CN112390799B - Nitrogen-containing heterocyclic 5-HT3 receptor regulator and preparation method and application thereof - Google Patents

Nitrogen-containing heterocyclic 5-HT3 receptor regulator and preparation method and application thereof Download PDF

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CN112390799B
CN112390799B CN202010819745.6A CN202010819745A CN112390799B CN 112390799 B CN112390799 B CN 112390799B CN 202010819745 A CN202010819745 A CN 202010819745A CN 112390799 B CN112390799 B CN 112390799B
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谢德建
陈方
李潇霞
刘嘉川
张伟
黄金昆
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Kelingyuan Biotechnology Shenzhen Co ltd
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Abstract

The invention provides a nitrogenous heterocyclic 5-HT3 receptor regulator and a preparation method and application thereof, and relates to the field of pharmaceutical chemistry. The nitrogen-containing heterocyclic 5-HT3 receptor modulator is a compound shown in formula I, or a salt, a stereoisomer, a tautomer, a prodrug, a solvate or a hydrate thereof. Experiments prove that the compound prepared by the invention has strong affinity to a 5-HT3 receptor, has high activity as a regulator of the 5-HT3 receptor, can be used for preparing the 5-HT3 receptor regulator, can also be used for preparing medicaments for treating diseases (such as irritable bowel syndrome, nausea, vomiting, gastroenteritis, gastric dysfunction, diarrhea, pain, carcinoid syndrome and drug addiction) related to the 5-HT3 receptor, and has good application prospect.

Description

Nitrogen-containing heterocyclic 5-HT3 receptor regulator and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a nitrogenous heterocyclic 5-HT3 receptor regulator and a preparation method and application thereof.
Background
The 5-hydroxytryptamine type 3 (also known as serotonin type 3, 5-HT3) receptor is expressed in the central nervous system involved in the emesis reflex, pain management, cognitive and anxiety control, and is also expressed in the gastrointestinal tract, and thus may have a modulating effect on gastrointestinal disorders such as irritable bowel syndrome, dyspepsia, gastroesophageal reflux disease and irritable bowel syndrome.
Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder with persistent or intermittent episodes manifested clinically by abdominal pain, abdominal distension, altered bowel habits and/or stool characteristics, lack of gastrointestinal structural and biochemical abnormalities. Compounds that alter the activity of certain 5-hydroxytryptamine receptors have been shown to be beneficial in the symptomatic treatment of Irritable Bowel Syndrome (IBS).
Among such 5-HT3 receptor modulators, the only drug is the FDA approved alosetron, which exited the market shortly after 2000 approval due to ischemic colitis in IBS patients. The FDA subsequently restored the drug because IBS patients were in greater demand, and alosetron tablets were approved in 2002 for patients with greater medical benefit than risk under the limiting conditions. Therefore, the development of safe 5-HT3 receptor modulators for the treatment of IBS is of great interest.
Carcinoids (carcinoids) are a rare, slow-growing tumor that produces small peptides or peptide hormones, the most common endocrine tumors of the gastrointestinal tract, and now ascribed to neuroendocrine tumors (NENs). Carcinoid syndrome is mainly symptomatic control with somatostatin analogues (SSAs). However, for the treatment of adult patients with Carcinoid Syndrome Diarrhea (CSD) who are not adequately controlled by SSAs therapy alone, tryptophan hydroxylase (TPH) in carcinoid tumor cells is targeted, the overproduction of serotonin (serotonin) is inhibited, the frequency of carcinoid syndrome diarrhea can be reduced, and symptoms can be significantly changed.
Nausea and Vomiting (CINV) caused by chemotherapy has an average incidence of up to 90%. It may make the patient less and less resistant, delay the improvement of the condition and cause negative consequences for the patient.
Postoperative nausea and vomiting (PONV) are the most common symptoms of patients after operation, and are influenced by various factors such as operation types, operation duration, narcotic drugs and methods, preoperative anxiety and the like, most of patients can suffer from PONV 24 hours after operation, and obvious nausea symptoms can appear before vomiting. Postoperative nausea and vomiting are also common postoperative complications, and it has been reported that the average incidence is 20% to 30%, even 70% in high risk patients. In addition to severe discomfort to the patient, nausea and vomiting may also cause medical complications such as wound dehiscence, bleeding, aspiration of pneumonia, water electrolyte disturbance, etc. Therefore, the prevention and treatment method of PONV is increasingly paid attention.
Studies have shown that modulation of the 5-HT3 receptor has therapeutic effects on IBS, CSD, CINV and PONV. The drug currently approved for the treatment of IBS that modulates 5 hydroxytryptamine 3 receptor activity is a 5-HT3 receptor antagonist, a drug that is fully antagonistic to 5-hydroxytryptamine 3 receptor activity, with adverse effects of constipation and colonic ischemia, and in severe cases even life threatening. Therefore, the preparation of more effective, safer, and more pharmacokinetic-competent 5-HT3 receptor modulators that meet clinical needs is critical for the treatment of a variety of diseases, including IBS, CSD, CINV, and PONV.
Disclosure of Invention
The invention aims to provide a 5-HT3 receptor modulator which is more effective, safer and better in pharmacokinetic performance.
The invention provides a compound shown as a formula I, or a salt, a stereoisomer, a tautomer, a prodrug, a solvate or a hydrate thereof:
Figure BDA0002634038700000021
wherein the content of the first and second substances,
x, Y is selected from CH or N, and at least one of X or Y is N;
z is selected from N or CR4；
L is selected from 0-8 alkylene, -C ═ O or-SO2；
R1Selected from hydrogen, deuterium, halogen, -OR4、-NR4R5、-NR4C(O)R5、-NR4C(O)2R5、-NR5C(O)R4、-S(O)R5、-CN、-C(O)R5、-C(O)NR4R5Substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C2～C8Alkynyl, substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8Alkoxy, substituted or unsubstituted C3～C8Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C8Alkyl, halogen, -CN, -OR7、-NR7R8Or phenyl; said phenyl being optionally substituted by halogen, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN, -OR7or-NR7R8Substituting for 1-3 times;
R2selected from H, deuterium, halogen, -OR4、-NR4R5、-NR4C(O)R5、-NR4C(O)2R5、-NR5C(O)R4、-S(O)R5、-CN、-C(O)R5、-C(O)NR4R5Substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C2～C8Alkynyl, substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8An alkoxy group; substituted or unsubstituted C3～C8Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C8Alkyl, halogen, -CN, -OR7、-NR7R8Or phenyl; said phenyl being optionally substituted by halogen, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN, -OR7or-NR7R8Substituting for 1-3 times;
R3selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amines; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C3Alkyl, halogen, -CN, -OR7Or NR7R8；
R4Selected from H, deuterium, halogen, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
R5selected from H, deuterium, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substitutedC1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
R7and R8Selected from H, deuterium, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
n is 0, 1 or 2;
when X is N, Y is CH, and N is 0, R3Saturated heterocyclic amines which are not substituted or unsubstituted.
Further, the compound is represented by formula II-1:
Figure BDA0002634038700000041
wherein the content of the first and second substances,
l is selected from 0-8 alkylene, -C ═ O or-SO2；
R1Selected from hydrogen, deuterium, halogen, -OR4、-NR4R5、-NR4C(O)R5、-NR4C(O)2R5、-NR5C(O)R4、-S(O)R5、-CN、-C(O)R5、-C(O)NR4R5Substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C2～C8Alkynyl, substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8Alkoxy, substituted or unsubstituted C3～C8Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said substitution is optionallyIs substituted by 1 to 3 substituents independently selected from C1～C8Alkyl, halogen, -CN, -OR7、-NR7R8Or phenyl; said phenyl being optionally substituted by halogen, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN, -OR7or-NR7R81-3 times of substitution;
R2selected from H, deuterium, halogen, -OR4、-NR4R5、-NR4C(O)R5、-NR4C(O)2R5、-NR5C(O)R4、-S(O)R5、-CN、-C(O)R5、-C(O)NR4R5Substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C2～C8Alkynyl, substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8An alkoxy group; substituted or unsubstituted C3～C8Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C8Alkyl, halogen, -CN, -OR7、-NR7R8Or phenyl; said phenyl being optionally substituted by halogen, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN, -OR7or-NR7R81-3 times of substitution;
R3selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amines; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C3Alkyl, halogen, -CN, -OR7Or NR7R8；
R4Selected from H, deuterium, halogen, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
R5selected from H, deuterium, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
R7and R8Selected from H, deuterium, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
n is 0, 1 or 2;
alternatively, the compound is represented by formula II-2:
Figure BDA0002634038700000051
wherein the content of the first and second substances,
l is selected from 0-8 alkylene, -C ═ O or-SO2；
R1Selected from hydrogen, deuterium, halogen, -OR4、-NR4R5、-NR4C(O)R5、-NR4C(O)2R5、-NR5C(O)R4、-S(O)R5、-CN、-C(O)R5、-C(O)NR4R5Substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C2～C8Alkynyl, substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8Alkoxy, substituted or unsubstituted C3～C8Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C8Alkyl, halogen, -CN, -OR7、-NR7R8Or phenyl; said phenyl being optionally substituted by halogen, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN, -OR7or-NR7R81-3 times of substitution;
R2selected from H, deuterium, halogen, -OR4、-NR4R5、-NR4C(O)R5、-NR4C(O)2R5、-NR5C(O)R4、-S(O)R5、-CN、-C(O)R5、-C(O)NR4R5Substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C2～C8Alkynyl, substituted or unsubstituted C1～C8Alkyl, substituted or unsubstituted C1～C8An alkoxy group; substituted or unsubstituted C3～C8Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C8Alkyl, halogen, -CN, -OR7、-NR7R8Or phenyl; said phenyl being optionally substituted by halogen, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN, -OR7or-NR7R81-3 times of substitution;
R3selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amines; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C3Alkyl, halogen, -CN, -OR7Or NR7R8；
R4Selected from H, deuterium, halogen, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
R5selected from H, deuterium, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
R7and R8Selected from H, deuterium, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
n is 0, 1 or 2;
when n is 0, R3Saturated heterocyclic amines which are not substituted or unsubstituted.
Further, the compound is represented by the formula III-1:
Figure BDA0002634038700000061
R3selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amines; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C3Alkyl, halogen, -CN, -OR7Or NR7R8；
R7And R8Selected from H, deuterium, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
n is 0, 1 or 2;
alternatively, the compound is represented by formula III-2:
Figure BDA0002634038700000071
R3selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amines; said substitution is optionally substituted with 1-3 substituents independently selected from C1～C3Alkyl, halogen, -CN, -OR7Or NR7R8；
R7And R8Selected from H, deuterium, substituted or unsubstituted C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy radical, C3～C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C1～C4Alkyl radical, C1～C4Haloalkyl, C1～C4Alkoxy, -CN is substituted for 1-3 times; said substituted C1～C4Alkyl is optionally substituted by C4～C8The cycloalkyl is substituted for 1 to 3 times;
n is 0, 1 or 2;
when n is 0, R3Saturated heterocyclic amines which are not substituted or unsubstituted.
Further, the air conditioner is provided with a fan,
R3is selected from
Figure BDA0002634038700000072
m is an integer of 1-4;
n is an integer of 0 to 4.
Further, the compound is one of the following structures:
Figure BDA0002634038700000073
further, the salt is a pharmaceutically acceptable salt;
preferably, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.
The present invention also provides a process for producing the aforementioned compound, a salt thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a solvate thereof, or a hydrate thereof,
the synthetic route of compound IV-1 is as follows:
Figure BDA0002634038700000081
and/or, the synthetic route of compound IV-2 is as follows:
Figure BDA0002634038700000091
and/or, the synthetic route of compound IV-3 is as follows:
Figure BDA0002634038700000092
and/or, the synthetic route of compound IV-4 is as follows:
Figure BDA0002634038700000093
the invention also provides application of the compound, the salt, the stereoisomer, the tautomer, the prodrug, the solvate or the hydrate of the compound in preparation of 5-HT3 receptor modulators.
Further, the 5-HT3 receptor modulator is a 5-HT3 receptor antagonist or a 5-HT3 partial agonist.
Further, the 5-HT3 receptor modulator is a medicament for the treatment of a 5-HT3 receptor-associated disorder selected from generalized anxiety disorder, social phobia, vertigo, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, bulimia nervosa, drug withdrawal effects, alcohol dependence, pain, sleep-related central apnea, chronic fatigue syndrome, central nervous system-related disorders, Parkinson's disease psychosis, schizophrenia, cognitive decline and deficiencies in schizophrenia, Parkinson's disease, Huntington's chorea, Alzheimer's disease, obesity, drug abuse disorders, dementia associated with neurodegenerative disorders, cognitive impairment, fibromyalgia syndrome, rosacea, cardiovascular disorders mediated by 5-hydroxytryptamine, emesis, gastrointestinal disorders, nausea, Gastroesophageal reflux disease, burkitt's lymphoma, bronchial asthma, pruritus, migraine and epilepsy, carcinoid syndrome, irritable bowel syndrome;
preferably, the nausea or vomiting includes chemotherapy-induced nausea or vomiting, postoperative-induced nausea or vomiting, radiation-induced nausea or vomiting.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, the salt thereof, the stereoisomer thereof, the tautomer thereof, the prodrug thereof, the solvate thereof or the hydrate thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutical composition is useful for the treatment of generalized anxiety disorder, social phobia, vertigo, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, bulimia nervosa, drug withdrawal effects, alcohol dependence, pain, sleep-related central apnea, chronic fatigue syndrome, central nervous system related disorders, Parkinson's disease psychosis, schizophrenia, cognitive decline and deficits in schizophrenia, Parkinson's disease, Huntington's chorea, Alzheimer's disease, obesity, drug abuse disorders, dementia associated with neurodegenerative disorders, cognitive deficits, fibromyalgia syndrome, rosacea, cardiovascular disorders mediated by 5-hydroxytryptamine, nausea, vomiting, gastrointestinal disorders, gastroesophageal reflux disease, Burkitt's lymphoma, bronchial asthma, pruritis, Parkinson's disease, cognitive impairment, fibromyalgia syndrome, acne rosacea, and other disorders, Migraine and epilepsy, carcinoid syndrome, irritable bowel syndrome;
preferably, the nausea or vomiting includes chemotherapy-induced nausea or vomiting, postoperative-induced nausea or vomiting, radiation-induced nausea or vomiting.
Further, the pharmaceutical composition is a medicament for treating schizophrenia, and the pharmaceutically acceptable auxiliary materials are selected from one or more of valproate, levopromazine, alprazolam, haloperidol, chlorpromazine, risperidone, paliperidone, olanzapine, ziprasidone, quetiapine, clozapine, lithium carbonate, diazepam, carbamazepine, a selective 5-hydroxytryptamine reuptake inhibitor, and tricyclic antidepressants;
or, the pharmaceutical composition is a medicament for the treatment of parkinson's disease, the pharmaceutically acceptable adjuvant is selected from one or more of transdermal rotigotine, rasagiline, safinamide, levodopa, carbidopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, amantadine, anticholinergics;
or, the pharmaceutical composition is a medicament for treating irritable bowel syndrome, the pharmaceutically acceptable excipient is selected from a second 5-hydroxytryptamine 5-HT3 receptor modulator or a 5-hydroxytryptamine 5-HT4 receptor modulator, wherein the second 5-hydroxytryptamine 5-HT3 receptor modulator or the 5-hydroxytryptamine 5-HT4 receptor modulator is selected from one or more of alosetron, renzapride, cilansetron, tegaserod, prucalopride, ondansetron, somatostatin analogs, muscarinic receptor antagonists, laxatives, antispasmodics, antidepressants, antidiarrheals, prokinetic agents, peripheral opiate narcotic antagonists;
or, the pharmaceutical composition is a medicament for treating nausea or vomiting, the pharmaceutically acceptable adjuvant is selected from one or more of dexamethasone, alosetron, alprazolam, aprepitant, dimenhydrinate, diphenhydramine, dolasetron, tetrahydrocannabinol, cannabirone, dronabinol, dapipritol, granisetron, haloperidol, lorazepam, metoclopramide, midazolam, olanzapine, ondansetron, palonosetron, prochlorperazine, prumipine, tropisetron.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
In the present invention, "substituted" means that a hydrogen atom in a molecule is replaced with another different atom or molecule, and includes 1, 2 or more hydrogen atoms on the same or different atoms in the molecule.
In the present invention, Ca～CbRefers to all groups or molecules containing a to b carbon atoms. Such as "C1～C8The alkyl group "includes all alkyl groups having 1 to 8 carbon atoms. The alkyl group may be a straight or branched chain alkyl group. Such as "C2～C8The alkenyl group "includes all alkenyl groups having 2 to 8 carbon atoms.
In the present invention, halogen means fluorine, chlorine, bromine and iodine.
In the present invention, "-OR4The structural formula is
Figure BDA0002634038700000111
“-NR4R5The structural formula is
Figure BDA0002634038700000112
“-NR4C(O)R5The structural formula is
Figure BDA0002634038700000113
“-NR4C(O)2R5The structural formula is
Figure BDA0002634038700000114
“-NR5C(O)R4The structural formula is
Figure BDA0002634038700000115
“-S(O)R5The structural formula is
Figure BDA0002634038700000116
“-C(O)R5The structural formula is
Figure BDA0002634038700000117
“-C(O)NR4R5The structural formula is
Figure BDA0002634038700000118
When L is 0 alkylene group in the present invention, the compound of the present invention has the formula
Figure BDA0002634038700000121
In the present invention, the saturated bicyclic ring has the structural formula:
Figure BDA0002634038700000122
wherein m is an integer of 1 to 4 (i.e., m is 1, 2, 3, 4), and n is an integer of 0 to 4 (i.e., n is 0, 1, 2, 3, 4).
In the present invention, the saturated heterocyclic amine has the structural formula:
Figure BDA0002634038700000123
Figure BDA0002634038700000124
wherein m is an integer of 1 to 4 (i.e., m is 1, 2, 3, 4), and n is an integer of 0 to 4 (i.e., n is 0, 1, 2, 3, 4).
The invention provides a nitrogen-containing heterocyclic compound and a preparation method thereof, and the compound can be used as a 5-HT3 receptor regulator. Experiments prove that the compound prepared by the invention has strong affinity to a 5-HT3 receptor, has high activity as a regulator of the 5-HT3 receptor, can be used for preparing the 5-HT3 receptor regulator, can also be used for preparing medicaments for treating diseases (such as irritable bowel syndrome, nausea, vomiting, gastroenteritis, gastric dysfunction, diarrhea, pain, carcinoid syndrome and drug addiction) related to the 5-HT3 receptor, and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1, 7- (quinuclidin-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000125
And [5,4,3-cd]Preparation of (E) -7-azaindazol-6 (7H) -one (Compound 1)
Compound 1 was prepared according to the following synthetic procedure.
Step 1: preparation of 3-benzyloxypropionic acid (Compound 1-2)
Figure BDA0002634038700000131
Preparation of jones reagent: concentrated sulfuric acid (6.3mL) was added dropwise to a solution of chromium trioxide (6.15g, 61.5mmol) dissolved in 12.5mL of water at 0 ℃ and then 12.5mL of water was added to the system and stirred at 0 ℃ for 1 hour (backup).
To a solution of 3-benzyloxy-1 propanol (5.0g, 30.1mmol) in 50mL of acetone at 0 deg.C was added dropwise Jones' reagent (24mL), and after the addition was complete, the mixture was stirred at 0 deg.C for 2 hours. The reaction solution was filtered to remove solid matter, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and dried to give a crude compound, 3-benzyloxypropionic acid (compound 1-2), weighing 5.0g, as a white oil, in 92% yield.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 180.1(M +1)+.
Step 2: preparation of ethyl 3-benzyloxypropionate (Compound 1-3)
Figure BDA0002634038700000132
Concentrated sulfuric acid (0.5mL) was added dropwise to a solution of compound 1-2(5.0g, 27.8mmol) in ethanol (50mL), and after the addition was complete, the temperature was raised to 80 ℃ and the reaction was stirred overnight. The next morning, the reaction mixture was concentrated under reduced pressure, spin-dried, and the residue was purified with silica gel column to give ethyl 3-benzyloxypropionate (compound 1-3) in a pale yellow oily substance (4.2 g, yield 64%).
Carrying out structural identification on the prepared compound: MS (ESI) M/z 209.1(M +1)+.
And step 3: preparation of 5-benzyloxy-3-oxovaleronitrile (Compound 1-4)
Figure BDA0002634038700000133
To a solution of acetonitrile (1.5g, 35.6mmol) in THF (20mL) at-78 deg.C was added n-BuLi (22.3mL, 35.6mmol) dropwise, completing the addition and reacting at-78 deg.C for 30 min. Thereafter, a solution of compounds 1 to 3(3.7g, 17.8mmol) dissolved in 10mL of THF was added dropwise to the reaction system, and the reaction was continued at-78 ℃ for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified with a silica gel column to give a pure 5-benzyloxy-3-oxovaleronitrile (Compound No. 1-4) weighing 2.2g and as a pale yellow solid in 61% yield.
To the prepared compoundAnd (3) carrying out structure identification: MS (ESI) M/z 204.1(M +1)+.
And 4, step 4: preparation of 5- (2-benzyloxyethyl) -2- (p-methoxybenzyl) -2H-3-aminopyrazole (Compound 1-5)
Figure BDA0002634038700000141
To a solution of 1-4(2.0g, 9.85mmol) in methanol (35mL) was added (4-methoxyphenyl) hydrazine hydrochloride (2.11g, 9.36mmol) and heated to 70 deg.C overnight under nitrogen. Spin-drying to obtain crude product, and pulping with methyl tert-butyl ether to obtain 5- (2-benzyloxyethyl) -2- (p-methoxybenzyl) -2H-3-aminopyrazole (compound 1-5) with weight of 2.0g, white solid, and 60% yield.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 338.2(M +1)+.
And 5: preparation of ethyl 3- (2-benzyloxyethyl) -6-hydroxy-1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (Compound 1-7)
Figure BDA0002634038700000142
To a solution of compound 1-5(1.5g, 4.45mmol) in acetic acid/water (1/20, 12mL) was added diethyl oxaloacetate sodium salt (compound 1-6) (1.12g, 5.34mmol), heated to 80 ℃ under nitrogen, and reacted overnight. The reaction solution was poured into water and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified with a silica gel column to give ethyl 3- (2-benzyloxyethyl) -6-hydroxy-1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 1-7) in a weight of 900mg as a white solid in a yield of 44%.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 462.2(M +1)+.
Step 6: preparation of ethyl 3- (2-benzyloxyethyl) -6-chloro-1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (Compound 1-8)
Figure BDA0002634038700000143
Oxalyl chloride (1.1mL) was added to a solution of DCE (25mL) containing DMF (1mL) at 0 ℃ and the reaction was allowed to proceed at room temperature for 10 minutes after completion of the addition. Thereafter, compounds 1 to 7(0.6g, 1.3mmol) were added to the reaction system. The mixture was stirred overnight at 80 ℃ under nitrogen. The reaction solution was poured into water and extracted twice with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate and spin dried. The residue was purified with a silica gel column to give ethyl 3- (2-benzyloxyethyl) -6-chloro-1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 1-8) in a weight of 500mg, as a colorless oil in a yield of 80%.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 480.2(M +1)+.
And 7: preparation of ethyl 3- (2-hydroxyethyl) -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (Compound 1-9)
Figure BDA0002634038700000151
To a solution of compounds 1-8(220mg, 0.925mmol) in methanol (15mL) was added 10% wet palladium on carbon (44 mg). 1atm under hydrogen, 50 ℃ for 3 hours. Filtering the reaction solution, and spin-drying the filter cake. The residue was purified with a silica gel column to give ethyl 3- (2-hydroxyethyl) -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 1-9) in a weight of 80mg as a colorless oil in a yield of 49%.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 356.2(M +1)+.
And 8: preparation of ethyl 1- (4-methoxybenzyl) -3- (2-oxoethyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (Compound 1-10)
Figure BDA0002634038700000152
To a solution of compounds 1-9(80mg, 0.23mmol) in dichloromethane (20mL) at 0 deg.C was added DMP (195mg, 0.46 mmol). Stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted twice with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate and spin dried. The residue was purified on a silica gel plate to give ethyl 1- (4-methoxybenzyl) -3- (2-oxoethyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 1-10) in a weight of 60mg as a yellow oil in a yield of 74%.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 354.1(M +1)+.
And step 9: preparation of ethyl 3- [2- (quinuclidin-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (Compound 1-11)
Figure BDA0002634038700000161
To a solution of compound 1-10(60mg, 0.17mmol) and S-3-aminoquinuclidine dihydrochloride (68mg, 0.34mmol) in methanol (8mL) was added 2 drops of glacial acetic acid. Stirred at room temperature for 1 hour. Sodium cyanoborohydride (43mg, 0.68mmol) was then added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted twice with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate and spin dried. The residue was purified by silica gel plate to obtain ethyl 3- [2- (quinuclidin-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 1-11) in a weight of 62mg as a yellow solid with a yield of 79%.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 464.2(M +1)+.
Step 10: preparation of sodium 3- [2- (quinuclidin-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (Compound 1-12)
Figure BDA0002634038700000162
To a solution of compounds 1-11(62mg, 0.134mmol) in THF (10mL) was added a solution of sodium hydroxide (55mg, 1.39mmol) in water (1 mL). Stir at room temperature overnight. The reaction solution is dried by spinning to obtain the sodium 3- [2- (quinuclidine-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 1-12), which is directly used in the next step without further purification.
Carrying out structural identification on the prepared compound: 436.2(M +1)+.
Step 11: 7- (quinuclidin-3-yl) -2- (4-methoxybenzyl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000164
And [5,4,3-cd]Preparation of (E) -7-azaindazol-6 (7H) -one (Compounds 1-13)
Figure BDA0002634038700000163
To a solution of compounds 1-12(90mg, crude) and DIEA (0.3mL) in THF (15mL) was added T3P (0.5 mL). Stir at room temperature overnight. The reaction solution was poured into water, and extracted twice with a mixed solution of dichloromethane/methanol (5/1 (v/v)). The organic phases were combined, dried over anhydrous sodium sulfate and spin dried. Purifying the residue with silica gel plate to obtain 7- (quinuclidin-3-yl) -2- (4-methoxybenzyl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000173
And [5,4,3-cd]7-azaindazol-6 (7H) -one (compounds 1-13), 45mg by weight, white solid, 80% yield.
Carrying out structural identification on the prepared compound: 418.2(M +1)+.
Step 12: 7- (quinuclidin-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000174
And [5,4,3-cd]Preparation of (E) -7-azaindazol-6 (7H) -one (Compound 1)
Figure BDA0002634038700000171
Compounds 1-13(45mg, 0.11mmol) were added to trifluoroacetic acid (5 mL). The reaction was heated to 75 ℃ overnight. The reaction solution was adjusted to pH 12 with 1M aqueous sodium hydroxide solution, and extracted twice with a mixed solution of dichloromethane/methanol 5/1 (v/v). The organic phases were combined, dried over anhydrous sodium sulfate and spin dried. Purifying the residue with silica gel plate to obtain 7- (quinuclidin-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000175
And [5,4,3-cd]7-azaindazol-6 (7H) -one (Compound 1), weighing 18mg, white solid, yield 55%.
The structure of the prepared compound 1 is identified:1HNMR(400MHz，DMSO-d6)，13.48(br,1H),7.66-7.77(m,2H),4.49(br,1H),4.11(br,1H),3.77(br,1H),3.15-3.16(m,2H),2.90-3.04(m,3H),2.55-2.77(m,3H),1.99(s,1H),1.43-1.68(m,3H),1.43(m,1H).MS(ESI)m/z:298.2(M+1)+.
example 2, 7- (quinuclidin-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000176
And [5,4,3-cd]Preparation of (E) -7-azaindol-6 (7H) -one (Compound 2)
Compound 2 was prepared according to the following synthetic procedure.
Step 1: preparation of 3-formyl-7-azaindole-4-carboxylic acid methyl ester (compound 2-3)
Figure BDA0002634038700000172
Adding 7-azaindole-4-carboxylic acid methyl ester (compound 2-1) (1g, 5.62mmol) into water (16mL), adding urotropine (compound 2-2) (1.6g, 11.4mmol) and glacial acetic acid (32 mL), gradually heating to 100 ℃, stirring for reaction for 12 hours, monitoring by TLC to complete the reaction, cooling to room temperature, pouring the reaction liquid into ice water (200mL), extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography (ethyl acetate: petroleum ether ═ 1:1, volume ratio, v/v) to obtain 3-aldehyde-7-azaindole-4-carboxylic acid methyl ester (compound 2-3), weighing 0.67g and yield of 56%.
Carrying out structural identification on the prepared compound: 207.1(M +1)+.
Step 2: preparation of 1- (p-methoxybenzyl) -3-aldehyde-7-azaindole-4-carboxylic acid methyl ester (compound 2-4)
Figure BDA0002634038700000181
Compound 2-3(0.8g, 3.88mmol) was added to DMF (25mL), p-methoxybenzyl bromide (1.17g, 5.82mmol) and cesium carbonate (2.54g, 7.80mmol) were added. Stir at room temperature overnight. The next morning TLC monitored the reaction was complete, and the reaction solution was poured into water and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oil, which was purified by column chromatography (ethyl acetate: petroleum ether: 1, volume ratio, v/v) to give 1- (p-methoxybenzyl) -3-formyl-7-azaindole-4-carboxylic acid methyl ester (compound 2-4) weighing 0.75g, as a pale yellow solid, in 59% yield.
Carrying out structural identification on the prepared compound: 327.3(M +1)+.
And step 3: preparation of methyl 1- (p-methoxybenzyl) -3- (2-methoxyvinyl) -3a,7 a-dihydro-1H-7-azaindole-4-carboxylate (Compound 2-5)
Figure BDA0002634038700000182
Compound 2-4(1.1g, 3.37mmol), methoxymethyltriphenylphosphonium chloride (1.38g, 4.05mmol) were added to tetrahydrofuran (20mL), cooled to 0 ℃ in an ice-water bath, and potassium tert-butoxide (708mg, 6.31mmol) was added in portions. After the addition, the reaction solution was warmed to room temperature and stirred for 1 hour. TLC monitored the reaction complete, poured the reaction into water and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 1- (p-methoxybenzyl) -3- (2-methoxyvinyl) -3a,7 a-dihydro-1H-7-azaindole-4-carboxylate (Compound 2-5) in a weight of 0.92g, 77% yield. The crude compounds 2-5 were used in the next step without further column chromatography purification.
Carrying out structural identification on the prepared compound: 355.4(M +1)+.
And 4, step 4: preparation of methyl 1- (4-methoxybenzyl) -3- (2-oxoethyl) -3a,7 a-dihydro-1H-7-azaindole-4-carboxylate (Compound 2-6)
Figure BDA0002634038700000191
To a solution of crude compound 2-5 (0.9g, 2.54mol) in tetrahydrofuran (10mL) was added hydrochloric acid (4.4mL, 26.3mmol, 6M). Stirred and heated to 60 ℃ for reaction for 2 hours. TLC showed the reaction was complete, the reaction was poured into water and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The residue was slurried with methyl tert-butyl ether to give methyl 1- (4-methoxybenzyl) -3- (2-oxoethyl) -3a,7 a-dihydro-1H-7-azaindole-4-carboxylate (Compound 2-6) as a pale yellow solid in a yield of 45% in two steps, 0.52 g.
Carrying out structural identification on the prepared compound: 341.3(M +1)+.
And 5: preparation of ethyl 3- [2- (quinuclidin-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-7-azaindole-4-carboxylate (Compound 2-8)
Figure BDA0002634038700000192
Compound 2-6(1.03g, 2.47mmol) was added dichloromethane (20mL), R-3-aminoquinuclidine dihydrochloride (compound 2-7) (737mg, 3.70mmol) and glacial acetic acid (741mg, 12.35 mmol). The reaction was stirred at room temperature for 4 hours. TLC showed disappearance of the starting compound 2-6 and completion of the reaction, and sodium cyanoborohydride (466mg, 7.41mmol) was added to the reaction solution, followed by stirring at room temperature overnight. The next morning, the reaction solution was poured into saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to give an oil. Column chromatography of the oily substance (ethyl acetate: petroleum ether: 1, volume ratio, v/v) gave 3- [2- (quinuclidin-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-7-azaindole-4-carboxylic acid ethyl ester (compound 2-8), weighing 486mg, pale yellow solid, yield 37%.
Carrying out structural identification on the prepared compound: 465.6(M +1)+.
Step 6: preparation of 3- [2- (quinuclidin-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-7-azaindole-4-carboxylic acid sodium salt (Compound 2-9)
Figure BDA0002634038700000201
To compounds 2 to 8(0.47mg, 0.92mmol) were added methanol (12mL) and sodium hydroxide (74mg, 1.85mmol), and the mixture was heated to 60 ℃ with stirring for reaction for 8 hours. TLC showed disappearance of starting compounds 2-8 and complete reaction. The reaction solution was taken out, cooled, poured into water, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to give a yellow solid product. The yellow solid product is purified by column chromatography to obtain sodium 3- [2- (quinuclidine-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-7-azaindole-4-carboxylate (compound 2-9), the weight is 0.37g, light yellow solid is obtained, and the yield is 81%.
Carrying out structural identification on the prepared compound: 436.5(M +1)+.
And 7: 7- (quinuclidin-3-yl) -2- (4-methoxybenzyl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000203
And [5,4,3-cd]Preparation of (E) -7-azaindol-6 (7H) -one (Compound 2-10)
Figure BDA0002634038700000202
To a solution of compounds 2-9(110mg) and DIEA (0.3mL) in THF (15mL) was added T3P (0.5 mL). Stir at room temperature overnight. The reaction solution was poured into water, and extracted twice with a mixed solution of dichloromethane/methanol (5/1 (v/v, volume ratio). The organic phases were combined, dried over anhydrous sodium sulfate and spin dried. Purifying the residue with silica gel plate to obtain 7- (quinuclidin-3-yl) -2- (4-methoxybenzyl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000204
And [5,4,3-cd]-7-azaindol-6 (7H) -one (compound 2-10), weighing 41mg, white solid, yield 75%.
Carrying out structural identification on the prepared compound: 419.5(M +1)+.
And 8: 7- (quinuclidin-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000205
And [5,4,3-cd]Preparation of (E) -7-azaindol-6 (7H) -one (Compound 2)
Figure BDA0002634038700000211
Compound 2-10(90mg, 0.21mmol), anisole (0.5mL), and trifluoroacetic acid (0.5mL) were mixed and stirred, and heated to 80 ℃ for reaction for 18 hours. TLC showed disappearance of the starting compound 2-10, and the reaction solution was taken out, cooled and spin-dried. To the residue was added 35% aqueous HCl (5mL), washed twice with methyl tert-butyl ether, and the aqueous layer was made alkaline with concentrated aqueous sodium hydroxide to pH 12. Stirring the obtained suspension for 1 hour, performing suction filtration, washing with water, collecting filter cake, and spin-drying to obtain 7- (quinuclidin-3-yl) -8, 9-dihydro-2H-aza-compound
Figure BDA0002634038700000213
And [5,4,3-cd]-7-azaindol-6 (7H) -one (compound 2), weighing 45mg, as a pale yellow solid, yield 72%.
The structure of the prepared compound 2 is identified:1HNMR(400MHz，DMSO-d6)，12.61(br,1H),7.70-7.97(m,2H),6.83(s,1H),4.35(br,1H),4.12(br,1H),3.56(br,1H),3.12-3.18(m,2H),2.79-3.01(m,3H),2.23-2.71(m,3H),1.97(s,1H),1.41-1.66(m,3H),1.45(m,1H).299.3(M+1)+.
example 3: 7- (8-methyl-8-azabicyclo [3,2,1]]Oct-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000214
And [5,4,3-cd]Preparation of (E) -7-azaindol-6 (7H) -one (Compound 3)
Compound 3 was prepared according to the following synthetic procedure.
Step 1: preparation of ethyl 3- [2- (8-methyl-8-azabicyclo [3,2,1] oct-3-yl) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (Compound 3-1)
Figure BDA0002634038700000212
To a solution of ethyl 1- (4-methoxybenzyl) -3- (2-oxoethyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 1-10, 130mg, 0.36mmol prepared in example 1) and 8-methyl-8-azabicyclo [3,2,1] oct-3-amine hydrochloride (77mg, 0.55mmol) in methanol (15mL) was added 4 drops of glacial acetic acid. Stirred at room temperature for 1 hour. Sodium cyanoborohydride (91mg, 1.44mmol) was then added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted twice with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate and spin dried. The residue was purified with a silica gel plate to give ethyl 3- [2- (8-methyl-8-azabicyclo [3,2,1] oct-3-yl) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 3-1) in a weight of 90mg as a yellow solid in a yield of 52%.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 477.3(M +1)+.
Step 2: preparation of sodium 3- [2- (8-methyl-8-azabicyclo [3,2,1] oct-3-yl) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (Compound 3-2)
Figure BDA0002634038700000221
To a solution of compound 3-1(47mg, 0.1mmol) in THF (8mL) was added a solution of sodium hydroxide (28mg, 0.7mmol) in water (0.8 mL). Stir at room temperature overnight. The reaction solution is dried by spinning to obtain the sodium 3- [2- (8-methyl-8-azabicyclo [3,2,1] oct-3-yl) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 3-2), which is directly used in the next step without further purification.
Carrying out structural identification on the prepared compound: 449.2(M +1)+.
And step 3: 7- (8-methyl-8-azabicyclo [3,2,1]]Oct-3-yl) -2- (4-methoxybenzyl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000223
And [5,4,3-cd]Preparation of (E) -7-azaindazol-6 (7H) -one (Compound 3-3)
Figure BDA0002634038700000222
To a solution of compound 3-2(90mg, crude) and DIEA (129mg) in THF (13mL) was added T3P (318 mgL). Stir at room temperature overnight. The reaction solution was poured into water, and extracted twice with a mixed solution of dichloromethane/methanol (5/1 (v/v, volume ratio). The organic phases were combined, dried over anhydrous sodium sulfate and spin dried. Purifying the residue with silica gel plate to obtain 7- (8-methyl-8-azabicyclo [3,2,1]]Oct-3-yl) -2- (4-methoxybenzyl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000224
And [5,4,3-cd]7-azaindazol-6 (7H) -one (compound 3-3), weighing 45mg, white solid, 80% yield.
Carrying out structural identification on the prepared compound: 432.2(M +1)+.
And 4, step 4: 7- (8-methyl-8-azabicyclo [3,2,1]]Oct-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000225
And [5,4,3-cd]Preparation of (E) -7-azaindazol-6 (7H) -one (Compound 3)
Figure BDA0002634038700000231
Compound 3-3(40mg, 0.11mmol) was added to trifluoroacetic acid (5 mL). The reaction was heated to 75 ℃ overnight. The reaction solution was adjusted to pH 12 with 1M aqueous sodium hydroxide solution, and extracted twice with a mixed solution of dichloromethane/methanol (5/1 (v/v, volume ratio). The organic phases were combined, dried over anhydrous sodium sulfate and spin dried. Purifying the residue with silica gel plate to obtain 7- (8-methyl-8-azabicyclo [3,2,1]]Oct-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000233
And [5,4,3-cd]7-azaindazol-6 (7H) -one (Compound 3), weight 17mg, white solid, yield 55%.
The structure of the prepared compound 3 is identified:1HNMR(400MHz，DMSO-d6)，12.97(br,1H),7.61-7.56(m,2H),4.38(br,1H),4.14(br,1H),3.76(br,1H),3.13-3.19(m,2H),2.45-3.06(m,3H),2.53-2.79(m,3H),1.93(s,1H),1.43-1.62(m,3H),1.43(m,1H).MS(ESI)m/z:312.2(M+1)+.
example 4: 7- (Inward-9-methyl-9-azabicyclo [3,3,1]]Nonan-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000234
And [5,4,3-cd]Preparation of (E) -7-azaindol-6 (7H) -one (Compound 4)
Compound 4 was prepared according to the following synthetic procedure.
Step 1: preparation of ethyl 3- [2- (endo-9-methyl-9-azabicyclo [3,3,1] nonane-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 4-1)
Figure BDA0002634038700000232
To a solution of ethyl 1- (4-methoxybenzyl) -3- (2-oxoethyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 1-10, 160mg, 0.45mmol prepared in example 1) and 3-tropaneamine hydrochloride (105mg, 0.68mmol) in methanol (20mL) was added 5 drops of glacial acetic acid. Stirred at room temperature for 1 hour. Sodium cyanoborohydride (113mg, 1.8mmol) was then added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted twice with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate and spin dried. The residue was purified with a silica gel plate to give ethyl 3- [2- (endo-9-methyl-9-azabicyclo [3,3,1] nonane-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 4-1) in a yield of 27% as a yellow solid, weighing 60 mg.
Carrying out structural identification on the prepared compound: MS (ESI) M/z 492.3(M +1)+.
Step 2: preparation of 3- [2- (endo-9-methyl-9-azabicyclo [3,3,1] nonane-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylic acid sodium salt (compound 4-2)
Figure BDA0002634038700000241
To a solution of compound 4-1(30mg, 0.06mmol) in THF (7mL) was added a solution of sodium hydroxide (16mg, 0.42mmol) in water (0.7 mL). The reaction was stirred at room temperature overnight. The reaction solution is spin-dried to obtain sodium 3- [2- (inward-9-methyl-9-azabicyclo [3,3,1] nonane-3-amino) ethyl ] -1- (4-methoxybenzyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-4-carboxylate (compound 4-2), and the sodium 3- [2- (inward-9-methyl-9-azabicyclo [3,3,1] nonane-3-amino) ethyl carboxylate is directly used for the next step without further column chromatography purification.
Carrying out structural identification on the prepared compound: 463.2(M +1)+.
And step 3: 7- (Inward-9-methyl-9-azabicyclo [3,3,1]]Nonan-3-yl) -2- (4-methoxybenzyl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000243
And [5,4,3-cd]Preparation of (E) -7-azaindazol-6 (7H) -one (Compound 4-3)
Figure BDA0002634038700000242
To a solution of compound 4-2(40mg, crude) and DIEA (73mg) in THF (10mL) was added T3P (191 mg). Stir at room temperature overnight. The reaction solution was poured into water, and extracted twice with a mixed solution of dichloromethane/methanol (5/1 (v/v, volume ratio). The organic phases were combined, dried over anhydrous sodium sulfate and spin dried. Purifying the residue with silica gel plate to obtain 7- (inward-9-methyl-9-azabicyclo [3,3,1]]Nonan-3-yl) -2- (4-methoxybenzyl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000244
And [5,4,3-cd]7-azaindazol-6 (7H) -one (compound 4-3), weighing 30mg, two-step yield 89%.
Carrying out structural identification on the prepared compound: 446.3(M +1)+.
And 4, step 4: 7- (Inward-9-methyl-9-azabicyclo [3,3,1]]Nonan-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000245
And [5,4,3-cd]Preparation of (E) -7-azaindazol-6 (7H) -one (Compound 4)
Figure BDA0002634038700000251
Compound 4-3(30mg, 0.067mmol) was added to trifluoroacetic acid (5 mL). The reaction was heated to 75 ℃ overnight. The reaction solution was adjusted to pH 12 with 1M aqueous sodium hydroxide solution, and extracted twice with a mixed solution of dichloromethane/methanol (5/1 (v/v, volume ratio). The organic phases were combined, dried over anhydrous sodium sulfate and spin dried. Purifying the residue with silica gel plate to obtain 7- (inward-9-methyl-9-azabicyclo [3,3,1]]Nonan-3-yl) -8, 9-dihydro-2H-aza
Figure BDA0002634038700000252
And [5,4,3-cd]7-azaindazol-6 (7H) -one (Compound 4), 5mg by weight, white solid, yield 23%.
The prepared compound 4 was subjected to structural identification:1HNMR(400MHz，DMSO-d6)，13.17(br,1H),7.64-7.79(m,2H),4.19(br,1H),4.15(br,1H),3.82(s,3H),3.73(br,1H),3.11-3.18(m,2H),2.91-3.89(m,3H),2.55-2.77(m,3H),1.99(s,1H),1.43-1.68(m,3H),1.43(m,1H).MS(ESI)m/z:326.2(M+1)+.
the advantageous effects of the present invention are demonstrated by specific test examples below
Test example 1 evaluation of affinity of the Compound of the present invention for human 5-HT3 receptor
1. Test method
The relative affinity of compounds for the human 5-HT3 receptor was measured in a radioligand binding assay using a Scintillation Proximity Assay (SPA) format. Test compounds were diluted to 10mM with 100% DMSO, then diluted with 100% DMSO at a 10 × assay concentration gradient in 96-well plates and further diluted with assay buffer to 4 × assay concentration. The test compound was mixed with 10nM [ 9-methyl-3H]BRL-43694(Perkin Elmer, Waltham, MA), 3. mu.g of human 5-HT3 receptor membrane (Perkin Elmer, Waltham, MA) and 0.5mg/mL SPA beads (WGA PVT, Amersham Biosciences) were incubated in 50mM Tris-HCl, pH 7.5, 3mM MgCl21Mm EDTA and 10% DMSO. The binding reaction was set up in a well of PicoPlates-96(Perkin Elmer, Waltham, Mass.) by the sequential addition of 50. mu.L of test compound or buffer, SPA beads, radioligand and 5-HT3 receptor membrane. After overnight incubation with stirring at room temperature, centrifugation was carried out at 1500rpm for 15 minutes and incubation was carried out for 30 minutes in the absence of light. Finally the radioactivity was read for 5 min in a TopCount microplate counter (Perkin Elmer). The total binding control contained only compound dilution buffer; non-specific binding was determined in the presence of 30. mu.M MDL-72222. Specific binding is determined by subtracting non-specific binding from total binding. All experiments were performed in duplicate for ten competing ligand concentrations. IC (integrated circuit)50Values were determined from specific binding data using xlfit4.1 curve fitting software from IDBS Ltd.
Experimental data and analysis: inhibition constant Ki ═ IC50(1+ (L/KD)), where L ═ the concentration of radioligand in the assay and KD ═ the affinity of the radioligand for the receptor.
2. Test results
This experiment tested the affinity of the compounds of the invention for the human 5-HT3 receptor, and the results are shown in Table 1 below.
TABLE 1 affinity of the compounds of the invention for the human 5-HT3 receptor
Cmpd. IC50(nmol) Ki(nmol)
1 288.3 52.23
2 1783 321.26
3 >10000 >1802
4 8955 1613.51
In summary, the present invention provides a nitrogen-containing heterocyclic compound and a method for preparing the same, which can be used as a 5-HT3 receptor modulator. Experiments prove that the compound prepared by the invention has strong affinity to a 5-HT3 receptor, has high activity as a regulator of the 5-HT3 receptor, can be used for preparing the 5-HT3 receptor regulator, can also be used for preparing medicaments for treating diseases (such as irritable bowel syndrome, nausea, vomiting, gastroenteritis, gastric dysfunction, diarrhea, pain, carcinoid syndrome and drug addiction) related to the 5-HT3 receptor, and has good application prospect.

Claims (5)

1. A compound, or a pharmaceutically acceptable salt thereof, characterized by: the compound is one of the following structures:
Figure FDA0003511385230000011
2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate or mandelate.
3. A process for preparing a compound of claim 1, or a salt thereof, wherein:
the synthetic route of compound IV-1 is as follows:
Figure FDA0003511385230000021
and/or, the synthetic route of compound IV-2 is as follows:
Figure FDA0003511385230000031
and/or, the synthetic route of compound IV-3 is as follows:
Figure FDA0003511385230000032
and/or, the synthetic route of compound IV-4 is as follows:
Figure FDA0003511385230000033
4. use of a compound according to claim 1 or 2, or a salt thereof, for the preparation of a 5-HT3 receptor modulator.
5. A pharmaceutical composition characterized by: the compound or the salt thereof as the active ingredient of the compound or the salt thereof as the claim 1 or 2, and pharmaceutically acceptable auxiliary materials.
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