CN109331185A - Drug containing Liver targeting ligands specific and pth receptor agonist - Google Patents

Drug containing Liver targeting ligands specific and pth receptor agonist Download PDF

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CN109331185A
CN109331185A CN201811452803.5A CN201811452803A CN109331185A CN 109331185 A CN109331185 A CN 109331185A CN 201811452803 A CN201811452803 A CN 201811452803A CN 109331185 A CN109331185 A CN 109331185A
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liver
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CN109331185B (en
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崔坤元
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Hangzhou Hejiya Biopharmaceutical Co.,Ltd.
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Xiamen Gamboli Biomedical Co Ltd
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Priority to PCT/CN2019/122318 priority patent/WO2020108657A1/en
Priority to JP2021531388A priority patent/JP7109674B2/en
Priority to US17/298,740 priority patent/US11690818B2/en
Priority to TW108143956A priority patent/TWI780380B/en
Priority to EP19889346.3A priority patent/EP3888685A4/en
Priority to AU2019388940A priority patent/AU2019388940B2/en
Priority to KR1020217020361A priority patent/KR102467932B1/en
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • 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

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Abstract

There is provided herein the drug in structure containing Liver targeting ligands specific and pth receptor agonist, it is to be connected Liver targeting ligands specific with pth receptor agonist by branch, connector and connection chain, becomes a new medicines structure.Thyroid Hormone Receptors (TRs) is divided into two hypotypes, and TR- α and TR- β, wherein TR- β is mainly expressed in liver, and TR- α is mainly expressed in heart, nervous system etc..In certain embodiments, it is expected that drug provided herein has the function of Liver targeting, pth receptor agonist specificity can be brought into liver, it is set not enter heart and its hetero-organization, side effect can be caused to the effect of its hetero-organization to avoid pth receptor agonist, and it is kept to treat the curative effect of disorders of lipid metabolism and related complication.

Description

Drug containing Liver targeting ligands specific and pth receptor agonist
Technical field
The present invention relates to biomedicine fields, and in particular to targeted drug field, more particularly, to liver-specific therapy liver The compound of source property disease.
Background technique
Asialoglycoprotein receptor (ASGPR) in liver is the specific expressed receptor of liver cell, is a kind of efficient Endocytosis receptor.Since glycoprotein various in the case of body physiological are after enzyme or sour water solution sialic acid, the secondary end exposed is Galactose residue, so the sugar of ASGPR specific binding is galactosyl, therefore also known as galactolipin specific receptor.Galactolipin, The monosaccharide such as galactosamine, N- acetylgalactosamine and polysaccharide molecule have high-affinity to it.ASGPR main Physiological Function is to mediate The removing of the substances such as Asialoglycoprotein, lipoprotein in blood, and with the liver diseases such as virus hepatitis, cirrhosis, liver cancer Occurrence and development have close ties.The discovery of this characteristic of ASGPR plays an important role to the diagnosis and treatment of liver diseases (AshwellG, HarfordJ, Carbohydrate specific Receptors of the Liver [J], AnnRevBiochem 1982 51:531-554)。
Monosaccharide or polysaccharide molecule utilize feasibility study of the receptor on cell membrane as targeting for drug delivery system Originate in 1971 (Benjamin G etc., Current Opinion in Drug Discovery&Development 5: 279-288；Rogers JC etc., Biochem Biophys Res Commun 45:622-629).ASGPR is to galactose molecule The characteristic of specific binding cause biological medicine research and development field attention (Schwartz AL etc., J.Biol.Chem.255: 9033–9036；M.Spiess, Biochemistry 29:10009-10018).This characteristic of ASGPR makes to contain in structure The delivering of the liver source property disease therapeuticing medicine of galactolipin or galactosamine and its derivative has targeting, can ensure that its drug effect occurs In liver, the distribution of other tissues is reduced, to reduce side effect of the drug to other positions.Early stage, researcher recognized To the advantage of ASGPR, and many effort are done, using this characteristic of ASGPR by genetic fragment by being connected to its spy Specific ligand galactolipin or acetylgalactosamine targeting be loaded into existing research in liver cell (Seymour L. J., Clin.Oncol.20:1668-1676).Studies have shown that the saccharide residue of cluster can be by occupying the combination of ASGPR receptor simultaneously Site and keep its compatibility 50~100 times higher than monosaccharide residue much higher than the tri- saccharide residue compatibility of saccharide residue of not cluster, parent With the order of power are as follows: four saccharide residues > tri- saccharide residues > > disaccharide residue > > monosaccharide residue.Four saccharide residues relative to three saccharide residues and Speech, and ASGPR compatibility without significantly improving, this may be derived from three saccharide residues and the combination of receptor be saturated.It is this Phenomenon is referred to as " at cluster effect " (cluster effect).
In early stage research, Merwin etc. (Merwin J R etc., Bioconjug Chem 1,994 5 (6): 612-620) is set Meter has synthesized the carrier system modified with three galactosamines, which is proved to Plasmid DNA can be mediated in animal body fast Speed is largely enriched in mouse liver, and successful expression luciferase has research to apply galactosamine in antisense nucleoside again later Sour (oligodeoxynucleoside methylphosphonate, oligodeoxynucleosidemethylphosphonate, Oligo-MP) (Hangeland J J etc., Bioconjug Chem 1,995 6 (6): 695-701), antisense peptide nucleic acid (antisense Peptide nucleic acid, asPNA) (Biessen E A, Bioconjug Chem 2,002 13 (2): 295-302) etc. Administration in, obtained comparatively ideal therapeutic effect.Alnylam Pharmaceuticals Inc. of the U.S. (Alnylam Pharmaceuticals Inc.) it made breakthrough progress in terms of using this of ASGPR characteristic administration mechanism, it produces Product ALN-TTRSC has been in II phase clinical stage for treating amyloid lesion.
Using the above-mentioned characteristic of ASGPR, it provided herein is the ligands specific containing ASGPR in a kind of structure and first shapes The compound of adrenoceptor agonist, be by branch, connector and connection chain by Liver targeting ligands specific and thyroxine by The connection of body agonist, becomes a new compound structure.
Thyroid Hormone Receptors (TRs) is divided into two hypotypes, and TR- α and TR- β, they are the nuclear hormones of two genes Receptor (Lazar M., Endocr.Rev.14:348-399).The two receptors due to tissue expression abundance difference and mediate Different physiological effect, that is to say, that the two receptors have different tissue specificity (Forrest D. etc., Thyroid 10:41-51).Wherein, TR- α be adjust heart rate (HR) major receptors (Johansson C. etc., Am J.Physiol.275: R640–R646.；Gloss B. etc., Endocrinology 142:544-551.), TR- β is mainly expressed in liver, and TR- β swashs Dynamic agent (thyroxine similar compound, a kind of noval chemical compound based on thyroid hormone structure of modification) is always to treat non-alcohol The important development field of property fatty liver (NAFLD) new drug, part new drug has progressed to clinical research, such as TRs selective agonist GC-1 (Sobetirome, a kind of TRs selective agonist are given the nonalcoholic fatty liver drug of great expectations, by Bristol-Myers Squibb exploitation) blood plasma cholesterol level can be effectively reduced, the key role of mouse is minimized, so And GC-1 also only shows the relatively low heart that enters, rather than the highly selective excitement of specificity T R- β excitement in it is expected Agent (Trost S etc., Endocrinology 141:3057-3064), is finally terminating at the clinical I phase stage.And another kind TRs Selective agonist KB2115 (common name Eprotrome is developed by Karo Bio company of the U.S.) is due to specific pharmacological Reason was terminated in the clinical III phase.The TR- beta-agonists for treating liver source property disease with clinical value must have wide Therapeutic dose range, without tachycardias and all its hetero-organizations side effect, to reduce cholesterol (TC) have it is highly selective and Safely and effectively, the TRs selective agonist and in developing at present can not fully meet these conditions.
Nonalcoholic fatty liver is caused by the factor except alcohol and other specific damage liver factors, is a kind of and fertilizer Fat, hypercholesterolemia and the related metabolic disease of diabetes, including simple fatty liver and the fatty developed by it Hepatitis (NASH) and cirrhosis.The method of therapy intervention is mainly based upon living-pattern preservation, including diet and movement at present (M é ndez-S á nchez N, waits 2007 27:1157-1165 of Liver Int；Oh MK etc., Aliment Pharmacol Ther 28:503-522), it there is no the therapeutic agent of approval.
The thyroid hormone [thyroxine (T4) and 3,3', tri- iodo- Levothyroxinnatrium (T3) of 5-] of physiological passes through a variety of Approach adjusts glucose and lipid-metabolism, and important physiological action is played in terms of the metabolism of lipid.By be widely distributed in Specific hormone receptor TR- α and the TR- β of whole body interacts and has an impact.TR- β is concentrated mainly on liver expression, to lipid Metabolism has a major impact, including reduces low-density lipoprotein (LDL) cholesterol, reduces whole body obesity and weight (Pramfalk C Deng Biochim Biophys Acta 1812:929- 937), and can be reduced by improving the lipid-metabolism rate of liver Lipid content.A result of study of Perra A etc. shows that T3 can inhibit hepatic cell fattydegeneration, and repairs fat and become The liver cell (Perra A etc., FASEB J 22:2981-2989) of property, this result of study show T3 in non-alcoholic fatty Outstanding potential treatment effect in terms of liver.
But excessive thyroid hormone easily causes side effect, especially to heart (including tachycardia and sudden death) And bone and muscle adverse reaction (Braverman LE etc., editors.Lippincott:The Thyroid 2000: 515-517).Due to these adverse effects of thyroid hormone, limit its in terms of nonalcoholic fatty liver treatment into one Step application.If side effect of the thyroid hormone to heart and other organs can be eliminated or be reduced, so that it may which acquisition can be pre- The therapeutic effect estimated.Using the transmitting of hepatic targeting by the thyroxine similar compound such as thyroid hormone, GC-1 and KB2115 It brings liver into, is allowed to that the other tissues entered outside liver are reduced or avoided, be one in terms for the treatment of NAFLD/NASH new drug development A innovation, this invention have clinical and reality economic significance.
Therefore, a kind for the treatment of liver that patent medicine is unable to by thyroid hormone T3, T4 and its metabolin or because of side effect is invented The a part of the thyroxine similar compound of source property disease as compound, preparation are directly targeted the new knot into liver cell Structure compound reduces side effect of the original drug to other tissues, has not only innovated Research idea, also improves current non-alcohol Property fatty liver treat status clinically without the effective medicine of specific aim.
Summary of the invention
The present invention utilizes the above-mentioned characteristic of asialoglycoprotein receptor, will be because side effect is unable to the treatment liver source of patent medicine The compound of property disease or candidate compound targeting bring liver into, treat corresponding disease.Saying more precisely, it is of the invention sharp With asialoglycoprotein receptor and its ligand high-affinity, a kind of compound is synthesized, enables the treatment institute of specificity Compound is brought into liver cell, and seldom or not enters the histocyte other than liver, to reduce treatment chemical combination Object is to side effect histiocytic outside liver.
The present invention is prepared for the drug containing Liver targeting ligands specific and pth receptor agonist in a kind of structure.
The Liver targeting ligands specific is gala carbohydrates and their derivative, preferably galactosamine, acetylgalactosamine Or trivalent acetylgalactosamine.
Liver targeting ligands specific X in the drug, pass sequentially through the branch L containing steric stabilization structure, connector B and Connection chain D is connect with pth receptor agonist T, the general structure (I) of the drug are as follows:
(X-L)n-B-D-T
Wherein n is the positive integer of 1-15.
General structure (I) the center tap B branching is multiple, and gained branch leads in formula (I) n (X-L) for connection structure With one (D-T).
In some preferred embodiments, when n is greater than 1, the structure of each X can be identical can also be different.
In some preferred embodiments, when n is greater than 1, the structure of each L, which can be, identical is also possible to difference 's.
As n=1, general structure (I) are as follows: X-L-B-D-T.
Work as n=2, when 3,4,5 or 6, the structure of general structure (I) is successively shown below:
The Liver targeting ligands specific is selected from one of flowering structure or a variety of: polysaccharide, polysaccharide derivates, monosaccharide and Monosaccharide derivatives.
The monosaccharide is selected from one of flowering structure or a variety of: mannose, galactolipin, D- arabinose, glucose, Fructose, xylose, aminoglucose, ribose.
The mannose is selected from one of flowering structure or a variety of: D- mannopyranose, L- mannopyranose, α-D- Furans mannose, β-D- furans mannose, α-D- mannopyranose, β-D- mannopyranose.
The galactolipin is selected from one of flowering structure or a variety of: L- galactolipin, D- galactolipin, α-D- galactopyranosyl Sugar, β-D- galactopyranose, α-D- galactofuranose, β-D- galactofuranose.
The glucose is selected from one of flowering structure or a variety of: D-Glucose, L- glucose, α-D- glucopyra Sugar, β-D- glucopyranose, α-D- glucofuranose, β-D- glucofuranose.
The fructose is selected from one of flowering structure or a variety of: α-D- fructofuranose, α-D- fructopyranose.
The xylose is selected from one of flowering structure or a variety of: D- furyl xylose, L- furyl xylose.
The ribose is selected from one of flowering structure or a variety of: ribose, D-ribose, L- ribose.
The monosaccharide derivatives are selected from one of flowering structure or a variety of: mannose derivative, galactose derivative, Portugal Grape sugar derivatives, ribose derivates and other derivatives.
The mannose derivative are as follows: two-O- methyl D of 4,6- dideoxy -4- formamido -2,3--mannopyranose.
The galactose derivative is selected from one of flowering structure or a variety of: α-D-galactosamine, N- acetyl group gala Thio-β-D- the galactopyranose of osamine, 4-.
The glucosan derivative is selected from one of flowering structure or a variety of: 2- amino -3-O- [(R) -1- carboxylic second Base] -2- deoxidation-β-D- glucopyranose, 2- deoxidation -2- methylamino-L- glucopyranose, 2- deoxidation -2- sulfoamino-group-D- Thio-β-D- the glucopyranose of glucopyranose, 5-, the thio -6-O- trityl-α-D- pyrrole of tri--O- acetyl group -1- of 2,3,4- Glucopyranoside glycosides methyl esters.
The ribose derivates are selected from one of flowering structure or a variety of: D-4- thioribose, L-4- thioribose.
Other described derivatives are selected from one of flowering structure or a variety of: 2,5- dehydration-D- allose nitrile, sialic acid, N- glycolyl-α-neuraminic acid, the thio-α-D- pyrans glucoheptose glycosides of tetra--O- acetyl group -2- deoxidation -1,5- of 3,4,6,7- two Ethyl ester.
The general structural Formula (II) of the Liver targeting ligands specific are as follows:
Wherein, R1、R2And R3It is hydrogen or hydroxyl protection base.
The hydroxyl protection base is selected from flowering structure: acyl group and silylation.
Preferably, the hydroxyl protection base, selected from flowering structure: acetyl group, benzoyl, phenoxy-acetyl, new penta Acyl group, isobutyryl, t-butyldimethylsilyi, t-butyldiphenylsilyl, triisopropylsilyl and isopropyl Base dimetylsilyl.
In some preferred embodiments, Liver targeting ligands specific described in Liver targeting ligands specific is selected from following knot One of structure is a variety of:
Wherein, R1 is selected from one or both of OH and NHCOOH.
In some preferred embodiments, Liver targeting ligands specific is acetylgalactosamine.
The branch L is selected from one of such as flowering structure or a variety of:
Wherein, in formula n1 be 1-10 positive integer, m be 1-5 positive integer, n2 be 0-20 integer, n3 be 1-12 just Integer, Z are H or CH3；The left distal end of branch L containing steric stabilization structure connects Liver targeting ligands specific X, right side end End and connector B left distal end part.
The connector B is selected from following structural formula:
Wherein, A1 is C, O, S or NH, the positive integer that r1 is 1 to 15；A2 be selected from C1- C10 linear paraffin, with amino, The segment of amide groups, phosphinylidyne root, thiophosphoryl oxygen atom, sulphur atom or cyclic compound, the integer that r2 is 0 to 15.
The connector B is selected from following structural formula:
Wherein, the positive integer that r1, r3, r4, r5 are 1 to 15；The positive integer that r6 is 1 to 20, the positive integer that r7 is 2 to 6, The positive integer that r8 is 1 to 3.
The connector B is selected from flowering structure:
The connection chain D, selected from carbonyl, amide groups, oxygen atom, sulphur atom, thiophosphoryl, phosphoryl or ring Position is answered to be connected with pth receptor agonist T-phase for carboxyl or amino in the end of the alkyl moiety of shape structure, connection chain D.
The connection chain D, can be selected from such as flowering structure:
Wherein, the positive integer that each n is 1 to 20, and each n is identical or different positive integer.
The connection chain D is selected from one of flowering structure:
The connection chain D does not include pyrrolidines or amide.
The connection chain D includes one kind of following structural formula: pyrrolidines, PEG, amide, amine, disulfide bond and at least two A amide.
The connection chain D is selected from one of flowering structure:
Wherein, each n be 1 to 20 in positive integer, each n be identical or different positive integer, p be 1 to 6 it is just whole Number；The positive integer that s is 2 to 13；R1 and R2 can be same or different substituent group, and structural formula may be below one Kind :-H ,-CH3、- CH-(CH3)2、-CH2-CH(CH3)2、-CH(CH3)-CH2-CH3、-CH2-C6H5、-C8NH6、- CH2-C6H4- OH、-CH2-COOH、-CH2-CONH2、-(CH2)2-COOH、-(CH2)4-NH2、- (CH2)2-CONH2、-(CH2)-S-CH3、-CH2- OH、-CH(CH3)-OH、-CH2-SH、- CH2-C3H3N2、-(CH2)3NHC(NH)NH2。
The connection chain D is selected from one of flowering structure:
In the drug general formula structure (X-L)nB group is selected from one of flowering structure, and (X-L)nThe right side end of-B End is connected with connection chain D left distal end:
The thryoid receptor activator has general structure below:
Wherein A is oxygen, sulphur, carbonic acyl radical, methylene or amino；R1 is C1-C4 straight chain or branch alkyl ,-CH2(azepine Ring) ,-CH (OH) (halogeno-benzene or aromatic hydrocarbon) ,-CH (OH) CH3, halogen atom or hydrogen；R2 is halogen atom ,-CH3Or hydrogen； R3 is halogen atom, CH3Or hydrogen；R4 is-CH2CH(NH)COOH、-OCH2COOH、-NHC(O)COOH、-CH2COOH、-NHC (O)CH2COOH、-CH2CH2COOH、-OCH2PO3 2-、-NHC(O)CH2COOH, OH, halogen atom or C1-C4 alkyl.
The pth receptor agonist is thyroxine (T4) or Lithyronine original propylhomoserin (T3) or its metabolism Object, pth receptor agonist structure are one of structure shown in following formula:
The pth receptor agonist is one of following features structure:
Wherein, R6 is C1-C4 linear or branched alkyl group or hydrogen；R5 is C1-C8 alkyl；R7 is halogen atom, C1-C4 Alkyl；R8 is C1-C4 linear or branched alkyl group or hydrogen；R9 is-CH2CH(NH)COOH、-OCH2COOH、-NHC(O)COOH、- CH2COOH、 NHC(O)CH2COOH、CH2CH2COOH、-OCH2PO3 2-、-NHC(O)CH2COOH, OH, halogen atom or C1-C4 Alkyl.
The structure of the pth receptor agonist are as follows:
Wherein X is oxygen, sulphur, carbonyl, methylene or amino；Y is one of C1-C5 alkyl carbon chain and C=C；R1 is The naphthenic base of halogen atom, trifluoromethyl, the alkyl of C1-C6, C3-C7；R2 and R3 is the alkyl or C3- of hydrogen, halogen atom, C1-C6 One or both of naphthenic base of C7, and R2 and R3 one of them must be hydrogen atom；R4 is hydrogen or the alkyl of C1-C4；R5 It is hydrogen or the alkyl of C1-C4；R6 is carboxylic acid or ester bond；R7 is hydrogen, acyl group or aroyl.
Specifically, the structure of the pth receptor agonist is one of having structure:
The general formula structure (X-L) of the drugn- B-D-T is one in structure shown in Kylo-0101 to Kylo-0104 Kind:
Application of the drug in the drug that preparation acts on pth receptor treatment liver source property disease.
The pth receptor is asialoglycoprotein receptor, and the liver source property disease is nonalcoholic fatty liver And nonalcoholic steatohepatitis.
Compared with prior art, the invention has the benefit that
(1) present invention treats disorders of lipid metabolism by the pth receptor in specific Liver targeting and activation liver cell And relevant complication, reverse non-alcohol fatty liver and non-alcohol fat hepatitis and liver fibrosis.
(2) there is provided herein the ligands specifics and thyroxine containing Liver targeting asialoglycoprotein receptor in structure The drug of receptor stimulating agent is by branch, connector and connection chain that Liver targeting ligands specific and pth receptor is exciting Agent connection, becomes a new compound structure.
(3) Thyroid Hormone Receptors (TRs) is divided into two hypotypes, and TR- α and TR- β, wherein TR- β is mainly expressed in liver, TR- α is mainly expressed in heart, nervous system etc., and drug provided by the invention has the function of Liver targeting, can be thyroxine Receptor stimulating agent specificity is brought into liver, it is made not enter heart and its hetero-organization, can be to avoid pth receptor Agonist should send out side effect to the effect of TR- α, and it is kept to treat the curative effect of disorders of lipid metabolism and relevant complication.
(4) the steric stabilization structure branch L contained, the effect in novel drugs is steric stabilizer, opposite to be free of steric hindrance The drug of structure, branch L can prevent or inhibit its combine drug intermolecular or intramolecular interaction.Also it can hinder The drug for hindering it to combine participates in electrostatic interaction.The electrostatic interaction is exactly between two or more substances due to just The Non-covalent binding that attraction between charge and negative electrical charge generates.In drug of the present invention, branch L can inhibit drug and blood The interaction of component, such as phagocytosis, and improve the molecule circulation time of its combination.
Detailed description of the invention
In order to keep the purpose of the present invention, technical scheme and beneficial effects clearer, the present invention provides following Detailed description of the invention:
Fig. 1 is Kylo-0101 high resolution mass spec figure；
Fig. 2 is Kylo-0102 high resolution mass spec figure；
Fig. 3 is Kylo-0103 high resolution mass spec figure；
Fig. 4 is the testing result of total cholesterol (TC) content in db/db mice serum in embodiment 4；
Fig. 5 is the testing result of low-density lipoprotein (LDL) content in db/db mice serum in embodiment 4；
Fig. 6 is the testing result of triglycerides (TG) content in db/db mice serum in embodiment 4；
Fig. 7 is the testing result of db/db bone mineral density in mice (BMD) in embodiment 4；
Fig. 8 is influence of the experimental drug to db/db mouse weight, fat content and Lean mass in embodiment 4；
Fig. 9 is influence of the Kylo-0101 of various dose to TC level in db/db mice serum in embodiment 5；
Figure 10 is influence of the Kylo-0101 of various dose to LDL level in db/db mice serum in embodiment 5；
Figure 11 is influence of the Kylo-0101 of various dose to TG level in db/db mice serum in embodiment 5；
Figure 12 is influence of the Kylo-0101 of various dose to db/db mouse weight in embodiment 5；
Figure 13 is in embodiment 5, and the Kylo-0101 of various dose is to the content of db/db mouse body fat and muscle It influences；
Figure 14 is influence of the Kylo-0101 of various dose to db/db bone mineral density in mice in embodiment 5；
Figure 15 is the influence of the Kylo-0101 of various dose to the weight of db/db liver in embodiment 5；
Figure 16 is in embodiment 5, and oil red and HE dye liver section Histopathology picture；
Figure 17 is in embodiment 5, and average quantization result is dyed in hepatic tissue pathology inspection；
Figure 18 is influence of the various dose Kylo-0101 to fT3 concentration in db/db mice serum in embodiment 5；
Figure 19 is in embodiment 5, and various dose Kylo-0101 influences the TSH in db/db mice serum.
Specific embodiment
Following example illustrate some embodiments disclosed by the invention, but are not limited to these.In addition, providing When specific embodiment, inventor contemplates the application of those specific embodiments.Such as with specific similar or similar chemistry The compound of structure, the treatment for different liver source property diseases.
Illustrate:
The Chinese of pip is piperidines；
The Chinese of DMF is N,N-dimethylformamide；
The Chinese of Dde-Lys (Fmoc)-OH is N-1- (4,4- dimethyl -2,6- dioxo hexamethylene subunit) ethyl - N'- fluorenylmethyloxycarbonyl-L-lysine；
The Chinese of HBTU is O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester；
The Chinese of DIPEA (DIEA) is n,N-diisopropylethylamine；
The Chinese of Fmoc-Glu-OtBu is fluorenylmethyloxycarbonyl-Pidolidone 1- tert-butyl ester；
The Chinese of TBTU is O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid；
The Chinese of ACN is acetonitrile；
The Chinese of MTBE is methyl tertiary butyl ether(MTBE)；
Chinese be solid phase carrier, such as resin (Resin)；
The ratio of involved two kinds of substances in the application, refers both to volume ratio in the case where no especially dated；
Content involved in the application refers both to concentration expressed in percentage by volume in the case where no especially dated.
Embodiment 1: the preparation of drug 1 (Kylo-0101)
(1) compound 1-1 generates compound 1-2 by chemical reaction as follows:
Weigh Compound 1-1 (0.31g, 0.1mmol) is poured into composite tube, is added pip/DMF (2ml/8ml), nitrogen drum Vacuum extracts after steeping 30-40min, reuses DMF cleaning compound 1-2, uses 10ml every time, rinses 3 times, washes away pip and anti- The impurity that should be generated；
(2) compound 1-2 generates compound 1-3 by chemical reaction as follows:
It weighs Dde-Lys (Fmoc)-OH (0.16g, 0.3mmol), HBTU (0.114g, 0.3mmol) and composite tube is added It is interior, it is added after DMF (10mL) dissolves the above solid and DIPEA (55 μ L) nitrogen bubbling 30-60min afterwards is added, reaction solution is removed Remaining solid chemical compound 1-3 is cleaned using DMF afterwards, uses 10ml every time, is rinsed 3 times, to remove HBTU, DIPEA and reaction The impurity of generation；
(3) compound 1-3 generates compound 1-4 by chemical reaction as follows:
Pip/DMF (2ml/8ml) is added into the composite tube equipped with compound 1-3, nitrogen is bubbled vacuum after 20- 30min The impurity that extraction liquid and reaction generate reuses DMF and cleans remaining solid chemical compound 1-4, use 10ml every time, rinses 2 times, the impurity of removal pip and reaction generation；
(4) compound 1-4 generates compound 1-5 by chemical reaction as follows:
It weighs Fmoc-Glu-OtBu (0.13g, 0.3mmol), HBTU (0.114g, 0.3mmol) and compound 1-4 is added In (0.1mmol), it is added after DMF (10mL) dissolves the above solid and DIPEA (55 μ L) nitrogen bubbling 15-30min afterwards is added, it will After reaction solution removes, remaining solid chemical compound 1-5 is cleaned using DMF, uses 10ml every time, is rinsed 3 times, removal HBTU, The impurity that DIPEA and reaction generate；
(5) compound 1-5 generates compound 1-6 by chemical reaction as follows:
Pip/DMF (2ml/8ml) is added in compound 1-5 (0.1mmol), vacuum is extracted out after nitrogen is bubbled 15- 30min The impurity that reaction solution and reaction generate reuses DMF and cleans remaining compound 1-6, use 10ml every time, rinses 6 times, wash away The impurity that pip and reaction generate；
(6) trilute generates compound 1-7 by chemical reaction as follows:
Trilute 0.5g is weighed, is placed in eggplant-shape bottle, dioxane 4ml, purified water 1ml, three is added Boc- acid anhydrides 232mg is added in ethamine 0.3ml, and room temperature is protected from light and is stirred to react 2h, adds water 4ml, and methylene chloride 10ml is added, and is added dropwise Salt acid for adjusting pH value is to 4；It stands, layering, the water layer 10ml that adds methylene chloride is extracted once again, merging organic layer；Add the anhydrous sulphur of 5g Sour sodium dries, filters, and filtrate is concentrated to dryness with revolving instrument；Petroleum ether 20ml mashing, filtering, filter cake 40ml stone is added in concentrate Oily ether washing, filter cake decompression are drawn dry；Obtain compound 1-7 (white solid) 630mg；
(7) compound 1-6 generates compound 1-8 by chemical reaction as follows:
Weigh Compound 1-7 (0.23g, 0.3mmol), HBTU (0.114g, 0.3mmol), which are added, contains 0.1mmol chemical combination In the composite tube of object 1-6, it is added after DMF (10mL) dissolves the above solid and DIPEA (55 μ L) is added, nitrogen is bubbled 10-20min, Remaining compound 1-8 is cleaned using DMF after reaction solution is removed, uses 10ml every time, is rinsed 3 times, removal HBTU, The active ester that DIPEA and reaction generate；
(8) compound 1-8 generates compound 1-9 by chemical reaction as follows:
Hydrazine hydrate/DMF (0.2ml/9.8ml) solution is added into compound 1-8 (0.1mmol), after nitrogen is bubbled 10min The DMF solution that hydrazine hydrate is removed using vacuum uses 10ml using DMF cleaning compound 1-9 every time, rinses 6 times, goes to remove water Close the impurity of hydrazine and reaction generation；
(9) preparation of compound 1-10:
Step 1:
1,5- glutaric acid list benzyl ester 0.21g is weighed, is dissolved with 2mlDMF, TBTU 0.36g and DIEA is then added 0.4ml is stirred to react 5 minutes, compound a 1.09g is dissolved in 10ml DMF, is slowly added in above-mentioned reaction solution, room temperature It is stirred to react overnight；Evaporated under reduced pressure reaction solution, after being evaporated, add methylene chloride 40ml, water 20ml, stirs 15 minutes, and layering is organic Layer is dry with 10g anhydrous sodium sulfate, and the organic layer after drying crosses chromatographic column (eluant, eluent: methylene chloride: methanol=1%-10%), The target substance compound to be collected is identified by contact plate (solvent contains volume ratio for the methylene chloride and methanol of 10:1) B, collects the eluant, eluent of the b of compound containing sterling, and evaporated under reduced pressure solvent obtains white products compound b 0.85g；
Step 2:
Compound b 0.85g to be thrown in 100ml single port bottle, adds palladium charcoal 127mg, water pump vacuumizes, hydrogen is mended, in triplicate, Overnight, second day, reaction solution TLC contact plate has no compound b point for pressurized with hydrogen reaction.It filters (12g diatomite drainage), decompression is steamed Dry filtrate, obtains compound 1-10 weight 90.76g.
(10) compound 1-9 and compound 1-10 generates compound 1-11 by chemical reaction as follows:
Weigh Compound 1-10 (0.57g, 0.3mmol), HBTU (0.114g, 0.3mmol), which are added, is equipped with compound 1-9 In the composite tube of (0.1mmol), it is added after DMF (10mL) dissolves the above solid and DIPEA (55 μ L) nitrogen bubbling 10- afterwards is added 20min cleans remaining compound 1-11 using DMF after removing reaction solution, uses 10ml every time, rinses；
(11) compound 1-11 generates compound 1-12 by chemical reaction as follows:
F solution (6ml, trifluoroacetic acid: tri isopropyl silane: water=90:3.5:5.5) is poured slowly into equipped with compound 1- In the centrifuge tube of 11 (0.3g, 0.05mmol), 30-35 DEG C of temperature, revolving speed 200r/min is controlled, cutting is taken out after 1 hour, mistake It filters off and removes solid, filtrate (5ml) is poured slowly into MTBE (20ml), and suspension is centrifuged with centrifuge, and revolving speed is set as 3000r/ Min, solid with being centrifuged again after MTBE (20ml) dispersion, are collected solid and are drained 1 hour with vacuum, obtain 46mg white powder again End, with compound 1-11 collecting rate for 34%；
By obtained white powder using loading after ACN/ water 2ml (0.2ml/1.8ml) dissolution, filler trade name GE is used Resource15RPC (50ml), mixture (ethane nitrile content 10%~90%) of the mobile phase for water and acetonitrile, gradient elution, and All over products is collected, 12mg sterling compound 1-12 is obtained after freeze-drying；
(12) compound 1-12 generates drug 1 (Kylo-0101) by chemical reaction as follows:
Sodium methoxide/methanol (20mg/ml) solution is added to the compound 1-12 (12mg, 0.0043mmol) after freeze-drying, if Set 30-35 DEG C of shaking table temperature, revolving speed 200r/min shakes 20min, reaction solution be added 1mol/L HCl (5-7 drop) adjusting pH to 7, using revolving solvent evaporated, 40-45 DEG C of bath temperature, residue be added ACN/ water 2ml (0.2ml/1.8ml) dissolution after on Sample, using filler trade name GE Resource15RPC (10ml), mobile phase is the mixture (ethane nitrile content of water and acetonitrile 10%~90%) it, is purified, elutes and collect all over products, 7mg sterling drug 1 (Kylo-0101) is obtained after freeze-drying, received Rate 67.3%, as shown in Figure 1, target peak is 1232.35108 (2+) when Kylo-0101 Mass Spectrometer Method mass-to-charge ratio is 2.
Embodiment 2: the preparation of drug 2 (Kylo-0102)
Compound 2-1 generates drug 2 (Kylo-0102) by chemical reaction as follows, the concrete composition of reactant It is as shown in table 14:
To sodium methoxide/methanol (20mg/5ml) solution is added in compound 2-1 (20mg, 0.0078mmol), shaking table is set 30-35 DEG C of temperature, revolving speed 200r/min, 30min is shaken, reaction solution is added 1mol/L HCl (5-7 drop) and adjusts pH to 7, uses Solvent evaporated is rotated, 40-45 DEG C of bath temperature, loading after ACN/ water (0.2ml/1.8ml) dissolution is added in residue, uses filler Trade name GE Resource15RPC (10ml), mobile phase are the mixture (ethane nitrile content 10%~90%) of water and acetonitrile, It is purified, elutes and collect all over products, obtain 12mg sterling drug 2 (Kylo-0102) after freeze-drying, yield 71.1%, such as Shown in Fig. 2, target when target product is 2201.55613 (1+) when Kylo-0102 Mass Spectrometer Method mass-to-charge ratio is 1, mass-to-charge ratio is 2 Product is 1111.75962 (2+).
Embodiment 3: the preparation method of drug 3 (Kylo-0103)
Compound 3-1 generates drug 3 (Kylo-0103) by chemical reaction as follows, the concrete composition of reactant It is as shown in Table 15:
Sodium methoxide/methanol (20mg/5ml) solution is added to compound 3-1 (20mg, 0.0076mmol), shaking table temperature is set 30-35 DEG C, revolving speed 200r/min of degree shakes 30min, and reaction solution is added 1mol/L HCl (5-7 drop) and adjusts pH to 7, uses rotation Solvent evaporated is steamed, 40-45 DEG C of bath temperature, loading after ACN/ water (0.2ml/1.8ml) dissolution is added in residue, uses filler quotient The name of an article is GE Resource15RPC (10ml), and mobile phase is the mixture (ethane nitrile content 10%~90%) of water and acetonitrile, into Row purifying, elutes and collects all over products, obtain 12.5mg sterling drug 3 (Kylo-0103) after freeze-drying, yield 72.7%, such as Shown in Fig. 3, target product is 2283.69975 (1+) when Kylo-0103 Mass Spectrometer Method mass-to-charge ratio is 1.
4 zoopery 1 of embodiment
Material: choosing 30 hereditary obese model mouse (db/db mouse) and be used as administration group, and 6 week old are male, and SPF grades, Nanjing University-Nanjing biological medicine research institute provides, production licence number: SCXK (Soviet Union) 2015-0001, animal certificate number NO.201820469.Use credit number: SCXK (Soviet Union) 2018-0027.Mouse need to first adapt to environment before testing, and selection health is small Mouse is as animal subject.The raising of IVC cage tool, stocking density are 5/cage, replace padding twice weekly.Experimental animal room requirement: 22~24 DEG C of room temperature, relative humidity 40~70%, automatic illuminating, (08: 00 separates lamp to 12h light and shade alternating, and 20 points close for 00 minute Lamp), experimental animal room standard meets People's Republic of China (PRC) national standard GB14925-2010.
Experimental drug: it is shown in Table 1.
Table 1
Remarks: Kylo-0100 T3, as positive control drug, experimental drug physiological saline solution.
Xylazine is combined Patients Under Ketamine Anesthesia agent and prepared: xylazine and ketamine concentration are respectively 10mg/ in mixed liquor Ml, 0.5mg/ml.
Grouping and dosage regimen are as shown in table 2.
Table 2
It weighs in twice a week, successive administration 21 days, after last time is administered, overnight fast 15-16 hours, CO2Mouse is put to death in anesthesia, and cardiac puncture acquires blood, is stored at room temperature 2 hours, and refrigerated centrifuge 3000RPM is centrifuged 10 minutes, is received Collection -80 DEG C of refrigerators of serum save backup.Using blood biochemistry instrument measurement serum in total cholesterol (TC), low-density lipoprotein (LDL), The content of triglycerides (TG).
When administration is intervened the 18th day, mouse peritoneal injecting narcotic (xylazine combines ketamine, 10ml/Kg, IP), bone The bone density and body fat ratio of close instrument detection mouse.
Experimental data in Fig. 4 shows that the serum TC of Kylo-0100~Kylo-0103 group mouse is horizontal obviously to compare physiology Saline control group is low, and reduced rate respectively reaches 34.68%, 52.25%, 37.61% and 44.37%.
Experimental data in Fig. 5 shows that the serum LDL levels of Kylo-0100~Kylo-0103 group mouse are obviously than life Reason saline control group is low, and reduced rate reaches 40.68%, 54.24%, 22.03% and 15.25%.
Experimental data in Fig. 6 shows that the serum TG levels of Kylo-0100~Kylo-0103 group mouse obviously compare physiology Saline control group is low, and reduced rate respectively reaches 42.55%, 62.42%, 44.88% and 43.94%.
Experimental data in Fig. 7 shows that the bone density (BMD) of Kylo-0100 group mouse is significantly lower than saline control The bone mineral density in mice of group；Wherein the bone density of Kylo-0101 administration group mouse is compared with saline control group, is not become substantially Change.
Experimental data in Fig. 8 shows, Kylo-0100 is to the weight obvious effect of mouse, wherein Kylo-0101 pairs The weight of mouse does not influence significantly, illustrates that Kylo-0101 acts predominantly on liver, does not generate the bad of entirety to mouse It influences.
5 zoopery 2 of embodiment
Animal and raising: choosing 36 6 week old heredity Mice model of obesity (db/db mouse) of male and 5 brood wild Type is provided as administration group, Nanjing University-Nanjing biological medicine research institute, production licence number: SCXK (Soviet Union) 2015-0001, Animal certificate number NO.201826897, uses credit number: SCXK (Soviet Union) 2018-0027.
Mouse need to first adapt to environment before testing, and select healthy mice as animal subject.The raising of IVC cage tool, stocking density For 5/cage, padding twice is replaced weekly.Experimental animal room requirement: 22~24 DEG C of room temperature, relative humidity 40~70% is automatic to shine Bright, 12h light and shade alternating (08: 00 separates lamp, and 20 points are turned off the light for 00 minute), experimental animal room standard meets state of the People's Republic of China (PRC) Mark GB14925-2010.
Experimental drug is as shown in table 3.
Table 3
Xylazine is combined Patients Under Ketamine Anesthesia agent and prepared: xylazine and ketamine concentration are respectively 10mg/ in mixed liquor Ml, 0.5mg/ml.
Grouping and dosage regimen, as shown in table 4.
Table 4
Remarks: institute gives drug physiological saline solution.
Experimental design: it before experiment starts, weighs in, is grouped at random according to weight.Mice Body is weighed with Thursday on every Mondays Weight.When administration is intervened the 18th day, mouse peritoneal injecting narcotic (xylazine combines ketamine, 10ml/kg, IP) anesthesia, inspection Survey the bone density and body fat ratio of mouse.Successive administration 21 days, after last time is administered, overnight fast 15-16 hours.CO2 Mouse is put to death in anesthesia, and cardiac puncture acquires whole blood, stands 2 hours collection serum.Serum is divided into three parts, and 100 μ l of portion detect blood Blood glucose, triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL-C), paddy in clear Pyruvic transaminase (ALT), glutamic-oxalacetic transaminease (AST), phosphate (AP) are horizontal；Divide equally for remaining two parts and is used for triiodothyronine The measurement of (T3 is combined and dissociated), thyroxine (T4 is combined and dissociated), TSH (thyrotropic hormone) content.Weigh liver weight Amount, cardiac weight；Liver is divided into three parts, a liquid nitrogen cryopreservation, and a 10% neutral formalin is fixed, a OCT (polyethylene glycol and The water soluble mixt of polyvinyl alcohol) frost embedding.
Fabric analysis and pathological examination: liver organization isopropanol was stood according to mass volume ratio 1:9 homogenized Centrifuging and taking supernatant after night, blood biochemistry detect the content of TC and TG in supernatant.To be immersed in the hepatic tissue in 10% neutral formalin into The embedding of row routine paraffin wax is sliced (3 μm) and is dehydrated mounting after hematoxylin-eosin (HE) dyeing, and observation hepatic disease situation is simultaneously Full slice scanning is taken pictures；The hepatic tissue being submerged in OCT carries out frozen section (5 μm), and oil red dyeing, bush uniformly dyeing core takes off Liver organization lipidosis situation is observed after water seal piece and is taken pictures.The liver fat of administration group and model control group is accumulated into situation It is compared.
Statistical analysis: quantitative target misses (Mean ± sem) using mean ± mean standard, examines (TTest2.3) using T Group difference comparison is carried out to model control group and remaining group, all statistical analysis are completed in Excel table.
Experimental data in Fig. 9 shows that TC level reduces in the mice serum in each dosage group of Kylo-0101, and is in Relationship is imitated in obvious agent, and when 30 μ g/kg dosage, serum TC level is reduced up to 48%.
Experimental data in Figure 10 shows that LDL level reduces in the mice serum in each dosage group of Kylo-0101, and Relationship is imitated in obvious agent, when 30 μ g/kg dosage, serum LDL level is reduced up to 58%.
Experimental data in Figure 11 shows that TG level reduces in the mice serum in each dosage group of Kylo-0101, and is in Relationship is imitated in obvious agent, and when 30 μ g/kg dosage, serum TG levels are reduced up to 41.8%.
Experimental data in Figure 12 shows that the mouse weight of each dosage group of Kylo-0101 has decline, but not significant.
Experimental data in Figure 13 shows that each dosage of Kylo-0101 is not substantially reduced intracorporal fat and muscle Content.
Experimental data in Figure 14 shows that the bone mineral density in mice of each dosage group of Kylo-0101 is compared with model control group, Substantially do not change.
Experimental data in Figure 15 shows that the increase of Kylo-0101 dosage and the weight of liver are reduced in more apparent Relationship is imitated in agent.
Oil red dyeing is mainly the specific stain of intracellular fat drips, through hyperchromatic fat drips dark color spots institute such as in Figure 16 Show, oil red dyes histopathologic examination the results show that compared to model control group, and tetra- dosage group fat drips of Kylo-0101 are positive Property dye levels obviously weaken, fat drips quantity significantly reduces, and be in significant agent validity response.Liver centrilobular steatosis Fat vacuole not of uniform size can be formed in liver cell, wherein forming such as Figure 16 after HE dyeing based on small vacuole Shown in light color spot.In Figure 16, HE stained slice histopathologic examination is the results show that Kylo-0101 tetra- dosage groups Hepatic cell fattydegeneration degree is significantly lower than model control group, and liver cell vacuole caused by the denaturation of liver section visible fat is obvious It reduces, and is in significant agent validity response.
Hepatic pathology inspection dyeing average quantization in Figure 17 is the results show that HE dyeing is with higher consistent with oil red dyeing Property, and the dosage of Kylo-0101 be 30 μ g/kg when, the fat content of liver drops to the almost liver with normally (wild type) mouse Dirty fat content is close.It is normal when it is generally acknowledged that normal average quantization value is less than 1.
The testing result of Figure 18 shows under each dosage of Kylo-0101 that fT3 concentration has increased slightly in mice serum, but does not have There is marked difference.
The testing result of Figure 19 shows that each dosage of Kylo-0101 does not have an impact TSH concentration in mice serum.
Influence of the 6 Liver targeting ligands specific X of embodiment to the Percentage bound of drug and ASGPR, heart rate and bone density
The difference of drug Kylo-0101 in table 5, Kylo-0105~Kylo-0107 are only that the difference of X structure, in table Experimental data show, in the identical situation of L, B, D, T structure, by change X structure can be to the combination of drug and ASGPR Rate, heart rate and bone density have an impact, wherein the effect of drug Kylo-0101 is best, has higher ASGPR Percentage bound Meanwhile the influence to heart rate and bone density is minimum.This illustrates that in the composition prepared by the present invention, Liver targeting specificity is matched Body X, although for being combined with ASGPR, certain influence can be also generated to the therapeutic efficiency of entire drug.
Table 5
Number 6 to 1 in table 5 indicates the Percentage bound for the drug and asialoglycoprotein receptor ASGPR that the combination is formed From high to low；It is from high to low to cardiac toxic and bone mineral density.
Influence of the branch L of 7 structure containing steric stabilization of embodiment to medicine stability
Table 6
Drug Kylo-0101, Kylo-0108~Kylo-0110 difference are only that the difference of L structure in table 6, in table Experimental data show, in the identical situation of X, B, D, T structure, by change L structure the stability of drug can be generated It influences, when the L structure selected in Kylo- 0101 and Kylo-0110 drug, the drug of high stability can be obtained.
Influence of the 8 connector B of embodiment to the Percentage bound of drug and ASGPR, heart rate and bone density
Drug Kylo-0101, Kylo-0111~Kylo-0113 difference are only that the difference of B structure in table 7, in table Experimental data show, in the identical situation of X, L, D, T structure, by change B structure can be to the combination of drug and ASGPR Rate, heart rate and bone density have an impact, and when the B structure selected in Kylo-0101 and Kylo-0112 drug, can obtain good Good receptor Percentage bound and lesser heart, bone density side effect.
In table 7 number 6 to 1, indicate the combination formed drug and asialoglycoprotein receptor ASGPR Percentage bound from It is high to low；It is from high to low to cardiac toxic and bone mineral density.
Table 7
Influence table 8 of the 9 connection chain D of embodiment to drug hypolipemic function
Remarks: the number in table 8 under TC, LDL and TG respectively represents the strong of the function of the composition reduction TC, LDL and TG Weak, number 6 to 1 indicates function by by force to weak.
The difference of drug Kylo-0101, Kylo-0102, Kylo-0114 are only that the difference of D structure in table 8.D is independent As a connection structure, there is no blood fat reducing functions, and still, the experimental data in table is shown, in X, L, B, T structure phase With in the case where, the function that the structure by changing D can reduce TC, TG and LDL to drug is had an impact.In experiment of the invention Under the conditions of, select the D in drug Kylo-0101 structure that can obtain optimal drop TC, TG and LDL effect.

Claims (26)

1. the drug in a kind of structure containing Liver targeting ligands specific and pth receptor agonist.
2. drug according to claim 1, it is characterised in that: the Liver targeting ligands specific is galactolipin and its spreads out Biology, preferably galactosamine, acetylgalactosamine or trivalent acetylgalactosamine.
3. -2 described in any item drugs according to claim 1, which is characterized in that the Liver targeting ligands specific X in structure, according to It is secondary to be connect by the branch L containing steric stabilization structure, connector B and connection chain D with pth receptor agonist T；The drug General structure (I) are as follows:
(X-L)n-B-D-T
Wherein n is the positive integer of 1-15.
4. drug according to claim 3, it is characterised in that: general structure (I) the center tap B branching is multiple, gained Branch is for n (X-L) and one (D-T) in connection structure general formula (I).
5. drug according to claim 3, it is characterised in that: as n=1, general structure (I) are as follows: X-L-B-D-T；Work as n When=2,3,4,5 or 6, general structure (I) is successively are as follows:
6. drug according to claim 1, it is characterised in that: the Liver targeting ligands specific is in flowering structure It is one or more: polysaccharide, polysaccharide derivates, monosaccharide and monosaccharide derivatives.
7. drug according to claim 2, it is characterised in that: the universal architecture formula (II) of the Liver targeting ligands specific Are as follows:
Wherein, R1, R2 and R3 are hydrogen or hydroxyl protection base.
8. drug according to claim 1, it is characterised in that: the Liver targeting ligands specific is in flowering structure It is one or more:
Wherein, R1 is selected from one or both of OH and NHCOOH.
9. drug according to claim 3, it is characterised in that: the branch L containing steric stabilization structure is selected from as follows One of structure is a variety of:
Wherein, in formula n1 be 1-10 positive integer, m be 1-5 positive integer, n2 be 0-20 integer, n3 be 1-12 positive integer, Z is H or CH3；The left distal end of branch L containing steric stabilization structure connects Liver targeting ligands specific X, right end connection Connector B left distal end part.
10. drug according to claim 3, it is characterised in that: connector B is selected from following structural formula:
Wherein, A1 is C, O, S or NH；R1 is the positive integer of 1-15；A2 be selected from C1-C10 linear paraffin, with amino, amide groups, The segment of phosphinylidyne root, thiophosphoryl, oxygen atom, sulphur atom or cyclic compound；R2 is the integer of 0-15.
11. drug according to claim 3, it is characterised in that: connector B is selected from following structural formula:
Wherein, r1, r3, r4, r5 are the positive integer of 1-15；R6 is the positive integer of 1-20, and r7 is the positive integer of 2-6, and r8 is 1-3's Positive integer.
12. drug according to claim 3, it is characterised in that: the connector B is selected from flowering structure:
13. drug according to claim 3, it is characterised in that: the connection chain D, selected from carbonyl, amide groups, Oxygen atom, sulphur atom, thiophosphoryl, phosphoryl or cyclic structure alkyl moiety, the right end and thyroid gland of connection chain D Plain receptor stimulating agent T-phase answers position to connect.
14. drug according to claim 3, it is characterised in that: the connection chain D is selected from one of flowering structure:
Wherein, each n is the positive integer of 1-20, and each n is identical or different positive integer.
15. drug according to claim 3, it is characterised in that: the connection chain D is selected from one of flowering structure:
16. drug according to claim 3, it is characterised in that: the connection chain D is selected from one of flowering structure:
Wherein each n is the positive integer in 1-20, and each n is identical or different positive integer, and p is the positive integer of 1-6；S is 2- 13 positive integer；R1 and R2 is same or different substituent group, and structural formula is with one of flowering structure :-H ,- CH3、-CH-(CH3)2、-CH2-CH(CH3)2、-CH(CH3)-CH2-CH3、-CH2-C6H5、-C8NH6、-CH2-C6H4-OH、-CH2- COOH、-CH2-CONH2、-(CH2)2-COOH、-(CH2)4-NH2、-(CH2)2-CONH2、-(CH2)-S-CH3、-CH2-OH、-CH (CH3)-OH、-CH2-SH、-CH2-C3H3N2、-(CH2)3NHC(NH)NH2。
17. drug according to claim 1, it is characterised in that: the thryoid receptor activator has knot below Structure general formula:
Wherein A is oxygen, sulphur, carbonic acyl radical, methylene or amino；R1 be C1-C4 linear or branched alkyl group ,-CH2 (azacyclo-) ,- CH (OH) (halogeno-benzene or aromatic hydrocarbon) ,-CH (OH) CH3, halogen atom or hydrogen；R2 is halogen atom ,-CH3Or hydrogen；R3 is Halogen atom, CH3Or hydrogen；R4 is-CH2CH(NH)COOH、-OCH2COOH、-NHC(O)COOH、-CH2COOH、-NHC(O) CH2COOH、-CH2CH2COOH、-OCH2PO3 2-、-NHC(O)CH2COOH ,-OH, halogen atom, C1-C4 alkyl.
18. drug according to claim 1, it is characterised in that: the thryoid receptor activator is thyroxine (T4) or Lithyronine original propylhomoserin (T3) or its metabolin.
19. according to drug described in claim 1, it is characterised in that: the thryoid receptor activator has having structure special Sign:
Wherein, R6 is C1-C4 linear or branched alkyl group, Huo Zheqing；R5 is C1-C8 alkyl；R7 is halogen atom or C1-C4 alkane Base；R8 is C1-C4 linear or branched alkyl group, Huo Zheqing；R9 is-CH2CH (NH) COOH ,-OCH2COOH ,-NHC (O) COOH ,- CH2COOH ,-NHC (O) CH2COOH, CH2CH2COOH ,-OCH2PO3 2-,-NHC (O) CH2COOH ,-OH, halogen atom or C1-C4 Alkyl.
20. according to drug described in claim 1, it is characterised in that: the pth receptor agonist has having structure Feature:
Wherein, X is oxygen, sulphur, carbonic acyl radical, methylene or amino；Y is one of C1-C5 alkyl carbon chain and C=C；R1 is halogen original The naphthenic base of son, trifluoromethyl, the alkyl of C1-C6 or C3-C7；R2 and R3 is hydrogen, halogen atom, the alkyl of C1-C6, C3-C7 It is one or two kinds of in naphthenic base, but R2 or R3 one of them must be hydrogen atom；R4 is hydrogen or the alkyl of C1-C4；R5 is The alkyl of hydrogen or C1-C4；R6 is carboxylic acid or ester bond；R7 is hydrogen, acyl group or aroyl.
21. drug according to claim 3, it is characterised in that: (X-L) n-B group in the drug general formula structure (I) Selected from one of flowering structure, and (X-L)nThe right end of-B is connected with the left distal end of connection chain D:
22. drug according to claim 3, it is characterised in that the general formula structure (X-L) of the drugn- B-D-T is Kylo- 0101 to one of structure shown in Kylo-0104:
23. the drug as described in any one of right 1-2 and claim 4-22 acts on pth receptor treatment in preparation Application in the drug of liver source property disease.
24. application according to claim 23, it is characterised in that: the pth receptor is Asialoglycoprotein Receptor, the liver source property disease are nonalcoholic fatty liver or nonalcoholic steatohepatitis.
25. a kind of pharmaceutical composition, which includes claim 1-2 and the described in any item medicines of claim 4-22 Object and pharmaceutically acceptable auxiliary material.
26. pharmaceutical composition according to claim 25, it is characterised in that: the pharmaceutical composition is injection or mouth Formulation.
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