CN108218946B - Deoxycholic acid compound, preparation method and application thereof - Google Patents
Deoxycholic acid compound, preparation method and application thereof Download PDFInfo
- Publication number
- CN108218946B CN108218946B CN201611162678.5A CN201611162678A CN108218946B CN 108218946 B CN108218946 B CN 108218946B CN 201611162678 A CN201611162678 A CN 201611162678A CN 108218946 B CN108218946 B CN 108218946B
- Authority
- CN
- China
- Prior art keywords
- acid
- alkyl
- compound
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a deoxycholic acid compound, a preparation method and application thereof. The invention provides a deoxycholic acid compound shown as a formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compound can shield the bitter taste of obeticholic acid or stimulate gastrointestinal tracts, has good water solubility and high bioavailability, can release obeticholic acid in intestinal tracts, and thus has the same pharmacological activity and better pharmacokinetic property.
Description
Technical Field
The invention relates to a deoxycholic acid compound, a preparation method and application thereof.
Background
Bile acids have a very valuable therapeutic activity and a long history of medical applications as therapeutically active agents, carriers and/or adjuvants, especially deoxycholic acid and its derivatives.
Chenodeoxycholic Acid (CDCA) mainly has the effect of reducing the saturation of cholesterol in bile, and after most patients take CDCA (when CDCA accounts for 70% of bile salt in bile), lipid restores to a micelle state, and cholesterol is in an unsaturated state, so that the cholesterol in calculus is dissolved and shed. The large dose of CDCA (10-15 mg/kg per day) can inhibit the synthesis of cholesterol and increase the secretion of bile of patients with cholelithiasis, but the secretion amount of bile salt and phospholipid in the patients is kept unchanged.
Ursodeoxycholic acid (UDCA) is used for increasing bile acid secretion, changing bile components, reducing cholesterol and cholesterol ester in bile, facilitating the gradual dissolution of cholesterol in gallstone, and preventing drug-induced calculus and treating fatty dysentery (after ileectomy). The UDCA is safe and effective for chronic active hepatitis patients and has no hepatotoxicity.
The 6-substituted derivative of chenodeoxycholic acid is semisynthetic derivative of chenodeoxycholic acid (CDCA), can activate Farnesoid X Receptor (FXR), and has cholestasis resisting and fibrosis resisting effects. FXR is a nuclear receptor, a bile acid sensor that regulates the synthesis of bile acids and the flow of bile in the liver, and has effects on bile homeostasis, lipid metabolism, carbohydrate metabolism, and inflammatory/immune responses. Research data show that 6-alpha-ethyl chenodeoxycholic acid (6-ECDCCA, OCA) has 100 times of activation effect on FXR compared with CDCA, and clinical studies show that OCA can be used for treating diseases related to Bile secretion, such as Primary Biliary Cirrhosis (PBC), Portal hypertension (Portal hypertension), nonalcoholic steatohepatitis (NASH), Bile acid diarrhea (Bile acid diarrhea), alcoholic hepatitis, Primary Sclerosing Cholangitis (PSC), and the like (Drug Discovery birth volume 17, Numbers 17/18,2012).
However, deoxycholic acid compounds (such as CDCA, UDCA or OCA) are insoluble in aqueous media at pH values of 1-8, have a very strong bitter taste, and the bitter taste lasts for several hours. The pKa values of both CDCA and OCA are 5, slightly acidic, and very low in water, where CDCA has a solubility of about 32. mu.M in water and OCA has a solubility of 9. mu.M (J.Pharmacol. Exp. Ther. July2014.350: 56-68). UDCA has a solubility of 53 μ M in water and is only completely soluble when the pH reaches 8.47, whereas when the pH is less than 8.4, part of ursodeoxycholic acid is not absorbed but converted to lithocholic acid by intestinal bacterial colonies (US 5380533).
Current oral bile acid formulations are predominantly immediate release or sustained release tablets or capsules, all of which suffer from incomplete absorption due to low bioavailability (European journal of Clinical investigation.1985,15, 171-178). Bile acids, especially ursodeoxycholic acid, have poor solubility in the gastro-duodenal jejunal content of fasted individuals, recovering swallow doses in the form of 21% to 50% solids, due to the very slow dissolution process of solid ursodeoxycholic acid in the gastrointestinal tract, with unpredictable variations in its dissolution process. Bile acids, in particular ursodeoxycholic acid, deoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, tauroursodeoxycholic acid and tauroursodeoxycholic acid, and the like, are particularly insoluble in acidic environments. However, as the pH in the intestine increases, the solubility of bile acids also increases very slowly and incompletely, and eventually bile acids become soluble in environments with pH of 8-9.5.
In order to overcome the slow absorption in the intestinal tract and the ineffective absorption due to incomplete and slow dissolution of bile acids, various pharmaceutical preparations, such as delayed release dosage forms containing strongly basic, water-soluble solid bile acids, have been newly developed. These newly developed pharmaceutical dosage forms are enteric-gastroresistant. These enteric-gastro resistant dosage forms remain intact in the acidic environment of the stomach, but release strongly basic solid bile acid salts in specific regions within a limited time immediately after they reach the small intestine (US5380533) and show better bioavailability than the currently marketed dosage forms. However, the preparation of "precise delayed release dosage forms" which can release the therapeutically active component by disintegration, dissolution and diffusion in predetermined areas within a limited time is extremely difficult and very expensive.
Therefore, there is a need in the art for deoxycholic acid compounds that can mask the bitter taste or gastrointestinal irritation of the existing obeticholic acid and have good water solubility and high bioavailability.
Disclosure of Invention
The technical problem to be solved by the invention is the defects of bitter taste or stimulation to gastrointestinal tract of the existing obeticholic acid, poor water solubility and low bioavailability, so that the deoxycholic acid compound, the preparation method and the application thereof are provided.
The invention provides a deoxycholic acid compound shown as a formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein the content of the first and second substances,
R1is-NR2R3Substituted C1～C4Alkyl group "(said" C)1～C4Alkyl "such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl; said "-NR2R3Substituted C1～C4Alkyl radicals "e.g.
C15～C21Alkyl (e.g. alkyl)
) Or C15～C21Alkenyl (e.g.
)；
R2Is hydrogen or C1～C10Alkyl (said "C)1～C10Alkyl "may be" C1～C4Alkyl groups "; said "C1～C4Alkyl "for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl), R3Is hydrogen or C1～C10Alkyl (said "C)1～C10Alkyl "may be" C1～C4Alkyl groups "; said "C1～C4Alkyl "such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl); or, R2、R3And together with the N atom to which they are attached form a 4-to 8-membered heterocyclic group (bThe "4-to 8-membered heterocyclic group" is preferably a 4-to 8-membered heterocyclic group having one or more heteroatoms selected from N, O and S and 1 to 3 heteroatoms, for example, morpholinyl group).
The "pharmaceutically acceptable salt" may be a hydrochloride salt.
According to a particular and preferred aspect of the invention, R1is-NR2R3Substituted C1～C4An alkyl group.
According to a particular and preferred aspect of the invention, R1Is C15～C21An alkyl group.
According to a particular and preferred aspect of the invention, R1Is C15～C21An alkenyl group.
Preferably, the deoxycholic acid compound shown in the formula I is: obeticholic acid dimethylglycinate-3-position, obeticholic acid (2-morpholinoacetic acid) ester-3-position, obeticholic acid (3-morpholinopropionic acid) ester-3-position, obeticholic acid palmitate-3-position, obeticholic acid linoleate-3-position, obeticholic acid arachidonate-3-position, obeticholic acid EPA ester-3-position or obeticholic acid DHA ester-3-position;
wherein EPA is eicosapentaenoic acid; DHA is docosahexaenoic acid.
Preferably, the pharmaceutically acceptable salt of the deoxycholic acid compound shown in the formula I is: 3-position hydrochloride of obeticholic acid (2-morpholone acetate) ester or 3-position hydrochloride of obeticholic acid (3-morpholone propionate)
The invention also provides a preparation method of the deoxycholic acid compound I,
when said R is1is-NR2R3Substituted C1～C4When alkyl, it comprises the following steps: in the hydrogen atmosphere, in methanol and in the presence of palladium carbon, carrying out deprotection reaction on the compound II to obtain a compound I;
when said R is1Is C15～C21Alkyl or C15～C21When alkenyl, it comprises the following steps: under the protection of nitrogen, carrying out deprotection reaction on a compound III in toluene in the presence of morpholine and palladium tetratriphenylphosphine to obtain a compound I;
the invention also provides a pharmaceutical composition, which comprises the deoxycholic acid compound I, a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients.
The invention also provides application of the deoxycholic acid compound I, a stereoisomer or a pharmaceutically acceptable salt thereof in preparation of FXR activity regulators. The FXR activity regulator can further regulate bile secretion or cholesterol metabolism, and is a bile secretion regulator or cholesterol metabolism regulator.
The invention also provides application of the deoxycholic acid compound I, the stereoisomer or the pharmaceutically acceptable salt thereof in preparation of medicaments for treating and/or preventing diseases regulated by FXR.
In the above-mentioned use, the FXR-regulated disease is preferably a disease associated with bile secretion, or a disease affected by cholesterol or bile acid levels; the disease associated with bile secretion is preferably cholesterolemia, primary biliary cirrhosis, portal hypertension, nonalcoholic steatohepatitis, bile acid diarrhea, alcoholic hepatitis, primary sclerosing cholangitis or atherosclerosis.
The invention also provides application of the deoxycholic acid compound I, the stereoisomer or the pharmaceutically acceptable salt thereof in preparing a bile secretion regulator.
The invention also provides the deoxycholic acid compound I, a stereoisomer or a pharmaceutically acceptable salt thereof, and application of the deoxycholic acid compound I, the stereoisomer or the pharmaceutically acceptable salt thereof in preparation of medicaments for preventing and/or treating diseases related to bile secretion. The disease associated with bile secretion is preferably cholesterolemia, primary biliary cirrhosis, portal hypertension, nonalcoholic steatohepatitis, bile acid diarrhea, alcoholic hepatitis, primary sclerosing cholangitis or atherosclerosis.
The invention also provides application of the deoxycholic acid compound I, the stereoisomer or the pharmaceutically acceptable salt thereof in preparation of cholesterol metabolism regulators.
The invention also provides the application of the deoxycholic acid compound I, the stereoisomer or the pharmaceutically acceptable salt thereof in preparing a medicament for treating and/or preventing diseases influenced by cholesterol or cholic acid level.
The present invention also provides a method of modulating FXR activity in a subject in need thereof comprising administering a therapeutically effective amount of deoxycholic acid compound I, described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Modulating the activity of said FXR may in turn modulate bile secretion or cholesterol metabolism.
The present invention also provides a method for treating and/or preventing FXR-modulated diseases, comprising administering to a subject in need thereof a therapeutically effective amount of deoxycholic acid compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described above.
In the above method, the FXR-modulated disease is preferably a disease associated with bile secretion, or a disease affected by cholesterol or bile acid levels; the disease associated with bile secretion is preferably cholesterolemia, primary biliary cirrhosis, portal hypertension, nonalcoholic steatohepatitis, bile acid diarrhea, alcoholic hepatitis, primary sclerosing cholangitis or atherosclerosis.
The present invention also provides a method of modulating cholesterol metabolism in a subject in need thereof comprising administering an amount of deoxycholic acid compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as described above effective to modulate cholesterol metabolism.
The present invention also provides a method for the treatment and/or prevention of diseases influenced by cholesterol or cholic acid levels, which comprises administering to a subject in need thereof a therapeutically effective amount of deoxycholic acid compound I as described above, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for modulating bile secretion in a subject in need thereof, comprising administering the deoxycholic acid compound I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof described above, which is effective in modulating bile secretion.
The present invention also provides a method for preventing and/or treating primary biliary cirrhosis in a subject in need thereof, comprising administering a therapeutically effective amount of deoxycholic acid compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as described above.
The present invention also provides a method of treating and/or treating portal hypertension in a subject in need thereof, comprising administering a therapeutically effective amount of deoxycholic acid compound I, described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for preventing and/or treating nonalcoholic steatohepatitis in a subject in need thereof, which comprises administering a therapeutically effective amount of the deoxycholic acid compound I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof described above.
The present invention also provides a method for preventing and/or treating bile acid diarrhea in a subject in need thereof, comprising administering a therapeutically effective amount of deoxycholic acid compound I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described above.
The present invention also provides a method of preventing and/or treating alcoholic hepatitis in a subject in need thereof, which comprises administering a therapeutically effective amount of deoxycholic acid compound I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described above.
The present invention also provides a method for preventing and/or treating primary sclerosing cholangitis in a subject in need thereof, comprising administering a therapeutically effective amount of deoxycholic acid compound I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described above.
The term Bz refers to benzyl.
In the present invention, terms used in the present application, including the specification and claims, are defined as follows, if not otherwise specified. It must be noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used, if not otherwise stated.
The term "alkyl" denotes a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 22 carbon atoms1～CnAlkyl means a saturated aliphatic hydrocarbon group of 1 to n carbon atoms, including straight and branched chain groups (e.g. "C)1～C22Alkyl "means that the group is alkyl and the number of carbon chain carbon atoms of the alkyl is between 1 and 22, i.e. alkyl containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 22 carbon atoms. The limitation of 1 to 22 does not include the number of carbon atoms substituted on the alkyl group, such as "alkyl" in the substituted alkylamino group, and when the number of carbon atoms is not particularly limited, it means that the number of carbon atoms of the specified alkyl group moiety is 1 to 22, and does not include the number of carbon atoms of the substituent on the alkyl group and the number of carbon atoms of the other substituents on the amino group.
The term "alkenyl" includes straight and branched chain hydrocarbon groups containing at least one carbon-carbon double bond and 2 to 22 carbon atoms.
The term "alkynyl" includes straight and branched chain hydrocarbon radicals containing at least one carbon-carbon triple bond and 2 to 22 carbon atoms.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "heterocyclyl" refers to a cyclic group of from 4 to 8 ring atoms containing a heteroatom such as N, O, S. In this group, the hetero atom may contain only a N atom, or may contain an O or S atom. The number of the hetero atoms may be one or more. The heterocyclic ring may be a saturated cycloalkane-like structure or an unsaturated aromatic ring-like structure. More specifically, the term nitrogen-containing heterocyclyl includes, but is not limited to, pyrrolyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, piperazinyl, pyrimidinyl, imidazolyl and the like. Heterocyclic rings may also include any polycyclic ring wherein any of the above heterocyclic rings may be fused to an aromatic ring.
The term "membered ring" includes any cyclic structure. The term "element" is intended to mean the number of backbone atoms constituting a ring. Thus, for example, cyclohexyl, pyridyl, pyranyl and thiopyranyl are six-membered rings; cyclopentyl, pyrrolyl, furanyl and thienyl are five-membered rings.
The term "optionally substituted" or "substituted" means that the reference group may be substituted with one or more additional groups individually and independently selected from one or more of the following groups: c1～C10Alkyl radical, C3～C20Cycloalkyl radical, C5～C20Aryl radical, C2～C20Heteroaryl group, C2～C20Heteroalicyclic hydrocarbon, hydroxy, C1～C5Alkoxy, alkylthio, arylthio, alkylsulfidenyl, arylsulfidenyl, alkylsulfonyl, arylsulfonyl, cyano, halo, carbonyl, thiocarbonyl, nitro, haloalkyl, fluoroalkyl or amino (including mono-and di-substituted amino groups and protected derivatives thereof), and when the number of substituents is plural, the substituents may be the same or different. By way of example, the optional substitution may be halide, -CN, -NO2Or LsRs, wherein each Ls is independently selected from the following bond: -O-, -C (═ O) O-, -S (═ O)2-、-NH-、-NHC(＝O)-、-C(＝O)NH-、S(＝O)2NH-、-NHS(＝O)2-OC (-O) NH-, -NHC (-O) O-or- (C)1～C10Alkyl groups); each Rs is selected from hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. Reference may be made to Greene and Wuts for protecting groups that may form protected derivatives of the above substituents. In one aspect, the optional substituents are selected from halogen, trifluoromethyl, hydroxy, cyano, nitro, -SO3H、-SO2NH2、-SO2Me、-NH2、-COOH、-CONH2、C1～C5Alkoxy, -N (CH)3)2And C1～C10An alkyl group.
In certain embodiments, the compounds have one or more optically active (or cis-trans) isomeric centers, and each center is independently present in R or S form (or "E or Z form"). In this case, the compound has one or more stereoisomers (e.g., cis, trans, diastereomers, enantiomers, epimers, etc.). The term "stereoisomer" includes not only the cis-trans isomers, diastereomers, enantiomers, epimers, etc., as described above, but also mixtures thereof. Each stereoisomer can be separated by conventional means (e.g., chromatographic resolution, chemical resolution, etc.).
The compounds mentioned herein include all and mixtures thereof. The method for separating the stereoisomers.
Furthermore, the compounds of the present invention can be isolated and purified after their preparation to obtain compositions containing the compounds in an amount equal to or greater than 99% by weight ("substantially pure" compounds), which are then used or formulated as described herein.
Such "substantially pure" compounds of the invention are also encompassed herein as part of the invention.
The methods and formulae described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs) or pharmaceutically acceptable salts of the compounds of formula I, and active metabolites of these compounds having the same activity. In some cases, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds mentioned herein. In a particular embodiment, the compound is present in the form of a solvate, a pharmaceutically acceptable solvent such as water or ethanol, and the like. In other embodiments, the compounds are present in unsolvated forms.
The term "acceptable", as used herein, means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic target.
The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: human, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; domestic animals such as rabbits, dogs; the experimental animals include rodents, such as rats, mice, guinea pigs and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the mammal of choice is a human.
The term "nuclear receptor" refers to a receptor that activates or inhibits transcription of one or more genes in the nucleus (but may also have a second messenger signaling effect), usually in conjunction with other transcription factors. Nuclear receptors are activated by the natural cognate ligand for the receptor. Nuclear receptors are usually found in the cytoplasm or nucleus, rather than membrane-bound.
Farnesoid X Receptor (FXR), a member of the nuclear receptor superfamily, is mainly expressed in the intestinal system and is involved in important links such as bile acid metabolism and cholesterol metabolism. In natural environment, the ligand comprises primary bile acid chenodeoxycholic acid, secondary cholic acid lithocholic acid, deoxycholic acid and the like.
The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is sufficient to effectively treat a disease or condition described herein. Although the amount of a compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, it can be determined in a routine manner by one skilled in the art.
The term "modulating" refers to treating, preventing, inhibiting, enhancing or inducing a function, condition or disorder.
As used herein, "treating" encompasses treating a disease or disorder described herein in a subject (preferably a human) and includes:
i. inhibiting the disease or disorder, i.e., arresting its development; or
Alleviating the disease or condition, i.e., causing regression of the condition.
The term "subject" refers to a warm-blooded animal, such as a mammal, preferably a human or a human child, that has, or is likely to have, one or more of the diseases and disorders described herein.
The term "biliary cirrhosis" refers to cirrhosis caused by biliary obstruction, cholestasis, and is divided into Primary Biliary Cirrhosis (PBC) and secondary biliary cirrhosis. Primary biliary cirrhosis is generally considered to be an autoimmune disease.
The term "portal hypertension" refers to a group of symptoms caused by persistent increases in portal pressure. Most are caused by cirrhosis, and a few are secondary to obstruction of the portal trunk or hepatic veins and other factors of unknown cause. Portal vein pressure increases when portal vein blood fails to flow back through the liver into the inferior vena cava.
The term "non-alcoholic fatty liver disease" refers to a metabolic stress liver injury closely associated with Insulin Resistance (IR) and genetic predisposition, with pathological changes similar to Alcoholic Liver Disease (ALD), but without a history of excessive alcohol consumption by patients, with a disease spectrum including non-alcoholic simple fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) and its associated cirrhosis and hepatocellular carcinoma.
The term "bile acid diarrhea" refers to diarrhea caused by the arrival of large amounts of bile acids in the colon when the ileum has a disorder of bile acid absorption.
The term "alcoholic hepatitis" refers to a liver disease caused by prolonged excessive drinking. It is clinically characterized by nausea, vomiting, jaundice, hepatomegaly and tenderness, and may be complicated with hepatic failure and upper gastrointestinal bleeding.
The term "primary sclerosing cholangitis" refers to a chronic cholestatic disease characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which in turn leads to multifocal bile duct stenosis. Most patients eventually develop cirrhosis, portal hypertension, and decompensation of liver function.
The terms "comprising," "such as," "for example," and the like are intended to be exemplary embodiments and do not limit the scope of the invention.
As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, particularly severity, delay onset, slow progression, or reduce duration of a condition. Whether fixed or temporary, sustained or intermittent, may be due to or associated with administration.
The term "pharmaceutical excipients" may be those excipients which are widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
All of the features described in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps involved in any method or process, may be present in any combination, except combinations where certain features or steps are mutually exclusive.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the deoxycholic acid compound can shield the bitter taste of obeticholic acid or stimulate gastrointestinal tracts, has good water solubility and high bioavailability, can release obeticholic acid in intestinal tracts, and thus has the same pharmacological activity and better pharmacokinetic property.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Abbreviations
NMR refers to nuclear magnetic resonance spectroscopy;
DMAP refers to 4-dimethylaminopyridine;
EDCI means 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride;
MS refers to mass spectrometry;
CDCA refers to chenodeoxycholic acid;
UDCA refers to ursodeoxycholic acid;
OCA means obeticholic acid;
HA means an organic or inorganic protonic acid;
1H-NMR spectra were obtained using a Bruker-400 NMR spectrometer with chemical shifts in parts per million and tetramethylsilane as internal standard. The coupling constant (J) is close to 0.1 Hz. The abbreviations used are as follows: s is the single multiplet; d is a doublet; t is a triplet; q is a quartet; qu is quintuple; m is a multiplet; br is the spectrum. Mass spectrometry a Waters 2795 single quadrupole mass spectrometer with electrospray ionization (ESI) was used. Column chromatography was performed using silica gel.
Example 1
Preparation of compound 3: obeticholic acid (3-morpholinopropionic acid) ester-3-position hydrochloride
The synthesis is carried out according to the following procedures:
intermediate 3-1:
dissolving OCA (2.00g,4.75mmol,1eq) in 10mL DMF, adding potassium carbonate (0.85g, 14.25mmol,3.0eq), reacting at room temperature for 30min, quickly dropwise adding benzyl chloride (0.61g,4.75mmol,1eq), reacting at room temperature overnight after finishing dropping, TLC shows that the raw material conversion is finished, dropwise adding water to quench, extracting for three times with ethyl acetate, combining organic layers, washing with water, washing with saturated sodium bicarbonate solution, washing with brine, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and performing silica gel column chromatography (PE/EA: 20/1) to obtain 1.850g of a white foamy solid.
Intermediate 3-2:
intermediate 3-1(0.250g,0.49mmol,1.0eq), 3-morpholinopropionic acid (0.078g,0.49mmol,1.0eq) and 4-dimethylaminopyridine (0.180g,1.47mmol,3.0eq) were added to 10mL of dichloromethane, EDCI (0.189g,0.98mmol,2.0eq) was added in portions, and the mixture was stirred at room temperature overnight. TLC showed complete conversion of starting material, quenched with water, extracted with DCM to give crude product, and chromatographed on silica gel (PE/EA 5/1) to give a pale yellow oil, 0.120 g.
Compound 3
Dissolving the intermediate 3-2(0.120g,0.19mmol) in 5ml of methanol, adding Pd/C (0.050g, 10%), stirring at room temperature for reaction overnight, TLC shows that the raw material conversion is finished, filtering, concentrating the filtrate under reduced pressure to dryness, adding saturated sodium carbonate for dissolution, washing once with ethyl acetate, adjusting the pH of an aqueous layer to 2-3 with 3N hydrochloric acid, extracting for three times with ethyl acetate, combining organic layers, washing once with water and common salt water respectively, drying, and concentrating to dryness to obtain a light yellow solid of 101 mg. The solid was added to HCl/dioxane and stirred for 30 minutes and concentrated to give the hydrochloride salt.
Example 2
Preparation of compound 7: EPA ester-3-position of obeticholic acid
The synthesis is carried out according to the following procedures:
intermediate 7-1:
dissolving OCA (1.00g,2.38mmol,1eq) in 10mL DMF, adding potassium carbonate (0.99g, 7.13mmol,3.0eq), reacting at room temperature for 30min, quickly dropwise adding 3-bromopropylene (0.35g,2.85mmol,1.2eq), reacting at room temperature overnight after finishing dropping, TLC indicating that the raw material is completely converted, dropwise adding water to quench, extracting for three times with ethyl acetate, combining organic layers, washing with water, washing with saturated sodium bicarbonate solution, washing with brine, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and performing silica gel column chromatography (PE/EA: 20/1) to obtain 0.950g of a white foamy solid.
Intermediate 7-2:
EPA (0.100g,0.33mmol,1.5eq) was dissolved in 5mL dichloromethane, 1mL thionyl chloride was added dropwise, stirred at room temperature for 1h, concentrated to dryness to give acid chloride. Intermediate 7-1(0.100g,0.22mmol,1.0eq) and TEA (0.066g,0.65mmol,3.0eq) were added to 10mL of dichloromethane, the above acid chloride was dissolved in 1mL of dichloromethane, and the reaction solution was added dropwise, followed by stirring at room temperature overnight. TLC showed complete conversion of starting material, quenched with water, extracted with DCM to give crude product, and chromatographed on silica gel (PE/EA 4/1) to give a pale yellow oil, 0.100 g.
Compound 7
Dissolving the intermediate 2(0.100g,0.13mmol,1.0eq) in 5ml of toluene, adding morpholine (0.234g,2.68mmol,20eq), replacing with nitrogen for three times, quickly adding palladium tetratriphenylphosphine, replacing with nitrogen for three times, stirring at room temperature for reaction overnight, TLC shows that the raw material conversion is finished, concentrating the filtrate under reduced pressure to dryness, and performing silica gel column chromatography (PE/EA: 3/1) to obtain 0.093g of light yellow oily substance.
Examples of compounds 1-2 were prepared according to the procedure described in example 1 (compound 3), and examples of compounds 4-6, 8 were prepared according to the procedure described in example 2 (compound 7), with only corresponding substitutions of the starting materials to give the target compounds. The example numbers, compound designations and HNMR/MS details are listed in the following table:
identification data:
effect examples in vivo metabolism test
It has been reported in the literature (J.Pharmacol.Exp.Ther.July2014.350:56-68) that CDCA and OCA are almost completely metabolized to taurine conjugates after entering target organs of the liver, and the taurine conjugates are used as active metabolites to promote bile secretion and exert medicinal effects. In order to compare the pharmacological differences between the compounds of the present invention and OCA, rats were gavaged with OCA and the compounds of the present invention, respectively, and the concentrations of taurine conjugates at different time points in the liver tissues of the target organs were measured (the present invention used a standard sample of purchased taurine conjugate of obeticholic acid as a control, and both were identical and could detect 526.5/79.8 ion pair, and thus, the compounds of the present invention were able to metabolize taurine conjugate of obeticholic acid). The concentration of the compound of the invention in liver tissue and blood was also determined, and surprisingly, all the compounds of the invention which had been tested in the gavage rat could not be detected within 4 hours, indicating that the compound of the invention rapidly decomposed back to OCA in the intestine and stomach. Certain prodrugs have extended half-lives and certain prodrugs have increased C as compared to obeticholic acid itselfmaxAnd exposure of the active metabolite taurine conjugate.
Liver tissue samples were processed as follows:
after thawing the liver tissue sample in a water bath at 37 ℃, weighing, according to the preliminary test results, about 1g, and adding 4mL of 10% methanol-physiological saline for homogenization. Taking 100 mu L of the tissue homogenate, placing the tissue homogenate into a 1.5mL Eppendorf plastic centrifuge tube, adding 10 mu L of an internal standard (the concentration of the internal standard is about 200ng/mL) solution, carrying out vortex mixing for 5s, adding 400 mu L of methanol, carrying out vortex oscillation for 30sec, centrifuging at 16000rpm for 10min, taking 100 mu L of supernatant, placing the supernatant into another 1.5mL Eppendorf plastic centrifuge tube, adding 200 mu L of pure water, carrying out vortex mixing for 30s, taking 100 mu L of supernatant, bottling, placing the supernatant into an autosampler for 10 mu L, and carrying out LC-MS/MS analysis.
The test results for preferred compounds of the invention are listed below:
the pharmacological data show that the obeticholic acid prodrug provided by the invention has better pharmacological properties than OCA, has longer half-life under the condition of the same effective dose, and has higher concentration of active metabolites in a liver target organ than OCA, so that the clinically planned dose is expected to be reduced, and the side effect is reduced.
Claims (10)
1. Deoxycholic acid compound shown as formula I or pharmaceutically acceptable salt thereof;
wherein the content of the first and second substances,
R1is-NR2R3Substituted C1～C4Alkyl radical ", C15～C21Alkyl or C15～C21An alkenyl group;
R2is hydrogen or C1～C10Alkyl radical, R3Is hydrogen or C1～C10An alkyl group; or, R2、R3And the N atom to which they are bonded together form a 4-to 8-membered heterocyclic group;
said R2In (1), "C" mentioned1～C10Alkyl is "C1～C4Alkyl groups ";
said R3In (1), "C" mentioned1～C10Alkyl is "C1～C4Alkyl groups ";
the 4-8-membered heterocyclic group is a 4-8-membered heterocyclic group with one or more heteroatoms selected from N, O and S and 1-3 heteroatoms.
2. Deoxycholic acid of formula I according to claim 1A compound or a pharmaceutically acceptable salt thereof, wherein R is1In (b), the C1～C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or, said R1In (b), the C15～C21Alkyl is
And/or, said R1In (b), the C15～C21Alkenyl is
3. The deoxycholic acid compound according to formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein R is selected from the group consisting of2When said "C" is present1～C10Alkyl is "C1～C4Alkyl, said "C1～C4Alkyl "is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or, said R3When said "C" is present1～C10Alkyl is "C1～C4Alkyl, said "C1～C4Alkyl "is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or, when the 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group in which one or more heteroatoms are selected from N, O and S and the number of the heteroatoms is 1-3, the 4-8 membered heterocyclic group in which one or more heteroatoms are selected from N, O and S and the number of the heteroatoms is 1-3 is a morpholinyl group.
4. Deoxycholic acid compound according to formula I, or a pharmaceutically acceptable salt thereof, according to claim 3, wherein "-NR is2R3Substituted C1～C4Alkyl is
5. The deoxycholic acid compound according to formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the deoxycholic acid compound according to formula I is: obeticholic acid dimethylglycinate-3-position, obeticholic acid (2-morpholinoacetic acid) ester-3-position, obeticholic acid (3-morpholinopropionic acid) ester-3-position, obeticholic acid palmitate-3-position, obeticholic acid linoleate-3-position, obeticholic acid arachidonate-3-position, obeticholic acid EPA ester-3-position or obeticholic acid DHA ester-3-position; wherein EPA is eicosapentaenoic acid; DHA is docosahexaenoic acid;
and/or the pharmaceutically acceptable salt of the deoxycholic acid compound shown as the formula I is: the 3-position hydrochloride of the ester of obeticholic acid (2-morpholine acetic acid) or the 3-position hydrochloride of the ester of obeticholic acid (3-morpholine propionic acid).
6. The method for preparing deoxycholic acid compounds represented by formula I according to any one of claims 1-5,
when said R is1is-NR2R3Substituted C1～C4When alkyl, it comprises the following steps: in the hydrogen atmosphere, in methanol and in the presence of palladium carbon, carrying out deprotection reaction on a compound II to obtain a compound I;
when said R is1Is C15～C21Alkyl or C15～C21When alkenyl, it comprises the following steps: under the protection of nitrogen, carrying out deprotection reaction on a compound III in toluene in the presence of morpholine and palladium tetratriphenylphosphine to obtain a compound I;
7. a pharmaceutical composition comprising deoxycholic acid compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, and one or more pharmaceutical excipients.
8. Use of deoxycholic acid compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 for the preparation of a medicament for the treatment and/or prevention of diseases modulated by FXR.
9. Use of deoxycholic acid compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 for the preparation of a medicament for the prevention and/or treatment of diseases related to bile secretion or affected by cholesterol or bile acid levels.
10. The use of claim 9, wherein the disorder associated with bile secretion is cholesterol gallstones, primary biliary cirrhosis, portal hypertension, non-alcoholic steatohepatitis, bile acid diarrhea, alcoholic hepatitis, primary sclerosing cholangitis, or atherosclerosis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611162678.5A CN108218946B (en) | 2016-12-15 | 2016-12-15 | Deoxycholic acid compound, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611162678.5A CN108218946B (en) | 2016-12-15 | 2016-12-15 | Deoxycholic acid compound, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108218946A CN108218946A (en) | 2018-06-29 |
| CN108218946B true CN108218946B (en) | 2021-04-16 |
Family
ID=62650629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611162678.5A Active CN108218946B (en) | 2016-12-15 | 2016-12-15 | Deoxycholic acid compound, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108218946B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111812264B (en) * | 2020-07-09 | 2021-06-15 | 苏州旭辉检测有限公司 | Biological sample analysis method of deoxycholic acid compound |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292290A (en) * | 2013-07-16 | 2015-01-21 | 中国人民解放军军事医学科学院毒物药物研究所 | Bile acid-drug conjugate with amino acid as connexon, and medical application thereof |
| CN104672290A (en) * | 2015-01-05 | 2015-06-03 | 北京普禄德医药科技有限公司 | Medicine for preventing or treating FXR-mediated diseases and preparation method and application of medicine |
| CN104774236A (en) * | 2014-01-13 | 2015-07-15 | 中国人民解放军军事医学科学院毒物药物研究所 | Fatty acid-bile acid conjugates having fat lowering activity, and medical uses thereof |
| WO2016161003A1 (en) * | 2015-03-31 | 2016-10-06 | Enanta Phamraceuticals, Inc. | Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof |
-
2016
- 2016-12-15 CN CN201611162678.5A patent/CN108218946B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292290A (en) * | 2013-07-16 | 2015-01-21 | 中国人民解放军军事医学科学院毒物药物研究所 | Bile acid-drug conjugate with amino acid as connexon, and medical application thereof |
| CN104774236A (en) * | 2014-01-13 | 2015-07-15 | 中国人民解放军军事医学科学院毒物药物研究所 | Fatty acid-bile acid conjugates having fat lowering activity, and medical uses thereof |
| CN104672290A (en) * | 2015-01-05 | 2015-06-03 | 北京普禄德医药科技有限公司 | Medicine for preventing or treating FXR-mediated diseases and preparation method and application of medicine |
| WO2016161003A1 (en) * | 2015-03-31 | 2016-10-06 | Enanta Phamraceuticals, Inc. | Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108218946A (en) | 2018-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6861703B2 (en) | TGR5 modifier and how to use it | |
| JP7021080B2 (en) | Farnesoid X Receptor Modulator | |
| JP6424231B2 (en) | Compositions and methods for modulating farnesoid X receptor | |
| ES2607852T3 (en) | The use of pregnan and androstane steroids for the manufacture of a pharmaceutical composition for the treatment of CNS disorders | |
| US20050171074A1 (en) | 3 alpha-hydroxy-3 beta-methoxymethyl-substituted steroids and the use thereof | |
| CN106518946A (en) | Sulfonylurea derivative and pharmaceutical composition and application thereof | |
| CN106083978A (en) | Sulfonyl amino carbonyl derivant, its pharmaceutical composition and application | |
| CN103391937A (en) | Compositions and methods for modulating farnesoid x receptors | |
| CN103370315A (en) | Compositions and methods for modulating farnesoid x receptors | |
| RU2659784C2 (en) | (n-substituted imidazole)-carboxylic ester chiral compound containing ether side chain, preparation method and application | |
| JP2007519757A (en) | Preparation method of pimecrolimus | |
| JP2005508368A (en) | Methods for treating diseases associated with high cholesterol levels | |
| JP2020503341A (en) | Antidepressant compounds and their production and use | |
| WO2016013030A2 (en) | Hydroxysteroid compounds, their intermediates, process of preparation, composition and uses thereof | |
| JP2021185186A (en) | Cftr regulators and methods for use thereof | |
| CN114456178A (en) | Application of tetrahydropyrimidine [1,2-b ] indazole-4-amine derivative as AhR inhibitor and preparation method thereof | |
| JP6842474B2 (en) | Steroid compounds, compositions containing the compounds and their use | |
| CN108218946B (en) | Deoxycholic acid compound, preparation method and application thereof | |
| PT90905B (en) | PROCESS FOR THE PREPARATION OF CONDENSED PIZANOL-3-OXO-PROPANONITRILE DERIVATIVES | |
| Ratni et al. | Discovery of tetrahydro-cyclopenta [b] indole as selective LXRs modulator | |
| WO2017120355A1 (en) | Dihydroquinolines and uses thereof | |
| EP3077363B1 (en) | Derivatives of tartaric acid | |
| ES2770128T3 (en) | Useful condensed tricyclic pyrazole derivatives useful for modulating farnesoid x receptors | |
| CN108218945B (en) | Deoxycholic acid derivative, preparation method, pharmaceutical composition and application thereof | |
| CN115160227A (en) | Heterozygote of R-or S-2- (1-acetoxy-n-pentyl) benzoic acid and 4-fluoro-edaravone, and preparation and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |