CN112851679A - 2, 4, 7-trisubstituted pyrimidoindole compound with antitumor effect - Google Patents
2, 4, 7-trisubstituted pyrimidoindole compound with antitumor effect Download PDFInfo
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Abstract
The invention relates to a series of 2, 4, 7-trisubstituted pyrimidoindole structural compounds, which can inhibit the growth of various tumor cells, and particularly can efficiently inhibit the proliferation of breast cancer, cervical cancer, gastric adenocarcinoma and liver cancer cells. In addition, the compound of the invention can inhibit the clonogenic formation of tumor cells and promote the apoptosis of tumor cells at very low concentration. The invention also relates to a preparation method of the compound and application of the compound in marking, diagnosing, preventing and treating or assisting treatment of tumors.
Description
Technical Field
The invention relates to a 2, 4, 7-trisubstituted pyrimidoindole compound, a preparation method thereof and application thereof in preventing and/or treating tumors.
Background
Malignant tumor is the first of ten common diseases in China, and seriously threatens the life of human beings. The morbidity of the medicine is increased year by year, and the mortality rate is more than 20 percent. In clinical treatment, surgery, radiotherapy and chemotherapy become basic means for treating tumors and have certain treatment effect on the tumors. However, the existing chemotherapy drugs in clinical application still have the problems of great adverse reaction, easy generation of drug resistance in long-term application and the like. Therefore, the search for anticancer drugs with good curative effect, low adverse reaction and long-term curative effect is an important subject of the current anticancer drug research.
In recent years, the research and development focus of people is also shifted from traditional cytotoxic drugs to targeted antitumor drugs. The targeted therapy can target the tumor site to kill the tumor cells with high selectivity aiming at the difference between normal cells and tumor cells. However, the targeted antitumor drug has the disadvantages of narrow adaptation, high price, easy generation of drug resistance and the like, so the broad-spectrum antitumor drug is still the mainstream drug of the clinical antitumor therapy at present.
The compound is a 2, 4, 7-trisubstituted pyrimidoindole structure, can inhibit the growth of various tumor cells, and particularly can efficiently kill breast cancer, cervical cancer, gastric adenocarcinoma and liver cancer cells. In addition, the compound of the invention can inhibit the clonogenic formation of tumor cells at very low concentrations, which has important clinical significance for inhibiting the growth of cancers. Therefore, the compounds have wide application prospects in marking, diagnosis, prevention and treatment or adjuvant therapy of tumors.
Disclosure of Invention
The invention mainly relates to a 2, 4, 7-trisubstituted pyrimidoindole compound, a preparation method thereof and application thereof in preventing and/or treating tumors.
The invention also provides processes and intermediates useful for preparing the compounds of the invention.
The invention also provides compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the invention or isomers, prodrugs, pharmaceutically acceptable salts, or solvates thereof.
The compounds of the present invention are useful for the prevention and/or treatment of cancer and its related disorders.
The compound can be used for preparing a pharmaceutical composition for preventing and/or treating tumors.
The compounds of the invention are useful for killing tumor cells.
The compounds of the invention are useful for inhibiting clonogenic formation of tumor cells.
The compounds of the invention are useful for promoting apoptosis of tumor cells.
The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more (preferably one to two) other drugs.
These and other features of the present invention will be presented in expanded form as the present disclosure continues.
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FIG. 1 Effect of XH003 Compound on the clonogenic potency of the breast cancer cell line MCF-7
Detailed Description
I. Definition of
As used above and throughout the specification of the present invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
the term "compounds of the invention" and equivalent expressions are intended to include the compounds of structural formula I as described hereinabove, which expressions include prodrugs, pharmaceutically acceptable salts and solvates, e.g. hydrates, as permitted hereinabove. Similarly, for intermediates, whether or not they are claimed per se, they are intended to include their salts and solvates (when the context permits). For clarity, specific examples are sometimes indicated herein when the context permits, but these examples are purely illustrative and are not intended to exclude other examples when the context permits.
The term "alkyl" means a straight or branched chain aliphatic hydrocarbon group which may have from about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, methylene, ethyl or propyl are attached to a linear alkyl chain. Examples of alkyl groups include methyl, methylene, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and 3-pentyl.
The term "alkoxy" refers to an alkyl-O-group, wherein the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.
The term "aryl" means a monocyclic or polycyclic ring system of 6 to about 14 carbon atoms, preferably 6 to about 10 carbon atoms. Representative aryl groups include phenyl and naphthyl.
The term "heteroaryl" means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the atoms in the ring system is an element other than carbon, such as nitrogen, oxygen or sulfur. In the case of polycyclic ring systems, since the ring system is defined as "heteroaryl", only one ring must be aromatic. Preferred heteroaryl groups contain about 5 to 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen atom of the heteroaryl group is optionally oxidized to the corresponding N-oxide. Representative heteroaryl groups include pyridyl, 2-oxo-pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, dihydroindolyl, 2-oxodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzo [1, 3] dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, 2, 3-dihydro-benzo [1, 4] dioxinyl, Benzo [1, 2, 3] triazinyl, benzo [1, 2, 4] triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6 aH-thieno [2, 3-d ] imidazolyl, 1H-pyrrolo [ [2, 3-b ] pyridyl, imidazo [1, 2-a ] pyridyl, pyrazolo [1, 5-a ] pyridyl, [1, 2, 4] triazolo [4, 3-a ] pyridyl, [1, 2, 4] triazolo [1, 5-a ] pyridyl, thieno [2, 3-b ] furyl, thieno [2, 3-b ] pyridyl, thieno [3, 2-b ] pyridyl, furo [2, 3-b ] pyridyl, furo [3, 2-b ] pyridyl, thieno [3, 2-d ] pyrimidyl, and, Furo [3, 2-d ] pyrimidinyl, thieno [2, 3-b ] pyrazinyl, imidazo [1, 2-a ] pyrazinyl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a ] pyrazinyl, 6, 7-dihydro-4H-pyrazolo [5, 1-c ] [1, 4] oxazinyl, 2-oxo-2, 3-dihydrobenzo [ d ] oxazolyl, 3-dimethyl-2-oxoindolinyl, 2-oxo-2, 3-dihydro-1H-pyrrolo [ [2, 3-b ] pyridinyl, benzo [ c ] [1, 2, 5] oxadiazolyl, benzo [ c ] [1, 2, 5] thiadiazolyl, 3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazinyl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a ] pyrazinyl, 3-oxo- [1, 2, 4] triazolo [4, 3-a ] pyridin-2 (3H) -yl and the like.
The term "non-aromatic heterocyclic ring" means a non-aromatic monocyclic ring system containing 3 to 10 atoms, preferably 4 to about 7 carbon atoms, wherein one or more of the atoms in the ring system is an element other than carbon, such as nitrogen, oxygen or sulfur. Representative non-aromatic heterocyclic groups include pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1-dioxothiomorpholino, piperazinyl, tetrahydro-2H-oxazinyl and the like.
The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo.
The term "substituted" or "substitution" of an atom means that one or more hydrogens on the designated atom is replaced with a substituent selected from the designated group, provided that the designated atom's normal valence is not exceeded. As referred to herein, the term "(substituted)" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valency is maintained and that the substitution results in a stable compound. When the substituent is a keto group (i.e., ═ O), then 2 hydrogens on the atom are replaced. The keto substituent is not present on the aromatic moiety. When referring to a ring system (e.g., carbocyclic or heterocyclic) substituted with a carbonyl group or a double bond, it is meant that the carbonyl group or double bond is part of the ring (i.e., within the ring). As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C-C, C-N or N-N).
Where a nitrogen atom (e.g., an amine) is present on a compound of the invention, it may be converted to an N-oxide by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to yield other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass the nitrogen shown and its N-oxide (N → O) derivatives.
The term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic acid addition salts, and base addition salts, of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts may be prepared by separately reacting the purified compound in free base form with a suitable organic or inorganic acid and isolating the salt so formed. Exemplary acid addition Salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphylate, mesylate, glucoheptonate, lactobionate (1 actibionate), sulfamate, malonate, salicylate, propionate, methylene-bis-b-hydroxynaphthoate, gentisate, isothionate, ditoluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinic acid lauryl sulfonate (quinateslaurylsulfate) and the like (see, e.g., Berge et al, "Pharmaceutical Salts", j.pharm.sci., 66: 1-9(1977) and Remington's Pharmaceutical Sciences, 17 th edition, MackPublishing Company, Easton, Pa., 1985, page 1418, hereby incorporated by reference in its entirety). Base addition salts may also be prepared by separately reacting the purified acid form of the compound with a suitable organic or inorganic base and isolating the salt so formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminium salts. Sodium and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide. Suitable amine base addition salts are prepared from amines which are sufficiently basic to form stable salts, and preferably include those amines commonly used in medicinal chemistry due to their low toxicity and acceptability for pharmaceutical use, examples of such amines include ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylhydroxymethylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, dicyclohexylamine, and the like.
The term "pharmaceutically acceptable prodrug" means a prodrug of a compound that can be used in accordance with the present invention, and, where possible, the zwitterionic form of the compound of the present invention, which prodrug, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for the intended use. The term "prodrug" means a compound that is rapidly transformed in vivo, for example by hydrolysis in blood, to yield the parent compound of the above formula. Functional groups that can be rapidly converted by metabolic cleavage in vivo form a class of groups that react with the carboxyl groups of the compounds of the present invention. The functional group includes, but is not limited to, groups such as alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), unsubstituted and substituted aroyl (e.g., benzoyl and substituted benzoyl), alkoxycarbonyl such as ethoxycarbonyl), trialkylsilyl (e.g., trimethyl and triethylsilyl), monoesters with dicarboxylic acids (e.g., succinyl), and the like. Since the metabolically cleavable group of the compounds useful in the present invention is readily cleaved in vivo, compounds bearing such a group may act as prodrugs. Compounds carrying metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of the improved solubility and/or absorption rate imparted to the parent compound by the presence of the metabolically cleavable group. The following documents provide a thorough discussion of prodrugs: design of Prodrugs, H.Bundgaard eds, Elsevier (1985); methods in Enzymology, K.Widder et al, Academic Press, 42, 309 & 396 (1985); a Textbook of Drug design Development, Krogsgaard-Larsen and H.Bundgaard eds, Chapter 5; "Design and applications of precursors" page 113 and 191 (1991); advanced Drug Delivery Reviews, h.bundgard, 8, pages 1-38 (1992); journal of Pharmaceutical Sciences, 77: 285 (1988); nakeya et al, chem.pharm.bull, 32: 692 (1984); higuchi et al, "Pro-drugs as novelderly Systems", volume 14 of a.c.s.symposium Series, and Bioreversible carrier in drug design, Edward b.roche editors, American Pharmaceutical Association and pergammonpress (1987), which are incorporated herein by reference in their entirety. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
The term "pharmaceutical composition" means a composition comprising a compound of formula (I) and, depending on the mode of administration and on the nature of the dosage form, at least one pharmaceutically acceptable ingredient selected from the group consisting of: carriers, diluents, adjuvants, excipients or excipients, for example preservatives, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example sugars, sodium chloride and the like are preferably included. Prolonged absorption of the injectable form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Examples of suitable carriers, diluents, solvents or excipients include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (e.g. olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, sodium citrate, calcium carbonate, dicalcium phosphate. Examples of disintegrants include starch, alginic acid and some complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycols.
The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable dosage form" means a dosage form of the compounds of the present invention, including, for example, tablets, troches, powders, elixirs, syrups, liquid preparations (including suspensions, sprays, inhalation tablets, lozenges, emulsions, solutions, granules, capsules, and suppositories), and liquid preparations for injection, including liposomal preparations. Formulation techniques and formulations are generally found in Remington's pharmaceutical Science, Mack Publishing co., Easton, PA, latest edition.
Preferred embodiments of the invention
In one aspect, the present invention provides a compound, or isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, selected from:
2-benzyl-4- (6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline-2-ethylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoline (XH003),
2-benzyl-4- (3-chloro-4-fluorophenylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoline (A001),
2-benzyl-4- (indole-3-ethylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] indole (A002),
2-benzyl-4- (4-hydroxyphenylethylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] oxindole (A003),
2-benzyl-4- (trans-4-hydroxycyclohexylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] oxindole (A004),
2-benzyl-4- (4-chloro-2-methylphenylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoline (A005),
2-benzyl-4- (3, 4-dimethoxyphenethylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] indole (A006),
2-benzyl-4- (4-methoxybenzene ethylamino) -7- (2-methyl tetrazole-5-yl) pyrimidine [4, 5] indole (A007),
2-benzyl-4- (3-ethynylphenylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] oxindole (A008),
2-benzyl-4- (4-tetrahydropyranylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] oxindole (A009),
2-benzyl-4- (dimethylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoles (A010).
The structural formula is shown as the following formula:
in one aspect, the present invention provides a compound selected from any subset list of compounds within the scope of the illustrative embodiments, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof.
III, other embodiments of the invention
In another embodiment, the present invention provides a pharmaceutical composition comprising a process for the preparation of at least one compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, comprising the steps of:
1)
2)
3)
4)
5)
6)
7) carrying out substitution reaction on the product obtained in the step 6) and an appropriately substituted amino group to obtain a corresponding final product.
In another embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the invention or its isomer, prodrug, pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides a pharmaceutical composition further comprising an additional therapeutic agent.
In another embodiment, the present invention provides a process for preparing a compound of the present invention.
In another embodiment, the present invention provides a process for preparing an intermediate of the compounds of the present invention.
In another embodiment, the present invention provides a method for the prevention and/or treatment of a cancer-related disorder, said method comprising administering to a patient in need of such prevention and/or treatment a therapeutically effective amount of at least one compound of the present invention or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof; optionally, the cancer is selected from one or more of breast cancer, cervical cancer, gastric cancer, and liver cancer.
In another embodiment, the present invention provides a therapeutic method for preventing and/or treating a cancer-related disorder using a compound of the present invention or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the present invention provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the prevention and/or treatment of a cancer-related disorder.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for inhibiting the growth of and/or killing tumor cells.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for inhibiting the growth of and/or killing breast cancer cells.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for inhibiting the growth of and/or killing cervical cancer cells.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for inhibiting gastric cancer cells and/or killing gastric cancer cell growth.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for inhibiting the growth of and/or killing liver cancer cells.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for inhibiting tumor cell clonogenic.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for inhibiting breast cancer cell clonogenesis.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for inhibiting the clonogenic formation of cervical cancer cells.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for inhibiting gastric cancer cell clonality.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for inhibiting the clonogenic formation of liver cancer cells.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for promoting apoptosis of tumor cells.
In another embodiment, the present invention also provides the use of a compound of the present invention, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for promoting apoptosis of breast cancer cells.
In another embodiment, the present invention also provides the use of a compound of the present invention or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for promoting apoptosis of cervical cancer cells.
In another embodiment, the present invention also provides the use of a compound of the present invention or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for promoting gastric cancer cell apoptosis.
In another embodiment, the present invention also provides the use of a compound of the present invention or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for promoting apoptosis of liver cancer cells.
The compound of the general formula (xvii) of the present invention can be produced by various known methods, and is not particularly limited.
Embodiments of the present invention will be described in detail with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
IV, specific examples
Example 1: synthesis of 2-benzyl-4- (6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline-2-ethylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indole (XH003)
1.15 Synthesis of (3-nitrophenyl) tetrazole (B001)
30.0g (202.69mmol) of m-nitrobenzonitrile, 14.5g (222.96mmol) of sodium azide and 45.7g (202.69mol) of zinc bromide are put into a 1000ml flask, 500ml of water is added, the mixture is refluxed and reacted for 24h at 100 ℃, then the temperature is reduced to room temperature, reaction liquid is poured into 500ml of water, 100ml of 3N hydrochloric acid is added, ethyl acetate (3 multiplied by 200ml) is used for extraction, an organic phase is collected, ethyl acetate is dried in a decompression mode to obtain white solid, 800ml of 0.25mol/L NaOH is added, stirring is carried out, white flocculent zinc hydroxide is re-precipitated after the solid is dissolved, suction filtration is carried out, the pH of filtrate is adjusted to 5 by 3.0mol/L of hydrochloric acid, a large amount of white solid is precipitated, 34.8g of dried white product is obtained, and the yield is 90%.
The structure of the product is confirmed:1H NMR(DMSO-d6，ppm)δ8.85-8.86(t，1H)，8.48-8.51(dt，1H)， 8.43-8.46(dq，1H)，7.91-7.95(t，1H)。
synthesis of 1.22-methyl-5- (3-nitrophenyl) tetrazole (B002)
Dissolving intermediate B00133.0 g (172.64mmol) in 150ml DMF, adding anhydrous potassium carbonate 28.63g (207.17mmol) and iodomethane 29.41g (207, 17mmol), reacting at 90 deg.C for 1h, cooling to room temperature until the reaction liquid turns dark yellow, slowly dropping the reaction liquid into 1L water to precipitate a large amount of white solid, filtering, and drying to obtain white solid. Recrystallization from ethyl acetate and petroleum ether gave 26g of product, 72.2% yield.
The structure of the product is confirmed:1H NMR(DMSO-d6，ppm)δ8.66-8.67(t，1H)，8.40-8.42(dt，1H)， 8.33-8.35(dt，1H)，7.81-7.85(t，1H)，4.46(s，3H)。
1.3 Synthesis of N-hydroxy-N-acetyl-4- (2-methyltetrazol-5-yl) aniline (B003)
Dissolving intermediate B00230 g (146.22mmol) in 350ml tetrahydrofuran at room temperature, adding NI powder 10.0g, cooling to 0 ℃ in an ice bath, dropwise adding hydrazine hydrate 7.3g (143, 49mmol) in batches, stirring for 30min at 0 ℃, slowly heating to room temperature to continue reacting for 24h, wherein the solution becomes light yellow, cooling to 0 ℃ after TLC monitors that raw materials disappear, adding sodium bicarbonate 54g with 4 equivalents, generating gas, stirring for 30mim, dropwise adding acetyl chloride 13.77g (175.46mmol) at 0 ℃, slowly heating to room temperature to react for 2h, performing suction filtration, washing filter cakes with tetrahydrofuran (3 × 50ml), collecting filtrate, and performing reduced pressure spin-drying on the tetrahydrofuran to obtain yellow solid. Recrystallization of the solid from ethyl acetate gave 28g of product in 84% yield.
The structure of the product is confirmed:1H NMR(DMSO-d6，ppm)δ10.83(s，1H)，8.43(s，1H)，7.82-7.84 (d，2H)，7.54-7.58(t，1H)，4.45(s，3H)，2.28(s，3H)。
synthesis of 1.42-amino-6- (2-methyltetrazole-5-) indole-3-carboxamide (B004)
Dissolving intermediate B00326.0g (111.48mmol) in 500ml of chloroform, dissolving part of solid, adding malononitrile 7.4g (111.48mmol), cooling to 0 ℃, stirring for 30 mm, slowly dropping triethylamine 11.28g (111.48mmol), stirring for 30min after dropping, slowly heating to room temperature, reacting for 1h, precipitating a large amount of solid, performing suction filtration, washing a filter cake with (3 x 50ml) of chloroform, placing the filter cake in a 500ml flask, adding triethylamine 11.28g (111.48mmol), methanol 200ml, performing reflux reaction for 10h, clarifying a reaction liquid, precipitating a large amount of off-white solid, concentrating the filtrate under reduced pressure, and performing suction filtration to obtain 16g of off-white solid, wherein the yield is 58%.
The structure of the product is confirmed:1H NMR(DMSO-d6，ppm)δ10.80(s，1H)，7.82(s，1H)，7.64-7.68 (q，2H)，7.03(s，2H)，6.60(s，2H)，4.39(s，3H)。
synthesis of 1.52-phenylacetylamino-6- (2-methyltetrazole-5-) indole-3-carboxamide (B005)
B00414.6g (56.34mmol) of B00414 is dissolved in 200ml of DMF, 17.1g (169.03mmol) of triethylamine and 17.42g (112.69mmol) of phenylacetyl chloride are added to react at 37 ℃ for 24h, the reaction solution is slowly dropped into 500ml of water, a large amount of yellow solid is precipitated, and the yellow solid is filtered by suction and dried. The solid was placed in a 500ml flask, 200ml of ethyl acetate was added, refluxed for 6h, and filtered with suction to give 15.0g of an off-white product with a yield of 70.9%.
The structure of the product is confirmed:1H NMR(DMSO-d6，ppm)δ12.23(s，1H)，11.76(s，1H)，8.29 (s，1H)，7.96-8.00(m，1H)，7.79-7.81(m，1H)，7.26-7.40(m，7H)，4.41(s，3H)， 3.91(s，2H)。
1.62-benzyl-7- (2-methyltetrazol-5-yl) -3H-4-oxo-pyrimidine [4, 5] indole (B006)
Dissolving intermediate B00516.3 g (43.4mmol) in 500ml isopropanol, adding potassium tert-butoxide 29.2g (260.4mmol), refluxing at 90 deg.C for 12h, concentrating the reaction solution under reduced pressure after the starting material point disappears, adding 300ml water, adjusting pH to 6 with 6mol/L hydrochloric acid solution, and filtering to obtain off-white solid. The solid was placed in a 1L flask, 500ml methanol was added, refluxing was carried out for 8h, suction filtration was carried out repeatedly for 3 times to obtain 11.6g of a white product with a yield of 74.8%.
The structure of the product is confirmed:1H NMR(DMSO-d6，ppm)δ12.48(b，1H)，12.40(b，1H)，8.07-8.20 (m，3H)，7.91-7.97(m，1H)，7.26-7.41(m，4H)，4.43(s，3H)，4.04(s，2H)。
synthesis of 72-benzyl-4-chloro-7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoline (B007)
Taking 6.3g (16.76mmol) of intermediate B0066 to a 250ml flask, adding 100ml of phosphorus oxychloride, refluxing for 12h at 110 ℃, concentrating the reaction solution under reduced pressure to about 20ml, slowly dropping into 500ml of ice water, stirring to separate out yellow solid, adjusting the pH to about 8 with 10% NaOH solution, filtering, drying to obtain 6.1g of yellow product, wherein the yield is 92%.
The structure of the product is confirmed:1H NMR(DMSO-d6，ppm)δ12.90(s，1H)，8.32-8.35(d，1H)，8.19 (s，1H)，8.04-8.07(dd，1H)，7.22-7.38(m，5H)，4.46(s，3H)，4.30(s，2H)。
1.82 Synthesis of- (6, 7-methoxy-3, 4-dihydroisoquinoline) -ethylenediamine
Dissolving bromoethylamine hydrobromide 10.0g (48.81mmol) and triethylamine 7.42g (73.22mmol) in 50ml of ethanol, carrying out ice bath to 0 ℃, dropwise adding Boc-anhydride 12.85g (58.57mmol), slowly heating to room temperature after dropwise adding to react for 15h, after the reaction is finished, carrying out reduced pressure spin-drying on the ethanol, adding 50ml of water, extracting with ethyl acetate (3 × 100ml), collecting an organic phase, drying with anhydrous sodium sulfate, and carrying out reduced pressure spin-drying on the ethyl acetate to obtain a light yellow oily product Boc-bromoethylamine 10.0g, wherein the yield is 91.4%.
Dissolving 2.0g (8.8mmol) of 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride in 25ml dichloromethane, adding 2.64g (26.12mmol) of triethylamine and 2.34g (10.45mmol) of Boc-bromoethylamine, stirring at room temperature overnight, pouring 50ml water into the reaction solution after the reaction, extracting the water layer with 3 × 50ml dichloromethane, collecting the organic phase, drying with anhydrous sodium sulfate, adding 4.0g silica gel powder, purifying the product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether ═ 1:1) to obtain 2.4g of light yellow oily product, adding 20ml dichloromethane, dropping trifluoroacetic acid in 1ml, stirring at room temperature for 6h, spinning dichloromethane under reduced pressure, adding 20ml water, adjusting pH to 10 with 10% sodium hydroxide solution, extracting with dichloromethane (3 × 50ml), collecting the organic phase, drying with anhydrous sodium sulfate, spinning dichloromethane under reduced pressure to obtain 1.6g of light yellow oily product, the yield was 95%. Directly used for the next reaction.
1.9 Synthesis of the target product XH003
Taking 0.4g (1.07mmol) of intermediate B007in 10ml DMSO, adding 0.3g (2.14mmol) of anhydrous potassium carbonate and 0.5g (2.14mmol) of 2- (6, 7-methoxy-3, 4-dihydroisoquinoline) -ethylenediamine, reacting at 90 ℃ for 8h, dropping the reaction liquid into ice water after the reaction is finished, precipitating a light yellow solid, carrying out suction filtration, drying, and recrystallizing the light yellow solid ethyl acetate to obtain XH0030.18g with the yield of 29%.
The structure of the product is confirmed:1H NMR(DMSO-d6，ppm)δ12.03(s，1H)，8.35-8.37(d，J＝8.2， 1H)，8.08(s，1H)，7.88-7.90(d，J＝8.2，1H)，7.39-7.41(d，J＝7.2，2H)，7.27-7.31 (d，J＝7.4，3H)，7.18-7.22(t，J＝7.3，1H)，6.63-6.66(m，2H)，4.43(s，3H)，4.08 (s，2H)，3.80-3.85(m，2H)，3.69-3.70(6H，2OMe)，3.58(s，2H)，2.71-2.76(m， 6H)；13C NMR(DMSO-d6，ppm)δ166.61，165.33，157.48，157.20，147.60，147.34， 139.86，136.83，129.62(2C)，128.57(2C)，127.11，126.47，126.39，122.82，121.84， 121.75，118.51，112.26，110.41，109.14，93.97，57.27，55.95，55.91，55.72， 51.12，46.29，38.33，28.70；LC/MS-m/z:576.4[M+1]+(exact mass:575.3)。
example 2: killing effect of compound XH003 on tumor cells
Preparing the digested cells into uniform single cell suspension by using a high-glucose DMEM complete culture medium, and adjusting the cell density to 10000 cells/hole; and (3) taking a 96-well plate, inoculating 100 mu l of cell suspension into each well, and putting the cell suspension into a carbon dioxide incubator for culture.
Grouping processing: after 24h of inoculation, the cells adhere to the wall, DMEM complete culture medium is used for dosing with the concentration of each group of drugs, the treatment is carried out for 24h or 48h respectively, the cell proliferation condition is detected by a CCK-8 method, the old culture medium is discarded, 100 mu l of working solution culture medium containing 10% CCK-8 is added, the culture medium is put into an incubator for continuous culture for 2h, after the incubation time is reached, a 96-hole cell culture plate is taken out, and the absorbance of each hole is measured at the wavelength of 450nm of an enzyme labeling instrument.
The survival rate is [ (experimental absorbance-blank well absorbance)/(control absorbance-blank well absorbance) ] × 100%
The results show that the compound XH003 has good killing effect on human breast cancer MCF-7 cells, human breast cancer MDA-MB-231 cells, human cervical cancer Hela cells, human cervical cancer C33A cells, human gastric adenocarcinoma BGC-823 cells, human liver cancer HepG2 cells and human liver cancer Huh-7 cells at lower concentration (see tables 1-7).
TABLE 1 killing of human breast cancer MCF-7 cells by compound XH003
**P<0.01 comparison with blank group
TABLE 2 killing of human breast cancer MDA-MB-231 cells by compound XH003
**P<0.01 comparison with blank group
TABLE 3 killing of human cervical carcinoma Hela cells by Compound XH003
**P<0.01 comparison with blank group
TABLE 4 killing of human cervical carcinoma C33A by compound XH003
*P<0.05，**P<0.01 comparison with blank group
TABLE 5 killing of human gastric adenocarcinoma BGC-823 cells by XH003 compound
**P<0.01 comparison with blank group
TABLE 6 killing of human hepatoma HepG2 cells by XH003 compound
*P<0.05，**P<0.01 comparison with blank group
TABLE 7 killing of human hepatoma Huh-7 cells by compound XH003
**P<0.01 comparison with blank group
Example 3: killing effect of compound A001-A010 on tumor cells
Preparing the digested cells into uniform single cell suspension by using a high-glucose DMEM complete culture medium, and adjusting the cell density to 10000 cells/hole; and (3) taking a 96-well plate, inoculating 100 mu l of cell suspension into each well, and putting the cell suspension into a carbon dioxide incubator for culture.
Grouping processing: after 24h of inoculation, the cells adhere to the wall, DMEM complete culture medium is used for dosing with the concentration of each group of drugs, the cells are treated for 48h respectively, the cell proliferation condition is detected by a CCK-8 method, the old culture medium is discarded, 100 mu l of culture medium containing 10% CCK-8 working solution is added, the culture medium is placed into an incubator for continuous culture for 2h, after the incubation time is reached, a 96-hole cell culture plate is taken out, and the absorbance of each hole is measured at the wavelength of 450nm of an enzyme labeling instrument.
The survival rate is [ (experimental absorbance-blank well absorbance)/(control absorbance-blank well absorbance) ] × 100%
Half maximal Inhibitory Concentration (IC) of each compound was calculated from Graph Pad Pro 5.050)。
The results show that Compounds A003, A004 and A010 IC5055.42 + -4.53, 59.97 + -3.34 and 44.45 + -2.56 respectively. Compounds A001, A002, A005, A006, A007, A008 and A009 human breast cancer MCF-7 cell IC50All above 80. mu.M (Table 8).
TABLE 8 Compounds A001-A010 human Breast cancer MCF-7 cell IC50 
Example 4: effect of Compound XH003 on Breast cancer MCF-7 cell clonogenic
The clonogenic capacity is an important index for reflecting the proliferation of tumor cells and the forming, cloning and growth capacities in a new microenvironment, and the following studies are carried out in order to further study the antitumor effect of the compound of the present invention.
MCF-7 cells in logarithmic growth phase were taken, digested with 0.25% trypsin containing EDTA and blown into single cells, respectively, and the cells were suspended in DMEM medium containing 10% fetal bovine serum for use. Counting cells, adjusting the cell density to 1000 cells/well, inoculating the cells in a 6-well plate, uniformly distributing the cells by a cross method, respectively adding compounds XH003(0.5 mu M, 1 mu M, 2.5 mu M and 5 mu M) with different concentrations into an experimental group after 24 hours of cell adherence, adding a complete culture medium into a blank control group, removing the cells after 24 hours of action, completely replacing the DMEM complete culture medium for 10 days, and replacing the culture medium every 2 days.
When macroscopic cloning appears in the culture dish and the count of the cells of the single clone colony visible under the microscope is more than 50, terminating the culture, discarding the culture solution, washing for 2 times by PBS, fixing the cells by 4% paraformaldehyde for 30min, adding 0.1% crystal violet for dyeing for 15min, washing with distilled water, drying, and taking pictures by an inverted microscope for observation and counting.
The results show that 0.5. mu.M, 1. mu.M, 2.5. mu.M and 5. mu.M compound XH003 all significantly reduced the clonogenic capacity of MCF-7 cells (see FIG. 1, Table 9).
TABLE 9 Effect of XH003 Compound on the clonogenic Capacity of Breast cancer cell lines MCF-7
**P<0.01 comparison with blank group
Example 5: flow cytometry for detecting influence of compound XH003 on breast cancer MCF-7 cell apoptosis
Apoptosis is one of the main ways of antitumor drugs to kill tumor cells, and the study further adopts a flow cytometer to detect the apoptosis of the compound XH003 on breast cancer MCF-7 cells. MCF-7 cells in the logarithmic growth phase were washed 1 time with PBS, digested with 0.25% trypsin and blown into single cells adjusted to 10 ten thousand/ml. And (3) inoculating 20 ten thousand cells into each 6-well plate, after 24 hours, administering XH003 compounds (1 mu M, 5 mu M and 10 mu M) with different concentrations to intervene in breast cancer MCF-7 cells, administering a complete culture medium to a blank control group, and after 24 hours, detecting the apoptosis condition by using a flow cytometer. The results show that the compound XH003 can obviously promote the apoptosis of the breast cancer cell line MCF-7 at 5 mu M and 10 mu M (Table 10).
Effect of Table 10 Compound XH003 on apoptosis of Breast cancer cell lines MCF-7
**P<0.01 comparison with blank group
Claims (10)
1. A compound, or isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, selected from:
2-benzyl-4- (6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline-2-ethylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] oxindole;
2-benzyl-4- (3-chloro-4-fluorophenylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] oxindole;
2-benzyl-4- (indol-3-ethylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] oxindole;
2-benzyl-4- (4-hydroxyphenylethylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] oxindole;
2-benzyl-4- (trans-4-hydroxycyclohexylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] oxindole;
2-benzyl-4- (4-chloro-2-methylphenylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoline;
2-benzyl-4- (3, 4-dimethoxyphenethylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoles;
2-benzyl-4- (4-methoxybenzylethylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] oxindole;
2-benzyl-4- (3-ethynylphenylamino) -7- (2-methyltetrazol-5-yl) pyrimidine [4, 5] oxindole;
2-benzyl-4- (4-tetrahydropyranylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoline;
2-benzyl-4- (dimethylamino) -7- (2-methyltetrazol-5-yl) pyrimido [4, 5] indoles.
2. The compound according to claim 1, which is preferably 2-benzyl-4- (6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline-2-ethylamino) -7- (2-methyltetrazol-5-yl) pyrimidino [4, 5] indole, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof.
3. A process for the preparation of a compound according to any one of the preceding claims, or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, said process comprising the steps of:
1)
2)
3)
4)
5)
6)
7) carrying out substitution reaction on the product obtained in the step 6) and an appropriately substituted amino group to obtain a corresponding final product.
4. A pharmaceutical composition comprising a compound according to any one of the preceding claims or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, a compound prepared by the preparation method according to claim 3 or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable adjuvants or excipients.
5. The pharmaceutical composition according to claim 4, for use in the prevention and/or treatment of cancer-related diseases; preferably, the cancer-related disease is selected from one or more of breast cancer, cervical cancer, gastric cancer and liver cancer; more preferably, the cancer-related disease is selected from breast cancer.
6. Use of a compound according to any one of the preceding claims or an isomer, prodrug, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the prevention and/or treatment of a cancer-related disease; preferably, the cancer-related disease is selected from one or more of breast cancer, cervical cancer, gastric cancer and liver cancer; more preferably, the cancer-related disease is selected from breast cancer.
7. The use according to any of the preceding claims, wherein the prevention and/or treatment of a cancer-related disease is of a primary cancer.
8. The use according to any of the preceding claims, wherein the prevention and/or treatment of a cancer related disease is by killing tumor cells.
9. Use according to any of the preceding claims, wherein the prevention and/or treatment of cancer related diseases is by inhibiting the clonogenic formation of tumor cells.
10. Use according to any of the preceding claims, wherein the prevention and/or treatment of cancer related diseases is by promoting apoptosis of tumor cells.
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