CN120865200A - Novel spiro compound, and pharmaceutical composition and application thereof - Google Patents
Novel spiro compound, and pharmaceutical composition and application thereofInfo
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- CN120865200A CN120865200A CN202510717063.7A CN202510717063A CN120865200A CN 120865200 A CN120865200 A CN 120865200A CN 202510717063 A CN202510717063 A CN 202510717063A CN 120865200 A CN120865200 A CN 120865200A
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Abstract
本发明公开了一种新型螺环化合物及其药物组合物和用途，所述新型螺环化合物如式(I)所示，其中各取代基的定义详见说明书；该化合物可用于制备预防或治疗头部疼痛疾病的药物。 This invention discloses a novel spirocyclic compound, its pharmaceutical composition, and its uses. The novel spirocyclic compound is shown in formula (I), wherein the definitions of each substituent are detailed in the specification. This compound can be used to prepare a drug for the prevention or treatment of headache.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a novel spiro compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof, and a pharmaceutical composition and application thereof.
Background
Migraine is a recurrent chronic neurological disorder whose pathogenesis is not completely defined. The symptoms of reversible nerves and whole body are continuously present for 4-72 hours, the symptoms are usually middle or severe, any part of the head can be involved, the symptoms usually are unilateral and pulsating, the daily activities can be aggravated, nausea and/or vomiting are usually accompanied, and part of patients are also accompanied by non-headache symptoms such as photophobia, aphonia anxiety, depression and the like. The incidence peak is 25-55 years old, and women are more than men. Migraine is classified by the world health organization as the third most common disease and the second most neurological disability disease in the world, and is arranged at the 3 rd place of the burden of the global disease, and the high morbidity, recurrence rate and disability of the cause seriously affect the life quality of patients, and bring heavy burden to families and society.
With the intensive research of migraine, calcitonin gene-related peptide (CGRP) was found to play an important role in the pathogenesis of migraine. CCRP has the functions of protecting blood vessels, promoting inflammation, regulating neuron sensitization and enhancing somatosensory pain, and the receptor of the CCRP is positioned at almost all possible sites related to migraine attack, so that the target spot is deeply excavated, and medicines with better efficacy can be still developed in the migraine treatment field.
Disclosure of Invention
The present inventors have developed a novel spiro compound having utility in the development of a medicament for the treatment of headache disorders.
In one aspect, the present invention provides a novel spiro compound, tautomer, stereoisomer, prodrug, and pharmaceutically acceptable salts thereof, as shown in (I):
in the formula (I) of the present invention,
W is O or S;
R 1、R2 and R 3 are each independently selected from hydrogen, deuterium, halogen and cyano;
R 4a、R4b、R5a and R 5b are each independently selected from hydrogen and deuterium;
r 6 and R 7 are each independently selected from hydrogen and deuterium;
R 8 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl,
The above-mentioned C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl groups may independently be optionally substituted with deuterium, halogen, hydroxy, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto-methyl, mercapto-ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl;
R 9a、R9b、R9c is independently selected from hydrogen and deuterium;
R 10a and R 10b are each independently selected from hydrogen and deuterium;
R 11、R12、R13、R14 and R 15 are each independently selected from hydrogen, deuterium and halogen;
G 1 and G 2 are independently selected from hydrogen,
Wherein, the
R a1 and R a2 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, or R a1、Ra2 are linked in any reasonable manner;
R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, C 3-10 heteroaryl, C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, C 3-10 heteroaryl optionally substituted with one or more of deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxy, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, C 1-6 alkoxy, C 1-6 alkylamino;
R c is selected from hydrogen, C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl, and the above C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl may be optionally substituted with one or more of deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methylsulfonyl, ethylsulfonyl;
R d1 and R d2 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or R d1、Rd2 are linked in any reasonable manner;
R e1 and R e2 are each independently selected from hydrogen metal ion, C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, C 3-10 heteroaryl, or R e1、Re2 are linked in any reasonable manner to form a ring, a C 1-6 alkyl group, a C 1-6 alkylamino group, a C, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, The C 3-10 heteroaryl group may be optionally substituted with one or more of deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl;
In particular the number of the elements to be processed,
When G 1 and G 2 are both hydrogen and R 8 is not substituted with deuterium, then either R1、R2、R3、R4a、R4b、R5a、R5b、R6、R7、R9a、R9b、R9c、R10a、R10b、R11、R12、R13、R14 or R 15 must be deuterium, or
When G 1 is not hydrogen, G 2 is hydrogen, and R 8 is not substituted with deuterium, and both R 11、R12 and R 15 are halogen, then one of R1、R2、R3、R4a、R4b、R5a、R5b、R6、R7、R9a、R9b、R9c、R10a、R10b、R13 and R 14 must be deuterium.
In some embodiments, in formula (I) above, W is O or S, preferably W is O.
In some embodiments, in formula (I) above, R 1 is selected from hydrogen, deuterium, halogen, and cyano, preferably R 1 is hydrogen and deuterium.
In some embodiments, in formula (I) above, R 2 is selected from hydrogen, deuterium, halogen, and cyano, preferably R 2 is hydrogen and deuterium.
In some embodiments, in formula (I) above, R 3 is selected from hydrogen, deuterium, halogen, and cyano, preferably R 3 is hydrogen and deuterium.
In some embodiments, in formula (I) above, R 4a is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 4b is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 5a is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 5b is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 6 is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 7 is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 8 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl, preferably R 8 is selected from C 1-6 alkyl, wherein,
The above-described C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclyl groups may independently be optionally substituted with one or more of deuterium, halogen, hydroxy, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, preferably the above-described alkyl groups may independently be optionally substituted with one or more of deuterium and halogen, more preferably the above-described alkyl groups may independently be optionally substituted with one or more of deuterium and F.
In some embodiments, in formula (I) above, R 9a is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 9b is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 9c is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 10a is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 10b is selected from hydrogen and deuterium.
In some embodiments, in formula (I) above, R 11 is selected from hydrogen, deuterium, and halogen.
In some embodiments, in formula (I) above, R 12 is selected from hydrogen, deuterium, and halogen.
In some embodiments, in formula (I) above, R 13 is selected from hydrogen, deuterium, and halogen.
In some embodiments, in formula (I) above, R 14 is selected from hydrogen, deuterium, and halogen.
In some embodiments, in formula (I) above, R 15 is selected from hydrogen, deuterium, and halogen.
In some embodiments, in formula (I) above, G 1 is selected from hydrogen, Wherein, the
Each of the above R a1 and R a2 is independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or R a1、Ra2 are linked in any reasonable manner to form a ring, preferably R a1 and R a2 are both hydrogen, or R a1 and R a2 are hydrogen and the other is methyl;
R b is selected from hydrogen, C 1-6 alkyl, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, C 3-10 heteroaryl, preferably R b is selected from C 1-6 alkyl, wherein,
The above-mentioned C 1-6 alkyl, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, C 3-10 heteroaryl groups may be optionally substituted with one or more of deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, C 1-6 alkoxy, C 1-6 alkylamino groups, preferably the above-mentioned alkyl groups may be optionally substituted with one or more of deuterium;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl, preferably R c is selected from the group consisting of C 1-6 alkyl, wherein,
The above-mentioned C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl groups may be optionally substituted with one or more deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, preferably,
The alkyl groups described above may be optionally substituted with one or more deuterium;
R d1 and R d2 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, or R d1、Rd2 are linked in any reasonable manner to form a ring preferably R a1 and R a2 are both hydrogen, or R a1 and R a2 are one hydrogen and the other methyl;
R e1 and R e2 are each independently selected from hydrogen, a metal ion, C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl and C 3-10 heteroaryl, or R e1、Re2 are linked in any reasonable manner to form a ring, preferably R e1 and R e2 are each independently selected from hydrogen, a metal ion and C 1-6 alkyl, wherein,
The above-mentioned C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl and C 3-10 heteroaryl groups may be optionally substituted with one or more of deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl.
In some embodiments, in formula (I) above, G 2 is selected from hydrogen, Preferably, G 2 is hydrogen, wherein,
Each of the above R a1 and R a2 is independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, or R a1、Ra2 are linked in any reasonable manner to form a ring, preferably R a1 and R a2 are both hydrogen, or R a1 and R a2 are hydrogen and the other is methyl;
R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, and C 3-10 heteroaryl, preferably R b is selected from the group consisting of C 1-6 alkyl, wherein,
The above-mentioned C 1-6 alkyl, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl and C 3-10 heteroaryl groups may be optionally substituted with one or more of deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, C 1-6 alkoxy, C 1-6 alkylamino groups, preferably the above-mentioned alkyl groups may be optionally substituted with one or more deuterium;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl and C 2-8 heterocyclyl, preferably R c is selected from the group consisting of C 1-6 alkyl, wherein,
The above-mentioned C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl and C 2-8 heterocyclyl groups may be optionally substituted with one or more of deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, preferably the above-mentioned alkyl groups may be optionally substituted with one or more deuterium;
R d1 and R d2 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, or R d1、Rd2 are linked in any reasonable manner to form a ring, preferably R a1 and R a2 are both hydrogen, or R a1 and R a2 are hydrogen and the other is methyl;
R e1 and R e2 are each independently selected from hydrogen, a metal ion, C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, C 3-10 heteroaryl, or R e1、Re2 are linked in any reasonable manner to form a ring, preferably R e1 and R e2 are each independently selected from hydrogen, a metal ion, C 1-6 alkyl, more preferably wherein,
The above-mentioned C 1-6 alkyl, C 1-6 alkylamino, C 3-10 carbocyclyl, C 2-8 heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-15 aryl, C 3-10 heteroaryl groups may be optionally substituted with one or more of deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto methyl, mercapto ethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl.
In particular the number of the elements to be processed,
When G 1 and G 2 are both hydrogen and R 8 is not substituted with deuterium, then either R1、R2、R3、R4a、R4b、R5a、R5b、R6、R7、R9a、R9b、R9c、R10a、R10b、R11、R12、R13、R14 or R 15 must be deuterium, or
When G 1 is not hydrogen, G 2 is hydrogen, and R 8 is not substituted with deuterium, and both R 11、R12 and R 15 are halogen, then one of R1、R2、R3、R4a、R4b、R5a、R5b、R6、R7、R9a、R9b、R9c、R10a、R10b、R13 and R 14 must be deuterium.
In some embodiments, the present invention provides the above-described novel spiro compounds, tautomers, stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, selected from the group consisting of the following compounds:
in another aspect, the present invention provides pharmaceutical compositions comprising the novel spiro compounds, tautomers, stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, as described above.
The invention discloses a pharmaceutical composition, which is composed of the compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof as active ingredients or main active ingredients and pharmaceutically acceptable carriers.
In yet another aspect, the present invention provides the use of the above novel spiro compounds, tautomers, stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, or the above pharmaceutical composition, for the preparation of a medicament for the treatment of diseases mediated by the calpain gene related peptide (Calcitonin GENE RELATED PEPTIDE, CGRP) receptor.
The invention provides application of the pharmaceutical composition in preparing medicines for treating CGRP receptor mediated diseases, wherein the medicines for treating the CGRP receptor mediated diseases are used for treating cardiovascular diseases, hypertension, diabetes, autoimmune diseases, organ pain, head pain, bone diseases and chronic obstructive pulmonary diseases.
The invention provides that the above medicament is useful for treating a headache disorder, wherein the headache is migraine.
In some embodiments, the novel compounds of the present invention may be formulated as pharmaceutical compositions for administration to a patient in a variety of suitably selected modes of administration, including systemic, e.g., oral or parenteral, by intravenous, intramuscular, transdermal, subcutaneous, and the like.
The compound disclosed by the invention has stronger CGRP receptor antagonistic activity and better migraine efficacy of rats, unexpectedly shows pharmacokinetic advantages of higher peak concentration, faster onset, longer half-life and larger exposure, and remarkably improves the curative effect and the administration convenience.
Definition:
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
Certain compounds of the invention may exist in unsolvated forms or solvated forms such as, for example, hydrated, ethanolic forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic ammonia, or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, and salts of amino acids (e.g., arginine, and the like), and salts of organic acids such as glucuronic acid, and the like. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
"Amino" herein refers to a functional group having 1 nitrogen atom and 0 to 2 hydrogen atoms.
Halogen herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
"C 1-6 alkyl" as used herein means a straight, branched or unbranched saturated aliphatic hydrocarbon group containing up to 6 carbon atoms, specific examples of alkyl groups are methyl, ethyl, isopropyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 2-dimethylpropyl, and the like.
"C 1-6 alkoxy" as used herein refers to an alkyl group containing up to 6 carbon atoms interrupted by an-O-, -OH group at any reasonable position, which may be straight-chain, branched or unbranched, and specific examples are methoxy, ethoxy, isopropoxy, tert-butoxy, isopentyloxy, cyclopentyloxy, 2-methoxybutyl, 2-ethoxypropyl, 2-hydroxybutyl, etc.
"C 1-6 alkylamino" as used herein means an alkyl group containing up to 6 carbon atoms inserted at any reasonable position with a-N-, -NH 2 group, which may be straight-chain, branched or unbranched, with specific examples being methylamino, ethylamino, isopropylamino, t-butylamino, cyclopentylamino, 2-methylaminobutyl, 2-ethylaminopropyl, 2-aminobutyl, etc.
"C 2-8 alkenyl" as used herein means a straight, branched or unbranched hydrocarbon group containing up to 8 carbon atoms in the molecule and containing at least one carbon-carbon double bond, specific examples being vinyl, allyl, cis-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-2-pentenyl, and the like.
"C 2-8 alkynyl" as used herein refers to a straight, branched or unbranched hydrocarbon group containing up to 8 carbon atoms in the molecule and containing at least one carbon-carbon triple bond, with specific examples being ethynyl, propargyl, methyl-isopropylethynyl, prop-1-ynylcyclopropanyl, 1-pentynyl, 5-methyl-3-hexynyl and the like.
"C 3-10 carbocyclyl" as used herein means a saturated or unsaturated aliphatic cyclic hydrocarbon group having 3 to 10 carbon atoms in the molecule, and specific examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, 1, 3-cyclohexanedienyl, and the like.
"C 2-8 heterocyclyl" as used herein means a saturated or unsaturated aliphatic cyclic group containing 2 to 8 carbon atoms and 1 to 6 heteroatoms in the molecule, and may contain one or more rings, each ring of such polycyclic heterocycloalkyl groups may have different attachment means, such as fused, bridged, spiro, etc., with specific examples being oxiranyl, pyrrolidinyl, furanyl, piperidinyl, piperazinyl, pyrazinyl, pyranyl, tetrahydro-3-thiophenyl, cyclopentenyl sulfide, etc.
"C 6-15 aromatic ring radical" as used herein means a radical containing 6 to 15 carbon atoms in the molecule and at least one aromatic ring, each ring of the polycyclic aromatic group may have different attachment means, such as fused, bridged, etc., in addition to covalent groups, and the fused rings may be saturated or unsaturated. Specific examples are phenyl, naphthyl, diphenyl, a-tetrahydronaphthyl, indenyl, indanyl, bunidazinyl, 3, 4-dihydro-1H-benzopyranyl and the like.
"C 3-10 heteroaryl" as used herein means an aromatic heterocyclic group containing 3 to 10 carbon atoms and 1 to 6 heteroatoms in the molecule, and each ring of the polycyclic aryl group may have different linkages, such as condensed, bridged, etc., in addition to covalent groups, and the condensed rings may be saturated or unsaturated. Specific examples are thienyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, thiazolyl, purinyl, 5,6,7, 8-tetrahydroquinolinyl and the like.
The hetero atom herein means an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, a boron atom, a selenium atom, or the like.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of a carrier capable of delivering an effective amount of the active agents of the present invention, which does not interfere with the biological activity of the active agents and which does not have toxic or side effects to the host or patient, including water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like.
The term "stereoisomer" refers to a compound that has the same chemical constitution but differs in the arrangement of atoms or groups in space.
Detailed Description
A number of exemplary methods for preparing the compounds of the present invention are provided in the examples below. The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. Certain compounds of the invention can be used as intermediates for preparing other compounds of the invention, the structure of all of which is determined by the fluid properties.
Materials in the examples of the present application were purchased commercially unless specifically indicated.
EXAMPLE 1 Synthesis of Compound ZJT-1
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of ZJT-1-1
ZJT-1-SM (17.16 g,0.05 mol) is added to DMF (100 mL) under nitrogen, and 1-phenylpropion (6.71 g,0.05 mol) is added and cesium carbonate (16.29 g,0.05 mol) and the system is reacted at 60℃for 10 hours.
Thin layer detection showed complete reaction. Filtration, concentration, dilution with water (100 mL), extraction of the aqueous phase with methylene chloride (100 mL. Times.3), washing with saturated brine (300 mL), drying over anhydrous sodium sulfate, filtration, concentration, and recrystallization of the resulting residue from ethanol/water gave ZJT-1, 9.28g (yield: 53.1%). ESI-MS (+): m/z=350.47 [ M+1].
Step 2 preparation of ZJT-1
ZJT-1-1 (6.99 g,0.02 mol) was added to tetrahydrofuran (90 mL), 2-trifluoroethylamine (1.98 g,0.02 mol) and acetic acid (3 mL) were further added under nitrogen, and after the system was reacted at room temperature for 5 hours, sodium cyanoborohydride (2.51 g,0.04 mol) was further added, and the reaction was continued for 3 hours.
Thin layer detection showed complete reaction. The system was neutralized by adding potassium carbonate, concentrated, diluted with water (100 mL), extracted with methylene chloride (100 mL. Times.3), combined with the organic phase, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated with the preparative liquid phase to give ZJT-1,1.45g (yield: 18.7%). ESI-MS (+): m/z=387.37 [ M+1].
EXAMPLE 2 Synthesis of Compound ZJT-2
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of ZJT-2-1
ZJT-2-SM (66.74 g,0.3 mol) was added to methylene chloride (500 mL) under nitrogen, and trimethylchlorosilane (32.59 g,0.3 mol) and triethylamine (60.71 g,0.6 mol) were further added, and the system was reacted at room temperature for 4 hours.
Thin layer detection showed complete reaction. The system was poured into water (500 mL), the solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained residue was separated by column chromatography to give ZJT-2-1,47.20g (yield: 53.4%). ESI-MS (+): m/z=293.31 [ M+1].
Step 2 preparation of ZJT-2-2
ZJT-2-1 (44.20 g,0.15 mol) is added into tetrahydrofuran (300 mL) under the protection of nitrogen, then lithium chloride (7.63 g,0.18 mol) is added, the system is cooled to-40 ℃, tetrahydrofuran solution (2.0M/90 mL) of diisopropyl magnesium chloride is slowly added dropwise, the system is warmed to room temperature after the dropwise addition, the reaction is carried out for 3 hours, then the temperature is reduced to-40 ℃, DMF (30 mL) is slowly added dropwise, the system is warmed to room temperature after the dropwise addition, and the reaction is continued for 10 hours.
Thin layer detection showed complete reaction. The system was poured into saturated ammonium chloride solution (300 mL), filtered, concentrated, the aqueous phase extracted with methylene chloride (300 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give residue which was separated by column chromatography to give ZJT-2, 26.14g (yield: 71.5%). ESI-MS (+): m/z=244.41 [ M+1].
Step 3 preparation of ZJT-2-3
7-Aza-indol-2-one (13.41 g,0.1 mol) was added to tetrahydrofuran (200 mL), followed by sodium ethoxide (13.61 g,0.2 mol) and stirring at room temperature for 2 hours under nitrogen, followed by addition of ZJT-2-2 (24.38 g,0.1 mol) in portions, and continuing the reaction for 12 hours.
The mixture was filtered, quenched with saturated ammonium chloride solution (200 mL), concentrated, and the residue recrystallized from ethanol/water, methanol (150 mL) was added to the resulting solid, followed by sodium borohydride (15.13 g,0.4 mol) and the reaction was continued at room temperature for 10 hours. Thin layer detection showed complete reaction. Filtration and concentration gave a residue, which was separated by column chromatography to give ZJT-2-3,14.66g (yield: 40.5%). ESI-MS (+): m/z=362.31 [ M+1].
Step 4 preparation of ZJT-2-4
ZJT-2-3 (10.86 g,0.03 mol) was added to methylene chloride (100 mL) under nitrogen protection, and hydrochloric acid solution (0.01M/30 mL) was added thereto, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was separated, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue.
The residue was added to DMF (50 mL) under nitrogen, followed by slow addition of phosphorus tribromoxide (12.90 g,0.045 mol), the internal temperature of the system was controlled to not exceed 5℃and the system was allowed to warm to room temperature for 4 hours after the dropwise addition. Thin layer detection showed complete reaction. The system was poured into ice water (500 mL), filtered, and the cake was dried to give ZJT-2-4,6.69g (yield: 63.2%). ESI-MS (+): m/z=351.87 [ M+1].
Step5 preparation of ZJT-2-5
ZJT-2-4 (5.29 g,0.015 mol) was added to tetrahydrofuran (80 mL) under nitrogen, and sodium hydroxide (1.20 g,0.03 mol) was added thereto and the system was stirred at room temperature for 24 hours.
Thin layer detection showed complete reaction. The filtrate was filtered, concentrated, and the resulting residue was recrystallized from ethanol/water to give ZJT-2-5,1.57g (yield: 38.5%). ESI-MS (+): m/z=272.41 [ M+1].
Step 6 preparation of ZJT-2
ZJT-2-5 (1.36 g,5 mmol) is added into ethanol (30 mL) under the protection of nitrogen, then carbon monoxide gas of 30psi is filled for reaction for 12 hours at 100 ℃, 50% sodium hydroxide aqueous solution is added after the reaction is detected to lead the pH of the system to be 11-12, and the system is heated to 80 ℃ for reaction for 4 hours.
Thin layer detection showed complete reaction. The system was adjusted to ph=3.0 with hydrochloric acid solution (2.0M), filtered, concentrated, the aqueous phase was extracted with dichloromethane (50 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue which was separated by column chromatography to give ZJT-2,0.59g (yield: 42.0%). ESI-MS (+): m/z=282.3 [ M+1]
EXAMPLE 3 Synthesis of Compound ZJT-3
The reaction formula:
ZJT-1 (1.16 g,3 mmol) is added to tetrahydrofuran (20 mL) under nitrogen protection, hydrochloric acid solution (1M/3 mL) is added, and the system is reacted for 1 hour at room temperature after the addition. Then, the pH was adjusted to 8-9 with triethylamine, concentrated, the aqueous phase was extracted with methylene chloride (40 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue.
ZJT-2 (0.84 g,3 mmol) was added to tetrahydrofuran (20 mL), and thionyl chloride (0.71 g,6 mmol) was further added under nitrogen protection, and the reaction was continued for 3 hours at room temperature after the addition, and the above-mentioned spare residue was added to the system, and triethylamine (0.91 g,9 mmol) was further added, and the reaction was continued for 4 hours.
Thin layer detection showed complete reaction. Concentration gave a residue, which was separated by column chromatography to give ZJT-3,0.46g (yield: 27.9%). ESI-MS (+): m/z=550.41 [ M+1].
EXAMPLE 4 Synthesis of Compound WUR-01
The reaction formula:
The preparation method comprises the following steps:
ZJT-3 (1.65 g,3 mol) was added to DMF (20 ml) under nitrogen, followed by 60% sodium hydrogen (0.24 g,6 mmol) and the system was stirred at room temperature for 0.5 h. Chloromethyl dimethyl carbonate (0.37 g,3 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-01,0.35g (yield: 18.5%). ESI-MS (+): m/z=638.71 [ M+1].
EXAMPLE 5 Synthesis of chemical Compound WUR-04
The reaction formula:
The preparation method comprises the following steps:
ZJT-3 (2.20 g,4 mol) was added to DMF (20 ml) under nitrogen, 60% sodium hydrogen (0.32 g,8 mmol) was added and the system was stirred at room temperature for 0.5 h.
Chloromethyl isobutyrate (0.55 g,4 mmol) was added and the reaction was continued for 12 hours. Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-04,0.36g (yield: 13.7%). ESI-MS (+): m/z=650.35 [ M+1].
EXAMPLE 6 Synthesis of Compound WUR-05
The reaction formula:
The preparation method comprises the following steps:
ZJT-3 (2.75 g,5 mol) was added to DMF (30 ml) under nitrogen, 60% sodium hydrogen (0.4 g,10 mmol) was added and the system was stirred at room temperature for 0.5 h.
Chloromethyl pivalate (0.75 g,5 mmol) was added and the reaction was continued for 12 hours. Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-005,0.65g (yield: 19.6%). ESI-MS (+): m/z=664.51 [ M+1].
EXAMPLE 7 Synthesis of Compound WUR-06
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of Compound WUR-06-1
ZJT-3 (2.75 g,5 mmol) is added to 30ml of methanol, and a 40% formaldehyde solution (10 ml) is added, heated to reflux, and reacted for 48 hours.
TLC monitoring showed complete reaction of starting material. Concentration gave a residue, 2.72g (yield: 93.7%). ESI-MS (+): m/z=580.41 [ M+1]
Step 2 preparation of Compound WUR-06
The above WUR-06-1 (2.32 g,4 mol) was added to DMF (20 ml) under nitrogen protection, 60% sodium hydrogen (0.32 g,8 mmol) was added and the system was stirred at room temperature for 0.5 hours. Chloromethyl dimethyl carbonate (0.5 g,4 mmol) was added thereto, and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. Concentrated, and the resulting residue was separated by preparative liquid phase to give WUR-06,0.33g (yield: 12.4%). ESI-MS (+): m/z=668.41 [ M+1]
EXAMPLE 8 Synthesis of Compound WUR-08
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of Compound WUR-08-1
ZJT-3 (3.30 g,6 mol) was added to DMF (40 ml) under nitrogen, 60% sodium hydrogen (0.48 g,12 mmol) was added and the system was stirred at room temperature for 0.5 hours.
Chloromethyl dibenzyl phosphate (1.96 g,6 mmol) was added thereto, and the reaction was continued for 12 hours. Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-08-1,0.94g (yield: 18.6%). ESI-MS (+): m/z=840.37 [ M+1]
Step 2 preparation of Compound WUR-08
WUR-08-1 (0.9 g,1.07 mmol) was added to methanol (30 ml) under nitrogen protection, palladium on carbon (0.09 g) was further added, and hydrogen was introduced and reacted at room temperature for 2 hours.
Thin layer detection showed complete reaction. Filtering and concentrating to obtain WUR-08,0.59g (yield 82.9%). ESI-MS (-): m/z=658.37 [ M-1].
EXAMPLE 9 Synthesis of Compound WUR-09
The reaction formula:
The preparation method comprises the following steps:
ZJT-3 (2.75 g,5 mol) was added to DMF (30 ml) under nitrogen, 60% sodium hydrogen (0.4 g,10 mmol) was added and the system was stirred at room temperature for 0.5 h.
Chloromethyl diethyl phosphate (1.01 g,5 mmol) was added and the reaction was continued for 12 hours. Thin layer detection showed complete reaction. Concentrated, and the resulting residue was separated by preparative liquid phase to give WUR-09,0.49g (yield: 13.6%). ESI-MS (+): m/z=716.11 [ M+1]
EXAMPLE 10 Synthesis of Compound WUR-12
The reaction formula:
The preparation method comprises the following steps:
WUR-08 (0.66 g,1.0 mmol) was added to acetonitrile (20 mL) under nitrogen protection, thionyl chloride (0.36 g,3.0 mmol) was added, after the addition was completed, the reaction was continued for 2 hours, triethylamine (0.40 g,4.0 mmol) was added to the system under ice bath conditions, propylene glycol (1 mL) was slowly added dropwise, and the reaction was continued for 1 hour after the addition.
Thin layer detection showed complete reaction. The system was concentrated, and the resulting residue was separated from the liquid phase to give WUR-12,0.17g (yield: 23.6%). ESI-MS (+): m/z=700.11 [ M+1]
EXAMPLE 11 Synthesis of Compound WUR-13
The reaction formula:
The preparation method comprises the following steps:
WUR-08 (0.66 g,1.0 mmol) was added to acetone (20 mL) under nitrogen, sodium hydroxide (0.12 g,3.0 mmol) was added, and after the addition was completed, the reaction was continued for 2 hours.
Ice water (30 mL) was added to the system, filtered, and the resulting solid was recrystallized from acetone/water to give compound WUR-13,0.16g (yield: 22.9%) ESI-MS (-):m/z= 328.52[ (M-2 Na)/2 ].
EXAMPLE 12 Synthesis of Compound WUR-14
The reaction formula:
The preparation method comprises the following steps:
WUR-06-1 (1.16 g,2 mol) was added to DMF (20 ml) under nitrogen protection, 60% sodium hydrogen (0.16 g,4 mmol) was added and the system was stirred at room temperature for 0.5 h. 1-chloro-ethyl methyl carbonate (0.28 g,2 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-14,0.19g (yield: 14.2%). ESI-MS (+): m/z=682.31 [ M+1].
EXAMPLE 13 Synthesis of Compound WUR-16
The reaction formula:
The preparation method comprises the following steps:
step 1 preparation of Compound ZJT-4
2, 2-Trifluoroacetamide (3.39 g,30 mmol) was added to tetrahydrofuran (50 mL), cooled to about 0℃and then added with lithium aluminum deuteride (2.52 g,60 mmol), slowly heated to 60℃under reflux for 4 hours after completion of the addition, cooled to 0℃after completion of the reaction, water (50 mL) was added to the slow phase system, 1% sodium hydroxide (50 mL) and water (150 mL) were further added, the reaction was quenched, filtered, the filter cake was washed with ethyl acetate and concentrated to give ZJT-4,2.35g (yield: 78.3%). ESI-MS (+): m/z=102.1 [ M+1].
Step 2 preparation of Compound WUR-16-1
ZJT-1-1 (6.99 g,0.02 mol) was added to tetrahydrofuran (90 mL), ZJT-4 (2.02 g,0.02 mol) and acetic acid (3 mL) were further added under nitrogen, and after the system was reacted at room temperature for 5 hours, cyano sodium borohydride (2.51 g,0.04 mol) was further added, and the reaction was continued for 3 hours.
Thin layer detection showed complete reaction. The system was neutralized by adding potassium carbonate, concentrated, diluted with water (100 ml), the aqueous phase was extracted with methylene chloride (100 ml. Times.3), the organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by the preparative liquid phase to give ZJT-16-1,1.52g (yield: 19.6%). ESI-MS (+): m/z=389.37 [ M+1].
Step 3 preparation of Compound WUR-16
WUR-16-1 (1.16 g,3 mmol) was added to tetrahydrofuran (30 ml) under nitrogen protection, hydrochloric acid solution (0.01M/3 ml) was further added, and the reaction was carried out at room temperature for 1 hour after the addition. Then, the pH was adjusted to 8-9 with triethylamine, concentrated, the aqueous phase was extracted with methylene chloride (50 ml. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue.
ZJT-2 (0.84 g,3 mmol) was added to tetrahydrofuran (20 ml), and thionyl chloride (0.71 g,6 mmol) was further added under nitrogen protection, and the reaction was continued for 3 hours at room temperature after the addition, and the above-mentioned spare residue was added to the system, and triethylamine (0.91 g,9 mmol) was further added, and the reaction was continued for 4 hours. Thin layer detection showed complete reaction. Concentration gave a residue, which was separated by column chromatography to give WUR-16,0.42g (yield: 25.3%). ESI-MS (+): m/z=552.41 [ M+1].
EXAMPLE 14 Synthesis of Compound ZJT-5
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of Compound ZJT-5-1
ZJT-1-SM (1.72 g,5 mmol) was added to DMF (50 mL) under nitrogen, and 1- (2, 3, 6-trifluorophenyl) propanone (0.94 g,5 mmol) was added and cesium carbonate (3.26 g,10 mmol) and the system reacted at 60℃for 10 hours.
Thin layer detection showed complete reaction. Filtration, concentration, dilution with water (100 ml), extraction of the aqueous phase with methylene chloride (100 ml. Times.3), washing with saturated brine (150 ml), drying over anhydrous sodium sulfate, filtration, concentration, and recrystallization of the resulting residue from ethanol/water gave ZJT-5-1,0.84g (yield: 47.3%). ESI-MS (+): m/z=355.27 [ M+1].
Step 2 preparation of Compound ZJT-5
ZJT-5-1 (0.71 g,2 mmol) was added to tetrahydrofuran (20 mL), 2-trifluoroethylamine (0.20 g,2 mmol) and acetic acid (0.3 mL) under nitrogen, and after the system was reacted at room temperature for 5 hours, sodium cyanoborohydride (0.25 g,4 mol) was further added, and the reaction was continued for 3 hours.
Thin layer detection showed complete reaction. The system was neutralized by adding potassium carbonate, concentrated, diluted with water (50 ml), extracted with methylene chloride (50 ml. Times.3), the organic phases were combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by the preparative liquid phase to give ZJT-5,0.16g (yield: 20.7%). ESI-MS (+): m/z=392.31 [ M+1].
EXAMPLE 15 Synthesis of Compound WUR-17
The reaction formula:
The preparation method comprises the following steps:
ZJT-5 (1.17 g,3 mmol) was added to tetrahydrofuran (20 ml) under nitrogen protection, and hydrochloric acid solution (1M/3 ml) was added thereto, and the reaction was carried out at room temperature for 1 hour after the addition. Then, the pH was adjusted to 8-9 with triethylamine, concentrated, the aqueous phase was extracted with methylene chloride (40 ml. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue.
ZJT-2 (0.84 g,3 mmol) was added to tetrahydrofuran (20 ml), and thionyl chloride (0.71 g,6 mmol) was further added under nitrogen protection, and the reaction was continued for 3 hours at room temperature after the addition, and the above-mentioned spare residue was added to the system, and triethylamine (0.91 g,9 mmol) was further added, and the reaction was continued for 4 hours. Thin layer detection showed complete reaction. Concentration gave a residue which was separated by column chromatography to give WUR-17,0.51g (yield: 30.9%). ESI-MS (+): m/z=555.41 [ M+1].
EXAMPLE 16 Synthesis of Compound WUR-19
The reaction formula:
The preparation method comprises the following steps:
WUR-16 (1.65 g,3 mol) was added to DMF (30 ml) under nitrogen protection, 60% sodium hydrogen (0.24 g,6 mmol) was added and the system was stirred at room temperature for 0.5 h.
Chloromethyl dimethyl carbonate (0.37 g,3 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-19,0.37g (yield: 19.4%). ESI-MS (+): m/z=640.21 [ M+1].
EXAMPLE 17 Synthesis of Compound WUR-21
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of Compound ZJT-6
Chloromethyl chloroformate (0.64 g,5 mmol) was added to dichloromethane (20 ml) under nitrogen, the system was cooled to 0 ℃, deuterated methanol-4 d (0.18 g,5 mmol) was added, triethylamine (0.51 g,5 mmol) was added, and the system temperature was controlled to not more than 5 ℃. After the addition, the system was stirred at room temperature for 1 hour.
The system was filtered and concentrated to give residue ZJT-6,0.62g (yield: 97.5%). ESI-MS (+): m/z=128.51 [ M+1]
Step 2 preparation of Compound WUR-21
ZJT-3 (1.65 g,3 mol) was added to DMF (30 ml) under nitrogen, followed by 60% sodium hydrogen (0.24 g,6 mmol) and the system was stirred at room temperature for 0.5 h.
ZJT-6 (0.38 g,3 mmol) was further added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-21,0.32g (yield: 16.4%). ESI-MS (+): m/z=641.28 [ M+1].
EXAMPLE 18 Synthesis of Compound WUR-22
The reaction formula:
The preparation method comprises the following steps:
WUR-16 (1.65 g,3 mol) was added to DMF (30 ml) under nitrogen protection, 60% sodium hydrogen (0.24 g,6 mmol) was added and the system was stirred at room temperature for 0.5 h.
ZJT-6 (0.38 g,3 mmol) was further added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-22,0.29g (yield: 15.3%). ESI-MS (+): m/z=643.51 [ M+1].
EXAMPLE 19 Synthesis of Compound WUR-23
The reaction formula:
The preparation method comprises the following steps:
WUR-16 (1.65 g,3 mol) was added to DMF (30 ml) under nitrogen protection, 60% sodium hydrogen (0.24 g,6 mmol) was added and the system was stirred at room temperature for 0.5 h.
Chloromethyl isobutyrate (0.41 g,3 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-23,0.31g (yield: 16.1%). ESI-MS (+): m/z=652.31 [ M+1].
EXAMPLE 20 Synthesis of Compound WUR-24
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of Compound WUR-24-1
WUR-16 (1.38 g,2.5 mmol) was added to methanol 20ml, and then 5ml of 40% formaldehyde solution was added, heated to reflux, and reacted for 48 hours, and liquid monitoring showed complete reaction of the starting materials. Concentrated to give a residue WUR-24-1,1.41g (yield: 97.3%) for use. ESI-MS (+): m/z=582.38 [ M+1]
Step 2 preparation of Compound WUR-24
Deuterated isobutyric acid-6 d (0.19 g,2 mmol) was added to DCM (20 ml), then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 0.77g,4 mmol), 4-dimethylaminopyridine (DMAP, 0.12,1 mmol) and finally WUR-24-1 (1.16 g,2 mmol) was added and stirred at room temperature for 24 hours.
The system was concentrated, and the obtained residue was subjected to column chromatography to obtain WUR-24,0.30g (yield: 22.8%). ESI-MS (+): m/z=658.18 [ M+1]
EXAMPLE 21 Synthesis of Compound WUR-26
The reaction formula:
The preparation method comprises the following steps:
Deuterated isobutyric acid-6 d (0.19 g,2 mmol) was added to DCM (20 ml), EDCI (0.77 g,4 mmol), DMAP (0.12 g,1 mmol) and finally WUR-06-1 (1.16 g,2 mmol) was added and stirred at room temperature for 24 hours.
Thin layer detection showed complete reaction. The system was concentrated, and the obtained residue was subjected to column chromatography to obtain WUR-26,0.28g (yield: 21.5%). ESI-MS (+): m/z=656.51 [ M+1].
EXAMPLE 22 Synthesis of Compound WUR-29
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of Compound WUR-29-1
WUR-16 (3.31 g,6 mmol) was added to DMF (60 ml) under nitrogen protection, 60% sodium hydrogen (0.48 g,12 mmol) was added and the system stirred at room temperature for 0.5 h. Chloromethyl dibenzyl phosphate (1.96 g,6 mmol) was added thereto, and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-08-1,1.95g (yield: 38.7%). ESI-MS (+): m/z=842.59 [ M+1].
Step 2 preparation of Compound WUR-29
WUR-29-1 (0.84 g,1 mmol) was added to methanol (20 ml) under nitrogen protection, palladium on carbon (0.04 g) was further added, and hydrogen was introduced and reacted at room temperature for 2 hours.
Thin layer detection showed complete reaction. Filtering and concentrating to obtain WUR-29,0.50g (yield 75.3%). ESI-MS (-): m/z=660.15 [ M-1].
EXAMPLE 23 Synthesis of Compound WUR-30
The reaction formula:
The preparation method comprises the following steps:
WUR-16 (1.10 g,2 mmol) was added to DMF (20 ml) under nitrogen protection, 60% sodium hydrogen (0.16 g,4 mmol) was added and the system stirred at room temperature for 0.5 h. Chloromethyl diethyl phosphate (0.41 g,2 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-30,0.21g (yield: 14.5%). ESI-MS (+): m/z=718.19 [ M+1]
EXAMPLE 24 Synthesis of Compound WUR-34
The reaction formula:
The preparation method comprises the following steps:
WUR-29 (1.98 g,3.0 mmol) was added to acetonitrile (30 mL) under nitrogen protection, thionyl chloride (0.71 g,6.0 mmol) was added, after the addition was completed, the reaction was continued for 2 hours, triethylamine (0.61 g,6.0 mmol) was added to the system under ice bath conditions, propylene glycol (3 mL) was slowly added dropwise, and the reaction was continued for 1 hour after the addition.
Thin layer detection showed complete reaction. The system was concentrated, and the resulting residue was separated from the liquid phase to give compound WUR-34,0.57g (yield: 27.3%). ESI-MS (+): m/z=702.31 [ M+1].
EXAMPLE 25 Synthesis of Compound ZJT-7
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of ZJT-7-1
ZJT-1-SM (1.72 g,5 mmol) was added to DMF (50 mL) under nitrogen, and 1- (2, 3, 6-trifluorophenyl) propanone (0.94 g,5 mmol) was added and cesium carbonate (3.26 g,10 mmol) and the system reacted at 60℃for 10 hours.
Thin layer detection showed complete reaction. Filtration, concentration, dilution with water (100 ml), extraction of the aqueous phase with methylene chloride (100 ml. Times.3), washing with saturated brine (150 ml), drying over anhydrous sodium sulfate, filtration, concentration, and recrystallization of the resulting residue from ethanol/water gave ZJT-7-1,1.18g (yield: 58.3%). ESI-MS (+): m/z=404.27 [ M+1].
Step 2 preparation of ZJT-7
ZJT-7-1 (0.81 g,2 mmol) was added to tetrahydrofuran (20 mL), ZJT-4 (0.2 g,2 mmol) and acetic acid (0.3 mL) were further added under nitrogen, and after the system was reacted at room temperature for 5 hours, sodium cyanoborohydride (0.25 g,4 mmol) was further added and the reaction was continued for 3 hours.
Thin layer detection showed complete reaction. The system was neutralized by adding potassium carbonate, concentrated, diluted with water (50 ml), the aqueous phase was extracted with methylene chloride (50 ml. Times.3), the organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was separated by the preparative liquid phase to give ZJT-7,0.16g (yield: 17.7%). ESI-MS (+): m/z=443.37 [ M+1].
EXAMPLE 26 Synthesis of Compound WUR-37
The reaction formula:
The preparation method comprises the following steps:
ZJT-7 (1.33 g,3 mmol) was added to tetrahydrofuran (30 ml) under nitrogen protection, and hydrochloric acid solution (1M/3 ml) was further added, and the reaction was carried out at room temperature for 1 hour after the addition. Then, the pH was adjusted to 8-9 with triethylamine, concentrated, the aqueous phase was extracted with methylene chloride (50 ml. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue.
ZJT-2 (0.84 g,3 mmol) was added to tetrahydrofuran (30 ml), and thionyl chloride (0.71 g,6 mmol) was further added under nitrogen protection, and the reaction was continued for 3 hours at room temperature after the addition, and the above-mentioned spare residue was added to the system, and triethylamine (0.91 g,9 mmol) was further added, and the reaction was continued for 4 hours.
Thin layer detection showed complete reaction. Concentration gave a residue, which was separated by column chromatography to give WUR-37,0.46g (yield: 25.4%). ESI-MS (+): m/z=606.43 [ M+1].
EXAMPLE 27 Synthesis of Compound WUR-40
The reaction formula:
The preparation method comprises the following steps:
WUR-37 (1.21 g,2 mol) was added to DMF (20 ml) under nitrogen protection, 60% sodium hydrogen (0.16 g,4 mmol) was added and the system was stirred at room temperature for 0.5 h.
Chloromethyl dimethyl carbonate (0.25 g,2 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-40,0.24g (yield: 17.3%). ESI-MS (+): m/z=694.31 [ M+1].
EXAMPLE 28 Synthesis of Compound ZJT-8
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of ZJT-8-1
ZJT-1-SM (0.69 g,2 mmol) was added to DMF (20 mL) under nitrogen, and 1- (2, 3, 6-trifluorophenyl) propanone (0.38 g,2 mmol) was added and cesium carbonate (1.30 g,4 mmol) and the system reacted at 60℃for 10 hours.
Thin layer detection showed complete reaction. Filtration, concentration, dilution with water (50 ml), extraction of the aqueous phase with methylene chloride (50 ml. Times.3), washing with saturated brine (150 ml), drying over anhydrous sodium sulfate, filtration, concentration, and recrystallization of the resulting residue from ethanol/water gave ZJT-8-1,0.48g (yield: 59.6%). ESI-MS (+): m/z=404.27 [ M+1].
Step 2 preparation of ZJT-8
ZJT-8-1 (0.40 g,1 mmol) was added to tetrahydrofuran (20 mL), 2-trifluoroethylamine (0.10 g,1 mmol) and acetic acid (0.15 mL) under nitrogen, and after the system was reacted at room temperature for 5 hours, sodium cyanoborohydride (0.13 g,2 mmol) was further added and the reaction was continued for 3 hours.
Thin layer detection showed complete reaction. The system was neutralized by adding potassium carbonate, concentrated, diluted with water (50 ml), the aqueous phase was extracted with methylene chloride (100 ml. Times.2), the organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by the preparative liquid phase to give ZJT-8,0.10g (yield: 23.8%). ESI-MS (+): m/z=441.17 [ M+1].
EXAMPLE 29 Synthesis of Compound WUR-41
The reaction formula:
The preparation method comprises the following steps:
Step 1 preparation of Compound WUR-41-1
ZJT-8 (1.32 g,3 mmol) was added to tetrahydrofuran (30 ml) under nitrogen protection, and hydrochloric acid solution (1M/3 ml) was added thereto, and the reaction was carried out at room temperature for 1 hour after the addition. Then, the pH was adjusted to 8-9 with triethylamine, concentrated, the aqueous phase was extracted with methylene chloride (40 ml. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue.
ZJT-2 (0.84 g,3 mmol) was added to tetrahydrofuran (30 ml), and thionyl chloride (0.71 g,6 mmol) was further added under nitrogen protection, and the reaction was continued for 3 hours at room temperature after the addition, and the above-mentioned spare residue was added to the system, and triethylamine (0.91 g,9 mmol) was further added, and the reaction was continued for 4 hours.
Thin layer detection showed complete reaction. Concentration gave a residue, which was separated by column chromatography to give WUR-41-1,0.68g (yield: 37.5%). ESI-MS (+): m/z=604.81 [ M+1]
Step 2 preparation of Compound WUR-41
WUR-41-1 (0.6 g,1 mol) was added to DMF (20 ml) under nitrogen protection, 60% sodium hydrogen (0.08 g,2 mmol) was added and the system was stirred at room temperature for 0.5 h. ZJT-6 (0.13 g,1 mmol) was further added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue obtained was concentrated and separated by the preparative liquid phase to give WUR-41,0.15g (yield: 20.9%). ESI-MS (+): m/z=695.51 [ M+1]
EXAMPLE 30 Synthesis of Compound WUR-42
The reaction formula:
The preparation method comprises the following steps:
WUR-37 (1.82 g,3 mol) was added to DMF (30 ml) under nitrogen protection, 60% sodium hydrogen (0.24 g,6 mmol) was added and the system was stirred at room temperature for 0.5 h.
ZJT-6 (0.38 g,3 mmol) was further added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-42,0.32g (yield: 15.3%). ESI-MS (+): m/z=697.51 [ M+1].
EXAMPLE 31 Synthesis of Compound WUR-43
The reaction formula:
The preparation method comprises the following steps:
WUR-37 (1.65 g,2 mol) was added to DMF (20 ml) under nitrogen protection, 60% sodium hydrogen (0.16 g,4 mmol) was added and the system was stirred at room temperature for 0.5 h.
Chloromethyl isobutyrate (0.27 g,2 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. Concentrated, and the resulting residue was separated by preparative liquid phase to give WUR-43,0.21g (yield: 14.7%). ESI-MS (+): m/z=706.72 [ M+1]
EXAMPLE 32 Synthesis of Compound WUR-46
The reaction formula:
The preparation method comprises the following steps:
step 1 preparation of Compound WUR-46-1
WUR-37 (1.82 g,3 mol) was added to DMF (30 ml) under nitrogen protection, 60% sodium hydrogen (0.24 g,6 mmol) was added and the system was stirred at room temperature for 0.5 h.
Chloromethyl dibenzyl phosphate (0.98 g,3 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. The residue was concentrated and separated by the preparative liquid phase to give WUR-46-1,2.11g (yield: 78.6%). ESI-MS (+): m/z=896.17 [ M+1]
Step 2 preparation of Compound WUR-46
WUR-46-1 (1.79 g,2 mmol) was added to methanol (30 ml) under nitrogen protection, palladium on carbon (0.09 g) was further added, and hydrogen was introduced and reacted at room temperature for 2 hours. Thin layer detection showed complete reaction. Filtering and concentrating to obtain WUR-46,0.60g (yield 42.1%). ESI-MS (+): m/z=716.17 [ M+1].
EXAMPLE 33 Synthesis of Compound WUR-47
The reaction formula:
The preparation method comprises the following steps:
WUR-37 (1.21 g,2 mol) was added to DMF (20 ml) under nitrogen protection, 60% sodium hydrogen (0.16 g,4 mmol) was added and the system was stirred at room temperature for 0.5 h. Chloromethyl diethyl phosphate (0.41 g,2 mmol) was added and the reaction was continued for 12 hours.
Thin layer detection showed complete reaction. Concentrated, and the resulting residue was separated by preparative liquid phase to give WUR-47,0.18g (yield: 11.6%). ESI-MS (+): m/z=772.11 [ M+1].
The following examples were synthesized in the same manner as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from the commercially available compounds.
EXAMPLE 34 determination of antagonistic Activity of Compounds of the invention against human CGRP receptor
Cell lines SK-N-MC cells stably expressing human CGRP receptor (available from Frebo biotechnology Co., guangzhou, cat# CB 310693428).
Culture medium MEM medium containing 10% Fetal Bovine Serum (FBS) and 1 Xpenicillin-streptomycin. The source is Gibco TM (Thermo FISHER SCIENTIFIC), FBS: #26140-079 (high quality fetal bovine serum).
Experiment buffer 1 XHBSS buffer containing 20mM HEPES, 0.1% BSA and 500. Mu.M IBMX. Source Servicebio (Whansai Vir Biotechnology Co., ltd.) G4203-500ML.
CAMP detection kit (Lysis Buffer) PERKINELMER CAMP KIT (TR-FRET method). The source is Perkinelmer (Perkin Elmer), TRF0262.
Device EnVision multifunctional enzyme labelling instrument (Perkinelmer).
Prior to the start of the experiment, SK-N-MC cells stably expressing CGRP receptor were digested with TrypLE, the digested cells were washed 3 times with assay buffer, the washed cells were collected and resuspended in appropriate amount of medium. Subsequently, the resuspended cells were inoculated in 384-well plates, the number of cells inoculated per well being 2×10 4, the volume of inoculation being 80 μl, left to stand and then pre-cultured in a 5% co 2, 37 ℃ incubator. The experimental drugs (comprising the compound of the invention and the control compounds Ubrogepant and Atogepant) are prepared into stock solution by using DMSO, the stock solution is diluted by 10 times by using the culture solution to obtain intermediate stock solution, and then the intermediate stock solution is diluted by 3 times by using the culture solution in a decreasing gradient to obtain the drug working solution with 10 concentration gradients. After adding 2.5. Mu.L of 10 gradients of the drug working solution to each well of the inoculated cells, they were incubated at 5% CO 2 for 10 minutes at 37 ℃. Subsequently, human α -CGRP was diluted with assay buffer to a concentration of 16nM working solution, 2.5 μl of each was added to each well and incubation was continued at 5% CO 2, 37℃for 30 min. After that, the Eu-CAMP TRACER and Ulight anti-cAMP antibodies after freeze thawing were diluted with lysisbuffer, 10. Mu.L of Eu-CAMP TRACER and 10. Mu. L ULight anti-cAMP antibodies were sequentially added to each well, and the reaction plate was centrifuged at 200g at room temperature for 30 seconds and allowed to stand for 1 hour. Each concentration was tested with 3 duplicate wells and with blank control wells (cell-containing, drug-free, DMSO content less than 0.1%) and negative control wells (cell-free, drug-free, DMSO content less than 0.1%). The TR-FRET signal was finally detected using the EnVision system and antagonistic IC 50 values for the human CGRP receptor were calculated for each compound by GRAPHPAD PRISM software. The final concentration of the compounds in the experiment is 0.0005-10.000 nM. The results are shown in Table 1.
TABLE 1 determination of antagonistic Activity of the inventive Compounds against human CGRP receptor
The results show that the compounds WUR-01 to WUR-36 of the present invention have more excellent CGRP receptor antagonistic activity than the control compound Ubrogepant, up to 30 times that of the control compound, and that the compounds WUR-37 to WUR-48 of the present invention also have more excellent CGRP receptor antagonistic activity than the control compound Atogepant, up to 20 times that of the control compound.
Example 35 pharmacodynamic test on nitroglycerin-induced migraine in rats
The instrument equipment comprises MuLtiskan Go full-wavelength enzyme-labeled instrument, a thermal-Fisher, a TGL-16B centrifuge, shanghai Anting scientific instrument factory, a TissueLyserII refiner, kaiji corporation (Shanghai), an OSB-2200 rotary evaporator, xiamen technology, inc., and a UV-8000S ultraviolet visible spectrophotometer, shanghai Yuan analysis instruments, inc.
The instrument equipment comprises MuLtiskan Go full-wavelength enzyme-labeled instrument, a thermal-Fisher, a TGL-16B centrifuge, shanghai Anting scientific instrument factory, a TissueLyserII refiner, kaiji corporation (Shanghai), an OSB-2200 rotary evaporator, xiamen technology, inc., and a UV-8000S ultraviolet visible spectrophotometer, shanghai Yuan analysis instruments, inc.
SPF-grade healthy, male SD rats (6 weeks old, weight 180+ -20 g) (purchased from Jiangsu Ji Kangyaku Biotechnology Co., ltd.) were randomly divided into 8 groups of 8 groups each of a blank group, a model group, a control group (Ubrogepant), a WUR-01 group, a WUR-05 group, a WUR-16 group, a WUR-19 group and a WUR-28 group. All rats were acclimatized for 7 days prior to the experiment and then subjected to the experiment after 12 hours of fasting without water withdrawal. On the day of the test, the test groups were each given 15mg/kg of the compound of the present invention or the control compound by gavage, except for the blank group and the model group, and the concentration of the drug for gavage administration was 1.5mg/mL (prepared by adding 150mg of the compound to 100mL of a 1% methylcellulose solution), and the blank group and the model group were given equal volumes of a 1% methylcellulose solution. After 30 minutes of administration, the rats of each group were subcutaneously and slowly injected with nitroglycerin (10 mg/kg) on the right side of the center of the back, except for a blank group, which was then injected with an equal volume of physiological saline, to induce a migraine model. Model group rats with ears reddening, frequent flexible head, increase of climbing cage behaviors and finally migraine typical manifestations such as lassitude, dullness and the like are used for judging whether the model construction is successful
Observing and detecting an index
(1) Animal behavioural investigation:
After the nitroglycerin is injected subcutaneously, a sectional counting method is adopted, every 30min is taken as a time period, and the number of times of deflection of the rat in three time periods within 0-90 min after model replication is observed. Number of deflection inhibition = (number of deflection of model group-number of deflection of administration group)/number of deflection of model group.
(2) Detection of bioactive substances in rat plasma:
after molding for 4 hours, rats were anesthetized with 10% chloral hydrate (3 mL kg -1), the abdominal aorta was bled, placed in a vacuum vessel with anticoagulant added, centrifuged (3000 r.min -1, 4 ℃ C., 10 min), plasma was isolated, and placed in a-80 ℃ refrigerator for cryopreservation to be tested. The ET and CGRP contents are determined by ELISA method strictly according to the instruction of the kit, and the NO content is determined by nitrate reductase method.
Statistical analysis
Experimental data were processed using SPSS23.0 software with mean and standard deviation ofThe comparison between groups is statistically significant using independent sample T test, with P <0.05 or P <0.01 indicating differences.
The effect of the drug on the flex head of the rats is shown in Table 2.
The effect of the drug on rat plasma NO, ET, CGRP is shown in table 3.
TABLE 2 influence of drugs on rat flex head
Note that * is P <0.01 compared to the blank group and Δ is P <0.01 compared to the model group.
Table 3. Effect of drug on rat plasma NO, ET, CGRP (n=8)
Note that P <0.01 compared to the blank group, delta is P <0.01 compared to the model group;
Experimental results show that the model group shows typical migraine symptoms such as binaural redness, frequent deflection, increase of climbing cage behaviors and the like, and the deflection frequency is obviously higher than that of a blank group (P < 0.01), which indicates that the migraine model is successfully constructed. Compared with a model group, in each time period of 0-90 min, the control group and the compound group have obvious inhibition effect on the deflection head of rats under the same dosage, and the compound group has obvious inhibition effect on the migraines of rats induced by nitroglycerin, which is superior to the compound group. For biochemical indexes, compared with a model group, NO and CGRP in a control group and a compound group of the invention are obviously reduced (P < 0.01), ET is obviously increased (P < 0.01), and the compound group data of the invention is more excellent than that of the compound in the control group. In conclusion, the compound disclosed by the invention can obviously influence the flex head behavior and biochemical indexes of a rat model with migraine induced by nitroglycerin, and has a more obvious effect of improving migraine symptoms than that of a compound in a control group.
EXAMPLE 36 in vivo pharmacokinetic study of Compounds in rats
The experimental animals were 18 male Sprague-Dawley (SD) rats with a body weight of 200+ -20 g. Rats were acclimatized to the laboratory animal center for 3 days prior to the experiment, with the environment controlled to be constant temperature (22.+ -. 2 ℃) and constant humidity (55%.+ -. 10%) and the illumination period being 12 hours of light-dark alternation. Rats were fasted and not watered for more than 12 hours before the start of the experiment. The administration was continued with a continuous fasting for 4 hours without water withdrawal.
Animals were grouped and dosed-experimental animals were randomly grouped into 6 groups of 3 animals each:
control group Ubrogepant (5.00 mg/kg)
Test group WUR-01 (5.80 mg/kg), WUR-05 (6.04 mg/kg), WUR-16 (5.02 mg/kg), WUR-19 (5.82 mg/kg), WUR-28 (6.06 mg/kg)
The doses are all administered according to equimolar principle (9.1 mu mol/kg is 2.5 mL/kg) and are administered by single oral gastric lavage mode. All experimental drugs are prepared at present.
The preparation of drug administration solution comprises accurately weighing appropriate amount of each test sample, placing into clean and dry reagent bottle, adding appropriate amount of 1% methylcellulose (CMC-Na) solution, and mixing by vortex to obtain oral administration gastric administration solution with required concentration. Each group was freshly prepared prior to use, ensuring solution stability.
Blood sampling and sample processing, namely, about 300 mu L of venous blood is collected through the eyesockets before administration (0 h) and 0.25h, 1h, 1.5h, 2h, 2.5h, 3h, 5h, 10h and 24h after administration and placed in an EP tube containing heparin anticoagulant. After the sample was placed in an ice bath for 15 minutes, it was centrifuged at 4000rpm for 10 minutes at 4℃to separate plasma, and 50. Mu.L of plasma was taken for subsequent drug concentration determination.
The detection method and the pharmacokinetic analysis are to quantitatively analyze the concentration of the drug in the blood plasma by adopting a liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology. The detection indexes of each group are Ubrogepant groups, WUR-01 groups and WUR-05 groups, namely, detecting the Ubrogepant concentration in blood plasma, and the detection indexes of each group are WUR-16 groups, WUR-19 groups and WUR-28 groups, namely, detecting the WUR-16 concentration in the blood plasma. The resulting concentration-time data was used to calculate the main pharmacokinetic parameters (Cmax, tmax, AUC, t 1/2, etc.), and was analyzed using the non-compartmental model method (non-compartmental analysis, NCA). The pharmacokinetic parameters of the intragastric administration in rats are shown in Table 4.
TABLE 4 pharmacokinetic parameters of compound intragastric administration
According to the data analysis, the compounds WUR-01, WUR-05, WUR-16, WUR-19 and WUR-28 of the present invention all showed significant advantages over the control compound Ubrogepant in terms of critical pharmacokinetic parameters, cmax (0.69-0.84. Mu.M) was significantly increased over Ubrogepant (0.45. Mu.M), peak concentration higher indicated a stronger drug effect, tmax (1.0-1.5 h) was almost half of Ubrogepant (2.6 h), peak time shorter indicated a more rapid pain relief in migraine episodes, AUC 0-24 (5.12-6.21. Mu.M.h) was almost twice as large as Ubrogepant (2.87. Mu.M.h), area under the curve increased indicated a higher systemic exposure and higher bioavailability, half-life T 1/2 (5.1-6.3 h) was 2-3 times that of Ubrogepant (2.1 h), half-life extension indicated less compliance in migraine episodes. Overall, the compound of the invention has the obvious advantages of faster effect, better curative effect, less administration frequency, better use compliance and the like under equimolar dose.
While the invention has been described with reference to the preferred embodiments, it is not intended to limit the invention thereto, and it is to be understood that other modifications and improvements may be made by those skilled in the art without departing from the spirit and scope of the invention, which is therefore defined by the appended claims.
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