CN112079832A - Medicine for treating hysteromyoma and preparation method thereof - Google Patents

Abstract

The invention relates to a medicine for treating uterine fibroids and a preparation method thereof. The medicine of the present invention is the compound shown in formula I, its pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug, which can inhibit the growth of uterine fibroids and can greatly reduce the size of the patient's body. It has a very good preventive and therapeutic effect on uterine fibroids, and can be used as a drug for the prevention and treatment of uterine fibroids. The compound of the invention has simple synthesis process, short route and low cost, does not need to use a very complicated process, is easy to scale up for production, and is especially suitable for industrial application.

Description

A kind of medicine for treating uterine fibroids and preparation method thereof

technical field

The present invention relates to the technical field of medicine. Specifically, the present invention relates to a medicament for treating uterine fibroids, and the present invention also relates to the use of the medicament and a preparation method thereof.

Background technique

Uterine fibroids are the most common benign tumors in female reproductive organs and one of the most common tumors in the human body. They are mainly formed by the proliferation of uterine smooth muscle cells with a small amount of fibrous connective tissue in between, but they are not the basic components of fibroids. part, it is also called uterine leiomyoma. Uterine fibroids are more common in women between the ages of 30 and 50, with the highest incidence at the age of 40 to 50, and are rare under the age of 20. After menopause, fibroids can gradually shrink. Clinically, it is divided into three types: intramural fibroids, subserosal fibroids, and submucosal fibroids according to the location of the disease. Symptoms are mostly abdominal pain, abdominal mass and uterine bleeding, which can lead to more serious infertility, secondary anemia, habitual abortion and premature delivery.

At present, the treatment of uterine fibroids is still mainly based on surgery. However, due to the trauma of the operation itself, the ultimate nature of total hysterectomy, and the recurrence of myomectomy, the patient's heart and physiology are under pressure, affecting Therefore, the drug therapy of uterine fibroids has received extensive attention from the medical community.

The treatment drugs for uterine fibroids mainly include the following categories: (1) Gonadotropin-releasing hormone agonists are commonly used leuprolide, goserelin, triptorelin, etc. It should not be used continuously for a long time. It is only used for pretreatment before surgery, generally for 3 to 6 months, so as not to cause severe menopausal symptoms caused by low estrogen. (2) Danazol is used for preoperative medication or treatment of inoperable uterine fibroids. Uterine fibroids can grow after stopping the drug. Taking danazol can cause liver damage, in addition to androgen-induced side effects. (3) Mifepristone is a progesterone antagonist. In recent years, it has been clinically used to treat uterine fibroids, which can reduce the volume of fibroids, but the fibroids often grow again after stopping the drug. (4) Tamoxifen (tamoxifen) can inhibit the growth of fibroids. But long-term application of individual patients with uterine fibroids increased, and even induced endometriosis and endometrial cancer. (5) androgen drugs commonly used drugs are methyltestosterone (methyl testosterone) and testosterone propionate (testosterone propionate), which can inhibit the growth of fibroids. The dose should be controlled to avoid virilization.

Because the existing drugs have the risks of incomplete treatment, easy recurrence, and large side effects, it is urgent to develop more drugs that can be used for the treatment of uterine fibroids.

SUMMARY OF THE INVENTION

In order to overcome the problems existing in the prior art, the present invention provides a medicine that can be used for the treatment of uterine fibroids, the medicine is the compound shown in the following formula I, its pharmaceutically acceptable salts, stereoisomers, Tautomers or Prodrugs:

In formula I,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane amino, di(C1-C6 alkyl) amino, C3-C6 cycloalkyl, -COR', -COOR', C6-C14 aryl, wherein the C1-C6 alkyl, C1-C6 alkoxy , C1-C6 alkylamino, two (C1-C6 alkyl) amino, C3-C6 cycloalkyl, C6-C14 aryl optionally by one or more selected from halogen, nitro, hydroxyl, cyano, Group substitution of C1-4 alkyl and C1-C4 alkoxy;

R' is selected from C1-C6 alkyl, C6-C14 aryl, wherein, the C1-C6 alkyl, C6-C14 aryl are optionally selected from halogen, hydroxyl, C1-C4 alkyl, C1-4 alkane group substitution of oxy;

R ₆ is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-C14 aryl, C6-C14 aryl C1-C6 alkyl, wherein, the C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-C14 aryl, C6-C14 aryl, C1-C6 alkyl optionally selected by one or more Groups substituted from halogen, nitro, hydroxy, cyano, C1-4 alkyl, C1-C4 alkoxy.

The compounds of the present invention may preferably be as follows:

Preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6- C10 aryl group, wherein, the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C6-C10 aryl group are optionally selected by one or more groups selected from halogen, nitro, hydroxyl, Group substitution of cyano, C1-4 alkyl, C1-C4 alkoxy.

Preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, wherein the C1-C6 alkyl, C1 -C6alkoxy is optionally substituted with one or more groups selected from halogen, C1-C4alkoxy.

Preferably, R ₁ is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl is optionally selected by one or more Halogen, C1-C4alkoxy group substitution.

Preferably, R ₂ is selected from hydrogen, deuterium, C1-C6 alkyl.

Preferably, R ₃ is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, wherein, said C1-C6 alkyl, C1-C6 alkoxy is optionally selected by one or more Group substitution of halogen, hydroxy, C1-C4 alkoxy.

Preferably, R ₄ is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl.

Preferably, R ₅ is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl.

Preferably, R' is selected from C1-C4 alkyl, C6-C10 aryl.

Preferably, R ₆ is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C6-C10 aryl, C6-C10 aryl C1-C6 alkyl, wherein, the C1-C6 Alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C6-C10 aryl, C6-C10 aryl, C1-C6 alkyl optionally by one or more selected from halogen, hydroxy, C1-4 alkane group, C1-C4 alkoxy group.

Preferably, R ₆ is selected from C1-C6 alkyl, C2-6 alkenyl, wherein, said C1-C6 alkyl, C2-6 alkenyl is optionally by one or more selected from halogen, hydroxyl, C1- 4 alkyl, C1-C4 alkoxy group substitution.

In a preferred embodiment, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 ring Alkyl, C6-C10 aryl, wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl are optionally selected from one or more halogens, Group substitution of nitro, hydroxyl, cyano, C1-4 alkyl, C1-C4 alkoxy; R ₆ is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C6- C10 aryl, C6-C10 aryl C1-C6 alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C6-C10 aryl, C6-C10 aryl C1 -C6 alkyl is optionally substituted with one or more groups selected from halogen, hydroxy, C1-4 alkyl, C1-C4 alkoxy.

In a preferred embodiment, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, wherein the C1- C6 alkyl, C1-C6 alkoxy are optionally substituted by one or more groups selected from halogen, C1-C4 alkoxy; R ₆ is selected from C1-C6 alkyl, C2-6 alkenyl, wherein , the C1-C6 alkyl group and C2-6 alkenyl group are optionally substituted by one or more groups selected from halogen, hydroxyl, C1-4 alkyl group, and C1-C4 alkoxy group.

In a preferred embodiment, R ₁ is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl is optionally replaced by one or More groups selected from halogen, C1-C4 alkoxy group; R ₂ is selected from hydrogen, deuterium, C1-C6 alkyl; R ₃ is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkane Oxy group, wherein the C1-C6 alkyl group and C1-C6 alkoxy group are optionally substituted by one or more groups selected from halogen, hydroxyl and C1-C4 alkoxy group; R ₄ is selected from hydrogen, Deuterium, C1-C6 alkyl, C3-C6 cycloalkyl; R ₅ is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl; R ₆ is selected from C1-C6 alkyl, C2-6 alkene group, wherein the C1-C6 alkyl group and C2-6 alkenyl group are optionally substituted by one or more groups selected from halogen, hydroxyl, C1-4 alkyl group, and C1-C4 alkoxy group.

In a preferred embodiment, R ₁ is selected from hydrogen, deuterium, C1-C6 alkyl; R ₂ is selected from hydrogen, deuterium; R ₃ is selected from hydrogen, deuterium, C1-C6 alkoxy; R ₄ is selected from hydrogen , deuterium; R ₅ is selected from hydrogen, deuterium; R ₆ is selected from C1-C6 alkyl, C2-6 alkenyl.

In a preferred embodiment, the compound is selected from:

The compounds represented by formula I provided by the present invention are hereinafter referred to as "compounds of the present invention". The compounds of the present invention include compounds in any form, such as free form, salt form, stereoisomer, tautomer or oxide form.

In one aspect, the present invention provides compounds of the present invention in salt form. The compounds of the present invention in the form of salts include both pharmaceutically acceptable salts, including non-pharmaceutically acceptable salts, and the non-pharmaceutically acceptable salts mainly refer to the salts used for preparation/isolation/purification. Compounds of the invention in free form can be converted into corresponding compounds in salt form; and vice versa.

The pharmaceutically acceptable salts include, but are not limited to, acid addition salts with acids such as selected from inorganic acids, acyclic aliphatic carboxylic or sulfonic acids containing no more than 12 carbon atoms and containing Aromatic carboxylic or sulfonic acids having not more than 4 aryl groups. Preferred acids are selected from hydrochloric acid, sulfuric acid, acetic acid, L-lactic acid, tartaric acid, L-malic acid, succinic acid, malonic acid, fumaric acid, glutaric acid, L-tartaric acid, D-tartaric acid, 2(S)- Hydroxypropionic acid, citric acid, malonic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, 4-methylbenzenesulfonic acid and pamoic acid, etc.

The compounds of the present invention may exist in the form of isomers as well as mixtures thereof; eg, tautomers, stereoisomers, enantiomers, diastereomers. The compounds of the invention may, for example, contain asymmetric carbon atoms and thus may exist in the form of enantiomers or diastereomers and mixtures thereof, for example in the form of racemates. The compounds of the present invention may exist in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration at the specific position of the compound.

The compounds of the present invention may be administered in prodrug form. Thus, certain derivatives, which themselves may have little or no pharmacological activity when administered into or on the body, are converted, for example, by hydrolytic cleavage into compounds of the invention having the desired activity. Such derivatives are called "prodrugs". Detailed information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (editor: E.B. Roche , American Pharmaceutical Association).

definition

The term "alkyl" includes saturated hydrocarbon groups including:

- Linear groups of up to 10 carbon atoms (C1-C10), or up to 6 carbon atoms (C1-C6), or up to 4 carbon atoms (C1-C4). Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, and n-butyl.

- Branched groups of 3 to 10 carbon atoms (C3-C10), or up to 7 carbon atoms (C3-C7), or up to 4 carbon atoms (C3-C4). Examples of such alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, and neopentyl.

The term "cycloalkyl" includes monocyclic saturated hydrocarbons of 3 to 7 carbon atoms, or 3 to 6 carbon atoms, or 3 and 5 carbon atoms. Examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "alkenyl" may be straight or branched chain, up to 10 carbon atoms (C2-C10), or up to 6 carbon atoms (C2-C6), or up to 4 carbon atoms ( C2-C4). Examples of such alkenyl groups include, but are not limited to, vinyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, and the like, but are not limited to this.

The term "alkynyl" may be straight or branched chain, up to 10 carbon atoms (C2-C10), or up to 6 carbon atoms (C2-C6), or up to 4 carbon atoms ( C2-C4). Examples of such alkyl groups include, but are not limited to, ethynyl, 1-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, and the like, but Not limited to this.

The term "aryl" includes carbocyclic aryl or biaryl groups. Carbocyclic aryl groups are aromatic cyclic hydrocarbons containing 6-14 carbon atoms, preferably 6-10 carbon atoms. It may be monocyclic, bicyclic or tricyclic, such as phenyl or naphthyl and the like.

The term "alkoxy" includes O-linked alkyl groups.

The term "alkylamino" includes N-linked alkyl groups.

Halo (halogen) is selected from F, Cl, Br and I unless otherwise specified.

Preparation

Another object of the present invention is to provide a kind of preparation method of the compound shown in formula I, described method comprises the following steps:

step 1

The amine compound of formula II is converted to the isocyanato compound of formula III by treatment with an isocyanating reagent in the presence of a base.

Wherein, the isocyanate-reagent is preferably phosgene, diphosgene, triphosgene and the like; the base is preferably triethylamine, N,N-diisopropylethylamine, pyridine and the like.

Step 2

Isocyanato compounds of formula III are reacted with amine compounds of formula IV in the presence or absence of a base to give urea compounds of formula V.

Among them, the base is preferably 4-dimethylaminopyridine, triethylamine, N,N-diisopropylethylamine, pyridine and the like.

Step 3

Urea compounds of formula V are converted to compounds of formula I in the presence or absence of a base.

Among them, the base is preferably sodium methoxide, sodium ethoxide, sodium hydride, sodium hydroxide, potassium hydroxide and the like.

Wherein, R is selected from C1-6 alkyl, preferably C1-4 alkyl; R ₁ -R ₆ are as described herein.

pharmaceutical composition

Another aspect of the present invention relates to a pharmaceutical composition comprising one or more compounds of formula I of the present invention, pharmaceutically acceptable salts, stereoisomers, tautomers or prodrugs thereof. Typically, the pharmaceutical composition of the present invention will comprise a compound of Formula I of the present invention, a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable carrier" refers to any suitable adjuvant, carrier, excipient or stabilizer, and may be in solid or liquid form, eg, tablets, capsules, powders, solutions, suspensions or emulsions.

Typically, the pharmaceutical compositions contain about 0.01-99%, preferably about 20-75%, of active compound together with adjuvants, carriers and/or excipients.

Solid unit dosage forms can be of conventional types. The solid form may be a capsule or the like, such as a conventional gelatin type containing a compound of the present invention and a carrier such as a lubricant and an inert filler (eg, lactose, sucrose, or cornstarch). In another embodiment, these compounds are prepared with conventional tablet bases such as lactose, sucrose or corn starch with binders such as acacia, corn starch or gelatin, disintegrants such as corn starch, potato starch or alginic acid and lubricants Tablets prepared with an agent such as stearic acid or magnesium stearate.

Described tablet, capsule etc. can also contain binder such as tragacanth gum, gum arabic, corn starch or gelatin; excipient such as calcium hydrogen phosphate; disintegrating agent such as corn starch, potato starch, alginic acid; lubricant such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

The active compounds of the present invention may be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be Mix directly with food.

For oral therapeutic administration, the active compounds can be mixed with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups and the like. These compositions and preparations should contain at least 0.1% active compound. Of course, the percentage of the compound in these compositions may vary and may conveniently be between about 2% and about 60% by weight of the unit dose. The amount of active compound in these therapeutically useful compositions is such that a suitable dosage can be obtained. Preferred compositions of the present invention are prepared so that an oral dosage unit contains from about 1 mg to 1000 mg of active compound.

The compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosage forms, which are administered as solutions or suspensions in physiologically acceptable diluents with pharmaceutical adjuvants, carriers or excipients. These adjuvants, carriers and/or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without added surfactants and other pharmaceutically and physiologically acceptable components. Illustrative oils are petroleum, animal, vegetable or artificial oils such as peanut, soybean or mineral oil. In general, water, saline, solutions of aqueous dextrose and related sugars, and glycols such as propylene glycol or polyethylene glycols are the preferred liquid carriers, especially for injectable solutions.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for extemporaneous reconstitution into sterile injectable solutions or dispersions. In all cases, the form should be sterile and fluid enough to facilitate easy injection. It should be stable under the conditions of manufacture and storage, and should be stored under conditions that are resistant to contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol, suitable mixtures thereof, and vegetable oils.

The active compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with surfactants such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are petroleum, animal, vegetable or artificial oils such as peanut, soybean or mineral oil. In general, water, saline, solutions of aqueous dextrose and related sugars, and glycols such as propylene glycol or polyethylene glycols are the preferred liquid carriers, especially for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The active compounds of the present invention may also be administered in the form of an aerosol. When used as an aerosol, the compounds of this invention in solution or suspension can be packaged in pressurized spray containers with a suitable propellant, eg, a hydrocarbon propellant such as a conventional Adjuvanted propane, butane or isobutane. The compounds of the present invention can also be administered in atmospheric form, such as in a nebulizer or nebulizer.

use

The compounds of the present invention are particularly suitable for the prevention or treatment of uterine fibroids. Therefore, another aspect of the present invention relates to a method for preventing or treating uterine fibroids, comprising providing the compound shown in formula I of the present invention, its pharmaceutically acceptable salts, stereoisomers, mutual Variant or prodrug.

Another aspect of the present invention relates to the use of a compound represented by formula I of the present invention, a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof in the preparation of a medicament for the prevention of or to treat uterine fibroids.

The compounds of the present invention may be used in combination or in combination with other agents useful in the treatment, prevention, inhibition or amelioration of diseases or conditions for which the compounds of the present invention are useful. To this end, the present invention provides a pharmaceutical combination, which comprises the compound represented by formula I of the present invention, its pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug and can be used for treatment, prevention , other agents that inhibit or ameliorate the diseases or conditions for which the compounds of the present invention are useful. In a preferred embodiment, the other agent may be selected from: gonadotropin-releasing hormone agonists such as, for example, leuprolide, goserelin, triptorelin, danazol, progestin antagonists such as Drugs such as mifepristone, tamoxifen (tamoxifen), androgen drugs such as methyltestosterone (methyl testosterone) and testosterone propionate (testosterone propionate).

Therefore, the present invention provides a method for preventing or treating uterine fibroids, comprising providing the compound shown in formula I of the present invention, its pharmaceutically acceptable salt, stereoisomer, tautomer to a patient in need Other agents useful for treating, preventing, inhibiting, or ameliorating the disease or condition for which the compounds of the present invention are useful are administered prior to, concurrently with, or subsequent to the body or prodrug. Said other agents may be selected from: GnRH agonists such as for example leuprolide, goserelin, triptorelin, danazol, progestin antagonists such as for example mifepristone, tamoxifen Xifen (tamoxifen), androgen drugs such as methyltestosterone (methyl testosterone) and testosterone propionate (testosterone propionate).

beneficial effect

The compound of the present invention can inhibit the growth of uterine fibroids, can greatly reduce the uterine fibroids in patients, has very good preventive and therapeutic effects on uterine fibroids, and can be used as a drug for the prevention and treatment of uterine fibroids. The compound of the invention has simple synthesis process, short route and low cost, does not need to use a very complicated process, is easy to scale up for production, and is especially suitable for industrial application.

Instruction drawings

Fig. 1 is the ¹ H NMR spectrum of the compound PQDO-1 of the present invention;

Fig. 2 is the ¹ H NMR spectrum of the compound PQDO-2 of the present invention;

Figure 3 is the ¹ H NMR spectrum of the compound PQDO-3 of the present invention;

Detailed ways

The present invention is described in more detail below to facilitate understanding of the present invention. It should be noted that the examples set forth below are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

Example 1: Preparation of 3-(1-Acetylpiperidin-4-yl)pyridine[3,2-h]quinazoline-2,4(1H,3H)-dione (Compound PQDO-1)

Methyl 8-aminoquinoline-7-carboxylate (10 mmol) was dissolved in 50 ml of tetrahydrofuran, then 2 ml of triethylamine was added, and after stirring for 5 minutes, 10 ml of tetrahydrofuran solvent of triphosgene (4 mmol) was added, and the mixture was heated at 50 °C was stirred for 2 hours. The insoluble matter was removed by filtration, the solvent was evaporated under reduced pressure, and the mixture was recrystallized from ethyl acetate. The recrystallized product was dissolved in 50 ml of tetrahydrofuran, and the solution was added to 20 ml of 1-(4-aminopiperidin-1-yl)ethane-1-one (10 mmol) and 4-dimethylaminopyridine (1.0 g) tetrahydrofuran solution and stirred at 55 °C for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 1 mol/l hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and recrystallized from ethanol. The recrystallized product was dissolved in 40 ml of methanol, sodium methoxide (28% methanol solution, 4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed successively with 1 mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate:cyclohexane=10:90) to obtain the title compound (1.77 g, yield 52.3%).

The characterization results of the product are as follows, which proves that the synthesized compound is the target compound 3-(1-acetylpiperidin-4-yl)pyridine[3,2-h]quinazoline-2,4(1H,3H)-dione (Compound PQDO-1).

MSm/z: C ₁₈ H ₁₈ N ₄ O ₃ theor. 338.1379; actual: 338.1353

Elemental Analysis: Theoretical C, 63.89; H, 5.36; N, 16.56; O, 14.18; Actual: C, 63.75; H, 5.25; N, 16.74; O, 14.26.

¹ HNMR (400MHz, DMSO-d ₆ )δ8.77(d,J=7.5Hz,1H),8.32(d,J=7.5Hz,1H),7.97(d,J=7.5Hz,1H),7.88( d, J=7.5Hz, 1H), 7.51(t, J=7.5Hz, 1H), 3.98(p, J=7.0Hz, 1H), 3.63(m, 2H), 3.54(m, 2H), 2.08( s, 3H), 2.03 (m, 4H). ¹ HNMR spectrum is shown in FIG. 1 .

Example 2: 9-methyl-3-(1-pivaloylpiperidin-4-yl)pyridine[3,2-h]quinazoline-2,4(1H,3H)-dione (compound PQDO -2) Preparation

2-Methyl-8-aminoquinoline-7-carboxylate methyl ester (10 mmol) was dissolved in 60 ml of tetrahydrofuran, then 2 ml of triethylamine was added, and after stirring for 5 minutes, 10 ml of tetrahydrofuran solvent of triphosgene (4 mmol) was added , the mixture was stirred at 65°C for 1.5 hours. The insoluble matter was removed by filtration, the solvent was evaporated under reduced pressure, and the mixture was recrystallized from ethyl acetate. The recrystallized product was dissolved in 60 ml of tetrahydrofuran, and the solution was added to 1-(4-aminopiperidin-1-yl)-2,2-dimethylpropan-1-one (10 mmol) and 4-dimethylamino pyridine (1.0 g) in 20 ml of tetrahydrofuran and stirred at 70°C for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 1 mol/l hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and recrystallized from ethanol. The recrystallized product was dissolved in 40 ml of methanol, and sodium methoxide (28% methanol solution, 4 ml) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed successively with 1 mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=20:80) to obtain the title compound (1.80 g, yield 45.6%).

The characterization results of the products are as follows, which proves that the synthesized compound is the target compound 9-methyl-3-(1-pivaloylpiperidin-4-yl)pyridine[3,2-h]quinazoline-2,4(1H ,3H)-dione (compound PQDO-2).

MSm/z: C ₂₂ H ₂₆ N ₄ O ₃ Theoretical 394.2005; Actual: 394.2019

Elemental Analysis: Theoretical C, 66.99; H, 6.64; N, 14.20; O, 12.17; Actual: C, 66.75; H, 6.78; N, 14.01; O, 12.37.

¹ HNMR (400MHz, DMSO-d ₆ )δ8.09(d,J=7.5Hz,1H),7.82(d,J=7.5Hz,1H),7.73(d,J=7.5Hz,1H),7.18( d, J=7.5Hz, 1H), 3.87 (p, J=7.0Hz, 1H), 3.52 (m, 2H), 3.44 (m, 2H), 2.47 (s, 3H), 1.91 (q, J=6.9 Hz, 4H), 1.11 (s, 9H). The ¹ HNMR spectrum is shown in FIG. 2 .

Example 3: 3-(1-Methacryloylpiperidin-4-yl)-7-methoxypyridine[3,2-h]quinazoline-2,4(1H,3H)-dione ( Preparation of compound PQDO-3)

Methyl 4-methoxy-8-aminoquinoline-7-carboxylate (10 mmol) was dissolved in 50 ml of tetrahydrofuran, then 2 ml of triethylamine was added, and after stirring for 5 minutes, 10 ml of triphosgene (4 mmol) in 10 ml of tetrahydrofuran was added solvent, and the mixture was stirred at 60°C for 2 hours. The insolubles were removed by filtration, the solvent was evaporated under reduced pressure, and the mixture was recrystallized from ethanol. The recrystallized product was dissolved in 60 ml of tetrahydrofuran, and the solution was added to 1-(4-aminopiperidin-1-yl)-2,2-methylprop-2-en-1-one and 4-dimethylamino pyridine (1.0 g) in 20 ml of tetrahydrofuran and stirred at 65°C for 4 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 1 mol/l hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and recrystallized from toluene. The recrystallized product was dissolved in 40 ml of methanol, sodium methoxide (28% methanol solution, 4 ml) was added, and the mixture was stirred at room temperature for 25 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed successively with 1 mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol: petroleum ether=5:95) to obtain the title compound (2.38 g, yield 60.4%).

The characterization results of the products are as follows, which proves that the synthesized compound is the target compound 3-(1-methacryloylpiperidin-4-yl)-7-methoxypyridine[3,2-h]quinazoline-2,4 (1H,3H)-diketone (compound PQDO-3).

MS m/z: Theoretical _394.1641 for _{C21H22N4O4 ;} actual: _394.1633

Elemental Analysis: Theoretical C, 63.95; H, 5.62; N, 14.20; O, 16.22; Actual: C, 63.77; H, 5.70; N, 14.29; O, 16.24.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.53 (d, J=7.5Hz, 1H), 8.07 (d, J=7.5Hz, 1H), 7.76 (d, J=7.6Hz, 1H), 7.04 (d, J=7.5Hz, 1H), 5.50(s, 2H), 3.87(p, J=7.0Hz, 1H), 3.77(s, 3H), 3.55(m, 2H), 3.40(m, 2H) , 1.97–1.88 (m, 4H), 1.86 (s, 3H). ¹ HNMR spectrum is shown in FIG. 3 .

Pharmacodynamic Test 1-In vitro inhibitory effect of the compounds of the present invention on human uterine fibroids

Uterine fibroids were cultured in DMEM-F12 medium (Hyclone) containing 10% fetal bovine serum (Gibco) at 37°C in a 5% _CO2 incubator, and the medium was changed every 3-5 days Routine culture was carried out at one time until the cells were confluent, and DMSO solutions of the compounds of the present invention PQDO-1 to PQDO-3 were added with gradient concentrations respectively. After 72 hours of culture, 20 μl of 5 mg/mL MTT (ApexBio Company) was added, and the cells were incubated for 4 hours. Carefully aspirated Medium, 150ul of DMSO was added to each well. The absorbance value of each well was measured at 490 nm with an enzyme-linked immunosorbent assay instrument, and the absorbance value and the proliferation rate were calculated. There were 6 duplicate wells in each group, which were repeated three times. Taking the cells without the active compound as the normal control, the degree of inhibition of the growth of fibroids after the addition of the active compound was calculated, the inhibition rate was calculated according to the following formula, and the median inhibitory concentration (IC ₅₀ value) was calculated by the regression equation.

1) Calculation of cell inhibition rate:

2) IC ₅₀ value calculation

The logarithmic value of the sample concentration and the cell inhibition rate were linearly regressed, and the IC ₅₀ value of the half-inhibitory concentration of the sample on the cells was calculated by software. The results are shown in Table 1 below:

Table 1: Inhibitory activity of the compounds of the present invention on uterine fibroids

It can be seen from the data in Table 1 that the compounds of the present invention have better inhibitory activity on uterine fibroids.

Pharmacodynamic Test 2 - Inhibitory effect of the compounds of the present invention on estrogen-induced uterine fibroids

A number of 4-week-old BALB/c rats (half male and half male) were selected; they were reared in an SPF environment, 12 hours of light and 12 hours of darkness were alternated periodically, and ultraviolet rays were irradiated regularly in the room. Strictly disinfect. After 2 days of adaptive feeding, the model was established with reference to the method reported in the literature (experimental research on the treatment of uterine fibroids with Gongning oral liquid, Yi Mingjuan et al., "Pharmacology and Clinical Medicine of Traditional Chinese Medicine", 1996, 12(4): 41-43). The group was given intramuscular injection of peanut oil suspension of estradiol benzoate, the amount of estradiol benzoate was 0.24 mg/Kg, once a day for 2 weeks. The blank control group was given intramuscular injection of 0.05 mL of high temperature sterilized peanut oil, once a day, for a total of 2 weeks. After 2 weeks, 40 rats whose uterine fibroids increased in size by about 1.2-1.3 cm were selected and randomly divided into model group, administration group (PQDO-1 to PQDO- ³ groups), Positive control group, 8 in each group. The administration group and the positive control group were administered the compounds of the present invention PQDO-1 to PQDO-3 and mifepristone by gavage, respectively, at a dose of 20 mg/Kg, once a day, for a total of 2 weeks. The model group was given a placebo. All the rats were sacrificed the next day after the last administration, and the tumor was dissected. The tumor volume (V)=(long diameter×short diameter ² )/2 was calculated according to the Steel formula, and the tumor volume was calculated.

Software was used for statistical analysis, measurement data were expressed as mean ± standard deviation (x ± s), and multiple comparisons of the mean of multiple samples were analyzed by variance analysis and SNK-q test. The results are shown in Table 2 below:

Table 2: The therapeutic effect of the compounds of the present invention on uterine fibroids

Note: *P<0.01 compared with the model group

As can be seen from the data in Table 2, the rats in the model group had significant uterine fibroids, indicating that the modeling was successful. However, after administration of the compound of the present invention for a period of time, the volume of uterine fibroids in rats was greatly reduced; compared with the positive control group, there was no significant difference in the volume of uterine fibroids in the rats in the administration group. The experimental results show that the compound of the present invention can also treat uterine fibroids in animal models, and the effect is comparable to that of current drugs, so it can be used as a drug for preventing and treating uterine fibroids.

The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the method of the present invention, several improvements and supplements can be made, and these improvements and supplements should also be regarded as It is the protection scope of the present invention.

Claims (10)

1. A compound of formula I, a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof:

in the formula I, the compound is shown in the specification,

R₁、R₂、R₃、R₄、R₅each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di (C1-C6 alkyl) amino, C3-C6 cycloalkyl, -COR ', -COOR', C6-C14 aryl, wherein said C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di (C1-C6 alkyl) amino, C3-C6 cycloalkyl, C6-C14 aryl is optionally substituted by one or more groups selected from halogen, nitro, hydroxy, cyano, C1-4 alkyl, C1-C4 alkoxy;

r' is selected from C1-C6 alkyl and C6-C14 aryl, wherein the C1-C6 alkyl and the C6-C14 aryl are optionally substituted by a group selected from halogen, hydroxyl, C1-C4 alkyl and C1-4 alkoxy;

R₆is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-C14 aryl, C6-C14 aryl C1-C6 alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-C14 aryl, C6-C14 aryl C1-C6 alkyl is optionally substituted by one or more groups selected from halogen, nitro, hydroxyl, cyano, C1-4 alkyl, C1-C4 alkoxy.

2. A compound of claim 1, wherein R is₁、R₂、R₃、R₄、R₅Each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl are optionally substituted by one or more groups selected from halogen, nitro, hydroxyl, cyano, C1-4 alkyl, C1-C4 alkoxy.

3. A compound of claim 1, wherein R is₁、R₂、R₃、R₄、R₅Each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, wherein, the C1-C6 alkyl, C1-C6 alkoxy is optionally substituted with one or more groups selected from halogen, C1-C4 alkoxy.

4. A compound of claim 1, wherein R is₆Is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C6-C10 aryl, C6-C10 aryl C1-C6 alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C6-C10 aryl, C6-C10 aryl C1-C6 alkyl is optionally substituted by one or more groups selected from halogen, hydroxyl, C1-4 alkyl and C1-C4 alkoxy.

5. A compound of claim 1, wherein R is₆Is selected from C1-C6 alkyl and C2-6 alkenyl, wherein the C1-C6 alkyl and the C2-6 alkenyl are optionally substituted by one or more groups selected from halogen, hydroxyl, C1-4 alkyl and C1-C4 alkoxy.

6. The compound of claim 1, wherein the compound is selected from the group consisting of:

7. a process for the preparation of a compound of formula I as claimed in claim 1, comprising the steps of:

step 1

The amine compound of formula II is treated with an isocyanating agent in the presence of a base to convert it to an isocyanato compound of formula III,

wherein, the isocyanating reagent is preferably phosgene, diphosgene, triphosgene and the like; the base is preferably triethylamine, N-diisopropylethylamine, pyridine, or the like;

step 2

Reacting the isocyanato compound of formula III with the amine compound of formula IV in the presence or absence of a base to obtain a urea compound of formula V,

wherein the base is preferably 4-dimethylaminopyridine, triethylamine, N-diisopropylethylamine, pyridine, or the like;

step 3

Converting a urea compound of formula V to a compound of formula I in the presence or absence of a base,

wherein the base is preferably sodium methoxide, sodium ethoxide, sodium hydride, sodium hydroxide, potassium hydroxide, or the like;

wherein R is selected from C1-6 alkyl, preferably C1-4 alkyl; r₁-R₆As claimed in claim 1.

8. A pharmaceutical composition comprising one or more compounds of formula I according to claim 1, a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

9. A pharmaceutical combination, characterized in that it comprises a compound of formula I according to claim 1, a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof and a further agent useful in the treatment, prevention, inhibition or amelioration of the diseases or conditions for which a compound of formula I is useful.

10. Use of a compound of formula I, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a prodrug thereof according to claim 1 for the preparation of a medicament for the prophylaxis or treatment of uterine fibroids.

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