WO2019179494A1 - Substituted pentadecanedioic acid compound and pharmaceutical composition and use thereof - Google Patents

Abstract

Provided are a substituted pentadecanedioic acid compound, a composition comprising the compound and a use thereof, the pentadecanedioic acid compound is a compound represented by formula (I), or a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate, a crystal form, a stereoisomer or an isotopic variation thereof, wherein the compound represented by formula (I) at least comprises one deuterium atom. The pentadecanedioic acid compound may be used for treating or preventing cardiovascular diseases or dyslipidemia, and has superior pharmacokinetic properties.

Description

Substituted pentadecanedioic acid compound and pharmaceutical composition and use thereof Technical field

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) The agent can be used for preventing or treating cardiovascular diseases and dyslipidemia diseases, and has more excellent pharmacokinetic properties.

Background technique

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.

At present, there are mainly the following hypolipidemic drugs used in clinical practice: statins, fibrates, niacin, cholesterol absorption inhibitors, and bile acid sequestrants. Guidelines for the prevention and treatment of blood lipids at home and abroad have clearly stated that LDL-C is the primary therapeutic target. The statin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is an effective drug for clinically reducing LDL-C and reducing the risk of cardiovascular disease. However, many people at high risk of cardiovascular disease can not reach the target value of LDL-C after taking statin therapy, and need to increase to several times the conventional dose to reduce the LDL-C level, but the adverse drug reaction will also be corresponding. increase. Although the safety and efficacy of these drugs are generally good, statin intolerance remains a major clinical problem. The main adverse reactions of statins are myopathy, elevated liver enzymes, and elevated blood sugar. Currently, only a small amount of 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.

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. Esperion plans to submit a new drug application (NDA) in the first half of 2019. The proposed product label will indicate that 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).

In addition, 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:

Poor absorption, distribution, metabolism, and/or excretion (ADME) properties are known to be the primary cause of clinical trial failure in many drug candidates. 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. In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.

Although ETC-1002 is effective in treating dyslipidemia and reducing diseases such as CVD, it has been found that a novel compound having a good oral bioavailability and a drug-forming condition for treating CVD and the like is a challenging task. Thus, there remains a need in the art to develop compounds having selective inhibitory activity or better pharmacodynamics/pharmacokinetics in the art, and the present invention provides such compounds.

Summary of invention

In view of the above technical problems, 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).

The term "compound of the invention" as used herein 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).

In this regard, the present invention adopts the following technical solutions:

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

among them,

R ^{1 is} selected from H or hydrazine;

Each of 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;

Provided that the above compound contains at least one ruthenium atom;

Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, polymorph, stereoisomer or isotopic variation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In a particular embodiment, a compound of the invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compounds of the invention are provided in a therapeutically effective amount. In a particular embodiment, the compounds of the invention are provided in a prophylactically effective amount. In a particular embodiment, the compositions of the invention comprise additional therapeutic agents. In a specific embodiment, the additional therapeutic agent is one or more statins or analogs thereof. In a specific embodiment, the additional therapeutic agent is ezetimibe or an analog thereof.

In another aspect, 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.

In another aspect, 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. In a specific embodiment, the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.

In another aspect, 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.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the <RTIgt;

Detailed description of the invention

definition

Chemical definition

The definitions of specific functional groups and chemical terms are described in more detail below.

When a range of values is recited, each value and sub-range within the range are intended to be included. For example, "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 ). The term " _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. Conventional 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. In some embodiments, 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. Unless otherwise specified, each of the cycloalkyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkane"base"). In some embodiments, a cycloalkyl group is an unsubstituted C _3-7 cycloalkyl group. In some embodiments, the carbocyclyl is a substituted _C3-7 cycloalkyl.

Other definitions

As used herein, unless otherwise specified, "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. The terms "one or more deuterated" are used interchangeably with "one or more deuterated".

As used herein, unless otherwise specified, "non-deuterated compound" means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).

The term "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. Examples of 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 . Certain 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.氚, 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. For example, 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.

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. The term "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 "solvate" refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio. "Hydrate" means a complex formed by the coordination of a compound of the invention with water.

The term "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. Thus, 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). Further, in the case of a carboxylic acid (-COOH), 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.

The term "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.

As used herein, 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. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human animal.

"Disease," "disorder," and "disorder" are used interchangeably herein.

The term "treatment" as used herein, unless otherwise indicated, 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").

Generally, an "effective amount" of a compound refers to an amount sufficient to cause a target biological response. As will be understood by one of ordinary skill in the art, 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, as used herein, 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. For example, 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.

detailed description

Compound

In one embodiment, the invention relates to a compound of formula (I):

among them,

R ^{1 is} selected from H or hydrazine;

Each of 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;

Provided that the above compound contains at least one ruthenium atom;

Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.

In a specific embodiment, 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; In another specific embodiment, 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 In another specific embodiment, R ⁶ and R ⁷ are each independently selected from methyl, or R ⁶ and R ⁷ are bonded to the atom to which they are attached, wherein the group is optionally 1. 2, 3, 4, 5, 6, 7 or 8 氘 replaced.

In another specific embodiment, 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 In another specific embodiment, 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. Butyl, cyclopentyl or cyclohexyl, wherein said group is optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 Substituted; in another specific embodiment, 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 氘 substituted.

In another embodiment, the invention relates to a compound of formula (Ia):

among them,

R ^{1 is} selected from H or hydrazine;

Each of 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 ;

Provided that if X ¹ , X ² , X ³ and X ⁴ are both CH ₃ , then at least one of R ¹ , each of R ² , R ³ , R ⁴ and R ⁵ is deuterium;

Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.

As a specific embodiment of the present invention, 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, more preferably twenty-seven atoms An atom, more preferably twenty-eight helium atoms, more preferably twenty-nine helium atoms, more preferably thirty helium atoms, more preferably thirty-one helium atoms, more preferably Thirty-two deuterium atoms, more preferably thirty-three deuterium atom.

As a specific embodiment of the present invention, 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%.

Specifically, in the present invention, 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. Preferably, more than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably More than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably More than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 95%, more preferably more than 99%.

In another specific embodiment, R ¹ of the compound of formula (Ia), each R ² , R ³ , R ⁴ or R ⁵ , X ¹ , X ² , X ³ or X ⁴ , at least one of which contains deuterium, More preferably two yttrium, more preferably three yttrium, more preferably four yttrium, more preferably five yttrium, more preferably six yttrium, more preferably seven yttrium, more preferably The earth contains eight cockroaches, preferably nine cockroaches, more preferably ten cockroaches, more preferably eleven cockroaches, more preferably twelve cockroaches, more preferably thirteen cockroaches, more preferably thirteen cockroaches, more The fourteenths of the good land contain 氘, preferably the fifteen 氘, more preferably sixteen 氘, more preferably seventeen 氘, more preferably eighteen 氘, more preferably nineteen Containing sputum, more preferably twenty sputum, more preferably twenty-one sputum, more preferably twenty-two sputum, more preferably twenty-three sputum, more preferably twenty-four氘, preferably twenty-five 氘, more preferably twenty-six 氘, more preferably twenty-seven 氘, more preferably twenty-eight 氘, more preferably twenty-nine氘, preferably thirty, including 氘, more preferably thirty-one 氘, more preferably thirty-two 氘, better Thirty-three containing deuterium. Specifically, 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.

As a specific embodiment of the invention, R ^{1 is} selected from hydrogen or hydrazine. In another specific embodiment, R ¹ is hydrogen; in another specific embodiment, R ¹ is deuterium.

As a specific embodiment of the invention, R ² , R ³ , R ⁴ or R ⁵ are each independently selected from H or hydrazine. In another specific embodiment, 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 -, -CH ₂ CD ₂ CH 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 CH ₂ CD ₂ -, -CH ₂ CD ₂ CH ₂ CH ₂ CD ₂ -, -CD ₂ CH ₂ CH ₂ CH ₂ CD ₂ -, -CH ₂ CH ₂ CD ₂ CD ₂ CH ₂ -, -CH ₂ CD ₂ CH ₂ CD ₂ CH ₂ -, -CD ₂ CH ₂ CH ₂ CD ₂ CH ₂ -, -CH ₂ CD ₂ CD ₂ CH ₂ CH ₂ -, -CD ₂ CH ₂ CD ₂ CH ₂ CH ₂ -, -CD ₂ CD ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CD ₂ CD ₂ CH ₂ CD ₂ -, -CD ₂ CH ₂ CD ₂ CH ₂ CD ₂ -, -CD ₂ CD ₂ CH ₂ CH ₂ CD ₂ -, -CH ₂ CH ₂ CD ₂ CD ₂ CD ₂ -, -CH ₂ CD ₂ CH ₂ CD ₂ CD ₂ -, -CD ₂ CH ₂ CH ₂ CD ₂ CD ₂ -, -CH ₂ CD ₂ CD ₂ CD ₂ CH ₂ -, -CD ₂ CH ₂ CD ₂ CD ₂ CH ₂ -, -CD ₂ CD ₂ CD ₂ CH ₂ CH ₂ -, -CH ₂ CD ₂ CD ₂ CD ₂ CD ₂ -, -CD ₂ CH ₂ CD ₂ CD ₂ CD ₂ -, - CD ₂ CD ₂ CD ₂ CH ₂ CD ₂ -, -CD ₂ CD ₂ CH ₂ CD ₂ CD ₂ -, -CD ₂ CH ₂ CD ₂ CD ₂ CD ₂ -, -CD ₂ CD ₂ CD ₂ CD ₂ CH ₂ - Or -CD ₂ CD ₂ CD ₂ CD ₂ CD ₂ -; 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 -, -CH ₂ CD ₂ CH ₂ CH ₂ CH ₂ - or -CD ₂ CH ₂ CH ₂ CH ₂ CH ₂ -; In another specific embodiment, -(CR ² R ³ ) ₅ - and -(CR ⁴ R ⁵ ) ₅ - are the same.

In a particular embodiment of the invention, X ¹ , X ² , X ³ or X ⁴ are each independently selected from CH ₃ , CH ₂ D, CHD ₂ or CD ₃ . In another specific embodiment, 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 ; In another specific embodiment, 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 ¹ , X ² , X ³ or X ⁴ are each independently It is selected from CH ₃ or CD ₃ . In another specific embodiment, X ¹ and X ² are the same. In another specific embodiment, X ³ and X ⁴ are the same. In another specific embodiment, X ¹ , X ² , X ³ and X ⁴ are both CH ₃ . In another specific embodiment, X ¹ , X ² , X ³ and X ⁴ are both CD ₃ .

In another embodiment, the invention relates to a compound of formula (Ib):

among them,

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;

Each of R ² , R ³ , R ⁴ and R ⁵ are each independently selected from H or hydrazine;

With the proviso that the above compound contains at least one ruthenium atom;

Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.

As a specific embodiment of the present invention, 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, more preferably twenty-seven atoms An atom, more preferably twenty-eight helium atoms, more preferably twenty-nine helium atoms.

As a specific embodiment of the present invention, 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%.

Specifically, in the present invention, R ¹ , R ⁶ ', R ^7' , R ^8' , R ^9' , R ^10' , R ^11' , R ^12' and R ^13' , and each R ² , R ³ , R ⁴ and R ⁵ each of the deuterated positions in the strontium isotope content of at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, more preferably More than 30%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably More than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 95%, more preferably more than 99%.

In another specific embodiment, R ¹ , R ⁶ ', R ^7' , R ^8' , R ^9' , R ^10' , R ^{11 '} , R ^{12 '} and R ^{13 '} of the compound of formula (Ib), And each of R ² , R ³ , R ⁴ and R ⁵ , at least one of which contains ruthenium, more preferably two ruthenium, more preferably three ruthenium, more preferably four ruthenium, more preferably five氘, preferably six 氘, preferably seven 氘, more preferably eight 氘, more preferably nine 氘, more preferably ten 氘, more preferably eleven氘, more preferably twelve 氘, more preferably thirteen 氘, more preferably fourteen 氘, more preferably fifteen 氘, more preferably sixteen 氘, more preferably Seventeen containing cockroaches, more preferably eighteen cockroaches, more preferably nineteen cockroaches, more preferably twenty cockroaches, more preferably twenty one cockroaches, more preferably twenty two Containing cockroaches, more preferably twenty-three cockroaches, more preferably twenty-four cockroaches, more preferably twenty-five cockroaches, more preferably twenty-six cockroaches, more preferably twenty-seven Containing cockroaches, more preferably twenty-eight cockroaches, more preferably twenty-nine cockroaches. Specifically, 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.

As a specific embodiment of the invention, R ^{1 is} selected from hydrogen or hydrazine. In another specific embodiment, R ¹ is hydrogen; in another specific embodiment, R ¹ is deuterium.

As a specific embodiment of the invention, R ² , R ³ , R ⁴ or R ⁵ are each independently selected from H or hydrazine. In another specific embodiment, 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 -, -CH ₂ CD ₂ CH 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 CH ₂ CD ₂ -, -CH ₂ CD ₂ CH ₂ CH ₂ CD ₂ -, -CD ₂ CH ₂ CH ₂ CH ₂ CD ₂ -, -CH ₂ CH ₂ CD ₂ CD ₂ CH ₂ -, -CH ₂ CD ₂ CH ₂ CD ₂ CH ₂ -, -CD ₂ CH ₂ CH ₂ CD ₂ CH ₂ -, -CH ₂ CD ₂ CD ₂ CH ₂ CH ₂ -, -CD ₂ CH ₂ CD ₂ CH ₂ CH ₂ -, -CD ₂ CD ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CD ₂ CD ₂ CH ₂ CD ₂ -, -CD ₂ CH ₂ CD ₂ CH ₂ CD ₂ -, -CD ₂ CD ₂ CH ₂ CH ₂ CD ₂ -, -CH ₂ CH ₂ CD ₂ CD ₂ CD ₂ -, -CH ₂ CD ₂ CH ₂ CD ₂ CD ₂ -, -CD ₂ CH ₂ CH ₂ CD ₂ CD ₂ -, -CH ₂ CD ₂ CD ₂ CD ₂ CH ₂ -, -CD ₂ CH ₂ CD ₂ CD ₂ CH ₂ -, -CD ₂ CD ₂ CD ₂ CH ₂ CH ₂ -, -CH ₂ CD ₂ CD ₂ CD ₂ CD ₂ -, -CD ₂ CH ₂ CD ₂ CD ₂ CD ₂ -, - CD ₂ CD ₂ CD ₂ CH ₂ CD ₂ -, -CD ₂ CD ₂ CH ₂ CD ₂ CD ₂ -, -CD ₂ CH ₂ CD ₂ CD ₂ CD ₂ -, -CD ₂ CD ₂ CD ₂ CD ₂ CH ₂ - Or -CD ₂ CD ₂ CD ₂ CD ₂ CD ₂ -; 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 -, -CH ₂ CD ₂ CH ₂ CH ₂ CH ₂ - or -CD ₂ CH ₂ CH ₂ CH ₂ CH ₂ -; In another specific embodiment, -(CR ² R ³ ) ₅ - and -(CR ⁴ R ⁵ ) ₅ - are the same.

As a specific embodiment of the present invention, 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; In a specific embodiment, R ⁶ 'is hydrogen; in another specific embodiment, R ⁶ 'is hydrazine; in another specific embodiment, R ⁷ 'is hydrogen; in another specific embodiment, R ⁷ '是氘; in another specific embodiment, R ⁸ 'is hydrogen; in another specific embodiment, R ⁸ 'is oxime; in another specific embodiment, R ⁹ 'is hydrogen; in another specific In an embodiment, R ⁹ 'is oxime; in another specific embodiment, R ¹⁰ 'is hydrogen; in another specific embodiment, R ¹⁰ 'is oxime; in another specific embodiment, R ¹¹ 'is Hydrogen; in another specific embodiment, R ¹¹ 'is hydrazine; in another specific embodiment, R ¹² 'is hydrogen; in another specific embodiment, R ¹² 'is hydrazine; in another embodiment Wherein R ¹³ 'is hydrogen; in another specific embodiment, R ¹³ 'is oxime; in another specific embodiment, R ⁶ ', R ^7' , R ^8' and R ^9' are hydrogen; In a specific embodiment, R ⁶ ' R ^{7 '} , R ^{8 '} and R ^{9 '} are deuterium; in another specific embodiment, R ^{10 '} , R ^{11 '} , R ^{12 '} and R ^{13 '} are hydrogen; in another specific embodiment, R ^10' , R ^11' , R ^12' and R ^13' are 氘.

In another embodiment, the invention relates to a compound of formula (X):

among them,

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;

Each of R ² , R ³ , R ⁴ and R ⁵ are each independently selected from H or hydrazine;

With the proviso that the above compound contains at least one ruthenium atom;

Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.

Furthermore, 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).

In another embodiment, the invention relates to a compound of formula (II):

among them,

R ¹ is selected H or deuterium;

Each of 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;

Provided that the above compound contains at least one ruthenium atom;

Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.

Furthermore, R ¹ -R ^{9 are} as defined for R ¹ -R ^{9 in} the compounds of formula (I).

In another embodiment, the invention relates to a compound of formula (IIa):

among them,

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 ;

Provided that if X ¹ , X ² , X ³ and X ⁴ are both CH ₃ , then at least one of R ¹ , each of R ² , R ³ , R ⁴ and R ⁵ is deuterium;

Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.

Furthermore, 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).

In another embodiment, the invention relates to a compound of formula (IIb):

among them,

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;

With the proviso that the above compound contains at least one ruthenium atom;

Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.

Furthermore, 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).

In a more specific embodiment, 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:

In a preferred embodiment of the invention, the compound does not include a non-deuterated compound.

Pharmaceutical composition and method of administration

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

The pharmaceutical 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. By "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. In general, 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. Preferably, 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 Segment polymer, polyethylene glycol and lanolin.

The pharmaceutical 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.

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.

For oral administration, 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. Such as 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.

The pharmaceutical 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.

treatment

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. As used herein, the term "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. As used herein, the term "dyslipidemia" refers to a disease that causes or manifests as an abnormal level of circulating lipids. To the extent that lipid levels in the blood are too high, 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.

The 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. In certain embodiments, 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, β-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.

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.

Combination therapy

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.

In a preferred embodiment, 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. In another preferred embodiment, the statin includes, but is not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin. In another preferred embodiment, a fixed dose combination of one or more statins with a compound of the invention can be formulated in a pharmaceutical composition.

In a preferred embodiment, 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. In another preferred embodiment, 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.

The structure of ezetimibe is:

In another preferred embodiment, 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.

Example

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Parts and percentages are parts by weight and percentage by weight unless otherwise stated.

Usually, in the preparation scheme, 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.

Example 1 Preparation of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid-8-d acid (Compound E-1).

Use the following route for synthesis:

Step 1 Synthesis of Compound 3

Compound 2 (2.0 g, 17.2 mmol) was slowly added dropwise to a solution of lithium diisopropylamide (LDA, 8.6 ml, 17.2 mmol, 2 mol/L) in THF (20 ml) at 0 ° C. After stirring for half an hour, the compound 1 (4.8 g, 20.7 mmol) was further added dropwise, and the mixture was stirred at room temperature for 12 h. The organic phases were combined, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: petroleum ether) to afford 3.0 g of colorless liquid.

Step 2 Synthesis of Compound 5

Sodium hydride (0.3 g, 12.4 mmol) was slowly added to compound 3 (3.0 g, 11.3 mmol), tetrabutylammonium iodide (0.42 g, 1.13 mmol) and compound 4 (1.1 g) under nitrogen. , 5.63 mmol) in DMSO (20 ml), EtOAc (20 mL), EtOAc (EtOAc) To about 30ml of solvent, add concentrated hydrochloric acid (15ml), stir at room temperature for 2h, then separate the organic phase, wash with sodium bicarbonate solution, remove the solvent, concentrate the column for separation (eluent: petroleum ether: ethyl acetate = 20:1), 1.2 g of a colorless liquid was obtained in a yield of 53%.

Step 3 Synthesis of Compound 6

Potassium hydroxide (0.56 g, 10.0 mmol) and water (3 ml) were added to a solution of compound 5 (1.0 g, 2.51 mmol) in methanol (10 ml), and the mixture was stirred at 80 ° C for 2 h, then cooled to room temperature, Methyl chloride (20 ml × 2) was extracted to remove impurities. The solution was adjusted to pH 2 with 2M hydrochloric acid, extracted with methyl tert-butyl ether (MTBE, 20 ml × 3), and the organic phase was combined and dried over anhydrous sodium sulfate. An oily product was obtained, which was then purified with a solvent (15 ml, n-hexane: MTBE = 2:1) to give a solid, which was filtered to give a white solid. LC-MS (APCI): m / z = 342.48 (M + 1) +.

Step 4 Synthesis of Compound E-1

NaBD ₄ (0.046 g, 1.16 mmol) was added to a solution of compound 6 (0.2 g, 0.58 mmol) in methanol (10 ml). The reaction was quenched with EtOAc (EtOAc)EtOAc. LC-MS (APCI): m / z = 345.51 (M + 1) +. _{^{1 H NMR (500MHz, CDCl 3}} ) δ5.30 (s, 1H), 1.57-1.49 (m, 4H), 1.41 (dd, J = 15.7,11.1Hz, 6H), 1.26 (dd, J = 12.3,3.9 Hz, 10H), 1.18 (d, J = 2.6 Hz, 12H).

Example 2 Preparation of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid-7,7,9,9-d ₄ acid (Compound E-2).

Use the following route for synthesis:

Step 1 Synthesis of Compound 7

The 1,5,7-azabicyclo [4.4.0] dec-5-ene (0.035g, 0.25mmol) was added to compound 5 (1.0g, 2.51mmol) in deuterated chloroform (CDCl _3, 10ml) After the reaction mixture was stirred at room temperature for 10 h, water (10 ml) was added and the mixture was evaporated. The organic phase was separated and washed with saturated sodium chloride.

Step 2 Synthesis of Compound 8

Sodium bismuth oxide (0.32 g, 8.0 mmol) and heavy water (3 ml) were added to a solution of compound 7 (0.8 g, 2.0 mmol) in deuterated methanol (10 ml). The mixture was stirred at 80 ° C for 2 h and then cooled to room temperature. Dichloromethane (20 ml × 2) was used for extraction to remove impurities. The solution was adjusted to pH 2 with 2M hydrochloric acid, and extracted with EtOAc (20 mL×3). The organic phase was combined and dried over anhydrous sodium sulfate. The mixture was slurried with a solvent (15 ml, n-hexane: hexanes: 2:1) to give a solid, which was filtered to give a white solid. LC-MS (APCI): m / z = 346.13 (M + 1) +.

Step 3 Synthesis of Compound E-2

NaBH ₄ (0.046 g, 1.16 mmol) was added to a solution of compound 8 (0.2 g, 0.58 mmol) in methanol (10 ml) at 0 ° C, and then allowed to react at low temperature for 2 h. The reaction was quenched with EtOAc (EtOAc)EtOAc. LC-MS (APCI): m / z = 348.60 (M + 1) +. _{^{1 H NMR (500MHz, CDCl 3}} ) δ5.25 (s, 1H), 3.50 ((s, 1H) 1.55-1.49 (m, 4H), 1.41-1.38 (m, 4H), 1.26-1.19 (m, 8H ), 1.16 (s, 12H).

Example 3 Preparation of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid-7,7,8,9,9-d ₅ acid (Compound E-3).

Use the following route for synthesis:

Step 1 Synthesis of Compound E-3

NaBD ₄ (0.046 g, 1.16 mmol) was added to a solution of compound 8 (0.2 g, 0.58 mmol) in methanol (10 ml) at 0 ° C. The reaction was quenched with EtOAc (EtOAc)EtOAc. LC-MS (APCI): m / z = 349.45 (M + 1) +. ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.26 (s, 1H), 1.58 - 1.47 (m, 4H), 1.45-1.38 (m, 4H), 1.28-1.20 (m, 8H), 1.19 (s, 12H) ).

Example 4 Preparation of 1,11-bis-(1-carboxycyclopropyl)undecane-6-ol-6-d (Compound E-1a).

Use the following route for synthesis:

Step 1 Synthesis of Compound 3a

Compound 1a (2.0 g, 14.1 mmol) was slowly added dropwise to a solution of lithium diisopropylamide (LDA, 7.1 ml, 14.1 mmol, 2 mol/L) in THF (20 ml) at -40 °C. After completion, the mixture was stirred for half an hour, and then 1-chloro-5-bromopentane (3.9 g, 21.1 mmol) was further added dropwise. After the completion of the dropwise addition, the reaction was continued at -5 ° C for 4 h, and saturated ammonium chloride (10 ml) was added to quench the reaction. Ethyl acetate (40 ml × 3) was extracted, and the organic phase was combined, and the solvent was removed, and the concentrate was subjected to column separation (eluent: petroleum ether) to obtain 1.8 g of a colorless liquid, yield 52.1%.

Step 2 Synthesis of Compound 4a

Compound 3a (1.8 g, 7.3 mmol), sodium iodide (1.64 g, 10.9 mmol), 2-butanone (20 ml) was added to the reactor and refluxed for 12 h. After completion of the reaction, water (10 ml) was added to quench the reaction. It was extracted with diethyl ether (30 ml * 2), dried over anhydrous sodium sulfate and evaporated to dryness

Step 3 Synthesis of Compound 5a

Potassium tert-butoxide (t-BuOK, 0.32 g, 2.85 mmol) was added to p-methylbenzenesulfonylmethyl isocyanide (0.5 g, 2.56 mmol) in dimethylacetamide under nitrogen (0 °C). DMAC, 20 ml) solution, after the addition, the compound 4a (0.95 g, 2.81 mmol) was slowly added dropwise, reacted at room temperature for 1 h, then cooled to 0 ° C, then potassium t-butoxide (0.32 g, 2.85 mmol) was added. After the addition, the compound 4a (0.95 g, 2.81 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 3 h. The reaction was quenched with ice water (20 ml). Dry, concentrate to about 30 ml of solvent, add concentrated hydrochloric acid (15 ml), stir at room temperature for 2 h, then separate the organic phase, wash with sodium bicarbonate solution, remove the solvent, concentrate the column for separation (eluent: petroleum ether: Ethyl acetate = 20:1) gave 1.1 g of a colorless liquid, yield 43%.

Step 4 Synthesis of Compound 6a

NaBD ₄ (0.056 g, 1.33 mmol) was added to a solution of compound 5a (0.3 g, 0.67 mmol) in methanol (10 ml) at 0 ° C. The reaction was quenched with EtOAc (EtOAc)EtOAc.

Step 5 Synthesis of Compound E-1a

Concentrated hydrochloric acid (10 ml) was added to a solution of Compound 6a (0.24 g, 0.51 mmol) in dioxane (10 ml). dried over anhydrous sodium sulfate, filtered and rotary evaporation, to give an oil product 110 mg, yield 61%, LC-MS (APCI ): m / z = 341.67 (m + 1) +. _{^{1 H NMR (500MHz, CDCl 3}} ) δ5.45 (s, 1H), 1.55-1.49 (m, 20H), 0.93 (m, 4H), 0.59 (m, 4H).

Example 5 Preparation of 1,11-bis-(1-carboxycyclopropyl)undecane-6-ol-5,5,7,7-d ₄ (Compound E-2a).

Use the following route for synthesis:

Step 1 Synthesis of Compound 7a

1,5,7-Triazabicyclo[4.4.0]non-5-ene (0.037 g, 0.26 mmol) was added to a solution of compound 5a (0.6 g, 1.33 mmol) in deuterated chloroform (10 ml). After the reaction mixture was stirred at room temperature for 10 hr, EtOAc (EtOAc m.

Step 2 Synthesis of Compound 8a

NaBH ₄ (0.034 g, 0.88 mmol) was added to a solution of compound 7a (0.2 g, 0.44 mmol) in methanol (10 ml). The reaction was quenched with EtOAc (EtOAc)EtOAc.

Step 3 Synthesis of Compound E-2a

Concentrated hydrochloric acid (10 ml) was added to a solution of compound 8a (0.14 g, 0.31 mmol) in dioxane (10 ml). over anhydrous sodium sulfate, filtered and rotary evaporation, to give an oil product 80mg, yield 79%, LC-MS (APCI ): m / z = 345.13 (m + 1) +. _{^{1 H NMR (500MHz, CDCl 3}} ) δ5.45 (s, 1H), 3.45 (s, 1H), 1.51-1.38 (m, 16H), 0.95 (m, 4H), 0.56 (m, 4H).

Example 6 Preparation of 1,11-bis-(1-carboxycyclopropyl)undecane-6-ol-5,5,6,7,7-d ₅ (Compound E-3a).

Use the following route for synthesis:

Step 1 Synthesis of Compound 9a

NaBD ₄ (0.034 g, 0.88 mmol) was added to a solution of compound 7a (0.2 g, 0.44 mmol) in methanol (10 ml). The reaction was quenched with EtOAc (EtOAc)EtOAc.

Step 2 Synthesis of Compound E-3a

Concentrated hydrochloric acid (10 ml) was added to a solution of compound 9a (0.15 g, 0.33 mmol) in dioxane (10 ml). over anhydrous sodium sulfate, filtered and rotary evaporation, to give an oil product 70mg, yield 64%, LC-MS (APCI ): m / z = 346.29 (m + 1) +. _{^{1 H NMR (500MHz, CDCl 3}} ) δ5.46 (s, 1H), 1.52-1.40 (m, 16H), 0.96 (m, 4H), 0.56 (m, 4H).

Example 7 Preparation of 8-hydroxy-2,2,14,14-tetrakis(methyl-d ₃ )pentadecanedioic acid (Compound E-4).

Use the following route for synthesis:

Step 1 Synthesis of Compound 10

Compound 9 (3.17 g, 17.2 mmol) was slowly added dropwise to a solution of lithium diisopropylamide (LDA, 8.6 ml, 17.2 mmol, 2 mol/L) in THF (20 ml) at 0 ° C. After stirring for half an hour, the compound 1 (4.8 g, 20.7 mmol) was further added dropwise, and the mixture was stirred at room temperature for 12 h. The organic phases were combined, the solvent was removed, and the concentrate was subjected to column separation (eluent: petroleum ether) to give 3.34 g of a colorless liquid, yield 58.2%.

Step 2 Synthesis of Compound 11

Sodium hydride (0.3 g, 12.4 mmol) was slowly added to compound 10 (3.76 g, 11.3 mmol), tetrabutyl iodide amine (0.42 g, 1.13 mmol) and compound 4 (1.1 g) under nitrogen. , 5.63 mmol) in DMSO (20 ml), EtOAc (20 mL), EtOAc (EtOAc) To about 30ml of solvent, add concentrated hydrochloric acid (15ml), stir at room temperature for 2h, then separate the organic phase, wash with sodium bicarbonate solution, remove the solvent, concentrate the column for separation (eluent: petroleum ether: ethyl acetate = 20:1), 1.35 g of a colorless liquid was obtained in a yield of 45%.

Step 3 Synthesis of Compound 12

Potassium hydroxide (0.56 g, 10.0 mmol) and water (3 ml) were added to a solution of compound 11 (1.34 g, 2.51 mmol) in methanol (10 ml), and the mixture was stirred at 80 ° C for 2 h, then cooled to room temperature, Methyl chloride (20 ml × 2) was extracted to remove impurities. The solution was adjusted to pH 2 with 2M hydrochloric acid, extracted with methyl tert-butyl ether (MTBE, 20 ml × 3), and the organic phase was combined and dried over anhydrous sodium sulfate. An oil was obtained, which was then purified with a solvent (15 ml, n-hexane: hexanes: 2:1) to give a solid, which was filtered to give a white solid. LC-MS (APCI): m / z = 355.48 (M + 1) +.

Step 4 Synthesis of Compound E-4

NaBH ₄ (0.046 g, 1.16 mmol) was added to a solution of compound 12 (0.2 g, 0.58 mmol) in methanol (10 ml) at 0 ° C. The reaction was quenched with EtOAc (EtOAc)EtOAc. LC-MS (APCI): m / z = 357.51 (M + 1) +. _{^{1 H NMR (500MHz, CDCl 3}} ) δ5.29 (s, 1H), 3.51 (m, 1H), 1.57-1.48 (m, 4H), 1.42 (dd, J = 15.7,11.1Hz, 6H), 1.25 ( Dd, J = 12.3, 3.9 Hz, 10H).

Biological activity test.

(1) Enzyme activity test

The inhibitory activity of the test substance against ACL (Sino Biological 11769-H07B) was measured using the ADP-GloTM Kinase Assay kit (Promega V9102) kit.

After the test compound was dissolved in DMSO, it was diluted by a 3-fold concentration gradient, 12 doses. 5 μL 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 μL of substrate and incubated at 25 ° C for 60 minutes. The final reaction concentrations in the system were: 3 nM ACL, 15 μM ATP, 3 μM CoA, 300 μM Citrate, 0.01% Brij35, 4 mM DTT, 1% DMSO. Concentrations of test compounds: 300, 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.137, 0.046, 0.015, 0.0051 and 0 μM. Then 10 μL of ADP Glo reagent was added and incubation was continued for 40 minutes at 25 °C. After completion of the reaction, 20 μL 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.

This assay data for compounds tested are presented in Table 1, wherein, A represents IC ₅₀ ≤50nM, B represents 50nM <IC ₅₀ ≤100nM, C represents 100nM <IC ₅₀ ≤150nM, C represents 150nM <IC ₅₀ ≤200nM, D represents an IC ₅₀ >200 nM. Table 1:

Example compound	ACL IC 50 (μM)
ETC-1002	D
Compound A	D
E-1	D
E-2	D
E-3	D

E-1a	C
E-2a	A
E-3a	D

(2) Metabolic stability evaluation

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).

Preparation of the stock solution: A certain amount of the powder of the example compound was accurately weighed and dissolved in 5 mM with DMSO.

Preparation of phosphate buffer (100 mM, pH 7.4): Mix 150 mL of 0.5 M potassium dihydrogen phosphate and 700 mL of 0.5 M potassium dihydrogen phosphate solution, and adjust the mixture with 0.5 M potassium dihydrogen phosphate solution. 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.

A solution of 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 μL of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 μL of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 μL of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.

Incubation of the sample: The stock solution of the corresponding compound was diluted to 0.25 mM with an aqueous solution containing 70% acetonitrile as a working solution, and was used. 398 μL of human liver microsomes or rat liver microsome dilutions were added to 96-well incubation plates (N=2), and 2 μL of 0.25 mM working solution was added and mixed.

Determination of metabolic stability: 300 μL 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 were placed in a 37 ° C water bath, shaken at 100 rpm, and pre-incubated for 5 min. 80 μL of the incubation solution was taken from each well of the incubation plate, added to the stopper plate, and mixed, and 20 μL of the NADPH regeneration system solution was added as a sample of 0 min. Then, 80 μL of the NADPH regeneration system solution was added to each well of the incubation plate to start the reaction and start timing. The corresponding compound had a reaction concentration of 1 μM and a protein concentration of 0.5 mg/mL. 100 μL 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 μL of the supernatant was taken into a 96-well plate to which 100 μL of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.

Data analysis: The peak area of the corresponding compound and the internal standard was detected by LC-MS/MS system, and the ratio of the peak area of the compound to the internal standard was calculated. The slope is measured by the natural logarithm of the percentage of the remaining amount of the compound versus time, and t _1/2 and CL _{int are} calculated according to the following formula, where V/M is equal to 1/protein concentration.

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.

Table 2:

(3) Rat pharmacokinetic experiments

Six male Sprague-Dawley rats, aged 7-8 weeks, weighing approximately 210 g, were divided into two groups of 3 animals each, and their pharmacokinetic differences were compared by intravenous or oral single dose of compound (10 mg/kg orally). .

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 μL of blood samples were collected from the eyelids in test tubes. There was 30 μL 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.

Immediately after the blood sample is collected, gently invert the tube at least 5 times to ensure adequate mixing and place on ice. Blood samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 μL 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.

Experiments have shown that the compounds of the present invention have better pharmacokinetic properties in animals than non-deuterated ETC-1002 and Compound A, and thus have better pharmacodynamics and therapeutic effects.

The above is a further detailed description of the present invention in connection with the specific preferred embodiments, and the specific embodiments of the present invention are not limited to the description. It will be apparent to those skilled in the art that the present invention may be made without departing from the spirit and scope of the invention.

Claims (11)

1. A compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystal form, stereoisomer or isotopic variation thereof:

   

   among them,

   R ^{1 is} selected from H or hydrazine;

   Each of 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;

   Provided that the above compound contains at least one ruthenium atom.
2. A compound according to claim 1 having the formula (II):

   

   R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} as defined in claim 1;

   Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.
3. A compound according to claim 1 or 2 having the formula (Ia):

   

   among them,

   R ^{1 is} selected from H or hydrazine;

   Each of 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 ;

   Provided that if X ¹ , X ² , X ³ and X ⁴ are both CH ₃ , then at least one of R ¹ , each of R ² , R ³ , R ⁴ and R ⁵ is hydrazine; or a pharmaceutically acceptable salt thereof , prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant.
4. A compound according to any one of claims 1 to 3 having the formula (IIa):

   

   among them,

   R ^{1 is} selected from H or hydrazine;

   R ^2, R ^3, R ⁴ and R ⁵ are each independently selected from H or deuterium;

   X ¹ , X ² , X ³ and X ⁴ are each independently selected from CH ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

   Provided that if X ¹ , X ² , X ³ and X ⁴ are both CH ₃ , then at least one of R ¹ , each of R ² , R ³ , R ⁴ and R ⁵ is hydrazine; or a pharmaceutically acceptable salt thereof , prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant.
5. A compound according to any one of claims 1 to 4 having the formula (Ib):

   

   among them,

   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;

   Each R ^2, R ^3, R ⁴ and R ⁵ are each independently selected from H or deuterium;

   With the proviso that the above compound contains at least one ruthenium atom;

   Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.
6. A compound according to any one of claims 1 to 5 having the formula (IIb):

   

   among them,

   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;

   With the proviso that the above compound contains at least one ruthenium atom;

   Or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof.
7. The compound according to claim 1, wherein the compound is selected from the group consisting of a compound thereof, or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, polymorph, stereoisomer or isotopic variation thereof:

   

   
8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound thereof, crystalline form , stereoisomers or isotopic variations.
9. A pharmaceutical composition according to claim 8 further comprising an additional therapeutic agent;

   Preferably wherein said additional therapeutic agent is one or more statins or analogues thereof;

   Preferably, wherein the additional therapeutic agent is ezetimibe or an analogue thereof.
10. A method for preventing or treating a cardiovascular disease and a dyslipidemia disease in a subject, comprising administering an effective amount of the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, a prodrug, Hydrate or solvent compound, crystalline form, stereoisomer or isotope variant, or the pharmaceutical composition of claim 8 or 9.
11. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof, or the drug of claim 8 or Use of a composition for the manufacture of a medicament for the prevention or treatment of cardiovascular diseases and dyslipidemia diseases.