CN109265380A

CN109265380A - Substituted propyl- 2- alkene -1- ketone compound and its pharmaceutical composition

Info

Publication number: CN109265380A
Application number: CN201811148247.2A
Authority: CN
Inventors: 王义汉; 李焕银
Original assignee: Shenzhen Rui Rui Rui Biological Medicine Co Ltd
Current assignee: Shenzhen Rui Rui Rui Biological Medicine Co Ltd
Priority date: 2017-10-18
Filing date: 2018-09-29
Publication date: 2019-01-25
Also published as: WO2019076190A1

Abstract

The present invention relates to 2 alkene -1- ketone compounds of propyl- substituted shown in formula (I) and its pharmaceutically acceptable salt, polymorphic, tautomer, stereoisomer, hydrate, solvated compounds or isotopic variations.The compound is PPAR α and PPAR delta agonists, therefore can be used for treating and/or prevent the method with disease caused by PPAR α and/or PPAR δ, such as in the treatment method of nonalcoholic fatty liver disease.The present invention also provides the pharmaceutical compositions comprising the compounds of this invention.

Description

Substituted prop-2-en-1-one compounds and pharmaceutical compositions thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a substituted propyl-2-en-1-one compound, a composition containing the compound and application of the compound.

Background

Peroxisome Proliferator-activated receptors (PPARs) are a class of nuclear receptors, nuclear transcription factors activated by ligands to date, three subtypes have been found: α, γ and δ, these receptors belong to the nuclear receptor and transcription factor superfamily, which are activated upon contact with certain fatty acids and/or their fat metabolites.the activated PPARs form heterodimers with 9-cis retinoic acid receptors (RXRs or retinoid X receptors) and bind to specific response elements (PPREs or Peroxisome Proliferator response elements) of target gene promoters, thereby providing transcriptional control.

PPAR α controls lipid metabolism (of the liver and muscles) and glucose homeostasis, influences intracellular lipid and carbohydrate metabolism by directly controlling the transcription of genes encoding proteins involved in lipid homeostasis, has anti-inflammatory and anti-proliferative effects, and prevents the atherogenic effect of cholesterol accumulation in macrophages by stimulating cholesterol efflux.

PPRA γ is a key regulator of adipogenesis. Furthermore, it is involved in lipid metabolism of mature adipocytes, glucose homeostasis, in particular insulin resistance, inflammation, macrophage cholesterol accumulation and cell proliferation. Therefore, PPRA γ plays a role in the pathogenesis of obesity, insulin resistance and diabetes.

PPRA delta is involved in the control of lipid and carbohydrate metabolism, energy balance, neural deformation, obesity, macrophage foam cell formation and inflammation.

In addition to the direct effect of PPAR ligands on the regulation of lipid and carbohydrate metabolism, these molecules have a pleiotropic spectrum of action due to the great diversity of PPAR target genes. These multiplicities make PPARs interesting therapeutic targets for treating and reducing overall risk of: atherosclerosis, cerebral ischemia, hypertension, diseases associated with cardiovascular formation (retinopathy, diabetes, etc.), inflammatory and autoimmune diseases (crohn's disease, psoriasis, multiple sclerosis, asthma, etc.), neoplastic diseases (carcinogenesis, etc.), neurodegenerative diseases, complications associated with metabolic syndrome, insulin resistance, diabetes, dyslipidemia, cardiovascular diseases, obesity, etc.

Elafinibor, also known as GFT-505 and chemically known as 1- (4-methylthiophenyl) -3- (3, 5-dimethyl-4-carboxydimethylmethoxyphenyl) prop-2-en-1-one (having the structure below), is a PPAR α/δ agonist developed by the company Genfit.

Currently, the study of Elafibranor for the treatment of non-alcoholic steatohepatitis (NASH) is in the third clinical stage, and for the treatment of Primary Biliary Cirrhosis (PBC), type 2 diabetes, dyslipidemia, atherosclerosis and insulin resistance is in the second clinical stage.

Despite the availability of elafinibrano, there is still a need for effective compounds with improved pharmacokinetic and/or pharmacodynamic profiles in the treatment of PPAR α/delta mediated related diseases.

Disclosure of Invention

The invention discloses a novel substituted prop-2-ene-1-one compound, a composition containing the compound and application thereof, which can be used for treating, preventing and relieving diseases mediated by PPAR α and/or PPAR delta.

In contrast, the invention adopts the following technical scheme:

in a first aspect of the invention, there is provided a compound of formula (I):

wherein,

R¹、R²、R³、R⁴、R⁶、R⁷and R⁸Is hydrogen;

X²、X³、X⁴and X⁵Is CH₃；

R⁵Selected from hydrogen or deuterium;

X¹is selected from CH₃Or CD₃；

Provided that if X is¹Is CH₃Then R⁵Is deuterium;

or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate, or isotopic variant thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In a specific embodiment, the compounds of the present invention are provided in an effective amount in the pharmaceutical composition. In particular embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In particular embodiments, the compounds of the present invention are provided in a prophylactically effective amount.

In another aspect, the present invention provides a method for preparing the pharmaceutical composition as described above, comprising the steps of: pharmaceutically acceptable excipients are mixed with the compounds of the present invention to form pharmaceutical compositions.

In a further aspect, the invention provides a method of treating and/or treating a condition associated with a disease caused by PPAR α and/or PPAR δ in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention, in particular embodiments, the PPAR α and/or PPAR δ is selected from any acute or chronic liver disease involving pathological destruction, inflammation, degeneration and/or proliferation of liver cells (including fatty liver disease, liver fibrosis, non-alcoholic steatohepatitis, primary biliary cirrhosis or alcoholic liver disease), complications associated with metabolic syndrome, insulin resistance, diabetes, dyslipidemia, atherosclerosis, cardiovascular disease, obesity, hypertension, inflammatory disease, fibrotic diseases (including pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, renal systemic fibrosis, Crohn's disease, old myocardial infarction, systemic sclerosis, fibrositis, or fibroblastic fibrosis, or chronic intrarenal cell adhesion, pancreatic cancer (including chronic renal cell hyperplasia, pancreatic cancer, pancreatic.

Detailed Description

Definition of

The term "deuterated" as used herein means that one or more hydrogens of a compound or group are replaced with deuterium; deuterium can be mono-, di-, poly-, or fully substituted. The terms "deuterated one or more" and "deuterated one or more" are used interchangeably.

"non-deuterated compound" refers to a compound containing deuterium at an atomic ratio not higher than the natural isotopic content of deuterium (0.015%).

The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively²H，³H，¹³C，¹⁴C，¹⁵N，¹⁷O，¹⁸O，³¹P，³²P，³⁵S，¹⁸F and³⁶and (4) Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g.³H and¹⁴among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e.³H and carbon-14, i.e.¹⁴C, their preparation and detection are relatively easy, and are the first choice among isotopes. Isotopically labeled compounds can be prepared by conventional methods by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents using the protocols set forth in the examples.

As used herein, the term "compounds of the present invention" refers to compounds of formula (I). The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).

As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts are described in detail by Berge et al in J.pharmaceutical Sciences (1977)66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are inorganicSalts with acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Salts formed using methods conventional in the art, e.g., ion exchange methods, are also included. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cypionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, picrate, etc, Stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Other pharmaceutically acceptable salts include, if appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio. "hydrate" refers to a complex formed by coordination of a compound of the present invention with water.

The compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomeric" forms, e.g., enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

The term "prodrug" includes a class of compounds which may be biologically active or inactive in nature and which, when administered by an appropriate method, undergo a metabolic or chemical reaction in the human body to convert it to a compound of formula (I), or a salt or solution of a compound of formula (I). The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone ester, sulfoxide ester, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and other forms of the compound.

As used herein, the term "subject" includes, but is not limited to: a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and/or a dog. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human animal.

"disease," "disorder," and "condition" are used interchangeably herein.

As used herein, unless otherwise specified, the term "treatment" includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also includes the effect that occurs before the subject begins to have the particular disease, disorder or condition ("prophylactic treatment").

Generally, an "effective amount" of a compound is an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on the following factors: for example, biological goals, pharmacokinetics of the compound, the disease being treated, mode of administration, and the age, health, and condition of the subject. An effective amount includes both therapeutically and prophylactically therapeutically effective amounts.

As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.

As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic efficacy of other prophylactic agents.

"combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form.

Compound (I)

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate, or isotopic variant thereof:

wherein,

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷and R⁸Each independently is from hydrogen or deuterium;

X¹、X²、X³、X⁴and X⁵Each independently is CH₃、CH₂D、CHD₂Or CD₃；

Provided that if X is¹、X²、X³、X⁴And X⁵Each is CH₃Then R¹、R²、R³、R⁴、R⁵、R⁶、R⁷And R⁸Is deuterium. As a preferred embodiment of the present invention, the compound of formula (I) contains at least one deuterium atom, more preferably two deuterium atoms, more preferably three deuterium atoms, more preferably four deuterium atoms, more preferably six deuterium atoms, more preferably seven deuterium atoms, more preferably nine deuterium atoms.

As a preferred embodiment of the present invention, the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.

Specifically, in the present invention R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、X¹、X²、X³、X⁴And X⁵The deuterium isotope content in each deuterated position is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, more preferably greater than 30%, more preferably greater than 35%, more preferably greater than 40%, more preferably greater than 45%, more preferably greater than 50%, more preferably greater than 55%, more preferably greater than 60%, more preferably greater than 65%, more preferably greater than 70%, more preferably greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 99%.

In another embodiment, R of the compound of formula (I)¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、X¹、X²、X³、X⁴And X⁵Preferably, at least one of the deuterium containing, more preferably two deuterium containing, more preferably three deuterium containing, more preferably four deuterium containing, more preferably five deuterium containing, more preferably six deuterium containing, more preferably seven deuterium containing, more preferably eight deuterium containing, more preferably nine deuterium containing, more preferably ten deuterium containing, more preferably eleven deuterium containing, more preferably twelve deuterium containing, more preferably thirteen deuterium containing, more preferably fourteen deuterium containing, more preferably fifteen deuterium containing, more preferably sixteen deuterium containing, more preferably seventeen deuterium containing, more preferably eighteen deuterium containing, more preferably nineteen deuterium containing, more preferably twenty one deuterium containing, more preferably twenty-two deuterium containing, more preferably twenty-three deuterium containing. In particular, the compounds of formula (I) contain at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty-one, twenty-two, twenty-three deuterium atoms.

As a preferred embodiment of the present invention, R¹、R²、R³Or R⁴Each independently from hydrogen or deuterium.

In another preferred embodiment, R¹Is deuterium.

In another preferred embodiment, R²Is deuterium.

In another preferred embodiment, R³Is deuterium.

In another preferred embodiment, R⁴Is deuterium.

In another preferred embodiment, R¹And R²Is deuterium.

In another preferred embodiment, R³And R⁴Is deuterium.

In another preferred embodiment, R¹、R²、R³And R⁴Is deuterium.

As a preferred embodiment of the present invention, R⁵Or R⁶Each independently from hydrogen or deuterium.

In another preferred embodiment, R⁵Is deuterium.

In another preferred embodiment, R⁶Is deuterium.

In another preferred embodiment, R⁵And R⁶Is deuterium.

As a preferred embodiment of the present invention, R⁷Or R⁸Each independently from hydrogen or deuterium.

In another preferred embodiment, R⁷Is deuterium.

In another preferred embodiment, R⁸Is deuterium.

In another preferred embodiment, R⁷And R⁸Is deuterium.

As a preferred embodiment of the present invention, X¹、X²、X³、X⁴And X⁵Each independently is CH₃、CH₂D、CHD₂Or CD₃。

In another preferred embodiment, X¹Is a CD₃。

In another preferred embodiment, X²And X³Is a CD₃。

In another preferred embodiment, X⁴And X⁵Is a CD₃。

In a preferred embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate, or isotopic variant thereof:

wherein,

R¹、R²、R³、R⁴、R⁶、R⁷and R⁸Is hydrogen;

X²、X³、X⁴and X⁵Is CH₃；

R⁵Selected from hydrogen or deuterium;

X¹is selected from CH₃Or CD₃；

Provided that if X is¹Is CH₃Then R⁵Is deuterium.

In one embodiment, R¹、R²、R³、R⁴、R⁶、R⁷And R⁸Is hydrogen, X²、X³、X⁴And X⁵Is CH₃，R⁵Is deuterium, X¹Is selected from CH₃Or CD₃。

In one embodiment, R¹、R²、R³、R⁴、R⁶、R⁷And R⁸Is hydrogen, X²、X³、X⁴And X⁵Is CH₃，X¹Is a CD₃，R⁵Selected from hydrogen or deuterium.

As a preferred embodiment of the present invention, the compound is selected from the group consisting of:

as a more preferred embodiment of the present invention, the compound is selected from:

in another preferred embodiment, the compound does not include non-deuterated compounds.

Pharmaceutical compositions and methods of administration

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of an active ingredient.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.5-2000mg of a compound of the invention per dose, more preferably, 1-500mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, duodenal, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert releasing agents conventionally employed in the art, such as water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide as well as oils, in particular cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances.

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

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds and compositions of the present invention may be administered alone or may be advantageously administered in combination with other therapeutic agents currently available or under development on the market for the treatment of metabolic and/or hepatic disorders, such as bismerlones, insulin, thiazolidinediones, glitazones, statins, cholesterol inhibitors and/or other lipid lowering drugs.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 0.5-2000mg, preferably 1-500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

Methods of treating diseases

The present invention provides a method of treating and/or preventing a disease-related disorder caused by PPAR α and/or PPAR δ in a subject in need thereof, comprising the step of administering to the subject in need thereof a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic derivative thereof, or a pharmaceutical composition as described herein.

The compounds of the invention are useful in the treatment of conditions caused by PPAR α and/or PPAR δ selected from any acute or chronic liver disease involving pathological destruction, inflammation, degeneration and/or proliferation of liver cells, complications associated with metabolic syndrome, insulin resistance, diabetes, dyslipidemia, atherosclerosis, cardiovascular disease, obesity, hypertension, inflammatory disease, fibrotic disease, neurodegenerative disease or cancer.

In particular, any acute or chronic liver disease involving pathological destruction, inflammation, degeneration and/or proliferation of liver cells for which the compounds of the invention are useful is liver fibrosis, cirrhosis or any other liver disease in which the plasma levels of some markers of liver cell damage, alteration or necrosis are elevated when compared to normal plasma levels. These biochemical markers associated with liver activity and status may be selected from those disclosed in the literature, in particular alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), Alkaline Phosphatase (AP), gamma-glutamyl transpeptidase (GGT), cytokeratin-18 (CK-18) or resistin. In a particular embodiment, the liver disease is fatty liver disease, wherein an increase in one or more of these markers is associated with a more or less pronounced steatosis in the liver, as may be confirmed by liver tissue biopsy. A non-exhaustive list of fatty liver diseases includes non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and fatty liver diseases associated with conditions such as hepatitis or metabolic syndrome (obesity, insulin resistance, hypertriglyceridemia, etc.). In a particular embodiment, the liver disease is primary biliary cirrhosis.

Fibrotic diseases treatable by the compounds of the present invention include, but are not limited to: pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, crohn's disease, old myocardial infarction, scleroderma/systemic sclerosis, joint fibrosis, or adhesive capsulitis.

Cancers treatable by the compounds of the invention include, but are not limited to: renal cell carcinoma, gastrointestinal stromal tumor (GIST), gastric cancer, liver cancer, meningioma associated with neurofibroma, pancreatic neuroendocrine tumor, pancreatic exocrine tumor, leukemia, myeloproliferative/myelodysplastic diseases, mastocytosis, dermatofibrosarcoma, solid cancer including breast cancer, lung cancer, thyroid cancer, or colorectal cancer, or prostate cancer.

The compounds of the present invention have a number of advantages over the non-deuterated compounds known in the prior art. The advantages of the invention include: first, the compounds and compositions of the present invention provide a more advantageous therapeutic tool for the treatment of liver disorders, particularly fatty liver diseases including NAFLD and NASH. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameters. In this case, the dosage can be varied and a long acting formulation formed, improving the applicability. Thirdly, the medicine concentration of the compound in the animal body is improved, and the medicine curative effect is improved. Fourth, certain metabolites are inhibited, increasing the safety of the compounds.

Examples

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Parts and percentages are parts and percentages by weight unless otherwise indicated.

Abbreviations used herein have the following meanings:

TsOMe: p-toluenesulfonic acid methyl ester

HCl: hydrogen chloride

i-PrOH: isopropanol (I-propanol)

In general, in the preparative schemes, each reaction is usually carried out in an inert solvent at a temperature ranging from room temperature to reflux temperature (e.g., from 0 ℃ to 100 ℃, preferably from 0 ℃ to 80 ℃). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 24 hours.

₃Example 1(E) -1- (4- ((methyl-d) thio) phenyl) -3- (3, 5-dimethyl-4-carboxydimethylmethoxy Preparation of phenyl) prop-2-en-1-one (Compound T-1).

The specific synthesis steps are as follows:

step 1 synthesis of compound 3.

To a 100mL single-neck flask equipped with magnetic stirring were added Compound 1(3.0g, 20mmol) and acetonitrile (20mL) in sequence, the mixture was stirred to clarify, and Compound 2(8.96g, 40mmol) and cesium carbonate (Cs) were added₂CO₃13g, 40mmol), reaction mixture N₂Heated to reflux under an atmosphere for 4 hours. Cooled to room temperature, ethyl acetate (30mL) was added, filtered, the filtrate was concentrated, and the residue was separated by silica gel column to give 980mg of a white solid with a yield of 16.8%. LC-MS (APCI) where M/z is 291(M-1) -.¹H NMR(300MHz,DMSO-d₆)δ9.87(s,1H),7.59(s,2H),2.24(s,6H),1.45(s,9H),1.39(s,6H).

Step 2 synthesis of compound 5.

To a 100mL single neck flask equipped with magnetic stirring was added Compound 4(3.0g, 20mmol) and acetonitrile (20mL) in sequence, the mixture was stirred to a clear solution, and TsOMe-d was added₃(4.5g24mmol) and potassium carbonate (3.3g, 24mmol), N₂The reaction was stirred at room temperature under an atmosphere overnight. Ethyl acetate (30mL) was added, the mixture was filtered, the filtrate was concentrated, and the filtrate was separated by a silica gel column to give 2.1g of a white solid with a yield of 60.2%.¹H NMR(300MHz,CDCl₃)δ7.86(d,J＝6.6Hz,2H),7.26(d,J＝6.6Hz,2H),2.53(s,3H).

Step 3 Synthesis of Compound T-1.

A25 mL single-neck flask equipped with magnetic stirring was charged with Compound 5(85mg, 0.5mmol), Compound 3(146mg, 0.5mmol), and HCl in i-PrOH (4mL, 5M) in that order, followed by reaction solution N₂The reaction was stirred at room temperature under an atmosphere for 4 hours. Vacuum concentrating, separating with silica gel column to obtain white solid 86mg with yield of 44%. LC-ms (apci) ═ 386(M-1) -.¹H NMR(300MHz,DMSO-d₆)δ12.91(br s,1H),8.09(d,J＝6.3Hz,2H),7.81(d,J＝12Hz,1H),7.61(d,J＝11.7Hz,1H),7.56(s,2H),7.39(d,J＝6.3Hz,2H),2.22(s,6H),1.39(s,6H).

Example 2(E) -1- (4- (methylthio) phenyl) -3- (3, 5-dimethyl-4-carboxydimethylmethoxyphenyl) Preparation of prop-2-en-1-one-2-d (Compound T-2).

The specific synthesis steps are as follows:

step 1 synthesis of compound 7.

A100 mL single neck flask equipped with magnetic stirring was charged with Compound 6(2.0g, 12.0mmol), dioxane (20mL) and heavy water (20mL) in sequence, the mixture was stirred to dissolve, and pyrrolidine (86mg, 1.2mmol), N, was added₂The reaction was stirred at room temperature under an atmosphere overnight. Adding ethyl acetate (C)20mL), the layers were separated, the aqueous phase was extracted with ethyl acetate (15mLx2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column to give 1.8g of a white solid with a yield of 90%.¹H NMR(300MHz,CDCl₃)δ7.86(d,J＝6.6Hz,2H),7.26(d,J＝6.6Hz,2H),2.57(s,3H).

Step 2 synthesis of compound 8.

A25 mL single-neck flask equipped with magnetic stirring was charged with Compound 7(85mg, 0.5mmol), Compound 3(146mg, 0.5mmol) and EtOD (3mL) in this order, the mixture was stirred to clarify, and a heavy aqueous solution of NaOD (50mg, 0.5mmol, 40% by mass) was added dropwise, after dropping, N₂The reaction was stirred at room temperature under an atmosphere overnight. Concentrating, and separating with silica gel column to obtain white solid 106mg with yield of 48%.¹H NMR(300MHz,DMSO-d₆)δ8.09(d,J＝6Hz,2H),7.61(s,1H),7.56(s,2H),7.40(d,J＝6.3Hz,2H),2.56(s,3H),2.21(s,6H),1.45(s,9H),1.38(s,6H).

Step 3 Synthesis of Compound T-2.

To a 25mL single neck flask equipped with magnetic stirring was added compound 8(106mg, 0.24mmol) and dichloromethane (5mL) in sequence, the supernatant stirred, and trifluoroacetic acid (TFA,1mL), N added dropwise₂The reaction was stirred at room temperature under an atmosphere for 1 hour. The mixture was concentrated and separated by means of a silica gel column to obtain 71mg of a white solid in a yield of 77%.¹H NMR(300MHz,DMSO-d₆)δ12.92(br s,1H),8.07(d,J＝6.3Hz,2H),7.59(s,1H),7.54(s,2H),7.38(d,J＝6.3Hz,2H),2.54(s,3H),2.20(s,6H),1.37(s,6H).

₃Example 3(E) -1- (4- ((methyl-d) thio) phenyl) -3- (3, 5-dimethyl-4-carboxydimethylmethoxy Preparation of phenyl) prop-2-en-1-one-2-d (Compound T-3).

The specific synthesis steps are as follows:

step 1 synthesis of compound 9.

A100 mL single-neck flask equipped with magnetic stirring was charged with Compound 5(2.0g, 12.0mmol), dioxane (20mL) and heavy water (20mL) in this order, stirred to dissolve, and then tetrahydropyrrole (86mg, 1.2mmol), N, were added₂The reaction was stirred at room temperature under an atmosphere overnight. Ethyl acetate (20mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (15mLx2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column to give 1.8g of a white solid with a yield of 90%.¹H NMR(300MHz,CDCl₃)δ7.86(d,J＝6.6Hz,2H),7.26(d,J＝6.6Hz,2H).

Step 2 synthesis of compound 10.

A25 mL single-neck flask equipped with magnetic stirring was charged with Compound 9(85mg, 0.5mmol), Compound 3(146mg, 0.5mmol) and EtOD (3mL) in this order, the mixture was stirred to clarify, and NaOD heavy water solution (50mg, 0.5mmol, 40% by mass) was added dropwise, after dropping, N₂The reaction was stirred at room temperature under an atmosphere overnight. Concentrating, and separating with silica gel column to obtain white solid 106mg with yield of 48%.¹HNMR(300MHz,DMSO-d₆)δ8.09(d,J＝6Hz,2H),7.61(s,1H),7.56(s,2H),7.40(d,J＝6.3Hz,2H),2.21(s,6H),1.45(s,9H),1.38(s,6H).

Step 3 Synthesis of Compound T-3.

To a 25mL single neck flask equipped with magnetic stirring was added compound 10(106mg, 0.24mmol) and dichloromethane (5mL) in sequence, the solution was stirred and trifluoroacetic acid (1mL), N, was added dropwise₂The reaction was stirred at room temperature under an atmosphere for 1 hour. The mixture was concentrated and separated by means of a silica gel column to obtain 71mg of a white solid in a yield of 77%.¹H NMR(300MHz,DMSO-d₆)δ12.92(br s,1H),8.07(d,J＝6.3Hz,2H),7.59(s,1H),7.54(s,2H),7.38(d,J＝6.3Hz,2H),2.20(s,6H),1.37(s,6H).

And (4) testing the biological activity.

(1) Evaluation of agonistic Activity of Compounds on PPAR α/Gamma

PPAR activation assays were performed in vitro in the RK13 fibroblast cell line and the transcriptional activity of chimeras consisting of the DNA binding domain of the yeast ga14 transcription factor and the ligand binding domain of different PPARs was determined. These latter results were then confirmed in cell lines according to the following methods:

taking RK13 cells as an example:

a. the culture method comprises the following steps:

RK13 cells were derived from BCACC (porton Down, UK) and grown in DMEM medium supplemented with 10% (V/V) fetal bovine serum, 100U/ml penicillin (Gibco, Paisley, UK) and 2mM L-glutamate (Gibco, Paisley, UK), with the culture medium being changed every other day. Cells were stored at 37 ℃ in humidified 95% air/5% CO₂In the atmosphere of (c).

b. Description of plastids for transfection

Raspe, Madsen et al have described the construction of plasmids pG5TkpGL3, pRL-CMV, pGa 14-hPPAR α, pGa 14-hPPAR γ and pGa14- φ (1999). pGa 14-hPPAR α and pGa 14-hPPAR γ by cloning into the pGa14- φ vector a PCR-amplified DNA fragment which corresponds to the DEF domain of the human PPPAR α and PPy γ nuclear receptor.

c. Transfection

RK13 cells were seeded in 24-well plates at 5X10 per well⁴Cells transfected with the plasmid pG5TkpGL3(50 ng/well), expression vector pGa 14-. phi., pGa 14-mPPAR α, pGa 14-hPPAR α, pGa 14-hPPARgamma (100 ng/well) and transfection efficiency control vector pRL-CMV (1 ng/well) for 2 hours and then incubated with test compounds for 36 hours^TMReporter Assay System kit (Promega, Madison, WLUSA) the fluorescein was determined as previously described according to the supplier's instructionsAn enzyme activity. The Protein content of the cell extracts was then determined using Bio-Rad Protein Assay (Bio-Rad, Munich, Germany) according to the supplier's instructions.

The compounds of the invention and the non-deuterated compound elafinigranor were tested in the above experiments and found to increase luciferase activity in cells treated with the compounds of the invention and transfected with pGa14-hPPPAR α and pGa14-hPPPAR γ plastids the induction of luciferase activity indicated that the compounds of the invention are PPAR α and PPPAR γ agonists, even with greater activity than the non-deuterated compound elafinigranor.

(2) Metabolic stability evaluation

Microsome experiment: human liver microsomes: 0.5mg/mL, Xenotech; rat liver microsomes: 0.5mg/mL, Xenotech; coenzyme (NADPH/NADH): 1mM, Sigma Life Science; magnesium chloride: 5mM, 100mM phosphate buffer (pH 7.4).

Preparing a stock solution: an amount of the compound of example was weighed out finely and dissolved in DMSO to 5mM each.

Preparation of phosphate buffer (100mM, pH 7.4): 150mL of 0.5M potassium dihydrogenphosphate and 700mL of 0.5M dipotassium hydrogenphosphate solution prepared in advance were mixed, the pH of the mixture was adjusted to 7.4 with the 0.5M dipotassium hydrogenphosphate solution, diluted 5-fold with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer solution (100mM) containing 100mM potassium phosphate and 3.3mM magnesium chloride at a pH of 7.4.

NADPH regenerating system solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM magnesium chloride) was prepared and placed on wet ice before use.

Preparing a stop solution: acetonitrile solution containing 50ng/mL propranolol hydrochloride and 200ng/mL tolbutamide (internal standard). 25057.5 mu L of phosphate buffer solution (pH7.4) is taken to a 50mL centrifuge tube, 812.5 mu L of human liver microsome is respectively added and mixed evenly, and liver microsome dilution liquid with the protein concentration of 0.625mg/mL is obtained. 25057.5 mu L of phosphate buffer (pH7.4) is taken to a 50mL centrifuge tube, 812.5 mu L of SD rat liver microsome is respectively added, and the mixture is mixed evenly to obtain liver microsome dilution with the protein concentration of 0.625 mg/mL.

Incubation of the samples: the stock solutions of the corresponding compounds were diluted to 0.25mM each with an aqueous solution containing 70% acetonitrile, and used as working solutions. 398. mu.L of human liver microsome or rat liver microsome dilutions were added to a 96-well plate (N2), 2. mu.L of 0.25mM working solution was added, and mixed well.

Determination of metabolic stability: 300. mu.L of pre-cooled stop solution was added to each well of a 96-well deep-well plate and placed on ice as a stop plate. The 96-well incubation plate and the NADPH regeneration system are placed in a 37 ℃ water bath box, shaken at 100 rpm and pre-incubated for 5 min. 80. mu.L of the incubation solution was taken out of each well of the incubation plate, added to the stop plate, mixed well, and supplemented with 20. mu.L of NADPH regenerating system solution as a 0min sample. Then 80. mu.L of NADPH regenerating system solution was added to each well of the incubation plate, the reaction was started, and the timer was started. The reaction concentration of the corresponding compound was 1. mu.M, and the protein concentration was 0.5 mg/mL. When the reaction was carried out for 10min, 30 min and 90min, 100. mu.L of each reaction solution was added to the stop plate and vortexed for 3min to terminate the reaction. The stop plates were centrifuged at 5000 Xg for 10min at 4 ℃. And (3) taking 100 mu L of supernatant to a 96-well plate in which 100 mu L of distilled water is added in advance, mixing uniformly, and performing sample analysis by adopting LC-MS/MS.

And (3) data analysis: and detecting peak areas of the corresponding compound and the internal standard through an LC-MS/MS system, and calculating the peak area ratio of the compound to the internal standard. The slope is determined by plotting the natural logarithm of the percentage of compound remaining against time and calculating t according to the following formula_1/2And CL_intWhere V/M is equal to 1/protein concentration.

The compounds of the invention and their non-deuterated compounds, elafinigranor, were compared in a simultaneous assay and evaluated for their metabolic stability in human and rat liver microsomes. The half-life and intrinsic hepatic clearance as indicators of metabolic stability are shown in table 1. The non-deuterated compound elafinibranor was used as a control in table 1. In human and rat liver microsome experiments, the compounds of the invention can significantly improve metabolic stability by comparison with the non-deuterated compound elafinigranor.

Table 1:

(3) pharmacokinetic experiment of rat

6 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups of 3 per group and compared for pharmacokinetic differences by intravenous or oral administration of a single dose of compound (10 mg/kg oral).

Rats were fed with standard feed and given water. Fasting began 16 hours prior to the experiment. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit at 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr post-dose.

The rats were briefly anesthetized after ether inhalation and 300 μ L of blood was collected from the orbit into a test tube. In the test tube there was 30. mu.L of 1% heparin salt solution. Before use, the tubes were dried overnight at 60 ℃. After completion of blood collection at the last time point, rats were sacrificed after ether anesthesia.

Immediately after blood collection, the tubes were gently inverted at least 5 times to ensure mixing and then placed on ice. The blood samples were centrifuged at 5000rpm for 5 minutes at 4 ℃ to separate the plasma from the erythrocytes. Pipette 100 μ L of plasma into a clean plastic centrifuge tube, designating the name of the compound and the time point. Plasma was stored at-80 ℃ before analysis. The concentration of the compounds of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

Experiments show that the compound has better pharmacokinetic property in animals, thereby having better pharmacodynamics and treatment effects.

The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate, or isotopic variant thereof:

wherein,

R¹、R²、R³、R⁴、R⁶、R⁷and R⁸Is derived from hydrogen;

X²、X³、X⁴and X⁵Is CH₃；

R⁵Selected from hydrogen or deuterium;

X¹is selected from CH₃Or CD₃；

Provided that if X is¹Is CH₃Then R⁵Is deuterium.

2. The compound of claim 1, wherein R⁵Is deuterium.

3. A compound according to claim 1 or 2, wherein X¹Is a CD₃。

4. The compound is selected from:

5. a pharmaceutical composition containing a pharmaceutically acceptable excipient and a compound of formula (I) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate, or isotopic variant thereof.

6. A method for the preparation of a medicament for the treatment and/or prevention of diseases caused by PPAR α and/or PPAR δ, of a compound of formula (I), or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate or isotopic variant thereof, as defined in any one of claims 1 to 4, or a pharmaceutical composition as defined in claim 5.

7. The method of claim 6, wherein the disease is any acute or chronic liver disease involving pathological destruction, inflammation, degeneration and/or proliferation of liver cells, complications associated with metabolic syndrome, insulin resistance, diabetes, dyslipidemia, atherosclerosis, cardiovascular disease, obesity, hypertension, inflammatory disease, fibrotic disease, neurodegenerative disease or cancer.

8. The method of claim 7, wherein the liver disease is fatty liver disease, hepatic fibrosis, non-alcoholic steatohepatitis, primary biliary cirrhosis, or alcoholic liver disease.

9. The method of claim 7, wherein the fibrotic disease is pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, crohn's disease, old myocardial infarction, scleroderma/systemic sclerosis, joint fibrosis, or adhesive capsulitis.

10. The method of claim 7, wherein the cancer is renal cell carcinoma, gastrointestinal stromal tumor (GIST), gastric cancer, liver cancer, meningioma associated with neurofibroma, pancreatic neuroendocrine tumor, pancreatic exocrine tumor, leukemia, myeloproliferative/myelodysplastic disease, mastocytosis, cutaneous fibrosarcoma, solid cancer including breast cancer, lung cancer, thyroid cancer, or colorectal cancer, or prostate cancer.