阅读说明：本技术 用于抑制肿瘤形成的材料 (Materials for inhibiting tumor formation ) 是由 不公告发明人 于 2020-06-19 设计创作，主要内容包括：用于抑制肿瘤形成的材料。提供了下式(1)表示的化合物在制备抑制肿瘤形成的药物中的用途,式中：R-(1)和R-(2)各自表示氢、卤素、羟基、取代或未取代的C-(1)-C-(30)烷基、取代或未取代的C-(1)-C-(30)烷氧基或取代或未取代的C-(3)-C-(30)环烷基；n表示1-10的整数；m表示1-100的整数。(A material for inhibiting tumor formation. There is provided the use of a compound represented by the following formula (1) in the manufacture of a medicament for inhibiting the formation of a tumour, wherein: r 1 And R 2 Each represents hydrogen, halogen, hydroxy, substituted or unsubstituted C 1 ‑C 30 Alkyl, substituted or unsubstituted C 1 ‑C 30 Alkoxy or substituted or unsubstituted C 3 ‑C 30 A cycloalkyl group; n represents an integer of 1 to 10; m represents an integer of 1 to 100.)

1. Use of a compound represented by the following formula (1) for the preparation of a medicament for inhibiting tumor formation:

in the formula: r₁And R₂Each represents hydrogen, halogen, hydroxy, substituted or unsubstituted C₁-C₃₀Alkyl, substituted or unsubstituted C₁-C₃₀Alkoxy or substituted or unsubstituted C₃-C₃₀A cycloalkyl group;

n represents an integer of 1 to 10;

m represents an integer of 1 to 100.

2. The use according to claim 1, wherein R is₁And R₂Each represents substituted or unsubstituted C₁-C₃₀Alkyl, preferably substituted or unsubstituted C₁-C₂₀Alkyl, more preferably substituted or unsubstituted C₁-C₁₅Alkyl, even more preferably substituted or unsubstituted C₁-C₁₀Alkyl, most preferably substituted or unsubstituted C₁-C₆An alkyl group.

3. The use according to claim 1, wherein R is₁And R₂Each independently represents substituted or unsubstituted C₁-C₃₀Alkoxy, preferably substituted or unsubstituted C₁-C₂₀Alkoxy, more preferably substituted or unsubstituted C₁-C₁₅Alkoxy, even more preferably substituted or unsubstituted C₁-C₁₀Alkoxy, most preferably substituted or unsubstituted C₁-C₆An alkoxy group.

4. The use according to claim 1, wherein R is₁And R₂Each independently represents substituted or unsubstituted C₃-C₃₀Cycloalkyl, preferably substituted or unsubstituted C₃-C₂₀Cycloalkyl, more preferably substituted or unsubstituted C₃-C₁₀Cycloalkyl, most preferably substituted or unsubstituted C₃-C₆A cycloalkyl group.

5. Use according to claim 1, wherein n represents 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

6. Use according to claim 1, wherein m represents 1-80, 1-60, 1-50, 1-40, 1-30, 1-20, 1-10, or 5-100, 10-100, 20-100, 30-100, 40-100, 50-100, 60-100.

7. The use according to claim 1, wherein the compound represented by formula 1 is represented by the following formula (2):

in the formula: x and y each represent an integer of 0 to 100, provided that x + y is not 0.

8. The use according to claim 1, wherein the compound is selected from polyethylene glycol, polypropylene glycol or a combination thereof; preferably, the compound is selected from the group consisting of polyethylene glycol having a molecular weight of 100-; preferably, the compound is selected from PEG200, PEG400, PEG600, and the like.

9. The use of claim 1, wherein said tumor comprises a benign tumor and a malignant tumor; preferably, benign tumors include mammary fibroids, cysts, lipomas, gallbladder polyps, nodules, and the like; the malignant tumor includes lung cancer, breast cancer, carcinoma of large intestine, hepatocarcinoma, brain cancer, osteocarcinoma, esophageal cancer, thyroid cancer, pancreatic cancer, endometrial cancer, ovarian cancer, cervical cancer, etc.

Technical Field

The present application relates to a material for inhibiting tumor formation.

Background

Polyether oligomers are commonly used as cosolvents (solubilizers) for pharmaceutical active ingredients. Generally, polyether oligomers used as co-solvents include polyethylene glycol (PEG), polypropylene glycol (PPG), and derivatives thereof. It is generally believed that these co-solvents are safe for the human body and do not interfere with the pharmaceutically active ingredient.

The tumor is a new organism formed by that certain cells of local tissues lose normal regulation and control on the growth of the local tissues at the gene level under the action of various carcinogenic factors, so that the local tissues are clonally abnormally proliferated. It is generally accepted that tumor cells are monoclonal, i.e., all tumor cells in a tumor are progeny of a mutated cell. Tumors are generally classified into two broad categories, benign and malignant. Benign tumors are commonly referred to as "tumors", malignant tumors from epithelial tissue as "carcinomas", and from mesenchymal tissue as "sarcomas". Certain such malignant tumors may also be referred to as "tumors" or "diseases," such as malignant lymphoma, seminoma, leukemia, hodgkin's disease, and the like. All malignant tumors are customarily known as cancers or carcinomas.

Currently, tumors (including benign tumors and malignant tumors) have an increasing impact on the health (including mental health) of the human body. Therefore, there is a high necessity for a new material which can be used for inhibiting tumor formation.

Disclosure of Invention

The present invention relates to a novel material which is useful for inhibiting the formation of tumors, including benign tumors and malignant tumors.

In one aspect, the present invention provides the use of a compound represented by the following formula (1) for the preparation of a medicament for inhibiting tumor formation:

in the formula: r₁And R₂Each represents hydrogen, halogen, hydroxy, substituted or unsubstituted C₁-C₃₀Alkyl, substituted or unsubstituted C₁-C₃₀Alkoxy or substituted or unsubstituted C₃-C₃₀A cycloalkyl group;

n represents an integer of 1 to 10;

m represents an integer of 1 to 100.

In one example of the present application, the R₁And R₂Each represents substituted or unsubstituted C₁-C₃₀Alkyl, preferably substituted or unsubstituted C₁-C₂₀Alkyl, more preferably substituted or unsubstituted C₁-C₁₅Alkyl, even more preferably substituted or unsubstituted C₁-C₁₀Alkyl, most preferably substituted or unsubstituted C₁-C₆An alkyl group.

In one example of the present application, the R₁And R₂Each independently represents substituted or unsubstituted C₁-C₃₀Alkoxy, preferably substituted or unsubstituted C₁-C₂₀Alkoxy, more preferably substituted or unsubstituted C₁-C₁₅Alkoxy, even more preferably substituted or unsubstituted C₁-C₁₀Alkoxy, most preferably substituted or unsubstituted C₁-C₆An alkoxy group.

In one example of the present application, the R₁And R₂Each independently represents substituted or unsubstituted C₃-C₃₀Cycloalkyl, preferably substituted or unsubstituted C₃-C₂₀Cycloalkyl, more preferably substituted or unsubstituted C₃-C₁₀Cycloalkyl, most preferably substituted or unsubstituted C₃-C₆A cycloalkyl group.

In one example of the present application, n represents 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In one example of the application, m represents 1-80, 1-60, 1-50, 1-40, 1-30, 1-20, 1-10, or 5-100, 10-100, 20-100, 30-100, 40-100, 50-100, 60-100.

In one example of the present application, the compound represented by formula 1 is represented by the following formula (2):

in the formula: x and y each represent an integer of 0 to 100, provided that x + y is not 0.

In one example of the present application, the compound is selected from polyethylene glycol, polypropylene glycol, or a combination thereof; preferably, the compound is selected from the group consisting of polyethylene glycol having a molecular weight of 100-; preferably, the compound is selected from PEG200, PEG400, PEG600, and the like.

In one example of the present application, the tumor includes benign tumors and malignant tumors; preferably, benign tumors include mammary fibroids, cysts, lipomas, gallbladder polyps, nodules, and the like; the malignant tumor includes lung cancer, breast cancer, carcinoma of large intestine, hepatocarcinoma, brain cancer, osteocarcinoma, esophageal cancer, thyroid cancer, pancreatic cancer, endometrial cancer, ovarian cancer, cervical cancer, etc.

Drawings

FIG. 1 depicts a comparison of tumor numbers in spontaneously tumorous rats in two groups of rats.

Detailed Description

In this context, percentages (%) or parts are percentages by weight or parts by weight relative to the composition, unless otherwise specified.

In this context, the individual components mentioned or their preferred components can be combined with one another to form new technical solutions, if not stated otherwise.

All embodiments and preferred embodiments mentioned herein can be combined with each other to form new solutions, if not specified otherwise.

In this context, all technical features mentioned herein, as well as preferred features, can be combined with each other to form new technical solutions, if not specifically stated.

In this context, the sum of the contents of the individual components in the composition is 100%, if not stated to the contrary.

In this context, the sum of the parts of the components in the composition may be 100 parts by weight, if not stated to the contrary.

In this context, unless otherwise stated, the numerical range "a-b" represents a shorthand representation of any combination of real numbers between a and b, where a and b are both real numbers. For example, a numerical range of "0 to 5" indicates that all real numbers between "0 to 5" have been listed herein, and "0 to 5" is only a shorthand representation of the combination of these numbers.

As used herein, unless otherwise indicated, the range of integer values "a-b" represents a shorthand representation of any combination of integers between a and b, where a and b are both integers. For example, an integer numerical range of "1-N" means 1, 2 … … N, where N is an integer.

In this context, unless otherwise stated, "combinations thereof" means multi-component mixtures of the individual elements mentioned, for example two, three, four and up to the maximum possible multi-component mixtures.

The term "a" or "an" as used herein means "at least one" if not otherwise specified.

Percentages (including weight percentages) recited herein are based on the total weight of the composition, unless otherwise specified.

The "ranges" disclosed herein are in the form of lower and upper limits. There may be one or more lower limits, and one or more upper limits, respectively. The given range is defined by the selection of a lower limit and an upper limit. The selected lower and upper limits define the boundaries of the particular range. All ranges that can be defined in this manner are inclusive and combinable, i.e., any lower limit can be combined with any upper limit to form a range. For example, ranges of 60-120 and 80-110 are listed for particular parameters, with the understanding that ranges of 60-110 and 80-120 are also contemplated. Furthermore, if the minimum range values 1 and 2 are listed, and if the maximum range values 3, 4, and 5 are listed, the following ranges are all contemplated: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5.

In this specification, the term "C" if not otherwise stated_n-C_m"denotes an organic group, n and m are integers, each of which may contain from n to m carbon atoms.

In the present specification, the term "alkyl" means, if not otherwise stated, a saturated hydrocarbon group which may be straight-chain or branched, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, inorganic and n-hexyl.

In the present specification, the term "cycloalkyl" denotes, if not otherwise stated, a saturated hydrocarbon group comprising one or more cycloalkyl rings, such as cyclopentyl, cyclooctyl and adamantyl.

In the present specification, the term "alkoxy" means, unless otherwise stated, a monovalent group consisting of an alkyl group plus an oxygen atom-RO (e.g., methoxy).

In the present specification, the term "alkenyl" denotes, if not otherwise stated, an unsaturated straight-chain or branched hydrocarbon radical containing one or more carbon-carbon double bonds, such as unsaturated straight-chain or branched (C)₂-C₂₂) Hydrocarbon radicals, e.g. vinyl, n-butylPropenyl and isopropenyl.

In this specification, unless otherwise stated, the term "substituted" or the like means that the group contains one or more substituents including, but not limited to, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, (C)₁-C₃₀) Alkyl (preferably (C)₁-C₆) Alkyl group), (C)₂-C₃₀) Alkenyl (preferably (C)₂-C₆) Alkenyl group), (C)₁-C₃₀) Alkoxy (preferably (C)₁-C₆) Alkoxy group), (C)₁-C₃₀) Alkylthio (preferably (C)₁-C₆) Alkylthio group), (C)₃-C₃₀) Cycloalkyl (preferably (C)₃-C₆) Cycloalkyl group), (C)₆-C₃₀) Aryl (preferably (C)₆-C₁₄) Aryl or C₆Aryl or phenyl) or amino.

In one aspect, the present invention provides the use of a compound represented by the following formula (1) for the preparation of a medicament for inhibiting tumor formation:

in the formula: r₁And R₂Each represents hydrogen, halogen, hydroxy, substituted or unsubstituted C₁-C₃₀Alkyl, substituted or unsubstituted C₁-C₃₀Alkoxy or substituted or unsubstituted C₃-C₃₀A cycloalkyl group;

n represents an integer of 1 to 10;

m represents an integer of 1 to 100.

In a preferred embodiment of the present application, said R₁And R₂Each represents substituted or unsubstituted C₁-C₃₀Alkyl, preferably substituted or unsubstituted C₁-C₂₀Alkyl, more preferably substituted or unsubstituted C₁-C₁₅Alkyl, even more preferably substituted or unsubstituted C₁-C₁₀Alkyl, most preferably substituted or unsubstituted C₁-C₆An alkyl group. In this specificationIn another example of (1), the R₁And R₂Each independently represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In one example of the present specification, the R is₁And R₂Each independently represents substituted or unsubstituted C₁-C₃₀Alkoxy, preferably substituted or unsubstituted C₁-C₂₀Alkoxy, more preferably substituted or unsubstituted C₁-C₁₅Alkoxy, even more preferably substituted or unsubstituted C₁-C₁₀Alkoxy, most preferably substituted or unsubstituted C₁-C₆An alkoxy group. In another example of the present specification, the R₁And R₂Each independently represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.

In one example of the present specification, the R is₁And R₂Each independently represents substituted or unsubstituted C₃-C₃₀Cycloalkyl, preferably substituted or unsubstituted C₃-C₂₀Cycloalkyl, more preferably substituted or unsubstituted C₃-C₁₀Cycloalkyl, most preferably substituted or unsubstituted C₃-C₆A cycloalkyl group. In another example of the present specification, the R₁And R₂Each independently represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one example of the present specification, halogen represents F, Cl, Br or I.

In one example of the present specification, n represents an integer of 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In one example of the present specification, m represents an integer of 1 to 100, such as 1 to 80, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10, or 5 to 100, 10 to 100, 20 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100.

In one example of the present specification, the compound represented by formula 1 is represented by the following formula (2):

in the formula: x and y each represent an integer of 0 to 100, provided that x + y is not 0.

In a preferred embodiment of the present application, x and y each represent an integer of 0 to 100, such as 1 to 80, 0 to 60, 0 to 50, 0 to 40, 0 to 30, 0 to 20, 0 to 10, or 5 to 100, 10 to 100, 20 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100.

In a preferred embodiment of the present application, x + y is an integer from 1 to 100, such as from 1 to 80, from 1 to 60, from 1 to 50, from 1 to 40, from 1 to 30, from 1 to 20, from 1 to 10, or from 5 to 100, from 10 to 100, from 20 to 100, from 30 to 100, from 40 to 100, from 50 to 100, from 60 to 100.

In one example of the present specification, the compound is selected from polyethylene glycol, polypropylene glycol, or a combination thereof. In a preferred embodiment of the present specification, the compound is selected from the group consisting of polyethylene glycol having a molecular weight of 100-2000, polypropylene glycol having a molecular weight of 100-2000, and combinations thereof. In yet another example of the present specification, the compound is selected from PEG200, PEG400, PEG600, and the like.

The compounds of formula (1) described in the present specification can be obtained by methods known in the art, and can be obtained commercially. For example, national drug group chemical agents, ltd.

The application also provides application of the compound shown in the formula (1) in drugs for inhibiting tumor formation.

The application also provides a compound shown as a formula (1) for inhibiting tumor formation.

The present application also provides a method for inhibiting tumor formation comprising administering a compound of formula (1) to a subject, including an animal or human, in need of inhibition of tumor formation.

In one example of the present application, the tumor includes, but is not limited to, benign tumors and malignant tumors. Typically, benign tumors include, but are not limited to, mammary fibroids, cysts, lipomas, gallbladder polyps, nodules, and the like; malignant tumors include, but are not limited to, lung cancer, breast cancer, colorectal cancer, liver cancer, brain cancer, bone cancer, esophageal cancer, thyroid cancer, pancreatic cancer, endometrial cancer, ovarian cancer, cervical cancer, and the like.

Specific embodiments of the present application will be described below with reference to examples, but the scope of the present application is not limited thereto.

Example 1

96 SPF grade SD rats (purchased from shanghai sipel-bikeka laboratory animals ltd) aged 18 months were divided into two groups: PEG400 treated group 36 and control group 60. The administration route is as follows: PEG400 (national drug group chemical Co., Ltd.) was diluted in animal drinking water and administered by oral route. The specific method comprises the following steps: PEG400 was diluted in rat drinking water to a final concentration of 0.4% (mass volume concentration). During the experiment, the general physiological status of the rats was observed twice a week, and the drugs and water were renewed and supplemented. The control rats received normal drinking water without PEG 400. The duration of the experimental observation was 6 months, and the observations showed that the average daily water intake of the rats was about 50ml, from which the average daily drug intake of the PEG-treated rats was estimated to be about 0.2 g.

The main observations are described below:

in rats with spontaneous tumors, the number of tumors carried per rat was significantly reduced on average in the PEG 400-treated group (fig. 1).

Among the spontaneously tumorous rats, the number of rats carrying 2 and more tumors in the PEG400 treated group was significantly lower than that of the control group (table 1).

TABLE 1 proportion of rats with 2 or more tumors among spontaneous tumor rats in PEG-treated group and control group

Note: statistical analysis was performed using Fisher's exact test.

Fisher's exact test, P0.0359

Spontaneous mastadenomas in rats were frequently found in superficial subcutaneous sites and were counted by visual observation.