HK1176291A

HK1176291A - Use of antioxidant inflammation modulators in manufacture of medicaments for treating obesity

Info

Publication number: HK1176291A
Application number: HK13103477.1A
Authority: HK
Inventors: 柯林．J．米尔; 华伦．赫夫
Original assignee: Reata Pharmaceuticals Holdings, LLC
Priority date: 2010-04-12
Filing date: 2011-04-12
Publication date: 2013-07-26

Description

Methods of treating obesity using antioxidant inflammation modulators

Background

This application claims priority benefits from U.S. provisional application 61/389,090 filed on day 10/1 of 2010 and U.S. provisional application 61/323,276 filed on day 12 of 2010, both of which are incorporated herein by reference in their entirety.

I. Field of the invention

The present invention relates generally to the fields of biology and medicine. More particularly, it relates to methods for the prevention and/or treatment of diseases, such as obesity, using Antioxidant Inflammation Modulators (AIMs).

II. Description of the related Art

Obesity has become a major health problem in the united states and other developed countries. In the united states, 65% of the adult population is considered overweight or obese, and over 30% of adults meet the criteria for obesity. The world health organization has estimated that more than 10 million adults worldwide are overweight, with 3 million people considered clinically obese (hotemisligiil, 2006). The incidence of obesity is also rapidly increasing in children in many countries. Obesity is a major risk factor for cardiovascular disease, stroke, insulin resistance, type 2 diabetes, liver disease, neurodegenerative disease, respiratory disease, and other serious diseases, and has been recognized as a risk factor for certain types of cancer, including breast cancer and colon cancer. In addition to its impact on physical health, obesity has significant adverse effects on quality of life and mental health. The already high incidence of obesity in many countries may increase due to an increasing sedentary lifestyle. In addition, some type of widely used antipsychotic drugs, particularly atypical antipsychotics, are associated with weight gain and increased risk of diabetes. These side effects present a barrier to patient compliance and significant other health risks to patients, as these drugs must be used over a long period of time to achieve adequate control of the mental symptoms, and patients with mental disorders often have poor compliance with the treatment.

Although it has been well established that weight loss can be achieved by reducing caloric intake and increasing physical activity, obesity has been a problematic problem in western countries, particularly in the united states. The discovery of safe and effective drugs to induce weight loss has been a major research goal for decades. However, drugs that have shown efficacy to date have significant side effects or only slight efficacy. For example, amphetamines have been used effectively as appetite suppressants, but have a strong risk of dependence and other side effects. The discovery of leptin, a peptide hormone that plays a major role in appetite regulation, is considered to be a potential breakthrough in the treatment of obesity, but in clinical trials, leptin is ineffective. Recently, cannabinoid receptor antagonists are under development as anti-obesity drugs, but have been shown to have unacceptable psychoactive side effects. Similarly, drugs designed to reduce fat absorption in the digestive tract are associated with significant gastrointestinal side effects.

Therefore, there is a clear need for new anti-obesity treatments. In particular, there is a need for anti-obesity treatments with limited side effects that can be safely used in combination with other drugs commonly used by obese patients, such as anti-diabetic drugs, anti-hypertensive drugs, cholesterol lowering agents and insulin. Thus, agents that can be used to treat obesity would represent a significant advance.

Disclosure of Invention

Thus, according to the present invention, there is provided a method of treating an overweight or obese subject with a selective activator of the antioxidant transcription factor Nrf2, such as an Antioxidant Inflammation Modulator (AIM), so as to reduce the subject's body weight. In some aspects, there is provided a method of reducing weight in a subject in need thereof, the method comprising administering to the subject an Antioxidant Inflammation Modulator (AIM) in an amount sufficient to reduce the weight of the subject. In some aspects, there is provided a method of pt in a subject in need thereof, the method comprising administering to the subject an Antioxidant Inflammation Modulator (AIM) in an amount sufficient to reduce the subject's body weight.

In some embodiments, the subject has excess body fat. In some embodiments, the subject is overweight. In some embodiments, the subject has a Body Mass Index (BMI) of 25kg/m²To 30kg/m². In some embodimentsThe subject is obese or exhibits one of a variety of symptoms of obesity. In some embodiments, the obesity is grade I. In some embodiments, the subject's BMI is 30kg/m²To 35kg/m². In some embodiments, the obesity is grade II. In some embodiments, the subject's BMI is 35kg/m²To 40kg/m². In some embodiments, the obesity is grade III. In some embodiments, the subject's BMI is 40kg/m²To 80kg/m². In some embodiments, the subject is a human subject.

In some variations of one or more of the embodiments above, the method reduces body weight of the subject by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65%. In some variations of one or more embodiments above, the method further selectively induces Nrf2 in the subject. In some variations of one or more of the embodiments above, the method further inhibits activation of NF- κ B in the subject.

In some variations of one or more of the embodiments above, the AIM is a compound of the formula:

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

hydrogen, hydroxy, alkyl_(C≤8)Substituted alkyl groups_(C≤8)Alkenyl radical_(C≤8)Substituted alkenyl groups_(C≤8)Alkoxy group_(C≤8)Or substituted alkoxy_(C≤8)(ii) a Or

R₁And R₂Are linked together and are alkanediyl_(C≤18)Alkenyldiyl group_(C≤18)(ii) a aryldiyl group_(C≤18)Alkoxy diyl group_(C≤18)Alkenyloxydiphenyl_(C≤18)Alkyl amino diyl group_(C≤18)Alkenylaminodiyl group_(C≤18)Or alkenylaminooxydiphenyl_(C≤18)；

Each R₃Independently are:

hydroxy, halo, oxo, amino, hydroxyamino, nitro, imino, cyano, azido, mercapto or thio;

alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkylene group(s)_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkoxyamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Acylamino group_(C≤12)Alkyl imino group_(C≤12)Alkenylimino radical_(C≤12)Alkynylimino group_(C≤12)Aryl imino group_(C≤12)Aralkyl imino group_(C≤12)Heteroaryl imino group_(C≤12)Heteroarylalkylimino radicals_(C≤12)Acylimino group_(C≤12)Or substituted versions of any of these groups; or

(R₃)_yAny two of R in₃Are linked together and are alkanediyl_(C≤18)Alkenyldiyl group_(C≤18)(ii) a aryldiyl group_(C≤18)Alkoxy diyl group_(C≤18)Alkenyloxydiphenyl_(C≤18)Alkyl amino diyl group_(C≤18)Alkenylaminodiyl group_(C≤18)Or alkenylaminooxydiphenyl_(C≤18)(ii) a And is

y is 0 to 8;

or a pharmaceutically acceptable salt or tautomer thereof.

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

Each R₃Independently are:

y is 0 to 8;

or a pharmaceutically acceptable salt or tautomer thereof.

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

Each R₃Independently are:

y is 0 to 7;

or a pharmaceutically acceptable salt or tautomer thereof.

In some embodiments, the AIM is a compound of the formula:

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

Each R₃Independently are:

y is 0 to 6;

or a pharmaceutically acceptable salt or tautomer thereof.

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

Each R₃Independently are:

y is 0 to 8;

or a pharmaceutically acceptable salt or tautomer thereof.

In some variations of one or more of the embodiments above, W is cyano, fluoro, or-CF₃。

wherein:

X₁and X₂Independently are:

hydrogen, hydroxy, halo, oxo, amino, hydroxyamino, nitro, imino, cyano, azido, mercapto or thio; or

Alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkylene group(s)_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkoxyamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Acylamino group_(C≤12)Alkyl imino group_(C≤12)Alkenylimino radical_(C≤12)Alkynylimino group_(C≤12)Aryl imino group_(C≤12)Aralkyl imino group_(C≤12)Heteroaryl imino group_(C≤12)Heteroarylalkylimino radicals_(C≤12)Acylimino group_(C≤12)Or substituted versions of any of these groups;

y is hydrogen, hydroxy, halo, amino, hydroxyamino, nitro, cyano, azido, mercapto, alkyl_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkoxyamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Or alkylsulfonylamino_(C≤12)(ii) a And is

Or a pharmaceutically acceptable salt or tautomer thereof.

In some embodiments, the AIM is bardoxolone methyl. In some embodiments, at least a portion of bardoxolone methyl exists as a crystalline form having an X-ray diffraction pattern (CuK α) comprising significant diffraction peaks at approximately 8.8, 12.9, 13.4, 14.2, and 17.4 ° 2 Θ. For example, in some embodiments, the X-ray diffraction pattern (CuK α) is substantially as shown in fig. 1A or fig. 1B. In some embodiments, at least a portion of the bardoxolone methyl is present as an amorphous form having an X-ray diffraction pattern (CuK α) and a T-ray diffraction pattern having a halo peak at approximately 13.5 ° 2 θ substantially as shown in figure 1C_g. In some embodiments, T_gValues range from about 120 ℃ to about 135 ℃. In some embodiments, T_gValues are in the range of about 125 ℃ to about 130 ℃.

In some variations of one or more of the embodiments above, a sufficient amount to reduce the subject's weight is a daily dose of about 0.1mg to about 30mg of AIM.

In some variations of one or more of the embodiments above, the AIM is administered orally, intra-arterially, or intravenously. In some variations of one or more of the embodiments described above, the AIM is formulated as a hard or soft capsule or tablet. In some variations of one or more of the embodiments described above, the AIM is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient, e.g., the excipient may be a methacrylic acid-ethyl acrylate copolymer. In some embodiments, the ratio of methacrylic acid to ethyl acrylate copolymer is 1: 1.

In some variations of one or more embodiments above, the subject's weight has been measured or will be measured. For example, in some embodiments, the subject's weight has been measured prior to administration of the AIM and will be measured after administration of the AIM.

In some variations of one or more of the embodiments above, the BMI of the subject has been measured or will be measured. For example, in some embodiments, the subject's BMI has been measured prior to administration of the AIM and will be measured after administration of the AIM.

In some variations of one or more embodiments above, the subject further has a renal disease, a cardiovascular disease, diabetes, an autoimmune disease, a respiratory disease, a neurodegenerative disease, a liver disease, an infectious disease, or a cancer, or has undergone or is about to undergo an organ or tissue transplant.

In some variations of one or more embodiments above, the subject does not also have kidney disease, cardiovascular disease, diabetes, autoimmune disease, respiratory disease, neurodegenerative disease, liver disease, infectious disease, or cancer, or has not or will not have undergone transplantation.

In some variations of one or more of the embodiments above, the subject has diabetes. In some variations of one or more of the embodiments above, the subject does not have diabetes. In some variations of one or more of the embodiments above, the subject exhibits one or more symptoms of diabetes. In some variations of one or more of the embodiments above, the subject does not exhibit any symptoms of diabetes. In some variations of one or more of the embodiments above, the subject has been identified as having diabetes. In some variations of one or more of the embodiments above, the subject has been identified as not having diabetes. In some variations of one or more of the embodiments above, the level of a diabetes marker in the subject has been measured or will be measured.

In some variations of one or more of the embodiments above, the subject has an elevated level of at least one biomarker associated with diabetes, cardiovascular disease, kidney disease, fatty liver disease, or metabolic syndrome. In some variations of one or more of the embodiments above, the subject does not have an elevated level of at least one biomarker associated with diabetes, cardiovascular disease, kidney disease, fatty liver disease, or metabolic syndrome. In some variations of one or more of the embodiments above, the subject does not have an elevated level of any one of the biomarkers associated with diabetes, cardiovascular disease, kidney disease, fatty liver disease, or metabolic syndrome. In some embodiments, the biomarker is a marker of insulin resistance, leptin resistance, adiponectin resistance, cardiovascular stress, or renal insufficiency. In some embodiments, the biomarker is a marker of insulin resistance. In some embodiments, the biomarker is fasting glucose or hemoglobin A1 c. In some embodiments, the biomarker is a marker of leptin resistance. In some embodiments, the biomarker is a marker of adiponectin resistance. In some embodiments, the biomarker is adiponectin. In some embodiments, the biomarker is a marker of cardiovascular stress. In some embodiments, the biomarker is circulating endothelial cells or C-reactive protein. In some embodiments, the biomarker is circulating endothelial cells. In some embodiments, the biomarker is iNOS-positive circulating endothelial cells. In some embodiments, the biomarker is a marker of kidney disease. In some embodiments, the biomarker is serum creatinine. In some embodiments, the biomarker is cystatin C. In some embodiments, the biomarker is uric acid.

In some variations of one or more of the embodiments above, the subject has Chronic Kidney Disease (CKD) or exhibits one or more symptoms of CKD. In some variations of one or more of the embodiments above, the subject does not have Chronic Kidney Disease (CKD). In some variations of one or more of the embodiments above, the subject does not exhibit any symptoms of CKD. In some variations of one or more of the embodiments above, the subject has been identified as having CKD. In some variations of one or more of the embodiments above, the subject has been identified as not having CKD. In some variations of one or more of the embodiments above, the level of a CKD marker in the subject has been measured or will be measured. In some embodiments, the CKD is characterized by a serum creatinine level of 1.3-3.0mg/DL when the subject is a human female or 1.5-3.0mg/DL when the subject is a human male. In some embodiments, the CKD is stage 4. In some variations of one or more of the embodiments above, the subject does not have stage 4 Chronic Kidney Disease (CKD).

In some variations of one or more of the embodiments above, the subject has Diabetic Nephropathy (DN) or exhibits one or more symptoms of DN. In some variations of one or more of the embodiments above, the subject does not have Diabetic Nephropathy (DN). In some variations of one or more of the embodiments above, the subject does not exhibit any symptoms of DN. In some embodiments, the subject has been identified as having a DN. In some embodiments, the subject has been identified as not having a DN. In some variations of one or more of the embodiments above, the level of a DN marker in the subject has been measured or will be measured.

In some variations of one or more of the embodiments above, administering the AIM results in an improvement in the subject's estimated glomerular filtration rate (eGFR). In some embodiments, the administering reduces serum creatinine levels in the subject. In some embodiments, the serum creatinine level in the blood of the subject has been measured or will be measured. In some variations of one or more of the embodiments above, a Blood Urea Nitrogen (BUN) level in the subject has been measured or will be measured.

In some variations of one or more of the embodiments above, the adiponectin level in the subject's blood has been measured or will be measured.

In some variations of one or more embodiments above, the level of angiotensin II in the subject has been measured or will be measured.

In some variations of one or more of the embodiments above, the subject has insulin resistance or exhibits one or more symptoms of insulin resistance. In some variations of one or more of the embodiments above, the subject does not have insulin resistance. In some variations of one or more of the embodiments above, the subject does not exhibit any symptoms of insulin resistance. In some embodiments, the subject has been identified as having insulin resistance. In some embodiments, the subject has been identified as not having insulin resistance. In some variations of one or more of the embodiments above, the level of an insulin resistance marker in the subject has been measured or will be measured. In some embodiments, the level of hemoglobin A1c in the subject has been measured or will be measured. In some embodiments, the subject's blood glucose level has been measured or will be measured. In some embodiments, the administering reduces the level of hemoglobin A1c or fasting glucose in the subject. In some embodiments, the level of fasting plasma glucose has been measured or will be measured in the subject. In some embodiments, the subject's insulin sensitivity has been measured or will be measured by the hyperinsulinemic euglycemic clamp test. In some embodiments, glucose utilization rate (GDR) has been measured or will be measured in the subject.

In some variations of one or more of the embodiments above, the subject has glucose intolerance or exhibits one or more symptoms of glucose intolerance. In some variations of one or more of the embodiments above, the subject does not have glucose intolerance. In some variations of one or more of the embodiments above, the subject does not exhibit any symptoms of glucose intolerance. In some embodiments, the subject has been identified as having glucose intolerance. In some embodiments, the subject has been identified as not having glucose intolerance. In some variations of one or more of the embodiments above, the level of a glucose intolerance marker in the subject has been measured or will be measured. In some embodiments, the level of hemoglobin A1c in the subject has been measured or will be measured. In some embodiments, the subject's blood glucose level has been measured or will be measured. In some embodiments, the administering reduces the level of hemoglobin A1c or fasting glucose in the subject. In some embodiments, the subject's fasting blood glucose level has been measured or will be measured. In some embodiments, the subject's insulin sensitivity has been measured or will be measured by the hyperinsulinemic euglycemic clamp test. In some embodiments, glucose utilization rate (GDR) has been measured or will be measured in the subject.

In some variations of one or more of the embodiments above, the subject has cardiovascular disease (CVD) or exhibits one or more symptoms of CVD. In some variations of one or more of the embodiments above, the subject does not have cardiovascular disease (CVD) or exhibits any symptoms of CVD. In some variations of one or more of the embodiments above, the subject does not exhibit any symptoms of CVD. In some variations of one or more of the embodiments above, the subject has been identified as having CVD. In some variations of one or more of the embodiments above, the subject has been identified as not having CVD. In some variations of one or more of the embodiments above, the level of a CVD marker in the subject has been measured or will be measured.

In some variations of one or more embodiments above, the number of Circulating Endothelial Cells (CECs) in the blood of the subject has been measured or will be measured. In some embodiments, the CECs are iNOS-positive circulating endothelial cells. In some embodiments, the administering further reduces the level of circulating endothelial cells in the subject. In some embodiments, the administering further reduces the level of hemoglobin A1c or fasting glucose in the subject.

In some variations of one or more of the embodiments above, the subject has or exhibits one or more symptoms of Fatty Liver Disease (FLD). In some variations of one or more of the embodiments above, the subject does not have Fatty Liver Disease (FLD) or exhibits no symptoms of FLD. In some variations of one or more of the embodiments above, the subject does not exhibit any symptoms of FLD. In some variations of one or more of the embodiments above, the subject has been identified as having FLD. In some variations of one or more of the embodiments above, the subject has been identified as not having FLD. In some variations of one or more of the embodiments above, the level of the FLD marker in the subject has been measured or will be measured.

In some variations of one or more of the embodiments above, the subject has been identified as having cancer. In some variations of one or more of the embodiments above, the subject has been identified as not having cancer. In some variations of one or more of the embodiments above, the subject has been identified as having cancer and diabetes. In some variations of one or more of the embodiments above, the subject has been identified as not having cancer and/or not having diabetes.

In some variations of one or more of the embodiments above, the non-obese subject does not significantly lose weight if the sufficient amount is administered to the non-obese subject.

In some embodiments, the compounds are formulated as hard or soft capsules, tablets, syrups, suspensions, solid dispersions, cachets (wafers), or elixirs. In some variations, the soft capsule is a gelatin capsule. In some variations, the compound is formulated as a solid dispersion. In some variations, the hard capsule, soft capsule, tablet, or cachet further comprises a protective coating. In some variations, the formulated compound comprises an agent that delays absorption. In some variations, the formulated compound further comprises an agent that increases dissolution or dispersion. In some variations, the compound is dispersed in a liposome, an oil-in-water emulsion, or a water-in-oil emulsion.

In some embodiments, a pharmaceutically effective amount is about 0.1mg to about 500mg of the compound per daily dose. In some variations, the daily dose is from about 1mg to about 300mg of the compound. In some variations, the daily dose is from about 10mg to about 200mg of the compound. In some variations, the daily dose is about 25mg of the compound. In other variations, the daily dose is about 75mg of the compound. In yet other variations, the daily dose is about 150mg of the compound. In other variations, the daily dose is from about 0.1mg to about 30mg of the compound. In some variations, the daily dose is about 0.5mg to about 20mg of the compound. In some variations, the daily dose is from about 1mg to about 15mg of the compound. In some variations, the daily dose is from about 1mg to about 10mg of the compound. In some variations, the daily dose is from about 1mg to about 5mg of the compound.

In some embodiments, the pharmaceutically effective amount is 0.01-25mg of the compound per kg of body weight per day. In some variations, the daily dose is 0.05-20mg of the compound per kg of body weight. In some variations, the daily dose is 0.1-10mg of the compound per kg of body weight. In some variations, the daily dose is 0.1-5mg of the compound per kg of body weight. In some variations, the daily dose is 0.1-2.5mg of the compound per kg of body weight.

In some embodiments, the pharmaceutically effective amount is administered as a single daily dose. In some embodiments, the pharmaceutically effective amount is administered in two or more doses per day.

In some embodiments, the subject is a primate. In some variations, the primate is a human. In other variations, the subject is a cow, horse, dog, cat, pig, mouse, rat, or guinea pig.

In another aspect, there is provided a method of reducing body weight in a subject, the method comprising administering to the subject a compound of the formula,

wherein the subject has been identified as (i) being overweight or obese; and (ii) does not have diabetes.

wherein:

(a) at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuK α) having a halo peak at approximately 13.5 ° 2 θ, and a T of about 120 ℃ to about 135 ℃, substantially as shown in FIG. 1C_g(ii) a And is

(b) Wherein the subject has been identified as

(i) Overweight or obese; and

(ii) does not suffer from diabetes.

In some embodiments, the subject is a human and the amount is a daily dose of 5mg to 50 mg. In some embodiments, the daily dose is about 10 mg. In some embodiments, the daily dose is about 20 mg. In some embodiments, the daily dose is about 40 mg.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. It is noted that merely because a particular compound is assigned to one particular formula does not mean that it may or may not belong to another formula.

Drawings

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIGS. 1A-C-RTA402 show X-ray powder diffraction (XRPD) patterns of form A and form B. Figure 1A shows unmicronized form a; figure 1B shows micronized form a; fig. 1C shows form B.

Figure 2-change in estimated GFR over time and magnitude of change in diabetic CKD patients treated with bardoxolone methyl for 24 weeks. Using the ITT population, based on the results of the longitudinal model, the estimated GFR changes for the dose group patients at 24 weeks. Data are expressed as mean ± standard error; n-57 (placebo, 25mg, and 75 mg); n-56 (150 mg).

Figure 3-change in body weight over time until the last dose was received. The figure compares the change in body weight over 52 weeks for the patient populations of examples 3 and 4. BL is the baseline. W is the number of weeks. D equals days.

Detailed Description

The present invention provides methods of using antioxidant inflammation modulator compounds that can be used, for example, to induce weight loss in patients with established obesity and its complications, with limited side effects. For example, bardoxolone methyl induces weight loss in clinically obese patients, while improving indicators of renal function, glycemic control and insulin resistance, as well as improving cardiovascular disease. This combined effect represents a significant advance in the state of the art. These and other aspects of the invention are described in more detail below.

Definition of

When used in the context of a chemical group, "hydrogen" refers to-H; "hydroxy" means-OH; "oxo" means ═ O; "halo" independently means-F, -Cl, -Br, or-I; "amino" means-NH₂(see the following definitions for amino-containing groups, such as alkylamino); "hydroxyamino" refers to-NHOH; "nitro" means-NO₂(ii) a Imino means NH (see below for definition of the term imino-containing groups, e.g. alkylimino); "cyano" means-CN; "azido" refers to-N₃(ii) a "phosphate" in the context of monovalent refers to-OP (O) (OH)₂Or a deprotonated form thereof; in the context of divalent, "phosphate" refers to-OP (O) (OH) O-or its deprotonated form; "mercapto" means-SH; "thio" means S; "thioether" means-S-; "sulfonamido" means-NHS (O)₂- (see below for the definition of the term sulfonamido-containing groups, e.g. alkyl sulfonamido); "Sulfonyl" means-S (O)₂- (see below for definitions of the term sulfonyl-containing groups, e.g. alkylsulfonyl); "sulfinyl" means-S (O) - (see below for the definition of the term sulfinyl-containing group, e.g., alkylsulfinyl); and "silyl" means-SiH₃(see the definition below for silyl-containing groups, e.g., alkylsilyl).

The symbol "-" refers to a single bond, "═ refers to a double bond, and" ≡ "refers to a triple bond. SymbolRepresents a single bond or a double bond. SymbolWhen drawn vertically across a bond indicates the point of attachment of the group. It is noted that for larger groups typically only the point of attachment is identified in this way in order to facilitate the reader's rapid and unambiguous identification of the point of attachment. SymbolMeans that the group attached to the butt end of the wedge-shaped line is "on the paperOut-of-plane "single bonds. SymbolRefers to the single bond "in the plane of the paper" of the group attached to the butt end of the wedge. SymbolRefers to a single bond wherein the configuration is unknown (e.g., R or S), the geometry is unknown (e.g., E or Z) or the compound is present as a mixture of configurations or geometries (e.g., a 50%/50% mixture).

When the group "R" is drawn on a ring system, for example a "floating group" in the following formula:

r may replace any hydrogen atom attached to any ring atom, including a drawn, implied or explicitly defined hydrogen, so long as a stable structure is formed.

When the group "R" is drawn to a fused ring system, such as a "floating group" in the formula:

r may replace any hydrogen attached to any ring atom of any fused ring unless otherwise specified. Alternative hydrogens include the depicted hydrogen (e.g., a hydrogen attached to a nitrogen in the above formula), implied hydrogens (e.g., a hydrogen of the above formula that is not shown but understood to be present), well defined hydrogens, and optionally hydrogens (the presence of which depends on the nature of the ring atoms (e.g., a hydrogen attached to group X when X is equal to-CH-), provided that a stable structure is to be formed.

When y is 2 and "(R)_y"is drawn as a floating group on a ring system having one or more ring atoms (with two replaceable hydrogens), such as a saturated ring carbon, for example when in the formula:

each of the two R groups may be located on the same or different ring atoms. For example, when R is methyl and two R groups are attached to the same ring atom, a gem-dimethyl group results. When specifically designated, two R groups may be joined together to form a divalent group, such as one of the divalent groups defined further below. When such divalent groups are attached to the same ring atom, a spiro ring structure will result.

In the case of double-bonded R groups (e.g., oxo, imino, thio, alkylene, etc.), any pair of implied or explicit hydrogen atoms attached to one ring atom may be replaced by an R group. This concept is exemplified as follows:

to represent

For the following groups, the following parenthetical subscripts further define the groups as follows: "(Cn)" definitionThe exact number of carbon atoms in the group (n). "(C.ltoreq.n)" defines the maximum number of carbon atoms (n) that can be present in a group, the minimum number of carbon atoms in such a group being at least 1, otherwise the number is as small as possible for the group in question, for example it is understood that in the group "alkenyl"_(C≤8)"the minimum number of carbon atoms is 2. For example, "alkoxy group_(C≤10)"denotes those alkoxy groups having from 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or any range derivable therein, such as 3 to 10 carbon atoms. (Cn-n ') defines the minimum (n) and maximum (n') values of carbon atoms in the group. Similarly, "alkyl group_(C2-10)"denotes those alkyl groups having from 2 to 10 carbon atoms, for example 2, 3, 4, 5, 6, 7, 8, 9 or 10, or any range derivable therein, for example 3 to 10 carbon atoms.

The term "alkyl", when used without the "substituted" modifier, refers to a non-aromatic monovalent group having a saturated carbon atom as the point of attachment, having a straight or branched chain, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. group-CH₃(Me)、-CH₂CH₃(Et)、-CH₂CH₂CH₃(n-Pr)、-CH(CH₃)₂(iso-Pr), -CH (CH)₂)₂(cyclopropyl), -CH₂CH₂CH₂CH₃(n-Bu)、-CH(CH₃)CH₂CH₃(sec-butyl), -CH₂CH(CH₃)₂(isobutyl), -C (CH)₃)₃(tert-butyl), -CH₂C(CH₃)₃(neopentyl), cyclobutyl, cyclopentyl, cyclohexyl and cyclohexylmethyl are non-limiting examples of alkyl groups. The term "substituted alkyl" refers to a non-aromatic monovalent group having a saturated carbon atom as the point of attachment, having a linear or branched, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and at least one atom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The following groups are non-limiting examples of substituted alkyl groups: -CH₂OH、-CH₂Cl、-CH₂Br、-CH₂SH、-CF₃、-CH₂CN、-CH₂C(O)H、-CH₂C(O)OH、-CH₂C(O)OCH₃、-CH₂C(O)NH₂、-CH₂C(O)NHCH₃、-CH₂C(O)CH₃、-CH₂OCH₃、-CH₂OCH₂CF₃、-CH₂OC(O)CH₃、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-CH₂CH₂Cl、-CH₂CH₂OH、-CH₂CF₃、-CH₂CH₂OC(O)CH₃、-CH₂CH₂NHCO₂C(CH₃)₃and-CH₂Si(CH₃)₃。

The term "alkanediyl", when used without the modifier "substituted", refers to a non-aromatic divalent group wherein the alkanediyl group is connected in two sigma-bonds, has one or two saturated carbon atoms as the point of attachment, has a linear or branched, cyclic or acyclic structure, has no carbon-carbon double or triple bonds, and has no atoms other than carbon and hydrogen. group-CH₂- (methylene), -CH₂CH₂-、-CH₂C(CH₃)₂CH₂-、-CH₂CH₂CH₂-andare non-limiting examples of alkanediyl. The term "substituted alkanediyl" refers to a non-aromatic monovalent group wherein an alkynediyl group is connected in two sigma-bonds, has one or two saturated carbon atoms as the point of attachment, has a linear or branched, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and at least one atom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The following groups are non-limiting examples of substituted alkanediyl groups: -CH (F) -, -CF₂-、-CH(Cl)-、-CH(OH)-、-CH(OCH₃) -and-CH₂CH(Cl)-。

The term "alkenyl", when used without the "substituted" modifier, refers to a monovalent group having a nonaromatic carbon atom as the point of attachment, having a straight or branched chain, cyclic, or acyclic structure, containing at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: -CH ═ CH₂(vinyl), -CH ═ CHCH₃、-CH＝CHCH₂CH₃、-CH₂CH＝CH₂(allyl), -CH₂CH＝CHCH₃and-CH ═ CH-C₆H₅. The term "substituted alkenyl" refers to a monovalent group having a non-aromatic carbon atom as a point of attachment, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, having a linear or branched, cyclic, or acyclic structure, and at least one atom is 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.

The term "alkenediyl", when used without the "substituted" modifier, refers to a non-aromatic divalent radical in which the alkenediyl is linked in two sigma-bonds, has two carbon atoms as points of attachment, has a linear or branched, cyclic or acyclic structure, contains at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The radicals-CH-, -CH-C (CH)₃)CH₂-、-CH＝CHCH₂-andare non-limiting examples of alkenediyl groups. The term "substituted enediyl" refers to a non-aromatic divalent group in which the enediyl group is linked in two sigma-bonds, has two carbon atoms as points of attachment, has a linear or branched, cyclic, or acyclic structure, contains at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and at least one atom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and SAnd (4) grouping. The following groups are non-limiting examples of substituted alkenediyl groups: -CF ═ CH-, -c (oh) ═ CH-, and-CH₂CH＝C(Cl)-。

The term "alkynyl", when used without the "substituted" modifier, refers to a monovalent group having a nonaromatic carbon atom as the point of attachment, having a straight or branched chain, cyclic, or acyclic structure, containing at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The group-C.ident.CH, -C.ident.CCH₃、-C≡CC₆H₅and-CH₂C≡CCH₃Are non-limiting examples of alkynyl groups. The term "substituted alkynyl" refers to a monovalent group having a nonaromatic carbon atom as the point of attachment and at least one carbon-carbon triple bond, having a linear or branched, cyclic, or acyclic structure, and at least one atom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The group-C ≡ CSi (CH)₃)₃Are non-limiting examples of substituted alkynyl groups.

The term "alkynediyl", when used without the "substituted" modifier, refers to a non-aromatic divalent group in which the alkynediyl group is linked in two sigma-bonds, has two carbon atoms as the point of attachment, has a linear or branched, cyclic or acyclic structure, contains at least one carbon-carbon triple bond, and is free of atoms other than carbon and hydrogen. The groups-C.ident.C-, -C.ident.CCH₂-and-C ≡ CCH (CH)₃) -is a non-limiting example of an alkyndiyl group. The term "substituted alkynediyl" refers to a non-aromatic divalent group in which the alkynediyl is linked in two sigma-bonds, has two carbon atoms as points of attachment, has a linear or branched, cyclic or acyclic structure, contains at least one carbon-carbon triple bond, and at least one atom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The groups-C.ident.CCFH-and-C.ident.CHCH (Cl) -are non-limiting examples of substituted alkynediyl groups.

The term "aryl", when used without the "substituted" modifier, refers to a monovalent group having an aromatic carbon atom as the point of attachmentThe carbon atoms form part of one or more six-membered aromatic ring structures, wherein the ring atoms are all carbon, and wherein the monovalent group does not contain atoms other than carbon and hydrogen. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl) phenyl, -C₆H₄CH₂CH₃(ethylphenyl), -C₆H₄CH₂CH₂CH₃(propylphenyl), -C₆H₄CH(CH₃)₂、-C₆H₄CH(CH₂)₂、-C₆H₃(CH₃)CH₂CH₃(methylethylphenyl), -C₆H₄CH＝CH₂(vinylphenyl), -C₆H₄CH＝CHCH₃、-C₆H₄C≡CH、-C₆H₄C≡CCH₃Naphthyl and monovalent radicals derived from biphenyl. The term "substituted aryl" refers to a monovalent group having, as a point of attachment, an aromatic carbon atom that forms part of one or more six-membered aromatic ring structures, wherein the ring atoms are all carbon, and wherein the monovalent group further has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. Non-limiting examples of substituted aryl groups include the groups: -C₆H₄F、-C₆H₄Cl、-C₆H₄Br、-C₆H₄I、-C₆H₄OH、-C₆H₄OCH₃、-C₆H₄OCH₂CH₃、-C₆H₄OC(O)CH₃、-C₆H₄NH₂、-C₆H₄NHCH₃、-C₆H₄N(CH₃)₂、-C₆H₄CH₂OH、-C₆H₄CH₂OC(O)CH₃、-C₆H₄CH₂NH₂、-C₆H₄CF₃、-C₆H₄CN、-C₆H₄CHO、-C₆H₄CHO、-C₆H₄C(O)CH₃、-C₆H₄C(O)C₆H₅、-C₆H₄CO₂H、-C₆H₄CO₂CH₃、-C₆H₄CONH₂、-C₆H₄CONHCH₃and-C₆H₄CON(CH₃)₂。

The term "aryldiyl," when used without the "substituted" modifier, refers to a divalent group wherein the aryldiyl is two sigma-linked, having as a point of attachment two aromatic carbon atoms that form part of one or more six-membered aromatic ring structures wherein the ring atoms are all carbon, and wherein the monovalent group contains no atoms other than carbon and hydrogen. Non-limiting examples of aryldiyl groups include:

the term "substituted aryldiyl" refers to a divalent group wherein the aryldiyl is linked in two sigma-bonds, having as a point of attachment two aromatic carbon atoms which form part of one or more six-membered aromatic ring structures wherein the ring atoms are all carbon, and wherein the divalent group further has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P and S.

The term "aralkyl", when used without the "substituted" modifier, refers to a monovalent group-alkanediyl-aryl, wherein the terms alkanediyl and aryl are each used in a manner consistent with the definition provided above. Non-limiting examples of aralkyl groups are: phenylmethyl (benzyl, Bn), 1-phenyl-ethyl, 2-phenyl-ethyl, indenyl and 2, 3-dihydro-indenyl, with the proviso that indenyl and 2, 3-dihydro-indenyl are only examples of aralkyl groups in which the point of attachment is in each case one of the saturated carbon atoms. When the term "aralkyl" is used in conjunction with the "substituted" modifier, either or both of the alkanediyl and aryl are substituted. Non-limiting examples of substituted aralkyl groups are: (3-chlorophenyl) -methyl, 2-oxo-2-phenyl-ethyl (phenylcarbonylmethyl), 2-chloro-2-phenyl-ethyl, a chromanyl group in which the point of attachment is one of the saturated carbon atoms, and a tetrahydroquinolinyl group in which the point of attachment is one of the saturated atoms.

The term "heteroaryl", when used without the "substituted" modifier, refers to a monovalent group having an aromatic carbon or nitrogen atom as the point of attachment, said carbon or nitrogen atom forming part of an aromatic ring structure in which at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the monovalent group contains no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. Non-limiting examples of aryl groups include acridinyl, furyl, imidazoimidazolyl, imidazopyrazolyl, imidazopyridyl, imidazopyrimidinyl, indolyl, indazolyl, methylpyridyl, and the like,Oxazolyl, phenylimidazolyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, tetrahydroquinolinyl, thienyl, triazinyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrroloimidazolyl, benzopyranyl (chromenyl) (where the point of attachment is one of the aromatic atoms), and chromanyl (where the point of attachment is one of the aromatic atoms). The term "substituted heteroaryl" refers to a monovalent group having an aromatic carbon or nitrogen atom as a point of attachment, said carbon or nitrogen atom forming part of an aromatic ring structure, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the monovalent group further has at least one atom independently selected from the group consisting of non-aromatic nitrogen, non-aromatic oxygen, non-aromatic sulfur, F, Cl, Br, I, Si, and P.

The term "heteroaryldiyl", when used without the "substituted" modifier, refers to a divalent group wherein the heteroaryldiyl group is joined in two sigma-bonds, having as a point of attachment two atoms (an aromatic carbon atom and/or an aromatic nitrogen atom) that form part of one or more six-membered aromatic ring structures wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the divalent group excludes atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. Non-limiting examples of heteroaryl diradicals include:

the term "substituted heteroaryldiyl" refers to a divalent group wherein the heteroaryldiyl group is connected in two sigma-bonds, having as a point of attachment an aromatic carbon atom or an aromatic nitrogen atom forming part of one or more six-membered aromatic ring structures wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the divalent group further has at least one atom independently selected from the group consisting of non-aromatic nitrogen, non-aromatic oxygen, non-aromatic sulfur, F, Cl, Br, I, Si, and P.

The term "heteroaralkyl", when used without the "substituted" modifier, refers to a monovalent group-alkanediyl-heteroaryl, wherein the terms alkanediyl and heteroaryl are each used in a manner consistent with the definition provided above. Non-limiting examples of aralkyl groups are: pyridylmethyl and thienylmethyl. When the term "heteroaralkyl" is used in conjunction with the "substituted" modifier, either or both of alkanediyl and heteroaryl are substituted.

The term "acyl", when used without the "substituted" modifier, refers to a monovalent group having the carbonyl carbon atom as the point of attachment, and also having a linear or branched, cyclic, or acyclic structure, and further having no other atoms than carbon or hydrogen other than the oxygen atom of the carbonyl group. The group-CHO, -C (O) CH₃(acetyl, Ac), -C (O) CH₂CH₃、-C(O)CH₂CH₂CH₃、-C(O)CH(CH₃)₂、-C(O)CH(CH₂)₂、-C(O)C₆H₅、-C(O)C₆H₄CH₃、-C(O)C₆H₄CH₂CH₃、-COC₆H₃(CH₃)₂and-C (O) CH₂C₆H₅Are non-limiting examples of acyl groups. Thus, the term "acyl" includes, but is not limited to, groups sometimes referred to as "alkylcarbonyl" and "arylcarbonyl". The term "substituted acyl" refers to a monovalent group having a carbonyl carbon atom as the point of attachment, and also having a linear or branched, cyclic, or acyclic structure, in addition to the carbonyl oxygen, having at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. group-C (O) CH₂CF₃、-CO₂H (carboxyl), -CO₂CH₃(methyl carboxyl), -CO₂CH₂CH₃、-CO₂CH₂CH₂CH₃、-CO₂C₆H₅、-CO₂CH(CH₃)₂、-CO₂CH(CH₂)₂、-C(O)NH₂(carbamoyl), -C (O) NHCH₃、-C(O)NHCH₂CH₃、-CONHCH(CH₃)₂、-CONHCH(CH₂)₂、-CON(CH₃)₂、-CONHCH₂CF₃-CO-pyridyl, -CO-imidazolyl and-C (O) N₃Are non-limiting examples of substituted acyl groups. The term "substituted acyl" includes, but is not limited to, "heteroarylcarbonyl" groups.

The term "alkylene", when used without the "substituted" modifier, refers to a divalent group ═ CRR ', where the alkylene is connected by one sigma-bond and one pi-bond, where R and R ' are independently hydrogen, alkyl, or R and R ' taken together represent alkanediyl. Non-limiting examples of alkylene groups include: CH (CH)₂、＝CH(CH₂CH₃) And ═ C (CH)₃)₂. The term "substituted alkylene" refers to a group ═ CRR ', where the alkylene group is connected by one sigma-bond and one pi-bond, where R and R' are independently hydrogen, alkyl, substituted alkyl, orR and R ' taken together represent a substituted alkanediyl group, with the proviso that either R and R ' is a substituted alkyl group or R and R ' taken together represent a substituted alkanediyl group.

The term "alkoxy", when used without the "substituted" modifier, refers to the group-OR, wherein R is alkyl, as that term is defined above. Non-limiting examples of alkoxy groups include: -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-OCH(CH₂)₂-O-cyclopentyl and-O-cyclohexyl. The term "substituted alkoxy" refers to the group-OR, wherein R is substituted alkyl, as that term is defined above. For example, -OCH₂CF₃Is a substituted alkoxy group.

The term "alkoxydiyl," when used without the "substituted" modifier, refers to a non-aromatic divalent group in which the alkoxydiyl group is linked in two sigma-bonds, having (a) two saturated carbon atoms as points of attachment, (b) one saturated carbon atom and one oxygen atom as points of attachment, or (c) two oxygen atoms as points of attachment, and also having a linear or branched, cyclic, or acyclic structure, no carbon-carbon double or triple bonds in the backbone of the group, no backbone atoms other than carbon or oxygen, and at least one of each of these atoms in the backbone of the group, and no side chains containing groups other than hydrogen or alkyl. group-O-CH₂CH₂-、-CH₂-O-CH₂CH₂-、-O-CH₂CH₂-O-and-O-CH₂-O-is a non-limiting example of an alkoxydiyl group. The term "substituted alkoxydiyl" refers to a divalent group that is linked in two sigma-bonds, having (a) two saturated carbon atoms as points of attachment, (b) one saturated carbon atom and one oxygen atom as points of attachment, or (c) two oxygen atoms as points of attachment, and also having a linear or branched, cyclic, or acyclic structure, no carbon-carbon double or triple bonds, and at least one atom is independently selected from the group consisting of N, F, Cl, Br, I, Si, P, and S, or has a structure that is linear or branched, has no carbon-carbon double or triple bond, and is a divalent group thatThere are additional oxygen atoms in addition to those in the backbone of the group. Non-limiting examples of substituted alkoxydiyl groups are the following groups: -O-CH₂C (OH) H-O-and-O-CH₂C(Cl)H-O-。

The terms "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", "heteroarylalkoxy", and "acyloxy", when used without the "substituted" modifier, refer to a group defined as-OR, wherein R is independently alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, as those terms are defined above. When any of the terms alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, and acyloxy are modified by "substituted," it refers to the group-OR, where R is substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, respectively.

The term "alkenyloxydiyl," when used without the "substituted" modifier, refers to a divalent group that is non-aromatic prior to attachment, wherein the alkenyloxydiyl group is linked in two sigma-bonds, which may be aromatic when attached, having (a) two carbon atoms as the point of attachment, (b) one carbon atom and one oxygen atom as the point of attachment, or (c) two oxygen atoms as the point of attachment, and also having a linear or branched, cyclic, or acyclic structure, at least one carbon-carbon double bond that is non-aromatic at least prior to attachment, further having no backbone atoms other than carbon or oxygen and at least one of these atoms in the backbone of the group, and no side chains containing groups other than hydrogen or alkyl. The radicals-O-CH ═ CH-, -O-CH ═ CHO-and-O-CH ═ CHCH₂-is a non-limiting example of an alkenyloxydiphenyl group. The term "substituted alkenyloxydiyl" refers to a divalent group that is non-aromatic prior to attachment, wherein the substituted alkenyloxydiyl group is linked in two sigma-bonds, which when attached can be aromatic, having (a) two carbon atoms as the point of attachment, (b) one carbon atom and one oxygen atom as the point of attachment, or (c) two oxygen atoms as the point of attachment, and also having a straight or branched, cyclic, or acyclic junctionAt least one carbon-carbon double bond that is non-aromatic at least prior to attachment, and at least one atom is independently selected from the group consisting of N, F, Cl, Br, I, Si, P, and S, or has an additional oxygen atom other than those in the backbone of the group. The following groups are non-limiting examples of substituted alkenyloxydiyl groups: -O-CH ═ c (oh) -O-and-O-CH ═ c (cl) -O-.

The term "alkylamino", when used without the "substituted" modifier, refers to the group-NHR, where R is alkyl, as that term is defined above. Non-limiting examples of alkylamino groups include: -NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-NHCH(CH₂)₂、-NHCH₂CH₂CH₂CH₃、-NHCH(CH₃)CH₂CH₃、-NHCH₂CH(CH₃)₂、-NHC(CH₃)₃-NH-cyclopentyl and-NH-cyclohexyl. The term "substituted alkylamino" refers to the group-NHR, where R is substituted alkyl, as that term is defined above. For example, -NHCH₂CF₃Is a substituted alkylamino group.

The term "dialkylamino," when used without the "substituted" modifier, refers to the group-NRR ', where R and R ' can be the same or different alkyl groups, or R and R ' can be taken together to represent an alkanediyl group having two or more saturated carbon atoms, wherein at least two saturated carbon atoms are attached to a nitrogen atom. Non-limiting examples of dialkylamino groups include: -NHC (CH)₃)₃、-N(CH₃)CH₂CH₃、-N(CH₂CH₃)₂N-pyrrolidinyl and N-piperidinyl. The term "substituted dialkylamino" refers to the group-NRR ', where R and R' can be the same or different substituted alkyl, one of R or R 'is alkyl and the other is substituted alkyl, or R and R' taken together represent a substituted alkanediyl group having two or more saturated carbon atoms wherein at least two saturated carbon atoms are attached to a nitrogen atom.

The terms "alkoxyamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heteroaralkylamino", and "alkylsulfonylamino", when used without the "substituted" modifier, refer to the group defined as — NHR, where R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and alkylsulfonyl, respectively, as those terms are defined above. A non-limiting example of an arylamino group is-NHC₆H₅. When any of the terms alkoxyamino, alkenylamino, alkynylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, and alkylsulfonylamino is modified by "substituted," it refers to the group-NHR, where R is substituted alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and alkylsulfonyl, respectively.

The term "acylamino" (acylamino), when used without the "substituted" modifier, refers to the group-NHR, wherein R is acyl, as that term is defined above. A non-limiting example of an acylamino group is-NHC (O) CH₃. When the term acylamino is used with the modifier "substituted", it refers to a group defined as-NHR, wherein R is a substituted acyl group, as that term is defined above. The group-NHC (O) OCH₃And NHC (O) NHCH₃Are non-limiting examples of substituted amido groups.

The term "alkylamino diradical," when used without the "substituted" modifier, refers to a divalent group that is not aromatic, wherein the alkylamino diradical is connected in two sigma-bonds, having (a) two saturated carbon atoms as points of attachment, (b) one saturated carbon atom and one nitrogen atom as points of attachment, or (c) two nitrogen atoms as points of attachment, and also having a linear or branched, cyclic, or acyclic structure with no carbon-carbon double or triple bonds in the backbone of the group, further having no backbone atoms other than carbon or nitrogen and at least one of these atoms in the backbone of the group, and no hydrogen or alkane hydrogenSide chains of groups other than radicals. The radical-NH-CH₂CH₂-、-CH₂-NH-CH₂CH₂-、-NH-CH₂CH₂-NH-and-NH-CH₂-NH-is a non-limiting example of an alkylaminodiyl group. The term "substituted alkylamino diradical" refers to a divalent group in which the substituted alkylamino diradical is connected in two sigma-bonds, has (a) two saturated carbon atoms as the point of attachment, (b) one saturated carbon atom and one nitrogen atom as the point of attachment, or (c) two nitrogen atoms as the point of attachment, and also has a linear or branched, cyclic or acyclic structure, no carbon-carbon double or triple bonds in the backbone of the group, and at least one atom is independently selected from the group consisting of O, F, Cl, Br, I, Si, P, and S, or has additional nitrogen atoms in addition to those in the backbone of the group. The following groups are non-limiting examples of substituted alkylaminodiyl groups:

-NH-CH₂c (OH) H-NH-and-NH-CH₂C(Cl)H-CH₂-。

The term "alkenylaminodiyl," when used without the "substituted" modifier, refers to a divalent group that is non-aromatic prior to attachment, wherein the alkenylaminodiyl group is connected in two sigma-bonds, which when attached may be aromatic, having (a) two carbon atoms as the point of attachment, (b) one carbon atom and one nitrogen atom as the point of attachment, or (c) two nitrogen atoms as the point of attachment, and also having a linear or branched, cyclic, or acyclic structure, at least one carbon-carbon double bond or carbon-nitrogen double bond that is non-aromatic at least prior to attachment, further having no backbone atom other than carbon or nitrogen and no side chains containing groups other than hydrogen or alkyl. The radicals-NH-CH ═ CH-, -NH-CH ═ N-and-NH-CH ═ CH-NH-are non-limiting examples of alkenylaminodiyl radicals. The term "substituted alkenylaminodiyl" refers to a divalent group that is non-aromatic prior to attachment, wherein the substituted alkenylaminodiyl group is connected in two sigma-bonds that, when attached, may be aromatic, having (a) two carbon atoms as the point of attachment, (b) one carbon atom and one nitrogen atom as the point of attachment, or (b)c) The two nitrogen atoms as the point of attachment also have a linear or branched, cyclic or acyclic structure, at least one carbon-carbon double bond or carbon-nitrogen double bond that is non-aromatic at least prior to attachment and at least one atom is independently selected from the group consisting of O, F, Cl, Br, I, Si, P and S, or has another nitrogen atom other than those in the main chain of the group. The following groups are non-limiting examples of substituted alkenylaminodiyl groups: -NH-CH ═ c (oh) -CH₂-and-N ═ chc (cl) H-.

The term "alkenylaminooxydiyl" when used without the "substituted" modifier refers to a divalent group in which the alkenylaminooxydiyl group is linked in two sigma-bonds, which may be aromatic when linked, has as a point of attachment two atoms selected from the group consisting of carbon, oxygen and nitrogen, and also has a linear or branched, cyclic or acyclic structure, at least one carbon-carbon double bond, carbon-nitrogen double bond or nitrogen-nitrogen double bond that is non-aromatic at least prior to linking, further has no backbone atoms other than carbon, nitrogen or oxygen and at least one of each of these three atoms in the backbone, and no side chains containing groups other than hydrogen or alkyl. The group-O-CH ═ N-is a non-limiting example of an alkenylaminooxydi group. The term "substituted alkenylaminooxydiphenyl" refers to a divalent group linked in two sigma bonds, which when linked may be aromatic, having as points of attachment two atoms selected from the group consisting of carbon, oxygen and nitrogen, and also having a linear or branched, cyclic or acyclic structure, at least one carbon-carbon or carbon-nitrogen double bond which is non-aromatic at least until the linkage is made and at least one atom is independently selected from the group consisting of F, Cl, Br, I, Si, P and S, or having one or more additional nitrogen and/or oxygen atoms other than those in the backbone of the group. The following groups are non-limiting examples of substituted alkenylaminooxydi-yl groups: -NH-CH ═ c (oh) -O-and-N ═ chc (cl) H — O-.

The term "alkylimino", when used without the "substituted" modifier, refers to the group NR, wherein the alkylimino group is attached by a sigma-bond anda pi-bond linkage, wherein R is alkyl, as that term is defined above. Non-limiting examples of alkylimino groups include: as NCH₃、＝NCH₂CH₃And ═ N-cyclohexyl. The term "substituted alkylimino" refers to the group NR, wherein alkylimino groups are linked by one sigma-and one pi-bond, wherein R is substituted alkyl, as that term is defined above. E.g., ═ NCH₂CF₃Is a substituted alkylimino group.

Similarly, the terms "alkenylimino", "alkynylimino", "arylimino", "aralkylimino", "heteroarylimino", "heteroaralkylimino", and "acylimino", when used without the "substituted" modifier, refer to a group defined as ═ NR, where the alkylimino group is connected by one σ -bond and one pi-bond, where R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, respectively, as those terms are defined above. When any of the terms alkenylimino, alkynylimino, arylimino, aralkylimino, and acylimino is modified by "substituted," it refers to a group where the alkylimino is connected by one sigma-bond and one pi-bond, where R is substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl, respectively.

The term "fluoroalkyl", when used without the "substituted" modifier, refers to an alkyl group, as that term is defined above, in which one or more fluorine has been substituted for a hydrogen. group-CH₂F、-CF₂H、-CF₃and-CH₂CF₃Are non-limiting examples of fluoroalkyl groups. The term "substituted fluoroalkyl" refers to a non-aromatic monovalent group having a saturated carbon atom as the point of attachment, having a linear or branched, cyclic or acyclic structure, at least one fluorine atom, no carbon-carbon double or triple bonds, and at least one atom independently selected from the group consisting of N, O, Cl, Br, I, Si, P, and S. The following groups are non-limiting examples of substituted fluoroalkyl groups: -CFHOH.

The term "alkylphosphate", when used without the "substituted" modifier, refers to the group-op (o) (oh) (or) wherein R is alkyl, as that term is defined above. Non-limiting examples of alkyl phosphates include: (O) OP (O), (OH) (OMe) and (O) (OH) (OEt). The term "substituted alkylphosphate ester" refers to the group-op (o) (oh) (or) wherein R is a substituted alkyl group as that term is defined above.

The term "dialkylphosphate", when used without the "substituted" modifier, refers to the group-op (o) (OR '), wherein R and R ' may be the same OR different alkyl groups, OR R and R ' may be taken together to represent an alkanediyl group having two OR more saturated carbon atoms, wherein at least two saturated carbon atoms are connected to the phosphorus atom through an oxygen atom. Non-limiting examples of dialkyl phosphates include: -OP (O) (OMe)₂OP (O) (OEt) (OMe) and OP (O) (OEt)₂. The term "substituted dialkylphosphate" refers to the group-op (o) (OR '), wherein R and R' may be the same OR different substituted alkyl, one of R OR R 'is alkyl and the other is substituted alkyl, OR R and R' may be taken together to represent a substituted alkanediyl group having two OR more saturated carbon atoms, wherein at least two saturated carbon atoms are connected to the phosphorus atom through an oxygen atom.

The term "alkylthio", when used without the "substituted" modifier, refers to the group-SR, wherein R is alkyl, as that term is defined above. Non-limiting examples of alkylthio groups include: -SCH₃、-SCH₂CH₃、-SCH₂CH₂CH₃、-SCH(CH₃)₂、-SCH(CH₂)₂-S-cyclopentyl and-S-cyclohexyl. The term "substituted alkylthio" refers to the group-SR, wherein R is substituted alkyl, as that term is defined above. For example, -SCH₂CF₃Is a substituted alkylthio group.

Similarly, the terms "alkenylthio", "alkynylthio", "arylthio", "aralkylthio", "heteroarylthio", "heteroarylalkylthio" and "acylthio", when used without the "substituted" modifier, refer to the group defined as-SR, wherein R is independently alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl and acyl, as those terms are defined above. When any of the terms alkenylthio, alkynylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, and acylthio is modified by "substituted," it refers to the group-SR, wherein R is independently substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and acyl.

The term "thioacyl", when used without the "substituted" modifier, refers to a monovalent group having as a point of attachment the carbon atom of the thiocarbonyl group, and also having a linear or branched, cyclic, or acyclic structure, with no additional atoms other than carbon or hydrogen other than the sulfur atom of the carbonyl group. The group-CHS, -C (S) CH₃、-C(S)CH₂CH₃、-C(S)CH₂CH₂CH₃、-C(S)CH(CH₃)₂、-C(S)CH(CH₂)₂、-C(S)C₆H₅、-C(S)C₆H₄CH₃、-C(S)C₆H₄CH₂CH₃、-C(S)C₆H₃(CH₃)₂and-C (S) CH₂C₆H₅Are non-limiting examples of thioacyl groups. The term "thioacyl" thus includes, but is not limited to, the groups sometimes referred to as "alkylthiocarbonyl" and "arylthiocarbonyl". The term "substituted thioacyl" refers to a radical having as a point of attachment a carbon atom that is part of a thiocarbonyl group, and also having a linear or branched, cyclic or acyclic structure, in addition to the sulfur atom of the carbonyl group, having at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The group-C (S) CH₂CF₃，-C(S)O₂H，-C(S)OCH₃、-C(S)OCH₂CH₃、-C(S)OCH₂CH₂CH₃、-C(S)OC₆H₅、-C(S)OCH(CH₃)₂、-C(S)OCH(CH₂)₂、-C(S)NH₂and-C (S) NHCH₃Are non-limiting examples of substituted thioacyl groups. The term "substituted thioacyl" includes, but is not limited to, a "heteroarylthiocarbonyl" group.

The term "alkylsulfonyl", when used without the modifier "substituted", refers to the group-S (O)₂R, wherein R is alkyl, as that term is defined above. Non-limiting examples of alkylsulfonyl groups include: -S (O)₂CH₃、-S(O)₂CH₂CH₃、-S(O)₂CH₂CH₂CH₃、-S(O)₂CH(CH₃)₂、-S(O)₂CH(CH₂)₂、-S(O)₂-cyclopentyl and-S (O)₂-cyclohexyl. The term "substituted alkylsulfonyl" refers to the group-S (O)₂R, wherein R is substituted alkyl, as that term is defined above. For example, -S (O)₂CH₂CF₃Is a substituted alkylsulfonyl group.

Similarly, the terms "alkenylsulfonyl", "alkynylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl", and "heteroaralkylsulfonyl", when used without the "substituted" modifier, refer to the substituents defined as-S (O)₂R, wherein R is independently alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, as those terms are defined above. When the term any of alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl and heteroaralkylsulfonyl is modified by "substituted", it refers to the group-S (O)₂R, wherein R is independently substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.

The term "alkylsulfinyl", when used without the "substituted" modifier, refers to the group-s (o) R, wherein R is alkyl, as that term is defined above. Non-limiting examples of alkylsulfinyl groups include: -S (O) CH₃、-S(O)CH₂CH₃、-S(O)CH₂CH₂CH₃、-S(O)CH(CH₃)₂、-S(O)CH(CH₂)₂-S (O) -cyclopentyl and-S (O) -cyclohexyl. The term "substituted alkylsulfinyl" refers to the group-s (o) R, where R is substituted alkyl, as that term is defined above. For example, -S (O) CH₂CF₃Is a substituted alkylsulfinyl group.

Similarly, the terms "alkenylsulfinyl", "alkynylsulfinyl", "arylsulfinyl", "aralkylsulfinyl", "heteroarylsulfinyl", and "heteroaralkylsulfinyl", when used without the "substituted" modifier, refer to the group defined as-s (o) R, wherein R is independently alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, as those terms are defined above. When any of the terms alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, aralkylsulfinyl, heteroarylsulfinyl, and heteroaralkylsulfinyl is modified by "substituted," it refers to the group-s (o) R, where R is substituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, respectively.

The term "alkylsilyl", when used without the "substituted" modifier, means defined as-SiH₂A monovalent group of R, -SiHRR ' or-SiRR ' R ', wherein R, R ' and R ' may be the same or different alkyl groups, or any combination of two of R, R ' and R ' may be taken together to represent an alkanediyl group. radical-SiH₂CH₃、-SiH(CH₃)₂、-Si(CH₃)₃and-Si (CH)₃)₂C(CH₃)₃Are non-limiting examples of unsubstituted alkylsilyl groups. The term "substituted alkylsilyl" refers to-SiH₂R, -SiHRR ' or-SiRR ' R ', wherein at least one of R, R ' and R ' is a substituted alkyl or two of R, R ' and R ' may be taken together to represent a substituted alkanediyl group. When more than one of R, R 'and R' is a substituted alkyl group, they may be the same or different. R, R 'and R' of either a substituted alkyl or a substituted alkanediyl groupMay be the same or different alkyl groups, or may be taken together to represent an alkanediyl group having two or more saturated carbon atoms, wherein at least two saturated carbon atoms are bonded to a silicon atom.

Further, the atoms comprising the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same number of atoms but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include¹³C and¹⁴C. similarly, it is contemplated that one or more carbon atoms of the compounds of the present invention may be replaced by silicon atoms. Furthermore, it is contemplated that one or more oxygen atoms of the compounds of the present invention may be replaced by a sulfur or selenium atom.

A single dashed line between two atoms indicates an optional bond. The bond may not be present at all, it may be present as a single bond, or it may be present as a double bond. If an atom is attached only to the dashed line, the atom itself is optional. It may be present or it may be absent.

A bond shown as a combination of a solid line and a dashed line indicates that the bond is a single bond or a double bond. Thus, for example, the structureComprises a structureAs will be understood by those skilled in the art, none of such ring atoms form part of more than one double bond.

Any undefined valency on an atom of a structure shown in this application implicitly denotes a hydrogen atom bonded to the atom.

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

The words "a" or "an" when used in conjunction with the term "comprising/having/containing/including" in the claims and/or the specification may mean "one", but also conform to the meaning of "one or more", "at least one" and "one or more".

Throughout this application, the term "about" is used to indicate that a value includes the inherent error variation for the device, the method used to determine the value, or the variation present in the study subject.

The terms "comprising," "having," and "including" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprising," "including," "having," "including," and "including," is open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to possessing only those one or more steps, and also encompasses other non-recited steps.

The term "effective" as used in the specification and/or claims means sufficient to achieve a desired, expected, or target result.

The term "hydrate" when used as a modifier of a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecule associated with each chemical molecule, for example in a solid form of the compound.

As used herein, the term "IC₅₀"refers to an inhibitory amount that is 50% of the maximal response obtained.

An "isomer" of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but the configuration of these atoms is different in three-dimensional space.

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

By "pharmaceutically acceptable" it is meant that it is useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic, non-biologically and otherwise undesirable, and include acceptable for veterinary use as well as human pharmaceutical use.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention as defined above which is pharmaceutically acceptable and which has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4' -methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, acetic acid, aliphatic monocarboxylic and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentylpropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, dodecylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o- (4-hydroxybenzoyl) benzoic acid, Oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-methylbenzenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, t-butylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts, which may be formed when an acidic proton present is capable of reacting 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 will be appreciated that the particular anion or cation forming part of any salt of the invention is not critical, so long as the salt as a whole is pharmaceutically acceptable. Additional examples of pharmaceutically acceptable Salts and methods of making and using the same are described in Handbook of Pharmaceutical Salts: properties, and Use (2002).

As used herein, "predominantly one enantiomer" means that the compound comprises at least about 85% of one enantiomer, or more preferably at least about 90% of one enantiomer, or even more preferably at least about 95% of one enantiomer, or most preferably at least about 99% of one enantiomer. Similarly, the phrase "substantially free of other optical isomers" means that the composition comprises at most about 15% of another enantiomer or diastereomer, more preferably at most about 10% of the other enantiomer or diastereomer, even more preferably at most about 5% of the other enantiomer or diastereomer, and most preferably at most about 1% of the other enantiomer or diastereomer.

"preventing" or "preventing" includes: (1) inhibiting the onset of the disease in a subject or patient who may be at risk for and/or susceptible to the disease but has not experienced or exhibited any or all of the pathology or symptomology of the disease, and/or (2) slowing the onset of the pathology or symptomology of the disease in a subject or patient who may be at risk for and/or susceptible to the disease but has not experienced or exhibited any or all of the pathology or symptomology of the disease.

By "prodrug" is meant a compound that is metabolically converted in vivo to an inhibitor according to the invention. The prodrug itself may or may not also have activity against a given target protein. For example, compounds containing a hydroxyl group can be administered as an ester that is converted to a hydroxyl compound in vivo by hydrolysis. Suitable esters that can be converted in vivo to hydroxy compounds include acetate, citrate, lactate, phosphate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis- β -hydroxynaphthoate, cholate, isethionate, di-p-methylbenzoyl tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, quinic acid ester, amino acid ester, and the like. Similarly, compounds containing amine groups may be administered as amides that are converted to amine compounds by hydrolysis in vivo.

"repeating units" are the simplest structural entities of certain substances, for example, backbones and/or polymers, whether organic, inorganic or metal-organic. In the case of polymer chains, the repeating units are linked together sequentially along the chain, as are the beads of a necklace. For example, in polyethylene, - [ -CH₂CH₂-]_nIn-is the repeating unit-CH₂CH₂-. The subscript "n" represents the degree of polymerization, i.e., the number of repeat units linked together. When the value of "n" is not yet determined, it simply indicates the repetition of the structural formula within parentheses as well as the polymeric nature of the material. The concept of repeating units is equally applicable to cases where the connectivity between repeating units extends in three dimensions, such as in metal organic frameworks, crosslinked polymers, thermoset polymers, and the like.

The term "saturated", when referring to an atom, means that the atom is attached to other atoms only by single bonds.

"stereoisomers" or "optical isomers" are isomers of a given compound in which the same atom is bonded to the same other atom, but the configuration of those atoms is different in three-dimensional space. "enantiomers" are stereoisomers of a given compound that are mirror images of each other, as are left and right handed. "diastereomer" is a stereoisomer of a given compound that is not an enantiomer.

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

"substituents convertible in vivo to Hydrogen"means any group that can be converted to a hydrogen atom by enzymatic or chemical means, including but not limited to hydrolysis and hydrogenolysis. Examples include hydrolyzable groups such as acyl groups, groups having oxycarbonyl groups, amino acid residues, peptide residues, o-nitrophenylsulfinyl groups, trimethylsilyl groups, tetrahydropyranyl groups, diphenylphosphinyl groups (phosphinyl groups), and the like. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, and the like. Examples of the group having an oxycarbonyl group include ethoxycarbonyl group, t-butoxycarbonyl group (-C (O) OC (CH)₃)₃) Benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, β - (p-toluenesulfonyl) ethoxycarbonyl, and the like. Suitable amino acid residues include, but are not limited to, 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), Set (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine), and β -Ala residues. Examples of suitable amino acid residues also include amino acid residues protected with a protecting group. Examples of suitable protecting groups include those typically employed in peptide synthesis, including acyl groups (e.g., formyl and acetyl), arylmethyloxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), t-butyloxycarbonyl (-C (O) OC (CH)₃)₃) And so on. Suitable peptide residues include peptide residues comprising 2 to 5 optional amino acid residues. The residues of these amino acids or peptides may exist in stereochemical configuration in D-form, L-form or mixtures thereof. Furthermore, the amino acid or peptide residue may have asymmetric carbon atoms. Examples of suitable amino acid residues having asymmetric carbon atoms include Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr residues. Examples of peptide residues having an asymmetric carbon atom include peptide residues having one or more constitutive amino acid residues containing an asymmetric carbon atom. Examples of suitable amino acid protecting groups include those typically employed in peptide synthesisThose, including acyl groups (e.g., formyl and acetyl), arylmethyloxycarbonyl groups (e.g., benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), t-butyloxycarbonyl group (-C (O)) OC (CH)₃)₃) And so on. Other examples of substituents "convertible to hydrogen in vivo" include reductively eliminable hydrogenolyzable groups. Examples of suitable reductively eliminable hydrogenolyzable groups include, but are not limited to, arylsulfonyl (e.g., o-toluenesulfonyl); methyl substituted with phenyl or benzyloxy (e.g., benzyl, trityl, and benzyloxymethyl); arylmethoxycarbonyl (e.g., benzyloxycarbonyl and o-methoxybenzyloxycarbonyl); and halogenated ethoxycarbonyl groups (such as β, β, β -trichloroethoxycarbonyl and β -iodoethoxycarbonyl).

By "therapeutically effective amount" or "pharmaceutically effective amount" is meant an amount sufficient to effect such treatment of a disease when administered to a subject or patient for the purpose of treating the disease.

"treating" or "treatment" includes (1) inhibiting the disease (e.g., arresting further development of the pathology and/or syndrome) in a subject or patient experiencing or exhibiting the pathology or syndrome of the disease, (2) ameliorating the disease (e.g., reversing the pathology and/or syndrome) in a subject or patient experiencing or exhibiting the pathology or syndrome of the disease, and/or (3) producing any measurable decline in the disease in a subject or patient experiencing or exhibiting the pathology or syndrome of the disease.

As used herein, the term "water soluble" means that the compound is soluble to the extent of at least 0.010 moles/liter in water or classified as soluble according to literature knowledge.

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

For any conflicting definition in any reference incorporated by reference herein, the above definition controls. However, the fact that certain terms are defined should not be construed to indicate that any terms not defined are unclear. Rather, it is to be understood that all terms used are intended to describe the invention under such conditions as would be understood by one of ordinary skill in the art to which the invention pertains and which is in practice.

Compounds for the treatment of obesity

In one aspect of the invention, there is provided a method of reducing body weight in a patient in need thereof, the method comprising administering to the subject an Antioxidant Inflammation Modulator (AIM) in an amount sufficient to reduce the body weight of the patient. These compounds and molecules containing similar structural features and pharmacology are known as antioxidant inflammation modulators or AIMs. A common structural feature of AIMs is the presence of at least one substructure comprising a CF having a nitrile group attached to the alpha carbon₃Alpha, beta-unsaturated carbonyl groups of radicals or other electron withdrawing groups. These compounds exhibit the ability to activate Nrf2, as measured by increased expression of one or more Nrf2 target genes (e.g., NQO1 or HO-1; Dinkova-Kostova et al, 2005); . In addition, these compounds are capable of indirectly and directly inhibiting proinflammatory transcription factors including NF-. kappa.B and STAT3(Ahmad et al, 2006; Ahmad et al, 2008). In some aspects, there is provided a method of inhibiting a weight gene (weight gene) in a subject in need thereof, the method comprising administering to the subject an Antioxidant Inflammation Modulator (AIM), including any of the specific compounds disclosed herein, in an amount sufficient to inhibit the weight gene in the subject. In some aspects, there is provided a method of preventing obesity in a subject in need thereof, the method comprising administering to the subject an Antioxidant Inflammation Modulator (AIM), including herein, in an amount sufficient to prevent obesity in the subjectAny one of the specific compounds disclosed. In some aspects, there is provided a method of preventing obesity progression in a subject in need thereof, the method comprising administering to the subject an Antioxidant Inflammation Modulator (AIM), including any of the specific compounds disclosed herein, in an amount sufficient to prevent obesity progression in the subject.

In some embodiments, the AIM is a selective activator of the antioxidant transcription factor Nrf 2. The AIM used by the present invention can be represented by the following sections:

wherein W is nitrile, CF₃Or other electron withdrawing group, and R₁And R₂As defined above and in the claims below. This pharmacophore (pharmacore) is found in many synthetic triterpenoids, such as those described by Honda et al (2000 a); honda et al, (2000 b); honda et al (2002); and those described in U.S. patent application publication nos. 2009/0326063, 2010/0056777, 2010/0048892, 2010/0048911, and 2010/0041904, which are incorporated herein by reference. This pharmacophore is also found in many other non-triterpenoid compounds, such as the tricyclic di-enones (e.g., TBE-31) presented in U.S. patent application publication nos. 2003/0232786 and 2008/0261985, both of which are incorporated herein by reference. This pharmacophore is also disclosed in U.S. patent application publication No. 2010/0048887, which is also incorporated herein by reference. Many of these compounds, both triterpenoids and non-triterpenoids, are highly potent selective activators of the antioxidant transcription factor Nrf 2. In addition, many of these compounds have been associated with a variety of anti-inflammatory related activities, including, for example, antiproliferative activity and/or antioxidant activity such as induction of heme oxygenase-1 (HO-1) in vitro and in vivo, induction of CD11b, inhibition of iNOS induction, inhibition of COX-2 induction, inhibition of NO production, induction of apoptosis in cancer cells, inhibition of NF-kB, activation of the JNK pathwayAnd stage 2 induction (increase NAD (P) H-quinone oxidoreductase and HO-1). Induction of stage 2 response is associated with activation of the transcription factor Nrf2, which has been shown to activate Antioxidant Response Elements (AREs) in the promoter regions of many antioxidant, anti-inflammatory and cytoprotective genes, and stage 2 activation is highly correlated with effective inhibition of NO production in activated macrophages (e.g., Dinkova-Kostova et al, 2005).

An AIM, bardoxolone methyl (BARD), is in late clinical trials for the treatment of chronic kidney disease. Data from these and other clinical trials have shown that BARD induces Nrf2 activity in blood cells at therapeutic doses. During the course of these studies, the inventors have identified clinical events in which overweight or obese patients show weight loss after treatment with bardoxolone methyl (table 1).

In certain embodiments, compounds susceptible to modification with the above pharmacophores include, but are not limited to, triterpenoids (non-limiting examples of which include argentatin, betulinic acid, lanostane, oleanolic acid, ursolic acid, glycyrrhetinic acid, boswellic acid, colatodiol, calendula glycol (calendulandiol) and jasmonic acid (moronic acid)), saponins (e.g., ginsenosides), carinthine (avicins), resveratrol, curcumin, gossypol, epigallocatechin-3-gallate (EGCG), gossypol, lapachol, other flavonoids (non-limiting examples of which include quercetin, daidzein, luteolin, coumarin, wogonin and baicalin), Dehydroandrosterone (DHEA), cholic acid, deoxycholic acid, ginsenosides (e.g., 20(S) -ginsenoside), silymarin, and/or a pharmaceutically acceptable salt thereof), and pharmaceutically acceptable salts thereof, Anthocyanidin, avenanthramide, cucurbitacin, aloesin, aloe-emodin and/or tubeimoside A.

Non-limiting examples of triterpenoids that may be used in accordance with the methods of the present invention are shown herein.

Non-limiting examples of non-triterpenoids that may be used in accordance with the methods of the invention are shown herein.

Although some of the most potent and selective known Nrf2 activators are AIM, compounds based on other molecular backbones have been reported to also activate Nrf 2. These include sulforaphane, oltipraz, dimethyl fumarate, statins, cyclopentenones, prostaglandins, and NO-donating molecules (see, e.g., Yates et al, 2006; 2009; Habeos et al, 2008; Nguyen et al, 2009; Kansanen et al, 2009; Kobayashi et al, 2009; Gao et al, 2006).

The compounds employed may be those available from Honda et al (2000 a); honda et al, (2000 b); honda et al (2002); and U.S. patent publication nos. 2009/0326063, 2010/0056777, 2010/0048892, 2010/0048911, 2010/0041904, 2003/0232786, 2008/0261985, and 2010/0048887, all of which are incorporated herein by reference. These methods can be further modified and optimized using organic chemistry principles and techniques as applied by those skilled in the art. Such principles and techniques are described, for example, in March's Advanced Organic Chemistry: reactions, Mechanisms, and structures (2007), also incorporated herein by reference.

The compounds employed in the methods of the invention may contain one or more asymmetrically substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms, epimeric forms, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. The compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral center of the compounds of the present invention may have an S or R configuration.

Polymorphic forms of the compounds of the invention, e.g., forms A and B of CDDO-Me, may be used according to the methods of the invention. Form B showed unexpectedly better bioavailability than form a. In particular, the bioavailability of CDDO-Me form B is higher than form a when monkeys are orally administered the two forms of gelatin capsules at equal doses. See U.S. patent application publication No. 2009/0048204, which is incorporated herein by reference in its entirety.

The "form A" (RTA-402) of CDDO-Me is unsolvated (non-hydrated) and can be characterized by a unique crystal structure having the space group P4 as well as a packed structure₃2₁2 (96), unit cell size ofAndand by usingThe co-stacking structure three molecules stack in a helical fashion along the crystalline b-axis. In some embodiments, form a can also be characterized by an X-ray powder diffraction (XRPD) pattern (cuka) comprising significant diffraction peaks at approximately 8.8, 12.9, 13.4, 14.2, and 17.4 ° 2 Θ. In some variations, the X-ray powder diffraction of form a is substantially as shown in fig. 1A and 1B.

Unlike form a, the "form B" of CDDO-Me is a single phase, lacking such a well-defined crystal structure. The type B samples did not show long range molecular correlation (i.e., more than about). Furthermore, the thermal analysis showed the glass transition temperature (T) of the B-type sample_g) In the range of about 120 c to about 130 c. Unlike it, disordered nanocrystalline materials do not exhibit T_gShowing only the melting temperature (T)_m) Above this temperature, the crystal structure becomes liquid. Form B is characterized by its XRPD spectrum (FIG. 1C), which is distinct from the XPRD spectrum of form A (see FIG. 1A or 1B). Since form B has no well-defined crystal structure, there are no distinct XRPD peaks (e.g., representing the XRPD peak of form a), but rather are characterized by a general "halo" XRPD pattern. In particular, non-crystalline form B belongs to the class of "X-ray amorphous" solids, since its XRPD pattern shows three or less dominant diffraction halos. Within this class, form B is a "glassy" material.

Forms A and B of CDDO-Me are readily prepared from various solutions of this compound. Form B can be prepared, for example, by rapid or slow evaporation in MTBE, THF, toluene or ethyl acetate. Form a can be made in several ways, including by rapid evaporation, slow evaporation, or slow cooling of CDDO-Me in ethanol or methanol. CDDO-Me is prepared in acetone and form a can be produced using a fast evaporation method or form B can be produced using a slow evaporation method.

Various characterization methods can be used together to distinguish CDDO-Me forms a and B from each other and from other CDDO-Me forms. Illustrative of techniques suitable for this purpose are solid-state Nuclear Magnetic Resonance (NMR), X-ray powder diffraction (comparing FIGS. 1A and 1B with FIG. 1C), X-ray crystal analysis, Differential Scanning Calorimetry (DSC), dynamic vapor adsorption/Desorption (DVS), Kafl Fischer analysis (KF), hot stage microscopy, modulated differential screening calorimetry, Fourier transform infrared spectroscopy (FT-IR), and Raman spectroscopy. Specifically, analysis of XRPD versus DSC data distinguishes between form a, form B and the hemi-benzoate (hemibenzanate) forms of CDDO-Me. See U.S. patent application publication No. 2009/0048204, which is incorporated herein by reference in its entirety.

Additional details regarding the CDDO-Me polymorphic form are described in U.S. patent application publication No. 2009/0048204, PCT publication No. WO 2009/023232, and PCT publication No. WO2010/093944, the entire contents of which are incorporated herein by reference.

Non-limiting specific formulations of the compounds disclosed herein include CDDO-Me polymer dispersions. See, for example, PCT publication No. WO2010/093944, the entire contents of which are incorporated herein by reference. Some of the formulations reported therein exhibit higher bioavailability than micronized form a formulations or nanocrystalline form a formulations. In addition, the polymer dispersion based formulations demonstrated a more unexpected improvement in oral bioavailability relative to the micronized form B formulations. For example, methacrylic acid copolymer, class C and HPMC-P formulations showed the highest bioavailability in monkey subjects. See, for example, PCT publication No. WO2010/093944, the entire contents of which are incorporated herein by reference.

The compounds employed in the methods of the invention may also exist in prodrug form. Since prodrugs are known to enhance many desirable properties of drugs, e.g., solubility, bioavailability, manufacturing, etc., the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the present invention contemplates prodrugs of the compounds of the invention as well as methods of delivering the prodrugs. Prodrugs of the compounds employed in the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Thus, prodrugs include, for example, compounds described herein wherein a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.

It should be recognized that the particular anion or cation forming part of any salt of the invention is not critical so long as the salt as a whole is pharmacologically acceptable. Other examples of pharmaceutically acceptable Salts and methods of making and using the same are described in Handbook of Pharmaceutical Salts: properties, and uses (2002), which is incorporated herein by reference.

The compounds employed in the process of the invention may also have the following advantages: they may be more effective, less toxic, more durable, more efficacious, produce fewer side effects, be more easily absorbed, and/or have better pharmacokinetic properties (e.g., higher oral bioavailability and/or lower clearance rates), and/or have other superior useful pharmacological, physical, or chemical properties than compounds known in the prior art for the indications described herein.

Diseases associated with inflammation and/or oxidative stress

Inflammation is a biological process that provides resistance to infectious or parasitic organisms and repairs damaged tissues. Inflammation is often characterized by local vasodilation, redness, swelling, and pain, recruitment of leukocytes to the site of infection or injury, production of inflammatory cytokines such as TNF- α and IL-1, and production of reactive oxygen or nitrogen species such as hydrogen peroxide, superoxide, and peroxynitrite. In the later stages of inflammation, tissue remodeling, angiogenesis and scarring (fibrosis) may occur as part of the wound healing process. Under normal circumstances, the inflammatory response is regulatory and transient, and subsides in a coordinated fashion once the infection or injury has been properly treated. However, if the regulatory mechanisms fail, acute inflammation can become widespread and life threatening. Alternatively, inflammation can become chronic and lead to cumulative tissue damage or systemic complications.

Many serious and intractable human diseases involve dysregulation of inflammatory processes, including diseases such as cancer, atherosclerosis and diabetes, which are traditionally not considered inflammatory diseases. In the case of cancer, the inflammatory process is associated with tumor formation, progression, metastasis and resistance to treatment. Atherosclerosis, which has long been regarded as a disorder of lipid metabolism, is now understood to be primarily an inflammatory disease in which activated macrophages play an important role in the formation and eventual rupture of atherosclerotic plaques. Activation of inflammatory signaling pathways has also been shown to play a role in the development of insulin resistance and in peripheral tissue damage associated with diabetic hyperglycemia. Overproduction of reactive oxygen and reactive nitrogen species such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite is a hallmark of inflammatory disease. Evidence of deregulated peroxynitrite production has been reported in a variety of diseases (Szabo et al, 2007; Schulz et al, 2008; Forstermann, 2006; Pall, 2007).

Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis and multiple sclerosis involve inappropriate and chronic activation of inflammatory processes in affected tissues, resulting from dysfunction of self-to non-self recognition and response mechanisms in the immune system. In neurodegenerative diseases such as alzheimer's disease and parkinson's disease, nerve damage is associated with activation of microglia and increased 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, is closely associated with the presence of chronic oxidative stress and inflammation, which leads to the development of fibrosis and ultimately the loss of organ function.

Many other conditions involve oxidative stress and inflammation in affected tissues, including inflammatory bowel disease; inflammatory skin diseases; mucositis associated with radiation therapy and chemotherapy; eye diseases such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; graft failure and rejection; ischemia-reperfusion injury; chronic pain; degenerative diseases of bones and joints, including osteoarthritis and osteoporosis; asthma and cystic fibrosis; spastic disorders; and neuropsychiatric disorders including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism spectrum disorder, and eating disorders such as anorexia nervosa. Dysregulation of inflammatory signaling pathways is believed to be a major factor in the pathology of muscle wasting diseases, including muscular dystrophy and various forms of cachexia.

A variety of life-threatening acute conditions are also involved in dysregulated inflammatory signaling, including acute organ failure involving the pancreas, kidneys, liver or lungs, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe burns and anaphylaxis.

Many complications of infectious diseases also involve dysregulation of the inflammatory response. While the inflammatory response can kill invading pathogens, an excessive inflammatory response can also be completely destructive and in some cases can be a major source of damage in the infected tissue. In addition, excessive inflammatory responses can also lead to systemic complications due to the overproduction of inflammatory cytokines such as TNF- α and IL-1. This is believed to be a factor in death due to severe influenza, severe acute respiratory syndrome, and sepsis.

Aberrant or overexpression of either iNOS or the cyclooxygenase-2 (COX-2) enzyme has been implicated in the pathogenesis of many disease processes. For example, it has been shown that NO is a potent mutagen (Tamir and Tannebaum, 1996), and that nitric oxide can also activate COX-2(Salvemini et al, 1994). Furthermore, iNOS is significantly increased in large intestine colon tumors induced by the carcinogen azoxymethane (Takahashi et al, 1997). A series of synthetic oleanolic acid triterpenoid analogs have been shown to be potent inhibitors of cellular inflammatory processes such as the induction of Inducible Nitric Oxide Synthase (iNOS) and COX-2 by IFN- γ in mouse macrophages. See Honda et al (2000 a); honda et al (2000b), and Honda et al (2002), which are all incorporated herein by reference.

In one aspect, the compounds disclosed herein are characterized in that they are capable of inhibiting nitric oxide production in macrophage-derived RAW 264.7 cells induced by exposure to γ -interferon. They are further characterized by their ability to induce the expression of antioxidant proteins such as NQO1 and the ability to decrease the expression of pro-inflammatory proteins such as COX-2 and Inducible Nitric Oxide Synthase (iNOS). These properties are relevant for the treatment of a large number of diseases involving disturbances of oxidative stress and inflammatory processes, including cancer, mucositis caused by radiotherapy 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 disease, neurodegenerative diseases, eye and retinal diseases, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel diseases, dermatitis and other skin diseases, sepsis, burns, convulsive diseases and neuropsychiatric diseases.

Without being bound by theory, it is believed that activation of the antioxidant/anti-inflammatory Keapl/Nrf2/ARE pathway is related to both anti-inflammatory and anti-cancer properties of the compounds disclosed herein.

In another aspect, the compounds disclosed herein may be used to treat a subject suffering from a disease caused by an elevated level of oxidative stress in one or more tissues. Oxidative stress results from abnormally high or sustained long levels of reactive oxygen species such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite (formed by the nitric oxide and superoxide reactions). Oxidative stress may be accompanied by acute or chronic inflammation. Oxidative stress can be caused by mitochondrial dysfunction, activation of immune cells such as macrophages and neutrophils, acute exposure to external effects such as ionizing radiation or cytotoxic chemotherapeutic agents (e.g., doxorubicin), trauma or other acute tissue injury, ischemia/reperfusion, poor circulation or anemia, local or systemic hypoxia or hyperoxia, elevated levels of inflammatory cytokines and other inflammation-related proteins, and/or other abnormal physiological states such as hyperglycemia or hypoglycemia.

In many animal models of such diseases, it has been demonstrated that stimulation of the Nrf2 pathway target gene-induced heme oxygenase (HO-1) expression has significant therapeutic effects, including models of myocardial infarction, renal failure, graft failure and rejection, stroke, cardiovascular disease, and autoimmune disease (e.g., Sacerdoti et al, 2005; Abraham & Kappas, 2005; Bach, 2006; Araujo et al, 2003; Liu et al, 2006; Ishikawa et al, 2001; Kruger et al, 2006; Satoh et al, 2006; Zhou et al, 2005; Morse and Choi, 2002). This enzyme breaks down free heme into iron, carbon monoxide (CO) and biliverdin, which is subsequently converted into the potent antioxidant molecule bilirubin.

In another aspect, the compounds of the invention may be used for the prevention or treatment of acute and chronic tissue injury or organ failure caused by oxidative stress with worsening inflammation. Examples of diseases in this class include: heart failure, liver failure, graft failure and rejection, renal failure, pancreatitis, fibrotic lung disease (especially cystic fibrosis and COPD), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury, glaucoma, stroke, autoimmune diseases, autism, macular degeneration, and muscular dystrophy. For example, in the case of autism, studies have shown that increased oxidative stress in the central nervous system contributes to disease progression (Chauhan and Chauhan, 2006).

Evidence also links oxidative stress and inflammation to the development and pathology of many other conditions of the central nervous system, including 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 behavioral syndromes such as attention deficit disorder. See, e.g., Dickerson et al, 2007; hanson et al, 2005; kendall-tatkett, 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; sarcoleilli et al, 2006; kawakami et al, 2006; ross et al, 2003, which are incorporated herein by reference in their entirety. For example, increased levels of inflammatory cytokines, including TNF, interferon-gamma and IL-6, are associated with severe psychiatric disorders (Dickerson et al, 2007). Microglial activation is also associated with severe psychiatric disorders. Therefore, down-regulation of inflammatory cytokines and inhibition of microglial over-activation would be beneficial for patients with schizophrenia, major depression, bipolar disorder, autism spectrum disorder, and other neuropsychiatric disorders.

Thus, in pathologies involving only oxidative stress or oxidative stress exacerbated by inflammation, treatment may comprise administering to the subject a therapeutically effective amount of a compound of the invention, such as those described above or throughout this specification. The treatment may be administered prophylactically (e.g., organ transplantation or radiation therapy to a cancer patient) prior to a predictable oxidative stress state, or it may be administered therapeutically in an environment involving established oxidative stress and inflammation.

The compounds disclosed herein may be of general application in the treatment of inflammatory diseases such as sepsis, dermatitis, autoimmune diseases and osteoarthritis. In one aspect, the compounds of the invention may be used to treat inflammatory pain and/or neuropathic pain, for example, by inducing Nrf2 and/or inhibiting NF- κ B.

The compounds of the invention may also have the following advantages: they may be more potent, less toxic, more durable, more efficacious, produce fewer side effects, be more easily absorbed, and/or have better pharmacokinetic properties (e.g., higher oral bioavailability and/or lower clearance rates), and/or have other superior useful pharmacological, physical, or chemical properties than compounds known in the art, whether for the above indications or other indications.

In one aspect, the compounds disclosed herein may function as Antioxidant Inflammation Modulators (AIMs) with potent anti-inflammatory properties that mimic the biological activity of cyclopentenone prostaglandins (cypgs). In one embodiment, the compounds disclosed herein can be used to control the production of pro-inflammatory cytokines by selectively targeting Regulatory Cysteine Residues (RCRs) on proteins that modulate the transcriptional activity of reduction-oxidation sensitive transcription factors. It has been demonstrated that activation of RCR by cyPG or AIM initiates a pro-resolution procedure in which the activities of antioxidant and cytoprotective transcription factor Nrf2 are effectively induced and the activities of pro-oxidant and pro-inflammatory transcription factors NF-. kappa.B and STAT are suppressed. This increases the production of antioxidant and reducing molecules (e.g., NQO1, HO-1, SOD1, and/or γ -GCS) and/or decreases oxidative stress and the production of pro-oxidant and pro-inflammatory molecules (e.g., iNOS, COX-2, and/or TNF- α).

In some embodiments, the compounds disclosed herein may be used for the treatment and prevention of 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 pathogenesis is believed to involve overproduction of nitric oxide or prostaglandins, and pathologies involving oxidative stress alone or exacerbated by inflammation.

Another aspect of inflammation is the production of inflammatory prostaglandins such as prostaglandin E. These molecules promote vasodilation, plasma extravasation, local pain, elevated temperature and other symptoms of inflammation. The enzyme COX-2 in its inducible form is associated with their production and high levels of COX-2 are found in inflamed tissues. Thus, inhibition of COX-2 can alleviate many symptoms of inflammation and many important anti-inflammatory drugs (e.g., ibuprofen and celecoxib) act by inhibiting COX-2 activity. However, recent studies have shown that a class of cyclopentenone prostaglandins (cypgs) (e.g., 15-deoxy prostaglandin J2, also known as PGJ2) play a role in stimulating coordinated resolution of inflammation (e.g., Rajakariar et al, 2007). COX-2 is also associated with the production of cyclopentenone prostaglandins. Thus, inhibition of COX-2 would interfere with complete resolution of inflammation, potentially promoting the persistence of activated immune cells in the tissue and leading to chronic "smoldering" inflammation. This result has led to an increased incidence of cardiovascular disease in patients who have been on selective COX-2 inhibitors for extended periods of time.

In one aspect, the compounds disclosed herein are useful for controlling the production of proinflammatory cytokines in a cell by selectively activating Regulatory Cysteine Residues (RCRs) on proteins that modulate the activity of redox-sensitive transcription factors. It has been shown that activation of RCR by cyPG initiates a pro-resolution procedure in which the activities of antioxidant and cytoprotective transcription factor Nrf2 are effectively induced and the activities of pro-oxidant and pro-inflammatory transcription factors NF-. kappa.B and STAT are suppressed. In some embodiments, this increases the production of antioxidant and reducing molecules (NQO1, HO-1, SOD1, γ -GCS) and decreases the production of oxidative stress and pro-oxidant and pro-inflammatory molecules (iNOS, COX-2, TNF- α). In some embodiments, the compounds of the invention can restore cells responsible for inflammatory events to a non-inflammatory state by promoting resolution of inflammation and limiting excessive tissue damage to the host.

A. Obesity

Another aspect of the invention relates to novel methods and compounds for the treatment and prevention of obesity. Obesity is a medical condition in which excess body fat accumulates to the point where it may have adverse effects on health. It is typically defined by Body Mass Index (BMI) and can also be evaluated in terms of fat distribution by waist-to-hip ratio and total cardiovascular risk factors. BMI is related to both body fat percentage and total fat.

BMI is calculated by dividing the subject's mass by the square of his height (in decimal units: kg/m)²). The definitions established by the World Health Organization (WHO) in 1997 and published in 2000 are listed below:

obesity increases the risk of many physical and mental disorders. These comorbidities are most often shown in metabolic syndrome, which is a combination of medical conditions including: type 2 diabetes, hypertension, high blood cholesterol and high triglyceride levels.

Numerous studies support the link between obesity and chronic "stasis" inflammatory states. Obesity is associated with overproduction of inflammatory cytokines and chronic activation of inflammatory signaling pathways, including the NF-kB pathway (hotemisligiil, 2006). Chronic inflammation in adipose tissue is associated with the development of insulin resistance in skeletal muscle (Guilherme et al, 2008). Chronic activation of the NF- κ 3 pathway has been shown to induce insulin resistance, and NF- κ B inhibition has been proposed as a therapeutic strategy for the treatment of type 2 diabetes (Arkan et al, 2005; Shoelson et al, 2006).

In a similar manner to the development of insulin resistance, obesity is associated with development of resistance to the action of leptin. Leptin, a peptide hormone, has complex biological effects but an important site of action is the basal part of the hypothalamus. This structure of the brain is known to play a controlling role in eating behavior and energy homeostasis. Recently, oxidative stress and activation of the NF-. kappa.B pathway in the hypothalamus have been shown to be associated with hypothalamic insulin and leptin resistance (Zhang et al, 2008). Activation of antioxidant transcription factor Nrf2 is known to inhibit NF- κ B activity, and activation of Nrf2 by semi-synthetic triterpenoids has been reported to inhibit the development of obesity in mice fed a high fat diet (Shin et al, 2009).

However, the effect of Nrf2 activation on body weight of adults who have developed obesity has not been reported. During clinical trials of bardoxolone methyl (BARD) in patients with chronic kidney disease and type 2 diabetes, the present inventors noted that substantially all patients treated with bardoxolone methyl lost weight significantly over a period of two months. The primary objective of this experiment was to study the effects of BARD on parameters associated with renal function, and secondary objectives were associated with glycemic control and cardiovascular disease. Body weight measurements are a routine component of the safety data set for this experiment. Treatment with BARD produced statistically significant improvements in indicators of renal function (serum creatinine, estimated glomerular filtration rate, serum phosphorus, blood urea nitrogen and uricemia), glycemic control (fasting blood glucose and percent hemoglobin Alc), and cardiovascular disease (circulating endothelial cells). The ability of BARD to promote weight loss while improving various indicators associated with obesity-related diseases is surprising and unprecedented.

In a clinical trial of bardoxolone methyl in patients with type 2 diabetes and chronic kidney disease, designed to measure the effect of the drug on indices of renal function, glycemic control, insulin resistance and cardiovascular disease, a clear improvement in all these parameters was noted. See example 1 below. The patient received 25mg bardoxolone methyl once a day for 28 days followed by 75mg once a day for 28 days. In this study, the protocol prescribes that patient body weight be obtained at baseline (day-1, 1 day prior to the start of dosing), day 28 and day 56. Weight data was obtained for all patients starting the study except one (the patient did not record baseline weight). Of the remaining patients, 14 of 17 lost weight at day 28 (mean weight loss was 1.6% of baseline weight) and 17 of 17 lost weight at day 56 (mean weight loss was 3.7% of baseline, median 3.1%). All patients, including those who did not obtain baseline weight, lost weight between days 28 and 56. Most of these patients were overweight or clinically obese (mean baseline body weight of 101 kg). As shown in table 1, all but 3 patients lost more than 2% of their baseline weight between day-1 and day 56. Overall, the drug is very well tolerated in these patients.

This combined effect (weight loss and improvement of indicators related to glycemic control, cardiovascular disease and renal function) is highly beneficial. As mentioned above, many drugs that have been shown to have the ability to induce weight loss also show unacceptable side effects. In addition to its excellent overall tolerance, bardoxolone methyl has been shown to have a beneficial effect on several indicators associated with severe obesity-related diseases.

A 12 month toxicology study of bardoxolone methyl was also performed in macaques and their body weights were monitored. All animals were healthy at the beginning of the study and within normal weight range of their age. Interestingly, animals of all groups treated with bardoxolone methyl gained a large amount of weight at both weeks 26 and 50. This is consistent with the observation that BARD does not indiscriminately induce weight loss. Conversely, in some embodiments, its effect appears to be selective for those patients who are overweight and/or obese.

B. Renal failure

Renal failure, which results in inadequate clearance of blood-derived metabolic wastes and abnormal electrolyte concentrations in the blood, is an important medical problem worldwide, particularly in developed countries. See U.S. patent application publication No. 2009/0326063a1, the entire contents of which are incorporated herein by reference. Diabetes and hypertension are among the most important causes of chronic renal failure (CKD), but are also associated with other diseases such as lupus. Acute renal failure can result from contact with certain drugs (e.g., acetaminophen) or toxic chemicals, or from ischemia-reperfusion injury associated with shock or surgical procedures such as transplantation, and can lead to chronic renal failure. In many patients, renal failure can progress to a stage where the patient requires routine dialysis or kidney transplantation to sustain life. These procedures are highly traumatic and are associated with significant side effects and quality of life issues. Although effective treatments exist for some of the complications of renal failure, such as hyperparathyroidism and hyperphosphatemia, no available method has been shown to stop or reverse the underlying progression of renal failure. Thus, agents that can improve impaired renal function would represent a significant advance in the treatment of renal failure.

Inflammation contributes significantly to the pathology of CKD. There is also a strong mechanistic link between oxidative stress and renal dysfunction. The NF-. kappa.B signaling pathway plays an important role in the development of CKD, because NF-. kappa.B regulates the transcription of MCP-1, a chemokine responsible for recruiting monocytes/macrophages to cause an inflammatory response and ultimately damage the kidney (Wardle, 2001). The Keapl/Nrf2/ARE pathway controls transcription of several genes encoding antioxidant enzymes, including heme oxygenase-1 (HO-1). Knockout of Nrf2 gene in female mice resulted in development of lupus-like glomerulonephritis (Yoh et al, 2001). Furthermore, several studies have demonstrated that HO-1 expression is induced in response to renal injury and inflammation and that the enzyme and its products bilirubin and carbon monoxide play a protective role in the kidney (Nath et al, 2006).

The glomerulus and the surrounding bowman's capsule constitute the basic functional unit of the kidney. Glomerular Filtration Rate (GFR) is a standard indicator of kidney function. Creatinine clearance is commonly used to measure GFR. However, serum creatinine levels are often used as a surrogate indicator of creatinine clearance. For example, excessive levels of serum creatinine are generally recognized as indicative of insufficient kidney function, and a decrease in serum creatinine over time is recognized as indicative of improved kidney function. Normal levels of creatinine in the blood are about 0.6 to 1.2 milligrams (mg) per deciliter (d1) in adult males and 0.5 to 1.1 milligrams per deciliter in adult females.

Acute Kidney Injury (AKI) can occur following ischemia-reperfusion, following treatment with certain pharmacological agents such as cisplatin and rapamycin, and following intravenous injection of radiocontrast agents for medical imaging. As in CKD, inflammation and oxidative stress trigger the pathology of AKI. The basic molecular mechanism of radiocontrast induced nephropathy (RCN) is not well understood; however, it is likely that the combination of events including prolonged vasoconstriction, impaired renal self-regulation and direct toxicity of the contrast agent all contribute to renal failure (Tumlin et al, 2006). Vasoconstriction results in reduced renal blood flow and causes ischemia-reperfusion and the production of reactive oxygen species. HO-1 is strongly induced in these conditions and HO-1 has been shown to prevent ischemia-reperfusion injury in several different organs, including the kidney (Nath et al, 2006). In particular, the induction of HO-1 has been shown to be protective in a rat model of RCN (Goodman et al, 2007). Reperfusion also causes an inflammatory response in part through activation of NF- κ B signaling (Nich01s, 2004). Targeting NF- κ B has been proposed as a therapeutic strategy to prevent organ damage (Zingarelli et al, 2003).

C. Cardiovascular diseases

Cardiovascular (CV) disease is one of the most important causes of death worldwide and is the leading cause of death in many developed countries. See U.S. patent application publication No. 2009/0326063a1, the entire contents of which are incorporated herein by reference. The etiology of CV disease is complex, but most of the etiologies are associated with inadequate or complete disruption of blood supply to key organs or tissues. Such diseases often result from the rupture of one or more atherosclerotic plaques, which leads to the formation of thrombi, blocking blood flow in critical blood vessels. Such thrombosis is a major cause of heart attack in which one or more coronary arteries are occluded and blood flow to the heart itself is interrupted. The resulting ischemia highly damages cardiac tissue, both due to hypoxia during the ischemic event and excessive formation of free radicals after restoration of blood flow (a phenomenon known as ischemia-reperfusion injury). During thrombotic stroke, similar damage occurs in the brain when cerebral arteries or other major blood vessels become occluded by thrombosis. In contrast, hemorrhagic stroke involves the rupture of blood vessels and the influx of blood into the surrounding brain tissue. This can lead to oxidative stress in the immediate area of bleeding due to the presence of large amounts of free heme and other active substances and to other ischemia of the brain due to impaired blood flow. Subarachnoid hemorrhage, often accompanied by cerebral vasospasm, also leads to ischemia/reperfusion injury in the brain.

Alternatively, atherosclerosis may thus widely progress to stenosis (narrowing of the artery) in critical blood vessels and long-term inadequate blood flow to critical organs, including the heart. Such chronic ischemia can result in many types of end organ damage, including cardiac hypertrophy associated with congestive heart failure.

Atherosclerosis occurs when physical defects or damage to the inner layer of the artery (endothelium) triggers an inflammatory response that includes proliferation of vascular smooth muscle and infiltration of leukocytes into the affected area, which results in an underlying defect in many forms of cardiovascular disease. Eventually, a complicated lesion called atherosclerotic plaque can form, consisting of the above-mentioned cells combined with deposits of cholesterol-carrying lipoproteins and other substances (e.g., Hansson and Anton, 2006).

Drug treatment of cardiovascular disease includes prophylactic treatments, such as the use of drugs aimed at lowering blood pressure or circulating levels of cholesterol and lipoproteins, and treatments designed to reduce platelet and other blood cell adhesion tendencies (thus reducing the rate of plaque development and the risk of thrombosis). More recently, drugs such as streptokinase and tissue plasminogen activator have been introduced and used to dissolve thrombi and restore blood flow. Surgical treatments include coronary artery bypass surgery to create an alternate blood supply, balloon angioplasty to compress plaque tissue and increase the diameter of the arterial lumen, and carotid endarterectomy to remove plaque tissue in the carotid artery. Such treatments, particularly balloon angioplasty, are accompanied by the use of stents, expandable mesh tubes designed to support the arterial wall of the affected area and maintain vessel patency. Recently, the use of drug eluting stents has become widespread to prevent postoperative restenosis (arterial restenosis) in the affected area. These devices are metal stents overcoated with a biocompatible polymeric matrix containing a drug that inhibits cell proliferation (e.g., paclitaxel or rapamycin). The polymer allows for slow, localized release of the drug in the affected area, minimizing non-target tissue contact. Despite the obvious benefits of such treatments, mortality from cardiovascular disease remains high and clearly does not meet the needs of cardiovascular disease treatment.

As mentioned above, it has been demonstrated that the induction of HO-1 is beneficial in many cardiovascular disease models and that low levels of HO-1 expression are clinically relevant for high risk of CV disease. Accordingly, the compounds disclosed herein may be used to treat or prevent a wide variety of cardiovascular diseases, including but not limited to atherosclerosis, hypertension, myocardial infarction, chronic heart failure, stroke, subarachnoid hemorrhage and restenosis.

D. Diabetes mellitus

Diabetes is a complex disease characterized by the inability of the body to regulate circulating levels of glucose. See U.S. patent application publication No. 2009/0326063a1, the entire contents of which are incorporated herein by reference. This deficiency may result from insulin deficiency, a peptide hormone that regulates glucose production and absorption in a variety of tissues. Insulin deficiency impairs the ability of muscle, fat and other tissues to properly absorb glucose, resulting in hyperglycemia (abnormally high levels of glucose in the blood). Most often, such insulin deficiencies result from insufficient production in pancreatic islet cells. In most cases, this results from autoimmune destruction of these cells, a condition known as type 1 or juvenile onset diabetes, but may also be caused by physical trauma or some other cause.

Diabetes is also caused when muscles and adipocytes become poorly responsive to insulin and improperly absorb glucose, resulting in hyperglycemia. This phenomenon is called insulin resistance, and the resulting condition is called type 2 diabetes. Type 2 diabetes is the most common type, which is highly associated with obesity and hypertension. Obesity is associated with an inflammatory state of adipose tissue that is thought to play a major role in the development of insulin resistance (e.g., Hotamisigil, 2006; Guilherm et al, 2008).

Diabetes is associated with damage to many tissues, largely because hyperglycemia (and hypoglycemia, which may result from too many or not timely administrations of insulin) is a significant source of oxidative stress. The development of chronic renal failure, retinopathy, peripheral neuropathy, peripheral vasculitis, and slow or completely unhealed skin ulcers are among the common complications of diabetes. Due to their ability to protect against oxidative stress, in particular by inducing the expression of HO-1, the compounds disclosed herein can be used to treat various complications of diabetes. As mentioned above (Cai et al, 2005), chronic inflammation and oxidative stress in the liver are suspected to be the major causative factors in the development of type 2 diabetes. In addition, PPAR γ agonists such as thiazolinediones are capable of reducing insulin resistance and are known to be effective treatments for type 2 diabetes.

Based on the experimental results obtained, including those given in the present application, the compounds and methods of the invention may be used to treat patients suffering from neuroinflammation.

The therapeutic effect of diabetes can be evaluated as follows. Both the biological and, if possible, clinical efficacy of the treatment method is assessed. For example, the disease manifests itself as an increase in blood glucose, and thus the biological efficacy of the treatment can be assessed by, for example, observing the return of the assessed blood glucose to normal levels. Measurement of a clinical endpoint that may give an indication of b-cell regeneration after, for example, a 6 month period, may indicate clinical efficacy of the treatment regimen.

E. Liver disease

Liver disease (also known as liver disease) is a broad term describing any single disease affecting the liver. Many are associated with jaundice caused by increased bilirubin levels in the system. Bilirubin is produced by the breakdown of hemoglobin from dead red blood cells; normally, the liver removes bilirubin from the blood and excretes it through the bile.

Various types of liver diseases include:

hepatitis, inflammation of the liver, mainly caused by various viruses as well as some toxicants (e.g., alcohol), autoimmunity (autoimmune hepatitis) or genetic disorders;

non-alcoholic propertyFatty liver diseaseA spectrum of diseases, associated with obesity, and characterized by high amounts of fat in the liver; can cause hepatitis, i.e., steatohepatitis and/or cirrhosis;

cirrhosis (formation of fibrous tissue in the liver, replacing dead hepatocytes), which is caused by viral hepatitis, alcohol abuse, or exposure to other hepatotoxic chemicals;

hemochromatosis, a genetic disease that causes iron to accumulate in the body and ultimately causes liver damage;

of the liverCancer treatment(primary hepatocellular carcinoma orBile duct cancerAnd metastatic cancer, usually from other parts of the gastrointestinal tract);

wilson's diseaseDisease, a genetic disease that causes the body to retain copper;

primary sclerosing cholangitis, an inflammatory disease of the bile duct, may be autoimmune in nature;

primary biliary cirrhosis, autoimmune disease of the small bile duct;

bulgarian syndrome, occlusion of the hepatic vein;

gilbert syndrome (A)Gilbert’s syndrome) A genetic disorder of bilirubin metabolism, found in about 5% of the population; and

a type II glycogen storage disease in a subject,glycogen accumulation leads to progressive muscle weakness throughout the body (myopathy) and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.

There are also many pediatric liver diseases including biliary atresia,Alpha-1 antitrypsin deficiency,Ai Ou Jile (alagille) syndromeAnd progressive familial intrahepatic cholestasisTo name just a few.

External signs of liver disease include tongue coating, halitosis, skin itching, excessive sweating, unpleasant body odor, dark under-eye circles, redness and itching of the eyes, rosacea, brown spots and scars on the skin, flushing facial appearance or excessive blood vessels on the face. Other symptoms include jaundice, black urine, white feces, bone loss, bleeding tendency, itching, small spider vessels visible on the skin, splenomegaly, peritoneal fluid accumulation, chills, pain from the biliary or pancreatic tract, and enlarged gall bladder.

Symptoms associated with liver dysfunction include both signs and a variety of symptoms associated with digestive problems, blood glucose problems, immune dysfunction, abnormal absorption of fat, and metabolic problems. Malabsorption of fat may lead to symptoms including dyspepsia, reflux, fat-soluble vitamin deficiency, hemorrhoids, gallstones, fatty-food intolerance, alcohol intolerance, nausea and vomiting attacks, abdominal bloating, and constipation.

Neurological disorders include depression, mood changes, especially anger and irritability, poor concentration and "brain confusionfoggy brain) ", body overheating, especially the face and torso, and recurrent headache associated with nausea (including migraine). Blood glucose problems include the desire to eat sugar, hypoglycemia, and unstable blood glucose levels, as well as the onset of type 2 diabetes.

Abnormalities in fat levels in the bloodstream include high or low levels of lipids. Hypercholesterolemia includes elevated LDL cholesterol, reduced HDL cholesterol, elevated triglycerides, arterial obstruction leading to hypertensive heart attacks and strokes, accumulation of fat in other body organs (steatosis of the organs), fatty masses in the skin (lipomas and other fatty tumors), substantial weight gain (which can lead to obesity), inability to lose weight even on diet, slow metabolism, belly humps (beer belly), cellulite, and/or fatty liver. Hypocholesterolemia is low total cholesterol, low LDL and VLDL cholesterol and/or low triglycerides.

There are many liver function tests used to test the proper function of the liver. These test blood for the presence of enzymes, metabolites or products that are normally most abundant in liver tissue. If alcohol-induced liver disease is suspected, blood tests and imaging tests (MRI, CT scan or ultrasound) may be helpful in diagnosing and eliminating other causes of liver disease but evidence is best established by liver biopsy.

A special X-ray known as hepatic angiography is used to study the veins and arteries that supply blood to the liver. Typically, radiography is only required if the CT scan or MRI shows no conclusive information. During hepatic angiography, a thin flexible tube is inserted into the blood vessel through an incision in the groin. A dye is then injected, which brightens the vessel for better visualization. This procedure is usually performed under local anesthesia and it is painless but may be uncomfortable.

Medical imagingTest ofAllowing the physician to examine the patient by viewing still and moving images of the patient's internal organs and tissues. One of the first types of tests that a patient may need to take is ultrasound. This is a routine procedure which does not cause any harm to the patient because it does not utilise the radiation waves. It usually takes 15 minutes to complete. The gel is applied to the skin prior to this procedure. Its main purpose is to help move easily and ensure that the sound waves are directed through the skin. The solid mass is converted into an image that the radiologist views on a monitor. The picture is recorded and the radiologist will make a report and will discuss the report with the patient's physician during a particular meeting.

CT scanning or computed tomography is a painless procedure used to obtain pictures of body organs and tissues. Unlike ultrasound, CT scanning utilizes radiation but with minimal risk. The tomogram taken by the CT scanner can show whether there are any abnormalities in the lungs, bones, soft tissues and blood vessels. It is used mostly for studying the abdomen and chest, and it may take 30 minutes. CT scanners are large machines in which the patient moves back and forth. Before the examination, the patient received an iodine dye into the vein, which helps to visualize the blood vessels and kidneys, and also makes it easier to observe the differences between normal and abnormal tissue in the liver and other organs.

Magnetic Resonance Imaging (MRI) enables more detailed images to be obtained than CT scans. It is a new technology for a type of tube scanner that forms a magnetic field by releasing radio frequency energy. MRI is most commonly used to observe and study tumors before and after treatment. It is a painless operation and a typical scanning period does not typically exceed 30 minutes. However, some patients may experience claustrophobia during scanning. Some patients with special implants may not be able to use MRI due to the presence of metal in their body.

Treatment of liver disease varies depending on the type of condition. Liver disease affects the proper functioning of the liver. Treatment of liver disease is often directed to relief of symptoms and complications. Most of the time is focused on avoiding risk factors.

All types of hepatitis are treated with intravenous therapeutic fluids due to dehydration resulting from vomiting and diarrhea. Typically, patients with less severe symptoms may be treated for the disease at home, otherwise hospitalization may be required. Drug therapy for nausea and vomiting is also available. Hepatitis b and c may become chronic and unfortunately, no drug prevents this. Once hepatitis b becomes chronic, it can be treated with antiviral drugs, but such drugs are not effective in all patients. Chronic hepatitis c is treated with so-called pegylated interferon alfa agents (Pegasys or PEG-Intron) which may be used in combination with an antiviral drug known as ribavirin. The treatment for chronic hepatitis b and c is made based on the results of several tests on liver function and the type of medication administered is decided after consultation with gastroenterologists and liver specialists. However, the use of interferons for the treatment of hepatitis c may be limited in cases of frequent alcohol abuse or drug abuse, in cases of depression, autoimmune diseases or low hemoglobin levels.

Treatment of cirrhosis is mainly aimed at alleviating complications. Drugs can be used to treat the underlying cause. Some of these drugs includeSteroids, penicillaminesAnd anti-inflammatory agents such as colchicine. Their effects are still under investigation and at this time they do not appear to improve the condition of the patient. Cirrhosis caused by portal hypertension can be treated with a beta blocker, which lowers blood pressure.

Pharmaceutical formulations and routes of administration

The compounds of the present disclosure can be administered by a variety of methods, such as orally or by injection (e.g., subcutaneously, intravenously, intraperitoneally, etc.). Depending on the route of administration, the active compound may be coated in a material to protect the compound from acids and other natural conditions that would inactivate the compound. They may also be administered by continuous infusion at the site of disease or trauma.

The compounds of the present disclosure may also be formulated and/or prepared in a variety of ways, including as solid dispersions. See, for example, PCT publication No. WO2010/093944, the entire contents of which are incorporated herein by reference.

In order to administer a therapeutic compound by means other than parenteral administration, it may be necessary to coat the compound with or co-administer the compound with a material that prevents its inactivation. For example, the therapeutic compound may be administered to the patient in a suitable carrier such as a liposome or diluent. Pharmaceutically acceptable diluents include saline and aqueous buffers. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al, 1984).

Therapeutic compounds may also be administered parenterally, intraperitoneally, intravertebrally, or intracerebrally. Liquid or semi-liquid dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under normal conditions of storage and use, these formulations may contain preservatives to prevent microbial growth.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (when water-soluble) or dispersions and sterile powders for the 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 such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride or polyalcohols such as mannitol and sorbitol in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in the appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying to obtain a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.

The therapeutic compound may be administered orally, e.g., with an inert diluent or an assimilable edible carrier. The therapeutic compound and other ingredients may also be enclosed in hard or soft shell gelatin capsules, compressed into tablets or incorporated directly into the diet of a subject. In certain embodiments, the compound, such as bardoxolone methyl, is configured as a capsule. For oral therapeutic administration, the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, cachets and the like. In some embodiments, the compound, e.g., bardoxolone methyl, is formulated as an ingestible tablet. Of course, the percentage of therapeutic compound in the compositions and formulations can vary. The amount of therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.

In some embodiments, the daily dose of the therapeutic compound for a human patient will be from 5mg to 500 mg. In some of these embodiments, the dose will be from 10mg to 300 mg. In some of these embodiments, the dose will be from 10mg to 250 mg. In some of these embodiments, the dose will be 25mg to 150 mg. For example, in some embodiments, the daily dose of bardoxolone methyl is about 25mg, about 75mg, or about 150 mg. In some embodiments, about 25mg, about 75mg, or about 150mg of bardoxolone methyl may be mixed with excipients and/or other pharmaceutically suitable ingredients into an ingestible capsule or tablet. In some of these embodiments, the bardoxolone methyl is in the form a.

In some embodiments, the daily dose of the therapeutic compound for a human patient will be from 5mg to 50 mg. In some of these embodiments, the dose will be from 10mg to 40 mg. For example, in some embodiments, the daily dose of bardoxolone methyl is about 10mg, about 20mg, or about 40 mg. In some embodiments, about 10mg, about 20mg, or about 40mg of bardoxolone methyl may be mixed with excipients and/or other pharmaceutically suitable ingredients into an ingestible capsule or tablet. In some of these embodiments, the bardoxolone methyl is in the form B. In some of these embodiments, the bardoxolone methyl will be in the form of a solid dispersion of form B. See, for example, PCT publication No. WO2010/093944, the entire contents of which are incorporated herein by reference.

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 physically discrete units suitable as unitary dosages for the subjects to be treated; each unit containing a predetermined amount of a therapeutic compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. The specifications for the dosage unit forms of the invention are determined by and directly depend on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of synthesizing such therapeutic compounds for the treatment of the selected patient condition.

The active compound is administered in a therapeutically effective dose sufficient to treat a condition associated with the condition of the patient. For example, the efficacy of a compound can be assessed in an animal model system, such as the model systems shown in the examples and figures, that is predictive of efficacy in treating a human disease.

The actual dose of a compound of the present disclosure or a composition comprising a compound of the present disclosure administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of the condition, type of disease to be treated, previous or concurrent therapeutic measures, the specific condition of the subject, and the route of administration. These factors can be determined by the skilled artisan. The practitioner responsible for administration will typically determine the concentration of one or more active ingredients in the composition and one or more appropriate dosages for the individual subject. If any complications occur, the dosage may be adjusted by the individual physician.

In addition to the dosages disclosed above, an effective amount of the compound may be administered in one or more doses per day for one or more days, from about 0.001mg/kg to about 1000mg/kg, from about 0.01mg/kg to about 750mg/kg, from about 100mg/kg to about 500mg/kg, from about 1.0mg/kg to about 250mg/kg, from about 10.0mg/kg to about 150mg/kg (depending, of course, on the mode of administration and the factors discussed above). Other suitable dosage ranges include 1mg to 10000 mg/day, 100mg to 10000 mg/day, 500mg to 10000 mg/day, and 500mg to 1000 mg/day. In some particular embodiments, the amount is less than 10,000 mg/day, ranging from 750mg to 9000 mg/day.

The effective amount may be less than 500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 25 mg/kg/day, less than 10 mg/kg/day, or less than 1 mg/kg/day. Alternatively in the range of 1 mg/kg/day to 200 mg/kg/day. For example, for the treatment of a diabetic patient, the dosage unit may be an amount that reduces blood glucose by at least 40% compared to an untreated subject. In another embodiment, the unit dose is an amount that reduces blood glucose to a level of ± 10% of the blood glucose level of the non-diabetic subject.

In other non-limiting examples, the dosage may also include a dosage selected from the group consisting of about 1 μ g/kg/body weight, about 5 μ g/kg/body weight, about 10 μ g/kg/body weight, about 50 μ g/kg/body weight, about 100 μ g/kg/body weight, about 200 μ g/kg/body weight, about 350 μ g/kg/body weight, about 500 μ g/kg/body weight, about 1 mg/kg/body weight, about 5 mg/kg/body weight, about 10 mg/kg/body weight, about 50 mg/kg/body weight, about 100 mg/kg/body weight, about 200 mg/kg/body weight, about 350 mg/kg/body weight, about 500 mg/kg/body weight to about 1000 mg/kg/body weight or higher, and any range derivable therein. In non-limiting examples of ranges derived from the values listed above, ranges of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 μ g/kg/body weight to about 500 mg/kg/body weight, and the like, can be administered based on the above values.

In certain embodiments, a pharmaceutical composition of the present disclosure may comprise, for example, at least about 0.1% of a compound of the present disclosure. In further embodiments, the compounds of the present disclosure may include, for example, between about 2% and about 75% of the unit weight, or between about 25% and about 60% of the unit weight, and any range derivable therein.

Single or multiple doses of the agent are contemplated. The desired time interval for multiple dose delivery can be determined by one of ordinary skill in the art using only routine experimentation. As an example, the subject may be administered two doses per day at intervals of about 12 hours. In some embodiments, the agent is administered once daily.

The one or more agents may be administered on a conventional schedule. As used herein, a conventional schedule refers to a predetermined period of time. The regular schedule may include time periods that are the same or different in length, so long as the schedule is predetermined. For example, a conventional schedule may include twice daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once monthly, or any set number of days or weeks in between, administration. Alternatively, the predetermined regular schedule may include two administrations per day for the first week, followed by one administration per day for several months, etc. In further embodiments, the present invention provides that one or more agents may be orally ingested and with timing dependent or independent of food intake. Thus, for example, the medicament may be ingested daily in the morning and/or daily in the evening, regardless of when the subject has eaten or will eat.

Combination therapy

In addition to use as monotherapeutic agents, the compounds of the present disclosure may also be used in combination therapy. Effective combination therapy can be achieved using a single composition or pharmaceutical formulation comprising two agents, or by administering two different compositions or formulations simultaneously, wherein one composition comprises a compound of the invention and the other comprises one or more second agents. Alternatively, treatment may be preceded or followed by other agents at minute to month intervals.

Various combinations may be employed, such as when a compound of the invention is "a" and "B" represents a 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

it is contemplated that other anti-inflammatory agents may be used in combination with the treatment of the present invention. For example, other COX inhibitors may be used, including aryl carboxylic acids (salicylic acid, acetylsalicylic acid, diflunisal, choline magnesium trisalicylate, salicylate, paracetamol, flufenamic acid, mefenamic acid, meclofenamic acid, and triflumic acid), aryl alkanoic acids (diclofenac, fencloc acid, alclofenac, chlorfenac, and chlorfenac,Fentiazac acid, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic acid, benzeneLoxifene, pirprofen, tolmetin, zomepirac, clininac, indomethacin, and sulindac) and enolic acids (phenylbutazone, oxybutyzone, azapropazone, feprazone, piroxicam, and isoxicam. See also U.S. patent No. 6,025,395, which is incorporated herein by reference.

Food and nutritional supplements that are reported to be beneficial for the treatment or prevention of parkinson's disease, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease and all other diseases whose pathogenesis is believed to involve overproduction of any of Nitric Oxide (NO) or prostaglandins, for example acetyl-L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine, vitamin C, L-dopa or a combination of several antioxidants, may be used in combination with the compounds of the present invention.

Other specific secondary treatments include immunosuppressants (for graft and autoimmune related RKD), antihypertensive drugs (for hypertension related RKD, e.g., angiotensin converting enzyme inhibitors and angiotensin receptor blockers), insulin (for diabetic RKD), lipid/cholesterol lowering agents (e.g., HMG-CoA reductase inhibitors such as atorvastatin or simvastatin), treatment of hyperphosphatemia or hyperparathyroidism associated with CKD (e.g., sevelamer acetate, cinacalcet hydrochloride), dialysis and dietary restrictions (e.g., protein, salt, fluid, potassium, phosphorus).

VIII example

The following examples are included to illustrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1 clinical weight loss data in phase 2 study

In a clinical trial of bardoxolone methyl in patients with type 2 diabetes and chronic kidney disease, designed to measure the effect of the drug on indices of renal function, glycemic control, insulin resistance and cardiovascular disease, a clear improvement in all these parameters was noted. See U.S. patent application publication No. 2009/0326063a1, the entire contents of which are incorporated herein by reference.

The patient received 25mg bardoxolone methyl once a day for 28 days (oral administration in capsule form), followed by 75mg once a day for 28 days (oral administration in capsule form). In this study, the protocol prescribes that patient body weight be obtained at baseline (day-1 (D-1) — 1 day prior to the start of dosing), day 28 (D28), and day 56 (D56). Weight data was obtained for all patients starting the study except one (the patient did not record baseline weight). Of the remaining patients, 14 of 17 lost weight at day 28 (mean weight loss was 1.6% of baseline weight) and 17 of 17 lost weight at day 56 (mean weight loss was 3.7% of baseline, median 3.1%). All patients, including those who did not obtain baseline weight, lost weight between days 28 and 56. Most of these patients were overweight or clinically obese (mean baseline body weight of 101 kg). As shown in table 1, all but 3 patients lost more than 2% of their baseline body weight between day-1 and day 56. Overall, the drug is very well tolerated in these patients. Additional patient data is provided in tables 2 and 3.

Prior to initiation of treatment, baseline values for basal clinical observations (e.g., weight, blood pressure, height) and serum creatinine, blood urea nitrogen, serum phosphorus, serum uric acid, angiotensin II, fasting plasma glucose, hemoglobin A1c, Circulating Endothelial Cells (CECs) and iNOS-positive CECs were recorded.

Parameters associated with renal function were significantly improved after 28 days of treatment (approximately 10% increase in eGFR) and after 56 days of further treatment (more than 20% increase in eGFR compared to baseline). More than 10% reduction in BUN, serum creatinine, uric acid and urinary albumin/creatinine ratio was also observed. Significant reductions in CEC and iNOS-positive CEC were also noted. The results are summarized in table 4.

Example 2 toxicity Studies in monkeys

Bardoxolone methyl and vehicle were administered once a day for 353 days during the study by oral gavage to a group of macaques. All animals were healthy at the beginning of the study and within normal weight range of their age. Dosage levels were 0, 30/5, 100/30, and 300 mg/kg/day and were administered in a dose volume of 3mL per dose. The control group received the vehicle in the same manner as the treatment group. The test article for each animal was added to the syringe containing the vehicle for each animal just prior to dosing and vortexed until thoroughly mixed to achieve the desired concentrations of 30, 100 and 300mg/mL until day 42 (week 6). During dosing, a syringe containing the test article formulation for each animal was pushed through the gavage tube. 1mL of the carrier rinse was then added to the administration syringe and administered. After two volumes of administration, 5mL of carrier rinse was used to wash the feeding tube and ensure that the entire amount of test article was administered to the animal. Analysis of whole blood samples from day 1 and day 28 indicated no significant difference between exposure at the three dose levels. Thus, adjusting the dose level allows different blood exposures to be examined. Dosing to all animals was discontinued for 4 days (days 43 to 46) during cycle 7. Initial dose levels of 30 and 100 mg/kg/day were reduced to 5 and 30 mg/kg/day, respectively, and doses were restored on days 47 to 353. The individual dose is based on the most recent body weight. The results of this study are summarized in table 5. All treatment groups gained weight during the study period, indicating that bardoxolone methyl treatment did not induce weight loss in healthy monkeys of normal weight.

Example 3 clinical weight loss data in phase 2b/3 study

The efficacy and safety of bardoxolone methyl was studied in a phase 2b/3 trial in patients with stage 3b or 4 CKD and type 2 diabetes. Body weight measurements were included as the underlying clinical parameters in the study.

F. Patient population

Study randomization in adults with moderate-to-severe CKD and type 2 diabetes with 20 to 45mL/min/1.73m²The GFR was estimated (using the MDRD formula). The screening estimated GFR was calculated as the mean of two estimated GFR results collected at least 5 days apart (not more than 25% apart) over a 3 week period. Requiring treatment with an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, or both for at least 3 months prior to screening, with a stable dose for at least 8 weeks; 98% of patients meet this criterion. Knockout criteria included type 1 diabetes, non-diabetic nephropathy, hemoglobin A1c > 10%, qtcfededericia interphase > 450 milliseconds, evidence of liver dysfunction and recent cardiovascular disease.

G. Design of research

Study 227 patients were randomized 1: 1 to receive placebo, 25, 75 or 150mg of bardoxolone methyl for 52 weeks, including titration to the indicated dose levels. The study had 4 phases: (1) 21-day screening/placebo run-in period; (2) 8-week titration to achieve randomized doses, extending to 20 weeks in patients who are poorly tolerated drugs or have abnormal laboratory test results that prevent final titration over 8 weeks; (3) dose maintenance period from end of titration to week 52; and (4) 4-week follow-up period after the last study drug administration. Study medication was orally administered 1 hour a day prior to food intake in the morning. The dose titration was performed as follows: (1) a placebo; (2)25 mg; (3)25mg, increasing to 75mg after 4 weeks; and (4)25mg, increasing to 75mg after 4 weeks, and further increasing to 150mg after another 4 weeks. Randomization was stratified by CKD staging (stage 3b vs. stage 4), urinary albumin/creatinine ratio (ACR;. vs. > 300mg/g), and glycemic control (hemoglobin A1c < vs. > 7%). An independent data security monitoring committee monitors the safety of the patient.

H. Procedure and results

Estimation of GFR and routine safety laboratory checks were done using a central laboratory at and every 4 weeks after screening. Adverse events and clinical laboratory parameters were assessed at each visit. Preliminary results, changes in GFR estimated from baseline at week 24, were analyzed after discontinuation of the study at or before the end of all randomized patients at week 24. The results of the study included changes from baseline at week 24 in serum creatinine, blood urea nitrogen, serum phosphorus, uric acid, ACR, hemoglobin A1c, and whole parathyroid hormone.

I. Patient characteristics

With respect to baseline variables (table 6), the treatment group was generally balanced, although the percentage of males in the placebo group (49%) was slightly lower than the treatment group (59%). The mean age was 67 years. The mean time between diagnosis and randomization of diabetes was 18 years; diabetes was well controlled with a mean baseline hemoglobin A1c of 7.2%. At the time of study entry, the mean estimated GFR was 32.4mL/min/1.73m²Wherein 62% of patients have stage 3b CKD and 38% have stage 4 CKD. The median baseline ACR was 596 mg/g. ACR > 300mg/g (macroalbuminuria), 30-300mg/g (microalbuminuria) and < 30mg/g each account for one third of the patients. 98% of patients receive ACE inhibitors, ARB treatment, or both; the remaining patients received exemption from inclusion criteria because they were intolerant to these drugs.

J. Preliminary results

At week 24, all bardoxolone methyl groups showed an estimated increase in GFR relative to both baseline and placebo groups changes, with mean increases of 8.3 + -1.1, 11.5 + -1.1 and 10.6 + -1.1 mL/min/1.73m compared to placebo in the 25, 75 and 150mg groups, respectively²(p < 0.001, all groups). The placebo group showed essentially no change (0.1. + -. 1.1mL/min/1.73 m)²) (Table 7). The difference between the 25 and 75mg groups was statistically significant (calculated p 0.039), but the difference between the 75 and 150mg groups was not statistically significant (p 0.54). An increase in estimated GFR was observed within 4 weeks of initiation of treatment in the bardoxolone methyl group, with a peak at the third12 weeks and held steady until week 24 (fig. 2). At week 24, 74% of bardoxolone methyl patients experienced an estimated GFR increase of more than 10% compared to single placebo patients (data not shown), and 24% of bardoxolone methyl patients reported an estimated GFR increase of more than 50%.

Most patients treated with bardoxolone methyl experience an improvement in the stage of CKD from stage 4 to stage 3b or from stage 3b to stage 3 a. The percentage of improvement in the placebo group was 17%, 53% in the 25mg group, 69% in the 75mg group, and 61% in the 150mg group. Furthermore, few patients experienced a worsening of the CKD staging in each bardoxolone methyl group compared to the placebo group (2 patients [ 4% ] in each bardoxolone methyl group compared to 7 patients [ 13% ] in the placebo group).

Body weight decreased over time in the active treatment group. In the 25, 75 and 150mg groups, the average body weight change at week 24 was-5.9, -4.7 and-5.8 kg, respectively, whereas no body weight change was observed in the placebo group.

Example 4 clinical weight loss resulting from 12 months of treatment

In a continuation of the study described in example 3, patients remained in their assigned treatment group (placebo, 25mg bardoxolone methyl/day, 75mg bardoxolone methyl/day, 150mg bardoxolone methyl/day) for an additional 28 weeks, resulting in a total treatment period of 52 weeks. The double-blind structure of the study was maintained throughout the 52 week period. At week 52, patients in all treatment groups lost additional weight relative to week 24. As shown in table 8, at least two thirds of patients treated with bardoxolone methyl reduced by more than 5kg by week 52 compared to 21% placebo-treated patients. Approximately one third of patients treated with bardoxolone methyl reduced by more than 10kg by week 52 compared to 6% of placebo-treated patients. Table 9 shows the body weight data in 4 week increments for each group over the entire 52 week treatment period. Treatment was discontinued in all groups at week 52 (including placebo), and final clinical and laboratory measurements were taken at week 56. The data in table 9 demonstrate that patients in the bardoxolone methyl treatment group lost weight at a relatively uniform rate over a 52 week treatment period.

TABLE 6 demographic data and baseline characteristics

TABLE 7 Change from baseline eGFR at week 24 using longitudinal model

TABLE 8 change in body weight from baseline to week 52

All methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the method and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Reference to the literature

The following references, to the extent they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

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Claims

1. A method of reducing body weight in a subject in need thereof, the method comprising administering to the subject an Antioxidant Inflammation Modulator (AIM) in an amount sufficient to reduce the subject's body weight.

2. The method of claim 1, wherein the subject has excess body fat.

3. The method of claim 1, wherein the subject is overweight.

4. The method of claim 1, wherein the subject's Body Mass Index (BMI) is 25kg/m²To 30kg/m²。

5. The method of claim 1, wherein the subject is obese or exhibits one of more symptoms of obesity.

6. The method of claim 5, wherein the obesity is class I obesity.

7. The method of claim 1, wherein the subject's BMI is 30kg/m²To 35kg/m²。

8. The method of claim 5, wherein the obesity is class II obesity.

9. The method of claim 1, wherein the subject's BMI is 35kg/m²To 40kg/m²。

10. The method of claim 5, wherein the obesity is grade III obesity.

11. The method of claim 1, wherein the subject's BMI is 40kg/m²To 80kg/m²。

12. The method of any one of claims 1-11, wherein the subject is a human subject.

13. The method of any one of claims 1-13, wherein the method further selectively induces Nrf2 in the subject.

14. The method of any one of claims 1-13, wherein the method further inhibits activation of NF- κ B in the subject.

15. The method of any one of claims 1-13, wherein the AIM is a compound of the formula:

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

Each R₃Independently are:

hydroxy, halo, oxo, amino, hydroxyamino, nitro, imino, cyano, azido, mercapto, or thio;

y is 0 to 8.

16. The method of any one of claims 15, wherein the AIM is a compound of the formula:

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

Each R₃Independently are:

or

y is 0 to 8.

17. The method of any one of claims 15, wherein the AIM is a compound of the formula:

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

Each R₃Independently are:

or

y is 0 to 7.

18. The method of any one of claims 15, wherein the AIM is a compound of the formula:

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

Each R₃Independently are:

or

y is 0 to 6.

19. The method of any one of claims 1-13, wherein the AIM is a compound of the formula:

wherein:

w is an electron withdrawing group;

R₁and R₂Each independently is:

hydrogen, hydroxy, alkyl_(C≤8)Substituted, byAlkyl radical_(C≤8)Alkenyl radical_(C≤8)Substituted alkenyl groups_(C≤8)Alkoxy group_(C≤8)Or substituted alkoxy_(C≤8)(ii) a Or

Each R₃Independently are:

alkyl radical_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkylene group(s)_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkoxyamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Alkyl sulfonyl amino_(C≤12)Acylamino group_(C≤12)Alkyl imino group_(C≤12)Alkenylimino radical_(C≤12)Alkynylimino group_(C≤12)Aryl imino group_(C≤12)Aralkyl imino group_(C≤12)Heteroaryl imino group_(C≤12)Heteroarylalkylimino radicals_(C≤12)Acylimino group_(C≤12)Or substitution of any of these groupsForms thereof;

or

y is 0 to 8.

20. The method of any one of claims 15-19, wherein W is cyano, fluoro, or-CF₃。

21. The method of claim 15, wherein the AIM is a compound of the formula:

wherein:

X₁and X₂Independently are:

hydrogen, hydroxy, halo, oxo, amino, hydroxyamino, nitro, imino, cyano, azido, mercapto, or thio; or

y is hydrogen, hydroxy, halo, amino, hydroxyamino, nitro, cyano, azido, mercapto, alkyl_(C≤12)Alkenyl radical_(C≤12)Alkynyl group_(C≤12)Aryl radical_(C≤12)Aralkyl group_(C≤12)Heteroaryl group_(C≤12)Heteroarylalkyl group_(C≤12)Acyl group_(C≤12)Alkoxy group_(C≤12)Alkenyloxy group_(C≤12)Alkynyloxy, alkynyloxy_(C≤12)Aryloxy group_(C≤12)(iii) aralkyloxy_(C≤12)Heteroaryloxy group_(C≤12)Hetero aralkyloxy group_(C≤12)(iii) acyloxy group_(C≤12)Alkylamino group_(C≤12)Dialkylamino group_(C≤12)Alkoxyamino group_(C≤12)Alkenylamino group_(C≤12)Alkynyl amino group_(C≤12)Arylamino group_(C≤12)Aralkylamino group_(C≤12)Heteroaryl amino_(C≤12)Heteroarylalkylamino, heteroarylalkylamino_(C≤12)Or alkylsulfonylamino_(C≤12)；。

22. The method of claim 21, wherein the AIM is bardoxolone methyl.

23. The process of claim 22, wherein at least a portion of the bardoxolone methyl is present in a crystalline form having an X-ray diffraction pattern (CuK α) comprising significant diffraction peaks at approximately 8.8, 12.9, 13.4, 14.2, and 17.4 ° 2 Θ.

24. The method of claim 23, wherein the X-ray diffraction pattern (CuK α) is substantially as shown in figure 1A or figure 1B.

25. The method of claim 22, wherein at least a portion of the bardoxolone methyl is present in an amorphous form having an X-ray diffraction pattern (CuK α) and a T-ray diffraction pattern having a halo peak at approximately 13.5 ° 2 Θ, substantially as shown in figure 1C_g。

26. The method of claim 25, wherein said T is_gValues range from about 120 ℃ to about 135 ℃.

27. The method of claim 26, wherein said T_gValues are in the range of about 125 ℃ to about 130 ℃.

28. The method of any one of claims 1-27, wherein the amount sufficient to reduce the subject's body weight is a daily dose of about 0.1mg to about 30mg of AIM.

29. The method of any one of claims 1-27, wherein the AIM is administered orally, intra-arterially, or intravenously.

30. The method of any one of claims 1-27, wherein the AIM is formulated as a hard or soft capsule or tablet.

31. The method of any one of claims 1-27, wherein the AIM is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient.

32. The method of claim 31, wherein the excipient is methacrylic acid-ethyl acrylate copolymer (1: 1).

33. The method of any one of claims 1-32, wherein the subject's body weight has been measured or will be measured.

34. The method of claim 33, wherein the subject's weight has been measured prior to administration of the AIM and will be measured after administration of the AIM.

35. The method of any one of claims 1-32, wherein the subject's BMI has been measured or will be measured.

36. The method of claim 35, wherein the subject's BMI has been measured prior to administration of the AIM and will be measured after administration of the AIM.

37. The method of any one of claims 1-36, wherein the subject further has a renal disease, a cardiovascular disease, diabetes, an autoimmune disease, a respiratory disease, a neurodegenerative disease, a liver disease, an infectious disease, a cancer, or has or will undergo transplantation.

38. The method of any one of claims 1-36, wherein the subject does not also have kidney disease, cardiovascular disease, diabetes, autoimmune disease, respiratory disease, neurodegenerative disease, liver disease, infectious disease, or cancer.

39. The method of any one of claims 1-36, wherein the subject has diabetes.

40. The method of any one of claims 1-36, wherein the subject does not have diabetes.

41. The method of any one of claims 1-36, wherein the subject exhibits one or more symptoms of diabetes.

42. The method of any one of claims 1-36, wherein the subject does not exhibit any symptoms of diabetes.

43. The method of any one of claims 1-36, wherein the subject has been identified as having diabetes.

44. The method of any one of claims 1-36, wherein the subject has been identified as not having diabetes.

45. The method of any one of claims 1-36, wherein the level of a diabetes marker in the subject has been measured or will be measured.

46. The method of any one of claims 1-36, wherein the subject has an elevated level of at least one biomarker associated with diabetes, cardiovascular disease, kidney disease, fatty liver disease, or metabolic syndrome.

47. The method of any one of claims 1-36, wherein the subject does not have an elevated level of at least one biomarker associated with diabetes, cardiovascular disease, kidney disease, fatty liver disease, or metabolic syndrome.

48. The method of any one of claims 1-36, wherein the subject does not have an elevated level of any one of the biomarkers associated with diabetes, cardiovascular disease, kidney disease, fatty liver disease, or metabolic syndrome.

49. The method of claim 46 or 47, wherein the biomarker is a marker of insulin resistance, leptin resistance, adiponectin resistance, cardiovascular stress, or renal insufficiency.

50. The method of claim 49, wherein the biomarker is a marker of insulin resistance.

51. The method of claim 50, wherein the biomarker is fasting glucose or hemoglobin A1 c.

52. The method of claim 49, wherein the biomarker is a marker of leptin resistance.

53. The method of claim 49, wherein the biomarker is a marker of adiponectin resistance.

54. The method of claim 53, wherein the biomarker is adiponectin.

55. The method of claim 49, wherein the biomarker is a marker of cardiovascular stress.

56. The method of claim 55, wherein the biomarker is circulating endothelial cells or C-reactive protein.

57. The method of claim 55, wherein the biomarker is circulating endothelial cells.

58. The method of claim 57, wherein the biomarker is iNOS-positive circulating endothelial cells.

59. The method of claim 49, wherein the biomarker is a marker of kidney disease.

60. The method of claim 59, wherein the biomarker is serum creatinine.

61. The method of claim 59, wherein said biomarker is cystatin C.

62. The method of claim 59, wherein the biomarker is uric acid.

63. The method of any one of claims 1-36, wherein the subject has Chronic Kidney Disease (CKD) or exhibits one or more symptoms of CKD.

64. The method of any one of claims 1-36, wherein the subject does not have Chronic Kidney Disease (CKD).

65. The method of any one of claims 1-36, wherein the subject does not exhibit any symptoms of CKD.

66. The method of any one of claims 1-36, wherein the subject has been identified as having CKD.

67. The method of any one of claims 1-36, wherein the subject has been identified as not having CKD.

68. The method of any one of claims 1-36, wherein the level of a CKD marker in the subject has been measured or will be measured.

69. The method of any one of claims 63-67, wherein the CKD is characterized by a serum creatinine level of 1.3-3.0mg/DL when the subject is a human female or 1.5-3.0mg/DL when the subject is a human male.

70. The method of claim 63, wherein the CKD is stage 4.

71. The method of any one of claims 1-36, wherein the subject does not have stage 4 Chronic Kidney Disease (CKD).

72. The method of any one of claims 1-36, wherein the subject has Diabetic Nephropathy (DN) or exhibits one or more symptoms of DN.

73. The method of any one of claims 1-36, wherein the subject does not have Diabetic Nephropathy (DN).

74. The method of any one of claims 1-36, wherein the subject does not exhibit any symptoms of DN.

75. The method of claim 72, wherein the subject has been identified as having a DN.

76. The method of claim 72, wherein the subject has been identified as not having a DN.

77. The method of any one of claims 1-36, wherein the level of a DN marker in the subject has been measured or will be measured.

78. The method of any one of claims 1-36, wherein the administration results in an improvement in the subject's estimated glomerular filtration rate (eGFR).

79. The method of claim 78, wherein said administering reduces serum creatinine levels in said subject.

80. The method of claim 79, wherein serum creatinine level in the blood of the subject has been measured or will be measured.

81. The method of any one of claims 1-36, wherein a Blood Urea Nitrogen (BUN) level in the subject has been measured or will be measured.

82. The method of any one of claims 1-36, wherein the level of adiponectin in the subject's blood has been measured or will be measured.

83. The method of any one of claims 1-36, wherein the level of angiotensin II in the subject has been measured or will be measured.

84. The method of any one of claims 1-36, wherein the subject has insulin resistance or exhibits one or more symptoms of insulin resistance.

85. The method of any one of claims 1-36, wherein the subject does not have insulin resistance.

86. The method of any one of claims 1-36, wherein the subject does not exhibit any symptoms of insulin resistance.

87. The method of claim 84, wherein the subject has been identified as having insulin resistance.

88. The method of claim 85, wherein the subject has been identified as not having insulin resistance.

89. The method of any one of claims 1-36, wherein the level of an insulin resistance marker in the subject has been measured or will be measured.

90. The method of claim 84, wherein the level of hemoglobin A1c in the subject has been measured or will be measured.

91. The method of claim 84, wherein the subject's blood glucose level has been measured or will be measured.

92. The method of claim 84, wherein the administration reduces the level of hemoglobin A1c or fasting glucose in the subject.

93. The method of claim 91, wherein the level of fasting glucose has been measured or will be measured in the subject.

94. The method of claim 84, wherein the subject's insulin sensitivity has been measured or will be measured by the hyperinsulinemic euglycemic clamp test.

95. The method of claim 84, wherein glucose utilization (GDR) has been measured or will be measured in the subject.

96. The method of any one of claims 1-36, wherein the subject has glucose intolerance or exhibits one or more symptoms of glucose intolerance.

97. The method of any one of claims 1-36, wherein the subject does not have glucose intolerance.

98. The method of any one of claims 1-36, wherein the subject does not exhibit any symptoms of glucose intolerance.

99. The method of claim 96, wherein the subject has been identified as having glucose intolerance.

100. The method of claim 97, wherein the subject has been identified as not having glucose intolerance.

101. The method of any one of claims 1-36, wherein the level of a glucose intolerance marker in the subject has been measured or will be measured.

102. The method of claim 96, wherein the level of hemoglobin A1c in the subject has been measured or will be measured.

103. The method of claim 96, wherein the subject's blood glucose level has been measured or will be measured.

104. The method of claim 96, wherein the administration reduces the level of hemoglobin A1c or fasting glucose in the subject.

105. The method of claim 103, wherein the level of fasting glucose has been measured or will be measured in the subject.

106. The method of claim 96, wherein the subject's insulin sensitivity has been measured or will be measured by the hyperinsulinemic euglycemic clamp test.

107. The method of claim 96, wherein glucose utilization (GDR) has been measured or will be measured in the subject.

108. The method of any one of claims 1-36, wherein the subject has cardiovascular disease (CVD) or exhibits one or more symptoms of CVD.

109. The method of any one of claims 1-36, wherein the subject does not have cardiovascular disease (CVD) or exhibit any symptoms of CVD.

110. The method of any one of claims 1-36, wherein the subject does not exhibit any symptoms of CVD.

111. The method of any one of claims 1-36, wherein the subject has been identified as having CVD.

112. The method of any one of claims 1-36, wherein the subject has been identified as not having CVD.

113. The method of any one of claims 1-36, wherein the level of a CVD marker in the subject has been measured or will be measured.

114. The method of any one of claims 1-36, wherein the number of Circulating Endothelial Cells (CECs) in the subject's blood has been measured or will be measured.

115. The method of claim 114, wherein the CECs are iNOS-positive circulating endothelial cells.

116. The method of claim 108, wherein the administration further reduces the level of circulating endothelial cells in the subject.

117. The method of claim 116, wherein the administration further reduces the level of hemoglobin A1c or fasting glucose in the subject.

118. A method according to one of claims 1-36, wherein the subject has or exhibits one or more symptoms of Fatty Liver Disease (FLD).

119. A method according to one of claims 1-36, wherein the subject does not suffer from Fatty Liver Disease (FLD) or exhibit any symptoms of FLD.

120. A method according to one of claims 1-36, wherein the subject does not exhibit any symptoms of FLD.

121. A method according to one of claims 1-36, wherein the subject has been identified as having FLD.

122. A method according to one of claims 1-36, wherein the subject has been identified as not having FLD.

123. A method according to one of claims 1-36, wherein the level of an FLD marker in the subject has been measured or will be measured.

124. The method of any one of claims 1-36, wherein the subject has been identified as having cancer.

125. The method of any one of claims 1-36, wherein the subject has been identified as not having cancer.

126. The method of any one of claims 1-36, wherein the subject has been identified as having cancer and diabetes.

127. The method of any one of claims 1-36, wherein the subject has been identified as not having cancer and diabetes.

128. The method of any one of claims 1-36, wherein if the sufficient amount is administered to a non-obese subject, the non-obese subject does not significantly lose weight.

129. A method of reducing body weight in a subject comprising administering to the subject a compound of the formula,

130. A method of reducing body weight in a subject comprising administering to the subject a compound of the formula,

wherein:

(b) Wherein the subject has been identified as

(i) Overweight or obese; and

(ii) does not suffer from diabetes.

131. The method of claim 130, wherein the subject is a human and the amount is a daily dose of 5mg to 50 mg.

132. The method of claim 131, wherein the daily dose is about 10 mg.

133. The method of claim 131, wherein the daily dose is about 20 mg.

134. The method of claim 131, wherein the daily dose is about 40 mg.