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WO2019179494A1 - Composé d'acide pentadécanedioïque substitué, composition pharmaceutique et utilisation associée - Google Patents

Composé d'acide pentadécanedioïque substitué, composition pharmaceutique et utilisation associée Download PDF

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Publication number
WO2019179494A1
WO2019179494A1 PCT/CN2019/079045 CN2019079045W WO2019179494A1 WO 2019179494 A1 WO2019179494 A1 WO 2019179494A1 CN 2019079045 W CN2019079045 W CN 2019079045W WO 2019179494 A1 WO2019179494 A1 WO 2019179494A1
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Prior art keywords
compound
pharmaceutically acceptable
independently selected
hydrazine
prodrug
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English (en)
Chinese (zh)
Inventor
王义汉
刘志强
赵九洋
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/29—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a substituted pentadecanedioic acid and a composition comprising the same and use thereof. More specifically, the present invention relates to certain hydrazine-substituted pentadecanedioic acids which are dually regulated as adenosine triphosphate-citrate lyase (ACL) and adenosine monophosphate-activated protein kinase (AMPK)
  • ACL adenosine triphosphate-citrate lyase
  • AMPK adenosine monophosphate-activated protein kinase
  • the agent can be used for preventing or treating cardiovascular diseases and dyslipidemia diseases, and has more excellent pharmacokinetic properties.
  • Hyperlipidemia is commonly called hyperlipidemia. Hyperlipidemia is the most important factor in causing atherosclerosis. There is a clear correlation between the incidence and mortality of cardiovascular and cerebrovascular diseases, and the mortality rate accounts for human mortality. above 50. At present, the dyslipidemia of people over 18 years old in China has reached 200 million, only 39% of them have received lipid-lowering therapy, and the low-density lipoprotein cholesterol (LDL-C) compliance rate is 25.8%. It can be seen that the chronic cardiovascular disease, which is dyslipidemia, seriously jeopardizes human health, and the current status of treatment is not optimistic. Therefore, effective prevention and treatment of dyslipidemia is the focus and difficulty of modern medicine.
  • LDL-C low-density lipoprotein cholesterol
  • statins hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor
  • HMG-CoA hydroxymethylglutaryl coenzyme A reductase inhibitor
  • statin intolerance remains a major clinical problem.
  • the main adverse reactions of statins are myopathy, elevated liver enzymes, and elevated blood sugar.
  • non-statin drugs have been shown to be effective in reducing LDL-C levels, such as PCSK9 inhibitors, but because of its subcutaneous route of administration and potential neurocognitive side effects, clinical treatment requires more convenient and safer medications.
  • Good lipid-lowering drugs are examples of non-statin drugs.
  • ETC-1002 (also known as Bempedoic acid, chemical name 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid having the following structural formula)
  • a novel lipid developed by Esperion Therapeutics, USA The drug is regulated, and its target is liver triphosphate citrate citrate (ACL) and adenosine monophosphate-activated protein kinase (AMPK).
  • Clinical trials have been conducted or are ongoing in multiple populations, including hypercholesterolemia, normal or elevated triglycerides, hypercholesterolemia and type 2 diabetes (DMt2), hypercholesterolemia and statin resistance. Medicine, patients with hypercholesterolemia and high blood pressure. In addition, studies have been conducted in combination with statins or ezetimibe.
  • ETC-1002 can be used as an adjunct to the maximum tolerant statin therapy in patients with hypercholesterolemia, especially in patients with atherosclerotic cardiovascular disease requiring additional reduction of LDL-C (atherosclerotic) Cardiac disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) in patients with high-risk cardiovascular disease (CVD).
  • ASCVD therosclerotic Cardiac disease
  • HeFH heterozygous familial hypercholesterolemia
  • WO2015143276A1 also discloses a series of novel lipid-regulating drugs whose targets are ACL and AMPK, and their chemical name 1,11-bis-(1-carboxycyclopropyl)undecane-6-ol (compound) A) and has the following structural formula:
  • ADME ulcerative co-oxidative desorption, distribution, metabolism, and/or excretion
  • Many of the drugs currently on the market also limit their range of applications due to poor ADME properties.
  • the rapid metabolism of drugs can lead to the inability of many drugs that could be effectively treated to treat diseases because they are too quickly removed from the body.
  • Frequent or high-dose medications may solve the problem of rapid drug clearance, but this approach can lead to problems such as poor patient compliance, side effects caused by high-dose medications, and increased treatment costs.
  • rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.
  • ETC-1002 is effective in treating dyslipidemia and reducing diseases such as CVD
  • a novel compound having a good oral bioavailability and a drug-forming condition for treating CVD and the like is a challenging task.
  • the present invention provides such compounds.
  • the present invention discloses a novel hydrazine-substituted pentadecanedioic acid, and compositions and uses thereof, which have lower side effects, better pharmacodynamics/pharmacokinetic properties, and are effective Treatment and/or cardiovascular disease and dyslipidemia (LDL-C and other markers such as: triglycerides, ApoB, hsCRP, non-HDL-C, HDL-C, LDL particle count, ApoAl).
  • LDL-C and other markers such as: triglycerides, ApoB, hsCRP, non-HDL-C, HDL-C, LDL particle count, ApoAl).
  • compound of the invention refers to a compound of formula (I).
  • the term also encompasses pharmaceutically acceptable salts, prodrugs, hydrates or solvate compounds, polymorphs, stereoisomers or isotopic variations of the compounds of formula (I).
  • R 1 is selected from H or hydrazine
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H or hydrazine;
  • R 6 and R 7 are each independently selected from C 1-6 alkyl or C 3-7 cycloalkyl, or R 6 and R 7 and the atom to which they are attached form a C 3-7 cycloalkyl; wherein said C 1-6 alkyl or C 3-7 cycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazines;
  • R 8 and R 9 are each independently selected from C 1-6 alkyl or C 3-7 cycloalkyl, or R 8 and R 9 and the atom to which they are attached form a C 3-7 cycloalkyl; wherein said C 1-6 alkyl or C 3-7 cycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazines;
  • the above compound contains at least one ruthenium atom
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the compositions of the invention comprise additional therapeutic agents.
  • the additional therapeutic agent is one or more statins or analogs thereof.
  • the additional therapeutic agent is ezetimibe or an analog thereof.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the present invention is also directed to a method of preventing or treating cardiovascular diseases and dyslipidemia diseases in a subject.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly.
  • the compound is administered chronically.
  • the invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a cardiovascular disease and a dyslipidemia.
  • C 1 -C 6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 - C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 C 4 -C 6 , C 4 -C 5 and C 5 -C 6 alkyl.
  • the "C 1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, a C 1-4 alkyl group is preferred. Examples of the C 1-6 alkyl group include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • C1-6 alkyl also includes heteroalkyl groups in which one or more (eg, 1, 2, 3 or 4) carbon atoms are heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) replacement.
  • the alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • alkyl abbreviations include: Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ).
  • C 3-7 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having from 3 to 7 ring carbon atoms and zero heteroatoms.
  • a C 3-6 cycloalkyl group is particularly preferred, more preferably a C 5-6 cycloalkyl group.
  • the cycloalkyl group also includes a ring system in which the above cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to be represented The number of carbons in the cycloalkyl system.
  • Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), and the like.
  • each of the cycloalkyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkane"base").
  • a cycloalkyl group is an unsubstituted C 3-7 cycloalkyl group.
  • the carbocyclyl is a substituted C3-7 cycloalkyl.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon 14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may be in amorphous or crystalline form. Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • crystalline form refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state. A drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • prodrug refers to a compound that is converted in vivo to an active form having its medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduction This article serves as a reference.
  • a prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo.
  • Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group.
  • representative examples of prodrugs include, but are not limited to, the hydroxy, thiol and amino functional acetate/amide, formate/amide and benzoate/amide derivatives of the compounds of formula (I).
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
  • crystalline form refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state.
  • a drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • the term "subject” includes, but is not limited to, a human (ie, a male or female of any age group, eg, a pediatric subject (eg, an infant, a child, adolescent) or an adult subject (eg, Young adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses , sheep, goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or disease (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a “therapeutically effective amount” of a compound, as used herein, is a quantity sufficient to provide a therapeutic benefit, or one or more associated with a disease, disorder, or condition, in the course of treating a disease, disorder, or condition, unless otherwise stated. Symptoms are delayed or minimized.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used 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 overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • the invention relates to a compound of formula (I):
  • R 1 is selected from H or hydrazine
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H or hydrazine;
  • R 6 and R 7 are each independently selected from C 1-6 alkyl or C 3-7 cycloalkyl, or R 6 and R 7 and the atom to which they are attached form a C 3-7 cycloalkyl; wherein said C 1-6 alkyl or C 3-7 cycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazines;
  • R 8 and R 9 are each independently selected from C 1-6 alkyl or C 3-7 cycloalkyl, or R 8 and R 9 and the atom to which they are attached form a C 3-7 cycloalkyl; wherein said C 1-6 alkyl or C 3-7 cycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazines;
  • the above compound contains at least one ruthenium atom
  • R 6 and R 7 are each independently selected from C 1-6 alkyl, or R 6 and R 7 are bonded to the atom to which they are attached to form a C 3-7 cycloalkyl group, wherein said C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazines;
  • R 6 and R 7 are each independently selected from methyl, ethyl, propyl, isopropyl, or the atoms to which R 6 and R 7 are attached form a cyclopropyl, cyclobutane a group, a cyclopentyl group or a cyclohexyl group, wherein the group is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazine
  • R 6 and R 7 are each independently selected from methyl, or R 6 and R 7 are bonded to the atom to
  • R 8 and R 9 are each independently selected from C 1-6 alkyl, or R 8 and R 9 are bonded to the atom to which they are attached to form a C 3-7 cycloalkyl group, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazines
  • R 8 and R 9 are each independently selected from methyl, ethyl, propyl, isopropyl, or R 8 and R 9 are bonded to the atom to which they are attached to form a cyclopropyl group.
  • R 8 and R 9 are each independently selected from methyl, or R 8 and R 9 and the atom to which they are attached form a cyclopropyl group, wherein said group is optionally 1 , 2, 3, 4, 5, 6, 7 or 8 ⁇ substituted.
  • the invention relates to a compound of formula (Ia):
  • R 1 is selected from H or hydrazine
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H or hydrazine;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 , CH 2 D, CHD 2 or CD 3 ;
  • the compound of the formula (Ia) contains at least one halogen atom, more preferably two germanium atoms, more preferably three germanium atoms, more preferably four germanium atoms, more preferably five germanium atoms.
  • An atom more preferably six helium atoms, more preferably seven helium atoms, more preferably eight helium atoms, more preferably nine helium atoms, more preferably ten helium atoms, more preferably eleven helium atoms More preferably twelve helium atoms, more preferably thirteen helium atoms, more preferably fourteen helium atoms, more preferably fifteen helium atoms, more preferably sixteen helium atoms, more preferably ten Seven helium atoms, more preferably eighteen helium atoms, more preferably nineteen helium atoms, more preferably twenty helium atoms, more preferably twenty one helium atoms, more preferably twenty-two helium atoms An atom, more preferably twenty-three helium atoms, more preferably twenty-four helium atoms, more preferably twenty-five helium atoms, more preferably twenty-six helium atoms,
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably more than 30%, more preferably more than 50%, more preferably more than 75%, more preferably more than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • R 1 , each R 2 , R 3 , R 4 or R 5 , X 1 , X 2 , X 3 or X 4 has a strontium isotope content of at least 5% in each metamorphic position.
  • the compound of the formula (Ia) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, ten Three, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four Twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three atomic atoms.
  • R 1 is selected from hydrogen or hydrazine. In another specific embodiment, R 1 is hydrogen; in another specific embodiment, R 1 is deuterium.
  • R 2 , R 3 , R 4 or R 5 are each independently selected from H or hydrazine.
  • R 2 is hydrogen; in another specific embodiment, R 2 is deuterium; in another specific embodiment, R 3 is hydrogen; in another specific embodiment, R 3 is In another specific embodiment, R 4 is hydrogen; in another specific embodiment, R 4 is deuterium; in another specific embodiment, R 5 is hydrogen; in another specific embodiment, R 5 is hydrazine; in another specific embodiment, -(CR 2 R 3 ) 5 - and -(CR 4 R 5 ) 5 - are each independently selected from -CH 2 CH 2 CH 2 CH 2 CD 2 -, - CH 2 CH 2 CH 2 CD 2 CH 2 -, -CH 2 CH 2 CD 2 CH 2 CH 2 -, -CD 2 CH 2 CH 2 CH 2 CH 2 - , -CH 2 CH 2 CH 2 CD 2 CD 2 -, -CH 2 CH 2 CD 2 CD 2 -, -CH 2 CH 2 CD 2 CD 2 -, -CH 2 CH 2 CD 2
  • X 1 , X 2 , X 3 or X 4 are each independently selected from CH 3 , CH 2 D, CHD 2 or CD 3 .
  • X 1 is CH 3 ; in another specific embodiment, X 1 is CH 2 D; in another specific embodiment, X 1 is CHD 2 ; in another specific embodiment X 1 is CD 3 ; in another specific embodiment, X 2 is CH 3 ; in another specific embodiment, X 2 is CH 2 D; in another specific embodiment, X 2 is CHD 2 ;
  • X 2 is CD 3 ; in another specific embodiment, X 3 is CH 3 ; in another specific embodiment, X 3 is CH 2 D; in another specific embodiment X 3 is CHD 2 ; In another specific embodiment, X 3 is CD 3 ; in another specific embodiment, X 4 is CH 3 ; in another specific embodiment, X 4 is CH 2 D; In another specific embodiment, X 4 is CHD 2 ; in another specific embodiment, X 4 is CD 3 ; in another specific embodiment, X 4 is CH 3
  • X 1 and X 2 are the same.
  • X 3 and X 4 are the same.
  • X 1 , X 2 , X 3 and X 4 are both CH 3 .
  • X 1 , X 2 , X 3 and X 4 are both CD 3 .
  • the invention relates to a compound of formula (Ib):
  • R 1 , R 6 ', R 7' , R 8 ' , R 9 ' , R 10 ' , R 11 ' , R 12 ' and R 13 ' are each independently selected from H or hydrazine;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H or hydrazine;
  • the above compound contains at least one ruthenium atom
  • the compound of the formula (Ib) contains at least one halogen atom, more preferably two germanium atoms, more preferably three germanium atoms, more preferably four germanium atoms, more preferably five germanium atoms.
  • An atom more preferably six helium atoms, more preferably seven helium atoms, more preferably eight helium atoms, more preferably nine helium atoms, more preferably ten helium atoms, more preferably eleven helium atoms More preferably twelve helium atoms, more preferably thirteen helium atoms, more preferably fourteen helium atoms, more preferably fifteen helium atoms, more preferably sixteen helium atoms, more preferably ten Seven helium atoms, more preferably eighteen helium atoms, more preferably nineteen helium atoms, more preferably twenty helium atoms, more preferably twenty one helium atoms, more preferably twenty-two helium atoms An atom, more preferably twenty-three helium atoms, more preferably twenty-four helium atoms, more preferably twenty-five helium atoms, more preferably twenty-six helium atoms,
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably more than 30%, more preferably more than 50%, more preferably more than 75%, more preferably more than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the compound of the formula (Ia) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, ten Three, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four Twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine atomic atoms.
  • R 1 is selected from hydrogen or hydrazine. In another specific embodiment, R 1 is hydrogen; in another specific embodiment, R 1 is deuterium.
  • R 2 , R 3 , R 4 or R 5 are each independently selected from H or hydrazine.
  • R 2 is hydrogen; in another specific embodiment, R 2 is deuterium; in another specific embodiment, R 3 is hydrogen; in another specific embodiment, R 3 is In another specific embodiment, R 4 is hydrogen; in another specific embodiment, R 4 is deuterium; in another specific embodiment, R 5 is hydrogen; in another specific embodiment, R 5 is hydrazine; in another specific embodiment, -(CR 2 R 3 ) 5 - and -(CR 4 R 5 ) 5 - are each independently selected from -CH 2 CH 2 CH 2 CH 2 CD 2 -, - CH 2 CH 2 CH 2 CD 2 CH 2 -, -CH 2 CH 2 CD 2 CH 2 CH 2 -, -CD 2 CH 2 CH 2 CH 2 CH 2 - , -CH 2 CH 2 CH 2 CD 2 CD 2 -, -CH 2 CH 2 CD 2 CD 2 -, -CH 2 CH 2 CD 2 CD 2 -, -CH 2 CH 2 CD 2
  • R 6 ', R 7' , R 8' , R 9' , R 10' , R 11 ' , R 12 ' and R 13 ' are each independently selected from H or hydrazine;
  • the invention relates to a compound of formula (X):
  • R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from H or hydrazine;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H or hydrazine;
  • the above compound contains at least one ruthenium atom
  • R 1 -R 5 and R 6 -R 13 are as defined for R 1 -R 5 and R 6' -R 13' in the compound of formula (Ib).
  • the invention relates to a compound of formula (II):
  • R 1 is selected H or deuterium
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H or hydrazine;
  • R 6 and R 7 are each independently selected from C 1-6 alkyl or C 3-7 cycloalkyl, or R 6 and R 7 and the atom to which they are attached form a C 3-7 cycloalkyl; wherein said C 1-6 alkyl or C 3-7 cycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazines;
  • R 8 and R 9 are each independently selected from C 1-6 alkyl or C 3-7 cycloalkyl, or R 8 and R 9 and the atom to which they are attached form a C 3-7 cycloalkyl; wherein said C 1-6 alkyl or C 3-7 cycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 hydrazines;
  • the above compound contains at least one ruthenium atom
  • R 1 -R 9 are as defined for R 1 -R 9 in the compounds of formula (I).
  • the invention relates to a compound of formula (IIa):
  • R 1 is selected from H or hydrazine
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H or hydrazine;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 , CH 2 D, CHD 2 or CD 3 ;
  • R 1 -R 5 and X 1 -X 4 are as defined for R 1 -R 5 and X 1 -X 4 in the compound of formula (Ia).
  • the invention relates to a compound of formula (IIb):
  • R 1 , R 6 ', R 7' , R 8 ' , R 9 ' , R 10 ' , R 11 ' , R 12 ' and R 13 ' are each independently selected from H or hydrazine;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H or hydrazine;
  • the above compound contains at least one ruthenium atom
  • R 1 -R 5 and R 6' -R 13' are as defined for R 1 -R 5 and R 6' -R 13' in the compound of formula (Ib).
  • the compound of the invention is selected from the group consisting of a compound, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, polymorph, stereoisomer or isotopic variation thereof:
  • the compound does not include a non-deuterated compound.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.5 to 2000 mg of the compound of the invention per agent, more preferably from 1 to 500 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable excipient” means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embedded Seg
  • compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules. , powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules. , powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the invention or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, ocular Internal, intramuscular, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol or phosphoric acid Calcium; silica; cross-linked hydroxymethylcellulose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, hydroxymethyl cellulose, cross-linked poly Vinyl pyrrolidone and the like.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compounds of the invention may be administered by any route and method of administration, for example by oral or parenteral (e.g., intravenous) administration.
  • a therapeutically effective amount of a compound of the invention is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the dosage frequency of the compounds of the invention is determined by the needs of the individual patient, for example, once or twice daily, or more times per day. Administration can be intermittent, for example, wherein the patient receives a daily dose of the compound of the invention over a period of several days, followed by a patient's daily dose of the compound of the invention over a period of several days or more.
  • the invention provides a method for preventing or treating a cardiovascular disease comprising administering to a subject a fixed dose of a compound of the invention or a composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • cardiovascular disease refers to diseases of the heart and circulatory system. These diseases are often associated with dyslipoproteinemia and/or dyslipidemia.
  • Cardiovascular diseases which the composition of the present invention can be used for prevention or treatment include, but are not limited to, atherosclerosis; atherosclerosis; stroke; ischemia; endothelial dysfunction, particularly dysfunction affecting vascular elasticity; peripheral vascular disease Coronary heart disease; myocardial infarction; cerebral infarction and restenosis.
  • the invention provides a method for preventing or treating dyslipidemia comprising administering to a subject a fixed dose of a compound of the invention or a composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • dyslipidemia refers to a disease that causes or manifests as an abnormal level of circulating lipids.
  • the compositions of the invention are administered to a patient to restore normal levels. Normal levels of lipids are reported in medical papers that have been known to those skilled in the art.
  • compositions of the present invention are useful for the prevention or treatment of dyslipidemia including, but not limited to, hyperlipidemia and low blood levels of high density lipoprotein (HDL) cholesterol.
  • the hyperlipidemia prevented or treated by a compound of the invention is familial hypercholesterolemia; familial combined hyperlipidemia; reduced or insufficient lipoprotein lipase levels or activity, including Reduction or deficiency caused by lipoprotein lipase mutation; hypertriglyceridemia; hypercholesterolemia; high blood concentration of urea (eg, ⁇ -OH butyric acid); high blood level of Lp(a) cholesterol; high blood Horizontal low-density lipoprotein (LDL) cholesterol; very low-density lipoprotein (VLDL) cholesterol at high blood levels and non-esterified fatty acids at high blood levels.
  • urea eg, ⁇ -OH butyric acid
  • the present invention further provides methods for altering lipid metabolism in a patient, for example, reducing LDL in a patient's blood, reducing triglyceride in a patient's blood, increasing the ratio of HDL to LDL in a patient's blood, and inhibiting saponification and/or Non-saponified fatty acid synthesis, the method comprising administering to the patient a compound of the invention or a composition comprising a compound of the invention in an amount effective to alter lipid metabolism.
  • the compounds of the invention may be used alone or in combination with one or more of the existing therapies for the above diseases.
  • Combination therapies according to the invention thus comprise the administration of at least one compound of the invention and the use of at least one other therapeutic agent.
  • One or more compounds of the invention and one or more additional therapeutic agents may be administered together or separately, and when administered separately, may be carried out simultaneously or sequentially in any order.
  • the amount and relative timing of administration of one or more compounds of the invention and one or more additional pharmaceutically active agents will be selected to achieve the desired combined therapeutic effect.
  • the method of the invention for preventing or treating cardiovascular disease and dyslipidemia comprises administering a therapeutically effective amount of a compound of the invention and one or more statins.
  • the statin includes, but is not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin.
  • a fixed dose combination of one or more statins with a compound of the invention can be formulated in a pharmaceutical composition.
  • the method of the invention for preventing or treating a cardiovascular disease and a dyslipidemia comprises administering a therapeutically effective amount of a compound of the invention and ezetimibe or an analog thereof.
  • ezetimibe may be referred to as 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3 -hydroxypropyl]-4(S)-[4-(phenylmethoxy)phenyl]-2-azetidinone; or (3R,4S)-1-(4-fluorophenyl) -3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.
  • ezetimibe The structure of ezetimibe is:
  • a fixed dose combination of ezetimibe with a compound of the invention can be formulated in a pharmaceutical composition.
  • the compounds of the present invention have a number of advantages over non-deuterated compounds known in the art.
  • Advantages of the present invention include: First, the compounds and compositions employing the technical solutions of the present invention provide a more advantageous therapeutic tool for the prevention or treatment of cardiovascular diseases and dyslipidemia diseases. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, the drug concentration of the compound in the animal is increased, and the drug efficacy is improved. Fourth, certain metabolites are inhibited and the safety of the compounds is increased.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • the inhibitory activity of the test substance against ACL was measured using the ADP-GloTM Kinase Assay kit (Promega V9102) kit.
  • test compound was dissolved in DMSO, it was diluted by a 3-fold concentration gradient, 12 doses.
  • 5 ⁇ L of ACL working solution and 100 nL of pre-diluted different concentrations of compound were transferred to a 384-well test plate (Perkin Elmer), each double-well well, mixed evenly and incubated at 25 ° C for 15 minutes.
  • the reaction was initiated by the addition of 5 ⁇ L of substrate and incubated at 25 ° C for 60 minutes.
  • the final reaction concentrations in the system were: 3 nM ACL, 15 ⁇ M ATP, 3 ⁇ M CoA, 300 ⁇ M Citrate, 0.01% Brij35, 4 mM DTT, 1% DMSO.
  • test compounds 300, 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.137, 0.046, 0.015, 0.0051 and 0 ⁇ M. Then 10 ⁇ L of ADP Glo reagent was added and incubation was continued for 40 minutes at 25 °C. After completion of the reaction, 20 ⁇ L of the detection reagent was added, and after incubation at 25 ° C for 40 minutes, the enzyme activity in the presence of each compound of the present invention was measured by an Envision plate reader (Perkin Elmer 2104), and the enzyme activities of the compounds at different concentrations were calculated. Inhibition activity. Then, according to the four-parameter equation, the inhibitory activity of the enzyme activity under different concentrations of the compound was fitted according to Graphpad 5.0 software, and the IC 50 value was calculated.
  • Example compound ACL IC 50 ( ⁇ M) ETC-1002 D Compound A D E-1 D E-2 D E-3 D
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the compounds of the present invention and their compounds without deuteration were simultaneously tested and compared for their metabolic stability in human and rat liver microsomes, and ETC-1002 was used as a control.
  • the results are summarized in Table 2 below. Representative compounds of the invention can significantly improve metabolic stability by comparison with ETC-1002 in human and rat liver microsome experiments.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of the plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound 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.

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Abstract

L'invention concerne un composé d'acide pentadécanedioïque substitué, une composition comprenant le composé et une utilisation associée, le composé d'acide pentadécanedioïque étant un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable, un promédicament, un hydrate ou un solvate, une forme cristalline, un stéréoisomère ou une variation isotopique de celui-ci, le composé représenté par la formule (I) comprenant au moins un atome de deutérium. Le composé d'acide pentadécanedioïque peut être utilisé pour traiter ou prévenir des maladies cardiovasculaires ou une dyslipidémie, et a des propriétés pharmacocinétiques supérieures.
PCT/CN2019/079045 2018-03-23 2019-03-21 Composé d'acide pentadécanedioïque substitué, composition pharmaceutique et utilisation associée Ceased WO2019179494A1 (fr)

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