EP4695266A1

EP4695266A1 - Substituted alkanoic-diacids compound and composition and use thereof

Info

Publication number: EP4695266A1
Application number: EP24788239.2A
Authority: EP
Inventors: Ke Xu; Anjin XIANYU; Helmut Haning; Shiqiang ZHOU
Original assignee: Shenzhen Moyuan Pharmaceuticals; Meta Pharmaceuticals Hk Ltd
Current assignee: Shenzhen Moyuan Pharmaceuticals; Meta Pharmaceuticals Hk Ltd
Priority date: 2023-04-14
Filing date: 2024-04-12
Publication date: 2026-02-18
Also published as: WO2024213143A1; CN120981471A; WO2024212248A1

Abstract

The present invention provides a novel compound or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, or a composition thereof; also provides useful for inhibiting ATP citrate lyase (ACLY) or increasing HDL levels, or lowering LDL levels.

Description

Substituted alkanoic-diacids compound and composition and use thereof

Cross-Reference To Related Applications
This application claims the benefit of international patent application PCT/CN2023/088528 filed April. 14, 2023 in the WIPO, with China State Intellectual Property Administration as the receiving office.

Field of the Invention

The invention relates to a novel compound or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof , or a composition thereof; also to useful for inhibiting ATP citrate lyase (ACLY) or increasing HDL levels, or lowering LDL levels, or preventing, managing, treating or lessening a disorder such as, aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy.

Background

ATP citrate lyase (ACLY) is a homotetrameric enzyme that catalyzes the ATP dependent cleavage of citrate into acetyl coenzyme A (acetyl-CoA) and oxaloacetate (OAA) . Acetyl-CoA is an important cellular metabolite and second messenger, thus ACLY enzymatic activity is positioned at the nexus of intermediary metabolism. The acetyl-CoA forming reaction is initiated upon phosphorylation of ACLY at histidine 760, which then catalyzes the formation of citryl phosphate followed by the formation of a citryl-CoA intermediate after a CoA attack. Finally, the citryl-CoA intermediate is cleaved, and acetyl-CoA and OAA are released. ACLY derived acetyl-CoA serves as the carbon source for the production of cholesterol in the mevalonate pathway and fatty acids (FA) in the de novo lipogenesis (DNL) pathway, and is also required for protein acetylation, thus linking cellular metabolism with the epigenome and gene regulation. Acetyl-CoA production therefore functions as a key metabolic checkpoint used by cells to coordinate cellular metabolism in response to nutrients and plays a key role in sterol and lipid production in a number of tissues. Thus, direct inhibition of ACLY activity may have important therapeutic implications for treating a wide range of diseases including hypercholesteremia and cardiovascular disease (CVD) , obesity, diabetes, insulin resistance, fatty liver disease, metabolic syndrome and cancer.
Fatty liver disorders, also known as fatty liver or fatty liver disease (FLD) , relate to a condition where large vacuoles of triglyceride fat accumulate in liver cells. In its early form, FLD is often relatively benign and may be reversible, but it can lead to more serious conditions. FLD may be categorized into two separate conditions: alcoholic FLD (also known as alcoholic steatosis; caused at least in part by alcohol abuse) and non-alcoholic FLD (NAFLD; not caused by alcohol abuse) . Both conditions often show micro-vesicular and macro-vesicular fatty changes at different stages of the disease. Accumulation of fat may also be accompanied by a progressive inflammation of the liver (hepatitis) , called steatohepatitis. Steatohepatitis may be further specified as alcoholic steatohepatitis and non-alcoholic steatohepatitis (NASH) . Non-alcoholic fatty liver disease-associated cirrhosis is the most severe form of the disease and is typically characterized by liver inflammation that leads to scarring of liver tissue.
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are common causes of chronic liver disease in the adult population and represent crucial risk factors for progression to liver cirrhosis, hepatocellular carcinoma, and liver failure. Some experts estimate that about two-thirds of obese adults and half of obese children may have fatty liver. The increased incidence of NAFLD and NASH may be linked to the increasing incidence of obesity in the United States.
Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies Patients with chronic liver disease, such as liver cirrhosis and fibrosis, are at increased risk for development of HCC. Thus, patients with chronic liver diseases should be closely monitored for development of HCC. Risk factors for HCC include cirrhosis, non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , chronic alcohol consumption, hepatitis B, and hepatitis C, type IIb hyperlipidemia, mixed dyslipidemia, obesity, and type 2 diabetes.
Low density lipoprotein (LDL) and high density lipoprotein (HDL) are the major cholesterol-carrier proteins. LDL is believed to be responsible for the delivery of cholesterol from the liver, where it is synthesized or obtained from dietary sources, to extrahepatic tissues in the body. The term "reverse cholesterol transport" describes the transport of cholesterol from extrahepatic tissues to the liver, where it is catabolized and eliminated. It is believed that plasma HDL particles play a major role in the reverse transport process, acting as scavengers of tissue cholesterol. HDL is also responsible for the removal of non-cholesterol lipid, oxidized cholesterol and other oxidized products from the bloodstream. Atherosclerosis, for example, is a slowly progressive disease characterized by the accumulation of cholesterol within the arterial wall. Compelling evidence supports the belief that lipids deposited in atherosclerotic lesions are derived primarily from plasma apolipoprotein B (apo B) -containing lipoproteins, which include chylomicrons, VLDL, DDL and LDL. The apo B-containing lipoprotein, and in particular LDL, has popularly become known as the "bad" cholesterol. In contrast, HDL serum levels correlate inversely with coronary heart disease. Indeed, high serum levels of HDL is regarded as a negative risk factor. It is hypothesized that high levels of plasma HDL are not only protective against coronary artery disease, but may actually induce regression of atherosclerotic plaque (e.g., see Badimon et al., 1992, Circulation 86: (Suppl. 111) 86-94; Dansky and'Fisher, 1999, Circulation 100: 1762-3. ) . Thus, HDL has popularly become known as the "good" cholesterol.

Summary of the Invention

The present invention relates to a compound or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, or a composition comprising the compound. The compound or composition has good effects and pharmacokinetic properties, they can be used to inhibit ATP citrate lyase or activate AMP-activated protein kinase; and to increase HDL levels or lower LDL levels. These novel compounds or compositions thereof are effective in treatment of diseases such as aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy; especially hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis and liver cirrhosis.
In one aspect, the invention provided a compound having formula I,
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylamino, (C1-C6) alkylthio, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl, (C1-C9) heteroaryl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C2-C6) heterocyclyl- (C1-C6) alkyl, (C6-C10) aryl- (C1-C6) alkyl or (C1-C9) heteroaryl- (C1-C6) alkyl; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;
each of n and m is independently 4, 5, 6, 7, 8, 9 or 10;
R is H, D, halo, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl or (C1-C9) heteroaryl; R is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;
G is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl or (C1-C9) heteroaryl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;
or G isor one or more deuterium substituted
or G is H, and at the same time, at least one R¹ is independently hydroxy;
each of Y¹ and Y² is independently -OH, - (C1-C6) alklene-OH, -C (=O) -OH, -C (=O) H, -C (=O) OR⁵, -S (=O) ₂OH, -S (=O) ₂NH₂,
or one of Y¹ and Y² is
R⁵ is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl, (C1-C9) heteroaryl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C2-C6) heterocyclyl- (C1-C6) alkyl, (C6-C10) aryl- (C1-C6) alkyl or (C1-C9) heteroaryl- (C1-C6) alkyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkoxy or (C1-C6) haloalkoxy;
each of R⁶ and R⁷ is independently H, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl; each of R⁶ and R⁷ is optionally and independently substitutled with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkoxy or phenyl.
In other aspect, the invention also provided a pharmaceutical composition comprising a compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof and a pharmaceutically acceptable vehicle, excipient, or diluent.
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for use in preventing, managing, treating or lessening a disorder relating to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof.
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for use in preventing, managing, treating or lessening a disorder by increasing HDL levels.
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for use in preventing, managing, treating or lessening a disorder by lowering LDL levels.
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for use in preventing, managing, treating or lessening aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient.
In other aspect, the invention also provided use of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition compirisng the compound in the manufacture of a medicament for preventing, managing, treating or lessening a disorder relating to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof.
In other aspect, the invention also provided use of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition compirisng the compound in the manufacture of a medicament for preventing, managing, treating or lessening a disorder by increasing HDL levels.
In other aspect, the invention also provided use of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition compirisng the compound in the manufacture of a medicament for preventing, managing, treating or lessening a disorder by lowering LDL levels.
In other aspect, the invention also provided use of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition compirisng the compound in the manufacture of a medicament for preventing, managing, treating or lessening aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient.
In other aspect, the invention also provided a method for preventing, managing, treating or lessening a disorder realting to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof, comprising administering to a mammal in need thereof an effective amount of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition comprising the compound.
In other aspect, the invention also provided a method for preventing, managing, treating or lessening a disorder by increasing HDL levels comprising administering to a mammal in need thereof an effective amount of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition comprising the compound.
In other aspect, the invention also provided a method for preventing, managing, treating or lessening a disorder by lowering LDL levels, comprising administering to a mammal in need thereof an effective amount of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition comprising the compound.
In other aspect, the invention also provided a method for preventing, managing, treating or lessening aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient, comprising administering to a patient in need of such treatment or prevention a therapeutically or proplyleufrally effective amount of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition comprising the compound.
The invention encompasses all combination of the particular embodiments recited herein, as if each had been separately, laboriously recited.
The invention encompasses all combination of the particular embodiments recited herein.
Description of the Embodiments
For a better understanding of the invention and to show how the same may be carried into effect, reference will now be made, purely by way of example, to the accompanying figures. With specific reference to the figures in detail, it is stressed that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the present invention only, and are presented for the purpose of providing what is believed to be the most useful and readily understood description of principles and conceptual aspects of the invention.
Definition
To facilitate an understanding of the present invention, a number of terms and phrases are defined below.
Unless the context requires otherwise, throughout the present disclosure and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to” .
Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment disclosed herein. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
The term “optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted heterocyclyl” means that the heterocyclyl radical may or may not be substituted and that the description includes both substituted heterocyclyl radicals and heterocyclyl radicals having no substitution.
The term “independently” with respect to substituents means that if a group that is substituted with more than one substituent, these substituents may be the same or different from each other. Similarly, if multiple atoms or groups are independently selected from a given group, the term “independently selected” or “independently is” means that each atom or group may be the same or different from the substituent of the other atom or group. Further, if a group can be more than one substituent, the term “independently selected” means that each group may be the same or different form the other group (s) .
The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.
The term “pharmaceutically acceptable salt” includes both an acid and a base addition salt. Pharmaceutically acceptable salts can be obtained by reacting the compound of the invention functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Pharmaceutically acceptable salts can also be obtained by reacting a compound of the invention functioning as an acid, with an inorganic or organic base to form a salt, for example, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, trimethylamine, etc. Those skilled in the art will further recognize that pharmaceutically acceptable salts can be prepared by reaction of the compounds of the invention with an appropriate inorganic or organic acid or base via any of a number of known methods.
The term “solvate” refers to a solvation complex. Solvates can be formed by solvation (the combination of solvent molecules with molecules or ions of the compounds of the invention) , or a solvate can be an aggregate that comprises a solute ion or molecule or a solvent molecule. The solvent can be water, in which case the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc. The solvate can be formed via hydration, including via absorption of moisture. A pharmaceutically acceptable salt can also be a solvate. Where a solvate is obtained via crystallization from a solvent, the solvent can be an alcohol, such as methanol or ethanol; an aldehyde; a ketone, such as acetone; or an ester, such as ethyl acetate.
The compounds of the invention can have one or more asymmetric centers and can thus be enantiomers, racemates, diastereomers, other stereoisomers and mixtures thereof. The compounds of the invention include all such possible isomers (including geometric isomers) , as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (-) , (R) -and (S) -, or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation or isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC) . When the compounds of the invention comprise an olefinic double bond or another center of geometric asymmetry, and unless specified otherwise, the compounds of the invention include both E and Z geometric isomers. Likewise, the compounds of the invention include all tautomeric forms.
As used herein, the term “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers” , which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. In any of the embodiments disclosed herein, compounds disclosed herein may be in the form of a stereoisomer thereof.
As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set-in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
The compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
As used herein, the term “metabolite” means a product of metabolism of the compound of present disclosure, or pharmaceutically acceptable salts, solvates, diastereomers, and polymorphs thereof, that exhibits a similar activity in vivo to the compound of present disclosure, or pharmaceutically acceptable salts, solvates, diastereomers, and polymorphs thereof.
As used herein, the term “prodrug” means the compound of present disclosure, or pharmaceutically acceptable salts, solvates, diastereomers, and polymorphs thereof covalently linked to one or more pro-moieties, such as an amino acid moiety or other water solubilizing moiety. The compound of present disclosure, or pharmaceutically acceptable salts, solvates, diastereomers, and polymorphs thereof may be released from the pro-moiety via hydrolytic, oxidative, and/or enzymatic release mechanisms. In an aspect, a prodrug composition of the present disclosure exhibits the added benefit of increased aqueous solubility, improved stability, and improved pharmacokinetic profiles. The pro-moiety may be selected to obtain desired prodrug characteristics. For example, the pro-moiety, e.g., an amino acid moiety or other water solubilizing moiety such as phosphate within R4, may be selected based on solubility, stability, bioavailability, and/or in vivo delivery or uptake. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates and benzoate derivatives) and carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy functional groups, esters (e.g., ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of the disclosure, and the like, See Bundegaard, H., Design of Prodrugs, p 1-92, Elesevier, New York-Oxford (1985) .
Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
The invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.
“Effective amount” or “therapeutically effective amount” refers to an amount of a compound according to the embodiments disclosed herein, which when administered to a patient in need thereof, is sufficient to effect treatment of disease-states, conditions, or disorders disclosed herein. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound according to the embodiments disclosed herein which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination, or coincidentally, with the compounds of the embodiments disclosed herein, and the age, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
A “subject” is a human or non-human mammal, e.g., a bovine, horse, feline, canine, rodent, or non-human primate. The human can be a male or female, child, adolescent or adult. The female can be premenarcheal or postmenarcheal.
“Mammal” includes a human, domestic animal such as a laboratory animal (e.g., mouse, rat, rabbit, monkey, dog, etc. ) and household pet (e.g., cat, dog, swine, cattle, sheep, goat, horse, rabbit) , and a non-domestic, wild animal.
The terms “treating” and “treatment” as used herein are intended to mean the administration of a compound or composition according to the present embodiments disclosed herein to alleviate or eliminate one or more symptoms of HIV infection and/or to reduce viral load in a patient. In certain embodiments, the terms “treating” and “treatment” also encompass the administration of a compound or composition according to the present embodiments disclosed herein post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to the present embodiments disclosed herein to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. The terms “treating” and “treatment” also encompass the administration of a compound or composition according to the present embodiments disclosed herein before the exposure of the individual to the virus (also called pre-exposure prophylaxis or PrEP) , to prevent HIV infection from taking hold if the individual is exposed to the virus and/or to keep the virus from establishing a permanent infection and/or to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood. The terms “treating” and “treatment” also encompass the administration of a compound or composition according to the present embodiments disclosed herein both before and after the exposure of the individual to the virus.
As used herein, the terms “preventing” and “prevention” refer to the administration of a compound, composition, or pharmaceutically salt according to the present disclosure pre-or post-exposure of the human to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood. The terms also refer to prevention of the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood. The terms include both pre-exposure prophylaxis (PrEP) , as well as post-exposure prophylaxis (PEP) and event driven or “on demand” prophylaxis. The terms also refer to prevention of perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. The terms also refer to prevention of transmission of HIV through blood transfusion.
All weight percentages (i.e., “%by weight” and “wt. %” and w/w) referenced herein, unless otherwise indicated, are relative to the total weight of the mixture or composition, as the case can be.
“Alkyl” refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms, and which is attached to an atom by a single bond. Alkyls with a number of carbon atoms ranging from 1 to 12 are included. An alkyl group with 1 to 12 carbon atoms is a C1-C12 alkyl, an alkyl group with 1 to 10 carbon atoms is a C1-C10 alkyl, an alkyl group with 1 to 6 carbon atoms is a C1-C6 alkyl and an alkyl group with 1 to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and C1 alkyl (i.e., methyl) . A C1-C6 alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and C1-C6 alkyls, but also includes C7, C8, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise, an alkyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Alkylene” refers to a fully saturated, straight or branched divalent hydrocarbon, and having from one to twelve carbon atoms. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, and the like. Each alkylene terminus is attached to an atom by a single bond. The points of attachment of the alkylene chain can be one or two atoms. Unless stated otherwise, an alkylene chain can be unsubstituted or substituted with a substituent disclosed herein.
“Alkenyl” refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to an atom by a single bond. Alkenyl groups with a number of carbon atoms ranging from 2 to 12 are included. An alkenyl group with 2 to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl group with 2 to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group with 2 to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl group with 2 to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C6 alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, C8, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl) , 1-propenyl, 2-propenyl (allyl) , iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise, an alkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Alkenylene” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene include ethenylene, propenylene, butenylene, and the like. Each terminus of the alkenylene chain is attached to an atom by a single bond. The points of attachment of the alkenylene chain can be through one two atoms. Unless stated otherwise, an alkenylene chain can be unsubstituted or substituted with a substituent disclosed herein.
“Alkynyl” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to an atom by a single bond. Alkynyl groups with a number of carbon atoms ranging from 2 to 12 are included. An alkynyl group having 2 to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl group with 2 to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group with 2 to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl group with 2 to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes C6 alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, C8, C9 and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise, an alkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Alkynylene” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 alkynylene include ethynylene, propynylene, butynylene, and the like. Each terminus of the alkynylene chain is attached to an atom through a single bond. The points of attachment of the alkynylene chain can be through one or two atoms. Unless stated otherwise, an alkynylene chain can be unsubstituted or substituted with a substituent disclosed herein.
“Alkoxy” refers to a radical of the formula -OR^a where R^a is an alkyl radical as defined herein. Unless stated otherwise, an alkoxy group can be unsubstituted or substituted with a substituent disclosed herein. In some embodiments, “alkoxy” is (C1-C6) alkoxy. In some embodiments, “alkoxy” is (C1-C4) alkoxy. In some embodiments, “alkoxy” is methoxy, ethoxy.
“Alkylamino” refers to a radical of the formula -NHR^a or -NR^aR^b, where R^a or R^b is an alkyl, alkenyl or alknyl radical as defined herein. Unless stated otherwise, an alkylamino group can be unsubstituted or substituted with a substituent disclosed herein. In some embodiments, “alkylamino” is (C1-C6) alkylamino; In some embodiments, “alkylamino” is (C1-C4) alkylamino; In some embodiments, “alkylamino” is methylamino or dimethylamino.
“Alkylthio” refers to a radical of the formula -SR^a where R^a is an alkyl, alkenyl or alknyl radical as defined herein. Unless stated otherwise, an alklthio group can be unsubstituted or substituted with a substituent disclosed herein. In some embodiments, “alkylthio” is (C1-C6) alkylthio; In some embodiments, “alkylthio” is (C1-C4) alkylthio; In some embodiments, “alkylthio” is methylthio or ethylthio.
“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. In some embodiments, “Aryl” comprise 6 to 10 carbon atoms, i.e. C6-C10 aryl. The aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aceanthrylenyl, acenaphthylenyl, acephenanthrylenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl, phenalenyl, phenanthrenyl, phenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise, the aryl can be unsubstituted or substituted with a substituent disclosed herein.
“Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to an atom by a single bond. In some embodiments, “cycloalkyl” comprises 3 to 7 carbon atoms, i.e. (C3-C7) cycloalkyl. In some embodiments, cycloalkyl” is (C3-C6) cycloalkyl. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. Unless stated otherwise, a cycloalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Aryloxy” refers to a radical of the formula -O (aryl) , wherein the aryl radical is as defined herein. Aryloxy includes, but are is not limited to, phenoxy (-O (phenyl) ) . Unless stated otherwise, an aryloxy group can be unsubstituted or substituted with a substituent disclosed herein.
“Cycloalkenyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting of carbon and hydrogen atoms and having one or more carbon-carbon double bonds. Cycloalkenyl can include fused or bridged ring systems, having from three to twenty carbon atoms, in some embodiments having from three to ten carbon atoms. A cycloalkenyl group is attached to an atom by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo [2.2.1] hept-2-enyl and the like. Unless stated otherwise, a cycloalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Cycloalkynyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from five to twenty carbon atoms, in some embodiments having from five to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless stated otherwise, a cycloalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Heterocyclyl” refers to a 3-to 20-membered non-aromatic, partially unsaturated, or aromatic ring radical which includes two to twelve carbon atoms and from one to six nitrogen, oxygen or sulfur heteroatoms. Heterocycly include heteroaryls as defined herein. Unless stated otherwise, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. In some embodiments, “Heterocyclyl” comprises 2 to 6 carbon atoms, i.e. (C2-C6) heterocyclyl. Examples of heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Unless stated otherwise, a heterocyclyl group can be unsubstituted or substituted with a substituent disclosed herein. In some embodiments,
“Heteroaryl” refers to a 5-to 20-membered ring system radical including hydrogen atoms, one to thirteen carbon atoms, one to six nitrogen, oxygen or sulfur heteroatoms, and at least one aromatic ring. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl) . Unless stated otherwise, a heteroaryl group can be unsubstituted or substituted. In some embodiments, “heteroaryl” has 1-9 carbon atoms, i.e. (C1-C9) heteroaryl; In some embodiments, “heteroaryl” has 1-5 carbon atoms, i.e. (C1-C5) heteroaryl.
“Cycloalkylalkyl” refers to a radical of the formula -Rb-Rd where Rb is an alkylene group as defined herein and Rd is a cycloalkyl radical as defined herein. Such as (C3-C7) cycloalkyl- (C1-C6) alkyl. Unless stated otherwise, a cycloalkylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined herein and Rc is an aryl radical as defined herein, such as (C6-C10) aryl- (C1-C6) alkyl, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise, an arylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Heterocyclylalkyl” refers to a radical of the formula -Rb-Rd where Rb is an alkylene group as defined herein and Rd is heterocyclyl radical as defined herein. Such as (C2-C6) heterocyclyl- (C1-C6) alkyl. Unless stated otherwise, a heterocyclylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
“Heteroarylalkyl” refers to a radical of the formula -Rb-Rd where Rb is an alkylene group as defined herein and Rd is heteroaryl radical as defined herein. Such as (C1-C9) heteroaryl- (C1-C6) alkyl. Unless stated otherwise, a heteroaryl group can be unsubstituted or substituted with a substituent disclosed herein.
“Halo” , “Hal” , or “halogen” refers to Br, Cl, F, or I.
“Amino” refers to -NH₂.
“Nitro” refers to -NO₂.
“Hydroxy” refers to -OH.
“Cyano” refers to -CN.
The term “substituted” , as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =O) , then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N) . “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
When any variable (e.g., R⁰) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁰ moieties, then the group may optionally be substituted with up to two R⁰ moieties and R⁰ at each occurrence is selected independently from the definition of R⁰. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
The Compounds of the Invention
In one aspect, the invention provided a compound having formula I:
a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylamino, (C1-C6) alkylthio, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl, (C1-C9) heteroaryl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C2-C6) heterocyclyl- (C1-C6) alkyl, (C6-C10) aryl- (C1-C6) alkyl or (C1-C9) heteroaryl- (C1-C6) alkyl; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; or R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;
each of n and m is independently 4, 5, 6, 7, 8, 9 or 10;
R is H, D, halo, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl or (C1-C9) heteroaryl; R is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;
G is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl or (C1-C9) heteroaryl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;
or G isor one or more deuterium substituted
or G is H, and at the same time, at least one R¹ is independently hydroxy;
each of Y¹ and Y² is independently -OH, - (C1-C6) alklene-OH, -C (=O) -OH, -C (=O) H, -C (=O) OR⁵, -S (=O) ₂OH, -S (=O) ₂NH₂,
R⁵ is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl, (C1-C9) heteroaryl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C2-C6) heterocyclyl- (C1-C6) alkyl, (C6-C10) aryl- (C1-C6) alkyl or (C1-C9) heteroaryl- (C1-C6) alkyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkoxy or (C1-C6) haloalkoxy;
each of R⁶ and R⁷ is independently H, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl; each of R⁶ and R⁷ is optionally and independently substitutled with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkoxy or phenyl.
In some embodiments, wherein G is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1, 4-dioxanyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, or cyano.
In some embodiments, wherein G is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, or cyano.
In some embodiments, wherein G is methyl, ethyl or cyclopropyl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, or cyano.
In some embodiments, wherein each of Y¹ and Y² is independently -OH, - (C1-C6) alkyl-OH, -C (=O) -OH, -C (=O) H, -C (=O) OR⁵, -S (=O) ₂OH or -S (=O) ₂NH₂;
R⁵ is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl, (C1-C9) heteroaryl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C2-C6) heterocyclyl- (C1-C6) alkyl, (C6-C10) aryl- (C1-C6) alkyl or (C1-C9) heteroaryl- (C1-C6) alkyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkoxy or (C1-C6) haloalkoxy.
In some embodiments, wherein each of Y¹ and Y² is independently -OH, -CH₂-OH, -CH₂CH₂-OH, -C (=O) -OH, -C (=O) H, -C (=O) OR⁵;
R⁵ is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1, 4-dioxanyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, methoxy, difluoromethoxy or trifluoromethoxy.
In some embodiments, wherein each of Y¹ and Y² is independently -OH, -CH₂-OH, -C (=O) -OH, - C(=O) H, -C (=O) OR⁵;
R⁵ is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1, 4-dioxanyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, cyano, methoxy, difluoromethoxy or trifluoromethoxy.
In some embodiments, wherein each of Y¹ and Y² is independently -CH₂-OH, -C (=O) -OH or -C (=O) OR⁵;
R⁵ is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, cyano, methoxy, difluoromethoxy or trifluoromethoxy.
In some embodiments, wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, halo, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylamino, (C1-C4) alkylthio, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C2-C5) heterocyclyl, phenyl, (C3-C6) cycloalkylmethyl, (C3-C6) cycloalkylethyl, (C2-C6) heterocyclylmehtyl, (C2-C6) heterocyclylehtyl, benzyl; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; or R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, or cyano;
each of n and m is independently 4, 5, 6, 7, 8, 9 or 10.
In some embodiments, wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, F, Cl, Br, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylamino, (C1-C4) alkylthio, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C2-C5) heterocyclyl, phenyl, (C3-C6) cycloalkylmethyl, (C3-C6) cycloalkylethyl, (C2-C6) heterocyclylmehtyl, (C2-C6) heterocyclylehtyl, benzyl; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; or R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br or cyano;
each of n and m is independently 4, 5, 6, 7, 8 or 9.
In some embodiments, wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, F, Cl, Br, F, Cl, Br, methyl, ethyl, methoxy, ethoxy; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; or R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br or cyano;
In some embodiments, when R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group, “R¹ and R² on the different atoms” means R¹ and R² are separated by 2, 3 or 4 atoms.
In some embodiments, when R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group, R³ and R⁴ on the different atoms means R³ and R⁴ are separated by 2, 3 or 4 atoms.
In some embodiments, when R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group, the number of the intervening atoms between R¹ and R³ is 3 or 4.
each of n and m is independently 4, 5, 6, 7, 8 or 9.
In some embodiments, wherein R is H, D, F, Cl, Br, cyano, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C2-C5) heterocyclyl, (C6-C10) aryl or (C1-C9) heteroaryl; R is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano.
In some embodiments, wherein R is H, D, F, Cl, Br, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methyl-d, methyl-d2 or methyl-d3.
In some embodiments, the compound of the invention has formula II, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
wherein each of k, g, j and v is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.
In some embodiments, the compound of the invention has formula III, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
wherein each of g1 and j1 is independently 3, 4, 5, 6 or 7.
In some embodiments, the compound of the invention has formulae IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
In some embodiments, the compound of the invention has formulae V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
In some embodiments, the compound of the invention has formulae VI, VII, VIII, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
In some embodiments, the compound of the invention has formulae IX, X, XI or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
In some embodiments, the compound of the invention has the following structure or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Pharmaceutical Compositions
In other aspect, the invention also provided a pharmaceutical composition comprising a compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof and a pharmaceutically acceptable vehicle, excipient, or diluent.
The invention provides pharmaceutical compositions comprising a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical compositions preferably comprise a therapeutically-effective amount of one or more of the carboxy-cyclopropyl undecanol compounds or pharmaceutically acceptable salts thereof described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) , tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption) , boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
The phrase “therapeutically-effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the sub-population of cells is in an animal. In certain embodiments, the sub-population of cells is in a human.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA) , sorbitol, tartaric acid, phosphoric acid, and the like.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual) , rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, or most preferably from about 10 percent to about 30 percent.
In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth) , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like) , the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose) , lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose) , surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient (s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils) , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides) . Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
The phrases “systemic administration, ” “administered systemically, ” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents) , the effective amount may be less than when the agent is used alone.
If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
Kits for Use in Medical Applications
Another aspect of the invention provides a kit for treating a disorder. The kit comprises: i) instructions for treating a liver disorder, such as nonalcoholic steatohepatitis; and ii) a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof, such as Compound A. The kit may comprise one or more unit dosage forms containing an amount of a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof, that is effective for treating said liver disorder.
The description above describes multiple aspects and embodiments of the invention, including methods of using a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof, compositions comprising a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof, and kits. The patent application specifically contemplates all combinations and permutations of the aspects and embodiments.
Methods of the Invention
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for inhibiting ATP-citrate lyase or activating AMP-activated protein kinase.
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for use in preventing, managing, treating or lessening a disorder relating to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof.
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for use in preventing, managing, treating or lessening a disorder by increasing HDL levels.
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for use in preventing, managing, treating or lessening a disorder by lowering LDL levels.
In other aspect, the invention also provided the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition comprising the compound for use in preventing, managing, treating or lessening aging, Alzheimer’s Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson’s disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient.
In other aspect, the invention also provided use of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition compirisng the compound in the manufacture of a medicament for preventing, managing, treating or lessening a disorder relating to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof.
In other aspect, the invention also provided use of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition compirisng the compound in the manufacture of a medicament for preventing, managing, treating or lessening a disorder by increasing HDL levels.
In other aspect, the invention also provided use of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition compirisng the compound in the manufacture of a medicament for preventing, managing, treating or lessening a disorder by lowering LDL levels.
In other aspect, the invention also provided use of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition compirisng the compound in the manufacture of a medicament for preventing, managing, treating or lessening aging, Alzheimer’s Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson’s disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient.
In other aspect, the invention also provided a method for preventing, managing, treating or lessening a disorder realting to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof, comprising administering to a mammal in need thereof an effective amount of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition comprising the compound.
In other aspect, the invention also provided a method for preventing, managing, treating or lessening a disorder by increasing HDL levels comprising administering to a mammal in need thereof an effective amount of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition comprising the compound.
In other aspect, the invention also provided a method for preventing, managing, treating or lessening a disorder by lowering LDL levels, comprising administering to a mammal in need thereof an effective amount of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition comprising the compound.
In other aspect, the invention also provided a method for preventing, managing, treating or lessening aging, Alzheimer’s Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson’s disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient, comprising administering to a patient in need of such treatment or prevention a therapeutically or proplyleufrally effective amount of the compound of the invention or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition comprising the compound.
In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof in the range from about 1 mg to about 1000 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof in the rage from about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, or about 1 mg to about 300 mg.
In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof in a daily dose ranging from about 1 mg to about 1000 mg or any amount ranging from and to these values. In some embodiments, the compound of the invention is administered to the subject in need thereof at a daily dose of about 1000 mg, about 950 mg, about 900 mg, about 850 mg, about 800 mg, about 750 mg, about 700 mg, about 650 mg, about 600 mg, about 550 mg, about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.
In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof once a day at a dose of about 1 mg to about 1000 mg or any amount ranging from and to these values.
In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof twice a day, each dose comprising the compound of the invention in about 1 mg to about 500 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof twice a day, each dose comprising the compound of the invention in about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.
In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof three times a day, each dose comprising the compound of the invention in about 1 mg to about 400 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof three times a day, each dose comprising the compound of the invention in about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.
In some embodiments of the methods as disclosed herein, the methods further comprise administering an effective amount of another pharmaceutically active agent. In some embodiments, the other pharmaceutically active agent is administered concurrently or sequentially with (prior or subsequent to) the administration of the compound of the invention or the composition of the invention. In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile-acid-binding-resin, a niacin, an anti-obesity drug, a hormone, a tyrophostine, a sulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein A-I agonist, apolipoprotein E agonist; a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-raising drug, an HDL enhancer, a regulator of the apolipoprotein A-I gene, a regulator of the apolipoprotein A-IV gene, a regulator of the apolipoprotein gene, an ATP citrate lyase modulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylase modulator, or an acetyl-CoA carboxylase allosteric inhibitor. In some embodiments, the other pharmaceutically active agent is lovastatin. In some embodiments, the other pharmaceutically active agent is sorafenib; taxol; carotuximab; pembrolizumab; lenvatinib; avelumab; durvalumab; tremelimumab; nivolumab; tazemetostat; cemiplimab; ABX196; T-cell receptor (TCR) immune cell therapy agent; IBI-302; namodenoson; MM-310; a tumor-injected oncolytic virus or gene-modified oncolytic virus such as, but not limited to, telomelysin and imlygic; or an immunomodulating gene-therapy agent such as MDA-7/IL-24, GLIPR1/RTVP-1, and REIC/Dkk-3.
In some embodiments of the methods as disclosed herein, the methods further comprises administering two or more other pharmaceutically active agents. In some embodiments, the methods of the invention comprise administering two or more other pharmaceutically active agents, optionally in combination. In some embodiments, the two or more other pharmaceutically active agents are oncolytic agents, such as, but not limited to, nanatinostat and valganciclovir. In other embodiments, the methods of the invention comprise orally administering a compound of the invention and further comprise administering a tumor-injected oncolytic treatment. In some embodiments, the combination is administered orally.
In some embodiments, the other pharmaceutically active agent is cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumub, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination (NS-0200) , IMM-124E, RG-125, vitamin E, cysteamine, selonsertib, losartan, R05093151, pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201/BMS-986263, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, solithromycin, 99m technetium-mebrofenin, tropifexor, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, or seladelpar.
In some embodiments of the methods as disclosed herein, the methods for treating or preventing a disease comprise administering an effective amount of (a) a compound of the invention and (b) another pharmaceutically active agent that is sorafenib, taxol, lenvatinib, tazemetostat, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, Rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, Berberine, L-Carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, Olesoxime, AKR-001, Seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, R07119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, R07070179, axitinib, sunitinib, or zotiraciclib citrate.
In some embodiments of the methods as disclosed herein, the methods for treating or preventing a disease comprise administering an effective amount of (a) a compound of the invention and (b) another pharmaceutically active agent that is sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, a gene-modified oncolytic virus, or an immunomodulating gene-therapy agent.
In some embodiments of the methods as disclosed herein, the methods further comprise administering radiation therapy to the subject. In some embodiments, the radiation therapy is gamma ray radiation therapy or x-ray radiation therapy. In some embodiments, the radiation therapy is administered via a gamma ray or x-ray radiation apparatus.
In some embodiments, the radiation therapy is administered concurrently with, prior to or subsequent to the administration of the compound of the invention or the composition of the invention. In some embodiments, the radiation therapy is administered prior to or subsequent to the administration of the compound of the invention or the composition of the invention.
Synthesis Examples
All reactions were carried out under an inert atmosphere of nitrogen or argon unless otherwise noted. DMF, DMSO, THF, DCM, DMAc, MeOH (99.9%, extra dry) was used as received. All other reagents were purchased commercially and used as received, unless otherwise noted. NMR spectra were recorded with Bruker spectrometers. 1H (400 MHz) and NMR chemical shifts are reported relative to internal TMS (δ = 0.00 ppm) or to residual protiated solvent. Data are presented as follows: chemical shift (ppm) , multiplicity (s= singlet, d =doublet, t = triplet, q = quartet, sept = septet, m = multiplet, br = broad) , coupling constant J (Hz) and integration.
Method A: Agilent 1260-6125B, Waters CORTECS C18+ column (4.6 mm × 30mm, 2.7μm) , Mobile phase A: . 0.01%TFA in water (include 10%ACN) ; Mobile phase B: 0.01%TFA in ACN; Flow rate: 3.0 mL/min; Gradient: 5-95%B (0.0-1.1 min) , 95%B (1.1-1.52 min) , 95-5%B (1.52-2.00 min) , posttime0.5min.
Method B: Shimadzu LCMS-2020, Waters CORTECS C18+ column (4.6 mm × 30mm, 2.7μm) , Mobile phase A: . 0.05%TFA in water (include 10%ACN) ; Mobile phase B: 0.05%FA in ACN; Flow rate: 3.0 mL/min; 5-95%B (0.0-1.1 min) , 95%B (1.1-1.50 min) , 95-5%B (1.50-1.52 min) , 5%B (1.52-2.00 min) .
Synthesis of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (M1)
Step 1: Synthesis of ethyl 7-bromo-2, 2-dimethylheptanoate
To a solution of ethyl 2-methylpropanoate (4.2 g, 36.16 mmol) in dry THF (40 mL) under N₂ atmosphere at -40 ℃ was added LDA (18.08 mL, 36.16 mmol) . The reaction mixture was stirred at -40 ℃ for 1 hour and then 1, 5-dibromopentane (11.64 g, 50.62 mmol) was added. The reaction mixture was stirred -40 ℃for 0.5 hour and then the reaction mixture was stirred for overnight at 25 ℃. The reaction mixture was poured into ice-water (20 mL) . The aqueous layer was extracted with EA (50 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) . The product was obtained as yellow oil (4.6 g, 48%) .
¹HNMR (CHLOROFORM-d) δ: 4.11 (q, J=7.1 Hz, 2H) , 3.37-3.43 (m, 2H) , 1.79-1.92 (m, 2H) , 1.49-1.55 (m, 2H) , 1.37-1.46 (m, 2H) , 1.25 (t, J=7.1 Hz, 5H) , 1.16 (s, 6H) .
Step 2: Synthesis of diethyl 8-cyano-2, 2, 14, 14-tetramethyl-8-tosylpentadecane dioate
To a solution of TosMIC (1.29 g, 6.60 mmol) and Bu₄NI (0.24 g, 0.66 mmol) in DMSO (50 mL) at 0 ℃ was added NaH (0.79 g, 19.80 mmol) under N₂ atmosphere. The reaction mixture was stirred at 25 ℃ for 30 min and then ethyl 7-bromo-2, 2-dimethylheptanoate (3.5 g, 13.20 mmol) was added. The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was quenched with ice-water (40 mL) at 0 ℃. The mixture was extracted with EA (50 mL × 2) . The combined organic layer was washed with 10%NH₄Cl solution (20 mL × 3) , brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) . The product was obtained as yellow oil (3.07 g, 41%) .
¹HNMR (400 MHz, CHLOROFORM-d) δ = 7.85 (d, J = 8.3 Hz, 2H) , 7.41 (d, J = 8.0Hz, 2H) , 4.14 -4.10 (m, 4H) , 2.49 (s, 3H) , 2.02 -1.84 (m, 4H) , 1.59 -1.41 (m, 8H) , 1.28 -1.23 (m, 12H) , 1.17 -1.13 (m, 12H) .
Step 3: Synthesis of 1-ethyl 15-methyl 2, 2, 14, 14-tetramethyl-8-oxopentadecane dioate
To a solution of diethyl 8-cyano-2, 2, 14, 14-tetramethyl-8-tosylpentadecanedioate (3.0 g, 5.32 mmol) in DCM (40 mL) was added HCl (15 mL) at room temperature. The reaction mixture was stirred at 25 ℃ for 4 hours. The reaction mixture diluted with H₂O (30 mL) . The aqueous layer was extracted with DCM (40 mL ×2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) . The product was obtained as colorless oil (1.90 g, 89%) .
¹HNMR (CHLOROFORM-d) δ: 4.11 (q, J=7.1 Hz, 4H) , 2.37 (t, J=7.4 Hz, 4H) , 1.52 (td, J=15.5, 7.1 Hz, 8H) , 1.18-1.31 (m, 14H) , 1.15 (s, 12H) .
Step 4: Synthesis of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate
To a solution of 1-ethyl 15-methyl 2, 2, 14, 14-tetramethyl-8-oxopentadecanedioate (1.9 g, 4.77 mmol) in dry MeOH (20 mL) was added NaBH₄ (0.18 g, 4.77 mmol) at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred at 0 ℃ for 4 hours. The reaction mixture was poured into ice-water (20 mL) . The aqueous layer was extracted with EA (30 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) =5/1) . The product was obtained as colorless oil. (1.90 g, 99%)
¹HNMR (400 MHz, CHLOROFORM-d) δ = 4.15 -4.07 (m, 4H) , 3.56 (br s, 1H) , 1.54 -1.47 (m, 4H) , 1.47 -1.32 (m, 8H) , 1.29 -1.20 (m, 14H) , 1.15 (s, 12H) .
Synthesis of Bempedoic Acid
To a solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (1.00 g, 2.50 mmol) in MeOH (8 mL) was added 20%KOH aq. (2 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brain, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 3/2) . The product was obtained as white solid (750 mg, 87%) .
MS (ESI, pos. ion) m/z: 345.3 [M+1] ⁺.
¹HNMR (DMSO-d₆) δ: 11.99 (br s, 2H) , 4.20 (br d, J=5.0 Hz, 1H) , 1.38-1.47 (m, 4H) 1.12-1.37 (m, 16H) , 1.06 (s, 12H) .
Example 1: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid (0004)
Step 1: Synthesis of diethyl 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioate
To a solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (200 mg, 0.50 mmol) in DCM (2 mL) was added CF₃SO₃Me (0.08 mL, 0.75 mmol) and 2, 6-di-tert-butylpyridine (0.22 mL, 1.00 mmol) . The reaction mixture was stirred for 18 hours at 40 ℃. The reaction mixture was diluted with DCM (20 mL) and washed with H₂O (10 mL) , brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (150 mg, 75%) .
Step 2: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid
To a solution of diethyl 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioate (150 mg, 0.36 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (110 mg, 85%) .
MS (ESI, pos. ion) m/z: 359.1 [M+1] ⁺;
¹HNMR (DMSO-d₆) δ: 11.14-12.65 (m, 2H) , 3.19 (s, 3H) , 3.08 (m, 1H) , 1.32-1.46 (m, 8H) , 1.15-1.29 (m, 12H) , 1.07 (s, 12H) .
Example 2: Synthesis of 8-ethoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid (0010)
Step 1: Synthesis of diethyl 8-ethoxy-2, 2, 14, 14-tetramethylpentadecanedioate
To the solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (150 mg, 0.37 mmol) in DCM (2 mL) was added 2, 6-Di-tert-Butylpridine (107.46 mg, 0.56 mmol) and Ethyl Triflate (133.40 mg, 0.75 mmol) . Then the mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was diluted with DCM (20 mL) and washed with H₂O (10 mL) , brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EA=20: 1 to give diethyl 8-ethoxy-2, 2, 14, 14-tetramethylpentadecanedioate (162 mg, 0.34 mmol, 91%) as yellow oil liquid.
¹HNMR (400 MHz, CHLOROFORM-d) δ = 4.17 -4.06 (m, 4H) , 3.51 -3.41 (m, 2H) , 3.23 -3.12 (m, 1H) , 1.53 -1.47 (m, 4H) , 1.46 -1.39 (m, 4H) , 1.33 (br d, J = 14.4 Hz, 18H) , 1.20 -1.17 (m, 3H) , 1.17 -1.13 (m, 12H) .
Step 2: Synthesis of 8-ethoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid
To the solution of diethyl 8-ethoxy-2, 2, 14, 14-tetramethylpentadecanedioate (162 mg, 0.38 mmol) in MeOH (1.6 mL) was added KOH (0.4 mL, 20%in H₂O) . Then the mixture was stirred at 70 ℃ overnight. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EA=4: 1 to give 8-ethoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid (110 mg, 0.30 mmol, 78%) as yellow oil liquid.
MS (ESI, pos. ion) m/z: 373.1 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 12.22 -11.77 (m, 2H) , 3.42 -3.36 (m, 2H) , 3.20 -3.14 (m, 1H) , 1.46 -1.39 (m, 4H) , 1.38 -1.31 (m, 4H) , 1.28 -1.13 (m, 12H) , 1.10 -1.02 (m, 15H) .
Example 3: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioic-7, 7, 9, 9-d₄ acid (0011)
Step 1: Synthesis of diethyl 2, 2, 14, 14-tetramethyl-8-oxopentadecanedioate-7, 7, 9, 9-d₄
To a solution of diethyl 2, 2, 14, 14-tetramethyl-8-oxopentadecanedioate (500 mg, 1.25 mmol) in CDCl₃ (3 mL) was added 1, 3, 4, 6, 7, 8-hexahydro-2H-pyrimido [1, 2-a] pyrimidine (18 mg, 0.13 mmol) . The reaction mixture was stirred for 48 hours. The reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was used for next step directly (460 mg, 91%) .
Step 2: Synthesis of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 9, 9-d₄
To a solution of diethyl 2, 2, 14, 14-tetramethyl-8-oxopentadecanedioate-7, 7, 9, 9-d4 (200 mg, 0.50 mmol) in dry MeOH (2 mL) was added NaBH₄ (19 mg, 0.05 mmol) at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred for 4 hours at 0 ℃. The reaction mixture was poured into ice-water (10 mL) . The aqueous layer was extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (170 mg, 84%) .
Step 3: Synthesis of diethyl 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 9, 9-d₄
To a solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 9, 9-d₄ (170 mg, 0.42 mmol) in DCM (2 mL) was added CF₃SO₃Me (138 mg, 0.84 mmol) and 2, 6-di-tert-butylpyridine (121 mg, 0.63 mmol) . The reaction mixture was stirred for 18 hours at 40 ℃. The reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (130 mg, 74 %) .
Step 4: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioic-7, 7, 9, 9-d₄ acid
To a solution of diethyl 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 9, 9-d₄ (130 mg, 0.31 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (45 mg, 40%) .
MS (ESI, pos. ion) m/z: 363.3 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d6) δ = 12.00 (br s, 2H) , 3.18 (s, 3H) , 3.06 (d, J = 4.8 Hz, 1H) , 1.46 -1.38 (m, 4H) , 1.22 -1.27 (m, 12H) , 1.06 (s, 12H) .
Example 4: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioic-7, 7, 8, 9, 9-d₅ acid (0012)
Step 1: Synthesis of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 8, 9, 9-d₅
To a solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 8, 9, 9-d5 (230 mg, 0.57 mmol) in MeOH (2 mL) was added NaBD₄ (24 mg, 0.57 mmol) at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred for 4 hours at 0 ℃. The reaction mixture was poured into ice-water (10 mL) . The aqueous layer was extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (220 mg, 95%) .
Step 2: Synthesis of diethyl 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 8, 9, 9-d₅
To a solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 8, 9, 9-d₅ (220 mg, 0.57 mmol) in DCM (2 mL) was added CF₃SO₃Me (187 mg, 1.14 mmol) and 2, 6-di-tert-butylpyridine (164 mg, 0.85 mmol) . The reaction mixture was stirred for 18 hours at 40 ℃. The reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (170 mg, 71%) .
Step 3: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioic-7, 7, 8, 9, 9-d₅ acid
To a solution of diethyl 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioate-7, 7, 8, 9, 9-d5 (170 mg, 0.41 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brain (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (70 mg, 47%) .
MS (ESI, pos. ion) m/z: 364.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d6) δ = 12.11 -11.89 (m, 2H) , 3.18 (s, 3H) , 1.46 -1.39 (m, 4H) , 1.22 ～1.27 (m, 12H) , 1.06 (s, 12H) .
Example 5: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioic-8-d acid (0013)
Step 1: Synthesis of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate-8-d
To a solution of diethyl 2, 2, 14, 14-tetramethyl-8-oxopentadecanedioate (200 mg, 0.50 mmol) in MeOH (2 mL) was added NaBD₄ (21 mg, 0.50 mmol) at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred for 4 hours at 0 ℃. The reaction mixture was poured into ice-water (10 mL) . The aqueous layer was extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (190 mg, 94%) .
Step 2: Synthesis of diethyl 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioate-8-d
To a solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate-8-d (160 mg, 0.40 mmol) in DCM (2 mL) was added CF₃SO₃Me (130 mg, 0.80 mmol) and 2, 6-di-tert-butylpyridine (114 mg, 0.60 mmol) . The reaction mixture was stirred for 18 hours at 40 ℃. The reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (130 mg, 78%) .
Step 3: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioic-8-d acid
To a solution of diethyl 8-methoxy-2, 2, 14, 14-tetramethylpentadecanedioate-8-d (130 mg, 0.31 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (70 mg, 47%) .
¹HNMR (400 MHz, DMSO-d6) δ = 11.99 (s, 2H) , 3.18 (s, 3H) , 1.45 -1.32 (m, 8H) , 1.28 -1.13 (m, 12H) , 1.06 (s, 12H) .
Example 6: Synthesis of 8- (methoxy-d3) -2, 2, 14, 14-tetramethylpentadecanedioic acid (0014)
Step 1: Synthesis of diethyl 8- (methoxy-d3) -2, 2, 14, 14-tetramethylpentadecane dioate
To a solution of NaH (39.94 mg, 1.00 mmol) in DMF (2 mL) in the microwave tube was added diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (100 mg, 0.25 mmol) at 0 ℃. The reaction mixture was stirred for 10 min and then CD₃I (0.06 mL, 1.00 mmol) was added. The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was quenched with H₂O (10 mL) and extracted with EA (20 mL) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (40 mg, 38.37%) .
Step 2: Synthesis of 8- (methoxy-d3) -2, 2, 14, 14-tetramethylpentadecanedioic acid
To a solution of diethyl 8- (methoxy-d3) -2, 2, 14, 14-tetramethylpentadecanedioate (40 mg, 0.10 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (24 mg, 69%) .
MS (ESI, pos. ion) m/z: 362.1 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ: 12.00 (br s, 2H) , 3.07 (t, J=5.5 Hz, 1H) , 1.32-1.46 (m, 8H) , 1.15-1.26 (m, 12H) , 1.06 (s, 12H) .
Example 7: Synthesis of 8-cyclopropoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid (0015)
Step 1: Synthesis of diethyl 2, 2, 14, 14-tetramethyl-8- (vinyloxy) pentadecanedioate
To a solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (340 mg, 0.85 mmol) in ethoxyethene (5 mL) was added o-Phenanthroline (77 mg, 0.42 mmol) and Pd (OAc) ₂ (95 mg, 0.42 mmol) under N₂ atmosphere. The reaction mixture was stirred for overnight at 45 ℃. The reaction mixture was diluted with EA (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (110 mg, 30%) .
Step 2: Synthesis of diethyl 8-cyclopropoxy-2, 2, 14, 14-tetramethylpentadecane dioate
To a solution of diethyl 2, 2, 14, 14-tetramethyl-8- (vinyloxy) pentadecanedioate (75 mg, 0.18 mmol) and diiodomethane (193 mg, 0.72 mmol) in DCM (2 mL) under N₂ atmosphere was added diethylzinc (0.72 mL, 0.72 mmol) at 0 ℃. The reaction mixture was stirred for 4 h at 0 ℃. The reaction mixture was quenched with saturated NH₄Cl solution (10 mL) and extracted with DCM (20 mL × 2) . The combined organic layer was washed with H₂O (10 mL) , brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (40 mg, 51%) .
Step 3: Synthesis of 8-cyclopropoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid
To a solution of diethyl 8-cyclopropoxy-2, 2, 14, 14-tetramethylpentadecanedioate (40 mg, 0.09 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (29 mg, 83%) .
MS (ESI, pos. ion) m/z: 384.1 [M+1] ⁺.
¹HNMR (DMSO-d₆) δ: 12.00 (br d, J=2.9 Hz, 2H) , 3.22-3.29 (m, 2H) , 1.33-1.47 (m, 8H) , 1.16-1.27 (m, 12H) , 1.06 (s, 12H) , 0.36-0.44 (m, 4H) .
Example 8: Synthesis of 2, 2, 14, 14-tetramethyl-8- (trifluoromethoxy) pentadecane dioic acid (0016)
Step 1: Synthesis of diethyl 2, 2, 14, 14-tetramethyl-8- (trifluoromethoxy) pentadecanedioate
To a 0.15 M solution of 1-TrifluoroMethyl-1, 2-benziodoxol-3 (1H) -one (143 mg, 0.45 mmol) in CDCl₃ (3 mL) was added (OTf) ₂Zn (45 mg, 0.12 mmol) and diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (500 mg, 1.25 mmol) under N₂ atmosphere. The reaction mixture was stirred for 3 d. TLC (PE: EA=10: 1) showed that R1 was not consumed but had new spot was detected. The reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (17 mg, 3 %) .
Step 2: Synthesis of 2, 2, 14, 14-tetramethyl-8- (trifluoromethoxy) pentadecane dioic acid
To a solution of diethyl 2, 2, 14, 14-tetramethyl-8- (trifluoromethoxy) pentadecanedioate (17 mg, 0.04 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (10 mL × 2) . The organic layer was washed with brine (5 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (13 mg, 87%) .
MS (ESI, pos. ion) m/z: 413.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 12.29 -11.73 (m, 2H) , 4.34 -4.27 (m, 1H) , 1.64 -1.51 (m, 4H) , 1.46 -1.38 (m, 4H) , 1.30 -1.15 (m, 12H) , 1.07 (s, 12H) .
Example 9: Synthesis of 8-methoxy-2, 2, 14, 14-tetramethylpentadecane-1, 15-diol (0017)
To the solution of ethyl 15-ethoxy-8-methoxy-2, 2, 14, 14-tetramethyl-15-oxopentadecanoate (120 mg, 0.29 mmol) in dry THF (1.5 mL) was added LiAlH₄ (44 mg, 1.16 mmol) at 0 ℃. The mixture was stirred at 20 ℃ overnight. Ice water was added slowly to quench the reaction, and then the mixture was extracted with DCM (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EA=6: 1 to give 8-methoxy-2, 2, 14, 14-tetramethylpentadecane-1, 15-diol (74 mg, 0.22 mmol, 77%) as colorless oil liquid.
MS (ESI, pos. ion) m/z: 331.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ: 4.38 (t, J=5.3 Hz, 2H) , 3.19 (s, 3H) , 3.03-3.12 (m, 5H) , 1.33-1.43 (m, 4H) , 1.10-1.30 (m, 16H) , 0.76 (s, 12H) .
Example 10: Synthesis of 8- (methoxy-d3) -2, 2, 14, 14-tetramethylpentadecanedioic-8-d acid (0018)
Step 1: Synthesis of diethyl 8- (methoxy-d₃) -2, 2, 14, 14-tetramethylpentadecane dioate-8-d
To a solution of NaH (120 mg, 2.99 mmol) in DMF (3 mL) in the microwave tube was added diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate-8-d (300 mg, 0.75 mmol) at 0 ℃. The reaction mixture was stirred for 10 min and then CD₃I (433 mg, 2.99 mmol) was added. The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was quenched with H₂O (10 mL) and extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (140 mg, 45%) .
Step 2: Synthesis of 8- (methoxy-d₃) -2, 2, 14, 14-tetramethylpentadecanedioic-8-d acid
To a solution of diethyl 8- (methoxy-d₃) -2, 2, 14, 14-tetramethylpentadecanedioate-8-d (140 mg, 0.33 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (70 mg, 58%) .
MS (ESI, pos. ion) m/z: 359.1 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 12.00 (br s, 2H) , 2.07 (s, 1H) , 1.47 -1.39 (m, 4H) , 1.35 (br s, 4H) , 1.28 -1.13 (m, 12H) , 1.07 (s, 12H) .
Example 11: Synthesis of 1, 1'- (6-methoxyundecane-1, 11-diyl) -bis (cyclopropane-1-carboxylic acid) (0019)
Step 1: Synthesis of diethyl 8- (methoxy-d₃) -2, 2, 14, 14-tetramethylpentadecane dioate-8-d
To the solution of LDA (17.58 mL, 35.16 mmol) in THF (50 mL) was added tert-butyl cyclopropane carboxylate (5000 mg, 35.16 mmol) slowly at -40 ℃ and stirred for 30 min. Then 1-Bromo-5-chloropentane (9783 mg, 52.74 mmol) was added to the mixture. After addition, the resulting was warmed to -5 ℃ and stirred for 4 h. The solution was cooled to 0 ℃ and quenched by aq. NH₄Cl (50 mL) , extracted with EA (80 mL ×2) . The organic layer was washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified purified by silica gel chromatography eluted with PE to give tert-butyl 1- (5-chloropentyl) cyclopropane-1-carboxylate (2900 mg, 11.75 mmol, 33%) as colorless oil.
¹HNMR (400 MHz, CHLOROFORM-d) δ = 3.58 -3.50 (m, 2H) , 1.83 -1.74 (m, 2H) , 1.56 -1.44 (m, 6H) , 1.44 -1.37 (m, 9H) , 1.15 -1.06 (m, 2H) , 0.65 (br s, 2H) .
Step 2: Synthesis of tert-butyl 1- (5-iodopentyl) cyclopropane-1-carboxylate
To the solution of 2-methylpropan-2-yl-1- (5-chloropentyl) cyclopropane-1-carboxylate (2000 mg, 8.10 mmol) in 2-butanone (25 mL) was added NaI (2429 mg, 16.21 mmol) . The mixture was stirred at 80 ℃ for 12 h. The reaction mixture was diluted with EA (40 mL) and washed with H₂O (30 mL) , brine (30 mL) , dried over Na₂SO₄, filtered and concentrated to afford crude product tert-butyl 1- (5-iodopentyl) cyclopropane-1-carboxylate (2150 mg, 6.36 mmol, 78%) .
¹HNMR (400 MHz, CHLOROFORM-d) δ = 3.23 -3.17 (m, 2H) , 1.83 (quin, J = 7.1 Hz, 2H) , 1.51 -1.46 (m, 4H) , 1.43 (s, 9H) , 1.41 (br s, 2H) , 1.14 -1.09 (m, 2H) , 0.64 -0.56 (m, 2H) .
Step 3: Synthesis of di-tert-butyl 1, 1'- (6-oxoundecane-1, 11-diyl) -bis (cyclopropane-1-carboxylate)
To the solution of TosMIC (820 mg, 4.2 mmol) in DMAC (30 mL) was added t-BuOK (504 mg, 4.50 mmol) . The mixture was stirred at 0 ℃ for 0.5 h and added tert-butyl-1- (5-iodopentyl) cyclopropane-1-carboxylate (1.50 g, 4.43 mmol) . The resulting was warmed to RT and stirred for 1 h, then the mixture was cooled to 0 ℃ again and added t-BuOK (450 mg, 4.50 mmol) . After 0.5 h, the tert-butyl -1- (5-iodopentyl) cyclopropane-1-carboxylate (1.61 g, 4.76 mmol) was added to the reaction. The resulting was stirred at RT for 2 h. The solution was cooled to 0 ℃ and the mixture was quenched by ice water (30 mL) , extracted with DCM (30 mL) . The organic phase was added conc. HCl (10 mL) dropwise and stirred for 2 h. The reaction mixture was diluted with DCM (20 mL) and washed with NaHCO₃ (30 mL) , brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified purified by silica gel chromatography eluted with PE: EA=20: 1 to give di-tert-butyl 1, 1'- (6-oxoundecane-1, 11-diyl) bis (cyclopropane-1-carboxylate) (840 mg, 20%) .
¹HNMR (400 MHz, CHLOROFORM-d) δ = 2.45 -2.32 (m, 4H) , 1.59 -1.53 (m, 4H) , 1.49 -1.44 (m, 8H) , 1.42 (s, 18H) , 1.31 -1.22 (m, 4H) , 1.16 -1.03 (m, 4H) , 0.64 -0.53 (m, 4H) .
Step 4: Synthesis of di-tert-butyl-1, 1'- (6-hydroxyundecane-1, 11-diyl) -bis (cyclopropane-1-carboxylate)
To the solution of di-tert-butyl-1, 1'- (6-oxoundecane-1, 11-diyl) -bis- (cyclopropane-1-carboxylate) (380 mg, 0.84 mmol) in MeOH (10 mL) was added NaBH4 (64 mg, 1.69 mmol) at 0 ℃ slowly. The mixture was stirred at 0 ℃ for 2 h. The solution was quenched by 0.5 mL HCl (1M) , diluted with H₂O (20 mL) and extracted with EA (20 mL × 2) . The organic layer was washed with brine (20 mL) , dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EA=6: 1 to give di-tert-butyl-1, 1'- (6-hydroxyundecane-1, 11-diyl) -bis - (cyclopropane-1-carboxylate) (330 mg, 0.73 mmol, 86%) .
¹HNMR (400 MHz, CHLOROFORM-d) δ = 3.63 -3.54 (m, 1H) , 1.61 -1.49 (m, 8H) , 1.44 -1.40 (m, 22H) , 1.39 (br s, 8H) , 1.13 -1.06 (m, 4H) , 0.63 -0.55 (m, 4H) .
Step 5: Synthesis of di-tert-butyl-1, 1'- (6-methoxyundecane-1, 11-diyl) -bis - (cyclopropane-1-carboxylate)
To the solution of 1, 1'- (6-hydroxyundecane-1, 11-diyl) -bis- (cyclopropane-1-carboxylate) (280 mg, 0.62 mmol) and 2, 6-Di-tert-Butylpridine (177 mg, 0.93 mmol) in DCM (3 mL) was added CF₃SO₂OMe (15mg, 0.09 mmol) . The mixture was stirred at 40 ℃ overnight. The reaction mixture was diluted with DCM (20 mL) and washed with H₂O (10 mL) , brine (10 mL) , dried over Na2SO4, filtered and concentrated. The crude product was purified purified by silica gel chromatography eluted with PE: EA=20: 1 to give di-tert-butyl-1, 1'- (6-methoxyundecane-1, 11-diyl) -bis- (cyclopropane-1-carboxylate) (200 mg, 0.43 mmol, 69%) as yellow oil.
¹HNMR (400 MHz, CHLOROFORM-d) δ = 3.35 -3.29 (m, 3H) , 3.15 -3.08 (m, 1H) , 1.51 -1.45 (m, 8H) , 1.43 (s, 18H) , 1.39 (br d, J = 7.8 Hz, 12H) , 1.13 -1.07 (m, 4H) , 0.62 -0.54 (m, 4H) .
Step 6: Synthesis of 1, 1'- (6-methoxyundecane-1, 11-diyl) -bis- (cyclopropane-1-carboxylic acid)
To the solution of di-tert-butyl-1, 1'- (6-methoxyundecane-1, 11-diyl) -bis - (cyclopropane-1-carboxylate) (200 mg, 0.43 mmol) in DCM (3 mL) was added CF₃COOH (1.5 mL) . The mixture was stirred at RT for 4 h. After completion, the mixture was concentrated to give crude product. The crude product was purified by silica gel chromatography eluted with PE: EA=4: 1 to give 1, 1'- (6-methoxyundecane-1, 11-diyl) bis (cyclopropane-1-carboxylic acid) (130 mg, 89 %) as yellow oil.
MS (ESI, pos. ion) m/z: 355.2 [M+1] ⁺
¹HNMR (400 MHz, DMSO-d6) δ = 11.96 (s, 2H) , 3.21 -3.16 (m, 3H) , 3.11 -3.04 (m, 1H) , 2.07 (s, 1H) , 1.47 -1.33 (m, 12H) , 1.27 -1.15 (m, 8H) , 1.03 -0.96 (m, 4H) , 0.68 -0.62 (m, 4H) .
Example 11: Synthesis of 7-methoxy-2, 2, 12, 12-tetramethyltridecanedioicacid (0020)
Step 1: Synthesis of ethyl 6-bromo-2, 2-dimethylhexanoate
To a solution of ethyl isobutyrate (5.00 g, 43.04 mmol, 1.0 eq) in THF (50 mL) was added LDA (21.52 mL, 43.04 mmol, 1.0 eq) dropwise at -40 ℃ under N₂ atmosphere. After addition, the reaction mixture was stirred at -40 ℃ for 30 min. Then 1, 4-dibromobutane (11.15 g, 51.65 mmol, 1.2 eq) was added to the reaction slowly, and the resulting was raised to room temperature and stirred for 2 h. After the reaction completion, the reaction mixture was quenched with aq. NH₄Cl (20 mL) and extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) . The product was obtained as colorless oil (3.30 g, 30%) .
Step 2: Synthesis of diethyl 7-isocyano-2, 2, 12, 12-tetramethyl-7-tosyltridecanedioate
To a solution of TBAI (140 mg, 0.38 mmol, 0.1 eq) and TosMIC (740 mg, 3.79 mmol, 1.0 eq) in DMSO (20 mL) was added NaH (455 mg, 11.37 mmol, 3.0 eq) slowly at room temperature. After 30 mins, the ethyl 6-bromo-2, 2-dimethylhexanoate (1.99 g, 7.96 mmol, 2.0 eq) was added, then the resulting was stirred at RT overnight. After the reaction completion, the reaction mixture was quenched with aq. NH₄Cl (50 mL) and extracted with EA (30 mL × 3) . The combined organic layer was washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) =10/1) . The product was obtained as colorless oil (1.30 g, 64%) .
Step 3: Synthesis of diethyl 2, 2, 12, 12-tetramethyl-7-oxotridecanedioate
To a solution of diethyl 7-isocyano-2, 2, 12, 12-tetramethyl-7-tosyltridecanedioate (1.2 g, 2.24 mmol, 1.0 eq) in DCM (10 mL) was added conc. HCl (5 mL) at 0 ℃. The resulting was stirred at 25 ℃ for 4 h. The reaction mixture was cooled to 0 ℃, quenched with aq. NaHCO₃ (30 mL) and extracted with DCM (30 mL × 2) . The combined organic layer was washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) . The product was obtained as colorless oil (700 mg, 84%) .
Step 4: Synthesis of diethyl 7-hydroxy-2, 2, 12, 12-tetramethyltridecanedioate
To a solution of diethyl 2, 2, 12, 12-tetramethyl-7-oxotridecanedioate (700 mg, 1.89 mmol, 1.0 eq) in MeOH (10 mL) was added NaBH₄ (143 mg, 3.78 mmol, 2.0 eq) slowly at 0 ℃. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 1 N aq. HCl (0.5 mL) and extracted with EA (10 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 4/1) . The product was obtained as colorless oil (600 mg, 85%) .
Step 5: Synthesis of diethyl 7-methoxy-2, 2, 12, 12-tetramethyltridecanedioate
To a solution of diethyl 7-hydroxy-2, 2, 12, 12-tetramethyltridecanedioate (300 mg, 0.81 mmol, 1.0 eq) in DCM (2 mL) was added 2, 6-Di-tertbutylpyridine (0.27 mL, 1.21 mmol, 1.5 eq) and CF₃SO₂OMe (159 mg, 0.97 mmol, 1.2 eq) at 0 ℃. The reaction mixture was stirred at 40 ℃ overnight. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) . The product was obtained as colorless oil (200 mg, 64%) .
Step 6: Synthesis of diethyl 7-methoxy-2, 2, 12, 12-tetramethyltridecanedioic acid
To a solution of diethyl 7-methoxy-2, 2, 12, 12-tetramethyltridecanedioate (200 mg, 0.52 mmol, 1.0 eq) in MeOH (3 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 80 ℃ overnight. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 4/1) . The product was obtained as colorless oil (69 mg, 40%) .
MS (ESI, neg. ion) m/z: 329.0 [M-1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (br s, 2H) , 3.20-3.17 (s, 3H) , 3.06 (t, J = 5.5Hz, 1H) , 1.48-1.40 (m, 4H) , 1.40 -1.33 (m, 4H) , 1.25-1.14 (m, 8H) , 1.09-1.03 (s, 12H) .
Example 12: Synthesis of 1- (12-carboxy-6-methoxy-12-methyltridecyl) cyclopropane-1-carboxylic acid (0021)
Step 1: Synthesis of ethyl 8-cyano-2, 2-dimethyl-8-tosyloctanoate
To a solution of ethyl 9-bromo-2, 2-dimethylnonanoate (2.04 g, 7.68 mmol) in DMF (10 mL) was added TosMIC (1.00 g, 5.12 mmol) , Bu₄NI (0.19 g, 0.51 mmol) and K₂CO₃ (1.06 g, 7.68 mmol) under N₂ atmosphere. The reaction mixture was stirred at 25 ℃ for 5 days. The reaction mixture was diluted with EA (50 mL) . The organic layer was washed with H₂O (20 mL × 3) and brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) ) . The product was obtained as colorless oil. (1.05 g, 54 %) .
Step 2: Synthesis of tert-butyl1- (6-cyano-13-ethoxy-12, 12-dimethyl-13-oxo-6-tosyltridecyl) cyclopropane-1-carboxylate
To a solution of t-BuOK (355 mg, 3.16 mmol) in DMA (2.4 mL) was added the solution of ethyl 8-cyano-2, 2-dimethyl-8-tosyloctanoate (800 mg, 2.11 mmol) in DMA (2.4 mL) drop-wise in 20 min at 0 ℃ under N₂. And then the mixture was added the solution of tert-butyl 1- (5-iodopentyl) cyclopropane-1-carboxylate (713 mg, 2.11 mmol) in DMA (2.4 mL) drop-wise in 10 min at 0 ℃. The reaction mixture was stirred for 2 hours at 25 ℃. The reaction mixture was added saturated NH₄Cl (10 mL) aqueous solution and extracted with EA (20 mL × 3) . The combined organic layer was washed with H₂O (20 mL × 2) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was used for next step directly. The crude product was obtained as yellow oil. (1.10 g, 88 %) .
Step 3: Synthesis of tert-butyl 1- (13-ethoxy-12, 12-dimethyl-6, 13-dioxotridecyl) cyclopropane-1-carboxylate
To a solution of tert-butyl1- (6-cyano-13-ethoxy-12, 12-dimethyl-13-oxo-6-tosyltridecyl) cyclopropane-1-carboxylate (1100 mg, 1.86 mmol) in DCM (6.6 mL) was added concentrated HCl (0.88 mL) at room temperature. The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture diluted with H₂O (20 mL) and DCM (30 mL) . The aqueous layer was extracted with DCM (20 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (460 mg, 58%) .
Step 4: Synthesis of tert-butyl -1- (13-ethoxy-6-hydroxy-12, 12-dimethyl-13-oxotridecyl) cyclopropane-1-carboxylate
To a solution of tert-butyl 1- (13-ethoxy-12, 12-dimethyl-6, 13-dioxotridecyl) cyclopropane-1-carboxylate (460 mg, 1.08 mmol) in MeOH (5 mL) was added NaBH₄ (41 mg, 1.08 mmol) at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred at 0 ℃ for 4 hours. The reaction mixture was poured into ice-H₂O (10 mL) . The aqueous layer was extracted with EA (30 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (380 mg, 82%) .
Step 5: Synthesis of 1- (13-ethoxy-6-methoxy-12, 12-dimethyl-13-oxotridecyl) cyclopropane-1-carboxylic acid
To a solution of tert-butyl1- (13-ethoxy-6-hydroxy-12, 12-dimethyl-13-oxotridecyl) cyclopropane-1-carboxylate (380 mg, 0.89 mmol) in DCM (4 mL) was added CF₃SO₃Me (293 mg, 1.78 mmol) and 2, 6-di-tert-butylpyridine (0.85 mg, 1.34 mmol) . The reaction mixture was stirred for 18 hours at 40 ℃. The reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) ) . The product was obtained as colorless oil. (100 mg, 29%) .
Step 6: Synthesis of 1- (12-carboxy-6-methoxy-12-methyltridecyl) cyclopropane-1-carboxylic acid
To a solution of 1- (13-ethoxy-6-methoxy-12, 12-dimethyl-13-oxotridecyl) cyclopropane-1-carboxylic acid (100 mg, 0.26 mmol) in MeOH (4 mL) was added 20%KOH (1 mL) solution. The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (60 mg, 59%) .
MS (ESI, pos. ion) m/z: 357.3 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 12.00 (br s, 2H) , 3.19 (s, 3H) , 3.14 -3.02 (m, 1H) , 1.45 -1.32 (m, 10H) , 1.29 -1.15 (m, 10H) , 1.07 (s, 6H) , 1.03 -0.98 (m, 2H) , 0.85 (br d, J = 6.6 Hz, 1H) , 0.72 -0.61 (m, 2H) .
Example 13: Synthesis of (8R, 9R) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioic acid (0022-a) and (8S, 9S) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioic acid (0022-b)
Step 1: Synthesis of 2- (hept-6-yn-1-yloxy) tetrahydro-2H-pyran
To a solution of hex-6-yn-1-ol (5.00 g, 44.58 mmol, 1.0 eq) in DCM (50 mL) was added PPTS (12.32 g, 49.03 mmol 1.1 eq) and DHP (4.50 g, 53.49 mmol, 1.2 eq) . The reaction mixture was stirred for overnight at 25 ℃. The reaction mixture was concentrated under vacuum. The residue was diluted with a mixture solvent of DCM (40 mL) in MTBE (50 mL) and stirred for 1 hour. The resulting was filtered and concentrated to give crude product, which was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as yellow oil (7.00 g, 80%) .
Step 2: Synthesis of 2- ( (5-bromopentyl) oxy) tetrahydro-2H-pyran
To a solution of 5-bromopentan-1-ol (5.00 g, 26.94 mmol) in DCM (60 mL) was added PPTS (7.45 g, 29.63 mmol, 1.1 eq) and DHP (3.17 g, 37.71 mmol, 1.2 eq) . The reaction mixture was stirred for overnight at 25 ℃. The reaction mixture was concentrated under vacuum. The residue was diluted with a mixture solvent of DCM (15 mL) in MTBE (80 mL) and stirred for 1 hour. The resulting was filtered and concentrated to give crude product, which was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as yellow oil (5.47 g, 80%) .
Step 3: Synthesis of 1, 12-bis ( (tetrahydro-2H-pyran-2-yl) oxy) dodec-6-yne
To a solution of 2- (hex-6-yn-1-yloxy) tetrahydro-2H-pyran (1.20 g, 6.11 mmol, 1.0 eq) in THF (20 mL) was added n-BuLi (392 mg, 6.11 mmol, 1.0 eq) dropwise at -40 ℃ under N₂. After addition, the HMPA (5 mL) was added. The resulting was stirred at -40 ℃ for 1 hours, and then 2- ( (5-bromopentyl) oxy) tetrahydro-2H-pyran (1.61 g, 6.42 mmol, 1.05 eq) was added solwly. The reaction mixture was stirred at -40 ℃ for 1 hour, and then stirred at 25 ℃ overnight. The reaction mixture quenched with NH₄Cl (30 mL) and extracted with EA (30 mL × 2) . The combined organic layer was washed with brine (20 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (1.320 g, 58%) .
Step 4: Synthesis of (E) -1, 12-bis ( (tetrahydro-2H-pyran-2-yl) oxy) dodec-6-ene
To a solution of LAH (942 mg, 24.83 mmol, 8.0 eq) in Diglyme (20 mL) was added 1, 12-bis ( (tetrahydro-2H-pyran-2-yl) oxy) dodec-6-yne (1300 mg, 3.55 mmol, 1.0 eq) at 25 ℃ under N₂ atmosphere. The reaction mixture was stirred at 140 ℃ for 12 hours. The reaction mixture was cooled to 0 ℃ and added water (0.9 mL) , 15%NaOH aqueous solution (0.9 mL) and water (2.7 mL) . The resulting was stirred for 15 min, added Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (1000 mg, 77%) .
Step 5: Synthesis of (E) -dodec-6-ene-1, 12-diol
To a solution of (E) -1, 12-bis ( (tetrahydro-2H-pyran-2-yl) oxy) dodec-6-ene (1000 mg, 2.71 mmol, 1.0 eq) in mixture solvent of MeOH (10 mL) in H₂O (1 mL) was added PTSA (98 mg, 0.52 mmol, 0.20 eq) . The reaction mixture was stirred at 25 ℃ overnight. The reaction mixture was diluted with EA (20 mL) and washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 1/1) ) . The product was obtained as white solid (250 mg, 46%) .
Step 6: Synthesis of (E) -1, 12-dibromododec-6-ene
To a solution of (E) -dodec-6-ene-1, 12-diol (250 mg, 1.25 mmol, 1.0 eq) and CBr₄ (1242 mg, 3.74 mmol, 3.0 eq) in DCM (8 mL) was added PPh₃ (982 mg, 3.74 mmol, 3.0 eq) at 0 ℃ under N₂. The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as white solid (340 mg, 84%) .
Step 7: Synthesis of diethyl (E) -2, 2, 15, 15-tetramethylhexadec-8-enedioate
To a solution of ethyl 2-methylpropanoate (483 mg, 4.16 mmol, 4.0 eq) in THF (4 mL) was added LDA (446 mg, 4.16 mmol, 4.0 eq) dropwise at -40 ℃ under N₂ atmosphere. The reaction mixture was stirred for 1 hour, and then (E) -1, 12-dibromododec-6-ene (340 mg, 1.04 mmol, 1.0 eq) was added. The reaction mixture was stirred at -40 ℃ for 0.5 hour, and then the reaction mixture was stirred for 18 hours at 25 ℃. The reaction mixture was quenched with ice-water (10 mL) and extracted with EA (10 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as yellow oil (300 mg, 73%) .
Step 8: Synthesis of diethyl (8R, 9R) -8, 9-dihydroxy-2, 2, 15, 15-tetramethylhexadecanedioate and diethyl (8S, 9S) -8, 9-dihydroxy-2, 2, 15, 15-tetramethylhexadecanedioate
To a solution of diethyl (E) -2, 2, 15, 15-tetramethylhexadec-8-enedioate (300 mg, 0.76 mmol, 1.0 eq) and NMO (222 mg, 1.89 mmol, 2.5 eq) in mixture solvent of THF (5 mL) in H₂O (5 mL) was added OsO₄ (4 mg, 0.02 mmol, 0.02 eq) at 0 ℃. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with aq. Na₂SO₃ (20 mL) and extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The mixture of two products was obtained as colorless oil (220 mg, 68%) .
Step 9: Synthesis of diethyl (8R, 9R) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioate and diethyl (8S, 9S) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioate
To a solution of (8R, 9R) -8, 9-dihydroxy-2, 2, 15, 15-tetramethylhexadecanedioate and diethyl (8S, 9S) -8, 9-dihydroxy-2, 2, 15, 15-tetramethylhexadecanedioate (170 mg, 0.39 mmol, 1.0 eq) in DCM (3 mL) was added CF₃SO₃Me (0.18 mL, 1.58 mmol, 4.0 eq) and 2, 6-di-tert-butylpyridine (0.27 mL, 1.18 mmol, 3.0 eq) . The reaction mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was diluted with DCM (20 mL) and washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The mixture of two products was obtained as colorless oil (80 mg, 44%) .
Step 10: Synthesis of (8R, 9R) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioic acid and (8S, 9S) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioic acid
To a solution of diethyl (8R, 9R) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioate and diethyl (8S, 9S) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioate (80 mg, 0.17 mmol, 1.0 eq) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 70 ℃ for 18 hours. The reaction mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The mixture of two products was obtained as colorless oil (30 mg, 43%) .
MS (ESI, neg. ion) m/z: 401.1 [M-1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.97 (br d, J = 1.1 Hz, 2H) , 3.28 (s, 6H) , 3.15 (br s, 2H) , 1.31-1.47 (m, 8H) , 1.14-1.29 (m, 12H) , 1.07 (s, 12H) .
Example 14: Synthesis of 10-methoxy-2, 2, 18, 18-tetramethylnonadecanedioic acid (0023)
Step 1: Synthesis of ethyl 9-bromo-2, 2-dimethylnonanoate
To a solution of ethyl 2-methylpropanoate (4.00 g, 34.44 mmol) in THF (40 mL) was added LDA (17.20 mL, 34.44 mmol) at -40 ℃ under N₂ atmosphere. The reaction mixture was stirred for 1 hour and then 1,7-dibromoheptane (12.40 g, 48.21 mmol) was added. The reaction mixture was stirred at -40 ℃ for 0.5 hour , and then the reaction mixture was warmed to 25 ℃ stirred for 8 h. The reaction mixture was poured into ice-H₂O (20 mL) . The aqueous layer was extracted with EA (50 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as yellow oil. (5.00 g, 49%) .
Step 2: Synthesis of diethyl 10-cyano-2, 2, 18, 18-tetramethyl-10-tosylnonadecanedioate
To a solution of TosMIC (1.50 g, 7.67 mmol) and Bu₄NI (0.28 g, 0.77 mmol) in DMSO (45 mL) was added NaH (0.92 g, 23.02 mmol) at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred at 25 ℃ for 30 min and then ethyl 9-bromo-2, 2-dimethylnonanoate (4.5 g, 15.35 mmol) was added. The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was quenched with ice-H₂O (40 mL) at 0 ℃. The mixture was extracted with EA (50 mL × 2) . The combined organic layer was washed with 10%HCl solution (20 mL × 3) , brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) ) . The product was obtained as yellow oil. (4.10 g, 43%) .
Step 3: Synthesis of diethyl 2, 2, 18, 18-tetramethyl-10-oxononadecanedioate
To a solution of diethyl 10-cyano-2, 2, 18, 18-tetramethyl-10-tosylnonadecanedioate (3.60 g, 5.81 mmol) in DCM (47 mL) was added conc. aqueous HCl (18 mL) at room temperature. The reaction mixture was stirred at 25 ℃ for 4 hours. The reaction mixture diluted with H₂O (30 mL) . The aqueous layer was extracted with DCM (40 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (2.50 g, 95%) .
Step 4: Synthesis of diethyl 10-hydroxy-2, 2, 18, 18-tetramethylnonadecanedioate
To a solution of diethyl 2, 2, 18, 18-tetramethyl-10-oxononadecanedioate (2.70 g, 5.94 mmol) in MeOH (30 mL) was added NaBH₄ (0.22 g, 5.94 mmol) at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred at 0 ℃ for 4 hours. The reaction mixture was poured into ice-H₂O (20 mL) . The aqueous layer was extracted with EA (30 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (2.60 g, 96%) .
Step 5: Synthesis of diethyl 10-methoxy-2, 2, 18, 18-tetramethylnonadecanedioate
To a solution of diethyl 10-hydroxy-2, 2, 18, 18-tetramethylnonadecanedioate (300 mg, 0.66 mmol) in DCM (3 mL) was added CF₃SO₃Me (0.15 mL, 1.31 mmol) and 2, 6-di-tert-butylpyridine (0.22 mL, 0.99 mmol) . The reaction mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (120 mg, 38%) .
Step 6: Synthesis of 10-methoxy-2, 2, 18, 18-tetramethylnonadecanedioic acid
To a solution of diethyl 10-methoxy-2, 2, 18, 18-tetramethylnonadecanedioate (120 mg, 0.25 mmol) in MeOH (4 mL) was added 20%KOH (1 mL) . The reaction mixture was stirred at 70 ℃ for 18 hours. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (70 mg, 66%)
MS (ESI, pos. ion) m/z: 415.1 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d6) δ = 12.00 (br s, 2H) , 3.19 (s, 3H) , 3.08 (br d, J = 5. Hz, 1H) , 1.46 -1.33 (m, 8H) , 1.30 -1.17 (m, 20H) , 1.07 (s, 12H) .
Example 15: Synthesis of (9R, 10R) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0045-a) and (9S, 10S) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0045-b)
Step 1: Synthesis of diethyl (9R, 10R) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate and diethyl (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of diethyl diethyl (E) -2, 2, 17, 17-tetramethyloctadec-9-enedioate (400 mg, 0.94 mmol, 1.0 eq) and NMO (276 mg, 2.35 mmol, 2.5 eq) in mixture solvent of THF (5 mL) in H₂O (5 mL) was added OsO₄ (5 mg, 0.02 mmol, 0.02 eq) at 0 ℃. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with aq. Na₂SO₃ (20 mL) and extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The mixture of two products was obtained as colorless oil (280 mg, 65%) .
Step 2: Synthesis of diethyl (9R, 10R) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioate and diethyl (9S, 10S) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of diethyl (9R, 10R) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate and diethyl (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate (200 mg, 0.44 mmol, 1.0 eq) in DCM (5 mL) was added CF₃SO₃Me (0.20 mL, 1.74 mmol, 4.0 eq) and 2, 6-di-tert-butylpyridine (0.29 mL, 1.31 mmol, 3.0 eq) . The reaction mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was diluted with DCM (20 mL) and washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The mixture of two products was obtained as colorless oil (40 mg, 19%) .
Step 3: Synthesis of (9R, 10R) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid and (9S, 10S) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of diethyl (9R, 10R) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioate and diethyl (9S, 10S) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioate (40 mg, 0.08 mmol, 1.0 eq) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 70 ℃ for 18 hours. The reaction mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The mixture of two products was obtained as colorless oil (20 mg, 57%) .
MS (ESI, neg. ion) m/z: 429.1 [M-1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (br s, 2H) , 3.28 (s, 6H) , 3.15 (br s, 2H) , 1.31-1.47 (m, 8H) , 1.23 (br s, 16H) , 1.06 (s, 12H) .
Example 16: Synthesis of 8- (difluoromethoxy) -2, 2, 14, 14-tetramethylpentadecanedioic acid (0046)
Step 1: Synthesis of diethyl 8- (difluoromethoxy) -2, 2, 14, 14-tetramethylpentadecanedioate
To the solution of diethyl 8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (200 mg, 0.50 mmol) in a mixture solvent of H₂O (0.3 mL) in DCM (0.1 mL) was added KHF₂ (312 mg, 4.00 mmol) at 0 ℃. TMS-CF₂Br (406 mg, 2.00 mmol) was added to the mixture after KHF₂ dissolved. Then the resulting was stirred at room temperature for 12 hours. The solution was diluted with H2O (10 mL) and extracted with DCM (10 mL × 3) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EA=10: 1 to give diethyl 8- (difluoromethoxy) -2, 2, 14, 14-tetramethylpentadecanedioate (120 mg, 0.27 mmol, 53%) as yellow oil liquid.
¹HNMR (400 MHz, CHLOROFORM-d) δ = 6.42 -5.99 (m, 1H) , 4.18 -4.08 (m, 4H) , 4.07 -3.99 (m, 1H) , 1.56 -1.46 (m, 8H) , 1.39 -1.20 (m, 18H) , 1.16 (s, 12H) .
Step 2: Synthesis of 8- (difluoromethoxy) -2, 2, 14, 14-tetramethylpentadecanedioic acid
To the solution of diethyl 8- (difluoromethoxy) -2, 2, 14, 14-tetramethylpentadecanedioate (100 mg, 0.22 mmol) in MeOH (0.8 mL) was added 20%KOH aq. (0.2 mL) . The resulting was stirred at 70 ℃ overnight. The reaction mixture was adjusted to pH=1 with 1 M HCl solution. The aqueous layer was extracted with EA (10 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified purified by silica gel chromatography eluted with PE: EA = 4: 1 to give 8- (difluoromethoxy) -2, 2, 14, 14-tetramethylpentadecanedioic acid (70 mg, 0.18 mmol, 80 %) as yellow oil liquid.
MS (ESI, pos. ion) m/z: 395.2 [M+H] ⁺, 417.2 [M+Na] ⁺
¹HNMR (400 MHz, DMSO-d₆) δ = 12.00 (s, 2H) , 6.85 -6.43 (m, 1H) , 4.01 (s, 1H) , 1.52 -1.37 (m, 8H) , 1.32 -1.16 (m, 12H) , 1.06 (s, 12H) .
Example 17: Synthesis of 6, 6'- (2-methoxycyclohexane-1, 3-diyl) bis (2, 2-dimethylhexanoic acid) (0047)
Step 1: Synthesis of diethyl 6, 6'- (2-oxocyclohexane-1, 3-diyl) bis (2, 2-dimethylhexanoate)
To a solution of cyclohexanone (100 mg, 1.02 mmol, 1.0 eq) in Toluene (5 mL) was added Potassium tert-butoxide (285 mg, 2.55 mmol, 2.5 eq) slowly at 0 ℃. The resulting was stirred at same temperature for 30 min, then the ethyl 6-bromo-2, 2-dimethylhexanoate (589 mg, 2.34 mmol, 2.3 eq) was added. The reaction mixture was raised to room temperature and stirred overnight. The reaction mixture was quenched with aq. NH₄Cl (10 mL) and extracted with EA (10 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) . The product was obtained as colorless oil (200 mg, 45%) .
Step 2: Synthesis of diethyl 6, 6'- (2-hydroxycyclohexane-1, 3-diyl) bis (2, 2-dimethylhexanoate)
To a solution of diethyl 6, 6'- (2-hydroxycyclohexane-1, 3-diyl) bis (2, 2-dimethylhexanoate) (200 mg, 0.46 mmol, 1.0 eq) in MeOH (2 mL) was added NaBH₄ (35 mg, 0.92 mmol, 2.0 eq) at 0 ℃. The reaction mixture was raised to room temperature and stirred for 2 h. The reaction mixture was quenched with 1 N aq. HCl (0.5 mL) and extracted with EA (5 mL × 2) . The combined organic layer was washed with brine (5 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO2, PE/EA (v/v) = 4/1) . The product was obtained as colorless oil (190 mg, 94%) .
Step 3: Synthesis of diethyl 6, 6'- (2-methoxycyclohexane-1, 3-diyl) bis (2, 2-dimethylhexanoate)
To a solution of diethyl 6, 6'- (2-hydroxycyclohexane-1, 3-diyl) bis (2, 2-dimethylhexanoate) (200 mg, 0.45 mmol, 1.0 eq) in DCM (2 mL) was added 2, 6-Di-tertbutylpyridine (0.15 mL, 0.68 mmol, 1.5 eq) and CF₃SO₂OMe (97 mg, 0.59 mmol, 1.3 eq) was added at 0 ℃. The reaction mixture was stirred at 40 ℃ overnight. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) . The product was obtained as colorless oil (178 mg, 86%) .
Step 6: Synthesis of 6, 6'- (2-methoxycyclohexane-1, 3-diyl) bis (2, 2-dimethylhexanoic acid)
To a solution of diethyl 6, 6'- (2-methoxycyclohexane-1, 3-diyl) bis (2, 2-dimethylhexanoate) (100 mg, 0.22 mmol, 1.0 eq) in MeOH (3 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 80 ℃overnight. The reaction mixture was adjusted to pH=1 with 1 N aq. HCl. The aqueous layer was extracted with EA (10 mL × 2) . The organic layer was washed with brine (5 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 4/1) . The product was obtained as colorless oil (70 mg, 79%) .
MS (ESI, neg. ion) m/z: 397.1 [M-1] ⁺ .
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (s, 2H) , 3.19 (s, 3H) , 2.92 -2.87 (m, 1H) , 1.54 -1.40 (m, 6H) , 1.35 -1.08 (m, 18H) , 1.06 (s, 12H) .
Example 18: Synthesis of 8-methoxy-2, 2, 14, 14-tetrakis (methyl-d₃) pentadecanedioic-8-d acid (0027)
Step 1: Synthesis of ethyl 7- (formyloxy) heptanoate
To a solution of ethyl 7-bromoheptanoate (5.00 g, 21.08 mmol) in formic acid (2 . 00 mL, 52.71 mmol) was added TEA (7.31 mL, 52.71 mmol) at 0 ℃. The reaction mixture was stirred for 24 h at 50 ℃. After the reaction completion, the mixture was diluted with EA (50 mL) and washed with 1 M HCl solution (20 mL) , saturated NaHCO₃ solution (20 mL) and brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (3.9 g, 91%) .
¹HNMR (400 MHz, METHANOL-d₄) δ = 8.10 (s, 1H) , 4.19 -4.10 (m, 4H) , 2.33 (t, J = 7.4 Hz, 2H) , 1.73 -1.60 (m, 4H) , 1.47 -1.35 (m, 4H) , 1.26 (t, J = 7.1 Hz, 3H) .
Step 2: Synthesis of ethyl 7-hydroxyheptanoate
To a solution of ethyl 7- (formyloxy) heptanoate (2.80 g, 13.84 mmol) in EtOH (30 mL) was added K₂CO₃ (3.8 g, 27.69 mmol) . The reaction mixture was stirred for 18 hours at 25 ℃. After the reaction completion, the mixture was diluted with EA (50 mL) and washed with H₂O (20 mL) and brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 3/1) ) . The product was obtained as colorless oil. (2.3 g, 95%) .
¹HNMR (400 MHz, DMSO-d₆) δ = 4.32 (t, J = 5.2 Hz, 1H) , 4.08 -4.02 (m, 2H) , 3.39 -3.34 (m, 2H) , 2.26 (t, J = 7.4 Hz, 2H) , 1.51 (br t, J = 7.3 Hz, 2H) , 1.44 -1.35 (m, 2H) , 1.26 (td, J = 3.3, 7.0 Hz, 4H) , 1.17 (t, J = 7.1 Hz, 3H) .
Step 3: Synthesis of ethyl 7- ( (tetrahydro-2H-pyran-2-yl) oxy) heptanoate
To a solution of ethyl 7-hydroxyheptanoate (2.00 g, 11.48 mmol) and DHP (1.06 g, 12.63 mmol) in DCM (20 mL) was added PPTS (2.90 g, 11.48 mmol) . The reaction mixture was stirred for 18 h at 25 ℃. The reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) ) . The product was obtained as colorless oil. (2.90 g, 97%)
Step 4: Synthesis of ethyl 2- (methyl-d₃) -7- ( (tetrahydro-2H-pyran-2-yl) oxy) heptanoate
To a solution of ethyl 7- ( (tetrahydro-2H-pyran-2-yl) oxy) heptanoate (1.00 g, 3.87 mmol) in THF (15 mL) was added LDA (4 . 84 mL, 9.68 mmol) dropwise at -78 ℃ under N₂. After addition, the reaction mixture was stirred for 1 hours at -78 ℃, and then CD₃I (1.40 g, 9.68 mmol) was added. The reaction mixture was stirred for 18 hours at 25 ℃. The reaction mixture was quenched with saturated NH₄Cl aqueous solution (20 mL) and extracted with EA (20 mL × 3) . The combined organic layer was washed with brine (10 mL × 2) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 25/1) ) . The product was obtained as colorless oil. (430 mg, 40%) .
¹HNMR (400 MHz, DMSO-d₆) δ = 4.54 -4.50 (m, 1H) , 4.09 -4.01 (m, 2H) , 3.72 (ddd, J = 3.0, 8.1, 11.2 Hz, 1H) , 3.59 (td, J = 6.7, 9.6 Hz, 1H) , 3.46 -3.37 (m, 1H) , 3.31 -3.26 (m, 1H) , 2.36 (t, J = 6.8 Hz, 1H) , 1.75 -1.65 (m, 1H) , 1.60 -1.35 (m, 9H) , 1.34 -1.23 (m, 4H) , 1.17 (t, J = 7.1 Hz, 3H) .
Step 5: Synthesis of ethyl 2, 2-bis (methyl-d₃) -7- ( (tetrahydro-2H-pyran-2-yl) oxy) heptanoate
To a solution of ethyl 2- (methyl-d₃) -7- ( (tetrahydro-2H-pyran-2-yl) oxy) heptanoate (1100 mg, 3.99 mmol) in THF (10 mL) was added LDA (5.00 mL, 9.99 mmol) dropwise at -78 ℃ under N₂. After addition, the reaction mixture was stirred for 1 hours at -78 ℃, and then CD₃I (1.45 g, 9.99mmol) was added. The reaction mixture was stirred for 18 hours at 25 ℃. The reaction mixture was quenched with saturated NH₄Cl aqueous solution (20 mL) and extracted with EA (20 mL × 3) . The combined organic layer was washed with brine (10 mL × 2) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 25/1) ) . The product was obtained as colorless oil. (790 mg, 67%)
¹HNMR (400 MHz, DMSO-d₆) δ = 4.52 (t, J = 3.3 Hz, 1H) , 4.04 (q, J = 7.1 Hz, 2H) , 3.72 (ddd, J =2.9, 8.1, 11.1 Hz, 1H) , 3.59 (td, J = 6.7, 9.6 Hz, 1H) , 3.46 -3.37 (m, 1H) , 3.31 -3.25 (m, 1H) , 1.78 -1.66 (m, 1H) , 1.65 -1.55 (m, 1H) , 1.54 -1.38 (m, 9H) , 1.35 -1.23 (m, 2H) , 1.22 -1.12 (m, 5H) .
Step 6: Synthesis of ethyl 7-hydroxy-2, 2-bis (methyl-d₃) heptanoate
To a solution of ethyl ethyl 2, 2-bis (methyl-d₃) -7- ( (tetrahydro-2H-pyran-2-yl) oxy) heptanoate (790 mg, 2.70 mmol) in mixture solvent of MeOH (10 mL) in H₂O (1 mL) was added PTSA (80 mg, 0.42 mmol) . The reaction mixture was stirred for 18 hours at 25 ℃. After the reaction completion, the mixture was diluted with EA (30 mL) , washed with H₂O (20 mL × 3) and brine (20 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 4/1) ) . The product was obtained as colorless oil. (400 mg, 71%) .
¹HNMR (400 MHz, DMSO-d6) δ = 4.32 (t, J = 5.2 Hz, 1H) , 4.04 (q, J = 7.1 Hz, 2H) , 3.39 -3.33 (m, 2H) , 1.48 -1.35 (m, 4H) , 1.26 -1.19 (m, 2H) , 1.18 -1.09 (m, 5H) .
Step 7: Synthesis of ethyl 7-bromo-2, 2-bis (methyl-d₃) heptanoate
To a solution of ethyl 7-hydroxy-2, 2-bis (methyl-d3) heptanoate (300 mg, 1.44 mmol) in DCM (5 mL) was added CBr₄ (716 mg, 2.16 mmol) under N₂. The resulting was added PPh₃ (566 mg, 2.16 mmol) at 0 ℃ and stirred for 1 hours at 25 ℃. After the reaction completion, the mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (350 mg, 86%)
¹HNMR (400 MHz, DMSO-d₆) δ = 4.05 (q, J = 7.1 Hz, 2H) , 3.51 (t, J = 6.7 Hz, 2H) , 1.83 -1.74 (m, 2H) , 1.50 -1.40 (m, 2H) , 1.39 -1.29 (m, 2H) , 1.23 -1.12 (m, 5H) .
Step 8: Synthesis of diethyl 8-cyano-2, 2, 14, 14-tetrakis (methyl-d₃) -8-tosylpentadecanedioate
To a solution of TosMIC (720 mg, 3.69 mmol) and Bu₄NI (136 mg, 0.37 mmol) in DMSO (20 mL) was added NaH (442 mg, 11.05 mmol) at 25 ℃ under N₂ atmosphere. The reaction mixture was stirred for 30 min at 25℃, and then ethyl 7-bromo-2, 2-bis (methyl-d₃) heptanoate (2.0 g, 7.37 mmol) was added. The reaction mixture was stirred for 1 hour at 25 ℃. After the reaction completion, the reaction mixture was quenched with ice-H₂O (20 mL) at 0 ℃ and extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) ) . The product was obtained as yellow oil. (1.6 g, 37%) .
Step 9: Synthesis of diethyl 2, 2, 14, 14-tetrakis (methyl-d₃) -8-oxopentadecanedioate
To a solution of diethyl 8-cyano-2, 2, 14, 14-tetrakis (methyl-d₃) -8-tosylpentadecanedioate (1.8 g, 3.13 mmol) in DCM (23 mL) was added HCl (12 mL, 12 N) at room temperature. The reaction mixture was stirred for 4 hours at 25 ℃. The reaction mixture diluted with H₂O (20 mL) and extracted with DCM (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (1.1 g, 85%)
Step 10: Synthesis of diethyl 8-hydroxy-2, 2, 14, 14-tetrakis (methyl-d₃) pentadecanedioate-8-d
To a solution of diethyl 2, 2, 14, 14-tetrakis (methyl-d₃) -8-oxopentadecanedioate (200 mg, 0.49 mmol) in MeOH (20 mL) was added NaBD₄ (21 mg, 0.49 mmol) at 0 ℃ under N2 atmosphere. The reaction mixture was stirred for 4 hours at 0 ℃. After the reaction completion, the reaction mixture was poured into ice-H₂O (10 mL) and extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (200 mg, 98%)
Step 11: Synthesis of diethyl 8-methoxy-2, 2, 14, 14-tetrakis (methyl-d₃) pentadecanedioate-8-d
To a solution of diethyl 8-hydroxy-2, 2, 14, 14-tetrakis (methyl-d₃) pentadecanedioate-8-d (200 mg, 0.48 mmol) in DCM (4 mL) was added CF₃SO₃Me (164 mg, 0.97 mmol) and 2, 6-di-tert-butylpyridine (138 mg, 0.73 mmol) . The reaction mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was diluted with DCM (20 mL) and washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (160 mg, 80 %) .
Step 12: Synthesis of 8-methoxy-2, 2, 14, 14-tetrakis (methyl-d₃) pentadecanedioic-8-d acid
To a solution of diethyl 8-methoxy-2, 2, 14, 14-tetrakis (methyl-d₃) pentadecanedioate-8-d (160 mg, 0.37 mmol) in MeOH (4 mL) was added 20%KOH (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. After the reaction completion, the mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 3/2) ) . The product was obtained as white solid. (100 mg, 72%)
MS (ESI, pos. ion) m/z: 372.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.98 (s, 2H) , 3.18 (s, 3H) , 1.45 -1.31 (m, 8H) , 1.28 -1.12 (m, 12H) .
Example 19: Synthesis of (8R, 9S) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioic acid (0028)
Step 1: Synthesis of diethyl 7, 7'- (oxirane-2, 3-diyl) bis (2, 2-dimethylheptanoate)
To a solution of diethyl (E) -2, 2, 15, 15-tetramethylhexadec-8-enedioate (650 mg, 1.64 mmol, 1.0 eq) in DCM (5 mL) was added m-CPBA (283 mg, 1.64 mmol, 1.0 eq) . The reaction mixture was stirred at rt for 2h. The reaction mixture was diluted with H₂O (20 mL) and extracted with DCM (20 mL × 2) . The combined organic layer was washed with NaHCO₃ (20 mL) and brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) ) . The product was obtained as colorless oil (550 mg, 81%) .
Step 2: Synthesis of diethyl (8R, 9S) -8-hydroxy-9-methoxy-2, 2, 15, 15-tetramethylhexadecanedioate
To a solution of diethyl 7, 7'- (oxirane-2, 3-diyl) bis (2, 2-dimethylheptanoate) (550 mg, 1.33 mmol, 1.0 eq) in MeOH (8 mL) was added H₂SO₄ (0.1 mL) . The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H₂O (20 mL) and extracted with DCM (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (500 mg, 87%) .
Step 3: Synthesis of diethyl (8R, 9S) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioate
To a solution of diethyl (8R, 9S) -8-hydroxy-9-methoxy-2, 2, 15, 15-tetramethylhexadecanedioate (200 mg, 0.46 mmol, 1.0 eq) in DCM (5 mL) was added CF₃SO₃Me (0.20 mL, 1.80 mmol, 4.0 eq) and 2, 6-di-tert-butylpyridine (0.30 mL, 1.35 mmol, 3.0 eq) . The reaction mixture was stirred at 40 ℃ for 18 hours. The reaction mixture was diluted with DCM (20 mL) and washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil (100 mg, 48%) .
Step 4: Synthesis of (8R, 9S) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioic acid
To a solution of diethyl (8R, 9S) -8, 9-dimethoxy-2, 2, 15, 15-tetramethylhexadecanedioate (100 mg, 0.22 mmol, 1.0 eq) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 70 ℃ for 18 hours. The reaction mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL ×2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (30 mg, 34%) .
MS (ESI, neg. ion) m/z: 401.1 [M-1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.65-12.32 (m, 2H) , 3.27 (s, 6H) , 3.13 (br d, J = 5.4 Hz, 2H) , 1.40-1.46 (m, 4H) , 1.35 (br s, 5H) , 1.14-1.28 (m, 11H) , 1.06 (s, 12H) .
Example 20: Synthesis of (9R, 10S) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0029)
Step 1: Synthesis of 2- (oct-7-yn-1-yloxy) tetrahydro-2H-pyran
To a solution of oct-7-yn-1-ol (8.00 g, 63.39 mmol) in DCM (80 mL) was added PPTS (17.52 g, 69.73 mmol) and DHP (6.40 g, 76.07 mmol) . The reaction mixture was stirred for overnight at 25 ℃. After the reaction completion, the mixture was concentrated under vacuum, and the residue was diluted with a mixture solvent of DCM (15 mL) in MTBE (90 mL) . The resulting was stirred for 1 hour and filtered, the filtrate was concentrated and purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as yellow oil. (12.00 g, 90%) .
Step 2: Synthesis of 2- ( (6-bromohexyl) oxy) tetrahydro-2H-pyran
To a solution of 6-bromohexan-1-ol (12.00 g, 66.27 mmol) in DCM (120 mL) was added PPTS (18.32 g, 72.90 mmol) and DHP (6.69 g, 79.53 mmol) . The reaction mixture was stirred for overnight at 25 ℃. After the reaction completion, the mixture was concentrated under vacuum, and the residue was diluted with a mixture solvent of DCM (15 mL) in MTBE (90 mL) . The resulting was stirred for 1 hour and filtered, the filtrate was concentrated and purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as yellow oil. (15.00 g, 85 %) .
Step 3: Synthesis of 1, 14-bis ( (tetrahydro-2H-pyran-2-yl) oxy) tetradec-7-yne
To a solution of 2- (oct-7-yn-1-yloxy) tetrahydro-2H-pyran (10.00 g, 47.55 mmol) in THF (100 mL) was added n-BuLi (31.00 mL, 49.93 mmol) dropwise at -40 ℃ under N₂. After addition, the HMPA (25 mL) was added. The reaction mixture was stirred for 1 h at -40 ℃, and then 2- ( (6-bromohexyl) oxy) tetrahydro-2H-pyran (13.24 g, 49.92 mmol) was added dropwise at -40 ℃. The resulting was stirred for 1 hour at -40 ℃ and stirred at 25 ℃ for 18 h. After the reaction completion, the reaction mixture quenched with NH₄Cl (100 mL) and extracted with EA (100 mL × 2) . The combined organic layer was washed with brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (10.00 g, 53%)
Step 4: Synthesis of (E) -1, 14-bis ( (tetrahydro-2H-pyran-2-yl) oxy) tetradec-7-ene
To a solution of LAH (6.73 g, 177.39 mmol) in Diglyme (150 mL) was added 1, 14-bis ( (tetrahydro-2H-pyran-2-yl) oxy) tetradec-7-yne (10 g, 25.34 mmol) slowly at 25 ℃ under N₂ atmosphere. The reaction mixture was stirred at 140 ℃ for 24 hours. After the reaction completion, the mixture was cooled to 0 ℃ and added water (7 mL) , 15%NaOH aqueous solution (7 mL) and water (21 mL) . The resulting was stirred for 15 min, and then Na₂SO₄ was added. The mixture was filtered and concentrated. The crude product (10.00 g) was used for next step directly.
Step 5: Synthesis of (E) -tetradec-7-ene-1, 14-diol
To a solution of (E) -1, 14-bis ( (tetrahydro-2H-pyran-2-yl) oxy) tetradec-7-ene (10.00 g) in mixture solvent of MeOH (100 mL) in H₂O (10 mL) was added PTSA (1 g) . The reaction mixture was stirred at 25 ℃for 18 h. After the reaction completion, the mixture was diluted with EA (100 mL) , washed with brine (50 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 1/1) ) . The product was obtained as white solid. (4.10 g, 71%)
Step 6: Synthesis of (E) -1, 14-dibromotetradec-7-ene
To a solution of (E) -tetradec-7-ene-1, 14-diol (4.10 g, 17.95 mmol) and CBr₄ (17.86 g, 53.86 mmol) in DCM (40 mL) was added PPh₃ (14.13 g, 53.86 mmol) at 0 ℃ under N₂. The reaction mixture was stirred for 1 hour at 25 ℃. After the reaction completion, the mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as white solid. (3.40 g, 53%)
Step 7: Synthesis of diethyl (E) -2, 2, 17, 17-tetramethyloctadec-9-enedioate
To a solution of ethyl 2-methylpropanoate (2.76 g, 23.72 mmol) in THF (20 mL) was added LDA (12.00 mL, 23.72 mmol) dropwise at -40 ℃ under N₂ atmosphere. After 1 h, the reaction mixture was added (E) -1, 14-dibromotetradec-7-ene (2.10g, 5.93 mmol) dropwise. After addition, the reaction mixture was stirred at -40 ℃ for 0.5 hour and warmed to 25 ℃ for 18 hours. After the reaction completion, the mixture was quenched with ice-H₂O (20 mL) and extracted with EA (30 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as yellow oil. (2.40 g, 95%)
Step 8: Synthesis of diethyl 8, 8'- (oxirane-2, 3-diyl) bis (2, 2-dimethyloctanoate)
To a solution of diethyl diethyl (E) -2, 2, 17, 17-tetramethyloctadec-9-enedioate (200 mg, 0.47 mmol) in DCM (5 mL) was added m-CPBA (97 mg, 0.56 mmol) . The reaction mixture was stirred at rt for 2 h. After the reaction completion, the mixture was added H₂O (20 mL) and extracted with DCM (20 mL × 2) . The combined organic layer was washed with NaHCO₃ (20 mL) and brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) ) . The product was obtained as colorless oil. (200 mg, 96%)
Step 9: Synthesis of diethyl (9S, 10R) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of diethyl 8, 8'- (oxirane-2, 3-diyl) bis (2, 2-dimethyloctanoate) (290 mg, 0.46 mmol) in MeOH (5 mL) was added H₂SO₄ (0.1 mL) . The reaction mixture was stirred at rt for 1 h. After the reaction completion, the mixture was added H₂O (20 mL) and extracted with DCM (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) . The product was obtained as colorless oil. (200 mg, 64%) .
Step 10: Synthesis of diethyl (9R, 10S) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of diethyl (9S, 10R) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (200 mg, 0.42 mmol) in DCM (5 mL) was added CF₃SO₃Me (0.10 mL, 0.85 mmol) and 2, 6-di-tert-butylpyridine (0.14 mL, 0.63 mmol) . The reaction mixture was stirred at 40 ℃ for 18 hours. After the reaction completion, the mixture was diluted with DCM (20 mL) and washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) =20/1) ) . The product was obtained as colorless oil (150 mg, 73%) .
Step 11: Synthesis of (9R, 10S) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of diethyl (9R, 10S) -9, 10-dimethoxy-2, 2, 17, 17-tetramethyloctadecanedioate (150 mg, 0.31 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 70 ℃ for 18 hours. After the reaction completion, the mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (80 mg, 60%)
MS (ESI, pos. ion) m/z: 431.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 12.00 (br s, 2H) , 3.28 (s, 6H) , 3.13 (br d, J = 5.5 Hz, 2H) , 1.46 -1.31 (m, 10H) , 1.28 -1.16 (m, 14H) , 1.07 (s, 12H) .
Example 21: Synthesis of 1- (12-carboxy-6-methoxy-12-methyltridecyl) cyclopropane-1-carboxylic acid (0048)
Step 1: Synthesis of diethyl 7-cyano-2, 2, 13, 13-tetramethyl-7-tosyltetradecanedioate
To a solution of t-BuOK (355 mg, 3.16 mmol, 1.5 eq) in DMA (5 mL) was added the solution of ethyl 8-cyano-2, 2-dimethyl-8-tosyloctanoate (800 mg, 2.11 mmol) in DMA (3 mL) dropwise at 0 ℃ under N₂. After 30 mins, the mixture was added the solution of tert-butyl 6-bromo-2, 2-dimethylhexanoate (589 mg, 2.11 mmol, 1.0 eq) in DMA (3 mL) dropwise at 0 ℃. Then the reaction mixture was stirred at 25 ℃ for 2 hours. After the reaction completion, the reaction mixture was added saturated NH₄Cl (10 mL) aqueous solution and extracted with EA (20 mL × 3) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was obtained as yellow oil. (1.10 g, crude) and used for next step directly.
Step 2: Synthesis of diethyl 2, 2, 13, 13-tetramethyl-7-oxotetradecanedioate
To a solution of diethyl 7-cyano-2, 2, 13, 13-tetramethyl-7-tosyltetradecanedioate (1100 mg, crude) in DCM (15 mL) was added concentrated HCl (2 mL) at room temperature. The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture diluted with H₂O (20 mL) and extracted with DCM (20 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (460 mg, 57%) .
Step 3: Synthesis of diethyl 7-hydroxy-2, 2, 13, 13-tetramethyltetradecanedioate
To a solution of tert-butyl 1- (13-ethoxy-12, 12-dimethyl-6, 13-dioxotridecyl) cyclopropane-1-carboxylate (460 mg, 1.20 mmol, 1.0 eq) in MeOH (5 mL) was added NaBH₄ (43 mg, 1.20 mmol, 1.0 eq) at 0 ℃under N₂ atmosphere. The reaction mixture was stirred at 0 ℃ for 4 hours. The reaction mixture was poured into ice-water (10 mL) . The aqueous layer was extracted with EA (30 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (380 mg, 82%) .
Step 6: Synthesis of diethyl 7-methoxy-2, 2, 13, 13-tetramethyltetradecanedioate
To a solution of diethyl 7-hydroxy-2, 2, 13, 13-tetramethyltetradecanedioate (380 mg, 0.89 mmol, 1.0 eq) in DCM (10 mL) was added CF₃SO₃Me (293 mg, 1.78 mmol, 2.0 eq) and 2, 6-di-tert-butylpyridine (0.85 mg, 1.34 mmol, 1.5 eq) . The reaction mixture was stirred for 18 hours at 40 ℃. The reaction mixture was diluted with DCM (20 mL) . The organic layer was washed with H₂O (10 mL) and brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) =10/1) ) . The product was obtained as colorless oil. (100 mg, 29%) .
Step 7: Synthesis of 7-methoxy-2, 2, 13, 13-tetramethyltetradecanedioic acid
To a solution of diethyl 7-methoxy-2, 2, 13, 13-tetramethyltetradecanedioate (100 mg, 0.26 mmol, 1.0 eq) in MeOH (4 mL) was added 20%KOH (1 mL) solution. The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 N aq. HCl. The aqueous layer was extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (60 mg, 59%) .
MS (ESI, neg. ion) m/z: 343.1 [M-1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 12.00 (br s, 2H) , 3.19 (s, 3H) , 3.07 (quin, J = 5.5 Hz, 1H) , 1.48 -1.31 (m, 8H) , 1.28 -1.13 (m, 10H) , 1.06 (s, 12H) .
Example 22: Synthesis of (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0049)
Step 1: Synthesis of diethyl (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of AD-mix-α (1520 mg) in a mixture solvent of t-BuOH (5 mL) in H₂O (5 mL) was added MeSO₂NH₂ (98 mg, 1.04 mmol) at 0 ℃. The reaction mixture was stirred for 10 min at 0 ℃, and then diethyl (E) -2, 2, 17, 17-tetramethyloctadec-9-enedioate (400 mg, 0.94 mmol) was added. The resulting was stirred for 24 hours at 25 ℃. After the reaction completion, the mixture was quenched with sat. Na₂SO₃ aq. and stirred for 1 hour. The mixture was extracted with EA (20 mL × 3) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 2/1) ) to afford desired product as colorless oil. (220 mg, 51%)
Step 2: Synthesis of (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of diethyl (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate (100 mg, 0.22 mmol) in MeOH (4 mL) was added 20%KOH solution (1 mL) . The reaction mixture was stirred at 70 ℃for 18 hours. After the reaction completion, the mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 2/1) ) . The product was obtained as white solid. (33 mg, 37%)
MS (ESI, pos. ion) m/z: 403.1 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.96 (s, 2H) , 4.13 (br s, 2H) , 3.19 (br d, J = 4.0 Hz, 2H) , 1.50 -1.34 (m, 8H) , 1.22 (br s, 16H) , 1.06 (s, 12H) .
Example 23: Synthesis of (9R, 10R) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0050)
Step 1: Synthesis of diethyl (9R, 10R) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of AD-mix-β (1520 mg) in a mixture solvent of t-BuOH (5 mL) in H₂O (5 mL) was added MeSO₂NH₂ (98 mg, 1.04 mmol) at 0 ℃. The reaction mixture was stirred for 10 min at 0 ℃, and then diethyl (E) -2, 2, 17, 17-tetramethyloctadec-9-enedioate (400 mg, 0.94 mmol) was added. The reaction mixture was stirred for 24 hours at 25 ℃. After the reaction completion, the mixture was quenched with sat. Na₂SO₃ aq. and stirred for 1 hour. The resulting was extracted with EA (20 mL × 3) and washed with brine (30 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) =2/1) ) to afford desired product as colorless oil. (120 mg, 28%)
Step 2: Synthesis of (9R, 10R) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of diethyl (9R, 10R) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate (110 mg, 0.22 mmol) in MeOH (4 mL) was added 20%KOH solution (1 mL) . The reaction mixture was stirred at 70 ℃for 18 hours. After the reaction completion, the mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 2/1) ) . The product was obtained as white solid. (28 mg, 37%)
MS (ESI, pos. ion) m/z: 403.1 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (br s, 2H) , 4.13 (br s, 2H) , 3.19 (br s, 2H) , 1.48 -1.32 (m, 8H) , 1.22 (br s, 16H) , 1.07 (s, 12H) .
Example 24: Synthesis of (9S, 10S) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0034)
Step 1: Synthesis of diethyl (9S, 10S) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of diethyl (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate (90 mg, 0.20 mmol) in DCM (2 mL) was added CF₃SO₃Me (98 mg, 0.60 mmol) and 2, 6-Bis (1, 1-dimethylethyl) pyridine (77 mg, 0.40 mmol) . The reaction mixture was stirred at 40 ℃ for 18 hours. After the reaction completion, the mixture was diluted with H₂O (10 mL) and extracted with DCM (20 mL × 3) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (70 mg, 75%)
Step 2: Synthesis of (9S, 10S) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of diethyl (9S, 10S) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (70 mg, 0.15 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 70 ℃for 18 hours. After the reaction completion, the mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (32 mg, 52%)
MS (ESI, pos. ion) m/z: 417.1 [M+1] ⁺
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (br s, 2H) , 4.28 (br d, J = 4.0 Hz, 1H) , 3.48 -3.39 (m, 1H) , 3.27 (s, 3H) , 3.00 -2.88 (m, 1H) , 1.50 -1.37 (m, 6H) , 1.30 -1.11 (m, 18H) , 1.06 (s, 12H) .
Example 25: Synthesis of (9R, 10R) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0035)
Step 1: Synthesis of diethyl (9R, 10R) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of diethyl (9R, 10R) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate (100 mg, 0.22 mmol) in DCM (3 mL) was added CF₃SO₃Me (107 mg, 0.65 mmol) and 2, 6-Bis (1, 1-dimethylethyl) pyridine (84 mg, 0.44 mmol) . The reaction mixture was stirred at 40 ℃ for 18 hours. After the reaction completion, the reaction mixture was diluted with H₂O (10 mL) and extracted with DCM (20 mL × 3) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (60 mg, 58%)
Step 2: Synthesis of (9R, 10R) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of diethyl (9R, 10R) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (60 mg, 0.15 mmol) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 70 ℃for 18 hours. After the reaction completion, the mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (28 mg, 53%)
MS (ESI, pos. ion) m/z: 417.1 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ= 11.99 (br s, 2H) , 4.28 (br d, J = 5.0 Hz, 1H) , 3.49 -3.39 (m, 1H) , 3.27 (s, 3H) , 2.94 (br d, J = 2.8 Hz, 1H) , 1.50 -1.38 (m, 6H) , 1.22 (br d, J = 7.3 Hz, 18H) , 1.06 (s, 12H) .
Example 26: Synthesis of (7R, 8R) -7, 8-dimethoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid (0051)
Step 1: Synthesis of 2- (hex-5-yn-1-yloxy) tetrahydro-2H-pyran
To a solution of hex-5-yn-1-ol (24.00 g, 244.55 mmol) in DCM (300 mL) was added PPTS (67.60 g, 269.00 mmol) and DHP (28.80 g, 342.37 mmol) . The reaction mixture was stirred at 25 ℃ overnight. After the reaction completion, the mixture was concentrated under vacuum. The residue was diluted with a mixture solvent of DCM (60 mL) in MTBE (200 mL) , stirred for 1 hour and filtered. The filtrate was concentrated to give crude product, which was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as yellow oil. (44.00 g, 98%)
Step 2: Synthesis of 2- ( (5-bromopentyl) oxy) tetrahydro-2H-pyran
To a solution of 5-bromopentan-1-ol (5.00 g, 26.94 mmol) in DCM (60 mL) was added PPTS (7.45 g, 29.63 mmol) and DHP (3.17 g, 37.71 mmol) . The reaction mixture was stirred at 25 ℃ overnight. After the reaction completion, the mixture was concentrated under vacuum. The residue was diluted with a mixture solvent of DCM (10 mL) in MTBE (80 mL) , stirred for 1 hour and filtered. The filtrate was concentrated to give crude product, which was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as yellow oil (5.47 g, 80%)
Step 3: Synthesis of 2, 2'- (undec-5-yne-1, 11-diylbis (oxy) ) bis (tetrahydro-2H-pyran)
To a solution of 2- (hex-5-yn-1-yloxy) tetrahydro-2H-pyran (6.00 g, 32.92 mmol) in THF (60 mL) was added n-BuLi (20.5 mL, 32.92 mmol) dropwise at -40 ℃ under N₂, and then HMPA (15 mL) was added. The reaction mixture was stirred for 1 hours at -40 ℃, and then 2- ( (5-bromopentyl) oxy) tetrahydro-2H-pyran (8.68 g, 34.57 mmol) was added dropwise. The resulting was stirred for 1 hour at -40 ℃ and swarmed to 25 ℃ for 18 h. After the reaction completion, the mixture was quenched with NH₄Cl (50 mL) and extracted with EA (50 mL × 2) . The combined organic layer was washed with brine (30 mL × 2) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (9.20 g, 79%)
Step 4: Synthesis of (E) -2, 2'- (undec-5-ene-1, 11-diylbis (oxy) ) bis (tetrahydro-2H-pyran)
To a solution of LAH (678 mg, 17.87 mmol) in Diglyme (20 mL) was added 2, 2'- (undec-5-yne-1, 11-diylbis (oxy) ) bis (tetrahydro-2H-pyran) (900 mg, 2.55 mmol) at 25 ℃ under N₂ atmosphere. The reaction mixture was stirred for 12 hours at 140 ℃. After the reaction completion, the mixture was cooled to 0 ℃ and added water (0.700 mL) , 15%NaOH aqueous solution (0.700 mL) and water (2.1 mL) The resulting was stirred for 15 min and added Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (680 mg, 75%)
Step 5: Synthesis of (E) -undec-5-ene-1, 11-diol
To a solution of (E) -2, 2'- (undec-5-ene-1, 11-diylbis (oxy) ) bis (tetrahydro-2H-pyran) (600 mg, 1.69 mmol) in mixture solvent of MeOH (10 mL) and H₂O (1 mL) was added PTSA (60 mg) . The reaction mixture was stirred at 25 ℃ overnight. After the reaction completion, the mixture was diluted with EA (20 mL) and washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 1/1) ) . The product was obtained as white solid. (300 mg, 95%)
Step 6: Synthesis of (E) -1, 11-dibromoundec-5-ene
To a solution of (E) -undec-5-ene-1, 11-diol (200 mg, 1.07 mmol) and CBr₄ (1068 mg, 3.22 mmol) in DCM (8 mL) was added PPh₃ (844 mg, 3.22 mmol) at 0 ℃ under N₂. The reaction mixture was stirred at 25 ℃for 1 hour. After the reaction completion, the mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as white solid. (270 mg, 80%)
Step 7: Synthesis of diethyl (E) -2, 2, 14, 14-tetramethylpentadec-7-enedioate
To a solution of ethyl 2-methylpropanoate (297 mg, 2.56 mmol) in THF (4 mL) was added LDA (2.6 mL, 2.56 mmol) dropwise at -40 ℃ under N₂ atmosphere. After addition, the reaction mixture was stirred for 1 hour, and then (E) -1, 11-dibromoundec-5-ene (200 mg, 0.64 mmol) was added. The resulting was stirred at 25 ℃for 18 hours. After the reaction completion, the reaction mixture was quenched with ice-H₂O (10 mL) and extracted with EA (10 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as yellow oil. (120 mg, 49%)
Step 8: Synthesis of diethyl (7R, 8R) -7, 8-dihydroxy-2, 2, 14, 14-tetramethylpentadecanedioate
To a solution of AD-Mix-β (3000 mg) in mixture solvent of t-BuOH (14 mL) in H₂O (14 mL) was added methane sulfonamide (219 mg, 2.30 mmol, 1.1 eq) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 10 min, and then the solution of diethyl (E) -2, 2, 14, 14-tetramethylpentadec-7-enedioate (800 mg, 2.09 mmol, 1.0 eq) in a mixture solvent of t-BuOH (5 mL) in H₂O (5 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. After the reaction completion, the reaction mixture was quenched with saturated Na₂SO₃ solution (20 mL) and extracted with EA (30 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 1/1) ) . The product was obtained as colorless oil. (240 mg, 27%)
Step 9: Synthesis of diethyl (7R, 8R) -7, 8-dimethoxy-2, 2, 14, 14-tetramethylpentadecanedioate
To a solution of diethyl (7R, 8R) -7, 8-dihydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (240 mg, 0.58 mmol, 1.0 eq) in DCM (3 mL) was added CF₃SO₃Me (0.13 mL, 1.15 mmol, 2.0 eq) and 2, 6-di-tert-butylpyridine (0.19 mL, 0.86 mmol, 1.5 eq) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 18 hours. After the reaction completion, the reaction mixture was diluted with DCM (20 mL) and washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (70 mg, 27%) .
Step 10: Synthesis of (7R, 8R) -7, 8-dimethoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid
To a solution of diethyl (7R, 8R) -7, 8-dimethoxy-2, 2, 14, 14-tetramethylpentadecanedioate (70 mg, 0.16 mmol, 1.0 eq) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred at 70 ℃ for 18 hours. After the reaction completion, the reaction mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The combined organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) =5/1) ) . The product was obtained as colorless oil. (28 mg, 45%) .
MS (ESI, pos. ion) m/z: 389.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (br s, 2H) , 3.28 (s, 6H) , 3.15 (br s, 2H) , 1.48 -1.33 (m, 8H) , 1.29 -1.16 (m, 10H) , 1.07 (s, 12H) .
Example 27: Synthesis of (7S, 8S) -7, 8-dimethoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid (0052)
Step 1: Synthesis of diethyl (7S, 8S) -7, 8-dihydroxy-2, 2, 14, 14-tetramethylpentadecanedioate
To a solution of AD-Mix-β (3000 mg) in mixture solvent of t-BuOH (14 mL) in H₂O (14 mL) was added methane sulfonamide (219 mg, 2.30 mmol, 1.1 eq) at 0 ℃. The reaction mixture was stirred for 10 min, and then the solution of diethyl (E) -2, 2, 14, 14-tetramethylpentadec-7-enedioate (800 mg, 2.09 mmol, 1.0 eq) in mixture solvent of t-BuOH (5 mL) in H₂O (5 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. After the rection completion, the reaction mixture was quenched with saturated Na₂SO₃ solution (20 mL) and extracted with EA (30 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 1/1) ) . The product was obtained as colorless oil. (640 mg, 73%)
Step 2: Synthesis of diethyl (7S, 8S) -7, 8-dimethoxy-2, 2, 14, 14-tetramethylpentadecanedioate
To a solution of diethyl (7S, 8S) -7, 8-dihydroxy-2, 2, 14, 14-tetramethylpentadecanedioate (400 mg, 0.96 mmol. 1.0 eq) in DCM (5 mL) was added CF₃SO₃Me (0.22 mL, 1.92 mmol, 2.0 eq) and 2, 6-di-tert-butylpyridine (0.32 mL, 1.44 mmol, 1.5 eq) at 0 ℃. The reaction mixture was stirred for 18 hours at 25 ℃. After the rection completion, the reaction mixture was diluted with DCM (20 mL) and washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (190 mg, 44%) .
Step 3: Synthesis of (7S, 8S) -7, 8-dimethoxy-2, 2, 14, 14-tetramethylpentadecanedioic acid
To a solution of diethyl (7R, 8R) -7, 8-dimethoxy-2, 2, 14, 14-tetramethylpentadecanedioate (190 mg, 0.43 mmol, 1.0 eq) in MeOH (4 mL) was added 20%KOH aq. (2 mL) . The reaction mixture was stirred at 70 ℃ for 18 hours. After the rection completion, the reaction mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (110 mg, 66%) .
MS (ESI, pos. ion) m/z: 389.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (br s, 2H) , 3.28 (s, 6H) , 3.15 (br s, 2H) , 1.49 -1.35 (m, 8H) , 1.28 -1.16 (m, 10H) , 1.07 (s, 12H) .
Example 28: Synthesis of (9S, 10S) -9- ( (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyl) oxy) -10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0040)
Step 1: Synthesis of di-tert-butyl (E) -2, 2, 17, 17-tetramethyloctadec-9-enedioate
To a solution of tert-butyl isobutyrate (1302 mg, 9.04 mmol, 4.0 eq) in THF (20 mL) was added LDA (4.52 mL, 9.04 mmol) dropwise at 0 ℃ under N₂ atmosphere. After 1 h, the reaction mixture was added (E) -1,14-dibromotetradec-7-ene (800 mg, 2.26 mmol, 1.0 eq) . After addition, the resulting was stirred at 0 ℃ for 0.5 hour and another 18 hours at 25 ℃. After the reaction completion, the reaction mixture was quenched with ice-H₂O (20 mL) and extracted with EA (30 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as yellow oil. (850 mg, 78%)
Step 2: Synthesis of di-tert-butyl (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of AD-MIX-α (1900 mg) in mixture solvent of t-BuOH (10 mL) in H₂O (10 mL) was added MeSO₂NH₂ (109 mg, 1.14 mmol, 1.1 eq) at 0 ℃. The reaction mixture was stirred for 10 min at 0 ℃, and then di-tert-butyl (E) -2, 2, 17, 17-tetramethyloctadec-9-enedioate (500 mg, 1.04 mmol, 1.0 eq) was added. The reaction mixture was stirred for 18 hours at RT. After the reaction completion, the reaction mixture was quenched with Na₂SO₃ (20 mL) and extracted with EA (30 mL × 3) . The combined organic layer was washed with brine (20 mL× 2) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 2/1) ) . The product was obtained as colorless oil. (480 mg, 89%)
Step 3: Synthesis of di-tert-butyl (9S, 10S) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of di-tert-butyl (9S, 10S) -9, 10-dihydroxy-2, 2, 17, 17-tetramethyloctadecanedioate (400 mg, 0.78 mmol, 1.0 eq) in THF (10 mL) was added NaH (47 mg, 1.17 mmol, 1.5 eq) at 0 ℃. The reaction mixture was stirred for 30 min, and then CH₃I (166 mg, 1.17 mmol, 1.5 eq) was added. The resulting was stirred at 25 ℃for 3 hours. After the reaction completion, the reaction mixture was quenched with H₂O (10 mL) and extracted with EA (20 mL × 3) . The combined organic layer was washed with brine (10 mL× 2) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) =5/1) ) . The product was obtained as colorless oil. (200 mg, 48%) .
Step 4: Synthesis of di-tert-butyl (9S, 10S) -9- ( (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyl) oxy) -10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of di-tert-butyl (9S, 10S) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (200 mg, 0.38 mmol, 1.0 eq) in THF (4 mL) was added Fenofibric acid (145 mg, 0.45 mmol, 1.2 eq) , DCC (117 mg, 0.57 mmol, 1.5 eq) and DMAP (9 mg, 0.08 mmol, 0.2 eq) . The reaction mixture was stirred at 25 ℃ for 18 hours. After the reaction completion, the reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (90 mg, 28%) .
Step 5: Synthesis of (9S, 10S) -9- ( (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyl) oxy) -10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of di-tert-butyl (9S, 10S) -9- ( (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyl) oxy) -10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (80 mg, 0.10 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1 mL) . The reaction mixture was stirred at 25 ℃ for 1 hour. After the reaction completion, the reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 1/1) ) . The product was obtained as yellow oil. (43 mg, 60%) .
MS (ESI, pos. ion) m/z: 717.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 12.10 -11.68 (m, 2H) , 7.71 (dd, J = 6.8, 8.6 Hz, 4H) , 7.65 -7.58 (m, 2H) , 6.91 (d, J = 8.8 Hz, 2H) , 4.98 -4.90 (m, 1H) , 3.26 (s, 3H) , 3.17 -3.10 (m, 1H) , 1.63 (s, 6H) , 1.55 -1.31 (m, 6H) , 1.12 (br s, 18H) , 1.03 (d, J = 3.4 Hz, 12H) .
Example 29: Synthesis of (9S, 10R) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0042)
Step 1: Synthesis of diethyl (9S, 10R) -9- ( (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyl) oxy) -10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of diethyl 9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (100 mg, 0.21 mmol, 1.0 eq) in THF (5 mL) was added DCC (65 mg, 0.32 mmol, 1.5 eq) , DMAP (3 mg, 0.02 mmol, 0.1 eq) and 2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoic acid (80 mg, 0.25 mmol, 1.2 eq) . The reaction mixture was stirred at rt overnight. The mixture was filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) and SFC. The product was obtained as colorless oil (50 mg, 31%) .
SFC conditions:
Analytical separation method
Instrument: Waters UPC2 analytical SFC (SFC-H)
Column: ChiralPak AD, 50×4.6mm I. D., 3μm
Mobile phase: A for CO₂ and B for Isopropanol (0.05%DEA)
Gradient: B 5-40%
Flow rate: 3 mL/min
Back pressure: 100 bar
Column temperature: 35℃
Wavelength: 220nm
Preparative separation method
Instrument: Waters 150 preparative SFC (SFC-26)
Column: ChiralPak AD, 250×30mm I. D., 10μm
Mobile phase: A for CO₂ and B for Isopropanol
Gradient: B 15%
Flow rate: 120 mL /min
Back pressure: 100 bar
Step 2: Synthesis of (9S, 10R) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of diethyl (9S, 10R) -9- ( (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyl) oxy) -10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (50 mg, 0.06 mmol, 1.0 eq) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (12 mg, 44%) .
MS (ESI, neg. ion) m/z: 415.1 [M-1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 12.00 (br s, 2H) , 4.34 (br d, J = 5.4 Hz, 1H) , 3.41 –3.36 (m, 1H) , 3.25 (s, 3H) , 2.90 (br d, J = 4.8 Hz, 1H) , 1.46 –1.40 (m, 6H) , 1.30 –1.16 (m, 18H) , 1.07 (s, 12H) .
Example 30: Synthesis of (9R, 10S) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid (0043)
Step 1: Synthesis of diethyl (9R, 10S) -9- ( (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyl) oxy) -10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate
To a solution of diethyl 9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (100 mg, 0.21 mmol, 1.0 eq) in THF (5 mL) was added DCC (65 mg, 0.32 mmol, 1.5 eq) , DMAP (3 mg, 0.02 mmol, 0.1 eq) and 2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoic acid (80 mg, 0.25 mmol, 1.2 eq) . The reaction mixture was stirred at rt overnight. The mixture was filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) and SFC. The product was obtained as colorless oil (50 mg, 31%) .
SFC conditions:
Analytical separation method
Instrument: Waters UPC2 analytical SFC (SFC-H)
Column: ChiralPak AD, 50×4.6mm I. D., 3μm
Mobile phase: A for CO₂ and B for Isopropanol (0.05%DEA)
Gradient: B 5-40%
Flow rate: 3 mL/min
Back pressure: 100 bar
Column temperature: 35℃
Wavelength: 220nm
Preparative separation method
Instrument: Waters 150 preparative SFC (SFC-26)
Column: ChiralPak AD, 250×30mm I. D., 10μm
Mobile phase: A for CO₂ and B for Isopropanol
Gradient: B 15%
Flow rate: 120 mL /min
Back pressure: 100 bar
Step 2: Synthesis of (9R, 10S) -9-hydroxy-10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioic acid
To a solution of diethyl (9R, 10S) -9- ( (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyl) oxy) -10-methoxy-2, 2, 17, 17-tetramethyloctadecanedioate (50 mg, 0.06 mmol, 1.0 eq) in MeOH (4 mL) was added 20%KOH aq. (1 mL) . The reaction mixture was stirred for 18 hours at 70 ℃. The reaction mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine (10 mL) , dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil (10 mg, 36%) .
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (br s, 2H) , 4.34 (d, J = 5.8 Hz, 1H) , 3.37 (br s, 1H) , 3.31 -3.20 (m, 3H) , 2.90 (brd, J = 4.6 Hz, 1H) , 1.46 -1.36 (m, 8H) , 1.29 (br s, 4H) , 1.23 -1.17 (m, 12H) , 1.07 (s, 12H) .
Example 31: Synthesis of 9-methoxy-2, 2, 16, 16-tetramethylheptadecanedioic acid (0044)
Step 1: Synthesis of ethyl 8-bromo-2, 2-dimethyloctanoate
To a solution of ethyl 2-methylpropanoate (4.00 g, 34.44 mmol, 1.0 eq ) in THF (40 mL) was added LDA (18.08 mL, 36.16 mmol, 1.05 eq) dropwise at -40 ℃ under N₂ atmosphere. After 1 hour, then 1, 6-dibromohexane (10.92 g, 44.77 mmol, 1.3 eq) was added. After addition, the resulting was stirred for 0.5 hour at -40 ℃, and then the reaction mixture was warmed to RT and stirred overnight. After the reaction completion, the reaction mixture was poured into ice-water (20 mL) and extracted with EA (50 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 50/1) ) . The product was obtained as yellow oil (3.30 g, 34%) .
Step 2: Synthesis of diethyl 9-cyano-2, 2, 16, 16-tetramethyl-9-tosylheptadecanedioate
To a solution of TosMIC (1.15 g, 5.91 mmol, 1.0 eq) and Bu₄NI (0.22 g, 0.59 mmol, 0.1 eq) in DMSO (50 mL) was added NaH (0.71 g, 17.73 mmol, 3.0 eq) at 25 ℃ under N₂ atmosphere. The reaction mixture was stirred for 30 min at 25 ℃, and then ethyl 8-bromo-2, 2-dimethyloctanoate (3.30 g, 11.82 mmol, 2.0 eq) was added. After 1 h, the reaction mixture was quenched with ice-water (40 mL) at 0 ℃ and extracted with EA (50 mL × 2) . The combined organic layer was washed with 10%HCl solution (20 mL × 3) , brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 10/1) ) . The product was obtained as yellow oil (2.60 g, 37%) .
Step 3: Synthesis of diethyl 2, 2, 16, 16-tetramethyl-9-oxoheptadecanedioate
To a solution of diethyl 9-cyano-2, 2, 16, 16-tetramethyl-9-tosylheptadecanedioate (2.60 g, 4.39 mmol, 1.0 eq) in DCM (30 mL) was added conc. HCl (2 mL) at room temperature. The reaction mixture was stirred at 25 ℃ for 4 hours. After the reaction completion, the reaction mixture diluted with H₂O (20 mL) and extracted with DCM (20 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (1.70 g, 91%) .
Step 4: Synthesis of diethyl 9-hydroxy-2, 2, 16, 16-tetramethylheptadecanedioate
To a solution of diethyl 2, 2, 16, 16-tetramethyl-9-oxoheptadecanedioate (1.70 g, 3.98 mmol, 1.0 eq) in MeOH (20 mL) was added NaBH₄ (0.15 g, 3.98 mmol, 1.0 eq) at 0 ℃ under N₂ atmosphere. The reaction mixture was stirred at 0 ℃ for 3 hours. After the reaction completion, the reaction mixture was poured into ice-water (20 mL) and extracted with EA (30 mL × 2) . The combined organic layer was washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 5/1) ) . The product was obtained as colorless oil. (1.40 g, 82%) .
Step 5: Synthesis of diethyl 9-methoxy-2, 2, 16, 16-tetramethylheptadecanedioate
To a solution of diethyl 9-hydroxy-2, 2, 16, 16-tetramethylheptadecanedioate (1400 mg, 3.27 mmol, 1.0 eq) in DCM (20 mL) was added CF₃SO₃Me (0.74 mL, 6.53, 2.0 eq mmol) and 2, 6-di-tert-butylpyridine (1.10 mL, 4.90 mmol, 1.0 eq) . The reaction mixture was stirred at 40 ℃ for 18 hours. After the reaction completion, the reaction mixture was diluted with DCM (20 mL) and washed brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 20/1) ) . The product was obtained as colorless oil. (900 mg, 62 %) .
Step 5: Synthesis of 9-methoxy-2, 2, 16, 16-tetramethylheptadecanedioic acid
To a solution of diethyl 9-methoxy-2, 2, 16, 16-tetramethylheptadecanedioate (900 mg, 2.03 mmol, 1.0 eq) in MeOH (8 mL) was added 20%KOH (2 mL) . The reaction mixture was stirred at 70 ℃ for 6 hours. After the reaction completion, the reaction mixture was adjusted to pH=1 with 1 M HCl solution and extracted with EA (20 mL × 2) . The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, PE/EA (v/v) = 3/2) ) . The product was obtained as white solid. (500 mg, 63%) .
MS (ESI, pos. ion) m/z: 387.2 [M+1] ⁺.
¹HNMR (400 MHz, DMSO-d₆) δ = 11.99 (br s, 2H) , 3.19 (s, 3H) , 3.08 (t, J = 5.6 Hz, 1H) , 1.49 -1.32 (m, 8H) , 1.31 -1.14 (m, 16H) , 1.06 (s, 12H) .
Biological Assays
Test 1: Effects of Illustrative Compounds of the Invention on the Sterols and Fatty acid Synthesis in Male ICRCD-1 Mouse Hepatocytes
1. Compound dilution
1.1 Solve compounds at 10 mM in DMSO.
1.2 Dilute compounds by 4-fold serial dilutions up to 7 doses. Add 10 μL compounds DMSO solution into 190 μL William’s E medium as intermediate solution (20-fold dilution, with 5%DMSO) .
1.3 Transfer 50 μL compounds intermediate solution into 24-well plate, then add 200 μL medium to each well (10-fold dilution, with 1%DMSO) .
2. Thaw cells and seed cell
2.1 Warmed up assay medium and thawing medium at 37 ℃ water bath for 20 minutes.
2.2 Immediately immersed the vial of Male ICRCD-1 Mouse Hepatocytes into a 37 ℃ water bath. Shake gently. This step can take 90-120 seconds.
2.3 Remove the vial from the water bath as soon as the contents are thawed, decontaminate by dipping in or spraying with 70%ethanol.
2.4 Transfer the content of vial into the pre-warmed 45 mL Thawing medium.
2.5 Centrifuge the Male ICRCD-1 Mouse Hepatocytes suspension at 100 x g in a room temperature centrifuge for 5 minutes.
2.6 Suspend and mix cell pellet with the 1 mL assay medium, then add another 4 mL assay medium to count.
3. Lyse cells by protocol
3.1 Prepare 24-well plates with 200ul Williams' Medium E medium in each well and with 50 ul diluted compounds,
3.2 Seed Male ICRCD-1 Mouse Hepatocytes in 24-well plates, 2x10⁵ cells/well/250 ul, incubated in a humidified incubator with 5%CO2 at 37℃.
3.3 Add 2 μCi [2-14C] -acetate into each well, incubate the plate in a humidified incubator with 5%CO2 at 37℃ for 3.5 h.
3.4 Transfer medium into 15 mL centrifuge tube, add 0.5 mL of 0.1M NaOH to each well and let sit at RT to lyse the cell monolayer, and then transfer the cell lysates into the corresponding 15 mL centrifuge tubes.
3.5 Add 1.0 mL of Ethanol and 0.17 mL 50%KOH to tubes and incubate at 90℃ in water bath for 1 hour.
3.6 Cool to room temperature, add 5 mL petroleum ether/tube, shake vigorously, centrifuge at 1500 rpm for 3 min. transfer 4 mL petro-ether layer to a glass tube (18×180 mm) .
3.7 Repeat step 3.6.
3.8 Acidify aqueous phase with 1 mL of concentrated HCl. Check pH of one or two extracts to make sure pH is below 1.
3.9 Add 5 mL petroleum ether/tube, shake vigorously, centrifuge at 1500 rpm for 3 min, transfer 4 mL petro-ether layer to a new glass tube (18×180 mm) .
3.10 Repeat step 3.9.
3.11 Evaporate pooled extracts to dryness at 64℃ in water bath for 30 min
3.12 Resolve fatty acid in 400 μL of chloroform-hexane (1: 1) .
3.13 Add 50ul into Isoplate-96 Microplate, add 200 uL UltimaGold and incubate 5 min, then read by MicroBeta.
4. Test Principle
4.1 The de novo lipogenesis (DNL) assay was selected for compound screening. Cells were laid in sterile culture wells, the compound to be tested and D- [U-¹⁴C] glucose were added, and the cells were allowed to take up extracellular D- [U-¹⁴C] glucose in the presence of the recipient compound and use it as a raw material to synthesize fatty acids with ¹⁴C-labeled fatty acids, and extract the ¹⁴C-labeled fatty acids from the cells. The ¹⁴C-labeled fatty acids are subjected to a scintillation solution that stimulates chemiluminescence, and the luminescence signal is detected using MicroBeta. The intensity of the luminescence signal is positively correlated with the ability of adipocytes to synthesize new lipids.
The EC₅₀ values are shown in table 1.
Table 1. Effect of Illustrative Compounds on the Sterols and Fatty acid Synthesis in Male ICRCD-1 Mouse Hepatocytes
A means EC50≤1 μM, B means 1μM≤EC50≤5μM, C means 5μM≤EC50≤10μM, D means EC50≥10μM.
Test 2: Liver microsome Stability Study
1. The master solution was prepared according to Table 2.
Table 2. Preparation of Master Solution
2. Two separated experiments were performed as follows. a) With NADPH: 10 μL of 20 mg/mL liver microsomes and 40 μL of 10 mM NADPH were added to the incubations. The final concentrations of microsomes and NADPH were 0.5 mg/mL and 1 mM, respectively. b) Without NADPH: 10 μL of 20 mg/mL liver microsomes and 40 μL of ultra-pure H₂O were added to the incubations. The final concentration of microsomes was 0.5 mg/mL.
3. The reaction was started with the addition of 4 μL of 100 μM test compound solution or control compound solution at the final concentration of 1 μM and carried out at 37 ℃.
4. Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45 and 60 min. The reaction was stopped by the addition of 4 volumes of cold acetonitrile with IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 2 μM ketoprofen) . Samples were centrifuged at 3, 220 g for 40 minutes. Aliquot of 100 μL of the supernatant was mixed with 100 μL of ultra-pure H₂O and then used for LC-MS/MS analysis.
5. Data Analysis, all calculations were carried out using Microsoft Excel.
Peak areas were determined from extracted ion chromatograms. The slope value was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve.
The in vitro half-life (in vitro t_1/2) was determined from the slope value:
in vitro t_1/2=0.693/k,
Where: k is the rate constant (k= -slope value)
Conversion of the in vitro t_1/2 (min) into the in vitro intrinsic clearance (in vitro CL_int, in μL/min/mg protein) was done using the following equation (mean of duplicate determinations) :
The results are shown in table 3.
Table 3. Summary of the Liver microsome Stability for Compounds
Test 3: Single dose plasma pharmacokinetic profile of compounds in male CD1 mice
1. Materials
The compounds of the invention.
2. Animals
Male CD1 mice were purchased from Si Bei Fu Laboratory Animal Technology Co. Ltd. The animals were 6-8 weeks old with body weights ranging between 20 and 30 g on the dosing date. Animals were housed in a 12h light/dark cycle environment. All animals for IV and PO administration were fasted overnight and fed after 4 hours collection.
3. Preparation of Dose
3.1 The IV dosing solution was prepared as a clear solution in PBS (with the final pH at 7.0～8.0) (adding 2eq NaOH) at a concentration of 4 mg/mL.
3.2 The oral dose solution was prepared as a solution in 1.5% (w/v) Carboxymethyl cellulose and 0.2 %tween 20 in DI water (adding 2eq NaOH) at a concentration of 2 mg/mL.
3.3 Pharmacokinetic parameters were calculated using the nominal dose values if the measured values were within 20%of the nominal values.
4. In Vivo Procedure
A total of six mice were dosed as shown in Table 4. Three mice were dosed IV via a bolus injection via vail vein. Three mice were dosed by oral gavage. Blood samples were collected by orbital sinus bleeding into tubes containing K2EDTA at pre-dose (PO only) , 5 min (IV only) , 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, and 48 h post-dose. Blood samples (～ 0.03 mL per time point and 0.3 mL at final time point via heart puncture) were centrifuged for 5 min at (4000 g) in a refrigerated (4 ℃) centrifuge and the collected plasma stored at -80 ℃ until analysis.
Table 4. Dosing Information
A: PBS (with the final pH at 7.0～8.0) (adding 2eq NaOH)
B: 1.5% (w/v) Carboxymethyl cellulose and 0.2 %tween 20 in DI water (adding 2eq NaOH)
5. Plasma Sample Analysis
5.1 Standard stock solution of the compound was prepared in DMSO at 1 mg/mL. Calibration standard working solutions were prepared at concentrations of 10, 20, 50, 100, 200, 500, 1000, 5000, 10000 ng/mL by serial dilution of the standard stock solution by DMSO. Quality control (QC) working solutions at concentrations of 20, 50, 500, and 8000 ng/mL were prepared by serial dilution of the standard stock solution by 50%acetonitrile in water. These QC samples were prepared on the day of the analysis in the same way as the calibration standards.
5.2 For the plasma sample treatment, 3 μL of each calibration standard working solution (10, 20, 50, 100, 200, 500, 1000, 5000, 10000 ng/mL ng/mL) was added to 30 μL of male blank CD1 mouse plasma to achieve calibration standards of 1-1000 ng/mL (1, 2, 5, 10, 20, 50, 100, 500, 1000 ng/mL) in a total volume of 33 μL. Four QC samples at 2 ng/mL (low-1) , 5 ng/mL (low-2) , 50 ng/mL (mid) , and 800 ng/mL (high) in blank plasma were prepared independently from those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as the calibration standards.
5.3 33 μL of standards, 33 μL of QC samples or 33 μL of unknown samples (30 μL of plasma sample with 3 μL of DMSO) were mixed with 200 μL of acetonitrile containing IS (dexamethasone 50 ng/mL) to precipitate proteins. Then the samples were vortex-mixed for 30 seconds. After centrifugation at 4000 rpm and 4 ℃ for 15 minutes, the aliquot supernatant was diluted at a ratio of 1: 2 with ultrapure water (v/v: 1/2) . Then 10 μL of the dilute plasma sample supernatant was injected onto the LC-MS/MS system for quantitative analysis.
6. LC-MS/MS Conditions
6.1 The LC-MS/MS system consisted of a Shimadzu Liquid Chromatograph LC-30 AD, Degasser DGU-20A5R, Communications Bus Module CBM-20A, Auto Sampler SIL-30AC, Shimadzu Rack Changer II, and a Shimadzu LCMS-8060 mass spectrometer. Chromatographic separation was achieved at room temperature on a Raptor Biphenyl 2.7μm 50×2.1mm for analysis of 0010. The mobile phase was composed of A: 5%acetonitrile in water containing 0.1%formic acid; and B: 95%acetonitrile in water containing 0.1%formic acid. The mobile phase flow rate used was 0.6 mL/min. The injection volume used was 10 μL.
6.2 Positive ion mode electrospray ionization (ESI) was performed to obtain protonated ions of 0010 and dexamethasone (IS) . The optimized transitions were m/z 373.15 to m/z 309.15 for CK-4015089 and m/z 393.30 to m/z 373.15 for dexamethasone IS.
7. Bioanalytical Criteria
7.1 The standard curve was performed in duplicate with nine standards, with all standards and the LLOQ falling within ±20%of the nominal value. The lower limit of quantitation (LLOQ) had a minimum signal to noise ratio of 3. Four duplicate QC’s at three concentrations (low, mid, and high QC) were incorporated into each run with the low QC no more than 3x LLOQ, the mid QC around the middle of the curve, and the high QC near the ULOQ (minimally 80%but less than
7.2 100%of the value of the highest standard) for the run and the mean value within ±20%of the theoretical value. The results of the QC’s provided the basis for accepting or rejecting the run. Each of the four QC’s were within 20%of their respective nominal values. The simplest model that adequately described the concentration-response relationship was linear regression with a weighting of 1/x2.
The results are shown in table 5 , table 6, table7 and table8.
Table 5. Summary of the Mean Pharmacokinetic Parameters in Mouse Plasma for Compounds (IV)
Table 6. Summary of the Mean Pharmacokinetic Parameters in Mouse Plasma for Compounds (PO)
Table7. Summary of Compound 0040 IV Plasma pharmacokinetic parameters
Table 8. Summary of Compound 0040 PO Plasma Pharmacokinetic Parameters in Mouse
The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illusfrations of a few aspects of the invention and any embodiments which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the appended claims.

Claims

A compound having formula I,

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylamino, (C1-C6) alkylthio, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl, (C1-C9) heteroaryl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C2-C6) heterocyclyl- (C1-C6) alkyl, (C6-C10) aryl- (C1-C6) alkyl or (C1-C9) heteroaryl- (C1-C6) alkyl; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; or R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;

each of n and m is independently 4, 5, 6, 7, 8, 9 or 10;

R is H, D, halo, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl or (C1-C9) heteroaryl; R is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;

G is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl or (C1-C9) heteroaryl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano;

or G isor one or more deuterium substituted

or G is H, and at the same time, at least one R¹ is independently hydroxy;

each of Y¹ and Y² is independently -OH, - (C1-C6) alklene-OH, -C (=O) -OH, -C (=O) H, -C (=O) OR⁵, -S (=O) ₂OH, -S (=O) ₂NH₂,

or one of Y¹ and Y² is

R⁵ is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl, (C1-C9) heteroaryl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C2-C6) heterocyclyl- (C1-C6) alkyl, (C6-C10) aryl- (C1-C6) alkyl or (C1-C9) heteroaryl- (C1-C6) alkyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkoxy or (C1-C6) haloalkoxy;

each of R⁶ and R⁷ is independently H, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl; each of R⁶ and R⁷ is optionally and independently substitutled with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkoxy or phenyl.
The compound of claim 1, wherein G is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1, 4-dioxanyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, or cyano.
The compound of claim 1, wherein G is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, or cyano.
The compound of claim 1, wherein G is methyl, ethyl or cyclopropyl; G is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, or cyano.
The compound of claim 1, wherein each of Y¹ and Y² is independently -OH, - (C1-C6) alkyl-OH, -C (=O) -OH, -C (=O) H, -C (=O) OR⁵, -S (=O) ₂OH or -S (=O) ₂NH₂;

R⁵ is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C2-C6) heterocyclyl, (C6-C10) aryl, (C1-C9) heteroaryl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C2-C6) heterocyclyl- (C1-C6) alkyl, (C6-C10) aryl- (C1-C6) alkyl or (C1-C9) heteroaryl- (C1-C6) alkyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, (C1-C6) alkoxy or (C1-C6) haloalkoxy.
The compound of claim 1, wherein each of Y¹ and Y² is independently -OH, -CH₂-OH, -CH₂CH₂-OH, -C (=O) -OH, -C (=O) H, -C (=O) OR⁵;

R⁵ is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1, 4-dioxanyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo, cyano, methoxy, difluoromethoxy or trifluoromethoxy.
The compound of claim 1, wherein each of Y¹ and Y² is independently -OH, -CH₂-OH, -C (=O) -OH, -C (=O) H, -C (=O) OR⁵;

R⁵ is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1, 4-dioxanyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, cyano, methoxy, difluoromethoxy or trifluoromethoxy.
The compound of claim 1, wherein each of Y¹ and Y² is independently -CH₂-OH, -C (=O) -OH or -C (=O) OR⁵;

R⁵ is methyl, ethyl, n-propyl, i-propyl, t-butyl, vinyl, allyl; R⁵ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, cyano, methoxy, difluoromethoxy or trifluoromethoxy.
The compound of claim 1, wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, halo, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylamino, (C1-C4) alkylthio, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C2-C5) heterocyclyl, phenyl, (C3-C6) cycloalkylmethyl, (C3-C6) cycloalkylethyl, (C2-C6) heterocyclylmehtyl, (C2-C6) heterocyclylehtyl, benzyl; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; or R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br, or cyano;

each of n and m is independently 4, 5, 6, 7, 8, 9 or 10.
The compound of claim 1, wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, F, Cl, Br, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylamino, (C1-C4) alkylthio, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C2-C5) heterocyclyl, phenyl, (C3-C6) cycloalkylmethyl, (C3-C6) cycloalkylethyl, (C2-C6) heterocyclylmehtyl, (C2-C6) heterocyclylehtyl, benzyl; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; or R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br or cyano;

each of n and m is independently 4, 5, 6, 7, 8 or 9.
The compound of claim 1, wherein each of R¹, R², R³ and R⁴ is independently H, D, amino, nitro, hydroxy, F, Cl, Br, F, Cl, Br, methyl, ethyl, methoxy, ethoxy; or R¹ and R² on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the same atom, taken together with the atom they are attached form a C=O, C=S, (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and R² on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R³ and R⁴ on the different atoms, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; or R¹ and its adjacent R², taken together with the atoms they are attached form a double bond; or R³ and its adjacent R⁴, taken together with the atoms they are attached form a double bond; or R¹ and R³, taken together with the intervening atoms form a (C3-C7) cycloakyl or (C2-C6) heterocyclyl group; each of R¹, R², R³ and R⁴ is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, F, Cl, Br or cyano;

each of n and m is independently 4, 5, 6, 7, 8 or 9.
The compound of claim 1, wherein R is H, D, F, Cl, Br, cyano, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C2-C5) heterocyclyl, (C6-C10) aryl or (C1-C9) heteroaryl; R is optionally and independently substituted with 1, 2, 3, 4 or 5 substituent groups selected from D, amino, nitro, hydroxy, halo or cyano.
The compound of claim 1, wherein R is H, D, F, Cl, Br, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methyl-d, methyl-d2 or methyl-d3.
The compound of any one of claims 1 to 13 having formula II, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein each of k, g, j and v is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.
The compound of any one of claims 1 to 13 having formula III, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein each of g1 and j1 is independently 3, 4, 5, 6 or 7.
The compound of claim 15 having formulae IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
The compound of claim 15 having formulae V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
The compound of any one of claims 1-17 having formulae VI, VII, VIII, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
The compound of any one of claims 1-17 having formulae IX, X, XI, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
The compound of any one of claims 1 to 19 having the following structure or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
A pharmaceutical composition comprising a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof and a pharmaceutically acceptable vehicle, excipient, or diluent.
The compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21 for use in preventing, managing, treating or lessening a disorder relating to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof.
The compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21 for use in preventing, managing, treating or lessening a disorder by increasing HDL levels.
The compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21 for use in preventing, managing, treating or lessening a disorder by lowering LDL levels.
The compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21 for use in preventing, managing, treating or lessening aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient.
Use of a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21 in the manufacture of a medicament for preventing, managing, treating or lessening a disorder relating to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof.
Use of a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21 in the manufacture of a medicament for preventing, managing, treating or lessening a disorder by increasing HDL levels.
Use of a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21 in the manufacture of a medicament for preventing, managing, treating or lessening a disorder by lowering LDL levels.
Use of a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21 in the manufacture of a medicament for preventing, managing, treating or lessening aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient.
A method for preventing, managing, treating or lessening a disorder realting to ATP-citrate lyase or AMP-activated protein kinase or a combination thereof, comprising administering to a mammal in need thereof an effective amount of a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21.
A method for preventing, managing, treating or lessening a disorder by increasing HDL levels comprising administering to a mammal in need thereof an effective amount of a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21.
A method for preventing, managing, treating or lessening a disorder by lowering LDL levels, comprising administering to a mammal in need thereof an effective amount of a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21.
A method for preventing, managing, treating or lessening aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, Upid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder, modulating C reactive protein, enhancing bile production, hepatocellular carcinoma (HCC) , non-alcoholic fatty liver disease (NAFLD) , nonalcoholic stetohepatitis (NASH) , liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, or acute fatty liver of pregnancy in a patient, comprising administering to a patient in need of such treatment or prevention a therapeutically or proplyleufrally effective amount of a compound of any one of claims 1 to 20 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutical composition of claim 21.