KR20160128444A - Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring - Google Patents

Abstract

상기 화학식에서,
변수는 본원에서 정의된 바와 같다.
약제학적 조성물, 키트 및 이러한 화합물을 포함하는 제조품, 당해 화합물의 제조방법 및 당해 화합물 제조용으로 유용한 중간체, 및 당해 화합물 및 조성물의 사용 방법도 또한 제공된다.The present invention provides, but is not limited to, novel oleanolic acid derivatives of the formula:

In the above formulas,
The variables are as defined herein.
Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds, methods of making the compounds and intermediates useful for preparing the compounds, and methods of using the compounds and compositions.

Description

Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring}

This application claims the advantage of the priority of U.S. Provisional Application No. 61/046,332, filed Apr. 18, 2008, and 61/111,333, filed Nov. 4, 2008, all of which are incorporated herein by reference in their entirety.

The present invention relates generally to the fields of biology and medicine. More particularly, the present invention relates to compounds and methods for the treatment and prevention of diseases, such as those associated with oxidative stress and inflammation.

A number of severe and refractory human diseases are associated with difficulty in controlling the inflammatory process, including, for example, diseases such as cancer, atherosclerosis and diabetes that are not traditionally observed as inflammatory conditions. Similarly, autoimmune diseases, such as rheumatoid arthritis, lupus, psoriasis, and multiple sclerosis, lead to dysfunction of self versus non-autocognitive and response mechanisms in the immune system, including inadequate and chronic activation of the inflammatory process in infected tissues. . In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, nerve damage is correlated with activation of microglia and elevated levels of proinflammatory proteins, such as inducible nitric oxide synthase (iNOS).

One aspect of inflammation is the production of inflammatory prostaglandins, for example prostaglandins E, in which the precursor is produced by the enzyme cyclo-oxygenase (COX-2). High levels of COX-2 are found in inflamed tissues. Consequently, inhibition of COX-2 is known to reduce a number of symptoms of inflammation, and a number of important anti-inflammatory agents (eg, ibuprofen and celecoxib) act by inhibiting COX-2 activity. However, recent studies have demonstrated that the class of cyclopentenone prostaglandins (eg 15-deoxy prostaglandins J2, a.k.a PGJ2) plays a role in stimulating the coordinated healing of inflammation. COX-2 is also involved in the production of cyclopentenone prostaglandins. As a result, inhibition of COX-2 can prevent complete healing of inflammation, potently promoting the persistence of activated immune cells in the tissue, leading to chronic "fumigation" inflammation. This effect is responsible for increasing the incidence of cardiovascular disease in patients using selective COX-2 inhibitors for long periods of time. Another important class of anti-inflammatory agents, corticosteroids, have a number of undesirable side effects and are often unsuitable for chronic use. New protein-based drugs, such as anti-TNF monoclonal antibodies, have proven to be effective for the treatment of certain autoimmune diseases, such as rheumatoid arthritis. However, these compounds must be administered by injection, are not effective in all patients, and can have serious side effects. In many severe forms of inflammation (eg sepsis, acute pancreatitis), existing drugs are ineffective. In addition, currently available drugs usually do not have significant antioxidant properties and are not effective in reducing the oxidative stress associated with overproduction of reactive oxygen species and related molecules, such as peroxynitrite. Therefore, there is an urgent need for improved therapeutic agents having antioxidant properties and anti-inflammatory properties.

A series of synthetic triterpenoid homologues of oleanolic acid have been shown to be inhibitors of cellular inflammatory processes, e.g., induction of inducible nitric oxide synthase (iNOS) in mouse macrophages and IFN-γ of COX-2 (see : Honda et al. (2000a); Honda et al. (2000b), and Honda et al . (2002), all incorporated herein by reference). For example, one of these, 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester (CDDO-Me), currently includes cancer and diabetic nephropathy. It is in clinical trials for various inflammation-related disorders. The pharmacology of these molecules is complex, as they have been shown to affect the function of many protein targets, thereby regulating the function of many important cellular signaling pathways involved in oxidative stress, cell cycle regulation, and inflammation ( Reference: Dinkova-Kostova et al . , Ahmad et al . , 2006; Ahmad et al . , 2008; Liby et al. ). It is desirable to synthesize novel candidates for the treatment or prevention of diseases in relation to various species of diseases that can be treated with compounds having variable predetermined biological activity profiles of known oleanolic acid derivatives and having strong antioxidant and anti-inflammatory effects. Do.

The present specification provides a novel compound having antioxidant properties and anti-inflammatory properties, a method for preparing the same, and a method for using the same. Hereinafter, a compound included in a general or specific formula or specifically named is referred to herein as a "compound of the present invention", a "compound of the present specification", and a "oleanolic acid derivative".

In some aspects, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof.

In Formula 1,

Y is cyano, heteroaryl _(C≤12) , substituted heteroaryl _(C≤12) or -C(O)R _a , where R _a is hydrogen, hydroxy, halo, amino, hydroxyamino, azi Do, silyl or mercapto; Alkyl _(C≤12) , alkenyl _(C≤12) , alkynyl _(C≤12) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤12) , heteroaralkyl _{( C≤12)} , alkoxy _(C≤12) , alkenyloxy _(C≤12) , alkynyloxy _(C≤12) , aryloxy _(C≤12) , aralkoxy _(C≤12) , heteroaryloxy _{( C≤12)} , heteroaralkoxy _(C≤12) , acyloxy _(C≤12) , alkylamino _(C≤12) , dialkylamino _(C≤12) , alkoxyamino _(C≤12) , alkenylamino _(C≤12) , alkynylamino _(C≤12) , arylamino _(C≤12) , _{aralkylamino (C≤12)} , heteroarylamino _(C≤12) , heteroaralkylamino _(C≤12) , alkyl-sulfonylamino _(C≤12), amido _(C≤12), alkylthio _(C≤12), an alkenyl thio _(C≤12), alkynyl thio _(C≤12), arylthio _{(C≤ 12)} , aralkylthio _(C≤12) , heteroarylthio _(C≤12) , heteroaralkylthio _(C≤12) , acylthio _(C≤12) , alkyl ammonium _(C≤12) , alkylsulfonium _(C≤12) , alkylsilyl _(C≤12) , or a substituted variant of any of these groups, or

를 형성하고, 여기서 R_d는 알킬_(C≤8), 알케닐_(C≤8), 아릴_(C≤8), 아르알킬_(C≤8), 헤테로아릴_(C≤8), 헤테로아르알킬_(C≤8) 또는 임의의 이들 그룹의 치환된 변형태이고;R _a also includes a nitrogen atom attached to carbon atom 13 and R _d

Wherein R _d is alkyl _(C≤8) , alkenyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , heteroaryl _(C≤8) , heteroaralkyl _{( C≤8)} or a substituted variant of any of these groups;

Z is a single or double bond, -O- or -NR _e -, wherein R _e is hydrogen, hydroxy, alkyl _(C≤8) or alkoxy _(C≤8) ;

X is OR _b , NR _b R _c or SR _b , wherein R _b and R _c are each independently hydrogen or hydroxy; Alkyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _{(C≤8 )} , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R _b is a double bond is part of a valence of R _b is a bond, and the member, when R _b is added to the member, the atoms binding R _b is part of a double bond;

R ₁ is hydrogen, cyano, hydroxy, halo or amino; Or alkyl _(C≤8), alkenyl _(C ≤8), alkynyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _(C≤8), alkylamino _(C≤8), arylamino _{(C≤8 )} , amido _(C≤8) , or a substituted variant of any of these groups;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) , or any of these groups Is a substituted variant of;

R ₃ is absent or hydrogen; Alkyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , acyl _(C≤8) , or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R ₃ is an oxygen atom is part of a double bond, R ₃ is a bond, a member, and if the added R ₃ is a member, an oxygen atom R ₃ is bonded is part of a double bond;

R ₄ and R ₅ are each independently alkyl _(C≦8) or substituted alkyl _(C≦8) ;

R ₆ is hydrogen, hydroxy or oxo;

R ₇ is hydrogen or hydroxy;

R _8, R _9, R ₁₀ and R ₁₁ are each independently hydrogen, hydroxy, alkyl _(C≤8), substituted alkyl _(C≤8), alkoxy _(C≤8) or substituted alkoxy _{(C≤8 )} .

In some embodiments, the compound is further defined as the following Formula 2 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 2,

Y is cyano or -C(O)R _a , wherein R _a is hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; Alkyl _(C≤12) , alkenyl _(C≤12) , alkynyl _(C≤12) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤12) , heteroaralkyl _{( C≤12)} , alkoxy _(C≤12) , alkenyloxy _(C≤12) , alkynyloxy _(C≤12) , aryloxy _(C≤12) , aralkoxy _(C≤12) , heteroaryloxy _{( C≤12)} , heteroaralkoxy _(C≤12) , acyloxy _(C≤12) , alkylamino _(C≤12) , dialkylamino _(C≤12) , alkoxyamino _(C≤12) , alkenylamino _(C≤12) , alkynylamino _(C≤12) , arylamino _(C≤12) , _{aralkylamino (C≤12)} , heteroarylamino _(C≤12) , heteroaralkylamino _(C≤12) , alkyl-sulfonylamino _(C≤12), amido _(C≤12), alkylthio _(C≤12), an alkenyl thio _(C≤12), alkynyl thio _(C≤12), arylthio _{(C≤ 12)} , aralkylthio _(C≤12) , heteroarylthio _(C≤12) , heteroaralkylthio _(C≤12) , acylthio _(C≤12) , alkyl ammonium _(C≤12) , alkylsulfonium _(C≦12) , alkylsilyl _(C≦12) or a substituted variant of any of these groups;

X is OR _b , NR _b R _c or SR _b , wherein R _b and R _c are each independently hydrogen or hydroxy; Alkyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _{(C≤8 )} , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R _b is a double bond is part of a valence of R _b is a bond, and the member, when R _b is added to the member, the atoms binding R _b is part of a double bond;

R ₁ is hydrogen, cyano, hydroxy, halo or amino; Or alkyl _(C≤8), alkenyl _(C ≤8), alkynyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _(C≤8), alkylamino _(C≤8), arylamino _{(C≤8 )} , amido _(C≤8) or a substituted variant of any of these groups;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or any of these groups Is a substituted variant;

R ₃ is absent or hydrogen; Alkyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , acyl _(C≤8) or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R ₃ is an oxygen atom is part of a double bond, R ₃ is a bond, a member, and if the added R ₃ is a member, an oxygen atom R ₃ is bonded is part of a double bond;

R ₄ and R ₅ are each independently alkyl _(C≦8) or substituted alkyl _(C≦8) ;

R ₆ and R ₇ are each independently hydrogen or hydroxy.

In some embodiments, the compound is further defined as the following Formula 3 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 3,

Y is cyano or -C(O)R _a , wherein R _a is hydrogen, hydroxy, halo, amino, azido, mercapto or silyl; Alkyl _(C≤12) , alkenyl _(C≤12) , alkynyl _(C≤12) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤12) , heteroaralkyl _{( C≤12)} , alkoxy _(C≤12) , alkenyloxy _(C≤12) , alkynyloxy _(C≤12) , aryloxy _(C≤12) , aralkoxy _(C≤12) , heteroaryloxy _{( C≤12)} , heteroaralkoxy _(C≤12) , acyloxy _(C≤12) , alkylamino _(C≤12) , alkoxyamino _(C≤12) , dialkylamino _(C≤12) , alkenylamino _(C≤12) , alkynylamino _(C≤12) , arylamino _(C≤12) , _{aralkylamino (C≤12)} , heteroarylamino _(C≤12) , heteroaralkylamino _(C≤12) , Amido _(C≦12) or a substituted variant of any of these groups;

X is OR _b , NR _b R _c or SR _b , wherein R _b and R _c are each independently hydrogen or hydroxy; Alkyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _{(C≤8 )} , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R _b is a double bond is part of a valence of R _b is a bond, and the member, when R _b is added to the member, the atoms binding R _b is part of a double bond;

R ₁ is hydrogen, cyano, hydroxy, halo or amino; Or alkyl _(C≤8), alkenyl _(C ≤8), alkynyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _(C≤8), alkylamino _(C≤8), arylamino _{(C≤8 )} , amido _(C≤8) or a substituted variant of any of these groups;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or any of these groups Is a substituted variant;

R ₄ is alkyl _(C≤8) or substituted alkyl _(C≤8) .

In some embodiments, the compound is further defined as the following Formula 4 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 4,

R _a is hydrogen, hydroxy, halo or amino; Or alkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , heteroaryl _(C≤8) , heteroaralkyl _(C≤8) , alkoxy _(C≤8) , alkenyloxy _(C≤8) , alkynyloxy _(C≤8) , aryloxy _(C≤8) , aralkoxy _(C≤8) , heteroaryloxy _(C≤8) , heteroaralkoxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , alkoxyamino _(C≤8) , dialkylamino _(C≤8) , alkenyl amino _(C≤8), alkynyl-amino _(C≤8), arylamino _(C≤8), aralkyl amino _(C≤8), heteroaryl amino _(C≤8), heteroaralkyl amino _{(C≤8 )} , amido _(C≤8) or a substituted variant of any of these groups;

X is OR _b or NR _b R _c , wherein R _b and R _c are each independently hydrogen or hydroxy; Alkyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _{(C≤8 )} , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R _b is a double bond is part of a valence of R _b is a bond, and the member, when R _b is added to the member, the atoms binding R _b is part of a double bond;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or any of these groups It is a substituted variant.

In some embodiments, the compound is further defined as the following Formula 5 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 5,

R _a is hydrogen, hydroxy, halo or amino; Alkyl _(C≤8), alkenyl _(C≤8), alkynyl _(C ≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _{( C≤8)} , alkoxy _(C≤8) , alkenyloxy _(C≤8) , alkynyloxy _(C≤8) , aryloxy _(C≤8) , aralkoxy _(C≤8) , heteroaryloxy _{( C≤8)} , heteroaralkoxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , alkoxyamino _(C≤8) , dialkylamino _(C≤8) , alkenylamino _(C≤8) , alkynylamino _(C≤8) , arylamino _(C≤8) , _{aralkylamino (C≤8)} , heteroarylamino _(C≤8) , heteroaralkylamino _(C≤8) , Amido _(C≤8) or a substituted variant of any of these groups;

R ₂ is cyano or fluoro; Or fluoroalkyl _(C≤5) , alkenyl _(C≤5) , alkynyl _(C≤5 ), heteroaryl _(C≤5) , acyl _(C≤5) , acyloxy _(C≤5) , ami Figure _(C≤5) or a substituted variant of any of these groups.

In some embodiments, the compound is further defined as the following Formula 6 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 6,

R _a is hydrogen, hydroxy, halo or amino; Or alkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , heteroaryl _(C≤8) , heteroaralkyl _(C≤8) , alkoxy _(C≤8) , alkenyloxy _(C≤8) , alkynyloxy _(C≤8) , aryloxy _(C≤8) , aralkoxy _(C≤8) , heteroaryloxy _(C≤8) , heteroaralkoxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , alkoxyamino _(C≤8) , dialkylamino _(C≤8) , alkenyl amino _(C≤8), alkynyl-amino _(C≤8), arylamino _(C≤8), aralkyl amino _(C≤8), heteroaryl amino _(C≤8), heteroaralkyl amino _{(C≤8 )} , amido _(C≤8) or a substituted variant of any of these groups.

In some embodiments, the compound is further defined as the following Formula 7 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 7,

R _a is alkoxy _(C1-4) , alkylamino _(C1-4) , alkoxyamino _(C1-4) , dialkylamino _(C1-4) or a substituted variant of any of these groups.

In some embodiments, the compound is further defined as the following Formula 8 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 8,

R _a is alkyl _(C1-4) or aralkoxy _(C7-8) , or a substituted variant of one of these groups.

In some embodiments, the compound is further defined as the following Formula 9 or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or optical isomer thereof:

In Chemical Formula 9,

R _a is hydrogen, hydroxy, amino, dimethylamino, methyl, methoxy, methoxyamino, benzyloxy or 2,2,2-trifluoroethylamino.

In some embodiments, the compound is further defined as the following Formula 10 or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or optical isomer thereof:

In Chemical Formula 10,

R _a is hydrogen, hydroxy, amino, methoxy or 2,2,2-trifluoroethylamino.

In some embodiments, the compound is further defined as Formula 11, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or optical isomer thereof.

In Formula 11,

R _d is alkyl _(C≤8) , alkenyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , heteroaryl _(C≤8) , heteroaralkyl _(C≤8) or Is a substituted variant of any of these groups.

In some embodiments, the compound is further defined as Formula 12, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or optical isomer thereof.

In Formula 12,

Y is heteroaryl _(C≤8) or substituted heteroaryl _(C≤8) .

In some embodiments, the compound is further defined as Formula 13 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 13,

Y is cyano or -C(O)R _a , wherein R _a is hydrogen, hydroxy, halo, amino, azido, mercapto or silyl; Or alkyl _(C≤12) , alkenyl _(C≤12) , alkynyl _(C≤12) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤12) , heteroaralkyl _(C≤12) , alkoxy _(C≤12) , alkenyloxy _(C≤12) , alkynyloxy _(C≤12) , aryloxy _(C≤12) , aralkoxy _(C≤12) , heteroaryloxy _(C≤12) , heteroaralkoxy _(C≤12) , acyloxy _(C≤12) , alkylamino _(C≤12) , alkoxyamino _(C≤12) , dialkylamino _(C≤12) , alkenyl amino _(C≤12), alkynyl-amino _(C≤12), arylamino _(C≤12), aralkyl amino _(C≤12), heteroaryl amino _(C≤12), heteroaralkyl amino _{(C≤12 )} , amido _(C≦12) or a substituted variant of any of these groups;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or any of these groups Is a substituted variant;

R ₃ is absent or hydrogen; Alkyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , acyl _(C≤8) or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R ₃ is an oxygen atom is part of a double bond, R ₃ is a bond, a member, and if the added R ₃ is a member, an oxygen atom R ₃ is bonded is part of a double bond;

R ₄ is alkyl _(C≤8) or substituted alkyl _(C≤8) .

In some embodiments, the compound is further defined as the following Formula 14 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 14,

Y is cyano or -C(O)R _a , wherein R _a is hydrogen, hydroxy, halo, amino, azido or mercapto; Alkyl _(C≤12) , alkenyl _(C≤12) , alkynyl _(C≤12) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤12) , heteroaralkyl _{( C≤12)} , alkoxy _(C≤12) , alkenyloxy _(C≤12) , alkynyloxy _(C≤12) , aryloxy _(C≤12) , aralkoxy _(C≤12) , heteroaryloxy _{( C≤12)} , heteroaralkoxy _(C≤12) , acyloxy _(C≤12) , alkylamino _(C≤12) , alkoxyamino _(C≤12) , dialkylamino _(C≤12) , alkenylamino _(C≤12) , alkynylamino _(C≤12) , arylamino _(C≤12) , _{aralkylamino (C≤12)} , heteroarylamino _(C≤12) , heteroaralkylamino _(C≤12) , Alkylsulfonylamino _(C≦12) , amido _(C≦12) or a substituted variant of any of these groups;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or any of these groups Is a substituted variant;

R ₃ is hydrogen; Alkyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , acyl _(C≤8) or a substituted variant of any of these groups; Or it is a substituent that can be converted to hydrogen in vivo.

In some embodiments, the compound is further defined as the following Formula 15 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 15,

X is OR _b , NR _b R _c or SR _b , wherein R _b and R _c are each independently hydrogen; Alkyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , acyl _(C≤8) or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R _b is a double bond is part of a valence of R _b is a bond, and the member, when R _b is added to the member, the atoms binding R _b is part of a double bond;

R ₁ is hydrogen, cyano, hydroxy, halo or amino; Or alkyl _(C≤8), alkenyl _(C ≤8), alkynyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _(C≤8), alkylamino _(C≤8), arylamino _{(C≤8 )} , amido _(C≤8) or a substituted variant of any of these groups;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or any of these groups Is a substituted variant;

R ₄ is alkyl _(C≤8) or substituted alkyl _(C≤8) .

In some embodiments, the compound is further defined as the following Formula 16 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 16,

X is OR _b or NR _b R _c , wherein R _b and R _c are each independently hydrogen; Alkyl _(C≤8 ), aryl _(C≤8) , aralkyl _(C≤8) , acyl _(C≤8) or a substituted variant of any of these groups; Or a substituent that can be converted to hydrogen in vivo;

However, R _b is a double bond is part of a valence of R _b is a bond, and the member, when R _b is added to the member, the atoms binding R _b is part of a double bond;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or any of these groups It is a substituted variant.

In some embodiments, the compound is further defined as the following Formula 17 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 17,

R _a is hydrogen, hydroxy, halo, amino, azido, mercapto or silyl; Alkyl _(C≤ 12), alkenyl _(C≤12) , alkynyl _(C≤12) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤12) , heteroaralkyl _{( C≤12)} , alkoxy _(C≤12) , alkenyloxy _(C≤12) , alkynyloxy _(C≤12) , aryloxy _(C≤12) , aralkoxy _(C≤12) , heteroaryloxy _{( C≤12)} , heteroaralkoxy _(C≤12) , acyloxy _(C≤12) , alkylamino _(C≤12) , alkoxyamino _(C≤12) , dialkylamino _(C≤12) , alkenylamino _(C≤12) , alkynylamino _(C≤12) , arylamino _(C≤12) , _{aralkylamino (C≤12)} , heteroarylamino _(C≤12) , heteroaralkylamino _(C≤12) , Amido _(C≦12) or a substituted variant of any of these groups;

R ₁ is hydrogen, cyano, hydroxy, halo or amino; Or alkyl _(C≤8), alkenyl _(C ≤8), alkynyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _(C≤8), alkylamino _(C≤8), arylamino _{(C≤8 )} , amido _(C≤8) or a substituted variant of any of these groups;

R ₂ is cyano, hydroxy, halo or amino; Or fluoroalkyl _(C≤8) , alkenyl _(C≤8) , alkynyl _(C≤8) , aryl _(C≤8) , heteroaryl _(C≤8) , acyl _(C≤8) , alkoxy _{( C≤8)} , aryloxy _(C≤8) , acyloxy _(C≤8) , alkylamino _(C≤8) , arylamino _(C≤8) , amido _(C≤8) or any of these groups It is a substituted variant.

In some embodiments, the compound is further defined as the following Formula 18 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, prodrug, or optical isomer thereof:

In Chemical Formula 18,

R _a is hydrogen, hydroxy, halo or amino; Or alkyl _(C≤6) , aryl _(C≤6) , aralkyl _(C≤6) , heteroaryl _(C≤6) , alkoxy _(C≤6) , aryloxy _(C≤6) , aralkoxy _{(C ≤6)} , alkylamino _(C≤6) , alkoxyamino _(C≤6) , alkoxyamino _(C≤6) , dialkylamino _(C≤6) , arylamino _(C≤6) , _{aralkylamino (C ≦6)} , heteroarylamino _{(C≦ 6), heteroarylamino (C≦6)} , amido _(C≦6) or a substituted variant of any of these groups.

In some aspects, the present disclosure provides Formula 19, or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof:

In Chemical Formula 19,

Y is cyano or -C(O)R _a , wherein R _a is hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; Or alkyl _(C≤12) , alkenyl _(C≤12) , alkynyl _(C≤12) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤12) , heteroaralkyl _(C≤12) , alkoxy _(C≤12) , alkenyloxy _(C≤12) , alkynyloxy _(C≤12) , aryloxy _(C≤12) , aralkoxy _(C≤12) , heteroaryloxy _(C≤12) , heteroaralkoxy _(C≤12) , acyloxy _(C≤12) , alkylamino _(C≤12) , dialkylamino _(C≤12) , alkoxyamino _(C≤12) , alkenyl amino _(C≤12), alkynyl-amino _(C≤12), arylamino _(C≤12), aralkyl amino _(C≤12), heteroaryl amino _(C≤12), heteroaralkyl amino _{(C≤12 )} , alkylsulfonylamino _(C≤12) , amido _(C≤12) , alkylthio _(C≤1) , alkenylthio _(C≤12) , alkynylthio _(C≤12) , arylthio _{(C ≤12),} are alkylthio _(C≤12), heteroarylthio _(C≤12), heteroaralkyl thio _(C≤12), acyl thio _(C≤12), alkylammonium _(C≤12), alkyl sulfonic _{Phonium (C≦12)} , alkylsilyl _(C≦12) or a substituted variant of any of these groups;

X is OR _b , NR _b R _c or SR _b , wherein R _b and R _c are each independently hydrogen; Alkyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , acyl _(C≤8) or a substituted variant of any of these groups;

However, R _b is a double bond is part of a valence of R _b is a bond, and the member, when R _b is added to the member, the atoms binding R _b is part of a double bond;

R ₁ is hydrogen, cyano, hydroxy, halo or amino; Or alkyl _(C≤8), alkenyl _(C ≤8), alkynyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _(C≤8), alkylamino _(C≤8), arylamino _{(C≤8 )} , amido _(C≤8) or a substituted variant of any of these groups.

In some aspects, the present disclosure provides Formula 20, or a salt, ester, hydrate, solvate, tautomer, or optical isomer thereof:

In Chemical Formula 20,

Y is cyano or -C(O)R _a , wherein R _a is hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; Alkyl _(C≤12) , alkenyl _(C≤12) , alkynyl _(C≤12) , aryl _(C≤12) , aralkyl _(C≤12) , heteroaryl _(C≤12) , heteroaralkyl _{( C≤12)} , alkoxy _(C≤12) , alkenyloxy _(C≤12) , alkynyloxy _(C≤12) , aryloxy _(C≤12) , aralkoxy _(C≤12) , heteroaryloxy _{( C≤12)} , heteroaralkoxy _(C≤12) , acyloxy _(C≤12) , alkylamino _(C≤12) , dialkylamino _(C≤12) , alkoxyamino _(C≤12) , alkenylamino _(C≤12) , alkynylamino _(C≤12) , arylamino _(C≤12) , _{aralkylamino (C≤12)} , heteroarylamino _(C≤12) , heteroaralkylamino _(C≤12) , alkyl-sulfonylamino _(C≤12), amido _(C≤12), alkylthio _(C≤1), an alkenyl thio _(C≤12), alkynyl thio _(C≤12), arylthio _{(C≤ 12)} , aralkylthio _(C≤12) , heteroarylthio _(C≤12) , heteroaralkylthio _(C≤12) , acylthio _(C≤12) , alkyl ammonium _(C≤12) , alkylsulfonium _(C≦12) , alkylsilyl _(C≦12) or a substituted variant of any of these groups;

X is OR _b , NR _b R _c or SR _b , wherein R _b and R _c are each independently hydrogen; Alkyl _(C≤8) , aryl _(C≤8) , aralkyl _(C≤8) , acyl _(C≤8) or a substituted variant of any of these groups;

However, R _b is a double bond is part of a valence of R _b is a bond, and the member, when R _b is added to the member, the atoms binding R _b is part of a double bond;

R ₁ is hydrogen, cyano, hydroxy, halo or amino; Or alkyl _(C≤8), alkenyl _(C ≤8), alkynyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _(C≤8), acyl _(C≤8), alkoxy _(C≤8), aryloxy _(C≤8), acyloxy _(C≤8), alkylamino _(C≤8), arylamino _{(C≤8 )} , amido _(C≤8) or a substituted variant of any of these groups,

R'is hydroxy, alkoxy _(C≤2) , substituted alkoxy _(C≤2) , aryloxy _(C≤2) , substituted aryloxy _(C≤2) , aralkoxy _(C≤2) , substituted Aralkoxy _(C≤2) , acyloxy _(C≤2) or substituted acyloxy _(C≤2) .

In a variation of each of the above embodiments containing a Z group, Z may be a single bond, O or NH. In a variation of each of the above embodiments containing the group X, X may be _{OR b.} In some variations, R _b is absent. In other variations, R _b is hydrogen. In other variations, X can be _{NR b.} In some variations, R _b can be hydroxy. In a variation of each of the above embodiments containing the Y group, Y may be cyano or -C(O)R _a . In some variations, R _a can be hydroxy. In some variations, R _a is alkoxy _(C≤6) , aryloxy _(C≤8) , aralkyloxy _(C≤8), or a substituted variant of any of these groups. In some of these variations, R _a can be alkoxy _(C2-6). In some of these variations, R _a can be alkoxy _(C1-5) or substituted alkoxy _(C1-5) . In some of these variations, R _a can be alkoxy _(C2-4) or substituted alkoxy _(C2-4) . In some of these variations, R _a can be alkoxy _(C1-4) or substituted alkoxy _(C1-4) . In some of these variations, R _a can be alkoxy _(C1-2) or substituted alkoxy _(C1-2) . For example, R _a can be methoxy. In some variations, R _a can be amino. In some byeonhyeongtae, R _a is alkyl, amino _(C1-6), alkoxyamino _(C1-6), arylamino _(C1-8), aralkyl, amino _(C1-8), dialkylamino _(C2-8), or any It may be a substituted variant of these groups of. In some of these variations, R _a can be alkylamino _(C2-6) or substituted alkylamino _(C2-6) . In some of these variations, R _a can be alkylamino _(C3-6). In some variations, R _a can be alkylamino _(C1-5) , dialkylamino _(C2-6), or a substituted variant of one of these groups. In some variations, R _a can be an alkylamino _(C2-4) , a dialkylamino _(C2-5), or a substituted variant of one of these groups. In some variations, R _a can be alkylamino _(C1-4) or substituted alkylamino _(C1-4) . In some variations, R _a can be alkylamino _(C1-3). In some of these variations, R _a can be methylamino or ethylamino. In some of these variations, R _a can be a substituted alkylamino _(C1-3) . For example, R _a can be 2,2,2-trifluoroethylamino. In some of these variations, R _a is alkyl _(C1-5) , aryl _(C≤8) , aralkyl _(C≤8) , heteroaralkyl _(C≤8) or a substituted variant of any of these groups. I can. In some of these variations, R _a can be heteroaryl _(C1-8) or substituted heteroaryl _(C1-8) . For example, R _a can be imidazolyl. In some of these variations, R _a can be -H.

In a variation of each of the above embodiments containing the _{R 1 group, R 1} may be -H, -OH or -F. For example, R ₁ can be -H. The above aspect containing the _{R 2 group} In each variant, R ₂ can be -CN. In some variations, R ₂ is substituted acyl _(C1-3) , For example, it may be -C(=O)NHS(=O) ₂ CH ₃ . In some variations, R ₂ can be a fluoroalkyl _(C≤8). For example, R ₂ may be -CF _3. In other variations, R ₂ is not fluoroalkyl _(C≤8) .

In variations of each of the above embodiments containing the _{R 3 group, R 3} may be hydrogen or acetyl. In another variation, R ₃ can be absent. In variations of each of the above embodiments containing the _{R 4 group, R 4} may be methyl or hydroxymethyl. In a variant of each of the above embodiments containing _{R 6} , R ₇ , R ₈ or R _{9 groups, R 6} , R ₇ , R ₈ or R ₉ may independently be hydrogen. In a variation of each of the above embodiments containing the _{R 10} or R _{11 group, R 10} or R ₁₁ may independently be methyl. In variations of each of the above embodiments containing the R'group, R'may be acetyloxy or hydroxy.

R _d In each variant of the above embodiment containing a group, R _d is alkyl _(C1-5) , aryl _(C≤8) , aralkyl _(C≤8) , heteroaralkyl _(C≤8) or any of these groups It may be a substituted variant. In some variations, R _d can be an alkyl _(C1-4) or a substituted variant thereof. In some variations, R _d can be alkyl _(C1-3) or a substituted variant thereof. In some variations, R _d can be an alkyl _(C1-2) or a substituted variant thereof.

Non-limiting examples of the compounds provided by the present invention include compounds according to the formulas given below, as well as pharmaceutically acceptable salts thereof. In certain embodiments, these compounds are substantially free of other optical isomers thereof.

Examples of specific compounds provided by this specification include:

(4a S ,6a R ,6b R ,8a R ,12a R ,14a R ,14b S )-methyl 11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14- Dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-icosahydropicene-4a- Carboxylate,

(4aS,6aR,6bR,8aR,12aR,14aR,14bS)-methyl11-cyano-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14,14a,14b-icosahydropicene-4a-carboxylate,

(4a S ,6a R ,6b R ,8a R ,12a R ,14a R ,14b S )-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-di Oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-icosahydropicene-4a-carboxylic acid ,

(4a R ,6a R ,6b R ,8a S ,12a S ,12b R ,14b R )-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4 ,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14b-icosahydropicene-2,8a-dicarbonitrile,

(4a S ,6a R ,6b R ,8a R ,12a R ,14a R ,14b S )-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-di Oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-icosahydropicene-4a-car Voxamide,

(4a R ,6a R ,6b R ,8a S ,12a S ,12b R ,14b R )-8a-formyl-4,4,6a,6b,11,11,14b-heptamethyl-3,13-di Oxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14b-icosahydropicene-2-carbo Nitrile,

(4a S ,6a R ,6b R ,8a R ,12a R ,14 R ,14a R ,14b S )-methyl11-cyano-14-hydroxy-2,2,6a,6b,9,9,12a -Heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-icosa Hydropicene-4a-carboxylate,

(4a S ,6a R ,6b R ,8a R ,12a R ,14a R ,14b S )-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-di Oxo-N-(2,2,2-trifluoroethyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13 ,14,14a,14b-icosahydropicene-4a-carboxamide,

(4a S ,6a R ,6b R ,8a R ,12a R ,12b R ,14 R ,14a R ,14b S )-2,2,2-trifluoroethyl 11-cyano-14-hydroxy-2 ,2,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a, 12b,13,14,14a,14b-icosahydropicene-4a-carboxylate,

(4a S ,6a R ,6b R ,8a R ,12a R ,12b R ,14a R ,14b S )-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10, 14-dioxo-N-(2,2,2-trifluoroethyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a, 12b,13,14,14a,14b-icosahydropicene-4a-carboxamide,

(4a S ,6a R ,6b R ,8a R ,12a R ,12b R ,14a R ,14b S )-N'-acetyl-11-cyano-2,2,6a,6b,9,9,12a- Heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b- Icosahydropicene-4a-carbohydrazide,

(4a S ,6a R ,6b R ,8a R ,12a R ,12b R ,14a R ,14b S )-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10, 14-dioxo-N-(2,2,2-trifluoroethyl)docosahydropicene-4a-carboxamide,

(4a R ,6a R ,6b R ,8a S ,12a S ,12b R ,14a R ,14b R )-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo- 8a-(2H-tetrazol-5-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a ,14b-icosahydropicene-2-carbonitrile,

(4a R ,6a R ,6b R ,8a S ,12a S ,12b R ,14a R ,14b R )-4,4,6a,6b,11,11,14b-heptamethyl-8a-(2-methyl- 2H-tetrazol-5-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13 ,14,14a,14b-icosahydropicene-2-carbonitrile,

(4a R ,6a R ,6b R ,8a S ,12a S ,12b R ,14a R ,14b R )-4,4,6a,6b,11,11,14b-heptamethyl-8a-(5-methyl- 1,3,4-oxadiazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12, 12a,12b,13,14,14a,14b-icosahydropicene-2-carbonitrile,

(4a R ,6a R ,6b R ,8a S ,12a S ,12b R ,14a R ,14b R )-4,4,6a,6b,11,11,14b-heptamethyl-8a-(5-methyl- 1,3,4-thiadiazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12, 12a,12b,13,14,14a,14b-icosahydropicene-2-carbonitrile,

(4a R ,6a R ,6b R ,8a S ,12a S ,12b R ,14a R ,14b R )-8a-acetyl-4,4,6a,6b,11,11,14b-heptamethyl-3,13 -Dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,14b-icosahydropicene-2 -Carbonitrile,

(4a S ,6a R ,6b R ,8a R ,12a R ,12b R ,14a R ,14b S )-benzyl 11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10 ,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-icosahydropicene -4a-carboxylate,

(4a S ,6a R ,6b R ,8a R ,12a R ,12b R ,14a R ,14b S )-11-cyano- N , N ,2,2,6a,6b,9,9,12a-nona Methyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-eco Tetrahydropicene-4a-carboxamide,

(4a S ,6a R ,6b R ,8a R ,12a R ,12b R ,14a R ,14b S )-11-cyano- N -methoxy-2,2,6a,6b,9,9,12a- Heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b- Icosahydropicene-4a-carboxamide

(4a S ,6a R ,6b R ,8a R ,12a R ,12b R ,14a R ,14b S )-methyl 11-cyano-14-(hydroxyimino)-2,2,6a,6b,9, 9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b -Icosahydropicene-4a-carboxylate,

(4a R ,6a R ,6b S ,8a S ,12a R ,15a R ,15b R )-methyl2-cyano-14-hydroxy-4,4,6a,6b,11,11,15b-heptamethyl -3-oxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,14,15,15a,15b-icosahydrodinaphtho [1,2- b :2',1'- d ]oxepin-8a-carboxylate, and

(4a R ,6a R ,6b S ,8a S ,12a R ,12b R ,15a R ,15b R )-methyl2-cyano-4,4,6a,6b,11,11,15b-heptamethyl-3 ,14-dioxo-4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,15,15a,15b-icosahydro- 3 H -dinaphtho[1,2- b :2',1'- d ]azepine-8a-carboxylate.

In some embodiments, the compounds herein exist in a pharmaceutically acceptable salt form. In other embodiments, the compounds herein are not in a pharmaceutically acceptable salt form. In some embodiments, the compounds herein exist in hydrate form. In other embodiments, the compounds herein are not in hydrate form. In some embodiments, the compounds herein exist in the form of solvates. In other embodiments, the compounds herein are not in the form of solvates.

In some embodiments, the compounds herein may be esters of the above formula. Esters can be produced, for example, from a condensation reaction between a hydroxy group of the formula and a carboxylic acid group of biotin. In other embodiments, the compounds herein are not esters.

In some embodiments, the compounds herein may exist as a mixture of stereoisomers. In other embodiments, the compounds herein exist as single stereoisomers.

In some embodiments, the compounds herein may be inhibitors of IFN-γ-induced nitrous oxide (NO) production _{, for example, in macrophages with an IC 50 value of less than 0.2 μM.}

Other general aspects of the present specification contemplate pharmaceutical compositions comprising a compound of the present specification and a pharmaceutically acceptable carrier as active ingredients. The composition may be, for example, oral, intra-fat, intra-arterial, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intracardiac, intraperitoneal, intrapleural, prostate, rectal, Intracapsular, intratracheal, intratumoral, intraumbilical, vaginal, intravenous, intravesicular, intravitreal, liposome, local, mucous membrane, oral, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, isthmus penetration, transdermal, Vaginal, creme, lipid composition, via catheter, via lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via local perfusion, direct bath treatment of target cells , Or a combination thereof. In a particular embodiment, the composition may be formulated for oral delivery. In a particular embodiment, the composition is formulated as hard or soft capsules, tablets, syrups, suspensions, wafers or elixirs. In certain embodiments, the soft capsule is a gelatin capsule. Certain compositions may include protective coatings, such as compositions formulated for oral delivery. Certain compositions further include agents that delay absorption, e.g., compositions formulated for oral delivery. Certain compositions may further include agents that enhance solubility or dispersibility, such as compositions formulated for oral administration. Certain compositions may include a compound of the present disclosure, wherein the compound is dispersed in a liposome, an oil-in-water emulsion or a water-in-oil emulsion.

Another general aspect of the present specification contemplates a method of treatment comprising administering to a subject a pharmaceutically effective compound of the present specification. The subject may be, for example, a person. These or any other methods herein may further comprise identifying a subject in need of treatment.

Other methods herein contemplate methods of treating cancer in a subject, including administering to the subject a pharmaceutically effective amount of a compound of the present disclosure. The cancer can be any form of cancer, such as carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma or seminoma. Other types of cancer include bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, colon cancer, endometrial cancer, esophageal cancer, genitourinary tract cancer, head cancer, laryngeal cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer. , Spleen cancer, small intestine cancer, colon cancer, stomach cancer or testicular cancer. In these and other methods, the subject may be a primate. In these and other methods, the subject may be a human. This or other methods may further comprise identifying the subject in need of treatment. The subject may have a family history of cancer or a patient history. In certain embodiments, the subject has cancer symptoms. The compounds of the present invention can be administered via the methods described herein, eg, topically. In certain embodiments, the compound is administered by direct intratumoral injection or by injection into the tumor vasculature. In certain embodiments, the compounds may be administered intravenously, intraarterial, intramuscularly, intraperitoneally, subcutaneously or orally.

In certain embodiments of a method of treating cancer in a subject comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, the pharmaceutically effective amount is 0.1 to 1000 mg/kg. In certain embodiments, the pharmaceutically effective amount is administered in a single dose per day. In certain embodiments, the pharmaceutically effective amount is administered in a dose of two or more times per day. The compounds can be administered, for example, by contacting tumor cells during ex vivo purging. Treatment methods may include one or more of the following: a) inducing cytotoxicity in tumor cells; b) kill tumor cells; c) induces apoptosis in tumor cells; d) induce differentiation of tumor cells; Or e) inhibits growth in tumor cells. Tumor cells can be any type of tumor cells, such as leukemia cells. Other types of cells include, for example, bladder cancer cells, breast cancer cells, lung cancer cells, colon cancer cells, prostate cancer cells, liver cancer cells, pancreatic cancer cells, gastric cancer cells, testicular cancer cells, brain cancer cells, ovarian cancer cells, lymph cancer cells, skin cancer. Cells, brain cancer cells, bone cancer cells, or soft tissue cancer cells.

Combination treatment regimens are also contemplated by this disclosure. For example, with respect to a method of treating cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, the method comprises administration of a pharmaceutically effective amount of a second drug, radiation therapy, gene therapy. And it may further include a treatment selected from the group consisting of surgery. These methods include (1) contacting the tumor cells with the compound prior to contacting the tumor cells with the second drug, (2) contacting the tumor cells with the second drug prior to contacting the tumor cells with the compound, or (3) contacting the tumor cells with the second drug. It may further comprise contacting the cell with the compound and the second drug at the same time. The second drug may, in certain embodiments, be an antibiotic, anti-inflammatory, anti-neoplastic, anti-proliferative, anti-viral, immunomodulatory or immunosuppressive agent. Second drugs are alkylating agents, androgen receptor modulators, cytoskeleton inhibitors, estrogen receptor modulators, histone-deacetylase inhibitors, HMG-CoA reductase inhibitors, prenyl-protein transferase inhibitors, retinoid receptor modulators, topoisomerase inhibitors. Or a tyrosine kinase inhibitor. In certain embodiments, the second drug is 5-azacytidine, 5-fluorouracil, 9-cis-retinic acid, actinomycin D, alitrethionine, all-trans-retinic acid, annamycin, axitinib , Belinostat, bevacizumab, bexarotene, boservinib, busulfan, capecitabine, carboplatin, carmustine, CD437, cediranib, cetuximab, chlorambucil, cisplatin, cyclophospha Mead, Cytarabine, Dacarbazine, Dasatinib, Daunorubicin, Decitabine, Docetaxel, Dolastatin-10, Doxyfluridine, Doxorubicin, Doxorubicin, Epirubicin, Erlotinib, Etoposide, Etopo Seed, gefitinib, gemcitabine, gemtuzumab, ozogamicin, hexamethylmelamine, idarubicin, ifosfamide, imatinib, irinotecan, isotretinoin, ixabepilone, lapatinib, LBH589, lomustine, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, MS-275, Neratinib, Nilotinib, Nitrosourea, Oxaliplatin, Paclitaxel, Plicamycin, Procarbazine, Semaxanib, semustine, sodium butyrate, sodium phenylacetate, streptozotocin, suberoylanilide hydroxamic acid, sunitinib, tamoxifen, teniposide, thiopheta, thioguanine, topotecan, TRAIL, trastuju Marb, tretinoin, tricholstatin A, valproic acid, valubicin, vandetanib, vinblastine, vincristine, vindesine or vinorelbine.

Also contemplated are methods of treating or preventing a disease having an inflammatory component in a subject, including administering to the subject a pharmaceutically effective amount of a compound of the present disclosure. The disease can be, for example, lupus or rheumatoid arthritis. The disease may be an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis. A disease with an inflammatory component may be a cardiovascular disease. The disease with the inflammatory component can be diabetes, for example type 1 or type 2 diabetes. The compounds herein can also be used to treat diabetes-related complications. Such complications are well known in the art, and for example, obesity, hypertension, atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, muscle necrosis, retinopathy and metabolic syndrome (syndrome Includes X). Diseases with an inflammatory component may be skin diseases, such as psoriasis, acne or atopic dermatitis. In the method of treating such skin diseases, administration of the compound of the present specification may be topical or oral, for example.

A disease with an inflammatory component may be a metabolic syndrome (syndrome X). Patients with this syndrome are characterized by having 3 or more symptoms selected from the following 5 symptom groups: (1) abnormal obesity; (2) hypertriglyceridemia; (3) low high density lipoprotein cholesterol (HDL); (4) hypertension; And (5) high fasting blood sugar, which may be a range feature of type 2 diabetes if the patient is also diabetic. Each of these symptoms is described in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670]. Patients with metabolic syndrome, whether with or without overt diabetes mellitus, are at risk of developing the macrovascular and microvascular complications listed above that cause type 2 diabetes, such as atherosclerosis and coronary heart disease. Increases.

Other general methods herein involve methods of treating or preventing cardiovascular disease in a subject, including administering to the subject a pharmaceutically effective amount of a compound of the present disclosure. The cardiovascular disease may be, for example, atherosclerosis, cardiomyopathy, congenital heart disease, congestive heart failure, myocarditis, rheumatic heart disease, valve disease, coronary artery disease, endocarditis or myocardial infarction. Combination therapy also anticipates this approach. For example, such methods may further comprise administering a pharmaceutically effective amount of a second drug. The second drug may be, for example, a cholesterol lowering drug, an antihyperlipidemic agent, a calcium channel blocker, an antihypertensive agent, or an HMG-CoA reductase inhibitor. Non-limiting examples of the second drug include amlodipine, aspirin, ezetimibe, felodipine, lactidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine or nitrendipine. Other non-limiting examples of the second drug include atenolol, bucindolol, carvedilol, clonidine, doxazoxine, indoramine, labetalol, methyldopa, metoprolol, nadolol, oxprenolol, phenoxybenzamine, pentol Lamin, pindolol, prazosin, propranolol, terazosin, timolol or tolazoline. The second drug may be, for example, a statin, such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin.

Also contemplated are methods of treating or preventing a neurodegenerative disease in a subject, including administering to the subject a pharmaceutically effective amount of a compound of the present disclosure. The neurodegenerative disease can be selected from the group consisting of, for example, Parkinson's disease, Alzheimer's disease, multiple sclerosis (MS), Huntington's disease and amyotrophic lateral sclerosis. In a particular embodiment, the neurodegenerative disease is Alzheimer's disease. In a particular embodiment, the neurodegenerative disease is MS, eg, primary progressive, relapsed-remission secondary progressive or progressive recurrent MS. The subject can be, for example, a primate. The subject can be a person.

In a particular embodiment of a method of treating or preventing a neurodegenerative disease in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, the treatment inhibits demyelination of neurons in the brain or spinal cord of the subject. In certain embodiments, treatment inhibits spiritual demyelination. In certain embodiments, the treatment inhibits the crossing of neuronal axons in the brain or spinal cord of the subject. In certain embodiments, the treatment inhibits the crossing of the neurite in the brain or spinal cord of the subject. In certain embodiments, the treatment inhibits neuronal apoptosis in the brain or spinal cord of the subject. In certain embodiments, the treatment stimulates remyelination of neuronal axons in the brain or spinal cord of the subject. In certain embodiments, treatment restores impaired function after MS attack. In certain embodiments, treatment prevents new MS attacks. In certain embodiments, treatment prevents a disorder resulting from an MS attack.

One general aspect of the present specification envisions a method of treating or preventing a disorder characterized by overexpression of the iNOS gene in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

Another general aspect of the present specification contemplates a method of inhibiting IFN-γ-induced nitric oxide production in a subject's cells, including administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

Another general method of the invention envisions a method of treating or preventing a disorder characterized by overexpression of the COX-2 gene in a subject, including administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

A method of treating kidney disease (RKD) in a patient, comprising administering to a subject a pharmaceutically effective amount of a compound of the present disclosure is also contemplated (see US Patent Application No. 12/352,473, incorporated herein by reference in its entirety. ]. RKD can be produced, for example, from toxic damage. Toxic damage can result from, for example, imaging agents or drugs. The drug can be, for example, a chemotherapeutic agent. RKD can result from ischemia/reperfusion injury in certain embodiments. In certain embodiments, RKD results from diabetes or hypertension. RKD can be produced from autoimmune diseases. RKD can be further defined as chronic RKD, or acute RKD.

In certain methods of treating kidney/kidney disease (RKD) in a subject, including administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, the subject has received or is receiving dialysis. In certain embodiments, the subject has received or is a candidate for a kidney transplant. Subject may be a primate. Primates can be humans. In this or other methods, the subject may be, for example, a cow, horse, dog, cat, pig, mouse, rat or guinea pig.

Methods of improving glomerular filtration rate or creatinine clearance in a subject, including administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, are also contemplated by the present disclosure.

In some embodiments, the present invention provides compounds useful for preventing and/or treating diseases or disorders in which the pathology is associated with oxidative stress, inflammation and/or dysregulation of the inflammatory signaling pathway. In some variations, the disease or disorder may be characterized by overexpression of inducible nitric oxide synthase (iNOS) and/or inducible cyclooxygenase (COX-2) in the infected tissue. In some variations, the disease or disorder can be characterized by overproduction of reactive oxygen species (ROS) or reactive nitrogen species (RNS), such as superoxide, hydrogen peroxide, nitric oxide, or peroxynitrite in the infected tissue. . In some variations, the disease or disorder is characterized by overproduction of inflammatory cytokines or other inflammation related proteins such as TNFα, IL-6, IL-1, IL-8, ICAM-1, VCAM-1 and VEGF. . Such diseases or disorders, in some embodiments, include undesired proliferation of certain cells, fibrosis associated with organ failure, or excessive scarring, as in the case of cancer (e.g., solid tumors, leukemia, myeloma, lymphoma and other cancers). do. Non-limiting examples of diseases or disorders include lupus, rheumatoid arthritis, juvenile onset diabetes, multiple sclerosis, psoriasis, and Crohn's disease. Further non-limiting examples include cardiovascular diseases such as atherosclerosis, heart failure, myocardial infarction, acute coronary syndrome, restenosis following vascular surgery, hypertension and vasculitis; Neurodegenerative or neuromuscular diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS and muscular dystrophy; Neurological disorders such as epilepsy and dystonia; Neuropsychiatric conditions such as major depression, bipolar disorder, post-traumatic stress disorder, schizophrenia, anorexia, ADHD and autism spectrum disorders; Retinal diseases such as vision loss, diabetic retinopathy, glaucoma and retinitis; Chronic and acute pain syndromes including inflammatory and neuropathic pain; Hearing loss and tinnitus; Diabetes, and diabetic complications including metabolic syndrome, diabetic nephropathy, diabetic neuropathy, diabetic ulcer; Respiratory diseases such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and cystic fibrosis; Inflammatory bowel disease; Osteoporosis, osteoarthritis, and other degenerative conditions of bone and cartilage; Acute or chronic organ failure including renal failure, liver failure (including cirrhosis and hepatitis) and pancreatitis; Ischemia-reperfusion injury associated with thrombotic or hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, myocardial infarction, shock or trauma; Organ or tissue transplant complications including acute or chronic graft failure or rejection and graft-to-host disease; Skin diseases including atopic dermatitis and acne; Sepsis and septic shock; Excessive inflammation associated with infection, including respiratory inflammation associated with inflenza and upper respiratory infection; Mucositis associated with cancer treatment, including radiation therapy or chemotherapy; And severe burns.

의 화합물을 표적 화합물을 형성하기 위한 세트의 조건하에서 산화제와 반응시킴을 포함하는, 화학식

의 표적 화합물(여기서, R_a는 알콕시_(C1-4)이다)의 제조방법을 포함할 수 있다.Methods of synthesizing the compounds herein are also contemplated. In a particular embodiment, the method comprises the formula

A formula comprising reacting a compound of with an oxidizing agent under a set of conditions to form a target compound.

It may include a method for preparing _a target compound of (wherein R a is alkoxy _(C1-4)).

Kits, e.g., comprising a compound of the present specification, and one or more forms of information selected from the group consisting of describing the disease state to which the compound is administered, storage information of the compound, administration information, and instructions on how to administer the compound. Kits containing instructions are also contemplated by this specification. Kits may contain a compound of the present disclosure in multiple dosage forms.

Other objects, features, and advantages of the present specification will become apparent from the following detailed description. However, the detailed description and specific examples describe specific aspects of the present invention, but are presented by way of example only, and various changes and modifications within the spirit and scope of the present invention are apparent to those skilled in the art from these detailed descriptions. Because it gets worse. Note that simply because a particular compound belongs to one particular general formula, it does not imply that it cannot also belong to another general formula.

The following figures form a part of this specification and are included to further demonstrate certain aspects of the specification. The invention may be better understood by reference to one of these drawings in conjunction with the detailed description of certain aspects presented herein.
1-8 and 32-34: Inhibition of NO production. RAW264.7 macrophages were pretreated with DMSO or drug at various concentrations (nM) for 2 hours and then treated with 20 ng/ml IFNγ for 24 hours. The NO concentration in the medium was measured using the Griess reagent system, and the cell viability was measured using the WST-1 reagent.
Figure 9: Inhibition of COX-2 induction. RAW264.7 cells were pretreated with the indicated compounds for 2 hours and then stimulated with 10 ng/ml IFNγ for an additional 24 hours. COX-2 protein levels were analyzed by immunoblotting assay. Actin was used as a load control. Room temperature A 402 and room temperature A 404 refer to comparative compounds 402 and 404 (see Example 1).
10-12: Inhibition of IL-6 induced STAT3 phosphorylation. HeLa cells were treated with the indicated compounds and concentrations for 6 hours and then stimulated with 20 ng/ml of IL-6 for 15 minutes. Phosphorylated STAT3 and total STAT3 levels were analyzed by immunoblotting assay. Compounds 402-52 and 402-53 are comparative compounds (see Example 1).
Figure 13: Inhibition of IL-6 induced STAT3 phosphorylation . HeLa cells were treated with DMSO or indicated compound at 2 μM for 6 hours and then stimulated with 20 ng/ml IL-6 for 15 minutes. Phosphorylated STAT3 and total STAT3 levels were analyzed by immunoblotting assay. Compounds 402-54, 402-55 and 402-56 are comparative compounds (see Example 1).
Figure 14: Inhibition of TNFα-induced IkBα degeneration. HeLa cells were treated with the indicated compounds and concentrations for 6 hours and then stimulated with 20 ng/ml TNFα for 15 minutes. Lysates were analyzed with antibodies against IkBα and actin.
15 and 16: Inhibition of NFkB activation. HeLa cells were cell-infected with pNF-kB-Luc (inducible) and pRL-TK (structural) reporter plasmids. After 24 hours, the cells were pretreated with the indicated compound for 2 hours. DMSO served as a vehicle control. After pretreatment, cells were stimulated with 20 ng/ml TNFα for 3 hours. Reporter activity was measured by the DualGlo luciferase reporter assay, and pNF-kB luciferase activity was normalized to pRL-TK luciferase activity. The superimposed induction of mean luciferase activity for unstimulated (-TNFα) samples is shown. Error bars represent SD of the mean of 6 samples.
Degree 17 to 20: Induction of HO-1. MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. HO-1 mRNA levels were quantified using qPCR and normalized to DMSO-treated samples running concurrently. The value is the average of the double wells.
Figure 21: HO-1, TrxR1 and γ-GCS. MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. HO-1, thioredoxin reductase-1 (TrxR1), and γ-glutamylcysteine synthase (γ-GCS) mRNA levels were quantified using qPCR and normalized to concurrently running DMSO-treated samples. . The value is the average of the double wells.
Degree 22: Induction of ITrxR1. MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. Thioredoxin reductase-1 (TrxR1) mRNA levels were quantified using qPCR and normalized to DMSO-treated samples running concurrently. The value is the average of the double wells. Compounds 401, 402-19 and 402-53 are comparative compounds (see Example 1). Compared to the results in Figure 25, it is demonstrated that high concentrations of compounds 402-02 and 404-02 are required to access the effects presented with unsaturated counterparts 402 and 404.
Figure 23: Induction of γ-GCS. MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. γ-glutamylcysteine synthase (γ-GCS) mRNA levels were quantified using qPCR and normalized to DMSO-treated samples running concurrently. The value is the average of the double wells. Compared to the results in Figure 26, it is demonstrated that high concentrations of compounds 402-02 and 404-02 are required to access the effects presented with unsaturated counterparts 402 and 404.
Figure 24: Induction of ferritin heavy chain. MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. Ferritin heavy chain mRNA levels were quantified using qPCR and normalized to DMSO-treated samples running concurrently. The value is the average of the double wells. Compared to the results in Figure 27, it is demonstrated that high concentrations of compounds 402-02 and 404-02 are required to access the effects presented with unsaturated counterparts 402 and 404.
Degree 25: Induction of TrxR1. MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. Thioredoxin reductase-1 (TrxR1) mRNA levels were quantified using qPCR and normalized to DMSO-treated samples running concurrently. The value is the average of the double wells. Compared to the results in Figure 22, it is demonstrated that high concentrations of compounds 402-02 and 404-02 are needed to access the effects presented with unsaturated counterparts 402 and 404.
Figure 26: Induction of γ-GCS. MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. γ-glutamylcysteine synthase (γ-GCS) mRNA levels were quantified using qPCR and normalized to DMSO-treated samples running concurrently. The value is the average of the double wells. Compared to the results in Figure 23, it is demonstrated that high concentrations of compounds 402-02 and 404-02 are required to access the effects presented with unsaturated counterparts 402 and 404.
Figure 27: Induction of ferritin heavy chain . MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. Ferritin heavy chain mRNA levels were quantified using qPCR and normalized to DMSO-treated samples running concurrently. The value is the average of the double wells. Compared to the results in Figure 24, it is demonstrated that high concentrations of compounds 402-02 and 404-02 are required to access the effects presented with unsaturated counterparts 402 and 404.
Figure 28: CDDO-TFEA (TP-500) is detected at a higher level than CDDO-EA (TP-319) in mouse brain. CD-1 mice were fed 200 or 400 mg/kg diet of TP-319 or TP-500 for 3.5 days, and TP levels in the brains of mice were analyzed by LC/MS. The structures of TP-319 and TP-500 are presented below.
Figures 29A and B-Weight change data of a face-to-face toxin test study of Compound 401 (Figure 29A) versus 401-02 (Figure 29B). The compound was evaluated for toxicity in mice in a 14-day study. Each compound was formulated in sesame oil and administered daily at 10, 50, 100 or 250 mg/kg (n = 4 per group) by oral feeding.
Figures 30A and B-Weight change data of a face-to-face toxin test study of Compound 402 (Figure 30A) versus 402-02 (Figure 30B). The compound was evaluated for toxicity in mice in a 14-day study. Each compound was formulated in sesame oil and administered daily at 10, 50, 100 or 250 mg/kg (n = 4 per group) by oral feeding.
Figures 31A and B-Weight change data of a face-to-face toxin test study of Compound 404 (Figure 31A) versus 404-02 (Figure 31B). The compound was evaluated for toxicity in mice in a 14-day study. Each compound was formulated in sesame oil and administered daily at 10, 50, 100 or 250 mg/kg (n = 4 per group) by oral feeding.

For example, novel compounds having antioxidant and anti-inflammatory properties, methods for their preparation, and methods of use thereof, including treatment and/or prevention of diseases, are described herein.

I. Definition

"Hydrogen" as used herein means -H; "Hydroxy" means -OH; "Oxo" means =O; "Halo" independently means -F, -Cl, -Br or -I; "Amino" means -NH ₂ (a group containing the term amino, eg see below for the definition of alkylamino); "Hydroxyamino" means -NHOH; "Nitro" means - NO ₂ ; Imino means =NH (a group containing the term imino, eg see below for the definition of alkylamino); "Cyano" means -CN; "Azido" means -N ₃ ; "Mercapto" means -SH; "Thio" means =S; "Sulfonamido" means -NHS(O) _2- (a group containing the term sulfonamido, for example, see below for the definition of alkylsulfonamido); "Sulfonyl" means -S(O) _2- (a group containing the term sulfonyl, eg, see below for the definition of alkylsulfonyl); "Silyl" means -SiH ₃ (the group(s) containing the term silyl, eg, see below for the definition of alkylsilyl).

For the following groups, the subscript of the following inset further defines the group as follows: "(Cn)" defines the exact number of carbon atoms (n) in the group. "(C≤n)" defines the maximum number of carbons (n) that can be present in a group, with one or more, but possibly a small, minimum number of carbons for the desired group. For example, in the group "alkenyl _(C≤8) ", the minimum number of carbons is understood to be 2. For example, "alkoxy _(C≤10) " is an alkoxy group having 1 to 10 carbon atoms (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or any derivable herein Range (eg, 3 to 10 carbon atoms). (Cn-n') defines both the minimum (n) and maximum (n') carbon number in the group. Similarly, “alkyl _(C2-10) ” refers to 2 to 10 carbon atoms (eg 2, 3, 4, 5, 6, 7, 8, 9 or 10, or any range derivable herein (eg 3 to 10 carbon atoms)).

The term "alkyl" when used without the modifier "substituted" is attached to a saturated carbon atom, straight or branched chain, cyclo, cyclic or bicyclic structure as the point of attachment, and does not have a carbon-carbon double or triple bond , Refers to a non-aromatic monovalent group having no atoms other than carbon and hydrogen. Group -CH ₃ (Me), -CH ₂ CH ₃ (Et), -CH ₂ CH ₂ CH ₃ ( n -Pr), -CH(CH ₃ ) ₂ ( iso -Pr), -CH(CH ₂ ) ₂ (Cyclopropyl), -CH ₂ CH ₂ CH ₂ CH ₃ ( n -Bu), -CH(CH ₃ )CH ₂ CH ₃ (secondary-butyl), -CH ₂ CH(CH ₃ ) ₂ (iso-butyl ), -C(CH ₃ ) ₃ (tert-butyl), -CH ₂ C(CH ₃ ) ₃ ( neo -pentyl), cyclobutyl, cyclopentyl, cyclohexyl and cyclohexylmethyl are non-limiting examples of alkyl groups. Yes. The term "substituted alkyl" has a saturated carbon atom, straight or branched chain, cyclo, cyclic or bicyclic structure as the point of attachment, has no carbon-carbon double or triple bonds, N, O, F, Cl, It means a non-aromatic monovalent group having one or more atoms independently selected from the group consisting of Br, I, Si, P and S. The following groups are non-limiting examples of substituted alkyl groups: -CH ₂ OH, -CH ₂ Cl, -CH ₂ Br, -CH ₂ SH, -CF ₃ , -CH ₂ CN, -CH ₂ C(O) H, -CH ₂ C(O)OH, -CH ₂ C(O)OCH ₃ , -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHCH ₃ , -CH ₂ C(O)CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CF ₃ , -CH ₂ OC(O)CH ₃ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ OH, -CH ₂ CF ₃ , -CH ₂ CH ₂ OC(O)CH ₃ , -CH ₂ CH ₂ NHCO ₂ C(CH ₃ ) ₃ and -CH ₂ Si(CH ₃ ) ₃ .

가 알칸디일 그룹의 비제한적인 예이다. 용어 "치환된 알칸디일"은 비방향족 1가 그룹을 의미하고, 여기서 알칸디일 그룹은 2개의 σ-결합, 부착점(들)으로서의 하나 또는 두 개의 포화된 탄소원자(들), 직쇄 또는 측쇄, 사이클로, 사이클릭 또는 비사이클릭 구조를 갖고, 탄소-탄소 이중 또는 삼중 결합을 갖지 않고, N, O, F, Cl, Br, I, Si, P 및 S로 이루어진 그룹으로부터 독립적으로 선택된 하나 이상의 원자를 갖는다. 다음 그룹이 치환된 알칸디일 그룹의 비제한적인 예이다: -CH(F)-, -CF₂-, -CH(Cl)-, -CH(OH)-, -CH(OCH₃)- 및 -CH₂CH(Cl)-.When used without the modifier “substituted”, the term “alkanediyl” refers to a non-aromatic divalent group, wherein an alkanediyl group is two σ-bonds, one or two saturated It has a carbon atom(s), straight chain or branched chain, cyclo, cyclic or acyclic structure, has no carbon-carbon double or triple bonds, and has no atoms other than carbon and hydrogen. Group -CH ₂ -(methylene), -CH ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -and

Is a non-limiting example of an alkandiyl group. The term “substituted alkanediyl” refers to a non-aromatic monovalent group, wherein the alkanediyl group is two σ-bonds, one or two saturated carbon atom(s) as point(s) of attachment, straight chain or One that has a side chain, cyclo, cyclic or acyclic structure, does not have a carbon-carbon double or triple bond, and is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P and S Has more than one atom. The following groups are non-limiting examples of substituted alkanediyl groups: -CH(F)-, -CF ₂ -, -CH(Cl)-, -CH(OH)-, -CH(OCH ₃ )- and -CH ₂ CH(Cl)-.

When used without the modifier "substituted", the term "alkenyl" has a non-aromatic carbon atom, straight or branched chain, cyclo, cyclic or acyclic structure, one or more non-aromatic carbon-carbon double bonds as the point of attachment, It means a monovalent group that does not have a carbon-carbon triple bond and does not have atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: -CH=CH ₂ (vinyl), -CH=CHCH ₃ , -CH=CHCH ₂ CH ₃ , -CH ₂ CH=CH ₂ (allyl), -CH ₂ CH=CHCH ₃ and -CH=CHC ₆ H ₅ . "Substituted alkenyl" has a non-aromatic carbon atom as a point of attachment, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, a straight or branched chain, cyclo, cyclic or acyclic structure, and It means a monovalent group having one or more atoms independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P and S. The groups -CH=CHF, -CH=CHCl and -CH=CHBr are non-limiting examples of substituted alkenyl groups.

는 알켄디일 그룹의 비제한적인 예이다. 용어 "치환된 알켄디일"은 비방향족 2가 그룹을 의미하고, 여기서 알켄디일 그룹은 2개의 σ-결합, 부착점으로서의 2개의 탄소원자, 직쇄 또는 측쇄, 사이클로, 사이클릭 또는 비사이클릭 구조, 하나 이상의 비방향족 탄소-탄소 이중 결합을 갖고, 탄소-탄소 삼중 결합을 갖지 않고, N, O, F, Cl, Br, I, Si, P 및 S로 이루어진 그룹으로부터 독립적으로 선택된 하나 이상의 원자를 갖다. 다음 그룹은 치환된 알케디일 그룹의 비제한적인 예이다: -CF=CH-, -C(OH)=CH- 및 -CH₂CH=C(Cl)-.The term "alkendiyl" when used without the modifier "substituted" refers to a non-aromatic divalent group, wherein the alkendiyl group is two σ-bonds, two carbon atoms as points of attachment, straight or branched chain, cyclo , Cyclic or acyclic structure, at least one non-aromatic carbon-carbon double bond is attached, it does not have a carbon-carbon triple bond, and atoms other than carbon and hydrogen are not attached. Group -CH=CH-, -CH=C(CH ₃ )CH ₂ -, -CH=CHCH ₂ -and

Is a non-limiting example of an alkendiyl group. The term "substituted alkendiyl" refers to a non-aromatic divalent group, wherein the alkendiyl group is two σ-bonds, two carbon atoms as points of attachment, straight or branched chain, cyclo, cyclic or acyclic Structure, one or more atoms independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P and S, having one or more non-aromatic carbon-carbon double bonds, no carbon-carbon triple bonds Bring The following groups are non-limiting examples of substituted alkediyl groups: -CF=CH-, -C(OH)=CH- and -CH ₂ CH=C(Cl)-.

The term "alkynyl" when used without the modifier "substituted" refers to a non-aromatic carbon atom as a point of attachment, straight or branched chain, cyclo, cyclic or acyclic structure, one or more carbon-carbon triple bonds attached, carbon and An atom other than hydrogen means a monovalent group to which no attachment is made. The groups -C≡CH, -C≡CCH ₃ , -C≡CC ₆ H ₅ and -CH ₂ C≡CCH ₃ are non-limiting examples of alkynyl groups. The term “substituted alkynyl” refers to a non-aromatic carbon atom as a point of attachment and one or more carbon-carbon triple bonds, straight or branched chain, cyclo, cyclic or bicyclic structures and N, O, F, Cl, Br, I, It is a monovalent group to which one or more atoms independently selected from the group consisting of Si, P and S are attached. The group -C≡CSi(CH ₃ ) ₃ is a non-limiting example of a substituted alkynyl group.

When used without the modifier "substituted", the term "alkyndiyl" refers to a non-aromatic divalent group, wherein the alkyndiyl group is two σ-bonds, two carbon atoms as points of attachment, straight or branched chain, cyclo, Cyclic or acyclic structure, at least one carbon-carbon triple bond is attached, and no atoms other than carbon and hydrogen are attached. Group -C≡C-, -C≡CCH _2- And -C≡CCH(CH ₃ )- is a non-limiting example of an alkyndiyl group. The term “substituted alkyndiyl” refers to a non-aromatic divalent group, wherein the alkyndiyl group is two σ-bonds, two carbon atoms as points of attachment, straight or branched chain, cyclo, cyclic or acyclic structure, At least one carbon-carbon triple bond and at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P and S are attached. The groups -C≡CCFH- and -C≡CHCH(Cl)- are non-limiting examples of substituted alkyndiyl groups.

When used without the modifier “substituted”, the term “aryl” refers to a monovalent group having an aromatic carbon atom as the point of attachment, and the carbon atom forms part of a 6-membered aromatic ring structure in which all ring atoms are carbon, and monovalent Groups are not composed of atoms other than carbon and hydrogen. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C ₆ H ₄ CH ₂ CH ₃ (ethylphenyl), -C ₆ H ₄ CH ₂ CH ₂ CH ₃ (propylphenyl), -C ₆ H ₄ CH(CH ₃ ) ₂ , -C ₆ H ₄ CH(CH ₂ ) ₂ , -C ₆ H ₃ (CH ₃ )CH ₂ CH ₃ (methylethylphenyl), -C ₆ H ₄ CH= CH ₂ (vinylphenyl), -C ₆ H ₄ CH=CHCH ₃ , -C ₆ H ₄ C≡CH, -C ₆ H ₄ C≡CCH ₃ , naphthyl, and monovalent groups derived from biphenyl do. The term "substituted aryl" refers to a monovalent group having an aromatic carbon atom as a point of attachment, the carbon atom forms part of a six-membered aromatic ring structure in which all ring atoms are carbon, and the monovalent group is further N, O , F, Cl, Br, I, Si, P and S. Non-limiting examples of substituted aryl groups include the following _{groups: -C 6 H 4 F, -C} 6 H 4 Cl, -C 6 H 4 Br, -C 6 H 4 I, - C 6 H 4 OH , -C ₆ H ₄ OCH ₃ , -C ₆ H ₄ OCH ₂ CH ₃ , -C ₆ H ₄ OC(O)CH ₃ , -C ₆ H ₄ NH ₂ , -C ₆ H ₄ NHCH ₃ , -C _{6 H 4 N (CH 3) 2} , -C 6 H 4 CH 2 OH, - C 6 H 4 CH 2 OC (O) CH 3, -C 6 H 4 CH 2 NH 2, -C 6 H 4 CF 3, -C ₆ H ₄ CN, -C ₆ H ₄ CHO, -C ₆ H ₄ CHO, -C ₆ H ₄ C(O)CH ₃ , -C ₆ H ₄ C(O)C ₆ H ₅ , -C ₆ H ₄ CO ₂ H, -C ₆ H ₄ CO ₂ CH ₃ , -C ₆ H ₄ CONH ₂ , -C ₆ H ₄ CONHCH ₃ and -C ₆ H ₄ CON(CH ₃ ) ₂ .

When used without the modifier "substituted", the term "areendiyl" refers to a divalent group, where the arendiyl group has two σ-bonds, two carbon atoms as attachment points are attached, and the aforementioned carbon atoms have all ring atoms Forms part of one or more six membered aromatic ring structure(s) that are carbon, and the monovalent group is not composed of atoms other than carbon and hydrogen. Non-limiting examples of Arendyl group include:

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The term "substituted arendiyl" refers to a divalent group, wherein the arendiyl group has two σ-bonds, two aromatic carbon atoms as attachment points are attached, and the above-described carbon atoms are at least one 6-membered ring whose ring atoms are all carbons. Forms part of the aromatic ring structure(s), and the divalent group further has one or more atoms independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P and S .

When used without the modifier "substituted", the term "aralkyl" refers to a monovalent group-alkanediyl-aryl in which the terms alkanediyl and aryl are used in a manner consistent with the definitions provided above, respectively. Non-limiting examples of aralkyl include phenylmethyl (benzyl, Bn), 1-phenyl-ethyl, 2-phenyl-ethyl, indenyl and 2,3-dihydro-indenyl, provided that indenyl and 2, 3-dihydro-indenyl is a simple example of aralkyl, as long as the point of attachment in each case is one of the saturated carbon atoms. When the term “aralkyl” is used with a “substituted” modifier, one or both of alkanediyl and aryl are substituted. Non-limiting examples of substituted aralkyl include (3-chlorophenyl)-methyl, 2-oxo-2-phenyl-ethyl (phenylcarbonylmethyl), 2-chloro-2-phenyl-ethyl, carbon with saturated attachment points. One of the atoms is chromanyl, and the attachment point is one of saturated carbon atoms, tetrahydroquinolinyl.

When used without the modifier "substituted", the term "heteroaryl" refers to a monovalent group having an aromatic carbon atom or a nitrogen atom as a point of attachment, and the above-described carbon atom or nitrogen atom is one or more of the ring atoms is nitrogen, oxygen Or it forms part of an aromatic ring which is sulfur, and the monovalent group is not composed of elements other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. Non-limiting examples of aryl groups include acridinyl, furanyl, imidazoimidazolyl, imidazopyrazolyl, imidazopyridinyl, imidazopyrimidinyl, indolyl, indazolinyl, methylpyridyl, oxa Zolyl, phenylimidazolyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, tetrahydroquinolinyl, thienyl, triazinyl, pyrrolopyridinyl, pyrrolopyr Midinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrroloimidazolyl, chromethyl (where the point of attachment is one of the aromatic atoms) and chromanyl (the point of attachment is one of the aromatic atoms). The term "substituted heteroaryl" refers to a monovalent group having an aromatic carbon atom or a nitrogen atom as the point of attachment, and the carbon atom or nitrogen atom refers to a part of an aromatic ring structure in which at least one of the ring atoms is nitrogen, oxygen, or sulfur. And the monovalent group further has one or more atoms independently from the group consisting of non-aromatic nitrogen, non-aromatic oxygen, non-aromatic sulfur, F, Cl, Br, I, Si and P.

When used without the modifier of "substituted", the term "heteroarenediyl" refers to a divalent group, wherein the heteroarenediyl group is attached to two σ-bonds, an aromatic carbon atom or a nitrogen atom as the point of attachment, wherein The carbon atoms form part of one or more six-membered aromatic ring structure(s) in which the ring atoms are all carbon, and the monovalent group is not composed of elements other than carbon and hydrogen. Non-limiting examples of heteroarenediyl groups include:

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The term "substituted heteroarenediyl" refers to a divalent group, wherein the heteroarenediyl group is two σ bonds, two aromatic carbon atoms as attachment points are attached, and the above-described carbon atoms are at least one 6, wherein the ring atoms are all carbons. Forming part of the original aromatic ring structure(s), the divalent group further has one or more atoms independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P and S.

When used without the modifier "substituted", the term "heteroaralkyl" means a monovalent group -alkanediyl-heteroaryl, wherein the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. do. Non-limiting examples of aralkyl are pyridylmethyl and thienylmethyl. When the term “heteroaralkyl” is used without a “substituted” modifier, one or both of alkanediyl and heteroaryl are substituted.

When used without the modifier "substituted", the term "acyl" has a carbon atom of a carbonyl group as the point of attachment, further has a straight or branched chain, cyclo, cyclic or bicyclic structure, and an oxygen atom of the carbonyl group In addition, it refers to a monovalent group that does not have additional atoms other than carbon or hydrogen. Group -CHO, -C(O)CH ₃ (acetyl, Ac), -C(O)CH ₂ CH ₃ , -C(O)CH ₂ CH ₂ CH ₃ , -C(O)CH(CH ₃ ) ₂ , -C(O)CH(CH ₂ ) ₂ , -C(O)C ₆ H ₅ , -C(O)C ₆ H ₄ CH ₃ , -C(O)C ₆ H ₄ CH ₂ CH ₃ ,- COC ₆ H ₃ (CH ₃ ) ₂ and -C(O)CH ₂ C ₆ H ₅ are non-limiting examples of acyl groups. Thus, the term “acyl” includes, but is not limited to, groups sometimes referred to as “alkyl carbonyl” and “aryl carbonyl” groups. The term "substituted acyl" has a carbon atom of the carbonyl group as the point of attachment, further has a straight or branched chain, cyclo, cyclic or bicyclic structure, and in addition to the oxygen atom of the carbonyl group, N, O, F, It means a monovalent group further having at least one atom independently selected from the group consisting of Cl, Br, I, Si, P and S. The group _{-C (O) CH 2 CF 3} , -CO 2 H ( carboxyl), -CO ₂ CH ₃ (methyl _{carboxylate), -CO 2 CH 2 CH 3} , - CO 2 CH 2 CH 2 CH 3, -CO 2 C ₆ H ₅ , -CO ₂ CH(CH ₃ ) ₂ , -CO ₂ CH(CH ₂ ) ₂ , -C(O)NH ₂ (carbamoyl), -C(O)NHCH ₃ , -C(O) NHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CONHCH(CH ₂ ) ₂ , -CON(CH ₃ ) ₂ , -CONHCH ₂ CF ₃ , -CO-pyridyl, -CO-imidazolyl and -C (O)N ₃ is a non-limiting example of a substituted acyl group. The term “substituted acyl” includes, but is not limited to, “heteroaryl carbonyl” groups.

When used without the modifier "substituted", the term "alkylidene" means a divalent group =CRR', wherein the alkylidene group is attached to one σ-bond and one π-bond, wherein R and R 'Is independently hydrogen or alkyl, or R and R'together represent alkanediyl. Non-limiting examples of alkylidene groups include =CH ₂ , =CH(CH ₂ CH ₃ ) and =C(CH ₃ ) ₂ . The term "substituted alkylidene" means a group =CRR', wherein the alkylidene group is attached to one σ-bond and one π-bond, wherein R and R'are independently hydrogen, alkyl or substituted Alkyl, or R and R'together represent substituted alkanediyl, provided that one of R and R'is substituted alkyl, or R and R'together represent substituted alkanediyl.

When used without the modifier "substituted", the term "alkoxy" refers to the group -OR, where R is alkyl as defined above. Non-limiting examples of alkoxy groups include -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OCH(CH ₂ ) ₂ , -O-cyclopentyl and O- Includes cyclohexyl. The term “substituted alkoxy” refers to the group -OR, where R is a substituted alkyl as defined above. For example, -OCH ₂ CF ₃ is a substituted alkoxy group.

Similarly, when used without the modifier "substituted", the terms "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", "heteroaralkoxy" and "acyl Oxy" means a group defined as -OR, wherein R is each alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl as defined above, the terms alkenyloxy, alkynyl When oxy, aryloxy, aralkyloxy and acyloxy are modified to "substituted", this means the group -OR, where R is each substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, hetero Aralkyl and acyl.

When used without the modifier "substituted", the term "alkylamino" refers to the group -NHR, where R is alkyl as defined above. Non-limiting examples of alkylamino groups are -NHCH ₃ , -NHCH ₂ CH ₃ , -NHCH ₂ CH ₂ CH ₃ , -NHCH(CH ₃ ) ₂ , -NHCH(CH ₂ ) ₂ , -NHCH ₂ CH ₂ CH ₂ CH ₃ , -NHCH(CH ₃ )CH ₂ CH ₃ , -NHCH ₂ CH(CH ₃ ) ₂ , -NHC(CH ₃ ) ₃ , -NH-cyclopentyl and -NH-cyclohexyl. The term "substituted alkylamino" refers to the group -NHR, where R is substituted alkyl as defined above. For example, -NHCH ₂ CF ₃ is a substituted alkylamino group.

When used without the modifier "substituted", the term "dialkylamino" refers to the group -NRR', wherein R and R'can be the same or different alkyl groups, or R and R'together are two or more nitrogen Represents an alkanediyl having two or more saturated carbon atoms attached to an atom. Non-limiting examples of the dialkylamino group is _{-NHC (CH 3) 3, -N} (CH 3) CH 2 CH 3, -N (CH 2 CH 3) 2, - N - pyrrolidinyl and N - piperidino Includes Neil. The term "substituted dialkylamino" refers to the group -NRR', wherein R and R'can be the same or different substituted alkyl groups, one of R or R'is alkyl and the other is substituted alkyl or , R and R'together may represent a substituted alkanediyl having two or more saturated carbon atoms, wherein two or more are attached to a nitrogen atom.

When used without the "substituted" modifier, the terms "alkoxyamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heteroaralkylamino""And"alkylsulfonylamino" means a group defined as -NHR, wherein R is each alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and alkyl, respectively as defined above. It is sulfonyl. A non-limiting example of an arylamino group is -NHC ₆ H ₅ . When the terms alkoxyamino, alkenylamino, alkynylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino and alkylsulfonylamino are modified to "substituted", this means the group -NHR, Wherein R is each substituted alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and alkylsulfonyl.

When used without the modifier "substituted", the term "amido" (acylamino) means the group -NHR, where R is an acyl as defined above. A non-limiting example of an acylamino group is -NHC(O)CH ₃ . When the term amido is used with a "substituted" modifier, it means a group defined as -NHR, where R is a substituted acyl as defined above. The groups -NHC(O)OCH ₃ and -NHC(O)NHCH ₃ are non-limiting examples of substituted amido groups.

When used without the modifier "substituted", the term "alkylimino" means a group =NR, wherein the alkylamido group is attached to one σ-bond and one π-bond, where R is defined above Is an alkyl as defined. Non-limiting examples of alkylimino groups include =NCH ₃ , =NCH ₂ CH ₃ and =N-cyclohexyl. The term "substituted alkylimino" means a group =NR, wherein the alkylimino group is attached to one σ-bond and one π-bond, wherein R is a substituted alkyl as defined above. For example, =NCH ₂ CF ₃ is a substituted alkylimino group.

Similarly, when used without the modifier "substituted", the terms "alkenylimino", "alkynylimino", "arylimino", "aralkylimino", "heteroarylimino", "hetero. Aralkylimino" and "acylimino" mean a group defined as =NR, wherein the alkylimino group is attached to one σ-bond and one π-bond, wherein R is each as defined above As alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl. When the terms alkenylimino, alkynylimino, arylimino, aralkylimino and acylimino are modified to "substituted", this means group =NR, where the alkylimino group is one σ A bond and one π-bond are attached, wherein R is each substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl.

When used without the modifier "substituted", the term "fluoroalkyl" means alkyl as defined above, wherein one or more fluorine is substituted with hydrogen. The groups -CH ₂ F, -CF ₃ and -CH ₂ CF ₃ are non-limiting examples of fluoroalkyl groups. The term "substituted fluoroalkyl" refers to a saturated carbon atom as a point of attachment, a straight or branched chain, a cyclo, cyclic or acyclic structure, having one or more fluorine atoms, no carbon-carbon double or triple bonds, and N , O, Cl, Br, I, Si, P and S means a non-aromatic monovalent group having one or more atoms independently selected from the group consisting of. The following groups are non-limiting examples of substituted fluoroalkyls: -CFHOH.

When used without the modifier "substituted", the term "alkylthio" refers to the group -SR, where R is alkyl as defined above. Non-limiting examples of alkylthio groups include -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH(CH ₃ ) ₂ , -SCH(CH ₂ ) ₂ , -S-cyclopentyl and- S-cyclohexyl is included. The term “substituted alkylthio” refers to the group -SR, where R is substituted alkyl as defined above. For example, -SCH ₂ CF ₃ is a substituted alkylthio group.

Similarly, when used without the modifier "substituted", the terms "alkenylthio", "alkynylthio", "arylthio", "aralkylthio", "heteroarylthio", "heteroaralkylthio" and "Acylthio" means a group defined as -SR, wherein R is each alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl as defined above. When the terms alkenylthio, alkynylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio and acylthio are modified to "substituted", this means the group -SR, where R is each substituted Alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl.

When used without the modifier "substituted", the term "thioacyl" has a carbon atom of a thiocarbonyl group as a point of attachment, further has a straight or branched chain, cyclo, cyclic or non-cyclic structure, and a sulfur atom of a carbonyl group In addition, it means a monovalent group that does not further have an additional atom other than carbon or hydrogen. Group -CHS, -C(S)CH ₃ , -C(S)CH ₂ CH ₃ , -C(S)CH ₂ CH ₂ CH ₃ , -C(S)CH(CH ₃ ) ₂ , -C(S )CH(CH ₂ ) ₂ , -C(S)C ₆ H ₅ , -C(S)C ₆ H ₄ CH ₃ , -C(S)C ₆ H ₄ CH ₂ CH ₃ , -C(S)C ₆ H ₃ (CH ₃ ) ₂ and -C(S)CH ₂ C ₆ H ₅ are non-limiting examples of thioacyl groups. Thus, the term “thioacyl” includes, but is not limited to, groups sometimes referred to as “alkyl thiocarbonyl” and “aryl thiocarbonyl” groups. The term "substituted thioacyl" has as a point of attachment a carbon atom that is part of a thiocarbonyl group, further has a straight or branched chain, cyclo, cyclic or bicyclic structure, and in addition to the sulfur atom of the carbonyl group, N, O, It means a radical further having at least one atom independently selected from the group consisting of F, Cl, Br, I, Si, P and S. Group -C(S)CH ₂ CF ₃ , -C(S)O ₂ H, -C(S)OCH ₃ , -C(S)OCH ₂ CH ₃ , -C(S)OCH ₂ CH ₂ CH ₃ , -C(S)OC ₆ H ₅ , -C(S)OCH(CH ₃ ) ₂ , -C(S)OCH(CH ₂ ) ₂ , -C(S)NH ₂ and -C(S)NHCH ₃ are It is a non-limiting example of a substituted thioacyl group. The term “substituted thioacyl” includes, but is not limited to, the group “heteroaryl thiocarbonyl”.

When used without the modifier "substituted", the term "alkylsulfonyl" refers to the group -S(O) ₂ R, where R is alkyl as defined above. Non-limiting examples of alkylsulfonyl groups are -S(O) ₂ CH ₃ , -S(O) ₂ CH ₂ CH ₃ , -S(O) ₂ CH ₂ CH ₂ CH ₃ , -S(O) ₂ CH (CH ₃ ) ₂ , -S(O) ₂ CH(CH ₂ ) ₂ , -S(O) ₂ -cyclopentyl and -S(O) ₂ -cyclohexyl. The term "substituted alkylsulfonyl" refers to the group -S(O) ₂ R, wherein R is a substituted alkyl as defined above. For example, -S(O) ₂ CH ₂ CF ₃ is a substituted alkylsulfonyl group.

Similarly, when used without the modifier "substituted", the terms "alkenylsulfonyl", "alkynylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl", and "heteroar. Alkylsulfonyl" refers to a group defined as -S(O) ₂ R, wherein R is each alkenyl, alkynyl, aryl, aralkyl, heteroaryl and heteroaralkyl as defined above. When the terms alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl and heteroaralkylsulfonyl are modified to "substituted", it means the group -S(O) ₂ R and , Wherein R is each substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl and heteroaralkyl.

When used without the modifier "substituted", the term "alkylammonium" _{refers to a group defined as -NH 2} R ⁺ , -NHRR' ⁺ or -NRR'R" ⁺ , wherein R, R'and R" Are the same or different alkyl groups or any combination of the two of R, R'and R" together may represent an alkanediyl. Non-limiting examples of alkylammonium cations include: -NH ₂ (CH ₃ ) ⁺ , -NH ₂ (CH ₂ CH ₃ )+, -NH ₂ (CH ₂ CH ₂ CH ₃ )+, -NH(CH ₃ ) ₂ ⁺ , -NH(CH ₂ CH ₃ ) ₂ ⁺ , -NH( CH ₂ CH ₂ CH ₃ ) ₂ ⁺ , -N(CH ₃ ) ₃ ⁺ , -N(CH ₃ )(CH ₂ CH ₃ ) ₂ ⁺ , -N(CH ₃ ) ₂ (CH ₂ CH ₃ ) ⁺ ,- NH ₂ C(CH ₃ ) ₃ ⁺ , -NH(cyclopentyl) ₂ ⁺ and -NH ₂ (cyclohexyl) ⁺ .The term "substituted alkylammonium" refers to -NH ₂ R ⁺ , -NHRR' ⁺ or -NRR'R" ⁺ , wherein at least one of R, R'and R" is a substituted alkyl, or two of R, R'and R" together may represent substituted alkanediyl. When one or more of R, R'and R" are substituted alkyl, they may be the same or different. Any R, R'and R" that are not substituted alkyl or substituted alkanediyl may be alkyl and , The same or different, or together may represent an alkanediyl having two or more carbon atoms, and two or more of these carbons are attached to the nitrogen atom shown in the formula.

When used without the modifier "substituted", the term "alkylsulfonium" refers to the group -SRR' ⁺ , wherein R and R'can be the same or different alkyl groups, or R and R'together are alkanediyl Can represent. Non-limiting examples of alkylsulfonium groups include: -SH(CH ₃ ) ⁺ , -SH(CH ₂ CH ₃ ) ⁺ , -SH(CH ₂ CH ₂ CH ₃ ) ⁺ , -S(CH ₃ ) ₂ ⁺ , -S(CH ₂ CH ₃ ) ₂ ⁺ , -S(CH ₂ CH ₂ CH ₃ ) ₂ ⁺ , -SH(cyclopentyl) ⁺ and -SH(cyclohexyl) ⁺ . The term "substituted alkylsulfonium" refers to the group -SRR' ⁺ , wherein R and R'are the same or different substituted alkyl groups, one of R or R'is alkyl, and the rest are substituted alkyl, or R and R'together may represent substituted alkanediyl. For example, -SH(CH ₂ CF ₃ ) ⁺ is a substituted alkylsulfonium group.

When used without the modifier "substituted", the term "alkylsilyl" refers to a _{monovalent group defined as -SiH 2} R, -SiHRR', or -SiRR'R", wherein R, R'and R" are It may be the same or different alkyl groups, or any combination of two of R, R'and R" together may represent an alkanediyl. Groups -SiH ₂ CH ₃ , -SiH(CH ₃ ) ₂ , -Si( CH ₃ ) ₃ and -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ are non-limiting examples of unsubstituted alkylsilyl groups The term “substituted alkylsilyl” refers to -SiH ₂ R, -SiHRR' or- SiRR'R", wherein one or more of R, R'and R" may be substituted alkyl, or two of R, R'and R" may represent alkanediyl substituted together. When one or more of R, R'and R" are substituted alkyl, they may be the same or different. Any R, R'and R" that are not substituted alkyl or substituted alkanediyl may be alkyl and , May be the same or different, or together may represent an alkanediyl having two or more saturated carbon atoms bonded to two or more silicon atoms.

In addition, the atoms constituting the compounds of the present specification include all isotopic forms of such atoms. Isotopes as used herein include atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include tritium and dihydrogen, and isotopes of carbon include ¹³ C and ¹⁴ C. Similarly, it is expected that one or more carbon atom(s) of the compounds herein may be substituted with silicon atom(s). In addition, it is expected that one or more oxygen atom(s) of the compounds of the present specification may be substituted with sulfur or selenium atom(s).

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The structure

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. Includes. One of skill in the art understands that none of the ring atoms described above form part of one or more double bonds.

Unrestricted valency for an atom of a structure presented herein implicitly refers to a hydrogen atom bonded to the atom.

The ring structure shown together with an unbonded “R” group describes that the hydrogen atom present on the ring may be substituted with the corresponding R group. In the case of a divalent R group (eg, oxo, imino, thio, alkylidene, etc.), any pair of intrinsic hydrogen atoms bonded to one atom of the ring may be substituted with the corresponding R group. This concept is illustrated below:

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Represents.

As used herein, “chiral adjuvant” refers to a removable chiral group capable of affecting the stereoselectivity of a reaction. Those skilled in the art are familiar with these compounds, and many are commercially available.

The words “a” and “an” when used in conjunction with the term “comprising” in the claims and/or specification may mean “a”, but also “one or more”, “at least one” and “one Or more than one.

Throughout this application, the term “about” is used to describe that the device used to measure the value, the intrinsic deviation of the error for the method, or the deviation that exists between study subjects.

The terms "include", "have" and "contain" are adjustable linking verbs. The form and meaning of one or more of these verbs, eg, “includes,” “includes,” “have,” “have,” “contains,” and “contains,” are also adjustable. For example, a method "comprising," "having," or "containing" one or more steps is not limited to including only methods comprising one or more steps, and also includes other non-listed steps.

As used in the specification and/or claims, the term “valid” means suitable to achieve the desired, expected or intended result.

When used as a modifier for a compound, the term “hydrate” means that the compound is less than one (eg, hemihydrate), one (eg, monohydrate) or It means that it has more than one (e.g. dihydrate) water molecule.

The term “IC ₅₀ ”as used herein refers to an inhibitory dose that is 50% of the maximum response obtained.

The "isomer" of the first compound is an individual compound in which each molecule contains the same constituent atoms as the first compound, but differs in the three-dimensional arrangement of these atoms.

As used herein, the term “patient” or “subject” refers to a living mammalian organism, eg, human, monkey, cow, sheep, goat, dog, cat, rat, rat, guinea pig or transgenic species thereof. do. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human subjects are adults, boys, infants and fetuses.

“Pharmaceutically acceptable” refers to those useful for preparing pharmaceutical compositions that are generally safe, non-toxic, non-biological and otherwise undesirable, and those that are acceptable for veterinary use as well as human pharmaceutical use. Includes.

"Pharmaceutically acceptable salt" means a salt of a compound of the present specification that is pharmaceutically acceptable and contains the desired pharmacological activity, as defined above. Such salts may be used with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; Or organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2- En-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphor Sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfate, Maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanic acid, propionic acid, p-toluene Acid addition salts formed with sulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts that can be formed when an acidic proton present can react with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It should be appreciated that the particular anions or cations that form part of the salts of the present invention are not critical as long as the salt as a whole is pharmacologically acceptable. Further examples of pharmaceutically acceptable salts and methods for preparing and using the same are described in the literature [See: Handbook of Pharmaceutical Salts : Properties , and Use (2002)].

As used herein, the term "mainly one enantiomer" means that the compound contains at least about 85%, or more preferably at least about 90%, even more preferably at least about 95%, or most preferably one enantiomer. It means that it contains about 99% or more. Similarly, the phrase “substantially free of other optical isomers” means that the composition contains no more than about 15%, more preferably no more than about 10%, and even more preferably no more than about 5% of other enantiomers or diastereomers. , Most preferably, it means containing less than about 1%.

“Preventing” or “preventing” means (1) inhibiting the onset of the disease in a subject or patient who has a risk for the disease and/or may be prone to it, but has not yet experienced or exhibited one or both of the pathology or symptoms of the disease. And/or (2) delaying the onset of the pathology or symptoms of the disease in a subject or patient who has a risk for the disease and/or may be prone to having it, but has not yet experienced or exhibited one or both of the pathology or symptoms of the disease. Includes.

"Prodrug" means a compound that is metabolically convertible in vivo to an inhibitor according to the present specification. The prodrug itself may or may not have an activity associated with a given target protein. For example, a compound comprising a hydroxy group can be administered as an ester that is converted to a hydroxy compound in vivo by hydrolysis. Suitable esters that can be converted to hydroxy compounds in vivo include acetate, citrate, lactate, phosphate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, Methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-p-toluoil tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate , Quinates, esters of amino acids, and the like. Similarly, compounds containing amino groups can be administered as amides that are converted to amine compounds in vivo by hydrolysis.

*When naming an atom, the term "saturated" means that the atom is attached to another atom only by a single bond.

"Stereoisomers" or "optical isomers" are isomers of a given compound in which the same atom is bonded to the same other atom, but the three-dimensional arrangement of these atoms is different. “Enantiomers” are stereoisomers of certain compounds that are mirror images of each other, such as the left and right hands. A “diastereomer” is a stereoisomer of a given compound that is not an enantiomer.

The present invention expects that in the case of a stereocenter or chiral axis for which stereochemistry is not defined, the stereocenter or chiral axis may exist as an R form, an S form, or a mixture of R and S forms including racemic and non-racemic mixtures. do.

"Substituent convertible to hydrogen in vivo" means any group convertible to a hydrogen atom by enzymatic or chemical means including, but not limited to, hydrolysis or hydrolysis. Examples thereof include an acyl group, a group having an oxycarbonyl group, an amino acid residue, a peptide residue, o-nitrophenylsulphenyl, trimethylsilyl, tetrahydropyranyl, diphenylphosphinyl, a hydroxy or alkoxy substituent on an imino group, etc. Includes. Examples of acyl groups include formyl, acetyl, trifluoroacetyl and the like. Examples of groups having an oxycarbonyl group include ethoxycarbonyl, tert-butoxycarbonyl-(C(O)OC(CH ₃ ) ₃ ), benzyloxycarbonyl, p -methoxybenzyloxycarbonyl, Vinyloxycarbonyl, β-( p -toluenesulfonyl)ethoxycarbonyl, and the like. Suitable amino acid residues are Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine), Ile (isoleucine). ), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine) ), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5Hyl (5-hydroxylysine), Orn (ornithine) and the residues of β-Ala, Not limited. Examples of suitable amino acid residues also include amino acid residues protected with a protecting group. Examples of suitable protecting groups are acyl groups (e.g. formyl and acetyl), arylmethyloxycarbonyl groups (e.g. benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert-butoxycarbonyl groups (- Includes those commonly used in peptide synthesis, including C(O)OC(CH ₃ ) _{3) and the like.} Suitable peptide residues include 2 to 5 peptide residues and optionally amino acid residues. The residues of these amino acids or peptides may exist in the stereochemical configuration of the D-form, L-form or mixtures thereof. In addition, the amino acid or peptide residue may have an asymmetric carbon atom. Examples of suitable amino acid residues having asymmetric carbon atoms include residues of Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetric carbon atom include peptide residues having one or more constituent amino acid residues having an asymmetric carbon atom. Examples of suitable amino acid protecting groups are acyl (e.g. formyl and acetyl), arylmethyloxycarbonyl groups (e.g. benzyloxycarbonyl and p -nitrobenzyloxycarbonyl), tert-butoxycarbonyl group (- Includes those commonly used in peptide synthesis, including C(O)OC(CH ₃ ) _{3) and the like.} Other examples of substituents "convertible to hydrogen in vivo" include reductively removable hydrolyzable groups. Examples of suitable reductively removable hydrolyzable groups include arylsulfonyl groups (eg o -toluenesulfonyl); Methyl groups substituted with phenyl or benzyloxy (eg benzyl, trityl and benzyloxymethyl); Arylmethoxycarbonyl groups such as benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl; And haloethoxycarbonyl groups (eg, β,β,β-trichloroethoxycarbonyl and β-iodoethoxycarbonyl).

"Therapeutically effective amount" or "pharmaceutically effective amount" means that when administered to a subject or patient to be treated for the disease, the amount is sufficient to effect such treatment for the disease.

“Treatment” or “treating” means (1) inhibiting the disease in a subject or patient experiencing or exhibiting the pathology and/or symptoms of the disease (eg, inhibiting the further development of the pathology and/or symptoms), and (2) Alleviating the disease (e.g., reversing the pathology and/or symptoms) in a subject or patient experiencing or exhibiting a pathology or symptom of the disease, and/or (3) measuring in a subject or patient experiencing or exhibiting the pathology or symptoms of the disease. It involves achieving a reduction in possible disease.

As used herein, the term “water soluble” means that the compound is soluble in water to an extent of at least 0.010 mol/l or classified as soluble according to prior literature.

Other abbreviations used herein are: DMSO, dimethyl sulfoxide; NO, nitric oxide; iNOS, an inducible nitric oxide synthase; COX-2, cyclooxygenase-2; NGF, nerve growth factor; IBMX, isobutylmethylxanthine; FBS, fetal bovine serum; GPDH, glycerol 3-phosphatase dehydrogenase; RXR, retinoid X receptor; TGF-β, transforming growth factor-β; IFNγ or IFN-γ, interferon-γ; LPS, bacterial endotoxin lipopolysaccharide; TNFα or TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; TCA, trichloroacetic acid; HO-1, an inducible heme oxygenase.

The above definitions supersede the definitions controversial in any reference incorporated herein by reference. However, the fact that a particular term is defined should not be considered to imply that any term not defined is infinite. Rather, all terms used are considered to describe the present invention in terms of such terms that one skilled in the art can recognize the scope and carry out the present specification.

II. Synthesis method

The compounds herein can be prepared using the methods outlined in the Examples section (Examples 2 and 3). These methods can be further modified and optimized using the principles and techniques of organic chemistry applied by those skilled in the art. These principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated herein by reference.

III. Biological activity of oleanolic acid derivatives

Both in vivo and in vitro biological activity results are provided throughout this specification . These include inhibition of NO production, inhibition of COX-2 induction, inhibition of IL-6-induced STAT3 phosphorylation, inhibition of IL-6-induced STAT3 phosphorylation, inhibition of TNFα-induced IkBα degeneration, inhibition of NFkB activation, Induction of HO-1, Nrf2 induction of HO-1, TrxR1 and γ-GCS, Induction of TrxR1, Induction of γ-GCS, Induction of ferritin heavy chain, Induction of TrxR1, Induction of γ-GCS, Induction of ferritin heavy chain Includes in vivo toxicity studies. See the drawings and the drawing description. The induction of NO production suppression and Nrf2 induction results can be summarized as shown in Tables 1 and 2 below, respectively. Additional results including toxicity studies are provided in the Examples section.

Suppression of IFNγ-induced NO production Compound ID(s) MW RAW264.7 (20 ng/ml IFN) NO IC ₅₀ WST-1 IC ₅₀ iNOS suppr. WB 63101 / 402-02/ dh402 507.70 ~12 nM 200 nM >90% 63102 / 404-02/ dh404 574.72 ~45 nM > 200 nM 63250 / 402-46 509.70 > 200 nM > 200 nM 63197 / 402-48 512.72 > 200 nM > 200 nM 63195 / 402-49 509.72 > 200 nM > 200 nM 63196 / 402-51 / dh401 493.68 ~75 nM > 200 nM 63252 / 402-57 474.68 ~5 nM > 200 nM 63205 / 402-59 492.69 ~25 nM > 200 nM 63206 / 402-64 477.68 ~10 nM > 200 nM 63207 / 402-66 509.72 ~50 nM > 200 nM 63219 / 402-78 509.72 ~150 nM > 200 nM 63229 517.71 > 200nM > 200nM 63230 531.74 ~50 nM > 200 nM 63227 576.73 > 200nM > 200nM 63219 509.72 ~150 nM > 200 nM 63223 576.73 > 200nM > 200nM 63237 572.70 ~80 nM > 200 nM 63268 576.75 > 200 nM > 200 nM 63274 547.81 ~ 70 nM > 200 nM 63289 525.73 > 200 nM > 200 nM 63295 522.73 ~ 20 nM > 200 nM 63296 522.73 ~ 200 nM > 200 nM 63308 491.70 ~ 25 nM > 200 nM 63323 583.80 ~ 40 nM See FIG. 33 63325 520.75 ~ 50 nM See FIG. 32 63326 552.79 ~ 50 nM See FIG. 34

Induction of HO-1, TrxR1 and γ-GCS in human melanoma cells Compound code Induction of Nrf2 target gene in MDA-MB-435 cells 400 nM* 250 nM ** HO-1 TrxR1 g-GCS HO-1 NQO1 g-GCS 63101(dh402) 4 47 53 3 2 5 63102(dh404) 3 2 4.5 63196(dh401) One 48 26 63252 5 3 63205 1.7 1.7 3.5 63206 2.5 1.8 4.5 63207 1.2 1.6 3.1 63237 3 2.3 6.4

Blank: Not measured.

* Data expressed as the observed induction rate for compound 402 (see structure below).

** Data expressed as a higher overlap induction than the DMSO control.

In certain embodiments, the compounds herein are capable of crossing the blood brain barrier to achieve therapeutically effective concentrations in the brain. Thus, they can be used to treat neurodegenerative diseases, brain cancer and other inflammatory conditions affecting the central nervous system. For example, compounds 404-02 have been shown to cross the blood-brain barrier and achieve high concentrations in central nervous system tissues after oral administration. Like other compounds herein, it promotes healing of innate and adaptive immune mediated inflammation by restoring redox homeostasis in inflamed tissue. It is a potent inducer of the antioxidant transcription factor Nrf2 and is an inhibitor of the pro-oxidant/proinflammatory transcription factor NF-κB and STAT. These biological pathways are involved in a wide range of diseases, including autoimmune conditions and a number of neurodegenerative diseases.

IV. Improved rodent toxicology

In certain embodiments, the invention provides compounds comprising low toxicity in rodents. In some cases, rodent toxicity has been observed in preclinical studies using some homologues containing carbon-carbon double bonds in the C-ring, including compounds 402 and 401. Compounds with saturated C-rings, in contrast, consistently showed low toxicity in rodents. As expected, low rodent toxicity provides an advantage, as high rodent toxicity can be an important complication in conducting preclinical studies required for the development and registration of therapeutic compounds for use in human or non-human animals. Examples of these effects are provided below.

For example, an initial study (Example 6) was conducted with Sprague Dawley rats using both compounds 402 and 402-02, indicating that compounds 402-02 were less toxic. In a further study (Example 7), six compounds (401, 402, 404, 401-2, 402-2 and 404-2) were evaluated for toxicity in mice in a 14-day study. At high doses (above 10 mg/kg/day) both compounds 401 and 402 caused a mortality rate of 50% or more, but compound 404 was non-toxic. In contrast, no mortality was observed in the compounds 402-2 and 404-2 groups, and only the highest dose resulted in any mortality of compounds 401-02. Body weight measurements (Figures 29-31) were consistent with mortality observations. Remarkably, the two highest doses of compounds 401 and 402 were fatal within 4 days in contrast to the effects of 401-2 and 402-2.

V. Inflammatory and/or oxidative stress related diseases

Inflammation is a biological process that provides resistance to infectious or parasitic organisms and restoration of damaged tissue. Inflammation is typically local vasodilation, redness, swelling and pain, rejuvenation of leukocytes at the site of infection or injury, production of inflammatory cytokines such as TNF-α and IL-1, and reactive oxygen or nitrogen species, such as For example, it is characterized by the production of hydrogen peroxide, superoxide and peroxynitrite. In the late stages of inflammation, tissue remodeling, angiogenesis and scarring (fibrosis) can occur as part of the wound healing process. Under normal circumstances, the inflammatory response is regulated, transient, and, once the transmission or damage is properly handled, heals in a coordinated manner. However, acute inflammation can be overkill and life threatening if the regulatory mechanisms fail. Alternatively, inflammation can become chronic and can lead to cumulative tissue damage or systemic complications.

Diseases that have not traditionally been observed as inflammatory conditions, such as cancer, atherosclerosis, and many severe refractory human diseases, including diabetes, are associated with dysregulation of the inflammatory process. In the case of cancer, the inflammatory process is associated with tumor formation, progression, metastasis and resistance to treatment. Atherosclerosis, which has been observed for a long time as a lipid metabolism disorder, is currently understood to be an inflammatory condition with activated macrophages that play an important role in the formation and final rupture of atherosclerotic plaques. Activation of the inflammatory signaling pathway has also been shown to play a role in the development of insulin resistance as well as in the peripheral tissue damage associated with diabetic hyperglycemia. Excess production of reactive oxygen species and reactive nitrogen species such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite is a hallmark of the inflammatory condition. Evidence for poorly controlled peroxynitrite production has been reported in a wide range of diseases (Szabo et al. al . , 2007; Schulz et al . , 2008; Forstermann, 2006; Pall, 2007).

Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis and multiple sclerosis are associated with inadequate chronic activation of the inflammatory process in infected tissues resulting from impairment of self-cognition versus non-self-cognition and response mechanisms in the immune system. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, nerve damage is correlated with activation of microglia and high levels of proinflammatory proteins, such as inducible nitric oxide synthase (iNOS). Chronic organ failure such as renal failure, heart failure and chronic obstructive pulmonary disease are closely related to the presence of chronic oxidative stress and inflammation leading to the development of fibrosis and a final loss of organ function.

Inflammatory bowel disease; Inflammatory skin disease; Mucositis associated with radiation therapy and chemotherapy; Eye diseases such as uveitis, glaucoma, vision loss and various forms of retinopathy; Transplant failure and rejection; Ischemia-reperfusion injury; Chronic pain; Degenerative conditions of bones and joints, including osteoarthritis and osteoporosis; Asthma and cystic fibrosis; Seizure disorder; And a number of other disorders including neuropsychiatric conditions including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism-spectrum disorder, and eating disorders such as anorexia, oxidative stress and infection. Includes inflammation in the tissues. Dysregulation of the inflammatory signaling pathway is considered to be a major factor in the pathology of muscular dystrophy, including muscular dystrophy and various forms of cachexia.

Various life-threatening acute disorders also signal acute organ failure, including the pancreas, kidneys, liver or lungs, myocardial infarction or acute coronary syndrome, uncontrolled inflammation including stroke, septic shock, trauma, severe burns and anaphylaxis. Entails.

Many complications of infectious diseases also involve difficulty in controlling the inflammatory response. While inflammatory reactions can kill invasive pathogens, excessive inflammatory reactions can also be very destructive and in some cases can be the primary cause of damage in infected tissues. In addition, excessive inflammatory responses can also lead to systemic complications due to overproduction of inflammatory cytokines such as TNF-α and IL-1. It is considered to be a factor in mortality arising from severe inflenza, severe acute respiratory syndrome and sepsis.

Abnormal or excessive expression of iNOS or cyclooxygenase-2 (COX2) is implicated in the etiology of many disease processes. For example, NO is a potent mutagen (Tamir and Tannebaum, 1996), and nitric oxide can also activate COX-2 (Salvemini et al. al . , 1994). In addition, there is a significant increase in iNOS in rat colon tumors induced by the carcinogen, azoxymethane (Takahashi et al. , 1997). A series of synthetic triterpenoid homologues of oleanolic acid have been shown to be potent inhibitors of cellular inflammatory processes, e.g., induction of inducible nitric oxide synthase (iNOS) and COX-2 by IFN-γ in mouse macrophages. [Reference: Honda et al . (2000a); Honda et al . (2000b) and Honda et al . (2002), all incorporated herein by reference].

In one aspect, the compounds of the invention are characterized by their ability to inhibit nitric oxide production in macrophage-derived RAW 264.7 cells induced by exposure to γ-interferon. They further induce the expression of antioxidant proteins such as NQO1 and characterize their ability to reduce the expression of pro-inflammatory proteins such as COX-2 and inducible nitric oxide synthase (iNOS). It is done. These properties include cancer, mucositis resulting from radiation therapy or chemotherapy, autoimmune diseases, cardiovascular diseases including atherosclerosis, ischemia-reperfusion injury, acute and chronic organ failure including renal failure and heart failure, respiratory diseases, diabetes and Diabetic complications, severe allergies, transplant rejection, graft-versus-host diseases, neurodegenerative diseases, eye and retinal diseases, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel disease, dermatitis and other skin diseases , Sepsis, burns, seizure disorders and neuropsychiatric disorders.

Without wishing to be bound by theory, the activation of the antioxidant/anti-inflammatory Keap1/Nrf2/ARE pathway is considered to be related to the anti-inflammatory and anti-carcinogenic properties of the oleanolic acid derivatives of the present invention.

In another aspect, the compounds of the present invention can be used to treat subjects with conditions caused by high levels of oxidative stress in one or more tissues. Oxidative stress is produced from abnormally high or prolonged levels of reactive oxygen species, such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite (formed by the reaction of nitric oxide and superoxide). Oxidative stress can be accompanied by acute or chronic inflammation. Oxidative stress is caused by mitochondrial dysfunction, by activation of immune cells, e.g. macrophages and neutrophils, by acute exposure to external agents, e.g., ionizing radiation or cytotoxic chemotherapeutic agents (e.g. doxorubicin). , By trauma or other acute tissue injury, by ischemia/reperfusion, by poor circulation or anemia, by local or systemic hypoxia or hyperxemia, by high levels of inflammatory cytokines and other inflammation related proteins, and/or It can be caused by other abnormal physiological conditions, such as high blood sugar or hypoglycemia.

In animal models of a number of these conditions, including models of myocardial infarction, renal failure, graft failure and rejection, stroke, cardiovascular disease and autoimmune disease, the target gene of the Nrf2 pathway, inducible heme oxygenase (HO-1) Stimulating expression has been shown to have a significant therapeutic effect (see: Sacerdotiet al ., 2005; Abraham & Kappas, 2005; Bach, 2006; Araujoet al ., 2003; Liuet al ., 2006; Ishikawaet al ., 2001; Krugeret al ., 2006; Satoh et al ., 2006; Zhouet al ., 2005; Morse and Choi, 2005; Morse and Choi, 2002). This enzyme destroys free heme into iron, carbon monoxide (CO) and biliverdin, which is subsequently converted into a potent antioxidant molecule, bilirubin.

In another aspect, the compounds of the present invention can be used to prevent or treat acute and chronic organ failure and tissue damage resulting from oxidative stress exacerbated by inflammation. Examples of diseases that fall into this category are heart failure, liver failure, transplant failure and rejection, kidney failure, pancreatitis, fibrotic lung disease (among others, cystic fibrosis and COPD), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury. , Glaucoma, stroke, autoimmune disease, autism, vision loss and muscular atrophy. In the case of autism, for example, studies suggest that increased oxidative stress in the central nervous system may be the cause of disease development (Chauhan and Chauhan, 2006).

Evidence also shows oxidative stress and inflammation in psychiatric disorders such as psychosis, major depression and bipolar disorder; Seizure disorders such as epilepsy; Pain and sensory syndromes such as migraine, neuropathic pain or tinnitus; And a behavior syndrome, e. G., The other coupled to the plurality of deployment and pathologies of the central nervous system disorders including attention deficit disorder (see: Dickerson et al . , 2007; Hanson et al . , 2005; Kendall-Tackett, 2007; Lencz et al . , 2007; Dudhgaonkar et al. ,2006; Lee et al . , 2007; Morris et al . , 2002; Ruster et al . , 2005; McIver et al . , 2005; Sarchielli et al . , 2006; Kawakami et al . , 2006; Ross et al . , 2003; All incorporated herein by reference). For example, high levels of inflammatory cytokines including TNF, interferon-γ and IL-6 are associated with major psychosis (Dickerson et al. , 2007). Microglia activation has also been linked to major psychosis. Thus, downregulation of inflammatory cytokines and inhibition of excessive activation of microglia may be beneficial for patients with schizophrenia, major depression, bipolar disorder, autism-spectrum disorder and other neuropsychiatric disorders.

Thus, in etiology involving oxidative stress alone or oxidative stress exacerbated by inflammation, treatment comprises administering to a subject a therapeutically effective amount of a compound of the invention, e.g., those described above or throughout this specification. can do. Treatment can be administered prophylactically prior to a foreseeable state of oxidative stress (eg, administration of organ transplantation or radiation therapy to a cancer patient) or therapeutically in settings that include chronic oxidative stress and inflammation.

The compounds of the present invention are generally applicable to the treatment of inflammatory conditions, such as sepsis, dermatitis, autoimmune diseases and osteoarthritis. In one aspect, compounds of the present invention can be used to treat inflammatory pain and/or neuropathic pain, for example by inducing Nrf2 and/or inhibiting NF-kB.

In one aspect, the compounds of the present invention can be used as antioxidant inflammation modulators (AIMs) with potent anti-inflammatory properties that mimic the biological activity of cyclopentenone prostaglandin (cyPG). In one embodiment, the compounds of the present invention can be used to modulate the production of pro-inflammatory cytokines by selectively targeting regulatory cysteine residues (RCR) on proteins that regulate the transcriptional activity of redox sensitive transcription factors. Activation of RCRs by cyPGs or AIMs is a pro-healing program in which the activity of antioxidant and cytoprotective transcription factor Nrf2 is strongly induced, and the activities of pro-oxidant and pro-inflammatory transcription factors NF-kB and STAT are inhibited. It has been shown to initiate. This increases the production of antioxidant and reducing molecules (e.g. NQO1, HO-1, SOD1 and/or γ-GCS) and/or oxidative stress and pro-oxidants and pro-inflammatory molecules (e.g. iNOS, COX-2). And/or reduce the production of TNF-α).

*In some embodiments, the compounds of the present invention may contain diseases such as cancer, inflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, autoimmune diseases such as rheumatoid arthritis, lupus, and MS, inflammatory bowel disease, all other diseases whose etiology is considered to be associated with overproduction of nitric oxide or prostaglandins, and pathologies involving oxidative stress alone or exacerbated by inflammation can be used for the treatment and prevention.

Another aspect of inflammation is the production of inflammatory prostaglandins, such as prostaglandin E. These molecules promote vasodilation, plasma eruption, local pain, elevated temperature, and other symptoms of inflammation. The inducible form of the enzyme COX-2 is involved in their production, and high levels of COX-2 are found in inflamed tissues. Consequently, inhibition of COX-2 can alleviate many symptoms of inflammation, and many important anti-inflammatory drugs (eg, ibuprofen and celecoxib) act by inhibiting COX-2 activity. However, recent studies demonstrate that the class of cyclopentenone prostaglandins (cyPGs) (e.g. 15-deoxyprostaglandins J2, aka PGJ2) plays a role in stimulating inflammation-regulated healing (Rajakariar et al. al. ,2007). COX-2 is also involved in the production of cyclopentenone prostaglandins. As a result, inhibition of COX-2 can prevent complete healing of inflammation, potently promoting the persistence of activated immune cells in the tissue and inducing chronic "fumigation" inflammation. This effect may be responsible for an increased incidence of cardiovascular disease in patients using long-term selective COX-2 inhibitors.

In one aspect, the compounds of the present invention can be used to regulate the production of proinflammatory cytokines in cells by selectively activating regulatory cysteine residues (RCR) on proteins that regulate the activity of redox-sensitive transcription factors. Activation of RCR by cyPG initiates a pro-healing program in which the activity of antioxidant and cytoprotective transcription factor Nrf2 is strongly induced, and the activity of pro-oxidative and pro-inflammatory transcription factors NF-kB and STAT is inhibited. Appeared. In some embodiments, it increases the production of antioxidant and reducing molecules (e.g. NQO1, HO-1, SOD1 and/or γ-GCS), oxidative stress and pro-oxidative and pro-inflammatory molecules (e.g. iNOS, COX -2 and/or TNF-α). In some embodiments, the compounds of the present invention are capable of stimulating the healing of inflammation and limiting excessive tissue damage in the host, thereby causing cells to accept inflammatory events and convert them to a non-inflammatory state.

A. Cancer

Additionally, the compounds herein can be used to induce apoptosis of tumor cells, induce cell differentiation, inhibit cancer cell proliferation, inhibit inflammatory responses, and/or act in chemoprophylactic doses. For example, the present invention provides novel compounds having one or more of the following properties: (1) the ability to induce apoptosis and to identify malignant and non-malignant cells, (2) at the submicromolar or nanomolar level. Active as an inhibitor of the proliferation of many malignant or premalignant cells, (3) the ability to inhibit the neosynthesis of inflammatory enzyme-induced nitric oxide synthase (iNOS), (4) the ability to inhibit NF-kB activation, and (5) ) Ability to induce the expression of heme oxygenase-1 (HO1).

Levels of iNOS and COX-2 are elevated in certain cancers and are associated with carcinogenesis, and COX-2 inhibitors have been shown to reduce the incidence of basal colony adenoma in humans (Rostomet al ., 2007; Brown and DuBois, 2005; Crowelet al ., 2003). iNOS is expressed in bone marrow-derived suppressor cells (MDSC) (see: Anguloet al ., 2000), COX-2 activity in tumor cells is prostaglandin E₂(PGE₂), which has been shown to induce the expression of arginase in MDSC (see: Sinhaet al., 2007). Arginase and iNOS are enzymes that use L-arginine as substrates and produce L-ornithine and urea, and L-citrulline and NO, respectively. Depletion of arginine from the tumor microenvironment by MDSC, combined with NO and peroxynitrite production, has been shown to inhibit proliferation and induce apoptosis of T-cells (Bronteet al., 2003). Inhibition of COX-2 and iNOS has been shown to reduce accumulation of MDSC, restore cytotoxic activity of tumor-associated T-cells, and delay tumor growth (Sinhaet al., 2007; Mazzoniet al., 2002; Zhouet al., 2007).

Inhibition of the NF-kB and JAK/STAT signaling pathways is implicated as a strategy to inhibit proliferation of cancer epithelial cells and induce their apoptosis. Activation of STAT3 and NF-kB has been shown to cause inhibition of apoptosis, promotion of proliferation, invasion and metastasis in cancer cells. Many of the target genes involved in these processes have been shown to be transcriptionally regulated by NF-kB and STAT3 (Yu et al. , 2007).

In addition to their direct role in cancer epithelial cells, NF-kB and STAT3 also play an important role in other cells found within the tumor microenvironment. Experiments in animal models demonstrate that NF-κB is required for both cancer cells and hematopoietic cells to proliferate the effects of inflammation upon cancer initiation and progression (Greten et al. , 2004). Inhibition of NF-κB in cancer and bone marrow cells reduces the number and size of tumors, respectively. Activation of STAT3 in cancer cells induces the production of a number of cytokines (IL-6, IL-10) that suppress the maturation of tumor-associated dendritic cells (DC). In addition, STAT3 is activated by these cytokines in the dendritic cells themselves. Inhibition of STAT3 in a mouse model of cancer restores DC maturation, promotes anti-tumor immunity, and inhibits tumor growth (Kortylewski et al. , 2005).

B. Treatment of multiple sclerosis and other neurodegenerative conditions

The compounds and methods of the present invention can be used to treat patients with multiple sclerosis (MS). MS is known to be an inflammatory condition of the central nervous system (William et al. , 1994; Merrill and Benvenist, 1996; Genain and Nauser, 1997). Based on a number of investigations, there is evidence to suggest that inflammatory, oxidative and/or immune mechanisms are involved in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and MS (see: Bagasra et al. , 1995; McGeer and McGeer, 1995; Simonian and Coyle, 1996; Kaltschmidt et al . , 1997). Both reactive astrocytes and activated microglia have been implicated in the causes of neurodegenerative disease (NDD) and neuroinflammatory disease (NID), and microglia as cells that synthesize both NO and prostaglandins as products of the reactive enzymes INOS and COX-2. Cells were specially highlighted. The neoplastic formation of these enzymes can be driven by inflammatory cytokines such as interferon-γ or interleukin-1. In addition, overproduction of NO leads to inflammatory cascade and/or oxidative damage in cells and tissues of a number of organs, including neurons and oligodendrocytes of the nervous system, with consequent expression in AD and MS, and possibly PD and ALS. Inducible (Coyle and Puttfarcken, 1993; Beal, 1996; Merrill and Benvenist, 1996; Simonian and Coyle, 1996; Vodovotz et al . , 1996). Epidemiologic data describe that chronic use of NSAIDs that block the synthesis of prostaglandins from arachidonate significantly lowers the risk of developing AD (McGeer et al. , 1996; Stewart et al. , 1997). Thus, agents that block the formation of NO and prostaglandins can be used in approaches to the prevention and treatment of NDD. Successful therapeutic candidates for treating these diseases typically require the ability to penetrate the blood-brain barrier. See US Patent Publication No. 2009/0060873, which is incorporated herein by reference in its entirety. See also, for example, the results presented for compounds 404-02 in Examples 4 and 5 below.

C. Neuroinflammation

The compounds and methods of the present invention can be used to treat patients with neuroinflammation. Neuroinflammation summarizes the view that microglia and astrocyte responses and actions in the central nervous system have essentially inflammatory properties, and that these responses are central to the etiology and progression of a wide variety of neurological disorders. This view originates in the field of Alzheimer's disease (see Griffin et al . , 1989; Rogers et al . , 1988), where this changes our understanding of the disease (Akiyama et al. , 2000). This view is based on other neurodegenerative diseases (Eikelenboom et al., 2002; Ishizawa and Dickson, 2001), ischemia/toxic diseases (Gehrmann et al. al . , 1995; Touzani et al . , 1999), tumor biology (Graeber et al . , 2002) and even normal brain development.

Neuroinflammation introduces a broad spectrum of complex cellular responses including activation of microglia and astrocytes, cytokines, chemokines, complementary proteins, acute phase proteins, oxidative damage and induction of related molecular processes. These events can have a detrimental effect on neuronal function, leading to neuronal damage, further glial cell activation, and eventually neurodegeneration.

D. Treatment of kidney failure

The compounds and methods of the present invention can be used to treat patients with renal failure. See US Patent Application No. 12/352,473, which is incorporated by reference in its entirety. Another aspect of the present specification relates to novel methods and compounds for treating and preventing kidney disease. Renal failure, which leads to inadequate clearance of metabolic waste products from the blood and abnormal concentrations of electrolytes in the blood, is a significant medical problem worldwide, especially in developed countries. Diabetes and hypertension are the most important causes of chronic kidney failure, also known as chronic kidney disease (CKD), and are associated with other conditions, such as lupus. Acute renal failure can result from exposure to certain drugs (e.g., acetaminophen) or toxic chemicals, or from shock or surgical procedures, e.g., ischemia-reperfusion injury associated with transplantation, and can lead to chronic renal failure. In many patients, renal failure progresses to a stage where the patient needs regular dialysis or kidney transplants to continue living. All of these procedures are highly invasive and are associated with significant side effects and quality of life. Although there are effective treatments for some complications of renal failure, such as hyperparathyroidism and hyperphosphatemia, none of the available treatments stopped or reversed the underlying progression of renal failure. Thus, agents capable of improving impaired renal function represent significant advances in the treatment of renal failure.

Inflammation contributes significantly to the pathology of CKD. There is also a strong mechanical bond between oxidative stress and kidney dysfunction. The NF-kB signaling pathway plays an important role in the progression of CKD because NF-kB regulates the transcription of chemokines and MCP-1, which causes the recovery of mononuclear cells/macrophages, and eventually causes an inflammatory response that damages the kidneys. (Reference: Wardle, 2001). The Keap1/Nrf2/ARE pathway regulates the transcription of a number of genes encoding antioxidant enzymes, including heme oxygenase-1 (HO-1). Removal of the Nrf2 gene in magnetic mice leads to the development of lupus-like glomerulonephritis (Yoh et al. , 2001). In addition, a number of studies have demonstrated that HO-1 expression is induced in response to kidney damage and inflammation, and that this enzyme and its products-bilirubin and carbon monoxide-play a protective role in the kidney (Nath et al. , 2006). ).

The glomerulus and surrounding Bowman capsules constitute the basic unit of action of the kidney. The glomerular filtration rate (GFR) is a standard measure of renal function. Creatinine clearance is commonly used to measure GFR. However, the level of serum creatinine is commonly used as a surrogate measure of creatinine clearance. For example, excessive levels of serum creatinine are generally tolerated to describe inadequate renal function, and a decrease in serum creatinine over time is tolerated as an indication of improved renal function. The normal level of creatinine in the blood is about 0.6 to 1.2 mg per deciliter (dl) for adult males and 0.5 to 1.1 mg/dl for adult females.

Acute kidney injury (AKI) can result in intravenous infusion of radiographic contrast agents used in medical imaging and subsequent ischemia-reperfusion treatment with certain pharmacological agents, such as cisplatin and rapamycin. As in CKD, inflammatory and oxidative stress contribute to the pathology of AKI. The molecular mechanisms underlying irradiation-induced nephropathy (RCN) are not fully understood, but a combination of events including prolonged vasoconstriction, impaired renal autoregulation and direct toxicity of contrast agents all contribute to renal failure (Tumlin et al. al . , 2006). Vasoconstriction leads to reduced renal blood flow, ischemia-reperfusion and the production of reactive oxygen species. HO-1 is strongly induced under these conditions and has been demonstrated to inhibit ischemia-reperfusion injury in a number of different organs, including the kidney (Nath et al. al . , 2006). Specifically, the induction of HO-1 has been shown to be protective in the rat model of RCN (Goodman et al. , 2007). Reperfusion, despite activation of NF-kB signaling, also partially induces an inflammatory response (Nichols, 2004). Targeting NF-kB has been proposed as a therapeutic strategy to inhibit organ damage (Zingarelli et al. , 2003).

E. Cardiovascular disease

The compounds and methods of the present invention can be used to treat patients with cardiovascular disease. See US Patent Application No. 12/352,473, which is incorporated herein by reference in its entirety. Cardiovascular (CV) disease is one of the most important causes of mortality worldwide and is a leading cause of death in many developed countries. The etiology of CV disease is complex, but most of the causes are related to the blood supply to improper or completely destroyed vital organs or tissues. Often, this condition results from the rupture of one or more atherosclerotic plaques, which leads to the formation of blood clots that block blood flow in critical vessels. Such thrombosis is a major cause of heart attack, in which one or more coronary arteries are blocked and blood flow to the heart itself is disturbed. The resulting ischemia is highly damaging to heart tissue from a lack of oxygen during an ischemic event and from excessive formation of free radicals after blood flow has been restored (a phenomenon known as ischemia-reperfusion injury). Similar damage occurs in the brain during thrombotic stroke when the cerebral artery or other major blood vessels are blocked by thrombosis. Hemorrhagic stroke, in contrast, involves rupture of blood vessels and bleeding into surrounding brain tissue. It creates an oxidative stress frame in the area near the hemorrhage, due to the presence of large amounts of free heme and other reactive species, and ischemia in other brain areas due to impaired blood flow. Subarachnoid hemorrhage, often accompanied by cerebral vasospasm, also causes ischemia/reperfusion injury in the brain.

Alternatively, atherosclerosis is very extensive in important blood vessels, so that sclerosis (a narrowing of the arteries) develops, and blood flow to important organs (including the heart) may become chronically insufficient. Such chronic ischemia can lead to many types of terminal organ damage, including cardiac hypertrophy associated with congestive heart failure.

Atherosclerosis, an underlying defect that induces many forms of cardiovascular disease, occurs when a physical defect or damage in the lining of an artery (endothelium) triggers an inflammatory reaction, including proliferation of vascular smooth muscle cells and penetration of white blood cells into the affected area. do. Eventually, it is possible to form complex lesions known as atherosclerotic plaques composed of the above-described cells combined with precipitates of cholesterol-containing lipoproteins and other substances (Hansson et al. , 2006).

Pharmaceutical treatment for cardiovascular disease is a prophylactic treatment, for example, the use of drugs to lower blood pressure or the circulating level of cholesterol and lipoproteins, as well as to reduce the tendency of platelets and other blood cells to adhere (thereby the rate of plaque progression). And reducing the risk of clot formation) and designed treatments. More recently, drugs such as streptokinase and tissue plasminogen activators have been introduced and used to dissolve thrombi and restore blood flow. Surgical surgical treatments include coronary artery bypass tissue grafts to create an alternative blood supply, instrument angioplasty to compress plaque tissue and increase the diameter of the arterial lumen, and carotid endarterectomy to remove plaque tissue from the carotid artery. Such treatment, particularly instrument angiogenesis, may involve the use of a stent, an expandable mesh tube designed to support the arterial wall and keep the blood vessel open in the affected area. Recently, drug-eluting stents have been commonly used to prevent postoperative restenosis (restriction of arteries) in an infected area. Such devices are wire stents coated with a biocompatible polymeric matrix containing a drug that inhibits cell proliferation (eg paclitaxel or rapamycin). The polymer allows for slow local release of the drug in the infected area with minimal exposure of non-target tissue. Despite the significant benefits provided by these treatments, the mortality rate from cardiovascular disease is still high, and there is a significant unmet need in the treatment of cardiovascular disease.

As noted above, induction of HO-1 has been shown to be beneficial for various cardiovascular disease models, and low levels of HO-1 expression are clinically correlated with increased CV disease risk. Accordingly, the compounds of the present invention can be used to treat or prevent various cardiovascular diseases including, but not limited to, atherosclerosis, hypertension, myocardial infarction, chronic heart failure, stroke, subarachnoid hemorrhage and restenosis.

F. Diabetes

The compounds and methods of the present invention can be used to treat diabetic patients. See US Patent Application No. 12/352,473, which is incorporated herein by reference in its entirety. Diabetes is a complex disease characterized by a physical disorder that regulates the level of circulation of Clucose. This disorder can result from a lack of insulin, a peptide hormone that regulates both production and absorption of glucose in various tissues. Deficient insulin impairs the ability of muscles, fat and other tissues to absorb glucose properly, leading to hyperglycemia (abnormally high levels of glucose in the blood). Most commonly, this insulin deficiency results from inappropriate production in the islet cells of the pancreas. In most cases, it results from the autoimmune destruction of these cells, a condition known as type 1 or juvenile onset diabetes, but may also be due to physical trauma or some other cause.

Diabetes also occurs when muscle and fat cells become less responsive to insulin and do not absorb glucose properly, leading to hyperglycemia. This phenomenon is known as insulin resistance and the resulting condition is known as type 2 diabetes. Type 2 diabetes, the most common form, is highly associated with obesity and high blood pressure. Obesity is associated with an inflammatory state of adipose tissue that is considered to play an important role in the development of insulin resistance (Hotamisligil, 2006; Guilherme et al. , 2008).

Diabetes is largely associated with damage to many tissues, since high blood sugar (and hypoglycemia that can result from excessive or poorly administered administration of insulin) is an important source of oxidative stress. Chronic renal failure, retinopathy, peripheral neuropathy, peripheral vasculitis and the development of skin ulcers that do not heal slowly or at all are common diabetes complications. Particularly because of their ability to protect against oxidative stress by inducing HO-1 expression, the compounds of the present invention can be used to treat many diabetic complications. As noted above (see: Cai et al . , 2005), chronic inflammation and oxidative stress in the liver are suspected to be the primary contributing factors in the development of type 2 diabetes. In addition, PPARγ agonists, such as thiazolidinedione, can reduce insulin resistance and are known to be effective treatments for type 2 diabetes.

Diabetes treatment effect can be evaluated as follows. Whenever possible, evaluate both the biological and clinical efficacy of the treatment type. For example, since the disease is expressed on its own by increased blood sugar, the biological efficacy of the treatment can thus be assessed, for example, by observation of the return of the assessed blood sugar towards the norm. Measurement of glycosylated hemoglobin, also referred to as A1c or HbA1c, is another parameter of glycemic control commonly used. For example, measuring a clinical endpoint that can provide indications of b-cell regeneration after 6 months can provide indications of the clinical efficacy of the treatment regimen.

G. Rheumatoid arthritis

The compounds and methods of the present invention can be used to treat patients with RA. Typically, the first signal of rheumatoid arthritis (RA) appears with the proliferation of synovial fibroblasts in the synovial lining layer and their adhesion to the joint surface in the joint margin (Lipsky, 1998). Subsequently, macrophages, T cells and other inflammatory cells recover within the joint, where they destroy bone and cartilage, which play a role in inflammation, and cytokines that cause chronic sequelae that induce tumor necrosis factor (TNF-α). Produces a number of mediators, including interleukin-1 (IL-1) (Dinarello, 1998; Arend and Dayer, 1995; van den Berg, 2001). The concentration of IL-1 in plasma is significantly higher in RA patients than in healthy individuals, and significantly plasma IL-1 levels are correlated with RA disease activity (Eastgate et al. , 1988). In addition, synovial fluid levels of IL-1 correlate with various radiographic and histological features of RA (Kahle et al. , 1992; Rooney et al. , 1990).

In normal joints, the effects of these and other pro-inflammatory cytokines are balanced by various anti-inflammatory cytokines and modulators (Burger and Dayer, 1995). The importance of this cytokine balance is exemplified in juvenile RA patients with periodic increases in fever throughout the day (Prieur et al. , 1987). After each peak in heat, factors that block the effect of IL-1 are found in serum and urine. This factor was isolated, cloned, and identified as an IL-1 receptor antagonist (IL-1ra), a member of the IL-1 gene family (Hannum et al . , 1990). As its name indicates, IL-1ra is a natural receptor antagonist that competes with IL-1 for binding to the type I IL-1 receptor and consequently blocks the effect of IL-1 (Arend et al. al . , 1998). Although a 10- to 100-fold excess of IL-1ra may be required to effectively block IL-1, synovial cells isolated from RA patients do not appear to produce enough IL-1ra to interfere with the effects of IL-1 (see : Firestein et al. , 1994; Fujikawa et al. , 1995).

H. Dry arthritis

The compounds and methods of the present invention can be used to treat psoriatic arthritis. Psoriasis is an inflammatory and proliferative skin disorder with a prevalence of 1.5 to 3%. About 20% of psoriasis patients develop a unique form of arthritis with multiple patterns (Gladman, 1992; Jones et al. al. ,1994; Gladman et al . , 1995). In some individuals, joint symptoms are present first, but in most cases skin psoriasis is present. About one-third of patients have their skin and joint disease worsening at the same time (Gladman et al. al . , 1987), and there is a local anatomical relationship between nail and distal limb joint disease (Jones et al . , 1994; Wright, 1956). The inflammatory process that combines skin, nail and joint diseases is difficult to identify, but immune-mediated pathologies are involved.

Psoriatic arthritis (PsA) is a chronic inflammatory arthrosis characterized by a combination of arthritis and psoriasis, and was recognized in 1964 as a clinical entity different from rheumatoid arthritis (RA) (Blumberg et al. al ., 1964). Subsequent studies indicate that PsA shares a number of genetic, etiological and clinical features with other spondyloarthropathies (SpAs), a disease group including ankylosing spondylitis, reactive arthritis and enteropathic arthritis (Wright. , 1979). The view that PsA belongs to the SpA group has recently gained additional support from burn studies demonstrating extensive osteoarthritis involving PsA rather than RA (McGonagle et al. al . , 1999; McGonagle et al . , 1998). More specifically, it was hypothesized that osteoarthritis occurred in SpAs and was one of the earliest events inducing joint synovitis when the inflamed muscle tendon touches (enteses) in the spine as well as bone remodeling and stiffness in the spine were in close contact with the peripheral joints. . However, the linkage between osteoarthritis and clinical manifestations in PsA is very unclear, as PsA can exist in a highly heterogeneous joint involvement pattern with varying degrees of severity (Marsal et al. , 1999; Salvarani et al ., 1998). Thus, other factors should be assumed to account for the diverse features of PsA, of which very few (eg, expression of the HLA-B27 molecule strongly associated with axonal disease) have been identified. As a result, it is still difficult to map disease expression to a specific pathogenesis mechanism, which means that the treatment of this condition is very experimental.

Family studies have suggested a genetic contribution to the development of PsA (Moll and Wright, 1973). Other chronic inflammatory forms of arthritis, such as ankylosing spondylitis and rheumatoid arthritis, are considered to have a complex genetic basis. However, the genetic component of PsA has been difficult to evaluate for a number of reasons. There is strong evidence for a genetic predisposition to psoriasis alone that can mask genetic factors important for the development of PsA. Although most of them allow PsA as an overt disease entity, sometimes there is a phenotype that overlaps with rheumatoid arthritis and ankylosing spondylitis. Further, PsA itself is not in a homogeneous state, and various subgroups have been proposed.

Increased amounts of TNF-α were found in psoriatic skin (Ettehadi et al . , 1994) And synovial fluid (see Partsch et al . , 1997) have been reported in both. A recent experiment is PsA ^(Reference: Mease et al . , 2000) and ankylosing spondylitis (Brandt et al . , 2000) showed positive benefits of anti-TNF treatment.

I. Reactive Arthritis

The compounds and methods of the present invention can be used to treat patients with reactive arthritis. In reactive arthritis (ReA), the mechanism of joint damage is unclear, but cytokines are likely to play an important role. Although a more dominant Th1 profile, high levels of interferon gamma (IFN-γ) and low levels of interleukin 4 (IL-4) were recorded (Lahesmaa et al . , 1992; Schlaak et al . , 1992; Simon et al . , 1993; Schlaak et al . , 1996; Kotake et al. , 1999; Ribbens et al . , 2000), and a number of studies have shown synovial membranes in patients with reactive arthritis compared to patients with rheumatoid arthritis (RA) (Simon et al. al . , 1994; Yin et al . , 1999) and synovial fluid (SF) (Yin et al . , 1999; Yin et al . , 1997) showed the relative dominance of IL-4 and IL-10 and the relative lack of IFN-γ and tumor necrosis factor alpha (TNF-α). Lower levels of TNF-α secretion in patients with reactive arthritis than in patients with RA have also been described after ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) (Braun et al. , 1999).

Clearance of reactive arthritis-related bacteria requires the production of appropriate levels of IFN-γ and TNF-α, while IL-10 has been claimed to act by inhibiting these responses (Autenrieth et al. al ., 1994; Sieper and Braun, 1995). IL-10 is induced by activated macrophages IL-12 and TNF-γ (see: de Waal et al . , 1991; Hart et al . , 1995; Chomarat et al . , 1995) and IFN-γ by T-cells (Macatonia et al . , 1993).

J. Enteropathic arthritis

The compounds and methods of the present invention can be used to treat patients with enteropathic arthritis. Typically enteropathic arthritis (EA) occurs with inflammatory bowel disease (IBD), for example, Crohn's disease or ulcerative colitis. It can also affect the spine and sacroiliac joints. Enteropathic arthritis generally involves peripheral joints in the lower extremities, such as the knee or ankle. It typically involves very few or a limited number of joints, and can be strictly dependent on the condition of the intestine. It occurs in about 11% of patients with ulcerative colitis and 21% of patients with Crohn's disease. Synovitis is generally self-limiting and non-deformable.

Enteropathic arthrosis involves the collection of rheumatoid conditions that share a binding to the GI pathology. These states of bacteria (e.g., Shigella (Shigella), Salmonella (Salmonella), Campylobacter (Campylobacter), Yersinia (Yersinia) species, Clostridium difficile silica bacteria (Clostridium difficile)), parasites (e.g., minutes nematode ( Strongyloides stercoralis ), Taenia saginata , Ramble flagellum ( Giardia lamblia ), roundworm ( Ascaris lumbricoides ), Cryptosporidium species )), and reactive (eg, infection-related) arthritis due to spondyloarthropathies associated with inflammatory bowel disease (IBD). Other conditions and disorders include intestinal bypass (common intestine), arthritis, celiac disease, Whipple disease and collagenous colitis.

K. Juvenile rheumatoid arthritis

The compounds and methods of the present invention can be used to treat patients with juvenile rheumatoid arthritis (JRA). Juvenile rheumatoid arthritis (JRA), the term for the most prevalent form of arthritis in adolescents, applies to a clan disease characterized by chronic inflammation and hypertrophy of the synovial membrane. The terms do not have the exact same meaning, but overlap with a clan disease called juvenile chronic arthritis and/or juvenile idiopathic arthritis in Europe.

Both the innate and adaptive immune systems use multiple cell types, a vast array of cell surface and secreted proteins, and a reciprocal network of positive and negative feedback (Lo et al. , 1999). In addition, although separable in thought, the innate and adaptive wings of the immune system are functionally intersected (Fearon and Locksley, 1996), and pathological events occurring at these intersections are responsible for the etiology of the chronic form of arthritis in adults and children. It is very easy to relate to understanding (Warrington, et al. , 2001).

Multi-joint JRA is a distinct clinical subtype characterized by inflammation and synovial proliferation in multiple joints (4 or more), including the small joints of the hand (Jarvis, 2002). This subtype of JRA can be severe, due to its multiple joint involvement and its rapidly progressing capacity over time. Although clinically distinct, multi-joint JRA is not homogeneous, and patients are variable in disease onset, age at onset, prognosis and response to treatment. These differences are very likely to reflect the spectrum of fluctuations in the nature of the immune and inflammatory attacks that can occur in this disease (Jarvis, 1998).

L. Early Inflammatory Arthritis

The compounds and methods of the present invention can be used to treat patients with early inflammatory arthritis. The clinical symptoms of different inflammatory arthrosis are similar at the beginning of the disease process. As a result, it is difficult to distinguish patients at risk of developing severe and persistent synovitis that induce erosive joint damage from patients whose arthritis is more self-limiting. This distinction is important for targeting therapies that appropriately treat patients with erosive disease aggressively and avoid unnecessary toxicity in patients with more self-limiting disease. Prevailing clinical criteria for diagnosing erosive arthrosis, e.g., rheumatoid arthritis (RA), are less effective in early disease, and traditional markers of disease activity, such as joint number and acute phase response, have poor outcomes. Probable patients are not adequately identified (Harrison et al. , 1998). Variable reflexes of pathological events occurring in the synovial membrane are most likely to be important prognostic values.

Recent efforts to identify predictors of poor outcomes in early inflammatory arthritis have identified the presence of RA specific autoantibodies, particularly antibodies to citrullineated peptides, associated with erosive and persistent disease in the early inflammatory arthritis cohort. Based on this, a cyclic citrullined peptide (CCP) was developed to help identify anti-CCP antibodies in patient serum. Using this approach, the presence of anti-CCP antibodies has been shown to be specific and sensitive to RA, can differentiate RA from other arthrosis, and potentially predict persistent erosive synovitis before these results are clinically manifested. I can. Importantly, anti-CCP antibodies are often detectable in serum for many years prior to clinical signs suggesting that they may be reflexes of subclinical immune events (Nielen et al. , 2004; Rantapaa-Dahlqvist et al. al. , 2003).

M. ankylosing spondylitis

The compounds and methods of the present invention can be used to treat patients with ankylosing spondylitis. AS is a subset of diseases within the broad class of diseases of spondyloarthropathies. Patients infected with various subsets of spondyloarthropathies often have very different disease etiologies ranging from bacterial infections to inheritance. Yet, in all subgroups, the end result of the disease process is axial arthritis. Despite the early clinical differences seen in various patient populations, many of them become almost identical after 10 to 12 years of disease course. Recent studies suggest that the average time from the onset of the disease to the clinical diagnosis of ankylosing spondylitis is 7.5 years (Khan, 1998). This same study suggests that spondyloarthropathy may have a prevalence close to that of rheumatoid arthritis (Feldtkeller et al. , 2003; Doran et al. , 2003).

AS is a chronic systemic inflammatory rheumatic disorder of the axial skeleton with or without extraskeletal expression. Although the sacroiliac joints and spine are primarily affected, the hip and shoulder joints, and less commonly the peripheral joints or certain extraarticular structures, such as the eye, vasculature, central system, and gastrointestinal system may also be included. Its etiology is not fully understood (Wordsworth, 1995; Calin and Taurog, 1998). It is strongly associated with the major histocompatibility class I (MHC I) HLA-B27 allele (Calin and Taurog, 1998). AS is fearful because of its potential for invading individuals in the midst of life and causing chronic pain and irreversible damage to tendons, ligaments, joints and bones (Brewerton et al. , 1973a; Brewerton et al. al . , 1973b; Schlosstein et al . , 1973). AS may occur alone or in combination with other forms of spondyloarthropathies, such as reactive arthritis, psoriasis, psoriatic arthritis, osteoarthritis, ulcerative colitis, irritable bowel disease or Crohn's disease, in which case it is secondary AS Classified as.

Typically, the site of infection includes the disco-vertebrae of the vertebrae, the osteophytes, the rib vertebrae and transverse rib joints, and the lateral ligament structures of the spine. Inflammation of the muscle tendon contact, the site of attachment of muscle tendons and ligaments to the bone, is also prominent in this disease (Calin and Taurog, 1998). It is known that the site of osteoadherent infection is infiltrated with plasma cells, lymphocytes, and polymorphonuclear cells. The inflammatory process often leads to gradual fibrous and osseous stiffness (Ball, 1971; Khan, 1990).

Delayed diagnosis is common because symptoms are often due to more common back problems. The dramatic loss of flexibility in the lumbar spine is an early sign of AS. Other common symptoms include chronic pain and stiffness in the lower back, usually starting from where the lower spine connects to the pelvis or hip. Although most symptoms begin in the lumbar and sacroiliac joint areas, they can also include the neck and upper back. Arthritis can also occur in the shoulders, hips and feet. Some patients have eye irritation, and in more severe cases, heart valve involvement will be observed.

The most frequent symptom is low back pain, but the disease can start abnormally in the peripheral joints, especially in children and women, rarely with acute iritis (full uveitis). Additional early symptoms and signs are diffuse rib-spine involvement, mild fever, fatigue, It is reduced rib cage swelling from loss of appetite, weight loss and hyperemia. Recurrent low back pain-often nocturnal and variable intensity-is the final disease, such as morning stiffness, which is usually relieved by activity. The flexed or bent posture soothes back pain and lateral muscle spasms, so some degree of kyphosis is common in untreated patients.

Systemic manifestations occur in one third of patients. In general, self-limiting recurrent acute iritis (all uveitis) is rarely chronic and severe enough to impair vision. Neurological signals can sometimes be generated from compressive neuromyositis or sciatica, vertebral fractures or subluxations, and Mami syndrome (consisting of weakness, nocturnal incontinence, reduced bladder and rectal sensation, and the absence of the Achilles tendon reflex). Cardiovascular manifestations can include aortic insufficiency, angina, pericarditis, and ECG conduction abnormalities. Rare lung finding is an upper lobe fibrosis with cavitation that can sometimes be mistaken for TB and can be complicated by infection with Aspergillus.

AS is characterized by a mild or moderate burst of active spondylitis alternating with a period of little or entirely inactive inflammation. Appropriate treatment for most patients leads to a completely productive life, with minimal or no disability, despite back stiffness. Sometimes, the process is serious and progressive, leading to overt neutralizing malformations. This prognosis is dire for patients with refractory iritis and rare patients with secondary amyloidosis.

N. Ulcerative Colitis

The compounds and methods of the present invention can be used to treat patients with ulcerative colitis. Ulcerative colitis is a disease that causes inflammation and wounds called ulcers in the lining of the large intestine. Inflammation usually occurs in the rectum and lower colon, but it can affect the entire colon. Ulcerative colitis rarely affects the small intestine except the distal end, which is called the distal ileum. Ulcerative colitis is also referred to as colitis or proctitis. Inflammation often causes the colon to empty, causing diarrhea. Ulcers form where inflammation kills the cells lining the colon, and the ulcers bleed and produce pus.

Ulcerative colitis is inflammatory bowel disease (IBD), a common name for a disease that causes inflammation in the small intestine and colon. Ulcerative colitis can be difficult to diagnose because its symptoms are similar to other bowel disorders and other forms of IBO, Crohn's disease. Crohn's disease differs from ulcerative colitis because it causes more severe inflammation within the intestinal wall. In addition, Crohn's disease generally occurs in the small intestine, but it can also occur in the oral cavity, esophagus, stomach, duodenum, colon, appendix and anus.

Ulcerative colitis can occur in people of any age, but most often starts at 15 to 30 years old, or less frequently at 50 to 70 years old. Children and adolescents sometimes develop the disease. Ulcerative colitis works equally in men and women, and appears to progress in some families. Theories about what causes ulcerative colitis are abundant, but none have been proven. The most popular theory is that the body's immune system responds to viruses or bacteria by triggering ongoing inflammation in the intestinal wall. People with ulcerative colitis have immune system abnormalities, but doctors do not know if these abnormalities are the cause or effect of the disease. Ulcerative colitis is not caused by mental distress or sensitivity to a particular food or food product, but these factors can cause symptoms in some people.

The most common symptoms of ulcerative colitis are abdominal pain and bloody diarrhea. Patients may also experience fatigue, weight loss, loss of appetite, rectal bleeding and loss of fluids and nutrients. About half of patients have mild symptoms. The rest suffer from frequent fever, bloody diarrhea, nausea and severe abdominal pain. Ulcerative colitis can also cause problems such as arthritis, eye inflammation, liver disease (hepatitis, cirrhosis and primary sclerosing cholangitis), osteoporosis, skin rash and anemia. No one is sure of why the problem occurs outside the colon. Scientists believe that these complications can occur if the immune system causes inflammation in other parts of the body. Some of these problems disappear when colitis is treated.

A complete physical examination and series of tests may be necessary to diagnose ulcerative colitis. Blood tests can be performed to check for anemia, which may indicate bleeding in the colon or rectum. Blood tests can also expose a high white blood cell count, which is a sign of inflammation somewhere in the body. By testing a fecal sample, the doctor can detect bleeding or infection in the colon or rectum. Your doctor may do a colonoscopy or sigmoidoscopy. For both tests, the doctor inserts an endoscope-a long flexible light tube connected to a computer and TV monitor-into the anus to see the interior of the colon and rectum. Your doctor may see inflammation, bleeding, or ulcers on the walls of your colon. During the test, the doctor may perform a biopsy, including taking a tissue sample from the lining of the colon for observation under a microscope. Barium enema x-rays of the colon may also be required. This procedure involves filling the colon with a barium, chalky white solution. Barium makes the x-ray film stand out white, allowing the doctor to clearly observe the colon, including any ulcers or other abnormalities present there.

Treatment of ulcerative colitis depends on the severity of the disease. Most people are treated with drugs. In severe cases, the patient may need surgery to remove the diseased colon. Surgery is the only treatment for ulcerative colitis. Some people whose symptoms are caused by certain foods can control their symptoms by avoiding foods that make their gut uncomfortable, such as high seasoned foods, fresh fruits and vegetables, or lactose (lactose). Each person may experience ulcerative colitis differently, so treatment is tailored to each individual. Mental and psychological support is important. Some people may have a period of relief that lasts for months or even years to go away. However, most patients' symptoms eventually recur. This pattern of change in disease means that you cannot always tell when treatment has helped. Some people with ulcerative colitis may need medical care for some time, along with regular doctor visits to monitor the condition.

O. Crohn's disease

The compounds and methods of the present invention can be used to treat patients with Crohn's disease. Another disorder for which immunosuppression has been attempted is Crohn's disease. Crohn's disease symptoms include intestinal inflammation and the development of intestinal stenosis and fistula, and neuropathy is often accompanied by these symptoms. Anti-inflammatory drugs such as 5-aminosalicylate (eg mesalamine) or corticosteroids are commonly prescribed, but not always effective ( observed in Botoman et al. , 1998). Immunosuppression by cyclosporine is sometimes beneficial in patients who are resistant or intolerant to corticosteroids (Brynskov et al. , 1989).

Efforts to develop diagnostic and therapeutic tools for Crohn's disease have focused on the pivotal role of cytokines (Schreiber, 1998; van Hogezand and Verspaget, 1998). Cytokines are small secreted proteins or factors (5 to 20 kD) that have specific effects on cell-to-cell interactions, cell-to-cell communication or other cellular behavior. Cytokines are produced by lymphocytes, in particular T _H 1 and T _H 2 lymphocytes, monocytes, intestinal macrophages, granulocytes, epithelial cells and fibroblasts (Rogler and Andus, 1998; Galley and Webster, 1996). Observed). Some cytokines are pro-inflammatory (eg, TNF-α, IL-1 (α and β), IL-6, IL-8, IL-12, or leukemia inhibitory factor [LIF]); Others are anti-inflammatory (eg, IL-1 receptor antagonists, IL-4, IL-10, IL-11 and TGF-β). However, there may be overlap in their effects under certain inflammatory conditions, and functional redundancy may exist.

In the case of activated Crohn's disease, high concentrations of TNF-α and IL-6 are secreted in blood circulation, and TNF-α, IL-1, IL-6 and IL-8 are locally excessively produced by mucosal cells. Become (id.; Funakoshi et al . , 1998). These cytokines can have a wide range of effects on physiological systems, including bone development, hematopoiesis and liver, thyroid and neuropsychiatric functions. In addition, for proinflammatory IL-1β, an imbalance of the IL-1β/IL-1ra ratio was observed in Crohn's disease patients (Rogler and Andus, 1998; Saiki et al. , 1998; Dionne et al. al . , 1998; Kuboyama, 1998). One study suggested that the cytokine profile in fecal samples may be a useful diagnostic tool for Crohn's disease (Saiki et al. , 1998).

Suggested treatments for Crohn's disease include the use of various cytokine antagonists (e.g. IL-1ra), inhibitors (e.g. inhibitors of IL-1β converting enzymes and antioxidants) and anti-cytokine antibodies (Rogler and Andus). , 1998; van Hogezand and Verspaget, 1998; Reimund et al . , 1998; Lugering et al . , 1998; McAlindon et al . , 1998). In particular, monoclonal antibodies against TNF-α have been attempted with some success in the treatment of Crohn's disease (Targan et al. al . , 1997; Stack et al . , 1997; van Dullemen et al . , 1995). These compounds can be used in combination therapy using the compounds of this disclosure.

Other approaches to the treatment of Crohn's disease have focused on at least partially eradicating the bacterial population that can induce an inflammatory response and replacing it with a non-pathogenic population. For example, U.S. Patent No. 5,599,795 describes a method of preventing and treating Crohn's disease in human patients. These methods are directed to sterilizing the intestine with one or more antibiotics and one or more antifungal agents to kill existing flora and to replace them with different, selective and well-characterized bacteria taken from normal humans. Borody may be washed and disease tested by fecal inoculum from human donors or by Bacteroides and Escherichia coli ( Escherichia). coli ) teaches a method of treating Crohn's disease by at least partially removing the largely present intestinal microflora with a new bacterial population introduced by a composition comprising species (see US Pat. No. 5,443,826).

P. Systemic lupus erythematosus

The compounds and methods of the present invention can be used to treat patients with SLE. There are also no known causes for autoimmune diseases such as systemic lupus erythematosus. Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by adhesion of autoantibodies and immune complexes in tissues to induce tissue damage (Kotzin, 1996). In contrast to autoimmune diseases such as MS and type 1 diabetes mellitus, SLE directly involves a number of organ systems, and its clinical manifestations are diverse and variable (see Kotzin and O'Dell, 1995). Observed by). For example, some patients may present predominantly skin rashes and joint pain, show spontaneous relief, and require some medication. The other end of the spectrum are patients with severe and progressive renal involvement requiring treatment with high doses of steroids and cytotoxic drugs such as cyclophosphamide (Kotzin, 1996).

Serological characteristics of SLE, and available primary diagnostic tests, increase serum levels of IgG antibodies that make up the cell nucleus, such as double-stranded DNA (dsDNA), single-stranded DNA (ss-DNA), and chromatin. . Among these autoantibodies, IgG anti-dsDNA antibodies play an important role in the development of lupus glomerulonephritis (GN) (Hahn and Tsao, 1993; Ohnishi et al. , 1994). Glomerulonephritis is a serious condition in which the capillary wall of the renal blood purifying glomerulus is thickened by adhesion of the glomerular basement membrane to the epithelial side. This disease is often chronic and progressive, and can lead to eventual renal failure.

Q. Irritable Bowel Syndrome

The compounds and methods of the present invention can be used to treat patients with irritable bowel syndrome (IBS). IBS is a functional disorder characterized by abdominal pain and altered bowel habits. This syndrome can begin in adulthood and can be associated with significant disability. This syndrome is not a homogeneous disorder. Rather, the subtype of IBS has been described on the basis of the dominant symptoms-diarrhea, constipation or pain. In the absence of “warning” symptoms such as fever, weight loss and gastrointestinal bleeding, limited post-treatment is necessary. Once IBS is diagnosed, an integrated treatment approach can effectively reduce the severity of symptoms. IBS is a common disorder, but its prevalence is variable. In general, IBS affects about 15% of adults in the United States and occurs about 3 times more frequently in women than in men (Jailwala et al. , 2000).

IBS occupies 2.4 million to 3.5 million internal physicians annually. This is not only the most common condition seen by gastroenterologists, but is also one of the most common gastrointestinal conditions seen by the attending physician (see Everhart et al. al . , 1991; Sandler, 1990).

IBS is also an expensive disorder. Compared to people without bowel symptoms, people with IBS miss three times as many working days and are more likely to report that they are too sick to be able to work (Drossman et al. , 1993; Drossman et al. , 1997). In addition, people with IBS incur health care costs of hundreds of dollars more than people without bowel disorders (Talley et al. , 1995).

There are no specific abnormalities due to exacerbation and alleviation of abdominal pain and altered bowel habits experienced by IBS patients. The evolutionary theory of IBS suggests dysregulation at different levels of the brain-intestinal axis. Movement disorders, visceral hypersensitivity, abnormal modulation of the central nervous system (CNS), and infection are all implicated. In addition, psychosocial factors play an important transforming role. Abnormal bowel movements have long been considered the etiology of IBS. The time required to pass through the small intestine after eating was found to be shorter in diarrhea-predominant IBS patients than in patients with constipation- or pain-dominated subtypes (Cann et al. , 1983).

In a small intestine study during fasting, both discontinuous cluster contractions and prolonged proliferative contractions were reported in IBS patients (Kellow and Phillips, 1987). They also experience pain with irregular contractions more frequently than healthy people (Kellow and Phillips, 1987; Horwitz and Fisher, 2001).

These motility findings are not due to the combination of overall symptoms in IBS patients, and in fact, most of these patients do not have obvious abnormalities (Rothstein, 2000). IBS patients have an increased sensitivity to visceral pain. Studies involving direct bowel instrument dilatation show that patients with IBS experience pain and bloating at much lower pressures and volumes than control subjects (Whitehead et al. , 1990). These patients maintain a normal perception of somatic stimulation.

A number of theories have been proposed to explain this phenomenon. For example, receptors in the intestine may have increased sensitivity in response to swelling or intraluminal contents. Neurons in the back horn of the spinal cord can have increased excitability. In addition, replacement in CNS processing of the senses may be included (Drossman et al. , 1997). Functional magnetic resonance imaging studies have recently shown that, compared to control studies, IBS patients have increased activation of the anterior target cortex, an important pain center, in response to painful rectal stimulation (Mertz et al. , 2000). .

Gradually, evidence suggests a relationship between infectious enteritis and subsequent development of IBS. Inflammatory cytokines can play an important role. Investigation of patients with a confirmed history of bacterial gastroenteritis (see: Neal et al . , 1997), 25% recorded constant changes in their bowel habits. The persistence of symptoms may be due to physiological stress during acute infection (Gwee et al. , 1999).

Recent data suggest that bacterial overgrowth in the small intestine may play a role in IBS symptoms. Suggest that there is. One study (see: Pimentel et al . , 2000), of the 202 IBS patients recommended for the hydrogen breath test, 157 (78%) had a positive test result for bacterial hyperplasia. Of the 47 subjects who underwent follow-up testing, 25 (53%) recorded improvement in symptoms (ie, abdominal pain and diarrhea) with antibiotic treatment.

IBS can provide a wide range of symptoms. However, abdominal pain and altered bowel habits remain as first characteristics. Abdominal discomfort is often described as spasmodic in nature and is located to the left of the lower quadrant, but the severity and location can vary widely. Patients can record diarrhea, constipation, or alternate episodes of diarrhea and constipation. Symptoms of diarrhea are usually described as small volumes of loose stool, and the stool is sometimes accompanied by a mucous discharge. Patients can also record abdominal bloating, urgency of excretion, incomplete defecation, and abdominal distention. Upper gastrointestinal symptoms such as gastroesophageal reflux, indigestion or nausea may also be present (Lynn and Friedman, 1993).

The persistence of symptoms is not an indication for further testing; This is characteristic of IBS, and is itself an expected symptom of the syndrome. More intensive diagnostic evaluation is directed to patients with worsening or changing symptoms. Indications for further testing also include the presence of warning symptoms, the onset of symptoms after age 50, and a family history of colon cancer. The examination may include a colonoscopy, a computed tomography of the abdomen and pelvis, and a barium examination of the small or large intestine.

R. Sjogren syndrome

The compounds and methods of the present invention can be used to treat patients with SS. Primary Sjogren syndrome (SS) primarily affects middle-aged women (female-to-male ratio 9:1), but is a chronic, slow-progressing systemic autoimmune disease that can occur in all ages, including childhood (Jonsson. et al . , 2002). It is characterized by lymphocyte infiltration and destruction of exocrine glands infiltrated by mononuclear cells including CD4+, CD8+ lymphocytes and B-cells (Jonsson et al. al . , 2002). In addition, outboard (systemic) expression is present in 1/3 of patients (Jonsson et al. , 2001).

Glandular lymphocyte infiltration is a progressive feature (Jonsson et al . , 1993), which, if widespread, can replace a large part of the institution. Interestingly, in some patients, glandular infiltrates are very similar to ectopic lymphatic microstructures in the salivary glands (denoted as extrauterine seed centers) (Salomonsson et al. , 2002; Xanthou et al. , 2001). In SS, ectopic GCs are defined as T and B cell aggregates of proliferative cells with a network of follicular dendritic cells and activated endothelial cells. These GC-like structures formed within the target tissue also express functionality with the production of autoantibodies (anti-Ro/SS and anti-La/SSB) (Salomonsson and Jonsson, 2003).

In other systemic autoimmune diseases, such as RA, factors important for ectopic GC have been identified. Rheumatic synovial tissue with GC has been shown to produce chemokines CXCL13, CCL21 and lymphotoxin (LT)-β (detected on follicular center and mantle layer B cells). Multiple regression analysis of these analytes identified CXCL13 and LT-β as single-lived cytokines predicting GC in rheumatoid synovitis (Weyand and Goronzy, 2003). Recently, CXCL13 and CXCR5 in the salivary glands have been shown to play an essential role in the inflammatory process by replenishing B and T cells and thus contributing to lymphocyte neoplasia and ectopic GC formation in SS (Salomonsson et al. , 2002).

S. psoriasis

The compounds and methods of the present invention can be used to treat patients with psoriasis. Psoriasis is a chronic skin disease of scaling and inflammation that affects 2 to 2.6% of the US population or 5.8 to 7.5 million people. Although the disease occurs in all age groups, it primarily affects adults. It appears almost equally in men and women. Psoriasis occurs when skin cells rise rapidly from their organs below the skin's surface and accumulate on the surface before they have a chance to mature. Usually this exercise (also called turnover) occurs in the mouth, and in psoriasis it can occur in just a few days. In its usual form, psoriasis causes patches of dark red (inflammatory) skin covered with silvery scales. These patches, sometimes referred to as plaques, generally feel itchy or sore. They often occur most frequently on the elbows, knees, other parts of the leg, scalp, waist, face, palms and soles, but they can occur on the skin somewhere in the body. The disease can also affect the fingernails, toenails, and soft tissues of the genitals and in the mouth. Although it is common for the skin around diseased joints to split, about 1 million people with psoriasis experience joint inflammation that produces symptoms of arthritis. This condition is called psoriatic arthritis.

Psoriasis is a skin disorder driven by the immune system, particularly comprising a form of white blood cells called T cells. Normally, T cells help protect the body from infection and disease. In the case of psoriasis, T cells are erroneously acted upon and activated to the extent that they induce inflammation of the skin cells and other immune responses that lead to rapid turnover. In about a third of these cases, a family history of psoriasis is present. Researchers studied multiple families infected with psoriasis and identified genes associated with the disease. People with psoriasis may notice that there is a time when their skin deteriorates and then improves. Conditions that can cause brightening include infection, stress, and climate change that dries out the skin. In addition, certain medications, including lithium and beta blockers that are prescribed for high blood pressure, can lead to breakout or exacerbation of the disease.

T. Infectious disease

The compounds herein may be useful in the treatment of infectious diseases, including viral and bacterial infections. As noted above, these infections can be associated with severe localized or systemic inflammatory reactions. For example, inflenza can cause severe inflammation of the lungs, and bacterial infection can cause a systemic hyper-inflammatory reaction, including overproduction of many inflammatory cytokines that are characteristic of sepsis. In addition, the compounds of the present invention may be useful for directly inhibiting the replication of viral pathogens. Previous studies have demonstrated that related compounds, such as CDDO, can inhibit the replication of HIV in macrophages (Vazquez et al. al . , 2005). Other studies have shown that inhibition of NF-κB signaling can inhibit inflenza virus replication, and that cyclopentenone prostaglandin can inhibit viral replication (Mazur et al. al . , 2007; Pica et al . , 2000).

VI. Pharmaceutical formulation and route of administration

The compounds of the present specification may be administered by various methods, for example, orally or by injection (eg, subcutaneous, intravenous, intraperitoneal, etc.). Depending on the route of administration, the active compound may be coated with a substance to protect it from the action of acids and other natural conditions that can inactivate the compound. They can also be administered by continuous perfusion/infusion of the disease or wound site.

In order to administer a therapeutic compound other than parenteral administration, it is necessary to coat the compound with a substance that inhibits its inactivation or to co-administer the compound with these substances. For example, the therapeutic compound can be administered to the patient in a suitable carrier, for example as a liposome or diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al. , 1984).

Therapeutic compounds can also be administered parenterally, intraperitoneally, in the spine or in the brain. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under normal conditions of storage and use, these preparations may contain preservatives to inhibit the growth of microorganisms.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (if water soluble) or dispersions and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, for example bacteria and fungi. The carrier may be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (eg glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof and vegetable oils. Adequate flowability can be maintained, for example, by the use of a coating, for example lecithin, with the maintenance of the required particle size in the case of dispersions and with the use of surfactants. Inhibition of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is desirable to include isotonic agents such as sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol in the composition. Prolonged absorption of the injectable composition can occur by including in the composition an agent that delays absorption, such as aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by introducing the therapeutic compound in the required amount in a suitable solvent with one or a combination of the ingredients listed above and then, if necessary, by filter sterilization. In general, dispersions are prepared by introducing the therapeutic compound into a sterile carrier containing a basic dispersion medium and other necessary ingredients from those listed above. In the case of sterile powders for preparing sterile injectable solutions, the preferred method of preparation is vacuum drying and freeze drying to produce a powder of the active ingredient (i.e. therapeutic compound) + additional desired ingredients from a pre-sterilized filtered solution thereof. to be.

The therapeutic compound can be administered orally, for example with an inert diluent or an assimilable edible carrier. Therapeutic compounds and other ingredients may also be contained in hard or soft shell gelatin capsules, compressed into tablets or introduced directly into the subject's diet. For oral therapeutic administration, the therapeutic compound can be introduced with excipients and used in the form of digestible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the composition and formulation can of course be variable. The amount of the therapeutic compound in such a therapeutically useful composition is such that a suitable dosage is obtained.

It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to a physically discrete unit suitable as a single dose to the subject to be treated, each unit comprising a predetermined amount of the therapeutic compound calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. Contains. The specification of the dosage unit form of the present invention includes (a) the unique properties of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the technical field of mixing the therapeutic compound for the treatment of a condition selected in a patient. Directed by, and accordingly.

The therapeutic compound can also be administered topically to the skin, eye or mucous membrane. Alternatively, if local delivery to the lungs is desired, the therapeutic compound can be administered by inhalation in dry powder or aerosol formulations.

The active compound is administered in a therapeutic dose sufficient to treat the condition associated with the condition in the patient. A "therapeutically effective amount" preferably determines the amount of symptoms of an infected patient's condition relative to an untreated subject by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, even more preferably. It is reduced by about 80% or more. For example, the efficacy of a compound can be assessed in an animal model system that can be a precursor to the efficacy of treating a disease in humans, for example, in the model system shown in the Examples and Figures.

The actual dosage of a compound of the present disclosure or a composition comprising a compound of the present disclosure administered to a subject is determined by physical and physiological factors such as age, sex, weight, severity of the condition, form of the disease to be treated, prior or simultaneous. It may depend on the therapeutic intervention, the subject's idiopathy and the route of administration. These factors can be determined by the skilled person. The healthcare practitioner responsible for administration typically determines the concentration of the active ingredient(s) in the composition and the dosage(s) suitable for the individual subject. Dosage can be adjusted by the individual physician in case of any complications.

Effective amounts are typically from about 0.001 mg/kg to about 1,000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg in one or more doses administered daily for one or several days (depending on the mode of administration and factors discussed above, of course). , From about 100 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg. Other suitable dosage ranges include 1 mg to 10,000 mg, 100 mg to 10,000 mg, 500 mg to 10,000 mg, and 500 mg to 1,000 mg per day. In some particular embodiments, the amount is less than 10,000 mg per day, such as in the range of 750 mg to 9,000 mg per day.

Effective amounts are less than 1mg/kg/day, less than 500mg/kg/day, less than 250mg/kg/day, less than 100mg/kg/day, less than 50mg/kg/day, less than 25mg/kg/day, or less than 10mg/kg/day I can. Alternatively, it may be in the range of 1 mg/kg/day to 200 mg/kg/day. For example, with regard to the treatment of a diabetic patient, the unit dose may be an amount that reduces blood sugar by 40% or more compared to an untreated subject. In another embodiment, the unit dose is an amount that reduces the blood sugar level to a level that is ±10% of the blood sugar level of a non-diabetic subject.

In other non-limiting examples, the dosage is also about 1 μg/kg/body weight, about 5 μg/kg/body weight, about 10 μg/kg/body weight, about 50 μg/kg/body weight, about 100 μg/weight per administration. kg/weight, about 200 μg/kg/weight, about 350 μg/kg/weight, about 500 μg/kg/weight, about 1 mg/kg/weight, about 5 mg/kg/weight, about 10 mg/kg/weight, about 50mg/kg/body weight, about 100mg/kg/body weight, about 200mg/kg/body weight, about 350mg/kg/body weight, about 500mg/kg/body weight to about 1,000mg/kg/body weight or more and any range derivable herein It may include. In a non-limiting example of a range derivable from the values listed herein, based on the values described above, about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 μg/kg/body weight to about 500 mg/kg/ It can be administered in a range such as body weight.

In certain embodiments, the pharmaceutical composition of the present disclosure may comprise, for example, about 0.1% or more of a compound of the present disclosure. In other embodiments, the compounds herein may comprise from about 2 to about 75% or from about 25 to about 60% by weight units and any range derivable herein.

Single or multiple doses of the formulation are expected. The preferred time interval for delivering multiple doses can be determined by a person skilled in the art using only routine experimentation. As an example, a subject may be administered two doses daily at about 12 hour intervals. In some embodiments, the formulation is administered once a day.

The agent(s) can be administered on a conventional schedule. As used herein, a typical schedule refers to any designated time. A typical schedule may include times of the same or different lengths as long as the schedule is predetermined. For example, a typical schedule is twice a day, every day, every two days, every three days, every four days, every five days, every six days, a week, a month, or a certain number of days or weeks in between. Each dose may be included. Alternatively, certain conventional schedules may include administration on a twice daily basis for the first week, followed by a daily basis for several months, and the like. In other aspects, the invention provides that the agent(s) can be orally ingested, the timing of which depends or does not depend on food intake. Thus, for example, the formulation can be taken every morning and/or every evening, regardless of when the subject ate or ate.

VII. Combination therapy

In addition to being used as monotherapy, the compounds herein may also find use in combination therapy. An effective combination therapy can be achieved simultaneously in a single composition or a pharmacological formulation comprising two agents, or two separate compositions or formulations, wherein one composition comprises a compound of the invention and the other comprises a second agent ( S). Alternatively, therapy may precede or follow other agent therapy at intervals of minutes to months.

Various combinations can be used, such as when the compound herein is “A” and “B” is the second agent, non-limiting examples of which are described below:

A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B

B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A

B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A

Administration of the compounds of the present specification to patients, in some cases, taking into account the toxicity of the drug, follows a general protocol for administering the drug. It is expected that the treatment cycle will be repeated as needed.

Beta interferon may be a suitable second agent. These are drugs derived from human cytokines that help regulate the immune system. These include interferon β-1b and interferon β-1a. Betacerone has been approved by the FDA for the regression form of secondary progressive MS. In addition, the FDA has approved the use of multiple β-interferons as a treatment for those who have experienced a single attack presenting multiple sclerosis and those who may be at risk of future attack and may be at risk of developing definite MS. For example, the risk of MS may be presented if an MRI scan of the brain reveals a lesion that predicts a high risk for conversion to clear MS.

Glatiramer acetate is a further example of a second agent that can be used in combination therapy. Glatiramer is currently used to treat relapsed palliative MS. It is made of four amino acids found in myelin. This drug is reported to stimulate T cells in the body's immune system, which transforms harmful pro-inflammatory agents into beneficial anti-inflammatory agents that act to reduce inflammation at the site of the lesion.

Another potent second agent is mitoxantrone, a chemotherapy drug used for many cancers. The drug is also FDA approved for the treatment of aggressive forms of relapsed palliative MS and certain forms of advanced MS. It is administered intravenously, usually every 3 months. This drug is effective, but is limited by cardiac toxicity. Novantrone has been approved by the FDA for secondary progressive, progressive-relapse and exacerbated relapse-remission MS.

Another strong second agent is natalizumab. In general, natalizumab acts by blocking the adhesion of immune cells to cerebrovascular vessels, which is an essential step in reducing the inflammatory action of immune cells on brain neurons by crossing immune cells in the brain. Natalizumab has been shown to significantly reduce the frequency of attacks in people with recurrent MS.

In the case of recurrent palliative MS, the patient can be administered a corticosteroid, such as methylprednisolone, as a second agent intravenously to terminate the attack soon and leave a slight persistent deficit.

Other common drugs for MS that can be used in combination with the oleanolic acid derivative of the present invention include immunosuppressive drugs such as azathioprine, cladribine and cyclophosphamide.

It is contemplated that other anti-inflammatory agents may be used with the treatment of the present invention. Arylcarboxylic acid (salicylic acid, acetylsalicylic acid, diflunisal, choline magnesium trisalicylate, salicylate, benorylate, flufenamic acid, mefenamic acid, meclofenamic acid and triflumic acid), arylalkanoic acid (diclofenac, fenkle Lofenac, Alclofenac, Penthiazac, Ibuprofen, Flurbiprofen, Ketoprofen, Naproxen, Fenoproxen, Fenbufen, Suprofen, Indoprofen, Thiaprofenic Acid, Benoxaprofen, Pirpro Pen, tolmethine, jomepirac, clofinac, indomethacin and sulindac) and enoleic acids (phenylbutazone, oxyfenbutazone, azapropazone, peprazone, piroxicam and isoxicam). Other COX inhibitors can be used. See U.S. Patent No. 6,025,395, which is incorporated herein by reference.

Histamine H2 receptor blockers including cimetidine, ranitidine, famotidine and nizatidine may also be used with the compounds of the present invention.

Treatment using acetylcholinesterase inhibitors, such as tacrine, donecortex, metriponate and rivastigmine, is envisaged to treat Alzheimer's disease and other diseases in combination with the compounds herein. Other acetylcholinesterase inhibitors, including rivastigmine and metriponate, can be developed that can be used once approved. Acetylcholinesterase inhibitors increase the amount of the neurotransmitter acetylcholine at the nerve endings by reducing its destruction by the enzyme cholinesterase.

MAO-B inhibitors, such as selegylene, can be used with the compounds of the present invention. Selegilene is used for Parkinson's disease and irreversibly inhibits monoamine oxidase form B (MAO-B). Monoamine oxidase is an enzyme that inactivates the monoamine neurotransmitters norepinephrine, serotonin and dopamine.

Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and etiology are nitric oxide (NO) or prostaglandins, such as acetyl-L-carnitine, octacosanol, evening primrose oil, vitamin B6, Dietary and nutritional supplements with recorded benefits for the treatment or prevention of tyrosine, phenylalanine, vitamin C, L-dopa or any other disease considered to be involved in the overproduction of combinations of multiple antioxidants are prepared with the compounds of the present invention. Can be used together.

For the treatment or prophylaxis of cancer, the compounds of the present invention can be used with radiation, chemotherapeutic agents such as cytotoxic agents such as anthracycline, vincristine, vinblastine, microtubule-targeting agents such as paclitaxel and Docetaxel, 5-FU and related agents, cisplatin and other platinum-containing compounds, irinotecan and topotecan, gemcitabine, temozolomide, etc., targeted therapy (e.g. imatinib, bortezomib, bevacizumab, rituximab, etc.) ) Or with one or more of the vaccine therapies designed to promote an enhanced immune response targeting cancer cells.

For the treatment or prevention of autoimmune diseases, the compounds of the present invention may be combined with one or more of corticosteroids, methotrexate, anti-TNF antibodies, other TNF-targeting protein therapy and NSAIDs. For the treatment or prophylaxis of cardiovascular diseases, the compounds of the present invention can be used in antithrombotic therapy, anti-cholesterol therapy, e.g., statins (e.g. atorvastatin) and surgical interventions, e.g. stenting or coronary artery bypass transplantation. Can be used together. For the treatment of osteoporosis, the compounds of the present invention can be combined with anti-osteosorbents, for example bisphosphonates or anabolic therapies, for example teriparatide or parathyroid hormones. For the treatment of neuropsychiatric conditions, the compounds of the present invention are used as antidepressants (e.g. imipramine or SSRIs, e.g. fluoxetine), antipsychotics (e.g. olanzapine, sertindol, risperidone), mood stabilizers (e.g. : Lithium, valproate semisodium), or other standard preparations, such as anxiolytics. For the treatment of neurological disorders, the compounds of the present invention can be used as anticonvulsants (e.g. valproate semisodium, gabapentin, phenytoin, carbamazepine and topiramate), antithrombotic agents (e.g. tissue plasminogen activators) or It may be combined with pain relievers (e.g. opioids, sodium channel blockers, and other anti-pain drugs).

For the treatment of oxidative stress related disorders, the compounds herein can be combined with tetrahydrobiopterin (BH4) or related compounds. BH4 is a cofactor for the constitutive form of nitric oxide synthase and can be reduced by reaction with peroxynitrite. Peroxynitrite is formed by the reaction of nitric oxide and superoxide. Thus, under conditions of oxidative stress, excessive levels of superoxide can reduce normal beneficial levels of nitric oxide by converting NO to peroxynitrite. The reduction of BH4 produced by reaction with peroxynitrite leads to "uncoupling" of nitric oxide synthase, causing them to form superoxides rather than NO. This adds to the oversupply of superoxide and prolongs the reduction of NO. The addition of exogenous BH4 can reverse this decoupling phenomenon to restore NO production and reduce the level of oxidative stress in tissues. This mechanism is expected to supplement the action of the compounds of the present invention, which, as discussed above and throughout the present invention, reduce oxidative stress by other means.

VIII. Example

The following examples are included to illustrate preferred embodiments of the present invention. It should be understood by those skilled in the art that the techniques described in the examples that follow represent techniques discovered by the inventors as sufficiently functioning in the practice of the invention, and thus can be regarded as constituting a preferred manner for their performance. do. However, those skilled in the art should understand that, in view of the present specification, many changes may be made in the specific embodiments described, and similar results may be obtained without departing from the spirit and scope of the present invention.

Example 1- Method and Materials

Nitric oxide production and cell viability. RAW264.7 macrophages were pretreated with DMSO or drug for 2 hours and then treated with recombinant mouse IFNγ (Sigma) for 24 hours. The NO concentration in the medium was measured using the Griess reagent system (Promega). Cell viability was measured using the WST-1 reagent (Roche).

STAT3 Phosphorylation. HeLa cells were treated with the indicated compounds and concentrations for 6 hours and then stimulated with 20 ng/ml of recombinant human IL-6 (R&D Systems) for 15 minutes. Lysates were either phosphorylated or immunoblotted with antibodies against total STAT3 (Cell Signaling).

NF - kB Activation. HeLa cells were cell-infected with pNF-kB-Luc (inducible, Stratagene) and pRL-TK (constitutive, Promega) reporter plasmids. After 24 hours, the cells were pretreated for 2 hours with the indicated compounds. DMSO serves as a vehicle control. After preliminary treatment, cells were stimulated with 20 ng/ml of recombinant human TNFα (BD Biosciences) for 3 hours. Reporter activity was measured using the DualGlo luciferase reporter system (Promega), and pNF-kB luciferase activity was normalized to pRL-TK luciferase activity. The overlapping induction of mean luciferase activity for unstimulated (-TNFα) samples is shown. Error bars represent SD of the mean of 6 samples.

IkBα degeneration. HeLa cells were treated with the indicated compounds and concentrations for 6 hours and then stimulated with 20 ng/ml of TNFα for 15 minutes. Lysates were blotted with antibodies against IkBα (Santa Cruz) and actin (Chemicon).

COX- 2 induction western Blot . RAW264.7 cells were pretreated with the indicated compounds for 2 hours and then stimulated for an additional 24 hours with 10 ng/ml IFNγ. COX-2 protein levels were analyzed by immunoblotting using antibodies from Santa Cruz. Actin was used as a load control.

Induction of Nrf2 target gene . MDA-MB-435 human melanoma cells were treated with vehicle (DMSO) or indicated compounds and concentrations for 16 hours. HO-1, thioredoxin reductase-1 (TrxR1), γ-glutamylcysteine synthase (γ-GCS), and ferritin heavy chain mRNA levels were quantified using qPCR and were in concurrent DMSO-treated samples. For standardization. The value is the average of the double wells. The primer sequence is as follows.

*HO-1 FW: TCCGATGGGTCCTTACACTC (SEQ ID NO:1),

HO-1 REV: TAGGCTCCTTCCTCCTTTCC (SEQ ID NO:2),

TrxR1 FW: GCAGCACTGAGTGGTCAAAA (SEQ ID NO:3),

*TrxR1 REV: GGTCAACTGCCTCAATTGCT (SEQ ID NO:4),

γ-GCS FW: GCTGTGGCTACTGCGGTATT (SEQ ID NO:5),

γ-GCS REV ATCTGCCTCAATGACACCAT (SEQ ID NO:6),

Ferritin HC FW: ATGAGCAGGTGAAAGCCATC (SEQ ID NO:7),

Ferritin HC REV: TAAAGGAAACCCCAACATGC (SEQ ID NO:8),

S9 FW: GATTACATCCTGGGCCTGAA (SEQ ID NO:9),

S9 REV: GAGCGCAGAGAGAAGTCGAT (SEQ ID NO:10).

Comparative compound . Some of the experimental results presented below and throughout this application provide data for the compounds discussed above as well as one or more of the triterpenoid derivatives presented in the table below.

Many of these compounds, including compounds 401, 402, 402-56 and 404, are described in Honda et al . (1998), Honda et al . (2000b), Honda et al . (2002), Yates et al. (2007), U.S. Patent No. 6,974,801, and U.S. Provisional Application Nos. 61/046,342, 61/046,352, 61/046,366, 61/111,269 and 61/111,294, all incorporated herein by reference. ]. The synthesis of other compounds is described in the following applications, filed concurrently with this application, each of which is incorporated herein by reference in its entirety [Reference: "Antioxidant Inflammation Modulators:" by Eric Anderson, Xin Jiang and Melean Visnick, filed on April 20, 2009. US patent application entitled "Oleanolic Acid Derivatives with Amino and Other Modifications At C-17"; US patent application entitled "Antioxidant Inflammation Modulators: Novel Derivatives of Oleanolic Acid" by Xin Jiang, Jack Greiner, Lester Maravetz, Stephen S. Szucs, Melean Visnick, filed April 20, 2009: April 20, 2009 As described in one or more of the US patent applications entitled "Antioxidant Inflammation Modulators: C-17 Homologated Oleanolic Acid Derivatives" by Xin Jiang, Xiaofeng Liu, Jack Greiner, Stephen S. Szucs, Melean Visnick, filed dated. It can be manufactured according to the method.

Measurement of aqueous solubility . The following procedure was used to obtain the aqueous solubility results summarized in Example 8.

Step 1. Determination of optimal UV/vis wavelength and standard curve generation for the compound of interest:

(1) For eight standard calibration curves (one plate), 34 mL of 50:50 (v:v) universal buffer: acetonitrile is prepared in a 50 mL tube.

(2) Using a multichannel pipette, dispense buffer: acetonitrile as follows (in μL) in a deep well plate:

(3) Using a multichannel pipette, dispense DMSO in the same plate as follows:

(4) Add 10 mM compound in DMSO into the plate as follows:

(5) Mix columns 1 and 2 by pipetting up and down 10 times, respectively. Mix columns 3 and 4 by pipetting up and down 10 times. Serially, dilute as follows (pipette up and down 10 times after each transfer):

Note: Columns 11 and 12 contain only DMSO, so the compound should not be transferred to these wells.

(6) Cover the plate with a lid and shake at room temperature for 20 minutes (200 to 300 rpm).

(7) All wells are mixed by pipetting up and down 10 times.

(8) Transfer 120 μL from each well to a UV transparent plate. Cover and shake for 3 to 5 minutes. Air bubbles in the wells are removed using a pipette.

(9) Read on a spectrophotometer from 220 nm to 500 nm in 10 nm increments.

Step 2. Compound Solubility Test Procedure using Millipore™ Multiscreen Solubility Filter Plates.

Consumer goods : Millipore™ Multiscreen ^R Soluble Filter Plate #MSSLBPC10

Greiner ^R 96-well disposable UV-star assay plate, VWR#655801

Greiner ^R 96-well polypropylene V-basal collection plate, VWR#651201

Universal aqueous buffer :

(a) 250 mL of nanopure water to prepare 500 mL of universal buffer; 1.36 mL (45 mM) ethanolamine; 3.08 g (45 mM) potassium dihydrogen phosphate; Add 2.21 g (45 mM) potassium acetate and mix thoroughly.

(b) Adjust the pH to 7.4 with HCl, and make 500 mL sufficiently with 0.15M KCl.

(c) Filter to remove particulates and reduce bacterial growth.

(d) Store in the dark at 4℃.

Solubility Protocol :

(a) 285 μL of universal aqueous buffer is added to the desired wells of a ^{Millipore™ Multiscreen R soluble filter plate.}

(b) Add 15 μL of 10 mM compound in DMSO to suitable wells. Only 15 μL of 100% DMSO is added to 6 wells of the blank filter plate.

(c) Mix wells by pipetting up and down 10 times using a multi-channel pipette. Be careful not to touch the filter in the plate with the tip.

(d) Cover the lid and gently shake the filter plate for 90 minutes at room temperature (200-300 rpm).

(e) Vacuum filtered aqueous solution from a multiscreen soluble filter plate in a polypropylene V-base plate.

(f) 60 μL of filtrate was applied to a UV transparent plate (Greiner ^R UV-Star analysis plate).

(g) 60 μL of acetonitrile is added to each well, and mixed by pipetting up and down 10 times.

(h) Cover and gently shake for 3 to 5 minutes. Remove air bubbles using a pipette.

(i) Measure the absorbance of each well in the plate on the spectrophotometer (UV/vis) at the desired wavelength. For compounds in plates with different absorbance peaks, set up a spectrophotometer to read the spectrum (e.g. 220 nm to 460 nm).

(j) The absorbance measured for each compound and the concentration are confirmed using a predetermined standard curve (see: Step 1).

Example 2- Synthesis of oleanolic acid derivative

The synthesis of compounds 402-02 and 402-51 starts from compound 1 (Scheme 1). Compound 1 was oxidized with bleach to give ketone 2 in 80% yield. Formylation of compound 2 with ethyl formate using sodium methoxide as a base gave compound 402-48 (70% yield), which was then treated with hydroxylamine hydrochloride in aqueous EtOH at 55° C. to obtain isoxazole 402 -49 was obtained in 93% yield. The cleavage of isoxazole under basic conditions gave α-cyanoketone 402-46 as a mixture in the form of ketone and enol in quantitative yield. Compound 402-46 was treated with 1,3-dibromo-5,5-dimethylhydantoin, and then HBr was removed using pyridine as a base to give compound 402-02 in 81% yield (compound 402-49 From), which was demethylated with LiI in reflux DMF to give acid 402-51 in 95% yield.

[Scheme 1]

Reagents and conditions available for Scheme 1 are as follows: (a) AcOH, bleach, room temperature, 1h, 80%; (b) HCO ₂ Et, NaOMe, 55° C., 24 h, 70%; (c) NH ₂ OH·HCl, 55° C., 16h, 93%; (d) NaOMe, 55° C., 2h, 100%; (e) (i) 1,3-dibromo-5,5-dimethylhydantoin, room temperature, 2h; (ii) pyridine, 55[deg.] C., 15h, 81%; (f) LiI, 160° C., 8h, 95%.

Compound 402-63 was oxidized with Dess-Martin periodinane to give aldehyde 402-64 in 47% yield (Scheme 2).

[Scheme 2]

Reagents and conditions available for Scheme 2 are as follows: (a) Death-Martin periodinane, NaHCO ₃ , room temperature, 1 h, 47%.

Synthesis of compounds 402-59 and 402-57 began with compounds 402-51. Compound 402-51 was treated with oxalyl chloride and catalytic DMF to give acid chloride 3. Compound 3 was treated with ammonia in methanol to give compound 402-59 (99% from compound 402-51). Dicyano compound 402-57 (45% yield) was obtained by dehydration of compound 402-59 using TFAA and Et _{3 N.}

[Scheme 3]

Reagents and conditions available for Scheme 3 are as follows: (a) (COCl) ₂ , DMF (catalyst), 0° C. to room temperature, 3 h; (b) NH ₃ (MeOH), 0° C. to room temperature, 5h, 99%; (c) TFAA, Et ₃ N, 0°C, 3h, 45%.

Compound 404-02 was synthesized from compound 3 as summarized in Scheme 4. Compound 3 was reacted with 2,2,2-trifluoroethylamine-HCl in toluene and water at 70° C. _{using NaHCO 3} as a base to give compound 404-02 in 69% yield.

[Scheme 4]

Reagents and conditions available for Scheme 4 are as follows: (a) 2,2,2-trifluoroethylamine-HCl, NaHCO ₃ , toluene, H ₂ O, 70° C., 69%.

[Scheme 5]

Reagents and conditions available for Scheme 5 are as follows: (a) LiAlH ₄ , THF, 0° C., 1.5 h, 38% for compound 4; For compound 5 34%; (b) NaOMe, 55° C., 7h, 94% for compound 6; 89% for compound 7; (c) (i) 1,3-dibromo-5,5-dimethylhydantoin, rt, 40 min; (ii) pyridine, 55° C., 25h, 35% for compounds 402-66; 32% for compound 63219.

Synthesis of compounds 402-66 started from isoxazole compounds 402-49. Reduction of the ketone in compounds 402-49 was _{achieved by treatment with LiAlH 4} in THF at 0° C. to give compounds 4 and 5 (as a 1:1 mixture of diastereomeric seat alcohols). Treatment of compound 4 with NaOMe in MeOH at 55° C. gives compound 6, which is present as a 3:2 mixture in the form of keto and enol tautomers. Compound 6 was brominated by treatment with 1,3-dibromo-5,5-dimethylhydantoin followed by pyridine followed by dehydrobromination to give compound 402-66 in 33% yield (from compound 4). . Using the same synthetic sequence, compound 5 was converted to compound 63219 in 28% total yield.

[Scheme 6]

Reagents and conditions available for Scheme 6 are as follows: (a) oxalyl chloride, rt, 2h; (b) NH ₂ NH ₂ -H ₂ O, 0° C., 30 min, 97%; (c) AcCl, Et ₃ N, rt, 1h, 77%; (d) NaOMe, rt, 10 min, 72%; (e) TsOH, 110° C., 1 h, 33%.

[Scheme 7]

Reagents and conditions available for Scheme 7 are as follows: (a) Et ₃ N, TFAA, rt, 1.5h, 85%; (b) Bu ₃ SnN ₃ , 150° C., 67%; (c)(i) HCO ₂ Et, NaOMe, 0° C. to room temperature, 1 h; (ii) NH ₂ OH·HCl, 60° C., 3h, 54%; (d) NaOMe, 55° C., 2h; (e) 1,3-dibromo-5,5-dimethylhydantoin, rt, 2h; (f) pyridine, 55° C., 16h, 60% for compound 63229; 69% for compound 63230; (g) TMSCHN ₂ , 0° C., 10 min, 77%.

[Scheme 8]

Reagents and conditions available for Scheme 8 are as follows: (a)i) NaOMe, HCO ₂ Et, 0° C. to room temperature; Concentrated HCl ii) NH ₂ OH-HCl, EtOH, H ₂ O, 60° C., 14h, 47%; (b) NaOMe, 55° C., 16 h, quantitative; (c)(i) 1,3-dibromo-5,5-dimethylhydantoin, room temperature, 3h; (ii) Pyridine, 55[deg.] C., 16h, 12%.

[Scheme 9]

Reagents and conditions available for Scheme 9 are as follows: (a) LiAlH ₄ , THF, 0° C., 2h, 19%; (b) NaOMe, 55° C., 7h, 92%; (c)(i) 1,3-dibromo-5,5-dimethylhydantoin, rt, 50 min; (ii) pyridine, 55°C, 7h, 56%.

[Scheme 10]

Reagents and conditions for Scheme 10: (a)(i) HCO ₂ Et, NaOMe, 0° C., 1.5 h; (ii) NH ₂ OH-HCl, 65° C., 3.5 h, 78%; (b) (i) oxalyl chloride, 0°C to room temperature, 2h; (ii) AcNHNH ₂ , Et ₃ N, 0° C. to room temperature, 30 minutes, 99%; (c) Laweson's reagent, 110° C., 30 minutes, 10% (for compound 21) and 29% (for compound 22); (d) NaOMe, 55° C., 2h, 73%; (e) (i) DBDMH, 0° C., 1 h; (ii) Pyridine, 55° C., 3h, 79%. Compound 18 is described in Honda et al. (2000a)].

[Scheme 11]

Reagents and conditions available for Scheme 11: (a) LAH, room temperature to 65° C., 1.5 h, 27%; (b) TEMPO, IPh(OAc) ₂ , room temperature, 72h, 77%; (c) (Ph ₃ PCH ₂ Cl) Cl/n-BuLi, THF, HMPA, 0° C. to room temperature, 87%; (d) MeLi, THF, 0° C. to room temperature, 91%; (e) PCC, NaOAc, CH ₂ Cl ₂ , room temperature, 78%; (f) HCO ₂ Et, NaOMe, 0° C. to room temperature; (g) NH ₂ OH·HCl, EtOH-H ₂ O, 60° C., 89% from compound 28; (h) NaOMe, 55° C., 3h; (i) DDQ, benzene, 85° C., 39% from compound 30.

[Scheme 12]

Reagents and conditions available for Scheme 12 are as follows: (a) HgSO ₄ , H ₂ SO ₄ , acetone/H ₂ O, 55° C., 20 h, 91%; (b)(i) 1,3-dibromo-5,5-dimethylhydantoin, 0°C, 3h; (ii) Pyridine, 55[deg.] C., 19h, 73%.

[Scheme 13]

Reagents and conditions for Scheme 13: (a) Benzyl bromide, DBU, 100° C., 6h, 65%.

[Scheme 14]

Reagents and conditions for Scheme 14: (a) MeONH ₂ -HCl, Et ₃ N, 40°C, 4h, 37%.

[Scheme 15]

Reagents and conditions for Scheme 15: (a) Me ₂ NH, 40° C., 71 h, 61%.

[Scheme 16]

Reagents and conditions available for Scheme 16 are as follows: (a) NH ₂ OH-HCl, NaOAc, EtOH, H ₂ O, 80° C., 27h, 72%; (b) NaOMe, MeOH, 55° C., 1 h; (c)(i) 1,3-dibromo-5,5-dimethylhydantoin, 0°C, 40 minutes; (ii) Pyridine, 55° C., 7h, 27% from compound 33.

[Scheme 17]

Reagents and conditions available for Scheme 17 are as follows: (a) POCl ₃ , pyridine, room temperature, 5h, 75%; (b) NaOMe, MeOH, 55°C, 4h, 93% (i) 1,3-dibromo-5,5-dimethylhydantoin, 0°C, 1h; (ii) Pyridine, 55[deg.] C., 23h, 93%.

[Scheme 18]

Reagents and conditions available for Scheme 18 are as follows: (a) m- CPBA, room temperature, 48h, 22%; (b) NaOMe, 55° C., 2h, 66%; (c)(i)DBDMH, 0°C, 1h; (ii) Pyridine, 55[deg.] C., 3h, 72%.

[Scheme 19]

Reagents and conditions available for Scheme 19 are as follows: (a) LiAlH ₄ , 0° C., 40 min, 62%; (b) NaOMe, 55° C., 2h, 83%; (c) (i) DBDMH, 0° C., 1 h; (ii) Pyridine, 55° C., 4h, 40%.

Example 3- Synthesis and characterization of oleanolic acid derivatives

Compound 2: Bleach (5.25% by weight of NaClO (aq), 129 mL, 91 mmol) was added to a stirred solution of Compound 1 (34.67 g, 71 mmol) in AcOH (471 mL) at room temperature. After stirring for 40 minutes, the reaction mixture was poured into ice water (1.5L) and stirred for 5 minutes. The white precipitate was collected by filtration and washed thoroughly with water. The filtered solid was dissolved in EtOAc, washed with NaHCO ₃ (aq) solution, dried over _{MgSO 4 and concentrated.} The obtained residue was purified by column chromatography (silica gel, 10 to 25% EtOAc in hexane) to give the product 2 (27.8 g, 80%) as a white effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.69 (s, 3H), 2.80 (m, 1H), 2.65 (d, 1H, J =4.0Hz), 2.53 (ddd, 1H, J =7.2,10.8,16.0Hz), 2.38 (ddd, 1H, J =3.6 ,6.8,16.0Hz), 2.16-2.30(m, 2H), 1.95(m, 1H), 1.89(m, 1H), 1.80(m, 2H), 1.62-1.73(m, 3H), 1.57(m, 2H), 1.47(m, 2H), 1.15-1.40(m,7H), 1.09(s, 3H), 1.05(s, 3H), 1.01(s, 3H), 0.99(s, 3H), 0.98(s , 3H), 0.95(s, 3H), 0.90(s, 3H); m/z 485.3 (M+1).

Compound 402-48: NaOMe solution (25% w/w in MeOH, 132.3 mL, 570 mmol) was added to a solution of Compound 2 (27.6 g, 57 mmol) in MeOH (250 mL) under nitrogen. The reaction mixture was heated to 55° C. in an oil bath, and HCO ₂ Et (93 mL, 1.15 mmol, 20 eq) was added dropwise through a dropping funnel. The reaction mixture was stirred at 55° C. for 24 hours and then at room temperature for an additional 40 hours. After evaporating off MeOH (150 mL), t- BuOMe (200 mL) was added and the mixture was cooled to 0°C. Then, 12N HCl(aq) (50 mL, 600 mmol, 10.5 eq) was added over 10 minutes, then the mixture was extracted with EtOAc. The combined extracts were washed with water, dried over _{MgSO 4 and concentrated.} The brown oil obtained was purified by column chromatography (silica gel, 5-10% EtOAC in hexane) to give the product 402-48 (20.5 g, 70%) as a white effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 14.89 (d, 1H, J =3.2Hz), 8.61(d, 1H, J =3.2Hz), 3.69(s, 3H), 2.80(m, 1H), 2.67(d, 1H, J=4.0Hz ), 2.20-2.34(m, 3H), 1.98(m, 1H), 1.62-1.92(m,6H), 1.10-1.56(m,10H), 1.20(s, 3H), 1.12(s, 3H), 1.02 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H); m/z 513.3 (M+1).

_{Compound 402-49: A mixture of compound 402-48 (20.3 g, 40 mmol) and NH 2} OH·HCl (4.12 g, 59 mmol) in EtOH (300 mL) and water (60 mL) was heated at 55° C. for 14 hours. After cooling to room temperature, EtOH was evaporated off, and the white slurry obtained was extracted with EtOAc. The combined organic extracts were washed with water, dried over _{MgSO 4 and concentrated.} The obtained residue was purified by column chromatography (silica gel, 10-20% EtOAc in hexane) to give the product 402-49 (18.8 g, 93%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 3.70 (s, 3H), 2.81 (m, 1H), 2.68 (d, 1H, J =4.4Hz), 2.37 (d, 1H, J=15.2Hz), 2.23-2.33 (m , 2H), 1.76-1.98(m,5H), 1.68(m, 3H), 1.11-1.62(m,9H), 1.32(s, 3H), 1.23(s, 3H), 1.02(s, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 0.91 (s, 3H), 0.84 (s, 3H); m/z 510.3 (M+1).

Compound 402-46: NaOMe (25% w/w in MeOH, 8.75 mL, 38 mmol) was added dropwise to a suspension (16.16 g, 31.7 mmol) of compound 402-49 in MeOH (55 mL) at 0° C. under _{N 2.} The reaction mixture was heated at 55° C. for 2 hours and then cooled to 0° C. t- BuOMe (150 mL) and 1N HCl (aq) (50 mL) were added successively, and the mixture was extracted with EtOAc. The combined organic extracts were washed with water _{, dried over MgSO 4} and concentrated to give compound 402-46 (17.80 g, 100%) as a white effervescent solid. Compound 402-46 is a mixture of two equilibrium forms, the enol form (shown in Scheme 1) and the ketone form in a 2:3 ratio. ¹ H NMR of the mixture: (400MHz, CDCl ₃ ) δ 5.69 (s, 0.4H), 3.87 (m, 0.6H), 2.80 (m, 1H), 2.65 (m, 1H), 0.82-2.30 (m, 44H) ); m/z 510.3 (M+1).

Compound 402-02: 1,3-dibromo-5,5-dimethylhydantoin (5.98 g, 20.9 mmol) was added to a solution of compound 402-46 (17.76 g, 35 mmol) in DMF (75 mL) at 10° C. Added. After stirring at room temperature for 2 hours, pyridine (8.5 mL, 105 mmol) was added and the reaction mixture was heated at 55° C. for 15 hours. After cooling to room temperature, the mixture was poured into water (700 mL) and stirred for 5 minutes. The pale brown precipitate was collected by filtration and washed with water. The solid _{was dissolved in CH 2} Cl ₂ , the solution was washed with 1N HCl (aq) and water, then dried over _{MgSO 4 and concentrated.} The obtained residue was purified by column chromatography (silica gel, 0-70% EtOAc in hexane) to give the product 402-02 (14.3 g, 81%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (s, 1H), 3.69 (s, 3H), 2.82 (m, 1H), 2.68 (d, 1H, J =4.4Hz), 2.44 (dd, 1H, J = 4.8, 16.0Hz), 2.35 (dd , 1H, J = 12.8, 16.0Hz), 1.86-2.00(m, 3H), 1.81(m, 1H), 1.60-1.71(m,4H), 1.42-1.55(m, 3H), 1.24(m, 1H) ), 1.10-1.24(m,4H), 1.22(s, 3H), 1.16(s, 3H), 1.15(s, 3H), 1.07(s, 3H), 0.99(s, 3H), 0.97(s, 3H), 0.92 (s, 3H); m/z 508.2 (M+1).

Compound 402-51: A nitrogen stream was bubbled through a stirred solution of Compound 402-02 (6.31 g, 12.4 mmol) and LiI (33.35 g, 248 mmol) in DMF (87 mL) at 160° C. for 8 hours. After cooling to 50° C., the reaction mixture was diluted with EtOAc (100 mL). Then, 1N HCl(aq) solution (30 mL) was added at room temperature, followed by stirring for 5 minutes. The mixture was extracted with EtOAc, and the combined organic extracts were washed with water, 10% Na ₂ S ₂ O ₃ (aq) and water, then dried over _{MgSO 4 and concentrated.} The obtained residue was purified by column chromatography (silica gel, _{5% to 50% EtOAc in CH 2} Cl ₂ ) to give acid 402-51 (6.02 g, 95%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.41 (bs, 1H), 7.65 (s, 1H), 2.80 (m, 1H), 2.74 (d, 1H, J =4.4Hz), 2.46 (dd, 1H, J = 4.8, 16.0Hz), 2.37 (dd , 1H, J = 12.8, 16.0Hz), 1.86-2.02(m,4H), 1.44-1.79(m,8H), 1.35(m, 1H), 1.12-1.29(m, 3H), 1.22(s, 3H) ), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 0.99 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H); m/z 494.3 (M+1).

Compound 402-64: NaHCO ₃ (78mg, 0.93mmol) and Deth-Martin periodinane (99mg, 0.23mmol) were continuously in a solution of compound 402-63 (45mg, 94mmol) _{in CH 2} Cl _{2 (5mL) at room temperature.} Added. After stirring for 1 hour, 5% Na ₂ S ₂ O ₃ (aq) solution was added. The reaction mixture was extracted with t- BuOMe, and the combined extracts _{were washed with NaHCO 3} (aq) solution, dried over _{MgSO 4 and concentrated.} The crude product obtained was purified by column chromatography (silica gel, 0% to 35% EtOAc in hexane) to give compound 402-64 (22 mg, 49%) as a white effervescent solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.33 (s, 1H), 7.62 (s, 1H), 2.61 (m, 1H), 2.50 (d, 1H, J= 4.4Hz), 2.45 (dd, 1H, J = 4.8,16.4Hz), 2.34 (dd , 1H, J=13.2,16.4Hz), 1.92-2.00(m, 2H), 1.88(m, 1H), 1.42-1.74(m,9H), 1.28-1.35(m, 2H), 1.21(s, 3H) ), 1.20(m, 1H), 1.15(s, 3H), 1.14(s, 3H), 1.12(m, 1H), 1.06(s, 3H), 0.97(s,6H), 0.93(s, 3H) ; m/z 478.2 (M+1).

Compound 402-59: To _{a solution of compound 402-51 (2.08 g, 4.21 mmol) in CH 2} Cl ₂ (28 mL) was successively added oxalyl chloride (1.07 mL, 12.64 mmol) and DMF (5 drops, catalyst) at 0° C. Added. The reaction was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated and dried in vacuo for 30 minutes to give acid chloride 3 as a yellow solid, which was used directly in the next step. Ammonia (2.0 M solution in MeOH, 11 mL, 22.00 mmol) was added to a solution of compound 3 (2.16 g, 4.21 mmol) in THF (28 mL) at 0°C. The reaction was warmed to room temperature and stirred for 5 hours. Then, the solvent was evaporated and the residue was extracted with EtOAc. The extract was washed with water, 1N HCl (aq) and water, _{then dried over MgSO 4} , filtered and concentrated to give compound 402-59 (2.06 g, 99%) as a pale yellow solid. A small amount (53 mg) was obtained by column chromatography. (Silica gel, CH ₂ Cl ₂ 0% to 25% EtOAc in) to give high purity compound 402-59 (14 mg, white solid) for biological assay: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (s, 1H), 5.63 (br s, 1H), 5.36 (br s, 1H), 2.90 (br d, 1H, J =5.2Hz), 2.71 (brd, 1H, J=12Hz), 2.42 (m , 2H), 1.96-2.10(m,4H), 1.78-1.90(m, 2H), 1.45-1.69(m,6H), 1.23-1.40(m,4H), 1.22(s, 3H), 1.16(s , 3H), 1.15 (s, 3H), 1.13 (s, 3H), 0.99 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H); m/z 493.3 (M+1).

Compound 402-57: A solution of compound 402-59 (2.01 g, 4.08 mmol) in _{CH 2} Cl _{2 (28 mL) was prepared and cooled to 0°C.} TFAA (0.91 mL, 6.55 mmol) and Et ₃ N (1.48 mL, 10.62 mmol) were added to this solution. After the reaction was stirred at 0° C. for 3 hours, it _{was quenched by adding a saturated NaHCO 3} (aq) solution (40 mL). After stirring for 10 minutes, the reaction mixture was extracted with _{CH 2} Cl _{2 and washed with saturated NaHCO 3} (aq), water, 1N HCl(aq) and water. The extract _{was dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 5% to 35% EtOAc in hexane). The purified product was polished with EtOH, then filtered and dried on a filter to give compound 402-57 (0.87 g, 45%) as a powdery white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (s, 1H), 3.04 (d, 1H, J =4.4Hz), 2.38-2.57 (m, 3H), 1.91-2.19 (m,5H), 1.61-1.78 (m,4H), 1.44-1.54 ( m, 3H), 1.32(s, 3H), 1.26-1.30(m,4H), 1.22(s, 3H), 1.19(s, 3H), 1.16(s, 3H), 0.99(s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); m/z 475.2 (M+1).

Compound 404-02: To a solution of compound 3 (3.03 g, 5.92 mmol) in toluene (84 mL) was added NaHCO ₃ (1.98 g). A solution of trifluoroethylamine hydrochloride (5.64 g, 41.62 mmol) in water (14 mL) was prepared and then added to the reaction. The reaction was heated to 70° C. and stirred for 2 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc and washed with brine. The combined extracts _{were dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, _{0% to 40% EtOAc in CH 2} Cl ₂ ) to give compound 404-02 (2.35 g, 69%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (s, 1H), 5.94 (br t, 1H, J =8Hz), 4.10 (m, 1H), 3.69-3.88 (m, 1H), 2.84 (d, 1H, J=8Hz), 2.78 (brd, 1H, J=16Hz), 2.38(m, 2H), 2.12(m, 1H), 2.06(m, 2H), 1.61-1.83(m,5H), 1.24-1.52(m,8H), 1.22 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H), 1.07 (s, 3H), 0.99 (s, 6H), 0.93 (s, 3H); m/z 575.3 (M+1).

Compounds 4 and 5: To a solution of compound 402-49 (395 mg, 0.775 mmol) in THF (7.8 mL) at 0°C was added LiAlH ₄ (1.0 M solution in THF, 0.78 mL, 0.780 mmol). After the reaction was stirred at 0° C. for 40 minutes, it was quenched by adding water (5 mL) and stirred for 5 minutes. The reaction mixture was extracted with EtOAc and washed with water. The emulsion was decomposed by addition of solid NaCl. The combined extracts _{were dried over Na 2} SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 10 to 70% EtOAc in hexane) to give compound 4 (151 mg, 38%) as a white solid and compound 5 (134 mg, 34%) as a white solid:

Compound 4: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.99 (s, 1H), 3.79 (m, 1H), 3.72 (s, 3H), 2.75 (m, 1H), 2.52 (d, 1H, J =14.4Hz), 1.95-2.11 (m, 2H), 1.57 -1.88(m, yyH), 1.24-1.54(m, yyH), 1.30(s, 3H), 1.20(s, 3H), 1.00(s, 3H), 0.93(s,6H), 0.92(s, 3H) ), 0.82 (s, 3H); m/z 512.3 (M+1).

Compound 5: m/z 494.3 (M-17), 434.3 (M-17-60).

Compound 6: To a solution of compound 4 (371 mg, 66 mmol) in MeOH (7.3 mL) was added NaOMe (25% by weight solution in MeOH, 0.42 mL, 1.837 mmol) at room temperature. The reaction was heated to 55° C. and stirred for 7 hours. After cooling the reaction to room temperature, the reaction mixture was diluted with MTBE (10 mL) and then quenched with 1N HCl (aq) (10 mL). The reaction mixture was extracted with EtOAc, washed with 1N HCl (aq) and brine. The combined extracts _{were dried over Na 2} SO ₄ , filtered and concentrated to give compound 6 (361 mg, 94%) as a white solid. Compound 6 is a mixture of two equilibrium forms, the enol form (shown in Scheme 5) and the ketone form in a 2:3 ratio. ¹ H NMR of the mixture: (400 MHz, CDCl ₃ ) δ 5.66 (d, 0.4H, J =4.8Hz), 4.09(br, 1H), 3.90(m,0.6H), 3.71(s,1.2H), 3.68(s,1.8H), 2.73(m, 1H) , 2.48 (m, 1H), 2.14-2.26 (m, 2H), 0.80-2.02 (m, 39H); m/z 494.3 (M-17), 434.3 (M-77).

Compound 402-66: A solution of compound 6 (361 mg, 0.705 mmol) in DMF (7.1 mL) was prepared. 1,3-dibromo-5,5-dimethylhydantoin (120mg, 0.420mmol) was added, and the reaction was stirred at room temperature for 1 hour. Pyridine (0.23 mL, 2.858 mmol) was added, and the reaction was heated to 55° C. and stirred for 10 hours. After cooling the reaction to room temperature, the reaction mixture was extracted with EtOAc and washed with 5% Na ₂ S ₂ O ₃ (aq), water, 1N HCl(aq) and water. The EtOAc extract _{was dried over Na 2} SO ₄ , filtered and evaporated. The crude product was purified by column chromatography (silica gel, 5% to 40% EtOAc in hexane) to give compound 402-66 (127 mg, 35% yield) as a white solid; ¹ H NMR (400MHz, CDCl ₃ ) δ 7.81 (s, 1H), 3.81 (ddd, 1H, J =4.8,10.8,15.6Hz), 3.72(s, 3H), 2.75(m, 1H), 2.01(m, 2H), 1.74-1.88(m, 3H), 1.24-1.72(m,15H), 1.19(s, 3H), 1.13(s, 3H), 1.12(s, 3H), 0.98(s, 3H), 0.96(s, 3H), 0.95(s , 3H), 0.94 (s, 3H); m/z 492.3 (M-17), 432.3 (M-77).

Compound 7: Compound 7 (96 mg, 89% yield) was prepared from compound 5 (108 mg, 0.211 mmol) using the procedure described for synthesizing compound 6 from compound 4: m/z 494.3 (M-17).

Compound 63219: Compound 63219 (30 mg, 32% yield) was prepared from compound 7 (95 mg, 0.186 mmol) using the procedure described for synthesizing compounds 402-66 from compound 6: ¹ H NMR (400 MHz, CDCl3 ) δ 7.81 (1H, s), 4.16 (1H, bs), 3.68 (3H, s), 2.44-2.54 (2H, m), 1.98-2.10 (2H, m), 1.78-1.94 (4H, m), 1.42-1.76 (7H, m), 1.00-1.42 (6H, m), 1.32 (3H, s), 1.23 (3H, s), 1.13 (3H, s), 1.11 (3H, s), 0.94 (3H, s), 0.93 (3H, s), 0.92 (3H, s); m/z 492.3 (M-17).

Compound 8: Oxalyl chloride (0.11 mL, 1.30 mmol) and a catalytic amount of DMF were successively added to a solution of compound 402-51 (200 mg, 0.41 mmol) _{in CH 2} Cl _{2 (4 mL) at 0°C.} The reaction mixture was warmed to room temperature and stirred for 2 hours. After evaporation of the solvent, the crude acid chloride was obtained as a pale yellow effervescent solid. Hydrazine hydrate (64% of hydrazine, 0.50 mL) was added to a solution of acid chloride _{in Et 2 O (8 mL) at 0°C.} After stirring for 30 minutes, CH ₂ Cl ₂ was added. The mixture was washed with water _{, dried over MgSO 4} , filtered and evaporated to give compound 8 (200 mg, 97% yield) as a white solid, which was used in the next step without further purification: m/z 508.3 (M +1).

Compound 9: Et ₃ N (0.12 mL, 0.86 mmol) and acetyl chloride (37 μL, 0.52 mmol) were sequentially added to a solution of compound 8 (200 mg, 0.39 mmol) _{in CH 2} Cl _{2 (4 mL) at room temperature.} After stirring for 30 minutes, Et ₃ N (0.36 mL, 2.59 mmol) and acetyl chloride (110 mL, 1.55 mmol) were added again. After stirring for an additional 30 minutes, the reaction was quenched by adding _{NaHCO 3 (aq.) solution.} The reaction mixture was transferred to a separatory funnel and extracted with EtOAc. The combined organic extracts were washed with water _{, dried over MgSO 4} , filtered and evaporated. The residue was purified by silica gel chromatography (0% to 75% EtOAc in hexane) to give compound 9 (180 mg, 77% yield) as a white effervescent solid: m/z 592.3 (M+1).

Compound 63264: NaOMe (25% w/w in MeOH, 0.14 mL, 0.61 mmol) was added to a solution of compound 9 (180 mg, 0.30 mmol) in MeOH (3 mL) at 0°C. After stirring at room temperature for 10 minutes, the reaction mixture was treated with t-BuOMe (10 mL) and 1N HCl (aq.) (1 mL), then transferred to a separatory funnel and extracted with EtOAc. The combined extracts _{were washed with NaHCO 3} (aq.) solution _{, dried over MgSO 4} , filtered and evaporated. The residue was purified by silica gel chromatography (0% to 100% EtOAc in hexane) to give compound 63264 (121 mg, 72% yield) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, 1H, J =4.4Hz), 7.77 (d, 1H, J=4.4Hz), 7.65 (s, 1H), 2.89 (d, 1H, J=4.4Hz), 2.82 (m, 1H), 2.34-2.45(m, 2H), 2.10(m, 1H), 2.08(s, 3H), 1.82-2.02(m,4H), 1.60-1.69(m, 3H), 1.44-1.53(m,4H), 1.16-1.40(m,4H), 1.22(s, 3H), 1.16(s, 3H), 1.15(s, 3H), 1.13(s, 3H), 0.99(s, 3H), 0.98(s, 3H) , 0.94(s, 3H); m/z 550.3 (M+1).

Compound 63267: A solution of compound 63264 (74 mg, 0.13 mmol) and TsOH (13 mg, 0.068 mmol) in toluene (5 mL) was heated to reflux for 1 hour with a Dean-Stark trap. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel _{, washed with NaHCO 3} (aq.) solution _{, dried over MgSO 4} , filtered and evaporated. The residue was purified by silica gel chromatography (0% to 100% EtOAc in hexane) to give compound 63267 (24 mg, 33% yield) as a white effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (s, 1H), 2.94 (m, 1H), 2.79 (d, 1H, J =4.4Hz), 2.54 (s, 3H), 2.46 (m, 1H), 2.34 (m, 1H), 2.21 (m , 1H), 1.84-2.06(m,5H), 1.56-1.70(m,4H), 1.24-1.47(m,5H), 1.23(s, 3H), 1.18(m, 1H), 1.15(s, 3H) ), 1.13 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H); m/z 532.3 (M+1).

Compound 11: Et ₃ N (1.46 mL, 10.49 mmol) and TFAA (0.88 mL, 6.33 mmol) was added sequentially to a solution of compound 10 (1.97 g, 4.20 mmol) _{in CH 2} Cl _{2 (42 mL) at 0°C.} After stirring for 1.5 hours, NaHCO ₃ (aq.) solution was added to the reaction mixture, which was then transferred to a separatory funnel and extracted with _{CH 2} Cl _2. The combined extracts _{were dried over MgSO 4} , filtered and evaporated. The residue was purified by silica gel chromatography (0% to 35% EtOAc in hexane) to give compound 11 (1.62 g, 85% yield) as a white solid: m/z 452.3.

Compound 12: A solution of Bu _{3 SnN 3} (1.00 mL, 3.62 mmol) and compound 11 (1.36 g, 3.02 mmol) in xylene (5.0 mL) was heated to reflux for 48 hours. After cooling to room temperature, the reaction mixture was subjected to silica gel chromatography (CH ₂ Cl ₂ 0% to 30% EtOAc in) to give compound 12 (994 mg, 67% yield) as a pale yellow effervescent solid: m/z 493.3 (M+1).

Compound 13: NaOMe solution (25% w/w in MeOH, 1.16 mL, 5.07 mmol) was added dropwise to a mixture of compound 12 (168 mg, 0.34 mmol) and HCO _{2 Et (0.82 mL, 10.19 mmol) at 0° C. under N 2} did. After stirring at room temperature for 1 hour, t- BuOMe (10 mL) was added. The mixture was cooled to 0° C., and 12N HCl(aq) (0.42 mL, 5.04 mmol) was added slowly. The mixture was transferred to a separatory funnel and extracted with EtOAc. The combined organic extracts were washed with water _{, dried over MgSO 4} and concentrated to give crude 2-formyl ketone, which was then NH ₂ OH HCl (36 mg, 0.51 mmol), EtOH (4 mL) and water (0.4 mL). And heated at 60° C. for 3 hours. After evaporation of EtOH, the obtained white slurry was transferred to a separatory funnel, and extracted with _{CH 2} Cl _2. The combined extracts were washed with water, dried over _{MgSO 4 and concentrated.} The residue was purified by column chromatography (silica gel, _{0% to 30% EtOAc in CH 2} Cl ₂ ) to give compound 13 (95 mg, 54% yield) as a white effervescent solid: m/z 520.3 (M+1) .

Compound 63229: Compound 63229 (12 mg, 60% yield) was prepared from compound 13 (20 mg, 0.038 mmol) using the procedure described for synthesizing compounds 402-66 from compound 4: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (s, 1H), 3.03 (m, 1H), 2.69 (d, 1H, J =4.0Hz), 2.52 (dd, 1H, J=4.4,16.8Hz), 2.29-2.36 (m, 2H), 1.96 -2.03(m, 3H), 1.56-1.82(m,6H), 1.25-1.57(m,6H), 1.22(s, 3H), 1.18(m, 1H), 1.13(s, 3H), 1.11(s , 3H), 1.04(s, 3H), 1.03(s, 3H), 0.98(s, 3H), 0.75(s, 3H); m/z 518.3 (M+1).

*Compound 14: TMSCHN ₂ ( _{2.0M in Et 2} O, 89 mL, 0.18 mmol) was added to a solution of compound 13 (84 mg, 0.16 mmol) in THF (1.25 mL) and MeOH (0.31 mL) at 0°C. After stirring at room temperature for 10 minutes, acetic acid was added to quench the reaction. The reaction mixture was diluted with EtOAc, transferred to a separatory funnel, washed with NaHCO ₃ (aq.) solution, dried over _{MgSO 4 and evaporated.} The residue was purified by column chromatography (silica gel, 0% to 60% EtOAc in hexane) to give compound 14 (67 mg, 77% yield) as a white solid: m/z 534.3 (M+1).

Compound 63230: Compound 63230 (45 mg, 69% yield) was prepared from compound 14 (65 mg, 0.12 mmol) using the procedure described for synthesizing compounds 402-66 from compound 4: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62 (s, 1H), 4.32 (s, 3H), 3.11 (m, 1H), 2.68 (d, 1H, J =4.4Hz), 2.42 (dd, 1H, J=4.8,16.4Hz), 2.27 (dd , 1H, J=13.2, 16.4Hz), 2.22(dd, 1H, J = 4.4, 14.8Hz), 1.94-2.04(m, 3H), 1.79(m, 1H), 1.54-1.63(m,5H), 1.36-1.50(m,4H), 1.26(m, 1H), 1.20(s, 3H), 1.13(m, 1H), 1.12(s, 3H), 1.09(s, 3H), 1.05(s, 3H) , 1.01 (s, 3H), 0.97 (s, 3H), 0.70 (s, 3H); m/z 532.3 (M+1).

Compound 63223: Using the procedure described for synthesizing compound 13 from compound 12, compound 63223 (1.95 g, 47% yield) was prepared from compound 15 (3.93 g, 7.12 mmol) as a pale yellow solid: ¹ H NMR ( 400 MHz, CDCl ₃ ) δ 7.98 (1H, s), 5.91 (1H, t, J= 6.0Hz), 4.00-4.15 (1H, m), 3.55-3.90 (1H, m), 2.72-2.82 (2H, m), 2.20-2.40(3H,m), 1.88-2.16(4H,m), 1.10-1.84(13H,m), 1.31(3H,s), 1.21(3H,s), 1.00(3H,s) , 0.98(6H,s), 0.91(3H,s), 0.82(3H,s); m/z 577.3 (M+H).

Compound 63227: Compound 63227 (1.64 g, quantitative yield) was prepared from compound 63223 (1.61 g, 2.79 mmol) using the procedure described for synthesizing compound 6 from compound 4: For the enol form, ¹ H NMR ( 400MHz, CDCl ₃ ): δ 5.91 (1H, t, J= 6.0Hz), 5.78 (1H, bs, enol), 4.00-4.16 (1H, m), 3.75-3.94 (1H, m), 2.70-2.85 (2H, m), 1.90-2.30 (5H, m), 0.80-1.88 (36H, m); m/z 577.3 (M+H) (for both enol and ketone isomers).

Compound 63237: A solution of the compound (1.61 g, 2.79 mmol) in DMF (9.3 mL) was prepared. 1,3-dibromo-5,5-dimethylhydantoin (456mg, 1.59mmol) was added, and the reaction was stirred at room temperature for 3 hours. Pyridine (0.67 mL, 8.33 mmol) was added, and the reaction was heated to 55° C. and stirred for 16 hours. After cooling the reaction to room temperature, the reaction mixture was extracted with EtOAc, washed with 5% Na ₂ S ₂ O ₃ (aq), 1N HCl(aq) and water. The EtOAc extract _{was dried over Na 2} SO ₄ , filtered and evaporated. Compound 63227 was the minimum component (18%) by crude LC-MS analysis. The crude product was purified by column chromatography (silica gel, 5% to 35% EtOAc in hexane) to give compound 63237 (188 mg, 12%) as a yellow effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (s, 1H), 3.82 (m, 2H), 2.91 (m, 1H), 2.54 (m, 1H), 2.41 (m, 1H), 2.08 (m, 1H), 1.83-1.94 (m, 2H) , 1.52-1.74 (m, 6H), 1.39 (s, 3H), 1.22 (s, 6H), 1.20-1.49 (m, 7H), 1.16 (s, 3H), 0.98 (s, 3H), 0.96 (s , 3H), 0.95 (s, 3H); m/z 573.3 (M+1).

Compound 16: Using the procedure described for synthesizing Compound 4 from Compound 402-49, Compound 16 (100 mg, 19% yield) was prepared from Compound 63223 (531 mg, 0.921 mmol): m/z 579.3 (M+ One).

Compound 17: Using the procedure described for synthesizing compound 6 from compound 4, compound 17 (90 mg, 92% yield) was prepared from compound 16 (98 mg, 0.169 mmol): m/z 561.3 (M-17) .

Compound 63268: Using the procedure described to synthesize compounds 402-66, compound 63268 (50 mg, 56% yield) was prepared from compound 17 (90 mg, 0.156 mmol): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (s, 1H), 6.09 (t, 1H, J= 6.4Hz), 4.06 (m, 1H), 3.89 (m, 1H), 3.78 (m, 1H), 2.70 (m, 1H), 1.98-2.05 (m, 2H), 1.84 (dd, 1H, J = 4.4,10.8Hz), 1.75 (ddd, 1H, J = 4.4, 13.6, 13.6Hz), 1.20-1.62 (m, 15H), 1.18 (s, 3H) ), 1.11(s, 3H), 1.10(s, 3H), 1.06(m, 1H), 0.98(s, 3H), 0.95(s, 3H), 0.94(s, 3H), 0.91(s, 3H) ; m/z 559.3 (M-17).

Compound 19: NaOMe (25 w/w% solution in MeOH, 7.29 mL, 31.88 mmol) was added to a solution of compound 18 (1.00 g, 2.12 mmol) in ethyl formate (5.13 mL, 63.78 mmol) at 0°C. After stirring for 1.5 hours, t- BuOMe (10 mL) and 12N (aq.) HCl (2.66 mL, 31.92 mmol) were sequentially added. After stirring for an additional 5 minutes, the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAc. The combined extracts were washed with water. The organic layer was separated _{, dried over MgSO 4} , filtered and concentrated. The crude product was _{mixed with NH 2} OH-HCl (0.22 g, 3.17 mmol), water (2 mL) and EtOH (35 mL). After heating the reaction mixture at 65° C. for 3.5 hours, EtOH was evaporated off. The residue was partitioned between EtOAc and water. The organic extract was separated _{, dried over MgSO 4} , filtered and evaporated. The residue was purified by silica gel chromatography (0% to 60% EtOAc in hexane) to give compound 19 (820 mg, 78% yield) as a white solid: m/z 496.3 (M+1).

Compound 20: Oxalyl chloride (110 μL, 1.30 mmol) was added to a solution of compound 19 (195 mg, 0.39 mmol) _{in CH 2} Cl _{2 (4 mL) at 0° C., followed by addition of a catalytic amount of DMF.} After the reaction was stirred at room temperature for 2 hours, CH ₂ Cl ₂ was evaporated under vacuum to give the acid chloride as a pale yellow effervescent solid. A _{solution of acethydrazide (50 mg, 0.67 mmol) in Et 3} N (113 μL, 0.81 mmol) and CH ₂ Cl ₂ (2 mL) was sequentially added to the acid chloride suspension in ether (4 mL) at 0°C. The reaction was warmed to room temperature and stirred for 30 minutes. Then EtOAc was added, and the crude mixture was transferred to a separatory funnel, which was washed with water, 1N (aq.) HCl, water. The organic layer was separated _{, dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 100% EtOAc in hexane) to give the product 20 (215 mg, 99% yield) as a white effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, 1H, J =5.2Hz), 8.05(d, 1H, J=5.2Hz), 8.00(s, 1H), 2.86(m, 2H), 2.34(m, 3H), 2.09(s, 3H) ), 1.80-2.18(m,8H), 1.34-1.74(m,7H), 1.33(s, 3H), 1.23(s, 3H), 1.16-1.26(m, 2H), 1.08(s, 3H), 1.00(s,6H), 0.93(s, 3H), 0.84(s, 3H).

Compound 21 and Compound 22: A suspension of Compound 20 (215 mg, 0.39 mmol) and Rawesone's reagent (190 mg, 0.47 mmol) in toluene was heated to reflux for 30 minutes. After cooling to room temperature, the reaction mixture was purified by column chromatography (silica gel, 0% to 65% EtOAc in hexane) to give the product 21 (21 mg, 10% yield) as a pale yellow effervescent solid: m/z 550.3 ( M+1). From the column, compound 22 (60 mg, 29% yield) was also obtained as a white effervescent solid: m/z 534.3 (M+1).

Compound 23: NaOMe (25 w/w% solution in MeOH, 17 μL, 0.074 mmol) was added to a solution of Compound 21 (33 mg, 0.060 mmol) in MeOH (0.6 mL) at room temperature. The reaction was then heated to 55° C. and stirred for 1 hour. After cooling to 0° C., t-BuOMe and 1N(aq.) HCl were added and stirred for 5 minutes. The reaction mixture was transferred to a separatory funnel, which was extracted with EtOAc. The combined EtOAc extracts were washed with water _{, dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 45% EtOAc in hexane) to give the product 23 (24 mg, 73% yield). Obtained as a white foamy solid: m/z 550.3 (M+1). Compound 23 is an isomeric mixture of ketones and enols.

Compound 63274: To a solution of Compound 23 (23 mg, 0.041 mmol) in DMF (0.3 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (6.1 mg, 0.021 mmol) at 0°C, The reaction was stirred at 0° C. for 1 hour. Then, pyridine (14 μL, 0.17 mmol) was added and the mixture was heated at 55° C. for 3 hours. After cooling to room temperature, the reaction was diluted with EtOAc, transferred to a separatory funnel, and washed with Na ₂ SO ₃ (aq.) solution and water. The organic layer was separated _{, dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 45% EtOAc in hexanes) to give product 63274 (18 mg, 79% yield) as a white effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (s, 1H), 2.97 (d, 1H, J =4.4Hz), 2.89 (m, 1H), 2.74 (s, 3H), 2.42 (dd, 1H, J=4.8, 16.4Hz), 2.29 (dd , 1H, J=13.6, 16.4Hz), 2.29(m, 1H), 2.02(m, 1H), 1.94(dd, 1H, J=4.8, 13.2Hz), 1.77-1.91(m, 3H), 1.52- 1.66(m,4H), 1.36-1.50(m,4H), 1.26(m, 1H), 1.19(s, 3H), 1.13(m, 1H), 1.11(s, 3H), 1.09(s, 3H) , 1.02(s, 3H), 1.00(s, 3H), 0.96(s, 3H), 0.80(s, 3H); m/z 548.3 (M+1).

Compound 24: A _{solution of LiAlH 4} (1.0 M in THF, 42 mL, 42 mmol) was added to a solution of Compound 1 (5.0 g, 10.3 mmol) in THF (100 mL) at room temperature under _{N 2.} After stirring at room temperature for 20 minutes, a LiAlH ₄ solution (1.0M in THF, 21 mL, 21 mmol) was added again and the reaction mixture was refluxed for 1 hour. After cooling to 0° C., water (10 mL) was added dropwise, followed by 1N HCl(aq) (300 mL). The mixture was extracted with EtOAc. The combined extracts were washed with water, dried over _{MgSO 4 and concentrated.} The obtained residue was _{mixed with CH 2} Cl ₂ (200 mL). The precipitated white solid was collected by filtration and washed with CH ₂ Cl ₂ (2x100 mL) to give compound 24 (500 mg, 10%) as a white solid. The combined filtrate was loaded onto a silica gel column and eluted with 0% to 100% EtOAc in hexanes to give additional compound 24 (800 mg, 17%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.79 (m, 1H), 3.54 (m, 2H), 3.20 (dd, 1H, J =4.8,10.8Hz), 1.98 (m, 1H), 1.12-1.88 (m,23H), 1.03 (s, 3H) , 0.98 (s, 6H), 0.91 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.77 (s, 3H), 0.65-1.10 (m, 3H); m/z 443.3 (MH ₂ O+1), 425.3 (100%, M-2xH ₂ O+1).

Compound 25: TEMPO (27mg × 4, 0.17mmol × 4) and IPh(OAc) ₂ (563mg ×4, 1.74mmol ×4) at room temperature for 0 hours, 2 hours, 24 hours and 48 hours CH ₂ Cl ₂ ( 200 mL) and water (0.1 mL) were added to a white slurry of compound 24 (725 mg, 1.59 mmol). After stirring at room temperature for 72 hours (total reaction time), the reaction mixture was changed to a clear pink solution, which was then transferred to a separatory funnel and _{washed with Na 2} SO ₃ (aq) solution. The organic phase was separated, _{dried over MgSO 4} , filtered and evaporated. The residue was purified by silica gel chromatography (0% to 75% EtOAc in hexane) to give compound 25 (560 mg, 77%) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.37 (d, 1H, J= 1.2Hz), 3.77(m, 1H), 3.18(dd, 1H, J = 4.8, 11.2Hz), 2.51(m, 1H), 0.98-1.87(m,23H), 0.97(s, 3H), 0.96(s, 3H), 0.94(s, 3H), 0.92(m, 1H), 0.90(s, 3H), 0.86(s, 3H), 0.82(s, 3H), 0.75(s, 3H), 0.65 (m, 1H); m/z 441.3 (MH ₂ O+1), 423.3 (M-2xH ₂ O+1).

_{Compound 26: To a stirred suspension of (Ph 3} PCH ₂ Cl) Cl (4.224 g, 12.1 mmol) in THF (13 mL) was added a solution of n- BuLi (4.8 mL, 11.64 mmol, 2.5M in hexane) at 0° C. It was added dropwise within minutes, then HMPA (2.4 mL) was added. The reaction was stirred at room temperature for 20 minutes, then compound 25 (1.332 g, 2.90 mmol) in THF (13.0 mL) was added within 1 minute. The reaction mixture was stirred at room temperature for 2 hours, then quenched with HCl (1N, 20 mL) and extracted with EtOAc (100 mL). The organic phase was washed with HCl (1N, 10 mL), NaCl (saturated, 20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 10% to 30% EtOAc in hexane) to give compound 26 (1.2508 g, 87.8%, mixture of E/Z isomers) as a white solid.

Compound 27: To a stirred solution of compound 26 (1.2508 g, 2.55 mmol) in THF (17 mL) was added dropwise a solution of MeLi (5.16 mL, 15.44 mmol, 3M in CH ₂ (OEt) _{2) within 1 minute at 0°C.} . The mixture was then stirred at room temperature for 28 hours and quenched with HCl (1N, 15 mL). The aqueous solution was extracted with EtOAc (2x100mL). The combined organic phases were washed with water and NaCl (saturated), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 27 (1.0630 g, 91.7%) as a white solid: m/z 437.3 (M- OH).

Compound 28: To a stirred mixture of Compound 27 (881.7 mg, 1.94 mmol) and NaOAc (628.6 mg, 4 eq.) in _{CH 2} Cl _{2 (40 mL) was added PCC (1.257 g, 3 eq.) in one portion at room temperature.} . The mixture was then stirred at room temperature for 5 hours and diluted with a solvent mixture of EtOAc/hexane (1:1, 50 mL). The mixture was loaded directly onto a pad of silica gel, then thoroughly eluted with a solvent mixture of EtOAc/hexane (1:1). The eluate was collected and concentrated to give a colorless crystalline product. This crude product was purified by column chromatography (silica gel, 0% to 10% to 25% EtOAc in hexane) to give compound 28 (685 mg, 78.8%) as a white solid: m/z 451.3 (M+1) .

Compound 29: To _{a stirred suspension of Compound 28 (22.0 mg, 0.0488 mmol) in HCO 2} Et (0.118 mL, 1.46 mmol) at 0° C. was added a solution of MeONa (0.167 mL, 0.732 mmol, 25% w/w in MeOH) Added. The mixture was then stirred at room temperature for 25 hours, diluted with TBME (1.4 mL) and quenched with HCl (0.126 mL, concentrated) followed by water (3 mL). The aqueous solution was extracted with EtOAc (10 mL). The combined organic phase was washed with brine (5 mL), Dried over Na ₂ SO ₄ , filtered and concentrated to give 29 as a pale yellow foam, which was used directly in the next step.

Compound 30: Compound 29 was dissolved in EtOH (2.1 mL). _{NH 2} OH·HCl (5.1 mg, 0.0732 mmol) and H ₂ O (0.27 mL) were added to this solution at room temperature. The mixture was heated at 60° C. for 18 hours and then cooled to room temperature. Organic volatiles were removed under vacuum. The resulting mixture was extracted with EtOAc (10 mL). The organic phase was washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 10% to 25% EtOAc in hexane) to give compound 30 (20.8 mg, 89.6% from compound 6) as a colorless crystalline solid: m/z 476.3 (M+1).

Compound 31: MeONa (23.8 μL, 0.105 mmol, 25% w/w in MeOH at 55° C. in a stirred suspension of compound 30 (20.8 mg, 0.0437 mmol) in a solvent mixture of MeOH (0.66 mL) and THF (0.11 mL) ) Was added. The mixture was then stirred at 55° C. for 3 hours, cooled to room temperature, and quenched with 1N HCl(aq) (5 mL). The mixture was extracted with EtOAc (15 mL). The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 31 as a pale yellow foam: m/z 476.3 (M-17).

Compound 63303: Compound 31 was dissolved in benzene (2 mL). To this solution was added a solution of DDQ (10.4 mg, 0.0458 mmol) in benzene (1 mL) at 85°C. The mixture was stirred at 85° C. for 1.5 hours, cooled to room temperature, and quenched with saturated NaHCO ₃ (aq) (5 mL). The mixture was extracted with EtOAc (30 mL). The organic phase was _{washed with saturated NaHCO 3} (aq) and brine, _{then dried over Na 2} SO ₄ , filtered and concentrated to give a solid residue (mixture of starting material and desired product), which was then pyridine (0.5 mL). _{Ac 2} O (50 μL) and DMAP (catalyst) were added to this solution at room temperature. The mixture was stirred at room temperature for 30 minutes and _{then quenched with NaHCO 3} (saturated). The mixture was extracted with EtOAc (20 mL). The organic phase was _{washed with NaHCO 3} (saturated), HCl (1N), brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a crude mixture, which was subjected to column chromatography (silica gel, 0% in hexane). -10% to 25% EtOAc) to give compound 63303 (8.1 mg, 39.1% from compound 30) as a colorless solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (s, 1H), 3.25 (d , 1H, J=4.0Hz), 2.25-2.52(m, 3H), 2.22(s, 1H), 1.78-2.15(m,5H), 1.44-1.76(m,9H), 1.08-1.36(m, 2H) ), 1.29(s, 3H), 1.23(s, 3H), 1.19(s, 3H), 1.17(s, 3H), 0.89(s, 3H), 0.94 (s, 3H), 0.91 (s, 3H) ; m/z 474.3 (M+1).

Compound 32: Compound 31 (95 mg, 0.2 mmol) was dissolved in a solvent mixture of acetone (3.5 mL) and water (1.5 mL). _{HgSO 4} (5.9 mg, 0.02 mmol) and H ₂ SO ₄ (2 drops, thick) were added to this solution at room temperature. The mixture was stirred at 55° C. for 20 hours, cooled to room temperature, and quenched with water (20 mL) and 1N HCl(aq) (10 mL). The mixture was extracted with EtOAc (30 mL). The organic phase was washed with 1N HCl (aq), water, saturated NaHCO ₃ (aq), brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a white solid, which was subjected to column chromatography (silica gel, 0%-10%-25% EtOAc in hexane) to give compound 32 (90.3 mg, 91.5%) as a white foam: m/z 494.3 (M+1).

Compound 63308: Compound 32 was converted to product TX63308 (36.1 mg, 73.4%) as a white foam using the procedure described for synthesizing product 63274 from compound 23: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (s , 1H), 2.75-2.85(m, 1H), 2.67(d, 1H, J=4.4Hz), 2.44 (dt, 1H, J=16.4, 4.8Hz), 2.35(dt, 1H, J=16.0, 13.2Hz), 2.16(s, 3H), 1.92-2.06(m, 3H), 1.30-1.76(m,12H), 1.18-1.29(m, 1H), 1.22(s, 3H) , 1.16 (s, 3H), 1.15 (s, 3H), 1.04 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H); m/z 492.3 (M+1).

Compound 63323: 1,8-diazabicyclo[5,4,0]undec-7-ene (0.18 mL, 1.204 mmol) was added to the compound 402-51 (402 mg, 0.814 mmol) in toluene (5.4 mL) at room temperature. Added to the suspension. After stirring for 2 minutes, benzyl bromide (0.12 mL, 1.009 mmol) was added. After the reaction mixture was heated at 100° C. for 6 hours, it was cooled to room temperature. The reaction was then diluted with EtOAc, transferred to a separatory funnel and washed with 1N HCl (aq) and brine. The organic extract was separated _{, dried over Na 2} SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 20% EtOAc in hexane) to give the product 63323 (308 mg, 65% yield) as a pale yellow effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (s, 1H), 7.30-7.37 (m, 5H), 5.21 (d, 1H, J =12.4Hz), 5.07 (d, 1H, J=12.4Hz), 2.84 (m, 1H), 2.47 (d , 1H, J=4.0Hz), 2.36 (dd, 1H, J=4.4, 16.0Hz), 2.17 (dd, 1H, J=13.6, 16.0Hz), 1.81-1.92 (m, 4H), 1.20-1.72 ( m, 12H), 1.19 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H), 0.99 (s, 3H), 0.90 (s, 6H), 0.65 (s, 3H); m/z 584.4 (M+1).

Compound 63325: MeONH ₂ -HCl (109 mg, 1.305 mmol), water (0.4 mL) and Et ₃ N (0.24 mL, 1.722 mmol) in a solution of compound 3 (439 mg, 0.857 mmol) in THF (4.2 mL) at room temperature It was added sequentially. The reaction was then heated at 40° C. for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc, transferred to a separatory funnel, and washed with 1N HCl (aq) and brine. The organic extract was separated _{, dried over Na 2} SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 10% to 75% EtOAc in hexane) to give the product 63325 (165 mg, 37% yield) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.63 (s, 1H), 3.76 (s, 3H), 2.86 (d, 1H, J =4.0Hz), 2.71 (m, 1H), 2.44 (dd, 1H, J=4.8, 16.4 Hz), 2.34 (dd, 1H, J=13.2, 16.4Hz), 1.91-2.08 (m, 3H), 1.74-1.90 (m, 2H), 1.59-1.68 (m, 3H), 1.40-1.50 (m, 4H), 1.21(s, 3H), 1.18-1.38(m, 4H), 1.15(s, 3H), 1.14(s, 3H), 1.12(s, 3H), 0.97(s, 3H), 0.96(s , 3H), 0.91 (s, 3H); m/z 523.4 (M+1).

Compound 63326: Me ₂ NH (2.0M in THF, 1.23 mL, 2.460 mmol) was added to a solution of compound 3 (408 mg, 0.797 mmol) in THF (4.1 mL) at room temperature. The reaction was then heated at 40° C. for 71 hours. Cooled to room temperature, the reaction was diluted with EtOAc, transferred to a separatory funnel, and washed with 1N HCl (aq) and brine. The organic extract was separated _{, dried over Na 2} SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 10 to 70% EtOAc in hexane) to give the product 63326 (254 mg, 61% yield) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 ( s, 1H), 3.06 (s, 6H), 2.97 (m, 1H), 2.29-2.42 (m, 2H), 1.94-2.06 (m, 3H), 1.74-1.85 (m, 2H), 1.61-1.67 ( m, 5H), 1.24-1.54 (m, 6H), 1.20 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 1.10 (m, 1H), 1.05 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H); m/z 521.4 (M+1).

Compound 33 : NH ₂ OH-HCl (705mg, 10.145mmol), NaOAc (1.169mg, 14.251mmol) and Water (3.3 mL) was added to a suspension of compound 402-49 (520 mg, 1.020 mmol) in EtOH (9.8 mL) at room temperature. After the reaction mixture was heated at 80° C. for 27 hours, it was cooled to room temperature. The reaction mixture was transferred to a separatory funnel, which was extracted with EtOAc. The combined organic extracts were washed with water and brine, _{then dried over Na 2} SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 20% EtOAc in hexane) to give the product 33 (387 mg, 72% yield) as a white solid: m/z 525.3 (M+1).

Compound 34: NaOMe (25 w/w% solution in MeOH, 0.12 mL, 0.525 mmol) was added to a solution of Compound 33 (128 mg, 0.244 mmol) in MeOH (1.2 mL) at room temperature. The reaction was then heated to 55° C. and stirred for 1 hour. After cooling to room temperature, the reaction was diluted with t- BuOMe (3 mL) and cooled to 0°C. 1N HCl(aq) (5 mL) was added. After stirring for an additional 5 minutes, the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAC. The combined EtOAc extracts were washed with water _{, dried over Na 2} SO ₄ , filtered and concentrated to give product 34 (131 mg) as a white solid: m/z 525.3 (M+1). Compound 34 is an isomeric mixture of C3 ketones and enols.

Compound 63295: 1,3-dibromo-5,5-dimethylhydantoin (40 mg, 0.140 mmol) in DMF (0.5 mL) was added to Compound 34 (126 mg, 0.240 mmol) in DMF (1.6 mL) at 0°C. Added to the solution. After stirring at 0° C. for 40 minutes, the reaction was treated with pyridine (40 μL, 0.495 mmol) and heated at 55° C. for 7 hours. After cooling to room temperature, brine was added and the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAC. The combined organic extracts were washed with brine, 10% Na ₂ SO ₃ (aq) solution, 1N HCl(aq) and water. The organic layer was separated and it _{was dried over Na 2} SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 20% EtOAc in hexane) to give the product 63295 (34 mg, 27% yield from compound 33) as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (s, 1H), 3.68 (s, 3H), 3.36 (dd, 1H, J=16.8, 4.8Hz), 2.82-2.91(m, 1H), 2.54(d, 1H, J=3.6Hz), 1.76-2.06 (m, 4H), 1.52-1.74 (m, 6H), 1.04-1.50 (m, 8H), 1.20 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H), 0.93 (s, 3H), 0.92 (s, 6H), 0.90 (s, 3H); m/z 523.3 (M+1);

Compound 35: _{POCl 3} (0.14 mL, 1.502 mmol) was added to a solution of Compound 33 (200 mg, 0.381 mmol) in pyridine (1.9 mL) at room temperature. After stirring for 5 hours, the reaction mixture was diluted with EtOAc (5 mL) and quenched with 1N HCl (aq) (5 mL). The reaction mixture was transferred to a separatory funnel, which was extracted with EtOAC. The combined organic extracts were washed with 1N HCl(aq) and brine, _{then dried over Na 2} SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 50% EtOAc in hexane) to give the product 35 (185 mg, 75% yield) as a colorless glassy solid: m/z 525.4 (M+1).

Compound 36: NaOMe (25w/w% solution in MeOH, 0.17 mL, 0.743 mmol) was added to a solution of compound 35 (177 mg, 0.337 mmol) in MeOH (1.7 mL) at room temperature. The reaction was then heated to 55° C. and stirred for 4 hours. After cooling to 0° C., t-BuOMe and 1N HCl(aq) were added and the reaction mixture was stirred for 5 minutes. Then, the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAc. The combined EtOAc extracts were washed with 1N HCl(aq) and brine, _{then dried over Na 2} SO ₄ , filtered and concentrated to give the product 36 (164 mg, 93% yield) as a white solid: m/z 525.4 ( M+1). Compound 36 is an isomeric mixture of C3 ketones and enols.

Compound 63296: 1,3-dibromo-5,5-dimethylhydantoin (53 mg, 0.185 mmol) in DMF (0.8 mL) was added to Compound 36 (163 mg, 0.311 mmol) in DMF (2.1 mL) at 0°C. Added to the solution. After stirring at 0° C. for 1 hour, the reaction was treated with pyridine (50 μL, 0.618 mmol) and heated at 55° C. for 23 hours. After cooling to room temperature, brine was added and the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAC. The combined organic extracts were washed with brine, 10% Na ₂ SO ₃ (aq) solution, 1N HCl(aq) and water, _{then dried over Na 2} SO ₄ , filtered, and concentrated to product 63296 (150 mg, 93% yield). Was obtained as a white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 5.57 (d, 1H, J=4.8Hz), 4.06(t, 1H, J=6.0Hz), 3.73(s, 3H), 2.68(dd, 1H, J=14.4, 10.4Hz), 2.48-2.60(m, 1H), 2.13(d, 1H, J=14.4Hz), 1.65-1.87(m, 3H), 1.19-1.64(m, 13H), 1.17(s, 3H), 1.13(s, 3H), 1.11(s, 3H), 1.06(s , 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.88 (s, 3H); m/z 523.3 (M+1).

Compound 37: m- CPBA (77%, 7.04 g, 31.52 mmol) was added to a solution of compound 402-49 (1.60 g, 3.15 mmol) _{in CH 2} Cl _{2 (28 mL) at room temperature.} After stirring for 8 hours, additional m- CPBA (77%, 3.52 g, 15.71 mmol) was added and the reaction was stirred for an additional 40 hours. Then, a _{solution of Na 2} SO ₃ (aq.) was added. After an additional 10 minutes, the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAC. The combined EtOAc extracts were washed with NaHCO ₃ (aq.) solution _{, dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 45% EtOAc in hexane) to give the product 37 (358 mg, 22% yield) as a white effervescent solid: m/z 526.3 (M+1).

Compound 38: NaOMe (25 w/w% solution in MeOH, 20 μL, 0.087 mmol) was added to a solution of Compound 37 (38 mg, 0.072 mmol) in MeOH (0.7 mL) at room temperature. The reaction was then heated to 55° C. and stirred for 2 hours. After cooling to 0° C., t-BuOMe and 1N(aq.) HCl were added. Then, the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAc. The combined EtOAc extracts were washed with water _{, dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 50% EtOAc in hexane) to give the product 38 (25 mg, 66% yield) as a white effervescent solid: m/z 526.4 (M+1). Compound 38 is an isomeric mixture of C3 ketones and enols.

Compound 63263: A solution of 1,3-dibromo-5,5-dimethylhydantoin (6.9 mg, 0.024 mmol) in DMF (0.2 mL) was added to Compound 38 (25 mg, 0.048) in DMF (0.8 mL) at 0°C. mmol). After stirring at 0° C. for 1 hour, the reaction was treated with pyridine (12 μL, 0.15 mmol) and heated at 55° C. for 3 hours. After cooling to room temperature, the reaction was diluted with EtOAc and transferred to a separatory funnel. This was _{washed with Na 2} SO ₃ (aq.) solution, 1N (aq.) HCl and water. The organic extract was separated, _{dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 45% EtOAc in hexane) to give the product 63263 (18 mg) as a white effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (s, 1 H ), 4.95 (d, 1H, J =7.2Hz), 3.73(s, 3H), 2.79(m, 2H), 2.37(d, 1H, J=14.4Hz), 1.92(m, 2H), 1.77(d , 1H, J=10.4Hz), 1.44-1.74(m, 8H), 1.20-1.41(m, 5H), 1.19(s, 3H), 1.15(s, 3H), 1.13(s, 3H), 1.08( s, 3H), 1.07 (s, 3H), 0.96 (s, 3H), 0.89 (s, 3H); m/z 524.3 (M+1).

Compound 39: LiAlH ₄ (2.0M in THF, 48 μL, 0.096 mmol) was added to a solution of Compound 37 (50 mg, 0.095 mmol) in THF (0.95 mL) at 0°C. After stirring for 40 minutes, the reaction was quenched by carefully adding water (1 mL). After stirring at room temperature for 10 minutes, the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAC. The combined organic extracts were washed with 1N (aq.) HCl and water _{, dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 40% EtOAc in hexane) to give product 39 (31 mg, 62% yield) as a white effervescent solid: m/z 528.3 (M+1). The stereochemical configuration of C12 was not assigned.

Compound 40: NaOMe (25 w/w% solution in MeOH, 16 μL, 0.070 mmol) was added to a solution of Compound 39 (30 mg, 0.057 mmol) in MeOH (0.6 mL) at room temperature. The reaction was then heated to 55° C. and then stirred for 2 hours. After cooling to 0° C., t-BuOMe and 1N(aq.) HCl were added. Then, the reaction mixture was transferred to a separatory funnel, which was extracted with EtOAc. The combined EtOAc extracts were washed with water _{, dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 40% EtOAc in hexanes) to give the product 40 (25 mg, 83% yield) as a white effervescent solid: m/z 510.3 (M-18+1) . Compound 40 is an isomeric mixture of C3 ketones and enols. The stereochemical configuration of C12 was not assigned.

Compound 63289: 1,3-dibromo-5,5-dimethylhydantoin (6.8 mg, 0.024 mmol) was added to a solution of compound 40 (25 mg, 0.047 mmol) in DMF (0.47 mL) at 0°C. After stirring at 0° C. for 1 hour, the reaction was treated with pyridine (12 μL, 0.15 mmol) and heated at 55° C. for 3 hours. After cooling to room temperature, the reaction was diluted with EtOAc, transferred to a separatory funnel, and washed with Na ₂ SO ₃ (aq.) solution, 1N(aq.) HCl and water. The organic extract was separated, _{dried over MgSO 4} , filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 40% EtOAc in hexane) to give the partially purified product 63289 (16 mg), which was again used as a preparative TLC plate (silica gel, 8% EtOAc in hexane). Elution) to give the product 63289 (10 mg, 40% yield) as a white effervescent solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (s, 1H), 5.12 (m, 1H), 4.33 ( d, 1H, J =6.8Hz), 3.71(s, 3H), 2.54(m, 1H), 2.43(d, 1H, J=2.8Hz), 1.21-1.96(m,18H), 1.19(s,6H) ), 1.13 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.88 (s, 3H); m/z 508.3 (M-18+1). The stereochemical configuration of C12 was not assigned.

Example 4- Ingestion of Compound 404-02 to CNS and Lungs of Monkey

Plasma concentration after oral administration: Compound 404-02 shows a high intake rate to the CNS and lungs of monkeys after oral administration: Compound 404-02 was administered to 2 male and 2 male cynomolgus monkeys by oral gavage. , 5, 25 or 75 mg/kg/day dose. Dosage was prepared in sesame oil, and individualized by body weight on the day of administration. Blood was collected before administration and on days 1 and 12 and at 1, 2, 4, 8 and 24 hours after administration. Blood samples were collected from the femoral artery/vein to determine compound 404-02 plasma concentration. Blood was placed in a tube containing K3EDTA and stored on ice until centrifugation at room temperature. Separated plasma was transferred to cryovial and stored at -80°C until sample processing and LC-MS/MS analysis. Extracted plasma standard curves were prepared from fresh stock solutions and analyzed before the samples were studied. Summary results are presented in Tables 3 and 4.

Population mean pharmacokinetic variable estimates were obtained by performing a noncompartmental analysis of 404-02 plasma concentration-versus-time data using ^{WinNonlin™ software version 5.2.} Over the irradiated dosage range, 404-02 is an increased oral clearance (Cl/F), _{a reciprocal shortening of the elimination half-life (T 1/2} ), and an apparent volume of distribution that increases with increasing dose (V _z /F). Showed dose-dependent kinematics. _{A 1.6-fold increase in the area under the concentration versus time curve for 24 hours} (AUC ₀ -24 hours) was observed at the 75 mg/kg dose level 12 days after dosing compared to the corresponding AUC on day 1. Condensation was not observed at any other dosage levels. _{The average maximal plasma concentrations (C max} ) observed for the 0.5, 5, 25 and 75 mg/kg/day dose groups on day 12 were 4.6, 12.7, 17.5 and 48.6 nM 404-02, respectively.

Table 3 shows the population mean plasma pharmacokinetics of 404-02 in cynomolgus monkeys (n=4) on study day 1. Pharmacokinetic parameters were obtained using noncompartmental analysis, WinNonlinTM version 5.2.

Plasma pharmacokinetics of 404-02 on day 1 Dosage (mg/kg/d) Average maximum 404-02 plasma concentration
(ng/mL)±SEM Average maximum 404-02 plasma concentration
(nM)±SEM 0.5 1.95±0.35 3.4±0.61 5 10.1±3.8 17.6±6.6 25 16.8±1.3 29.3±2.3 75 19.4±2.7 33.8±4.7

Plasma pharmacokinetics at day 12 404-02 Dosage (mg/kg/d) Average maximum 404-02 plasma concentration
(ng/mL)±SEM Average maximum 404-02 plasma concentration
(nM)±SEM 0.5 2.65±0.6 4.6±1.0 5 7.3±1.7 12.7±2.9 25 10.0±3.7 17.5±6.4 75 28.0±12.2 48.6±12.2

Table 4 shows the population mean plasma pharmacokinetics of 404-02 in cynomolgus monkeys (n=4) on study day 12. Pharmacokinetic parameters were obtained using noncompartmental analysis using ^{WinNonlin™ version 5.2 software.}

CNS and lung concentration after oral administration: In addition to the control (non-treatment) group containing 2 animals per sex, 2 male and 2 male cynomolgus monkeys were gavated with Compound 404-02 0.5, 5, 25 Alternatively, it was administered at a dose of 75 mg/kg/day. Animals were sacrificed about 3 hours after administration on the 15th day, and then brain and lung tissues were collected. Each sample collected was washed with 1x isotonic phosphate buffered saline and blotted dry before weighing. The collected tissue slices were transferred to a clear vial and stored at -80°C until treatment and LC-MS/MS analysis. A standard curve for 404-02 in this tissue homogenate was derived and used to quantify the 15 day sample.

The concentration of 404-02 required to inhibit 50% production of nitric oxide (NO) in interferon-gamma-stimulated macrophages is about 45 nM. As evidenced from the data, 0.5 mg/kg orally administered at the lowest dose in this study for 15 days induces an average 404-02 CNS concentration, 2,162 nM, which is a significant _{IC 50 value for NO production in vitro.} Exceeds. CNS penetration provides great therapeutic space at all doses tested (Table 2c). For example, after administration of 0.5, 5, 25 and 75 mg/kg/day 404-02, the average 404-02 CNS concentration was 48, 44, 37 and 75 compared to the dose required to inhibit inflammation in vitro. It indicates that it is more than twice as long. For comparison, the average 404-02 lung tissue exposure at 75 mg/kg/day 404-02 showed a 133-fold increase (Table 2d). A nonlinear arrangement of 404-02 was observed in the CNS and lung tissue, suggesting that 404-02 is taken up by the saturable mechanism(s) for membrane cross-transport and/or intercellular binding. In addition, concentrations of 404-02 in monkey CNS and lung tissue exceed plasma levels. Table 5 shows the population mean 404-02 cynomolgus monkey CNS tissue exposure at day 15. Table 6 shows the population mean 404-02 cynomolgus monkey lung tissue content on day 15.

CNS tissue content/concentration on day 15 of 404-02 Dosage (mg/kg/day) Average 404-02 CNS tissue content
(ng/g)±SEM Average 404-02 CNS tissue concentration
(nM) ^* ±SEM 0.5 1198±712 2087±1239 5 1090±564 1900±982 25 930±352 1618±612 75 1898±496 3305±864 * Conversion based on the assumption that the density of the tissue is equal to 1 g/mL of water

Lung tissue content/concentration on day 15 of 404-02 Dosage (mg/kg/day) Average 404-02 lung tissue content
(ng/g)±SEM Average 404-02 lung tissue concentration
(nM) ^* ±SEM 0.5 705±292 1227±508 5 24±15 55±27 25 141±50 246±87 75 3405±824 5929±1435

Example 5- Intake of 404-02 into the CNS and lungs of rats

Compound 404-02 reaches high concentrations in the lungs and CNS of rats after oral administration: To evaluate basic pharmacokinetic parameters after oral administration, Compound 404-02 was administered to 9 male and 9 magnetic Sprague Dawley (SD) rats. 02 was administered at a dose of 1, 10 or 50 mg/kg through gavage. The dosage was prepared in sesame oil, and individualized with the body weight on the day of administration. Blood was collected at 0, 1, 2, 4, 8 and 24 hours after administration on days 1 and 15. Blood was collected from the Anhwa cavity after inhalation of carbon dioxide/oxygen to determine the 404-02 plasma concentration. Plasma was transferred to Creevial and stored at -80°C until treatment and LC-MS/MS analysis. The summary results for days 1 and 15 are shown in Tables 2a and 2b, respectively. A standard curve was derived for 404-02 in rat plasma, and the quantification of the experimental results was based on this standard curve.

Table 7 shows the population mean plasma pharmacokinetics of 404-02 in SD rats (n=9/sex/dose level) on study day 1. Pharmacokinetic parameters were obtained using noncompartmental analysis, WinNonlinTM version 5.2.

Pharmacokinetic parameters on day 1 Dosage (mg/kg/day) Average maximum 404-02 plasma concentration
(ng/mL)±SEM Average maximum 404-02 plasma concentration
(nM)±SEM One 3.3±0.65 5.7±1.1 10 66±16.5 116±28.7 50 713±98.2 1241±171

Table 8 shows the population mean plasma pharmacokinetics of 404-02 in SD rats (n=9/sex/dose level) on study day 15. Pharmacokinetic parameters were obtained using noncompartmental analysis, WinNonlin ^™ version 5.2.

Pharmacokinetic parameters on day 15 Dosage (mg/kg/day) Average maximum 404-02 plasma concentration
(ng/mL)±SEM Average maximum 404-02 plasma concentration
(nM)±SEM One 6.3±0.9 11.0±1.6 10 144±24.3 210±42.3 50 1129±114 1966±199

To test tissue concentration after oral administration, 5 male and 5 male Sprague Dawley (SD) rats were administered 404-02 by gavage at 1, 10, 50 or 150 mg/kg/day. The dosage was prepared in sesame oil, and individualized according to the body weight on the day of administration. Animals were sacrificed about 3 hours after administration on the 15th day of the study, and then brain and lung specimens were collected. Each sample collected was washed with 1x isotonic phosphate buffered saline and blotted dry before weighing. Tissue slices were transferred to Creevial and stored at -80°C until processing and LC-MS/MS analysis. Summary results for CNS and lung samples are presented in Tables 9 and 10, respectively. Standard curves for 404-02 of these tissues were derived.

Population mean 404-02 CNS tissue content in SD rats on day 15 Dosage (mg/kg/day) Average 404-02 CNS tissue content
(ng/g=ng/mL) ^* ±SEM Average 404-02 CNS tissue concentration
(nM) ^* ±SEM One 29±6.8 51±11.8 10 421±99 733±173 50 750±108 1306±188 150 640±82 1114±143 * Conversion based on the assumption that the density of the tissue is equal to 1 g/mL of water

Population mean 404-02 lung tissue content in SD rats on day 15 Dosage (mg/kg/day) Average dh404 lung tissue content
(ng/g=ng/mL) ^* ±SEM Mean dh404 lung tissue concentration
(nM) ^* ±SEM One 558±123 972±215 10 4032±928 7020±1616 50 7165±1221 12474±2126 150 9719±1643 16921±2860 * Conversion based on the assumption that the density of the tissue is equal to 1 g/mL of water

Example 6-Comparison of Rodent Toxicity of Compound 402 and 402-02

The study was conducted on Sprague Dawley rats using compounds 402 and 404-02. Animals were administered orally once daily for 7 days. The low dose 402 group had elevated total bilirubin and GGT levels as well as suppressed weight gain. All high-dose animals treated with 402 were sacrificed at death on day 6 prior to study completion. GGT and total bilirubin levels were also high in these animals. However, toxicity assessed by clinical observation, weight gain, GGT and total bilirubin was not observed in all animals treated with 402-02 (Table 11). In a second study involving oral administration to Sprague-Dawley rats for 14 days, 402-02 achieved blood levels comparable to 402. However, no significant toxicity assessed by weight loss, clinical observation, and GGT and total bilirubin increase for the control group at doses of 1,500 mg/m ^{2 /day or less for 14 days was observed, which was observed at room temperature A in this species.} It is 50 times higher than the 402's MTD.

Comparison of compounds 4020-02 and 402 for rodent toxicity Time/Dose Level Survival rate Weight vs. control GGT(U/L) Total bilirubin (mg/dL) Day 7 Study-Crystalline Forms of 402 and 402-02 Vehicle control 4/4 (100%) 100% <5 0.13 402- 60mg/m ² /day 4/4 (100%) 35% 8.7 0.25 402- 180mg/m ² /day 0/4 (0%) NA 5.0 0.78 402-02- 60mg/m ² /day 4/4 (100%) 106% <5 0.20 402-02-180mg/m ² /day 4/4 (100%) 132% <5 0.20 14-day study-crystalline form of 404-02 Vehicle control 10/10 (100%) 100% <5 0.20 402-02- 60mg/m ² /day 10/10 (100%) 95% <5 0.24 402-02- 180mg/m ² /day 5/5 (100%) 102% <5 0.22 402-02- 600mg/m ² /day 5/5 (100%) 96% <5 0.20 402-02- 1500mg/m ² /day 5/5 (100%) 105% <5 0.20

Example 7- Comparison of toxicity in mice

In this study, six compounds (401, 402, 404, 401-2, 402-2 and 404-2) were evaluated for toxicity in a 14-day study in mice. Each compound was formulated in sesame oil and administered daily at 10, 50, 100 or 250 mg/kg (n = 4/group) by gavage. At high doses (above 10 mg/kg/day), 401 and 402 both induced a mortality rate of 50% or higher; 404 was non-toxic. In contrast, no mortality was observed in the 402-2 and 404-02 groups, only the highest dose of 401-02 induced mortality (Table 12). Body weight measurements (Figures 29-31) were consistent with mortality observations. The two highest doses of 401 and 402 were fatal within 4 days, in contrast to the effects of 401-2 and 402-2.

Mortality observed in 14-day toxicity study Group Compound Dose
(mg/kg) Schedule N Number
of Deaths Comments One vehicle QD14, D1-14 4 0 2 401 10 QD14, D1-14 4 0 3 401 50 QD14, D1-14 4 2 4 401 100 QD14, D1-14 4 4 5 401 250 QD14, D1-14 4 4 6 401-02 10 QD14, D1-14 4 0 7 401-02 50 QD14, D1-14 4 One* *Due to gavage injury 8 401-02 100 QD14, D1-14 4 0 9 401-02 250 QD14, D1-14 4 One Sacrificed due to weightless on Day 11 10 402 10 QD14, D1-14 4 0 11 402 50 QD14, D1-14 4 4 12 402 100 QD14, D1-14 4 4 13 402 250 QD14, D1-14 4 4 14 402-02 10 QD14, D1-14 4 0 15 402-02 50 QD14, ID1-14 4 0 15 402-02 100 QD14, D1-14 4 0 17 402-02 250 QD14, D1-14 4 0 la 404 10 QD14, D1-14 4 0 19 404 50 QD14, D1-14 4 0 20 404 100 QD14, D1-14 4 0 21 404 250 QD14, D1-14 4 0 22 404-02 10 QD14, D1-14 4 0 23 404-02 50 QD14, D1-14 4 0 22 404-02 100 QD14, D1-14 4 0 23 404-02 250 QD14, D1-14 4 0

In the second experiment, only six additional compounds with different degrees of saturation or unsaturation of the C ring were administered orally daily for 9 days using sesame oil as vehicle to test toxicity in mice. In this study, no significant toxicity was observed. The deaths of both animals were due to gavage errors during administration of the test item. Compared to the vehicle treated control, no significant weight difference was observed in any group. The results are summarized in Table 13 below. As in the case of compounds 402-2, 401-2 and 404-2, compounds having a degree of saturation in the C ring exhibit consistently low toxicity in rodents. Compounds with insufficient saturation in the C ring exhibit significant rodent toxicity in some cases (eg 401 and 402). As expected, low rodent toxicity provides an advantage, as high rodent toxicity can be a significant complication in conducting preclinical studies required for the development and registration of therapeutic compounds for use in human or non-human animals.

Additional mouse toxicity results compound Dosage (daily, p.o.) Fatality rate 63112 3 mg/kg 0/5 10 mg/kg 0/5 30 mg/kg 1/5 63323 3 mg/kg 0/5 10 mg/kg 0/5 30 mg/kg 0/5 63324 3 mg/kg 0/5 10 mg/kg 0/5 30 mg/kg 0/5 63325 3 mg/kg 0/5 10 mg/kg 0/5 30 mg/kg 0/5 63166 3 mg/kg 0/5 10 mg/kg 0/5 30 mg/kg 0/5 63326 3 mg/kg 0/5 10 mg/kg 1/5 30 mg/kg 0/5

Example 8- Aqueous solubility of oleanolic acid derivatives

The aqueous solubility of the compounds presented herein was determined using the procedure outlined in Example 1.

Compound ID(s) rescue Water soluble ( mM) 63097(402)

1.46 63102(dh404)

0.06 63198

163.6 63202

1.89 63208

9.49 63214

112.2 63219

13.58 63221

8.78 63226

0.71 63231

1.23 63232

0.75 63237

5.16

* * * * * * * * * * * * * * * *

All of the methods described and claimed herein can be made and performed without undue experimentation in light of this specification. Although the compositions and methods of the present invention have been described with respect to preferred embodiments, it is understood that various modifications can be applied to the steps and sequence of steps of the methods and methods described herein without departing from the concept, spirit and scope of the present invention. It is self-evident to those skilled in the field. More specifically, it is apparent that certain chemically and physiologically relevant agents may be substituted with the agents described herein, but the same or similar results are achieved. All such similar substituents and modifications apparent to those skilled in the art are considered to fall within the spirit, scope and concept of the present invention as defined by the appended claims.

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<110> REATA PHARMACEUTICALS, INC. <120> ANTIOXIDANT INFLAMMATION MODULATORS: OLEANIC ACID DERIVATIVES WITH SATURATION IN THE C-RING <130> PM033214KR <150> 61/046,332 <151> 2008-04-18 <150> 61/111,333 <151> 2008-11-04 <160> 10 <170> KopatentIn 1.71 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 1 tccgatgggt ccttacactc 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 2 taggctcctt cctcctttcc 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 3 gcagcactga gtggtcaaaa 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 4 ggtcaactgc ctcaattgct 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 5 gctgtggcta ctgcggtatt 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 6 atctgcctca atgacaccat 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 7 atgagcaggt gaaagccatc 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 8 taaaggaaac cccaacatgc 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 9 gattacatcc tgggcctgaa 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Synthetic primer <400> 10 gagcgcagag agaagtcgat 20

Claims (1)

A compound selected from one of compounds of the formula:

(I),
In the formula, R _a is hydrogen, hydroxy, halo or amino; Or alkyl _(C≤8), alkenyl _(C≤8), alkynyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _{(C 8)} , alkoxy _{(C 8)} , alkenyloxy _{(C 8)} , alkynyloxy _{(C 8)} , aryloxy _{(C 8)} , aralkoxy _{(C 8)} , heteroaryloxy _(C≤8), hetero aralkoxy _(C≤8), acyloxy _(C≤8), alkylamino _(C≤8), alkoxyamino _(C≤8), dialkylamino _(C≤8), alkenyl _{(C? 8)} , heteroarylamino ₍ C _{? 8)} , heteroaralkylamino _{(C? 8)} , _{aralkylamino )} , Amido _{(C &lt}; _{= 8)} , or a substituted form of any of these groups, or a pharmaceutically acceptable salt or tautomer thereof;

(II),
Wherein, R _d is alkyl _(C≤8), alkenyl _(C≤8), aryl _(C≤8), aralkyl _(C≤8), heteroaryl _(C≤8), heteroaralkyl _{(C≤ 8)} , or a substituted form of any one of these groups, or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof;

(III),
_Wherein Y is heteroaryl _{(C? 8)} or substituted heteroaryl _{(C? 8)} , or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof;

(IV); And

(V).

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