CN108558760B - Aromatic amide compounds, preparation method and application thereof - Google Patents

Aromatic amide compounds, preparation method and application thereof Download PDF

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CN108558760B
CN108558760B CN201810529542.6A CN201810529542A CN108558760B CN 108558760 B CN108558760 B CN 108558760B CN 201810529542 A CN201810529542 A CN 201810529542A CN 108558760 B CN108558760 B CN 108558760B
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杨国宏
何君泽
段美娟
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Abstract

The invention relates to an aromatic amide compound shown in a general formula I, a preparation method thereof, a pharmaceutical composition and a pharmaceutical preparation containing the compound shown in the general formula I, and application of the compound shown in the general formula I in preparation of drugs for treating androgen-related diseases, wherein R in the general formula1、R2、R3、R4、R5、R6X, Y, Q and n are as defined in the specification. The compound shown in the general formula I can be combined with an androgen receptor, has antiandrogen resistance and can degrade the activity of the androgen receptor. The compounds can be used alone or as a composition for the treatment of various androgen-related diseases, such as prostate cancer, prostatic hyperplasia, milkAdenocarcinoma, bladder cancer, etc., and can also be used for treating acne, hirsutism, alopecia, etc.

Description

Aromatic amide compounds, preparation method and application thereof
Technical Field
The invention relates to a class of aromatic amide compounds, a preparation method thereof and application thereof as a medicament, wherein the compounds have the functions of resisting androgen and degrading androgen receptors, and can be used for treating androgen-related diseases such as prostatic cancer, prostatic hyperplasia, breast cancer, bladder cancer, acne, hirsutism, alopecia and the like.
Background
The androgen receptor belongs to the family of nuclear receptors, and is a receptor for nuclear transcription factors induced by ligands. The androgen receptor is an important cell-regulatory protein that plays an important role in a range of physiological processes, including the development and maintenance of secondary male sexual characteristics, including muscle and bone mass, male hair, prostate growth, sperm development, and the like, by endogenous androgens. Endogenous steroidal androgens are known as male sex hormones, including testosterone and Dihydrotestosterone (DHT). Testosterone, the major steroidal androgen found in the serum of men, is secreted mainly by the testes. In many peripheral tissues, such as the prostate and skin, testosterone is converted by 5 α -reductase to the more active androgen Dihydrotestosterone (DHT).
Many diseases are associated with androgen levels. Male sex hormone levels decline gradually with age, with muscle loss, osteoporosis, decreased sexual function, and the like. Conversely, androgen levels in the body can also cause androgen-related disorders such as prostate cancer, prostatic hyperplasia, acne, hirsutism, alopecia, and the like.
Prostate cancer is hormone dependent, and thus endocrine treatment of prostate cancer is the oldest used, the most mature, and the most effective means. As early as 1941, Huggins and Hodges discovered that surgical castration, such as surgical removal of bilateral testes to eliminate testosterone sources, and estrogens delayed the progression of metastatic prostate cancer, and demonstrated for the first time the responsiveness of prostate cancer to androgen ablation. However, clinical studies have shown that the androgen content in blood can be reduced by simply cutting off testis, but the androgen content in prostate tissue cannot be greatly reduced because there is an enzyme system for synthesizing androgen by using steroid secreted by adrenal gland as raw material in prostate tissue, and the androgen can be converted into more active androgen dihydrotestosterone. Therefore, even if castration therapy is adopted, anti-androgen medication is necessary for prostate cancer.
The use of anti-androgen drugs (androgen antagonists) to competitively block the binding of androgens to androgen receptors on prostate cells is the current standard treatment for prostate cancer. Common non-steroidal androgen receptor antagonists are Flutamide (Flutamide), bicalutamide (bicalutamide), and Enzalutamide (Enzalutamide, trade name: Xtandi).
Flutamide (Flutamide) is the first generation of nonsteroidal androgen receptor antagonists (Endocrinology 1972, 91, 427-437; Biochemical Society Transactions 1979, 7, 565-569; Journal of Steroid Biochemistry 1975, 6, 815-819), the metabolite 2-hydroxyflutamide is its primary active form, and can bind to androgen receptors in target tissues, block dihydrotestosterone from binding to androgen receptors, inhibit testosterone uptake in target tissues, and thus act as an antiandrogen. Due to the large dose, the long-term administration can cause the development of the breasts of men, accompanied by tumors and tenderness, nausea, vomiting, diarrhea, occasional skin reactions, anemia of denatured red blood proteins, and leukopenia and thrombocytopenia. In addition, flutamide is prone to produce anti-androgen withdrawal syndrome during treatment, and few patients have hepatotoxicity and other problems.
Figure 100002_DEST_PATH_IMAGE002
Bicalutamide (bicalutamide) is a second generation nonsteroidal androgen receptor antagonist (The Journal of Endocrinology 1987, 113, R7-R9; Urologic Clinics of North America 1991, 18, 99-110). The drug is a racemic isomer, and the active ingredient of the drug is a levorotatory isomer. Besides the antiandrogen effect, the bicalutamide has higher curative effect than flutamide, and the side effect is reduced by 70%. Similar to flutamide, the compound can be combined with androgen receptor in target tissue, block dihydrotestosterone from being combined with androgen receptor, inhibit target tissue from taking up testosterone, and thus play a role in antiandrogen. The disadvantage is that after a certain median period (typically 18-24 months) almost all patients eventually develop hormone-refractory prostate cancer. In addition, bicalutamide also causes problems in the treatment such as anti-androgen withdrawal syndrome.
Figure 100002_DEST_PATH_IMAGE004
Enzalutamide (Enzalutamide, trade name: Xtandi), a third generation non-steroidal androgen receptor antagonist (Archives of pharmaceutical Research 2015, 38(11): 2076-82), is approved by the U.S. FDA for marketing in 2012. Is stronger androgen receptor antagonism and adds a new medicine for endocrine treatment. The disadvantage is that it is expensive and also develops hormone-resistant prostate cancer. In addition, enzalutamide has been found to have side effects in therapy that can cause convulsions in patients and thus its use has been limited.
Figure 100002_DEST_PATH_IMAGE006
Therefore, the development of novel antiandrogen drugs which are safer and more effective than the existing drugs is of great value and position in research on the treatment of androgen-related diseases.
Disclosure of Invention
The invention aims to find a novel, safe and effective antiandrogen drug.
The present inventors have intensively studied to achieve the above object and, as a result, have found that: the aromatic amide compounds having a specific structure have anti-androgen activity and have an effect of degrading androgen receptor, and are safer and more effective than the existing drugs, thereby completing the present invention.
That is, the present invention provides an aromatic amide compound represented by the following general formula I or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as the present compound), which is a novel compound having anti-androgen activity and having an effect of degrading androgen receptor, more safely and effectively than existing drugs, and can be used for treating androgen-related diseases, such as prostate cancer, prostatic hyperplasia, breast cancer, bladder cancer, acne, hirsutism, alopecia, and the like.
Figure DEST_PATH_IMAGE008
Wherein R is1And R2Each independently is a hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, cyano, nitro, halogen or amino, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6Cycloalkyl is optionally substituted with 1 or more halogen atoms;
R3and R4Each independently is a hydrogen atom, a hydroxyl group, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl or C3-6A cycloalkyl group;
R5and R6Each independently is a hydrogen atom, a halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, cyano, nitro, amino, C1-6Alkylcarbonyl, hydroxy C1-6Alkyl radical, C1-6alkyl-NH-C (= O) -or aryl, said C1-6Alkyl radical、C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl and aryl optionally being selected from C1-61 or more substituents selected from alkyl, halogen, cyano and nitro;
x is a carbon atom or a nitrogen atom; and
y and Q are each independently a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom; n is 2 or 3.
In a preferred embodiment of the invention, R1And R2Each independently a hydrogen atom, C optionally substituted with 1 or more halogen atoms1-6Alkyl, cyano, nitro, halogen or amino, more preferably R1And R2Each independently is a hydrogen atom, cyano group, nitro group, halogen or C substituted by 1 to 3 halogen atoms1-4Alkyl, wherein said C substituted by 1 to 3 halogen atoms1-4The alkyl group is preferably C substituted by 1 to 3 fluorine atoms1-4The alkyl group is more preferably a methyl group substituted with 1 to 3 fluorine atoms, and particularly preferably a trifluoromethyl group.
In a preferred embodiment of the invention, R3And R4Each independently is a hydrogen atom, a hydroxyl group, or C1-6Alkyl, more preferably R3And R4Each independently is a hydrogen atom, a hydroxyl group, or C1-4Alkyl, particularly preferably R3And R4Each independently is hydroxy or methyl.
In a preferred embodiment of the invention, R5And R6Each independently is a hydrogen atom, a halogen, C optionally substituted with 1 or more halogen atoms1-6Alkyl, cyano, nitro, C1-4Alkylcarbonyl, hydroxy C1-4Alkyl radical, C1-4alkyl-NH-C (= O) -or aryl;
preferably R5And R6Each independently a hydrogen atom, a halogen, C substituted with 1 to 3 halogen atoms1-4Alkyl, cyano, nitro, C1-4Alkylcarbonyl, 1-hydroxyethyl, N-methylcarbamoyl or aryl. Wherein said C substituted by 1 to 3 halogen atoms1-4The alkyl group is preferably substituted by 1 to 3 fluorine atomsSubstituted C1-4Alkyl, more preferably methyl substituted with 1 to 3 fluorine atoms, particularly preferably trifluoromethyl, C1-4The alkylcarbonyl group is preferably acetyl.
In a preferred embodiment of the present invention, Y and Q are each independently a carbon atom, or a nitrogen atom; preferably, Y and Q are both carbon or nitrogen atoms.
In a preferred embodiment of the present invention, the aromatic amide compound of the present invention has a structure represented by the following general formula II:
Figure DEST_PATH_IMAGE010
wherein R is1、R2、R3、R4、R5、R6And X are as defined above, respectively.
In a preferred embodiment of the present invention, the aromatic amide compound of the present invention has a structure represented by the following general formula III:
Figure DEST_PATH_IMAGE012
wherein R is1、R2、R3、R4、R5、R6And X are as defined above, respectively.
Having chiral atoms in the molecules of the above formulas I, II and III, the compounds of the present invention may be racemic, levorotatory (R configuration) and/or dextrorotatory (S configuration) in the present invention. Therefore, the invention also includes stereoisomers of the aromatic amide compounds shown in the general formula I or pharmaceutically acceptable salts thereof, namely, levorotatory, dextrorotatory and/or racemic bodies of the aromatic amide compounds.
In a preferred embodiment of the present invention, the compound represented by the general formula I of the present invention is preferably the following aromatic amide compounds and pharmaceutically acceptable salts thereof:
Figure DEST_PATH_IMAGE014
Figure DEST_PATH_IMAGE016
Figure DEST_PATH_IMAGE018
。
the invention also includes aromatic amide compounds shown in the general formula I, pharmaceutically acceptable salts thereof or hydrates of stereoisomers, in-vivo primary and/or secondary metabolites and prodrugs thereof.
Examples of the in vivo primary metabolites include:
Figure DEST_PATH_IMAGE020
an in vivo primary metabolite of an aromatic amide compound represented by the general formula I
Figure DEST_PATH_IMAGE022
An in vivo primary metabolite of an aromatic amide compound represented by the general formula I
Figure DEST_PATH_IMAGE024
An in vivo primary metabolite of an aromatic amide compound represented by the general formula I
Figure DEST_PATH_IMAGE026
An in vivo primary metabolite of an aromatic amide compound represented by the general formula I.
Examples of in vivo secondary metabolites include:
Figure DEST_PATH_IMAGE028
examples of the in vivo primary plus secondary metabolites include:
Figure DEST_PATH_IMAGE030
Figure DEST_PATH_IMAGE032
。
examples of prodrugs include, for example:
Figure DEST_PATH_IMAGE034
Figure DEST_PATH_IMAGE036
Figure DEST_PATH_IMAGE038
Figure DEST_PATH_IMAGE040
。
another object of the present invention is to provide a method for preparing the aromatic amide compound represented by the general formula I, which comprises the steps of: compounds IV and V, both commercially available or synthesized according to the methods described in Tetrahedron 1979, 2337-2343 and Tetrahedron 1979, 2345-2352, respectively, are reacted to give compounds VI, which are then reacted with azide compounds, such as sodium azide (NaN)3) The reaction is converted into a compound VII. The compound VII is reduced to the compound VIII by catalytic hydrogenation. Compound VIII and Compound IX in EDCI ([ 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide](1-Ethyl-3- (3-methylenepropyl) carbodiimide)) and HOBt (Hydroxybenzotriazole) (when IX is an acid) or under alkaline conditions (IX is acyl chloride) to produce the target compound of the general structural formula I, which has the following chemical reaction formula:
Figure DEST_PATH_IMAGE042
。
the corresponding chiral compounds can be prepared by first commercially available or optically pure starting compounds X or XV (synthesized according to the methods Tetrahedron 1979, 2337-2343, Tetrahedron 1979, 2345-2352) and then synthesizing the target compound, for example the target compound (XIV) in S configuration, according to the following routes:
Figure DEST_PATH_IMAGE044
and synthesizing the target compound (XIX) with R configuration:
Figure DEST_PATH_IMAGE046
wherein R is shown in the chemical reaction formula1、R2、R5、R6The definitions of X, Y, Q and n are given for R as described in formula I1、R2、R5、R6X, Y, Q and n are as defined.
The invention relates to compounds of formula (I) (wherein R is3Is methyl, R4Hydroxyl) can also be synthesized according to the following route: reacting compound XX with peroxide (as oxidant) such as peroxyacetic acid, trifluoroperoxyacetic acid, hydrogen peroxide, peroxybenzoic acid, etc. to obtain epoxy compound XXI, and reacting with azide compound such as sodium azide (NaN)3) The reaction is converted to compound XXII. Compound XXII is then reduced by catalytic hydrogenation to compound XXIII. Compound XXIII and compound IX are reacted in the presence of EDCI and HOBt (IX is an acid) or under basic conditions (IX is an acid chloride) to give compound XXIV.
Figure DEST_PATH_IMAGE048
Wherein R is shown in the chemical reaction formula1、R2、R5、R6The definitions of X, Y, Q and n are the same as in formula I above.
Wherein "
Figure DEST_PATH_IMAGE050
"denotes that the compound IX is
Figure DEST_PATH_IMAGE052
(acid) or
Figure DEST_PATH_IMAGE054
(acid chloride).
The invention further aims to provide application of the aromatic amide compound shown in the general formula I or the pharmaceutically acceptable salt thereof in preparing medicines for treating or preventing androgen-related diseases.
It is a further object of the present invention to provide a method for treating or preventing androgen associated diseases comprising administering to a mammal in need thereof a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the androgen associated diseases include prostate cancer, prostatic hyperplasia, breast cancer, bladder cancer, acne, hirsutism, alopecia, and the like.
In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.
In the present invention, "C1-6The alkyl group "means a linear or branched aliphatic saturated hydrocarbon group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a hexyl group. Among them, C having 1 to 4 carbon atoms is preferable1-4An alkyl group, more preferably C having 1 to 3 carbon atoms1-3An alkyl group.
In the present invention, "C2-6Alkenyl "means having an unsaturated bisExamples of the linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms in the bond include a vinyl group, a 1-propenyl group, a 2-methyl-1-propenyl group, a 2-methyl-2-propenyl group, a 2-buten-1-yl group, a 3-buten-1-yl group, a 2-penten-1-yl group, a 3-penten-1-yl group, a 4-penten-1-yl group, a 5-hexen-1-yl group, a 4-hexen-1-yl group, a 3-hexen-1-yl group, and a 2-hexen-1-yl group. Among them, C having 2 to 4 carbon atoms is preferable2-4An alkenyl group, more preferably C having 2 to 3 carbon atoms2-3An alkenyl group.
In the present invention, "C2-6The alkynyl group "refers to a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms and having an unsaturated triple bond, and examples thereof include ethynyl, 1-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, 4-hexyn-1-yl, 3-hexyn-1-yl and 2-hexyn-1-yl. Among them, C having 2 to 4 carbon atoms is preferable2-4Alkynyl, more preferably C having 2 to 3 carbon atoms2-3Alkynyl.
In the present invention, "C3-6The cycloalkyl group "means a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
In the present invention, "C1-6Alkoxy "means bonding with" C "as defined above1-6Examples of the "oxy group of the alkyl group" include: methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
In the present invention, "C1-6Alkylcarbonyl "means" C "as defined above1-6Examples of the group in which the alkyl group "is bonded to a carbonyl group (= O)) include: acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.
In the present invention, "hydroxy group C1-6Alkyl "means" C "as defined above1-6Examples of the group in which the alkyl group is "substituted with a hydroxyl group include: 1-hydroxyethyl group (
Figure DEST_PATH_IMAGE056
) 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl and the like.
In the above definition, for example, "C" is1"C" of "etc. represents a carbon atom, and the attached numbers represent the number of carbon atoms. For example, "C1-6"represents a range of 1 to 6 carbon atoms.
In the present invention, the expression "optionally substituted with 1 or more groups (substituents)" means that the group to be substituted is optionally substituted with 1 or more same or different groups (substituents) at any position of the group to be substituted. For example, "C1-6Alkyl optionally substituted by 1 or more halogen atoms "means C1-6The alkyl group may be unsubstituted or may be at C1-6Any substitutable position of the alkyl group is substituted with 1 or more halogen atoms.
In the present invention, in the ring on the right side of the formula "
Figure DEST_PATH_IMAGE058
"means that the ring is an unsaturated ring.
In the present invention, the term "aryl" means a 5-to 10-membered aromatic monocyclic or bicyclic carbocyclic group or a monocyclic or bicyclic heterocyclic group containing a heteroatom selected from N, O and S, wherein one ring of the bicyclic system may be hydrogenated, which is unsubstituted or substituted by a substituent; including, for example, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, imidazolyl, pyranyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thienyl, purinyl, benzofuryl, benzothienyl, diazinyl, isobenzothienyl, isobenzofuryl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, and the like; the substituent is selected from hydrogen atom, alkyl, halogen, trifluoromethyl, cyano, nitro, and the like.
In the present invention, the term "pharmaceutically acceptable salt" refers to a salt formed by reacting a pharmaceutically nontoxic acid with a basic moiety of a compound of the present invention represented by general formula I, and includes, for example, hydrochloride, acetate, hydrobromide, sulfate, bisulfate, carbonate, bicarbonate, sulfite, phosphate, biphosphate, oxalate, malonate, valerate, borate, p-toluenesulfonate, methanesulfonate, tartrate, benzoate, lactate, citrate, maleate, fumarate, malate, salicylate, mandelate, succinate, gluconate, lactobionate, and the like. Such salts may be prepared by methods well known to those skilled in the art.
Experiments prove that the compound shown in the general formula I can be combined with an androgen receptor, has obvious androgen resistance and can degrade the activity of the androgen receptor. The compounds can be used alone or as compositions for the treatment of various androgen-associated diseases, including, for example, prostate cancer, prostatic hyperplasia, breast cancer, bladder cancer, and for the treatment of acne, hirsutism, alopecia, and the like.
Therefore, the invention also provides a pharmaceutical composition containing the compound shown in the general formula I or pharmaceutically acceptable salt thereof, and a pharmaceutical preparation containing the compound shown in the general formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier may include pharmaceutically acceptable carriers conventional in the art, such as diluents, fillers, binders, disintegrants, lubricants, solvents, solubilizers, and the like; including but not limited to, for example, starch, powdered sugar, calcium phosphate, magnesium stearate, talc, dextrin, cellulose and its derivatives, microcrystalline cellulose, polyethylene glycol, physiological saline, glucose solution, and the like.
The pharmaceutical compositions and formulations of the present invention may also include various other conventional additives such as preserving, emulsifying, suspending, flavoring, and the like.
The pharmaceutical composition of the present invention can be prepared into any suitable pharmaceutically acceptable dosage form including, but not limited to, for example, tablets, capsules, pills, granules, syrups, injections, solutions, suspensions, and the like.
The compounds of formula I of the present invention or pharmaceutically acceptable salts thereof can be administered to mammals, e.g., humans, by any effective route, including oral, intravenous, intraperitoneal, intramuscular, topical, transdermal, ocular, nasal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, and the like. They may be administered alone or in combination with other active ingredients. An effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof of the present invention can be determined by one skilled in the art, for example, by the attending physician, using conventional methods. In determining an effective amount of a compound of the present invention, a number of factors should be considered by the attending physician, including but not limited to; the specific compound to be administered; combinations with other agents; species, size, age and general health of the mammal; the severity of the disease; the response of the individual patient; the mode of administration; bioavailability characteristics of the administered formulation; the selected dosage regimen; the use of other concomitant medications; and other related circumstances, etc. The usual dosage is from 10 to 1000 mg.
Detailed Description
The present invention will be described in further detail with reference to the following examples, and it is apparent that the described examples are only a part of the present invention, and not all of it. These examples are intended to illustrate the invention only and should not be construed as limiting the scope of the invention. All other technical solutions, which can be obtained by a person skilled in the art without any inventive effort based on the embodiments of the present invention, are within the scope of the present invention.
In the examples, the abbreviation THF stands for tetrahydrofuran, DMSO-d6Represents deuterated dimethyl sulfoxide, DMSO represents dimethyl sulfoxide, HPLC represents high performance liquid chromatography, EDCI represents [ 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide](1-Ethyl-3- (3-dimethylamino) carbodiimide), DIPEA for (N, N-Diisopropylethylamine), HOBT for (Hydroxybenzotriazole) (Hydroxybenzotriazole), and DMF for dimethylformamide.
1H NMR was determined using a Bruker AVANCE II 400MHz NMR spectrometer, where s represents a single peak, bs or brs represents a broad single peak, d represents a doublet, m represents a multiplet, and Ar is an aryl group. Mass spectrometry was performed using a Bruker amaZon SL mass spectrometer. High resolution Mass spectrometry was performed using a Waters acquisition HPLC + Xeno G2-S TOF Mass. The high pressure liquid chromatography assay uses SHIMADZU CBM-20A. Thin layer chromatography assay was performed using Silica gel 60F254 plates (Merck).
I. Examples of preparation of Compounds
Example 1
（S) -5-acetyl-N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazole-3-carboxamide (C)18H16F3N5O4) Preparation of
Figure DEST_PATH_IMAGE060
First step reaction
Thionyl chloride (2.4 ml, 33.6 mmol) was added dropwise to a solution of (R) -3-bromo-2-hydroxy-2-methylpropionic acid (5.11 g, 28 mmol) in 30ml of THF at a temperature controlled at 0-12 ℃ over 10 minutes. The resulting mixture was stirred under the same conditions for 2 hours. The internal temperature was adjusted to about-5 ℃ and triethylamine (Et) was slowly added to the reaction mixture3N) (5.0 ml, 36.4 mmol, 1.3 eq) and the internal temperature during the addition was below 12 ℃. Stirred for 20 minutes under the same reaction conditions. Subsequently, a solution of 4-cyano-3-trifluoromethyl-aniline (4.0 g, 21 mmol) in 40mL of THF was added dropwise thereto, and the resulting mixture was stirred at 50 ℃ for two hours. The reaction was cooled to 20 + -5 deg.C, then water (15 ml, 2.9 vol.) and toluene (20 ml, 4.0 vol.) were added, the mixture was stirred briefly and separated, the organic phases were washed with water (15 ml, 2.9 vol.), the organic phases were combined and concentrated to 5 + -0.5 vol (6.4 wt.) by distillation under reduced pressure, the temperature was maintained below 50 deg.C during the distillation. Toluene (31 ml, 6 vol) was added to the concentrate, diluted to 5. + -. 0.5 vol (6.4 wt), the temperature adjusted to 2.5. + -. 2.5 ℃ and stirred at this temperature for one hourSeed crystals (0.018 g, 0.005 wt.) were added, stirring was continued for one hour, filtration was carried out, and the filter cake was washed twice with toluene (8.5 ml each time, 1.7 vol). The batch was then dried in a vacuum oven to give 5.8 g of (R) -3-bromo-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide. The yield was 59%, the HPLC (mobile phase water and acetonitrile) purity was 99% (220nm),99% (254nm), the optical HPLC purity was 99%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ10.52 (s, 1H, NH), 8.55(d, J=1.6Hz,1H, ArH), 8.31(dd, J=8.2Hz, J=1.6Hz, 1H, ArH), 8.11(d, J=8.2Hz, 1H, ArH), 6.40(s, 1H, OH), 3.84(d, J=10.4Hz, 1H, CH), 3.60(d, J=10.4Hz, 1H, CH), 1.50(s, 3H, CH3)。
mass spectrum: (ESI, Positive) 351.9[ M + H]+。
Second step reaction
To a 250mL round bottom flask was added (R) -3-bromo-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (2.00 g, 5.696 mmol), 40mL anhydrous DMSO as solvent, and sodium azide (sodium azide) (1.84 g, 0.02848 mol) was added, and then the reaction was stirred at room temperature under argon atmosphere for 3 days.
After completion of the reaction was confirmed by thin layer chromatography (developing solvent hexane: ethyl acetate = 2: 1), ethyl acetate and water were added, the two phases were separated, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and solvent-exchanged to methanol, and the crude product (S) -3-azido-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide was directly used in the next reaction.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, CDCl3) δ9.00(bs, 1H, NH), 8.08(s, 1H, ArH), 7.95(d, J=8.4 Hz, 1H, ArH), 7.81(d, J=8.4 Hz, 1H, ArH), 3.92 (d, J=12.4Hz, 1H, CH), 3.50 (d, J=12.4Hz, 1H, CH), 2.96 (s, 1H, OH), 1.54 (s, 3H, CH3)。
mass spectrum: (ESI, Negative): 312.18 [ M-H]-; (ESI, Positive): 314.03 [M+H]+。
The third step of reaction
A solution of (S) -3-azido-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (1.78 g, 5.696 mmol) in methanol (30mL) was catalytically hydrogenated with palladium on carbon (30 psi) and reacted for 3-4 hours.
After completion of the reaction by thin layer chromatography, celite was filtered and drained to give a yellow/light brown powder which was dried to give (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide 1.57 g in about 96% yield.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, CDCl3) δ9.01(bs, 1H, NH), 8.10(s, 1H, ArH), 7.98(d, J=8.6Hz, 1H, ArH), 7.79(d, J=8.6Hz, 1H, ArH), 5.10(m, 2H, NH2), 4.12 (d, J=12.4Hz, 1H, CH), 3.75 (d, J=12.4Hz, 1H, CH), 3.02(s, 1H, OH), 1.51 (s, 3H, CH3)。
mass spectrum: (ESI, Positive) 288.09 [ M + H]+。
The fourth reaction step
In a 100mL round bottom flask was added 5-acetyl-1H-pyrazole-3-carboxylic acid (0.13 g, 0.8355 mmol), 2.0mL anhydrous DMF as solvent, followed by EDCI (0.16 g, 1.0444 mmol), DIPEA (0.18 g, 1.3926 mmol) and HOBT (32 mg, 0.2098 mmol), and the resulting mixture was stirred for 20 min. Another starting material, (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.20 g, 0.6963 mmol) was dissolved in 5.0mL anhydrous DMF and added to the above mixture, and the reaction was stirred at room temperature under argon atmosphere for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 9: 1), purification, 0.14 g of pale yellow powdery substance was obtained, yield was about 50%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 14.19(s, 1H, pyrazole-NH), 10.53(s, 1H, NH), 8.50(s, 1H, ArH), 8.35(br s, 1H, NH), 8.26(d, J =8.8Hz, 1H, ArH), 8.09(d, J =8.8Hz, 1H, ArH), 7.37(s, 1H, pyrazole-H), 6.20(s, 1H, OH), 3.62-3.58(m, 2H, CH), 1H, NH, rh, ir2), 1.99(s, 3H, CH3), 1.38(s, 3H, CH3)。
Mass spectrum: (ESI, Negative): 422.16 [ M-H]-。
Example 2
N-(S) Preparation of- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -5- (1-hydroxyethyl) -1H-pyrazole-3-carboxamide
Figure DEST_PATH_IMAGE062
Adding (to a 100mL round-bottom flask)S) -5-acetyl-N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazole-3-carboxamide (0.10 g, 0.2362 mmol), 5mL absolute ethanol as solvent, to this reaction was slowly added a suspension of sodium borohydride (22 mg, 0.5905 mmol) and ethanol, and the reaction was stirred under argon at room temperature overnight.
After completion of the reaction by thin layer chromatography, 0.5mL of water and 1mL of 0.5M HCl were added, the mixture was stirred briefly and concentrated to dryness by distillation under reduced pressure, dichloromethane (20 mL) was added and the organic phase was dissolved with NaHCO3Aqueous solution, brine washing, drying over magnesium sulfate, filtration and suction drying to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 9: 1), purification gave 76 mg of a pale yellow powdery substance with a yield of about 76%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 13.56(s, 1H, pyrazole-NH), 10.52(s, 1H, NH), 8.49(s, 1H, ArH), 8.33(br s, 1H, NH), 8.25(d, J =8.8Hz, 1H, ArH), 8.09(d, J =8.8Hz, 1H, ArH), 7.31(s, 1H, pyrazole-H), 6.20(s, 1H, OH), 4.68-4.62(m, 1H, CH), 3.64-3.58(m, 3H, OH + CH), and so forth2), 1.51(s, 3H, CH3), 1.38(s, 3H, CH3)。
Mass spectrum: (ESI, negative) M/z 424.10 [ M-H]-。
Example 3
(S) -N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -5-trifluoromethyl-1H-pyrazole-3-carboxamide (C)17H13F6N5O3) Preparation of
Figure DEST_PATH_IMAGE064
5-trifluoromethyl-1H pyrazole-3-carboxylic acid (0.23 g, 1.253 mmol), 2.3mL anhydrous DMF as solvent, EDCI (0.24 g, 1.567 mmol), DIPEA (0.27 g, 2.089 mmol) and HOBT (48 mg, 0.3133 mmol) were added to a 100mL round-bottomed flask and stirred for 20 min. A solution of the other starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.30 g, 1.044 mmol) in 6.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 9: 1), purification, 0.23 g of pale yellow powdery material was obtained, yield was about 50%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 14.41(s, 1H, pyrazole-NH), 10.50(s, 1H, NH), 8.58(s, 1H, NH), 8.48(s, 1H, ArH), 8.26(d, J =8.0Hz, 1H, ArH), 8.09(d, J =8.0Hz, 1H, ArH), 7.36(s, 1H, pyrazole-H), 6.12(s, 1H, OH), 3.67-3.45(m, 2H, CH, OH)2), 1.39(s, 3H, CH3)。
Mass spectrum: (ESI, Negative): 448.00 [ M-H]-。
Example 4
(S) -5-chloro-N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazole-3-carboxamide (C)16H13ClF3N5O3) Preparation of
Figure DEST_PATH_IMAGE066
5-chloro-1H-pyrazole-3-carboxylic acid (0.122 g, 0.8355 mmol), 1.5mL anhydrous DMF as solvent, EDCI (0.16 g, 1.0444 mmol), DIPEA (0.24mL, 1.3926 mmol) and HOBT (32 mg, 0.2089 mmol) were added to a 100mL round-bottomed flask and stirred for 20 min. A solution of the other starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.20 g, 0.6963 mmol) in 4.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 9: 1), purification, 0.15 g of pale yellow powdery substance was obtained, yield was about 51.0%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 13.79(s, 1H, NH), 10.50(s, 1H, NH), 8.50(s, 1H, ArH), 8.44(bs, 1H, NH), 8.25(d, J =8.2Hz, 1H, ArH), 8.10(d, J =8.2Hz, 1H, ArH), 6.93(s, 1H, pyrazole-H), 6.11(s, 1H, OH), 3.66-3.61(m, 1H, CH, OH)2), 3.54-3.50(m, 1H, CH2), 1.38(s, 3H, CH3)。
Mass spectrum: (ESI, Negative) M/z 414.25 [ M-H]-。
Example 5
(S) -5-bromo-N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazole-3-carboxamide (C)16H13BrF3N5O3) Preparation of
Figure DEST_PATH_IMAGE068
To a 100mL round bottom flask was added 5-bromo-1H-pyrazole-3-carboxylic acid (0.16 g, 0.8355 mmol), 1.5mL anhydrous DMF as solvent, followed by EDCI (0.16 g, 1.0444 mmol), DIPEA (0.24mL, 1.3926 mmol) and HOBT (32 mg, 0.2089 mmol), and stirred for 20 min. A solution of the other starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.20 g, 0.6963 mmol) in 4.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 9: 1), purification, 0.176 g of pale yellow powdery substance was obtained, yield was about 55.0%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 13.82(s, 1H, NH), 10.49(s, 1H, NH), 8.51(m, 2H), 8.27(d, J =8.2Hz, 1H, ArH), 8.08(d, J =8.2Hz, 1H, ArH), 7.38(s, 1H, pyrazole-H), 6.13(s, 1H, OH), 3.65-3.50(m, 2H, CH)2), 1.39(s, 3H, CH3)。
Mass spectrum: (ESI, Negative) M/z 457.97 [ M-H]-。
Example 6
(S) -N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -5-nitro-1H-pyrazole-3-carboxamide (C)16H13F3N6O5) Preparation of
Figure DEST_PATH_IMAGE070
5-Nitro-1H-pyrazole-3-carboxylic acid (0.13 g, 0.8355 mmol), 1.5mL anhydrous DMF as solvent, EDCI (0.16 g, 1.0444 mmol), DIPEA (0.24mL, 1.3926 mmol) and HOBT (32 mg, 0.2089 mmol) were added to a 100mL round-bottomed flask and stirred for 20 min. A solution of the other starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.20 g, 0.6963 mmol) in 4.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 9: 1), purification, 0.14 g of yellow powdery substance was obtained, yield was about 48.0%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 14.62(s, 1H, NH), 10.54(s, 1H, NH), 8.59(s, 1H, NH), 8.50(s, 1H, ArH), 8.27(d, J =8.8Hz, 1H, ArH), 8.09(d, J =8.8Hz, 1H, ArH), 7.41(s, 1H, pyrazole-H), 6.22(s, 1H, OH), 3.70-3.51(m, 2H, CH, OH)2), 1.39(s, 3H, CH3)。
Mass spectrum: (ESI, Negative) M/z 425.03 [ M-H]-。
Example 7
(S) -5-cyano-N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazole-3-carboxamide (C)17H13F3N6O3) Preparation of
Figure DEST_PATH_IMAGE072
To a 100mL round bottom flask was added 5-cyano-1H-pyrazole-3-carboxylic acid (0.115 g, 0.8355 mmol), 1.5mL anhydrous DMF as solvent, followed by EDCI (0.16 g, 1.0444 mmol), DIPEA (0.24mL, 1.3926 mmol) and HOBT (32 mg, 0.2089 mmol), and stirred for 20 min. A solution of the other starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.20 g, 0.6963 mmol) in 4.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 95: 5), purification, 0.15 g of pale yellow powdery material was obtained, yield was about 54.0%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 14.53(s, 1H, NH), 10.52(s, 1H, NH), 8.58(s, 1H, NH), 8.49(s, 1H, ArH), 8.26(d, J =8.4Hz, 1H, ArH), 8.09(d, J =8.4Hz, 1H, ArH), 7.39(s, 1H, pyrazole-H), 6.19(s, 1H, OH), 3.68-3.52(m, 2H, CH, OH)2), 1.38(s, 3H, CH3)。
Mass spectrum: (ESI, Negative) M/z 405.05 [ M-H]-。
Example 8
(S) -N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -5- (4-fluorophenyl) -1H-pyrazole-3-carboxamide (C)22H17F4N5O3) Preparation of
Figure DEST_PATH_IMAGE074
To a 100mL round bottom flask was added 5- (4-fluoro-phenyl) -1H-pyrazole-3-carboxylic acid (0.17 g, 0.8355 mmol), 1.7mL anhydrous DMF as solvent, followed by EDCI (0.16 g, 1.0444 mmol), DIPEA (0.24mL, 1.3926 mmol) and HOBT (32 mg, 0.2089 mmol), and stirred for 20 min. A solution of the other starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.20 g, 0.6963 mmol) in 4.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 95: 5), purification, 0.17 g of pale yellow powdery material was obtained, yield was about 50.0%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 14.20(s, 1H, NH), 10.51(s, 1H, NH), 8.52-8.50(m, 2H), 8.25(d, J =8.8Hz, 1H, ArH), 8.09(d, J =8.8Hz, 1H, ArH), 7.65-7.57(m, 2H, ArH), 7.36(s, 1H, pyrazole-H), 7.16-7.06(m, 2H, ArH), 6.15(s, 1H, OH), 3.66-3.53(m, 2H, CH-H), c, H, 7H, 7, and H, 7H, and 3.152), 1.38(s, 3H, CH3)。
Mass spectrum: (ESI, Negative) M/z 474.08 [ M-H]-。
Example 9
(S) -N- (3- (3-chloro-4-cyano-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -5-trifluoromethyl-1H-pyrazole-3-carboxamide (C)16H13ClF3N5O3) Preparation of
Figure DEST_PATH_IMAGE076
First step reaction
Thionyl chloride (2.38 ml, 32.787 mmol) was added dropwise to a solution of (R) -3-bromo-2-hydroxy-2-methylpropionic acid (5.00 g, 27.322 mmol) in 30ml of THF at a temperature controlled at 0-12 ℃ over 10 minutes. The resulting mixture was stirred under the same conditions for 2 hours. The internal temperature was adjusted to about-5 ℃ and triethylamine (4.95 ml, 35.52 mmol, 1.3 eq) was slowly added to the reaction mixture at an internal temperature of less than 12 ℃ during the addition. Stirred for 20 minutes under the same reaction conditions. A solution of 3-chloro-4-cyano-aniline (3.96 g, 25.96 mmol) in 40mL THF was then added dropwise thereto and the resulting mixture was stirred at 50 ℃ for two hours. Separation by silica gel column chromatography (mobile phase hexane: ethyl acetate = 2: 1), purification, drying in a vacuum oven, yielded 7.30 g of (R) -3-bromo-N- (3-chloro-4-cyano-phenyl) -2-hydroxy-2-methylpropanamide. Yield 88.6%, HPLC purity 99% (220nm),99% (254 nm).
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ10.22 (s, 1H, NH), 8.13(d, J=2.0Hz,1H, ArH), 7.88(dd, J=8.2Hz, J=2.0Hz, 1H, ArH), 7.80(d, J=8.2Hz, 1H, ArH), 6.20(s, 1H, OH), 3.94(d, J=10.4Hz, 1H, CH), 3.72(d, J=10.4Hz, 1H, CH), 1.48(s, 3H, CH3)。
mass spectrum: (ESI, Positive) 351.99 [ M + H]+。
Second step reaction
To a 250mL round bottom flask was added (R) -3-bromo-N- (3-chloro-4-cyano-phenyl) -2-hydroxy-2-methylpropanamide (2.00 g, 6.278 mmol), 40mL of anhydrous DMSO was added as a solvent, sodium azide (sodium azide) (2.05 g, 0.03149 mol) was added, and then the reaction was stirred at 80 ℃ under argon atmosphere overnight.
After completion of the reaction, ethyl acetate and water were added, the two phases were separated, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and solvent-exchanged to methanol, and the initial product (S) -3-azido-N- (3-chloro-4-cyano-phenyl) -2-hydroxy-2-methylpropanamide was used directly in the next reaction.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ8.95(bs, 1H, NH), 8.03(s, 1H, ArH), 7.86(d, J=8.4 Hz, 1H, ArH), 7.74(d, J=8.4 Hz, 1H, ArH), 3.91(d, J=12.4 Hz, 1H, CH), 3.49(d, J=12.4 Hz, 1H, CH), 2.95(s, 1H, OH), 1.56(s, 3H, CH3)。
mass spectrum: (ESI, Negative): 278.42[ M-H]-; (ESI, Positive): 280.03[M+H]+。
The third step of reaction
A solution of (S) -3-azido-N- (3-chloro-4-cyano-phenyl) -2-hydroxy-2-methylpropanamide (1.68 g, 5.9739 mmol) in methanol (30mL) was catalytically hydrogenated with palladium on carbon (30 psi) and reacted for 3-4 hours.
After completion of the reaction as determined by thin layer chromatography, celite was filtered and the residue was drained to give 1.47 g of (S) -3-amino-N- (3-chloro-4-cyano-phenyl) -2-hydroxy-2-methylpropanamide as a yellow/light brown powder in about 97% yield.
Mass spectrum: (ESI, Positive) 254.03 [ M + H]+。
The fourth reaction step
5-trifluoromethyl-1H-pyrazole-3-carboxylic acid (0.256 g, 1.4191 mmol), 2.6mL anhydrous DMF as solvent, EDCI (0.275 g, 1.7748 mmol), DIPEA (0.41mL, 2.365 mmol) and HOBT (54 mg, 0.3548 mmol) were added to a 100mL round-bottomed flask and stirred for 20 min. A solution of the other starting material (S) -3-amino-N- (3-chloro-4-cyano-phenyl) -2-hydroxy-2-methylpropanamide (0.30 g, 1.1826 mmol) in 6.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction was confirmed by thin layer chromatography (dichloromethane: methanol = 9:1 as a developing solvent), ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to obtain an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 9: 1), purification, 0.30 g of pale yellow powdery substance was obtained, yield was about 61.0%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 14.40(s, 1H, NH), 10.42(s, 1H, NH), 8.49(s, 1H, NH), 8.11(d, J =1.6Hz, 1H, ArH), 7.86(d, J =8.8Hz, J =1.6Hz, 1H, ArH), 7.81(d, J =8.8Hz, 1H, ArH), 7.34(s, 1H, pyrazole-H), 6.10(s, 1H, OH), 3.65-3.51(m, 2H, CH, OH), c, H, and H2), 1.42(s, 3H, CH3)。
Mass spectrum: (ESI, Negative) M/z 414.03 [ M-H]-。
Example 10
(S) -N- (3- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -5-trifluoromethyl-1H-pyrazole-3-carboxamide (C)16H12F6N6O3) Preparation of
Figure DEST_PATH_IMAGE078
First step reaction
Thionyl chloride (2.39 ml, 32.79 mmol) was added dropwise to a solution of (R) -3-bromo-2-hydroxy-2-methylpropionic acid (5.00 g, 27.322 mmol) in 30ml of THF at a temperature controlled at 0-12 ℃ over 10 minutes. The resulting mixture was stirred under the same conditions for 2 hours. The internal temperature was adjusted to about-5 ℃ and triethylamine (4.95 ml, 35.52 mmol, 1.3 eq) was slowly added to the reaction mixture at an internal temperature of less than 12 ℃ during the addition. Stirred for 20 minutes under the same reaction conditions. Subsequently, a solution of 5-amino-3-trifluoromethyl-2-cyanopyridine (4.86 g, 25.97 mmol) in 40mL of THF was added thereto, and the resulting mixture was stirred at 50 ℃ for two hours. The reaction was cooled to 20 ± 5 ℃, then water (15 ml, 2.9 vol) and ethyl acetate (20 ml, 4.0 vol) were added, the mixture was stirred briefly and separated, the organic phases were washed once with water (15 ml, 2.9 vol), the organic phases were combined and concentrated to dryness by distillation under reduced pressure. The residue was separated by silica gel column chromatography (mobile phase hexane: ethyl acetate = 2: 1), purified, and dried in a vacuum oven to give 7.77 g of (R) -3-bromo-N- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -2-hydroxy-2-methylpropanamide. Yield 85%, HPLC purity 99% (220nm),99% (254 nm).
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ10.82(s, 1H, NH), 9.41(d, J=2.0Hz, 1H, ArH), 8.90(d, J=2.0Hz, 1H, ArH), 6.51(s, 1H, OH), 3.84(d, J=10.4Hz, 1H, CH), 3.61(d, J=10.4Hz, 1H, CH), 1.50(s, 3H, CH3)。
mass spectrum: (ESI, Positive) 351.9915 [ M + H]+。
Second step reaction
To a 250mL round bottom flask was added (R) -3-bromo-N- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -2-hydroxy-2-methylpropanamide (2.00 g, 5.680 mmol), 40mL of anhydrous DMSO was added as a solvent, sodium azide (sodium azide) (1.85 g, 0.0288 mol) was added, and the reaction was stirred at 80 ℃ for 14 hours under argon.
After completion of the reaction as confirmed by thin layer chromatography, ethyl acetate and water were added and the two phases were separated, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and solvent-exchanged to methanol, and the crude product (S) -3-azido-N- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -2-hydroxy-2-methylpropanamide was used directly in the next reaction.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, CDCl3) δ9.18(bs, 1H, NH), 8.92(s, 1H, ArH), 8.55(s, 1H, ArH), 3.94(d, J=12.4Hz, 1H, CH), 3.52(d, J=12.4Hz, 1H, CH), 2.97(s, 1H, OH), 1.55 (s, 3H, CH3)。
mass spectrum: (ESI, Negative): 313.16[ M-H]-; (ESI, Positive): 315.04[M+H]+。
The third step of reaction
A solution of (S) -3-azido-N- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -2-hydroxy-2-methylpropanamide (1.78 g, 5.6607 mmol) in methanol (30mL) was catalytically hydrogenated over palladium on carbon (30 psi) and reacted for 3-4 hours.
After completion of the reaction as determined by thin layer chromatography, celite was filtered, drained and dried to give (S) -3-amino-N- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -2-hydroxy-2-methylpropanamide as a yellow/light brown powder in about 95% yield.
Mass spectrum: (ESI, Positive) 289.09 [ M + H]+。
The fourth reaction step
5-trifluoromethyl-1H-pyrazole-3-carboxylic acid (0.225 g, 1.2490 mmol) was added to a 100mL round-bottomed flask, 2.3mL anhydrous DMF was added as a solvent, EDCI (0.24 g, 1.5612 mmol), DIPEA (0.26mL, 2.0817 mmol) and HOBT (48 mg, 0.3123 mmol) were added, and the mixture was stirred for 20 minutes. A solution of the other starting material (S) -3-amino-N- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -2-hydroxy-2-methylpropanamide (0.30 g, 1.0408 mmol) in 6.0mL anhydrous DMF was added and the reaction was stirred at room temperature under argon for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 7: 1), purification, 0.28 g of pale yellow powdery substance was obtained, yield was about 60.0%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) Δ 14.42(s, 1H, NH), 10.73(s, 1H, NH), 9.32(s, 1H, ArH), 8.82(s, 1H, ArH), 8.60(s, 1H, NH), 7.39(s, 1H, pyrazole-H), 6.41(s, 1H, OH), 3.69-3.55(m, 2H, CH)2), 1.39(s, 3H, CH3)。
Mass spectrum: (ESI, Negative) M/z 449.05 [ M-H]-。
Example 11
(S) -N- (3- (6-cyano-pyridin-3-yl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -5-trifluoromethyl-1H-pyrazole-3-carboxamide (C)15H13F3N6O3) Preparation of
Figure DEST_PATH_IMAGE080
First step reaction
Thionyl chloride (2.39 ml, 32.79 mmol) was added dropwise to a solution of (R) -3-bromo-2-hydroxy-2-methylpropionic acid (5.00 g, 27.322 mmol) in 30ml of THF at a temperature controlled at 0-12 ℃ over 10 minutes. The resulting mixture was stirred under the same conditions for 2 hours. The internal temperature was adjusted to about-5 ℃ and Et3N (4.95 mL, 35.52 mmol, 1.3 eq) was slowly added to the reaction mixture at an internal temperature of less than 12 ℃ during the addition. Stirred for 20 minutes under the same reaction conditions. Subsequently, a solution of 5-amino-2-cyanopyridine (3.09 g, 25.96 mmol) in 40mL of THF was added dropwise thereto, and the resulting mixture was stirred at 50 ℃ for two hours. The reaction was cooled to 20 ± 5 ℃, then water (15 ml, 2.9 vol) and ethyl acetate (20 ml, 4.0 vol) were added, the mixture was stirred briefly and separated, the organic phases were washed once with water (15 ml, 2.9 vol), the organic phases were combined and concentrated to dryness by distillation under reduced pressure. Separation by silica gel column chromatography (mobile phase dichloromethane: methanol = 19: 1), purification, drying in a vacuum oven, yielded 6.64 g of (R) -3-bromo-N- (6-cyano-pyridin-3-yl) -2-hydroxy-2-methylpropanamide. Yield 85%, HPLC purity 99% (220nm),99% (254 nm).
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 10.42(s, 1H, NH), 9.12(d, J=2.4Hz, 1H, ArH), 8.44(dd, J=8.8Hz, J=2.4Hz, 1H, ArH), 8.00(d, J=8.8Hz, 1H, ArH), 6.40(s, 1H, OH), 3.83(d, J=10.4Hz, 1H, CH), 3.59(d, J=10.4Hz, 1H, CH), 1.49(s, 3H, CH3)。
mass spectrum: (ESI, Positive) 284.0042 [ M + H]+。
Second step reaction
To a 250mL round bottom flask was added (R) -3-bromo-N- (6-cyano-pyridin-3-yl) -2-hydroxy-2-methylpropanamide (2.00 g, 7.0395 mmol), 40mL anhydrous DMSO as solvent, and sodium azide (2.29 g, 0.035198 mol) was added, and then the reaction was stirred under argon at 80 ℃ overnight.
After the completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and solvent-exchanged to methanol, and the crude product (S) -3-azido-N- (6-cyano-pyridin-3-yl) -2-hydroxy-2-methylpropanamide was used directly in the next reaction.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, CDCl3) δ8.98(bs, 1H, NH), 8.77(d, J=2.0Hz,1H, ArH), 8.45(dd, J=8.6Hz, 1H, ArH), 7.79(d, J=8.6Hz, 1H, ArH), 3.93(d, J=12.4Hz, 1H, CH), 3.51(d, J=12.4Hz, 1H, CH), 2.98(s, 1H, OH), 1.55 (s, 3H, CH3)。
mass spectrum: (ESI, Negative): 245.17[ M-H]-; (ESI, Positive): 247.05[M+H]+。
The third step of reaction
A solution of (S) -3-azido-N- (6-cyano-pyridin-3-yl) -2-hydroxy-2-methylpropanamide (1.73 g, 7.0262 mmol) in methanol (30mL) was catalytically hydrogenated with palladium on carbon (30 psi) and reacted for 3-4 hours.
After completion of the reaction by thin layer chromatography, celite was filtered, drained and dried to give (S) -3-amino-N- (6-cyano-pyridin-3-yl) -2-hydroxy-2-methylpropanamide as a yellow/light brown powder in about 95% yield.
Mass spectrum: (ESI, Positive) 221.09 [ M + H]+。
The fourth reaction step
5-trifluoromethyl-1H-pyrazole-3-carboxylic acid (0.294 g, 1.6347 mmol) was added to a 100mL round-bottomed flask, 3.0mL anhydrous DMF was added as a solvent, EDCI (0.32 g, 2.0433 mmol), DIPEA (0.48mL, 2.7244 mmol) and HOBT (63 mg, 0.4087 mmol) were added, and the mixture was stirred for 20 minutes. A solution of the other starting material (S) -3-amino-N- (6-cyano-pyridin-3-yl) -2-hydroxy-2-methylpropanamide (0.30 g, 1.622 mmol) in 6.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Silica gel column chromatography (mobile phase dichloromethane: methanol = 7: 1), purification, drying, afforded the title compound as a pale yellow powder, 0.21 g, with a yield of about 41.0%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ 14.45(s, 1H, NH), 10.54(s, 1H, NH), 9.31(d, J =2.4Hz, 1H, ArH), 8.50-8.47(m, 2H), 8.05(d, J =8.8Hz, 1H, ArH), 7.36(s, 1H, pyrazole-H), 6.13(s, 1H, OH), 3.68-3.49(m, 2H, CH), c2), 1.39(s, 3H, CH3)。
Mass spectrum: (ESI, Negative) M/z 381.02 [ M-H]-。
Example 12
(S) -N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -4-fluorobenzamide (C)19H15F4N3O3) Preparation of
Figure DEST_PATH_IMAGE082
A100 mL round bottom flask was charged with the starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.22 g, 0.7659 mmol), anhydrous THF 10mL as solvent, argon blanketed, cooled to 0 deg.C, 4-fluorobenzoyl chloride (0.14mL, 1.1489 mmol, 1.5equ) added, stirred for 10 min, and triethylamine (Et) added dropwise3N, 0.32mL, 2.2977 mmol, 3equ), the temperature was raised to room temperature, and the reaction was stirred for 5-6 hours.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. Silica gel column chromatography (mobile phase dichloromethane: ethyl acetate = 19: 1), purification, oven drying, afforded the title compound as an off-white powder, 0.16 g, with about 50% yield.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ10.52(s, 1H, NH), 8.50-8.48(m, 2H, NH+ArH), 8.25(d, J=8.2Hz, 1H, ArH), 8.09(d, J=8.2Hz, 1H, ArH), 7.91-7.87(m, 2H, ArH), 7.30-7.26(m, 2H, ArH), 6.19(s, 1H, OH), 3.66-3.54(m, 2H, CH2), 1.38(s, 3H, CH3)。
mass spectrum: (ESI, Negative) M/z 408.06 [ M-H]-。
Example 13
(S) -N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -4- (trifluoromethyl) -benzamide (C)20H15F6N3O3) Preparation of
Figure DEST_PATH_IMAGE084
In a 100mL round bottom flask was added the starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.25 g, 0.8704 mmol), 10mL of anhydrous THF was added as solvent, argon protected, the temperature was lowered to 0 ℃, 4- (trifluoromethyl) -benzoyl chloride (0.55mL, 1.0444 mmol, 1.2 eq) was added, stirring was performed for 10 minutes, triethylamine (Et 3N, 0.24mL, 1.7408 mmol, 2.0 eq) was added dropwise, the temperature was raised to room temperature, stirring was performed, and the reaction time was 5-6 hours.
After the completion of the reaction, the reaction was terminated by adding water, ethyl acetate and water were added, the two phases were separated, and the organic phase was dried by suction to give an oily substance. This was separated by silica gel column chromatography (mobile phase dichloromethane: ethyl acetate = 9: 1), purified and dried to obtain 0.29 g of the objective compound as an off-white powder with a yield of about 72%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ10.54(s, 1H, NH), 8.52-8.48(m, 2H, NH+ArH), 8.26(d, J=8.4Hz, 1H, ArH), 8.14(d, J=8.4Hz, 1H, ArH), 8.01-7.97(m, 2H, ArH), 7.54-7.50(m, 2H, ArH), 6.21(s, 1H, OH), 3.70-3.58(m, 2H, CH2), 1.39(s, 3H, CH3)。
mass spectrum: (ESI, Negative) M/z 458.02 [ M-H]-。
Example 14
(S) -N1- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -N4-methyl-terephthalamide (C)21H19F3N4O4) Preparation of
Figure DEST_PATH_IMAGE086
N-Methyl-terephthalic acid monoamide (N-Methyl-terephthalic acid) (0.21 g, 1.0444 mmol), EDCI (0.20 g, 1.3055 mmol), HOBT (40 mg, 0.2611 mmol), DIPEA (0.30mL, 1.7401 mmol) and 2.0mL of anhydrous DMF as a solvent were added to a 100mL round bottom flask and stirred for 20 minutes. A solution of the other starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.25 g, 0.8704 mmol) in 5.0mL anhydrous DMF was added and the reaction was stirred at rt under argon shield for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. This was separated by silica gel column chromatography (mobile phase dichloromethane: ethyl acetate = 9: 1), purified and dried to obtain 0.18 g of the objective compound as an off-white powder with a yield of about 46%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ10.49(s, 1H, NH), 8.48-8.45(m, 2H, NH+ArH), 8.21(d, J=8.4Hz, 1H, ArH), 8.06(d, J=8.4Hz, 1H, ArH), 7.87-7.83(m, 2H, ArH), 7.31-7.24(m, 2H, ArH), 6.17(s, 1H, OH), 3.64-3.51(m, 2H, CH2), 1.37(s, 3H, CH3)。
mass spectrum: (ESI, Negative) M/z 447.09 [ M-H]-。
Example 15
(S) -4-acetyl-N- (3- (4-cyano-3-trifluoromethyl-phenyl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -3-fluoro-benzamide (C)21H17F4N3O4) Preparation of
Figure DEST_PATH_IMAGE088
To a 100mL round bottom flask was added 4-acetyl-3-fluoro-benzoic acid (0.19 g, 1.0444 mmol), EDCI (0.20 g, 1.055 mmol), HOBT (40 mg, 0.2611 mmol), DIPEA (0.30mL, 1.7401 mmol), and 2.0mL anhydrous DMF as solvent and stirred for 20 min. To this was added a solution of the other starting material (S) -3-amino-N- (4-cyano-3-trifluoromethyl-phenyl) -2-hydroxy-2-methylpropanamide (0.25 g, 0.8704 mmol) dissolved in 5.0mL of anhydrous DMF, and the reaction was stirred at room temperature under argon atmosphere for 3 days.
After completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to give an oily substance. This was separated by silica gel column chromatography (mobile phase dichloromethane: ethyl acetate = 9: 1), purified and dried to give 0.18 g of the objective compound as pale yellow powder with a yield of about 46%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ10.53(s, 1H, NH), 8.51-8.47(m, 2H, NH+ArH), 8.27(d, J=8.6Hz, 1H, ArH), 8.10(d, J=8.6Hz, 1H, ArH), 8.01-7.96(m, 2H, ArH), 7.42(d, J=2.0Hz, 1H, ArH), 6.22(s, 1H, OH), 3.71-3.59(m, 2H, CH2), 1.41(s, 3H, CH3)。
mass spectrum: (ESI, Negative) M/z 450.07 [ M-H]-。
Example 16
(S) -N- (3- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -amino) -2-hydroxy-2-methyl-3-oxopropyl) -4-fluorobenzamide (C)18H14F4N4O3) Preparation of
Figure DEST_PATH_IMAGE090
The starting material (S) -3-amino-N- (6-cyano-5-trifluoromethyl-pyridin-3-yl) -2-hydroxy-2-methylpropanamide (0.20 g, 0.6939 mmol) was added to a 100mL round bottom flask, and anhydrous THF 10mL was added as a solvent, argon protected, the temperature was lowered to 0 ℃, 4-fluorobenzoyl chloride (0.10mL, 1.3878 mmol, 1.2 eq) was added, stirring was carried out for 10 minutes, triethylamine (Et 3N, 0.19mL, 1.3878 mmol, 2.0 eq) was added dropwise, the temperature was raised to room temperature, stirring was carried out, and the reaction time was 5-6 hours.
After the completion of the reaction, the reaction was terminated by adding water, ethyl acetate and water were added, the two phases were separated, and the organic phase was dried by suction to give an oily substance. This was separated by silica gel column chromatography (mobile phase dichloromethane: methanol = 95: 5), purified and dried to obtain 0.21 g of the objective compound as an off-white powder with a yield of about 75%.
Nuclear magnetic resonance spectroscopy:1H NMR (400 MHz, DMSO-d6) δ10.52(s, 1H, NH), 9.31(s, 1H, ArH), 8.80(s, 1H, ArH), 8.50-8.48(m, 1H, NH), 7.91-7.86(m, 2H, ArH), 7.31-7.26(m, 2H, ArH), 6.19(s, 1H, OH), 3.67-3.53(m, 2H, CH2), 1.38(s, 3H, CH3)。
mass spectrum: (ESI, Negative) M/z 409.05 [ M-H]-。
Formulation preparation example
Formulation example a: preparation of injection
The preparation comprises the following components:
EXAMPLE 3 Compound 25g
Polysorbate 8020 g
Mannitol 10g
Water for injection to 5000ml
(II) the preparation method comprises the following steps:
adding the compound in example 3, polysorbate 80 and mannitol into 4000 m1 water for injection according to a formula, stirring to dissolve, adding water for injection to reach the total amount of 5000m1, continuing stirring, performing sterile filtration through a 0.22um microporous filter membrane, filling the filtrate into 5ml ampoules (with the specification of 20 mg/ampoule) with each 5m1 in a sterile manner, sealing, and sterilizing.
Formulation example B: preparation of tablets
Composition of formula (I)
Prescription 2-1 formula I Compound tablet prescription (dosage per 1000 tablets)
Figure DEST_PATH_IMAGE092
Prescription 2-2 formula I Compound tablet prescription (dosage per 1000 tablets)
Figure DEST_PATH_IMAGE094
Prescription 2-3 formula I Compound tablet prescription (every 1000 tablets dose)
Figure DEST_PATH_IMAGE096
(II) preparation process
According to the formula proportion of the tablet in the embodiment 3, the lactose and the microcrystalline cellulose in the embodiment 3 are micronized according to the ratio of 200:100:40, the microcrystalline cellulose sieved by a 80-mesh sieve, the pregelatinized starch, the aerosil and the sodium carboxymethyl starch are added according to the formula proportion and are uniformly mixed, then a proper amount of 0.3% HPMC solution is added to prepare a soft material, the 18-mesh sieve is used for granulation, the drying is carried out at 60 ℃ (the moisture content of the granules is controlled to be about 3%), the magnesium stearate sieved by the 80-mesh sieve is added to be uniformly mixed with the granules, the granules are sieved by a 16-mesh sieve, and the mixture is tableted and packaged.
Detection of biological Activity
Reagent and instrumentation: dihydrotestosterone with radiolabel (DHT-d 3) and unlabelled Dihydrotestosterone (DHT) were purchased from Sigma-Aldrich (St. Louis, MO). Scintillation solution (scintillation solution) was purchased from Perkin Elmer Life Sciences (Boston, MA). Hydroxyapatite (HAP) suspensions were purchased from Bio-Rad Laboratories (Hercules, Calif.). Buffer (containing 10 mM Tris, 1.5 mM disodium EDTA, 0.25M sucrose, 10 mM sodium molybdate, and 1 mM PMSF and then adjusted to pH 7.4). Hydroxyapatite (HAP) lotion (containing 50 mM Tris and 1 mM KH)2PO4The pH was then adjusted to 7.4).
In the present invention, the biological activity of the aromatic amide compound represented by the general formula I is measured by the following method. Some of the compounds of the present invention and control compounds obtained in the preparation examples were dissolved in DMSO to prepare a stock solution of a certain concentration, which was diluted with DMSO to several concentration gradients, and each concentration was diluted with a buffer (10)-1nM to 104nM) at 4 ℃ in a refrigerator until use. Androgen receptor (prepared in male SD rats)Prostate, male Sprague-Dawley rat 200-. The dihydrotestosterone bound to the androgen receptor is retained in the precipitated particles by adsorption onto hydroxyapatite, thereby achieving the objective of separating bound from unbound radiolabeled ligand. Scintillation solution (scintillation solution) was added to the pellet, mixed well and subjected to radioactive intensity detection using a WALLACE MicroBeta Trilux liquid scintillation counter (Perkin Elmer). Processing data according to the detected radioactive intensity values of the concentration gradients to obtain IC50And KiThe value is obtained. Specific biological activities (androgen receptor ligand radioligand competition results) are given in the following table:
Figure DEST_PATH_IMAGE098
Figure DEST_PATH_IMAGE100
the results of the bioactivity assays in the above table show that the compounds of the invention bind more strongly to the androgen receptor and have greater resistance to androgen receptor activity than the positive controls (bicalutamide, and enzalutamide). Therefore, the compound can be developed into novel aromatic amide antiandrogen medicaments which are safer and more effective than the existing medicaments, and has important value and position in the research of treating androgen-related diseases.
The compound can be used for treating various androgen-related diseases such as prostatic cancer, prostatic hyperplasia, breast cancer and bladder cancer singly or as a composition, and can also be used for treating diseases such as acne, hirsutism, alopecia and the like.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, or direct or indirect applications in other related fields, which are made by the present disclosure, are included in the scope of the present invention.

Claims (11)

1. An aromatic amide compound represented by the following general formula II:
Figure DEST_PATH_IMAGE001
wherein R is1And R2Each independently is a hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, cyano, nitro, halogen or amino, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6Cycloalkyl is optionally substituted with 1 or more halogen atoms;
R3is hydroxy, and R4Is hydrogen atom, hydroxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl or C3-6A cycloalkyl group;
R5and R6Each independently is hydrogen atom, halogen, cyano, nitro, amino, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, C1-6Alkylcarbonyl, hydroxy C1-6Alkyl radical, C1-6alkyl-NH-C (= O) -, phenyl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl and phenyl optionally being selected from C1-61 or more substituents selected from alkyl, halogen, cyano and nitro; and
x is a carbon atom or a nitrogen atom.
2. The aromatic amide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1And R2Each independently is a hydrogen atom, a cyano group, a nitro group, a halogen or C optionally substituted by 1 to 3 halogen atoms1-4An alkyl group.
3. The aromatic amide compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4Is a hydrogen atom, a hydroxyl group, or C1-4An alkyl group.
4. The aromatic amide compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R5And R6Each independently a hydrogen atom, a halogen, C optionally substituted with 1 to 3 halogen atoms1-4Alkyl, cyano, nitro, C1-4Alkylcarbonyl, 1-hydroxyethyl, N-methylcarbamoyl or phenyl.
5. The aromatic amide compound according to claim 1 or 2, which is a racemate, a levorotatory isomer and/or a dextrorotatory isomer, or a pharmaceutically acceptable salt thereof.
6. The aromatic amide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aromatic amide compound is selected from the group consisting of:
Figure DEST_PATH_IMAGE002
Figure DEST_PATH_IMAGE003
and
Figure DEST_PATH_IMAGE004
。
7. the method for producing an aromatic amide compound according to claim 1, comprising the steps of: reacting the compound IV with the compound V to obtain a compound VI, and then reacting the obtained compound VI with an azide compound to convert the compound VI into a compound VII; carrying out catalytic hydrogenation reduction on the compound VII to obtain a compound VIII;
when the compound IX is an acid, reacting the compound VIII with the compound IX in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and hydroxybenzotriazole, and when the compound IX is an acid chloride, reacting the compound VIII with the compound IX under basic conditions to form the target compound shown in the general formula I,
Figure DEST_PATH_IMAGE005
wherein the group "
Figure DEST_PATH_IMAGE006
'is'
Figure DEST_PATH_IMAGE007
", R shown in the above formula1、R2、R3、R4、R5、R6And X is as defined for R in claim 11、R2、R3、R4、R5、R6And X are as defined.
8. A pharmaceutical composition comprising the aromatic amide compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier or diluent and the aromatic amide compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof.
10. Use of the aromatic amide compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of androgen-associated diseases.
11. The use according to claim 10, wherein the androgen associated disease is prostate cancer, prostatic hyperplasia, breast cancer, bladder cancer, acne, hirsutism, or alopecia.
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WO1998022432A1 (en) * 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same
WO2011035143A2 (en) * 2009-09-17 2011-03-24 The Regents Of The University Of Michigan Methods and compositions for inhibiting rho-mediated diseases and conditions

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WO1998022432A1 (en) * 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same
WO2011035143A2 (en) * 2009-09-17 2011-03-24 The Regents Of The University Of Michigan Methods and compositions for inhibiting rho-mediated diseases and conditions

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