WO2014190942A1 - Composé d'indole, et procédé de préparation, composition pharmaceutique et utilisation de celui-ci - Google Patents

Composé d'indole, et procédé de préparation, composition pharmaceutique et utilisation de celui-ci Download PDF

Info

Publication number
WO2014190942A1
WO2014190942A1 PCT/CN2014/078980 CN2014078980W WO2014190942A1 WO 2014190942 A1 WO2014190942 A1 WO 2014190942A1 CN 2014078980 W CN2014078980 W CN 2014078980W WO 2014190942 A1 WO2014190942 A1 WO 2014190942A1
Authority
WO
WIPO (PCT)
Prior art keywords
branched
substituted
unsubstituted
straight
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2014/078980
Other languages
English (en)
Chinese (zh)
Inventor
柳红
谢欣
赵飞
李静
栗增
陈颖
孙海丰
周宇
蒋华良
陈凯先
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Publication of WO2014190942A1 publication Critical patent/WO2014190942A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • a class of terpenoids, preparation methods thereof, pharmaceutical compositions and applications A class of terpenoids, preparation methods thereof, pharmaceutical compositions and applications
  • the invention relates to the field of medicinal chemistry and chemotherapy.
  • the present invention relates to a class of terpenoids of the formula (I), a process for the preparation thereof, a pharmaceutical composition thereof and a medicament for the treatment of a disease associated with the ⁇ -adrenergic receptor, in particular benign prostatic hyperplasia , urinary retention, bladder outlet obstruction and other urinary system diseases.
  • Benign prostatic hyperplasia is a common physiological disease in middle-aged and elderly men. With the inevitable population aging, the incidence of benign prostatic hyperplasia has been greatly improved compared with the previous one. It has become a middle-aged male in China. One of the most common geriatric diseases. Data show that the incidence of benign prostatic hyperplasia is very low before the age of 40, while about half of men over the age of 50 have benign prostatic hyperplasia, and nearly 90% of those aged 80 have the disease. Benign prostatic hyperplasia is a benign adenoma hyperplasia of cells in the peri-urethral region of the prostate.
  • progenitor gland hyperplasia is one of the common diseases of domestic and foreign middle-aged men, which greatly reduces the quality of life of patients.
  • the pathogenesis of benign prostatic hyperplasia is complex and related to a variety of enzymes and receptors.
  • the main drugs for clinical treatment of BPH are: ⁇ -adrenergic receptor antagonist, 5 ⁇ -reductase inhibitor, natural product preparation and the like.
  • the two major drugs for the treatment of sputum, 5 ⁇ -reductase inhibitors and ⁇ -receptor antagonists, are treated separately for the prostate volume and smooth muscle tone that cause symptoms of benign prostatic hyperplasia; in theory, the presence of hyperplasia is positive. It is dependent on these two important factors: static factors and kinetic factors, the two together affect the extent of the disease.
  • on-adrenoceptor antagonists can quickly relieve symptoms, but can not significantly reduce the size of the prostate and early development of such drugs often have serious adverse reactions.
  • 5 ⁇ -reductase inhibitors can reduce the size of the prostate and fundamentally relieve symptoms, but have a poor effect on small-sized sputum and slower onset.
  • Adrenergic receptors are classified into ⁇ -receptors and ⁇ -receptors, which are subdivided into several receptor subtypes.
  • the alpha-adrenergic receptor is a family of 7 transmembrane G-protein coupled receptors (GPCRs) that are widely distributed in various organs, tissues and cells of the body.
  • GPCRs transmembrane G-protein coupled receptors
  • the ⁇ -adrenergic receptor ( ⁇ -ARs) is divided into two types, ⁇ and ⁇ 2 . Studies have shown that there are mainly type 0 receptors in the matrix components of the prostate and in the glandular epithelium.
  • Molecular cloning methods have isolated and identified three on-receptor subtypes of ⁇ 1 ⁇ , ⁇ 1 ⁇ and a 1D , with a 1A -ARs accounting for approximately 70% of the total on-ARs in the human prostate and urinary tract system.
  • alpha 1 ⁇ -receptors are mainly distributed in the prostate, urethra and bladder triangle, vas deferens, ⁇ 1 ⁇ -receptors are distributed in blood vessels, and a 1D -receptors are distributed in bladder detrusor and ureter smooth muscle.
  • the density of o-ARs increased significantly.
  • the distribution characteristics of 0 ⁇ - 1 ⁇ subtypes vary with age. The correlation between age and distribution is to understand and treat benign prostatic hyperplasia and lower urinary tract system symptoms, and develop on-adrenergic receptor antagonism. The agent is of great significance.
  • the kinetics of BPH are dependent on the contraction of stromal smooth muscle, which is caused by on-adrenergic receptor-mediated sympathetic stimulation.
  • the stimulation of ai- ARs can cause contraction of the smooth muscle of the prostate, leading to a occlusive increase in urethral pressure, causing obstruction of the urine flow and symptoms of bladder irritation.
  • ai- ARs mediate smooth muscle contraction through a series of phosphatase C activation processes that produce second messenger-trisphosphate and diacylglycerol downstream, resulting in endogenous Ca 2+ Release to regulate gene expression.
  • ⁇ 1 ⁇ -adrenergic receptor is an ideal target for treatment, and its blockade has been shown to be effective in reducing the contraction frequency of prostate smooth muscle and improving bladder emptying.
  • Blockade of ⁇ 1 ⁇ -adrenergic receptors can lead to vascular smooth muscle relaxation, arteriovenous dilatation, and decreased peripheral resistance, which may cause side effects such as dizziness and hypotension in some patients.
  • Activation of a 1D -adrenergic receptors can lead to hyperactivity of the detrusor, which can reduce the occurrence of emptying symptoms, which has been confirmed in animal experiments.
  • a combination of a 1A and a 1D -adrenergic receptor inhibitors is a very effective drug for the control of benign prostatic hyperplasia. Because it contains the ability to reduce the frequency of contraction of the smooth muscle of the prostate and inhibit the detrusor dysfunction, in addition to avoid cardiovascular side effects caused by a 1B - adrenergic block.
  • Phenoxybenzamine The first generation of a receptor blockers that were developed and utilized to effectively alleviate the symptoms of benign prostatic hyperplasia were Phenoxybenzamine.
  • the phenoxybenzamine structure contains a ⁇ -chloroethylamine structure, which is easily reacted with other enzymes in the body, so that toxicity and side effects are more.
  • non-selective alpha receptor blocker it blocks the presynaptic alpha 2 receptor while blocking the receptor, thus promoting the release of norepinephrine, which can cause heart rate and myocardial contractility. Increase, causing adverse reactions.
  • non-selective 0 ⁇ /01 2 receptor blockers is limited by their multiple side effects, including: syncope, orthostatic hypotension, reflex tachycardia, arrhythmia, etc. These side effects are mainly derived from alpha 2 receptor blockade.
  • a second-generation ⁇ -adrenergic receptor antagonist with high selectivity for ⁇ receptor has emerged (eg, prazosin, terazosin, doxazosin, alfuzosin) .
  • the on-adrenergic receptor relieves the contraction of the prostate and urethral smooth muscle caused by the sympathetic nerve, and reduces the symptoms of urethral obstruction in terms of kinetics.
  • oxazoazines have the structural nucleus of quinazoline and are currently commonly used in the clinical treatment of sputum and its lower urinary tract symptoms (LUTS).
  • the present invention provides a class of terpenoids, a preparation method thereof, a pharmaceutical composition thereof and a urinary system disease thereof for treating diseases associated with ⁇ -adrenergic receptors, particularly benign prostatic hyperplasia, urinary retention, bladder outlet obstruction, and the like Applications.
  • One aspect of the present invention provides a quinone compound represented by the formula (I), and a pharmaceutically acceptable salt, a crystalline hydrate thereof, a solvate or a mixture thereof.
  • Another aspect of the present invention provides a process for producing an intermediate of the compound of the formula (I), that is, a compound of the formula (II).
  • Another aspect of the present invention provides a process for the preparation of a compound of the formula (III) which is another intermediate required for the preparation of the compound of the formula (I).
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I), a pharmaceutically acceptable salt thereof, a crystalline hydrate, and a solvate thereof.
  • a compound of the formula (I), and a pharmaceutically acceptable salt, a crystalline hydrate thereof, a solvate thereof or a mixture thereof for the preparation of a disease associated with on-adrenergic receptors are provided.
  • a pharmaceutically acceptable salt, a crystalline hydrate thereof, a solvate thereof or a mixture thereof for the preparation of a disease associated with on-adrenergic receptors.
  • Still another aspect of the present invention provides a method of treating a urinary system disease associated with an alpha-adrenergic receptor, particularly a benign prostatic hyperplasia, urinary retention, bladder outlet obstruction, comprising administering a therapeutically effective amount to a subject in need of such treatment.
  • a urinary system disease associated with an alpha-adrenergic receptor particularly a benign prostatic hyperplasia, urinary retention, bladder outlet obstruction
  • administering a therapeutically effective amount to a subject in need of such treatment.
  • R 2 , R 3 , R 4 , R 5 represent a substituent on the benzene ring, each independently selected from the group consisting of hydrogen, halogen, amino, carboxyl, cyano, nitro, hydroxy, unsubstituted or straight from C2-C6 A chain or branched alkenyl or halogen-substituted C1-C6 straight or branched fluorenyl group, a C1-C6 straight or branched decyloxy group unsubstituted or substituted by a C3-C6 cyclodecyl group or a halogen, C2-C12 straight or branched alkenyl group unsubstituted or substituted by halogen, C2-C12 straight or branched alkynyl group unsubstituted or substituted by halogen, C3-C6 unsubstituted or substituted by halogen Cyclodecyl, unsubstituted or substituted by halogen
  • the two adjacent substituents of Ri, R 2 , R 3 , R 4 , and R 5 together with the carbon atom to which the benzene ring is attached may form a hetero atom containing 1 to 3 selected from N, 0 and S.
  • 5-6 membered heterocyclic ring preferably forming a 5-6 membered heterocyclic ring containing 1 to 2 hetero atoms selected from 0 and S; more preferably forming a dioxole ring;
  • R 6 is selected from hydrogen, unsubstituted or substituted by halogen, C 1 -C 6 straight or branched fluorenylcarbonyl, and unsubstituted or halogenated,
  • a C1-C6 linear or branched fluorenyl group a C1-C6 linear or branched decyloxy-substituted benzoyl group; preferably selected from the group consisting of hydrogen,
  • a C1-C4 linear or branched fluorenyl group and a C1-C4 straight or branched fluorenylcarbonyl group which is unsubstituted or substituted by 1-3 halogens; More preferably selected from the group consisting of hydrogen, methyl, acetyl and trifluoroacetyl;
  • R 7 is selected from the group consisting of hydrogen, a C1-C6 linear or branched fluorenyl group, and a C1-C6 linear or branched fluorenyloxy group; preferably a hydrazine group selected from hydrogen and a C1-C4 straight or branched chain; More preferably selected from the group consisting of hydrogen and methyl;
  • the anthraquinone compound represented by the formula (I) of the present invention may be a R-isomer, an S-isomer and a racemate, and is preferably a R-isomer.
  • a C1-C6 straight or branched fluorenyl group selected from the group consisting of hydrogen, halogen, amino, carboxyl, cyano, nitro, hydroxy, unsubstituted or substituted by C2-C6 straight or branched alkenyl or halogen, a C1-C6 straight or branched decyloxy group which is unsubstituted or substituted by a C3-C6 cyclodecyl group or a halogen, a C2-C12 straight or branched alkenyl group which is unsubstituted or substituted by a halogen, unsubstituted or C2-C12 straight or branched alkynyl substituted by halogen, C3-C6 cyclodecyl unsubstituted or substituted by halogen, C3-C6 cyclodecyl unsubstituted or substituted by halogen, unsubstituted or Halogen-substi
  • R 2 is selected from hydrogen, halogen, unsubstituted or C1-C6 straight or branched fluorenyl substituted by C2-C6 straight or branched alkenyl or halogen; preferably selected from hydrogen, halogen and unsubstituted or a C2-C4 linear or branched alkenyl or halogen-substituted C1-C4 straight or branched fluorenyl group; more preferably selected from the group consisting of hydrogen, fluorine, chlorine, bromine and unsubstituted or substituted by 1-3 halogens a C 1 -C 4 linear or branched fluorenyl group; most preferably selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl and ethyl;
  • R 3 is selected from hydrogen, halogen, unsubstituted or C1-C6 straight or branched fluorenyl substituted by C2-C6 straight or branched alkenyl or halogen, unsubstituted or substituted by 1-3 halogen C2-C12 linear or branched alkenyl; preferably selected from hydrogen, halogen and C1-C4 straight or branched fluorene unsubstituted or substituted by C2-C4 straight or branched alkenyl or halogen More preferably selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and a C1-C4 straight or branched fluorenyl group which is unsubstituted or substituted by a vinyl group or 1-3 halogens; most preferably selected from the group consisting of hydrogen, methyl, and Base, allyl, fluorine, chlorine and bromine;
  • R 4 is selected from hydrogen, halogen, unsubstituted or C1-C6 straight or branched fluorenyl substituted by C2-C6 straight or branched alkenyl or halogen, and unsubstituted or substituted by 1-3 halogen C2-C12 straight or branched alkenyl; preferably selected from hydrogen, halogen and C1-C4 straight or branched, unsubstituted or substituted by C2-C4 straight or branched alkenyl or halogen Sulfhydryl; more preferably C1-C4 straight or branched fluorenyl, fluorine, chlorine and bromine selected from hydrogen, unsubstituted or substituted by vinyl or 1-3 halogen; more preferably selected from hydrogen, methyl, Ethyl, allyl, fluorine, chlorine and bromine;
  • R 3 and may together with the carbon atom to which it is attached on the benzene ring constitutes 1 to 3 selected from 0 and S a 5- to 6-membered heterocyclic ring of a hetero atom; preferably a 5- to 6-membered heterocyclic ring having 1 to 2 hetero atoms selected from 0 and S; more preferably forming a dioxole ring;
  • R 5 is selected from the group consisting of hydrogen, halogen, amino, carboxy, cyano, nitro, hydroxy, unsubstituted or C1-C6 straight or branched fluorenyl substituted by C2-C6 straight or branched alkenyl or halogen a C1-C6 straight or branched decyloxy group which is unsubstituted or substituted by a C3-C6 cyclodecyl group or a halogen, a C2-C12 straight or branched alkenyl group which is unsubstituted or substituted by a halogen, unsubstituted Or a C2-C12 straight or branched alkynyl group substituted by halogen, a C3-C6 cyclodecyl group which is unsubstituted or substituted by halogen, a C3-C6 cyclodecyloxy group which is unsubstituted or substituted by halogen, un
  • R 6 is selected from hydrogen, unsubstituted or substituted by halogen, C 1 -C 6 straight or branched fluorenylcarbonyl, and unsubstituted or halogenated, C 1 -C 6 straight or branched fluorenyl, C 1 -C 6 straight a branched or branched methoxy-substituted benzoyl group; preferably selected from hydrogen and a C1-C4 straight or branched fluorenylcarbonyl group which is unsubstituted or substituted by 1-3 halogens; preferably selected from hydrogen, acetyl and Trifluoroacetyl group;
  • R 7 is selected from the group consisting of hydrogen, a C1-C6 linear or branched fluorenyl group, and a C1-C6 linear or branched fluorenyloxy group; preferably a hydrazine group selected from hydrogen and a C1-C4 straight or branched chain; More preferably selected from the group consisting of hydrogen and methyl; most preferably hydrogen;
  • the pharmaceutically acceptable salt includes a non-toxic salt formed by reacting with a mineral acid or an organic acid
  • the inorganic acid is not limitedly selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and amine sulfonate.
  • Acid and phosphoric acid the organic acid being selected, without limitation, from propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid and aspartic acid.
  • the halogen is fluorine, chlorine, bromine or iodine.
  • Ri, R 2 , R 3 , R 4 , R 5 are each independently selected from the group consisting of hydrogen, halogen, unsubstituted or C2-C6 straight or branched alkenyl or halogen.
  • R 6 is selected from hydrogen or a C 1 -C 6 straight or branched fluorenylcarbonyl group which is unsubstituted or substituted by halogen
  • R 7 is selected from the group consisting of hydrogen.
  • Ri, R 2 , R 3 , R 4 , R 5 are each independently selected from H, F, Cl, Br, unsubstituted or C2-C6 straight or branched alkenyl or halogen.
  • At least one of Ri, R 2 , R 3 , R 4 , R 5 is a C1-C6 straight chain unsubstituted or substituted by a C2-C6 straight or branched alkenyl or halogen or Branched fluorenyl, C3-C6 cyclodecyloxy which is unsubstituted or substituted by halogen, C1-C6 straight or branched decyloxy which is unsubstituted or substituted by C3-C6 cyclodecyl or halogen.
  • At least one of Ri, R 2 , R 3 , R 4 , R 5 is selected from the group consisting of cyclopropoxy, methoxy, ethoxy, propoxy, (CH 3 ) 3 CCH 2 0-, (CH 3 ) 3 CO-, (CF 3 ) 3 CO-.
  • the compound of the present invention has a chiral center and may be an R-isomer, an S-isomer, and a racemate, and is preferably a R-isomer.
  • the present invention provides a process for producing a compound represented by the formula (I).
  • the preparation of the compound represented by the general formula (I) requires the preparation of the following two intermediates, an intermediate ( ⁇ ) and an intermediate (III).
  • Raw materials and reagents used in the present invention such as commercial
  • Reaction route 1 includes the following reaction steps:
  • Step la nucleophilic substitution reaction of compound la with methyl bromoacetate to obtain compound lb; wherein the nucleophilic substitution reaction can be carried out in the presence of a base, such as potassium carbonate, cesium carbonate, potassium phosphate, Sodium hydroxide or potassium hydroxide, preferably potassium carbonate;
  • the reaction solvent may be, for example, acetone, acetonitrile, tetrahydrofuran or hydrazine, hydrazine-dimethylformamide, preferably acetone;
  • Step lb Compound lb is subjected to amine transesterification with hydrazine, hydrazine-dimethylhydroxylamine hydrochloride to obtain compound lc; the amine transesterification reaction can be carried out in the presence of a catalyst such as trimethylaluminum, and the reaction solvent can be, for example, none.
  • a catalyst such as trimethylaluminum
  • the reaction solvent can be, for example, none.
  • Step lc The compound lc is subjected to a reduction reaction to obtain a compound Id; wherein the reduction reaction can be carried out using a reducing agent such as lithium aluminum hydride; the reaction solvent can be, for example, anhydrous tetrahydrofuran.
  • a reducing agent such as lithium aluminum hydride
  • the reaction solvent can be, for example, anhydrous tetrahydrofuran.
  • Reaction route 2 includes the following reaction steps:
  • Step 3a Compound 3a is subjected to a nucleophilic substitution reaction with 2-bromo-1-ethanol or 3-bromo-1-propanol or 4-bromo-1-butanol to obtain compound 3b; wherein the nucleophilic substitution reaction can be carried out Reflowing in the presence of a base for 12-20 hours, the base may be, for example, potassium carbonate; the reaction solvent may be, for example, acetonitrile;
  • Step 3b Compound 3b is acylated with an acylating reagent to obtain compound 3c; wherein the acylation reaction can be carried out in the presence of a base, and the acylating agent can be, for example, an acid chloride, for example, a halogen, C1-C6 straight A chain or branched fluorenyl group, a C1-C6 linear or branched decyloxy substituted or unsubstituted benzoyl chloride or an unsubstituted or substituted 1-3 halogen substituted C1-C6 straight or branched fluorene
  • the base may be, for example, triethylamine; the reaction solvent may be, for example, anhydrous dichloromethane;
  • Step 3c the compound 3c is subjected to a formylation reaction with hydrazine, hydrazine-dimethylformamide to obtain a compound 3d; wherein the formylation reaction can be carried out in the presence of a catalyst such as phosphorus oxychloride, for example, the reaction solvent can be It is anhydrous 1,2-one gas;
  • Step 3d The compound 3d is subjected to a condensation reaction with nitroacetamidine to obtain a compound 3e; wherein the condensation reaction can be carried out in the presence of a catalyst such as ammonium acetate; the reaction solvent can be, for example, a mixed solvent of acetic acid and nitroacetamidine. ;
  • Step 3e Compound 3e is subjected to a reduction reaction to obtain a compound 3f; wherein the reduction reaction can be used as an example a reducing agent such as sodium borohydride; the reaction solvent may be, for example, a mixed solvent of dichloromethane and methanol;
  • Step 3f the compound 3f is subjected to a formylation reaction with hydrazine and hydrazine-dimethylformamide to obtain a compound 2a; wherein the formylation reaction can be carried out in the presence of a catalyst such as phosphorus oxychloride, for example, the reaction solvent can be Is ⁇ , ⁇ -dimethylformamide;
  • a catalyst such as phosphorus oxychloride
  • the reaction solvent can be Is ⁇ , ⁇ -dimethylformamide
  • Step 2a Compound 2a is subjected to an oxidation reaction to obtain a compound 2b; wherein, the oxidation reaction may use, for example, an oxidizing agent of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (abbreviated as DDQ);
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • the reaction solvent may be, for example, ethyl acetate, dichloromethane or 1,4-dioxane;
  • Step 2b Compound 2b is subjected to a condensation reaction with hydroxylamine hydrochloride to obtain compound 2c; wherein the condensation reaction can be carried out in the presence of a base and a dehydrating agent, and the base can be, for example, pyridine; and the dehydrating agent can be, for example, acetic anhydride;
  • the solvent may be, for example, anhydrous tetrahydrofuran;
  • Step 2c Compound 2c is subjected to a reduction reaction to obtain a compound 2d; wherein, the reduction reaction may use, for example, a reducing agent of 10% palladium carbon; and the reaction solvent may be, for example, methanol, tetrahydrofuran or a mixed solvent of methanol and tetrahydrofuran;
  • Step 2d Compound 2d is resolved to give compound 2e and compound 2f; the resolving agent may be, for example, L-(+)-tartaric acid or L-(-)-tartaric acid; and the reaction solvent may be, for example, acetone.
  • the resolving agent may be, for example, L-(+)-tartaric acid or L-(-)-tartaric acid; and the reaction solvent may be, for example, acetone.
  • Step 4a The intermediate (II) and the intermediate (III) are subjected to a reductive amination reaction to obtain a compound 4a; wherein the reductive amination can be carried out, for example, in the presence of sodium borohydride or sodium cyanoborohydride, a reaction solvent For example, 1,2-dichloroethane;
  • Step 4b Compound 4a is subjected to a hydrolysis reaction to obtain a compound 4b; wherein the hydrolysis can be carried out, for example, in the presence of a base, which may be, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide; the reaction solvent may be, for example, a mixed solvent of water and methanol;
  • a base which may be, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide
  • the reaction solvent may be, for example, a mixed solvent of water and methanol
  • Step 4c The compound 4b is subjected to a hydrolysis reaction to obtain a compound 4c; wherein the hydrolysis reaction can be carried out in the presence of a catalyst such as a base and hydrogen peroxide, the base being, for example, sodium hydroxide; and the reaction solvent being, for example, dimethyl Sulfoxide; or
  • a catalyst such as a base and hydrogen peroxide
  • the base being, for example, sodium hydroxide
  • the reaction solvent being, for example, dimethyl Sulfoxide
  • Step 4d nucleophilic substitution reaction of compound 4a with benzyl bromide to obtain compound 4d; wherein, the nucleophilic substitution reaction can be carried out, for example, in the presence of a base, such as potassium carbonate; and the reaction solvent can be, for example, acetone.
  • Step 4e Compound 4d is subjected to a hydrolysis reaction to obtain a compound 4e; wherein, the hydrolysis reaction can be, for example, In the presence of a base, the base may be, for example, potassium hydroxide, sodium hydroxide, or lithium hydroxide; the reaction solvent may be, for example, a mixed solvent of water and methanol;
  • Step 4f The compound 4e is subjected to a hydrolysis reaction to obtain a compound 4f; wherein the hydrolysis reaction can be carried out in the presence of a catalyst such as a base and hydrogen peroxide, the base being, for example, sodium hydroxide; and the reaction solvent being, for example, dimethyl Sulfoxide
  • a catalyst such as a base and hydrogen peroxide
  • the base being, for example, sodium hydroxide
  • the reaction solvent being, for example, dimethyl Sulfoxide
  • Step 4g compound 4f is acylated with an acylating reagent to obtain compound 4g; wherein the acylation reaction can be carried out in the presence of a base, and the acylating agent can be, for example, an acid chloride, for example, halogen, C1-C6 straight A chain or branched fluorenyl group, a C1-C6 straight or branched decyloxy substituted or unsubstituted benzoyl chloride, unsubstituted or substituted by a 1-3 halogen to a C1-C6 straight or branched decanoyl chloride
  • the base may be, for example, triethylamine;
  • the reaction solvent may be, for example, anhydrous dichloromethane;
  • Step 4h 4 g of the compound is subjected to hydrogenation debenzylation to obtain a compound 4h; wherein, the hydrodebenzylation reaction may use, for example, a reducing agent of 10% palladium carbon; and the reaction solvent may be, for example, methanol, tetrahydrofuran or a mixed solvent of methanol and tetrahydrofuran.
  • the hydrodebenzylation reaction may use, for example, a reducing agent of 10% palladium carbon
  • the reaction solvent may be, for example, methanol, tetrahydrofuran or a mixed solvent of methanol and tetrahydrofuran.
  • Ri ⁇ R 7 is the same as defined above except that R 6 is not hydrogen.
  • the present inventors have found through experiments that the compound of the general formula (I) has excellent ⁇ 1 -adrenergic receptor antagonistic activity and selectivity, and thus the compound of the present invention can be used for preparing an experimental model tool related to on-adrenergic receptors. Or the preparation of a medicament for the treatment and prevention of diseases associated with on-adrenergic receptors, especially urinary system diseases such as benign prostatic hyperplasia, urinary retention, bladder outlet obstruction.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, crystalline hydrate thereof, and solvate thereof, and one or more pharmaceutically acceptable Accepted carrier.
  • the pharmaceutically acceptable salt thereof includes a non-toxic salt formed by reacting with an inorganic acid or an organic acid, and the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, and phosphoric acid, and the organic acid includes propionic acid. , oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid.
  • the pharmaceutical composition may further contain conventional additives such as odorants and flavoring agents.
  • the pharmaceutical composition provided by the present invention preferably contains, in a weight ratio of 1 to 99%, one or more selected from the group consisting of a compound of the formula (I), a pharmaceutically acceptable salt thereof, a crystalline hydrate and a solvate thereof.
  • the active ingredient preferably, the active ingredient is from 65% to 99% by weight based on the total weight of the pharmaceutical composition, the remainder being a pharmaceutically acceptable carrier and/or conventional additives.
  • the compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be presented in a suitable solid or liquid carrier or diluent. Neutralizes a suitable sterilizing device for injection or drip.
  • compositions of the present invention can be prepared according to conventional methods of preparation in the pharmaceutical arts.
  • the formulation of the formulation may comprise 0.05-200 mg, preferably 0.1 mg-100 mg of one or more selected from the group consisting of the compound of the formula (I), a pharmaceutically acceptable salt thereof, a crystalline hydrate and a solvate thereof. .
  • the compounds and pharmaceutical compositions of this invention may be administered to mammals clinically, including humans and animals, and may be administered by the oral, nasal, dermal, pulmonary or gastrointestinal routes.
  • the most preferred route of administration is oral.
  • the present invention also provides a method of treating a urinary system disease associated with an alpha-adrenergic receptor, particularly a benign prostatic hyperplasia, urinary retention, bladder outlet obstruction, including administration to a subject in need of such treatment.
  • An effective amount is selected from one or more of the compounds of the formula (I) and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof.
  • Example 1 1-(3-Hydroxypropyl)-5-[(2R)-2-[2,6-dimethyl-phenoxy]ethylamino]propyl]-indole-7- Amide (DC371801) (as shown in Reaction Scheme 1 and Reaction Scheme 2, the corresponding two intermediates are prepared first, and then prepared by Reaction Scheme 3 shown in Reaction Scheme 3 (DC471801)
  • reaction solution is concentrated to remove most of the methanol, and then After adding 600 ml of ethyl acetate, a saturated aqueous solution of ammonium chloride was added thereto, and a large amount of a white solid was obtained, which was filtered, and the filtrate was washed three times with water (200 ml of EtOAc). g, yield 91%.
  • the 1-(3-benzoyloxypropyl)-7-cyano-5-(2-nitropropyl)-indole (47 g) obtained in the previous step was dissolved in a mixed solvent of 400 ml of methanol and 400 ml of tetrahydrofuran.
  • the 1-(3-benzoyloxypropyl)-7-cyano-5-(2-aminopropyl)-indole 5g obtained in the previous step was dissolved in acetone 30 ml, and added dropwise thereto under stirring.
  • 1.2 g of L-(+)-tartaric acid aqueous solution (1.2 g of L-(+)-tartaric acid dissolved in 30 ml of water) was stirred for 12 h, and a large amount of solid was precipitated, and filtered to give the desired product, L-(+)-tartrate, 2.0 g.
  • the obtained solid was dissolved in 80 ml of water, and the mixture was adjusted to pH 10 with a saturated aqueous solution of sodium carbonate, and extracted twice with ethyl acetate (100 ⁇ 2). The organic layer was combined, dried and concentrated to give a pale yellow oily solid 1.8 g. .
  • the 1-(3-benzoyloxypropyl)-7-cyano-5-(2-aminopropyl)-indole 5g obtained in the step 1.9 is dissolved in 30 ml of acetone, and added dropwise thereto under stirring.
  • 1.2 g of L-(-)-tartaric acid aqueous solution (1.2 g of L-(-)-tartaric acid dissolved in 30 ml of water) was stirred for 12 hours, and a large amount of solid was precipitated, and filtered to give the desired product L-(-)-tartrate 2.0 g.
  • N-methyl-N-methoxy-5-ethyl-2-(2,2,2-trifluoroethoxy)-phenoxyacetamide (3.5 g) obtained in the previous step was dissolved in anhydrous tetrahydrofuran. 414mg of lithium tetrahydrogenate was added slowly to the batch at -78 °C, and the reaction was carried out for 3 hours. The reaction solution was added dropwise with water to quench the lithium tetrahydrogenate. The filtrate was dried and concentrated to give a white solid. g, yield 91%.
  • the 2-methoxy-4-ethyl-phenol in the step 5.1 was replaced with 2-methoxy-4-bromo-phenol, and the iodonium in the step 5.4 was replaced with 1 -Bromo-2,2-dimethylpropanthine.
  • Example 2 5 l-( 3 -Hydroxypropyl) -5 -[( 2 R)-2- 2- [ 2 -[ 5 -fluoro- 2 -( 2 , 2 , 2 -trifluoroethoxy)phenoxy Ethylamino]propyl]-indole-7-carboxamide (DC471825)
  • the 2-methoxy-4-ethyl-phenol in the step 5.1 was replaced with 2-methoxy-4-fluoro-phenol, and the iodonium in the step 5.4 was replaced with 1 -Bromo-2,2-dimethylpropanthine.
  • Example 32 l-(3-Hydroxypropyl)-5-[(2R)-2-[2-[5-methyl-2-(2,2,2-trifluoroethoxy)phenoxy ]ethylamino]propyl]-indole-7-carboxamide (DC471832)
  • Example 35 l-(3-Hydroxypropyl)-5-[(2R)-2-[2-[4-methyl-2-cyclopropoxy-phenoxy]ethylamino]propyl] - ⁇ -7-carboxamide (DC471835) Following the preparation of Example 5, the 2-methoxy-4-ethyl-phenol in step 5.1 was replaced with 2-methoxy-4-methyl-phenol, and the iodonium in step 5.4 was replaced with Made from bromocyclopropane. NMR (400 MHz,
  • Example 36 l-(3-Hydroxypropyl)-5-[(2R)-2-[2-[4-methyl-2-cyclopropoxy-phenoxy]ethylamino]propyl ] - ⁇ _ 7 _carboxamide (DC471836)
  • Example 3 9 l-( 3 -Hydroxypropyl) - 5 -[( 2 R)- 2 -[ 2 -[ 5 -chloro- 2 -( 2 , 2 , 2 -trifluoroethoxy)phenoxy Ethylamino]propyl]-indole-7-carboxamide (DC471839)
  • the 2-methoxy-4-ethyl-phenol in the step 5.1 was replaced with 2-methoxy-4-chloro-phenol, and the iodonium in the step 5.4 was replaced with 1 -Bromo-2,2-dimethylpropanthine.
  • Example 46 l-(3-Hydroxypropyl)-5-[(2R)-2-[2-[5-allyl-2-(2,2,2-trifluoroethoxy)phenoxy Ethylamino]propyl]-indole-7-carboxamide (DC471846)
  • Example 53 l-(3-Hydroxypropyl)-5-[(2R)-2-[2-bromo-4-fluoro-phenoxy]ethylamino]propyl]-indole-7- Amide (DC471853) According to the preparation method of Example 1, the 2,6-dimethylphenol in the step 1.12 was replaced with 2-bromo-4-fluoro-phenol.
  • Example 54 l-(3-Hydroxypropyl)-5-[(2R)-2-[2-ethyl-phenoxy]ethylamino]propyl]-indole-7-carboxamide (DC471854 )
  • step 1.1 the 3-bromo-1-propanol in step 1.1 was replaced with 2-bromo-1-ethanol, and the steps were as follows.
  • step 1.1 Following the preparation of Example 1, the 3-bromo-1-propanol in step 1.1 was replaced with 4-bromo-1-butanol.
  • the 3-bromo-1-propanol in the step 1.1 was replaced with 2-bromo-1-ethanol, and the 2,6-dimethylphenoxyacetaldehyde in the step 1.15 was replaced with 5 -Fluoro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde, 5-fluoro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde
  • the preparation method of Example 4 was prepared by substituting 2-methoxy-4-ethyl-phenol in Step 4.1 with 2-methoxy-4-fluoro-phenol.
  • Example 5 9 l- (4 - hydroxybutyl) - 5 - [(2 R ) - 2 - [2 - [5 - fluoro - 2 - (2, 2, 2 - trifluoroethoxy) phenoxy Ethylamino]propyl]-indole-7-carboxamide (DC471859)
  • Example 1 In the preparation method of Example 1, the 3-bromo-1-propanol in the step 1.1 was replaced with 4-bromo-1-butanol, and the 2,6-dimethylphenoxyacetaldehyde in the step 1.15 was replaced with 5-fluoro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde, 5-fluoro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde.
  • the preparation method of Example 4 was prepared by replacing 2-methoxy-4-ethyl-phenol in Step 4.1 with 2-methoxy-4-fluoro-phenol.
  • Example 1 1-(3-benzoyloxypropyl)-7-cyano-5-[(2R)-2-aminopropyl]-indole was replaced by 1 in the step 1.15.
  • -(3-benzoyloxypropyl)-7-cyano-5-(2-aminopropyl)-indole replacing 2,6-dimethylphenoxyacetaldehyde in step 1.15 with 4 -Fluoro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde, 4-fluoro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde
  • the preparation method of Example 4 was prepared by substituting 2-methoxy-4-ethyl-phenol in Step 4.1 with 2-methoxy-5-fluoro-phenol.
  • Example 61 l- (3 - hydroxypropyl) _ 5 - [(2 S ) - 2 - [2 _ [4 - fluoro - 2 - (2, 2, 2 - trifluoroethoxy) phenoxy ]ethylamino]propyl]-indole-7-carboxamide (DC471861)
  • Example 6 3 l-( 3 -Hydroxypropyl) - 5 -[( 2 S)- 2 -[ 2 -[ 5 -fluoro- 2 -( 2 , 2 , 2 -trifluoroethoxy)phenoxy Ethylamino]propyl]-indole-7-carboxamide (DC471863)
  • Example 65 l-(3-Hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino] Propyl] - ⁇ -7-carboxamide (DC471865)
  • Example 66 l- (3 - acetoxypropyl) - 5 - [(2 R ) - 2 - [2 - [2 - (2, 2, 2 - trifluoroethoxy) phenoxy] acetate Amino]propyl]-indole-7-carboxamide (DC471866)
  • reaction solution is concentrated to remove most of the methanol, and then After adding 600 ml of ethyl acetate, a saturated aqueous solution of ammonium chloride was added thereto, and a large amount of a white solid was obtained, which was filtered, and the filtrate was washed three times with water (200 ml of EtOAc). g, yield 91%.
  • the 1-(3-benzoyloxypropyl)-7-cyano-5-(2-aminopropyl)-indole 5g obtained in the previous step was dissolved in acetone 30 ml, and added dropwise thereto under stirring.
  • 1.2 g of L-(+)-tartaric acid aqueous solution (1.2 g of L-(+)-tartaric acid dissolved in 30 ml of water) was stirred for 12 h, and a large amount of solid was precipitated, and filtered to give the desired product, L-(+)-tartrate, 2.0 g.
  • the obtained solid was dissolved in 80 ml of water, and the mixture was adjusted to pH 10 with a saturated aqueous solution of sodium carbonate, and extracted twice with ethyl acetate (100 ⁇ 2). The organic layer was combined, dried and concentrated to give a pale yellow oily solid 1.8 g. .
  • Example 68 l-(3-Acetoxypropyl)-2-methyl-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)benzene Oxy]ethylamino]propyl]-indole-7-carboxamide (DC471868)
  • Example 66 According to the preparation method of Example 66, the indoline in the step 66.1 was replaced with 2-methyl-indoline.
  • Example 1 According to the preparation method of Example 1, the dihydroanthracene in the step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in the step 1.15 was replaced with 5-B.
  • Example 70 l-(3-Hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[4-ethyl-2-ethoxy-phenoxy]ethylamino ]propyl] - ⁇ -7-carboxamide (DC471870)
  • Example 1 According to the preparation method of Example 1, the indoline in step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in step 1.15 was replaced by 2-B.
  • Oxy-4-ethyl-phenoxyacetaldehyde (2-ethoxy-4-ethyl-phenoxyacetaldehyde was prepared in the same manner as in Example 5).
  • Example 1 According to the preparation method of Example 1, the indoline in step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in step 1.15 was replaced with 5-bromo.
  • Preparation method of -2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde (5-bromo-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde Example 4, replacing 2-methoxy-4-ethyl-phenol in 4.1 with 2-methoxy-4-bromo-phenol).
  • Example 72 l-(3-Hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[4-bromo-2-ethoxy-phenoxy]ethylamino] Propyl]-indole-7-carboxamide (DC471872)
  • Example 1 According to the preparation method of Example 1, the indoline in step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in step 1.15 was replaced with 4-bromo.
  • 2-ethoxy-phenoxyacetaldehyde (4-bromo-2-ethoxy-phenoxyacetaldehyde is prepared in the same manner as in Example 5, 2-methoxy-4-ethyl- in step 5.1
  • the phenol was replaced by 2-methoxy-4-bromo-benzene.
  • Example 7 3 l-( 3 -Hydroxypropyl) _ 2 _methyl _ 5 -[( 2 R)- 2 -[ 2 _[ 4 -Fluoro 2 -(2, 2 , 2 -Trifluoroethyl Oxy)phenoxy]ethylamino]propyl]-indole-7-carboxamide (DC471873)
  • Example 2 According to the preparation method of Example 1, the dihydroanthracene in the step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in the step 1.15 was replaced with 4-fluorine.
  • Preparation method of -2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde (4-fluoro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde Example 4 prepared by replacing 2-methoxy-4-ethyl-phenol in step 4.1 with 2-methoxy-5-fluoro-phenol).
  • the dihydroanthracene in the step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in the step 1.15 was replaced with 5-fluorine.
  • 2-ethoxy-phenoxyacetaldehyde (5-fluoro-2-ethoxy-phenoxyacetaldehyde is prepared in the same manner as in Example 5, 2-methoxy-4-ethyl- in step 5.1
  • the phenol was replaced by 2-methoxy-5-fluoro-phenol.
  • Example 75 l-(3-Hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[5-fluoro-2-(2,2,2-trifluoroethoxy) Phenoxy]ethylamino]propyl]-indole-7-carboxamide (DC471875)
  • Example 2 According to the preparation method of Example 1, the dihydroanthracene in the step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in the step 1.15 was replaced with 5-fluorine.
  • Preparation method of -2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde (5-fluoro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde Example 4, prepared by replacing 2-methoxy-4-ethyl-phenol in step 4.1 with 2-methoxy-4-fluoro-phenol).
  • the indoline in step 1.1 was replaced with 2-methyl-indoline, and the step was carried out.
  • Example 77 l-(3-Hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[5-methyl-2-(2,2,2-trifluoroethoxy) Phenoxy]ethylamino]propyl]-indole-7-carboxamide (DC471877)
  • Example 1 According to the preparation method of Example 1, the indoline in step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in step 1.15 was replaced with 5-a.
  • Preparation of keto-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde (5-methyl-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde The same procedure as in Example 4 was carried out by replacing 2-methoxy-4-ethyl-phenol in step 4.1 with 2-methoxy-4-methyl-phenol.
  • Example 78 l-(3-Hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[4-methyl-2-ethoxy-phenoxy]ethylamino ]propyl] - ⁇ _ 7 _carboxamide (DC471878)
  • the indoline in step 1.1 was replaced with 2-methyl-indoline, and the step was carried out.
  • Example 1 According to the preparation method of Example 1, the indoline in step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in step 1.15 was replaced with 5-chloro.
  • Preparation method of -2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde (5-chloro-2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde Example 4, prepared by replacing 2-methoxy-4-ethyl-phenol in step 4.1 with 2-methoxy-4-chloro-phenol).
  • the dihydroanthracene in the step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in the step 1.15 was replaced with 4-chloro.
  • 2-ethoxy-phenoxyacetaldehyde (4-chloro-2-ethoxy-phenoxyacetaldehyde was prepared in the same manner as in Example 5, 2-methoxy-4-ethyl- in step 5.1
  • the phenol is replaced by 2-methoxy-4-chloro-phenol).
  • Example 81 l- (3 _-hydroxypropyl) - 2 - methyl - 5 - [(2 R) - 2 - [2 - [2 - (2, 2, 2 - trifluoroethoxy) phenoxy Ethylamino]propyl]-indole-7-carboxamide (DC471881)
  • the dihydroanthracene in the step 1.1 was replaced with 2-methyl-indoline, and the 2,6-dimethylphenoxyacetaldehyde in the step 1.15 was replaced by 2-( 2,2,2-Trifluoroethoxy)-phenoxyacetaldehyde (wherein 2-(2,2,2-trifluoroethoxy)-phenoxyacetaldehyde is prepared according to the method of Example 4
  • the preparation method is prepared by replacing 2-methoxy-4-ethyl-phenol in step 4.1 with 2-methoxy-phenol.
  • the indoline in step 1.1 was replaced with 2-methyl-indoline, and the step was carried out.
  • HEK293 cells stably expressing ⁇ 1 ⁇ -adrenergic receptor (a 1A -AR) and G protein Gal6 were seeded in 96-well plates, and after 24 hours of culture, the medium was removed, and 40 ⁇ of 2 M Fluo- was added per well.
  • Hank Balanced Salt Solution Contains 5.4 mM KCl, 0.3 mM Na 2 HP0 4 , 0.4 mM KH 2 PO 4 , 4.2 mM NaHC0 3 , 1.3 mM CaCl 2 , 0.5 mM MgCl 2 , 0.6 mM MgSO 4 , 137 mM NaCl, 5.6 mM D-glucose and 250 ⁇ M sulfinpyrazone, ⁇ 7.4) Incubate for 45 minutes in an incubator.
  • Reaction rate % (D-B) / (S-B) * 100%;
  • D is the peak of the calcium flow signal evoked by phenylephrine after incubation with the test drug
  • B is the peak of the calcium flow signal evoked by phenylephrine after incubation with the 10 ⁇ positive control drug Tamsulosin
  • the response rate of different doses of the same drug was analyzed by GraphPad Prism software, and the dose response curve was obtained and the IC 5Q value was measured. Data are expressed as mean ⁇ standard deviation and are the results of three independent experiments, each of which is three replicate wells.
  • the compounds of the present invention are highly active in a 1A -AR antagonist, the IC 50 of all compounds of lower than 20 nM, IC 5Q 6 compounds less than 1 nM. Such compounds have good application prospects against benign prostatic hyperplasia and thus have good commercial value.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un composé d'indole, et son procédé de préparation, une composition pharmaceutique et son utilisation. En particulier, le composé d'indole possède une structure telle que représentée dans la formule générale (I), et peut être utilisé dans le traitement de maladies associées aux adrénorécepteurs α1, notamment des maladies urinaires telles que l'adénome de la prostate bénigne, la rétention d'urine, et l'obstruction à la sortie de la vessie.
PCT/CN2014/078980 2013-05-30 2014-05-30 Composé d'indole, et procédé de préparation, composition pharmaceutique et utilisation de celui-ci Ceased WO2014190942A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310211442.6A CN104211631A (zh) 2013-05-30 2013-05-30 一类吲哚类化合物、其制备方法、药物组合物及应用
CN201310211442.6 2013-05-30

Publications (1)

Publication Number Publication Date
WO2014190942A1 true WO2014190942A1 (fr) 2014-12-04

Family

ID=51988032

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/078980 Ceased WO2014190942A1 (fr) 2013-05-30 2014-05-30 Composé d'indole, et procédé de préparation, composition pharmaceutique et utilisation de celui-ci

Country Status (2)

Country Link
CN (1) CN104211631A (fr)
WO (1) WO2014190942A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111116448B (zh) * 2019-11-29 2022-01-04 北京鑫开元医药科技有限公司 一种吲哚衍生物的制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015202A1 (fr) * 1997-09-22 1999-04-01 Kissei Pharmaceutical Co., Ltd. Medicaments contre la dysurie resultant d'une hypertrophie de la prostate
CN1291976A (zh) * 1998-02-27 2001-04-18 橘生药品工业株式会社 吲哚衍生物及其药物组合物
US20030166705A1 (en) * 2000-05-15 2003-09-04 Hiroo Nitta Water-based liquid preparation
CN101993406A (zh) * 2009-08-27 2011-03-30 浙江华海药业股份有限公司 光学活性的吲哚啉化合物及其制备方法
US20120165548A1 (en) * 2009-09-12 2012-06-28 Sandoz Ag Process for the preparation of indoline derivatives and their intermediates thereof
WO2012096904A1 (fr) * 2011-01-13 2012-07-19 Watson Pharmaceuticals, Inc. Procédé de traitement d'une prostatite
WO2013061338A1 (fr) * 2011-08-24 2013-05-02 Cadila Healthcare Limited Compositions pharmaceutiques de silodosine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3331048B2 (ja) * 1994-06-01 2002-10-07 キッセイ薬品工業株式会社 インドール誘導体

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015202A1 (fr) * 1997-09-22 1999-04-01 Kissei Pharmaceutical Co., Ltd. Medicaments contre la dysurie resultant d'une hypertrophie de la prostate
CN1291976A (zh) * 1998-02-27 2001-04-18 橘生药品工业株式会社 吲哚衍生物及其药物组合物
US20030166705A1 (en) * 2000-05-15 2003-09-04 Hiroo Nitta Water-based liquid preparation
CN101993406A (zh) * 2009-08-27 2011-03-30 浙江华海药业股份有限公司 光学活性的吲哚啉化合物及其制备方法
US20120165548A1 (en) * 2009-09-12 2012-06-28 Sandoz Ag Process for the preparation of indoline derivatives and their intermediates thereof
WO2012096904A1 (fr) * 2011-01-13 2012-07-19 Watson Pharmaceuticals, Inc. Procédé de traitement d'une prostatite
WO2013061338A1 (fr) * 2011-08-24 2013-05-02 Cadila Healthcare Limited Compositions pharmaceutiques de silodosine

Also Published As

Publication number Publication date
CN104211631A (zh) 2014-12-17

Similar Documents

Publication Publication Date Title
KR100251571B1 (ko) 5-ht₁수용체 효능제로서의 테트라하이드로카르바죤 유도체의 용도
ES2443127T3 (es) Nuevos derivados tricíclicos o sales de éstos farmacéuticamente aceptables, su procedimiento de fabricación y composiciones farmacéuticas que los contienen
US20230140635A1 (en) 3-(2-(Aminoethyl)-Indol-4-ol Derivatives, Methods of Preparation Thereof, and the Use as 5-HT2 Receptor Modulators
CN102234279A (zh) 苦参酸衍生物及其制备方法和用途
JP2010285433A (ja) アミノアルコール誘導体、それを含有する医薬組成物およびそれらの用途
JP2014532052A (ja) ＨＩＦ−１α活性を阻害する新規化合物及びその製造方法
EP2521714B1 (fr) Composés sulfones aromatiques utiles dans le traitement de maladies du système nerveux central
FR2930249A1 (fr) Nouveaux derives de 3-aminoalkyl-1,3-dihydro-2h-indol-2-one, leur preparation et leur application en therapeutique.
ES2866324T3 (es) Derivados de 1-(1-hidroxi-2,3-dihidro-1H-inden5-il)-urea y compuestos similares como activadores del canal KCNQ2-5 para el tratamiento de la disuria
WO2005040093A1 (fr) Derive d'amino-alcool, composition pharmaceutique contenant ce dernier, et leur utilisation
CN104326963A (zh) 一类二氢吲哚类化合物、其制备方法、药物组合物及应用
CN110446495A (zh) 含有7元氮杂杂环的δ阿片受体调节化合物及其使用和制备方法
EP2953947A1 (fr) 3,5-diaryl-azaindoles comme inhibiteurs de la protéine dyrk1a pour le traitement des déficiences cognitives liées au syndrome de down et à la maladie d'alzheimer
WO2014190942A1 (fr) Composé d'indole, et procédé de préparation, composition pharmaceutique et utilisation de celui-ci
WO2000035890A1 (fr) Nouveaux composes heterocycliques et compositions de medicaments les renfermant
US20250090491A1 (en) Antiviral 1,3-di-oxo-indene compounds
CN101262864A (zh) 饱和o-杂环取代的烷酰胺
CN106420754A (zh) 苯并五元氮杂环基哌嗪衍生物的用途
JP4563817B2 (ja) インドール誘導体およびその５−ｈｔ配位子としての使用
WO2002074306A1 (fr) Remedes pour la steatose hepatique
JPWO2006132192A1 (ja) 新規２−キノロン誘導体
KR100874209B1 (ko) 3,10-다이하이드로-1Ｈ-[1,4]다이아제피노[5,6-ｂ]인돌-2-온 유도체 및 약학적으로 허용 가능한 염, 그의 제조방법및 그의 용도
WO2016034637A1 (fr) Derives de n-aryl-tricyclopyrimidine-2-amine polyethers macrocycliques comme inhibiteurs de la ftl3 et jak
CN118930552A (zh) 异苯并呋喃-1(3h)-酮类化合物及其制备方法、药物组合物和用途
WO2000005209A1 (fr) GUAIACOXYPROPANOLAMINES A ACTIVITE α/β-ADRENOLYTIQUE

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14805088

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14805088

Country of ref document: EP

Kind code of ref document: A1