CA2252717C - Colchicine-skeleton compounds, their use as medicaments and compositions containing them - Google Patents
Colchicine-skeleton compounds, their use as medicaments and compositions containing them Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
- C07C2603/34—Benzoheptalenes; Hydrogenated benzoheptalenes
Abstract
The present invention relates to colchicine and thiocolchicine derivates of formula I
(see formula I) wherein R is a methoxy or methylthio group and R1 is a straight or branched alkyl or alkenyl group having 1 to 6 carbon atoms, or an alicyclic or heterocyclic moiety, a saturated or unsaturated mono or dicarboxylic or amino acidic acyl residue or a .beta.-D-glucose or 6-deoxygalatose residue, with the proviso that, when R is methoxy, R1 is different from methyl or acetyl which can be obtained from these molecules by functionalization of the C-7 to ketone or functionalization of the amino group. Said compounds have a marked antiblastic activity both on the normal cancer cells and the chemoresistant phenotype. The compounds of the invention can be administered both by injection and orally.
(see formula I) wherein R is a methoxy or methylthio group and R1 is a straight or branched alkyl or alkenyl group having 1 to 6 carbon atoms, or an alicyclic or heterocyclic moiety, a saturated or unsaturated mono or dicarboxylic or amino acidic acyl residue or a .beta.-D-glucose or 6-deoxygalatose residue, with the proviso that, when R is methoxy, R1 is different from methyl or acetyl which can be obtained from these molecules by functionalization of the C-7 to ketone or functionalization of the amino group. Said compounds have a marked antiblastic activity both on the normal cancer cells and the chemoresistant phenotype. The compounds of the invention can be administered both by injection and orally.
Description
Technological background The present invention relates to novel colchicine derivatives having antiproliferative, antineoplastic and antiinflammatory activities, the methods for the preparation thereof and the pharmaceutical formulations containing them.
Colchicine is a known pseudo-alkaloid widely used for a very long time in therapy for the treatment of gout, a pathology on which it acts very quickly and specifically, even though it should be used for short times due to its toxicity. A colchicine derivative, namely thiocolchicoside, is widely used to treat contractures and in inflammatory conditions on skeletal muscles. In addition, colchicine is a very potent antiblastic agent, which acts blocking the formation of the mitotic spindle during cell division; this latter aspect has been investigated thoroughly for any antineoplastic activity and a great deal of colchicine derivatives have been prepared to this purpose.
Colchicine as such and a number of its derivatives could not be used clinically due to their high toxicity, and therefore their unacceptable risk/benefit ratio. Only one colchicine derivative, demecolcine, is used in some degree in oncology for the treatment of some leukemia forms.
Therefore the problem exist of the availability of antineoplastic medicaments having a satisfactory risk/benefit ratio, i.e. a high therapeutical activity with poor or no side-effects.
Another problem in the antineoplastic field is the resistance to the medicament which takes place in specific phenotypes.
Now it has surprisingly been found that some colchicine derivatives have a high cytotoxic activity both on the normal cancerous cells and on the corresponding resistant phenotype {MDR).
The compounds of the invention are potent apoptosis inducers, proving to be markedly better than the compounds of the prior art. Due to their lipophilic, characteristics, the compounds are particularly bioavailable after oral administration. Moreover, the compounds of the present invention can be administered by the parenteral or topical routes as well.
Disclosure of the invention The present invention relates to compounds of formula {I) OMe ~ ~ ~ (I) OMe R
wherein R is a methoxy or methylthio group and R1 is a straight or branched alkyl or alkenyi group having 1 to 6 carbon atoms, or an alicyclic or heterocyclic moiety, a saturated or unsaturated mono or dicarboxylic or amino acidic acyl residue or a p-D-glucose or 6-deoxygalactose I
Colchicine is a known pseudo-alkaloid widely used for a very long time in therapy for the treatment of gout, a pathology on which it acts very quickly and specifically, even though it should be used for short times due to its toxicity. A colchicine derivative, namely thiocolchicoside, is widely used to treat contractures and in inflammatory conditions on skeletal muscles. In addition, colchicine is a very potent antiblastic agent, which acts blocking the formation of the mitotic spindle during cell division; this latter aspect has been investigated thoroughly for any antineoplastic activity and a great deal of colchicine derivatives have been prepared to this purpose.
Colchicine as such and a number of its derivatives could not be used clinically due to their high toxicity, and therefore their unacceptable risk/benefit ratio. Only one colchicine derivative, demecolcine, is used in some degree in oncology for the treatment of some leukemia forms.
Therefore the problem exist of the availability of antineoplastic medicaments having a satisfactory risk/benefit ratio, i.e. a high therapeutical activity with poor or no side-effects.
Another problem in the antineoplastic field is the resistance to the medicament which takes place in specific phenotypes.
Now it has surprisingly been found that some colchicine derivatives have a high cytotoxic activity both on the normal cancerous cells and on the corresponding resistant phenotype {MDR).
The compounds of the invention are potent apoptosis inducers, proving to be markedly better than the compounds of the prior art. Due to their lipophilic, characteristics, the compounds are particularly bioavailable after oral administration. Moreover, the compounds of the present invention can be administered by the parenteral or topical routes as well.
Disclosure of the invention The present invention relates to compounds of formula {I) OMe ~ ~ ~ (I) OMe R
wherein R is a methoxy or methylthio group and R1 is a straight or branched alkyl or alkenyi group having 1 to 6 carbon atoms, or an alicyclic or heterocyclic moiety, a saturated or unsaturated mono or dicarboxylic or amino acidic acyl residue or a p-D-glucose or 6-deoxygalactose I
residue, with the proviso that, when R is methoxy, R1 is different from methyl or acetyl.
Examples of alkyl group are methyl, ethyl, propyl, isopropyl, n-butyl, ~ iso-butyl, t-butyl, pentyl, neopentyl, hexyl.
Examples of alkenyl group are propenyl, 1-butenyl, 2-butenyl, 1-pentenyl.
Examples of alicyclic group are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Examples of heterocyclic group are benzotriazolyl, methyltetrazolyl.
Examples of aryl residue are ximenoyl, succinyl, aspartyl.
The compounds of formula I are prepared starting from the natural compounds colchicine or thiocolchicine or from the C3-derivatives thereof commercially available or obtainable with methods known in literature. As described in literature, the C3 derivatives can be prepared reacting the 3-0-dimethyl derivative with an alkyl or acyl halide. The hydrolysis of said compounds with stzong mineral acid aqueous solutions allows to obtain selectively, changing the temperature and the reaction time, the corresponding N-deacetyl derivatives. In particular, the deacetylation of thiocolchicine or of the C3 derivatives thereof can be carried out subjecting the compounds to acidic hydrolysis; in the case of thiocolchicine, the hydrolysis with halo acids or, more preferably, with sulfuric acid (20$ H2S04 - 120 h), allows to obtain N
deacetyithiocolchicine and 3-demethyl-N
deacetylthiocolchicine in nearly quantitative yields.
The N-deacetyl derivatives are reacted with 4-formyl-1-methylpyridinium-p-toluenesulfonate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to prepare the compounds of formula I.
Alternatively, reacting the N-d eacetyl derivatives with 2,3-ditert-butyl-1,2-benzoquinon e, the compounds of formula II are obtained:
R1 (II) R
wherein R and R1 have the meanings de scribed above.
A further of the present invention are the compounds of formula II.
20 The compounds object of the invention exhibit a remarkable antineoplastic activity both in vitro and in vi vo .
The table shows the antimitotic activity of the compounds of the invention on cultured breast tumour 25 explants normal (MCF-7) or resistant to both adriamycin and vinblastin (MCF7-ADR), compared with colchicine and Taxol'" .
TABLE
Compounds IC50 (nM) 5 _________________ _______________________ ________________ Colchicine 12,000 1.8 6,600 Compound Ia 15 6.2 2.4 Compound Ib 40 23 1.7 Compound IIa 52 17 3.0 Taxol 2,400 2.3 1,043 This table evidences that the compounds of the invention have significant advantages on the resistant cell lines, which are nowadays considered the main target of cytotoxic medicaments.
Moreover, the compounds according to the present invention have antiinflammatory and antiarthritis activities (degenerative rheumatoid arthritis and similar pathologies) and they can be incorporated in pharmaceutical formulations useful for the administration of the medicament for the indicated pathology. Formulations for the intravenous, oral, transdermal, epicutaneous administrations can conveniently be prepared.
Among the excipients useful to prepare said formulations, natural and synthetic phospholipids proved to be particularly useful for preparing liposomial forms for the parenteral and/or topical routes. The same formulations proved to be useful in the topical treatment of cutaneous epitheliomas and in cutaneous hyperproliferative conditions, such as psoriasis. In the specific antineoplastic field, besides the phospholipids which allow the administration of the medicament in the liposomial form, some surfactants such as polyethoxylated castor oils or polysorbates acting synergistically with the active ingredient, turned out to be particularly useful. Preferably the active principle is micronized to dissolve the compound in water. A surprisingly active, convenient form is the complex of these compounds with cyciodextrins.
In oncology, the products are used at dosages from 1 to 100 mg/m2.
The following examples further illustrate the invention.
BXa~Ble 1 Preparation of Thiocolchicone from N-deacetylthiocolchi-cane (Ia: R = SMe; R1 = Me) 100 ml of CH2C12 and 30 ml of DMF are mixed under nitrogen atmosphere, then 4 g of deacetylthiocolchicine (M.W. 373, 10.7 mmol) and 24,2 g of 4-formyl-1-methylpyridinium p-toluenesulfonate (M. W. 279, 15 mmol) are added; the whole is refluxed for 3 hours or anyhow until the amine disappears. The solution is cooled at 0°C and then added with 1.94 g of DBU (M. W. 152, 12,8 mmol), drop by drop, to obtain a dark red solution.
After 15 minutes, 150 ml of an oxalic acid aqueous solution are added, the mixture is left to react overnight, then repeatedly extracted with CH2C12; dried over sodium sulfate and the solvent is evaporated off to dryness. The residue is crystallized from ethyl acetate to obtain a 78% yield. Thiocolchicone has the following chemical-physical and spectroscopical characteristics.
M.p. 212'C
MS (E.I.): 372 m /z (35%) - 344 (55%) (6%) ( 13% ) - 301 ( - 287 ( 8% ) 7 ( 4% 243 ( 4% ) 4% ) - 26 ) - - 215 (4%) - 84 (64%) 49 (100%).
-1H-NMR (300 MHz, CDC13) ppm molt int type J(Hz) J(Hz) J(Hz) 2.45 s 3H SME
2.68 ddd 1H H-5eq. 13.4 4.8 1.9 2.81 ddd 1H H-6ax 16.6 13.4 4.8 2.95 ddd 1H H-6eq 16.6 5.5 1.9 3.11 ddd=td 1H H-Sax 13.1 13.5 5.6 3.57 s 3H OMe 3.88 s 3H OMe 3.90 s 3H OMe 6.56 s 1H H-4 6.96 s 1H H-8 7.07 AB 1H H-11 10.2 7.27 AB. 1H H-12 10.2 13C_NMR (300 MHz, CDC13):
15.8 ppm (SMe) - 30.0 (C-5) - .0 (C-6) - 56.7 (OMe-3) -61.8 ~OMe-2) - 61.8 (OMe-1) - 107.8 (C-4) - 125.3 (C-12b) - 127.0 (C-1 1) - 130.7 (C-8)- 134.4 (C-4a) - 136.1 (C-12a) - 136.5 (C-12) - 142.3 (C-2) 150.4 (C-1) - -152.6 (C-7a) - 154.6 .7 (C-10)- 182.9 (C-9) (C-3) - 160 - 206.2 (C-7).
Examgle 2 Preparation of colchicone from N-deacetyl-colchicine (Ib . R = OMe; R1 = Me) 3.58 g of N-deacetylcolchicine are treated according to the procedure of Example 1. 2.6 g of colchicone are obtained, having the following chemical-physical and spectroscopical characteristics.
MS ( E . I . ) : 356 m/z ( 100% ) - 328 ( 95% ) - 313 ( 25% ) - 300 (22%) - 285 (18%) - 271 (26%) - 253 (13%) - 238 (8%) -227 (13%) - 199 (16%) - 171 (11%).
1H-NMR (300 MHz, CDC13) ppm molt int type J{Hz) J(Hz) J(Hz) 2.67 ddd 1H H-5~i 13.7 5.0 2.2 2.82 ddd 1H H-6p 16.6 13.6 5.0 2.95 ddd 1H H-6a 16.6 5.4 2.2 3.11 ddd 1H H-5a 13.7 13.6 5.4 3.55 s 3H OMe-1 3.86 s 3H OMe-2 3.87 s 3H OMe-3 4.00 s 3H OMe-10 6.54 s 1H H-4 6.85 d 1H H-11 10.7 7.12 s 1H H-8 7.24 d 1H H-12 10.7 13C-NMR (300 MHz, CDC13):
29.27 ppm (C-5) - 43.33 (C-6) - 55.96 (OMe-10) - 56.44 (OMe-3) - 61.07 (OMe-2) - 61.12 (OMe-1) - 106.96 (C-4) 112.40 (C-11) - 124.50 (C-12b) - 132.00 {C-4a) - 132.80 (C-8) - 135.30 (C-12) - 136.15 (C-12a) - 141.80 (C-2) -150.16 (C-1) - 151.83 (C-7a) - 153.70 (C-3) - 164.10 (C-10) - 179.40 (C-9) - 205.60 (C-7).
Example 3 Preparation of the condensation product between Thiocolchicine and 3,5-ditert-butyl-1,2-benzoquinone (IIa: R SMe; R1 = Me) =
500 mg of deacetylthiocolchicine (M. W. 373, 1.34 mmol) and 590 mg of 3,5-di-tert-butyl-1,2-benzoquinone (M.W. 220, 2.69 mmol) are dissolved in 50 ml of methanol, under normal atmosphere.
The reaction is followed by TLC (CH2C12:acetone 30:1) and after about 18 hours the solvent is evaporated off under vacuum.
The warm crude is dissolved in 1 volume of ethyl acetate, 1-1.5 volumes of hexane are added and the mixture is cooled on ice.
The reaction product is recovered by filtration, the yield being 70%. This compound has the following chemical-physical and spectrosc opical characteristics.
M.p. 238' C with decomposition MS (E.I.) : 573 m/z (33%) - 558 (1%) - 545 (100%) - 530 (9%j - 514 (7%) -314 (4%) - 301 (4%) - 265 (7%) (7%).
1H-NMR (3 00 MHz, CDC13) ppm molt int type J(Hz) J(Hz) 1.30 s 9H tBu 1.40 s 9H tBu 2.45 s 3H SMe 3.05 dd 1H H-5 14.0 4.0 3.30 dd 1H H-5 14.0 4.0 3.55 s 3H OMe 3.83 s 3H OMe 3.87 s 3H OMe 3.86 t 1H H-6 4.0 6.65 s 1H H-4 7.08 d 1H H-11 11.0 7.20 d 1H H-5' 2.0 7.26 d 1H H-3' 2.0 7.28 d 1H H-12 11.0 7.33 s 1H H-8 5 13C-NMR (300~MHz, CDC13):
15.71 ppm (SMe) - 30.33 ( 0313) - 31.95 ( 0313) -34.96 (( 03,13) - 35.25 ( 0313) - 36.60 (C-5) - 56.41 (OMe-3) - 61.81 (OMe-1) - 61.64 (OMe-2) - 76.47 (C-6) -109.80 (C-4) - 123.56 (C-5') - 124.61 (C-3') - 125.75 10 (C-12b) - 126.80 (C-11) - 132.28 (C-4') - 133.58 (C-6') - 135.13 (C-8) - 135.47 (C-4a) - 136.10 (C-12) - 137.01 - (C-12a) - 142.35 (C-2) - 143.21 (C-7a) - 144.88 (C-2')- 147.19 (C-1') - 152.06 (C-1) - 153.78 (C-3) -159.85 (C-10) - 164.68 (C-7) - 182.26 (C-9).
Example 4 Preparation of tablets containing compound (Ia) Compound Ia 25 mg Lactose 47 mg Microcrystalline cellulose 20 mg Cross-linked sodium carboxymethyl cellulose 5 mg Colloidal silica 1 mg Talc 1 mg Magnesium stearate 1 mg Example 5 Preparation of a liposome cream containing compound (IIa) Compound IIa 0.20 g Phosphatidylcholine 20.00 g Cholesterol 0.50 g Butylhydroxytoluene 0.01 g 95~ Ethanol 8.00 g Disodium edetate 0.15 g Imidazolidinyl urea 0.30 g Sodium dehydroacetate 0.20 g Hydroxyethyl cellulose (Natrosol 250 HHX-Aqualon) 2.00 g Distilled water 67.75 Example 6 Preparation of an injectable solution containing compound (Ia) Compound Ia 15 mg PEG-660 12-hydroxystearate 2.500 mg Propylene glycol 2.000 mg alcohol q.s. to 5 ml
Examples of alkyl group are methyl, ethyl, propyl, isopropyl, n-butyl, ~ iso-butyl, t-butyl, pentyl, neopentyl, hexyl.
Examples of alkenyl group are propenyl, 1-butenyl, 2-butenyl, 1-pentenyl.
Examples of alicyclic group are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Examples of heterocyclic group are benzotriazolyl, methyltetrazolyl.
Examples of aryl residue are ximenoyl, succinyl, aspartyl.
The compounds of formula I are prepared starting from the natural compounds colchicine or thiocolchicine or from the C3-derivatives thereof commercially available or obtainable with methods known in literature. As described in literature, the C3 derivatives can be prepared reacting the 3-0-dimethyl derivative with an alkyl or acyl halide. The hydrolysis of said compounds with stzong mineral acid aqueous solutions allows to obtain selectively, changing the temperature and the reaction time, the corresponding N-deacetyl derivatives. In particular, the deacetylation of thiocolchicine or of the C3 derivatives thereof can be carried out subjecting the compounds to acidic hydrolysis; in the case of thiocolchicine, the hydrolysis with halo acids or, more preferably, with sulfuric acid (20$ H2S04 - 120 h), allows to obtain N
deacetyithiocolchicine and 3-demethyl-N
deacetylthiocolchicine in nearly quantitative yields.
The N-deacetyl derivatives are reacted with 4-formyl-1-methylpyridinium-p-toluenesulfonate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to prepare the compounds of formula I.
Alternatively, reacting the N-d eacetyl derivatives with 2,3-ditert-butyl-1,2-benzoquinon e, the compounds of formula II are obtained:
R1 (II) R
wherein R and R1 have the meanings de scribed above.
A further of the present invention are the compounds of formula II.
20 The compounds object of the invention exhibit a remarkable antineoplastic activity both in vitro and in vi vo .
The table shows the antimitotic activity of the compounds of the invention on cultured breast tumour 25 explants normal (MCF-7) or resistant to both adriamycin and vinblastin (MCF7-ADR), compared with colchicine and Taxol'" .
TABLE
Compounds IC50 (nM) 5 _________________ _______________________ ________________ Colchicine 12,000 1.8 6,600 Compound Ia 15 6.2 2.4 Compound Ib 40 23 1.7 Compound IIa 52 17 3.0 Taxol 2,400 2.3 1,043 This table evidences that the compounds of the invention have significant advantages on the resistant cell lines, which are nowadays considered the main target of cytotoxic medicaments.
Moreover, the compounds according to the present invention have antiinflammatory and antiarthritis activities (degenerative rheumatoid arthritis and similar pathologies) and they can be incorporated in pharmaceutical formulations useful for the administration of the medicament for the indicated pathology. Formulations for the intravenous, oral, transdermal, epicutaneous administrations can conveniently be prepared.
Among the excipients useful to prepare said formulations, natural and synthetic phospholipids proved to be particularly useful for preparing liposomial forms for the parenteral and/or topical routes. The same formulations proved to be useful in the topical treatment of cutaneous epitheliomas and in cutaneous hyperproliferative conditions, such as psoriasis. In the specific antineoplastic field, besides the phospholipids which allow the administration of the medicament in the liposomial form, some surfactants such as polyethoxylated castor oils or polysorbates acting synergistically with the active ingredient, turned out to be particularly useful. Preferably the active principle is micronized to dissolve the compound in water. A surprisingly active, convenient form is the complex of these compounds with cyciodextrins.
In oncology, the products are used at dosages from 1 to 100 mg/m2.
The following examples further illustrate the invention.
BXa~Ble 1 Preparation of Thiocolchicone from N-deacetylthiocolchi-cane (Ia: R = SMe; R1 = Me) 100 ml of CH2C12 and 30 ml of DMF are mixed under nitrogen atmosphere, then 4 g of deacetylthiocolchicine (M.W. 373, 10.7 mmol) and 24,2 g of 4-formyl-1-methylpyridinium p-toluenesulfonate (M. W. 279, 15 mmol) are added; the whole is refluxed for 3 hours or anyhow until the amine disappears. The solution is cooled at 0°C and then added with 1.94 g of DBU (M. W. 152, 12,8 mmol), drop by drop, to obtain a dark red solution.
After 15 minutes, 150 ml of an oxalic acid aqueous solution are added, the mixture is left to react overnight, then repeatedly extracted with CH2C12; dried over sodium sulfate and the solvent is evaporated off to dryness. The residue is crystallized from ethyl acetate to obtain a 78% yield. Thiocolchicone has the following chemical-physical and spectroscopical characteristics.
M.p. 212'C
MS (E.I.): 372 m /z (35%) - 344 (55%) (6%) ( 13% ) - 301 ( - 287 ( 8% ) 7 ( 4% 243 ( 4% ) 4% ) - 26 ) - - 215 (4%) - 84 (64%) 49 (100%).
-1H-NMR (300 MHz, CDC13) ppm molt int type J(Hz) J(Hz) J(Hz) 2.45 s 3H SME
2.68 ddd 1H H-5eq. 13.4 4.8 1.9 2.81 ddd 1H H-6ax 16.6 13.4 4.8 2.95 ddd 1H H-6eq 16.6 5.5 1.9 3.11 ddd=td 1H H-Sax 13.1 13.5 5.6 3.57 s 3H OMe 3.88 s 3H OMe 3.90 s 3H OMe 6.56 s 1H H-4 6.96 s 1H H-8 7.07 AB 1H H-11 10.2 7.27 AB. 1H H-12 10.2 13C_NMR (300 MHz, CDC13):
15.8 ppm (SMe) - 30.0 (C-5) - .0 (C-6) - 56.7 (OMe-3) -61.8 ~OMe-2) - 61.8 (OMe-1) - 107.8 (C-4) - 125.3 (C-12b) - 127.0 (C-1 1) - 130.7 (C-8)- 134.4 (C-4a) - 136.1 (C-12a) - 136.5 (C-12) - 142.3 (C-2) 150.4 (C-1) - -152.6 (C-7a) - 154.6 .7 (C-10)- 182.9 (C-9) (C-3) - 160 - 206.2 (C-7).
Examgle 2 Preparation of colchicone from N-deacetyl-colchicine (Ib . R = OMe; R1 = Me) 3.58 g of N-deacetylcolchicine are treated according to the procedure of Example 1. 2.6 g of colchicone are obtained, having the following chemical-physical and spectroscopical characteristics.
MS ( E . I . ) : 356 m/z ( 100% ) - 328 ( 95% ) - 313 ( 25% ) - 300 (22%) - 285 (18%) - 271 (26%) - 253 (13%) - 238 (8%) -227 (13%) - 199 (16%) - 171 (11%).
1H-NMR (300 MHz, CDC13) ppm molt int type J{Hz) J(Hz) J(Hz) 2.67 ddd 1H H-5~i 13.7 5.0 2.2 2.82 ddd 1H H-6p 16.6 13.6 5.0 2.95 ddd 1H H-6a 16.6 5.4 2.2 3.11 ddd 1H H-5a 13.7 13.6 5.4 3.55 s 3H OMe-1 3.86 s 3H OMe-2 3.87 s 3H OMe-3 4.00 s 3H OMe-10 6.54 s 1H H-4 6.85 d 1H H-11 10.7 7.12 s 1H H-8 7.24 d 1H H-12 10.7 13C-NMR (300 MHz, CDC13):
29.27 ppm (C-5) - 43.33 (C-6) - 55.96 (OMe-10) - 56.44 (OMe-3) - 61.07 (OMe-2) - 61.12 (OMe-1) - 106.96 (C-4) 112.40 (C-11) - 124.50 (C-12b) - 132.00 {C-4a) - 132.80 (C-8) - 135.30 (C-12) - 136.15 (C-12a) - 141.80 (C-2) -150.16 (C-1) - 151.83 (C-7a) - 153.70 (C-3) - 164.10 (C-10) - 179.40 (C-9) - 205.60 (C-7).
Example 3 Preparation of the condensation product between Thiocolchicine and 3,5-ditert-butyl-1,2-benzoquinone (IIa: R SMe; R1 = Me) =
500 mg of deacetylthiocolchicine (M. W. 373, 1.34 mmol) and 590 mg of 3,5-di-tert-butyl-1,2-benzoquinone (M.W. 220, 2.69 mmol) are dissolved in 50 ml of methanol, under normal atmosphere.
The reaction is followed by TLC (CH2C12:acetone 30:1) and after about 18 hours the solvent is evaporated off under vacuum.
The warm crude is dissolved in 1 volume of ethyl acetate, 1-1.5 volumes of hexane are added and the mixture is cooled on ice.
The reaction product is recovered by filtration, the yield being 70%. This compound has the following chemical-physical and spectrosc opical characteristics.
M.p. 238' C with decomposition MS (E.I.) : 573 m/z (33%) - 558 (1%) - 545 (100%) - 530 (9%j - 514 (7%) -314 (4%) - 301 (4%) - 265 (7%) (7%).
1H-NMR (3 00 MHz, CDC13) ppm molt int type J(Hz) J(Hz) 1.30 s 9H tBu 1.40 s 9H tBu 2.45 s 3H SMe 3.05 dd 1H H-5 14.0 4.0 3.30 dd 1H H-5 14.0 4.0 3.55 s 3H OMe 3.83 s 3H OMe 3.87 s 3H OMe 3.86 t 1H H-6 4.0 6.65 s 1H H-4 7.08 d 1H H-11 11.0 7.20 d 1H H-5' 2.0 7.26 d 1H H-3' 2.0 7.28 d 1H H-12 11.0 7.33 s 1H H-8 5 13C-NMR (300~MHz, CDC13):
15.71 ppm (SMe) - 30.33 ( 0313) - 31.95 ( 0313) -34.96 (( 03,13) - 35.25 ( 0313) - 36.60 (C-5) - 56.41 (OMe-3) - 61.81 (OMe-1) - 61.64 (OMe-2) - 76.47 (C-6) -109.80 (C-4) - 123.56 (C-5') - 124.61 (C-3') - 125.75 10 (C-12b) - 126.80 (C-11) - 132.28 (C-4') - 133.58 (C-6') - 135.13 (C-8) - 135.47 (C-4a) - 136.10 (C-12) - 137.01 - (C-12a) - 142.35 (C-2) - 143.21 (C-7a) - 144.88 (C-2')- 147.19 (C-1') - 152.06 (C-1) - 153.78 (C-3) -159.85 (C-10) - 164.68 (C-7) - 182.26 (C-9).
Example 4 Preparation of tablets containing compound (Ia) Compound Ia 25 mg Lactose 47 mg Microcrystalline cellulose 20 mg Cross-linked sodium carboxymethyl cellulose 5 mg Colloidal silica 1 mg Talc 1 mg Magnesium stearate 1 mg Example 5 Preparation of a liposome cream containing compound (IIa) Compound IIa 0.20 g Phosphatidylcholine 20.00 g Cholesterol 0.50 g Butylhydroxytoluene 0.01 g 95~ Ethanol 8.00 g Disodium edetate 0.15 g Imidazolidinyl urea 0.30 g Sodium dehydroacetate 0.20 g Hydroxyethyl cellulose (Natrosol 250 HHX-Aqualon) 2.00 g Distilled water 67.75 Example 6 Preparation of an injectable solution containing compound (Ia) Compound Ia 15 mg PEG-660 12-hydroxystearate 2.500 mg Propylene glycol 2.000 mg alcohol q.s. to 5 ml
Claims (22)
1. Compounds of formula I
wherein R is a methoxy or methylthio group and R1 is a straight or branched alkyl or alkenyl group having 1 to 6 carbon atoms, or a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzotriazolyl or methyltertrazolyl moiety, a saturated or unsaturated mono or dicarboxylic or amino acidic acyl residue or a .beta.-D-glucose or 6-deoxygalactose residue, with the proviso that, when R is methoxy, R1 is different from methyl or acetyl.
wherein R is a methoxy or methylthio group and R1 is a straight or branched alkyl or alkenyl group having 1 to 6 carbon atoms, or a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzotriazolyl or methyltertrazolyl moiety, a saturated or unsaturated mono or dicarboxylic or amino acidic acyl residue or a .beta.-D-glucose or 6-deoxygalactose residue, with the proviso that, when R is methoxy, R1 is different from methyl or acetyl.
2. Compounds according to claim 1, wherein R is methoxy.
3. Compounds according to claim 1, wherein R is methylthio.
4. Compound according to claim 2, wherein R1 is methyl.
5. Compound according to claim 3, wherein R1 is methyl.
6. Compounds of formula II
wherein R and R1 and have the meanings defined in claim 1.
wherein R and R1 and have the meanings defined in claim 1.
7. Compounds according to claim 6, wherein R is methoxy.
8. Compounds according to claim 6, wherein R is methylthio.
9. Compound according to claim 8, wherein R1 is methyl.
10. A process for the preparation of the compounds as defined in any one of claims 1 to 5, which comprises reacting N-deacetylcolchicine or N-deacetylthiocolchicine with 4-formyl-1-methylpyridinium p-toluenesulfonate and 1,8-diazabicyclo[5.4.0]undec-7-ene.
11. A process for the preparation of the compounds as defined in any one of claims 6 to 9, which comprises reacting N-deacetylcolchicine or N-deacetylthiocolchicine with 3,5-ditert-butyl-1,2-benzoquinone.
12. Use of the compounds as defined in any one of claims 1 to 9 as medicaments.
13. Use of the compounds as defined in any one of claims 1 to 9 for the preparation of a medicament with antineoplastic or antiproliferative activity.
14. Use of the compounds as defined in any one of claims 1 to 9 for the preparation of a medicament with antiinflammatory and antiarthritis activities.
15. Pharmaceutical compositions containing an effective amount of a compound as defined in any one of claims 1 to 9 in admixture with a pharmaceutically acceptable carrier or diluent.
16. Compositions according to claim 15, suitable for parenteral administration.
17. Compositions according to claim 15, suitable for enteral administration.
18. Compositions according to claim 15, suitable for topical administration.
19. Compositions according to claim 16 or 18 in the form of liposomial formulations.
20. Compositions according to any one of claims 15 to 19, containing a surfactant.
21. Compositions according to claim 20, wherein the surfactant is polyethoxylated castor oil or polysorbate.
22. Compositions according to any one of claims 15 to 19, containing the active ingredient in the form of a complex with cyclodextrin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI96A001168 | 1996-06-07 | ||
| IT96MI001168A IT1283110B1 (en) | 1996-06-07 | 1996-06-07 | COLCHYCINE SKELETON COMPOUNDS, THEIR USE AS DRUGS AND COMPOSITIONS THAT CONTAIN THEM |
| PCT/EP1997/002577 WO1997047577A1 (en) | 1996-06-07 | 1997-05-21 | Colchicine-skeleton compounds, their use as medicaments and compositions containing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2252717A1 CA2252717A1 (en) | 1997-12-18 |
| CA2252717C true CA2252717C (en) | 2006-10-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002252717A Expired - Fee Related CA2252717C (en) | 1996-06-07 | 1997-05-21 | Colchicine-skeleton compounds, their use as medicaments and compositions containing them |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2252717C (en) |
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1997
- 1997-05-21 CA CA002252717A patent/CA2252717C/en not_active Expired - Fee Related
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| Publication number | Publication date |
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| CA2252717A1 (en) | 1997-12-18 |
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