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CN113979963B - Compound as thyroid hormone beta receptor agonist and application thereof - Google Patents

Compound as thyroid hormone beta receptor agonist and application thereof Download PDF

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CN113979963B
CN113979963B CN202111593914.XA CN202111593914A CN113979963B CN 113979963 B CN113979963 B CN 113979963B CN 202111593914 A CN202111593914 A CN 202111593914A CN 113979963 B CN113979963 B CN 113979963B
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pharmaceutically acceptable
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CN113979963A (en
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赵一爽
张振伟
施晶晶
杨生生
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Kaisi Kaidi Shanghai Pharmaceutical Technology Co ltd
Kaisi Kaixu Shanghai Pharmaceutical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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Abstract

The invention relates to a compound serving as a thyroid hormone beta receptor agonist and application thereof, and further relates to a compound shown as a formula (1) or a pharmaceutically acceptable form thereof, a pharmaceutical composition containing the compound and a preparation method of the compound. The compound or the pharmaceutical composition can be used for preparing medicines for preventing, treating or alleviating diseases modulated by thyroid hormone beta receptors.

Description

Compound as thyroid hormone beta receptor agonist and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a compound serving as a thyroid hormone beta receptor agonist, a medicinal composition containing the same, a preparation method of the medicinal composition, and application of the medicinal composition in preparation of medicines for preventing, treating or relieving diseases modulated by thyroid hormone beta receptors.
Background
Thyroid Hormone (TH) is synthesized in the thyroid gland in response to Thyroid Stimulating Hormone (TSH) secreted by the pituitary. Thyroxine plays a very important role in regulating body growth, development, metabolism, and matrix balance. Thyroid hormones function by binding to Thyroid Hormone Receptors (THR). The THRs belong to the nuclear receptor superfamily, which forms heterodimers with their common ligand, retinoid X receptors, and function as ligand-induced transcription factors. Like other nuclear receptors, THRs have a ligand binding domain and a DNA binding domain, and regulate gene expression through ligand-dependent interaction with DNA response elements (thyroid response elements, THREs).
Currently, there are two subtypes of THR: THR α and THR β. THR alpha is mainly distributed in heart tissues and plays an important role in regulating and controlling the functions of the heart. THR β is expressed mainly in the liver and pituitary, regulates the metabolism of fatty acids and cholesterol, and regulates thyroid stimulating hormone secretion. THR α and THR β are both expressed in Brown Adipose Tissue (BAT) and play important roles in regulating basal oxygen consumption, fat storage, lipogenesis and lipolysis (Oppenheimer et al, J.Clin. invest.87 (1): 125-32 (1991)).
THR agonists increase metabolic rate, oxygen consumption and thermogenesis, promote cholesterol metabolism to bile acids, and, in addition, lower the lipoprotein levels associated with atherosclerosis. The liver and heart are the major target organs for THR agonists. Genes involved in the synthesis and metabolism of fatty acids and cholesterol are mainly regulated in the liver and affect carbohydrates by increasing glycogenolysis and gluconeogenesis and decreasing the action of insulin. In the heart, systemic vascular resistance can be reduced, blood volume increased and inotropic and chronotropic effects produced.
The THR beta agonist can also improve the metabolism of cell lipid and play the role of reducing cholesterol and blood fat. Therefore, it is of great interest to research and develop THR β agonists for the treatment and/or prevention of diseases modulated by thyroid hormone receptors.
Disclosure of Invention
Through a large number of researches, a series of compounds serving as thyroid hormone beta receptor agonists are discovered and have potential value of preventing and/or treating diseases regulated by thyroid hormone beta receptors.
In a first aspect, the present invention provides a compound having the structure of formula (1) or a pharmaceutically acceptable form thereof:
Figure DEST_PATH_IMAGE002
wherein,
R1and R2Independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, C1-6Alkyl radical, C1-6Alkoxy radical, C6-10Aryl, 5-12 membered heteroaryl, - (C)1-6Alkylene) -C6-10Aryl, - (C)1-6Alkylene) - (5-12 membered heteroaryl), C3-8Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, aryl, heteroaryl, alkylene, cycloalkyl or heterocyclyl being optionally substituted with one or more substituents independently selected from halogen, cyano, amino, nitro, hydroxy, -OCF3、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-S(=O)-NH2、-S(=O)NH(C1-4Alkyl), -S (= O) N (C)1-4Alkyl radical)2、-S(=O)2-NH2、-S(=O)2NH(C1-4Alkyl), -S (= O)2N(C1-4Alkyl radical)2、-C(=O)-NH2、-C(=O)NH(C1-4Alkyl), -C (= O) N (C)1-4Alkyl radical)2、-C(=O)-C1-4Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy or C3-6A cycloalkyl group,
when two or more substituents are present, the two substituents optionally form C together with the atom to which they are attached6-10Aryl, 5-12 membered heteroaryl, C3-8Cycloalkyl or a 3-to 8-membered heterocyclic group,
or, R1And R2Together with the atom to which they are attached form C6-10Aryl, 5-12 membered heteroaryl、C3-8Cycloalkyl or a 3-to 8-membered heterocyclic group,
R3and R4Independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, C1-6Alkyl or C1-6An alkoxy group,
L1is selected from CH2The content of the nitrogen is NH or O,
L2is selected from the group consisting of NH or O,
ring A is selected from
Figure DEST_PATH_IMAGE004
、
Figure DEST_PATH_IMAGE006
Or
Figure DEST_PATH_IMAGE008
，
The pharmaceutically acceptable form is selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotopic labels, metabolites and prodrugs.
In some embodiments, R in the compound of formula (1) or a pharmaceutically acceptable form thereof, described above1And R2Independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, - (C)1-6Alkylene) -C6-10Aryl or- (C)1-6Alkylene) - (5-12 membered heteroaryl), said alkyl, alkoxy, aryl, heteroaryl or alkylene optionally substituted with one or more substituents independently selected from halogen, cyano, amino, nitro, hydroxy, -OCF3、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-S(=O)-NH2、-S(=O)NH(C1-4Alkyl), -S (= O) N (C)1-4Alkyl radical)2、-S(=O)2-NH2、-S(=O)2NH(C1-4Alkyl), -S (= O)2N(C1-4Alkyl radical)2、-C(=O)-NH2、-C(=O)NH(C1-4Alkyl), -C (= O) N (C)1-4Alkyl radical)2、-C(=O)-C1-4Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy or C3-6A cycloalkyl group.
In some preferred embodiments, R in the compound of formula (1) above or a pharmaceutically acceptable form thereof1And R2Independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, C1-4Alkyl, - (C)1-4Alkylene) -C6-10Aryl or- (C)1-4Alkylene) - (5-12 membered heteroaryl), said alkyl, aryl, heteroaryl or alkylene optionally substituted with one or more substituents independently selected from halogen, cyano, amino, nitro, hydroxy, -OCF3、-NH(C1-4Alkyl), -N (C)1-4Alkyl radical)2、-C(=O)-NH2、-C(=O)NH(C1-4Alkyl), -C (= O) N (C)1-4Alkyl radical)2、-C(=O)-C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy or C3-6A cycloalkyl group.
In some more preferred embodiments, R in the compound of formula (1) above or a pharmaceutically acceptable form thereof2Is hydrogen, R1Selected from halogen, cyano, amino, nitro, hydroxy, C1-4Alkyl, - (C)1-4Alkylene) -phenyl, - (C)1-4Alkylene) -pyridyl or- (C)1-4Alkylene) -furyl, said alkyl, phenyl, pyridyl, furyl or alkylene being optionally substituted with one or more substituents independently selected from halogen, cyano, amino, nitro, hydroxy, C1-4Alkyl radical, C1-4Alkoxy or C3-6Cycloalkyl substituents.
In some particularly preferred embodiments, R in the compound of formula (1) above or a pharmaceutically acceptable form thereof2Is hydrogen, R1Is selected from
Figure DEST_PATH_IMAGE010
、
Figure DEST_PATH_IMAGE012
、
Figure DEST_PATH_IMAGE014
、
Figure DEST_PATH_IMAGE016
、
Figure DEST_PATH_IMAGE018
、
Figure DEST_PATH_IMAGE020
Or
Figure DEST_PATH_IMAGE022
。
In some embodiments, R in the compound of formula (1) or a pharmaceutically acceptable form thereof, described above1And R2Together with the atom to which they are attached form C6-10And (4) an aryl group.
In some preferred embodiments, R in the compound of formula (1) above or a pharmaceutically acceptable form thereof1And R2Together with the atoms to which they are attached form a phenyl group.
In some embodiments, R in the compound of formula (1) or a pharmaceutically acceptable form thereof, described above3And R4Independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy or C1-6An alkyl group.
In some preferred embodiments, R in the compound of formula (1) above or a pharmaceutically acceptable form thereof3And R4Independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy or C1-4An alkyl group.
In some more preferred embodiments, R in the compound of formula (1) above or a pharmaceutically acceptable form thereof3And R4Independently selected from halogen or methyl.
In some particularly preferred embodiments, R in the compound of formula (1) above or a pharmaceutically acceptable form thereof3And R4Independently selected from Cl, Br or methyl.
In some embodiments, the compound of formula (1) or a pharmaceutically acceptable form thereof described above is a compound having the structure of formula (2) or formula (3) or a pharmaceutically acceptable form thereof:
Figure DEST_PATH_IMAGE024
wherein R is1、R3、R4And ring A is as defined in formula (1).
In some embodiments, the compound of formula (1) or a pharmaceutically acceptable form thereof described above is a compound having the structure of formula (4) or formula (5) or a pharmaceutically acceptable form thereof:
Figure DEST_PATH_IMAGE026
wherein R is1、R2、R3、R4、L1And L2As defined in formula (1).
It will be understood by those skilled in the art that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments resulting from the combination of features from one embodiment or preferred features with features from another embodiment or preferred features are also included within the scope of the present invention.
In a second aspect, the present invention also provides the following compounds, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof:
Figure DEST_PATH_IMAGE028
。
in a third aspect, the present invention provides a process for the preparation of a compound having the structure of formula (4) or formula (5), comprising the steps of:
step 1: synthesis of intermediates M1, M2
Figure DEST_PATH_IMAGE030
(a) Taking a compound shown in a general formula I as an initial raw material, and introducing a hydroxyl protecting group under the action of alkali to obtain a compound shown in a general formula II;
(b) reacting the intermediate obtained by reacting the compound shown in the general formula II with a lithium reagent at low temperature with the compound shown in the general formula III to obtain a compound shown in the general formula IV;
(c) the compound shown in the formula IV is reacted with a reducing agent to obtain a compound shown in a formula M1.
Figure DEST_PATH_IMAGE032
(d) Reacting a compound shown in a general formula V serving as a starting material with a compound shown in a general formula VI under the action of alkali to obtain a compound shown in a general formula VII;
(e) reacting the compound shown in the general formula VII with a reducing agent to obtain a compound shown in a general formula M2;
wherein Bn is benzyl, R1、R2、R3、R4、L1And L2As defined in formula (1); PG is a hydroxyl protecting group selected from the group consisting of p-nitrobenzoate, acetyl, methyl, allyl, trityl, methoxymethyl, 2-tetrahydropyran, t-butyldimethylsilyl, preferably t-butyldimethylsilyl or methyl.
In some embodiments, step 1 (a) above is performed in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine, imidazole, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, preferably imidazole.
In some embodiments, step (b) above in step 1 is performed under low temperature conditions, which means-50 ℃ to-80 ℃, preferably-78 ℃.
In some embodiments, step 1 above (b) is performed in the presence of a lithium reagent selected from the group consisting of methyllithium, ethyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, preferably n-butyllithium.
In some embodiments, step 1 (c) above is performed in the presence of a reducing agent selected from the group consisting of 5% palladium on carbon, 10% palladium on carbon, 20% palladium on carbon, 10% palladium on calcium carbonate, 5% platinum on carbon, preferably 10% palladium on carbon.
In some embodiments, step (d) above in step 1 is performed in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine, imidazole, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, preferably cesium carbonate.
In some embodiments, step 1, above, (e) is performed in the presence of a reducing agent selected from iron, zinc, raney nickel, palladium on carbon, platinum on carbon, sodium sulfide, sodium disulfide, lithium aluminum hydride, sodium borohydride, preferably iron.
Step 2: synthesis of Compound represented by the formula (4) or (5)
Figure DEST_PATH_IMAGE034
(g) Reacting the compound shown in the general formula M (M1 or M2) with ethyl bromoacetate under the action of alkali to obtain a compound shown in the general formula IX;
(h) reacting the compound shown in the general formula IX with hydrazine hydrate to obtain a compound shown in the general formula X;
(i) reacting the compound shown in the general formula X with phosgene, triphosgene, carbonyl diimidazole or N, N' -disuccinimidyl carbonate under the action of alkali to obtain a compound shown in a general formula XI;
(j) removing a hydroxyl protecting group from the compound shown in the general formula XI to obtain a compound shown in a formula (4);
Figure DEST_PATH_IMAGE036
(l) Reacting the compound shown in the general formula M (M1 or M2) with bromoacetonitrile under the action of alkali to obtain a compound shown in a general formula XIII;
(m) reacting the compound shown in the general formula XIII with hydroxylamine hydrochloride under the action of alkali to obtain a compound shown in the general formula XIV;
(N) reacting the compound shown in the general formula XIV with phosgene, triphosgene, carbonyl diimidazole or N, N' -disuccinimidyl carbonate under the action of alkali to obtain a compound shown in the general formula XV;
(o) removing the hydroxyl protecting group from the compound represented by the general formula XV to obtain a compound represented by the formula (5);
wherein R is1、R2、R3、R4、L1And L2As defined in formula (1); PG is a hydroxyl protecting group selected from the group consisting of p-nitrobenzoate, acetyl, methyl, allyl, trityl, methoxymethyl, 2-tetrahydropyran, t-butyldimethylsilyl, preferably t-butyldimethylsilyl or methyl.
In some embodiments, step 2 (g) above is performed in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine, imidazole, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, preferably cesium carbonate.
In some embodiments, step 2 (i) above is performed in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine, imidazole, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, preferably 1, 8-diazabicycloundec-7-ene.
In some embodiments, step 2 above is performed in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine, imidazole, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, preferably cesium carbonate.
In some embodiments, step 2 (m) above is performed in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine, imidazole, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, preferably triethylamine.
In some embodiments, step 2 above wherein (n) is performed in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine, imidazole, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, preferably 1, 8-diazabicycloundecen-7-ene.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formulae (1) to (5) above, or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.
In a fifth aspect, the present invention provides a compound of formulae (1) to (5) above, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above, for use as a thyroid hormone beta receptor agonist, for the prevention and/or treatment of a disease or condition mediated at least in part by the thyroid hormone beta receptor.
In a sixth aspect, the present invention provides the use of a compound of formulae (1) to (5) above, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by thyroid hormone β receptor (e.g. a metabolic disease such as non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis or hypothyroidism).
In a seventh aspect, the present invention provides a method for the prevention and/or treatment of a disease or condition mediated at least in part by thyroid hormone beta receptor, comprising the steps of: administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of formulae (1) to (5) above or a pharmaceutically acceptable form thereof or a pharmaceutical composition as described above.
The present invention is not limited to the specific embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
Definition of terms
The following terms have the following meanings in the present invention unless otherwise specified.
The terms "comprises," "comprising," "includes," "including," "has," "having" or "containing," or any other variation thereof, are intended to cover a non-exclusive or open-ended inclusion. For example, a composition, method, or apparatus that comprises a list of elements is not necessarily limited to only those elements explicitly listed, but may include other elements not explicitly listed or inherent to such composition, method, or apparatus.
When the lower and upper limits of a range of values are disclosed, any value or any sub-range falling within the range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b," or equivalently "about a-b") is to be understood to encompass each number and subrange therein. For example, "C1-4"is to be understood to cover any subrange therein as well as each point value, e.g. C2-4、C3-4、C1-2、C1-3、C1-4Etc. and C1、C2、C3、C4And the like. Also for example, "5-10 way" should be understood to encompass any subrange therein as well as each point value, e.g., 5-6 way, 5-7 way, 5-8 way, 5-9 way, 6-7 way, 6-8 way, etc., as well as 5, 6, 7, 8, 9, 10 way, etc.
The term "substituted" and other variations thereof herein mean that one or more (e.g., 1,2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on the designated atom is replaced with other equivalents, provided that the designated atom or group of atoms does not exceed the normal valence under the current circumstances and that a stable compound can be formed. If an atom or group of atoms is described as "optionally substituted with … …," it may be substituted or unsubstituted. Unless otherwise indicated, the attachment site of a substituent herein may be from any suitable position of the substituent. When a linkage in a substituent is shown across a chemical bond between two atoms attached to each other in a ring system, it means that the substituent may be attached to any one of the ring atoms in the ring system.
The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to an excipient that is administered with a therapeutic agent, and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable carriers that may be used in the present invention include, but are not limited to: a) a diluent; b) a lubricant; c) a binder; d) a disintegrant; e) absorbents, coloring, flavoring and/or sweetening agents; f) an emulsifier or dispersant; and/or g) substances that enhance the absorption of the compounds, and the like.
The pharmaceutical compositions described above may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes or as an inhalant.
The above administration route can be achieved by a suitable dosage form. Dosage forms that may be used in the present invention include, but are not limited to: tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
When administered orally, the above pharmaceutical compositions may be formulated into any orally acceptable dosage form, including, but not limited to, tablets, capsules, aqueous solutions, aqueous suspensions, and the like.
The pharmaceutical compositions described above may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions, or sterile injectable aqueous or oleaginous solutions. Among the carriers that can be used are, but not limited to: water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
The above pharmaceutical composition may comprise 0.01mg to 1000mg of at least one compound of the above formulae (1) to (6) or a pharmaceutically acceptable form thereof.
The term "a disease or condition mediated at least in part by the thyroid hormone beta receptor" refers to a disease that involves at least a portion of the factors associated with the thyroid hormone beta receptor in its pathogenesis, such as metabolic diseases, e.g., non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis, or hypothyroidism.
The term "effective amount" refers to a dose that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., an individual) and is sufficient to achieve a desired prophylactic and/or therapeutic effect.
The dosing regimen may be adjusted to provide the best desired response. For example, it may be administered in a single dose, may be administered in divided doses over time, or may be administered after proportionally decreasing or increasing the dose as the case may be. It will be appreciated that for any particular individual, the specific dosage regimen will be adjusted as needed and as the professional judgment of the person administering the composition or supervising it.
The term "in need thereof" refers to a judgment by a physician or other caregiver that an individual needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors within the physician's or other caregiver's expertise.
The term "individual" (or subject) refers to a human or non-human animal. The subject of the invention includes both subjects (patients) suffering from a disease and/or disorder and normal subjects. Non-human animals of the invention include all vertebrates, e.g., non-mammals, such as birds, amphibians, reptiles, and the like, and mammals, e.g., non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, and the like).
The term "treating" refers to alleviating or eliminating the disease or disorder in question. A subject is successfully "treated" if the subject receives a therapeutic amount of a compound of the invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, and the subject exhibits an observable and/or detectable remission and/or improvement of at least one of the indications and symptoms. It is understood that treatment includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result. In particular, "treatment" means that the compound of the invention or a pharmaceutically acceptable form thereof or the pharmaceutical composition of the invention can achieve at least one of the following effects, for example: (1) preventing disease from occurring in an animal that may be predisposed to the disease but has not yet experienced or exhibited disease pathology or symptomology; (2) inhibiting disease in an animal experiencing or exhibiting disease pathology or symptomatology (i.e., arresting further development of pathology and/or symptomatology); (3) ameliorating the disease (i.e., reversing pathology and/or symptomatology) in an animal experiencing or exhibiting disease pathology or symptomatology.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or inorganic/organic base, such salts also being referred to as acid addition salts or base addition salts. For a review of suitable salts see, for example, Jusiak, Soczewinski,et al., Remington’s Pharmaceutical Sciences [M], Mack Publishing Company2005 and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [ M], Wiley-VCH, 2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and that hydrolyzes in vivo to a compound of the invention or a salt thereof. Pharmaceutically acceptable esters generally include, but are not limited to, esters of the compounds of the present invention with pharmaceutically acceptable carboxylic or sulfonic acids, such esters also being referred to as carboxylic or sulfonic esters.
The term "isomers" refers to compounds having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms, due to the same number and type of atoms.
The term "stereoisomer" (or "optical isomer") refers to a stable isomer having a perpendicular plane of asymmetry due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) that enables rotation of plane polarized light. Since the compounds of the present invention contain asymmetric centers as well as other chemical structures that may lead to stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.
The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "solvate" refers to a substance formed by the binding of a compound of the present invention (or a pharmaceutically acceptable salt thereof) to at least one solvent molecule by non-covalent intermolecular forces. For example, solvates include, but are not limited to, hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, and the like), ethanolates, acetonates, and the like.
The term "nitroxide" refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound. For example, the nitrogen atom in the parent nucleus of a compound of formula I may form the corresponding nitroxide.
The term "isotopic label" refers to a derivatized compound formed by replacing a particular atom in a compound of the invention with its isotopic atom. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as, but not limited to2H(D)、3H(T)、13C、14C、15N、17O、18O、18F、31P、32P、35S、36S and37Cl。
the term "metabolite" refers to a derivative compound formed after the compounds of the present invention are metabolized. Further information on metabolism can be found in Goodman and Gilman's: The pharmaceutical Basis of Therapeutics (9)th ed.) [M]McGraw-Hill International proportions, 1996. The present invention encompasses all possible metabolite forms of the compounds of the invention, i.e. substances formed in the body of the individual to whom the compounds of the invention are administered. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized by assays.
The term "prodrug" refers to a derivative compound that is capable of providing, directly or indirectly, a compound of the invention upon administration to a subject. Particularly preferred derivative compounds or prodrugs are those that increase the bioavailability of the compounds of the invention when administered to a subject (e.g., more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, see, e.g., T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [ J], American Chemical SocietyVol. 14, 1975. Furthermore, the present invention also encompasses compounds of the present invention containing protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, for example as described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis [ M], John Wiley & SonsProtecting groups as described in 2006. These protecting groups may be removed at a suitable subsequent stage using methods known in the art.
The term "independently" means that at least two groups (or ring systems) present in a structure that are the same or similar in value can have the same or different meaning in a particular instance. For example, substituent X and substituent Y are independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when substituent X is hydrogen, substituent Y may be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X may be hydrogen, or may be halogen, hydroxy, cyano, alkyl or aryl.
The term "halogen", when used herein alone or in combination with other groups, refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
The term "alkyl", when used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group. For example, the term "C" as used in the present invention1-6Alkyl "refers to an alkyl group having 1 to 6 carbon atoms. For example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. Alkyl groups may be optionally substituted or unsubstituted.
The term "alkylene" as used herein, alone or in combination with other groups, refers to a straight or branched chain divalent saturated aliphatic hydrocarbon group, wherein the two groups (or segments) to which it is attached may be attached to either the same carbon atom or to different carbon atoms. For example, the term "C" as used herein1-6The alkylene group "means an alkylene group having 1 to 6 carbon atoms (e.g., methylene, 1-ethylene, 1, 2-propylene, 1, 3-butylene, etc.). The alkylene group may be optionally substituted or unsubstituted.
The term "alkoxy" as used herein alone or in combination with other groups, refers to an alkyl group attached to the remainder of the molecule through an oxygen atom. For example, alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted.
The term "cycloalkyl" as used herein alone or in combination with other groups means saturatedOr partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon groups. For example, the term "C" as used in the present invention3-6Cycloalkyl "refers to cycloalkyl groups having 3 to 6 carbon atoms. For example, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.
The term "heterocyclyl", alone or in combination with other groups, as used herein, refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged or spiro) nonaromatic group having ring atoms consisting of carbon atoms and at least one heteroatom selected from N, O and S, wherein the S atom is optionally substituted to form S (= O), S (= O)2Or S (= O) (= NR)x)，RxIndependently selected from H or C1-4An alkyl group. If the valence requirement is met, the heterocyclyl group may be attached to the remainder of the molecule through any one of the ring atoms. For example, the term "3-8 membered heterocyclic group" as used in the present invention means a heterocyclic group having 3 to 8 ring atoms. Common heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, or trithianyl. The heterocyclic group in the present invention is optionally substituted with one or more substituents described herein.
The term "aryl" as used herein alone or in combination with other groups refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated pi-electron system. For example, the term "C" as used in the present invention6-10Aryl "refers to an aryl group having 6 to 10 carbon atoms. Common aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like. Aryl groups in the present invention are optionally substituted with one or more substituents described herein.
The term "heteroaryl" as used herein alone or in combination with other groups refers to a compound having a conjugated pi-electron systemA monocyclic or fused polycyclic aromatic group whose ring atoms are composed of carbon atoms and at least one heteroatom selected from N, O and S. Heteroaryl groups, if the valence requirement is met, may be attached to the rest of the molecule through any one of the ring atoms. For example, the term "5-12 membered heteroaryl" as used herein refers to heteroaryl groups having 5 to 12 ring atoms. Common heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and its benzo derivatives, pyrrolopyridyl, pyrrolopyrazinyl, pyrazolopyridyl, imidazopyridinyl, pyrrolopyrimidyl, purinyl, and the like. Heteroaryl groups in the present invention are optionally substituted with one or more substituents described herein (e.g., halogen, C)1-6Alkyl, etc.).
The term "hydroxy" when used herein alone or in combination with other groups means-OH.
The term "cyano," when used herein alone or in combination with other groups, refers to — CN.
The term "amino" as used herein, alone or in combination with other groups, refers to-NH2。
The term "nitro" as used herein, alone or in combination with other groups, refers to-NO2。
Detailed Description
In order to make the objects and technical solutions of the present invention clearer, embodiments of the present invention will be described in detail below with reference to examples. It will be understood by those skilled in the art that the following examples are illustrative of the present invention only and should not be taken as limiting the scope of the invention.
The reagents or instruments used in the examples are all conventional products which are commercially available. Those who do not have specific conditions noted are conducted under conventional conditions or conditions recommended by the manufacturer. The term "room temperature" used in the present invention means 20 ℃. + -. 5 ℃. As used herein, the term "about" when used in reference to a value or range of values is intended to encompass the value or range of values and tolerances acceptable to those skilled in the art for that value or range of values, e.g., within ± 10%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, etc.
The structures of the compounds described in the following examples were determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS).
Nuclear Magnetic Resonance (NMR) measuring apparatus Bruker 400 MHz NMR was used, and deuterated methanol (CD) was used as a measuring solvent3OD), deuterated chloroform (CDCl)3) Hexadeuterio dimethyl sulfoxide (DMSO-d)6) The internal standard substance is Tetramethylsilane (TMS). In that1In H NMR, part of hydrogen may not be peaked due to interference by a salt or a solvent.
Abbreviations in the Nuclear Magnetic Resonance (NMR) data in the following examples represent the following meanings:
s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet, qd: quartet, ddd: double doublet, ddt: double triplet, dddd: double doublet, m: multiplet, br: broad peak, J: coupling constant, Hz: hertz, δ: chemical shift.
All chemical shift (δ) values are given in parts per million (ppm).
Mass Spectrometry (MS) was performed using an Agilent 6120B mass spectrometer with an electrospray ion source (ESI).
HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150X 4.6mm, 5 μm column).
The thin layer chromatography silica gel plate is Qingdao sea GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.2mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5 mm.
Column chromatography generally uses Qingdao ocean 200-mesh and 300-mesh silica gel as a carrier.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: the volume ratio of the solvent in the petroleum ether and ethyl acetate system is adjusted according to different polarities of the compounds, and a small amount of triethylamine, an acidic or basic reagent and the like can be added for adjustment.
Synthesis of Compounds
Synthesis example 1: synthesis of intermediate M1 a:
Figure DEST_PATH_IMAGE038
step a: tert-butyldiphenylchlorosilane (TBDPSCl) (25.7mmol) was added dropwise at 0 ℃ to a solution of Ia (11.68mmol) and imidazole (77.1mmol) in N, N-Dimethylformamide (DMF) (25mL), which was dissolved, and then stirred at room temperature overnight. After completion of the reaction, ethyl acetate (100mL) was added, the organic phases were washed with saturated brine, and the combined organic phases were concentrated to give a crude product. The colorless oil IIa (4.1g, yield 78%) was then isolated by column chromatography, MS (ESI, m/z): 453[ M + H ]]+。
1H NMR (400 MHz, DMSO-d 6) δ 7.66-7.61 (m, 5H), 7.49-7.42 (m, 5H), 7.34 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.21 (d, J = 8.4 Hz, 1H), 3.49-3.45 (m, 1H), 1.25 (d, J = 7.2 Hz, 6H), 1.03 (s, 9H)。
Step b: under the protection of nitrogen, 2.5M n-butyl lithium n-hexane solution (4mL, 9.98mmol) is slowly dropped into Tetrahydrofuran (THF) (30mL) with IIa (4.1g, 9.07mmol) dissolved therein at-78 ℃, the obtained mixed solution is continuously stirred for 15 minutes at-78 ℃, then IIIa (2.18g, 9.07mmol) THF (10mL) solution is dropped into the mixed solution, and the stirring is continuously carried out for 6 hours at-78 ℃. After the reaction is finished, adding 1N hydrochloric acid at-78 ℃ to quench the reaction, adding ethyl acetate (50mL) and reactingThe organic phases were washed with saturated brine, combined and concentrated to give crude product. Then, IVa (3.1g, yield 56%) was obtained as a colorless oil by column chromatography, MS (ESI, m/z): 615[ M + H ]]+。
1H NMR (400 MHz, CDCl3) δ 7.71-7.68 (m, 4H), 7.43-7.28 (m, 11H), 6.62 (s, 2H), 6.46 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 6.19 (s, 1H), 5.02 (s, 2H), 4.16-4.10 (m, 1H), 3.59-3.54 (m, 1H), 2.49 (s, 6H), 1.27 (d, J = 7.2 Hz, 6H), 1.11 (s, 9H)。
Step c: an ethanol solution to which IVa (3.1g, 5.05mmol) and 10% palladium on carbon (620mg) were added was replaced with hydrogen gas and then stirred at room temperature overnight, after the reaction was completed, concentrated by filtration, and then isolated by column chromatography to give M1a (2.3g, yield 90%), MS (ESI, M/z): 509[ M + H]+
1H NMR (400 MHz, CDCl3) δ 7.70-7.67 (m, 4H), 7.40-7.32 (m, 6H), 6.95 (s, 1H), 6.50 (s, 2H), 6.25 (s, 2H), 4.55 (s, 1H), 3.82 (s, 2H), 3.56-3.49 (m, 1H), 2.14 (s, 6H), 1.25 (d, J = 6.8 Hz, 6H), 1.09 (s, 9H).
Synthesis example 2: synthesis of intermediate M2 a:
Figure DEST_PATH_IMAGE040
step d: va (332mg, 2mmol) and sodium hydroxide (80mg, 2mmol) are added into DMF (4mL) at 0 ℃, after stirring for one hour, VIa (350mg, 1.67mmol) are added, stirring is continued for 16 hours at room temperature, after the reaction is finished, ethyl acetate (10mL) is added, the organic phases are washed by saturated saline water, and the combined organic phases are concentrated to obtain a crude product. Then isolated by column chromatography to yield yellow solid VIIa (535mg, yield 90%), MS (ESI, m/z): 356[ M + H ]]+。
Step e: VIIa (535mg, 1.5mmol), iron powder (420mg, 7.5mmol) and ammonium chloride (642mg, 12mmol) are added into a mixed solution of ethanol (20mL) and water (10mL), stirred for 2 hours at 50 ℃ under the protection of nitrogen, and reacted to obtain a solutionAfter pooling, concentration was filtered, ethyl acetate (50mL) was added, the organic phases washed with saturated brine, the combined organic phases concentrated to give the crude product. Then, by column chromatography, M2a (463mg, yield 95%) was obtained as a pale yellow solid, MS (ESI, M/z): 326[ M + H]+。
Example 1: synthesis of Compound 1
Figure DEST_PATH_IMAGE042
The synthetic route is as follows:
Figure DEST_PATH_IMAGE044
step l: adding M1a (400mg, 0.79mmol) and bromoacetonitrile XII (189mg, 1.57mmol) into DMF (10mL), stirring, then adding potassium carbonate (543mg, 3.94mmol), stirring at 50 ℃ for 18 hours under the protection of nitrogen, adding ethyl acetate (80mL) after the reaction is finished, washing organic phases with saturated saline water, combining the organic phases, and concentrating to obtain a crude product. Then, XIIIa (210mg, 49% yield) was isolated by column chromatography as a pale yellow oil, MS (ESI, m/z): 565[ M + H2O]+。
Step m: adding XIIIa (210mg, 0.38mmol) and hydroxylamine hydrochloride (81mg, 1.15mmol) into ethanol (10mL), stirring, then adding triethylamine (116mg, 1.15mmol), stirring overnight at 100 ℃ under the protection of nitrogen, concentrating after the reaction is finished, adding ethyl acetate (20mL), washing organic phases with saturated saline solution, combining the organic phases, and concentrating to obtain a crude product. Then, XIVa (72mg, yield 32%) as a colorless oil was isolated by column chromatography, MS (ESI, m/z): 598[ M + H ]2O]+。
Step n: XIVa (72mg, 0.12mmol) and N, N' -disuccinimidyl carbonate (153.6mg, 0.6mmol) are added into THF (2mL) and stirred, then triethylamine (63mg, 0.6mmol) is added, stirring is carried out for 3 hours at 80 ℃ under the protection of nitrogen, ethyl acetate (10mL) is added after the reaction is finished, the organic phases are washed by saturated saline water, and the combined organic phases are concentrated to obtain a crude product. Then separating by column chromatography to obtain colorless oilForm XVa (27mg, yield 36%), MS (ESI, m/z): 624[ M + H2O]+。
Step o: XVa (27mg, 0.04mmol) was added to THF (2mL) and stirred, then 1.0M tetrabutylammonium fluoride in tetrahydrofuran (1mL) was added, stirred overnight at room temperature under nitrogen, after the reaction was complete ethyl acetate (10mL) was added, the organic phases were washed with saturated brine and combined and concentrated to give the crude product. Then, the white solid compound 1(5.4mg, yield 33%) was obtained by column chromatography
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (s, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.75 (s, 2H), 6.60 (d, J = 8.4 Hz, 1H), 6.50 – 6.40 (m, 1H), 5.09 (s, 2H), 3.80 (s, 2H), 3.13 – 3.09 (m, 1H), 2.17 (s, 6H), 1.08 (d, J = 6.8 Hz, 6H)。
Example 2: synthesis of Compound 2
Figure DEST_PATH_IMAGE046
Step g: m1a (508mg, 1mmol) and ethyl bromoacetate VIIIa (334mg, 2mmol) were added to DMF (10mL) and stirred, then cesium carbonate (1.63g, 5mmol) was added and stirred at room temperature for 2 hours under nitrogen, ethyl acetate (80mL) was added after the reaction was complete, the organic phases were washed with saturated brine and concentrated to give the crude product. Then, IXa was isolated by column chromatography as a colorless oil (576mg, 97% yield), MS (ESI, m/z): 612[ M + H ]2O]+。
Step h: adding IXa (576mg, 0.93mmol) into ethanol (4mL), stirring, then adding hydrazine hydrate (2mL), stirring at 100 ℃ for 6 hours under the protection of nitrogen, adding water (10mL) after the reaction is finished, quenching the reaction, concentrating to remove ethanol, then adding ethyl acetate (20mL) for extraction, washing organic phases with saturated saline solution, combining the organic phases, and concentrating to obtain a crude product. Then, white solid Xa (528.6mg, yield 98%) was obtained by column chromatography, MS (ESI, m/z): 581[ M + H]+。
Step i: xa (528.6mg, 0.91mmol)And N, N' -disuccinimidyl carbonate (1.16g, 4.54mmol) are added into THF (10mL) and stirred, then triethylamine (459mg, 4.54mmol) is added, stirring is carried out for 3 hours at 80 ℃ under the protection of nitrogen, ethyl acetate (50mL) is added after the reaction is finished, the organic phases are washed by saturated saline solution, and the combined organic phases are concentrated to obtain a crude product. Then, XIa (325mg, yield 59%) as a colorless oil was obtained by column chromatography, MS (ESI, m/z): 624[ M + H2O]+。
Step j: XIa (325mg, 0.53mmol) was added to THF (5mL) and stirred, then 1.0M tetrabutylammonium fluoride in tetrahydrofuran (13mL) was added, stirred overnight at room temperature under nitrogen, after the reaction was complete ethyl acetate (50mL) was added, the organic phases were washed with saturated brine and combined and concentrated to give the crude product. Compound 2 was then isolated by column chromatography as a yellow solid (37mg, yield 19%).
1H NMR (400 MHz, DMSO-d 6) δ 12.50 (s, 1H), 8.99 (s, 1H), 6.83 (s, 1H), 6.73 (s, 2H), 6.60 (d, J = 8.4 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H), 3.80 (s, 2H), 3.16 – 3.06 (m, 1H), 2.16 (s, 6H), 1.09 (d, J = 6.8 Hz, 6H)。
Example 3: synthesis of Compound 3
Figure DEST_PATH_IMAGE048
The synthetic route is as follows:
Figure DEST_PATH_IMAGE050
intermediate M1b was synthesized by substituting Ib for Ia of starting material Ia with reference to the synthesis of intermediate M1a, and then compound 3 was obtained as a pale yellow solid according to the synthesis of example 1 (45.8mg, yield 21%).
1H NMR (400 MHz, DMSO-d 6) δ 9.15 (s, 1H), 7.23 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 3H), 6.73 (s, 1H), 6.69 (s, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 4.79 (s, 2H), 3.78 (s, 2H), 3.75 (s, 2H), 2.12 (s, 6H)。
Example 4: synthesis of Compound 4
Figure DEST_PATH_IMAGE052
The synthetic route is as follows:
Figure DEST_PATH_IMAGE054
compound 4 (220mg, 63%) was obtained as a colorless oil according to the synthesis method of example 2.
1H NMR (400 MHz, DMSO-d 6) δ 12.51 (s, 1H), 9.16 (s, 1H), 7.27 – 7.19 (m, 2H), 7.15 (d, J = 7.6 Hz, 3H), 6.73 (s, 1H), 6.71 (s, 2H), 6.66 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H), 3.78 (s, 2H), 3.76 (s, 2H), 2.13 (s, 6H)。
Example 5: synthesis of Compound 5
Figure DEST_PATH_IMAGE056
XIVb was obtained according to the synthesis method of example 3, and then Compound 5 was synthesized by the following route.
Figure DEST_PATH_IMAGE058
Step n': XIVb (200mg, 0.32mmol), N' -thiocarbonyldiimidazole (0.38 mmol) and 1, 4-dioxane (2mL) were charged into a round-bottomed flask, followed by 1, 8-diazabicyclo [5.4.0] undec-7-ene (0.38 mmol), and the mixture was heated to 100 ℃ for 3 hours. The reaction was cooled to room temperature, diluted with water (5mL), adjusted to pH 3 with 1M aqueous hydrochloric acid, and extracted with ethyl acetate (4mL each 3 times). The organic phases were combined, washed with saturated brine, and the crude product was concentrated and subjected to silica gel column chromatography to give XVc (60 mg, yield 28%).
Step o: XVc (60 mg, 0.09mmol) was added to THF (2mL) and stirred, then a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.5mL) was added, stirred overnight at room temperature under nitrogen, after the reaction was complete ethyl acetate (10mL) was added, the organic phases were washed with saturated brine and combined and concentrated to give the crude product. Then, red solid compound 5(21.6mg, yield 56%) was obtained by column chromatography separation, LCMS: [ M + H ]]+ =433。
1H NMR (400 MHz, DMSO-d 6) δ 9.16 (s, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.13 (d, J = 7.6 Hz, 3H), 6.72 (s, 3H), 6.65 (d, J = 8.4 Hz, 1H), 6.56 – 6.50 (m, 1H), 5.09 (s, 2H), 3.76 (d, J = 2.8 Hz, 4H), 2.14 (s, 6H)。
Example 6: synthesis of Compound 6
Figure DEST_PATH_IMAGE060
The synthetic route is as follows:
Figure DEST_PATH_IMAGE062
synthesis of reference Compound 3 starting material IIIa was replaced with IIIb to give intermediate M1c, which was then continued to give Compound 6 as a white solid (58.9mg, 68% yield).
1H NMR (400 MHz, DMSO-d 6) δ 9.27 (s, 1H), 7.27 (s, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.18 – 7.13 (m, 3H), 6.86 (d, J = 2.4 Hz, 1H), 6.76 – 6.65 (m, 2H), 5.25 (s, 2H), 4.02 (s, 2H), 3.79 (s, 2H)。
Example 7: synthesis of Compound 7
Figure DEST_PATH_IMAGE064
The synthetic route is as follows:
Figure DEST_PATH_IMAGE066
compound 7 (34.3mg, yield 44%) was synthesized as a white solid according to the synthesis method of example 2 from intermediate M1 c.
1H NMR (400 MHz, DMSO-d 6) δ 7.26 – 7.21 (m, 4H), 7.18 – 7.13 (m, 3H), 6.85 (s, 1H), 6.75 – 6.65 (m, 2H), 5.09 (s, 2H), 4.01 (s, 2H), 3.79 (s, 2H)。
Example 8: synthesis of Compound 8
Figure DEST_PATH_IMAGE068
The synthetic route is as follows:
Figure DEST_PATH_IMAGE070
synthesis of intermediate M1d, substituting the starting material Ia for Ic with reference to the synthesis of intermediate M1a, followed by the synthesis of example 2 gave compound 8 as a pale yellow solid (13.1mg, yield 7%).
1H NMR (400 MHz, DMSO-d 6) δ 12.52 (s, 1H), 9.89 (s, 1H), 8.23 – 8.13 (m, 2H), 7.63 – 7.55 (m, 1H), 7.49 (t, J = 7.6 Hz, 1H), 6.81 (s, 2H), 6.64 (d, J = 7.6 Hz, 1H), 6.29 (d, J = 7.6 Hz, 1H), 5.03 (s, 2H), 4.19 (s, 2H), 2.09 (s, 6H)。
Example 9: synthesis of Compound 9
Figure DEST_PATH_IMAGE072
The synthetic route is as follows:
Figure DEST_PATH_IMAGE074
starting from intermediate M2a, yellow solid XVe (410mg, yield 97%) was obtained according to the synthesis method of example 1, which was added to dichloromethane (5mL) and stirred at-70 ℃, then 1.0M boron tribromide solution (2.4mL) was added, after the dropwise addition was completed, the temperature was slowly raised to room temperature and stirring was continued overnight, after the reaction was completed, methanol (5mL) was added at 0 ℃ to quench the reaction, and the reaction was concentrated to give a crude product. Then, the white solid compound 9(150mg, yield 38%) was obtained by column chromatography separation, LCMS: [ M + H ]]+ =410。
1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 6.81 (s, 2H), 6.66 – 6.62 (m, 2H), 6.62 – 6.58 (m, 1H), 6.28 – 6.23 (m, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.16 – 3.12 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H)。
Example 10: synthesis of Compound 10
Figure DEST_PATH_IMAGE076
The synthetic route is as follows:
Figure DEST_PATH_IMAGE078
the reaction was carried out by the synthetic route of intermediate M2a, substituting VIa for VIb as the starting material, to give intermediate M2b, and then compound 10(550mg, yield 66%) was obtained as a white solid according to the synthetic method of example 9.
1H NMR (400 MHz, DMSO-d 6) δ 8.98 (s, 1H), 6.98 (s, 2H), 6.66 – 6.60 (m, 2H), 6.56 (t, J = 6.0 Hz, 1H), 6.26 – 6.21 (m, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.15 – 3.10 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H)。
Example 11: synthesis of Compound 11
Figure DEST_PATH_IMAGE080
The synthetic route is as follows:
Figure DEST_PATH_IMAGE082
the reaction was carried out by the synthetic route of intermediate M2a, substituting VIa as the starting material for VIc, to give intermediate M2c, and then, according to the synthetic method of example 9, compound 11 was obtained as a white solid (40mg, yield 36%).
1H NMR (400 MHz, DMSO-d 6) δ 8.81 (s, 1H), 6.63 – 6.57 (m, 2H), 6.39 (s, 2H), 6.21 – 6.16 (m, 1H), 5.87 (t, J = 6.0 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 3.17 – 3.09 (m, 1H), 1.95 (s, 6H), 1.09 (d, J = 6.8 Hz, 6H)。
Example 12: synthesis of Compound 12
Figure DEST_PATH_IMAGE084
The synthetic route is as follows:
Figure DEST_PATH_IMAGE086
after substituting the starting material Va with Vb, the reaction was carried out according to the synthetic route for intermediate M2a to give intermediate M2d, and then compound 12 was obtained as a white solid (75mg, yield 58%) according to the synthetic method of example 9.
1H NMR (400 MHz, DMSO-d 6) δ 9.12 (s, 1H), 7.27 – 7.08 (m, 5H), 6.78 (s, 2H), 6.71 – 6.64 (m, J = 8.4 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 6.56 – 6.52 (m, 1H), 6.37 – 6.29 (m, 1H), 4.26 (d, J = 6.0 Hz, 2H), 3.79 (s, 2H)。
Example 13: synthesis of Compound 13
Figure DEST_PATH_IMAGE088
The synthetic route is as follows:
Figure DEST_PATH_IMAGE090
the starting material VIa was changed to VIb, and the reaction was carried out according to the synthetic route for intermediate M2d to give intermediate M2e, and then according to the synthetic method of example 9, white solid compound 13(51mg, yield 47%) was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 9.10 (s, 1H), 7.26 – 7.19 (m, 5H), 7.19 – 7.09 (m, 2H), 6.95 (s, 1H), 6.69 – 6.64 (m, 2H), 6.59 – 6.53 (m, 1H), 6.53 – 6.49 (m, 1H), 6.30 (d, J = 8.4 Hz, 1H), 4.28 – 4.22 (m, 2H), 3.79 (s, 2H)。
Example 14: synthesis of Compound 14
Figure DEST_PATH_IMAGE092
The synthetic route is as follows:
Figure DEST_PATH_IMAGE094
the starting material VIa was replaced with VIc, and the reaction was carried out according to the synthetic route for intermediate M2d to give intermediate M2f, and then compound 14 was obtained as a white solid (146mg, yield 67%) according to the synthetic method of example 9.
1H NMR (400 MHz, DMSO-d 6) δ 12.32 (s,1H), 8.96 (s, 1H), 7.26 – 7.19 (m, 2H), 7.17 – 7.06 (m, 3H), 6.64 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H), 6.35 (s, 1H), 6.27 (d, J = 6.8 Hz, 1H), 5.90 – 5.78 (m, 1H), 4.16 – 4.11 (m, 2H), 3.77 (s, 2H), 1.90 (s, 6H)。
Example 15: synthesis of Compound 15
Figure DEST_PATH_IMAGE096
The synthetic route is as follows:
Figure DEST_PATH_IMAGE098
after the intermediate M2g was obtained by a synthetic reaction in which the raw material Va was changed to Vc and the intermediate M2a was synthesized, compound 15(146mg, yield 67%) was obtained as a white solid according to the synthetic method of example 9.
1H NMR (400 MHz, DMSO-d 6) δ 9.24 (s, 1H), 7.34 – 7.11 (m, 4H), 6.81 (s, 2H), 6.72 (d, J = 8.8 Hz, 1H), 6.71 – 6.64 (m, 1H), 6.62 (d, J = 2.8 Hz, 1H), 6.39 (dd, J = 8.8, 3.2 Hz, 1H), 4.24 (d, J = 6.0 Hz, 2H), 3.82 (s, 2H).
Example 16: synthesis of Compound 16
Figure DEST_PATH_IMAGE100
The synthetic route is as follows:
Figure DEST_PATH_IMAGE102
the starting material Va was replaced with Vd, and the reaction was carried out according to the synthetic route for intermediate M2a to give intermediate M2h, which was then synthesized in accordance with the method of example 9 to give compound 16 as a white solid (13.4mg, yield 17%).
1H NMR (400 MHz, DMSO-d 6) δ 9.21 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.76 (s, 2H), 6.68 (d, J = 8.8 Hz, 1H), 6.60 – 6.51 (m, 2H), 6.37 – 6.29 (m, 1H), 4.12 (d, J = 5.6 Hz, 2H), 3.77 (s, 2H)。
Example 17: synthesis of Compound 17
Figure DEST_PATH_IMAGE104
The synthetic route is as follows:
Figure DEST_PATH_IMAGE106
after the reaction was carried out by replacing the raw material Va with Ve according to the synthetic route of the intermediate M2a to obtain an intermediate M2i, compound 17(7.4mg, yield 9%) was obtained as a white solid according to the synthetic method of example 9.
1H NMR (400 MHz, DMSO-d 6) δ 9.11 (s, 1H), 7.10 – 7.00 (m, 4H), 6.78 (s, 2H), 6.67 (d, J = 8.8 Hz, 1H), 6.60 (t, J = 6.0 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.34 – 6.25 (m, 1H), 4.15 (d, J = 6.0 Hz, 2H), 3.74 (s, 2H), 2.22 (s, 3H).
Pharmacological Activity test
Experimental example 1: method for detecting agonistic activity of compound on THR alpha/beta based on time-resolved fluorescence resonance energy transfer (THR-FRET)
1. Construction of THR alpha/beta overexpression vector
THR alpha/beta LBD domain (domain) sequences were found by consulting NCBI, pET21-His-GST-dLBT-THR alpha LBD and pET21-His-GST-dLBT-THR beta LBD overexpression vectors were constructed by the fusion (fusion) method, and sequencing confirmed the accuracy of the sequences.
2. Prokaryotic expression recombinant protein of escherichia coli
The correctly sequenced THR alpha LBD and THR beta LBD overexpression vectors were transferred into E.coli cells BL21(DE3), spread on agar plates with ampicillin resistance, picked up for amplification in LB medium and transferred to 1L LB at a ratio of 1:100 for mass culture. When the OD was 0.8-1.2, 0.5mM isopropyl-beta-D-thiogalactopyranoside (IPTG) was added and induction was carried out overnight at 18 ℃. Collecting bacteria, crushing, and purifying by GST column and molecular sieve to obtain His-GST-dLBT-THR alpha LBD and His-GST-dLBT-THR beta LBD proteins. The concentration of the protein measured by the raw Bradford protein quantification kit was 24. mu.M and 23. mu.M, respectively.
3. Compound preparation and reaction system preparation
The protein was removed from the-80 ℃ freezer, in which the protein with the GST-tagged THR α/β LBD domain and the Eu-labeled GST antibody were thawed slowly on ice, and a detection buffer containing Dithiothreitol (DTT) at a final concentration of 5mM was prepared.
3.1 preparation of Compounds
The starting concentration of compound was 100 μ M in DMSO, and the compound (100 μ M in DMSO) was diluted 3-fold with an equal gradient of DMSO to give 11 equal gradients, which were then further diluted 50-fold with assay containing 5mM DTT.
3.2 preparation of THR-FRET reaction System
The final concentrations of all components were calculated according to a system with a final volume of 20. mu.L per well, and 18. mu.L of protein, polypeptide and antibody reaction mixtures per well were prepared by adding GST-tagged THR α/β protein, SRC2 (LKEKHKILHRLLQDSSSPV) polypeptide, XL665(Cisobio, #610SAXLB), and Eu-labeled GST antibody to 18. mu.L of detection buffer containing 5mM DTT at final concentrations of 2nM, 200nM, 0.05nM, and 7.6nM, respectively.
mu.L of the reaction mixture and 2. mu.L of the diluted compound were added to the optiplate-384 well plate and reacted at room temperature for 24 hours.
3.3 reading plate
And (3) reading the plate by using an MD i3X multifunctional microplate reader, wherein the wavelengths of excitation light and emission light are 340nm and 665nm respectively. The light intensity of 616nm wavelength generated by exciting europium by using 340nm wavelength light of the MD i3X multifunctional microplate reader is used as a background, the activating degrees of THR alpha and THR beta of different compounds are different, the emitting light intensity of 665nm wavelength generated by exciting XL665 nm wavelength by using 616nm wavelength light is different, the intensity ratio of the two wavelengths (665 nm and 616 nm) is used as the activating activity of the compounds to the THR alpha or THR beta, the normalization treatment is carried out according to the ratio of a solvent DMSO group, the dose-reaction curve is fitted by using GraphPad Prism6.0 software according to four parameters, and the EC50 value is calculated.
4. Results
Experimental data show that the compound has stronger THR beta agonistic activity and certain THR alpha/beta selectivity. The specific data are shown in Table 1.
Figure DEST_PATH_IMAGE108
Experimental example 2: method for detecting THR alpha and THR beta agonistic activity of compound based on reporter gene activity detection
1. Method of producing a composite material
1.1 construction and preparation of plasmids pGAL4-FXR-LBD and pG5-Luc
pGAL4-THR alpha-LBD and pGAL4-THR beta-LBD plasmids used by the reporter gene detection system are constructed according to a conventional molecular cloning method. The method mainly comprises the following steps: inserting cDNA sequences of THR alpha (NM-003250) and THR beta (NM-000461) corresponding to the amino acid sequences of THR alpha (163-407AA) and THR beta (217-461AA) into BamHI and NotI enzyme cutting sites of a pGAL4 vector by utilizing a PCR technology to obtain pGAL4-THR alpha-LBD and pGAL4-THR beta-LBD plasmids; pG5-Luc (# E249A) and pRL-TK (# E2241) plasmids were purchased from Promega; by using CaCl2The plasmid was transformed into DH 5. alpha. E.coli, further cultured and amplified, and then purified with a plasmid extraction kit (TIANGEN, # D107) to obtain the corresponding plasmid DNA.
1.2 plasmid cotransfection of HEK293T cells and Compound treatment
HEK293T cells were transfected at 1X 10 the day before plasmid transfection4Density per well was seeded in 96-well plates. Cell transfection was performed according to the instructions for the transfection reagent FuGENE HD (Promega, # E2311). The method mainly comprises the following steps: in one well, for example, plasmids pGAL4-THR α -LBD or pGAL4-THR β -LBD, pG5-Luc and pRL-TK were added to 10uL of Opti-MEM I medium (Gibco, #11058021) at ratios of 20 ng, 50 ng and 5 ng and mixed; then 0.25uL of FuGENE HD is added, after being uniformly mixed, the mixture is kept stand for 5min at room temperature; this 10uL mixture was then added to the wells containing 100uL of medium. 6h after cell cotransfection, diluting the compound with dimethyl sulfoxide at 3 times gradient with 1uM as the highest concentration, adding 10 concentrations into cell culture solution for treatment for 24h, dividing into 2 multiple wells, and repeating three timesIodothyronine (T3) was a positive control.
1.3 Dual-Glo Luciferase assay
After 24h of compound treatment, the cells were tested according to the instructions of Dual-Glo Luciferase Assay System (Promega, # E2940). The method mainly comprises the following steps: discarding 50uL of culture solution in each hole, adding 50uL of Dual-Glo Luciferase reagent, and oscillating for 10min at room temperature; taking 80uL of the lysis reaction solution to a white opaque optiPlate-96 pore plate, and detecting the luminescence signal value (Firefly-Luc) of Firefly luciferase (Firefly luciferase) by using an MD i3x multifunctional microplate reader; then adding 40uL Dual-Glo Stop and Glo reagents, and oscillating for 10min at room temperature; the luminescence signal value (Renilla-Luc) of Renilla luciferase (Renilla luciferase) was detected using an MD i3x multi-functional microplate reader. EC50 values were calculated by fitting four parameters to a dose-response curve using GraphPad prism6.0 software, using the ratio of Firefly-Luc/Renilla-Luc as the compound's activation activity for THR and normalization to the ratio of the solvent DMSO groups.
2. Results
Experimental data show that the compound has stronger THR beta agonistic activity and certain THR alpha/beta selectivity. The specific data are shown in Table 2.
Figure DEST_PATH_IMAGE110

Claims (9)

1. A compound having the structure of formula (3) or a pharmaceutically acceptable salt thereof:
Figure DEST_PATH_IMAGE001
wherein,
R1selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, C1-6Alkyl, - (C)1-6Alkylene) -C6-10Aryl, said alkyl, aryl, alkylene being optionally substituted with one or more substituents independently selected from halogen, cyano, amino, nitroHydroxy, C1-6An alkyl group, a carboxyl group,
R3and R4Independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, C1-6An alkyl group, a carboxyl group,
ring A is selected from
Figure DEST_PATH_IMAGE003
、
Figure DEST_PATH_IMAGE005
Or
Figure DEST_PATH_IMAGE007
。
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
R1is selected from
Figure DEST_PATH_IMAGE009
、
Figure DEST_PATH_IMAGE011
、
Figure DEST_PATH_IMAGE013
、
Figure DEST_PATH_IMAGE015
、
Figure DEST_PATH_IMAGE017
、
Figure DEST_PATH_IMAGE019
Or
Figure DEST_PATH_IMAGE021
。
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof,
R3and R4Independently selected from Cl, Br or methyl.
4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the following compounds, or pharmaceutically acceptable salts thereof:
Figure DEST_PATH_IMAGE023
。
5. a pharmaceutical composition comprising a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 5, which is a thyroid hormone beta receptor agonist.
7. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by the thyroid hormone β receptor.
8. The use according to claim 7, wherein the disease is a metabolic disease.
9. The use according to claim 7, wherein the disease is selected from non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis or hypothyroidism.
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CN113474335A (en) * 2019-02-21 2021-10-01 南京瑞捷医药科技有限公司 Novel compounds and their use as thyroid hormone receptor agonists
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