Semi-synthetic taxanes and pharmaceutical compositions based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new semi-synthetic taxanes of the formula (1):

wherein R and R1 can be similar or different and represent hydrogen atom (H), (C1-C18)-acyl group, benzoyl group; R2 and R3 represent hydrogen atom (H) or R2 and R3 in common form carbonate or thiocarbonate residue; R4 represents benzoyl group optionally substituted at meta-position; R' represents hydrogen atom (H) or (C1-C4)-alkyl; R'' represents (C1-C4)-alkyl or phenyl; R''' represents tert.-butoxy-group under condition that R and R1 both can't represent hydrogen atom (H). Also, invention relates to a pharmaceutical composition based on compounds of the formula (1) eliciting an anti-tumor, anti-angiogenic and anti-arthrosis effect. Invention provides preparing new compounds eliciting cytotoxicity comparable with cytotoxicity of other taxanes but showing reduced systemic toxicity that can be administrated by intravenous and oral routes.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

6 cl, 1 tbl, 7 ex

 

The present invention relates to a derivative SECO-baccatin III.

Diterpenes having taxonomy skeleton, in particular, paclitaxel and docetaxel, are currently used in medicine for the treatment of tumors of different origin.

However, current derivative texana have significant side effects, and quickly induce resistance movement, like other anticancer medicines.

The present invention relates to a derivative SECO-baccatin III, which is disclosed in US 5756776 characterized by bioavailability when administered orally, reduced toxicity and extremely high angiogenic activity.

Compounds of the present invention have the General formula (I):

where:

- R and R1that may be the same or different, represent hydrogen, C1-C18acyl group, optionally substituted arilou group or group-CONR6R7in which R6and R7that may be the same or different, represent a C1-C4alkyl, benzyl or phenyl group;

- R2represents hydrogen or together with R3forms a carbonate or thiocarbonate balance;

- R3represents adored or group-OR 5where R5represents hydrogen, or together with R2forms a carbonate or thiocarbonate balance;

- R4represents benzoyloxy group, optionally substituted in the meta-position, or heterology group;

R' represents hydrogen or C1-C4alkyl;

R represents a C1-C4alkyl, C2-C6alkenyl, aryl or hetaryl;

R"' represents a C1-C4alkyl, C1-C18acyl, aryl or tert-butoxy group;

provided that R and R1can not both represent hydrogen.

C1-C18the acyl group preferably represents groups such as formyl, acetyl, n-propanol, n-hexanol.

Optionally substituted arolina group is preferably benzoyl, optionally substituted with one or three substituents selected from halogen atoms or C1-C4of alkyl, C1-C4alkoxy, C1-C4halogenoalkane, C1-C4halogenoalkane, cyano and nitro groups.

Meta-substituted benzoline group preferably represents a 3-halogenmethyl or 3-methoxybenzoyl group.

Petrolina group preferably represents a 5 - or 6-membered heteroaryl containing in the ring one or two atoms of oxygen, nitrogen or sulfur and replaced the carb is Niley group, for example, 2 - or 3-thenoyl, nicotinoyl or 2 - or 3-furoyl.

Aryl preferably represents phenyl, hetaryl preferably represents 2 - or 3-furyl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl.

A preferred group of compounds of formula (I) represents a group in which:

R and R1which are identical, represent a C1-C18acyl group, optionally substituted benzoyloxy group, as defined above, or the group,- CONR6R7more preferably R and R1are acetyl or 3,4,5-trimethoxybenzoyl;

R2represents hydrogen;

R3represents hydrogen;

R4represents a benzoyl;

R' represents hydrogen or methyl;

R represents a C1-C4alkyl or C1-C6alkenyl, more preferably isobutyl or Isobutanol;

R"' represents a tert-butoxy group.

Another group of preferred compounds is the group in which R represents hydrogen and R1represents acyl, aroyl or group CONR6R7as defined above, R2and R3represent hydrogen, R4represents benzoyl, R1represents hydrogen or methyl, R" represents a C1-C4alkyl or C2-C 6alkenyl, and R"' represents a tert-butoxy.

Etherification of hydroxyl groups at positions C-7 and C-9 induces, in comparison with known compounds, increased cytotoxic activity in resistant cell lines, as well as improved absorption when administered orally. Compounds according to the invention are less active than paclitaxel, taken as a comparative drug, binding to tubulin, but have comparable cytotoxicity in sensitive tumor cells. These compounds mainly differ from the compounds of the prior art by antiangiogenic activity. The table shows the activity in vivo of some derivatives of C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III and C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-1,14-carbonate-baccatin III, with the same isuserinrole chain.

Angiogenic activity was evaluated in the test Matrigel in which angiogenesis was induced using FGF-2 (150 mg/pellet), absorbed on the Matrigel pellets (12.5 mg/ml, 0.5 ml), which were subcutaneously injected with mice C57BL6N.

The test compound was administered orally daily or intraperitoneally every other day, at concentrations indicated in the table. After 7 days the angiogenic response was assessed by measuring the content of hemoglobin is in the granules according to the method of Drabkin.

Table

Antiangiogenic activity in vivo of the compounds of example II.
ConnectionHemoglobin g/DL%
Control0,01±0,001-
FGF-20,03±0,001+ 300
Example II
90 mg/kg b0,015±0,001- 50
150 mg/kg p/o0,009±0,001- 70
Example VII
50 mg/kg b0,014- 40
100 mg/kg p/o0,009- 70

Compounds according to the invention is produced by interaction of C-SECO-10-dehydro-10-deazetil-7,9-hydroxy baccatin III, described in US 5756776, with a reactive carboxylic acid derivative (acid chloride or anhydride), in accordance with known methods of acylation.

Complex diesters C7 and C9 can be obtained by using at least two equivalents of a reactive derivative. Urethane groups can be introduced by conventional methods, for example by reacting phosgene and an amine of formula R6R7NH.

Compounds of the ATEM is subjected to interaction, in accordance with known methods, with ezoterikovym derived, usually oxazolidinone derivative, which upon treatment with acid under mild conditions gives compound (I).

Compounds according to the invention are characterized by low systemic toxicity: at doses that are effective for the inhibition of tumor growth, they do not cause any weight loss or obvious neurotoxicity; the "Nude" mice that were transplanted tumor cells, the dose of paclitaxel, which is used as a comparative drug, causing the same antitumor activity, also caused tremors and weight loss up to 20%.

Compounds of the present invention, due to their high solubility in water, can easily be formulated in the form of drugs for injection.

The compound (I) can also be formulated in the form of conventional pharmaceutical forms for oral administration (capsules or tablets).

Because they are of low toxicity, the compounds (I) can be administered intravenously at doses up to 600 mg/m2and oral at doses up to 1000 mg/m2. The dose can be reduced to 50 mg/m2in the treatment of rheumatoid arthritis.

The following examples in more detail to illustrate the invention without limiting its scope.

Example I - getting C-SECO-10-dehydro-10-deazetil-7,9-bis-AC is Teal-baccatin III.

To a solution of 300 mg of 10-dehydro-10-deacetylbaccatin III in 5 ml of methanol was added 1 EQ. CeCl3·3H2Oh and the reaction mixture is stirred for 10 minutes After complete dissolution of the added in small portions 80 mg NaBH4. After 10 min the solution is treated with an equal volume of aqueous solution of NH4Cl and extracted with CH2Cl2. Chlorinated solvent is removed, the residue is transferred in 1 ml of pyridine, cooled to 0°C for 1 hour, then add 150 mg of acetic anhydride. The solution is kept for 2 hours at 0°C, then diluted with 10 ml of water and subjected to back extraction with CH2Cl2. Chlorinated solvent is distilled off in vacuum and the residue chromatographic on silica gel, elwira a mixture of n-hexane/ethyl acetate, to obtain 260 mg of C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III (m/z 630).

Example II - 13-[(2R, 3S)-3-isobutyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III.

630 mg of C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III is dissolved in 5 ml of toluene and added 335 mg dicyclohexylcarbodiimide (DCC), 50 mg of (4S,5R)-N-BOC-2-(2,4-acid)-4-isobutyl-5-oxazolidinecarboxylate acid and 20 mg of 4-dimethylaminopyridine. The solution is heated at 60°within 24 hours, then treated with ethyl acetate and a saturated solution of NaHCO . The organic phase is dried and filtered through silica gel to remove urea. The solvent is evaporated in vacuo to dryness and the residue is transferred into a solution of methanol/hydrochloric acid, keeping the temperature at 0°C for 1 hour. The solution is neutralized to pH 5, then diluted with water and the desired connection back extracted with CH2Cl2. The solvent is evaporated to obtain 700 mg of 13-[(2R, 3S)-3-isobutyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III.

White powder, TPL 91°;1H-NMR (300 M Hz, CDCl360° δ 8,03 (2H, d, AA'-Bz)to 7.61 (1H, t, C-Bz)of 7.48 (2H, t, BB'-Bz)of 6.17 (1H, Shir. t, J=7 Hz, H-13), 5,63 (1H, d, J=8 Hz, H-2), at 5.27 (1H, d, J=10 Hz, H-5), 5,16 (1H, Shir. d, J=8 Hz, H-20a)and 4.65 (1H, d, J=9.5 Hz, NH), 4,39 (1H, d, J=8 Hz, H-3), 4,32 (1H, Shir. d, J=8 Hz, H-20b), or 4.31 (1H, m, H-7a), 4,25 (1H, d, J=3 Hz, H-2'), 4,18 (1H, m, H-3'), of 4.12 (1H, m, H-7b), 2,89 (1H, m, H-14a), the 2.46 (2H, m, H-6A b H-14b), of 2.28 (3H, s, SLA), 2,22 (3H, s, SLA), 2,10 (1H, m, H-6b), was 1.94 (3H, s, H-19), OF 1.85 (3H, Shir. C, H-18), to 1.60 (1H, m, H-4 a), of 1.42 (1H, m, H-4'b), 1,30 (N, s, BOC), OF 1.26 (3H, s, H-17), 1,19 (3H, s, H-16), 0,99 (6N, d, J=7 Hz, H-6' and H-7'); HREIMS m/z [M]+(871,3999) (calculated for C45H61NO16, 871,3990).

Example III - 13-[(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III.

630 mg of C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III is dissolved in 5 ml of toluene and d is billaut 335 mg DCC, 525 mg of (4S, 5R)-N-Boc-2-(2,4-acid)-4-isobutyl-5-oxazolidinecarboxylate acid and 20 mg of 4-dimethylaminopyridine.

The solution is heated at 60°within 24 hours, then treated with ethyl acetate and a saturated solution of NaHCO3. The organic phase is dried and filtered through silica gel to remove urea. The solvent is evaporated in vacuo to dryness and the residue is transferred into a solution of methanol/hydrochloric acid, keeping the temperature at 0°C for 1 hour. The solution is neutralized to pH 5, then diluted with water and the desired connection back extracted with CH2Cl2. The solvent is evaporated to obtain 700 mg of 13-[(2R, 3S)-3-isobutyl-2-hydroxy-3-tert-butoxycarbonylamino] -C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III, which is crystallized from ethyl acetate to obtain 645 mg of pure compound.

White powder, TPL 110°;1H-NMR (300 MHz, CDCl360° δ 8,03 (2H, d, AA'-Bz)to 7.61 (1H, t, C-Bz)of 7.48 (2H, t, BB'-Bz)of 6.17 (1H, Shir. t, J=7 Hz, H-13), 5-63 (1H, d, J=8 Hz, H-2), 5-27 (1H, d, J=10 Hz, H-5), 5,16 (1H, Shir. d, J=8 Hz, H-20a)and 4.65 (1H, d, J=9.5 Hz, NH), 4,39 (1H, d, J=8 Hz, H-3), 4,32 (1H, Shir. d, J=8 Hz, H-20b), or 4.31 (1H, m, H-7a), from 5.29 (1H, d, J=9.4 Hz, H), of 4.67 (1H, Shir. s, H-2'), of 4.12 (1H, m, H-7b), 2,89 (1H, m, H-14a), the 2.46 (2H, m, H-6A and H-14b), of 2.28 (3H, s, SLA), 2,22 (3H, s, SLA), 2,10 (1H, m, H-6b), was 1.94 (3H, s, H-19), OF 1.85 (3H, Shir. C, H-18), 7,42 (5H, s, 3'Ph), 1,39 (N, s, tBu), of 1.26 (3H, s, H-17), 1,19 (3H, s, H-16).

Example IV - obtain the-SECO-10-dehydro-10-deazetil-7,9-bis-trimethoxybenzoyl-baccatin III.

To a solution of 546 mg of C-SECO-10-dehydro-10-deazetil-baccatin III in 3 ml of pyridine added in small portions 575 mg trimethoxybenzylamine. After 3 hours the solution is poured into 30 ml of water and extracted with CH2Cl2; the organic phase is washed with acid to remove the pyridine. The solvent is evaporated to obtain 905 mg of C-SECO-10-dehydro-10-deazetil-7,9-bis-trimethoxybenzoyl-baccatin III (m/z 936).

Example V - 13-[(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-dehydro-10-deazetil-7,9-bis-trimethoxybenzoyl-baccatin III.

930 mg of 13-[(2R, 3S)-C-SECO-10-dehydro-10-deazetil-7,9-bis-trimethoxybenzoyl-baccatin III is dissolved in 15 ml of toluene and added 335 mg DCC, 525 mg of (4S, 5R)-N-Boc-2-(2,4-acid)-4-isobutyl-5-oxazolidinecarboxylate acid and 20 mg of 4-dimethylaminopyridine. The solution is heated at 60°within 24 hours, then treated with ethyl acetate and a saturated solution of NaHCO3. The organic phase is dried and filtered through silica gel to remove urea. The solvent is evaporated in vacuo to dryness and the residue is transferred into a solution of methanol/hydrochloric acid, keeping the temperature at 0°C for 1 hour. The solution is neutralized to pH 5, then diluted with water and the desired connection back extracted with CH2Cl2. The solvent is evaporated to obtain 940 mg of 13-[(2R, S)-3-isobutyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-dehydro-10-deazetil-7,9-bis-trimethoxybenzoyl-baccatin III, which is crystallized from ethyl acetate to obtain 878 mg of pure compound.

Example VI - getting 1,14-carbonate C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III.

1 g 10-deazetil-14β-hydroxyacetone III, obtained as described in US 5698712, dissolved in methanol and treated with 6 g of Cu(SLA)2and the reaction mixture is stirred for 120 hours. The salt is filtered off, the solvent is removed and the residue chromatographic on a column of silica gel, elwira mix 6:4 hexane/ethyl acetate, to obtain 0.9 g 1,14-carbonate 10-dehydro-10-deazetil-14β-hydroxyacetone III (M+568). 300 mg of this compound was dissolved in methanol and treated with 1 EQ. CeCl3·3H2Oh and the reaction mixture is stirred for 10 minutes. After complete dissolution of the added in small portions 80 mg NaBH4. After 10 minutes the solution is treated with an equal volume of aqueous solution of NH4Cl and extracted with CH2Cl2. Chlorinated solvent is removed, the residue is transferred in 1 ml of pyridine, cooled to 0°C for 1 hour, then added with stirring to 150 mg of acetic anhydride. The solution is kept for 2 hours at a temperature of 0°C, then diluted with 10 ml of water and back extracted with the help of CH2Cl2. Chlorinated solvent is distilled off in vacuum and the residue chromatographic on silica gel, elwira a mixture of n-Huck is an/ethyl acetate to obtain 250 mg 1,14-carbonate C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III (m/z 658).

Example VII - getting 1,14-carbonate 13-[(2R, 3S)-3-isobutyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III.

600 mg 1,14-carbonate C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III treated as described in Example II, to obtain 680 mg specified in the connection header.

White powder, TPL 121°;1H NMR (300 MHz, CDCl360° δ 8,03 (2H, d, AA'-Bz)to 7.61 (1H, t, C-Bz)of 7.48 (2H, t, BB'-Bz), 6,44 (1H, Shir. d, J=7 Hz, H-13), 5,63 (1H, d, J=8 Hz, H-2), at 5.27 (1H, d, J=10 Hz, H-5), 5,16 (1H, Shir. d, J=8 Hz, H-20A)and 4.65 (1H, d, J=9.5 Hz, NH), 4,39 (1H, d, J=8 Hz, H-3), 4,32 (1H, Shir. d, J=8 Hz, H-20b), or 4.31 (1H, m, H-7a), 4,30 (1H, d, J=3 Hz, H-2'), 4,08 (1H, m, H-3'), of 4.12 (1H, m, H-7b), 4,84 (1H, d, H-14a, 7 Hz), 2,46 (1H, m, H-6A), 2-28 (3H, s, SLA), 2,22 (3H with, SLA), 2,10 (1H, m, H-6b), was 1.94 (3H, s, H-19), OF 1.85 (3H, Shir. C, H-18), to 1.60 (1H, m, H-4 a), of 1.42 (1H, m, H-4'b), 1,30 (N, s, BOC), OF 1.26 (3H, s, H-17), 1,19 (3H, s, H-16), 0,99 (6N, d, J=7 Hz, H-6' and H-7').

1. Semi-synthetic taxanes of the formula (I)

where R and R1that may be the same or different, represent hydrogen, C1-C18acyl group, benzoyloxy group;

R2and R3represent hydrogen or together R2and R3form a carbonate or thiocarbonate balance;

R4represents benzoyloxy group, optionally substituted in the meta position;

R' represented yet a hydrogen or C 1-C4alkyl;

R represents a C1-C4alkyl or phenyl;

R"' represents a tert-butoxy group;

provided that R and R1can not both represent hydrogen.

2. Compounds according to claim 1, where

R and R1which are identical, represent a C1-C18acyl group, more preferably R and R1represent acetyl, or benzoyloxy group;

R2represents hydrogen;

R3represents hydrogen;

R4represents a benzoyl;

R' represents hydrogen or methyl;

R represents a C1-C4alkyl, more preferably isobutyl;

R"' represents a tert-butoxy group.

3. Compounds according to claim 1, where R represents hydrogen and R1represents acyl, benzoyl, R2and R3represent hydrogen, R4represents benzoyl, R' represents hydrogen or methyl, R" represents a C1-C4alkyl and R"' represents a tert-butoxy.

4. The compound according to claim 1, chosen from:

13-[(2R,3S)-3-isobutyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III

13-[(2R,3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-is ahydro-10-deazetil-7,9-bis-acetyl-baccatin III

1,14 carbonate 13-[(2R,3S)-3-isobutyl-2-hydroxy-3-tert-butoxycarbonylamino]-C-SECO-10-dehydro-10-deazetil-7,9-bis-acetyl-baccatin III.

5. Pharmaceutical composition having antitumor and antiangiogenic activity, containing as active ingredient a compound according to claims 1 to 4 in a mixture with a suitable carrier.

6. The compound according to claims 1 to 4 to obtain antitumor, antiangiogenic and antistrange medicines.



 

Same patents:

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivative of taxane of the formula (I):

that elicits strong antitumor effect. Also, invention relates to intermediates substances, a method for preparing compound of the formula (I), a method for preparing 1,14-β-hydroxy-1,14-carbonate-baccatin III-derivatives substituted with isoserine residue at position 3 and to pharmaceutical composition based on compounds of the formula (I). Invention provides preparing new derivative of taxane that elicits higher activity and reduced toxicity as compared with paclitaxel.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compound.

10 cl, 7 tbl, 6 ex

The invention relates to new S-4 carbonate-bearing similarly to taxanes of formula 1 and their pharmaceutical salts:

where R denotes phenyl, isopropyl or tert.butyl; R1denotes-C(O)RZin which RZmeans (CH3)3CO-, (CH3)3CLO2-, CH3(CH2)3Oh, cyclobutyl, cyclohexyloxy or 2-furyl and R2denotes CH3C(O)O-, and also to pharmaceutical compositions based on them and their use as protophobic agents to treat diseases of humans and animals

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

The invention relates to a new method of acylation of the hydroxyl group taxane, including processing taxane allermuir agent selected from the group consisting of anhydrides, dicarbonate, thiodicarb and isocyanate in the reaction mixture containing less than one equivalent of base for each equivalent taxane, preferably 1:1-1:100, with the formation of the C(10) acylated taxane

The invention relates to a new method of obtaining Taxol, its analogs and their intermediates, including the stage of protection of the hydroxy-group at C-7 position 9-dihydro-13-deacetylbaccatin III a suitable protecting group; oxidation of the hydroxy-group in position C-9; and attaching a suitable side chain at position C-13

The invention relates to a new method of obtaining paclitaxel - anticancer agent and intermediate products for its partial synthesis: the compound of formula (II)

< / BR>
where a represents a group

< / BR>
R1the protection group of the hydroxyl or hydrogen atom, and R2is a hydrogen atom,

and the compound of formula (III)

< / BR>
where each of the groups R4and R5- aryl, and each of the groups R6and R7- halogenated methyl

The invention relates to chemistry, in particular to pharmaceutical chemistry, and can be used for the production of anticancer drug

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EFFECT: reduced risk of tumor recurrence.

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6 cl, 1 dwg

FIELD: medicine, oncourology.

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EFFECT: higher efficiency of therapy.

1 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with treating tumors of external reproductive organs in dogs: in preoperational period for 3 d one should introduce 20%-hypertonic solution of ACD-2 fraction upon 0.5%-novocaine solution at 0.1-0.3 ml working solution/cu. cm tumor into tumor basis, at not more than 0.4 ml pure ACD-2/10 kg canine body weight. One should dissect the tumor within the limits of healthy tissue, close vessels and wound defect after removing the tumor due to electrocoagulation of submucous layer at scab's development.

EFFECT: higher efficiency of therapy.

1 ex

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EFFECT: prevented traumatism of urinary bladder due to single introduction of catheter and assured continuous action of drugs without development of immune complications.

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EFFECT: increased assortment of immunostimulating agents.

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EFFECT: improved treatment method.

2 ex

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SUBSTANCE: invention relates to an anti-tumor agent representing benzoic acid amide (benzamide). Benzamide is used in the range of doses from 25 to 100 mg/kg.

EFFECT: expanded assortment of agents of indicated designation.

2 cl, 1 tbl

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

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