CN117143170A - Intestinal targeting pentacyclic triterpene TGR5 receptor agonist, and preparation method and application thereof - Google Patents

Intestinal targeting pentacyclic triterpene TGR5 receptor agonist, and preparation method and application thereof Download PDF

Info

Publication number
CN117143170A
CN117143170A CN202210564624.0A CN202210564624A CN117143170A CN 117143170 A CN117143170 A CN 117143170A CN 202210564624 A CN202210564624 A CN 202210564624A CN 117143170 A CN117143170 A CN 117143170A
Authority
CN
China
Prior art keywords
group
glucosamine
compound
mmol
meglumine
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.)
Pending
Application number
CN202210564624.0A
Other languages
Chinese (zh)
Inventor
南发俊
谢欣
卓宁
贠盈
张晨露
蓝园
郭世猛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CN202210564624.0A priority Critical patent/CN117143170A/en
Priority to PCT/CN2023/095370 priority patent/WO2023226904A1/en
Publication of CN117143170A publication Critical patent/CN117143170A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an intestinal targeting pentacyclic triterpene TGR5 receptor agonist, a preparation method and application thereof, wherein the structure is shown as a formula I, and the definition of each substituent is described in the specification and the claims. The compounds of the invention are useful as TGR5 receptor agonists for the preparation of medicaments for the treatment of diabetes, obesity, hyperlipidemia, liver injury and inflammationMedicament for treating sexual diseases.

Description

Intestinal targeting pentacyclic triterpene TGR5 receptor agonist, and preparation method and application thereof
Technical Field
The invention relates to a TGR5 (bile acid G protein coupled receptor) agonist, a preparation method and application thereof.
Background
TGR5 is a G-protein coupled receptor that can be activated by bile acid, also called G-protein bile acid-activated receptor 1 (GPBAR 1) or membrane bile acid receptor (M-BAR), and is a membrane protein containing 330 amino acids and having a 7-time transmembrane structure. TGR5 is expressed in various organs such as gallbladder, bile duct epithelial cells, brown adipose tissue, muscle, intestine, kidney, stomach, liver, lung, spleen, placenta, and brain. After binding to the ligand, TGR5 activates adenylate cyclase, elevating intracellular cyclic adenosine monophosphate (cAMP) levels, activating downstream target genes, playing different physiological roles in different tissues. In enteroendocrine cells, the elevation of cAMP level can promote the release of glucagon-like peptide 1 (GLP-1), so that insulin secretion is promoted, the sensitivity of an organism to insulin is improved, the release of peptide YY (PYY) can be induced, and appetite is reduced; therefore, TGR5 agonists are expected to be useful for the development of therapeutic drugs for diseases such as type 2 diabetes and inflammatory bowel disease.
TGR5 agonists that have been reported to date can be classified into steroids, triterpenes and synthetic small molecules depending on the type of structure. Steroid agonists are represented by INT-777 (J.Med. Chem.2009, 52, 7958-7961). INT-777 can increase the bile flow of mice, remarkably reduce weight gain and obesity, improve liver function, and reduce steatosis and fibrosis, but INT777 can cause obvious gallbladder filling phenomenon (Am J Physiol Gastrointest Liver Physiol,2019,316,412-424), and the further development of the compounds is limited by larger cholecystokinin side effects; most of synthesized small molecule TGR5 agonists have strong agonistic activity,but also side effects such as gallbladder filling, itching (J Clin invest.2013;123 (4): 1513-1530) and increased heart rate and cardiac output due to systemic vasodilation (BBA-Molecular Basis of disease.2018,1864, 1319-1325); natural triterpenes such as oleanolic acid, betulinic acid and ursolic acid all have TGR5 agonistic activity, and betulinic acid is widely studied. Compound 18dia 2 (EC) obtained by structural modification of betulinic acid has been reported 50 =0.12 μm) (j.med.chem.2010, 53,178-90), but the in vivo pharmacodynamic experiments in mice did not show significant hypoglycemic activity, probably due to the large lipid solubility leading to low bioavailability thereof.
A series of TGR5 agonists were obtained by reversing the hydroxyl group at position C3 of betulinic acid to mimic the bile acid structure, wherein compound 13 alpha activity was comparable to INT-777 and GLP-1 secretion by NCI-H716 cells could be promoted in vitro (Acta Pharmacol sin.2014;35 (11): 1463-1472; WO 201510449), but did not show significant hypoglycemic activity after oral administration, probably because of poor solubility and permeability due to excessive lipid solubility of the compound, which was unable to permeate cell membranes. Whereas TGR5 is located on the basal membrane side of intestinal L cells, so 13 a cannot reach the basal membrane side of L cells to agonize TGR5. After further structural modification, a series of TGR5 agonists with improved physicochemical properties and activity (J Med chem.2021;64 (16): 12181-12199; WO 2021078150) are obtained, wherein the 11d-Na compound has strong agonistic activity and improved permeability, and is used for humanizing TGR5 H88Y Mice exhibit significant hypoglycemic effects and are able to stimulate GLP-1 and insulin secretion, but their high plasma exposure, which systemically agonizes TGR5 leading to gallbladder filling.
In order to eliminate the various adverse effects caused by systemic agonism of TGR5, it is desirable to reduce systemic exposure of the compound and it is necessary to develop TGR5 agonists with intestinal tissue selectivity. Depending on the profile of the intestinal TGR5, an ideal intestinal selective TGR5 agonist would need to be able to agonize TGR5 partially across the intestinal L cell basement membrane and be able to return to the intestinal lumen without entering the systemic circulation, which would require a decrease in the permeability of the compound. Researchers have reduced compound permeability by a variety of means (J Med chem.2015;58 (8): 3315-3328;Sci Rep.2016;6:28676;J Med Chem.2018;61 (17): 7589-7613;RSC Med Chem.2021;12 (3): 394-405;ACS Med Chem Lett.2017;8 (5): 560-565;J Med Chem.2017;60 (10): 4185-4211;J Med Chem.2021;64 (3): 1593-1610) and all improved cholecystokinin upon short term administration.
Disclosure of Invention
The object of the present invention is to provide pentacyclic triterpenes as TGR5 receptor agonists.
In a first aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof,
in the method, in the process of the invention,
r is amino acid, amino sugar or
Wherein the amino acid is selected from the group consisting of: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine;
the amino sugar is selected from: glucosamine, meglumine, aminomannose, and galactosamine;
a is O, CR a Or NR (NR) b Wherein R is a And R is b Each independently is hydrogen, substituted or unsubstitutedC1-C4 alkyl;
b is- (CH) 2 ) n -、-(O-(CH 2 ) n ) m -、-O-(CH 2 ) n -O-、-((CH 2 ) n -O) m -、-(CH 2 ) n -O-(CH 2 ) m -, a C3-C8 cycloalkyl or a 3-8 membered heterocycle, n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8;
R 1 is H, C-C4 alkyl, sulfonic acid group (-SO) 3 H) Sulfonate (-OSO) 3 H) Phosphate group (-PO) 3 H 2 ) Phosphate group (-OPO) 3 H 2 ) Glucopyranosyl, glucosamine, meglumine,Wherein R is c Is a glucosamine group or a meglumine group; x is CH 2 NH or O, R d Is a glucosyl group or +.>Wherein R is e Is a glucosamine group or a meglumine group.
In another preferred embodiment, R is an amino acid selected from the group consisting of: arginine, asparagine, glutamine, glycine, lysine, serine, threonine.
In another preferred embodiment, R is selected from:
in another preferred embodiment, the amino sugar is selected from the group consisting of: glucosamine, meglumine, D-glucosamine, D-galactosamine, D-mannosamine.
In another preferred embodiment, the amino sugar is selected from the group consisting of:
in another preferred embodiment, R isWherein A is NH;
b is- (CH) 2 ) n -、-(O-(CH 2 ) n ) m -、-(O-(CH 2 ) n O) m -、-((CH 2 ) n -O) m -、-(CH 2 ) n -O-(CH 2 ) m -, C4-C6 cycloalkyl or 4-6 membered heterocycle, n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8;
R 1 is H, C-C4 alkyl, sulfonic acid group (-SO) 3 H) Sulfonate (-OSO) 3 H) Phosphate group (-PO) 3 H 2 ) Phosphate group (-OPO) 3 H 2 ) Glucopyranosyl, meglumine orWherein R is c Is a glucosamine group or a meglumine group.
In a further preferred embodiment of the present invention,selected from the group consisting of: glucopyranosyl-piperidine ring-, -piperidine ring-SO 3 H. -piperidine ring-OSO 3 H. -piperidine ring-OPO 3 H 2 -piperidine ring-PO 3 H 2 Glucosamine-based CO- (O- (CH) 2 ) n ) m -, a part of glucosamine-based CO- (O- (CH) 2 ) n O) m -, a part of glucosamine group- (CH) 2 ) n -, a part of glucosamine-based CO- (CH) 2 ) n -, a part of glucosamine-based CO- ((CH) 2 ) n -O) m -, a part of glucosamine group- (O- (CH) 2 ) n ) m -, a part of glucosamine group- (O- (CH) 2 ) n O) m -, a part of glucosamine group- ((CH) 2 ) n -O) m -, a part of glucopyranosyl-cyclohexyl- -cyclohexyl-SO 3 H、-cyclohexyl-OSO 3 H. -cyclohexyl-OPO 3 H 2 -cyclohexyl-PO 3 H 2 -cyclohexyl-glucamine, - (CH) 2 ) n -OPO 3 H 2 、-(O-(CH 2 ) n ) m -OPO 3 H 2 、-(CH 2 ) n -PO 3 H 2 、-(O-(CH 2 ) n ) m -PO 3 H 2 、-(CH 2 ) n -O-(CH 2 ) m -SO 3 H、-O-(CH 2 ) n -SO 3 H、-(CH 2 ) n -SO 3 H、-(CH 2 ) n -OSO 3 H、-((CH 2 ) n -O) m -C1-C4 alkyl, - ((CH) 2 ) n -O) m -H；
n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8.
In another preferred embodiment, A is NH; b is selected from the group consisting of: piperidine ring, - (CH) 2 ) n -、-((CH 2 ) n -O) m -、-(O(CH 2 ) n ) m -、-O-(CH 2 ) n O-、-(CH 2 ) n -O-(CH 2 ) m -；
R1 is selected from the group consisting of: H. C1-C4 alkyl, glucopyranosyl, -SO 3 H、-OSO 3 H. -CO- (D-glucosamine), -OPO 3 H 2 、-PO 3 H 2 D-glucosamine;
n is 1, 2, 3, 4, 5 or 6; m is 1, 2, 3, 4, 5 or 6.
In another preferred embodiment, the glucosamine is D-glucosamine. In another preferred embodiment, the glucosamine group is D-glucosamine group.
In another preferred embodiment, the compound is selected from: T1-T41 compounds.
In a second aspect of the present invention, there is provided a process for preparing the compound of the first aspect, wherein betulinic acid is used as a raw material, carbamate is introduced into the hydroxyl group at the C3 position, hydroxyl is introduced into the double bond at the C20 position, carbamate is introduced, and finally benzyl protecting group on the carboxyl group at the C17 position is removed by hydrogenation, thereby obtaining the compound.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising:
a compound of the first aspect or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
The novel compounds provided by the invention can be used singly or mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to prepare tablets, capsules, granules, syrups and the like for oral administration. The pharmaceutical composition can be prepared according to a conventional pharmaceutical method.
In another preferred embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent. Preferably, the at least one other therapeutic agent comprised in the pharmaceutical composition is selected from the group consisting of other anticancer agents, immunomodulators, antiallergic agents, anti-emetic agents, pain relieving agents, cytoprotective agents and combinations thereof.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the active ingredient of the present invention (the compound of the first aspect or a pharmaceutically acceptable salt thereof) without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (e.g. sodium lauryl sulphate), colouring agents, flavouring agents, stabilisers, anti-oxidantsChemical agents, preservatives, pyrogen-free water, and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
In a fourth aspect of the invention, there is provided the use of a compound according to the first aspect or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the third aspect:
(i) For the preparation of bile acid G protein coupled receptor (TGR 5) agonists; or (b)
(ii) Is used for preparing medicines for treating metabolic diseases.
In another preferred embodiment, the metabolic disease is selected from: diabetes, obesity, hyperlipidemia, liver injury, and inflammatory diseases.
The pentacyclic triterpene compound provided by the invention can effectively excite the TGR5 receptor, and part of the compounds can excite the TGR5 receptor at nanomolar concentration, and compared with the existing TGR5 agonists of natural sources, the pentacyclic triterpene compound has more excellent TGR5 agonist activity, richer natural sources and simpler and more convenient synthesis method.
It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.
Drawings
Figure 1 shows the results of oral glucose tolerance experiments on blood glucose levels in compound mice.
Figure 2 shows the area under the compound mice oral glucose tolerance experimental curve results.
Figure 3 shows the results of a compound 7 day mouse cholesterol toxicity experiment.
Detailed Description
The inventor of the application researches and develops a pentacyclic triterpene compound, which is mainly characterized in that carbamate at the C29 position is introduced with a plurality of large polar groups to obtain a series of intestinal targeted pentacyclic triterpene compounds with obviously improved physicochemical properties, the intestinal distribution of the pentacyclic triterpene compounds is obviously increased compared with the compounds disclosed before, the pentacyclic triterpene compounds have no obvious cholecystokinin, and the pentacyclic triterpene compounds are hopeful to become novel medicines for treating metabolic diseases represented by diabetes.
Terminology
In the present invention, the halogen is F, cl, br or I.
In the present invention, the term "C1-C6" means having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "3-10 membered" means having 3-10 ring atoms, and so on.
In the present invention, the term "alkyl" means a saturated linear or branched hydrocarbon moiety, e.g., the term "C1-C8 alkyl" refers to a straight or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, including without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like; ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present invention, the term "alkoxy" means-O-alkyl. For example, the term "C1-C6 alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, n-propoxy, isopropoxy, butoxy and the like.
In the present invention, the term "cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon moiety, for example the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl" and "C3-C6 cycloalkyl" have similar meanings. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
In the present invention, the term "heterocyclyl" or "heterocycloalkyl" means a cyclic group containing at least one ring heteroatom (e.g., N, O or S). For example, the term "3-12 membered heterocyclic group" means a saturated or unsaturated 3-12 membered cyclic group containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen in the ring, such as a dioxolyl group, a tetrahydropyridinyl group, a dihydropyridinyl group, a dihydrofuryl group, a dihydrothienyl group and the like. The term "3-7 membered heterocyclyl" has similar meaning.
In the present invention, the term "3-7 membered nitrogen-containing heterocycle" refers to a cycloalkyl ring having 3-7 ring atoms and containing 1, 2 or 3N atoms, including, without limitation, a cyclopropane ring, a cyclobutane ring, a cycloheptane ring, and the like.
In the present invention unless otherwise indicated,representing the ligation site.
Unless otherwise indicated, alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups include, but are not limited to: hydroxy, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfinyl, arylsulfinyl, C1-C10 alkylimino, C1-C10 alkylsulfonimino, arylsulfonyl imino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureyl, cyano, acyl, thio acyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl may also be fused to each other.
In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution. The disubstitution means having two substituents and so on.
Unless specifically indicated otherwise, the structural formulae described herein are intended to include all tautomeric, optical, and stereoisomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example R, S configuration with asymmetric centers, the (Z), (E) isomers and the conformational isomers of (Z), (E) of double bonds. Thus, individual stereochemical isomers, tautomers or enantiomers, diastereomers or geometric isomers or conformational isomers or mixtures of tautomers of the compounds of the invention are all within the scope of the invention.
The term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thus interconvert. For example, proton tautomers (i.e., proton transfer) include interconversions by proton transfer, such as 1H-indazole with 2H-indazole, 1H-benzo [ d ] imidazole with 3H-benzo [ d ] imidazole, valence tautomers include interconversions by recombination of some bonding electrons.
In this context, the pharmaceutically acceptable salts are not particularly limited, and preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates; the inorganic acid salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; the organic acid salts include formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, and the like; the alkyl sulfonate includes methyl sulfonate, ethyl sulfonate, etc.; the arylsulfonate includes benzenesulfonate, p-toluenesulfonate and the like.
Compounds of formula (I)
The pentacyclic triterpene compound is a series of compounds with good TGR5 agonistic activity, which are obtained by introducing a large polar group into an active insensitive site of the compound. The structure is shown as a general formula I.
Compared with the early-stage compounds, the compounds have low permeability, so that the compounds have good intestinal tissue distribution specificity. Wherein the compound T8, T14 has significantly reduced permeability compared to the reported class of compounds (T8:<0.32×10 - 6 cm/s,T14:0.55×10 -6 cm/s), the efflux rate is remarkably improved (T8:>17.8, T14:7.81), has high distribution in the small intestine, low distribution in blood plasma, liver and gall bladder, has good intestinal tissue distribution selectivity, shows obvious hypoglycemic activity in vivo, particularly does not show obvious gall bladder filling, and obviously improves gall bladder toxicity.
In conclusion, the TGR5 receptor agonist provided by the invention has good activity, simultaneously improves physicochemical properties, has intestinal tissue distribution specificity, effectively improves gallbladder side effects, and is expected to be further developed into a novel medicament for treating type II diabetes and other metabolic diseases.
Preparation method
The pentacyclic triterpene compound of the invention can be prepared by the following route.
Route 1
In the above formula, R' is:
route 2
In the above-mentioned method, the step of,selected from the group consisting of: - (CH) 2 ) n -、-((CH 2 ) n -O) m -、-(O(CH 2 ) n ) m -、-O-(CH 2 ) n O-、/>-(CH 2 ) n -O-(CH 2 ) m -; n is 1, 2, 3, 4, 5 or 6; m is 1, 2, 3, 4, 5 or 6.
Route 3
In the above-mentioned method, the step of,selected from the group consisting of: - (CH) 2 ) n -、-((CH 2 ) n -O) m -、-(O(CH 2 ) n ) m -、-O-(CH 2 ) n O-、、-(CH 2 ) n -O-(CH 2 ) m -; n is 1, 2, 3, 4, 5 or 6; m is 1, 2, 3, 4, 5 or 6.
Route 4
Route 5
In the above-mentioned method, the step of,the method comprises the following steps: - (CH) 2 ) n -; n is 6, 1, 2, 3, 4 or 5.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions (e.g.those described in Sambrook et al, molecular cloning: A laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989)) or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
In the following preparation examples, MR was measured by means of a AVANCE III M instrument manufactured by Bruker and NMR calibration was carried out: δH7.26ppm (CDCl) 3 )，2.50ppm(DMSO-d 6 ) The method comprises the steps of carrying out a first treatment on the surface of the Mass spectra were measured using an Agilent 1200Quadrupole LC/MS simadzu GCMS-QP 5050A; reagents are mainly provided by Shanghai chemical reagent company; the TLC thin layer chromatography silica gel plate is manufactured by Shandong tobacco Confucius silica gel development Co., ltd, model HSGF 254; the normal phase column chromatography silica gel used for purifying the compounds is produced by ocean chemical plants of Qingdao in Shandong, and has the model of zcx-11 and 200-300 meshes.
The chinese abbreviations herein correspond to the following:
DMAP 4-dimethylaminopyridine; DCM: dichloromethane; DMF: n, N-dimethylformamide; THF: tetrahydrofuran.
Example 1
(1) The betulinic acid benzyl is protected and then the hydroxyl is turned over to obtain an intermediate S1. 1 H NMR(300MHz,CDCl 3 )δ7.37-7.31(m,5H),5.17-5.06 (m, 2H), 4.72 (s, 1H), 4.60-4.58 (m, 1H), 3.39-3.36 (m, 1H), 3.06-2.98 (m, 1H), 2.29-2.13 (m, 3H), 1.98-1.02 (m, other alicyclic protons), 0.96 (s, 3H), 0.92 (s, 3H), 0.81 (s, 6H), 0.76 (s, 3H).
(2) Intermediate S1 (30.0 g,54.94 mmol), DMAP (33.0 g,270.11 mmol) was dissolved in dry DCM (200 mL), a solution of p-nitrophenyl chloroformate (22.2 g,110.14 mmol) in dry DCM (100 mL) was added dropwise at 0deg.C, after returning to room temperature and stirring for 5 hours, cyclopropylamine (19.2 mL,270.11 mmol) was added dropwise, stirring overnight at room temperature and the next day TLC showed complete reaction. The DCM was taken out, extracted with ethyl acetate (3X 500 mL), and the combined organic layers were washed with saturated ammonium chloride solution, deionized water and saturated brine, respectively, dried over sodium sulfate and concentrated, and the product S2 34.57g (54.88 mmol) was isolated by column chromatography in the yield: 99.89%. 1 H NMR(300MHz,CDCl 3 ) Delta 7.37-7.31 (m, 5H), 5.17-5.07 (m, 2H), 4.72 (d, 1H, j=2.4 Hz), 4.59 (s, 1H), 4.50 (s, 1H), 3.06-2.97 (m, 1H), 2.58 (s, 1H), 2.30-2.13 (m, 3H), 1.94-1.01 (m, other alicyclic protons), 0.96 (s, 3H), 0.86 (s, 6H), 0.81 (s, 3H), 0.76 (s, 3H), 0.72-0.68 (m, 2H), 0.56-0.50 (m, 2H).
(3) S2 (34.57 g,54.88 mmol) was dissolved in dry THF (200 mL) and 10M BH was added dropwise at 0deg.C 3 -Me 2 S (6.58 mL,65.80 mmol), after stirring for 1 hour, TLC detected that the basic reaction was complete. Ethanol (30 mL), saturated sodium carbonate solution (50 mL) and 30% hydrogen peroxide solution (20 mL) were added sequentially to the reaction solution, and the mixture was stirred at room temperature for 2 hours, and the reaction was complete by TLC. The remaining hydrogen peroxide was neutralized with saturated sodium sulfite solution, extracted with ethyl acetate (3×500 mL), and the combined organic layers were washed with deionized water, 1N diluted hydrochloric acid and saturated brine, respectively, and concentrated by drying over sodium sulfate, and separated by column chromatography to give compound S3.05 g (37.12 mmol), yield: 67.63%. 1 H NMR(300MHz,CDCl 3 ) Delta 7.37-7.31 (m, 5H), 5.15-5.05 (m, 2H), 4.85 (br s, 1H), 4.51 (s, 1H), 3.80-3.75 (m, 1H), 3.45-3.39 (m, 1H), 2.58 (s, 1H), 2.38-2.17 (m, 4H), 1.91-1.05 (m, other alicyclic protons), 0.97-0.95 (m, 6H), 0.86-0.83 (m, 9H), 0.75-0.68 (m, 5H), 0.56-0.51 (m, 2H).
(4) Intermediate S3 (24.05 g,37.12 mmol), DMAP (9.07 g,74.24 mmol) was dissolved in dry DCM (200 mL) after 0.5 h at 0deg.CA solution of p-nitrophenyl chloroformate (14.96 g,74.22 mmol) in dry DCM (50 mL) was added dropwise and after returning to room temperature, stirring was continued for 2 hours and TLC monitoring showed completion of the reaction. The DCM was spun off and extracted with ethyl acetate (3X 300 mL) and the combined organic layers were washed with saturated ammonium chloride solution, deionized water and saturated brine, respectively, dried over anhydrous sodium sulfate and concentrated, and the product S4.35 g (31.18 mmol) was isolated by column chromatography in yield: 84.00%. 1 H NMR(300MHz,CDCl 3 ) Delta 8.32-8.26 (m, 2H), 7.40-7.30 (m, 7H), 5.16-5.06 (m, 2H), 4.85 (br s, 1H), 4.50 (s, 1H), 4.42-4.37 (m, 1H), 4.11-4.04 (m, 1H), 2.56 (s, 1H), 2.46-2.39 (m, 1H), 2.32-2.16 (m, 3H), 1.91-1.07 (m, other alicyclic protons), 1.02 (d, 3H, J=6.9 Hz), 0.96 (s, 3H), 0.86-0.83 (m, 9H), 0.75 (s, 3H), 0.71-0.65 (m, 2H), 0.53-0.48 (m, 2H).
(5) S4 (50 mg,0.06 mmol), benzyl glycinate hydrochloride (37.2 mg,0.18 mmol), DMAP (37.5 mg,0.31 mmol) was dissolved in dry DCM (2 mL) and stirred overnight at room temperature, the next day TLC indicated complete reaction. The DCM was spun off and extracted with ethyl acetate (3X 20 mL) and the combined organic layers were washed with saturated ammonium chloride solution, deionized water and saturated brine, respectively, dried over sodium sulfate and concentrated to give 33.5mg (0.040 mmol) of product by column chromatography, yield: 66.54%. 1 H NMR (400 mhz, chloroform-d) delta 7.40-7.29 (m, 10H), 5.19 (s, 2H), 5.16 (s, 2H), 5.09 (dd, j=20.6, 12.0hz, 2H), 4.89 (s, 1H), 4.50 (t, j=2.8 hz, 1H), 4.19 (s, 1H), 4.02 (d, j=5.2 hz, 2H), 3.86 (s, 1H), 2.57 (s, 1H), 2.34 (tt, j=10.8, 2.8hz, 1H), 2.29-2.25 (m, 1H), 2.19 (td, j=11.6, 4.0hz, 1H), 2.02-2.00 (m, 1H), 1.87 (d, j=14.4 hz, 1H), 1.82 (dd, j=12.4, 7.2hz, 2H), 3.86 (s, 1H), 2.57 (s, 1H), 2.34 (tt, j=10.8, 2.8hz, 1H), 2.29-2.25 (td, 1H), 2.0hz, 1H), 2.82 (d, 1.7 hz, 1H), 1.82 (d, 1.7 hz, 1H), 0.0H), 0H (0.0H).
(6) The product of the previous step was dissolved in ethyl acetate: tertiary butanol=1: 1 (10 mL) was replaced with nitrogen, and 10% Pd (OH) was added rapidly 2 And (C) replacing nitrogen, replacing hydrogen, and stirring at room temperature. After 24 hours the reaction was complete by TLC. After nitrogen exchange, pd (OH) was filtered off 2 After spin-drying the reaction mixture, column chromatography was carried out with an eluent system of 10:1 methylene chloride/methanol to give product T1.2 mg (0.014 mmol) as a white solid, which was collectedThe rate is as follows: 35.09%. 1 H NMR(400MHz,Methanol-d 4 ) Delta 4.45 (t, j=2.8 hz, 1H), 4.26 (d, j=10.4 hz, 1H), 3.87 (t, j=9.6 hz, 1H), 3.82 (s, 2H), 2.51 (s, 1H), 2.35-2.29 (m, 2H), 2.24-2.20 (m, 1H), 2.02 (s, 1H), 1.93 (t, j=14.0 hz, 1H), 1.82 (dd, j=12.0, 7.2hz, 1H), 1.71-1.25 (m, other alicyclic protons), 1.15 (d, j=13.6 hz, 1H), 1.01 (s, 3H), 0.98-0.97 (m, 6H), 0.90 (s, 6H), 0.87 (s, 3H), 0.65 (s, 2H), 0.47 (s, 2H).
In a similar manner as in example 1, intermediate S4 was reacted with different amines to give the following compounds:
/>
/>
/>
example 2
(1) S4 (100 mg,0.12 mmol), ethanolamine (22.27. Mu.L, 0.37 mmol), DMAP (75.13 mg,0.61 mmol) were dissolved in dry DCM (4 mL), stirred overnight at room temperature, and the next day TLC showed completion of the reaction. The DCM was spun off and extracted with ethyl acetate (3X 50 mL) and the combined organic layers were washed with saturated ammonium chloride solution, deionized water and saturated brine, respectively, dried over sodium sulfate and concentrated to give 90.6mg (0.12 mmol) of product by column chromatography, yield: 100%. 1 HNMR(400MHz,Chloroform-d)δ7.35–7.29(m,5H),5.14–5.05(m,3H),4.98(s,1H),4.49(t,J＝2.8Hz,1H),4.17(d,J＝10.4hz, 1H), 3.83 (t, j=9.6 hz, 1H), 3.72 (t, j=5.2 hz, 2H), 3.37-3.31 (m, 2H), 2.60-2.56 (m, 1H), 2.34 (tt, j=10.8, 3.2hz, 1H), 2.29-2.25 (m, 1H), 2.22-2.16 (m, 1H), 2.03-1.97 (m, 1H), 1.89-1.80 (m, 2H), 1.70-1.05 (m, other alicyclic protons), 0.95 (s, 3H), 0.93 (d, j=6.4 hz, 3H), 0.86 (s, 6H), 0.82 (s, 3H), 0.74 (s, 3H), 0.72-0.69 (m, 2H), 0.55-0.51 (m, 2H).
(2) The product of the previous step (90.6 mg,0.12 mmol), triethylamine (85.78. Mu.L, 0.62 mmol) were dissolved in dry DCM (4 mL), and after 0.5 h a solution of p-nitrophenyl chloroformate (74.64 g,0.37 mmol) in dry DCM (50 mL) was added dropwise and after returning to room temperature and stirring was continued for 2h, TLC monitoring showed completion. The DCM was spun off and extracted with ethyl acetate (3X 50 mL) and the combined organic layers were washed with deionized water, dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next step.
(3) The crude product of the previous step, D-glucosamine (67.09 g,0.37 mmol) was dissolved in dry DMF (200 mL), triethylamine (85.78. Mu.L, 0.62 mmol) was added dropwise and stirred at room temperature for 4 hours, and TLC monitoring showed completion of the reaction. DMF was taken off and the product was isolated by column chromatography as 82.6mg (0.088 mmol) yield: 73.15%. 1 H NMR(400MHz,Methanol-d 4 ) Delta 7.39-7.29 (m, 5H), 5.11 (dd, j=26.8, 12.0hz, 2H), 4.44 (s, 1H), 4.20 (dd, j=11.2, 4.4hz, 1H), 4.11-4.05 (m, 2H), 3.86-3.74 (m, 4H), 3.71-3.68 (m, 1H), 3.65-3.60 (m, 2H), 3.36 (dd, j=14.6, 5.2hz, 3H), 3.21 (dd, j=13.6, 7.2hz, 1H), 2.51 (tt, j=7.2, 3.6hz, 1H), 2.35-2.18 (m, 3H), 2.02-1.99 (m, 1H), 1.91 (t, j=15.2 hz, 1H), 1.80 (dd, j=14.6, 5.2hz, 3H), 3.21 (dd, j=13.6, 7.2hz, 1H), 2.51 (dd, 1.6, 1H), 2 j=0.6 hz, 1H), 2.0.0 (0H), 1 s (0.6, 6hz, 1H), 1.0 s (0.8H), 0.6H).
(4) Compound T20 (58.1 mg, 77.58%) was obtained by a similar debenzylation procedure. 1 H NMR(400MHz,Methanol-d 4 ) Delta 4.45 (t, j=2.8 hz, 1H), 4.21 (dd, j=10.8, 4.8hz, 1H), 4.07 (t, j=5.6 hz, 2H), 3.87-3.75 (m, 4H), 3.72-3.68 (m, 1H), 3.65-3.60 (m, 2H), 3.38-3.34 (m, 3H), 3.21 (dd, j=13.8, 7.6hz, 1H), 2.53-2.49 (m, 1H), 2.35-2.29 (m, 2H), 2.23 (dt, j=12.4, 3.2hz, 1H), 2.01-1.90 (m, 2H), 1.83 (dd, j=12.0, 7.2hz, 1H), 1.70-1.22 (m, other lipids Fat ring protons), 1.18-1.14 (m, 1H), 1.00 (s, 3H), 0.97 (s, 3H), 0.96 (d, j=6.8 hz, 3H), 0.90 (s, 6H), 0.87 (s, 3H), 0.66 (s, 2H), 0.48 (s, 2H).
In a similar manner as in example 2, the following compounds were obtained as carbamates after reaction of intermediate S4 with different linker:
/>
/>
example 3
(1) The product of example 2 (1) (50 mg,0.068 mmol), 1,2, 4-triazole (9.40 mg,0.14 mmol), diphenylN, N' -diisopropylphosphoramidite (28.19 mg,0.082 mmol) and sodium bicarbonate (28.57 mg,0.34 mmol) were dissolved in dry DCE (2 mL) and stirred overnight at 65℃and TLC monitoring showed complete reaction. 1mL of THF was added and 30% hydrogen peroxide (0.5 mL) was added dropwise at 0deg.C and stirred for 5 min, TLC monitoring showed complete reaction and quenched by the addition of 5mL of saturated sodium sulfite solution. After dilution with water, extraction with dichloromethane (3×50 mL), the combined organic layers were washed with deionized water and saturated brine, respectively, dried over sodium sulfate and concentrated, and separated by column chromatography to give 41.8mg (0.042 mmol) of the product in yield: 61.74%. 1 H NMR (400 mhz, chloroform-d) delta 7.38-7.29 (m, 15H), 5.13-5.01 (m, 6H), 4.50 (t, j=2.4 hz, 1H), 4.16-4.13 (m, 1H), 4.00 (dt, j=8.0, 5.2hz, 2H), 3.79 (t, j=9.2 hz, 1H), 3.35 (q, j=5.2 hz, 2H), 2.57 (s, 1H), 2.37-2.31 (m, 1H), 2.28-2.24 (m, 1H), 2.22-2.15 (m, 1H), 1.99 (d, j=6.8 hz, 1H), 1.89-1.79 (m, 2H), 1.63-1.04 (m, other fats Cyclic protons), 0.93 (s, 3H), 0.91 (d, j=7.2 hz, 3H), 0.86 (s, 3H), 0.84 (s, 2H), 0.81 (s, 4H), 0.73 (s, 3H), 0.71-0.66 (m, 2H), 0.53-0.50 (m, 2H).
(2) A similar debenzylation procedure gave product T28 (21.4 mg, 70.29%). 1 H NMR(400MHz,Methanol-d 4 ) δ4.45 (t, j=2.8 hz, 1H), 4.22 (d, j=6.4 hz, 1H), 3.90 (dd, j=12.0 hz,6.0hz, 2H), 3.83 (t, j=9.2 hz, 1H), 2.51 (s, 1H), 2.32 (s, 2H), 2.24-2.20 (m, 1H), 2.01-1.90 (m, 2H), 1.82 (dd, j=12.2, 7.2hz, 1H), 1.73-1.22 (m, other fat ring protons), 1.15 (d, j=13.2 hz, 1H), 1.00 (s, 3H), 0.97-0.95 (m, 6H), 0.90 (s, 6H), 0.87 (s, 3H), 0.64 (s, 2H), 0.48 (s, 2H).
In a similar manner as in example 3, the following compounds were obtained as phosphate esters after reaction of intermediate S4 with different linker:
/>
example 4
(1) The product of S4 by condensing the procedure of example 2 (1) with diglycolamine (50 mg,0.064 mmol), carbon tetrabromide (63.86 mg,0.19 mmol), triphenylphosphine (50.51 mg,0.19 mmol) was dissolved in dry DCM (4 mL) and stirred at room temperature for 4 hours, and TLC monitoring showed completion of the reaction. DCM was spun off and the product isolated by column chromatography to give 60.5mg (0.072 mmol), yield: 100%. 1 H NMR (400 mhz, chloroform-d) delta 7.35-7.29 (m, 5H), 5.13-5.05 (m, 3H), 4.92 (s, 1H), 4.50 (s, 1H), 4.17 (s, 1H), 3.84 (t, j=9.6 hz, 1H), 3.78 (t, j=5.6 hz, 2H), 3.58 (t, j=4.8 hz, 2H), 3.47 (t, j=5.6 hz, 2H), 3.39 (dd, j=10.8, 5.6hz, 2H), 2.59 (s, 1H), 2.37-2.31 (m, 1H), 2.29-2.25 (m, 1H), 2.22-2.16 (m, 1H), 2.01 (d, j=8.4, 1H), 1.89-1.79 (m, 2H), 1.06 (m-63.63, other (s, 1H) Alicyclic protons), 0.96 (s, 3H), 0.93 (d, j=6.8 hz, 3H), 0.86 (s, 6H), 0.82 (s, 3H), 0.74 (s, 3H), 0.73-0.69 (m, 2H), 0.55-0.51 (m, 2H).
(2) 42.0mg (0.050 mmol) of the product of the previous step was dissolved in 4mL of ethanol: water = 1: to the solution 1 was added anhydrous sodium sulfite (31.51 mg,0.25 mmol), stirred at 100℃under reflux overnight, and the next day TLC indicated that the reaction was complete. Returning to room temperature, the solvent was removed by column chromatography to give 29.1mg (0.034 mmol) of product in yield: 69.19%. 1 H NMR(400MHz,Methanol-d 4 ) Delta 7.39-7.31 (m, 5H), 5.11 (dd, j=28.4, 12.0hz, 2H), 4.44 (t, j=2.8 hz, 1H), 4.20 (dd, j=10.8, 4.8hz, 1H), 3.85 (t, j=6.8 hz, 3H), 3.53 (t, j=5.6 hz, 2H), 3.30-3.28 (m, 2H), 3.12 (t, j=6.8 hz, 2H), 2.53-2.48 (m, 1H), 2.31-2.17 (m, 3H), 2.03-1.88 (m, 2H), 1.79 (dd, j=12.2, 6.4hz, 1H), 1.60-1.25 (m, other alicyclic protons), 1.09-1.05 (m, 1H), 0.97 (s, 3H), 0.4 hz, 2.48(s), 2.31-2.17 (m, 3H), 2.03-1.88 (m, 1H), 1.3H), 1.60-1.25 (m, 3H), 0.9 (s, 3 s, 3.3H).
(3) A similar debenzylation procedure gave product T33 (11.0 mg, 42.32%). 1 H NMR(400MHz,Methanol-d 4 ) δ4.44 (t, j=2.8 hz, 1H), 4.21 (dd, j=10.8, 4.8hz, 1H), 3.85 (t, j=6.8 hz, 3H), 3.54 (t, j=5.4 hz, 2H), 3.30-3.29 (m, 2H), 3.12 (t, j=6.8 hz, 2H), 2.51 (s, 1H), 2.41-2.31 (m, 2H), 2.23 (d, j=12.8 hz, 1H), 2.02 (d, j=2.8 hz, 1H), 1.93 (t, j=13.2 hz, 1H), 1.83 (dd, j=11.8, 7.6hz, 1H), 1.72-1.22 (m, other aliphatic ring protons), 1.14 (d, j=13.2 hz, 1H), 1.00 (s, 3H), 0.99.8 hz, 3.96(s), 0.96 s (s, 0.0H), 0.96 s (s, 0.90 s, 0H).
In a similar manner as in example 5, the reaction of intermediate S4 with different linker to form sulfonic acid gives the following compounds:
example 5
(1) EXAMPLE 2 [ (- ]1) Carbon tetrabromide (135.35 mg,0.41 mmol), triphenylphosphine (107.05 mg,0.41 mmol) was dissolved in dry DCM (4 mL), stirred at room temperature for 4 hours, and TLC monitoring showed complete reaction. DCM was spun off and the product isolated by column chromatography as 108.6mg (0.14 mmol), yield: 100%. 1 H NMR (400 mhz, chloroform-d) delta 7.36-7.30 (m, 5H), 5.14-5.06 (m, 3H), 4.98 (s, 1H), 4.51 (s, 1H), 4.16 (d, j=9.6 hz, 1H), 3.88 (t, j=8.8 hz, 1H), 3.60 (d, j=7.6 hz, 2H), 3.48 (t, j=5.6 hz, 2H), 2.59 (s, 1H), 2.36 (tt, j=10.8, 3.2hz, 1H), 2.30-2.26 (m, 1H), 2.23-2.17 (m, 1H), 2.05-2.00 (m, 1H), 1.90-1.81 (m, 2H), 1.65-1.07 (m, other alicyclic protons), 0.96 (s, 3H), 0.86 (d, 6 hz), 3.82 (s, 3.82H), 0.70-2.82 (m, 3H).
(2) The product of the previous step (50 mg,0.063 mmol), dibenzyl phosphite (21.06 mg,0.094 mmol) and cesium carbonate (40.83 mg,0.12 mmol) were dissolved in dry DMF (4 mL) and stirred overnight at room temperature, the next day TLC indicated complete reaction. DMF was taken off, extracted with ethyl acetate (3X 50 mL), the combined organic layers were washed with deionized water and saturated brine, respectively, dried over sodium sulfate and concentrated, and the product S5.3 mg (0.046 mmol) was isolated by column chromatography, yield: 73.82%. 1 H NMR (400 mhz, chloroform-d) delta 7.34 (s, 15H), 5.21 (t, j=6.0 hz, 1H), 5.09 (d, j=8.8 hz, 2H), 5.03 (d, j=10.0 hz, 2H), 4.97 (t, j=9.6 hz, 2H), 4.50 (s, 1H), 4.14-4.11 (m, 1H), 3.79 (t, j=9.2 hz, 1H), 3.41 (dt, j=20.0, 6.8hz, 2H), 2.57 (s, 1H), 2.32 (t, j=11.2 hz, 1H), 2.27-2.24 (m, 1H), 2.18 (t, j=12.0 hz, 1H), 2.04-1.95 (m, 3H), 1.85-1.78 (m, 2H), 1.62-1.05 (m, 1.2H), 3.8 hz, 3.20.0H), 3.41 (s, 1H), 3.32 (j=20.0, 6.8hz, 2H), 2.27-2.24 (m, 1H), 2.18 (t, j=12.0 hz, 1H), 3.0H (s, 3.8 hz, 3.6H).
(3) A similar debenzylation procedure gave product T38 (21.7 mg, 66.17%). 1 H NMR(400MHz,Methanol-d 4 ) δ4.45 (s, 1H), 4.21 (s, 1H), 3.84 (s, 1H), 3.39 (s, 2H), 2.51 (s, 1H), 2.32 (s, 2H), 2.22 (d, j=12.4 hz, 1H), 1.99 (s, 1H), 1.93 (s, 3H), 1.81 (d, j=9.6 hz, 1H), 1.59-1.22 (m, other alicyclic protons), 1.15 (d, j=13.2 hz, 1H), 1.00 (s, 3H), 0.97 (s, 6H), 0.90 (s, 6H), 0.87 (s, 3H), 0.65 (s, 2H), 0.49 (s, 2H).
Example 6
(1) The product S6 (200 mg,0.27 mmol) of example 2 (1), dess-Martin oxidant (346.24 mg,0.82 mmol) was dissolved in dry DCM (8 mL) and stirred at room temperature for 2 hours, TLC monitoring showed complete reaction. The combined organic layers were washed with saturated sodium sulfite solution, saturated sodium bicarbonate solution, deionized water and saturated brine, respectively, and concentrated by drying over sodium sulfate, and the product was isolated by column chromatography to yield S7.0 mg (0.21 mmol), yield: 78.82%, directly next step.
(2) S7 (156.0 mg,0.21 mmol) and D-glucosamine (42.40 mg,0.23 mmol) were dissolved in methanol (4 mL), a drop of acetic acid was added, stirring was performed for 30min, sodium cyanoborohydride (40.12 mg,0.64 mmol) was added, stirring was performed at room temperature overnight, and TLC monitoring showed completion of the reaction. The combined organic layers were washed with saturated sodium bicarbonate solution, deionized water and saturated brine, respectively, and concentrated by drying over sodium sulfate, and the product was isolated by column chromatography to give S8.6 mg (0.026 mmol), yield: 12.53%. 1 H NMR(400MHz,Methanol-d 4 ) Delta 7.39-7.31 (m, 5H), 5.11 (dd, j=30.0, 12.4hz, 2H), 4.44 (t, j=2.8 hz, 1H), 4.24 (dd, j=10.6, 4.0hz, 1H), 4.08 (dt, j=8.0, 4.4hz, 1H), 3.87-3.83 (m, 2H), 3.78 (dd, j=10.2, 2.8hz, 1H), 3.72-3.64 (m, 3H), 3.49-3.44 (m, 2H), 3.26-3.16 (m, 3H), 2.53-2.48 (m, 1H), 2.32 (t, j=12.0 hz, 1H), 2.28-2.18 (m, 2H), 2.03-1.98 (m, 1H), 1.97-1.89 (m, 1H), 1.72-3.64 (m, 3H), 3.49-3.44 (m, 3.48 (m, 3H), 3.53-2.48 (m, 1H), 2.48 (1.0-0H), 1.6 (m, 1H), 1.6-0H (1H), 1.6.6H (m, 6H), 1.0H).
(3) A similar debenzylation procedure gave product T39 (11.6 mg, 54.63%). 1 H NMR(400MHz,Methanol-d 4 )δ4.44(s,1H),4.28–4.25(m,1H),4.08(dt,J＝8.4,4.0Hz,1H),3.89–3.84(m,2H),3.78(dd,J＝10.2,2.8Hz,1H),3.71–3.64(m,3H),3.46(t,J＝6.0Hz,2H),3.25–3.17(m,3H),2.51(s,1H),2.34(s,2H),2.23(d,J＝12.4Hz,1H),2.00–1.90(m,2H),1.83(dd,J＝12.07.2hz, 1H), 1.68-1.14 (m, other alicyclic protons), 0.99 (s, 3H), 0.98-0.97 (m, 6H), 0.90 (s, 7H), 0.87 (s, 3H), 0.65 (s, 2H), 0.48 (s, 2H).
Example 7
(1) The product of the condensation of example S4 and n-propanol amine (150 mg,0.20 mmol), dess-Martin oxidant (169.87 mg,0.40 mmol) was dissolved in dry DCM (6 mL) and stirred at room temperature for 2 hours, and TLC monitoring showed completion of the reaction. The combined organic layers were washed with saturated sodium sulfite solution, saturated sodium bicarbonate solution, deionized water and saturated brine, respectively, and concentrated by drying over sodium sulfate, and the product was isolated by column chromatography (139.0 mg, 0.19 mmol), yield: 93.03%, directly next step.
(2) The product of the previous step (70 mg,0.094 mmol) was dissolved in t-butanol (4 mL), 2-methyl-2-butene (65.72 mg,0.94 mmol) was added, a mixed solution of sodium chlorite (25.42 mg,0.28 mmol) and sodium dihydrogen phosphate (56.21 mg,0.47 mmol) in 4mL water was added and stirred at room temperature for 2 hours, and TLC monitoring showed completion of the reaction. Extraction with ethyl acetate (3X 50 mL) and washing of the combined organic layers with deionized water and saturated brine, respectively, drying and concentration over sodium sulfate, column chromatography gave 59.6mg (0.078 mmol) of product, yield: 83.09%. 1 H NMR(400MHz,Methanol-d 4 ) Delta 7.40-7.31 (m, 5H), 5.11 (dd, j=29.2, 12.0hz, 2H), 4.44 (s, 1H), 4.19 (dd, j=10.8, 4.8hz, 1H), 3.83 (dd, j=11.0, 7.6hz, 1H), 3.35 (t, j=6.8 hz, 2H), 2.50 (t, j=6.8 hz, 3H), 2.31-2.16 (m, 3H), 1.92 (t, j=14.4 hz, 1H), 1.79 (dd, j=12.2, 6.0hz, 1H), 1.59-1.53 (m, 6H), 1.45-1.22 (m, other fat ring protons), 1.07 (d, j=13.2 hz, 1H), 0.97 (s, 3H), 0.94 (d, j=7.89 hz, 3H), 1.3 s (3 s), 0.47 (s, 3H).
(3) The product of the previous step (50 mg,0.065 mmol), D-glucosamine (17.81 mg,0.098 mmol), EDCI (25.12 mg,0.13 mmol), HOBt (17.71 mg,0.13 mmol), DIPEA (33.87 mg,0.26 mmol) were dissolved in dry DMF (4 mL), stirred overnight at room temperature and monitored by TLC to show completion of the reaction. Spin-off solventColumn chromatography separation of the product yields 27.9mg (0.030 mmol) of product, yield: 46.34%. 1 H NMR(400MHz,Methanol-d 4 ) Delta 7.39-7.30 (m, 5H), 5.17-5.05 (m, 2H), 4.44 (s, 1H), 4.19 (d, j=6.8 hz, 1H), 3.85-3.76 (m, 4H), 3.73-3.64 (m, 3H), 3.40-3.35 (m, 4H), 2.51 (s, 1H), 2.43 (t, j=6.8 hz, 2H), 2.31-2.20 (m, 3H), 2.01-1.89 (m, 2H), 1.79 (dd, j=12.2, 6.4hz, 1H), 1.60-1.51 (m, 6H), 1.45-1.24 (m, other fat ring protons), 1.07 (d, j=12.8 hz, 1H), 0.96 (s, 3H), 0.94 (d, j=6.89 hz, 3H), 0.31-2.20 (m, 3H), 2.01-1.89 (m, 2H), 1.60-1.51 (m, 1H), 1.45-1.24 (m, 3H), 0.47 (s, 3H).
(4) A similar debenzylation procedure gave product T40 (15.8 mg, 62.99%). 1 H NMR(400MHz,Methanol-d 4 ) Delta 4.45 (t, j=2.8 hz, 1H), 4.21 (dd, j=10.8, 4.4hz, 1H), 3.87-3.82 (m, 3H), 3.79-3.66 (m, 4H), 3.42-3.36 (m, 4H), 2.52 (s, 1H), 2.46 (t, j=6.8 hz, 2H), 2.33 (s, 2H), 2.25-2.19 (m, 1H), 2.01-1.90 (m, 2H), 1.83 (dd, j=12.0, 7.2hz, 1H), 1.70-1.24 (m, other alicyclic protons), 1.15 (d, j=13.6 hz, 1H), 1.00 (s, 3H), 0.98 (s, 3H), 0.95 (d, j=6.8 hz, 3H), 0.90 (s, 6H), 0.66 (s, 2H).
In a similar manner to example 7, intermediate S4 was reacted with a different linker and oxidized to carboxylic acid and condensed to give the following compound:
example 8TGR5 receptor agonistic Activity test example
1. Purpose of experiment
HEK293 cells transiently transformed with TGR5 were stimulated with compounds and then assayed for TGR5 agonism using Homogeneous Time Resolved Fluorescence (HTRF).
2. Principle of experiment
TGR5 is a bile acid membrane receptor, also a member of the GPCR family, with regulatory effects on the metabolism of bile acids, lipids and carbohydrates. TGR5 is coupled to Gs protein and, upon activation, further activates adenylate cyclase, producing a second messenger cAMP. HTRF is a method of detecting cAMP content that combines two techniques, fluorescence resonance energy transfer (FRET, fluorescence Resonance Energy Transfer) and time resolved fluorescence (TRF, time Resolved Fluorescence). The Eu-containing hole compound is used as a fluorescence donor, the emission spectrum of the Eu-containing hole compound is overlapped with the excitation spectrum of a fluorescence acceptor to a certain extent, fluorescence is generated by inducing the acceptor through FRET, the fluorescence lifetime of Eu is long, and a fluorescence signal emitted by the acceptor can be distinguished from a fluorescence background through TRF. The fluorescent donor is bound to the cAMP-specific antibody while the cAMP is labeled with the fluorescent acceptor, which are brought close to each other by an antigen-antibody specific recognition reaction, FRET is generated, and cAMP produced by the cells competes with the labeled cAMP for the antibody binding site, resulting in a decrease in fluorescence intensity. The effect of the compounds on TGR5 was investigated in this experiment with TGR5 agonist INT777 as positive control.
3. Experimental sample
The compound is dissolved in DMSO before the test, mother liquor is prepared, and the compound is diluted to the required concentration by culture solution when in use.
4. Experimental method
4.1 test compounds were formulated with 1xPBS at 2-fold final concentration, 100. Mu.M, 10. Mu.M, 1. Mu.M, 100nM, 10nM, 1nM, 0.1nM, DMSO (1% DMSO per well).
4.2 cell treatment:
(1) Cells were digested with pancreatin and then suspended with serum-free culture.
(2) Cell density was determined and IBMX (final concentration 500. Mu.M) was added simultaneously to the serum-free culture broth with cell count of 2000/5. Mu.l/well.
(3) 5. Mu.L of the test compound and 5. Mu.L of the IBMX-containing cell suspension were added and mixed, the 384 well plate was closed with tinfoil, and the reaction was carried out at room temperature for not more than 30 minutes in the dark.
4.3 detection substrate configuration
(1) mu.L of cAMP-d2 is diluted to 20. Mu.L with cAMP & cGMP conjugates & lysies buffer.
(2) mu.L of anti-cAMP-Cryptoate was diluted to 20. Mu.L with cAMP & cGMP conjugates & lysies buffer.
(3) After 30 minutes, 5. Mu.L (1.3.1) +5. Mu.L (1.3.2) was added, and the 384 well plate was closed with tinfoil and reacted at room temperature for 30 minutes in a dark place.
4.4 After 60 minutes, envision2101 multi-function microplate reader (PerkinElmer) read.
5. Test results
/>
Note that: EC (EC) 50 Half 50% of the effective concentration was evaluated for TGR5 agonistic activity of the sample drug. 1-10 mu M, ",0.1-1 mu M: ",100-1nM: "***"
6. Discussion of the invention
As can be seen from the results of the TGR5 receptor agonistic activity test in the above table, most of the disclosed compounds of the present invention have human TGR5 receptor agonistic activity comparable to INT 777.
EXAMPLE 9 Compound Caco-2 Single layer cell permeability test example
1. Experimental operation
1.1 Caco-2 cell culture
Caco-2 cells were cultured in a high sugar DMEM medium at 37℃in an incubator with 5% CO2 and 90% relative air humidity, and 10% fetal bovine serum, 10mmol/L HEPES, 1mmol/L sodium pyruvate, 1% glutamine, 1% nonessential amino acids, 100U/mL penicillin and 100. Mu.g/mL streptomycin were added to the medium. Every 7 days, the generation is transmitted, and the generation ratio is 1:10. The experiment used cells between 40 and 60 passages.
1.2 Caco-2 cell monolayer model establishment
Caco-2 cells were cultured at a rate of 2X 10 5 The culture medium was inoculated into 400. Mu.L of each well of a Millicell-24 well plate at a concentration of/mL, 800. Mu.L of the culture medium was added to the basal side, and at 37℃5% CO 2 Is cultured in an incubator of (a). The cells were inoculated for 72 hours, then changed, and cultured for 21 days at intervals.
1.3 Caco-2 cell monolayer model validation
After 21 days of culture, useTEER values detect the degree of tightness of a cell monolayer, typically greater than 200Ω cm 2 The single-layer compact and complete structure can be considered. Higher TEER values indicate denser monolayers, typically not exceeding 1000 Ω cm 2 . Caco-2 cells were cultured in Millicell plates in this experiment and transmembrane resistance was measured by a resistance meter Millicell-ERS II at day 21.
1.4 test Compounds double-sided Transporter experiments
Drug transport from the top layer (side a) to the basal layer (side B) and side B to side a of the cell was examined. The test method is as follows: after washing the cells three times with HBSS, the corresponding concentrations of the compounds were added to the corresponding cell wells (pH 6.8 on the A side and pH7.4 on the B side), respectively. Incubation was carried out in an incubator at 37℃for 95 minutes, sampling at the dosing side at 5 minutes and 95 minutes, and sampling at the receiving side at 35 minutes and 95 minutes, respectively. The concentration of the sample was measured by LC-MS/MS. To verify cells, a standard curve was fitted using expected Fabs and Papp values for several positive control compounds. The Papp values of the test compounds were determined and their Fabs values were calculated from the standard curve.
2. Experimental results
3. Discussion of the invention
The results are shown in the table above: compared with the compound 11d-Na, after the compound with a large polar group is introduced into the molecule, the permeation rates of T8, T10, T11 and T14 on two sides of the membrane are obviously different, which indicates that T8, T10, T11 and T14 can be substrates of Pgp proteins, the compound excretion rate is higher, and the compound entering the systemic circulation from the intestinal tract can be reduced, so that the intestinal tract targeting is realized.
Example 10 Compound tissue distribution test example
1. Experimental operation
Male ICR mice were fasted for more than 12 hours, were given free water, and were fed 4 hours after gavage administration. At 0.25, 0.5, 1, 2, 3, 4 and 8 hours, 3 animals were harvested per time point. The animals were sacrificed by anaesthesia at the set time point, the liver, small intestine and gall bladder (containing bile) tissues were collected, washed clean with ice physiological saline, and frozen at-20 ℃ after the filter paper was sucked dry. Meanwhile, 0.2ml of blood is taken from the retrobulbar venous plexus and hepatic portal vein respectively at the set time points, and the blood is placed in an EDTA-K2 test tube and centrifuged at 11000rpm for 5min, and the blood plasma is separated and frozen at-20 ℃. Another 6 animals were given to collect the blank tissue. Determination of the concentration of the original drug
2. Experimental results
Compounds of formula (I) T8 T10 T11 T14
Maximum plasma concentration (ng/mL) 1.61 1.41 7.83 2.43
Peak time of plasma (min) 60 15 120 240
Maximum liver concentration (ng/g) 13.7 250 7.19 160
Maximum concentration of small intestine (ng/g) 15447 12993 16136 11013
Maximum concentration of gallbladder (ng/g) 35.9 301 1730 3498
3. Discussion of the invention
The compounds T8, T10, T11 and T14 are mainly distributed in the intestinal tract, and the contents of the compounds in the blood plasma, the liver and the gall bladder are extremely low, so that better intestinal targeting is reflected.
EXAMPLE 11 Compound mice oral glucose tolerance test
Mice were fasted overnight and then intragastrically with 0.5% methylcellulose (control group) or compound (n=8 per treatment group), respectively. Glucose was administered 1 time after 3 hours (3 g/kg oral). Tail mark blood samples were collected at designated time points and blood glucose levels were measured with a glucometer.
The experimental results are shown in fig. 1 and 2, and compared with the control group, the blood glucose content (fig. 1) and the area under the curve (fig. 2) of the mice in the T8 and T14 administration groups are reduced, and the results show that: the compound T8 and T14 show obvious hypoglycemic activity.
Example 12 Compound 7 day mouse Cholesterol toxicity experiment
TGR5 for 8 week old H88Y Mice were randomly grouped, 4 per group. Control group 1 (no egg yolk subsequently) control group 2 (egg yolk) and normal administration group, respectively.
1) On days 1 to 6, the mice in the control group are orally infused with 200 mu L of stomach purified water daily, and the mice in the administration group are orally infused with 100mg/kg of stomach compound daily;
2) Food was removed late on day 6, normal drinking water, mice starved overnight (12 h);
3) 1 raw egg is prepared, egg yolk is taken out, after being scattered, egg yolk membrane is picked out to be in a uniform sticky state, after the 7 th day mice are infused with stomach water or compound for 3 hours, 200 mu L of stomach-infusing purified water is orally taken in a control group 1, and 200 mu L of stomach-infusing egg yolk liquid is orally taken in a control group 2 and an administration group;
4) After 15min of stomach-lavage of the yolk, dissecting the mice, completely taking out the gall bladder, and putting the gall bladder into 1 XPBS buffer for temporary storage;
5) After all gall bladder was removed, the recordings were photographed and weighed.
The experimental results are shown in fig. 3, and compounds T8, T14 did not cause gall bladder filling and did not exhibit gall bladder toxicity after 7 days of administration, as compared to the control.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
in the method, in the process of the application,
r is amino acid, amino sugar or
Wherein the amino acid is selected from the group consisting of: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine;
the amino sugar is selected from: glucosamine, meglumine, aminomannose, and galactosamine;
a is O, CR a Or NR (NR) b Wherein R is a And R is b Each independently is hydrogen, substituted or unsubstituted C1-C4 alkyl;
b is- (CH) 2 ) n -、-(O-(CH 2 ) n ) m -、-O-(CH 2 ) n -O-、-((CH 2 ) n -O) m -、-(CH 2 ) n -O-(CH 2 ) m -, a C3-C8 cycloalkyl or a 3-8 membered heterocycle, n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8;
R 1 Is H, C-C4 alkyl, sulfonic acid group (-SO) 3 H) Sulfonate (-OSO) 3 H) Phosphate group (-PO) 3 H 2 ) Phosphate group (-OPO) 3 H 2 ) Glucopyranosyl, glucosamine, meglumine,Wherein R is c Is a glucosamine group or a meglumine group; x is CH 2 NH or O, R d Is a glucosyl group or +.>Wherein R is e Is a glucosamine group or a meglumine group.
2. The compound of claim 1, wherein R is an amino acid selected from the group consisting of: arginine, asparagine, glutamine, glycine, lysine, serine, threonine.
3. The compound of claim 1, wherein the amino sugar is selected from the group consisting of: glucosamine, meglumine, D-glucosamine, D-galactosamine, D-mannosamine.
4. The compound of claim 1 wherein R is
Wherein A is NH;
b is- (CH) 2 ) n -、-(O-(CH 2 ) n ) m -、-(O-(CH 2 ) n O) m -、-((CH 2 ) n -O) m -、-(CH 2 ) n -O-(CH 2 ) m -, C4-C6 cycloalkyl or 4-6 membered heterocycle, n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8;
R 1 is H, C-C4 alkyl, sulfonic acid group (-SO) 3 H) Sulfonate (-OSO) 3 H) Phosphate group (-PO) 3 H 2 ) Phosphate group (-OPO) 3 H 2 ) Glucopyranosyl, meglumine orWherein R is c Is a glucosamine group or a meglumine group.
5. A compound according to claim 1 wherein, Selected from the group consisting of: glucopyranosyl-piperidine ring-, -piperidine ring-SO 3 H. -piperidine ring-OSO 3 H. -piperidine ring-OPO 3 H 2 -piperidine ring-PO 3 H 2 Glucosamine-based CO- (O- (CH) 2 ) n ) m -, a part of glucosamine-based CO- (O- (CH) 2 ) n O) m -, a part of glucosamine group- (CH) 2 ) n -, a part of glucosamine-based CO- (CH) 2 ) n -, a part of glucosamine-based CO- ((CH) 2 ) n -O) m -, a part of glucosamine group- (O- (CH) 2 ) n ) m -, a part of glucosamine group- (O- (CH) 2 ) n O) m -, a part of grape wineSugar amine group- ((CH) 2 ) n -O) m -, a part of glucopyranosyl-cyclohexyl- -cyclohexyl-SO 3 H. -cyclohexyl-OSO 3 H. -cyclohexyl-OPO 3 H 2 -cyclohexyl-PO 3 H 2 -cyclohexyl-glucamine, - (CH) 2 ) n -OPO 3 H 2 、-(O-(CH 2 ) n ) m -OPO 3 H 2 、-(CH 2 ) n -PO 3 H 2 、-(O-(CH 2 ) n ) m -PO 3 H 2 、-(CH 2 ) n -O-(CH 2 ) m -SO 3 H、-O-(CH 2 ) n -SO 3 H、-(CH 2 ) n -SO 3 H、-(CH 2 ) n -OSO 3 H、-((CH 2 ) n -O) m -C1-C4 alkyl, - ((CH) 2 ) n -O) m -H；
n is 1, 2, 3, 4, 5 or 6;
m is 1, 2, 3, 4, 5 or 6.
6. The compound of claim 1, wherein the compound is:
7. the method for preparing the compound according to claim 1, wherein betulinic acid is used as a raw material, carbamate is introduced into a hydroxyl group at a C3 position, hydroxyl is introduced into a double bond at a C20 position, carbamate is introduced, and benzyl protecting group on a carboxyl group at a C17 position is removed by hydrogenation.
8. A pharmaceutical composition comprising:
the compound of claim 1 or a pharmaceutically acceptable salt thereof; and
A pharmaceutically acceptable carrier.
9. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, (i) for the preparation of a bile acid G protein coupled receptor (TGR 5) agonist; or (ii) for the preparation of a medicament for the treatment of metabolic disorders.
10. The use according to claim 9, wherein the metabolic disease is selected from the group consisting of: diabetes, obesity, hyperlipidemia, liver injury, and inflammatory diseases.
CN202210564624.0A 2022-05-23 2022-05-23 Intestinal targeting pentacyclic triterpene TGR5 receptor agonist, and preparation method and application thereof Pending CN117143170A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202210564624.0A CN117143170A (en) 2022-05-23 2022-05-23 Intestinal targeting pentacyclic triterpene TGR5 receptor agonist, and preparation method and application thereof
PCT/CN2023/095370 WO2023226904A1 (en) 2022-05-23 2023-05-19 Intestinal tract targeted pentacyclic triterpene tgr5 receptor agonist, preparation method therefor and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210564624.0A CN117143170A (en) 2022-05-23 2022-05-23 Intestinal targeting pentacyclic triterpene TGR5 receptor agonist, and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN117143170A true CN117143170A (en) 2023-12-01

Family

ID=88885447

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210564624.0A Pending CN117143170A (en) 2022-05-23 2022-05-23 Intestinal targeting pentacyclic triterpene TGR5 receptor agonist, and preparation method and application thereof

Country Status (2)

Country Link
CN (1) CN117143170A (en)
WO (1) WO2023226904A1 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014071506A1 (en) * 2012-11-09 2014-05-15 Bioniche Life Sciences Inc. Compounds for reducing glucocorticoids, and methods of treatment thereof
CN104910239B (en) * 2014-03-14 2018-12-07 中国科学院上海药物研究所 Pentacyclic triterpenoid and preparation method thereof, pharmaceutical composition and purposes
CN109517022B (en) * 2017-09-18 2022-09-13 中国科学院上海药物研究所 Pentacyclic triterpenoid and preparation method, pharmaceutical composition and application thereof
CN112694514B (en) * 2019-10-23 2022-09-23 中国科学院上海药物研究所 Pentacyclic triterpenoid TGR5 receptor agonist, and preparation method and application thereof

Also Published As

Publication number Publication date
WO2023226904A1 (en) 2023-11-30

Similar Documents

Publication Publication Date Title
US4968672A (en) Adenosine receptor prodrugs
US20210269475A1 (en) Farnesoid x receptor modulators
KR20150028971A (en) Solid forms of an antiviral compound
CN111132984A (en) Salts of apoptosis signal-regulating kinase 1 inhibitors and crystalline forms thereof
US20210323935A1 (en) Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
WO2010099698A1 (en) Salts of tetrahydroimidazo [1,5-a] pyrazine derivatives, preparation methods and pharmaceutical use thereof
US7932249B2 (en) Olanzapine pamoate dihydrate
CA3195264A1 (en) Crystal forms of glp-1r agonists and uses thereof
JP2022549923A (en) Crystal forms of N-hetero pentacyclic ring-containing capsid protein assembly inhibitors and uses thereof
US20130005696A1 (en) Bufadienolide derivatives, preparing process thereof, composition comprising the same and the use thereof
KR20140051813A (en) Polymorphs of cddo ethyl ester and uses thereof
Qian et al. Discovery of novel cholic acid derivatives as highly potent agonists for G protein-coupled bile acid receptor
CN113387932B (en) Bifunctional compound for inducing BRD4 protein degradation
US20230026869A1 (en) Crystal form of nucleoprotein inhibitor and use thereof
CN111630047A (en) Benzoazaheterocycle compound containing carboxylic acid group and preparation method and application thereof
CN117143170A (en) Intestinal targeting pentacyclic triterpene TGR5 receptor agonist, and preparation method and application thereof
CN112694514B (en) Pentacyclic triterpenoid TGR5 receptor agonist, and preparation method and application thereof
JP2001527079A (en) 3&#39;-epimer derivative of K-252a
Toth et al. Lipidic peptides. II. Synthesis, activity and transport of anti-inflammatory benzoquinolizine-lipidic peptide conjugates
KR102397741B1 (en) Crystal forms of tricyclic compounds and uses thereof
JP7244487B2 (en) Crystalline or amorphous steroidal derivative FXR agonist, its preparation method and use
NO883263L (en) PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZIMIDAZOLE DERIVATIVES.
CN114907344B (en) Beta-carboline-1-propionic acid and indole derivatives, and preparation method and application thereof
CN111763173B (en) Phenethyl imidazole derivative and application thereof
WO2023246839A1 (en) Salt of thieno[2,3-d]imidazole compound, crystal form thereof and pharmaceutical use 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