阅读说明：本技术 Nlrp3炎症小体抑制剂及其制备方法和应用 (NLRP3 inflammasome inhibitor and preparation method and application thereof ) 是由 叶娜 郑龙太 镇学初 李婉婉 曹忠强 于 2019-04-29 设计创作，主要内容包括：本发明涉及一类含一个或多个取代基的1,2,3,5,6,7六氢对称引达省类化合物、其药剂学上可接受的盐、酯或水合物,其制备方法,包含该化合物的药物组合物及其作为新型NLRP3炎症小体抑制剂在制备预防和/或治疗与NLRP3炎症小体相关疾病的药物中的应用。(The invention relates to a 1,2,3,5,6,7 hexahydro symmetrical indacene compound containing one or more substituents, a pharmaceutically acceptable salt, ester or hydrate thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as a novel NLRP3 inflammation body inhibitor in preparing medicaments for preventing and/or treating diseases related to NLRP3 inflammation bodies.)

1. A1, 2,3,5,6,7 hexahydro-sym-indacene compound as shown in formula (1), and a pharmaceutically acceptable salt, ester or hydrate thereof:

wherein X is

Y is

n is any integer of 1-4; m is any integer of 0-4;

A. b and E are independently selected from hydrogen, C1-C8 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, halogen, C1-C8 haloalkyl, cyano, nitro, aryl, hydroxy, carboxy, C1-C8 alkoxy, alkoxyacyl, amino, amido, acyloxy, acyl, sulfonyl, sulfonamido, urea, thiourea or carbamoyl;

Or A and B, or A and E, taken together with the atoms to which they are attached, form a substituted or unsubstituted aliphatic, heterocyclic, aromatic, or heteroaromatic ring; substituents on the substituted aliphatic, heterocyclic, aromatic or heteroaromatic ring are selected from hydrogen, C1-C8 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, halogen, C1-C8 haloalkyl, cyano, nitro, aryl, hydroxyl, carboxyl, C1-C8 alkoxy, alkoxyacyl, amino, amido, acyloxy, acyl, sulfonyl, sulfonamido, urea, thiourea or carbamoyl;

represents a C4-C8 aliphatic ring, a C6-C10 aromatic ring, a 4-8 membered heterocyclic ring containing 1-3 atoms selected from N, O and S atoms, or a 5-8 membered heteroaromatic ring containing 1-3 atoms selected from N, O and S atoms.

2. The 1,2,3,5,6,7 hexahydro-symmetric indacene compound, a pharmaceutically acceptable salt, ester, or hydrate thereof according to claim 1, wherein: the pharmaceutically acceptable salt is a salt formed by a compound shown in a formula (1) and an inorganic acid or an organic acid, the pharmaceutically acceptable ester is an ester formed by the compound shown in the formula (1) and an acid or an alcohol, and the pharmaceutically acceptable hydrate is an aqueous compound formed by the compound shown in the formula (1) and water through a coordination bond or a covalent bond.

3. The 1,2,3,5,6,7 hexahydro-symmetric indacene compound, a pharmaceutically acceptable salt, ester, or hydrate thereof according to claim 1, wherein:

A. two of B and E are hydrogen and the other is selected from C1-C8 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, halogen, haloalkyl, cyano, nitro, aryl, hydroxy, carboxy, C1-C8 alkoxy, alkoxyacyl, amino, amido, acyloxy, acyl, sulfonyl, sulfonamido, urea, thiourea or carbamoyl;

4. The 1,2,3,5,6,7 hexahydro-symmetrical indacene compound, a pharmaceutically acceptable salt, ester, or hydrate thereof according to claim 3, wherein: y is

5. A process for the preparation of a 1,2,3,5,6,7 hexahydrosymmetrical indacene compound of formula (1) according to any one of claims 1 to 4,

when X is

reacting a compound shown in a formula (2) with a compound shown in a formula (3) in an organic solvent at 60-70 ℃ under the action of CDI and DBU, and obtaining a 1,2,3,5,6,7 hexahydro symmetrical indacene compound shown in a formula (4) after the reaction is completed:

When X is

reacting a compound shown as a formula (5) with a compound shown as a formula (3) in an organic solvent at 20-30 ℃ under the action of HOBt, EDCI and triethylamine, and obtaining a 1,2,3,5,6,7 hexahydro symmetric indacene compound shown as a formula (6) after the reaction is completed:

6. a pharmaceutical composition characterized by: comprising the 1,2,3,5,6,7 hexahydro-sym-indacene compound of any one of claims 1-4, a pharmaceutically acceptable salt, ester, or hydrate thereof.

7. An inhibitor of NLRP3 inflammasome, characterized by: comprising the 1,2,3,5,6,7 hexahydro-sym-indacene compound of any one of claims 1-4, a pharmaceutically acceptable salt, ester, or hydrate thereof.

8. Use of the 1,2,3,5,6,7 hexahydro-symmetric indacene compound of any one of claims 1-4, a pharmaceutically acceptable salt, ester or hydrate thereof as an NLRP3 inflammasome inhibitor for the manufacture of a medicament for the prevention and/or treatment of a disease associated with NLRP3 inflammasome.

9. Use according to claim 8, characterized in that: the diseases related to NLRP3 inflammatory bodies comprise congenital immune syndrome and adaptive immune syndrome.

10. Use according to claim 9, characterized in that: the adaptive immune syndrome comprises gout, type II diabetes, atherosclerosis or Alzheimer disease.

Technical Field

The invention relates to the field of pharmacology, and particularly relates to an NLRP3 inflammasome inhibitor and a preparation method and application thereof.

Background

The innate immunity is the first barrier of the body, has a clearing effect on foreign pathogens, and can guide the body to generate an effective adaptive immune response. The recognition and interaction of Pattern Recognition Receptors (PRRs) on the surface of innate immune cells with pathogen-associated molecular patterns (PAMPs) on the surface of pathogenic organisms is critical to the initiation of innate immunity. NLRs are important members of the cytoplasmic PRR family, are intracellular sensing molecules, and play unique functions in innate immunity. Among them, NLRP is the largest subfamily among NLPs, and has 14 family members in total, and a characteristic PYD effector domain.

The NLRP3 inflammasome is a multi-protein complex, consists of an innate immune receptor NLRP3, a street protein ASC and Caspase-1, and is the most studied inflammasome at present. NLRP3 inflammasome produces anti-inflammatory effects by priming and activating two phases. In the first priming phase, TLR ligands induce transcription of NF-kB mediated precursors of NLRP3 and IL-1 β precursors in the nucleus. The second phase is the activation phase, which requires second messengers such as ATP, nigericin, uric acid crystals, beta amyloid fibers, etc. to trigger pro-inflammatory reactions, activating the precursor of NLRP3, followed by oligomerization of the sensor protein. Then recruiting the adaptor protein ASC to combine with Caspase-1 precursor into an inflammasome, the assembly of which leads to the cleavage and activation of Caspase-1 precursor, on the one hand, the induction of the maturation and secretion of the proinflammatory factor IL-1 beta and on the other hand, the programmed cell death.

When the NLRP3 inflammasome has abnormal functions, it will initiate or promote the occurrence and development of a variety of human serious diseases. NLRP3 self-gene mutations are often associated with a series of inherited autoinflammatory diseases collectively referred to as cryopyrin-associated periodic syndrome (CAPS). The three common CAPS are Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal multisystem inflammatory disease (NO-MID) according to the severity of the disease from low to high. When NLRP3 is abnormally activated by various metabolites (including hyperglycemia, saturated fatty acids, cholesterol crystals, uric acid crystals, beta-amyloid, etc.), it may play an important role in the development of type 2 diabetes, atherosclerosis, gout, neurodegenerative diseases, multiple sclerosis, etc.

To date, although no NLRP3 inhibitor has entered clinical studies, a number of small molecules have been reported to effectively inhibit activation of NLRP3 inflammasome, such as MCC950, Parthenolide, BAY11-7082, INF39, CY-09, and the like.

Wherein MCC950 efficiently inhibits IL-1 beta release without blocking TNF-a, IC₅₀Is 7.5nM, has excellent pharmacokinetic property and is a powerful inhibitor of NLRP3 inflammasome which can be orally taken. At a plurality ofIn an in vivo mouse model of NLRP3 related diseases, such as multiple sclerosis, cold inflammatory related periodic syndrome, Parkinson's disease, Alzheimer's disease and the like, MCC950 shows remarkable activity and shows good development prospect.

However, the specific mechanism of action of MCC950 is not clarified in the existing literature report, and the existence of potential off-target effect of the substance is not clear. Although MCC950 has been reported to undergo oxidation reactions under the action of human liver microsomes in vitro to produce major metabolite I, based on the complex metabolic environment in the human body, it is speculated from the prior literature that furan ring and aminosulfonylurea linker fragments may be metabolized in vivo by CYP450 enzyme systems to produce active intermediates II and III, respectively (as shown in fig. 1). The intermediate II can perform 1, 2-addition or 1, 4-addition with key amino acid residues in vivo so as to form a conjugate with the biological macromolecule; isocyanate III may also form conjugates with biological macromolecules such as glutathione; and a series of metabolites are generated, so that the metabolism of drug molecules is inactivated, even the hepatotoxicity is caused, and potential safety hazards can be caused.

Disclosure of Invention

In order to solve the technical problems, the invention aims to provide an NLRP3 inflammation corpuscle inhibitor, a preparation method and application thereof, wherein the NLRP3 inflammation corpuscle inhibitor is a 1,2,3,5,6,7 hexahydro symmetrical indacene compound or a derivative thereof containing one or more substituents.

The first purpose of the invention is to provide a 1,2,3,5,6,7 hexahydro symmetrical indacene compound shown as a formula (1), and a pharmaceutically acceptable salt, ester or hydrate thereof:

wherein X is

Y is,

n is any integer of 1-4; m is any integer of 0-4; A. b and E are independently selected from hydrogen, C1-C8 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, halogen, C1-C8 haloalkyl, cyano, nitro, aryl, hydroxy, carboxy, C1-C8 alkoxy, alkoxyacyl, amino, amido, acyloxy, acyl, sulfonyl, sulfonamido, urea, thiourea or carbamoyl;

or A and B, or A and E, taken together with the atoms to which they are attached, form a substituted or unsubstituted aliphatic, heterocyclic, aromatic, or heteroaromatic ring; substituents on the substituted aliphatic, heterocyclic, aromatic or heteroaromatic ring are selected from hydrogen, C1-C8 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, halogen, C1-C8 haloalkyl, cyano, nitro, aryl, hydroxyl, carboxyl, C1-C8 alkoxy, alkoxyacyl, amino, amido, acyloxy, acyl, sulfonyl, sulfonamido, urea, thiourea or carbamoyl;

Represents a C4-C8 aliphatic ring, a C6-C10 aromatic ring, a 4-8 membered heteroaromatic ring containing 1-3 atoms selected from N, O and S atoms, or a 5-8 membered heteroaromatic ring containing 1-3 atoms selected from N, O and S atoms.

Further, the pharmaceutically acceptable salt is a salt formed by the compound shown in the formula (1) and an inorganic acid or an organic acid, the pharmaceutically acceptable ester is an ester formed by the compound shown in the formula (1) and an acid (carboxylic acid or inorganic oxygen acid) or an alcohol, and the pharmaceutically acceptable hydrate is an aqueous compound formed by the compound shown in the formula (1) and water through a coordination bond or a covalent bond.

Preferably, in formula (1), two of A, B and E are hydrogen, and the other is selected from C1-C8 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, halogen, haloalkyl, cyano, nitro, aryl, hydroxyl, carboxyl, C1-C8 alkoxy, alkoxyacyl, amino, amido, acyloxy, acyl, sulfonyl, sulfonamido, urea, thiourea or carbamoyl;

selected from the group consisting of C6-C10 aromatic rings, 4-8 membered heterocyclic rings containing 1-3 atoms selected from N, O and S, or 5-8 membered aromatic heterocyclic rings containing 1-3 atoms selected from N, O and S.

Preferably, in formula (1), Y is

m is an integer of 0 to 4, preferably m is 0 or 1.

More preferably, in formula (1), X is Y is

In the present invention, the halogen may be fluorine, chlorine, bromine or iodine;

the number and kind of halogens in the haloalkyl group are not limited, such as trifluoromethyl, difluoromethyl, monofluoromethyl or trifluoroethyl;

the alkenyl group can be ethylene, propylene, butylene, styrene or phenylpropylene;

the alkynyl can be acetylene, propine, butyne, phenylacetylene or phenylpropyne;

alkyl (R)₁) Alkoxy (R)₁O-), alkoxyacyl (R)₁OC (═ O) -), amide (R)₁C (═ O) N-), acyloxy (R)₁C (═ O) O-), acyl (R)₁C (═ O) -), sulfonyl (R)₁S(O)₂-), sulfonamido (R)₁S(O)₂NH-), carbamoyl (R)₁(R₂) NC (═ O) -), aminomonoyl (R)₁N(R₂) C (═ S) -), urea (R)₁N(R₂) C (═ O) NH —), thiourea (R)₁N(R₂) C (═ S) NH —), alkoxyacyl methyl (R)₁OC(＝O)CH₂-), alkylamino (R)₁NH-) and dialkylamino (R)₁(R₂) N-), R in the above groups₁Or R₂Specifically included are aliphatic alkyl groups and aromatic alkyl groups, wherein:

the aliphatic alkyl group is preferably a C1-C8 alkyl group, such as a straight-chain alkyl group, a branched-chain alkyl group, a spirocycloalkyl group, a bridged cycloalkyl group, an alkenylalkyl group, an alkynylalkyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an alkoxyalkyl group, an alkoxyacylalkyl group, a cycloalkylalkyl group, preferably, without limitation, including: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, allyl, propargyl, cyclobutenyl, or cyclohexenyl;

Aromatic alkyl groups include, but are not limited to: substituted or unsubstituted benzyl, phenethyl, phenylisopropyl, phenylpropyl, and the like;

aromatic rings include, without limitation: substituted or unsubstituted benzene ring, naphthalene ring, benzene ring, etc.;

aromatic heterocycles include, but are not limited to: substituted or unsubstituted aromatic and benzo heterocycles, including without limitation quinoline, isoquinoline, indole, benzofuran, furan, benzothiophene, thiophene, pyridine, pyrrole, and the like;

in addition, carbamoyl (R)₁(R₂) NC (═ O) -), aminomonoyl (R)₁N(R₂) C (═ S) -), urea (R)₁N(R₂) C (═ O) NH —), thiourea (R)₁N(R₂) C (═ S) NH-), dialkylamino (R)₁(R₂) In N-) R₁And R₂And may also form cyclic amines with the N atom to which they are attached, such as piperazine, piperidine, morpholine or tetrahydropyrrole;

more preferably, the structural formula of the 1,2,3,5,6,7 hexahydro-symmetric indacene compound of the present invention is as follows:

the second purpose of the invention is to provide a preparation method of the 1,2,3,5,6,7 hexahydro symmetrical indacene compound shown in the formula (1):

when X isThe preparation method of the 1,2,3,5,6,7 hexahydro-symmetric indacene compound shown in the formula (1) comprises the following steps:

reacting a compound shown in a formula (2) with a compound shown in a formula (3) in an organic solvent at 60-70 ℃ under the action of CDI and DBU, and obtaining a 1,2,3,5,6,7 hexahydro symmetrical indacene compound shown in a formula (4) after the reaction is completed:

When X isThe preparation method of the 1,2,3,5,6,7 hexahydro-symmetric indacene compound shown in the formula (1) comprises the following steps:

reacting a compound shown as a formula (5) with a compound shown as a formula (3) in an organic solvent at 20-30 ℃ under the action of HOBt, EDCI and triethylamine, and obtaining a 1,2,3,5,6,7 hexahydro symmetric indacene compound shown as a formula (6) after the reaction is completed:

further, the synthesis of the compounds of formula (2) can be carried out according to the references ASC.Med.chem.Lett.2016,7, 1034-1038 or Bioorganic & medicinal chemistry letters,13(5),837-840,2003, the reaction scheme being as follows:

further, the synthesis of the compounds represented by the general formula (5) can be carried out according to the references ASC.Med.chem.Lett.2016,7, 1034-Shi 1038, the reaction scheme is as follows:

unless otherwise specified, BuOH in the present invention is t-butanol, Et₃N is triethylamine, CDI is N, N-carbonyldiimidazole, DBU is 1, 8-diazabicycloundece-7-ene, HCl is hydrochloric acid, EA is ethyl acetate, DCM is dichloromethane, THF is tetrahydrofuran; BOC is di-tert-butyl dicarbonate, dioxan is 1, 4-dioxane, HOBt is 1-hydroxyphenyltriazole, EDCI is 1-ethyl- (3-dimethylaminopropyl) carbodiimides.

The third objective of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of the above-mentioned 1,2,3,5,6,7 hexahydro-sym-indacene compound, and a pharmaceutically acceptable salt, ester or hydrate thereof.

The fourth purpose of the invention is to disclose the application of the 1,2,3,5,6,7 hexahydro symmetric indacene compound, and the pharmaceutically acceptable salt, ester or hydrate thereof as the NLRP3 inflammation body inhibitor in the preparation of the drugs for preventing and/or treating the diseases related to the NLRP3 inflammation body.

Further, diseases associated with NLRP3 inflammasome include innate immune syndrome and adaptive immune syndrome.

Further, the adaptive immune syndrome includes gout, type ii diabetes, atherosclerosis, or alzheimer's disease.

By the scheme, the invention at least has the following advantages:

on the basis of keeping 1,2,3,5,6,7 hexahydro symmetric indacene amine on the left side of MCC950, the potential toxic metabolic sites are modified, particularly, a benzene ring containing a substituent group is introduced to replace a furan ring on the right side and other linkers are used for replacing amino sulfonylureas, so that a novel 1,2,3,5,6,7 hexahydro symmetric indacene derivative is provided to be used as an NLRP3 inflammasome inhibitor to prepare a medicament for preventing and/or treating NLRP3 related diseases.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.

Drawings

FIG. 1 is a schematic representation of the putative metabolites of MCC950 that are oxidized in vivo.

Detailed Description

The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

In the following examples of the present invention,¹H-NMR is measured by an Agilent 400MHz or 600MHz instrument; GCTPremier for MS^TM(CI) mass spectrometry measurements, EI source (70eV) except for indication; all solvents are redistilled before use, and the used anhydrous solvents are obtained by drying according to a standard method; all reactions were carried out under nitrogen protection and TLC tracking except for the indication, and the post-treatment was carried out by washing with saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate; purifying the product by using silica gel (200-300 meshes) column chromatography except the specification; wherein the silica gel (200-300 meshes) is produced by Qingdao ocean factory, and the GF254 thin-layer silica gel plate is produced by Yangtai Jianyou silica gel development company Limited.

In the following examples, the compounds correspond to the compounds mentioned above in the description.