CN109796519B - Steroid compound and application thereof - Google Patents
Steroid compound and application thereof Download PDFInfo
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- CN109796519B CN109796519B CN201910088901.3A CN201910088901A CN109796519B CN 109796519 B CN109796519 B CN 109796519B CN 201910088901 A CN201910088901 A CN 201910088901A CN 109796519 B CN109796519 B CN 109796519B
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Abstract
The invention relates to a series of steroid compounds, a preparation method and application thereof, in particular to a compound shown as a formula I, an isomer, a pharmaceutically acceptable salt or a chemical protection form thereof, a preparation method thereof and application thereof in preparing medicaments for treating cancers, aging and hormone-related diseases. The compound of the invention has better activity for inhibiting malignant tumors such as melanoma, prostatic cancer and the like and resisting aging and the like.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a series of steroid compounds, and a preparation method and application thereof.
Background
The steroid compound is widely existed in animal and plant bodies, has various biological activities and is very widely applied. With the development of biology and chemical technology, steroids have been found to have the effects of treating rheumatism, cardiovascular diseases, collagen diseases, lymphatic leukemia, tumors, endocrine dyscrasia and the like, and delaying aging. For example, the CYP17 inhibitor abiraterone is clinically combined with prednisone to treat the prostate cancer patients who have received paclitaxel chemotherapy and then have a metastasis tendency, so that the life quality of the patients can be obviously improved, and the life cycle of the patients can be prolonged; dehydroepiandrosterone, has therapeutic effect on senile cognitive dysfunction, osteoporosis, immunologic hypofunction, and tumor.
Disclosure of Invention
The invention solves the technical problem of disclosing a steroid compound with the activities of resisting tumor, resisting aging and the like.
The second technical problem to be solved by the invention is to disclose the application of the steroid compound in the aspects of cancer resistance, aging resistance and the like.
In particular, the first aspect of the invention provides a steroid compound (formula I), an isomer, a pharmaceutically acceptable salt or a chemically protected form thereof.
Wherein, the first and the second end of the pipe are connected with each other,
r is aliphatic alkyl, aryl OR 10 、-N R 11 R 12 ；
R 1 、R 2 、R 3 、R 4 、R 5 、R 10 、R 11 、R 12 Each independently selected from hydrogen, aliphatic radicals, aryl radicals, acyl radicals;
A. b is independently selected from-O-, -NH-and R 6 A substituted amino group,
or when A is nitrogenAt atom time, R 1 Or R 2 Together with a form a 5 to 8 membered ring;
or R when B is a nitrogen atom 3 Or R 4 Together with B form a 5 to 8 membered ring;
R 6 is aliphatic alkyl and acyl;
wherein when R is 1 And R 2 When the two are different, the asymmetric carbon is in an L configuration or a D-configuration; when R is 3 And R 4 When different, the asymmetric carbon is in an L configuration or a D-configuration;
wherein the aliphatic hydrocarbon group, aryl group, acyl group are unsubstituted or each independently substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, carbonyl, carboxyl, sulfydryl, sulfenyl, guanidino, amino, alkylamino, acylamino, aliphatic hydrocarbon group, aryl;
in one embodiment of the present invention, the aliphatic hydrocarbon group mentioned above is an alkyl group, an alkenyl group, an alkynyl group;
the aryl is aromatic alkyl and aromatic heterocyclic radical;
further, the alkyl is a straight-chain alkyl of 1 to 10 carbon atoms, a branched-chain alkyl of 1 to 10 carbon atoms, an alicyclic group of 1 to 10 carbon atoms, a heterocycloalkyl group of 1 to 10 carbon atoms;
the alkenyl is a straight chain alkenyl with 1-10 carbon atoms, a branched alkenyl with 1-10 carbon atoms, a cycloalkenyl with 1-10 carbon atoms, or a heterocyclic alkenyl with 1-10 carbon atoms;
the alkynyl is straight-chain alkynyl with 1-4 carbon atoms and a branched chain;
further, the alkyl, alkenyl, alkynyl, aryl, heteroaryl groups are unsubstituted or each independently substituted with one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of: halogen, amino, hydroxyl, mercapto, nitro, cyano, carboxyl, acyl, epoxy, sulfonyl, arylsulfonamido, trifluoromethyl, 2-imidazolyl, 2-oxazolyl, phenyl, alkyl of 1 to 10 carbon atoms, hydrocarbonoxy of 1 to 10 carbon atoms, alkylamino of 1 to 10 carbon atoms, alkylsulfonylamino of 1 to 10 carbon atoms, aminoalkyl of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, hydrocarbonacyl of 1 to 10 carbon atoms, amido of 1 to 10 carbon atoms, acyloxy of 1 to 10 carbon atoms, acylthio of 1 to 10 carbon atoms, carboxyalkyl of 1 to 10 carbon atoms, or carboxyalkyl of 1 to 10 carbon atoms in the form of the corresponding ester, amide, ammonium salt, sodium salt, potassium salt;
the halogen is fluorine, chlorine, bromine or iodine.
In one embodiment of the present invention, the acyl group is an acyl group containing 1 to 20 carbon atoms;
wherein, the acyl with 1 to 20 carbon atoms is a straight chain, has a side chain, or contains a heteroatom, an unsaturated bond or a cyclic structure;
further, the acyl group having 1 to 20 carbon atoms is substituted with 1 or more substituents selected from the group consisting of a substituent selected from the group consisting of: hydrogen, halogen, amino, hydroxyl, carboxyl, sulfydryl, guanidino, alkylamino, arene group, alkyl, alkenyl, alkynyl, aralkyl, arene heterocyclic group; each substituent is the same or different;
wherein the halogen is fluorine, chlorine, bromine or iodine;
the R is 6 Is aliphatic alkyl and acyl; wherein, the substituents of the aliphatic alkyl and acyl are defined as above;
the hydrocarbon in the hydrocarbon sulfenyl and the hydrocarbon amino contains 1-4 carbon atoms.
In one embodiment of the present invention, the aromatic hydrocarbon group includes, but is not limited to, the following groups: phenyl, naphthyl, biphenyl;
the aralkyl group includes, but is not limited to, the following groups: benzyl, phenethyl, naphthylmethyl, pyridylmethyl;
the aromatic heterocyclic group includes, but is not limited to, the following groups: benzimidazolyl, imidazophenyl, indolyl, benzofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazole, pyridyl, quinolinyl, pyrimidinyl, piperazinyl, pyrazinyl, furophenyl, thiazolophenyl, pyridoimidazolyl, imidazopyridinyl;
wherein the hydrogen of the aromatic ring of said phenyl, naphthyl, naphthylmethyl, indolyl, benzimidazolyl, imidazophenyl, benzofuranyl, biphenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, quinolinyl, pyrimidinyl, piperazinyl, pyrazinyl, furophenyl, thiazolophenyl, pyridoimidazolyl, imidazopyridinyl, benzyl, phenethyl, naphthylmethyl, picolyl is unsubstituted or each independently substituted with one or more (e.g. 1, 2, 3 or 4) substituents selected from: halogen, amino, hydroxyl, mercapto, nitro, cyano, carboxyl, sulfonyl, arylsulfonamido, trifluoromethyl, 2-imidazolyl, 2-oxazolyl, phenyl, alkyl of 1 to 10 carbon atoms, hydrocarbyloxy of 1 to 10 carbon atoms, hydrocarbylamino of 1 to 10 carbon atoms, alkylsulfonylamino of 1 to 10 carbon atoms, aminoalkyl of 1 to 10 carbon atoms, hydrocarbylthio of 1 to 10 carbon atoms, hydrocarbonyl of 1 to 10 carbon atoms, amido of 1 to 10 carbon atoms, acyloxy of 1 to 10 carbon atoms, acylthio of 1 to 10 carbon atoms, carboxyalkyl of 1 to 10 carbon atoms, or carboxyalkyl of 1 to 10 carbon atoms in the form of the corresponding ester, amide, ammonium salt, sodium salt, potassium salt; each substituent may be the same or different.
In one embodiment of the present invention, the alkyl group is a group including, but not limited to, the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl, phenethyl, phenylpropyl;
the alkenyl group includes, but is not limited to, the following groups: vinyl, n-propenyl, allyl, 1-butenyl, 2-butenyl, isobutenyl;
the alkynyl group includes but is not limited to the following groups: ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl.
In one embodiment of the present invention, the hydrocarbyloxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, isopropenyloxy, propenyloxy, isobutenyloxy, 2-alkenylbutoxy;
the aminoalkyl groups are: aminomethyl, aminoethyl, amino-n-propyl, (2-amino) propyl, amino-n-butyl, (2-amino) butyl, (3-amino) butyl, (2-amino-2-methyl) propyl;
the hydrocarbon amino group is: n-methylamino, N-dimethylamino, N-ethylamino, (N-methyl, N-ethyl) amino, N-diethylamino, N-N-propylamino, N-isopropylamino, (N-methyl, N-N-propyl) amino, N-N-butylamino, N-isobutylamino, N-sec-butylamino, N-tert-butylamino;
the hydrocarbon acyl is: formyl, acetyl, propionyl, levulinoyl, butyryl, isobutyryl, cinnamoyl, maleoyl, fumaroyl, succinyl, pivaloyl;
the amido groups are: methoxycarbonylamino, ethoxycarboxamido, benzyloxycarboxamido, allyloxycarbonylamino, acetylamino, propionylamino, allylamido, butyrylamino, isobutyramido, monosuccinamido, succinimidyl, cinnamoylamino, pivaloylamino;
the acyloxy is methoxy formyloxy, ethoxy formyloxy, benzyloxy formyloxy, allyloxy formyloxy, acetoxyl, propionyloxy, allyloxy, butyryloxy, isobutyryloxy, succinoyloxy, cinnamoyloxy and pivaloyloxy;
the hydrocarbon sulfur base is methylthio, ethylsulfur base, propylsulfur base, isopropylsulfur base, butylsulfur base, vinylsulfur base, propenylthio base, isopropenylsulfur base.
The acylthio is methoxycarbonylthio, ethoxyformylthio, benzyloxyformylthio, allyloxymethylthio, acetylthio, propionylthio, allylylthio, butyrylthio, isobutyrylthio, succinylthio or cinnamoylthio.
In one embodiment of the invention, the acyl group is an acyl group containing 1 to 18 carbon atoms; wherein, the acyl with 1 to 18 carbon atoms is a straight chain, has a side chain, contains heteroatoms, contains unsaturated bonds or has a cyclic structure;
further, the acyl group of 1 to 18 carbon atoms is substituted with an amino group or R at the alpha-position of the carbonyl group 6 Substituted amino substitution; wherein R is 6 Is aliphatic alkyl and acyl; the definition of the aliphatic alkyl and acyl is as described above;
further preferably, the aliphatic hydrocarbon group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl;
acyl includes formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, glycyl, L (or D) -leucyl, L (or D) -valyl, L (or D) -alanyl, L (or D) -isoleucyl, L (or D) -prolyl, L (or D) -hydroxyproliyl, L (or D) -methionyl, L (or D) -threonyl, L (or D) -seryl, L (or D) -cysteinyl, L (or D) -aspartyl-acyl, L (or D) -glutamyl, L (or D) -lysyl, L (or D) -arginyl, L (or D) -phenylalanyl, L (or D) -tryptophanyl, L (or D) -histidyl, L (or D) -tyrosyl, L (or D) -naphthoyl, L (or D) -alanyl;
in one embodiment of the present invention, the substrate is,
r is selected from alkyl of 1-10 carbon atoms, alkenyl of 1-10 carbon atoms, aralkyl of 1-10 carbon atoms, alkylaryl of 1-12 carbon atoms, aryl hydrocarbon of 1-12 carbon atoms, aromatic heterocyclic radical, -OR 10 、-N R 11 R 12 ；
A. B is independently selected from-O-, -NH-and R 6 A substituted amino group,
R 1 、R 2 、R 3 、R 4 each independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 1 to 10 carbon atoms, aralkyl of 1 to 10 carbon atoms, alkylaryl of 1 to 12 carbon atoms, acyl of 1 to 18 carbon atoms;
R 5 、R 6 each independently selected from hydrogen, methyl, acyl of 1 to 18 carbon atoms;
R 10 、R 11 、R 12 each independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, acyl of 1 to 10 carbon atoms;
wherein said alkyl of 1 to 10 carbon atoms, alkenyl of 1 to 10 carbon atoms, aralkyl of 1 to 10 carbon atoms, alkylaryl of 1 to 12 carbon atoms, acyl of 1 to 10 carbon atoms, aryl hydrocarbon of 1 to 12 carbon atoms, arylheterocyclyl, acyl of 1 to 18 carbon atoms, each independently substituted with one or more (e.g., 1, 2, 3, or 4) substituents selected from: hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, methoxy, ethoxy, and the like;
or when A is a nitrogen atom, R 1 Or R 2 Together with a form a 5-membered ring;
or R when B is a nitrogen atom 3 Or R 4 Together with B, form a 5-membered ring.
In a preferred embodiment of the present invention,
r is selected from alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, aralkyl of 1-10 carbon atoms, alkylaryl of 1-12 carbon atoms, aryl hydrocarbon of 1-12 carbon atoms, aromatic heterocyclic radical, -OR 10 、-N R 11 R 12 ；
A. B is independently selected from-O-, -NH-and R 6 A substituted amino group,
R 1 、R 2 、R 3 、R 4 each independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, aralkyl of 1 to 10 carbon atoms, alkylaryl of 1 to 12 carbon atoms, acyl of 1 to 10 carbon atoms;
R 5 、R 6 each independently selected from hydrogen, methyl, acyl of 1-10 carbon atoms;
R 10 、R 11 、R 12 each independently selected from hydrogen, alkyl of 1-4 carbon atoms, acyl of 1-4 carbon atoms
Wherein the content of the first and second substances,
the aromatic heterocyclic group, the alkyl group of 1 to 4 carbon atoms, the alkenyl group of 1 to 4 carbon atoms, the aralkyl group of 1 to 10 carbon atoms, the alkylaryl group of 1 to 12 carbon atoms, the aromatic hydrocarbon group of 1 to 12 carbon atoms, each independently substituted with one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, mercapto, methoxy, ethoxy;
1 to 1 ofAlpha to the carbonyl group in an acyl group having 0 carbon atoms by amino groups or R 6 Substituted amino substitution;
or when A is a nitrogen atom, R 1 Or R 2 Together with A form a 5-membered ring;
or R when B is a nitrogen atom 3 Or R 4 Together with B, form a 5-membered ring.
In a preferred embodiment of the present invention,
r is selected from the group consisting of pyridyl, naphthyl, p-tolyl, hydroxy, methoxy, quinolinyl, benzimidazolyl, imidazophenyl, imidazopyridinyl, pyridoimidazolyl, amino, N-dimethylamino, propionyloxy, N-acetylamino;
A. b is independently selected from-O-, -NH-and R 6 A substituted amino group,
R 1 、R 2 、R 3 、R 4 each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl, phenethyl, p-fluorophenyl methyl, p-methoxybenzyl, p-chlorobenzyl, p-fluorobenzyl, selenomethyl, indolylmethyl, hydroxymethyl, p-hydroxyphenylmethyl, methylmercaptoethyl, imidazolemethyl, aminoacylethyl, thiomethyl, thioethyl, vinyl, propenyl, 1-hydroxyethyl;
R 5 、R 6 selected from the group consisting of hydrogen, methyl, glycyl, L-leucyl, D-leucyl, L-valinyl, D-valinyl, N-methyl-L-valinyl, N- (L-phenylalanyl) -L-prolyl, N- (L-leucyl) -L-leucyl, N- (L-leucyl) -D-leucyl, N- (D-leucyl) -L-leucyl, N- (L-leucyl) -L-valinyl, N- (L-leucyl) -D-valinyl, N-leucyl, L-leucyl, and L-leucyl N- (D-leucyl) -D-valyl, N- (D-leucyl) -L-valyl, L-alanyl, D-alanyl, L-isoleucyl, D-isoleucyl, L-prolyl, D-prolyl, L-hydroxyprolinyl, D-hydroxyprolinyl, L-methionyl, D-methionyl, L-threonyl, D-threonyl, L-seryl, D-seryl, L-cysteinyl, D-cysteinylAcyl, L-aspartyl, D-aspartyl, L-asparagine-acyl, D-asparagine-acyl, L-glutamyl, D-glutamyl, L-glutamine-acyl, D-glutamine-acyl, L-lysyl, D-lysyl, L-arginyl, D-arginyl, L-phenylalanyl, D-phenylalanyl, L-tryptophanyl, D-tryptophanyl, L-histidyl, D-histidyl, L-tyrosyl, D-tyrosyl, L-naphthylalanyl, D-naphthylalanyl, L-quinolinylalaninyl D-quinolinylalaninyl;
or when A is a nitrogen atom, R 1 Or R 2 Together with A form a 5-membered ring;
or R when B is a nitrogen atom 3 Or R 4 Together with B, form a 5-membered ring.
Preferred but not limiting compounds of the invention are the following (table 1), isomers, pharmaceutically acceptable salts or chemically protected forms thereof:
TABLE 1
The invention also provides a preparation method of the compound, wherein the compound shown in the formula I can be prepared through the following reaction route:
when an alcohol, a primary amine or a secondary amine is present in the compound II, the compound of formula I is synthesized by the following scheme I
Route I:
carrying out protection reaction on the compound II to obtain a compound IV, carrying out condensation reaction on the compound III and the compound IV to obtain a compound V, and carrying out deprotection to obtain a target product compound shown as a formula I;
when no alcohol, primary amine or secondary amine is present in compound II, the compound of formula I is synthesized as shown in scheme II
Route II:
and carrying out condensation reaction on the compound II and the compound III to obtain a target product compound shown in the formula I.
The specific conditions of the above-mentioned reaction steps are known in the art, and the present invention is not particularly limited thereto. In light of the teaching of the present invention and the common general knowledge in the art, those skilled in the art can make selective substitutions on each substituent in the general formula to prepare different compounds, and these alternatives and substitutions are all within the scope of the present invention.
The present invention also provides a pharmaceutical composition comprising a compound according to any one of the first aspect of the present invention, an isomer, a pharmaceutically acceptable salt or a chemically protected form thereof, and optionally, one or more pharmaceutically acceptable carriers or excipients.
The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.
Vectors described herein include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, wool fat.
The excipient refers to an additive in the medicinal preparation except the main medicament. The composition has stable properties, no incompatibility with main drug, no side effect, no influence on curative effect, no deformation, crack, mildew, moth-eaten feeling, no harm to human body, no physiological effect, no chemical or physical effect with main drug, no influence on content determination of main drug, etc. Such as binders, fillers, disintegrants, lubricants in tablets; wine, vinegar, medicinal juice, etc. in the Chinese medicinal pill; base portion in semisolid formulations ointments, creams; preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, tonicity adjusting agents, colorants and the like in liquid preparations can all be referred to as excipients.
The compounds of the present invention, isomers, pharmaceutically acceptable salts or chemically protected forms thereof may be administered by the following routes: parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes, or as inhalants. The pharmaceutical compositions may optionally be administered in combination with other agents that have at least some effect in the treatment of various diseases.
The compounds of the present invention, isomers, pharmaceutically acceptable salts or chemically protected forms thereof may be formulated into various suitable dosage forms depending on the route of administration.
In general, an effective amount of a compound of the invention, isomer, pharmaceutically acceptable salt or chemically protected form thereof, contained in a composition of the invention in an amount sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg of body weight/day to about 10,000mg/kg of body weight/day. Suitably, the dose is from about 0.01 mg/kg body weight/day to about 1000mg/kg body weight/day. The dosage range may be about 0.01 to 1000mg/kg of subject body weight per day, every second day or every third day, more usually 0.1 to 500mg/kg of subject body weight. In prophylactic applications, relatively low doses are administered chronically at relatively infrequent intervals. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or halted, and preferably until the individual exhibits a partial or complete improvement in the symptoms of the disease, after which a prophylactic regimen can be administered to the patient.
The invention also provides the use of a compound of any one of the first aspect of the invention, its isomer, pharmaceutically acceptable salt or chemically protected form, or a pharmaceutical composition thereof, in the preparation of medicaments for resisting tumor, aging and the like.
The invention also provides the use of a compound according to any one of the first aspect of the invention, an isomer, a pharmaceutically acceptable salt or a chemically protected form thereof or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of diseases associated with tumour, ageing etc.
The present invention also provides a compound according to any one of the first aspect of the present invention, an isomer, a pharmaceutically acceptable salt or a chemically protected form thereof, or a pharmaceutical composition thereof, for use in the treatment of diseases associated with tumor, aging and the like.
The present invention also provides a method of treating diseases associated with tumor, aging, etc., which comprises administering to a subject in need thereof an effective amount of a compound according to any one of the first aspect of the present invention, its isomer, pharmaceutically acceptable salt or chemically protected form or pharmaceutical composition thereof.
The tumor in the anti-tumor of the invention is prostate cancer tumor and melanoma.
The "pharmaceutically acceptable salt" of the present invention includes conventional salts with pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases. Examples of suitable acid forming salts include salts formed from hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, trifluoroacetic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, maleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic, p-toluenesulfonic, hydroxynaphthoic, hydroiodic, malic, mandelic, gluconic, tannic and the like. Examples of suitable base forming salts include sodium, potassium, magnesium, lithium, aluminum, calcium, zinc, N' -dibenzylethylenediamine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and the like.
The steroid compound of the invention has obvious inhibition effect on tumors and shows good anticancer activity on prostate cancer inhibition. When the compound is used for treating the prostatic cancer, the compound is beneficial to improving and reducing the toxicity to the liver and the toxicity to the heart, improving the bioavailability, reducing the administration dosage and improving the administration safety. In addition, the steroid compound of the invention has the function of obviously prolonging the life of organisms.
Detailed Description
The invention will be further elucidated with reference to the following examples, without the scope of the invention being limited thereto. The percentages stated in the present invention are percentages by weight, unless otherwise indicated.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are commercially available, and are not indicated by manufacturers.
The structure of the compound is determined by nuclear magnetic resonance 1 HNMR). 1 The HNMR is measured by a JEOL Eclipse 400 nuclear magnetic instrument, the measuring solvent is deuterated chloroform, the internal standard is Tetramethylsilane (TMS), and the chemical shift is given by taking 10-6 (ppm) as a unit;
preparation of high performance liquid phase liquid chromatograph was prepared using shimadzu LC-8A.
Thin layer chromatography silica gel plate (TLC) an aluminum plate (20X 20 cm) from Merck was used, and the specification for separation and purification by thin layer chromatography was GF 254.
The reaction was monitored by Thin Layer Chromatography (TLC) or LCMS using the following developer systems: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent is regulated according to different polarities of the compounds or by adding triethylamine and the like.
The column chromatography generally uses 200-300 mesh silica gel as a carrier. The system of eluents comprises: the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of triethylamine can be added for adjustment.
In the examples, the reaction temperature is room temperature (20 ℃ to 35 ℃);
the reagent used in the present invention was purchased from the national chemical group, aladdin reagent, inc.
In the conventional syntheses as well as examples and intermediate syntheses, the meanings of the abbreviations are as follows:
HOBt: 1-hydroxybenzotriazoles
DCC dicyclohexylcarbodiimide
DCM: methylene dichloride
DIEA: n, N-diisopropylethylamine
Gly: glycine
Leu: leucine and its use as a pharmaceutical
Val: valine
Ala: alanine
Phe: phenylalanine
Pro: proline
Boc: a tert-butoxycarbonyl group;
general procedure A (when R 5 When hydrogen):
adding 1mmol of compound III, 1mmol of compound IV, 1.5mmol of DCC and 1.5mmol of HOBt into a reaction bottle filled with 25mL of dichloromethane, dropwise adding 3mmol of DIPEA under stirring at normal temperature, and continuing stirring at normal temperature for 10 hours after dropwise adding. After the reaction was completed, methylene chloride was removed under reduced pressure,the residue was taken up in 100mL of water, adjusted to pH 7 with 10% hydrochloric acid, extracted with dichloromethane, the organic phases combined, anhydrous Na 2 SO 4 Drying, filtering, decompressing the filtrate to remove the solvent, and purifying the residue by silica gel column chromatography to obtain an intermediate compound V.
The intermediate compound V is dissolved in 10mL of methanol, 0.1g of 5% palladium on carbon is added, and hydrogen is introduced under normal pressure until the reaction is completed. Filtering, decompressing and removing the solvent to obtain the target product compound I with the yield of 28-85 percent.
Synthesis of general procedure B (when R is 5 When not hydrogen):
adding 1mmol of compound II, 1mmol of compound III, 1.5mmol of DCC and 1.5mmol of HOBt into a reaction bottle filled with 25mL of dichloromethane, dropwise adding 3mmol of DIPEA under normal temperature stirring, and continuing to stir at normal temperature for 10 hours after dropwise adding. After the reaction was complete, the dichloromethane was removed under reduced pressure, 100mL of water were added to the residue, the pH was adjusted to 7 with 10% hydrochloric acid, extraction was carried out with dichloromethane, the organic phases were combined and Na anhydrous 2 SO 4 And (5) drying. Filtering, decompressing the filtrate to remove the solvent, and purifying the remainder by silica gel column chromatography to obtain the target product compound I with the yield of 13-70%.
Example 1 Synthesis of Compound 1
Synthesized from 1mmol abiraterone, 1mmol Bn-Gly-Gly-COOH, 1.5mmol DCC and 1.5mmol HOBt,0.1g Pd on carbon by the general method A to obtain the title compound with a yield of 78%.
1H NMR(500MHz,CDCl3),δ：8.61(d,J＝2Hz,1H),8.46-8.45(m,1H),7.69(s,1H),7.65-7.63(m,1H),7.23-7.20(m,1H),5.99-5.98(m,1H),5.42(d,J＝5Hz,1H),4.72-4.66(m,1H),4.06(d,J＝5Hz,2H),3.41(s,2H),2.37(d,J＝7Hz,2H),2.28-2.24(m,1H),2.09-2.02(m,3H),1.89-1.86(m,2H),1.78-1,46(m,9H),1.25-1.04(m,8H)。
Example 2 Synthesis of Compound 2
Synthesized by 1mmol of abiraterone, 1mmol of Bn-L-Ala-Gly-COOH, 1.5mmol of DCC and 1.5mmol of HOBt, and 0.1g of palladium on carbon according to general method A, the title compound was obtained with a yield of 70%.
1H NMR(500MHz，CDCl3),δ：8.62(d,J＝2Hz,1H),8.46-8.45(m,1H),7.72(s,1H),7.65-7.63(m,1H),7.23-7.20(m,1H),6.00-5.99(m,1H),5.42(d,J＝5Hz,1H),4.71-4.67(m,1H),4.05-3.98(m,2H),3.56-3.53(m,1H),2.37(d,J＝7Hz,2H),2.29-2.24(m,1H),2.09-2.02(m,3H),1.91-1.86(m,2H),1.47-1.78(m,9H),1.36(d,J＝7Hz，3H)，1.25-1.04(m,8H)。
Example 3 Synthesis of Compound 3
Synthesized from 1mmol of abiraterone, 1mmol of Bn-L-Leu-Gly-COOH, 1.5mmol of DCC and 1.5mmol of HOBt, and 0.1g of palladium on carbon by the general method A, the title compound was obtained with a yield of 65%.
1H NMR(500MHz，CDCl3),δ：8.62(d,J＝5Hz,1H),8.46-8.45(m,1H),7.73(s,1H),7.65-7.63(m,1H),7.23-7.20(m,1H),6.00(s,1H),5.42(d,J＝7Hz,1H),4.71-4.66(m,1H),4.03-4.01(m,2H),3.45-3.42(m,1H),2.37(d,J＝7Hz,2H),2.29-2.24(m,1H),2.10-2.02(m,3H),1.92-1.86(m,2H),1.78-1.36(m,12H),1.19-1.05(m,8H),0.95(dd,J＝6.5HzJ＝15Hz,6H)。
Example 4 Synthesis of Compound 4
Synthesized from 1mmol of abiraterone, 1mmol of Bn-L-Val-Gly-COOH, 1.5mmol of DCC and 1.5mmol of HOBt, and 0.1g of palladium on carbon by the general method A, the title compound was obtained with a yield of 85%.
1HNMR(500MHz,CDCl3),8.62(s,1H),8.46(s,1H),7.76(s,1H),7.64(d,J＝8Hz,1H),7.23-7.21(m,1H),6.00-5.99(m,1H),5.42(d,J＝4.5Hz,1H),4.71-4.67(m,1H),4.08-3.98(m,2H),3.31(s,1H),2.37(d,J＝7.5Hz,2H),2.32-2.24(m,2H),2.09-2.02(m,3H),1.91-1.85(m,2H),1.78-1,46(m,9H),1.18-1.00(m,11H),0.88(d,J＝4Hz,3H)。
Example 5 Synthesis of Compound 9
Synthesized by 1mmol of abiraterone, 1mmol of N, N-Di-CH3-D-Val-Gly-COOH, 1.5mmol of DCC and 1.5mmol of HOBt by the general method B to obtain white solid with the yield of 33 percent.
1HNMR(500MHz,CDCl3),8.62(s,1H),8.46(s,1H),7.76(s,1H),7.64(d,J＝8Hz,1H),7.23-7.21(m,1H),6.00-5.99(m,1H),5.42(d,J＝4.5Hz,1H),4.71-4.67(m,1H),4.08-3.98(m,2H),3.31(s,1H),2.37(d,J＝7.5Hz,2H),2.32-2.24(m,8H),2.09-2.02(m,3H),1.91-1.85(m,2H),1.78-1,46(m,9H),1.18-1.00(m,11H),0.88(d,J＝4Hz,3H)。
Example 6 Synthesis of Compound 15
Synthesized by 1mmol of abiraterone, 1mmol of N-CH3-Bn-D-Val-Gly-COOH, 1.5mmol of DCC and 1.5mmol of HOBt and 0.1g of palladium carbon according to the method A to obtain white solid with the yield of 33 percent.
1H NMR(500MHz，CDCl3),δ：8.62(d,J＝2Hz,1H),8.46-8.45(m,1H),7.72(s,1H),7.65-7.63(m,1H),7.23-7.20(m,1H),6.00-5.99(m,1H),5.42(d,J＝5Hz,1H),4.71-4.67(m,1H),4.16(s,2H)4.05-3.98(m,2H),3.56-3.53(m,1H),2.37(d,J＝7Hz,2H),2.29-2.24(m,1H),2.09-2.02(m,4H),1.91-1.86(m,2H),1.47-1.78(m,10H),1.36(d,J＝7Hz，3H)，1.25-1.04(m,10H)。
Example 7 Synthesis of Compound 16
Synthesized by 1mmol of abiraterone, 1mmol of Bn-Gly-D-Ala-Gly-COOH, 1.5mmol of DCC and 1.5mmol of HOBt and 0.1g of palladium carbon according to the general method A, white solid is obtained, and the yield is 41%.
1HNMR(500MHz,CDCl3),8.62(s,1H),8.46(d,1H),8.03(s,2H),7.76(d,1H),7.64(m,1H),6.00-5.99(m,1H),5.42(m,1H),4.71(m,1H),4.08-3.98(m,3H),3.54(s,2H),2.37(d,J＝7.5Hz,2H),2.32-2.24(m,2H),2.09-2.02(m,3H),1.91-1.85(m,2H),1.78-1,46(m,7H),1.18-1.00(m,9H),0.88(d,J＝4Hz,3H)。
Example 8 Synthesis of Compound 18
Synthesized by 1mmol of abiraterone, 1mmol of Bn-L-Val-Gly-Gly-COOH, 1.5mmol of DCC and 1.5mmol of HOBt and 0.1g of palladium carbon according to a general method A to obtain a white solid with the yield of 41 percent.
1H NMR(500MHz,CDCl3),δ：8.61(d,J＝2Hz,1H),8.46-8.45(m,1H),7.69(s,1H),7.65-7.63(m,1H),7.23-7.20(m,1H),5.99-5.98(m,1H),5.42(d,J＝5Hz,1H),4.16(m,2H),4.06(d,J＝5Hz,2H),3.99(m,1H),3.41(s,2H),2.37(d,J＝7Hz,2H),2.28-2.24(m,2H),2.09-2.02(m,3H),1.89-1.86(m,2H),1.78-1,46(m,9H),1.25-1.04(m,14H)。
Example 9 Synthesis of Compound 25
Synthesized by 1mmol of abiraterone, 1mmol of N-benzyl-L-cysteinyl-2-phenethylglycine, 1.5mmol of DCC and 1.5mmol of HOBt and 0.1g of palladium carbon according to the general method A to obtain white solid with the yield of 40 percent.
1H NMR(500MHz,CDCl3),δ：8.48(s,1H),8.33(d,1H),8.03(s,1H),7.70(d,1H),7.40-7.29(m,5H),5.99-5.98(m,1H),5.42(d,J＝5Hz,1H),4.52(t,1H),3.99(m,1H),3.88(m,1H),3.19(m,1H),2.94(m,1H),2.55(t,2H),3.41(s,2H),2.28-2.24(m,3H),2.09-2.02(m,3H),1.89-1.86(m,2H),1.78-1,46(m,9H),1.25-1.04(m,8H)。
Example 10 Synthesis of Compound 28
Synthesized by gamma-ionone 1mmol, bn-Gly-Gly-COOH 1mmol, DCC 1.5mmol, HOBt 1.5mmol, and palladium 0.1g on carbon according to general method A to obtain a white solid with a yield of 36%.
1H NMR(500MHz,CDCl3),δ：8.18(s,1H),8.03(t,1H),7.76(d,1H),7.46(s,1H),7.07(d,1H),5.99-5.98(m,1H),5.42(m,1H),5.0(m,1H),4.16(s,2H),3.99(m,1H),3.8(m,1H),3.37-3.33(m,2H),2.12-2.08(m,2H),2.09-2.02(m,3H),1.89-1.86(m,2H),1.78-1,46(m,9H),1.25-1.04(m,8H)。
Example 11 Synthesis of Compound 38
Synthesized by general method A from 1mmol of III (R = acetylamino), 1mmol Bn-Gly-Gly-COOH, 1.5mmol DCC and 1.5mmol HOBt,0.1g palladium on carbon to give the title compound in 78% yield.
1H NMR(500MHz,CDCl3),δ：8.03-8.0(m,2H),5.37(t,1H),5.03(t,1H),4.16(s,2H),3.99(m,1H),3.80(s,2H),2.37-2.33(m,3H),2.12-2.08(m,3H),1.86(s,3H),1.78-1,46(m,9H),1.25-1.04(m,8H)。
Test example 12 mouse prostate cancer model test
SPF-grade KM mice, male, 6-7 weeks old, and 15-20g in body weight. The mice were divided into tumor-bearing control group and administration group, RM-1 cells in logarithmic growth phase were collected, seeded at a cell density of 5X 106cells/mL, and the right anterior axilla of the mice were swabbed with 75% alcohol, 0.2mL each. After tumorigenesis, 200 mu l of normal saline is orally injected into a tumor-bearing control group every day, 0.04mg/g of abiraterone acetate and 0.04mg/g of an abiraterone derivative are orally injected into an administration group, a neck is removed after 30 days of administration, mice are killed, subcutaneous tumors are separated and weighed. Tumor weight of a group of rats treated with drug was compared with tumor weight of a tumor-bearing control group to calculate percent tumor inhibition. The results are shown in Table 2.
Tumor inhibition rate% = (tumor weight of tumor-bearing control group-tumor weight of compound sample)/tumor weight of tumor-bearing control group = 100%
TABLE 2 inhibition of prostate cancer in mice
| Compound (I) | Tumor weight (g) | Percent of tumor inhibition |
| Tumor-bearing control group | 5 | -- |
| Compound 1 | 2 | 60％ |
| Compound 2 | 3 | 40％ |
| Compound 3 | 1.3 | 74％ |
| Compound 4 | 1.7 | 66％ |
| Compound 15 | 2.8 | 44％ |
| Compound 16 | 3 | 40％ |
| Compound 18 | 2.5 | 50％ |
| Compound 25 | 2.4 | 52％ |
| Compound 28 | 3.3 | 34％ |
| Compound 38 | 2 | 60％ |
| Abiraterone acetate | 3.5 | 30％ |
The data of the prostate cancer inhibition test of mice in table 2 show that the prostate cancer inhibition rates of the compound 1, the compound 2, the compound 3, the compound 4, the compound 15, the compound 16, the compound 18, the compound 25, the compound 28 and the compound 38 of the present invention are greater than 34% relative to the 30% of abiraterone, and the prostate cancer inhibition rates of the compound 1, the compound 3, the compound 4, the compound 18, the compound 25 and the compound 38 are greater than 50%, which shows superior prostate cancer inhibition effects.
Other compounds of the invention also have similar tumor suppression effects as those described above.
Test example 13 mouse melanoma model test
SPF-grade KM mice, male, 6-7 weeks old, and 15-20g in body weight. The mice were divided into tumor-bearing control group and administration group, B16 cells in logarithmic growth phase were collected, seeded at a cell density of 5X 106cells/mL, and the right anterior limb armpit of the mice was swabbed with 75% alcohol, 0.2mL each injection. After tumorigenesis, 200 mu l of normal saline is orally injected into a tumor-bearing control group every day, 0.04mg/g of abiraterone acetate and 0.04mg/g of an abiraterone derivative are orally injected into an administration group, a neck is removed after 30 days of administration, mice are killed, subcutaneous tumors are separated and weighed. The tumor weights of the drug-treated group of mice were compared to the tumor weight of the tumor-bearing control group to calculate the percent tumor inhibition. The results are shown in Table 3.
Tumor inhibition rate% = (tumor weight of tumor-bearing control group-tumor weight of compound sample)/tumor weight of tumor-bearing control group = 100%
TABLE 3 mouse melanoma inhibition
| Compound (I) | Tumor weight (g) | The tumor inhibition rate% |
| Tumor-bearing control group | 6 | -- |
| Compound 1 | 2.5 | 58％ |
| Compound 2 | 3.1 | 48％ |
| Compound 3 | 1.5 | 75％ |
| Compound 4 | 1.7 | 72％ |
| Compound 15 | 3 | 50％ |
| Compound 16 | 3 | 50％ |
| Compound 18 | 3.5 | 42％ |
| Compound 25 | 2.7 | 52％ |
| Compound 28 | 3.5 | 38％ |
| Compound 38 | 2.2 | 63％ |
| Abiraterone | 4 | 33％ |
As shown in table 3, the melanoma inhibitory test data of mice showed that the melanoma inhibitory rates of the compound 1, the compound 2, the compound 3, the compound 4, the compound 15, the compound 16, the compound 18, the compound 25, the compound 28 and the compound 38 of the present invention were more than 38% relative to the 33% melanoma inhibitory rate of abiraterone, and the melanoma inhibitory rates of the compound 1, the compound 3, the compound 4, the compound 15, the compound 16, the compound 25 and the compound 38 were more than 50%, which showed superior melanoma inhibitory effects.
Other compounds of the invention also have similar tumor suppression effects as those described above.
Test example 14, caenorhabditis elegans anti-aging test
Selecting 50C L4-stage C.elegans of each group which are synchronized by referring to a report method of Wangliping and the like (anti-aging effect of emblic leafflower fruits on C.elegans, journal of Jilin university (science edition), 2018,3, 738-742), and selecting the groups to which the medicine is added; nematodes were scored as 0d starting from the synchronized egg and the day of dosing was based on nematode age. As the nematode can continuously lay eggs to 8d, in the initial administration period, namely the L4 period, in order to prevent the development of eggs and larvae from interfering with the determination, the nematodes with the determination are picked into a new plate every day; NGM plates were incubated in an incubator at 20 ℃. Picking the adult insects into a new plate once every two days after the adult insects do not lay eggs any more; when the nematode did not react to the picker by repeated gentle touch, the nematode was scored as dead. When the nematode is dead on climbing the wall or dead due to the insect bag, the nematode is recorded as lost; the insects were picked each day until all died. The life test was repeated three more times. The test results are as follows:
TABLE 4 Effect of Compounds on nematode longevity at 2mg/mL concentration
The data in Table 4 show that the compound 4, the compound 5, the compound 28 and the compound 32 can prolong the life of the nematode by more than 8 percent; the compound 4 and the compound 32 can prolong the service life of the nematodes by more than 16%, which shows that the compounds 4, 5, 28 and 32 have an anti-aging effect on the nematodes;
other compounds of the invention also have anti-aging effects similar to those described above.
Claims (5)
1. A compound of formula I, or a pharmaceutically acceptable salt thereof;
wherein the formula I is selected from the following compounds:
2. a process for the preparation of a compound according to claim 1, comprising the steps of:
when an alcohol, a primary amine or a secondary amine is present in compound II, the compound of formula I is synthesized as shown in scheme I
Route I:
carrying out protection reaction on the compound II to obtain a compound IV, carrying out condensation reaction on the compound III and the compound IV to obtain a compound V, and carrying out deprotection to obtain a target product compound shown as a formula I;
when no alcohol, primary amine or secondary amine is present in compound II, the compound of formula I is synthesized as shown in scheme II
Route II:
and carrying out condensation reaction on the compound II and the compound III to obtain a target product compound shown in the formula I.
3. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof; and optionally, one or more pharmaceutically acceptable carriers or excipients.
4. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3, in the manufacture of an anti-aging medicament.
5. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3, in the preparation of an anti-neoplastic drug; the tumor is prostate cancer tumor and melanoma.
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