WO2022110052A1 - 一种含氮杂环类5-ht3受体调节剂及其制备方法和用途 - Google Patents
一种含氮杂环类5-ht3受体调节剂及其制备方法和用途 Download PDFInfo
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- WO2022110052A1 WO2022110052A1 PCT/CN2020/132398 CN2020132398W WO2022110052A1 WO 2022110052 A1 WO2022110052 A1 WO 2022110052A1 CN 2020132398 W CN2020132398 W CN 2020132398W WO 2022110052 A1 WO2022110052 A1 WO 2022110052A1
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- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
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- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- QCSBPPMUEVMAPS-UHFFFAOYSA-M sodium;2,2-diethyl-4-hydroxy-3,4-dioxobutanoate Chemical compound [Na+].CCC(CC)(C(O)=O)C(=O)C([O-])=O QCSBPPMUEVMAPS-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the invention relates to the field of medicinal chemistry, in particular to a nitrogen-containing heterocyclic 5-HT3 receptor modulator and a preparation method and application thereof.
- Serotonin type 3 also known as serotonin type 3, 5-HT3 receptors are expressed in the central nervous system involved in the gag reflex, pain processing, cognition and anxiety control, and also in the gastrointestinal Gastrointestinal disorders such as irritable bowel syndrome, dyspepsia, gastroesophageal reflux disease and irritable bowel syndrome play a modulating role.
- Irritable bowel syndrome is a persistent or intermittent functional gastrointestinal disorder characterized by abdominal pain, bloating, altered bowel habits and/or stool characteristics, lack of gastrointestinal structure, and Biochemical abnormalities. Compounds that alter the activity of certain serotonin receptors have been shown to be beneficial in the symptomatic treatment of irritable bowel syndrome (IBS).
- 5-HT3 receptor modulators The only drug in this class of 5-HT3 receptor modulators is FDA-approved alosetron, which was withdrawn from the market shortly after its approval in 2000 because of ischemic colitis in patients with IBS . The drug was later reinstated by the FDA due to high demand from IBS patients, and alosetron tablets were approved in 2002 for limited use in patients where the medical benefits outweighed the risks. Therefore, it is of great significance to develop safe 5-HT3 receptor modulators for the treatment of IBS.
- Carcinoids are rare, slow-growing tumors that can produce small molecule polypeptides or peptide hormones. They are the most common endocrine tumors in the gastrointestinal tract and are now classified as neuroendocrine neoplasms (NENs). ). Carcinoid syndrome is mainly controlled by somatostatin analogs (SSAs). However, for the treatment of adult patients with carcinoid syndrome diarrhea (CSD) whose disease cannot be adequately controlled by SSAs alone, targeting tryptophan hydroxylase (TPH) in carcinoid tumor cells and inhibiting excess serotonin production, can reduce the frequency of carcinoid syndrome diarrhea and significantly change the symptoms.
- SSAs somatostatin analogs
- TPH tryptophan hydroxylase
- CINV chemotherapy-induced nausea and vomiting
- Postoperative nausea and vomiting is the most common symptom after surgery, and is affected by various factors such as the type of surgery, duration of surgery, anesthetic drugs and methods, and preoperative anxiety. PONV occurs in the last 24 hours, with marked nausea before vomiting. Postoperative nausea and vomiting is also a common postoperative complication, with a reported average incidence of 20% to 30%, and even up to 70% in high-risk patients. In addition to causing severe discomfort to patients, nausea and vomiting may also cause medical complications, such as wound dehiscence, bleeding, aspiration pneumonia, and water and electrolyte disturbances. Therefore, people's attention has been paid to the prevention and treatment of PONV.
- 5-HT3 receptor antagonists which are a drug that completely antagonizes the activity of serotonin 3 receptors, and its adverse reactions are constipation and colonic Ischemia, even life-threatening in severe cases. Therefore, the preparation of more effective, safer and better pharmacokinetic 5-HT3 receptor modulators that can meet clinical needs is the key to the treatment of various diseases including IBS, CSD, CINV and PONV.
- the purpose of the present invention is to provide a more effective, safer and better pharmacokinetic 5-HT3 receptor modulator.
- the present invention provides the compound represented by formula I, or its salt, or its stereoisomer, or its tautomer, or its prodrug, or its solvate, or its hydrate:
- X and Y are selected from CH or N, and at least one of X or Y is N;
- Z is selected from N or CR 4 ;
- R 1 is selected from hydrogen, deuterium, halogen, -OR 4 , -NR 4 R 5 , -NR 4 C(O)R 5 , -NR 4 C(O) 2 R 5 , -NR 5 C(O)R 4 , -S(O)R 5 , -CN, -C(O)R 5 , -C(O)NR 4 R 5 , substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 ⁇ C8alkynyl , substituted or unsubstituted C1 ⁇ C8alkyl , substituted or unsubstituted C1 ⁇ C8alkoxy , substituted or unsubstituted C3 ⁇ C8cycloalkyl , substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl; the substitution is optionally substituted by 1-3 substituents independently selected from C
- R 2 is selected from H, deuterium, halogen, -OR 4 , -NR 4 R 5 , -NR 4 C(O)R 5 , -NR 4 C(O) 2 R 5 , -NR 5 C(O)R 4 , -S(O)R 5 , -CN, -C(O)R 5 , -C(O)NR 4 R 5 , substituted or unsubstituted C 2 to C 8 alkenyl, substituted or unsubstituted C 2 ⁇ C8alkynyl , substituted or unsubstituted C1 ⁇ C8alkyl , substituted or unsubstituted C1 ⁇ C8alkoxy ; substituted or unsubstituted C3 ⁇ C8cycloalkyl , substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl; the substitution is optionally substituted by 1 to 3 substituents independently selected from C
- R 3 is selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amine; the substitution is optionally substituted by 1 to 3 substituents, and the substituents are independently selected from C 1 -C 3 alkyl, halogen, -CN, -OR 7 or NR 7 R 8 ;
- R 4 is selected from H, deuterium, halogen, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkane base, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- R 5 is selected from H, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, substituted or Unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- R 7 and R 8 are selected from H, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl , substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 halogen Alkyl, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- n 0, 1 or 2;
- R3 is not a substituted or unsubstituted saturated heterocyclic amine.
- R 1 is selected from hydrogen, deuterium, halogen, -OR 4 , -NR 4 R 5 , -NR 4 C(O)R 5 , -NR 4 C(O) 2 R 5 , -NR 5 C(O)R 4 , -S(O)R 5 , -CN, -C(O)R 5 , -C(O)NR 4 R 5 , substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 ⁇ C8alkynyl , substituted or unsubstituted C1 ⁇ C8alkyl , substituted or unsubstituted C1 ⁇ C8alkoxy , substituted or unsubstituted C3 ⁇ C8cycloalkyl , substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl; the substitution is optionally substituted by 1-3 substituents independently selected from C
- R 2 is selected from H, deuterium, halogen, -OR 4 , -NR 4 R 5 , -NR 4 C(O)R 5 , -NR 4 C(O) 2 R 5 , -NR 5 C(O)R 4 , -S(O)R 5 , -CN, -C(O)R 5 , -C(O)NR 4 R 5 , substituted or unsubstituted C 2 to C 8 alkenyl, substituted or unsubstituted C 2 ⁇ C8alkynyl , substituted or unsubstituted C1 ⁇ C8alkyl , substituted or unsubstituted C1 ⁇ C8alkoxy ; substituted or unsubstituted C3 ⁇ C8cycloalkyl , substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl; the substitution is optionally substituted by 1 to 3 substituents independently selected from C
- R 3 is selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amine; the substitution is optionally substituted by 1 to 3 substituents, and the substituents are independently selected from C 1 -C 3 alkyl, halogen, -CN, -OR 7 or NR 7 R 8 ;
- R 4 is selected from H, deuterium, halogen, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkane base, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- R 5 is selected from H, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, substituted or Unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- R 7 and R 8 are selected from H, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkane base, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- n 0, 1 or 2;
- R 1 is selected from hydrogen, deuterium, halogen, -OR 4 , -NR 4 R 5 , -NR 4 C(O)R 5 , -NR 4 C(O) 2 R 5 , -NR 5 C(O)R 4 , -S(O)R 5 , -CN, -C(O)R 5 , -C(O)NR 4 R 5 , substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 ⁇ C8alkynyl , substituted or unsubstituted C1 ⁇ C8alkyl , substituted or unsubstituted C1 ⁇ C8alkoxy , substituted or unsubstituted C3 ⁇ C8cycloalkyl , substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl; the substitution is optionally substituted by 1-3 substituents independently selected from C
- R 2 is selected from H, deuterium, halogen, -OR 4 , -NR 4 R 5 , -NR 4 C(O)R 5 , -NR 4 C(O) 2 R 5 , -NR 5 C(O)R 4 , -S(O)R 5 , -CN, -C(O)R 5 , -C(O)NR 4 R 5 , substituted or unsubstituted C 2 to C 8 alkenyl, substituted or unsubstituted C 2 ⁇ C8alkynyl , substituted or unsubstituted C1 ⁇ C8alkyl , substituted or unsubstituted C1 ⁇ C8alkoxy ; substituted or unsubstituted C3 ⁇ C8cycloalkyl , substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl; the substitution is optionally substituted by 1 to 3 substituents independently selected from C
- R 3 is selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amine; the substitution is optionally substituted by 1 to 3 substituents, and the substituents are independently selected from C 1 -C 3 alkyl, halogen, -CN, -OR 7 or NR 7 R 8 ;
- R 4 is selected from H, deuterium, halogen, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkane base, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- R 5 is selected from H, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, substituted or Unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- R 7 and R 8 are selected from H, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkane base, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- n 0, 1 or 2;
- R3 is not a substituted or unsubstituted saturated heterocyclic amine.
- R 3 is selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amine; the substitution is optionally substituted by 1 to 3 substituents, and the substituents are independently selected from C 1 -C 3 alkyl, halogen, -CN, -OR 7 or NR 7 R 8 ;
- R 7 and R 8 are selected from H, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkane base, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- n 0, 1 or 2;
- R 3 is selected from substituted or unsubstituted saturated bicyclic, substituted or unsubstituted saturated heterocyclic amine; the substitution is optionally substituted by 1 to 3 substituents, and the substituents are independently selected from C 1 -C 3 alkyl, halogen, -CN, -OR 7 or NR 7 R 8 ;
- R 7 and R 8 are selected from H, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein said substituted phenyl or benzyl is optionally substituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkane base, C 1 -C 4 alkoxy, -CN are substituted 1-3 times; the substituted C 1 -C 4 alkyl is optionally substituted 1-3 times by C 4 -C 8 cycloalkyl;
- n 0, 1 or 2;
- R3 is not a substituted or unsubstituted saturated heterocyclic amine.
- R 3 is selected from
- n is an integer from 1 to 4.
- n is an integer of 0-4.
- the salt is a pharmaceutically acceptable salt
- the pharmaceutically acceptable salts are hydrochloride, hydrobromide, sulfate, phosphate, mesylate, triflate, benzenesulfonate, p-toluenesulfonate , 1-naphthalene sulfonate, 2-naphthalene sulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate salts, maleates, benzoates, salicylates, phenylacetates, mandelates.
- the present invention also provides a method for preparing the aforementioned compound, its salt, its stereoisomer, its tautomer, its prodrug, its solvate or its hydrate,
- the present invention also provides the use of the aforementioned compounds, their salts, their stereoisomers, their tautomers, their prodrugs, their solvates or their hydrates in the preparation of 5-HT3 receptor modulators.
- the 5-HT3 receptor modulator is a 5-HT3 receptor antagonist or a partial 5-HT3 agonist.
- the 5-HT3 receptor modulator is a medicine for the treatment of diseases related to 5-HT3 receptors, and the diseases are generalized anxiety disorder, social phobia, vertigo, obsessive-compulsive disorder, panic disorder, post-traumatic Nervous 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 disease, Alzheimer's disease, Alzheimer's disease, obesity, substance use disorders, neurodegenerative disease-related dementia, cognitive impairment, fiber Myalgia syndrome, rosacea, serotonin-mediated cardiovascular disorders, nausea, vomiting, gastrointestinal disorders, gastroesophageal reflux disease, Burkitt lymphoma, bronchial asthma, pruritus, migraine and epilepsy, Carcinoid syndrome, irritable bowel syndrome;
- the nausea or vomiting includes chemotherapy-induced nausea or vomiting, postoperative nausea or vomiting, radiation-induced nausea or vomiting.
- the present invention also provides a pharmaceutical composition, which is composed of the aforementioned compound, its salt, its stereoisomer, its tautomer, its prodrug, its solvate or its hydrate as active ingredients, A preparation prepared by adding pharmaceutically acceptable excipients.
- the pharmaceutical composition is used 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 disease , Alzheimer's disease, Alzheimer's disease, obesity, substance use disorders, neurodegenerative disease-related dementia, cognitive impairment, fibromyalgia syndrome, rosacea, serotonin-mediated cardiovascular disease, Nausea, vomiting, gastrointestinal disorders, gastroesophageal reflux disease, Burkitt lymphoma, bronchial asthma, pruritus, migraine, and drugs for epilepsy, carcinoid syndrome, and irritable bowel syndrome;
- the nausea or vomiting includes chemotherapy-induced nausea or vomiting, postoperative nausea or vomiting, radiation-induced nausea or vomiting.
- the pharmaceutical composition is a medicine for the treatment of schizophrenia
- the pharmaceutically acceptable adjuvant is selected from valproate, levomepromazine, alprazolam, haloperidol, chlorpromazine oxazine, risperidone, paliperidone, olanzapine, ziprasidone, quetiapine, clozapine, lithium carbonate, diazepam, carbamazepine, selective serotonin reuptake inhibitors, one or more of the tricyclic antidepressants;
- the pharmaceutical composition is a medicine for the treatment of Parkinson's disease
- the pharmaceutically acceptable adjuvant is selected from transdermal rotigotine, rasagiline, safinamide, levodopa, carbido
- barium dopamine agonists
- COMT inhibitors COMT inhibitors
- MAO-B inhibitors amantadine, anticholinergics
- the pharmaceutical composition is a medicine for the treatment of irritable bowel syndrome
- the pharmaceutically acceptable adjuvant is selected from a second serotonin 5-HT3 receptor modulator or a serotonin 5-HT4 receptor Modulator, wherein the second serotonin 5-HT3 receptor modulator or serotonin 5-HT4 receptor modulator is selected from alosetron, renzapride, cilansetron, tegaserod , prucalopride, ondansetron, somatostatin analogs, muscarinic receptor antagonists, laxatives, antispasmodics, antidepressants, antidiarrheals, prokinetics, peripheral opioid anesthetics one or more of the antagonists;
- the pharmaceutical composition is a medicine for treating nausea or vomiting
- the pharmaceutically acceptable adjuvant is selected from dexamethasone, alosetron, alprazolam, aprepitant, dimenhydrinate , diphenhydramine, dolasetron, tetrahydrocannabinol, nabrone, dronabinol, daperidol, granisetron, haloperidol, lorazepam, metoclopramide, mida One or more of zolam, olanzapine, ondansetron, palonosetron, prochlorperazine, promethazine, and 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) nomenclature system.
- substitution means that the hydrogen atoms in the molecule are replaced by other different atoms or molecules, including the replacement of one, two or more hydrogen atoms on the same or different atoms in the molecule.
- C a to C b refer to all groups or molecules containing a to b carbon atoms.
- C1 - C8 alkyl includes all alkyl groups containing 1 to 8 carbon atoms.
- Alkyl groups can be straight or branched chain alkyl groups.
- C 2 -C 8 alkenyl includes all alkenyl groups containing 2 to 8 carbon atoms.
- halogen means fluorine, chlorine, bromine and iodine.
- the structural formula of "-OR 4 " is: The structural formula of "-NR 4 R 5 " is The structural formula of "-NR 4 C(O)R 5 " is The structural formula of "-NR 4 C(O) 2 R 5 " is The structural formula of "-NR 5 C(O)R 4 " is The structural formula of "-S(O)R 5 " is The structural formula of "-C(O)R 5 " is The structural formula of "-C(O)NR 4 R 5 " is:
- the present invention provides a nitrogen-containing heterocyclic compound and a preparation method thereof.
- the compound can be used as a 5-HT3 receptor modulator.
- the compound prepared by the present invention has a strong affinity for 5-HT3 receptor, and has high activity as a modulator of 5-HT3 receptor, and can be used to prepare a modulator of 5-HT3 receptor.
- drugs for the treatment of diseases related to 5-HT3 receptors such as irritable bowel syndrome, nausea, vomiting, gastroenteritis, gastric dysfunction, diarrhea, pain, carcinoid syndrome, and drug addiction
- diseases related to 5-HT3 receptors such as irritable bowel syndrome, nausea, vomiting, gastroenteritis, gastric dysfunction, diarrhea, pain, carcinoid syndrome, and drug addiction
- the raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available products.
- Compound 1 was prepared according to the following synthetic procedure.
- n-BuLi (22.3 mL, 35.6 mmol) was added dropwise to a solution of acetonitrile (1.5 g, 35.6 mmol) in THF (20 mL), the addition was complete, and the reaction was performed at -78 °C for 30 minutes.
- a solution of compound 1-3 (3.7 g, 17.8 mmol) dissolved in 10 mL of THF was added dropwise to the reaction system, the dropwise addition was completed, and the reaction was continued at -78 °C for 2 hours.
- the reaction solution was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate.
- Step 4 Preparation of 5-(2-benzyloxyethyl)-2-(p-methoxybenzyl)-2H-3-aminopyrazole (compound 1-5)
- Step 8 1-(4-Methoxybenzyl)-3-(2-oxoethyl)-3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid Preparation of ethyl esters (compounds 1-10)
- Step 9 3-[2-(Quinuclidin-3-amino)ethyl]-1-(4-methoxybenzyl)-3a,7a-dihydro-1H-pyrazolo[3,4- b] Preparation of ethyl pyridine-4-carboxylate (compound 1-11)
- Step 10 3-[2-(Quinuclidin-3-amino)ethyl]-1-(4-methoxybenzyl)-3a,7a-dihydro-1H-pyrazolo[3,4- b] Preparation of sodium pyridine-4-carboxylate (compound 1-12)
- the structure of the prepared compound was identified: 436.2(M+1) + .
- Step 11 7-(quinuclidin-3-yl)-2-(4-methoxybenzyl)-8,9-dihydro-2H-aza Preparation of [5,4,3-cd]-7-azaindazol-6(7H)-one (Compound 1-13)
- the structure of the prepared compound was identified: 418.2(M+1) + .
- Step 12 7-(quinuclidin-3-yl)-8,9-dihydro-2H-aza Preparation of [5,4,3-cd]-7-azaindazol-6(7H)-one (Compound 1)
- Compound 2 was prepared according to the following synthetic procedure.
- the structure of the prepared compound was identified: 207.1(M+1) + .
- Step 2 Preparation of methyl 1-(p-methoxybenzyl)-3-aldehyde-7-azaindole-4-carboxylate (compound 2-4)
- the structure of the prepared compound was identified: 355.4(M+1) + .
- Step 5 3-[2-(quinuclidin-3-amino)ethyl]-1-(4-methoxybenzyl)-3a,7a-dihydro-1H-7-azaindole-4 - Preparation of ethyl formate (compound 2-8)
- the structure of the prepared compound was identified: 465.6(M+1) + .
- Step 6 3-[2-(Quinuclidin-3-amino)ethyl]-1-(4-methoxybenzyl)-3a,7a-dihydro-1H-7-azaindole-4 - Preparation of sodium formate (compound 2-9)
- the yellow solid product was purified by column chromatography to obtain 3-[2-(quinuclidin-3-amino)ethyl]-1-(4-methoxybenzyl)-3a,7a-dihydro-1H-7- Sodium azaindole-4-carboxylate (compound 2-9), weight 0.37 g, pale yellow solid, yield 81%.
- the structure of the prepared compound was identified: 436.5(M+1) + .
- Step 7 7-(quinuclidin-3-yl)-2-(4-methoxybenzyl)-8,9-dihydro-2H-aza Preparation of [5,4,3-cd]-7-azaindole-6(7H)-one (Compound 2-10)
- the structure of the prepared compound was identified: 419.5(M+1) + .
- Step 8 7-(quinuclidin-3-yl)-8,9-dihydro-2H-aza Preparation of [5,4,3-cd]-7-azaindole-6(7H)-one (Compound 2)
- Compound 3 was prepared according to the following synthetic procedure.
- Step 1 3-[2-(8-Methyl-8-azabicyclo[3,2,1]oct-3-yl)ethyl]-1-(4-methoxybenzyl)-3a, Preparation of 7a-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (compound 3-1)
- Step 2 3-[2-(8-Methyl-8-azabicyclo[3,2,1]oct-3-yl)ethyl]-1-(4-methoxybenzyl)-3a, Preparation of sodium 7a-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (compound 3-2)
- the structure of the prepared compound was identified: 449.2(M+1) + .
- the structure of the prepared compound was identified: 432.2(M+1) + .
- Step 4 7-(8-Methyl-8-azabicyclo[3,2,1]oct-3-yl)-8,9-dihydro-2H-aza Preparation of [5,4,3-cd]-7-azaindazol-6(7H)-one (Compound 3)
- Compound 4 was prepared according to the following synthetic procedure.
- Step 1 3-[2-(Endo-9-methyl-9-azabicyclo[3,3,1]nonane-3-amino)ethyl]-1-(4-methoxybenzyl) Preparation of -3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (compound 4-1)
- Step 2 3-[2-(Endo-9-methyl-9-azabicyclo[3,3,1]nonane-3-amino)ethyl]-1-(4-methoxybenzyl) - Preparation of sodium 3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (compound 4-2)
- the structure of the prepared compound was identified: 463.2(M+1) + .
- Step 3 7-(Endo-9-methyl-9-azabicyclo[3,3,1]nonan-3-yl)-2-(4-methoxybenzyl)-8,9-di Hydrogen-2H-aza Preparation of [5,4,3-cd]-7-azaindazol-6(7H)-one (Compound 4-3)
- the structure of the prepared compound was identified: 446.3(M+1) + .
- Step 4 7-(Endo-9-methyl-9-azabicyclo[3,3,1]nonan-3-yl)-8,9-dihydro-2H-aza Preparation of [5,4,3-cd]-7-azaindazol-6(7H)-one (Compound 4)
- 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 10 mM with 100% DMSO, then serially diluted with 100% DMSO at 10X assay concentration in 96-well plates, and further diluted to 4X assay concentration with assay buffer.
- Test compounds were mixed with 10 nM [9-methyl- 3H ]BRL-43694 (Perkin Elmer, Waltham, MA), 3 ⁇ g of human 5-HT3 receptor membrane (Perkin Elmer, Waltham, MA) in a final volume of 0.2 mL.
- SPA beads 0.5 mg/mL SPA beads (WGA PVT, Amersham Biosciences) were incubated in 50 mM Tris-HCl, pH 7.5, 3 mM MgCl2 , 1 Mm EDTA and 10% DMSO. Binding reactions were set up in wells of PicoPlates-96 (Perkin Elmer, Waltham, MA) by sequentially adding 50 ⁇ L of test compound or buffer, SPA beads, radioligand and 5-HT3 receptor membrane. After overnight incubation at room temperature with stirring, centrifugation at 1500 rpm for 15 minutes and incubation in the dark for 30 minutes. Finally radioactivity was read in a TopCount microplate counter (Perkin Elmer) for 5 minutes.
- the total binding control was compound dilution buffer only; non-specific binding was determined in the presence of 30 ⁇ M MDL-72222. Specific binding was determined by subtracting nonspecific binding from total binding. All experiments were performed in duplicate for ten competing ligand concentrations. IC50 values were determined from specific binding data using Xlfit4.1 curve fitting software from IDBS Ltd.
- the present invention provides a nitrogen-containing heterocyclic compound and a preparation method thereof, which can be used as a 5-HT3 receptor modulator.
- the compound prepared by the present invention has a strong affinity for 5-HT3 receptor, and has high activity as a modulator of 5-HT3 receptor, and can be used to prepare a modulator of 5-HT3 receptor.
- drugs for the treatment of diseases related to 5-HT3 receptors such as irritable bowel syndrome, nausea, vomiting, gastroenteritis, gastric dysfunction, diarrhea, pain, carcinoid syndrome, and drug addiction
- diseases related to 5-HT3 receptors such as irritable bowel syndrome, nausea, vomiting, gastroenteritis, gastric dysfunction, diarrhea, pain, carcinoid syndrome, and drug addiction
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Abstract
一种含氮杂环类5-HT3受体调节剂及其制备方法和用途,涉及药物化学领域。该含氮杂环类5-HT3受体调节剂是式I所示的化合物、或其盐、或其立体异构体、或其互变异构体、或其前药、或其溶剂合物、或其水合物。实验证明,制备的化合物对5-HT3受体具有很强的亲和力,作为5-HT3受体的调节剂具有很高的活性,可以用于制备5-HT3受体调节剂,还可以用于制备治疗与5-HT3受体相关的疾病(如肠易激综合征、恶心、呕吐、肠胃炎、胃功能紊乱、腹泻、疼痛、类癌综合征、以及药物成瘾)的药物,具有良好的应用前景。
Description
本发明涉及药物化学领域,具体涉及一种含氮杂环类5-HT3受体调节剂及其制备方法和用途。
5-羟色胺3型(又称血清素3型,5-HT3)受体在涉及呕吐反射、疼痛处理、认知和焦虑控制的中枢神经系统中表达,并且在胃肠道中也有表达,因此可对胃肠道病症(如肠易激综合征、消化不良、胃食管反流疾病和激燥性肠综合征)起到调节作用。
肠易激综合征(irritable bowel syndrome,IBS)是一种持续或间歇发作的功能性胃肠道疾病,临床表现为腹痛、腹胀、排便习惯和(或)大便性状改变、缺乏胃肠道结构和生化异常。改变某些5-羟色胺受体活性的化合物已显示出有益于肠易激综合征(irritable bowel syndrome,IBS)的症状治疗。
在这类5-HT3受体调节剂中,仅有的药物为FDA批准的阿洛司琼,2000年获批后不久,因为在IBS患者中出现缺血性结肠炎,阿洛司琼退出市场。后来因为IBS患者需求较大,FDA恢复了该药物,于2002年批准阿洛司琼片剂在限制条件下用于医疗益处超过风险的患者。因此,研发安全的5-HT3受体调节剂用于治疗IBS具有重要的意义。
类癌(carcinoid)是一种罕见的、生长缓慢的、能产生小分子多肽类或肽类激素的肿瘤,是胃肠道最常见的内分泌肿瘤,现已归属于神经内分泌肿瘤(neuroendocrine neoplasms,NENs)。类癌综合征主要采用生长抑素类似物(SSAs)控制症状。但是对于单独接受SSAs疗法无法充分控制病情的类癌综合征腹泻(CSD)成人患者的治疗,靶向类癌肿瘤细胞内的色氨酸羟化酶(TPH),抑制血清素(serotonin)的过量生产,能降低类癌综合征腹泻的频率,显著改变症状。
由化学疗法引起的恶心和呕吐(chemotherapy-induced nausea and vomiting,CINV),平均发生率为高达90%。其可能使患者抵抗力越来越差,延缓病情的改善,对病人造成负面的结果。
术后恶心呕吐(postoperative nausea and vomiting,PONV)是患者手术后最常见症状,受手术类型、手术持续的时间、麻醉药物和方法及术前焦虑等多种因素的影响,绝大多数患者在术后24小时会发生PONV,呕吐前会出现明显恶心症状。术后恶心呕吐也是常见的术后并发症,据报道它的平均发生 率为20%~30%,在高风险病人中甚至达70%。恶心呕吐除了带给患者严重的不适,也可能引起医疗方面的并发症,如伤口裂开、出血、吸人性肺炎、水电解质紊乱等。所以对PONV的防治方法日益受到人们的重视。
研究显示,调节5-HT3受体对IBS、CSD、CINV和PONV均有治疗效果。目前被批准用于治疗IBS的调节5羟色胺3受体活性的药物为5-HT3受体拮抗剂,它是一种对5-羟色胺3受体活性完全拮抗的药物,其不良反应为便秘和结肠缺血,严重时甚至威胁生命。因此,制备出能够满足临床需求的、更有效、更安全、药代动力学性能更好的5-HT3受体调节剂是治疗包括IBS、CSD、CINV和PONV在内的多种疾病的关键。
发明内容
本发明的目的在于提供一种更有效、更安全、药代动力学性能更好的5-HT3受体调节剂。
本发明提供了式I所示的化合物、或其盐、或其立体异构体、或其互变异构体、或其前药、或其溶剂合物、或其水合物:
其中,
X、Y选自CH或N,且X或Y至少有一个为N;
Z选自N或CR
4;
L选自0~8个亚烷基、-C=O或-SO
2;
R
1选自氢、氘、卤素、-OR
4、-NR
4R
5、-NR
4C(O)R
5、-NR
4C(O)
2R
5、-NR
5C(O)R
4、-S(O)R
5、-CN、-C(O)R
5、-C(O)NR
4R
5、取代或未取代的C
2~C
8烯基、取代或未取代的C
2~C
8炔基、取代或未取代的C
1~C
8烷基、取代或未取代的C
1~C
8烷氧基、取代或未取代的C
3~C
8环烷基,取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
8烷基、卤素、-CN、-OR
7、-NR
7R
8或苯基;所述苯基任选地被卤素、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN、-OR
7或-NR
7R
8取代1~3次;
R
2选自H、氘、卤素、-OR
4、-NR
4R
5、-NR
4C(O)R
5、-NR
4C(O)
2R
5、-NR
5C(O)R
4、-S(O)R
5、-CN、-C(O)R
5、-C(O)NR
4R
5、取代或未取代的C
2~C
8烯基、取代或未取代的C
2~C
8炔基、取代或未取代的C
1~C
8烷基、取代或未取代的C
1~C
8烷氧基;取代或未取代的C
3~C
8环烷基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
8烷基、卤素、-CN、-OR
7、-NR
7R
8或苯基;所述苯基任选地被卤素、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN、-OR
7或-NR
7R
8取代1~3次;
R
3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
3烷基、卤素、-CN,-OR
7或NR
7R
8;
R
4选自H、氘、卤素、取代或未取代的C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
R
5选自H、氘、取代或未取代的C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
R
7和R
8选自H、氘、取代或未取代的C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
n为0、1或2;
当X为N,Y为CH,n为0时,R
3不为取代或未取代的饱和的杂环胺。
进一步地,所述化合物如式II-1所示:
其中,
L选自0~8个亚烷基、-C=O或-SO
2;
R
1选自氢、氘、卤素、-OR
4、-NR
4R
5、-NR
4C(O)R
5、-NR
4C(O)
2R
5、-NR
5C(O)R
4、-S(O)R
5、-CN、-C(O)R
5、-C(O)NR
4R
5、取代或未取代的C
2~C
8烯基、取代或未取代的C
2~C
8炔基、取代或未取代的C
1~C
8烷基、取代或未取代的C
1~C
8烷氧基、取代或未取代的C
3~C
8环烷基,取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
8烷基、卤素、-CN、-OR
7、-NR
7R
8或苯基;所述苯基任选地被卤素、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN、-OR
7或-NR
7R
8取代1-3次;
R
2选自H、氘、卤素、-OR
4、-NR
4R
5、-NR
4C(O)R
5、-NR
4C(O)
2R
5、-NR
5C(O)R
4、-S(O)R
5、-CN、-C(O)R
5、-C(O)NR
4R
5、取代或未取代的C
2~C
8烯基、取代或未取代的C
2~C
8炔基、取代或未取代的C
1~C
8烷基、取代或未取代的C
1~C
8烷氧基;取代或未取代的C
3~C
8环烷基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
8烷基、卤素、-CN、-OR
7、-NR
7R
8或苯基;所述苯基任选地被卤素、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN、-OR
7或-NR
7R
8取代1-3次;
R
3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
3烷基、卤素、-CN,-OR
7或NR
7R
8;
R
4选自H、氘、卤素、取代或未取代的C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
R
5选自H、氘、取代或未取代的C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取 代1~3次;
R
7和R
8选自H、氘、取代或未取代C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
n为0、1或2;
或者,所述化合物如式II-2所示:
其中,
L选自0~8个亚烷基、-C=O或-SO
2;
R
1选自氢、氘、卤素、-OR
4、-NR
4R
5、-NR
4C(O)R
5、-NR
4C(O)
2R
5、-NR
5C(O)R
4、-S(O)R
5、-CN、-C(O)R
5、-C(O)NR
4R
5、取代或未取代的C
2~C
8烯基、取代或未取代的C
2~C
8炔基、取代或未取代的C
1~C
8烷基、取代或未取代的C
1~C
8烷氧基、取代或未取代的C
3~C
8环烷基,取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
8烷基、卤素、-CN、-OR
7、-NR
7R
8或苯基;所述苯基任选地被卤素、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN、-OR
7或-NR
7R
8取代1-3次;
R
2选自H、氘、卤素、-OR
4、-NR
4R
5、-NR
4C(O)R
5、-NR
4C(O)
2R
5、-NR
5C(O)R
4、-S(O)R
5、-CN、-C(O)R
5、-C(O)NR
4R
5、取代或未取代的C
2~C
8烯基、取代或未取代的C
2~C
8炔基、取代或未取代的C
1~C
8烷基、取代或未取代的C
1~C
8烷氧基;取代或未取代的C
3~C
8环烷基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
8烷基、卤素、-CN、-OR
7、-NR
7R
8或苯基;所述苯基任选地被卤素、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN、-OR
7或-NR
7R
8取代1-3次;
R
3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
3烷基、卤素、-CN,-OR
7或NR
7R
8;
R
4选自H、氘、卤素、取代或未取代的C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中 所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
R
5选自H、氘、取代或未取代的C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
R
7和R
8选自H、氘、取代或未取代C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
n为0、1或2;
当n为0时,R
3不为取代或未取代的饱和的杂环胺。
进一步地,所述化合物如式III-1所示:
R
3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
3烷基、卤素、-CN,-OR
7或NR
7R
8;
R
7和R
8选自H、氘、取代或未取代C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
n为0、1或2;
或者,所述化合物如式III-2所示:
R
3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C
1~C
3烷基、卤素、-CN,-OR
7或NR
7R
8;
R
7和R
8选自H、氘、取代或未取代C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、C
3~C
6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C
1~C
4烷基、C
1~C
4卤烷基、C
1~C
4烷氧基、-CN取代1-3次;所述取代的C
1~C
4烷基任选地被C
4~C
8环烷基取代1~3次;
n为0、1或2;
当n为0时,R
3不为取代或未取代的饱和的杂环胺。
进一步地,
m为1~4的整数;
n为0~4的整数。
进一步地,所述化合物为如下结构之一:
进一步地,所述的盐为药学上可接受的盐;
优选地,所述的药学上可接受的盐为盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、三氟甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、1-萘磺酸盐、2-萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、乳酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、 扁桃酸盐。
本发明还提供了一种制备前述的化合物、其盐、其立体异构体、其互变异构体、其前药、其溶剂合物或其水合物的方法,
化合物IV-1的合成路线如下:
和/或,化合物IV-2的合成路线如下:
和/或,化合物IV-3的合成路线如下:
和/或,化合物IV-4的合成路线如下:
本发明还提供了前述的化合物、其盐、其立体异构体、其互变异构体、其前药、其溶剂合物或其水合物在制备5-HT3受体调节剂上的用途。
进一步地,所述5-HT3受体调节剂为5-HT3受体拮抗剂或5-HT3部分激 动剂。
进一步地,所述5-HT3受体调节剂为治疗与5-HT3受体相关的疾病的药物,所述疾病为广泛性焦虑障碍、社交恐怖症、眩晕、强迫症、惊恐性障碍、创伤后精神紧张性障碍、神经性贪食症、药物戒断效应、酒精依赖、疼痛、睡眠相关的中枢性呼吸暂停、慢性疲劳综合征、中枢神经系统相关的疾病、帕金森病精神病、精神分裂症、精神分裂症中的认知减退和缺陷、帕金森病、亨廷顿氏舞蹈症、早老性痴呆、阿尔兹海默病、肥胖症、药物滥用障碍、神经退行性疾病相关的痴呆、认知缺损、纤维肌痛综合征、红斑痤疮、由5-羟色胺介导的心血管疾患、恶心、呕吐、胃肠疾患、胃食管反流病、伯基特淋巴瘤、支气管哮喘、瘙痒症、偏头痛以及癫痫、类癌综合征、肠易激综合征;
优选地,所述恶心或呕吐包括化学疗法引起的恶心或呕吐、手术后引起的恶心或呕吐、放射引起的恶心或呕吐。
本发明还提供了一种药物组合物,它是由前述的化合物、其盐、其立体异构体、其互变异构体、其前药、其溶剂合物或其水合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
进一步地,所述药物组合物用于治疗广泛性焦虑障碍、社交恐怖症、眩晕、强迫症、惊恐性障碍、创伤后精神紧张性障碍、神经性贪食症、药物戒断效应、酒精依赖、疼痛、睡眠相关的中枢性呼吸暂停、慢性疲劳综合征、中枢神经系统相关的疾病、帕金森病精神病、精神分裂症、精神分裂症中的认知减退和缺陷、帕金森病、亨廷顿氏舞蹈症、早老性痴呆、阿尔兹海默病、肥胖症、药物滥用障碍、神经退行性疾病相关的痴呆、认知缺损、纤维肌痛综合征、红斑痤疮、由5-羟色胺介导的心血管疾患、恶心、呕吐、胃肠疾患、胃食管反流病、伯基特淋巴瘤、支气管哮喘、瘙痒症、偏头痛以及癫痫、类癌综合征、肠易激综合征的药物;
优选地,所述恶心或呕吐包括化学疗法引起的恶心或呕吐、手术后引起的恶心或呕吐、放射引起的恶心或呕吐。
进一步地,所述药物组合物是用于治疗精神分裂症的药物,所述药学上可接受的辅料选自丙戊酸盐、左美丙嗪、阿普唑仑、氟派啶醇、氯丙嗪、利哌利酮、帕潘立酮、奥氮平、齐拉西酮、喹硫平、氯氮平、碳酸锂、地西泮、卡马西平、选择性5-羟色胺再摄取抑制剂、三环抗抑郁药中的一种或多种;
或,所述药物组合物是用于治疗帕金森病的药物,所述药学上可接受的辅料选自透皮罗替戈汀、雷沙吉兰、沙芬酰胺、左旋多巴、卡比多巴、多巴胺激动剂、COMT抑制剂、MAO-B抑制剂、金刚烷胺、抗胆碱能药中的一种或多种;
或,所述药物组合物是用于治疗肠易激综合征的药物,所述药学上可接受的辅料选自第二5-羟色胺5-HT3受体调节剂或5-羟色胺5-HT4受体调节剂,其中所述第二5-羟色胺5-HT3受体调节剂或5-羟色胺5-HT4受体调节剂选自阿洛司琼、伦扎必利、西兰司琼、替加色罗、普卢卡必利、昂丹司琼、生长抑素类似物、毒蕈碱受体拮抗剂、缓泻药、镇痉药、抗抑郁药、止泻剂、 促动力剂、外周阿片制剂麻醉药拮抗剂中的一种或多种;
或,所述药物组合物是用于治疗恶心或呕吐的药物,所述药学上可接受的辅料选自地塞米松、阿洛司琼、阿普唑仑、阿瑞吡坦、茶苯海明、苯海拉明、多拉司琼、四氢大麻酚、大麻隆、屈大麻酚、达哌啶醇、格拉司琼、氟派啶醇、劳拉西泮、甲氧氯普胺、咪达唑仑、奥氮平、昂丹司琼、帕洛诺司琼、丙氯拉嗪、普鲁米近、托烷司琼中的一种或多种。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
本发明中,“取代”是指分子中的氢原子被其它不同的原子或分子所替换,包括该分子中相同或不同原子上的1个、2个或多个氢原子被替换。
本发明中,C
a~C
b是指所有含a~b个碳原子的基团或分子。比如“C
1~C
8烷基”包括含1~8个碳原子的所有烷基。烷基可以是直链或支链烷基。比如“C
2~C
8烯基”包括含2~8个碳原子的所有烯基。
本发明中,卤素是指氟、氯、溴、碘。
本发明中,“-OR
4”的结构式为
“-NR
4R
5”的结构式为
“-NR
4C(O)R
5”的结构式为
“-NR
4C(O)
2R
5”的结构式为
“-NR
5C(O)R
4”的结构式为
“-S(O)R
5”的结构式为
“-C(O)R
5”的结构式为
“-C(O)NR
4R
5”的结构式为
本发明提供了一种含氮杂环类化合物及其制备方法,该化合物能够用作5-HT3受体调节剂。实验证明,本发明制备的化合物对5-HT3受体具有很强的亲和力,作为5-HT3受体的调节剂具有很高的活性,可以用于制备5-HT3受体调节剂,还可以用于制备治疗与5-HT3受体相关的疾病(如肠易激综合征、恶心、呕吐、肠胃炎、胃功能紊乱、腹泻、疼痛、类癌综合征、以及药物成瘾)的药物,具有良好的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
根据以下合成步骤,制备化合物1。
步骤1:3-苄氧基丙酸(化合物1-2)的制备
琼斯试剂的制备:0℃下,向溶于12.5mL水的三氧化铬(6.15g,61.5mmol)溶液中逐滴加入浓硫酸(6.3mL),加完浓硫酸,再向体系中加入12.5mL水,0℃下搅拌1小时(备用)。
0℃下,向溶于50mL丙酮的3-苄氧基-1丙醇(5.0g,30.1mmol)溶液中逐滴加入琼斯试剂(24mL),滴加完毕,0℃搅拌2小时。反应液抽滤除去固体物质,然后滤液减压浓缩,旋干,残渣溶于乙酸乙酯,水洗,饱和盐水洗涤,无水硫酸钠干燥,旋干得粗品化合物3-苄氧基丙酸(化合物1-2),重5.0g,白色油状物,收率92%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:180.1(M+1)
+.
步骤2:3-苄氧基丙酸乙酯(化合物1-3)的制备
向装有化合物1-2(5.0g,27.8mmol)的乙醇(50mL)溶液中逐滴加入浓硫酸(0.5mL),滴加完毕,升温至80℃,搅拌反应过夜。次日早上,反应液减压浓缩,旋干,残渣硅胶柱纯化得3-苄氧基丙酸乙酯(化合物1-3),重4.2g,浅黄色油状物,收率64%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:209.1(M+1)
+.
步骤3:5-苄氧基-3-氧代戊腈(化合物1-4)的制备
-78℃下,向装有乙腈(1.5g,35.6mmol)的THF(20mL)溶液中逐滴加入n-BuLi(22.3mL,35.6mmol),滴加完毕,-78℃反应30分钟。之后,将溶于10mL THF的化合物1-3(3.7g,17.8mmol)的溶液逐滴加入到反应体系中,滴加完毕,-78℃继续反应2小时。反应液用饱和氯化铵溶液淬灭,用乙酸乙酯萃取两次。合并乙酸乙酯层,用水和饱和盐水洗涤,无水硫酸钠干燥,旋干。残渣硅胶柱纯化得纯品5-苄氧基-3-氧代戊腈(化合物1-4),重 2.2g,浅黄色固体,61%收率。
对制得的化合物进行结构鉴定:MS(ESI)m/z:204.1(M+1)
+.
步骤4:5-(2-苄氧基乙基)-2-(对甲氧基苄基)-2H-3-氨基吡唑(化合物1-5)的制备
向装有化合物1-4(2.0g,9.85mmol)的甲醇(35mL)溶液中加入(4-甲氧苯基)肼盐酸盐(2.11g,9.36mmol),反应氮气保护,加热至70℃反应过夜。旋干得粗品,粗品用甲基叔丁醚打浆得5-(2-苄氧基乙基)-2-(对甲氧基苄基)-2H-3-氨基吡唑(化合物1-5),重2.0g,白色固体,60%收率。
对制得的化合物进行结构鉴定:MS(ESI)m/z:338.2(M+1)
+.
步骤5:3-(2-苄氧基乙基)-6-羟基-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑[3,4-b]吡啶-4-甲酸乙酯(化合物1-7)的制备
向装有化合物1-5(1.5g,4.45mmol)的醋酸/水(体积比=1/20,12mL)溶液中加入草酰乙酸二乙酯钠盐(化合物1-6)(1.12g,5.34mmol),反应氮气保护,加热至80℃,反应过夜。反应液倒入水中,用乙酸乙酯萃取三次。合并乙酸乙酯层,用水和饱和盐水洗涤,无水硫酸钠干燥,旋干。残渣硅胶柱纯化得3-(2-苄氧基乙基)-6-羟基-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑[3,4-b]吡啶-4-甲酸乙酯(化合物1-7),重900mg,白色固体,收率44%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:462.2(M+1)
+.
步骤6:3-(2-苄氧基乙基)-6-氯-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑[3,4-b]吡啶-4-甲酸乙酯(化合物1-8)的制备
0℃下,向装有DMF(1mL)的DCE(25mL)溶液中加入草酰氯(1.1mL),滴加完毕,室温反应10分钟。之后,将化合物1-7(0.6g,1.3mmol)加入到反应体系中。反应氮气保护下80℃搅拌过夜。反应液倒入水中,用二氯甲烷萃取两次。合并二氯甲烷层,无水硫酸钠干燥,旋干。残渣硅胶柱纯化得3-(2-苄氧基乙基)-6-氯-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑[3,4-b]吡啶-4-甲酸乙酯(化合物1-8),重500mg,无色油状物,收率80%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:480.2(M+1)
+.
步骤7:3-(2-羟基乙基)-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物1-9)的制备
向装有化合物1-8(220mg,0.925mmol)的甲醇(15mL)溶液中加入10%的湿钯碳(44mg)。1atm氢气下,50℃搅拌3小时。反应液过滤,滤饼旋干。残渣硅胶柱纯化得3-(2-羟基乙基)-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物1-9),重80mg,无色油状物,收率49%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:356.2(M+1)
+.
步骤8:1-(4-甲氧基苄基)-3-(2-氧代乙基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物1-10)的制备
0℃下,向装有化合物1-9(80mg,0.23mmol)的二氯甲烷(20mL)溶液中加入DMP(195mg,0.46mmol)。室温搅拌2小时。反应液倒入水中,用二氯甲烷萃取两次。合并二氯甲烷层,无水硫酸钠干燥,旋干。残渣硅胶板纯化得1-(4-甲氧基苄基)-3-(2-氧代乙基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物1-10),重60mg,黄色油状物,收率74%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:354.1(M+1)
+.
步骤9:3-[2-(奎宁环-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物1-11)的制备
向装有化合物1-10(60mg,0.17mmol)和S-3-氨基奎宁环二盐酸盐(68mg,0.34mmol)的甲醇(8mL)溶液中加入2滴冰乙酸。室温搅拌1小时。然后向反应液中加入氰基硼氢化钠(43mg,0.68mmol),室温搅拌过夜。反应液倒入水中,用二氯甲烷萃取两次。合并二氯甲烷层,无水硫酸钠干燥,旋干。残渣硅胶板纯化得3-[2-(奎宁环-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物1-11),重62mg,黄色固体,收率79%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:464.2(M+1)
+.
步骤10:3-[2-(奎宁环-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸钠(化合物1-12)的制备
向装有化合物1-11(62mg,0.134mmol)的THF(10mL)溶液中加入氢氧化钠(55mg,1.39mmol)的水(1mL)溶液。室温搅拌过夜。反应液旋干得3-[2-(奎宁环-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸钠(化合物1-12),未进一步纯化直接用于下一步。
对制得的化合物进行结构鉴定:436.2(M+1)
+.
向装有化合物1-12(90mg,粗品)和DIEA(0.3mL)的THF(15mL) 溶液中加入T
3P(0.5mL)。室温搅拌过夜。反应液倒入水中,用二氯甲烷/甲醇=5/1(v/v)的混合溶液萃取两次。合并有机相,无水硫酸钠干燥,旋干。残渣硅胶板纯化得7-(奎宁环-3-基)-2-(4-甲氧基苄基)-8,9-二氢-2H-氮杂
并[5,4,3-cd]-7-氮杂吲唑-6(7H)-酮(化合物1-13),重45mg,白色固体,80%收率。
对制得的化合物进行结构鉴定:418.2(M+1)
+.
将化合物1-13(45mg,0.11mmol)加入三氟乙酸(5mL)中。加热至75℃反应过夜。反应液用1M氢氧化钠水溶液调碱至pH 12,用二氯甲烷/甲醇=5/1(v/v)的混合溶液萃取两次。合并有机相,无水硫酸钠干燥,旋干。残渣硅胶板纯化得7-(奎宁环-3-基)-8,9-二氢-2H-氮杂
并[5,4,3-cd]-7-氮杂吲唑-6(7H)-酮(化合物1),重18mg,白色固体,收率55%。
对制得的化合物1进行结构鉴定:
1HNMR(400MHz,DMSO-d
6),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)
+.
根据以下合成步骤,制备化合物2。
步骤1:3-醛基-7-氮杂吲哚-4-甲酸甲酯(化合物2-3)的制备
将7-氮杂吲哚-4-甲酸甲酯(化合物2-1)(1g,5.62mmol)加入水(16mL)中,加入乌洛托品(化合物2-2)(1.6g,11.4mmol),冰醋酸(32毫升),逐渐加热至100℃,搅拌反应12小时,TLC监控反应完全,冷却至室温,将反应液倾入冰水(200mL)中,乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析(乙酸乙酯:石油醚=1:1,体积比,v/v),得3-醛 基-7-氮杂吲哚-4-甲酸甲酯(化合物2-3),重0.67g,收率56%。
对制得的化合物进行结构鉴定:207.1(M+1)
+.
步骤2:1-(对甲氧基苄基)-3-醛基-7-氮杂吲哚-4-甲酸甲酯(化合物2-4)的制备
将化合物2-3(0.8g,3.88mmol)加入DMF(25mL)中,加入对甲氧基苄溴(1.17g,5.82mmol)和碳酸铯(2.54g,7.80mmol)。室温搅拌过夜。次日早上TLC监控反应完全,反应液倒入水中,用乙酸乙酯萃取两次。合并乙酸乙酯层,用水和饱和盐水洗涤,无水硫酸钠干燥,减压浓缩得油状物,柱层析(乙酸乙酯:石油醚=1:1,体积比,v/v)纯化得1-(对甲氧基苄基)-3-醛基-7-氮杂吲哚-4-甲酸甲酯(化合物2-4),重0.75g,浅黄色固体,收率59%。
对制得的化合物进行结构鉴定:327.3(M+1)
+.
步骤3:1-(对甲氧基苄基)-3-(2-甲氧乙烯基)-3a,7a-二氢-1H-7-氮杂吲哚-4-甲酸甲酯(化合物2-5)的制备
将化合物2-4(1.1g,3.37mmol)、甲氧基甲基三苯基氯化膦(1.38g,4.05mmol)加入四氢呋喃(20mL)中,冰水浴冷却至0℃,分批加入叔丁醇钾(708mg,6.31mmol)。加毕,反应液升至室温搅拌1小时。TLC监控反应完全,将反应液倒入水中,用乙酸乙酯萃取两次。合并乙酸乙酯层,用水和饱和盐水洗涤,无水硫酸钠干燥,减压浓缩得1-(对甲氧基苄基)-3-(2-甲氧乙烯基)-3a,7a-二氢-1H--7-氮杂吲哚-4-甲酸甲酯(化合物2-5),重0.92g,收率77%。化合物2-5粗品未进一步柱层析纯化直接用于下一步。
对制得的化合物进行结构鉴定:355.4(M+1)
+.
步骤4:1-(4-甲氧基苄基)-3-(2-氧代乙基)-3a,7a-二氢-1H-7-氮杂吲哚-4-甲酸甲酯(化合物2-6)的制备
化合物2-5粗品(0.9g,2.54mol)的四氢呋喃(10mL)溶液中,加入盐酸(4.4mL,26.3mmol,6M)。搅拌,加热至60℃反应2小时。TLC显示反应完全,将反应液倒入水中,用乙酸乙酯萃取两次。合并乙酸乙酯层,用饱和盐水洗涤,无水硫酸钠干燥,旋干。残渣用甲基叔丁基醚打浆得1-(4-甲氧基苄基)-3-(2-氧代乙基)-3a,7a-二氢-1H-7-氮杂吲哚-4-甲酸甲酯(化合物2-6),重0.52g,浅黄色固体,两步收率45%。
对制得的化合物进行结构鉴定:341.3(M+1)
+.
步骤5:3-[2-(奎宁环-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-7-氮杂吲哚-4-甲酸乙酯(化合物2-8)的制备
化合物2-6(1.03g,2.47mmol)加入二氯甲烷(20mL),R-3-氨基奎宁环二盐酸盐(化合物2-7)(737mg,3.70mmol)和冰乙酸(741mg,12.35mmol)。室温搅拌反应4小时。TLC显示原料化合物2-6消失,反应完全,向反应液中加入氰基硼氢化钠(466mg,7.41mmol),室温搅拌过夜。次日早上,将反应液倒入饱和碳酸氢钠水溶液中,用二氯甲烷萃取两次。合并二氯甲烷层,无水硫酸钠干燥,减压浓缩除去溶剂得油状物。油状物柱层析(乙酸乙酯:石油醚=1:1,体积比,v/v),得3-[2-(奎宁环-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-7-氮杂吲哚-4-甲酸乙酯(化合物2-8),重486mg,浅黄色固体,收率37%。
对制得的化合物进行结构鉴定:465.6(M+1)
+.
步骤6:3-[2-(奎宁环-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-7-氮杂吲哚-4-甲酸钠(化合物2-9)的制备
化合物2-8(0.47mg,0.92mmol)加入甲醇(12mL),氢氧化钠(74mg,1.85mmol),搅拌加热至60℃反应8小时。TLC显示原料化合物2-8消失,反应完全。反应液取出冷却,倒入水中,用乙酸乙酯萃取两次。合并乙酸乙酯层,用水和饱和盐水洗涤,无水硫酸钠干燥,减压浓缩除去溶剂,得黄色固体产物。将黄色固体产物柱层析纯化得3-[2-(奎宁环-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-7-氮杂吲哚-4-甲酸钠(化合物2-9),重0.37g,浅黄色固体,收率81%。
对制得的化合物进行结构鉴定:436.5(M+1)
+.
向装有化合物2-9(110mg)和DIEA(0.3mL)的THF(15mL)溶液中加入T
3P(0.5mL)。室温搅拌过夜。反应液倒入水中,用二氯甲烷/甲醇=5/1(v/v,体积比)的混合溶液萃取两次。合并有机相,无水硫酸钠干燥,旋干。残渣硅胶板纯化得7-(奎宁环-3-基)-2-(4-甲氧基苄基)-8,9-二氢-2H-氮杂
并[5,4,3-cd]-7-氮杂吲哚-6(7H)-酮(化合物2-10),重41mg,白色固体,收率75%。
对制得的化合物进行结构鉴定:419.5(M+1)
+.
化合物2-10(90mg,0.21mmol),苯甲醚(0.5mL),三氟乙酸(0.5mL)混合搅拌,加热至80℃反应18小时。TLC显示原料化合物2-10消失,将反应液取出冷却,旋干。向残渣中加入35%的HCl水溶液(5mL),用甲基叔丁基醚洗两次,水层用浓氢氧化钠水溶液调碱至pH 12。所得混悬液搅拌1小时,抽滤,水洗,滤饼收集旋干得7-(奎宁环-3-基)-8,9-二氢-2H-氮杂
并[5,4,3-cd]-7-氮杂吲哚-6(7H)-酮(化合物2),重45mg,浅黄色固体,收率72%。
对制得的化合物2进行结构鉴定:
1HNMR(400MHz,DMSO-d
6),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)
+.
根据以下合成步骤,制备化合物3。
步骤1:3-[2-(8-甲基-8-氮杂双环[3,2,1]辛-3-基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物3-1)的制备
向装有1-(4-甲氧基苄基)-3-(2-氧代乙基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(实施例1中制备的化合物1-10,130mg,0.36mmol)和8-甲基-8-氮杂双环[3,2,1]辛-3-胺盐酸盐(77mg,0.55mmol)的甲醇(15mL)溶液中加入4滴冰乙酸。室温搅拌1小时。然后向反应液中加入氰基硼氢化钠(91mg,1.44mmol),室温搅拌过夜。反应液倒入水中,用二氯甲烷萃取两次。合并二氯甲烷层,无水硫酸钠干燥,旋干。残渣硅胶板纯化得3-[2-(8-甲基-8-氮杂双环[3,2,1]辛-3-基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物3-1),重90mg,黄色固体,收率52%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:477.3(M+1)
+.
步骤2:3-[2-(8-甲基-8-氮杂双环[3,2,1]辛-3-基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸钠(化合物3-2)的制备
向装有化合物3-1(47mg,0.1mmol)的THF(8mL)溶液中加入氢氧化钠(28mg,0.7mmol)的水(0.8mL)溶液。室温搅拌过夜。反应液旋干得3-[2-(8-甲基-8-氮杂双环[3,2,1]辛-3-基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸钠(化合物3-2),未进一步纯化直接用于下一步。
对制得的化合物进行结构鉴定:449.2(M+1)
+.
向装有化合物3-2(90mg,粗品)和DIEA(129mg)的THF(13mL)溶液中加入T
3P(318mgL)。室温搅拌过夜。反应液倒入水中,用二氯甲烷/甲醇=5/1(v/v,体积比)的混合溶液萃取两次。合并有机相,无水硫酸钠干燥,旋干。残渣硅胶板纯化得7-(8-甲基-8-氮杂双环[3,2,1]辛-3-基)-2-(4-甲氧基苄基)-8,9-二氢-2H-氮杂
并[5,4,3-cd]-7-氮杂吲唑-6(7H)-酮(化合物3-3),重45mg,白色固体,80%收率。
对制得的化合物进行结构鉴定:432.2(M+1)
+.
将化合物3-3(40mg,0.11mmol)加入三氟乙酸(5mL)中。加热至75℃反应过夜。反应液用1M氢氧化钠水溶液调碱至pH 12,用二氯甲烷/甲醇=5/1(v/v,体积比)的混合溶液萃取两次。合并有机相,无水硫酸钠干燥,旋干。残渣硅胶板纯化得7-(8-甲基-8-氮杂双环[3,2,1]辛-3-基)-8,9-二氢-2H-氮杂
并[5,4,3-cd]-7-氮杂吲唑-6(7H)-酮(化合物3),重17mg,白色固体,收率55%。
对制得的化合物3进行结构鉴定:
1HNMR(400MHz,DMSO-d
6),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)
+.
根据以下合成步骤,制备化合物4。
步骤1:3-[2-(内向-9-甲基-9-氮杂双环[3,3,1]壬烷-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物4-1)的制备
向装有1-(4-甲氧基苄基)-3-(2-氧代乙基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(实施例1中制备的化合物1-10,160mg,0.45mmol)和3-高托品烷胺盐酸盐(105mg,0.68mmol)的甲醇(20mL)溶液中加入5滴冰乙酸。室温搅拌1小时。然后向反应液中加入氰基硼氢化钠(113mg,1.8mmol),室温搅拌过夜。反应液倒入水中,用二氯甲烷萃取两次。合并二氯甲烷层,无水硫酸钠干燥,旋干。残渣硅胶板纯化得3-[2-(内向-9-甲基-9-氮杂双环[3,3,1]壬烷-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸乙酯(化合物4-1),重60mg,黄色固体,收率27%。
对制得的化合物进行结构鉴定:MS(ESI)m/z:492.3(M+1)
+.
步骤2:3-[2-(内向-9-甲基-9-氮杂双环[3,3,1]壬烷-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸钠(化合物4-2)的制备
向装有化合物4-1(30mg,0.06mmol)的THF(7mL)溶液中加入氢氧化钠(16mg,0.42mmol)的水(0.7mL)溶液。反应室温搅拌过夜。反应液旋干得3-[2-(内向-9-甲基-9-氮杂双环[3,3,1]壬烷-3-氨基)乙基]-1-(4-甲氧基苄基)-3a,7a-二氢-1H-吡唑并[3,4-b]吡啶-4-甲酸钠(化合物4-2),未进一步柱层析纯化直接用于下一步。
对制得的化合物进行结构鉴定:463.2(M+1)
+.
向装有化合物4-2(40mg,粗品)和DIEA(73mg)的THF(10mL)溶液中加入T
3P(191mg)。室温搅拌过夜。反应液倒入水中,用二氯甲烷/甲醇=5/1(v/v,体积比)的混合溶液萃取两次。合并有机相,无水硫酸钠干燥,旋干。残渣硅胶板纯化得7-(内向-9-甲基-9-氮杂双环[3,3,1]壬烷-3-基)-2-(4-甲氧基苄基)-8,9-二氢-2H-氮杂
并[5,4,3-cd]-7-氮杂吲唑-6(7H)-酮(化合物4-3),重30mg,两步收率89%。
对制得的化合物进行结构鉴定:446.3(M+1)
+.
将化合物4-3(30mg,0.067mmol)加入三氟乙酸(5mL)中。加热至75℃反应过夜。反应液用1M氢氧化钠水溶液调碱至pH 12,用二氯甲烷/甲醇=5/1(v/v,体积比)的混合溶液萃取两次。合并有机相,无水硫酸钠干燥,旋干。残渣硅胶板纯化得7-(内向-9-甲基-9-氮杂双环[3,3,1]壬烷-3-基)-8,9-二氢-2H-氮杂
并[5,4,3-cd]-7-氮杂吲唑-6(7H)-酮(化合物4),重5mg,白色固体,收率23%。
对制得的化合物4进行结构鉴定:
1HNMR(400MHz,DMSO-d
6),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)
+.
以下通过具体的试验例证明本发明的有益效果
试验例1、本发明化合物对人5-HT3受体的亲和力评价
1、试验方法
使用闪烁亲近测定(SPA)形式在放射性配体结合测定中测量化合物对人5-HT3受体的相对亲和力。将受试化合物用100%DMSO稀释至10mM,然后在96孔板中用100%DMSO以10×测定浓度梯度稀释,并进一步用测定缓冲液稀释至4×测定浓度。将受试化合物与终体积为0.2mL的10nM[9-甲基-
3H]BRL-43694(Perkin Elmer,Waltham,MA)、3μg的人5-HT3受体膜(Perkin Elmer,Waltham,MA)和0.5mg/mL SPA珠(WGA PVT,Amersham Biosciences)孵育在50mM Tris-HCl,pH 7.5、3mM MgCl
2、1Mm EDTA和10%DMSO中。通过连续地添加50μL的受试化合物或缓冲液、SPA珠、放射性配体和5-HT3受体膜,将结合反应设置在PicoPlates-96(Perkin Elmer,Waltham,MA)的孔中。室温搅拌过夜孵育后,以1500rpm离心15分钟,避光孵育30分钟。最后在TopCount微板计数器(Perkin Elmer)中读取5分钟放射活性。总结合对照为只含有化合物稀释缓冲液;非特异性结合是在存在30μM MDL-72222的情况下确定的。特异性结合是通过从总结合中减去非特异性结合来确定。所有实验是十个竞争配体浓度一式两份进行。IC
50值是使用来自IDBS Ltd的Xlfit4.1曲线拟合软件由特异性结合数据确定的。
实验数据及分析:抑制常数Ki=IC
50/(1+(L/KD)),其中L=在测定中 放射性配体的浓度,KD=放射性配体对受体的亲和力。
2、试验结果
本实验测试本发明化合物对人5-HT3受体的亲和力,实验结果如下表1所示。
表1.本发明化合物对人5-HT3受体的亲和力
Cmpd. | IC 50(nmol) | Ki(nmol) |
1 | 288.3 | 52.23 |
2 | 1783 | 321.26 |
3 | >10000 | >1802 |
4 | 8955 | 1613.51 |
综上,本发明提供了一种含氮杂环类化合物及其制备方法,该化合物能够用作5-HT3受体调节剂。实验证明,本发明制备的化合物对5-HT3受体具有很强的亲和力,作为5-HT3受体的调节剂具有很高的活性,可以用于制备5-HT3受体调节剂,还可以用于制备治疗与5-HT3受体相关的疾病(如肠易激综合征、恶心、呕吐、肠胃炎、胃功能紊乱、腹泻、疼痛、类癌综合征、以及药物成瘾)的药物,具有良好的应用前景。
Claims (13)
- 式I所示的化合物、或其盐、或其立体异构体、或其互变异构体、或其前药、或其溶剂合物、或其水合物:其中,X、Y选自CH或N,且X或Y至少有一个为N;Z选自N或CR 4;L选自0~8个亚烷基、-C=O或-SO 2;R 1选自氢、氘、卤素、-OR 4、-NR 4R 5、-NR 4C(O)R 5、-NR 4C(O) 2R 5、-NR 5C(O)R 4、-S(O)R 5、-CN、-C(O)R 5、-C(O)NR 4R 5、取代或未取代的C 2~C 8烯基、取代或未取代的C 2~C 8炔基、取代或未取代的C 1~C 8烷基、取代或未取代的C 1~C 8烷氧基、取代或未取代的C 3~C 8环烷基,取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 8烷基、卤素、-CN、-OR 7、-NR 7R 8或苯基;所述苯基任选地被卤素、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN、-OR 7或-NR 7R 8取代1~3次;R 2选自H、氘、卤素、-OR 4、-NR 4R 5、-NR 4C(O)R 5、-NR 4C(O) 2R 5、-NR 5C(O)R 4、-S(O)R 5、-CN、-C(O)R 5、-C(O)NR 4R 5、取代或未取代的C 2~C 8烯基、取代或未取代的C 2~C 8炔基、取代或未取代的C 1~C 8烷基、取代或未取代的C 1~C 8烷氧基;取代或未取代的C 3~C 8环烷基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 8烷基、卤素、-CN、-OR 7、-NR 7R 8或苯基;所述苯基任选地被卤素、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN、-OR 7或-NR 7R 8取代1~3次;R 3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 3烷基、卤素、-CN,-OR 7或NR 7R 8;R 4选自H、氘、卤素、取代或未取代的C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;R 5选自H、氘、取代或未取代的C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;R 7和R 8选自H、氘、取代或未取代的C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;n为0、1或2;当X为N,Y为CH,n为0时,R 3不为取代或未取代的饱和的杂环胺。
- 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其互变异构体、或其前药、或其溶剂合物、或其水合物,其特征在于:所述化合物如式II-1所示:其中,L选自0~8个亚烷基、-C=O或-SO 2;R 1选自氢、氘、卤素、-OR 4、-NR 4R 5、-NR 4C(O)R 5、-NR 4C(O) 2R 5、-NR 5C(O)R 4、-S(O)R 5、-CN、-C(O)R 5、-C(O)NR 4R 5、取代或未取代的C 2~C 8烯基、取代或未取代的C 2~C 8炔基、取代或未取代的C 1~C 8烷基、取代或未取代的C 1~C 8烷氧基、取代或未取代的C 3~C 8环烷基,取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代 基独立地选自C 1~C 8烷基、卤素、-CN、-OR 7、-NR 7R 8或苯基;所述苯基任选地被卤素、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN、-OR 7或-NR 7R 8取代1-3次;R 2选自H、氘、卤素、-OR 4、-NR 4R 5、-NR 4C(O)R 5、-NR 4C(O) 2R 5、-NR 5C(O)R 4、-S(O)R 5、-CN、-C(O)R 5、-C(O)NR 4R 5、取代或未取代的C 2~C 8烯基、取代或未取代的C 2~C 8炔基、取代或未取代的C 1~C 8烷基、取代或未取代的C 1~C 8烷氧基;取代或未取代的C 3~C 8环烷基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 8烷基、卤素、-CN、-OR 7、-NR 7R 8或苯基;所述苯基任选地被卤素、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN、-OR 7或-NR 7R 8取代1-3次;R 3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 3烷基、卤素、-CN,-OR 7或NR 7R 8;R 4选自H、氘、卤素、取代或未取代的C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;R 5选自H、氘、取代或未取代的C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;R 7和R 8选自H、氘、取代或未取代C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;n为0、1或2;或者,所述化合物如式II-2所示:其中,L选自0~8个亚烷基、-C=O或-SO 2;R 1选自氢、氘、卤素、-OR 4、-NR 4R 5、-NR 4C(O)R 5、-NR 4C(O) 2R 5、-NR 5C(O)R 4、-S(O)R 5、-CN、-C(O)R 5、-C(O)NR 4R 5、取代或未取代的C 2~C 8烯基、取代或未取代的C 2~C 8炔基、取代或未取代的C 1~C 8烷基、取代或未取代的C 1~C 8烷氧基、取代或未取代的C 3~C 8环烷基,取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 8烷基、卤素、-CN、-OR 7、-NR 7R 8或苯基;所述苯基任选地被卤素、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN、-OR 7或-NR 7R 8取代1-3次;R 2选自H、氘、卤素、-OR 4、-NR 4R 5、-NR 4C(O)R 5、-NR 4C(O) 2R 5、-NR 5C(O)R 4、-S(O)R 5、-CN、-C(O)R 5、-C(O)NR 4R 5、取代或未取代的C 2~C 8烯基、取代或未取代的C 2~C 8炔基、取代或未取代的C 1~C 8烷基、取代或未取代的C 1~C 8烷氧基;取代或未取代的C 3~C 8环烷基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 8烷基、卤素、-CN、-OR 7、-NR 7R 8或苯基;所述苯基任选地被卤素、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN、-OR 7或-NR 7R 8取代1-3次;R 3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 3烷基、卤素、-CN,-OR 7或NR 7R 8;R 4选自H、氘、卤素、取代或未取代的C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;R 5选自H、氘、取代或未取代的C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;R 7和R 8选自H、氘、取代或未取代C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;n为0、1或2;当n为0时,R 3不为取代或未取代的饱和的杂环胺。
- 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其互变异构体、或其前药、或其溶剂合物、或其水合物,其特征在于:所述化合物如式III-1所示:R 3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 3烷基、卤素、-CN,-OR 7或NR 7R 8;R 7和R 8选自H、氘、取代或未取代C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;n为0、1或2;或者,所述化合物如式III-2所示:R 3选自取代或未取代的饱和的二环、取代或未取代的饱和的杂环胺;所述取代为任选地被1~3个取代基取代,所述取代基独立地选自C 1~C 3烷基、卤素、-CN,-OR 7或NR 7R 8;R 7和R 8选自H、氘、取代或未取代C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、C 3~C 6环烷基、取代或未取代的苯基、取代或未取代的苄基;其中所述取代的苯基或苄基任选地被卤素、氰基、C 1~C 4烷基、C 1~C 4卤烷基、C 1~C 4烷氧基、-CN取代1-3次;所述取代的C 1~C 4烷基任选地被C 4~C 8环烷基取代1~3次;n为0、1或2;当n为0时,R 3不为取代或未取代的饱和的杂环胺。
- 根据权利要求1~5任一项所述的化合物、其盐、其立体异构体、其互变异构体、其前药、其溶剂合物或其水合物,其特征在于:所述的盐为药学上可接受的盐;优选地,所述的药学上可接受的盐为盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、三氟甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、1-萘磺酸盐、2-萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、乳酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、扁桃酸盐。
- 权利要求1~6任一项所述的化合物、其盐、其立体异构体、其互变异构体、其前药、其溶剂合物或其水合物在制备5-HT3受体调节剂上的用途。
- 根据权利要求8所述的用途,其特征在于:所述5-HT3受体调节剂 为5-HT3受体拮抗剂或5-HT3部分激动剂。
- 根据权利要求9所述的用途,其特征在于:所述5-HT3受体调节剂为治疗与5-HT3受体相关的疾病的药物,所述疾病为广泛性焦虑障碍、社交恐怖症、眩晕、强迫症、惊恐性障碍、创伤后精神紧张性障碍、神经性贪食症、药物戒断效应、酒精依赖、疼痛、睡眠相关的中枢性呼吸暂停、慢性疲劳综合征、中枢神经系统相关的疾病、帕金森病精神病、精神分裂症、精神分裂症中的认知减退和缺陷、帕金森病、亨廷顿氏舞蹈症、早老性痴呆、阿尔兹海默病、肥胖症、药物滥用障碍、神经退行性疾病相关的痴呆、认知缺损、纤维肌痛综合征、红斑痤疮、由5-羟色胺介导的心血管疾患、恶心、呕吐、胃肠疾患、胃食管反流病、伯基特淋巴瘤、支气管哮喘、瘙痒症、偏头痛以及癫痫、类癌综合征、肠易激综合征;优选地,所述恶心或呕吐包括化学疗法引起的恶心或呕吐、手术后引起的恶心或呕吐、放射引起的恶心或呕吐。
- 一种药物组合物,其特征在于:它是由权利要求1~6任一项所述的化合物、其盐、其立体异构体、其互变异构体、其前药、其溶剂合物或其水合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
- 根据权利要求11所述的药物组合物,其特征在于:所述药物组合物用于治疗广泛性焦虑障碍、社交恐怖症、眩晕、强迫症、惊恐性障碍、创伤后精神紧张性障碍、神经性贪食症、药物戒断效应、酒精依赖、疼痛、睡眠相关的中枢性呼吸暂停、慢性疲劳综合征、中枢神经系统相关的疾病、帕金森病精神病、精神分裂症、精神分裂症中的认知减退和缺陷、帕金森病、亨廷顿氏舞蹈症、早老性痴呆、阿尔兹海默病、肥胖症、药物滥用障碍、神经退行性疾病相关的痴呆、认知缺损、纤维肌痛综合征、红斑痤疮、由5-羟色胺介导的心血管疾患、恶心、呕吐、胃肠疾患、胃食管反流病、伯基特淋巴瘤、支气管哮喘、瘙痒症、偏头痛以及癫痫、类癌综合征、肠易激综合征的药物;优选地,所述恶心或呕吐包括化学疗法引起的恶心或呕吐、手术后引起的恶心或呕吐、放射引起的恶心或呕吐。
- 根据权利要求12所述的药物组合物,其特征在于:所述药物组合物是用于治疗精神分裂症的药物,所述药学上可接受的辅料选自丙戊酸盐、左美丙嗪、阿普唑仑、氟派啶醇、氯丙嗪、利哌利酮、帕潘立酮、奥氮平、齐拉西酮、喹硫平、氯氮平、碳酸锂、地西泮、卡马西平、选择性5-羟色胺再摄取抑制剂、三环抗抑郁药中的一种或多种;或,所述药物组合物是用于治疗帕金森病的药物,所述药学上可接受的辅料选自透皮罗替戈汀、雷沙吉兰、沙芬酰胺、左旋多巴、卡比多巴、多巴胺激动剂、COMT抑制剂、MAO-B抑制剂、金刚烷胺、抗胆碱能药中的一种或多种;或,所述药物组合物是用于治疗肠易激综合征的药物,所述药学上可接受的辅料选自第二5-羟色胺5-HT3受体调节剂或5-羟色胺5-HT4受体调节 剂,其中所述第二5-羟色胺5-HT3受体调节剂或5-羟色胺5-HT4受体调节剂选自阿洛司琼、伦扎必利、西兰司琼、替加色罗、普卢卡必利、昂丹司琼、生长抑素类似物、毒蕈碱受体拮抗剂、缓泻药、镇痉药、抗抑郁药、止泻剂、促动力剂、外周阿片制剂麻醉药拮抗剂中的一种或多种;或,所述药物组合物是用于治疗恶心或呕吐的药物,所述药学上可接受的辅料选自地塞米松、阿洛司琼、阿普唑仑、阿瑞吡坦、茶苯海明、苯海拉明、多拉司琼、四氢大麻酚、大麻隆、屈大麻酚、达哌啶醇、格拉司琼、氟派啶醇、劳拉西泮、甲氧氯普胺、咪达唑仑、奥氮平、昂丹司琼、帕洛诺司琼、丙氯拉嗪、普鲁米近、托烷司琼中的一种或多种。
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