CN108218946A - A kind of deoxycholic aicd class compound, preparation method and application - Google Patents
A kind of deoxycholic aicd class compound, preparation method and application Download PDFInfo
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- CN108218946A CN108218946A CN201611162678.5A CN201611162678A CN108218946A CN 108218946 A CN108218946 A CN 108218946A CN 201611162678 A CN201611162678 A CN 201611162678A CN 108218946 A CN108218946 A CN 108218946A
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- 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
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- 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
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- 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
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Abstract
The invention discloses a kind of deoxycholic aicd class compound, preparation method and applications.The present invention provides a kind of deoxycholic aicd class compound, its stereoisomer or its pharmaceutically acceptable salts shown in formula I.Such compound can shield the bitter taste of shellfish cholic acid difficult to understand or the stimulation to gastrointestinal tract, and good water solubility, bioavilability is high, shellfish cholic acid difficult to understand can be released in enteron aisle, so as to have identical pharmacological activity, more preferably pharmacokinetic property.
Description
Technical field
The present invention relates to a kind of deoxycholic aicd class compound, preparation method and applications.
Background technology
Bile acid has very valuable therapeutic activity and with a long history as therapeutically active agent, carrier and/or adjuvant
Medical applications, especially deoxycholic aicd and its derivative.
Chenodeoxycholic acid (CDCA) main function is the saturation degree for reducing bile inner cholesterol, and most patients take
After CDCA (when CDCA accounts for 70% of cholate in bile), lipid restores protomere state, and cholesterol is at undersaturated condition,
So as to which the cholesterol in calculus be made to dissolve, come off.The CDCA (daily 10~15mg/kg) of large dosage can inhibit the conjunction of cholesterol
Into, and increase the secretion of Bile of Patients with Cholelithiasis, but cholate therein and phosphatide secretory volume remain unchanged.
Ursodesoxycholic acid (UDCA) medically for increasing bile acid secretion, and change bile component, is reduced in bile
Cholesterol and cholesterol ester, the cholesterol be conducive in gall stone gradually dissolve, it can also be used to preventive medicine physical property calculus and
Treat stearrhea (ileal resection is postoperative).Chronic active hepatitis patient is safe and effective using UDCA, no hepatotoxicity wind agitation.
And 6 substitutive derivatives of chenodeoxycholic acid, be semi-synthetic chenodeoxycholic acid (CDCA) derivative, can activate
Farnesoid X receptor (FXR) has anti-silt courage, the effect of anti-fibrosis.FXR is a kind of nuclear receptor, is a kind of cholic acid sensor,
The flowing of the synthesis of controllable cholic acid and bile in liver, simultaneously for bile homeostasis, lipid-metabolism, glycometabolism and
Inflammation/immune response has effect.Data shows 6- α-ethyl chenodeoxycholic acid (6-ECDCA, OCA) swashing for FXR
Effect living is 100 times of CDCA, and clinical research shows that OCA can be used for treating primary biliary cirrhosis (PBC), Men Jing
Arteries and veins high pressure (Portal hypertension), nonalcoholic steatohepatitis (NASH), bile acidity diarrhea (Bile acid
Diarrhea), disease (Drug related with choleresis such as alcoholic hepatitis, primary sclerotic cholangitis (PSC)
Discovery Today.Volume 17,Numbers 17/18,2012)。
However, deoxycholic aicd class compound (such as CDCA, UDCA or OCA), does not dissolve in the environment of being 1~8 in pH value and contains
Aqueous medium has extremely strong bitter taste, and bitter taste lasts for hours.The pKa value of CDCA and OCA is 5, faintly acid is shown, in water
In solubility it is very low, wherein, the solubility of CDCA in water is about 32 μM, and OCA be 9 μM
(J.Pharmacol.Exp.Ther.July2014.350:56-68).Solubility is 53 μM in UDCA water, and only works as pH value
Reach 8.47 and just will appear and be completely dissolved, and when pH value is less than 8.4, part ursodesoxycholic acid cannot not only be absorbed, instead
By enteric bacteria colony transformation into lithocholic acid (US5380533).
Oral cholic acid preparation is mainly the tablet or capsule for releasing immediately or being sustained at present, since bioavilability is low, institute
There are these preparations there are the shortcomings that endless hypersorption (European Journa of Clinical
Investigation.1985,15,171-178).Bile acid, especially ursol deoxycholic aicd refer in the stomach-ten two of fasted subjects
Solubility in intestines jejunal contents is bad, and be recovered to 21%~50% solid form swallows dosage, this is because solid
The course of dissolution of ursol deoxycholic aicd in the gastrointestinal tract is very slow, and its course of dissolution is with caused by unpredictable variation.
Bile acid, especially ursol deoxycholic aicd, deoxycholic aicd, chenodeoxycholic acid, hyodesoxycholic acid, ox sulphur ursol deoxycholic aicd and ox
Sulphur chenodeoxycholic acid etc. does not dissolve in acidic environment especially.However, with the increase of pH value in enteron aisle, the solubility of bile acid is also
Slowly and incompletely increase very much, final bile acid just becomes solvable in the environment of being 8~9.5 in pH value.
In order to overcome the slow-absorbing in enteron aisle and the invalid absorption caused by the incomplete and slow mechanism dissolved of bile acid,
Through a variety of pharmaceutical preparations newly developed, such as the delayed release dosage forms of the water-soluble solid bile acid containing strong basicity.These are new
The pharmaceutical dosage form of exploitation is enteric-resistance to gastric pattern.These enterics-resistance to stomach dosage form keeps complete under acidic environment under one's belt, but works as
They release strong basicity solid bile salts (US5380533) in finite time in specific region immediately after reaching small intestine,
Show the bioavilability better than presently commercially available dosage form.However, it is possible to by finite time presumptive area be disintegrated, it is molten
Solution and the preparation for spreading " the accurate delayed release dosage forms " to discharge therapeutic activity component, are exceedingly difficult and very expensive.
Therefore, stimulation of this field there is an urgent need for a kind of bitter taste that can shield existing shellfish cholic acid difficult to understand or to gastrointestinal tract, with
And good water solubility, the high deoxycholic aicd class compound of bioavilability.
Invention content
The technical problems to be solved by the invention are the bitter taste of existing shellfish cholic acid difficult to understand or the stimulation to gastrointestinal tract, Yi Jishui
Dissolubility is poor, bioavilability it is low wait the defects of, so, the present invention provides a kind of deoxycholic aicd class compound, preparation methods
And application, such compound can shield the bitter taste of shellfish cholic acid difficult to understand or the stimulation to gastrointestinal tract, good water solubility, bioavilability is high,
Shellfish cholic acid difficult to understand can be released in enteron aisle, so as to have identical pharmacological activity, more preferably pharmacokinetic property.
The present invention provides a kind of deoxycholic aicd class compound shown in formula I, its stereoisomer or its pharmaceutically may be used
The salt of receiving；
Wherein,
R1For "-NR2R3Substituted C1~C4Alkyl " (" the C1~C4Alkyl " such as methyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group or tertiary butyl, preferably methyl or ethyl；"-the NR2R3Substituted C1~C4Alkyl " example
Such as)、C15~C21Alkyl (such as) or C15~C21
Alkenyl (such as )；
R2For hydrogen or C1~C10The alkyl (" C1~C10Alkyl " can be " C1~C4Alkyl "；" the C1~C4Alkane
Base " such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl, preferably methyl), R3For hydrogen or C1
~C10The alkyl (" C1~C10Alkyl " can be " C1~C4Alkyl "；" the C1~C4Alkyl " such as methyl, ethyl, just
Propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl, preferably methyl)；Alternatively, R2、R3And the N being connected with them is former
4~8 circle heterocyclic ring bases are collectively formed in son, and (" 4~8 circle heterocyclic ring base " is preferably " one kind of hetero atom in N, O and S
Or a variety of, heteroatomic number be 1~3,4~8 circle heterocyclic ring bases ", such as morpholinyl).
" pharmaceutically acceptable salt " can be hydrochloride.
One according to the present invention specific and preferred aspect, R1For-NR2R3Substituted C1~C4Alkyl.
One according to the present invention specific and preferred aspect, R1For C15~C21Alkyl.
One according to the present invention specific and preferred aspect, R1For C15~C21Alkenyl.
Preferably, the deoxycholic aicd class compound shown in formula I is：Shellfish cholic acid dimethylglycine ester -3- difficult to understand
Position, shellfish cholic acid (2- morpholines acetic acid) ester -3- difficult to understand, shellfish cholic acid (3- morpholines propionic acid) ester -3- difficult to understand, shellfish cholic acid palmitic acid difficult to understand
Ester -3-, shellfish cholic acid linoleate -3- difficult to understand, shellfish cholic acid arachidonate -3- difficult to understand, Austria's shellfish cholic acid EPA ester -3- or
Shellfish cholic acid DHA ester -3- difficult to understand；
Wherein, EPA is eicosapentaenoic acid；DHA is 22 carbon, six diluted acid.
Preferably, the pharmaceutically acceptable salt of the deoxycholic aicd class compound shown in formula I is：Shellfish cholic acid difficult to understand
- 3- hydrochlorides of (2- morpholines acetic acid) ester or shellfish cholic acid (3- morpholines propionic acid) -3- hydrochlorides of ester difficult to understand
The present invention also provides the preparation method of above-mentioned deoxycholic aicd class compound I,
As the R1For-NR2R3Substituted C1~C4During alkyl, include the following steps：Under an atmosphere of hydrogen, in methanol
In, in the presence of palladium carbon, compound II is subjected to deprotection reaction, obtains compound I；
As the R1For C15~C21Alkyl or C15~C21During alkenyl, include the following steps：Under nitrogen protection, exist
In toluene, in the presence of morpholine and tetra-triphenylphosphine palladium, compound III is subjected to deprotection reaction, obtains compound I i.e.
It can；
The present invention also provides a kind of pharmaceutical compositions, and it includes above-mentioned deoxycholic aicd class compound I, its alloisomerisms
Body or its pharmaceutically acceptable salt and one or more excipient substances.
The present invention also provides above-mentioned deoxycholic aicd class compound I, its stereoisomer or its is pharmaceutically acceptable
Application of the salt in FXR active regulators are prepared.The FXR active regulators can and then adjust choleresis or cholesterol generation
It thanks, as choleresis conditioning agent or cholesterol metabolic conditioning agent.
The present invention also provides above-mentioned deoxycholic aicd class compound I, its stereoisomer or its is pharmaceutically acceptable
The application of salt in medicine preparation, the drug are used to treat and/or prevent the disease adjusted by FXR.
In the applications described above, the disease adjusted by FXR be preferably the disease related with choleresis or
The disease influenced by cholesterol or bile acid levels；The disease related with choleresis is preferably cholesterol gallstones
Disease, primary biliary cirrhosis, portal hypertension, nonalcoholic steatohepatitis, bile acidity diarrhea, alcoholic hepatitis, original
Hair property sclerosing cholangitis or atherosclerosis.
The present invention also provides above-mentioned deoxycholic aicd class compound I, its stereoisomer or its is pharmaceutically acceptable
Application of the salt in choleresis conditioning agent is prepared.
The present invention also provides above-mentioned deoxycholic aicd class compound I, its stereoisomer or its is pharmaceutically acceptable
Salt, application in medicine preparation, the drug are used to prevent and/or treat the disease related with choleresis.Described
The disease related with choleresis be preferably cholesterol gallstones disease, primary biliary cirrhosis, portal hypertension,
Nonalcoholic steatohepatitis, bile acidity diarrhea, alcoholic hepatitis, primary sclerotic cholangitis or atherosclerosis.
The present invention also provides above-mentioned deoxycholic aicd class compound I, its stereoisomer or its is pharmaceutically acceptable
Application of the salt in cholesterol metabolic conditioning agent is prepared.
The present invention also provides above-mentioned deoxycholic aicd class compound I, its stereoisomer or its is pharmaceutically acceptable
The application of salt in medicine preparation, the drug are used to treat and/or prevent the disease influenced by cholesterol or bile acid levels.
The method of the FXR activity of its subject is needed the present invention also provides a kind of adjusting, is had including giving treatment
Above-mentioned deoxycholic aicd class compound I, its stereoisomer or its pharmaceutically acceptable salt of effect amount.Adjust the FXR
Activity can and then adjust choleresis or cholesterol metabolic.
The present invention also provides it is a kind of treat and/or prevention by the FXR diseases adjusted method, including to needs its
Subject gives the above-mentioned deoxycholic aicd class compound I of therapeutically effective amount, its stereoisomer or its is pharmaceutically acceptable
Salt.
In the methods described above, the disease adjusted by FXR be preferably the disease related with choleresis or
The disease influenced by cholesterol or bile acid levels；The disease related with choleresis is preferably cholesterol gallstones
Disease, primary biliary cirrhosis, portal hypertension, nonalcoholic steatohepatitis, bile acidity diarrhea, alcoholic hepatitis, original
Hair property sclerosing cholangitis or atherosclerosis.
The method of the cholesterol metabolic of its subject is needed the present invention also provides a kind of adjusting, including giving effectively
Adjust above-mentioned deoxycholic aicd class compound I, its stereoisomer or its pharmaceutically acceptable salt of cholesterol metabolic amount.
The present invention also provides a kind for the treatment of and/or prevent the method for disease influenced by cholesterol or bile acid levels,
Including to need its subject give the above-mentioned deoxycholic aicd class compound I of therapeutically effective amount, its stereoisomer or its
Pharmaceutically acceptable salt.
The method of the choleresis of its subject is needed the present invention also provides a kind of adjusting, including giving effective tune
Save above-mentioned deoxycholic aicd class compound I, its stereoisomer or its pharmaceutically acceptable salt of choleresis.
The side of the primary biliary cirrhosis of its subject is needed the present invention also provides a kind of prevention and/or treatment
Method, including giving the above-mentioned deoxycholic aicd class compound I of therapeutically effective amount, its stereoisomer or its is pharmaceutically acceptable
Salt.
The method of the portal hypertension of its subject, packet are needed the present invention also provides a kind for the treatment of and/or treatment
Include above-mentioned deoxycholic aicd class compound I, its stereoisomer or its pharmaceutically acceptable salt for giving therapeutically effective amount.
The side of the nonalcoholic steatohepatitis of its subject is needed the present invention also provides a kind of prevention and/or treatment
Method, including giving the above-mentioned deoxycholic aicd class compound I of therapeutically effective amount, its stereoisomer or its is pharmaceutically acceptable
Salt.
The method of the bile acidity diarrhea of its subject is needed the present invention also provides a kind of prevention and/or treatment,
Above-mentioned deoxycholic aicd class compound I, its stereoisomer or its pharmaceutically acceptable salt including giving therapeutically effective amount.
The method of the alcoholic hepatitis of its subject, packet are needed the present invention also provides a kind of prevention and/or treatment
Include above-mentioned deoxycholic aicd class compound I, its stereoisomer or its pharmaceutically acceptable salt for giving therapeutically effective amount.
The side of the primary sclerotic cholangitis of its subject is needed the present invention also provides a kind of prevention and/or treatment
Method, including giving the above-mentioned deoxycholic aicd class compound I of therapeutically effective amount, its stereoisomer or its is pharmaceutically acceptable
Salt.
Term Bz refers to benzyl.
In the present invention, if without other explanation, for the present patent application, including the art in specification and claims
Language is defined as follows.It has to be noticed that in the specification and the appended claims, if nothing clearly dictates otherwise in text, odd number
Form "one" include plural references.If without other explanation, mass spectrum, nuclear-magnetism, HPLC, protein chemistry, biochemistry, again are used
The conventional method of group DNA technique and pharmacology.
Term " alkyl " refer to linear chain or branch chain saturation, containing 1~22 carbon atom (aliphatic hydrocarbon group；C1~CnAlkane
Base then represents the aliphatic group of the saturation of 1~n carbon atom, including straight chain and branched group (such as " C1~C22Alkyl " refers to this
Group is alkyl, and the carbochain amount of carbon atom of alkyl is between 1~22, i.e., containing 1 carbon atom, 2 carbon atoms or 3 carbon originals
Son etc., until including the alkyl of 22 carbon atoms.And 1~22 limitation does not include the substituted carbon atom number on alkyl,
Such as replace " alkyl " in alkylamino, when its carbon atom number is not particularly limited, only refer to the carbon of the moieties wherein indicated
Atomicity is 1~22, and does not include the carbon atom number of substituent group on alkyl and the carbon original of other substituent groups on amino
Subnumber.
Straight chain and branched hydrocarbyl of the term " alkenyl " including containing at least one carbon-carbon double bond and 2~22 carbon atoms.
Straight chain and branched hydrocarbyl of the term " alkynyl " including containing at least one triple carbon-carbon bonds and 2~22 carbon atoms.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " heterocycle " refers to containing the heteroatomic cyclic group by 4 to 8 annular atoms such as N, O, S.In the group,
Hetero atom can contain only N atoms, can also contain O or S atom.Wherein heteroatomic number can be one, or
It is multiple.The heterocycle can be the class cycloalkane structure of saturation, or undersaturated aromatic ring class formation.More specifically, the term
Nitrogen heterocycle includes but not limited to pyrrole radicals, nafoxidine base, piperidyl, piperazinyl, morpholinyl, piperazinyl, pyrimidine radicals, miaow
Oxazolyl etc..Heterocycle may also include any polycyclic, and the above-mentioned heterocycle of any of which can be condensed in aromatic ring.
Term " round rings " includes any cyclic structure.Term " member " means the quantity for representing the skeletal atom for forming ring.This
Sample, e.g., cyclohexyl, pyridyl group, pyranose and thiapyran base are hexatomic rings；Cyclopenta, pyrrole radicals, furyl and thienyl are five yuan
Ring.
Term " optionally substitution " or " substitution " refer to can be replaced with reference to group by one or more additional groups, additional base
Group is individually and independently selected from one or more of following groups：C1~C10Alkyl, C3~C20Cycloalkyl, C5~C20Virtue
Base, C2~C20Heteroaryl, C2~C20Heterolipid cyclic hydrocarbon, hydroxyl, C1~C5Alkoxy, alkylthio group, arylthio, alkane sulfoxide group, fragrant sulfoxide
Base, alkane sulfuryl, fragrant sulfuryl, cyano, halogen, carbonyl, thiocarbonyl, nitro, alkylhalide group, fluoroalkyl or amino are (including monosubstituted
With disubstituted amine groups and its protected derivative), when substituent group is multiple, the substituent group is identical or not
Together.For example, optionally substitution can be halide ,-CN ,-NO2Or LsRs, wherein each Ls independences are selected from following one
A key：- O- ,-C (=O)-,-C (=O) O- ,-S- ,-S (=O)-,-S (=O)2,-NH- ,-NHC (=O)-,-C (=O)
NH-, S (=O)2NH- ,-NHS (=O)2,-OC (=O) NH- ,-NHC (=O) O- or-(C1~C10Alkyl)；Each Rs is selected from
Hydrogen, alkyl, fluoroalkyl, miscellaneous alkyl, cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl.The protection that more than substituent group can be formed is spread out
The protecting group of biology can refer to Greene and Wuts.On the one hand, optional substituent group is selected from halogen, trifluoromethyl, hydroxyl, cyanogen
Base, nitro ,-SO3H、-SO2NH2、-SO2Me、-NH2、-COOH、-CONH2、C1~C5Alkoxy ,-N (CH3)2And C1~C10Alkane
Base.
In certain specific embodiments, the compound has one or more optically-actives (or along anti-) stereogenic centers, and every
A center is individually present with R or S types (or " E or Z-type ").At this point, the compound has one or more stereoisomer (examples
Such as cis-trans-isomer, diastereomer, enantiomer, epimer).Term " stereoisomer " is not only including above-mentioned along anti-
Isomers, diastereomer, enantiomer, epimer etc. further include their mixture.Each stereoisomer can pass through
Conventional means (such as Chromatographic resolution, chemical resolution etc.) are isolated.
Compound includes all and their mixture as mentioned herein.The method of Enantiomer separation is obtained.
In addition, the compounds of this invention can obtain composition through detaching and purifying after its preparation, contain by weight
The compound (" substantially pure " compound) of amount equal to or more than 99%, it is then as described herein to use or prepare.
" substantially pure " the compounds of this invention is also covered by the part as the present invention in this article.
Method described herein and molecular formula include the use of N- oxide (if appropriate)s, and crystal form is (also referred to as more
Crystal form) or compound of Formula I pharmaceutically acceptable salt and active metabolite with these identical active compounds.
In some cases, compound exists possibly as tautomer.All tautomers include changing as mentioned herein
Within the scope of conjunction object.In some specific embodiment, the compound exists with solvate forms, pharmaceutically acceptable
Solvent such as water or ethyl alcohol etc..In other specific embodiments, the compound exists with nonsolvated forms.
Term " acceptable " as used herein, refers to a prescription component or active constituent is good for general treatment target
Health does not have excessive adverse effect.
Term " subject " or " patient " are including mammal and nonmammalian.Mammal includes but not limited to, and feeds
Newborn class：People, non-human primates such as orangutan, ape and monkey class；Agricultural animal such as ox, horse, goat, sheep, pig；Domestic animal such as rabbit, dog；It is real
It tests animal and includes rodent, such as rat, mouse and cavy.Non-mammalian animal includes but not limited to, bird, fish etc..It is excellent one
It selects in example, selected mammal is people.
Term " nuclear receptor " refers to usually activate together with other transcription factors or inhibits one or more bases in nucleus
The receptor of the transcription (but can also have the effect of second messenger's signal transduction) of cause.Nuclear receptor is lived by the native homologous ligand of receptor
Change.Nuclear receptor is commonly found in cytoplasm or nucleus, and what non-film combined.
Farnesoid X receptor (FXR) is a member of nuclear receptor superfamily, it is mainly expressed among intestinal tract, participates in courage
The important links such as juice acid metabolic and cholesterol metabolic.Its ligand includes primary bile acid chenodeoxycholic acid, secondary in natural environment
Grade cholic acid lithocholic acid, deoxycholic aicd etc..
Term " therapeutically effective amount " refers to be enough effectively to treat disease or illness as described herein when giving subject
The amount of compound.Although the amount for forming the compound of " therapeutically effective amount " will be according to compound, illness and its severity and desire
It treats the age of subject and changes, but can in a usual manner be determined by those skilled in the art.
Term " adjust (modulating/modulate) " refers to treat, prevents, inhibits, enhancing or inducing function, the patient's condition
Or illness.
" treatment (treating/treatment) " is covered in treatment subject (the preferably mankind) herein as used herein
The disease or illness, and including：
I. inhibit disease or illness, that is, prevent its development；Or
Ii. alleviate disease or illness, that is, illness is caused to subside.
Term " subject " refers to suffer from or may be moved with the homoiothermy of one or more diseases as described herein and illness
Object, such as mammal, the preferably mankind or human child.
Term " biliary cirrhosis " refers to that, because of biliary obstruction, hepatic sclerosis caused by cholestasis divides primary biliary
Property hepatic sclerosis (PBC) and secondary biliary cirrhosis.It is generally acknowledged that primary biliary cirrhosis is a kind of autoimmune
Disease.
Term " portal hypertension " refers to that is persistently increased a caused syndrome by portal venous pressure.It is most of hard by liver
Change causes, and minority is secondary to the unknown other factors of main portal vein or hepatic venous obstruction and reason.When portal vein cannot
Passing through liver and passing back into inferior caval vein will cause portal venous pressure to increase.
Term " non-alcohol fatty liver " refer to it is a kind of with insulin resistance (insulin resistance, IR) and
The closely related metabolic stress hepar damnification of inheritance susceptible, pathological change and alcoholic liver disease (alcoholic liver
Disease, ALD) it is similar, but patient, without excessive drinking history, spectrum of disease includes non-alcoholic simple fatty liver
(nonalcoholic simple fatty liver, NAFL), nonalcoholic fatty liver disease (nonalcoholic
Steatohepatitis, NASH) and its related liver cirrhosis and hepatocellular carcinoma.
When term " bile acidity diarrhea " refers to ileal absorption bile acid obstacle, a large amount of bile acids are reached caused by colon
Diarrhea.
Term " alcoholic hepatitis " refers to a kind of liver diseases caused by long-term excessive consumption of alcohol.Its main clinical characteristics is to dislike
The heart, vomiting, jaundice, liver enlargement and tenderness, can concurrently liver failure and upper gastrointestinal bleeding etc..
Term " primary sclerotic cholangitis " refers to chronic cholestatic disease, it is characterized in that extrahepatic duct inflammation
And fibrosis, and then lead to multifocal stenosis of bile duct.Most patients finally develop into hepatic sclerosis, portal hypertension and liver function
Decompensation.
Term " comprising ", " ", " such as " etc. mean exemplary implementation and do not limit the scope of the invention.
As used herein, a certain compound or pharmaceutical composition after administration, can obtain a certain disease, symptom or situation
To improvement, espespecially its severity is improved, delayed onset, is slowed down disease progression or is reduced the state of an illness duration.No matter fix
Administration or interim administration are administered continuously or interrupted continuous administration, can be attributed to or the situation related with administration.
Term " pharmaceutic adjuvant " can be those auxiliary materials widely used in drug production field.Auxiliary material is mainly used for offer one
A safe and stable and functional pharmaceutical composition, can be with providing method, and active constituent is with institute after making subject's receiving administration
Expected rate, which dissolves out or subject is promoted to receive active constituent after composition is administered, effectively to be absorbed.The pharmaceutic adjuvant
It can be inert filler or certain function is provided, such as stablize the whole pH value of the composition or prevent composition active
The degradation of ingredient.The pharmaceutic adjuvant can include one or more in following auxiliary material：Adhesive, suspending agent, emulsification
Agent, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, antitack agent, glidant, wetting agent, gelling agent, suction
Receive delayed-action activator, dissolution inhibitor, reinforcing agent, adsorbent, buffer, chelating agent, preservative, colorant, corrigent and sweetener.
All features (including any claim and abstract) for being described in the present specification and/or any
All steps involved in method or process are possible to exist with any one combination, unless certain features or step are same
It is excluded each other in one combination.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is：The deoxycholic aicd class compound of the present invention can shield the bitter taste of shellfish cholic acid difficult to understand
Or the stimulation to gastrointestinal tract, good water solubility, bioavilability is high, and shellfish cholic acid difficult to understand can be released in enteron aisle, identical so as to have
Pharmacological activity, more preferably pharmacokinetic property.
Specific embodiment
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.Test method without specific conditions in the following example, according to conventional methods and conditions or according to quotient
Product specification selects.
Abbreviation
NMR refers to nuclear magnetic resonance spectroscopy；
DMAP refers to 4-dimethylaminopyridine；
EDCI refers to 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate；
MS refers to mass spectrography；
CDCA refers to chenodeoxycholic acid；
UDCA refers to ursodesoxycholic acid；
OCA refers to shellfish cholic acid difficult to understand；
HA refers to organic or inorganic Bronsted acid；
1H-NMR spectrums are using Bruker-400 Nuclear Magnetic Resonance, and the unit of chemical shift is hundred a ten thousandths, and internal standard is four
Methyl-monosilane.Coupling constant (J) is close to 0.1Hz.The abbreviation used is as described below：S is singlet；D is doublet；T is three
Weight peak；Q is quartet；Qu is quintet；M is multiplet；Br is spectrum.Mass spectrum is using Waters 2795 with electron spray electricity
Substance quadrupole mass spectrometer from (ESI).Column chromatography is carried out using silica gel.
Embodiment 1
Prepare compound 3：Shellfish cholic acid (3- morpholines propionic acid) -3- hydrochlorides of ester difficult to understand
It is synthesized according to following flow：
Intermediate 3-1：
OCA (2.00g, 4.75mmol, 1eq) is dissolved in 10mL DMF, add in potassium carbonate (0.85g, 14.25mmol,
3.0eq), 30min is reacted at room temperature, fast drop enters benzyl chloride (0.61g, 4.75mmol, 1eq), drips and finishes room temperature reaction overnight, TLC
Display raw material conversion finishes, and instills water quenching and goes out, and ethyl acetate extracts three times, and organic layer merges washing, saturated sodium bicarbonate solution
Washing, brine It, anhydrous sodium sulfate drying, concentration are dry that crude product, silica gel column chromatography (PE/EA=20/1) obtain white foam
Shape solid 1.850g.
Intermediate 3-2：
By intermediate 3-1 (0.250g, 0.49mmol, 1.0eq), 3- morpholines propionic acid (0.078g, 0.49mmol, 1.0eq)
With 4-dimethylaminopyridine (0.180g, 1.47mmol, 3.0eq), add in 10mL dichloromethane, be added portionwise EDCI (0.189g,
0.98mmol, 2.0eq), it finishes and is stirred overnight at room temperature.After TLC shows raw material conversion, water quenching is added to go out, DCM extracts slightly
Product, silica gel column chromatography (PE/EA=5/1) obtain pale yellow oil 0.120g.
Compound 3
Intermediate 3-2 (0.120g, 0.19mmol) is dissolved in 5ml methanol, adds in Pd/C (0.050g, 10%), room
Temperature is stirred to react overnight, and TLC shows that raw material conversion finishes, and filters, and filtrate decompression concentration is dry, adds in saturated sodium carbonate dissolving, second
Acetoacetic ester washs one time, and water layer 3N hydrochloric acid adjusts pH=2-3, and ethyl acetate extracts three times, and organic layer uses water respectively after merging
With brine It one time, concentrate dry to obtain faint yellow solid 101mg after dry.The solid is added in HCl/dioxane and is stirred
Hydrochloride is concentrated to give after 30 minutes.
Embodiment 2
Prepare compound 7：Shellfish cholic acid EPA ester -3- difficult to understand
It is synthesized according to following flow：
Intermediate 7-1：
OCA (1.00g, 2.38mmol, 1eq) is dissolved in 10mL DMF, add in potassium carbonate (0.99g, 7.13mmol,
3.0eq), 30min is reacted at room temperature, fast drop enters 3- bromopropenes (0.35g, 2.85mmol, 1.2eq), and drop, which finishes, to be reacted at room temperature
Night, TLC show that raw material conversion finishes, and instillation water quenching is gone out, and ethyl acetate extracts three times, and organic layer merges washing, unsaturated carbonate hydrogen
Sodium solution washs, brine It, anhydrous sodium sulfate drying, and concentration is dry that crude product, silica gel column chromatography (PE/EA=20/1) obtain in vain
Color foaming solid 0.950g.
Intermediate 7-2：
EPA (0.100g, 0.33mmol, 1.5eq) is dissolved in 5ml dichloromethane, instills 1mL thionyl chlorides, room temperature is stirred
1h is mixed, acyl chlorides is done to obtain in concentration.By intermediate 7-1 (0.100g, 0.22mmol, 1.0eq) and TEA (0.066g, 0.65mmol,
10mL dichloromethane 3.0eq) is added in, more than acyl chlorides is dissolved in after 1mL dichloromethane and is added dropwise to reaction solution, drop, which finishes, to be stirred at room temperature
Night.After TLC shows raw material conversion, water quenching is added to go out, DCM extracts to obtain crude product, and silica gel column chromatography (PE/EA=4/1) obtains yellowish
Color grease 0.100g.
Compound 7
Intermediate 2 (0.100g, 0.13mmol, 1.0eq) is dissolved in 5ml toluene, addition morpholine (0.234g,
2.68mmol, 20eq), nitrogen rapidly joins tetra-triphenylphosphine palladium after replacing three times, after nitrogen is replaced three times, reaction is stirred at room temperature
It stays overnight, TLC shows that raw material conversion finishes, and filtrate decompression concentration is dry, and silica gel column chromatography (PE/EA=3/1) obtains pale yellow oil
0.093g。
Prepared by the step of embodiment of compound 1~2 is described with reference to embodiment 1 (compound 3), the reality of compound 4~6,8
It applies the step of example is described with reference to embodiment 2 (compound 7) to prepare, only reaction raw materials be replaced accordingly, to obtain target
Compound.Embodiment number, compound mark and HNMR/MS details are listed in the table below：
Appraising datum：
Metabolism in effect example body
(J.Pharmacol.Exp.Ther.July 2014.350 according to the literature:56-68), CDCA and OCA enter liver
Taurine conjugate object is almost metabolized as after dirty target organ, and taurine conjugate object promotes bile point as active metabolite
It secretes, plays drug effect.In order to compare the compound of the present invention with OCA medicines for property qualitative difference, difference gavage rat OCA and the present invention
Compound, then measure target organ hepatic tissue in different time points taurine conjugate object concentration (present invention using purchase
Shellfish cholic acid taurine conjugate object standard items difficult to understand are as control, the conjugate that either standard items or the present invention are metabolized out, equal energy
Detect the ion pair of 526.5/79.8, the two is same substance, and therefore, the equal energy metabolism of the compound of the present invention goes out shellfish cholic acid difficult to understand
Taurine conjugate object).For the compound of the present invention, its concentration in hepatic tissue and blood also is had detected simultaneously, makes us frightened
Happiness is that all the compounds of this invention for having done the experiment of gavage rat can't detect in 4 hours, illustrates the chemical combination of the present invention
Object can return OCA by fast decoupled in stomach.With shellfish cholic acid difficult to understand in itself compared with, certain prodrugs extend half-life period, and certain prodrugs carry
High CmaxAnd the exposed amount of active metabolite taurine conjugate object.
Hepatic tissue sample treatment is as follows：
After thawing under the 37 DEG C of water-baths of hepatic tissue sample, weigh, according to trial test as a result, weighing about 1g, 10% methanol of addition-
Physiological saline 4mL, is homogenized.Wherein 100 μ L tissue homogenates is taken to be placed in a 1.5mL Eppendorf plastic centrifuge tubes,
Internal standard (internal standard concentration about 200ng/mL) solution of 10 μ L is added in, vortex mixed 5s adds in 400 μ L methanol, vortex oscillation
30sec centrifuges 10min in 16000rpm, divides and 100 μ L of supernatant is taken to be placed in another 1.5mL Eppendorf plastic centrifuge tubes,
200 μ L pure water are added in, vortex mixed 30s divides and 100 μ L is taken to bottle, and is placed in 10 μ L of automatic sampling in injector, carries out LC-MS/MS
Analysis.
The result of the test of preferred the compound of the present invention is listed as follows：
The above medicine codes or data illustrates that some shellfish cholic acid prodrugs difficult to understand provided by the invention have more better in itself than OCA
Medicine is for property, and under equally effective dose profile, half-life period is longer, while the compounds of this invention is more living in liver target organ than OCA
Property metabolin concentration higher, so as to be expected to reduce clinical plan dosage, reduce side effect.
Claims (10)
1. a kind of deoxycholic aicd class compound, its stereoisomer or its pharmaceutically acceptable salt shown in formula I；
Wherein,
R1For "-NR2R3Substituted C1~C4Alkyl ", C15~C21Alkyl or C15~C21Alkenyl；
R2For hydrogen or C1~C10Alkyl, R3For hydrogen or C1~C10Alkyl；Alternatively, R2、R3And the common shape of N atoms being connected with them
Into 4~8 circle heterocyclic ring bases.
2. as described in claim 1 deoxycholic aicd class compound shown in formula I, its stereoisomer or its can pharmaceutically connect
The salt received, which is characterized in that the R1In, the C1~C4Alkyl for methyl, ethyl, n-propyl, isopropyl, normal-butyl,
Isobutyl group or tertiary butyl；
And/or the R1In, the C15~C21Alkyl is
And/or the R1In, the C15~C21Alkenyl is
And/or the R2In, " the C1~C10Alkyl " is " C1~C4Alkyl "；
And/or the R3In, " the C1~C10Alkyl " is " C1~C4Alkyl "；
And/or " 4~8 circle heterocyclic ring base " is " one or more, heteroatomic number of the hetero atom in N, O and S
For 1~3,4~8 circle heterocyclic ring bases ".
3. as claimed in claim 2 deoxycholic aicd class compound shown in formula I, its stereoisomer or its can pharmaceutically connect
The salt received, which is characterized in that the R2In, as " the C1~C10Alkyl " is " C1~C4During alkyl ", " C1~C4
Alkyl " is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or the R3In, as " the C1~C10Alkyl " is " C1~C4During alkyl ", " C1~C4Alkyl " is
Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or it is that " hetero atom is one or more, heteroatomic a in N, O and S when " 4~8 circle heterocyclic ring base "
Number for 1~3,4~8 circle heterocyclic ring bases " when, described " one or more, heteroatomic in N, O and S of hetero atom
Number be 1~3,4~8 circle heterocyclic ring bases " be morpholinyl.
4. as claimed in claim 3 deoxycholic aicd class compound shown in formula I, its stereoisomer or its can pharmaceutically connect
The salt received, which is characterized in that the "-NR2R3Substituted C1~C4Alkyl " is
5. as described in claim 1 deoxycholic aicd class compound shown in formula I, its stereoisomer or its can pharmaceutically connect
The salt received, which is characterized in that the deoxycholic aicd class compound shown in formula I is：Shellfish cholic acid dimethylglycine ester difficult to understand-
3-, shellfish cholic acid (2- morpholines acetic acid) ester -3- difficult to understand, shellfish cholic acid (3- morpholines propionic acid) ester -3- difficult to understand, Austria shellfish cholic acid palm
Acid esters -3-, shellfish cholic acid linoleate -3- difficult to understand, shellfish cholic acid arachidonate -3- difficult to understand, shellfish cholic acid EPA ester -3- difficult to understand
Or shellfish cholic acid DHA ester -3- difficult to understand；Wherein, EPA is eicosapentaenoic acid；DHA is 22 carbon, six diluted acid；
And/or the pharmaceutically acceptable salt of the deoxycholic aicd class compound shown in formula I is：Shellfish cholic acid (2- difficult to understand
Coffee quinoline acetic acid) -3- hydrochlorides of ester or shellfish cholic acid (3- morpholines propionic acid) -3- hydrochlorides of ester difficult to understand.
6. such as the preparation method of deoxycholic aicd class compound shown in formula I according to any one of claims 1 to 5,
As the R1For-NR2R3Substituted C1~C4During alkyl, include the following steps：Under an atmosphere of hydrogen, in methyl alcohol,
In the presence of palladium carbon, compound II is subjected to deprotection reaction, obtains the compound I；
As the R1For C15~C21Alkyl or C15~C21During alkenyl, include the following steps：Under nitrogen protection, in toluene
In, in the presence of morpholine and tetra-triphenylphosphine palladium, compound III is subjected to deprotection reaction, obtains the compound I i.e.
It can；
7. a kind of pharmaceutical composition, it includes deoxycholic aicd class compound I such as according to any one of claims 1 to 5, it is vertical
Body isomers or its pharmaceutically acceptable salt and one or more excipient substances.
8. as deoxycholic aicd class compound I according to any one of claims 1 to 5, its stereoisomer or its pharmaceutically may be used
The salt of receiving, application in medicine preparation, the drug are used to treat and/or prevent the disease adjusted by FXR.
9. as deoxycholic aicd class compound I according to any one of claims 1 to 5, its stereoisomer or its pharmaceutically may be used
The salt of receiving, application in medicine preparation, the drug for prevent and/or treat the disease related with choleresis,
Or the disease influenced by cholesterol or bile acid levels.
10. application as claimed in claim 9, which is characterized in that the disease related with choleresis is cholesterol
Gall stone, primary biliary cirrhosis, portal hypertension, nonalcoholic steatohepatitis, bile acidity diarrhea, alcoholic liver
Scorching, primary sclerotic cholangitis or atherosclerosis.
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| WO2016161003A1 (en) * | 2015-03-31 | 2016-10-06 | Enanta Phamraceuticals, Inc. | Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof |
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| 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 |
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| 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 |
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