AU646166B2 - 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

P/00/011 2015191 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990 16

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT 4 .4 o Application 1K.rnber: Lodged: Invention Title: NOVEL 1,5-DIYNE-3-CYCLOALKENES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAID COMPOUNDS *4 4 The following statement is a full description of this invention, including the best method of performing it known to u NOVEL 1,5-DIYNE-3-CYCLOALKENES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAID COMPOUNDS ADIR ET COMPAGNIE 1 RUE CARLE HEBERT F-92415 COURBEVOIE CEDEX e o e oo a f INVENTORS: J.M.

C.

G.

BEAU

CREVISY

ATASSI

A. PIERRE SThe present invention relates to novel 1,5-diyne- 3-cycloalkene derivatives, the process for their preparation and the pharmaceutical compositions which contain them.

Esperamicins and caiicheamicins belong to two families of natural antibiotics possessing anti-tumor properties which are distinctly more powerful than those of the known anti-cancer compounds described by B. LONG et al. (Proc. Natl. Acad.

Sci., 2-6, 1989).

The anti-tumor properties of the two series of compounds are due to the presence of a 1,5-diyne-3- cyclo.lkene ring common to these two families (Nature, 1 0 3S., 566-567, 1991).

The present invention relates to 1,5-diyne-3- cycloalkene derivatives which, in addition to the fact that they are novel, have particularly intense anti-tumor properties.

The invention relates more particularly to novel 1,5-diyne-3- 1 5 cycloalkene derivatives corresponding to the general formula (CH2)n (n ^0O R

C

y (iR' S 20 in which: R Ra R represents a hydrogen atom, a straight-chain or branched (C1-Cs) acyl radical or a glycoside radical.

R' represents a hydrogen atom, 2.25 or, together form

R'

n is 1 or 2, and

R

1 and R 2 simultaneously represent two hydrogen atoms or, ".together with the double bond to which they are attached, form a phenyl ring, their isomers and enantiomers.

-2 The invention also extends to the process for the preparation of the compounds of formula characterised in that (Z)-1,2-dichloroethylene or 1,2- dibromobenzene is reacted in an anhydrous medium, under an inert atmosphere, with an alcohol of formula (II): (CH2)n/OH (II) in which n has the same meaning as in formula in the presence of a palladium catalyst prepared from tetrakis(triphenylphosphine)palladium, n-propylamine and copper iodide, in accordance with the techniques described by K. SONOGASHIRA et al.

(Tetrahedron lett. 4467-4470, 1975) and D. GUILLERM (Tetrahedron lett., 26, 3811-3812, 1985), S to lead to the compound of formula (III): RI X R2 (CH2)n

OH

in which n, RI and R2 have the same meaning as in formula and X represents a chlorine or bromine atom depending on the starting material used, which compound is coupled, as above, in the presence of tetrakis- (triphenylphosphine)palladium, n-propylamine and copper iodide, with trimethylsilylacetylene, in an anhydrous medium, under an inert 2 0 atmosphere, to lead to the compound of formula (IV): Si(CH 3 )3 R1

(IV)

'(CH2)n

OH

-3in which n, RI and R2 have the same meaning as in formula which compound is subjected to a desilylation in an anhydrous basic medium, under an inert atmosphere, to lead to the compound of formula

(V)

RI1 :R2

OH

in which n, R 1 and R2 have the same meaning as in formula with which iodine is reacted, in an anhydrous organic medium in the presence of morpholine, under an inert atmosphere, to lead to the compound of formula (VI): .I R2 R. (CH2)n

OH

*R1 (CH2)nA 0 in which n, RI and R2 have the same meaning as in formula which compound cyclis subjected to oxidation in the presence of hromium chlorideinium containing 1.3% of nickel chloride in suspension in anhydrous tetlorochromaurae in a ambienhydrous organic medium,ture, under an inert atmosphere, 20 accordance with the tchniques described by K. AKA et al., (etrahedrond of formula (VII): *R2 (CH2ln 0 in which n, RI and R2 have the same meaning as in formula which is cyclised with the aid of a mixture of chromium chloride containing 1.3% of nickel chloride in suspension in anhydrous tetrahydrofuran, at ambient temperature, under an inert atmosphere, in accordance with the techniques described by K. TAKAI et al., (Tetrahedron lett., 26, 5585-5588, 1985) and T.D. AICHER (Tetrahedron lett., 28, 3463- 3466, 1987), to lead to the compound compounds of formula of formula a particular case of the (CH2)n OH

ROH

Ri R2 (I/a) in which n has the same meaning as in formula which compound is: either converted to the corresponding ester, under an inert atmosphere, to lead to the compound of formula a particular case of compounds of formula d

S.

S

(CH2)n 0 ac O a R1 R2 (I/b)

S.

55S*

S

S

3.5 455*..

in which n, R1 and R2 have the same meaning as in formula represents a straight-chain or branched (C1-C6) acyl group, or oxidized in the presence of pyridinium chlorochromate, to lead to the compound of formula a particular compounds of formula and ac case of the (CH2)n R1 R2 (I/c) in which n, R1 and R2 have the same meaning as in formula or glycosylated in the presence of acetyl glycoside trichloroacetamidate and then deacetylated after separating the isomers if appropriate, to lead to the compound of formula a particular case of the compounds of formula (CH2)n 0 gly (I/d) R1 R2 in which n, Ri and R2 have the same meaning as in formula and glyc represents a glycoside group, which compounds of formula and are purified, if necessary, using a conventional preparation technique and the isomers of said compounds being separated, if desired, using a conventional separation technique.

The compounds of the invention have very valuable pharmacological properties. They inhibit the proliferation of L 1210 (murine leukaemia) :0 cells in culture, which is predicative of a good anti-tumor activity in animals and also in man.

9 The present invention also relates to the pharmaceutical compositions containing, as active principle, at least one compound of general formula S(I) or one of its addition salts with a pharmaceutically acceptable acid, 5 on its own or in combination with one or more non-toxic, inert excipients or vehicles.

Amongst the pharmaceutical compositions according to the invention, those which may be mentioned more particularly are those which are suitable for oral, parenteral or nasal administration, simple or coated tablets, 20 sublingual tablets, capsules, suppositories, creams, ointments, dermal gels and aerosols.

The dosage varies depending on the age and the weight of the patient, the nature and the severity of the disease and the mode of administration. The latter may be oral, nasal, rectal or parenteral. In general, the dosage ranges between 0.2 and 200 mg for a treatment taken in one or more doses per 24 hours.

-6- The following examples illustrate the invention and do not limit iL in any way.

EXAMPLE 1: 1,5-diyne-(3Z)-cyclodecen-7-ol Stage A: 8-chloro-5-yne-7-octen-1-ol 650 pi (7.01 mmol) of n-propylamine, 480 p1 (4.26 mmol) of 420 pl (5.40 mmol) of cis- dichloroethylene and 35 mg (0.184 mmol) of copper iodide are added successively to a solution of 85 mg (0.074 mmol) of tetrakis(triphenylphosphine)palladium in 8 ml of anhydrous benzene.

The reaction mixture is heated for 100 minutes at 40 0 C 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, dried and then evaporated. The expected product is obtained in the form of a colourless liquid after purification by chromatography on silica using a (40/1) dichloromethane/acetone mixture as elution solvent.

Yield: 78% Mass spectrum: chemical ionisation (NH3) M NH4+ m/z 176 Stage B: 10-trimethylsilyl-5,9-diyne-7-decen-1-ol 516 mg (3.25 mmol) of the compound obtained in stage A, in 7 ml of anhydrous benzene, are treated with 500 pl (6.08 mmol) of n-propylamine, 70 mg (0.061 mmol) of tetrakis(triphenylphosphine)palladium, 32 mg (0.168 mmol) of copper iodide and 650 pI (4.51 mmol) of trimethylsilylacetylene.

The reaction mixture is stirred for 100 minutes at ambient 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 (40/1/0.04) dichloromethane/acetone/triethylamine mixture as elution solvent.

Yield: 82% -7- Stage C: 5,9-diyne-7-decen-1-ol 1.12 g (5.08 mmol) of the compound obtained in stage B, in solution in ml of anhydrous methanol, are treated with 770 mg (5.57 mmol) of potassium carbonate at ambient temperature, under an inert atmosphere, for minutes. 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, af-r purification by liquid chromatography on silica using a (20/1) dichloromethane/acetone mixture as elution solvent.

Yield: Mass spectrum: chemical ionisation (NH3) M +NH4+ m/z 166 Stage D: 10-iodo-5,9-diyne-7-decen-1-ol 2.49 ml (28.55 mmol) of morpholine are added to a solution containing 2.42 g (9.53 mmol) of iodine in 20 ml of anhydrous benzene heated to 450C.

After stirring for 20 'iinutes at 45°C, under an inert atmosphere, 675 mg (4.55 mmol) of the compound obtained in stage C, in solution in 5 ml of anhydrous benzene, are added. The reaction mixture is stirred for a further 3 hours at 45°C, concentrated, taken up in diethyl ether and washed successively with a saturated aqueous solution of sodium chloride, a 20% aqueous solution of sodium dihydrogen phosphate, a 20% aqueous solution of sodium thiosulfate, a 10% aqueous solution of sodium eoae bicarbonate and then with water. The organic phase is then washed and evaporated. The expected product is then obtained, in the form of an oil, after purification by chromatography on silica using a (1/1) hexane/diethyl ether mixture as elution solvent.

Yield: Mass spectrum: Chemical ionisation (NH3) M NH4+ m/z 292 -8- Stage E: 10-iodo-5,9-diyne-7-decen-l-al 250 mg (1.16 mmol) of pyridinium chlorochromate and 2 ml of dichloromethane are stirred in activated molecular sieve (41) i.n powder form for 20 minutes, at ambient temperature, under an inert atmosphere. 94 mg (0.343 mmol) of the compound obtained in stage D, in solution in 3 ml of anhydrous dichloromethane, are added to the above mixture. The mixture is stirred for a further 30 minutes at ambient temperature and 20 ml of diethyl ether are then added. The reaction mixture is then filtered and then concentrated. The expected product is obtained after purification by chromatography on silica using a hexane/diethyl ether mixture as elution solvent.

Yield: 83% Mass spectrum: Chemical ionisation (NH3) M NH4+ m/z 290 oeas t Stage F: ',5-diyne-3-cyclodecen-7-ol 181 mg (1.47 mmol) of chromium chloride containing 1.3% of nickel chloride in suspension in 20 ml of tetrahydrofuran are stirred for 20 minutes at ambient temperature, under an inert atmosphere. 78 mg (0.29 mmol) oi the compound obtained in stage E, in solution in 9 ml of tetrahydrofuran, are added very slowly to the above mixture. After the addition, which takes about 2 hours 40 minutes, the reaction mixture is concentrated and "sken up in ethyl acetate. The organic phase is washed with a saturated ',,a.eaous solution of sodium chloride, dried and then evaporated. The expected product is obtained in the form of an oil after purification by liquid *"25 chromatography on silica using a (75/25/0.1) hexane/ethyl acetate/triethylamine mixture as elution solvent.

Yield: 34% Mass spectrum: Chemical ionisation (NH 3 M NH4+ m/z 164 -9- EXAMPLE 2: 7-acetoxy-1,5-diyne-3-cyclodecene 14.6 mg (0.1 mmol) of the compound obtained in Example I 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 successively with water, a 50% aqueous solution of potassium hydrogen sulfate, a 50% aqueous solution of sodium bicarbonate and then with 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 (83/17/0.1) hexane/ethyl acetate/triethylamine mixture as elut'on solvent.

Yield: 59% Mass spectrum: Electronic impact M m/z 188 EXAMPLE 3: 1,5-diyne-3-cycloundecen-7-ol 1 The expected product is obtained by following the procedure as in Example 1 but using 6-heptyn-l-ol in place of 5-hexyn-l-ol in stage A.

Yield (stage F) 76% Mass spectrum: Chemical ionisation (NH 3 SM NH 4 m/z 178 EXAMPLE 4: 7-acetoxy-1,5-diyne-3-cycloundecene The expected product is obtained by following the procedure as in Example 2 but replacing the compound of Example 1 by the compound of Example 3.

Yield: Mass spectrum: Electronic impact M m/z 202 10 EXAMPLE 5: 7-hydroxy-benzoj~cjcyclodeca- The expected product is obtained by following the procedure as in Example 1 but replacing cis-dichloro-ethylene by 1,2-dibromobenzene in stage A.

Mass spectrum: Electronic impact M :m/z =196~ EXAMPLE 6: 7-acetoxy-benzo[clcyclodeca-1 The expected product is obtained by following the procedure as in Example 2 but replacing the compound of Example 1 by the compound of Example Yield; Mass spectrum: Electronic impact M m/z =238 EXAMPLE 7; 7-oxo-benzo~clcyclodeca-1 The expected product is obtained by oxidation of the compound of Example in the presence of pyridinium chlorochromate.

Yield:, Mass spectrum: Electronic impact M m/z 194I EXAMPLE 8: 7-(fP-D-glucopyranosyl)benzo[c]cyclodeca-1 diyne, isomer 1 and EXAMPLE 9 7-(fP-D-glucopyranosyl)benzo[clcyclodeca-1,5- diyne, isomer 2 EXAMPLE 8: 7-(P-D-glucopyranosyl)benzo[cecyclodeca-1,5- diyne, isomer 1 Stage A: 7-(P-D-2,3,4,6-tetra-0-acetylgluopyranosyl)benzo~clcyclodecaisomer 1- ~413 mmol of the compound obtained in Example 5 and of 2,3,)4,6-tetra-Oacetyl-a-D-glucopyranosyl trichloroacetanidate prepared in accordance with the process described by Schmidt and Michel (Angew. Chem., Int. Ed. Engl., .12, 1980, 731-732) are stirred in 2 ml of anhydirous toluene for 3 hours 11 under an inert atmosphere in the presence of molecular sieve The mixture is cooled to -780C and 92 pl of boron trifluoride etherate in toluene are then added. After the temperature has returned to 00C, the mixture is neutralized with ethyl- diisopropylamine and then filtered and the filtrate is evaporated.

The expected product, isomer 1, is purified and separated from isomer 2 by chromatography on silica gel using a hexane/ethyl acetate mixture as eluent.

Optical rotation: [a]D20 50° (C 1 mg/ml/CHCl3) Stage B: 7-(P-D-glucopyranosyl)benzo[c]cyclodeca-1,5- diyne, isomer 1 The product obtained in the preceding stage, in solution in a (1/1) dichloromethane/methanol mixture, is treated with a catalytic amount of sodium methanolate at ambient temperature, under an inert atmosphere. The reaction mixture is then neutralized on Amberlite resin (IRC 50 H+ form) and then filtered. The expected product is then obtained after filtration, evaporation of the solvent and purification by chromatography on silica gel using a dichloromethane/methanol mixture as eluent.

Yield: Melting point: 123°C (MeOH) Optical rotation: [a]D20 -18°C (C 0.85 mg/ml acetone)

C

EXAMPLE 9: 7-(P-D-glucopyranosyl)benzo[c]cyclodeca-1,5- diyne, isomer 2 The expected product is obtained by following the procedure as in stage B of Example 8, using isomer 2 from stage A of Example 8 as the starting material.

Yield: Melting point: 1260C Optical rotation: [a]D20 770 (C 1.2 mg/ml CHC13/MeOH 12 PHARMACOLOGICAL STUDY OF THE DERIVATIVES OF THE INVENTION EXAMPLE 10: in vitro cytotoxicity L 1210 (murine leukaemia) cells are cultured in RPMI 1640 supplemented by fetal calf serum, 2 mM L-glutamine, 100 units/ml penicillin, 100 pg/ml streptomycin and 10 mM Hepes (pH The inhibition of cell growth is determined using the "Microculture Tetrazolium Assay" described by M.

ALLEY et al., (Cancer Res., 48, 589-601, 1988).

The results of this test are expressed as IC50, the concentration resulting in 50% inhibition of cell growth. The reference product used is BCNU, a highly active alkylating agent used in medicine.

During this test, the IC50 of the compound of Example 2 is 5.6 uM and that of the compound of Example 7 is 0.5 M, whereas that of BCNU is 6.4 pM.

PHARMACEUTICAL COMPOSITION .i EXAMPLE 11: Tablet: preparation formulation for 1000 tablets containing a ;'15 dose of 2 mg Compound of Example 2 2 g Hydroxypropylcellulose 2 g Wheat starch 10 g Lactose 100 g 20 Magnesium stearate 3 g Talc 3 g

Claims (6)

1. Compounds of formula 0- R (C in which: R1 R2 R represents a hydrogen atom, a straight-chain or branched (C 1 acyl radical or a glycoside radical, R' represents a hydrogen atom, or together form =,0 n is 1 or 2, and R 1 and R 2 simultaneously represent two hydrogen atoms or, S. together with the double bond to which they are attached, form a phenyl ring, their isomers and enantiomers. o

2. Compounds of formula according to claim 1, in which n is 1.

3. Compound of formula according to claim 1, which is 7-acetoxy-1,5- diyne-3-cyclodecene, as well as its enantiomers.

4. Process for the preparation of the compounds of formula according to claim 1, characterized in that (Z)-1,2-dichloroethylene or 1,2-dibromobenzene is reacted in an anhydrous medium, under an inert atmosphere, with an alcohol of formula (II): (cH2)n ok (T in which n has the same meaning as in formula in the presence of a palladium catalyst prepared from tetrakis(triphenylphosphine)palladium, n- propylamine and copper iodide, to lead to the compound of formula Ill: 0 o 14 S( I II) R2 I (CH2)n/\H (I) in which n, R1 and R2 have the same meaning as in formula and X represents a chlorine or bromine atom depending on the starting material used, which compound is coupled, as above, in the presence of S tetrakis(triphenylphosphine)palladium, n-propylamine and copper iodide, with trimethylsilylacetylene, in an anhydrous medium, under an inert atmosphere, to lead to the compound of formula (IV): SiSi(CH3)3 ~(IV) R2 (CH2)n OH in which n, RI and R2 have the same meaning as in formula which compound is subjected to a desilylation in an anhydrous basic medium, under an inert atmosphere, *5 to lead to the compound of formula :R::R2 (CH2)n/ OH 0 "5 in which n, R1 and R2 have the same meaning as in formula S with which iodine is reacted, in an anhydrous organic medium in the presence of morpholine, under an inert atmosphere, to lead to the compound of formula (VI): I R1 (VI) R2 (CH2)n /H 15 in which n, R1 and R2 have the same meaning as in formula which compound is subjected to oxidation in the presence of pyridinium chlorochromate in an anhydrous organic medium, under an inert atmosphere, to lead to the compound of formula (VII): R1 (VII) R2 (CH2)nA in which n, Ri and R2 have the same meaning as in formula which is cyclised with the aid of a mixture of chromium chloride containing 1.3% of nickel chloride in suspension in anhydrous tetrahydrofuran, at ambient temperature, under an inert atmosphere, 10 to lead to the compound of formula a particular case of the compounds of formula (CH2)nO R1 R2 OC in which n has the same meaning as in formula which compound is: 5 either converted to the corresponding ester, under an inert atmosphere, C to lead to the compound of formula a particular case of compounds of formula -(CH2)n 0 ac (I/b) R1 R2 in which n, R1 and R2 have the same meaning as in formula and ac represents a straight-chain or branched (Ci-C6) acyl group, 16 or oxidized in the presence of pyridinium chlorochromate, to lead to the compound of formula a particular case of the compounds of formula (CH2)n 0 R1 R2 in which n, RI and R2 have the same meaning as in formula or glycosylated in the presence of acetyl glycoside trichloroacetamidate and then deacetylated after separating the isomers if appropriate, to lead to the compound of formula a particular case uf the compounds of formula (CH2)n O gly 0*e* I d) Ri R2 in which n, R1 and R2 have the same meaning as in formula and glyc represents a glycoside group, which compounds of formula and are purified, if necessary, using a conventional preparation technique and the isomers of said compounds being separated, if desired, using a conventional separation technique.

5. Pharmaceutical compositions containing, as active principle, at least one compound according to any one of claims 1 to 3, -n irts-ewn-P in combination with one or more pharmaceutically acceptable, non-toxic, inert excipients or vehicles.

6. Pharmaceutical compositions according to claim 5, containing at least one active principle according to any one of claims 1 to 3 useful in the treatment of cancer. DATED this 9th day of June 1992. ADIR ET CCMPAGNIE fO S WATERMARK PATENT TRADEMARK ATTORNEYS npT "THE ATRIUM", 290 BURWOOD ROAD j HAWTHORN. VIC. 3122. ABSTRACT NOVEL 1,5-DIYNE-3-CYCLOALKENES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAID COMPOUNDS Compounds of formula Co R in which: R1 R2 R represents a hydrogen atom, a straight-chain or branched (C 1 -C 6 acyl radical or a glycoside radical, R' represents a hydrogen atom, or, together form o n is 1 or 2, and R 1 and R 2 simultaneously represent two hydrogen atoms or, together with the double bond to which they are attached, form a phenyl M e ring, Medicaments.