阅读说明：本技术 用于治疗nash和用于预防nash诱导的hcc的方法 (Methods for treating NASH and for preventing NASH-induced HCC ) 是由 M·A·费布瑞奥 J·曼德尔 于 2018-06-08 设计创作，主要内容包括：本发明涉及治疗非酒精性脂肪性肝炎(NASH)的方法和预防NASH诱导的肝细胞癌(HCC)的方法,所述方法包括施用单独的O-(3-哌啶-1-基-2-羟基-1-丙基)-烟酰胺肟(BGP15)或其与白细胞介素-6受体跨信号转导应答的抑制剂、特别是gp130Fc的组合。(The present invention relates to methods of treating non-alcoholic steatohepatitis (NASH) and methods of preventing NASH-induced hepatocellular carcinoma (HCC) comprising administering O- (3-piperidin-1-yl-2-hydroxy-1-propyl) -nicotinamide oxime (BGP15) alone or in combination with an inhibitor of interleukin-6 receptor cross-signaling responses, particularly gp130 Fc.)

1. A method of treating NASH in a subject, comprising administering to the subject a compound of formula I, a tautomer, an enantiomer, or a pharmaceutically acceptable salt thereof,

2. a method of preventing NASH-induced HCC in a subject, comprising administering to a subject affected by NASH a compound of formula I, a tautomer, enantiomer or pharmaceutically acceptable salt thereof,

3. the method of claim 1 or 2, further comprising administering to the individual a combination of BGP15 and an inhibitor of interleukin-6 receptor cross-signaling response.

4. The method of claim 3, wherein the inhibitor is gp130Fc or a functional derivative thereof.

Technical Field

The present invention relates to methods of treating nonalcoholic steatohepatitis (NASH) and methods of preventing NASH-induced hepatocellular carcinoma (HCC) comprising administering O- (3-piperidin-1-yl-2-hydroxy-1-propyl) -nicotinamide oxime (nicotinic amidoxime) (BGP15) alone or in combination with an inhibitor of interleukin-6 receptor cross-signaling response, particularly gp130 Fc.

Background

Hepatocellular carcinoma (HCC) is one of the most common and fatal cancers worldwide. The incidence of HCC has tripled over the past thirty years in developed countries and has become the fastest rising cause of cancer-related deaths (El-Serag et al, 2014), which was originally thought to be the result of the emergence of the Hepatitis C Virus (HCV). It is noteworthy, however, that only 50% of the significant increases in HCC in developed countries may be associated with HCV. Up to 50% of new HCCs are "virus-free" patients (El-Serag,2011), where the etiology of the disease remains unclear until recently (Starley et al, 2010). Most HCC patients that are "virus-free" present with obesity, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH) (Cohen et al, 2011). It is estimated that at least 25% of the population in developed countries suffer from NAFLD (Lazo et al, 2013), with up to 8% of them showing some degree of NASH (Clark et al, 2003).

There is a need for agents that can treat NASH and prevent NASH patients from developing HCC.

A compound of the formula I,

o- (3-piperidin-1-yl-2-hydroxy-1-propyl) -nicotinamide oxime, also known as BGP15, is the most well known in the art for the treatment of diabetes (Liter a-Nagy et al, 2014). WO2013024311 and Gehrig et al (2012) describe the use of BGP15 for the treatment of muscle atrophy, mainly by reducing skeletal muscle fibrosis. WO2005123049 describes the effect of BGP15 on mitochondrial generation and its possible use in muscle regeneration. WO9713504 describes the use of BGP15 for neurodegenerative disorders, myopathies and various diseases of mitochondrial origin.

Nagy et al (2010) describe how BGP15 prevents AIF mitochondrial translocation to the nucleus and mitochondrial depolarization in hepatocytes. WO2005123049 discloses that BGP15 can increase the number of mitochondria in various tissues.

BGP15 is also known for the treatment of acquired myopathy (acquired muscle myopathy) and rhabdomyolysis (WO2013003593), traumatic brain injury (Eroglu et al, 2014), peripheral neuropathy (Bardos et al, 2003) and atrial fibrillation and heart failure (Sapra et al, 2014). Wu et al (2015) describe how BGP15 increases mtDNA content in oocytes. Halmosi et al (2001) and Szabados et al (2000) show how BGP15 protects cardiac cells from Reactive Oxygen Species (ROS) -induced mitochondrial inactivation through its PARP-inhibitory effect. Farkas et al (2002) discuss the effects of BGP15 on skin mitochondria related to its anti-PARP activity.

Brief description of the invention

As shown by Nakagawa et al (2014) and Maurel et al (2014), MUP-uPA mice fed a High Fat Diet (HFD) resulted in these animals developing diseased liver that recapitulates the human characteristics of NASH. Most importantly, these mice showed more liver damage, significant liver inflammation, and thus, NASH and developed into steatoinflammatory (steatohepatitis) HCC.

Treatment of HFD-fed MUP-uPA mice with BGP15 resulted in an improvement of the disorder.

Thus, in a first embodiment, there is provided a method of treating NASH in a subject, comprising administering to the subject a compound of formula I, a tautomer, an enantiomer, or a pharmaceutically acceptable salt thereof.

In a second embodiment, there is provided a method of preventing NASH-induced HCC in an individual, comprising administering to the individual affected by NASH a compound of formula I, a tautomer, enantiomer or pharmaceutically acceptable salt thereof.

Detailed Description

As noted above, in a first embodiment, there is provided a method of treating NASH in a subject comprising administering to the subject a compound of formula I, a tautomer, an enantiomer, or a pharmaceutically acceptable salt thereof.

As described above, in a second embodiment, there is provided a method of preventing NASH-induced HCC in a subject, comprising administering to a subject affected by NASH a compound of formula I, a tautomer, enantiomer or pharmaceutically acceptable salt thereof.

Previous studies have demonstrated that liver inflammation can be reduced by inhibiting interleukin-6 receptor cross-signaling responses in HFD-fed mice (Kraakman et al 2015).

Treatment with gp130Fc, an inhibitor of interleukin-6 receptor cross-signaling response, can be conveniently mimicked in vivo by using transgenic mice overexpressing gp130 protein (Kraakman et al 2015).

Treatment of HFD-fed gp130 overexpressing MUP-uPA mice with BGP15 resulted in an improvement of the disorder. Thus, in certain embodiments, the methods of the invention further comprise administering to the individual a combination of BGP15 and an inhibitor of interleukin-6 receptor cross-signaling responses.

In a particular embodiment, the interleukin-6 receptor trans-signaling response inhibitor is gp130Fc or a functional derivative thereof.

Preparation

The compositions provided herein can be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binders, fillers, lubricants, disintegrants, and wetting agents. The tablets may be coated according to methods well known in the art.

The compositions provided herein may also be liquid formulations including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. The compositions may also be formulated as a dry product for reconstitution with water or other suitable carrier before use. Such liquid formulations may contain additives including, but not limited to, suspending agents, emulsifying agents, non-aqueous vehicles, and preservatives.

The compositions provided herein may also be formulated as suppositories, which may contain a suppository base including, but not limited to, cocoa butter or glycerides.

The compositions provided herein may also be formulated for inhalation, which may be in forms including, but not limited to: solutions, suspensions or emulsions, which may be administered as a dry powder or in aerosol form using a propellant, such as dichlorodifluoromethane or trichlorofluoromethane.

The compositions provided herein may also be formulated into transdermal formulations comprising aqueous or non-aqueous carriers, including but not limited to creams, ointments, lotions, pastes, medicated ointments, patches, or films.

The compositions provided herein can also be formulated for parenteral administration, including but not limited to administration by injection or continuous infusion. Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents including, but not limited to, suspending, stabilizing and dispersing agents.

Administration of drugs

Administration of the compositions using the methods described herein can be oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, inhalation, buccal, or a combination thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular.

In certain embodiments of the invention, BGP15 is administered in combination with one or more other pharmaceutically active agents. The phrase "combination" as used herein refers to an active agent that is administered simultaneously to an individual. It is understood that two (or more) active agents are considered to be administered "in combination" whenever an individual is exposed to the two (or more) active agents simultaneously. Each of the two or more active agents may be administered according to a different regimen; it is not necessary to administer separate doses of different active agents simultaneously or in the same composition. Rather, two (or more) active agents are considered to be administered "in combination" as long as they remain in the individual.

Dosage form

The method can comprise administering a therapeutically effective amount of the composition to a patient in need thereof. The therapeutically effective amount required for therapy varies with the nature of the condition to be treated, the duration of time it is desired that hematopoietic stem cells be added to the blood stream, and the age/condition of the patient. In general, however, the dose for adult treatment will typically be in the range of 0.001mg/kg to about 200mg/kg per day. The dose may be from about 1 μ g/kg to about 100 μ g/kg per day. The desired dose may conveniently be administered in a single dose, or in multiple doses at appropriate intervals, for example two, three, four or more sub-doses per day. Multiple doses may be desired or required.

The dose can be any dose including, but not limited to, about 0.1. mu.g/kg, 0.2. mu.g/kg, 0.3. mu.g/kg, 0.4. mu.g/kg, 0.5. mu.g/kg, 0.6. mu.g/kg, 0.7. mu.g/kg, 0.8. mu.g/kg, 0.9. mu.g/kg, 1. mu.g/kg, 25. mu.g/kg, 50. mu.g/kg, 75. mu.g/kg, 100. mu.g/kg, 125. mu.g/kg, 150. mu.g/kg, 175. mu.g/kg, 200. mu.g/kg, 225. mu.g/kg, 250. mu.g/kg, 275. g/kg, 300. mu.g/kg, 325. mu.g/kg, 350. mu.g/kg, 375. mu.g/kg, 400. mu.g/kg, 425. mu.g/kg, 450. mu.g/kg, 475. mu.g, 525. mu.g/kg, 550. mu.g/kg, 575. mu.g/kg, 600. mu.g/kg, 625. mu.g/kg, 650. mu.g/kg, 675. mu.g/kg, 700. mu.g/kg, 725. mu.g/kg, 750. mu.g/kg, 775. mu.g/kg, 800. mu.g/kg, 825. mu.g/kg, 850. mu.g/kg, 875. mu.g/kg, 900. mu.g/kg, 925. mu.g/kg, 950. mu.g/kg, 975. mu.g/kg or 1 mg/kg.

Drawings

FIG. 1A depicts the level of fibrosis shown by Sirius red staining (Sirius red staining) of hepatocytes from wild type mice fed Chow or HFD diet and MUP-uPA mice treated or untreated with BGP15 on HFD diet.

Figure 1B depicts sirius red staining of MUP-uPA mice on the HFD diet, treated or untreated with BGP 15. FIG. 2 depicts ALT levels in Wild Type (WT) and MUP-uPA mice (Mup) fed Chow or HFD diets treated or untreated with BGP 15.

Examples

The invention will now be illustrated by means of non-limiting examples.