Geranyl compounds, pharmaceutical composition based on thereof and using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to geranyl compounds represented by the following formulas (I-1) , (I-2) or (I-3) wherein R1 means compounds of the following formulas: or R2 means a group remaining after removing all carboxyl groups presenting in carboxylic acid chosen from group consisting of malic acid, citric acid, succinic acid, fumaric acid and others; m = 1, 2 or 3; n = 0, 1 or 2, and m + n represent a number of carboxylic groups presenting in indicated carboxylic acid; R3 means p-hydroxyphenyl or mercapto-group. Also, invention relates to derivatives of mevalonic acid represented by the following formula (I-4): wherein R means -CH2OH or CH3. Also, invention to an antitumor agent comprising as an active component geranyl compound of formulas (I-1), (I-2) or (I-3) or derivative of mevalonic acid of the formula (I-4), and optionally a pharmaceutically acceptable carrier or solvent. Also, invention relates to a method for treatment of liver cancer based on using geranyl compound of formulas (I-1), (I-2) or (I-3), or derivative of mevalonic acid of the formula (I-4) and using proposed compounds in manufacturing an antitumor agent. Invention provides using geranyl compounds or derivatives of mevalonic acid as antitumor agents.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 3 tbl, 17 ex

 

The technical field

This invention relates to new gerrilyn compounds or derivatives of avalonbay acid, and their use as anticancer agents.

Background of invention

Many gerbillinae connection with 1,5-diene structure, are present in vivo and, as you know, in vivo are precursors of substances having a polyene structure and exhibiting various physiological effect. These substances having a 1,5-diene structure, and derived from them the polyene invariably occur from avalonbay acid and is obtained by biosynthesis.

Attention was drawn to such gerbillinae connection with 1,5-diene structure, geranium acid or geraniums, and, in addition, mevalonic acid, which is the basis for the biosynthesis of polyene synthesized various derivatives geranium acid or gerbillinae and avalonbay acid, and investigated their physiological activity, in particular anti-tumor activity and toxicity, and accomplished this invention.

Description of the invention

This invention is gerbillinae compounds represented by the following formulas (I-1), (I-2) or (I-3):

in which

R1oz ACHAT

R2mean residual group remaining after removing all carboxyl groups present in the carboxylic acid selected from the group consisting of malic acid, citric acid, succinic acid, fumaric acid, 2-oxoglutaric acid, pyruvic acid, p-perusaamiaisella acid, retinoic acid, tyrosine, cysteine, glutamic acid and serine, and when the hydroxyl(s) or amino group present in the residual group, they can be optionally protected by acyl (e.g. lower alkanoyl) or benzyloxycarbonyl(s) group(s)

m is 1, 2 or 3,

n is 0, 1 or 2,

m+n together show the number of carboxyl groups that are present in the specified carboxylic acid, and

R3means p-hydroxyphenyl or mercaptopropyl.

This invention is also derived avalonbay acid represented by the following formula (I-4):

(I-4)

in which R4means-CH2HE or-CH3.

These kernelsource derivative of the above formula (I-1) include the following five compounds:

N-geranylgeranyl

N-geranylacetone

N-galactosylceramide

N-glucosylceramide

and N-furazolidone

Gerbillinae derivative represented by the above formula (I-2) include, for example, the following connections.

N,N'-veranlassung diamid

O-acetyl-N-geranylgeranyl monoamide

O-acetyl-N,N'-veranlassung diamid

N,N',N"-trigonelline triamide

N-greenlantern monoamide

N,N'-degranulating diamid

N,N'-digeronimo diamid

N-geranylgeranyl monoamide

N,N'-digernes-2-oxoglutarate diamid

N-geranylgeranyl

N-geranyl-p-pyrovalerone

Tyrosinekinase

N-acetyltransferase

Containername

Glutamine degerenergie

Stringerbell

and N-gerbillinae

And gerbillinae derivative of the above formula (I-3) include the following two connections:

N-Granollers

and N-geranylated

Derivatives avalonbay acid of the above formula (I-4) include, for example, the following:

N-glucosideuronic

N-galactosylceramide

and N-furazolidone

(27)

Among the compounds of formula (I-1), compounds of formulas (1) and (2) can be obtained, for example, exposing geranylated the amidation reaction with a reactive derivative (e.g., mixed acid anhydride, active complex ether, galogenangidridy or the like) glucuronic acid or galacturonic acid, the hydroxyl group of which is protected acyl groups (e.g. acetyl).

Of the compounds of formula (I-1), compounds of formulas (3) through (5) can be obtained, for example, exposing the reactive derivative of geranium acid (e.g., mixed acid anhydride, active ester, halogenmethyl or the like) the amidation reaction using galactosamine is, glucosamine or fucosamine.

This amidation reaction can be carried out by conventional in the field of peptide chemistry methods the amidation reaction, usually in an adequate inert organic solvent (e.g. tetrahydrofuran, chloroform, N,N-dimethylformamide, dichloromethane or the like) or in the water when cooled to approximately 0°With or heated to about 60°C, preferably at from about 0°C to room temperature.

Used the ratio of gerbillinae to reactive derivative of glucuronic acid and galacturonic acid, the hydroxyl group of which is protected, is not strictly limited, but is generally preferable to use geraniums within 1-2 moles per mole of the reactive derivative.

Used the ratio of galactosamine, glucosamine or fucosamine to reactive derivative of geranium acid is also not strictly limited, but is generally preferable to use galactosamine, glucosamine or fucosamine within 1-2 moles per mole of the reactive derivative.

When you are protecting a hydroxyl group, after the amidation reaction these protective groups are removed by reaction of the removal of protection, such as hydrolysis, to obtain garnishing derivatives of the formula (I-1).

Kernelsource derivatives of the formula (I-1), we obtain the e by the above reactions, can be isolated from reaction mixtures and purified by conventional means, for example, extraction, crystallization, chromatography and the like.

Gerbillinae derivative of the above formula (I-2) can be obtained, for example, by carrying out the amidation reaction of gerbillinae with a reactive derivative (e.g., mixed acid anhydride, active complex ether, galogenangidridy and the like) carboxylic acid represented by the formula (II):

in which R2, m and n have the previously submitted values, in which the hydroxyl(s) or amino group(s) protected(s) - acyl (e.g. lower alkanoyl, such as acetyl), benzyloxycarbonyl and similar groups.

This amidation reaction can be carried out by conventional in the field of peptide chemistry methods the amidation reaction, usually in a suitable inert organic solvent (e.g. tetrahydrofuran, simple ether, dichloromethane, chloroform, N,N-dimethylformamide and the like) when cooled to approximately 0°With or heated to about 60°C, preferably at from about 0°C to room temperature.

Used the ratio of gerbillinae to reactive carboxylic acid derivative of the formula (II) varies depending on the number gerbiling groups (m)to be entered into carboxylic acid, while it is generally preferable to use a ratio in the range of from 1 mole to (m+2) moles per mole of the reactive derivative.

When you are protecting a hydroxyl or amino group, after the amidation reaction are removed, when necessary, through reaction of the removal of protection, such as hydrolysis, to obtain gerbilling derivatives of the formula (I-2).

These gerbillinae derivatives of the formula (I-3) can also be obtained, for example, exposing the reactive derivative of geranium acid (for example, mixed angelicity, active ester, halogenmethyl and the like) the amidation reaction with tyrosine or cysteine.

This amidation reaction can also be carried out by conventional in the field of peptide chemistry methods the amidation reaction, usually in an adequate inert organic solvent (e.g. tetrahydrofuran, simple ether, dichloromethane, chloroform, N,N-dimethylformamide and the like) or in the water when cooled to approximately 0°With or heated to about 60°C, preferably at from about 0°C to room temperature.

Used the ratio of tyrosine or cysteine to the reactive derivative of geranium acid is not strictly limited, but it is generally preferable to use one interval within 1-2 moles per mole of the reactive derivative.

Such geranium is an amide derivative of the formula (I-2) or (I-3), obtained by the above reactions can be isolated from reaction mixtures and purified by conventional methods, for example, extraction, crystallization, chromatography and the like.

Derivatives avalonbay acid of the formula (I-4) can be obtained, for example, by the reaction of amino sugar that is represented by the following formula:

in which R4has previously submitted value, or its salts with mevalonate or metalloligands.

This reaction of the amino sugar of the formula (III) or its salt with mevalonate or metalorganic (for example, metalorganic) can be carried out in water or a suitable inert organic solvent (e.g. N,N-dimethylformamide, tetrahydrofuran, chloroform or the like) at a temperature between room temperature and the boiling temperature of the solvent, preferably from about 40°With up to about 70°C.

Used the ratio of mevalonate or maalaiskunta to the amino sugar of the formula (III) are not strictly limited, but is usually preferably 1-2 mol of mevalonate or metalorganic per mole of the amino sugar of the formula (III).

When the salt of the amino sugar of the formula (III) or metalorganic used as an initial matter, it is often desirable to carry out the above reaction with doba the population base, for example tertiary amines, such as N-methylpiperidin; or inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and the like.

Derivatives avalonbay acid of the formula (I-4)obtained by the above reaction can be isolated from reaction mixtures and purified by conventional methods such as extraction, crystallization, chromatography and the like.

Compounds of formula (I-1) to (I-4), proposed by this invention have excellent antitumor activity, which is clear from the following evaluation of the antitumor effect.

Evaluation of the antitumor effect

Cell carcinoma HuH-7 (strain dendriform cells human hepatoma), implanted or subinventory under the skin on the back of 5-week old females "Nude" mice (BALB/C, Ninox)were removed aseptically and crushed into pieces with a size 5·5 mm in Sauternes phosphate solution (PBS, FSB), part of which is then implanted under the skin on the back "Nude" mice.

Each test substance was dissolved in corn oil and the solution was administered intraperitoneally naked mouse sequentially, once per day at a speed of 250 μg/mouse for 3 weeks, starting with the period of one week after implantation. After stopping the introduction of carcinoma were extracted and produced weighing to calculate against the tumor effect and weight loss mouse according to the following equations. For tests used six mice per group; the group, which was introduced only solvent (corn oil), represented the control group:

Antitumor effect (%)

The average tumor weight of the test group

=――――――――――――――――――――――――― · 100

The average weight of tumors in the control group

Weight loss (%)

The average body weight of the mice of the test group

=―――――――――――――――――――――――――― · 100

The average body weight of mice in the control group

Evaluation of antitumor effect and weight loss was performed according to the following standard, where the values for the control group was taken as 100%.

Antitumor effect

-: > 100%, +/-: 100˜75%, +:75˜50%, ++:50˜25%, +++:25˜0%

Weight loss

-: > 110%, +/-: 110˜100%, +: 100˜95%, ++:95˜90%, +++:<90%

The degree of destruction

(degree of loss during the test period)

-: no

+/-: the death occurred with the introduction of high concentrations of

(500 μg/mouse)

+: 1-3 mice were killed

++: 3-5 mice were killed

+++to: all 6 mice were killed

Synthetic evaluation

-: weak anti-tumor effect and a very strong toxicity against mouse-master

<> +/-: logged weak antitumor effect and toxicity for mouse-owner also observed

+: visible fixed level of antitumor effect, but the toxicity to the mouse host also strong

++: visible strong antitumor effect and toxicity for mouse host weak

+++: visible strong anti-tumor effects and no toxicity to the mouse host

The results are shown in the following tables 1-3.

Table 1
The test substanceAntitumor effectToxicitySynthetic estimation
Weight lossThe degree of destruction
N-geranylgeranyl+++/--++
N-geranylacetone++++/-+/-
N-galactosylceramide++++-+++
N-furazolidone+++/--+++

Table 2
The test substanceAntitumor effectToxicitySynthetic estimation
Weight lossThe degree of destruction
N,N`-veranlassung diamid++-++
N,N`-digeronimo diamid+++/--++
N-geranyl-4-pyrovalerone++--+++
N-Granollers+++/--++
Tyrosinekinase++/--+
N-acetyltransferase+ +/--+
Table 3
The test substanceAntitumor effectToxicitySynthetic estimation
Weight lossThe degree of destruction
N-glucosideuronic+++/--+++

As can be seen from the presented results, the compounds of this invention of formula c (I-1) to (I-4) have excellent antitumor activity against cells HuH-7 and, in addition, almost no toxicity, and is expected to be useful as anticancer agents for the treatment and the treatment of various solid malignant tumors submitted to liver cancer.

When the compound of the present invention is used as a drug, such as an antitumor agent, it can be administered orally or parenterally (for example by intravenous injection, intramuscular injection, subcutaneous injection and the like). Effective the first dose is changed in a wide range, depending on the individual symptoms of the patient, severity of disease, body weight, age and diagnosis of the doctor, etc. Usually, however, considering the case of administration by injection, the dose may be equal to from about 1 to about 50 mg/kg/day, which can be entered at one time or many times, fractional per day.

When the compound of the present invention is used as a drug, an effective dose of a compound can be made in the formulation with a pharmaceutically acceptable carrier or diluent (e.g., filler, solvent, and other excipients) in the form of a preparation suitable for administration in a dosage of, for example, tablets, powder, granules, capsules, pills with intersolubility coating, coated tablets, syrup, elixir, liquid, suspension, emulsion and the like.

As carriers or solvents suitable for manufacturing the dosage form can be called, for example, such excipients as starch, lactose, sucrose, mannitol, carboxymethylcellulose and the like; lubricants such as magnesium stearate, sodium lauryl sulphate, talc and the like; binders such as dextrin, microcrystalline cellulose, polyvinylpyrrolidone, Arabian gum, corn starch, gelatin and the like; disintegrators, such as the potato starch, carboxymethylcellulose and the like; dilution solvents, such as water for injection, saline solution, aqueous dextrose, vegetable oil for injection, propylene glycol, polyethylene glycol, and the like. In addition, when necessary, can be included tools, corrective taste and smell, a dye, a tool for creating isotonicity, stabilizer, antiseptic, sedative (calming) tool, and the like.

In the pharmaceutical preparations according to this invention, can also be included, when necessary, other pharmacologically active substances.

Hereinafter the invention is explained more specifically with reference to working examples.

Examples

Example of synthesis 1

Synthesis of N-geranylgeranylated

To tertrahydrofuran ring solution (THF) (20 ml)containing O-tetraazacyclooctane acid (3,62 g, 10 mmol), was added triethylamine (1.01 g, 10 mmol) and the solution was cooled to 0°C. To this solution drops solution was added isobutylphthalate (of 1.37 g, 10 mmol) in THF (5 ml) at 0°With subsequent 30-minute stirring. In the resulting solution drops solution was added gerbillinae (1,53 g, 10 mmol) in THF (5 ml) with subsequent one-hour stirring at 0°and an additional 4-hour stirring at room temperature. The settlement of the e end of the reaction was added 150 ml of chloroform and the chloroform layer was three times washed, each time 50 ml of water. The chloroform layer was dried over magnesium sulfate, the chloroform was concentrated and the residue was purified column chromatography on silica gel. The result has been 3.58 g (73,5%) N-geranyl-O-tetraacetylethylenediamine in the form of a viscous oily substance from his hexane-acetone (3:1) distillate.

1H NMR (CDCl3) δ = 1,58 (3H, c), of 1.65 (3H, c), by 1.68 (3H, c), a 2.01 (3H, c), 2,02 (3H, c), is 2.05 (3H, c), of 2.15 (3H, c), 2,02-2,11 (4H, m), 3,70-a 3.83 (1H, m), 3,83-of 3.96 (1H, m), 5,00-5,17 (2H, m), from 5.29 (1H, d, J=10,8 Hz), of 5.39 (1H, d, J=10,8 Hz), 6,29-6,46 (2H, m).

3.58 g (7 mmol) of the above product was dissolved in 30 ml of ethanol, was added 35 ml of 1N aqueous sodium hydroxide solution and was stirred for 2 hours at room temperature. Then to the reaction mixture was added 35 ml of 1N hydrochloric acid are condensed under reduced pressure. To the residue was added 150 ml of ethanol and the precipitated sodium chloride was filtered. The filtrate again are condensed and the residue was divided by column chromatography on silica gel. From hexane-ethanol (3:1) of distillate was obtained of 1.95 g of N-geranylgeranylated in the form of a viscous coupling. To this product was added ether to spend crystallization and vacuum filtration was received of 1.03 g of crystallized compound named in the heading. The yield was 45%.

1H NMR (DMSO-d6) δ = 1,50 (3H, c), of 1.55 (3H, c), and 1.56 (3H, c), 1,86-2,04 (4H, m), 3,48 is 3.76 (2H, m), 3,80-3,94 (H, m)4,07-4,84 (3H, m), 4,99 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=9.6 Hz).

Example of synthesis 2

Synthesis of N-geranylgeranyl

Synthesis example 1 was repeated except that O-tetraazacyclooctane acid was used instead of O-tetraazacyclooctane acid to obtain the compound named in the heading.

1H NMR (DMSO-d6) δ = 1,60 (3H, c), by 1.68 (3H, c), is 1.73 (3H, c), 2,07-of 2.09 (4H, m), to 3.58-3,62 (2H, m), 3,81-of 3.95 (2H, m), 4,07-a 4.86 (3H, m), of 5.05-5,09 (1H, m), are 5.36-of 5.40 (1H, m).

Example of synthesis 3

Synthesis of N-galactosylceramide

To a THF-solution (20 ml)containing geranium acid (0.84 g, 5 mmol), was added triethylamine (0.51 g, 5 mmol) and cooled to 0°From where then drops was added a THF solution (5 ml)containing isobutylparaben (0.68 g, 5 mmol), followed by 30 minutes stirring at 0°C. Then hydrochloride galactosamine (1.08 g, 5 mmol) was dissolved in 10 ml of water, then added 5 ml of 1N sodium hydroxide, and this solution was added to the reaction mixture all at once. After subsequent stirring for one hour at 0°and for a further 4 hours at room temperature, the reaction mixture are condensed under reduced pressure. To the residue was added 150 ml of acetone and the precipitated sodium chloride was filtered. The filtrate are condensed again and the residue was divided by column chromatography on silica gel. As a result of exon-ethanol (2:1) distillate received this product as a viscous oily substance, to which was added a minimum amount of ether to crystallize the product. By subsequent vacuum filtration was received 0,754 g of compound named in the heading. The yield was 46%, and the melting temperature was in the range of 85-87°C.

1H NMR (DMSO-d6) δ = 1,53 (3H, c), of 1.57 (3H, c)to 1.59 (3H, c), 1,95 for 2.01 (4H, m), 3,63-with 3.79 (7H, m), 4,25-4,60 (3H, m), 4,85 to 4.92 (1H, m), 5,00-5,08 (1H, m), 6,25 of 6.31 (1H, m).

Example of synthesis 4

Synthesis of N-glucosylceramide

Example of synthesis 3 was repeated, except that glucosamine hydrochloride was used instead of hydrochloride galactosamine obtaining compound named in the heading.

1H NMR (DMSO-d6) δ = 1,54 (3H, c)to 1.60 (3H, c), 2,03 (3H, c), 1,96-of 2.20 (4H, m), 3,38-3,61 (4H, m), of 4.38-of 4.66 (3H, m), of 5.75 (1H, c), 6,34-to 6.39 (1H, m).

Example of synthesis of 5

Synthesis of N-fokusiranja

Example of synthesis 3 was repeated, except that the hydrochloride of fucosamine used instead of hydrochloride galactosamine obtaining compound named in the heading.

1H NMR (DMSO-d6) δ = 1,31 (3H, d, J=5.4 Hz), 1,53 (3H, c)to 1.60 (3H, c), 1,72 (3H, c), 1,97-of 2.05 (4H, m), 3,88-of 3.95 (2H, m), 4,21-4,24 (1H, m), of 4.44-to 4.46 (1H, m), 4,82-to 4.87 (1H, m), 5,00-5,13 (1H, m).

Example of synthesis 6

Synthesis of N,N'-digeronimo diamide

To tertrahydrofuran ring solution (THF) (20 ml)containing fumaric acid (0,58 g, 5 mmol), was added triethyl is in (1.01 g, 10 mmol) and cooled the solution to 0°that drops was added a THF solution (5 ml)containing isobutylparaben (1,53 g, 10 mmol). When continued adding, began to form a white precipitate. After 30 minutes stirring at 0°With this system drops was added a THF solution (5 ml)containing geraniums (1,53 g, 10 mmol), followed by one-hour stirring at 0°and an additional 4-hour stirring at room temperature. After the reaction was added to 50 ml of water to the reaction mixture, which then was extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. Filtering the magnesium sulfate, the chloroform layer are condensed to obtain a white crystalline substance. Precrystallization the substance of ethanol, was obtained 1.07 g of the compound named in the heading. The yield was 55%.

1H NMR (CDCl3) δ = 1,60 (6H, c)of 1.62 (6H, c), by 1.68 (6H, c), 2,01 is 2.10 (8H, m), of 3.95 (4H, t, J=9.6 Hz), 5,04-5,09 (2H, m), 5,20-a 5.25 (2H, m)5,94 (2H, Sirs), of 6.90 (2H, c), 7,26 (2H, c).

Example of synthesis of 7

The synthesis example 6 was repeated, except that fumaric acid was replaced with the corresponding carboxylic acid, previously represented by formula (II) in each cycle to obtain the following compounds:

N-geranylgeranyl

1H NMR (CDCl3) δ = 1,55 (3H, c), of 1.64 (3H, c), equal to 1.82 (3H, c), and 2.0 (3H, c), 1,92-2,12 (4H, m), a-3.84 (2H, d, J=7,2 Hz), 4,96-5,12 (1H, m), 5,22 to 5.35 (1H, m).

N,N'-veranlassung diamide

1H NMR (CDCl3) δ = 1,58 (6H, c)of 1.64 (6H, c)to 1.67 (6H, c), 1,94-2,14 (8H, m)to 2.54 (1H, DD, J=4,8, 14,8 Hz), and 2.79 (1H, DD, J=3.2, and 14.4 Hz), 3.75 to 3,93 (4H, m), 4,32-and 4.40 (1H, m), 5,00-5,10 (2H, m), 5,10-5,22 (2H, m).

O-acetyl-N-germanlanguage monoamide

1H NMR (CDCl3) δ = 1,60 (3H, c), by 1.68 (3H, c), was 1.69 (3H, c), 1,96-2,11 (4H, m), 2,19 (3H, c), 2,65 (1H, DD, J=9,6, 22,8 Hz)of 3.00 (1H, DD, J=2,4, 22,8 Hz) 3,79-to 3.89 (2H, m), 4,51-4,56 (1H, m), to 5.08 (1H, t, J=7.2 Hz), by 5.18 (1H, t, J=6.0 Hz).

O-acetyl-N,N'-veranlassung diamide, which was synthesized in the same manner, using monoamide N-geraniales acid as the starting material.

1H NMR (CDCl3) δ = 1,59 (6N, c), 1,67 (6N, (c), by 1.68 (6H, c), 1,94 is 2.01 (8H, m)of 2.16 (3H, c), to 2.55 (1H, DD, J=13,2, of 22.8 Hz), of 2.97 (1H, DD, J=2,4, and 22.8 Hz), 3,79-to 3.89 (4H, m), 4,34-and 4.40 (1H, m), 5,02-5,10 (2H, m), 5,10-5,20 (2H, m).

N,N',N"-trigonelline triamide

1H NMR (CDCl3) δ = 1,60 (N, c)of 1.66 (N, c), by 1.68 (9H, c), 1,98-of 2.08 (12H, m), 3,76 (6H, t, J=6.3 Hz), 4.26 deaths (4H, c), 5,07 (6H, t, J=6.0 Hz), 5,20 (6H, t, J=7.2 Hz).

N-greenlantern monoamide

1H NMR (CDCl3) δ = 1,60 (3H, c), of 1.70 (3H, c), 1,72 (3H, c), 1,92-of 2.15 (4H, m), 2,52 (2H, t, J=9.6 Hz), 2,70 (2H, t, J=9.6 Hz), 3,80-are 3.90 (2H, m), to 5.08 (1H, t, J=9.6 Hz), is 5.18 (1H, t, J=6.0 Hz), 5,61 (1H, Sirs).

N,N'-degranulating diamide, which was synthesized in the same manner, using monoamide N-greenlantern acid as the starting material.

1H NMR (CDCl3) ´ = 1,60 (6H, c)of 1.66 (6H, c), was 1.69 (6H, c), 1,97-2,11 (4H, m), 2,53 (4H, c), a-3.84 (4H, t, J=5.5 Hz), 5,07 (2H, t, J=4,9 Hz)to 5.17 (2H, t, J=5.5 Hz), 5,90 (2H, Sirs).

N-geranyllinalool monoamide

1H NMR (CDCl3) δ = 1,59 (3H, c)to 1.67 (3H, c), of 1.70 (3H, c), 1,94-of 2.16 (4H, m), 3,88-Android 4.04 (2H, m), is 5.06 (1H, t, J=7.2 Hz), to 5.21 (1H, t, J=4,8 Hz), 6,30 (1H, d, J=12.0 Hz), 6,46 (1H, d, J=12.0 Hz).

N,N'-digernes-2-oxoglutarate diamide

1H NMR (CDCl3) δ = 1,60 (6H, c), by 1.68 (12H, c), 1,94 and 2.13 (8H, m), 2,69 (2H, t, J=6.3 Hz), 3,26 (2H, t, J=6.3 Hz), 3,81-Android 4.04 (4H, m), 5,02-5,10 (2H, m), 5,15-5,22 (2H, m).

N-geranyl-p-perusaamiaisella

1H NMR (CDCl3) δ = 1,60 (3H, c), by 1.68 (3H, c), of 1.70 (3H, c), 2,03-2,11 (4H, m), 2,17 (3H, c), 3.95 to Android 4.04 (2H, m), a 4.83 (1H, Sirs), 5,09 (1H, t, J=6.6 Hz), 5,28 (1H, t, J=6.9 Hz),5,94 (1H, Sirs), only 6.64 (2H, d, J=8.7 Hz), 7,60 (2H, d, J-8.7 Hz).

N-gerbillinae

1H NMR (CDCl3) δ = 1,03 (6N, c), 1,12-to 1.63 (6H, m), 1,60 (3H, c), of 1.66 (3H, c), by 1.68 (3H, c), 1,72 (3H, c), 1,87-of 1.93 (4H, m), a 2.01 (3H, c), is 2.37 (3H, c), 3,82-to 3.92 (2H, m), 5,03-5,24 (2H, m), 5,80 (1H, c), 6,12-6,40 (3H, m), 7,02 (1H, d, J=12.0 Hz), 7,07 (1H, d, J=12.0 Hz).

Example of synthesis 8

Synthesis of N-geranylacetone

To a THF-solution (20 ml)containing geranium acid (1.68 g, 10 mmol), was added triethylamine (1.01 g, 10 mmol) and cooled it to 0°and there drops was added a THF solution (5 ml) isobutylphthalate (of 1.37 g, 10 mmol) followed 30 min stirring at 0°C. To the reaction mixture was added a solution of cysteine (1.35 g, 10 mmol), which was dissolved in 1N-sodium hydroxide (10ml), with the subsequent one is hour stirring at 0° With and additional 4-hour stirring at room temperature. After the reaction to the reaction mixture were added 10 ml of 1N hydrochloric acid and was stirred for 10 minutes at room temperature. Then the reaction mixture are condensed using a rotary evaporator. To the residue was added ethanol, after which the precipitated sodium chloride was removed by filtration. The ethanol solution again are condensed under reduced pressure using an evaporator, and the residue was divided by column chromatography on silica gel. Thus received 0,556 g of compound named in the heading of hexane-acetone (2:1) distillate. The output amounted to 19.5%:

1H NMR (CDCl3) δ = 1,59 (6H, c), by 1.68 (3H, c), 2,00-2,24 (4H, m), 2,60-2,77 (1H, m), 3.00 and-3,30 (2H, m), 4,48-4,58 (1H, m), 5,00-5,13 (1H, m), 8,96 (1H, c).

Example 9 synthesis

N-Granollers

The synthesis example 8 was repeated, except that the cysteine is replaced by tyrosine, to obtain the compound named in the heading:

1H NMR (CDCl3) δ = 1,55 (6H, c)of 1.64 (3H, c), 1,96 is 2.00 (4H, m), 2,90-3,17 (2H, m), 4,81-5,06 (3H, m), 6,40-7,21 (4H, m), 7,25 (1H, c).

Example 10 synthesis

The synthesis of glutamine degranulated

To a THF-solution (20ml) N-benzyloxycarbonylamino acid (2,634 g, 9.4 mmol) was added triethylamine (1,899 g of 18.8 mmol) and cooled to 0°C. To this mixture drops was added a THF solution (10 ml) is isobutylphthalate (2,566 g, 18,8 mmol) followed 30 min stirring at 0°C. Then drops was added a THF solution (10 ml) gerbillinae (2,880 g of 18.8 mmol) followed a one-hour stirring at 0°and an additional 4-hour stirring at room temperature. After completion of the reaction system was added 150 ml of chloroform and the chloroform solution was washed with water and dried over magnesium sulfate. The organic solution was removed using an evaporator, and the residue was divided by column chromatography on silica gel. So got 3,g N-benzyloxycarbonylglycine of degranulated from hexane-acetone (2:1) distillate. The output amounted to 58.6%.

Then N-benzyloxycarbonylglycine degerenergie (3,034 g, 5.5 mmol) was dissolved in methanol (20 ml) and to this solution was added 20 ml of 1N sodium hydroxide solution and subsequent 5-hour stirring at room temperature. The reaction mixture are condensed using an evaporator and the residue was divided by column chromatography on silica gel to obtain the target compounds from hexane-ethanol (3:1) distillate. Since the thus obtained product was viscous and amorphous, this product was added ether for crystallization. After vacuum-filtering system received 852 mg of target compound. The output amounted to 37.2%.

1H NMR (CDCl3) δ = 1,8 (12H, c)1,61 (6N, c), a 1.75-2,12 (8H, m), 2,32 of $ 2.53 (2H, m), 3,54-3,88 (7H, m), 4,88-to 5.21 (4H, m).

Example 11 synthesis

By repeating the synthesis example 10, except that N-benzyloxycarbonylglycine acid was replaced by tyrosine, N-acetyltyrosine, cysteine or serine, were obtained the following compounds. When used N-acetyltyrosine, the subsequent operation of removing protection did not.

Tyrosinekinase

1H NMR (CDCl3) δ = 1,59 (3H, c)to 1.67 (6H, c), 1,82-to 2.18 (4H, m), 2,99-to 3.09 (2H, m), 3,74-of 3.78 (2H, m), 4,99-5,26 (3H, m), 7,17-the 7.43 (5H, m).

N-acetyltransferase

1H NMR (CDCl3) δ = 1,60 (3H, c), by 1.68 (3H, c), to 1.98 (3H, c), 2,00-2,11 (4H, m)to 2.18 (3H, c), 2,90-of 3.00 (2H, m), 3,69-with 3.79 (2H, m), 4,59 (1H, DD, J=15,6, 9.6 Hz), 5,00-5,10 (2H, m), 6,70 (2H, d, J=7.8 Hz), 7,01 (2H, d, J=7.8 Hz), 7,27 (1H, c).

Containername

1H NMR (CDCl3) δ = 1,58 (3H, c), of 1.66 (3H, c)to 1.67 (3H, c), 1,93 is 2.10 (4H, m), 2,83-and 3.16 (2H, m), 3,83-4,08 (3H, m), 5,03-5,19 (2H, m), 7,33 (1H, c).

Stringerbell

1H NMR (CDCl3) δ = 1,59 (3H, c), by 1.68 (6H, c)1,95 with 2.14 (4H, m), 3,80-of 3.95 (2H, m), 4,34-4,47 (2H, m), of 4.67 (1H, t, J=10,8 Hz), is 5.06 (1H, t, J=6.0 Hz), to 5.17 (1H, t, J=6.0 Hz), 6,77 (2H, Sirs).

Example 12 synthesis

Synthesis of N-glucosylceramide

The glucosamine hydrochloride (2.16 g, 10 mmol) was dissolved in 20 ml of water and to aqueous solution was added 10 ml of 1N sodium hydroxide solution and mevalonate (1,30 g, 10 mmol) followed 5 hours by heating under stirring at 55°C. After the reaction re Klenow mixture are condensed under reduced pressure. To the residue was added 100 ml of methanol, after which the residue was filtered. The filtrate again are condensed using an evaporator and the residue was divided by column chromatography on silica gel to obtain 1.45 g of the target product from the ethanol distillate. The yield was 47%. Because the resulting product was a viscous oily substance were added minimum amount of dichloromethane to carry out crystallization. After vacuum-filtering received 1.10 g of the compound named in the heading, which was highly hygroscopic and its melting point could be defined:

1H NMR (DMSO-d6) δ = 1,00 (3H, c), 1,44-to 1.59 (2H, m), 2,47 (2H, c), 2,96-3,74 (10H, m), 4.04 the-5,08 (3H, m).

Example of synthesis 13

Synthesis of N-galactosylceramide

The synthesis example 12 was repeated, except that glucosamine hydrochloride was replaced hydrochloride galactosamine obtaining compound named in the heading:

1H NMR (DMSO-d6) δ = 1,08 (3H, c), 1,51-to 1.61 (2H, m)2,44 (2N, c), 2,74-5,16 (13H, m).

Example 14 synthesis

Synthesis of N-tukosmeshenija

The synthesis example 12 was repeated, except that glucosamine hydrochloride was replaced by the hydrochloride of fucosamine obtaining compound named in the heading:

1H NMR (DMSO-d6) δ = 1,06 (3H, c), of 1.20 (3H, d, J=24,0 Hz), 1,54-of 1.62 (2H, m)2,44 (2H, c), 2,7-5,15 (12H, m).

Example 1 drug

Two (2) grams of N-galactosylceramide was dissolved in 1 liter of water for injection at room temperature, isothermal sodium chloride, poured into ampoules and sealed. One (1) ml of the drug for injection contains 2 mg of the active ingredient.

Example product 2

Two (2) grams of N,N'-veranlassung diamide was dissolved in 1 liter of water for injection at room temperature, isothermal sodium chloride, poured into ampoules and sealed. One (1) ml of the drug for injection contains 2 mg of the active ingredient.

The example of the drug 3

Two (2) grams of N-glucosylceramide was dissolved in 1 liter of water for injection at room temperature, isothermal sodium chloride, poured into ampoules and sealed. One (1) ml of the drug for injection contains 2 mg of the active ingredient.

1. Gerbillinae compounds represented by the following formulas (I-1), (I-2) or (I-3):

in which

R1means

R2mean residual group remaining after removing all carboxyl groups present in the carboxylic acid selected from the group, with Toyama of malic acid, citric acid, succinic acid, fumaric acid, 2-oxoglutaric acid, pyruvic acid, p-perusaamiaisella acid, retinoic acid, tyrosine, cysteine, glutamic acid and serine, and when the residual group are hydroxyl or amino group(s), they can be optionally protected by acyl (e.g. lower alkanoyl) or benzyloxycarbonyl(s)group(s)

m is 1, 2 or 3,

n is 0, 1 or 2, and

m+n represents the number of carboxyl groups that are present in the specified carboxylic acid, and

R3denotes p-hydroxyphenyl or mercaptopropyl.

2. Derivatives avalonbay acid represented by the following formula (1-4):

in which R4denotes-CH2N or CH3.

3. Antitumor agent containing as an active ingredient gerbillinae compound of the formula (I-1), (I-2) or (I-3), which presents in claim 1, or a derivative avalonbay acid of the formula (I-4), which is presented in section 2, and optionally a pharmaceutically acceptable carrier or solvent.

4. A method of treating liver cancer, comprising the administration to a patient effective antitumor amount gerbiling compounds of formulas (I-1), (I-2) or (I-3), before whom tableno in claim 1, or the derived avalonbay acid of the formula (I-4), which is presented in section 2.

5. Use gerbiling the compounds of formula (I-1), (I-2) or (I-3), which presents in claim 1, or a derivative avalonbay acid of the formula (I-4), which is presented in section 2, for the treatment of liver cancer.

6. Use gerbiling the compounds of formula (I-1), (I-2) or (I-3), which presents in claim 1, or a derivative avalonbay acid of the formula (I-4), which is presented in section 2, for the production of antitumor agents.



 

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