HK1051973B - Condensation derivatives of thiocolchicine and baccatin and composition thereof - Google Patents

Description

condensation derivatives of thiocolchicine and baccatin and compositions thereof

The invention relates to N-deacetylthiocolchicine and 10-deacetylbaccatin III derivatives of formula (I)

Wherein: -n is an integer from 0 to 8; -R is a residue of formula a), b), c), d) or e):

wherein: -R₁And R₂Which may be the same or different, is hydrogen or a group of the formula:

n is preferably an integer of 1 to 7, more preferably 1.

Colchicine and thiocolchicine are known antibacterial compounds that are capable of destabilizing microtubules by interaction with tubulin.

Colchicine is currently used in the treatment of gout and related inflammatory diseases, but its use is limited to the acute phase due to its high degree of gastrointestinal toxicity.

Many colchicine or thiocolchicine derivatives have been studied in view of their potential use as antitumor drugs, but the efforts of researchers have not been successful so far due to the generally very limited therapeutic index of these compounds.

Only one colchicine derivative, decarbonylcolchicine, has been used in the past for the clinical treatment of leukemia, but with extreme success.

Similarly, the antiproliferative activity of taxane (taxane) derivatives (paclitaxel and derivatives) is related to their ability to bind irreversibly to the alpha and beta forms of tubulin in microtubules. Oxenethane and phenyl on the isoserine side chain have been shown to be essential for activity; in fact, baccatin lacking the isoserine side chain has virtually no antiproliferative activity, as compared to panitexi and the other C of isoserine₁₃Esters are distinct in that they can form bonds with two different positions of microtubules to prevent depolymerization and thus inhibit mitotic spindle activity.

Surprisingly, it has now been found that compounds of formula (I) have antiproliferative activity, although they lack affinity for tubulin during both the assembly and disassembly steps of microtubules.

Thus, the activity of the compounds of formula (I) is caused by an unexpected mechanism of action, which has not been proven from the prior knowledge in the field of antimicrotubulin drugs.

The compounds of the invention have potent antimitotic activity and are characterized by a favourable therapeutic index making them suitable for the treatment of various forms of tumours and degenerative rheumatoid arthritis, a disease characterized by excessive proliferation and abnormal migration of leukocytes.

The compounds (I) have cytotoxicity similar to that of the most effective antitumor drugs, but have a remarkably broad spectrum of action, especially on those cells resistant to known drugs.

Compound (I) is prepared by reacting N-deacetylthiocolchicine and a dicarboxylic acid reactive derivative in an anhydrous solvent under conditions such that an N-monoacetylated product is obtained which is subsequently reacted with a baccatin III derivative optionally protected in position 7, 13 or 10, depending on the desired compound, in the presence of a suitable condensing agent, such as dicyclohexylcarbodiimide. Removing any protecting groups optionally present, and/or optionally acylating the hydroxyl group on the baccatin III residue to directly yield compound (I).

When R in compound (I) is a group of formula c), the reaction can be carried out without prior protection of the other hydroxyl groups present on the taxane compound due to the reactivity of the hydroxyl groups in the isoserine chain.

Examples of suitable dicarboxylic acid reactive derivatives include acid halides, acid chlorides, reactive anhydrides or esters.

Alternatively, it is also possible to acylate the taxane derivative with a dicarboxylic acid and then to condense the product obtained with N-deacetylthiocolchicine.

The compounds of the present invention are useful in the treatment of proliferative diseases, especially tumors of various origins, rheumatoid arthritis or other degenerative diseases in which antiproliferative and anti-inflammatory effects are indicated.

For this purpose, the compounds of the formula (I) are administered in the form of pharmaceutical compositions suitable for oral, parenteral, epidermal or transdermal administration. The dose of the compound of formula (I) is from 1 to 100mg/m depending on the route of administration²The body area changes. These compounds are preferably administered orally.

Examples of compositions include capsules, tablets, bottles, creams, solutions, granules.

The following examples describe the invention in more detail.

Example 1

a) 100mg of deacetylthiocolchicine (0.268mmol, M.W.373g/mol) was dissolved in 5ml of anhydrous dioxane, then 27mg of succinic anhydride (0.268mmol, M.W.100g/mol) was added and the reaction mixture was heated at 60 ℃ for 5 hours. Monitoring by TLC: AcOEt/MeOH 4: 1. Dioxane was removed by evaporation and the product was not purified for subsequent reaction. 130mg of product are obtained.

b) 126mg of the product of step a) (0.268mmol, M.W.473g/mol) are dissolved in 8ml of anhydrous toluene. 187mg of 7-Tes baccatin (0.268mmol, M.W.700g/mol), 66mg of DCC (0.321mmol, M.W.206g/mol) and 13mg of DMAP (0.1mmol, M.W.122g/mol) were added. The mixture was stirred at room temperature for about 12 hours until the starting product disappeared. Monitoring by TLC: AcOEt/MeOH 4: 1. The mixture was filtered through Celite and evaporated to dryness. The crude product was purified on a column (silica gel) using AcOEt/hexane 9: 1 as eluent to give 120mg of the protected condensation product and 80mg of the product which had been deprotected in the 7-position.

c) 120mg of the product of step b) (0.103mmol, M.W.1155g/mol) were dissolved in 5ml of MeOH/AcCl (5ml of methanol and 35. mu.l of AcCl). The reaction was completed in 15 minutes. Bicarbonate was added to the mixture and extracted with AcOEt to give 100mg of the product of formula (I) wherein n is 1 and R is a residue of formula a).

Example 2

a) 100mg of 10-O-succinyl-7-Tes baccatin III (M.W.699g/mol, 0.14mmol) and 54mg of N-deacetylthiocolchicine (M.W.373g/ml, 0.14mmol) were dissolved in 5ml of anhydrous methanol, and 2ml of dichloromethane were added. 31mg of DCC (M.W.206g/mol, 0.15mmol) and 8.5mg of DMAP (M.W.122g/mol, 0.07mmol) were added at room temperature. After one day, the reaction was filtered through Celite, washed with toluene and evaporated to dryness. In a flash column (silica gel, eluent CH)₂Cl₂MeOH 25: 1) to yield 70mg of product.

b) 200mg (0.213mmol) of the product from step a) are dissolved in 14ml of dry toluene. 183mg of an oxazolidine derivative of the formula (hereinafter referred to as SHA-9) (0.426mmol) were added:

and 88mg of DCC (0.426mmol) and 26mg of DMAP (0.213mmol), and the mixture was stirred at room temperature. Monitoring by TLC: CH (CH)₂Cl₂MeOH 25: 1. After 4 hours the reaction mixture was filtered through Celite and purified by column chromatography to yield 240mg of product.

c) 160mg of the product of step b) (0.12mmol M.W.1338) were dissolved in 3.2ml of a solution obtained by dissolving 70. mu.l of AcCl in 10ml of MeOH. Half an hour later, 5% NaHCO was added to the reaction mixture₃By CH₂Cl₂The solvent was extracted, dried and evaporated. Purification by flash chromatography gave 97mg of compound of formula (I) wherein n is 1 and R is the residue of formula b).

Example 3

70mg of panituixi (0.038mmol, M.W.1824) were dissolved in 5ml of anhydrous dioxane. DCC (1.5 equiv.), DMAP (5% mol) and the product of example 1a were added. The mixture was stirred at 110 ℃ for 2 hours, then 10mg of the product from example 1a and 11mg of DCC were added. Thereafter, the reaction was left at room temperature for 48 hours, and then heated at 110 ℃ for another 24 hours. The solvent was removed by evaporation and the residue was purified by flash chromatography (AcOEt: MeOH 99: 1) to give 21mg of compound (I) wherein n is 1 and R is the residue of formula c).

Example 4

a) To a solution of 7-succinyl-10, 13-di Tes-baccatin III (390mg, 0.479mmol, M.W.814) in 10ml THF at 0 deg.C was added a solution of TBAF (1M in THF, 0.96 mmol). The mixture was left at 0 ℃ for 1 hour 30 minutes and then at room temperature for 2 hours. Thereafter, 1 equivalent of TBAF was added and the reaction was continued until complete removal of the protecting group. Adding water to the reaction mixture and extracting with AcOEt; the aqueous phase was acidified with 1N HCl and extracted with AcOEt to yield 350mg of product.

b) Reacting the compound of step a) (0.479mmol) with TIO-NH₂(0.479mmol), DCC (1.5 equiv.) and DMAP (50% mol) in toluene-THF for 1 h. The reaction mixture was filtered through Celite and passed through CC (CH)₂Cl₂MeOH ═ 25: 1) to give the compound of formula (I) wherein n is 1 and R is a residue of formula d).

Example 5

200mg of the compound of example 4 (0.206mmol) were dissolved in 14ml of toluene-anhydrous THF. 177mg of SHA9(2 equiv.), 84mg of DCC (2 equiv.) and 26mg of DMAP (0.206mmol) were added to the mixture, which was stirred at room temperature. Monitoring by TLC: CH (CH)₂Cl₂MeOH 25: 1. After 4 hours, the reaction mixture was filtered through Celite and purified on a chromatography column. The product obtained is dissolved in a solution of 4.8ml 70. mu.l AcCl in 10ml MeOH. Half an hour later, 5% NaHCO was added to the reaction₃And use CH in combination₂Cl₂And (4) extracting. The extract was dried and the solvent was removed by evaporation. Purifying the residue by flash chromatography to obtain 110mg of compound (I) wherein n is 1 and R is a residue of formula e) wherein R is₁And R₂Is a group of the formula:

Claims (4)

1. A compound of formula (I)

Wherein:

-n is an integer from 0 to 8;

-R is a residue of formula a), b), c), d) or e):

wherein:

-R₁and R₂Which may be the same or different, is hydrogen or a group of the formula:

2. the compound of claim 1, wherein n is an integer from 1 to 7.

3. The compound of claim 2, wherein n is 1.

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 in association with a suitable carrier.