IE65580B1 - Novel 1,5-diyne-3-cycloalkenes process for their preparation and the pharmaceutical compositions containing said compounds - Google Patents

Abstract

Compounds of formula (I): <IMAGE> in which: R represents a hydrogen atom, a linear or branched (C1-C6) acyl radical or a glycoside radical, n is equal to 1 or 2, R1 and R2 simultaneously represent two hydrogen atoms or, with the double bond to which they are attached, form a phenyl ring. Medicaments.

Description

The present invention relates to new 1,5-diyne-3-cycloalkene compounds, a process for their preparation, and pharmaceutical compositions containing them.

The esperamicines and calicheamicines belong to two 5 natural antibiotic families possessing anti-tumour properties that are distinctly more powerful than that of the known anticancer compounds as described by B. LONG g£ al. (Proc. Natl. Acad. Sci., 86. 2-6, 1989).

The anti-tumour properties of those two series of 10 compounds are due to the presence of a l,5-diyne-3cycloalkene ring common to the two families (Nature, 389. 566-567, 1991).

The present invention relates to 1,5-diyne-3-cycloalkene compounds which, in addition to the fact that they are novel, also exhibit particularly intense anti-tumour properties.

The invention relates more especially to new l,5-diyne-3cycloalkene compounds corresponding to the general formula (I) : - R R' (I) wherein : represents a (ci"c6)-acyi hydrogen atom, a linear or branched radical or a glycoside radical, R* represents a hydrogen atom or 0-R R IO represents ^,C=0 , Π is 1 or 2, and Rl and R2 represent simultaneously two hydrogen atoms or form with the double bond to which they are attached a phenyl ring, and their isomers and enantiomers.

The invention relates also to a process for the preparation of the compounds of formula (I), characterised in that (Z)-l,2-dichloroethylene or 1,2-dibromobenzene is reacted in an anhydrous medium and under an inert atmosphere with an alcohol of formula (IX) : S=-^\«:H2)nAoH (ID wherein n is as defined in formula (I), in the presence of a palladium catalyst prepared from tetrakis(triphenylphosphine)palladium, n-propylamine and copper iodide, in accordance with the methods described by K. SONOGASHIRA et al. (Tetrahedron lett. 4467-4470, 1975) and D. GUILLERM (Tetrahedron lett., 26, 3811-3812, 1985), to yield the compound of formula (III) : R1 «2 x(CH2)n / ^OH wherein n, R^ and R2 are as defined for formula (I) and X represents a chlorine or bromine atom, depending on the starting material used, which is coupled, as above, in the presence of tetrakis(triphenylphosphine)palladium, n-propylamine and copper iodide, with trimethylsilylacetylene in an anhydrous medium and under an inert atmosphere to yield the compound of formula (IV) : wherein n, Ri and R2are as defined in formula (I), which is subjected to desilylation in an anhydrous basic medium and under an inert atmosphere to yield the compound of formula (V) : (V) wherein n, Ri and R2 are as defined in formula (I), which is reacted with iodine in an anhydrous organic medium in the presence of morpholine and under an inert atmosphere to yield the compound of formula (VI) : (VI) wherein n, Rj and R2 are as defined in formula (I), which is subjected to oxidation in the presence of pyridinium chlorochromate in an anhydrous organic medium and under an inert atmosphere to yield the compound of formula (VII) : which is cyclised with the aid of a mixture of chromium chloride containing 1.3 % of nickel chloride in suspen10 sion in anhydrous tetrahydrofuran, at ambient temperature and under an inert atmosphere, in accordance with the methods described by K. TAKAI et al. (Tetrahedron lett., 26, 5585-5588, 1985) and T.D. AICHER (Tetrahedron lett., 28, 3463-3466, 1987), to yield the compound of formula (I/a), a particular case of the compounds of formula (I): wherein n is as defined in formula (I), which is : - converted into the corresponding ester under an inert 20 atmosphere to yield the compound of formula (I/b), a particular case of the compounds of formula (I), ' (I/b) wherein n, and R2 are as defined in formula (I), and 5 ac represents a linear or branched (C^-Cgi-acyl group, - or oxidised in the presence of pyridinium chlorochromate to yield the compound of formula (I/c), a particular case of the compounds of formula (I), (I/c) wherein n, R^ and R2 are as defined in formula (I), - or glycosylated in the trichloroacetamidate and separation of the isomers presence of acetylglycoside then deacetylated after optional to yield the compound of formula (I/d), a particular case of the compounds of formula (I), (I/d) wherein n, and R2 are as defined in formula (Σ'; and glyc represents a glycoside group, which compounds of formulae (I/a), (I/b), (I/c) and (I/d) are purified, where appropriate, in accordance with a conventional preparation technique and the isomers of which are separated, if desired, in accordance with a conventional separation technique.

The compounds of the invention have very valuable pharmacological properties. They inhibit the prolifera10 tion of L 1210 cells (murine leukaemia) in culture, which is predictive of a good anti-tumour activity in animals and also in man.

The present invention also relates to pharmaceutical compositions containing as active ingredient at least one compound of the general formula I or an addition salt thereof with a pharmaceutically acceptable acid, alone or in combination with one or more inert, non-tcxic excipients or carriers.

Among the pharmaceutically acceptable compositions 2o according to the invention there may be mentioned more especially those which are suitable for oral, parenteral or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, suppositories, creams, ointments, dermal gels and aerosols.

The dosage varies in accordance with the age and weight of the patient, the nature and severity cf the disorder and also the route of administration, which may be oral, nasal, rectal or parenteral. Generally, it ranges from 0.2 to 200 mg for a treatment of one or more administrations per 24 hours.

The following Examples illustrate the invention without limiting it in any way, EXAMPLE 3. : l,5-Diyne-(3Z)-cyclodecen-7-ol Step A : 8-Chloro-5-yne-7-octen-l-ol 650 μΐ (7.01 mmols) of n-propylamine, 480 μΐ (4.26 mmols) of 5-hexyn-l-ol, 420 μΐ (5.40 mmols) of cis-dichloroethylene and 35 mg (0.184 mmol) of copper iodide are added in succession to a solution of 85 mg (0.074 mmol) of tetrakis (triphenylphosphine) palladium in 8 ml of ]0 anhydrous benzene.

The reaction mixture is heated for 100 minutes at 404 C under an inert atmosphere and then concentrated and taken up in diethyl ether. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried and then evaporated. The expected product is obtained in the form of a colourless liquid after purification by chromatography on silica using a mixture of dichloromethane and acetone (40/1) as eluant.

Xield : 78 % 2q Mass spectrum : chemical ionisation (NH3) M + NH4+ : m/z = 176 Step B : 10-Trimethylsilyl-5,9-diyne-7-decen-l-ol 516 mg (3.25 mmols) of the compound obtained in Step A in 7 ml of anhydrous benzene are treated with 500 μΐ (6.08 mmols) of n-propylamine, 70 mg (0.061 mmol) of tetrakis(triphenylphosphine)palladium, 32 mg (0.168 mmol) of copper iodide and 650 μΐ (4.51 mmols) of trimethylsilylacetylene. The reaction mixture is stirred for 100 minutes at ambier.t temperature under an inert atmosphere, then concentrated and taken up in diethyl ether. The organic phase is washed with a saturated aqueous solution of sodium chloride and then with water, dried and evaporated. The expected product is obtained in the form of an oil after purification by liquid chromatography on silica using a mixture of dichloromethane, acetone and triethylamine (40/1/0.04) as eluant.

Yield : 82 % Step C : 5,9-Diyne-7-decen-l-ol 1.12 g (5.08 mmols) of the compound obtained in Step B dissolved in 10 ml of anhydrous methanol are treated with 770 mg (5.57 mmols) of potassium carbonate for 15 minutes at ambient temperature under an inert atmosphere. The reaction mixture is then concentrated, taken up in dichloromethane and washed with water. The organic phase is then dried and evaporated. The expected product is obtained in the form of a colourless oil after purification by liquid chromatography on silica using a mixture of dichloromethane and acetone (20/1) as eluant.

Yjgld. : 90 % Mass spectrum : chemical ionisation (NH3) M + NH4+ : m/2 = 166 Step D : 10—Iodo—5,5-diyne—7-decen-l-ol 2.49 ml (28.55 mmols) of morpholine are added to a solution, heated to 45’C, containing 2.42 g (9.53 mmols) of iodine in 20 ml of anhydrous benzene. After 20 minutes' stirring at 451C, under an inert atmosphere, 675 mg (4.55 mmols) of the compound obtained in Step C dissolved in 5 ml of anhydrous benzene are added. The reaction mixture is maintained at 45 *C for 3 hours with stirring, concentrated, taken up in diethyl ether, and washed in succession with a saturated aqueous solution of sodium chloride, an aqueous 20 % sodium dihydrogen phosphate solution, an aqueous 20 % sodium thiosulphate solution, an aqueous 10 % sodium hydrogen carbonate solution and water. The organic phase is then washed and evaporated. The expected product is obtained in the form of an oil after purification by chromatography on silica using a mixture of hexane and diethyl ether (1/1) as eluant.

Yield : 80 % Mass spectrum : chemical ionisation (NH3) ’5 M + NH4+ : m/2 = 292 Step E : 10-Iodo-5,9-diyne-7-decen-l-al 250 mg (1.16 mmols) of pyridinium chlorochromate and 2 ml of dichloromethane are stirred for 20 minutes in activated molecular sieve (4&) in powder form at ambient temperature and under an inert atmosphere. 94 mg (0.343 mmol) of the compound obtained in Step D dissolved in 3 ml of anhydrous dichloromethane are added to the preceding mixture. The whole is stirred for 30 minutes at ambient temperature and then 20 ml of diethyl ether are added. The reaction mixture is then filtered and subsequently concentrated. The expected product is obtained after purification by chromatography on silica using a mixture of hexane and diethyl ether (1/1) as eluant.

Yield : 83 % Mass spectrum : chemical ionisation (NH3) M + NH4+ : m/2 = 290 Step F : l,5-Diyne-3-cyclodecen-7-ol 181 mg (1.47 mmols) of chromium chloride containing 1.3 % of nickel chloride suspended in 20 ml of tetrahydrofuran are stirred for 20 minutes at ambient temperature under an inert atmosphere. 78 mg (0.29 mmol) of the compound obtained in Step E dissolved in 9 ml of tetrahydrofuran are added very slowly to the preceding mixture. After the addition, which lasts about 2 hours 40 minutes, the reaction mixture is concentrated and taken up in ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried and then evaporated. The expected product is obtained in the form of an oil after purification by liquid chromatography on silica using a mixture of hexane, ethyl acetate and triethylamine (75/25/0.1) as eluant.

Yield : 34 % Mass spectrum : chemical ionisation (NH3) M + NH4+ : m/2 = 164 EXAMPLE 2 : 7-Acetoxy-1,5-diyne-3-cyclodecene 14.6 mg (0.1 mmol) of the compound obtained in Example 1 are treated with 1 ml of pyridine and 0.5 ml of acetic anhydride for 45 minutes at ambient temperature under an inert atmosphere. The reaction mixture is diluted with diethyl ether and washed in succession with water, an aqueous 50 % potassium hydrogen sulphate solution, an aqueous 50 % sodium hydrogen carbonate solution and water. The organic phase is dried and then evaporated. The expected product is obtained in the form of an oil after purification by liquid chromatography on silica using a mixture of hexane, ethyl acetate and triethyl11 amine (83/17/0.1) as eluant.

Yield : 59 % Mass spectrum : electron bombardment M : m/z = 188 EXAMPLE 3 : 1,5-Diyne-3-cycloundecen-7-ol The expected product is obtained by proceeding as in Example 1 but using 6-heptyn-l-ol instead of 5-hexyn-l-ol in Step A.

Yield (Step F) : 76 % 1 θ Mass spectrum : chemical ionisation (NH3) M + NH4+ ·. m/z = 178 EXAMPLE 4 : 7-Acetoxy-l, 5-diyne-3-eye loundecene The expected product is obtained by proceeding as in Example 2 but with replacement of the compound of Example 15 1 by the compound of Example 3.

Yield : 90 % Mass spectrum : electron bombardment M : m/z = 202 EXAMPLE 5 : 7-Hydroxy_benzo[c]cyclodeca-l,5-diyne The expected product is obtained by proceeding as in Example 1 but with the replacement of cis-dichloroethylene by 1,2-dibromobenzene in Step A.

Mass spectrum : electron bombardment M : m/2 = 196 EXAMPLE 6 : 7-Acetoxy-benzo[c]cyclodeca-l, 5-diyne The expected product is obtained by proceeding as in 5 Example 2 but with replacement of the compound of Example 1 by the compound of Example 5.

Yield : 70 % Mass spectrum : electron bombardment M : m/2 = 238 EXAMPLE 7 : 7-Oxo-benzo[c ]cyclodeca-l, 5-diyne The expected product is obtained by oxidation of the compound of Example 5 in the presence of pyridinium chlorochromate.

Yield : 70 % Mass spectrum : electron bombardment M : m/2 = 194 EXAMPLE 8 : 7-(B-D-Glucopyranosy1 )benzo[c]cyclodeca-l, 5diyne, isomer 1 and EXAMPLE 9 : 7-(B-D-Glucopyranosyl )benzo[c]cyclodeca-l, 52o diyne, isomer 2 EXAMPLE 8 : 7-(B-D-Glucopyranosy1)benzo[c]cyclodeca-l,5 diyne„ isomer 1 Step A : 7-(B-D-2,3,4,6-tetra-0-acetylglucopyranosyl) benzo (c]cyclodeca-l, 5-diyne, isomer 1 413 mmols of the compound obtained in Example 5 and of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl trichloroacetamidate prepared in accordance with the process described by Schmidt and Michel (Angew. Chem., Int. Ed. b Engl., 19. 1980, 731-732) are stirred in 2 ml of anhydrous toluene for 3 hours under an inert atmosphere in < the presence of molecular sieve (4&). The mixture is cooled to -78‘C, and 92 μΐ of boron trifluoride etherate in toluene are then added. After returning to 0"C, the mixture is neutralised with ethyl di isopropylamine and then filtered and evaporated.

The expected product, isomer 1, is purified and isomer 2 is separated by chromatography on silica gel using a mixture of hexane and ethyl acetate (3/1) as eluant.

Index of rotation : [α]θ° = -50* (c = 1 mg/ml/CHCl3) Step B : 7-(B-D-Glucopyranosyl)benzo[c]cyclodeca-1,5-diyne, isomer 1 The product obtained in the preceding Step dissolved in a mixture of dichloromethane and methanol (1/1) is treated with a catalytic amount of sodium methylate at ambient temperature under an inert atmosphere. The reaction mixture is then neutralised on Amberlite resin (IRC 50 H+ form) and subsequently filtered. The expected product is then obtained after filtration, evaporation of the solvent and purification by chromatography on silica gel using a mixture of dichloromethane and methanol (6/1) as eluant.

Yield : 80 % r Melting point : 123*C (MeOH) Index of rotation : [a]* - -18* (c = 0.85 rag/ml acetone) EXAMPLE 9 : 7-( B-D-Glucopyranosyl )benzo[c]cyclodeca-l, 5diyne, isomer 2 The expected product is obtained by proceeding as in Step B of Example 8, starting from isomer 2 of Step A of Example 8.

Yield : 80 % Melting point : 126*C * on Index of rotation : [a]Q = +77* (c = 1.2 mg/ml CHCl3/MeOH (1/1)) PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE 10 : Cytotoxicity in vitro L 1210 cells (murine leukaemia) are cultured in RPMI 1640 supplemented with 10 % foetal calf serum, 2 mM L-glutamine, 100 units/ml penicillin, 100 Mg/ml streptomycin and 10 mM Hepes (pH : 7.4). The inhibition of cell growth is measured in accordance with the Microculture Tetrazolium Assay described by M. ALLEY et al. (Cancer Res., 589-601, 1988).

The results of the test are expressed as IC5q, the concentration that inhibits cell growth by 50 %. The reference product used is BCNU, a very active alkylating agent used clinically.

In this test, the IC50 of the compound of Example 2 is .6 μΜ, that of the compound of Example 7 is 0.5 μΜ, whilst that of BCNU is 6.4 μΜ.

PHARMACEUTICAL COMPOSITION EXAMPLE 11 : Tablet : formulation for the preparation of 1000 2 mg tablets compound of Example 2 .......................... 2g hydroxypropylcellulose ......................... 2 g wheat starch ................................... 10 g lactose ........................................ 100 g magnesium stearate ............................. 3 g talc ........................................... 3 g

Claims (11)

1. Compounds of formula (I): wherein: represents a hydrogen atom, a linear or branched (Cj-CgJ-acyl radical or a glycoside radical, R' represents a hydrogen atom or represents n is 1 or 2, and 10 R 3 and R 2 represent simultaneously two hydrogen atoms or form with the double bond to which they are attached a phenyl ring, and their isomers and enantiomers.

2. Compounds of formula (I) according to claim 1, 15 wherein a is 1.

3. Compound of formula (I) according to claim 1 that is 7-acetoxy-l,5-diyne-3-cyclodecene and also its enantiomers .

4. Process for the preparation of the compounds of formula (I) according to claim 1, characterised in that (Z)-l,2-dichloroethylene or 1,2-dibromobenzene is reacted in an anhydrous medium and under an inert atmosphere with 5. An alcohol of formula (II): (II) wherein π is as defined in formula (I), in the presence of a palladium catalyst prepared from tetrakis(triphenylphosphine)palladium, n-propylamine and 10 copper iodide, to yield the compound of formula (III): (III) OH wherein q, R 3 and R 2 are as defined in formula (I) and X represents a chlorine or bromine atom, depending on the starting material used, 15 which is coupled, as above, in the presence of tetrakis(triphenylphosphine)palladium, n-propylamine and copper iodide with trimethylsilylacetylene in an anhydrous medium and under an inert atmosphere to yield the compound of formula (IV): (IV) wherein n, Rj and R 2 are as defined in forinula (I), which is subjected to desilylation in an anhydrous basic medium and under an inert atmosphere to yield the compound of formula (V): (V), wherein q, R^ and R 2 are as defined in formula (I), with which is reacted iodine in an anhydrous organic medium in the presence of morpholine and under an inert atmosphere 10 to yield the compound of formula (VI): (VI), wherein η, and R 2 are as defined in formula (I), which is subjected to oxidation in the presence of pyridinium chlorochromate in an anhydrous organic medium 15 and under an inert atmosphere to yield the compound of formula (VII): (. < wherein n, Ri and R 2 are as defined in formula (I), which is cyclised with the aid of a mixture of chromium chloride containing 1.3 % of nickel chloride in suspen5 sion in anhydrous tetrahydrofuran at ambient temperature and under an inert atmosphere to yield the compound of formula (I/a), a particular case of the compounds of formula (I) : 10 wherein n is as defined in formula (I), which is: - converted into the corresponding ester under an inert atmosphere to yield the compound of formula (I/b), a particular case of the compounds of formula (I) , (I/b) wherein n, and R 2 are as defined in formula (I) and ac represents a linear or branched (C^-Cgi-acyl group, - or oxidised in the presence of pyridinium chloro chromate to yield the compound of formula (I/c), a particular case of the compounds of formula (I), (I/c) wherein q, and R 2 are as defined in formula (I), - or glycosylated in the presence of acetylglycoside 10 trichloroacetamidate and then deacetylated after optional separation of the isomers to yield the compound of formula (I/d), a particular case of the compounds of formula (I), (I/d) 15 wherein q, and R 2 are as defined in formula (I) and give represents a glycoside group, which compounds of formulae (I/a), (I/b), (I/c) and (I/d) are purified, where appropriate, in accordance with a conventional preparation technique and the isomers of which are separated, if desired, in accordance with a conventional separation technique.

5. Pharmaceutical compositions containing as active ingredient at least one compound according to any one of claims 1 to 3, alone or in combination with one or more pharmaceutically acceptable non-toxic, inert excipients or carriers.

6. Pharmaceutical compositions according to claim 5 containing at least one active ingredient according to any one of claims 1 to 3 for use in the treatment of cancer.

7. A compound substantially as hereinbefore described with reference to the Examples.

8. A process substantially as hereinbefore described with reference to the Examples.

9. A composition substantially as hereinbefore described with reference to the Examples.

10. Use of a compound as claimed in any of claims I to 3 for the preparation of a medicament for use in a method of prophylaxis or treatment.

11. A use substantially as hereinbefore described with reference to the Examples.