formed was collected by vacuum filtration and washed with 1-propanol (30 mL). The off-white solid was dried under vacuum until a constant weight was reached to give 4.3 g of the desired product. Low resolution mass spectrometry (APCI) m / z 308 [M + H] ⁺ . The remaining steps were performed in a manner similar to that shown in steps A to H of Example 1.

（実施例３）
（３Ｒ，５Ｒ）−７−（２−ベンジルカルバモイル−３−イソプロピル−５−ピリジン−３−イル−３Ｈ−イミダゾール−４−イル）−３，５−ジヒドロキシ−ヘプタン酸ナトリウム塩

ステップＡ
４−ブロモ−５−ホルミル−１−イソプロピル−１Ｈ−イミダゾール−２−カルボン酸ベンジルアミド

Using a reaction scheme similar to that shown in Example 2, a compound having a variation of R ⁴ was prepared. Table II shows representative compounds along with characteristic data.

(Example 3)
(3R, 5R) -7- (2-Benzylcarbamoyl-3-isopropyl-5-pyridin-3-yl-3H-imidazol-4-yl) -3,5-dihydroxy-heptanoic acid sodium salt

Step A
4-Bromo-5-formyl-1-isopropyl-1H-imidazole-2-carboxylic acid benzylamide

2,4,5 tribromo-1-isopropyl-1H-imidazole (2.0 g, 5.8 mmol) (from tribromoindole to iPrI / K ₂ CO ₃ / DMF / A dry THF (20 mL) solution of (manufactured at 60 ° C.) was treated with n-butyllithium (3.91 mL, 6.05 mmol, 1.6 M hexane solution) under a nitrogen atmosphere. The resulting solution was stirred at −78 ° C. for 5 minutes and then treated with benzyl isocyanate (0.71 mL, 5.8 mmol). The reaction mixture was stirred at −78 ° C. for 10 minutes, at which point the cooling bath was replaced with an ice water bath. After 20 minutes, analysis of the reaction mixture by loop injection mass spectrometry showed a new mass corresponding to the desired addition product: MS
APCI 401.9 [M + H]. The reaction mixture was again cooled to −78 ° C. and treated with a further equimolar amount of n-butyllithium (3.91 mL, 6.05 mmol, 1.6 M hexane solution). The solution was stirred at −78 ° C. for 5 minutes, then treated with DMF (0.89 mL, 11.53 mmol) and stirred with cooling for 15 minutes. The reaction mixture was stirred at −78 ° C. for 10 minutes, at which point the cooling bath was replaced with an ice water bath. After 30 minutes, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated NH ₄ Cl and brine, dried (MgSO ₄ ) and concentrated to give a yellow solid. Flash chromatography (SiO _2, ethyl acetate / hexane 1: 19 to 1: 4) to give the desired product as a colorless solid; Yield: 1.24g (61.4%); mp = 128-129 ° C (ethyl acetate-hexane); MS
APCI 350, 352 [M + H]).
Step B
5-Formyl-1-isopropyl-4-pyridin-3-yl-1H-imidazole-2-carboxylic acid benzylamide

4-Bromo-5-formyl-1-isopropyl-1H-imidazole-2-carboxylic acid benzylamide (0.87 g, 2.48 mmol) and toluene / ethanol / 2M
A mixture of Na ₂ CO ₃ (15 mL, 1: 1: 1) was briefly blown with argon, followed by 3-pyridylboronic acid (0.37 g, 2.98 mmol) and tetrakistriphenylphosphine palladium (0.14 g, 0 .12 mmol). The resulting mixture was heated at 70 ° C. for 12 hours. Analysis by TLC (5% MeOH / DCM) showed that the starting material was completely consumed. The reaction mixture was diluted with ethyl acetate and the organic layer was separated, washed with saturated NaHCO ₃ (2 ×), washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a yellow oil. Flash chromatography _{(SiO 2, CH 2 Cl 2} / methanol 100: 0 to 97: 3) to give the desired product as a colorless solid. Yield: 0.59 g (68%); MS
APCI349 [M + H]; ¹ H-NMR (CDCl ₃ ) δ (9.86 s, 1 H), (8.84 d, J = 2.2 Hz, 1 H), (8.68 d, J = 4.8 Hz, 1 H), (8.04bs, 1H), (7.93d, 1H), (7.67m, 1H), (7.54-7.28m, 5H), (6.35m, 1H), (4.62d, J = 6.1 Hz, 2H), (1.63d, J = 7.1 Hz, 6H).
Step C
7- (2-Benzylcarbamoyl-3-isopropyl-5-pyridin-3-yl-3H-imidazol-4-yl) -3- (tert-butyl-dimethyl-silanyloxy) -5-oxo-hept-6-ene Acid methyl ester

5-Formyl-1-isopropyl-4-pyridin-3yl-1Himidazole-2-carboxylic acid benzylamide (0.55 g, 1.58 mmol) and 3- (tert-butyl-dimethyl-silanyloxy) -5-oxo- A solution of 6- (triphenyl-15-phosphanylidene) -hexanoic acid methyl ester (0.89 g, 1.66 mmol) in toluene (10 mL) was heated to reflux overnight. The solvent was removed under vacuum to give an orange oil (1.74 g). Purification by flash chromatography (SiO ₂ , CH ₂ Cl ₂ / hexane / MeOH 80: 20: 0 to 97: 0: 3: 3) gave an orange oil that was powdered (hexane-ethyl acetate). And filtered to remove triphenylphosphine oxide. Yield: 0.98 g (100%); MS
APCI605 [M + H]. ¹ H-NMR (CDCl ₃ ) δ (8.81 dd, J = 2.2, 0.7 Hz, 1 H), (8.60 dd, J = 4.9, 1.7 Hz, 1 H), (7.85 s, 1H), (7.85d, J = 0.49Hz, 1H), (7.73-7.65m, 3H), (7.56-7.53m, 1H), (7.49-7.45m, 1H), (7.37-7.32 m, 7H), (6.34d, J = 15.9 Hz, 1H), (6.10bs1H), (4.60d, J = 6.1 Hz, 3H), ( 3.67s, 3H), (2.72m, 2H), (2.50m, 2H), (1.65d, J = 7.1 Hz, 6H), (0.81s, 9H), (0.05, s, 3H), (0.00s, 3H); * but material had triphenylphosphine oxide as an impurity, it to the following reaction Mom was used.

ステップＡ
５−ジメトキシメチル−１−エチル−４−（４−フルオロ−フェニル）−１Ｈ−イミダゾール

The remaining steps were performed in the same manner as steps E to H of Example 1. Example 4 illustrates a method for preparing a compound of formula I wherein R ¹ is ethyl, R ² is benzylcarbamoyl, and R ⁴ is 4-fluorophenyl. Compounds with variations of R ¹ are shown in Table III following Example 4.
Example 4
3R, 5R) -7- [2-Benzylcarbamoyl-3-ethyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid sodium salt

Step A
5-Dimethoxymethyl-1-ethyl-4- (4-fluoro-phenyl) -1H-imidazole

A solution of dimethoxy-acetaldehyde (2.2 mL, 8.6 mmol, 45% methyl-tert-butyl ether solution) and ethylamine (10.4 mL, 20.7 mmol) in anhydrous tetrahydrofuran (30 mL) was approximately 3 at ambient temperature under a nitrogen atmosphere. Stir for hours. α- (p-Toluenesulfonyl) -4-fluorobenzylisonitrile (2.0 g, 6.9 mmol) was added and the mixture was stirred at ambient temperature for an additional 18 hours. The resulting yellow slurry was concentrated under vacuum to 30% of the initial volume. Water (15 mL) was added and the mixture was extracted 3 times with ethyl acetate. The combined extracts were washed with 1m sodium hydroxide solution (20 mL) and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo to give a crude oil, which was purified by silica chromatography (10-80% ethyl acetate / hexanes) to give 1.13 g of the desired product as a pale yellow oil. Low resolution mass spectrometry (APCI) m / z 265 [M + H] ⁺ .
Step B
5-Dimethoxymethyl-1-ethyl-4- (4-fluoro-phenyl) -1H-imidazole-2-carboxylic acid benzylamide

A stirred solution of 5-dimethoxymethyl-1-ethyl-4- (4-fluoro-phenyl) -1H-imidazole (1.13 g, 4.3 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to −78 ° C. and the temperature was- Treated with n-butyllithium (3.2 mL, 6.3 mmol, 2.0 M pentane solution) while maintaining below 70 ° C. After 30 minutes, the reaction mixture was treated with isocyanatomethyl-benzene (1.06 mL, 8.5 mmol) and allowed to warm to ambient temperature for 30 minutes. Saturated sodium bicarbonate solution (20 mL) was added and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined extracts were concentrated under vacuum to give a yellow slurry and triturated with 1-propanol. The fine white precipitate was removed by vacuum filtration and washed with 1-propanol. The filtrate was concentrated in vacuo to give a yellow oil. The oil was purified by silica chromatography (10-60% ethyl acetate / hexane) to give 1.51 g of the desired product as a pale yellow oil. Low resolution mass spectrometry (APCI) m / z 398 [M + H] ⁺ .

  Steps C to H were performed in the same manner as in Example 1.

（実施例５）
（３Ｒ，５Ｒ）−７−［５−（４−フルオロ−フェニル）−３−イソプロピル−２−フェニルメタンスルホニル−３Ｈ−イミダゾール−４−イル］−３，５−ジヒドロキシ−ヘプタン酸ナトリウム塩

ステップＡ
５−（４−フルオロ−フェニル）−３−イソプロピル−２−フェニルメタンスルホニル−３Ｈ−イミダゾール−４−カルボアルデヒド

A compound having a variation of R ¹ was prepared using a reaction scheme similar to that shown in Example 4. Representative compounds are shown in Table III with characterization data.

(Example 5)
(3R, 5R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid sodium salt

Step A
5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazole-4-carbaldehyde

A solution of 5-dimethyloxymethyl-4- (4-fluoro-phenyl) -1-isopropyl-1H-imidazole (510 mg, 1.8 mmol) in anhydrous tetrahydrofuran (15 mL) was added at −78 ° C. (dry ice / acetone under nitrogen atmosphere). N-butyllithium (1.4 mL, 2.8 mmol, 2.0 M pentane solution) was added dropwise with a syringe while maintaining the temperature below -70 ° C. The reaction mixture was stirred at −78 ° C. for 30 minutes, then treated with benzyl disulfide (1.15 g, 4.6 mmol) and stirred at −78 ° C. for 1 hour. The reaction mixture was removed from the cooling bath and allowed to warm to ambient temperature. The reaction mixture was concentrated after 2 hours under a stream of dry nitrogen to 50% of the initial volume, then diluted with methylene chloride (10 mL) and 3-chloro-perbenzoic acid (2.05 g, 9. 15 mmol, 77%). The resulting mixture was stirred at ambient temperature for 30 minutes, then treated with a second aliquot of 3-chloro-perbenzoic acid (2.05 g, 9.15 mmol, 77%) and stirred at ambient temperature for 18 hours. 3-Chlorobenzoic acid was removed by filtration and the filter cake was washed with chloroform (10 mL). The filtrate was treated with 3-chloro-perbenzoic acid (2.05 g, 9.15 mmol, 77%), stirred at ambient temperature for 10 minutes and filtered again. The filtrate was concentrated in vacuo and the crude product was partitioned between CH ₂ Cl ₂ and 1M sodium hydroxide solution. The organic layer was removed, washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a yellow oil. Flash chromatography (SiO _2, ethyl acetate / hexane 1: 9 to 6: 4) was purified with the desired product as a amorphous powder. Low resolution mass spectrometry (APCI) m / z 387 [M + H] ⁺ .
Step B
(R) -3- (tert-Butyl-dimethyl-silanyloxy) -7- [5- (4-fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -5 Oxo-hept-6-enoic acid methyl ester

5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazole-4-carbaldehyde (0.318 g, 0.82 mmol) and (R) -3- (tert-butyl-dimethyl) -Silanyloxy) -5-oxo-6- (triphenyl-λ-5-phosphanylidene) -hexanoic acid methyl ester (0.66 g, 1.2 mmol) in toluene (5 mL) was heated to reflux under a nitrogen atmosphere for 24 hours. did. The cooled reaction mixture was concentrated under vacuum to give an orange oil. Flash chromatography (SiO _2, ethyl acetate / hexane 3: 17-1: 1) to give the desired product in a red-orange glassy; yield: 0.347 g; low resolution mass spectrometry ( APCI) m / z 643 [M + H] ⁺ . )
Step C
(R) -3- (tert-Butyl-dimethyl-silanyloxy) -7- [5- (4-fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -5 Oxo-heptanoic acid methyl ester

(R) -3- (tert-Butyl-dimethyl-silanyloxy) -7- [5- (4-fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -5 A solution of oxo-hept-6-enoic acid methyl ester (374 mg, 0.54 mmol) in methanol-tetrahydrofuran (1: 1) under a hydrogen atmosphere (4295 psi / mol) in 5% Pd / BaSO ₄ (0.2 g) Hydrogenated for 1 hour. The reaction mixture was filtered through celite and concentrated under vacuum to give the desired product as a pale yellow glass; yield: 0.366 g; low resolution mass spectrometry (APCI) m / z 645 [M + H] ⁺ . ¹ H-NMR (400 MHz, chloroform-D) δ ppm-0.0 (m, 3H), 0.1 (m, 3H), 0.8 (m, 9H), 1.3 (m, 6H), 1 .4 (s, 1H), 2.5 (d, J = 6.1 Hz, 2H), 2.6 (m, 3H), 3.1 (t, J = 8.1 Hz, 2H), 3.7 (M, 3H), 4.5 (m, 1H), 4.8 (d, J = 9.0 Hz, 2H), 5.0 (s, 1H), 7.1 (ddd, J = 8.7) 6.7, 2.2 Hz, 2H), 7.3 (m, 5H), 7.6 (m, 2H)
Step D
(R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -3-hydroxy-5-oxo-heptanoic acid methyl ester

In a 50 mL polypropylene conical tube, (R) -3- (tert-butyl-dimethyl-silanyloxy) -7- [5- (4-fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazole-4 A solution of -yl] -5-oxo-heptanoic acid methyl ester (0.366 g, 0.57 mmol) in tetrahydrofuran (10 mL) was treated with hydrogen fluoride-pyridine (3 mL, 70). The resulting mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was treated with 1M sodium carbonate solution (40 mL, pH = 11), diluted with water and extracted with ethyl acetate (3 × 15 mL). The combined extracts were washed with saturated sodium bicarbonate solution, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the crude product as an orange glass; yield : 0.290 g; Low-resolution mass spectrometry (APCI) 531 [M + H] ⁺ .
Step E
(3R, 5R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid methyl ester

(R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -3-hydroxy-5-oxo-heptanoic acid methyl ester (290 mg , 0.547 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled to −78 ° C. (dry ice-acetone bath) under a nitrogen atmosphere and treated with diethylmethoxyborane (0.222 mL, 1.64 mmol). The reaction mixture was stirred at −78 ° C. for 30 minutes, then solid sodium borohydride (29 mg, 0.77 mmol, Aldrich).
Chemical Co. ). Stirring was continued at −78 ° C. for 2 hours. The reaction mixture was quenched with glacial acetic acid (6 drops), warmed to 0 ° C. and treated with 2-aminoethanol (0.198 mL, 3.28 mmol). After stirring for 30 minutes at ambient temperature, the reaction mixture was basified (pH 11) with saturated sodium bicarbonate solution (20 mL), diluted with water and extracted with dichloromethane. The combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give crude glassy. Flash chromatography (SiO _2, ethyl acetate / hexane 1: 4 to 3: 2) to give a pale yellow glassy the desired product; yield: 0.151 g; low resolution mass spectrometry ( APCI) m / z 533 [M + H] ⁺ . ¹ H-NMR (400 MHz, chloroform-D) δ ppm 0.9 (m, 3H), 1.3 (m, 1H), 1.4 (m, 5H), 1.5 (m, 1H), 1.7 (M, 1H), 1.9 (m, 1H), 2.4 (dd, J = 15.6, 6.6 Hz, 1H), 2.6 (dd, J = 15.6, 6.6 Hz, 1H), 2.9 (m, 1H), 3.2 (m, 1H), 3.7 (m, 3H), 3.9 (m, 1H), 4.3 (m, 1H), 4. 8 (m, 2H), 5.0 (m, 1H), 7.1 (m, 2H), 7.3 (m, 5H), 7.6 (m, 2H)
Step F
(3R, 5R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2phenylmethanesulfonyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid sodium salt

ステップＡ
（３Ｒ）−７−（２−ベンジルカルバモイル−５−ブロモ−３−イソプロピル−３Ｈ−イミダゾール−４−イル）−３−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−５−オキソ−ヘプト−６−エン酸メチルエステル

(3R, 5R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid methyl ester (151 mg , 0.284 mmol) in tetrahydrofuran-water (2 mL, 1: 1) was treated with aqueous sodium hydroxide (0.269 mL, 1M). The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and lyophilized to give the desired product as a fluffy pale yellow powder (yield: 0.138 g; low resolution mass spectrometry (APCI) m / z 519 [M + H + .CHN combustion analysis: Theoretical value: C = 54.38%, H = 5.92%, N = 4.88%: Actual measurement value: C = 53.99%, H = 5.83%, N = 4.67%
(Example 6)
(3R, 5S) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3,5-dihydroxy-hept-6-enoic acid sodium salt

Step A
(3R) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3- (tert-butyl-dimethyl-silanyloxy) -5-oxo-hept-6-ene Acid methyl ester

Production method: 4-Bromo-5-formyl-1-isopropyl-1H-imidazole-2-carboxylic acid benzylamide (632 mg, 1.80 mmol) and (3R) -3- (tert-butyl-dimethyl-silanyloxy) -5 A solution of -oxo-6- (triphenyl-15-phosphanylidene) -hexanoic acid methyl ester (1.18 g, 2.21 mmol) in toluene (8 mL) was heated under reflux conditions for 19 hours. The reaction mixture was concentrated under vacuum. Silica gel chromatography [gradient elution, dichloromethane to dichloromethane-methanol (9: 1)] gave 299 mg of product and a batch with impurities. The latter was repurified and an additional 170 mg (43% overall yield) of (3R) -7- (2-benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3- (tert- Butyl-dimethyl-silanyloxy) -5-oxohept-6-enoic acid methyl ester was obtained as a brown film. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.76 (br
t, J = 6.0 Hz, 1H), 7.60 (d, J = 15.9 Hz, 1H), 7.38-7.27 (m, 5H), 7.15 (d, J = 15.9 Hz) , 1H), 6.19 (m, 1H), 4.69 (m, 1H), 4.55 (d, J = 6.1 Hz, 2H), 3.68 (s, 3H), 2.90 ( m, 2H), 2.58 (m, 2H), 1.59 (dd, J = 7.1, 2.0 Hz, 6H), 0.83 (s, 9H), 0.08 (s, 3H) , 0.05 (s, 3H). MS _{(APCI +):} Found for _{C 28 H 40 BrN 3 O 5} Si: m / z606.2,608.2 [M + H] +.
Step B
(3R, 5S) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3- (tert-butyl-dimethyl-silanyloxy) -5-hydroxy-hept-6 -Enoic acid methyl ester and (3R, 5R) -7- (2-benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3- (tert-butyl-dimethyl-silanyloxy) -5 -Hydroxy-hept-6-enoic acid methyl ester

Production method:
(3R) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3- (tert-butyl-dimethyl-silanyloxy) -5-oxo-hept-6-ene A solution of acid methyl ester in methanol (7 mL) was cooled to −78 ° C. and treated with sodium borohydride (30 mg, 0.79 mmol). The resulting reaction mixture was stirred at −78 ° C. for 45 minutes. Further portion of sodium borohydride (20 mg, 0.53 mmol) was added and the reaction mixture was stirred at −78 ° C. for an additional 45 minutes. The reaction mixture was quenched with water (1 mL), diluted with ethyl acetate (40 mL) and warmed to ambient temperature. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated in vacuo. Silica gel chromatography [gradient elution, dichloromethane to dichloromethane-ether (19: 1)] first recovered the starting material (40 mg), followed by prematurely moving antialcohol (3R, 5R) -7- (2-benzyl Carbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3- (tert-butyl-dimethyl-silanyloxy) -5-hydroxy-hept-6-enoic acid methyl ester (16 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.71 (brt, J = 5.9 Hz, 1H), 7.38-7.27 (m, 5H), 6.57 (dd, J = 15.9, 1.7 Hz, 1H), 6.39 (dd, J = 15.9, 4.6 Hz, 1H), 6.01 (m, 1H), 4.63 (m, 1H), 4.54 (d, J = 6.1 Hz, 2H), 4.52 (m, 1H), 3.69 (s, 3H), 3.35 (brs, 1H), 2.66 (m, 2H), 1.85 (m , 2H), 1.54 (dd, J = 6.9, 0.9 Hz, 6H), 0.90 (s, 9H) 0.15 (s, 3H), 0.11 (s, 3H). _{C 28 H 42 BrN 3 O 5} Si of MS (APCI +) ^{Found: m / z608.2,610.2 [M + H} ] +.

Further elution with dichloromethane-ether (19: 1) gave a fraction (112 mg) containing both syn and antialcohol. Synalcohol (3R, 5S) -7- (2-benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3- (tert-butyl), a pure fraction that migrates late -Dimethyl-silanyloxy) -5-hydroxy-hept-6-enoic acid methyl ester (28 mg) eluted last. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.72 (brt, J = 6.0 Hz, 1H), 7.36-7.27 (m, 5H), 6.56 (dd, J = 15.9, 1.7 Hz, 1 H), 6.41 (dd, J = 15.9, 4.9 Hz, 1 H), 5.99 (br m, 1 H), 4.55 (m, 1 H), 4.45 (d , J = 6.1 Hz, 2H), 4.41 (m, 1H), 3.68 (s, 3H), 3.08 (brd, J = 6.8 Hz, 1H), 2.61 (m, 2H), 1.92 (ddd, J = 14.4, 4.9, 3.2 Hz, 1H), 1.80 (ddd, J = 14.4, 8.5, 7.3 Hz, 1H), 1 .54 (d, J = 6.8 Hz, 6H), 0.91 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H). MS (APCI ⁺ ) measured value of C ₂₈ H ₄₂ BrN ₃ O ₅ Si: m / z 608.2, 610.2 [M + H] ⁺ .
Step C
(3R, 5S) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3,5-dihydroxy-hept-6-enoic acid methyl ester and (3R, 5S ) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3,5-dihydroxy-hept-6-enoic acid methyl ester and 4-bromo-5-[( 2S, 4R) -2- (4-Hydroxy-6-oxo-tetrahydro-pyran-2-yl) -vinyl] -1-isopropyl-1H-imidazole-2-carboxylic acid benzylamide

(3R, 5S) -7- (2benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3- (tert-butyl-dimethyl-silanyloxy) -5-hydroxy-hept-6- A solution of enoic acid methyl ester (50 mg, 0.082 mmol) in tetrahydrofuran (5 mL) was cooled to 0 ° C. and treated with tetrabutylammonium fluoride (0.12 mL, 1.0 M tetrahydrofuran solution). The reaction mixture was stirred at 0 ° C. for 45 minutes. Saturated aqueous ammonium chloride (1 mL) was added and the reaction was partitioned between ethyl acetate-hexane (1: 1, 40 mL) and water (10 mL). The organic layer was washed with water (2 × 10 mL) and saturated brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. By silica gel chromatography [gradient elution, dichloromethane to dichloromethane-methanol (9: 1)], (3R, 5S) -7- (2-benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) 3,5-Dihydroxy-hept-6-enoic acid methyl ester and 4-bromo-5-[(2S, 4R) -2- (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -vinyl A 2: 1 mixture of -1-isopropyl-1H-imidazole-2-carboxylic acid benzylamide (28 mg, 70% yield) was obtained.
Step D
(3R, 5S) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3,5-dihydroxy-hept-6-enoic acid sodium salt

ステップＡ
４−（４−フルオロフェニル）−１−イソプロピル−５−メチル−１Ｈ−イミダゾール３−オキシド

The product of Step C (28 mg, 0.058 mmol) was dissolved in tetrahydrofuran (1.0 mL) and water (1.0 mL). Aqueous sodium hydroxide solution (0.055 mL of 1.0 M solution) was added. The resulting reaction mixture was stirred at room temperature for 2 hours. Tetrahydrofuran was removed under vacuum and the remaining aqueous solution was frozen (−78 ° C. bath), lyophilized under high vacuum and (3R, 5S) -7- (2-benzylcarbamoyl-5-bromo-3-isopropyl). -3H-imidazol-4-yl) -3,5-dihydroxy-hept-6-enoic acid sodium salt (28.7 mg, 99% yield) was obtained as a fluffy white powder. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (brt, J = 6.2 Hz, 1H), 7.32-7.18 (m, 5H), 6.45 (d, J = 16. 1 Hz, 1 H), 6.32 (dd, J = 16.1, 4.7 Hz, 1 H), 5.61 (m, 1 H), 5.31 (brs, 1 H), 4.37-4.30 ( m, 3H), 3.76 (m, 1H), 2.02 (dd, 3 = 14.9, 3.8 Hz, 1H), 1.82 (dd, J = 14.9, 8.2 Hz, 1H) ), 1.56 (m, 1H), 1.45 (m, 1H), 1.42 (d, J = 7.0 Hz, 6H). MS (APCI ⁺ ) found for C ₂₁ H ₂₅ BrN ₃ O ₅ Na: m / z 480.0, 482.0 [C ₂₁ H ₂₆ BrN ₃ O ₅ + H] ⁺ . Elemental _{analysis: C 21 H 25 BrN 3 O} 5 Na · H 2 O of theory / Found: C, 48.47 / 48.66; H , 5.23 / 4.87; 8.08 / 7. 76.
(Example 7)
(3R, 5R) -7- [5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxyheptanoic acid sodium salt salt

Step A
4- (4-Fluorophenyl) -1-isopropyl-5-methyl-1H-imidazole 3-oxide

1- (4-Fluorophenyl) -1,2-propanedione 1-oxime (44.3 g, 245 mmol, International Publication No. WO 00/153585, PCT / US00 / 05241) and 1,3,5-triisopropylhexahydro -A homogeneous mixture of syn-triazine (17.7 g, 83.2 mmol) in absolute ethanol (315 mL) was heated to reflux under a nitrogen atmosphere for 5 hours and then the solvent was removed under vacuum. The residue was triturated with diethyl ether (400 mL), the solid product was filtered off and dried under vacuum to give 53.7 g (94%) of the title compound as a white solid (mp 153-156 ° C .; MS (APCl ) M / z 235).
Step B
[4- (4Fluorophenyl) -1-isopropyl-5-methyl-1H-imidazol-2-yl] methylamine

To a stirred solution of 4- (4-fluorophenyl) -1-isopropyl-5-methyl-1H-imidazole 3-oxide (6.00 g, 25.6 mmol) from Step A in anhydrous methylene chloride (50 mL) under a nitrogen atmosphere. At 0 ° C., a solution of methyl isothiocyanate (1.97 g, 26.9 mmol) in anhydrous methylene chloride (20 mL) was added dropwise. The resulting homogeneous mixture was stirred at ambient temperature for 2 days, then concentrated and dried under vacuum to give ~ 6.3 g (~ 99%, purity ~ 90%) of the title compound as an amber foam (MS (APCI) m / z 248), which was used in the next step without further purification.
Step C
N- [4- (4-Fluorophenyl) -1-isopropyl-5-methyl-1H-imidazol-2-yl] -N-methyl-methanesulfonamide

[4- (4-Fluorophenyl) -1-isopropyl-5-methyl-1H-imidazol-2-yl] methylamine from Step B (4.00 g, 16.2 mmol) and triethylamine (3.38 mL, 24. 3 mmol) of anhydrous methylene chloride (50 mL) was cooled to −20 ° C. under a nitrogen atmosphere, and a solution of methanesulfonyl chloride (1.31 mL, 17.0 mmol) in anhydrous methylene chloride (15 mL) was added dropwise over 40 minutes. did. The resulting mixture was stirred at −20 ° C. for 4 hours, then diluted with methylene chloride (30 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and brine (25 mL), dried over anhydrous Na ₂ SO _4. Concentrated in vacuo. The residue was purified by silica gel chromatography (15-30% ethyl acetate / hexane) to give 1.68 g (32%) of the title compound as a white solid (mp 98-101 ° C .; MS (APCI +) m / z 326). .
Step D
N- [4- (4-Fluorophenyl) -5-formyl-1-isopropyl-1H-imidazol-2-yl] -N-methyl-methanesulfonamide

Of N- [4- (4-Fluorophenyl) -1-isopropyl-5-methyl-1H-imidazol-2-yl] -N-methyl-methanesulfonamide (1.65 g, 5.07 mmol) from Step C A stirred solution of a mixture of tetrahydrofuran (50 mL), water (50 mL) and glacial acetic acid (13 mL) was treated with small portions of ceric ammonium nitrate (11.3 g, 20.6 mmol) over 15 minutes. The resulting pale yellow homogeneous mixture was stirred at ambient temperature for 2 hours and then added to ice water (200 mL) with vigorous stirring. The mixture was extracted with methylene chloride (200 mL) and the organic phase was carefully washed with saturated aqueous sodium bicarbonate (100 mL) and brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (15-25% ethyl acetate / hexane) to give 1.06 g (65%) of the title compound as a white solid (mp 119-123 ° C .; MS (APC ⁺ ) m / z 340 ).
Step E
N- [4- (4-Fluorophenyl) -5-hydroxymethyl-1-isopropyl-1H-imidazol-2-yl] -N-methyl-methanesulfonamide

Of N- [4- (4-Fluorophenyl) -5-formyl-1-isopropyl-1H-imidazol-2-yl] -N-methyl-methanesulfonamide (0.865 g, 2.55 mmol) from Step D An anhydrous tetrahydrofuran (25 mL) stirred solution was cooled in an ice-salt bath under a nitrogen atmosphere, and lithium tri-tert-butoxyaluminum hydride (1M tetrahydrofuran solution, 3.82 mL) was added dropwise over 5 minutes. The resulting homogeneous mixture was stirred for 1.5 hours at −5 to 0 ° C. and then slowly quenched with saturated aqueous ammonium chloride (10 mL). The resulting heterogeneous mixture was diluted with 1M hydrochloric acid (25 mL) and ethyl acetate (50 mL) and stirred for 10 minutes to dissolve the solid, then the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL) and the combined organic phases were washed with brine (50 mL), dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (1-5% methanol / dichloromethane) to give 0.86 g (94%) of the title compound as a white solid; mp 173-174 ° C .; MS (APC +) m / z 342).
Step F
[5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-ylmethyl] triphenylphosphonium bromide

N- [4- (4-Fluorophenyl) -5-hydroxymethyl-1-isopropyl-1H-imidazol-2-yl] -N-methyl-methanesulfonamide from Step E (0.855 g, 2.50 mmol) To a stirred solution of dry acetonitrile (50 mL) was added triphenylphosphine hydrobromide (0.857 g, 2.50 mmol) under a nitrogen atmosphere. The resulting homogeneous mixture was placed in a 65 ° C. heating bath and stirred at this temperature for 2 days. The heating bath was removed and the mixture was stirred at ambient temperature over the weekend, then concentrated in vacuo to give 1.67 g (95%, purity ˜90%) of the title compound as an off-white amorphous solid (MS (APCR ) M / z 586), which was used without further purification.
Step G
((4R, 6S) -6- {2- [5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -vinyl} -2 , 2-Dimethyl- [1,3] dioxan-4-yl) acetic acid tert-butyl ester

[5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-ylmethyl] triphenylphosphonium bromide from step F (1.34 g, 2.01 mmol) ) In dry dimethyl sulfoxide (9 mL) and tetrahydrofuran (45 mL) was cooled to −78 ° C. under a nitrogen atmosphere to obtain a white slurry, which was stirred over 2 minutes with vigorous stirring over sodium bis (trimethylsilyl) amide (1M tetrahydrofuran solution). , 2.41 mL) was added dropwise. The resulting yellow slurry was stirred at −78 ° C. for 7-8 minutes, then over 2 minutes ((4R, 6S) -6-formyl-2,2-dimethyl- [1,3] dioxan-4-yl). Acetic acid tert-butyl ester (0.779 g, 3.02 mmol, Syn. Comm. 2003, 33 (13), 2275-83, also known as: (3R, 5S) -6-oxo-3,5-O-isopropylidene- A solution of tert-butyl 3,5-dihydroxyhexanoate) in anhydrous tetrahydrofuran (2.2 mL) was added dropwise. The mixture was stirred at −78 ° C. for 30 minutes, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was then slowly quenched with saturated aqueous ammonium chloride (10 mL) and partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous MgSO ₄ , concentrated in vacuo, the residue was purified by silica gel chromatography (20-30% ethyl acetate / hexanes) 73 g of the title compound (˜4: 1 mixture of cis / trans alkene isomers) was obtained as a white amorphous solid. The product mixture was used for the next step. MS (APCI) m / z 566.
Step H
(3R, 5S) -7- [5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxyhept- 6-enoic acid tert-butyl ester

((4R, 6S) -6- {2- [5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl]-from step G Vinyl} -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid tert-butyl ester (0.335 g, 0.592 mmol) in methanol (24 mL) was added with 1N hydrochloric acid (1.48 mL). Worked and the mixture was stirred overnight at ambient temperature. The solvent was removed in vacuo, the residue was diluted with water (20 mL) and ethyl acetate (25 mL), and the layers were separated. The organic phase was washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , concentrated in vacuo, and the residue was purified by silica gel chromatography (50% ethyl acetate / hexanes) to give 247 mg (79%) Of the title compound (mixture of cis / trans alkene isomers) was obtained as a white amorphous solid; (MS (APCI ⁺ ) m / z 526).
Step I
(3R, 5R) -7- [5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxyheptanoic acid tert -Butyl ester

(3R, 5S) -7- [5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5- from Step H A solution of dihydroxyhept-6-enoic acid tert-butyl ester (0.449 g, 0.854 mmol) in methanol (16 mL) was treated with 10% palladium / carbon (0.10 g) and the mixture was under a hydrogen atmosphere (50 psi). 1. Shake on a pearl apparatus for 1.75 hours. The mixture was then filtered through celite to remove the catalyst, the filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (50% ethyl acetate / hexanes) to yield 301 mg (67%) of the title compound as a white amorphous (MS (APCI +) m / z 528).
Step J
(3R, 5R) -7- [5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxyheptanoic acid sodium salt salt

(3R, 5R) -7- [5- (4-Fluorophenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5- from Step I A solution of dihydroxyheptanoic acid tert-butyl ester (0.250 g, 0.474 mmol) in methanol (15 mL) is treated with aqueous sodium hydroxide (1.028 N, 0.495 mL) and the reaction mixture is stirred at ambient temperature for 26 hours. did. The solvent was removed in vacuo and the residue was dissolved in a minimum amount of 10% methanol / dichloromethane (˜3 mL), diluted with additional methylene chloride (10 mL) and filtered to remove any remaining sodium hydroxide. The filtrate was concentrated in vacuo, the residue was triturated with diethyl ether (˜20 mL), the solid was collected by filtration and dried under vacuum to give 220 mg (94%) of the title compound as a white amorphous solid. . NMR (400 MHz, DMSO-d ₆ ) δ 7.60, 7.47, 7.14, 4.92, 4.51, 3.73, 3.65, 3.24, 3.10, 2.90, 2 ^{.70,1.99,1.78,1.60,1.45,1.32; MS (APCI -) m} / z470.
(Example 8)
(3R, 5R) -7- [5- (4-Fluorophenyl) -3-isopropyl-2- (phenylmethanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxyheptanoic acid Sodium salt

In a manner similar to that described in Steps CJ of Example 7, the title compound was prepared by replacing methanesulfonyl chloride in Step C with benzylsulfonyl chloride. MS (APCI ^<+> ) m / z 548; mp 191-194 [deg.] C (decomposition).
Example 9
(3R, 5R) -7- [2- (Benzenesulfonyl-methyl-amino) -5- (4-fluorophenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxyheptanoic acid sodium salt salt

In a manner similar to that described in Steps CJ of Example 7, the title compound was prepared by replacing methanesulfonyl chloride in Step C with benzenesulfonyl chloride. NMR (400 MHz, DMSO-d ₆ ) δ 7.87, 7.73, 7.63, 7.51, 7.12, 4.93, 4.59, 3.73, 3.68, 2.94, 2 ^{.72,1.98,1.79,1.62,1.50,1.43,1.32; MS (APCI -) m} / z532.
(Example 10)
(3R, 5R) -7- [2- (Acetyl-methyl-amino) -5- (4-fluorophenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxyheptanoic acid sodium salt

ステップＡ
５−ジメトキシメチル−４−（４−フルオロフェニル）−１−イソプロピル−１Ｈ−イミダゾール−２−カルボキシアルデヒド

[4- (4-Fluorophenyl) -1-isopropyl-5-methyl-1H-imidazol-2-yl] methylamine (3.10 g, 12.5 mmol) and pyridine (2. A stirred solution of 03 mL, 25.1 mmol) in anhydrous methylene chloride (50 mL) was treated with acetic anhydride (1.42 mL, 15.0 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature over the weekend, diluted with methylene chloride (50 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and brine (25 mL), dried over anhydrous Na ₂ SO ₄ , Concentrated under vacuum. The residue was purified by silica gel chromatography (30-80% ethyl acetate / hexane) to give 1.16 g (32%, purity-80%) of N- [4- (4-fluorophenyl) -1-isopropyl-5. -Methyl-1H-imidazol-2-yl] -N-methyl-acetamide was obtained as an amber amorphous solid, which was used without further purification. An analytical sample was prepared by radial chromatography (4% methanol / dichloromethane; 2000 micron silica gel rotor) to give a white solid; (mp 108-111 ° C .; MS (APCI ⁺ ) m / z 290). The remaining steps were carried out in the same manner as Steps DJ in Example 7 to give the title compound as a white solid. NMR (400 MHz, DMSO-d ₆ ) δ 7.60, 7.52, 7.13, 4.92, 4.37, 3.73, 3.65, 3.00, 2.95, 2.75, 1 ^{.99,1.78,1.70,1.62,1.45,1.32; MS (APCI -) m} / z434.
(Example 11)
(3R, 5R) -7- {5- (4-Fluorophenyl) -3-isopropyl-2-[(methanesulfonyl-methyl-amino) -methyl] -3H-imidazol-4-yl} -3,5- Dihydroxyheptanoic acid sodium salt

Step A
5-Dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazole-2-carboxaldehyde

To a stirred solution of lithium diisopropylamide (1.5 M cyclohexane solution, 9.67 mL, 14.5 mmol) in anhydrous tetrahydrofuran (43 mL) at −78 ° C. under a nitrogen atmosphere, 5-dimethoxymethyl from Step A of Example 1 A solution of -4- (4-fluorophenyl) -1-isopropyl-1H-imidazole (3.67 g, 13.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise over 8 minutes. The resulting mixture was stirred at −78 ° C. for 25 minutes and then treated with N, N-dimethylformamide (4.08 mL, 52.7 mmol). After stirring at −78 ° C. for an additional 30 minutes, the mixture was allowed to warm to ambient temperature, then quenched with saturated aqueous ammonium chloride (25 mL) and diluted with ethyl acetate (50 mL) and water (25 mL). The layers were separated and the organic phase was washed with water (50 mL) and brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (25% ethyl acetate / hexane) to give 3.41 g (84%) of the title compound as a white solid; (mp 98-99 ° C .; MS (APCI ⁺ ) m / z 307) .
Step B
[5-Dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazol-2-ylmethyl] -methyl-amine

To a stirred solution of 5-dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazole-2-carboxaldehyde (2.90 g, 9.47 mmol) from Step A in methanol (20 mL) was added at 0 ° C. Then, methylamine (2M methanol solution, 28.4 mL) was added dropwise under a nitrogen atmosphere, stirred at 0 ° C. for 20 minutes, and then sodium borohydride (0.716 g, 18.9 mmol) was added little by little over 15 minutes. It was. The resulting homogeneous mixture was stirred at 0 ° C. for 15 minutes, then at ambient temperature for 2.5 hours, and then the solvent was removed under vacuum. The residue was diluted with dichloromethane (150 mL) and ice-saturated saturated aqueous sodium bicarbonate was slowly added while the slurry was vigorously stirred. The biphasic mixture is stirred until gas evolution ceases, the layers are separated, the organic phase is washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a quantitative collection. The title compound was obtained as an opaque viscous oil; (MS (APC) m / z 322). This was used without further purification.
Step C
N- [5 dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazol-2-ylmethyl] -N-methyl-methanesulfonamide

[5-Dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazol-2-ylmethyl] -methyl-amine (1.36 g, 4.23 mmol) and triethylamine (0.885 mL) from Step B , 6.35 mmol) in anhydrous methylene chloride (42 mL) was cooled to 0 ° C. under a nitrogen atmosphere and treated with methanesulfonyl chloride (0.36 mL, 4.65 mmol). The resulting mixture was stirred at 0 ° C. for 1.5 h, then diluted with methylene chloride (20 mL), washed with saturated aqueous sodium bicarbonate (30 mL) and brine (15 mL), dried over anhydrous Na ₂ SO ₄ And concentrated under vacuum. The residue was purified by silica gel chromatography (40-80% ethyl acetate / hexane) to give 80% yield of the title compound as a white solid; (mp 136-138 ° C .; MS (APCI ⁺ ) m / z 400).
Step D
N- [4- (4-Fluorophenyl) -5-formyl-1-isopropyl-1H-imidazol-2-ylmethyl] -N-methyl-methanesulfonamide

N- [5-Dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazol-2-ylmethyl] -N-methyl-methanesulfonamide (1.28 g, 3.20 mmol) from Step C A stirred solution of dry dichloromethane (5 mL) was treated with trifluoroacetic acid (7.5 mL) under a nitrogen atmosphere, stirred for 1 h at ambient temperature and concentrated in vacuo. The residue was diluted with 1M aqueous sodium hydroxide solution (50 mL) and extracted with dichloromethane (2 × 50 mL), the combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and dried under vacuum. Concentration gave 1.11 g (98%) of the title compound as a white solid; (MS (APCI ⁺ ) m / z 354).

ステップＡ
Ｎ−［５−ジメトキシメチル−４−（４−フルオロフェニル）−１−イソプロピル−１Ｈ−イミダゾール−２−イルメチル］−Ｎ−メチル−ベンゼンスルホンアミド

The remaining steps were performed in a similar manner as steps EJ of Example 7, and (3R, 5R) -7- {5- (4-fluorophenyl) -3-isopropyl-2-[(methanesulfonyl-methyl -Amino) -methyl] -3H-imidazol-4-yl} -3,5 dihydroxyheptanoic acid sodium salt was obtained as a white solid; mp 177-180 [deg.] C; MS (APCI ^<+> ) m / z 484.
(Example 12)
(3R, 5R) -7- [2-[(Benzenesulfonyl-methyl-amino) -methyl] -5- (4-fluorophenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5- Dihydroxyheptanoic acid sodium salt

Step A
N- [5-Dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazol-2-ylmethyl] -N-methyl-benzenesulfonamide

In a manner similar to that described in Step C of Example 11, the title compound was prepared by replacing methanesulfonyl chloride with benzenesulfonyl chloride. Mp 112-113 ° C; MS (APCI ⁺ ) m / z 462.
Step B
N- [4- (4-Fluorophenyl) -5-formyl-1-isopropyl-1H-imidazol-2-ylmethyl] -N-methyl-benzenesulfonamide

In a manner similar to that described in Step D of Example 11, N- [5-Dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazol-2-ylmethyl] -N— Methyl-methanesulfonamide was changed to N- [5-dimethoxymethyl-4- (4-fluorophenyl) -1-isopropyl-1H-imidazol-2-ylmethyl] -N-methyl-benzenesulfonamide to give the title compound Manufactured. MS (APCI ^<+> ) m / z 416.

The remaining steps are carried out in a manner similar to steps EJ of Example 7, and (3R, 5R) -7- [2-[(benzenesulfonyl-methyl-amino) -methyl] -5- (4-fluoro Phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxyheptanoic acid sodium salt was obtained as a white amorphous solid. NMR (400 MHz, DMSO-d ₆ ) δ 7.87, 7.73, 7.63, 7.51, 7.12, 4.93, 4.59, 3.73, 3.68, 2.94, 2 ^{.72,1.99,1.79,1.62,1.51,1.44,1.32; MS (APCI -) m} / z546.
(Formulation)

  The compounds of the present invention, including the compounds exemplified herein and all compounds of formula I, referred to below as “compound (s)” can be administered alone or in combination with one or more therapeutic agents. They treat, prevent, for example, dyslipidemia, non-insulin dependent diabetes, obesity, hyperglycemia, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertriglyceridemia, or hyperinsulinemia Or other drugs that regulate.

  The compounds are therefore suitable for formulations for convenient administration to mammals for the prevention and treatment of such disorders.

The following examples further illustrate typical formulations of the compounds provided by the present invention.

For intravenous administration to a patient, the above ingredients are mixed and dissolved in physiological saline.

The ingredients are mixed uniformly and compressed into tablets suitable for oral administration to patients.

The ingredients are mixed and milled to obtain a raw material suitable for filling hard gelatin capsules for administration to a patient.

  The ingredients are melted and mixed and then poured into a mold containing a total weight of 2.5 g.

While embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. It is understood that the terminology used herein is for description rather than limitation and that various changes can be made without departing from the spirit and scope of the invention.
(Biological assay)

The compounds of the present invention have shown HMG Co-A reductase inhibitory activity by standard assays commonly used by those skilled in the art (eg, J. of Lipid Research 1998; 39: 75-84; Analytical Biochemistry, 1991). ;
196: 211-214; RR 740-01077 Pharmacology 8-Nov-82). Accordingly, such compounds and formulations containing such compounds are particularly useful for the treatment, regulation or prevention of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia or atherosclerosis.
A. ) In vitro assay

Rat Liver Microsome Isolation Procedure: Male Sprague Dawley Rat (Charles
River) was given a rat chow containing 2.5% cholestyramine for 5 days and then sacrificed. The liver was minced and homogenized 10 times in an ice bath in sucrose solution for homogenization. Dilute the homogenate to a final volume of 200 mL and sorvall
Centrifugation was performed for 15 minutes at 5 ° C. and 10,000 rpm (12,000 × G). The upper fat layer was removed and the supernatant was decanted into a new tube. This step was repeated once more, then the supernatant was transferred to an ultracentrifuge tube and centrifuged at 36,000 rpm (105,000 × G) for 1 hour at 5 ° C. Discard the resulting supernatant and add 0.2M to the final pellet of 15mL
KH ₂ PO ₄ was added. The pellet was gently homogenized about 10 times by hand. Samples were pooled and diluted with buffer to a final volume of 60 mL. Pierce
The protein concentration of the homogenate was measured by the Raleigh method using a BCA (bicinchoninic acid) kit manufactured by Chemical Company. A 1 mL aliquot of microsomes was stored frozen in liquid nitrogen.

HMG CoA (3- hydroxy-3-methyl-glutaryl-CoA) reductase Assay: Materials and ^Methods: [3- l4 C] -HMG
CoA (57.0 mCi / mmol) was purchased from Amersham Biosciences, UK. HMG CoA, mevalonolactone, β-NADPH (β-nicotinamide adenine dinucleotide phosphate (reduced form)) is Sigma
Purchased from Chemical Co. AG1-8X resin was purchased from Bio-Rad Laboratory.

1 μL of dimethyl sulfoxide (DMSO) or 1 μL of DMSO containing the test compound at a concentration sufficient to give a final assay concentration of 0.1 nM to 1 mM is placed in each well of a Corning 96-well plate and 50 μg / mL rat 34 μL of buffer containing liver microsomes (100 mM
NaH ₂ PO ₄ , 10 mM imidazole and 10 mM EDTA (ethylenediaminetetraacetic acid)) were added to each well. After incubation for 30 minutes on ice, 15 mM
NADPH, 25 mM DTT and ^l4 C-HMG CoA of 15μl containing (dithiothreitol) (0.024μCi) was added and incubated for a further 45 minutes at 37 ° C.. The reaction was stopped by adding 10 μL of HCl and then 5 μL of mevalonolactone was added. Plates were incubated overnight at room temperature to lactonize from mevalonic acid to mevalonolactone. The incubated sample was added to a column containing 300 μL of AG1-X8 anion exchange resin in a Corning filter plate. The eluent was collected in a Corning 96 well capture plate. Scintillation cocktail (Ultima-Flo-M) was added to each well and the plate was counted with a Trilux Microbeta Counter. IC ₅₀ values were calculated with GraphPad software (Prism).

procedure:
1. Add 1 μl DMSO or compound to the wells according to protocol.
2. Add 35 μL of incubation buffer containing rat microsomes to each well. Incubate for 30 minutes at 4 ° C.
Add ^l4 C-HMG CoA of 3.15μL. Incubate at 37 ° C for 45 minutes.
4. Add 10 μL HCl stop reagent.
Add 5.5 μL of mevalonolactone. Incubate overnight at room temperature.
6). Add contents to AG1-X8 anion exchange resin in Corning filter plate.
7). Collect the eluent in the Corning capture plate.
8). Add scintillation cocktail Ultima-Flo-M.
9. Measure with a Trilux Microbeta Counter.
10. IC ₅₀ values are calculated.

The compounds of the invention exhibit a range of IC ₅₀ values less than about 500 nM. Preferred compounds of the invention exhibit a range of IC ₅₀ values less than about 100 nM. More preferred compounds of the invention exhibit a range of IC ₅₀ values less than about 20 nM. For example, the compound of Example 1 has an IC ₅₀ of 9.75 nM, the compound of Example 7 has an IC ₅₀ of 6.6 nM, and the first listed material in Table I is 3.6 nM. IC ₅₀ .
B. Cell assay

Protocol for Sterol Biosynthesis in Rat Hepatocytes: Cell Culture, Compound Treatment and Cell Labeling: Frozen rat hepatocytes purchased from XenoTech (Product Number; N400572) at a concentration of 10 ⁵ cells / well in a 6-well collagen I coat It was applied on a plate. 10% FBS (fetal bovine serum) and 10 mM
DMEM (Dulbecco's modified Eagle's medium) (Gibco, product number; 11054-020) containing HEPES (N-2-hydroxyethyl-piperazine-N ¹ -2 ethanesulfonic acid) (Gibco product number; 15630-080) Cells were cultured for 24 hours. Cells were preincubated with compound for 4 hours, then incubated for an additional 4 hours in medium containing 1 μCi / mL ¹⁴ C acetic acid to label. After labeling, the cells are 150 mM
It was washed twice with 5 mM MOPS (3- [N-morpholino] propanesulfonic acid) solution containing NaCl and 1 mM EDTA and collected in a lysis buffer containing 10% KOH and 80% (volume) ethanol.

Cholesterol extraction and data analysis: Cell lysates were saponified at 60 ° C. for 2 hours to separate labeled cholesterol from labeled non-cholesterol lipids. The lysate was then mixed with 0.5 volume H ₂ O and 2 volumes hexane and then stirred vigorously for 30 minutes. After separating the two phases, the upper phase solution was collected and combined with 5 volumes of scintillation cocktail. ^The amount of ¹⁴ C cholesterol was quantified by liquid scintillation counting. IC ₅₀ values were calculated with GraphPad software (Prism 3.03). The compounds of the invention exhibit a range of IC ₅₀ values less than about 1000 nM. Preferred compounds of the invention exhibit a range of IC ₅₀ values less than about 100 nM. For example, the compound of Example 1 has an _{IC 50} value of 0.73 nM, the compound of Example 7 has an _{IC 50} value of 0.99NM, initially coming out compounds of Table I of 0.71nM IC ₅₀ .
C. ) Protocol for sterol biosynthesis in L6 rat myoblasts:

Cell culture, compound treatment and cell labeling: L6 rat myoblasts purchased from ATCC (CRL-1458) were cultured in T-150 bent culture flasks and spread on 12-well culture plates at a concentration of 60,000 cells / well. did. Until confluence is reached in DMEM (Dulbecco's Modified Eagle Medium) (Gibco, Product Number; 10567-014) containing 10% heat-inactivated FBS (Fetal Bovine Serum) (Gibco product number; 10082-139) for 72 hours. Cells were cultured. Cells are preincubated for 3 hours in medium containing compound and 0.2% DMSO (dimethyl sulfoxide), and an additional 3 hours in medium containing compound, 0.2% DMSO and 1 μCi / mL ¹⁴ C acetic acid. Labeled by incubating. After labeling, the cells were washed once with lxPBS (Gibco product number; 14190-144) and then lysed overnight at 4 ° C. in a buffer containing 10% KOH and 78% (volume) ethanol.

Cholesterol extraction and data analysis: Lipid ester bonds were hydrolyzed by saponifying the lysate for 2 hours at 60 ° C. Sterols (including cholesterol) were extracted from the saponified lysate by combining with 3 volumes of hexane and mixing 6 times with a pipette. The upper organic phase solution is recovered and an equal volume of 1N
Combined with KOH / 50% methanol and mixed 6 times with pipette. The upper organic phase was collected on scintillant-coated plates (Wallac serial number; 1450-501) and evaporated at room temperature for 3 hours to remove hexane. The amount of ¹⁴ C cholesterol was quantified by scintillation counting on a Trilux 1450 plate reader (Wallac). formula:
^{y = Bmax (l- (x n} / K n + x n)) + y2
Using the sigmoid inhibition curve model, the Microsoft excel 2000 data analysis wizard calculated the IC ₅₀ value from the% inhibition relative to the compound concentration compared to the negative control. Here, K is the IC ₅₀ value of the inhibition curve, X is the inhibitor concentration, Y is the inhibited reaction, and Bmax + Y2 is the limiting reaction when X approaches 0. The compounds of the present invention have L6IC ₅₀ values greater than about 0.5 nM. For example, the compound of Example 1 has an L6IC ₅₀ of 227 nM, the compound of Example 7 has an L6IC ₅₀ of 4330 nM, and the first emerging material in Table I has an L6IC ₅₀ of 0.84 nM. Preferred compounds of the invention exhibit hepatocyte selectivity greater than about 1000 ((L6IC ₅₀ / rat hepatocyte IC ₅₀ )> 1000) and have an L6IC ₅₀ greater than about 1 nM.

Claims (15)

A compound having formula I, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of a prodrug

(Where
----------- is one bond or no bond;
R ¹ is H; C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl;
R ² is H; halogen; optionally substituted C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; optionally substituted aryl, aralkyl, heteroaryl or heteroaralkyl;
_{^{R 6 R 7 NS (O)}} 2 -; R 8 S (O) n - ;-( CH 2) n COR ';-( CH 2) n NR 6 R 7 ;-( CH 2) n COOR'; or R ⁶ R ⁷ NC (O) —;
R ⁶ and R ⁷ are each independently H; substituted with halogen, OR ′, (CH ₂ ) _n COOR ′, (CH ₂ ) _n CONR′R ″, (CH ₂ ) _n SO ₂ R ′ or CN Optionally aryl, aralkyl, heteroaryl or heteroaralkyl;
Be _(CH 2) n CONR'R "or _{(CH 2) n SO 2 R} '; optionally substituted _C 1 _{-C 10 alkyl; (CH 2) n COR'} ; (CH 2) n COOR ' Or N, R ⁶ and R ⁷ together form an optionally substituted 4-11 membered ring containing up to two heteroatoms optionally selected from O, N and S;
R ⁴ is an optionally substituted C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; H; halo; optionally substituted aryl or heteroaryl;
R ⁸ is an optionally substituted aryl, aralkyl, alkyl, heteroaryl or heteroaralkyl;
R ′ and R ″ are each independently H, optionally substituted C ₁ -C ₁₂ alkyl, aryl or aralkyl; and n is 0-2. The compound of claim 1, wherein R ¹ is C _1-3 alkyl, or a pharmaceutically acceptable salt, solvate, or composition thereof. R ² is _{^{R 6 R 7 NS (O)}} 2 - or ^{R 6 R 7 NC (O)} - The compound of claim 1 or a pharmaceutically acceptable salt, solvate or composition. R ² is _{- (CH} 2) n ^NR 6 ^{R 7,} compounds of claim 1 or a pharmaceutically acceptable salt, solvate or composition. The compound of claim 1, or a pharmaceutically acceptable salt, solvate or composition thereof, wherein R ⁴ is H; optionally substituted lower alkyl, phenyl or heteroaryl. 2. The compound of formula I of claim 1 selected from the group consisting of:
(3R, 5R) -7- [2-Benzylcarbamoyl-5- (3,4-difluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
(3R, 5R) -7- [2-Benzylcarbamoyl-3-propyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
(3R, 5R) -7- [2-Benzylcarbamoyl-3-isobutyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
(3R, 5R) -7- [2-Benzylcarbamoyl-3-ethyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
(3R, 5R) -7- [2-Benzylcarbamoyl-3-isopropyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
(3R, 5R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenethylcarbamoyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
(3R, 5R) -7- [2- (4-Fluoro-benzylcarbamoyl) -3-propyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptane acid;
(3R, 5R) -7- [2-phenylcarbamoyl-3-propyl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; and pharmaceuticals thereof Acceptable salts, amides and esters. 2. The compound of formula I of claim 1 selected from the group consisting of:
(3R, 5R) -7- [2- (4-Fluoro-benzylcarbamoyl) -5- (4-fluoro-3-methyl-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5 -Dihydroxy-heptanoic acid;
(3R, 5R) -7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
(3R, 5R) -7- (2-Benzylcarbamoyl-3-isopropyl-5-pyridin-3-yl-3H-imidazol-4-yl) -3,5-dihydroxy-heptanoic acid;
(3R, 5S) -7- (2-Benzylcarbamoyl-5-bromo-3-isopropyl-3H-imidazol-4-yl) -3,5-dihydroxy-hept-6-enoic acid; and pharmaceutically acceptable thereof Possible salts, amides and esters. 2. The compound of formula I of claim 1 selected from the group consisting of:
(3R, 5R) -3,5-dihydroxy-7- [3-isopropyl-5-phenyl-2-((R) -1-phenyl-ethylcarbamoyl) -3H-imidazol-4-yl] -heptanoic acid;
(3R, 5R) -3,5-dihydroxy-7- [3-isopropyl-5-phenyl-2-((S) -1-phenyl-ethylcarbamoyl) -3H-imidazol-4-yl] -heptanoic acid;
7- [5- (4-Fluoro-phenyl) -3-isopropyl-2- (methanesulfonyl-methyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-methanesulfonylamino-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [5- (4-Fluoro-phenyl) -3-isopropyl-2- (methyl-phenylmethanesulfonyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylmethanesulfonylamino-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2-Benzenesulfonylamino-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2- (Benzenesulfonyl-methyl-amino) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2- (acetyl-methyl-amino) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2-acetylamino-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2- (acetyl-benzyl-amino) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2- (Benzoyl-methyl-amino) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2-Benzoylamino-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylacetylamino-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [5- (4-Fluoro-phenyl) -3-isopropyl-2- (methyl-phenylacetyl-amino) -3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2- (Benzyl-methanesulfonyl-amino) -5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-methylsulfamoyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [2-Benzylsulfamoyl-5- (4-fluoro-phenyl) -3-isopropyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid;
7- [5- (4-Fluoro-phenyl) -3-isopropyl-2-phenylsulfamoyl-3H-imidazol-4-yl] -3,5-dihydroxy-heptanoic acid; and (3R, 5R) -7 -{5- (4-fluoro-phenyl) -3-isopropyl-2-[(pyridin-3-ylmethyl) -carbamoyl] -3H-imidazol-4-yl} -3,5-dihydroxy-heptanoic acid; Pharmaceutically acceptable salts, amides and esters. 9. Stereoisomers of compounds of formula I according to any one of claims 1 to 8, selected from (3R, 5R) -isomers and (3R, 5S) -isomers, or pharmaceutically An acceptable salt, solvate or composition. A stereoisomer of a compound of formula I according to any one of claims 1 to 8, selected from the (3S, 5R) -isomer and the (3S, 5S) -isomer, or a pharmaceutically acceptable salt thereof. An acceptable salt, solvate or composition. 11. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of diseases for which an HMG Co-A reductase inhibitor is indicated. , Solvates, or compositions. A combination of a compound of formula I according to any one of claims 1 to 10 and another pharmaceutically active drug. The other pharmaceutically active drug is CTEP inhibitor, PPAR-activator, MTP / apo B secretion inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, fibrate, niacin, ion exchange resin, antioxidant, 13. The combination of claim 12, which is an ACAT inhibitor, bile capture agent, antihypertensive agent, or acetylcholinesterase inhibitor. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 10 or a combination according to any one of claims 12 to 13; and a pharmaceutically acceptable carrier, diluent or vehicle. object. 14. A compound of formula I according to any one of claims 1 to 10, a combination according to any one of claims 12 to 13 for the manufacture of a medicament for the treatment of atherosclerosis, Or use of the composition of claim 14.