CN116925087A - Diaryl tetraglycoluril carboxylate and application thereof - Google Patents

Diaryl tetraglycoluril carboxylate and application thereof Download PDF

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CN116925087A
CN116925087A CN202310881173.8A CN202310881173A CN116925087A CN 116925087 A CN116925087 A CN 116925087A CN 202310881173 A CN202310881173 A CN 202310881173A CN 116925087 A CN116925087 A CN 116925087A
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黎占亭
张丹维
周伟
吴岩
杨靖宇
刘月阳
王辉
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Fudan University
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Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention relates to diaryl tetraglycoluril carboxylate with a structure shown in a formula I and application thereof, in particular to a compound capable of rapidly antagonizing an imidazolium salt macrocyclic muscle relaxant, reducing neuromuscular blocking time and reducing requirements on medical conditions.

Description

Diaryl tetraglycoluril carboxylate and application thereof
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to diaryl tetraglycoluril carboxylate and application of the diaryl tetraglycoluril carboxylate in antagonizing neuromuscular blocking agents.
Background
Over four hundred million patients worldwide receive injections of neuromuscular blocking or relaxing agents (hereinafter referred to as muscle relaxants) during general anesthesia surgery to achieve skeletal muscle relaxation and secure intubation, providing safety assurance for surgery. Currently, non-depolarizing muscle relaxants such as ammonium steroid rocuronium bromide, vecuronium bromide, panturonium bromide and benzylisoquinoline cis-atracurium besilate occupy more than 95% of the share in clinical use. Among these, medium aged rocuronium bromide, vecuronium bromide and cisatracurium besylate again occupy more than 95% of the clinical share, with clinical maintenance muscle relaxation times typically within 50 minutes. But for longer procedures, either a time-shared re-or multiple injections, or continuous instillation of the muscle relaxant, are required. This increases the amount of medication, increasing the economic burden on the patient, especially for patients with surgery for up to several hours or more. On the other hand, re-time injection or continuous instillation of muscle relaxant requires more stringent clinical care and higher medical equipment safeguards to control the amount of administration and the level of muscle relaxation, and also requires more experienced and highly skilled anesthesiologists and nurses to determine reasonable injection times and injection metering, thus resulting in higher clinical surgical requirements and costs.
Li and the like recently disclose an imidazolium salt macrocyclic long-acting muscle relaxant with the characteristic of non-depolarizing muscle relaxant, and one injection can realize rapid onset and deep muscle relaxation lasting for a plurality of hours for rats. The imidazolium salt macrocyclic muscle relaxant can theoretically realize deep muscle relaxation for adults for more than 10 hours by comparing and calculating with the effective muscle relaxation time of rocuronium bromide, and can cover more than 98% of clinical operations. The scheme has the advantages of simpler administration for long-time operation, ensuring more stable muscle relaxation state during the operation, improving operation vision and operation conditions, reducing postoperative pain and complications and the like. However, if there is no specific antagonist capable of being rapidly reversed clinically, the residual probability of the myorelaxant is high, spontaneous breathing cannot be timely recovered after the operation, and various respiratory complications such as postoperative upper airway obstruction, postoperative pulmonary complications, hypoxia and hypercapnia are easily caused.
Therefore, aiming at the novel imidazolium salt macrocyclic long-acting deep muscle relaxant, it is necessary to develop a class of antagonists capable of specifically, rapidly and fully eliminating the residual muscle relaxation.
In summary, there is a great need in the art for an antagonist that satisfies a variety of muscle relaxants in order to satisfy the antagonism of clinical neuromuscular blocking.
Disclosure of Invention
It is an object of the present invention to provide a diaryl tetraglycoluril carboxylate compound.
It is another object of the present invention to provide the use of diaryl tetraglycoluril carboxylate compounds for the rapid antagonism of imidazolium salt macrocyclic muscle relaxants.
In a first aspect of the present invention there is provided a compound of formula I, or a pharmaceutically acceptable salt, crystalline form, hydrate or solvate thereof,
in the method, in the process of the invention,
each R is 1 Each independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or two adjacent R 1 Together with the carbon atoms to which they are attached form a substituted or unsubstituted C3-C20 carbocyclic ring or a 3-20 membered carbocyclic ring;
each R is 2 Each independently selected from substituted or unsubstituted C1-C20 alkylene, substituted or unsubstituted C1-C20 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S;
each R is 3 Each independently selected from H, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 heteroalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl, or two adjacent R' S 3 Together with the carbon atoms to which they are attached form a substituted or unsubstituted group selected from the group consisting of: C3-C A 20-carbon ring, a 3-20 membered carbon heterocycle, a C5-C20 aromatic ring, a 5-20 membered heteroaromatic ring;
each M is independently selected from the group consisting of: na (Na) + 、K + 、Li + 、Mg 2+ 、Ca 2+ 、NH 4 + Or an ammonium salt substituted with one or more groups each independently selected from C1-4 alkyl or C6-10 aryl;
unless otherwise indicated, the substitution means that a hydrogen on a group is substituted with one or more groups selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
In a further preferred embodiment of the present invention,
each R is 1 Each independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, or two adjacent R 1 Together with the carbon atoms to which they are attached form a substituted or unsubstituted C3-C10 carbocyclic ring or a 3-10 membered carbocyclic ring;
each R is 2 Each independently selected from substituted or unsubstituted C2-C10 alkylene, substituted or unsubstituted C1-C10 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S;
each R is 3 Each independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, or two adjacent R' S 3 Together with the carbon atoms to which they are attached form a substituted or unsubstituted group selected from the group consisting of: a C3-C10 carbocyclic ring, a 3-10 membered carbocyclic ring, a C5-C10 aromatic ring, a 5-10 membered heteroaromatic ring;
each M is independently selected from the group consisting of: na (Na) + 、K + 、Li + 、Mg 2+ 、Ca 2+ 、NH 4 + Or an ammonium salt substituted with one or more groups each independently selected from C1-4 alkyl or C6-10 aryl;
wherein, the substitution means that hydrogen on the group is substituted by one or more groups selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
In another preferred embodiment, each R 2 Each independently selected from substituted or unsubstituted C3-C20 alkylene, substituted or unsubstituted C3-C20 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S.
In another preferred embodiment, each R 2 Each independently selected from substituted or unsubstituted C3-C10 alkylene, substituted or unsubstituted C3-C10 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S.
In another preferred embodiment, each R 2 Each independently selected from substituted or unsubstituted C3-C6 alkylene, substituted or unsubstituted C3-C6 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S.
In a further preferred embodiment of the present invention,
each R is 1 Each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or two adjacent R 1 Together with the carbon atoms to which they are attached form a substituted or unsubstituted C3-C7 carbocyclic ring or a 3-7 membered carbocyclic ring;
each R is 2 Each independently selected from substituted or unsubstituted C3-C6 alkylene, substituted or unsubstituted C1-C6 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S;
each R is 3 Each independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclyl, or two adjacent R' S 3 Together with the carbon atoms to which they are attached form a substituted or unsubstituted group selected from the group consisting of: a C3-C7 carbocyclic ring, a 3-7 membered carbocyclic ring, a C5-C8 aromatic ring, a 5-8 membered heteroaromatic ring;
each M is independently selected from the group consisting of: na (Na) + 、K + 、Li + 、Mg 2+ 、Ca 2+ 、NH 4 + Or an ammonium salt substituted with one or more groups each independently selected from C1-4 alkyl or C6-8 aryl;
wherein, the substitution means that hydrogen on the group is substituted by one or more groups selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
In another preferred embodiment, each R 1 Each independently selected from substituted or unsubstituted C1-C4 alkyl; each R is 2 Each independently is- (CH) 2 ) n -, wherein n is 2,3 or 4; wherein, the substitution means that hydrogen on the group is substituted by one or more groups selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
In a further preferred embodiment of the present invention,wherein G is H, or one or more groups selected from the group consisting of: halogen, amino, C1-C6 alkyl or C1-C6 alkoxy.
In another preferred embodiment, each R 1 Each independently selected from substituted or unsubstituted C1-C6 alkyl; preferably methyl.
In another preferred embodiment, each R 2 Each independently selected from substituted or unsubstituted C1-C6 alkylene.
In another preferred embodiment, each R 2 Each independently is propylene.
In another preferred embodiment, each R 3 Each independently selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, or both Adjacent R 3 Together with the carbon atoms to which they are attached form a substituted or unsubstituted group selected from the group consisting of: benzene ring, naphthalene ring, cyclohexane.
In another preferred embodiment, each M is independently Na + 。
In another preferred embodiment, the compound is selected from the group consisting of:
in a second aspect of the invention there is provided the use of a compound according to the first aspect of the invention as an antagonist of a neuromuscular blocker.
In another preferred embodiment, the neuromuscular blocking agent is a non-depolarizing muscle relaxant.
In another preferred embodiment, the neuromuscular blocking agent is selected from the group consisting of: imidazolium salt macrocyclic compounds.
In another preferred embodiment, the neuromuscular blocking agent is selected from the group consisting of: cis-atracurium, rocuronium bromide, imidazolium macrocyclic compounds, or combinations thereof.
In another preferred embodiment, the neuromuscular blocking agent is an imidazolium salt macrocyclic compound having the structure shown in formula A,
in the method, in the process of the invention,
each R is 1 Each independently selected from the group consisting of: H. d, substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 Cycloalkyl radicalsA substituted or unsubstituted 3-20 membered heterocyclic group containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;
each R is 2 Each independently selected from the group consisting of: H. substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R 2 Together with the carbon atoms to which they are attached form a group selected from the group consisting of: substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-20 membered heteroaryl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;
Each Y and Z is independently selected from the group consisting of: unsubstituted or substituted C 1-20 Alkylene, substituted or unsubstituted C containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur 1-20 Alkylene, substituted or unsubstituted C 3-20 Cycloalkylene, substituted or unsubstituted C 5-20 Arylene, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-20 membered heteroarylene;
l is selected from the group consisting of: no, O, NH, C 1-10 Alkylene, S, phenylene;
ar1, ar2 are each independently none, C 6-10 Arylene or 5-8 membered heteroarylene;
x is a pharmaceutically acceptable anion which is trimmed with the 4-valent cationic imidazolium salt macrocycle in the structure of formula A;
unless otherwise specified, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: halogen, nitro, amino, cyano, hydroxyRadicals, amide radicals, trifluoromethyl radicals, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
In another preferred embodiment, the 4-valent cationic imidazolium salt macrocycle in the imidazolium salt macrocycle of the structure shown in formula a is selected from the group consisting of:
wherein X is one or more anions which are macrocyclic trim with a 4-valent cationic imidazolium salt, each of said anions being independently selected from the group consisting of: cl - 、Br - 、I - 、SO 4 2- 、HSO 4 - 、PO 4 3- 、HOPO 3 2- 、(HO) 2 PO 2 - 、R’CO 2 - 、 - O 2 C(CH 2 ) n CO 2 - (n＝0-20)、ArCO 2 - 、R’SO 3 - 、ArSO 3 - 、R’PO 3 - 、ArPO 3 - Alginate, citrate, aspartate, camphorate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurate, 2-hydroxyethylsulfonate, lactate, maleate, nicotinate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, tartrate; wherein R' is a substituted or unsubstituted C 1-10 Alkyl, ar is substituted or unsubstituted C 5-7 Aryl or substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S;
wherein, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterogeniesCyclic group, C 1-6 An alkoxycarbonyl group.
In another preferred embodiment, the compound is selected from the group consisting of:
wherein X is an anion which is coordinated with the macrocyclic ring of the 4-valent cationic imidazolium salt, said anion being selected from the group consisting of: cl - 、Br - 、I - 、SO 4 2- 、HSO 4 - 、PO 4 3- 、HOPO 3 2- 、(HO) 2 PO 2 - 、R’CO 2 - 、 - O 2 C(CH 2 ) n CO 2 - (n＝0-20)、ArCO 2 - 、R’SO 3 - 、ArSO 3 - 、R’PO 3 - 、ArPO 3 - Alginate, citrate, aspartate, camphorate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurate, 2-hydroxyethylsulfonate, lactate, maleate, nicotinate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, tartrate; wherein R' is a substituted or unsubstituted C 1-10 Alkyl, ar is substituted or unsubstituted C 5-7 Aryl or substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S.
In a third aspect of the present invention, there is provided a process for the preparation of a compound according to the first aspect of the present invention, comprising the steps of:
(a) Reacting a compound of formula a with a compound of formula b in the presence of a base to obtain a compound of formula c;
(b) Demethylating the compound of formula c to obtain a compound of formula d;
(c) Reacting a compound of formula d with a glycoluril tetramer of a compound of formula e in the presence of TFA, and then adding hydroxide MOH for hydrolysis to obtain the compound shown in the formula I;
wherein each R 1 、R 2 、R 3 M are each as described in the first aspect of the invention.
In another preferred embodiment, the hydroxide MOH is selected from the group consisting of: naOH, KOH, liOH Ca (OH) 2 ，Mg(OH) 2 Ammonia, or a combination thereof.
In another preferred embodiment, in step (a), the base is potassium carbonate, sodium carbonate, naOH, KOH, liOH, or a combination thereof.
In a fourth aspect of the invention, there is provided a pharmaceutical composition or formulation comprising:
(a) The diarylhydrotetraglycoluril tetracarboxylic acid salt compound according to the first aspect of the present invention as an active ingredient, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof;
(b) Pharmaceutically acceptable carriers or excipients.
In another preferred embodiment, the carrier is water for injection, physiological saline or aqueous dextrose solution.
In another preferred embodiment, the composition or formulation is in the form of an oral or injectable dosage form.
In a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising
(a) The diarylhydrotetraglycoluril tetracarboxylic acid salt compound according to the first aspect of the present invention as a first active ingredient, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof;
(b) An imidazolium salt macrocyclic compound neuromuscular blocking agent represented by formula a as a second active ingredient;
wherein R is 1 、R 2 Y, X, Z are defined as described above; and
(c) Pharmaceutically acceptable carriers or excipients.
In a sixth aspect of the invention, there is provided a kit comprising
(1) The active ingredient is the diarylhydrotetraglycoluril tetracarboxylic acid salt compound according to the first aspect of the invention, or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof; or the pharmaceutical composition of the fourth aspect;
(2) An imidazolium salt macrocyclic compound neuromuscular blocking agent represented by formula a;
wherein R is 1 、R 2 Y, X, Z are as defined above;
And/or (3) optional instructions.
In another preferred embodiment, the instructions are for the manner of ingestion and dosage.
In a seventh aspect of the invention, there is provided a method of antagonizing neuromuscular blockade comprising:
administering to a subject in need thereof a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, to antagonize neuromuscular blockade and rapidly restore muscle physiological function.
In another preferred embodiment, the subject is a mammal, preferably a rodent or primate, more preferably a mouse, rat or human.
In another preferred embodiment, the method is non-diagnostic, non-therapeutic in vitro.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventors have conducted extensive and intensive studies to provide, for the first time, a diaryl tetraglycoluril carboxylate compound which is useful for antagonizing the rapid onset of the neuromuscular blocker imidazolium salt macrocycle. The compound provided by the invention has a rapid antagonism effect on the long-acting myorelaxant and the quick-acting imidazolium salt compound, can obviously reduce the complexity and technical difficulty of the implementation process of the anesthetizing myorelaxant in clinical operation, reduces the requirements on anesthetizing personnel and detection instruments, and is beneficial to reducing the cost. Based on this, the inventors completed the present invention.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
The minimum and maximum number of carbon atoms in the hydrocarbon group are represented by a prefix, e.g., prefix C m -C n Alkyl means any alkyl group containing from "m" to "n" carbon atoms. Thus, for example, C1-C3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms.
As used herein, "C 1-20 Alkyl "means a straight or branched chain alkyl- (CH) comprising 1 to 20 carbon atoms 2 ) n-1 CH 3 (n=1 to 20), such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., or the like.
As used herein, "1-20 membered heteroalkyl" refers to C 1-20 A group in which one or more carbon atoms in the alkyl chain are replaced by heteroatoms selected from nitrogen, oxygen and sulfur, e.g., 1-8 membered heteroalkyl means CH 3 -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -, or CH 3 -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -O-and the like.
As used herein, "2-20 membered heteroalkenyl" refers to a group in which one or more carbon atoms in the alkenyl chain of C2-20 are replaced with heteroatoms selected from nitrogen, oxygen and sulfur, e.g., 2-7 membered heteroalkenyl refers to CH 3 -CH 2 -CH 2 -O-CH 2 -ch=ch-, or CH 3 -S-CH 2 -CH 2 -O-ch=ch-and the like.
As used herein, "2-20 membered heteroalkynyl" refers to a group in which one or more carbon atoms in the alkynyl chain of C2-20 are replaced with heteroatoms selected from nitrogen, oxygen and sulfur, e.g., 2-7 membered heteroalkynyl refers to CH 3 -CH 2 -CH 2 -O-CH 2 -C.ident.C-, or CH 3 -S-CH 2 -CH 2 -O-C≡C-and the like.
As used herein, "C 3-20 Cycloalkyl "means cycloalkyl containing 3 to 20 carbon atoms or cycloalkyl having a side chain, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
As used herein, the term "active ingredient" refers to a diaryl tetraglyurea carboxylate compound represented by formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. It is understood that the active ingredient also includes mixtures of such compounds.
As used herein, the term "hydrate" refers to a complex of a compound of the present invention coordinated to water.
As used herein, the term "solvate" refers to a compound of the invention that coordinates to a solvent molecule to form a complex in a specific ratio.
As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6-14) carbon atoms having a single ring (e.g., phenyl) or a fused ring (e.g., naphthyl or anthracenyl) that may be non-aromatic (e.g., 2-benzoxazolone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, etc.) if the point of attachment is on an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 12 (preferably 3 to 10) carbon atoms, having a single ring or multiple rings (including fused systems, bridged ring systems and spiro ring systems). In a fused ring system, one or more of the rings may be cycloalkyl, heterocyclic, aryl or heteroaryl, provided that the attachment site is a ring through the cycloalkyl. Examples of suitable cycloalkyl groups include: for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.
As used herein, the term "heteroaryl" refers to an aromatic group having 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring, such heteroaryl groups may be monocyclic (e.g., pyridyl or furyl) or fused rings (e.g., indolizinyl or benzothienyl), wherein the fused rings may be non-aromatic and/or contain one heteroatom, so long as the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the ring atoms nitrogen and/or sulfur of the heteroaryl group are optionally oxidized to an N-oxide (N-O), sulfinyl or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furyl. In one embodiment, heteroaryl refers to a 3-14 membered heteroaryl, preferably a 5-12 membered heteroaryl.
As used herein, the term "substituted heteroaryl" refers to heteroaryl substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.
Animal activity tests and acute toxicity tests in the present invention related tests were performed using SD rats.
As used herein, unless specifically indicated, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
As used herein, the term "effective amount" or "effective dose" refers to an amount that is functional or active in and acceptable to a human and/or animal.
Neuromuscular blocking or muscle relaxing agents
Neuromuscular blocking or muscle relaxant (abbreviated as muscle relaxant) is widely used in clinical practice to relax skeletal muscle, thereby facilitating intubation or improving surgical conditions. Muscle relaxants are classified into depolarizing and non-depolarizing types according to the mechanism of action: the depolarization type muscle relaxant is combined with N2 choline receptor on the motor nerve endplate membrane, so that the response of muscle cells to acetylcholine is weakened or eliminated; non-depolarizing muscle relaxants compete with acetylcholine for N2 choline receptors on the skeletal muscle motor endplate membranes, resulting in skeletal muscle relaxation. More non-depolarizing muscle relaxants used clinically are classified into amino steroid derivatives (such as rocuronium bromide, vecuronium bromide, panturonium bromide and the like) and benzyl isoquinoline derivatives (such as cisatracurium besylate) according to different chemical structures.
In particular, the compounds of formula I provided by the invention are capable of specifically antagonizing macrocyclic compounds of formula A containing four imidazolium groups, or pharmaceutically acceptable salts, hydrates or solvates thereof.
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In the method, in the process of the invention,
each R is 1 Each independently selected from the group consisting of: H. d, substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;
each R is 2 Each independently selected from the group consisting of: H. substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R 2 Together with the carbon atoms to which they are attached form a group selected from the group consisting of: substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-20 membered heteroaryl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;
each Y and Z is independently selected from the group consisting of: unsubstituted or substituted C 1-20 Alkylene, substituted or unsubstituted C containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur 1-20 Alkylene, substituted or unsubstituted C 3-20 Cycloalkylene, substituted or unsubstituted C 5-20 Arylene, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-20 membered heteroarylene;
l is selected from the group consisting of: no, O, NH, C 1-10 Alkylene, S, phenylene;
ar1, ar2 are each independently none, C 6-10 Arylene or 5-8 membered heteroarylene;
x is a pharmaceutically acceptable anion which is trimmed with the 4-valent cationic imidazolium salt macrocycle in the structure of formula A;
Unless otherwise specified, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
In another preferred embodiment, each R 1 Each independently selected from the group consisting of: H. d, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted 2-6 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 2-6 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;
each R is 2 Each independently selected from the group consisting of: each R is 2 Each independently selected from the group consisting of: H. substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted 2-6 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 2-6 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R 2 Together with the carbon atoms to which they are attached form a group selected from the group consisting of: substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 3-7 membered heterocyclyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-7 membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;
each Y and Z is independently selected from the group consisting of: unsubstituted or substituted C 1-10 Alkylene, substituted or unsubstituted 1-10 membered alkylene containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-10 Cycloalkylene, substituted or unsubstituted C 5-10 Arylene, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-10 membered heteroaryl；
L is selected from the group consisting of: none, O, S, NH, C 1-6 An alkylene group, a phenylene group;
ar1, ar2 are each independently absent, phenylene or five membered heteroarylene;
unless otherwise specified, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
In another preferred embodiment, each R 1 Each independently selected from the group consisting of: H. d, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 3-7 Cycloalkyl;
each R is 2 Each independently selected from the group consisting of: H. substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 1-6 membered heteroalkyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R 2 Together with the carbon atoms to which they are attached form a group selected from the group consisting of: substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted phenyl;
each Y and Z is independently an unsubstituted, substituted or unsubstituted C 1-7 Alkylene, substituted or unsubstituted 1-7 membered alkylene containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-7 Cycloalkylene, substituted or unsubstituted phenyl, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-8 membered heteroaryl;
l is selected from the group consisting of: none, O, S, NH, C 1-6 An alkylene group, a phenylene group;
Ar1, ar2 are each independently absent, phenylene or five membered heteroarylene;
the substitution means that one or more hydrogens on the group are selected from the group consisting ofGroup substitution of the following groups: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
In a further preferred embodiment of the present invention,selected from->Wherein n=1, 2; g is H, or one or more groups selected from the group consisting of: c (C) 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 An alkoxycarbonyl group.
In another preferred embodiment, each Y and Z is independently an absent, or substituted or unsubstituted group selected from the group consisting of: wherein, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: c (C) 1-6 Alkyl, halogen, C 1-6 Alkoxycarbonyl or amido.
In another preferred embodiment, each R2 is independently hydrogen, or two adjacent R2's together with the carbon atom to which they are attached form a substituted or unsubstituted benzene ring, a cyclopentyl group, or a cyclohexenyl group.
In another preferred embodiment, the compound of formula a consists of a 4-valent cationic imidazolium salt macrocycle and an anion X that is complementary to the 4-valent cationic imidazolium salt macrocycle; wherein X is one or more anions selected from the group consisting of: cl - 、Br - 、I - 、SO 4 2- 、HSO 4 - 、PO 4 3- 、HOPO 3 2- 、(HO) 2 PO 2 - 、R’CO 2 - 、 - O 2 C(CH 2 ) n CO 2 - (n＝0-20)、ArCO 2 - 、R’SO 3 - 、ArSO 3 - 、R’PO 3 - 、ArPO 3 - Alginate, citrate, aspartate, camphorate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurate, 2-hydroxyethylsulfonate, lactate, maleate, nicotinate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, tartrate; wherein R' is a substituted or unsubstituted C 1-10 Alkyl, ar is substituted or unsubstituted C 5-7 Aryl or substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S; wherein, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group. X represents the total of the valence states of the anions to be 4, so as to carry out macrocyclic balancing with the 4-valence cationic imidazolium salt, wherein the anions represented by X can be 4 monovalent anions, 2 divalent anions, 1 divalent anion and 2 monovalent anions; or one 1-valent anion and 1 trivalent anion; wherein, the monovalent anions in the 4 monovalent anions can be the same or different, and the divalent anions in the 2 divalent anions can be the same or different.
In another preferred embodiment, the compound of formula a is selected from the group consisting of:
nervomuscular blocker antagonists-diaryl tetraglycoluril carboxylate compounds of formula I
The invention provides a diaryl tetraglycoluril carboxylate compound with a structure shown in a formula I;
wherein each group is as defined in the first aspect of the invention.
The invention discloses application of diaryl tetraglycoluril carboxylate compounds in rapidly and fully antagonizing neuromuscular blocking activity generated by the imidazolium salt macrocyclic compound. The diaryl tetraglycoluril carboxylate antagonist disclosed by the invention and the published imidazolium salt macrocyclic long-acting muscle relaxant form partner medicaments, so that the quick acting and long-acting muscle relaxation of the imidazolium salt muscle relaxant can be realized by one-time injection in theory, the clinical application of quick recovery of the tetraglycoluril carboxylate antagonist after the operation is finished can be realized, and the operation safety can be improved. The quick antagonism of the diaryl tetraglycoluril carboxylate antagonist improves the drug property of the imidazole onium salt macrocyclic compound as a long-acting muscle relaxant, can obviously reduce the complexity and technical difficulty of the implementation process of anesthesia muscle relaxation in clinical operation, reduce the requirements on related medical detection instruments, reduce the requirements on the experience and professional ability of anesthesia and nursing staff, can obviously improve the degree of flow of the muscle relaxation and antagonism treatment in the anesthesia operation, is beneficial to reducing the comprehensive cost of the muscle relaxation and antagonism treatment, and realizes the clinical demands which cannot be realized at present and are not met.
In a preferred embodiment, the compounds of formula I according to the invention can also be used in combination with clinically useful neuromuscular blocking agents, for example neostigmine, sodium sulmore gluconate.
Preparation method
The process for preparing the compound of the formula (I) according to the present invention is described in more detail below, but these specific processes do not limit the present invention in any way. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily carried out by one of ordinary skill in the art to which the present invention pertains.
Specifically, the compounds of formula I of the present invention are prepared by the steps shown below:
(a) Reacting a compound of formula a with a compound of formula b in the presence of a base to obtain a compound of formula c;
(b) Demethylating the compound of formula c to obtain a compound of formula d;
(c) Reacting a compound of formula d with a glycoluril tetramer of formula e in the presence of TFA, and then adding hydroxide MOH for hydrolysis to obtain a compound of formula I according to the first aspect of the invention;
wherein each of R1, R2, R3, M is as described in the first aspect of the invention.
In a preferred embodiment, the hydroxide MOH is selected from the group consisting of: naOH, KOH, liOH Ca (OH) 2 ，Mg(OH) 2 Ammonia, or a combination thereof.
In a preferred embodiment, in step (a), the base is potassium carbonate, sodium carbonate, naOH, KOH, liOH, or a combination thereof.
Pharmaceutical composition
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet or injection.
The "active ingredient" refers to the compound of the general formula I or pharmaceutically acceptable salt, hydrate or solvate thereof.
As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts may be prepared in situ at the final isolation and purification of the compounds of formula I or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group, respectively. Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethane sulfonate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoate, caproate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphtyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. In addition, the basic nitrogen-containing groups may be quaternized with the following agents: alkyl halides, such as methyl, ethyl, propyl, butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, and the like. Thus obtaining a water-soluble or oil-soluble or dispersible product. Examples of acids that may be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid. The base addition salts may be prepared in situ upon final isolation and purification of the compounds of formula I, or by reacting the carboxylic acid moiety with a suitable base (e.g. a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate) or ammonia, or an organic primary, secondary or tertiary amine, respectively. Pharmaceutically acceptable salts include, but are not limited to, alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful in forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
Suitable pharmaceutically acceptable carriers or excipients include: such as treatments and drug delivery modifiers and accelerators, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, low melting waxes, ion exchange resins and the like, and combinations of any two or more thereof. The liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including petroleum, animal, vegetable or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, mack pub.co., new jersey (1991), incorporated herein by reference.
The pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antineoplastic agents).
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
Compared with the prior art, the invention has the main advantages that:
(1) The diaryl tetraglycoluril carboxylate compound shown in the formula I can rapidly antagonize the non-depolarizing neuromuscular blocker imidazolium salt macrocyclic compound.
(2) The diaryl tetraglycoluril carboxylate compound shown in the formula I can also rapidly antagonize the non-depolarizing neuromuscular blocker cis-atracurium which is clinically used.
(3) The diaryl tetraglycoluril carboxylate compound shown in the formula I has good biocompatibility.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Example 1:
the preparation of compound I-1 was carried out by the following synthetic route:
the specific operation is as follows: compound 1c: 1, 4-Naphthol 1a (2.4 g,15 mmol), methyl 4-bromobutyrate 1b (5.43 g,30 mmol) and K 2 CO 3 (5.43 g,30 mmol) to 50mL CH 3 In CN. After heating and refluxing for 12 hours, the mixture was cooled to room temperature. FiltrationThe insoluble material was removed, the solution was concentrated by rotary evaporator, and the resulting solid was dissolved in methylene chloride (30 mL), washed with water (30 mL. Times.3), and dehydrated with anhydrous sodium sulfate. The crude product was isolated by column chromatography (dichloromethane/hexane 1:1) to give compound 1c (3.21 g,59% yield). 1 H NMR(400MHz,CDCl 3 )δ8.19(dd,J＝6.7,3.3Hz,2H),7.50(dd,J＝6.4,3.3Hz,2H),6.67(s,2H),4.14(t,J＝6.0Hz,4H),3.70(s,6H),2.63(t,J＝7.3Hz,4H),2.30-2.20(m,4H).HR-MS,[M+Na] + calcd:383.1465,found 383.1455.
Compound 1d: compound 1c (0.72 g,2 mmol) was dispersed in 5mL of methanol and 5mL of water, and sodium hydroxide (0.48 g,12 mmol) was added to the solution. Heating to 60 ℃ and stirring for 12 hours, removing methanol by rotary evaporation, adding 5mL of deionized water, and filtering to obtain a clear solution. 2M hydrochloric acid is added dropwise until the pH value is 3-4. The precipitated solid was dried by filtration to give compound 1d (0.615 g, yield 93%). 1 H NMR(400MHz,DMSO-d 6 )δ12.14(s,2H),8.13(dd,J＝6.1,2.9Hz,2H),7.54(dd,J＝6.4,3.2Hz,2H),6.83(s,2H),4.10(t,J＝6.2Hz,4H),2.48(t,J＝7.2Hz,4H),2.11-2.04(m,4H).HR-MS,[M-H + ] - calcd:331.1176,found 331.1187.
Compound I-1: tetraglycoluril 1e (0.47 g,0.602 mmol) and Compound 1d (0.60 g,1.81 mmol) were dispersed in trifluoroacetic acid (6 mL). The mixed solution was heated to 70℃and reacted for 3 hours, the solution gradually changed from brown to dark brown. After the reaction was completed, the reaction solution was poured into 80mL of methanol, and the precipitate was filtered and dried. The solid was dispersed in water and 3M NaOH solution was added dropwise until the pH was approximately 8-9. The solvent was removed by rotary evaporation to give a yellow solid. The solid was then recrystallized from water and ethanol to give compound I-1 (0.225 g, yield 30%) as a pale yellow solid. 1 H NMR(400MHz,D 2 O)δ7.86(dd,J＝6.5,3.3Hz,4H),7.29(dd,J＝6.5,3.3Hz,4H),5.63-5.54(m,6H),5.44(d,J＝8.9Hz,2H),5.37-5.33(m,6H),4.54(d,J＝15.9Hz,4H),4.27(d,J＝15.7Hz,4H),4.17-4.11(m,4H),4.08-4.04(d,J＝15.3Hz,2H),3.88-3.82(m,4H),2.51-2.37(m,8H),2.16-2.09(m,8H),1.83(s,6H),1.79(s,6H).HR-MS,[M+2H] 2+ calcd:749.2266,found 749.2282.
Example 2
The preparation of compound I-2 is carried out by the following synthetic route, the specific procedure being the same as that of preparation of I-1:
compound 2c: the yield thereof was found to be 63%. 1 H NMR(400MHz,CDCl 3 )δ6.61(s,2H),3.93(t,J＝6.0Hz,4H),3.69(s,6H),2.55(t,J＝7.4Hz,4H),2.15(s,6H),2.13-2.08(m,4H).HR-MS,[M+Na] + Calcd.:361.1622,found 361.1624.
Compound 2d: the yield was 92%. 1 H NMR(400MHz,DMSO-d 6 )δ6.68(s,2H),3.88(t,J＝6.2Hz,4H),2.39(t,J＝7.3Hz,4H),2.08(s,6H),1.96-1.89(m,4H).HR-MS,[M-H + ] - calcd.:309.1333,found 309.1345.
Compound I-2: the yield was 27%. 1 H NMR(400MHz,D 2 O)δ5.72(d,J＝15.3Hz,2H),5.62(d,J＝15.7Hz,4H),5.46(AB,J＝9.2Hz,4H),5.19(d,J＝16.1Hz,4H),4.39(d,J＝16.1Hz,4H),4.29(d,J＝15.7Hz,4H),4.14(d,J＝15.4Hz,2H),3.94-3.89(m,4H),3.68-3.62(m,4H),2.45-2.41(m,8H),2.12-2.05(m,8H),1.97(s,12H),1.83(s,6H),1.76(s,6H).HR-MS,[M-3Na+4H + ] + :1387.5314,found 1387.5321.
Example 3
The preparation of compound I-3 is carried out by the following synthetic route, wherein compound 1d is reacted instead of compound 3a, the specific procedure being the same as the preparation of I-1:
compound I-3: the yield was 30%. 1 H NMR(400MHz,D 2 O)δ6.88(s,4H),5.69(d,J＝15.3Hz,2H),5.59(d,J＝15.7Hz,4H),5.49-5.41(m,4H),5.36(d,J＝16.2Hz,4H),4.30-4.25(m,8H),4.14(d,J＝15.3Hz,2H),3.92(brs,8H),2.44-2.29(m,8H),2.02-1.97(m,8H),1.82(s,6H),1.78(s,6H).HR-MS(M+H) + calcd:1397.4146,found1397.4140.
Example 4
Diaryl sodium tetraglycoluril carboxylate antagonism imidazolium salt macrocyclic muscle relaxant activity assay: the effect of the compounds of the invention on antagonizing the activity of the imidazolium macrocyclic muscle-relaxant in vivo is illustrated by the antagonism of the neuromuscular blockade induced by the imidazolium macrocyclic muscle-relaxant in SD rats by compound I-1.
The specific operation process is as follows: SD rats weighing 180-240 g (each test group contains 2 animals each, each macrocyclic neuromuscular blocker, sodium diarylhydroglycollate was formulated as an injection during the test using physiological saline as solvent, all injection procedures were completed within 5 seconds, the same applies below), 5% isoflurane was used to induce anesthesia of the rats, the right hind leg hair of the rats was shaved, and 10% Na was used 2 The S solution is used for removing the right hind legs and nearby hairs of the rat, and an electrode plate is stuck to stimulate the quadriceps femoris of the rat. The twitch response of the quadriceps muscle was measured by an acceleration sensor of the muscle relaxometer and the values were recorded. The muscle relaxometer was switched to "cal" mode and stimulated continuously with a 10mA current at a frequency of 1Hz until the twitch height reached steady state. The instrument mode is then changed to "TOF" mode, and the stimulation of the femoral nerve is continued for 10s at 2Hz frequency cycle intervals until T1 stabilizes and TOF>90%. The rats were intubated and mechanically ventilated with a tidal volume of 1.7mL and a respiratory rate of 80 beats/min. Anesthesia was maintained with 1% isoflurane and the ventilation flow rate was controlled at 0.6L/min. The corresponding dose of the imidazolium salt macrocyclic muscle relaxant was injected via the tail vein (the doses given are shown in table 1). After reaching full neuromuscular blockade (or maximum neuromuscular blockade, or deep muscle relaxation), i.e. TOF of 0, compound I-1 (dose 10 mg/kg) was injected for antagonism. TOF value recovery was measured and recorded, with TOF values recovered above 90% being considered complete antagonism.
The results show that the different imidazolium salt macrocyclic muscle relaxants reaching deep muscle relaxation can be completely antagonized by the compound I-1, and the fact that the compound I-1 disclosed by the invention can specifically antagonize the imidazolium salt macrocyclic muscle relaxants is shown.
TABLE 1
Imidazolium salt macrocyclic muscle relaxant Dosage (mg/kg) Results of Compound I-1 (10 mg/kg)
IMC-1 1.5 Complete antagonism
IMC-2 0.6 Complete antagonism
IMC-5 1.8 Complete antagonism
IMC-7 1.2 Complete antagonism
IMC-8 0.3 Complete antagonism
IMC-9 0.6 Complete antagonism
IMC-10 1.0 Complete antagonism
IMC-14 0.04 Complete antagonism
IMC-15 0.04 Complete antagonism
IMC-17 0.04 Complete antagonism
IMC-18 0.04 Complete antagonism
IMC-19 0.04 Complete antagonism
Example 5
Acute toxicity experiments using ICR mice (3 in each case) to determine sodium diaryl tetraglycoluril carboxylate, maximum tolerated doses of 550, 1000 and 1100mg/kg for compounds I-1, I-2 and I-3, respectively, were determined.
Example 6
Compound I-1 antagonizes the imidazolium macrocyclic muscle relaxant assay at specific doses. Taking the neuromuscular blockade induced by the compound I-1 antagonizing the imidazolium macrocyclic muscle relaxant IMC-7 in SD rats as an example, the dose-effect relationship of the different doses of the compound I-1 antagonizing the imidazolium macrocyclic muscle relaxant in organisms is illustrated.
The procedure was as in example 4, and after anesthesia, the rats were given with a muscle relaxant, and IMC-7 (1.6 mg/kg, twice ED 90) and Compound I-1 (2.5 mg/kg, 5mg/kg and 25 mg/kg) were each formulated as injections with physiological saline, the volumes of which were controlled to 0.5mL. The corresponding dose of the imidazolium macrocyclic muscle relaxant IMC-7 was injected via the tail vein. Upon reaching full neuromuscular resistance hysteresis, i.e. tof=0, t1=0, 0.5mL placebo or the above dose of compound I-1 was injected. TOF recovery time (TOF > 90%) was measured and recorded to assess the onset of antagonistic neuromuscular blockade in vivo. Since the TOF test period of the myorelaxometer was 10s, the recovery time for the first test to not fully antagonize and for the second test to have fully antagonize was recorded as <20s.
The results are shown in Table 2, where only placebo is present and up to 4021s is required for spontaneous recovery, but where the rate of antagonism of compound I-1 is in a significant dose-response relationship and where complete antagonism is achieved at a dose of 25mg/kg for less than 20s, the time period is reduced to 1/250 of the placebo group, demonstrating that compound I-1 can specifically, rapidly and efficiently antagonize the imidazolium salt macrocyclic muscle relaxant.
TABLE 2
Example 7
Compound I-2 antagonizes IMC-7 muscle relaxant activity assay at specific doses. The procedure is as in example 6, with the average recovery times listed in Table 3. At a dose of 25mg/kg, the average recovery time was less than 20 seconds.
TABLE 3 Table 3
Example 8
Compound I-3 antagonizes IMC-7 muscle relaxant activity assays at specific doses. The procedure is as in example 6, with the average recovery times listed in Table 4. At a dose of 25mg/kg, the average recovery time was less than 20 seconds.
TABLE 4 Table 4
Example 9
Compound I-1 antagonizes IMC-8 muscle relaxant activity assays at specific doses. The IMC-8 (0.3 mg/kg, twice ED 90) and compound I-1 (1 mg/kg, 2mg/kg and 10 mg/kg) were each formulated as injections with physiological saline, and the injection volume was controlled to 0.5mL. The procedure is as in example 6, with the average recovery times listed in Table 5. At a dose of 10mg/kg, the average recovery time was less than 20 seconds.
TABLE 5
Example 10
Compound I-2 antagonizes IMC-8 muscle relaxant activity assays at specific doses. The procedure is as in example 9, with the average recovery times listed in Table 6. At a dose of 10mg/kg, the average recovery time was less than 20 seconds.
TABLE 6
Example 11
Compound I-3 antagonizes IMC-8 muscle relaxant activity assays at specific doses. The procedure is as in example 9, with the average recovery times listed in Table 7. At a dose of 10mg/kg, the average recovery time was less than 30 seconds.
TABLE 7
Example 12
Compound I-1 antagonizes IMC-19 muscle relaxant activity assays at specific doses. The IMC-19 (0.04-0.6 mg/kg,2.5-37.5 times ED 90) and the compound I-1 (10 mg/kg) of the imidazolium salt macrocyclic muscle relaxant are respectively prepared into injections by using physiological saline, and the volume of the injections is controlled to be 0.5mL. The procedure is as in example 6, with the average recovery times listed in Table 8. At a dose of 10mg/kg, the average recovery time was less than 20 seconds.
TABLE 8
Example 13
Assays for antagonizing clinically useful cisatracurium myorelaxant activity using compound I-1. Cisatracurium (0.6 mg/kg, twice ED 90) and compound I-1 (80 mg/kg) were respectively formulated into injections with physiological saline, and the injection volume was controlled to be 0.5mL. The procedure is as in example 6 with an average recovery time of 34 seconds, demonstrating a good antagonistic effect against currently clinically used muscle relaxants. Compound I-2 (80 mg/kg) antagonizes cisatracurium with an average recovery time of 65 seconds, indicating that it also has a certain antagonistic effect.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (12)

1. A compound of formula I, or a pharmaceutically acceptable salt, form, hydrate or solvate thereof,
in the method, in the process of the application,
each R is 1 Each independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or two adjacent R 1 Together with the carbon atoms to which they are attached form a substituent or an unsubstitutedSubstituted C3-C20 carbocycles or 3-20 membered carboheterocycles;
each R is 2 Each independently selected from substituted or unsubstituted C1-C20 alkylene, substituted or unsubstituted C1-C20 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S;
each R is 3 Each independently selected from H, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 heteroalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl, or two adjacent R' S 3 Together with the carbon atoms to which they are attached form a substituted or unsubstituted group selected from the group consisting of: a C3-C20 carbocyclic ring, a 3-20 membered carbocyclic ring, a C5-C20 aromatic ring, a 5-20 membered heteroaromatic ring;
each M is independently selected from the group consisting of: na (Na) + 、K + 、Li + 、Mg 2+ 、Ca 2+ 、NH 4 + Or an ammonium salt substituted with one or more groups each independently selected from C1-4 alkyl or C6-10 aryl;
unless otherwise indicated, the substitution means that a hydrogen on a group is substituted with one or more groups selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
2. A compound according to claim 1 wherein,
each R is 1 Each independently selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, or two adjacent R 1 Together with the carbon atoms to which they are attached form a substituted or unsubstituted C3-C10 carbocyclic ring or a 3-10 membered carbocyclic ring;
each R is 2 Each independently selected from substituted or unsubstituted C2-C10 alkylene, substituted or unsubstituted C1-C10 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S;
each R is 3 Each independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, or two adjacent R' S 3 Together with the carbon atoms to which they are attached form a substituted or unsubstituted group selected from the group consisting of: a C3-C10 carbocyclic ring, a 3-10 membered carbocyclic ring, a C5-C10 aromatic ring, a 5-10 membered heteroaromatic ring;
each M is independently selected from the group consisting of: na (Na) + 、K + 、Li + 、Mg 2+ 、Ca 2+ 、NH 4 + Or an ammonium salt substituted with one or more groups each independently selected from C1-4 alkyl or C6-10 aryl.
3. A compound according to claim 1 wherein,
each R is 1 Each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or two adjacent R 1 Together with the carbon atoms to which they are attached form a substituted or unsubstituted C3-C7 carbocyclic ring or a 3-7 membered carbocyclic ring;
each R is 2 Each independently selected from substituted or unsubstituted C3-C6 alkylene, substituted or unsubstituted C1-C6 heteroalkylene containing 1 to 3 heteroatoms selected from N, O and S;
each R is 3 Each independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclyl, or two adjacent R' S 3 Together with the carbon atoms to which they are attached form a substituted or unsubstituted group selected from the group consisting of: a C3-C7 carbocyclic ring, a 3-7 membered carbocyclic ring, a C5-C8 aromatic ring, a 5-8 membered heteroaromatic ring;
Each M is independently selected from the group consisting of: na (Na) + 、K + 、Li + 、Mg 2+ 、Ca 2+ 、NH 4 + Or an ammonium salt substituted with one or more groups each independently selected from C1-4 alkyl or C6-8 aryl.
4. The compound of claim 1, wherein each R 1 Each independently selected from substituted or unsubstituted C1-C4 alkyl; each R is 2 Each independently is- (CH) 2 ) n -, where n is 2,3 or 4.
5. A compound according to claim 1 wherein,is-> Wherein G is H, or one or more groups selected from the group consisting of: halogen, amino, C1-C6 alkyl or C1-C6 alkoxy.
6. The compound of claim 1, wherein said compound is selected from the group consisting of:
7. the use of a compound according to claim 1 as an antagonist of neuromuscular blocking agents.
8. The use of claim 7, wherein the neuromuscular blocking agent is an imidazolium salt macrocyclic compound having the structure of formula A,
in the method, in the process of the invention,
each R is 1 Each independently selected from the group consisting of: H. d, substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;
each R is 2 Each independently selected from the group consisting of: H. substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted 1-20 membered heteroalkyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkenyl, substituted or unsubstituted 2-20 membered heteroalkenyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 2-20 Alkynyl, substituted or unsubstituted 2-20 membered heteroalkynyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or two adjacent R 2 Together with the carbon atoms to which they are attached form a group selected from the group consisting of: substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, or substituted or unsubstituted 5-20 membered heteroaryl containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;
Each Y and Z is independently selected from the group consisting of: unsubstituted or substituted C 1-20 Alkylene, substituted or unsubstituted C containing 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur 1-20 Alkylene, substituted or unsubstituted C 3-20 Cycloalkylene, substituted or unsubstituted C 5-20 Arylene, substituted or unsubstituted Ar1-L-Ar2, substituted or unsubstituted 5-20 membered heteroarylene;
l is selected from the group consisting of: no, O, NH, C 1-10 Alkylene, S, phenylene;
ar1, ar2 are each independently none, C 6-10 Arylene or 5-8 membered heteroarylene;
x is one or more pharmaceutically acceptable anions which are trimmed with the 4-valent cationic imidazolium salt macrocycle in the structure of formula A;
unless otherwise specified, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
9. The use according to claim 8, wherein the 4-valent cationic imidazolium salt macrocycle of formula a is selected from the group consisting of:
wherein X is one or more anions which are macrocyclic trim with a 4-valent cationic imidazolium salt, each of said anions being independently selected from the group consisting of: cl - 、Br - 、I - 、SO 4 2- 、HSO 4 - 、PO 4 3- 、HOPO 3 2- 、(HO) 2 PO 2 - 、R’CO 2 - 、 - O 2 C(CH 2 ) n CO 2 - (n＝0-20)、ArCO 2 - 、R’SO 3 - 、ArSO 3 - 、R’PO 3 - 、ArPO 3 - Alginate, citrate, aspartate, camphorsulfonate, digluconate, glycerophosphate, fumarate, taurate, 2-hydroxyethylsulfonate, lactate, maleate,nicotinate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, tartrate; wherein R' is a substituted or unsubstituted C 1-10 Alkyl, ar is substituted or unsubstituted C 5-7 Aryl or substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S;
wherein, the substitution means that one or more hydrogens on the group are replaced with a group selected from the group consisting of: halogen, nitro, amino, cyano, hydroxy, amido, trifluoromethyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, phenyl, benzyl, 3-6 membered heterocyclyl, C 1-6 An alkoxycarbonyl group.
10. A process for the preparation of a compound as claimed in claim 1, comprising the steps of:
(a) Reacting a compound of formula a with a compound of formula b in the presence of a base to obtain a compound of formula c;
(b) Demethylating the compound of formula c to obtain a compound of formula d;
(c) Reacting a compound of formula d with a glycoluril tetramer of formula e in the presence of TFA, and then adding hydroxide MOH for hydrolysis to obtain a compound of claim 1 shown in formula I;
Wherein each R 1 、R 2 、R 3 M is as defined in claim 1.
11. A pharmaceutical composition or formulation comprising:
(a) The diarylhydrotetraglycoluril tetracarboxylic acid salt compound according to claim 1, or a pharmaceutically acceptable salt, crystal form, hydrate, or solvate thereof, as an active ingredient;
(b) Pharmaceutically acceptable carriers or excipients.
12. A pharmaceutical composition comprising
(a) The diarylhydrotetraglycoluril tetracarboxylic acid salt compound of claim 1, or a pharmaceutically acceptable salt, crystal form, hydrate, or solvate thereof, as a first active ingredient;
(b) An imidazolium salt macrocyclic compound neuromuscular blocking agent represented by formula a as a second active ingredient;
wherein R is 1 、R 2 Y, X, Z are as defined in claim 8; and
(c) Pharmaceutically acceptable carriers or excipients.
CN202310881173.8A 2023-07-18 2023-07-18 Diaryl tetraglycoluril carboxylate and application thereof Pending CN116925087A (en)

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