Derivatives of colchicine, methods for their preparation and pharmaceutical compositions based on them

 

(57) Abstract:

The invention relates to the derivatives of colchicine formula (I), where R denotes methoxy or methylthiourea; R1means a linear or branched C1- C6alkyl, provided that when R is methoxy, R1cannot be methyl; and compounds of formula II, where R is methylthio; R1means a linear or branched C1- C6-alkyl. Compound I is produced by interaction of the N-th deacetylation-colchicine or N-deacetylbaccatin with 1,8-diazabicyclo[5,4,0] undec-7-Yong. The compound (II) is produced by interaction of the N-th deacetylation-colchicine 3.5 ditretbutyl-1,2-benzoquinone. The compounds I and II antineoplastic and antiproliferative activity, which allows their use in pharmaceutical compositions as the active ingredient, suitable for local use. 6 C. and 7 C.p. f-crystals, 5 PL.

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This invention relates to new derivatives of colchicine with antiproliferative, antitumor and anti-inflammatory activities, methods for their preparation and the pharmaceutical compositions.

Colchicine is known pseudohalogen, widely used in the Yan quickly and specifically, despite the fact that it should be used short-term due to its toxicity. Derived colchicine called thiocolchicoside, widely used for the treatment of contractures and inflammatory conditions of skeletal muscles. In addition, colchicine is a very strong antibioticskin agent (prevents growth), providing a blocking effect on the formation of the mitotic spindle structure during cell division; this last aspect is deeply investigated in respect of any antitumor activity, and to this end there were a large number of derivatives of colchicine. Colchicine itself and some of its derivatives may not be used clinically due to their high toxicity and, therefore, unacceptable risk/benefit. Only one derived colchicine - demecolcine used to some extent in Oncology for the treatment of some forms of leukemia.

Thus, there are problems of availability of anticancer drugs having a satisfactory coefficient of risk/benefit, i.e. high therapeutic efficacy in mild or absent side effects.

Another problem in protivo is.

Now unexpectedly discovered that certain derivatives of colchicine have high cytotoxic effect on normal cancer cells and the corresponding resistant phenotype (MDR).

Compounds according to the invention are effective inducers of apoptosis, proved to be significantly better than the compounds known from the prior art. Due to their lipophilic properties, connections, especially bioavailable after oral administration. In addition, the compounds of this invention can be introduced with equal success parenterally or locally.

Description of the invention

This invention relates to compounds of the formula I

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where R denotes methoxy or methylthio group, a R1denotes a linear or branched alkyl group with 1-6 carbon atoms.

Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, ISO-butyl, tert-butyl, pentyl, neopentyl, hexyl.

The compounds of formula I receive from natural compounds colchicine or thiocolchicine or their C3-derived, manufactured, or produced the well-known literature methods. As described in the literature, C3-derivatives Moi aqueous solutions of strong inorganic acids allows you to selectively receive, by varying the temperature and the reaction time corresponding to the N-deazetil-derivatives. In particular, the deacetylation thiocolchicine or C3-derivatives can be performed by carrying out acid hydrolysis of compounds; in the case of thiocolchicine hydrolysis by gallogermanate or, more preferably, sulfuric acid (20% H2SO4- 120 h) allows to obtain N-deacetylbaccatin and 3-dimethyl-N-deacetylbaccatin with almost quantitative yields.

To obtain the compounds of formula I spend the reaction of N-deazetil-derivatives with 4-formyl-1-methylpyridinium-p-toluene-sulfonate and 1,8-diazabicyclo[5.4.0]undec-7-Yong (DBU).

Alternatively, the reaction of N-deazetil derived from 2,3-decret-butyl-1,2-benzoquinone obtain the compounds of formula II

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where R is methylthio, R1denotes a linear or branched C1-6alkyl group.

The next objective of the present invention are the compounds of formula II.

Proposed by the present invention compounds possess significant antitumor activity both in vitro and in vivo. Table 1 shows protiwaritmicescoe action of the compounds according to the invention on the explants cultivated tumor of the breast is chitina and Taxol.

Table 1 shows that the compounds according to the invention have significant advantages in resistant cell lines, which are currently considered as the main target of cytotoxic drugs.

Also a comparison was made between the compounds of the present invention (Ia, IIA and a compound in which R=OCH3 and R"=isopropyl) with the closest structural analogue connection for U.S. patent 3442953. The procedure used for analysis of cytotoxicity, published in the Alley, M. C. et al., Cancer Research 48, 589, 1988. As shown in the following table 2, the compounds of the present invention is more effective in the inhibition of cell lines and tumors.

In addition, the compounds of this invention have anti-inflammatory and anti-arthritis activity (degenerative rheumatoid arthritis and similar pathology) and can be included in pharmaceutical compositions used in the introduction of medication from said pathology. They are suitable for obtaining compositions intravenous, oral, transdermal, and subcutaneous injections.

Among is used for obtaining the compounds of the excipients of natural and synthetic phospholipids are submitted to the acce formulations proposed for use in the local treatment of skin epithelium and in cases of hyperproliferative skin conditions such as psoriasis. In specific antitumor area, in addition to phospholipids, which allow the introduction of the drug in liposomal form, proved to be particularly useful some surface-active compounds, such as polyethoxysiloxane castor oil or Polysorbate, interacting synergistically with the active ingredient. Preferably, the active component micronizer to dissolve the compound in water. Unusually active, a convenient form is the complex of these compounds with cyclodextrins.

In Oncology products used in doses of 1 to 100 mg/m2.

The following examples additionally illustrate the invention.

IN1NMR spectra:

Hz - Hz

ppm - m D.

molt -

int fin

type - the type

eq. - equal

Ah - axial

s - singlet

t - triplet

d - doublet

ddd - triple doublet

EXAMPLE 1

Getting thiocolchicine of N-diacetylhydrazine.

(la:R=SMe; Ri=Me)

100 ml of CH2CL2and 30 ml of DMF are mixed in a nitrogen atmosphere, then add 4 g of diacetylhydrazine (M. C. 373, to 10.7 mmol) and 24.2 g of p-toluensulfonate 4-formyl-1-methylpyridine (M. C. 279,15 mmol what eslovenia Amin. The solution is cooled to 0oC and then added dropwise 1,94 g of DBU (M. C. 152, 12.8 mmol) to give a dark red solution. After 15 minutes, add 150 ml of an aqueous solution of oxalic acid, the mixture is left to react overnight, then repeatedly extracted with CH2CL2, dried over sodium sulfate and the solvent evaporated to dryness. The residue is crystallized from ethyl acetate, giving 78% yield. Thiocolchicine has the following physico-chemical and spectroscopic characteristics (see tab. 3 at the end of text).

EXAMPLE 2

Getting colchicina of N-deazetil-colchicine

(Ib:R=ome; R1=Me)

3.58 g of N-deacetylbaccatin treated according to the method of example 1. Obtain 2.6 g colchicina having the following physico-chemical and spectroscopic characteristics (see tab. 4 at the end of text).

EXAMPLE 3

Getting 3-0-isopropyl-colchicine

3.8 g 3-0-isopropyl-N-deacetylbaccatin dissolved in 100 ml of CH2CL2and add 25 g of 4-formyl-1-methylpyridinium-p-toluensulfonate; the reaction mixture is refluxed for 2.5 hours. The solution is cooled to 0oC and then added dropwise to 2 g of DBU with obtaining dark-red solution.

After 15 minutes add tracerout CH2Cl2.

The solvent is evaporated to dryness and the residue vykristallizovyvalas from a mixture of ethyl acetate/acetone to obtain 3-0-isopropyl-colchicine.

So pl. 222o-4oWITH

MS(that is, 1.): 384 m/z

EXAMPLE 4

Getting 3-0-isopropyl-thiocolchicine

3.8 g 3-0-isopropyl-N-diacetylhydrazine dissolved in 100 ml of CH2CL2and add 25 g of 4-formyl-1-methylpyridinium-p-toluensulfonate; the reaction mixture is refluxed for 2.5 hours. The solution is cooled at 0oC and then added dropwise to 2 g of DBU with obtaining dark-red solution.

After 15 minutes, add 150 ml of an aqueous solution of oxalic acid, the mixture is left to react overnight, then repeatedly extracted with CH2CL2.

The solvent is evaporated to dryness and the residue vykristallizovyvalas from a mixture of ethyl acetate/acetone to obtain 3-0-isopropyl-thiocolchicine.

MS(E. I.): 396 m/z

EXAMPLE 5

The product of condensation of thiocolchicine and 3.5-ditretbutyl-1,2-benzoquinone

(IIa:R=SMe; R1=Me)

500 mg diacetylhydrazine (M. C. 373, of 1.34 mmol) and 590 mg of 3,5-decret-butyl-1,2-benzoquinone (M. C. 220, 2,69 mmol) is dissolved in 50 ml of methanol under normal atmosphere hours the solvent is evaporated in vacuum.

Warm the crude product is dissolved in 1 volume of ethyl acetate, add 1-1,5 volumes of hexane and the mixture is cooled with ice. The reaction product produce by filtration, the yield is 70%. This compound has the following physico-chemical and spectroscopic characteristics (see tab. 5 at the end of text).

EXAMPLE 6

The composition of the tablets containing the compound (Ia)

The compound (Ia) - 25 mg

Lactose - 47 mg

Microcrystalline cellulose 20 mg

Cross-linked sodium carboxymethyl cellulose, 5 mg

Colloidal silicon dioxide 1 mg

Talc 1 mg

Magnesium stearate 1 mg

A. Mix all the above ingredients except the sodium croscarmelose, talc and magnesium stearate.

C. Skip the mixture of (A) through a sieve of 60 mesh.

C. Transfer) in a cubic mixer and mix to obtain a homogeneous mixture.

D. Add sodium to croscarmelose to C) and mix for 5 minutes.

E. Skip stearate and talc through a sieve of 60 mesh.

F. Mixing of E and D in a cubic mixer for 2 minutes.

G. Press 100 mg of the mixture (F) into tablets using concave punch (6 mm diameter).

EXAMPLE 7

The composition of whether esterol - 0.50 g

Equivalent of 0.01 g

95% Ethanol - 8.00 g

Disodium edetate - 0.15 g

Imidazolidinyl-urea - 0,30 g

Dehydroacetate sodium - 0.20 g

Hydroxyethylcellulose (Natrosol 250 HHX-Aqualon) - 2,00 g

Distilled water - 67,75

A. Melt phosphatidylcholine, add 95% ethanol and stirred to obtain a transparent liquid.

C. Heat phase a and add under stirring until complete dissolution of the cholesterol that is equivalent.

Back To phase In the add connection IIA and stirred to obtain a transparent viscous liquid. Heated to 40oC.

D. In distilled water to dissolve disodium edetate, imidazolidinedione and dihydroxyacetone sodium. Heated to 40oC.

That is To add phase D phase With vigorous stirring under vacuum.

F. Dispersing the hydroxyethyl cellulose in the phase E to gel formation.

EXAMPLE 8

Obtaining solution for injection containing the compound (Ia)

The compound (Ia) - 15 mg

PEG-660 12-hydroxystearate - 2,500 mg

Propylene glycol - 1,000 mg

Alcohol q.s. to 5 ml

A. To propylene glycol with stirring, add the alcohol.

Century, When intensive paramasivan is Holocene transparent liquid.

D. dilute to volume with ethanol and stirred to obtain a transparent liquid.

EXAMPLE 9

Obtaining solution for injection containing the compound (Ia)

Compound Ia - 15 mg

Polyethoxysiloxane castor oil - 2,500 mg

Propylene glycol - 1,000 mg

Alcohol - enough to 5 ml

A. To propylene glycol with stirring, add the alcohol.

C. With vigorous stirring to phase A. add polyethoxysiloxane castor oil.

Back To phase In the add connection Ia and stirred to obtain a transparent liquid.

D. dilute to volume with ethanol and stirred to obtain a transparent liquid.

1. Derived colchicine formula I,

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where R denotes methoxy or methylthiourea;

R1denotes a linear or branched alkyl group with 1-6 carbon atoms, provided that when R is methoxy, R1cannot denote methyl.

2. Connection on p. 1, where R denotes methoxy.

3. Connection on p. 1, where R is methylthio.

4. Connection on p. 3, where R1denotes methyl.

5. The compounds of formula II

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6. Connection on p. 5, where R1denotes methyl.

7. The method of obtaining the compounds according to paragraphs.1-4, comprising the reaction of N-deacetylbaccatin or N-diacetylhydrazine with p-toluensulfonate 4-formyl-1-methylpyridine and 1,8-diazabicyclo[5.4.0]undec-7-Yong.

8. The method of obtaining the compounds according to paragraphs.5 and 6, comprising the reaction of N-diacetylhydrazine with a 3.5-ditretbutyl-1,2-benzoquinone.

9. Connection PP.1-6, with antitumor, antiproliferative activity.

10. Pharmaceutical composition having antitumor activity, comprising an effective amount of the compounds according to paragraphs.1-4 as an active ingredient.

11. Pharmaceutical composition having antitumor activity, comprising an effective amount of the compounds according to paragraphs.5-6 as the active ingredient.

12. Composition according to any one of paragraphs.10 and 11, suitable for local use.

13. Composition according to one of paragraphs.10-12 containing polyethoxysiloxane castor oil as a surfactant.

 

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