CN106146537B - Isoxazoline and isoxazolidine substituted artemisinin derivative, preparation method and application thereof - Google Patents
Isoxazoline and isoxazolidine substituted artemisinin derivative, preparation method and application thereof Download PDFInfo
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- CN106146537B CN106146537B CN201510129923.1A CN201510129923A CN106146537B CN 106146537 B CN106146537 B CN 106146537B CN 201510129923 A CN201510129923 A CN 201510129923A CN 106146537 B CN106146537 B CN 106146537B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
The invention provides an artemisinin derivative containing isoxazoline and isoxazolidine substitution, a preparation method and application thereof, and particularly provides a compound shown as a formula I. Wherein, the definition of each group is described in the specification. The compound has the tumor cell proliferation inhibiting activity and can be used for preparing diseases related to tumor cell proliferation.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an artemisinin derivative containing isoxazoline and isoxazolidine, a preparation method thereof, a pharmaceutical composition and application thereof in preparation of anti-cancer drugs.
Background
Artemisinin is extracted from Artemisia annua L of Compositae, and contains peroxy bridge group sesquiterpene lactone. Artemisinin and its derivatives such as artemether, artesunate, dihydroartemisinin and the like have been clinically used as antimalarials with high efficiency and low toxicity for many years. With the intensive research on the pharmacology of the artemisinin, the artemisinin also has various biological activities of schistosomiasis resistance, fungi resistance, tumor resistance and the like; among them, the role of artemisinin in antitumor is receiving increasing attention.
In 1991, the selective killing activity of artemisinin on leukemia P388 was first reported by Deng Ming, et al, Chinese scholars. Then, scholars at home and abroad deeply research the anti-cancer activity of artesunate, and find that the artesunate has the strongest activity on leukemia cells and colon cancer cells and is also effective on breast cancer melanoma, ovarian cancer, prostatic cancer, renal cell carcinoma and the like (Efferth et al, Int J Oncol 2001,18: 767-. In order to find more active anticancer compounds, a number of artemisinin derivatives were sequentially synthesized and screened. Plum et al found that some α -cyanodihydroartemisinin benzyl ethers were very potent in cytotoxic effect on P388 and A549 (plum et al, Bioorg Med Chem Lett 2011,11: 5-8). Artemisinin dimers and trimers have also been reported in large numbers, with many compounds having growth inhibitory effects on tumor cells (Posner GH et al, J Med Chem 1999,42: 4275-3280; Jung M et al, J Med Chem 2003,46: 987-994). However, the artemisinin-modified derivatives still cannot be really applied to clinic.
In view of the above, there is a need in the art to develop new clinically useful artemisinin derivatives.
Disclosure of Invention
The invention aims to provide an artemisinin derivative with a novel structure.
In a first aspect of the present invention, there is provided a compound of formula I:
wherein the content of the first and second substances,
n is 0 or 1;
R1and R2Each independently selected from the group consisting of: none, hydrogen, substituted or unsubstituted C1-C16Wherein said substituent means that one or more hydrogen atoms of the group are substituted with a substituent selected from the group consisting of: c1-C16Alkyl of (C)1-C6Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino, halogen, nitro, cyano, -OC (O) R6、-COOR6(ii) a And R is1And R2Is not absent or hydrogen at the same time;
or, R1And R2And adjacent carbon atoms and nitrogen atoms together form a substituted or unsubstituted heterocyclic ring, wherein said heterocyclic ring has 1 to 4 heteroatoms selected from the group consisting of: o, S, NR5(ii) a Wherein, the heterocyclic ring can optionally have one or more substituents R4And said R is4Selected from the group consisting of: substituted or unsubstituted C1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl substituted secondary or tertiary amino, carboxyl, -NHC (O) R6、-CONHR6Halogen, nitro, cyano, -OC (O) R6、-COOR6Substituted or unsubstituted heterocyclic ring;
R3selected from the group consisting of: hydrogen, hydroxy, amino, C1-C6Alkyl substituted secondary or tertiary amino, halogen;
R5selected from the group consisting of: H. c1-C6Alkyl of, -C (O) R6、-C(O)2R6、-S(O)2R6、-S(O)R6；
X is H, O, hydroxy, halogen, OR-OR7；
R6Is H or substituted or unsubstituted C1-C16Alkyl groups of (a);
R7selected from the group consisting of: H. substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6An acyl group; wherein the substituents may be C1-C4Alkoxy, hydroxy, carboxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino groups, halogen, nitro, cyano, -OC (O) R6，-COOR6A heterocycle which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: c1-C6Alkyl radical, C1-C4Alkoxy, amino of (a);
the dotted line position is a saturated single bond or an unsaturated double bond;
unless specified, everywhere substituted as described above means that one or more substituents on the group are substituted with a substituent selected from the group consisting of: c1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino, carboxyl, -NHC (O) R6，-CONHR6Halogen, nitro, cyano, -OC (O) R6，-COOR6Wherein R is6Is H or substituted or unsubstituted C1-C16Alkyl group of (1).
In another preferred embodiment, the compound of formula (I) has a structure selected from the group consisting of:
wherein n is 0 or 1;
m is 0 to 3;
x is H, O, hydroxy, halogen, OR-OR7；
R2Selected from the group consisting of: H. c10-C16Substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein said substitution is a groupOne or more hydrogen atoms of the group are substituted with a substituent selected from the group consisting of: c1-C4Alkoxy, hydroxy, halogen, nitro, cyano, -OC (O) R6or-COOR6；
R3Selected from the group consisting of: hydrogen, hydroxy, halogen;
R4is one or more substituents selected from the group consisting of: H. substituted or unsubstituted C1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino group of-NHC (O) R6、-CONHR6Halogen, nitro, cyano, -OC (O) R6、-COOR6A heterocycle which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: c1-C6Alkyl radical, C1-C4Alkoxy, amino of (a);
y is CH2O, S, or NR5(ii) a Wherein R is5Selected from the group consisting of: H. c1-C6Alkyl of, -C (O) R6、-COOR6、-S(O)2R6、-S(O)R6(ii) a Preferably C1-C4Alkyl groups of (a);
R6is H or substituted or unsubstituted C1-C16Alkyl groups of (a);
R7selected from the group consisting of: H. substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6An acyl group; wherein the substituents may be C1-C4Alkoxy, hydroxy, carboxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino groups, halogen, nitro, cyano, -OC (O) R6，-COOR6A heterocycle which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: c1-C6Alkyl radical, C1-C4Alkoxy group and amino group.
In another preferred embodiment, the compound of formula (I) has a structure selected from the group consisting of:
wherein the content of the first and second substances,
m is 0, 1 or 2;
k is 8 to 14; preferably 9, 10, 11, 12, 13, 14;
i is 0, 1, 2 and 3, preferably 0 and 1;
y is CH2、O、S、NR5Preferably, R5Is methyl;
preferably, R4Selected from the group consisting of: c1-C4Alkoxy, hydroxy, halogen, nitro, cyano, -CONHR6，-COOR6Substituted or unsubstituted heterocyclic ring.
In another preferred embodiment, in the compound, R1、R2、R3、R4、R5、R6、R7Any of X, Y, n, m, k, i is a group corresponding to a particular compound described in the examples of the present invention.
In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:
in a second aspect of the invention, there is provided a process for the preparation of a compound of formula (I) as described in the first aspect of the invention, said process comprising step (b), and optionally step (c):
(b) reacting the intermediate 1 with nitrile oxide to obtain a product 2;
(c) carrying out reduction reaction on the product 2 to reduce carbonyl, and then reacting with orthoformate to obtain a product 3;
or the reaction comprises step (d), and optionally step (e), or optionally step (f) and optionally (g):
(d) intermediate 1 with Nitrone
Reacting to obtain a product 4;
(e) carrying out reduction reaction on the product 4, reducing carbonyl of the product, and reacting the product with orthoformate to obtain a product 5; wherein i is as defined above;
(f) carrying out reduction reaction on the product 4 to reduce carbonyl of the product, and then reacting the product with bromoethanol to obtain an intermediate 6;
(g) with intermediates 6 andMH undergoes a substitution reaction to give a compound of formula 7; wherein M is selected from the group consisting of: a heterocycle containing 1 to 3 heteroatoms unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: c1-C6Alkyl radical, C1-C4Alkoxy, amino of (a);
or said reaction comprises step (d), and optionally step (h)
(d) Intermediate 1 with nitrones
Reacting to obtain a product 4;
(h) the product 4 reacts with ferrous chloride to obtain a product 8;
or the reaction comprises step (i):
(i) intermediate 1 with Nitrone
Reacting to obtain an intermediate 9; wherein Y is as defined above.
Or the reaction comprises step (j), and optionally step (k):
(j) reacting with artemisinin to obtain an intermediate 10;
(k) carrying out a reaction by using the intermediate 10 to obtain an intermediate 11;
wherein, unless otherwise specified, the definitions of the groups are as described above.
In a third aspect of the present invention, there is provided a use of a compound of formula (I), an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof as shown in the first aspect of the present invention, for: (a) non-therapeutically inhibiting the activity of tumor cells in vitro; and (b) preparing a medicament for treating tumors.
In another preferred embodiment, the tumor cell is selected from the group consisting of: KB cells, KB/VCR cells, A549 cells, or a combination thereof; and/or
The tumor is selected from the group consisting of: lung cancer, colon cancer, oral epithelial cancer, gastric cancer, or leukemia.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising: a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition is for the treatment or prevention of a tumor, preferably a tumor selected from the group consisting of: lung cancer, colon cancer, oral epithelial cancer, gastric cancer, or leukemia.
In a fifth aspect of the invention, there is provided a method of non-therapeutically inhibiting tumor cell activity in vitro, the method comprising: administering to the subject an inhibitory effective amount of a compound of formula (I) as described in the first aspect of the invention.
In another preferred embodiment, the inhibiting effective amount is 50. mu.M or less, preferably 20. mu.M or less.
In a sixth aspect of the present invention, there is provided a method for treating or preventing a tumor, the method comprising the steps of: administering to a subject being treated or prevented a therapeutically effective amount of a compound of formula (I) as described in the first aspect of the invention.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor designs and synthesizes a new spiro artemisinin derivative containing isoxazoline and isoxazolidine based on the prior art, and the result shows that the derivative has antitumor activity of different degrees by screening antitumor activity of a plurality of tumor cells in vitro. Based on the above findings, the inventors have completed the present invention.
Term(s) for
As used herein, the term "halogen" means F, Cl, Br or I.
The term "C1-C6Alkyl "refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the main chain, the term" C1-C16Alkyl "and" C1-C16Alkyl "has a similar meaning, and representative examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
The term "C1-C10Alkoxy "refers to a straight or branched chain alkoxy group having 1 to 10 carbon atoms in the main chain, the term" C1-C6Alkoxy "has a similar meaning and is representative of examples such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
The term "halogenated C1-C10Alkyl "refers to C wherein one or more hydrogen atoms of the group are replaced by halogen atoms1-C10Alkyl, the term "halo C1-C6Alkyl "has a similar meaning, and representative examples are trifluoromethyl and the like.
In the present invention, the term "aryl" means a monocyclic aromatic group or a fused or non-fused polycyclic aromatic group having 6 to 14 carbon atoms, in the case of a polycyclic one, as long as one carbocyclic ring is aromatic.
In the present invention, the term "heteroaryl" refers to an aromatic cyclic group containing 1 to 4 heteroatoms as ring members in the ring. Heteroatom means nitrogen, oxygen or sulfur. Heteroaryl groups can be monocyclic heteroaryl groups having 5 to 7 ring atoms, or bicyclic heteroaryl groups having 7 to 12 ring atoms, including without limitation thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, and the like.
In the present invention, the term "heterocycle" includes aliphatic heterocycles or aromatic heterocycles of 3 to 14 carbon atoms, which may be condensed or non-condensed polycyclic rings having 1 to 4 hetero rings as ring members, and the hetero atoms refer to nitrogen, oxygen or sulfur.
In the present invention, the term "substituted" means that one or more substituents on a group are substituted with a substituent selected from the group consisting of: c1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino, carboxyl, -NHC (O) R6，-CONHR6Halogen, nitro, cyano, -OC (O) R6，-COOR6Wherein R is6Is H or substituted or unsubstituted C1-C16Alkyl group of (1).
In the present invention, "pharmaceutically acceptable salt" refers to an organic acid salt of a compound with an organic acid of a pharmaceutically acceptable anion, including but not limited to p-toluenesulfonate, methanesulfonate, malate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, lactate, maleate, and the like; suitable inorganic salts may also be formed, including but not limited to hydrochlorides, sulfates, nitrates, phosphates, hydrobromides, hydroiodides, and the like.
In the present invention, the term "prodrug" refers to a derivative of a compound of formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which may have only weak or no activity by itself, but which can be converted into the corresponding biologically active form under physiological conditions after administration.
In the present invention, each chiral center may be either R-type or S-type, unless otherwise specified.
Compounds of formula I and their preparation
The invention provides a compound shown as the following formula I:
wherein the content of the first and second substances,
n is 0 or 1;
R1and R2Each independently selected from the group consisting of: none, hydrogen, substituted or unsubstituted C1-C16Wherein said substituent means that one or more hydrogen atoms of the group are substituted with a substituent selected from the group consisting of: c1-C16Alkyl of (C)1-C6Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino, halogen, nitro, cyano, -OC (O) R6、-COOR6(ii) a And R is1And R2Is not absent or hydrogen at the same time;
or, R1And R2And adjacent carbon atoms and nitrogen atoms together form a substituted or unsubstituted heterocyclic ring, wherein said heterocyclic ring has 1 to 4 heteroatoms selected from the group consisting of: o, S, NR5(ii) a Wherein, the heterocyclic ring can optionally have one or more substituents R4And said R is4Selected from the group consisting of: substituted or unsubstituted C1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl substituted secondary or tertiary amino, carboxyl, -NHC (O) R6、-CONHR6Halogen, nitro, cyano, -OC (O) R6、-COOR6Substituted or unsubstituted heterocyclic ring;
R3selected from the group consisting of: hydrogen, hydroxy, amino, C1-C6Alkyl substituted secondary or tertiary amino, halogen;
R5selected from the group consisting of: H. c1-C6Alkyl of, -C (O) R6、-C(O)2R6、-S(O)2R6、-S(O)R6；
X is H, O, hydroxy, halogen, OR-OR7；
R6Is H or substituted or unsubstituted C1-C16Alkyl groups of (a);
R7selected from the group consisting of: H. substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6An acyl group; wherein the substituents may be C1-C4Alkoxy, hydroxy, carboxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino groups, halogen, nitro, cyano, -OC (O) R6，-COOR6A heterocycle which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: c1-C6Alkyl radical, C1-C4Alkoxy, amino of (a);
the dotted line position is a saturated single bond or an unsaturated double bond;
unless specified, everywhere substituted as described above means that one or more substituents on the group are substituted with a substituent selected from the group consisting of: c1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino, carboxyl, -NHC (O) R6，-CONHR6Halogen, nitro, cyano, -OC (O) R6，-COOR6Wherein R is6Is H or substituted or unsubstituted C1-C16Alkyl group of (1).
In another preferred embodiment, the compound of formula (I) has a structure selected from the group consisting of:
wherein n is 0 or 1;
m is 0 to 3;
x is H, O, hydroxy, halogen, OR-OR7；
R2Selected from the group consisting of: H. c10-C16Substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein said substitution is one or more of the groupsAnd each hydrogen atom is substituted with a substituent selected from the group consisting of: c1-C4Alkoxy, hydroxy, halogen, nitro, cyano, -OC (O) R6or-COOR6；
R3Selected from the group consisting of: hydrogen, hydroxy, halogen;
R4is one or more substituents selected from the group consisting of: H. substituted or unsubstituted C1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino group of-NHC (O) R6、-CONHR6Halogen, nitro, cyano, -OC (O) R6、-COOR6A heterocycle which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: c1-C6Alkyl radical, C1-C4Alkoxy, amino of (a);
y is CH2O, S, or NR5(ii) a Wherein R is5Selected from the group consisting of: H. c1-C6Alkyl of, -C (O) R6、-COOR6、-S(O)2R6、-S(O)R6(ii) a Preferably C1-C4Alkyl groups of (a);
R6is H or substituted or unsubstituted C1-C16Alkyl groups of (a);
R7selected from the group consisting of: H. substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6An acyl group; wherein the substituents may be C1-C4Alkoxy, hydroxy, carboxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino groups, halogen, nitro, cyano, -OC (O) R6，-COOR6A heterocycle which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: c1-C6Alkyl radical, C1-C4Alkoxy group and amino group.
In another preferred embodiment, the compound of formula (I) has a structure selected from the group consisting of:
wherein the content of the first and second substances,
m is 0, 1 or 2;
k is 8 to 14; preferably 9, 10, 11, 12, 13, 14;
i is 0, 1, 2 and 3, preferably 0 and 1;
y is CH2、O、S、NR5Preferably, R5Is methyl;
preferably, R4Selected from the group consisting of: c1-C4Alkoxy, hydroxy, halogen, nitro, cyano, -CONHR6，-COOR6Substituted or unsubstituted heterocyclic ring.
In another preferred embodiment, in the compound, R1、R2、R3、R4、R5、R6、R7Any of X, Y, n, m, k, i is a group corresponding to a particular compound described in the examples of the present invention.
The invention also provides a preparation method of the compound shown in the formula I, which can be one of the following methods:
(a) obtaining an intermediate 1 from artemisinin by a known reaction;
(b) the intermediate 1 reacts with nitrile oxide to obtain a product 2, namely an artemisinin derivative with a general formula (II);
(c) the product 2 is reduced by carbonyl group and then reacts with orthoformate to form a product 3, which is also an artemisinin derivative of the general formula (II);
(d) the intermediate 1 reacts with nitrobenzene containing benzene ring to obtain a product 4, namely an artemisinin derivative shown in a general formula (IV);
(e) the product IV is reduced by carbonyl and then reacts with orthoformate to form a product 5, which is also an artemisinin derivative shown in a general formula (IV);
(f, g) reduction of product 4 by carbonyl followed by bromoethanol to give intermediate 6, which is further substituted to give another class of artemisinin derivatives represented by general formula (IV);
(h) the product 4 reacts with ferrous chloride to obtain a product 8;
(i) reacting the intermediate 1 with another kind of nitrone to obtain an artemisinin derivative with a general formula (III);
(j, k) artemisinin is reacted as known to give intermediate 10, which is then subjected to the same procedure as a and d to give another class of deoxy artemisinin derivatives.
Wherein m, i, Y, R2And R4The definitions of (a) are the same as the previous definitions.
Pharmaceutical compositions and methods of administration
The compound has excellent tumor cell proliferation inhibiting activity, so that the compound, various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving diseases related to tumor cell proliferation. According to the prior art, the compounds of the invention are useful for the treatment of the following diseases: lung cancer, colon cancer, oral epithelial cancer, stomach cancer, leukemia, and the like.
The artemisinin derivatives of the invention can exist in optically pure form or in stereoisomeric form, and these stereoisomers can be enantiomers or diastereomers, as well as mixtures of each of them.
In addition, the invention also comprises prodrugs of the compounds of the general formula I. According to the present invention, prodrugs are derivatives of the compounds of formula I, optical isomers thereof or pharmaceutically acceptable salts thereof, which may themselves have only weak or no activity, but which may be converted to the corresponding biologically active form under physiological conditions after administration.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 5 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. Unless otherwise indicated, the preparation and testing methods and equipment employed in the present invention are conventional in the art. All reagents used were analytically or chemically pure.
Example 1 Synthesis of Compound S0
The reaction process is shown as scheme 1:
Scheme 1
intermediate 1 was prepared as described in J.Med.chem.1997,40,633-638.
Intermediate 2 was prepared by reference to Bioorganic & Medicinal Chemistry letters.2003,13, 1795-.
Intermediate 1(56mg, 0.2mmol) was dissolved in 2ml of dry CH2Cl2, intermediate 2(33mg, 0.21mmol) was added, cooled to 0 deg.C, triethylamine (24mg, 0.22mmol) was added dropwise slowly and the reaction was stopped at room temperature for about 12 hours until disappearance of intermediate 1 by TLC. 15ml of water was added, CH2Cl2 was extracted three times, and the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and column chromatography was performed to give 73mg of the title compound as a white solid.
1H NMR(300MHz,Chloroform-d)δ7.70–7.66(m,2H),7.40-7.38(m,3H),6.01(s,1H),3.97(d,J＝17.9Hz,1H),3.67(d,J＝17.9Hz,1H),2.50–2.32(m,2H),2.26-2.20(dd,J＝13.2,4.1Hz,1H),2.14–2.20(m,2H),1.86-1.80(m,1H),1.56–1.31(m,7H),1.15–1.00(m,4H).
Examples 2 to 8 the corresponding aldehyde was used instead of benzaldehyde and all reaction steps were the same as in example 1.
Example 2 Synthesis of Compound S1
1H NMR(300MHz,Chloroform-d)δ7.58(d,J＝8.0Hz,1H),6.87(d,J＝8.1Hz,1H),5.97(s,1H),3.91(d,J＝17.7Hz,1H),3.81(s,3H),3.61(d,J＝17.7Hz,1H),2.41-2.29(m,2H),2.21-2.15(m,1H),2.10–1.97(m,2H),1.82-1.77(m,1H),1.54–1.28(m,7H),1.12–0.97(m,4H).
Example 3 Synthesis of Compound S2
1H NMR(300MHz,Chloroform-d)δ7.70–7.66(m,2H),7.40-7.38(m,3H),6.01(s,1H),3.97(d,J＝17.9Hz,1H),3.67(d,J＝17.9Hz,1H),2.50–2.32(m,2H),2.26-2.20(dd,J＝13.2,4.1Hz,1H),2.14–2.20(m,2H),1.86-1.80(m,1H),1.56–1.31(m,7H),1.15–1.00(m,4H).
Example 4 Synthesis of Compound S3
1H NMR(300MHz,Chloroform-d)δ7.35–7.24(m,3H),5.98(s,1H),3.83(d,J＝18.3Hz,1H),3.65(d,J＝18.3Hz,1H),2.50–2.18(m,3H),2.14–1.89(m,2H),1.91–1.73(m,1H),1.54–1.29(m,7H),1.21–0.85(m,4H).
Example 5 Synthesis of Compound S4
1H NMR(300MHz,Chloroform-d)δ7.37(s,1H),7.01(d,J＝8.4Hz,1H),6.80(d,J＝8.3Hz,1H),5.98(s,1H),3.95-3.88(m,4H),3.61(d,J＝17.6Hz,1H),2.45–1.97(m,5H),1.83-1.77(m,1H),1.51–1.28(m,7H),1.12–0.92(m,4H).
Example 6 Synthesis of Compound S5
1H NMR(300MHz,Chloroform-d)δ6.86(s,2H),5.99(s,1H),3.91(d,J＝17.7Hz,1H),3.85(s,9H),3.59(d,J＝17.6Hz,1H),2.44–1.97(m,5H),1.83–1.77(m,1H),1.51–1.33(m,7H),1.12–0.98(m,4H).
Example 7 Synthesis of Compound S6
1H NMR(400MHz,Chloroform-d)δ8.07(d,J＝6Hz,2H),7.75(d,J＝6Hz,2H),6.03(s,1H),4.01-3.95(m,4H),3.69(d,J＝17.9Hz,1H),2.48–2.02(m,5H),1.87-1.83(m,1H),1.50–1.31(m,7H),1.13–1.02(m,4H).
Example 8 Synthesis of Compound S7
1H NMR(300MHz,Chloroform-d)δ5.92(s,1H),3.47(d,J＝18.1Hz,1H),3.21(d,J＝18.1Hz,1H),2.48–2.20(m,4H),2.14–1.91(m,3H),1.86–1.71(m,1H),1.61–1.13(m,25H),1.12–0.91(m,4H),0.89–0.80(m,3H).
Example 9 Synthesis of Compound S8
The reaction process is shown as scheme 2:
Scheme 2
preparation of intermediate 3 is referred to J.org.chem.2009,74, 6365-6367
Intermediate 3(17mg, 0.2mmol) was dissolved in 2ml of dry toluene, intermediate 1(56mg, 0.2mmol) was added and stirred at room temperature for about 12 hours until intermediate 1 was no longer reduced and the reaction was stopped. The solvent was evaporated under reduced pressure and column chromatography was performed to give 36mg of the title compound as a white solid.
1H NMR(300MHz,Chloroform-d)δ5.92(s,1H),3.72–3.66(m,1H),3.58-3.50(m,1H),3.13–2.95(m,2H),2.69-2.63(m,1H),2.41–1.89(m,8H),1.80–1.73(m,2H),1.50–1.25(m,7H),1.16–0.98(m,4H).
Examples 10 to 17 the pyrrole was replaced by the corresponding secondary amine and all reaction steps were the same as in example 9.
Example 10 Synthesis of Compound S9
1H NMR(300MHz,Chloroform-d)δ5.92(s,1H),3.64–3.40(m,2H),3.13-2.72(m,2H),2.41–1.68(m,13H),1.51–1.23(m,7H),1.09–0.94(m,4H).
Example 11 Synthesis of Compound S10
1H NMR(300MHz,Chloroform-d)δ7.16–7.04(m,4H),5.95(s,1H),4.60-4.53(m,1H),3.59–3.32(m,3H),3.06–2.81(m,3H),2.44–2.35(m,2H),2.13–1.77(m,4H),1.47-1.23(m,7H),1.13-0.98(m,4H).
Example 12 and example 13 Synthesis of Compounds S11 and S12
6-methoxy-2-oxo-3, 4-dihydroisoquinoline (36mg, 0.2mmol) was dissolved in 2ml of dry toluene, and intermediate 1(56mg, 0.2mmol) was added thereto, and stirred at room temperature for about 12 hours until intermediate 1 was no longer reduced, and the reaction was stopped. The solvent was evaporated under reduced pressure and column chromatography was performed to give compound S1231 mg, compound S1315 mg as a white solid.
Compound S11:1H NMR(300MHz,Chloroform-d)δ6.99(d,J＝8.4Hz,1H),6.75(d,J＝8.4Hz,1H),6.66(s,1H),5.97(s,1H),4.58-4.52(m,1H),3.78(s,3H),3.61-3.52(m,1H),3.41-3.32(m,2H),3.10-2.99(m,1H),2.89-2.81(m,2H),2.46–2.37(m,2H),2.17-2.00(m,3H),1.84-1.79(m,1H),1.55–1.23(m,7H),1.19–0.96(m,4H).
compound S12:1H NMR(300MHz,Chloroform-d)δ7.01(d,J＝8.4Hz,1H),6.72(d,J＝8.4Hz,1H),6.61(s,1H),5.88(s,1H),4.95-4.89(m,1H),3.75(s,3H),3.41-3.36(m,1H),3.21–2.94(m,3H),2.74–2.52(m,2H),2.36-2.27(m,2H),2.05–1.70(m,4H),1.45–1.23(m,7H),1.09–0.95(m,4H).
synthesis of examples 14 and 15, Compounds S13 and S14
6, 7-dimethoxy-2-oxo-3, 4-dihydroisoquinoline (41mg, 0.2mmol) was dissolved in 2ml of dry toluene, and intermediate 1(56mg, 0.2mmol) was added thereto, followed by stirring at room temperature for about 12 hours until intermediate 1 was no longer reduced, and the reaction was stopped. The solvent was evaporated under reduced pressure and subjected to column chromatography to give compound S1426 mg and compound S1512 mg as white solids.
Compound S13:1H NMR(300MHz,Chloroform-d)δ6.58(s,1H),6.51(s,1H),5.95(s,1H),4.50-4.44(m,1H),3.82(s,6H),3.58-3.50(m,1H),3.36-3.27(m,2H),2.99–2.70(m,3H),2.41–2.35(m,2H),2.12–1.97(m,3H),1.82–1.77(m,1H),1.51-1.23(m,7H),1.12–0.98(m,4H).
compound S14:1H NMR(300MHz,Chloroform-d)δ6.56(s,21H),5.89(s,1H),4.93-4.87(m,1H),3.82(s,6H),3.38–2.98(m,4H),2.67-2.54(m,2H),2.41-2,28(m,2H),2.06–1.75(m,4H),1.45-1.23(m,7H),1.04-0.95(m,4H).
example 16 Synthesis of Compound S15
The reaction process is shown as scheme 3:
Scheme 3
morpholine (176mg, 2mmol), dissolved in 3ml methanol, Na added at room temperature2WO4(33mg, 0.1mmol), 30% H was added slowly2O2(620ul, 6mmol) and reacted at room temperature for 30 minutes. Adding water, extracting with dichloromethane, washing the organic phase with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. Solvent is dried by decompression and spinningAnd performing column chromatography separation to obtain 589mg of an intermediate.
Intermediate 5(20mg, 0.2mmol) was dissolved in 2ml of dry toluene, intermediate 1(56mg, 0.2mmol) was added and stirred at room temperature for about 12 hours until intermediate 1 was no longer reduced and the reaction was stopped. The solvent was evaporated under reduced pressure and column chromatography was performed to give compound S1729 mg as a white solid.
1H NMR(300MHz,Chloroform-d)δ5.91(s,1H),4.09–3.38(m,6H),3.17–3.12(m,1H),2.93–2.73(m,2H),2.40–2.19(m,2H),2.06-1.92(m,3H),1.77–1.72(m,1H),1.47–1.14(m,7H),1.10–0.94(m,4H).
Example 17 and example 18 the morpholine was replaced by the corresponding substituted piperidine and all the reaction steps were identical to example 18.
Example 17 Synthesis of Compound S16
1H NMR(300MHz,Chloroform-d)δ5.89(s,1H),4.14–4.08(m,1H),3.75–3.38(m,3H),2.96–2.62(m,2H),2.47–1.71(m,11H),1.49–0.95(m,11H).
Example 18 Synthesis of Compound S17
1H NMR(300MHz,Chloroform-d)δ5.92(s,0.55H),5.88(s,0.45H),3.70-3.67(m,4H),3.49–3.21(m,2H),2.95–2.75(m,2H),2.53–1.72(m,15H),1.50–0.85(m,12H).
Example 19 Synthesis of Compound S18
As shown in scheme 4:
Scheme 4
compound S12(150mg, 0.328mmol) was dissolved in 5ml of anhydrous methanol, cooled to-2 ℃ and sodium borohydride (25mg, 0.656mmol) was slowly added and reacted at-2 ℃ for 2 hours. Adding 100ul of mixed solvent of formic acid and 1ml of methanol, spin-drying the solvent under reduced pressure, adding water and CH2Cl2Extracting, washing with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. The solvent was dried by rotary evaporation under reduced pressure to give 142mg of a white solid.
1H NMR(300MHz,Chloroform-d)δ6.99(d,J＝8.3Hz,1H),6.72(d,J＝8.3Hz,1H),6.60(s,1H),5.54(s,0.7H),5.34(s,0.38H),5.23(d,J＝6.8Hz,0.76H),5.04(s,0.30H),4.55-4.50(m,1H),3.75(s,3H),3.54-3.46(m,1H),3.28–3.16(m,2H),2.97–2.79(m,3H),2.53–1.92(m,6H),1.69–1.65(m,2H),1.48–1.25(m,6H),1.04-0.94(m,4H).
Example 20 the corresponding starting material was used in place of S12 and the reaction procedure was the same as in example 19.
Example 20 Synthesis of Compound S19
1H NMR(300MHz,Chloroform-d)δ7.21–6.91(m,4H),5.56(s,0.61H),5.35(S,0.39),5.24(s,0.62H),5.08(s,0.41H),4.61-4.56(m,1H),3.84–2.69(m,6H),2.67–1.62(m,8H),1.58–1.16(m,6H),1.14–0.80(m,4H).
Example 21 and example 22, Synthesis of Compound S20 and Compound S21
Compound S18(23mg, 0.05mmol) was dissolved in 1ml of methanol, and trimethyl orthoformate (55ul, 0.5mmol) and p-toluenesulfonic acid (18mg, 0.1mmol) were added to react at 50 ℃ for 3 hours. Adding water, extracting with dichloromethane, washing the organic phase with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. And (4) decompressing, spin-drying the solvent, and performing column chromatography separation to obtain the compounds S2013 mg and S217 mg which are white solids.
Compound S20:1H NMR(500MHz,Chloroform-d)δ7.09(d,J＝8.4Hz,1H),6.78(dd,J＝8.6,2.7Hz,1H),6.64(d,J＝2.7Hz,1H),5.45(s,1H),4.60(s,1H),4.27(s,1H),3.80(s,3H),3.41–3.23(m,6H),2.73–2.62(m,1H),2.41–2.24(m,2H),2.09–1.91(m,4H),1.68–1.28(m,7H),1.00-0.89(m,4H).
compound S21:1H NMR(300MHz,Chloroform-d)δ7.03(d,J＝8.5Hz,1H),6.69(d,J＝8.4Hz,1H),6.59(s,1H),5.36(s,1H),4.64(s,1H),4.54-4.47(m,1H),3.75(s,3H),3.50(s,3H),3.33–2.89(m,4H),2.78–2.67(m,2H),2.41-2.30(m,2H),2.06–1.87(m,3H),1.73–1.25(m,8H),1.08–0.94(m,4H).
example 23 and example 24, Synthesis of Compound S22 and Compound S23
Compound S18(23mg, 0.05mmol) was dissolved in 1ml of ethanol, and triethyl orthoformate (83ul, 0.5mmol) and p-toluenesulfonic acid (18mg, 0.1mmol) were added to react at 50 ℃ for 3 hours. Adding water, extracting with dichloromethane, washing the organic phase with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. And (4) decompressing, spin-drying the solvent, and performing column chromatography separation to obtain the compounds S2214 mg and S237 mg which are white solids.
Compound S22:1H NMR(400MHz,Chloroform-d)δ7.06(d,J＝8.5Hz,1H),6.75(dd,J＝8.5,2.7Hz,1H),6.60(d,J＝2.6Hz,1H),5.43(s,1H),4.57-4.54(m,1H),4.31(s,1H),3.77(s,3H),3.73-3.66(m,1H),3.47–3.19(m,4H),3.06–3.01(m,1H),2.66-2.64(m,2H),2.35–2.19(m,2H),2.06–1.90(m,4H),1.65-1.61(m,1H),1.52-1.41(m,4H),1.33–1.23(m,2H),1.12(t,J＝7.1Hz,3H),0.99-0.93(m,4H).
compound S23:1H NMR(400MHz,Chloroform-d)δ7.06(d,J＝8.4Hz,1H),6.72(d,J＝8.4Hz,1H),6.61(s,1H),5.37(s,1H),4.73(s,1H),4.55-4.50(m,1H),4.00–3.96(m,1H),3.77(s,3H),357-3.49(m,1H),3.41-3.35(m,1H),3.20-3.09(m,2H),2.99-2.93(m,1H),2.83–2.75(m,2H),2.37–2.32(m,2H),2.07–1.89(m,3H),1.72–1.69(m,1H),1.49-1.29(m,7H),1.15(t,J＝7.1Hz,3H),1.05–0.95(m,4H).
example 25 and example 26, Synthesis of Compound S24 and Compound S25
Compound S3(23mg, 0.05mmol) was dissolved in 1ml of methanol, and trimethyl orthoformate (55ul, 0.5mmol) and p-toluenesulfonic acid (18mg, 0.1mmol) were added to react at 50 ℃ for 3 hours. Adding water, extracting with dichloromethane, washing the organic phase with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. And (4) decompressing, spin-drying the solvent, and performing column chromatography separation to obtain the compounds S2413 mg and S257 mg which are white solids.
Compound S24:1H NMR(300MHz,Chloroform-d)δ7.34–7.27(m,3H),5.53(s,1H),4.88(s,1H),3.61–3.57(m,5H),2.39–2.18(m,2H),2.15–2.02(m,2H),1.94-1.88(m,1H),1.73–1.68(m,1H),1.54–1.25(m,7H),1.02–0.97(m,4H).
compound S25:1H NMR(300MHz,Chloroform-d)δ7.33–7.23(m,3H),5.43(s,1H),4.79(s,1H),3.82(d,J＝18.2Hz,1H),3.58–3.46(m,4H),2.37–2.31(m,2H),2.09–1.86(m,3H),1.76–1.70(m,1H),1.56–1.23(m,7H),1.08–0.94(m,4H).
example 27 and example 28, Synthesis of Compound S26 and Compound S27
Compound S2(87mg, 0.2mmol) was dissolved in 1ml of methanol, and trimethyl orthoformate (219ul, 2mmol) and p-toluenesulfonic acid (41mg, 0.24mmol) were added to react at 50 ℃ for 3 hours. Adding water, extracting with dichloromethane, washing the organic phase with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. And (4) decompressing, spin-drying the solvent, and performing column chromatography separation to obtain the compounds S2658 mg and S2727 mg which are white solids.
Compound S26:1H NMR(400MHz,Chloroform-d)δ7.63(d,J＝8.1Hz,2H),7.36(d,J＝8.2Hz,2H),5.52(s,1H),4.62(s,1H),3.71–3.52(m,5H),2.39–2.32(m,1H),2.21–1.89(m,4H),1.69-1.62(m,1H),1.53–1.25(m,7H),1.08-0.92(m,4H).
compound S27:1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝8.0Hz,2H),7.34(d,J＝8.4Hz,2H),5.43(s,1H),3.93(d,J＝18.0Hz,1H),3.51(s,3H),3.35(d,J＝18.0Hz,1H),2.37–2.29(m,2H),2.09–1.89(m,5H),1.76-1.67(m,1H),1.61–1.29(m,7H),1.09–0.93(m,4H).
example 29 and example 30, Synthesis of Compound S28 and Compound S29
Compound S18(46mg, 0.1mmol) was dissolved in 2ml dry dichloromethane, cooled to 0 deg.C, DAST (26ul, 0.2mmol) was added slowly and the reaction was raised to 40 deg.C for 3 hours. Adding water, extracting with dichloromethane, washing the organic layer with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. The solvent is dried by decompression and column chromatography purification is carried out to obtain the compounds S2828 mg and S2911 mg which are white solids.
Compound S28:1H NMR(400MHz,Chloroform-d)δ7.04(d,J＝8.7Hz,1H),6.76(d,J＝8.5,1H),6.62(s,1H),5.58(s,1H),5.04(d,J＝53.3Hz,1H),4.58-4.56(m,1H),3.78(s,3H),3.38–3.23(m,3H),3.07–3.03(m,1H),2.70–2.56(m,2H),2.40–2.30(m,2H),2.08–1.88(m,3H),1.78–1.65(m,2H),1.53–1.25(m,6H),1.03-0.93(m,4H).
compound S29:1H NMR(400MHz,Chloroform-d)δ7.06(d,J＝8.4Hz,1H),6.74(dd,J＝8.5,2.7Hz,1H),6.62(d,J＝2.7Hz,1H),5.55(d,J＝52.9Hz,1H),5.47(s,1H),4.56(dd,J＝10.7,6.2Hz,1H),3.77(s,2H),3.27–3.15(m,3H),3.00(m,1H),2.79–2.68(m,2H),2.42-2.34(m,2H),2.09–1.91(m,3H),1.75-1.71(m,1H),1.53-1.42(m,4H),1.36-1.26(m,3H),1.08–0.97(m,4H).
example 31 Synthesis of Compound S30
Compound S18(15mg, 0.033mmol) was dissolved in 1ml of dichloromethane, succinic anhydride (7mg, 0.066mmol) was added, cooling was performed to 0 ℃, DMAP (4mg, 0.033mmol) was added, reaction was performed at 0 ℃ for 0.5 hours, and reaction was performed at room temperature for 1 hour. Water was added thereto, the PH was adjusted to 3 with 10% dilute hydrochloric acid, dichloromethane was extracted, the organic layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure to give 18mg of a white solid.
1H NMR(300MHz,Chloroform-d)δ7.08(d,J＝8.6Hz,1H),6.76(dd,J＝8.3,2.6Hz,1H),6.58(d,J＝2.7Hz,1H),5.99(s,1H),5.52(s,0.18H),5.44(s,0.83H),461-4.56(m,1H),3.74-3.73(m,4H),3.35–3.28(m,2H),3.15-3.09(m,1H),2.92-2.81(m,2H),2.64-2.61(m,1H),2.49–2.23(m,4H),2.15–1.87(m,4H),1.73-1.64(m,1H),1.48–1.29(m,7H),1.07-0.95(m,4H).
Example 32 Synthesis of Compound S31
As shown in scheme 5:
Scheme 5
compound S18(70mg, 0.15mmol) was dissolved in 2ml of dry dichloromethane and DBU (4ul, 0.03mmol), CCl were added at room temperature3CN (75ul, 0.75mmol), reacting at room temperature for 30 min at 0 deg.C, cooling to 0 deg.C, adding 2-bromoethanol (53ul, 0.75mmol), slowly adding TMSOTf (6ul, 0.03mmol), and reacting at room temperature for 1 hr. Adding water, extracting with dichloromethane, washing the organic layer with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. The solvent was dried by rotary evaporation under reduced pressure, and purified by column chromatography to give an intermediate 537 mg.
Intermediate 5(25mg, 0.05mmol) was dissolved in dry 1ml acetonitrile and K was added2CO3(35mg, 0.25mmol) and morpholine (22mg, 0.05mmol) were reacted at 50 ℃ for 12 hours until the starting material disappeared completely. Adding water, extracting with dichloromethane, washing the organic layer with water, washing with saturated salt water, and drying with anhydrous sodium sulfate. And (4) decompressing, spin-drying the solvent, and purifying by column chromatography to obtain the compound S3122 mg.
Intermediate 5:1H NMR(300MHz,Chloroform-d)δ7.05(d,J＝8.4Hz,1H),6.74(d,J＝8.4Hz,1H),6.59(s,1H),5.54(s,1H),4.55-4.50(m,1H),4.29(s,1H),3.93–3.61(m,5H),3.49–2.93(m,7H),2.68-2.62(m,2H),2.37–1.85(m,4H),1.66–1.53(m,1H),1.49–1.23(m,7H),1.00–0.83(m,4H).
compound S31:1H NMR(300MHz,Chloroform-d)δ7.04(d,J＝8.4Hz,1H),6.73(dd,J＝8.5,2.6Hz,1H),6.58(d,J＝2.6Hz,1H),5.60(s,1H),4.54–4.31(m,1H),4.31(s,1H),3.76–3.66(m,7H),3.51–3.18(m,4H),3.02–2.15(m,11H),2.04–1.86(m,4H),1.63-1.58(m,1H),1.50–1.24(m,7H),0.98–0.90(m,4H).
examples 33 to 34 were carried out using the corresponding secondary amines in place of morpholine, and all the reaction procedures were the same as in example 34.
Example 33 Synthesis of Compound S32
1H NMR(300MHz,Chloroform-d)δ7.03(d,J＝8.4Hz,1H),6.77–6.68(d,J＝8.4Hz,1H),6.57(s,1H),5.56(s,1H),4.53-4.43(m,1H),4.31(s,1H),3.75(s,3H),3.51–2.95(m,6H),2.70–1.83(m,20H),1.62–1.23(m,8H),0.97-0.85(m,4H).
Example 34 Synthesis of Compound S33
1H NMR(300MHz,Chloroform-d)δ7.03(d,J＝8.6Hz,1H),6.72(d,J＝8.5Hz,1H),6.58(s,1H),5.62(s,1H),5.05(m,2H),4.54-4.49(m,1H),4.34(s,1H),3.88–3.74(m,4H),3.61–3.46(m,3H),3.35–2.55(m,11H),2.34–1.78(m,6H),1.58-1.53(m,1H),1.38–1.19(m,7H),0.95-0.85(m,4H).
Example 35 and example 36, Synthesis of Compound S34 and Compound S35
As shown in scheme 6:
Scheme 6
synthesis of intermediate 6 is described in Bioorganic & Medicinal chemistry 2009,17, 1325-
The synthesis of intermediate 7 is referred to J.Med.chem.1997,40,633-638.
Intermediate 7:1H NMR(300MHz,Chloroform-d)δ6.39(s,1H),5.76(s,1H),5.61(s,1H),2.80–2.74(m,1H),1.93–1.12(m,12H),1.08–0.85(m,4H).
synthesis of compounds S34 and S35 reference was made to the synthesis of compound S8.
Compound S34:1H NMR(300MHz,Chloroform-d)δ7.03(d,J＝8.1Hz,1H),6.75(d,J＝8.7Hz,1H),6.66(s,1H),5.78(s,1H),4.58-4.51(m,1H),3.78(s,3H),3.57–3.49(m,1H),3.40–3.35(m,2H),3.11-3.01(m,1H),2.83-2.78(m,1H),2.64-2.55(m,1H),2.45–2.28(m,2H),1.95–1.78(m,2H),1.68–1.44(m,5H),1.27–0.88(m,8H).
compound S35:1H NMR(300MHz,Chloroform-d)δ6.98(d,J＝8.5Hz,1H),6.73(d,J＝8.5Hz,1H),6.62(s,1H),5.70(s,1H),4.89-4.83(m,1H),3.76(s,3H),3.40-3.37(m,1H),3.06–2.85(m,3H),2.77–2.54(m,2H),2.35–2.29(m,1H),2.13-2.09(m,1H),1.92–1.69(m,3H),1.57-1.49(m,4H),1.30–0.85(m,8H).
example 37 Synthesis of Compound S36
Compound S12(46mg, 0.1mmol) was dissolved in dry 2ml acetonitrile, nitrogen was replaced and FeSO was added4.7H2O (28mg, 0.1mmol), reacted at 37 ℃ for 5 h. Filtering, vacuum evaporating to remove solvent, and purifying by column chromatography to obtain compound S3619 mg as white solid.
1H NMR(300MHz,Chloroform-d)δ7.02(d,J＝8.5Hz,1H),6.72(d,J＝8.5Hz,1H),6.63(s,1H),5.71(s,1H),4.54-4.48(m,1H),3.75(s,3H),3.62(s,1H),3.53–3.24(m,3H),3.09-2.98(m,1H),2.81-2.74(m,1H),2.61–2.33(m,4H),2.02–1.94(m,1H),1.85–1.81(m,1H),1.59-1.51(m,J＝8.7Hz,5H),1.21–0.91(m,6H).
Example 38 Synthesis of Compound S37
As shown in scheme 7
schem 7
1-Boc-4-piperidinecarboxylic acid (1.145g, 5mmol) was dissolved in 40ml of dichloromethane, HATU (3.802g, 10mmol) was added, and after stirring at room temperature for ten minutes, tetradecylamine (1.065g, 5mmol), HOAT (0.681g, 5mmol) and DIPEA (1.938g, 15mmol) were added in that order. After stirring at room temperature for two hours, the mixture was washed with 5% dilute hydrochloric acid, saturated sodium bicarbonate, water, saturated common salt water, anhydrous sodium sulfate, and the solvent was dried by spin-drying under reduced pressure, and the resulting crude product was dissolved in 50ml of dichloromethane, and trifluoroacetic acid (5.7g, 50mmol) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was made weakly alkaline with 10% sodium hydroxide, the organic layer was separated and washed with water, with saturated saline, and dried over anhydrous sodium sulfate. The solvent was spin-dried under reduced pressure to give intermediate 8.
Intermediate 8(65mg, 0.2mmol) was dissolved in 2ml chloroform, Davis oxidant (53mg, 0.2mmol) was added at room temperature, and the mixture was stirred at room temperature for one hour. Directly spin-drying, dissolving, and purifying with column to obtain intermediate 929 mg.
Intermediate 9(26mg, 0.077mmol) was dissolved in 2ml of dry toluene, intermediate 1(43mg, 0.153mmol) was added and stirred at room temperature for about 12 hours until intermediate 1 was no longer reduced and the reaction was stopped. The solvent was evaporated under reduced pressure and column chromatography was performed to give compound S3719 mg as a white solid.
Intermediate 8:1H NMR(300MHz,Chloroform-d)δ5.52-5.49(m,1H),3.25-3.11(m,4H),2.61(t,J＝12.0Hz,2H),2.23-2.15(m,1H),1.95-1.78(m,5H),1.66–1.21(m,24H),0.88–0.83(m,3H).
intermediate 9: 1H NMR (300MHz, Chloroform-d) Δ 7.16(s,1H),6.20-6.13(m,1H),3.91-3.71(m,2H),3.28-3.14-2.15(m,2H),2.85-2.41(m,3H), 2.23-2.04 (m,2H),1.54-1.15(m, 24H), 0.91-0.82 (m,3H).
Compound S37:1H NMR(300MHz,Chloroform-d)δ5.93(s,1H),5.62(s,0.73H),5.55(s,0.27H),3.67-3.59(m,1H),3.46-3.41(m,1H),3.24-3.17(m,2H),2.82-2.79(m,2H),2.50–1.73(m,12H),1.50–0.83(m,38H).
example 39 determination of antitumor Activity of artemisinin derivatives
The compounds of the invention were tested for their inhibitory activity at the cellular level on tumor cell proliferation by the following pharmacological experiments:
(1) experimental Material
Tumor cell lines: human oral squamous carcinoma KB cell, vincristine-resistant KB-VCR cell, human non-small cell lung cancer A549 cell
Reagent: artemisinin, the artemisinin derivative of the invention
(2) Experimental methods
By adopting an SRB method and taking artemisinin as a positive control, the proliferation inhibition effect of the artemisinin derivative on KB, KB/VCR and A549 cells is evaluated. The compounds were used in the experiments with a maximum final concentration of 20. mu.M, diluted 5-fold downward, and treated for 72 hours in 6 concentration gradients.
(3) Results of the experiment
The results are shown in Table 1.
TABLE 1 examples the proliferation inhibitory activity of artemisinin derivatives on tumor cells
Note: ND means that the compound was not subjected to the activity assay.
The experimental results show that: compared with artemisinin, the artemisinin derivative has different degrees of enhancement on the proliferation inhibition effect of KB, KB/VCR and A549 cells. Among them, S8, S11 and S13 provide over 20 times of inhibition effect on KB, KB/VCR and A549 cell proliferation, so the compounds of the invention have better application prospect.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A compound of formula II, III or IV having a structure selected from the group consisting of:
wherein n is 0 or 1;
m is 0 to 3;
x is H, O, hydroxy, halogen, OR-OR7；
R2Selected from the group consisting of: hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: c1-C16Alkyl of (C)1-C6Alkoxy, hydroxy, halogen, -OC (O) R6、-COOR6(ii) a The aryl is a monocyclic aromatic group containing 6 carbon atoms; the heteroaryl group is a monocyclic heteroaryl group having 5 to 7 ring atoms, and 1 to 4 heteroatoms are included as ring members, and the heteroatom means nitrogen, oxygen or sulfur; r3Selected from the group consisting of: hydrogen, hydroxy;
R4is one or more substituents selected from the group consisting of: H. substituted or unsubstituted C1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino group of-NHC (O) R6、-CONHR6Halogen, nitro, cyano, -OC (O) R6、-COOR6；
Y is CH2O, S, or NR5(ii) a Wherein R is5Selected from the group consisting of: H. c1-C6Alkyl of, -C (O) R6、-COOR6、-S(O)2R6、-S(O)R6；
R6Is H or substituted or unsubstituted C1-C16Alkyl groups of (a);
R7selected from the group consisting of: H. substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6An acyl group; wherein the substituents may be C1-C4Alkoxy, hydroxy, carboxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino groups, halogen, nitro, cyano, -OC (O) R6，-COOR6；
Or said compound has a structure selected from the group consisting of:
wherein k is 8, 9, 10, 11, 12, 13, 14;
i is 0, 1, 2 and 3;
unless specified, everywhere substituted as described above means that one or more substituents on the group are substituted with a substituent selected from the group consisting of: c1-C6Alkyl of (C)1-C4Alkoxy, hydroxy, amino, C1-C6Alkyl-substituted secondary or tertiary amino, carboxyl, -NHC (O) R6，-CONHR6Halogen, nitro, cyano, -OC (O) R6，-COOR6Wherein R is6Is H or substituted or unsubstituted C1-C16Alkyl group of (1).
2. The compound of formula (I) according to claim 1, having a structure selected from the group consisting of:
wherein the content of the first and second substances,
m is 0, 1 or 2;
k is 8, 9, 10, 11, 12, 13, 14;
i is 0, 1, 2 and 3;
R4is one or more substituents selected from the group consisting of: c1-C4Alkoxy, hydroxy, halogen, nitro, cyano, -CONHR6，-COOR6；
Y is CH2、O、S、NR5。
3. A compound of formula (I) as claimed in claim 2 wherein R is4Selected from the group consisting of: c1-C4Alkoxy, hydroxy, halogen, -CONHR6，-COOR6。
4. A compound of formula (I) according to claim 1, selected from the group consisting of:
5. a compound selected from the group consisting of:
6. a process for the preparation of a compound of formula (I) as claimed in claim 1, comprising step (b), and optionally step (c):
(b) from intermediate 1 with nitrile oxides
Reacting to obtain a product 2;
(c) carrying out reduction reaction on the product 2 to reduce carbonyl, and then reacting with trimethyl orthoformate to obtain a product 3;
or the reaction comprises step (d), and optionally step (e), or optionally step (f) and optionally (g):
(d) intermediate 1 with nitrones
Reacting to obtain a product 4;
(e) carrying out reduction reaction on the product 4, reducing carbonyl of the product, and reacting the product with orthoformate to obtain a product 5; wherein i is 0 or 1;
(f) carrying out reduction reaction on the product 4 to reduce carbonyl of the product, and then reacting the product with bromoethanol to obtain an intermediate 6;
(g) intermediate 6 is used to obtain the compound of formula 7; wherein M is selected from the group consisting of:
or said reaction comprises step (d), and optionally step (h)
(d) Intermediate 1 with nitrones
Reacting to obtain a product 4;
(h) the product 4 reacts with ferrous chloride to obtain a product 8;
or the reaction comprises step (i):
(i) intermediate 1 with nitrones
Reacting to obtain an intermediate 9; wherein Y is as defined in claim 3;
or the reaction comprises step (j), and optionally step (k):
(j) reacting with artemisinin to obtain an intermediate 10;
(k) carrying out a reaction by using the intermediate 10 to obtain an intermediate 11;
wherein, unless otherwise specified, the definitions of the groups are as described in claim 1;
the orthoformate is trimethyl orthoformate or triethyl orthoformate.
7. Use of a compound of formula (I), its optical isomers, its pharmaceutically acceptable salts, as claimed in claim 1, for the preparation of a medicament for the treatment of tumors.
8. The use of claim 7, wherein the tumor is selected from the group consisting of: lung cancer, colon cancer, oral epithelial cancer, gastric cancer, or leukemia.
9. The use of claim 8, wherein the tumor is selected from the group consisting of: squamous cell carcinoma of oral cavity, human non-small cell lung cancer.
10. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
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| CN104211712A (en) * | 2013-06-04 | 2014-12-17 | 中国科学院上海药物研究所 | Artemisinin derivative containing heteroaryl piperidine, preparation method and application thereof |
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| CN104211712A (en) * | 2013-06-04 | 2014-12-17 | 中国科学院上海药物研究所 | Artemisinin derivative containing heteroaryl piperidine, preparation method and application thereof |
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