NZ243548A - Taxol analogues, preparation and pharmaceutical compositions - Google Patents
Taxol analogues, preparation and pharmaceutical compositionsInfo
- Publication number
- NZ243548A NZ243548A NZ24354892A NZ24354892A NZ243548A NZ 243548 A NZ243548 A NZ 243548A NZ 24354892 A NZ24354892 A NZ 24354892A NZ 24354892 A NZ24354892 A NZ 24354892A NZ 243548 A NZ243548 A NZ 243548A
- Authority
- NZ
- New Zealand
- Prior art keywords
- radical
- carbon atoms
- radicals
- formula
- alkyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £43548
24 35 4 8
I r.'orlty Zi".~'
Ik?!;
: GQl02>pS~!iLf; a Coiokosla.; n tprfoifizlfr^ JM.
P'opc
Pubiicc^on Data: P.O. Journal, i\"
26 JUL 1994
NEW ZEALAND PATENTS ACT, 1953
No.:
Date:
COMPLETE SPECIFICATION NEW TAXOL ANALOGUES. THEIR PREPARATION AND COMPOSITIONS
CONTAINING THEM
We, RHONE-POULENC RORER S A, a French body corporate, of 20 Avenue Raymond Aron, F 92160, Antony, France hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
(followed by page - la -)
24 3 5 4 8
1 a
The present invention provides, as new compounds, the taxol analogues of formula:
R1 "°v 0 t>"R2
(i)
in which
- Ar represents an aryl radical,
- R represents
- a radical of formula:
R70- (II)
in which R7 represents a linear or branched alkyl radical 10 containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicyclo-alkyl radical 15 containing 7 to 10 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, 20 piperidino or morpholino radicals, 1-piperazinyl radicals
243548
2
(optionally substituted at the 4-position with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 5 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl, cyano and carboxyl radicals and alkyloxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms,
- or a phenyl radical optionally substituted with one or 10 more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms and alkyloxy radicals containing 1 to 4 carbon atoms,
- or a saturated or unsaturated 4- or 6-membered nitrogenous heterocyclic radical optionally substituted by
one or more alkyl radicals containing 1 to 4 carbon atoms each,
the said cycloalkyl, cycloalkenyl or bicycloalkyl radicals being optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms each,
R, and R2, which may be identical or different, represent a
£ N /
hydrogen atom or a radical of formula:
fj<y
I* n FEB 19943
R3\
*4
^NCO—
in which R3 and R4, which may be identical or different,
24 3 5 4 8
3
represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in a linear or branched chain, optionally substituted:
a) by a hydroxyl or carboxyl radical or an alkyloxy-carbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms and is optionally substituted by a phenyl radical, or b) by a radical of formula:
RS\
n— <iv>
R6
in which R5 and R^ which may be identical or different,
represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in a linear or branched chain, or alternatively R5 and R6, together with the nitrogen atom to f
which they are linked, form a saturated or unsaturated 5-
• • s/*-
or 6-membered heterocycle optionally containing a second// 1 %
fi*i hetero atom chosen from nitrogen atoms (optionally _
\ '' FEB 1994,.
substituted by an alkyl radical containing 1 to 4 carbon^ ,/
atoms or a benzyl radical), oxygen atoms and .sulphur atoms^--or alternatively R3 and R4, together with the nitrogen__atoHi 2 0 to which they are linked, form a saturated or unsaturated 5- or 6-membered heterocycle optionally containing a second hetero atom chosen from nitrogen atoms (optionally substituted by an alkyl radical containing 1 to 4 carbon atoms or a benzyl radical), oxygen atoms and sulphur atoms, 25 at least one of the symbols Rj or R2 representing a radical
24 3 5 4 8
4
of formula (III), and where they exist, their acid addition salts.
Preferably, Ar represents a phenyl or a- or /8-naphthyl radical optionally substituted by one or more 5 atoms or radicals chosen from halogen (fluorine, chlorine, bromine, iodine) atoms and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, arylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, 10 carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, the alkyl radicals and alkyl portions of the other radicals containing 1 to 4 carbon atoms each, the alkenyl and alkynyl radicals containing 3 to 8 carbon atoms each and 15 the aryl radicals being phenyl or a- or /?-naphthyl radicals.
More especially, Ar represents a phenyl radical optionally substituted by one or more identical or different atoms or radicals chosen from halogen atoms and 20 alkyl, alkoxy, amino, alkylamino, dialkyl-amino, acylamino, alkoxycarbonylamino and trifluoro-methyl radicals.
Still more especially, Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom, or by an alkyl (methyl), alkoxy(methoxy), 25 dialkylamino (dimethylamino), acylamino (acetylamino) or alkoxycarbonylamino (tert-butoxycarbonylamino) radical.
According to the present invention, the taxol analogues of formula (I) are obtained by the action of an
amine of formula:
24 3 5 4 8
\
nh
(V)
in which R3 and R4 are defined as above, on a taxane derivative of formula:
ci3cch2ocoo r-conh
oh
0 ocooch2cci3
ococ6h5
(VI)
in which r and Ar are defined as above, to obtain a product of formula:
r-conh o
G1"°<41 0 O-G2
(VII)
OCOCgHg in which R and Ar are as defined above and Gt and G2 each 10 represent a radical of formula (III) or a protective group (CCl3CH2OCO-) , at least one of the radicals Gl and G2 representing a radical of formula (III), followed, if necessary, by replacement of the protective group(s)
6
24 3 5 4 8
(CCl3CH2OCO-) by a hydrogen atom.
In general, the action of the amine of formula (V) on the taxane derivative of formula (VI) is carried out in an inert organic solvent such as a halogenated aliphatic 5 hydrocarbon, e.g. methylene chloride, at a temperature between 0°C and the boiling point of the reaction mixture. In order to avoid attack at the 7-position, it is especially advantageous to work in methylene chloride at a temperature below 50°C. By working at a temperature above 10 50°C, optionally in the presence of a sufficient excess of amine of formula (V), a mixture is formed of the products of formula (VII) in which one of the radicals Gj or G2 represents a radical of formula (III), or alternatively in which both radicals Gl and G2 each represent a radical of 15 formula (III).
Replacement of the protective group represented by Gj or G2 is generally performed by treatment with zinc in acetic acid, optionally in the presence of methanol, at a temperature of between 30 and 80°C. 20 The products of formula (I) may be separated from their mixtures by preparative chromatography on suitable supports.
The products of formula (I) obtained by the process of the invention may be purified by physical 25 methods such as crystallisation or chromatography on a suitable support.
The products of formula (I) may be optionally converted into acid addition salts with inorganic acids
24 3 5 A 8
(hydrochloric, sulphuric, nitric, phosphoric acids) or organic acids (acetic, oxalic, maleic, fumaric acids).
The products of formula (VI) may be obtained by the processes described in European Patents EP-O,253,738 5 and EP-0,253,739.
The products of formula (I), and especially those in which R represents a t-butoxy radical, possess noteworthy biological properties.
In vitro, measurement of the biological 10 activity is performed on tubulin extracted from porcine brain by the method of M.L. Shelanski et al. , Proc. Natl.
Acad. Sci. USA, 70, 765-768 (1973). Study of the depolymerisation of microtubules to tubulin is performed according to the method of G. Chauviere et al., C.R. Acad. 15 Sci., 293. Series II, 501-503 (1981). In this study, the products of formula (I) were shown to be at least as active as taxol.
In vivo, the products of formula (I) were shown to be active in mice grafted with B16 melanoma at doses of 20 between 1 and 10 mg/kg administered intraperitoneally, as well as against other liquid or solid tumours.
Moreover, the products of formula (I) have better solubility in water than taxol or the taxane derivatives which form the subject of European Patent 25 EP-0,253,738.
The Examples which follow illustrate the present invention.
8
24 3 5
EXAMPLE 1
4a-Acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-ljS-hydroxy-9-oxo-7/3,10/3-bis [(2,2,2-trichloroethoxy) -carbonyloxy]-ll-taxen-13a-yl (2R,3S)-3-t-butoxy-5 carbonylamino-2-hydroxy-3-phenylpropionate (365 mg),
dissolved in methylene chloride (10 cc), is introduced into a round-bottomed flask eguipped with a magnetic stirrer and a condenser. 3-Dimethylaminopropylamine (80 /xl) is added. The reaction mixture is heated to 40°C under an argon 10 atmosphere for 4 hours. The solution is washed with water (2 x 10 cc). After drying and evaporation of the solvent, the residue obtained is purified by preparative-layer chromatography on silica, eluting with a methylene chloride/methanol (8:2 by volume) mixture. 4a-Acetoxy-2a-15 benzoyloxy-5/3,20-epoxy-l/3-hydroxy-9-oxo-10/3- [ (3-dimethyl-aminopropyl) amino-carbonyloxy] -7/3- (2, 2, 2-trichloroethoxy) -carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-t-butoxycarbonyl amino-2-hydroxy-3-phenylpropionate (250 mg) is thereby obtained, the structure of which product is confirmed by 2 0 the proton nuclear magnetic resonance spectrum determined in deuterated chloroform, the chemical shifts being expressed in ppm and the coupling constants (J) in hertz: 1.16 (s, 3H) ; 1.25 (s, 3H) ; 1.35 (s, 9H) ; 1.83 (s, 3H) ; 1.93 (s, 3H); 2.26 (s, 6H); 2.38 (s, 3H); 3.25 (m, 2H); 25 3.93 (d, J = 7, 1H); 4.16 and 4.33 (2d, J = 9, 2H); 4.62
(s, broad, 1H); 4.73 and 4.99 (2d, J = 12, 2H); 4.96 (d, J = 9, 1H); 5.29 (d, J = 9, 1H); 5.47 (d, J = 9, 1H) ; 5.54 (m, 1H); 5.66 (d, J = 7, 1H); 6.19 (t, J = 9, 1H); 6.29 (s,
24 3548
9
1H); 7.37 (5H); 7.49, 7.62 and 8.09 (5H).
Powdered zinc (130 mg) is added to a solution of the product obtained above (137 mg) in an acetic acid/methanol (1:1 by volume) mixture. The reaction mixture 5 is stirred at 60°C for 1 hour. After filtration and concentration to dryness, the residue is taken up with water and then extracted with ethyl acetate. After settling has taken place, followed by separation and drying, the organic phases are concentrated to dryness. The residue 10 obtained is purified by preparative-layer chromatography on silica, eluting with a methylene chloride/methanol (8:2 by volume) mixture. 4a-Acetoxy-2a-benzoyloxy-5/3,20-epoxy-lj3, 7/3-dihydroxy-9-oxo-10jS- (3-
dimethylaminopropyl)aminocarbonyloxy-ll-taxen-13a-yl 15 (2R,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate (73 mg) is thereby obtained, which product possesses the following characteristics:
- ultraviolet spectrum (ethanol):
X max = 230 nm (e = 12,700) 20 X max = 275 nm (e = 1040)
- infrared spectrum (in solution in methylene chloride): main characteristic absorption bands at 3400, 2960 and 1729 cm'1
- proton nuclear magnetic resonance spectrum:
1.18 (s, 3H); 1.23 (s, 3H); 1.33 (s, 9H); 1.66 (s, 3H); 1.87 (s, 3H); 2.28 (s, 6H); 2.38 (s, 3H); 3.20 (m, 2H); 3.78 (d, J = 7, 1H); 4.17 and 4.31 (2d, J = 8, 2H); 4.43 (dd, J = 6 and 12, 1H); 4.62 (s, broad, 1H); 4.97 (d, J =
? 4 3
9, 1H); 5.26 (d, J = 9, 1H); 5.54 (d, J = 9, 1H); 5.66 (d, J = 7, 1H); 6.21 (m, 2H); 7.39 (5H); 7.51, 7.62 and 8.11 (5H)
- mass spectrum (FAB): 936 (MH+).
0.1M hydrochloric acid solution (0.780 cc) is added to a solution of the product obtained above in ethanol (0.5 cc). The reaction mixture is concentrated to dryness and then lyophilised. 4a-Acetoxy-2a-benzoyloxy-5/3,20-epoxy 1/3, 7/3-dihydroxy-9-oxo-10/3- (3-10 dimethylaminopropyl)aminocarbonyloxy-ll-taxen-13a-yl (2R,3 S)-3-t-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate hydrochloride is thereby obtained, the characteristics of which product are as follows:
- optical rotation [a]^0 = -29° (c = 0.4; ethanol)
- proton nuclear magnetic resonance spectrum (CDC13/CD30D): 1.16 (s, 3H); 1.21 (s, 3H); 1.40 (s, 9H); 1.66 (s, 3H) ; 1.93 (s, 3H); 2.38 (s, 3H); 2.83 (s, 6H); 3.16 (m, 2H); 3.81 (d, J = 7, 1H); 4.23 and 4.31 (2d, J = 8, 2H); 4.38 (m, 1H) ; 4.58 (m, 1H) ; 4.99 (d, J = 9, 1H) ; 5.16 (s, 1H) ; 20 5.66 (d, J = 7, 1H); 6.16 (t, J = 9, 1H); 6.26 (s, 1H); 7.37 (5H); 7.52, 7.70 and 8.09 (5H).
EXAMPLE 2
3-Dimethylaminopropylamine (0.50 cc) is added to a solution, maintained under an argon atmosphere, of 25 4-acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-9-oxo-7/3,10/3 bis[(2,2,2-trichloroethoxy)carbonyloxy]-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (4.63 g) in acetonitrile (100 cc). The
? 4 3 5 4 8
n reaction medium is heated with stirring for 3 hours to a temperature in the region of 60°C, then cooled to a temperature in the region of 2 0°C and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. A white 5 porous solid (5.3 g) is obtained, which product is purified by chromatography on silica (0.063-0.2 mm) (150 g)
contained in a column 4 cm in diameter [eluent: dichloromethane/methanol (95:5 by volume)], collecting 100-cc fractions. Fractions 1 to 10 are discarded and 10 chromatography is then continued, eluting with a dichloromethane/methanol (80:20 by volume) mixture.
Fractions 17 to 3 0 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. A mixture (2.57 g) in the, molar proportions 15 66:33 of the two substitution derivatives, with [(3-dimethyl-aminopropyl)carbamoyloxy] at the 10- and 7-positions, respectively, is thereby obtained.
The above mixture is separated by high performance liquid chromatography on a support (4 00 g), the 20 preparation of which is described below, contained in a column 25 cm in length and 6 cm in diameter with a hexane/ethanol (80:20:2.5 by volume) mixture as mobile phase at a flow rate of 45 cc/minute. The following are obtained in successive order of elution: 25 - 4-acetoxy-2a-benzoyloxy-5/?, 2 0-epoxy-l-hydroxy-7jS-[ (3-dimethylaminopropyl) carbamoyloxy ] -9-oxo-10/?- (2, 2,2-trichloroethoxy) carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (0.46 g),
24 3 5 4 8
12
in the form of a white porous solid,
- 4-acetoxy-2a-benzoyloxy-5j3 ,20-epoxy-l-hydroxy-10/3-[ (3-dimethylaminopropyl) carbamoyloxy] -9-oxo-7/3- (2,2,2-trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-5 butoxycarbonylamino-2-hydroxy-3-phenylpropionate (0.81 g) ,
in the form of a white porous solid.
The support may be prepared in the following manner:
In a 6-litre three-necked flask, aminopropyl 10 silica (100 A - 10 /xm - NH2; Macherey-Nagel) (600 g) is suspended in dimethylformamide (2 litres). ll-(N-tert-Butoxycarbonylamino)undecanoic anhydride (95 g) is added and the reaction mixture is stirred for 18 hours at a temperature in the region of 20°C. The silica is separated 15 by filtration and washed successively with dichloromethane (2 x 1500 cc) and then dimethyl-formamide (2 x 1500 cc).
The silica thus washed is resuspended in dimethylformamide (2 litres), 11-(N-tert-butoxycarbonylamino)undecanoic anhydride (95 g) is added and the reaction mixture is then 2 0 stirred for 18 hours at a temperature in the region of 20°C.
The silica is separated by filtration, washed successively with dichloromethane (2 x 600 cc), tetra-hydrofuran (2 x 600 cc), methanol (2 x 600 cc) and diethyl 25 ether (2 x 600 cc) and then dried under reduced pressure at a temperature in the region of 20°C. Silica referred to by the name "BOC-Cn-Cj-silica" (610 g) is thereby obtained in the form of a white powder, the structure of which is
24 3 5 4 8
13
confirmed by the infrared spectrum and the elemental analysis (found) of which is: C%=8.8;H%=1.7;N%=
1.2.
In a 6-litre three-necked flask, "BOC-Cn-C3-5 silica" silica (607 g) is suspended in dichloromethane (2 litres) and pyridine (69 cc). Dimethyloctylchlorosilane (530 cc) is added dropwise and the reaction mixture is then stirred for 16 hours at a temperature in the region of 20°C. The solid obtained is separated by filtration, washed 10 successively with dichloromethane (2x1 litre), methanol (2xi litre), tetrahydrofuran (2x1 litre),
dichloromethane (2 x l litre) and diethyl ether (2xi litre) and then dried under reduced pressure at a temperature in the region of 20°C. Silica referred to by 15 the name "B0C-Cu-C3-silica-0-Si (CH3) 2(CH2) 7CH3" (712 g) is thereby obtained in the form of a white powder, the structure of which is confirmed by the infrared spectrum and the elemental analysis (found) of which is:
C % = 12.1; H % = 2.4; N % = 1.0.
In a 6-litre three-necked flask, "BOC-Cn-Cj-
silica-O-Si(CH3)2(CH2)7CH3" silica (711 g) is suspended in a solution (2200 cc) containing 6 % by volume of trifluoroacetic acid in dichloromethane. The reaction mixture is stirred for 5 hours at a temperature in the 25 region of 20°C. The silica is separated by filtration,
washed successively with dichloromethane (2 x i litre), a dichloromethane/diisopropylethylamine (70:30 by volume)
mixture (2x1 litre), dichloromethane (1 litre),
2 4 3 5 4 8
14
tetrahydrofuran (2 x i litre), methanol (2 x l litre) and diethyl ether (2 x l litre) and then dried under reduced pressure at a temperature in the region of 50°C. The silica thus washed and dried is resuspended in a solution 5 (2 litres) containing 6 % by volume of trifluoroacetic acid in dichloromethane.
The reaction mixture is stirred for 16 hours at a temperature in the region of 20°C. The silica is separated by filtration, washed successively with 10 dichloromethane (2 x 1.5 litres), a dichloromethane/diisopropyl ethylamine (70:30 by volume) mixture (2x1 litre), dichlormethane (1.5 litres), tetrahydrofuran (2x2 litres), methanol (2x2 litres) and diethyl ether (2x2 litres) and then dried under reduced 15 pressure at a temperature in the region of 50°C. Silica referred to by the name "C,,-C3-silica-0-Si (CH3)2(CH2)7CH3" (607 g) is thereby obtained in the form of a white powder, the structure of which is confirmed by the infrared spectrum and the elemental analysis (found) of which is C % 20 = 8.8; H % = 1.7; N % = 1.3.
In a 4-litre three-necked flask, "Cn-C3-silica-O-Si (CH3) 2 (CH2) 7CH3" silica (4 00 g) is suspended in dimethylformamide (1800 cc). 3,5-Dinitrobenzoyl-D-phenylglycine (42 g) and 2-ethoxy-l-ethoxycarbonyl-l,2-25 dihydroquinoline (30 g) are added and the reaction mixture is stirred for 16 hours at a temperature in the region of 20°C. The silica is separated by filtration and washed successively with dichloromethane (2 x l litre),
• ? 4 3 5
tetrahydrofuran (2x1 litre), methanol (2x1 litre) and diethyl ether (2 x i litre). The silica thus washed is resuspended in dimethylformamide (2 litres), 2-ethoxy-l-ethoxycarbony1-1,2-dihydroquinoline (30 g) and 3,5-5 dinitrobenzoyl-D-phenylglycine (42 g) are added and the reaction mixture is then stirred for 5 hours at a temperature in the region of 20°C. The silica is separated by filtration, washed successively with dimethylformamide (2x1 litre), dichloromethane (2 x l litre), 10 tetrahydrofuran (2 x l litre), methanol (2x1 litre) and diethyl ether (2 x l litre) and then dried under reduced pressure at a temperature in the region of 140°C. Silica referred to by the name "DNB-D-Phg-Cn-C3-silica-0-Si (CH3) 2)7CH3" (434 g) is thereby obtained in the form of a 15 white powder, the structure of which is confirmed by the infrared spectrum and the elemental analysis (found) of which is: C % = 12.3; H % = 1.8; N % = 2.1.
In a four-litre three-necked flask, "DNB-D-Phg-Cn-C3-silica-0-Si (CH3) 2 (CH2) 7CH3" silica (434 g) is 20 suspended in dichloromethane (1.3 litres),
dimethyloctylmethoxysilane (100 cc) is added and the reaction mixture is then stirred for 54 hours at a temperature in the region of 20°C. The silica is separated by filtration, washed successively with dichloromethane 25 (2xi litre), methanol (2 x l litre), tetrahydrofuran (2xi litre) and dichloromethane (2 x l litre) and then dried under reduced pressure at a temperature in the region of 140°C. Silica referred to by the name "reoctylated "DNB-
^435
16
D-Phg-Cn-C3-silica-0-Si (CH3) 2 (CH2) 7CH3" (425 g) is thereby obtained in the form of a white powder, the structure of which is confirmed by the infrared spectrum and the elemental analysis (found) of which is: C % = 12.7; H % = 5 1.9, N % = 2.0.
In a 4-litre three-necked flask, "reoctylated DNB-D-Phg-Cn-C3-silica-0-Si (CH3)2(CH2)7CH3" silica (425 g) is suspended in dichloromethane (1.3 litres).
Trimethylsilylimidazole (545 cc) is added dropwise and the 10 reaction mixture is stirred for 15 hours at a temperature in the region of 20°C. The solid obtained is separated by filtration, washed successively with tetrahydrofuran (2xi litre), methanol (2 x l litre), acetone (2xi litre) and dichloromethane (2 x l litre) and then 15 dried under reduced pressure at a temperature in the region of 20°C. Silica referred to by the name DNB-D-Phg-Cn-C3-silica-[O-Si (CH3) 2(CH2)7CH3]11 (431 g) is thereby obtained in the form of a white powder, the structure of which is confirmed by the infrared spectrum and the elemental 2 0 analysis (found) of which is: C % = 13.7; H % = 2.2; N % = 2.0.
11-(N-tert-Butoxycarbonylamino)undecanoic anhydride may be prepared in the following manner: a solution of N,N-dicyclohexylcarbodiimide (10.63 g) in 25 ethyl acetate (120 cc) is added in the course of 10 minutes to a solution, maintained at a temperature in the region of 5°C, of 11-(N-tert-butoxycarbonylamino)undecanoic acid (30.1 g) in ethyl acetate (480 cc). The reaction mixture is
24 3 5 4 8
17
stirred for 1 hour at a temperature in the region of 5°C and then for 16 hours at a temperature in the region of 20°C. The precipitate is separated by filtration and washed with ethyl acetate (30 cc).The filtrate is concentrated 5 under reduced pressure at 30°C. The solid obtained is dried under vacuum at a temperature in the region of 30°C. 11-(N-tert-Butoxycarbonylamino)undecanoic anhydride (31 g), m.p. 58°C, is thereby obtained.
11-(N-tert-Butoxycarbonylamino)undecanoic acid 10 may be prepared according to the method described by J.T. SPARROW, J. Org. Chem., 41, 1350 (1976).
A solution of 4-acetoxy-2a-benzoyloxy-5j8,20-epoxy-l-hydroxy-10/3- [ (3 -dimethylaminopropyl) carbamoyl-oxy]-9-OXO-7/3- (2,2, 2-trichloroethoxy) carbonyloxy-ll-taxen-13a-yl 15 (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-
phenylpropionate (104 mg), obtained above, in a mixture of methanol (8 cc) and acetic acid (8 cc) is heated with stirring and under an argon atmosphere to a temperature in the region of 60°C, and then treated with powdered zinc 20 (1.2 g). The reaction mixture is then stirred for 1 hour 30 minutes at 60°C, thereafter cooled to a temperature in the region of 20°C and filtered through sintered glass covered with Celite. The sintered glass is washed with dichloromethane (3x5 cc) and the filtrates are combined 25 and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C.
The residue is treated with water (5 cc) and ethyl acetate (5 cc). The aqeuous phase is separated after
^4 3 5 4 8
18
settling has taken place and then re-extracted with ethyl acetate (3x5 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 4 0°C.
4-Acetoxy-2a-benzoyloxy-5/3,2 0-epoxy-l,7/3-dihydroxy-10j3-[ (3-dimethylaminopropyl)carbamoyloxy]-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate (19 mg)is obtained in the form of a white porous solid, the characteristics of which product are as 10 follows:
- NMR spectrum (400 MHz; CDCl3)
S (ppm) : 1.30 (2s, 3H each; -CH3 16 and 17); 1.38 (s, 9H: -C(CH3)3); 1.70 (s, 3H: -CH3 18 or 19); 1.90 (s, 3H: -CH3 18 or 19); 1.90 [m, 2H: -NHCH2CH2CH2N (CH3) 2] ; 2.2 to 2.90 [m, 15 15H: - (CH2) - 6, -CH2- 14, -CH2N(CH3)2, -N(CH3)2, -C0CH3] ; 3.2 and 3.4 [2m, 2H: -NHCH2CH2CH2N (CH3) 2] ; 3.8 (d, 1H: -H3) ; 4.2 and 4.34 (AB, 2H: -CH2- 20); 4.45 (dd, 1H, J = 11 and 7: -H7); 4.66 (bs, 1H: -H2'); 5.0 (bd, 1H, J = 9: -H5); 5.3 (bs, 1H; -H3') ; 5.6 [bd, 1H: -NHCH2CH2CH2N(CH3)2] ; 5.68 (d, 20 1H, J = 7: -H2); 6.25 (m, 2H: -H13 and -H10); 6.4 [bs, 1H: -NHCOOC(CH3)3] ; 7.2 to 7.4 (mt, 5H: -0^3'); 7.5 [t, 2H, J = 7.5: -OCOC6H5 (-H3 and -H5) ] ; 7.64 [t, 1H: -OCOC6H5 (-H4) ] ; 8.12 [d, 2H: -OCOC6H5 (-H2 and -H6) ] .
A solution of 4-acetoxy-2a-benzoyloxy-5j8,20-25 epoxy-l-hydroxy-7/3-[ (3-dimethylaminopropyl) carbamoyl-oxy] -9-oxo-10/3- (2,2 , 2-trichloroethoxy) carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (59 mg), obtained above, in a mixture of
9 4 3 5
19
methanol (6 cc) and acetic acid (6 cc) is heated with stirring and under a nitrogen atmosphere to a temperature in the region of 60°C, and then treated with powdered zinc (1.2 g). The reaction mixture is then stirred for 1 hour 30 5 minutes at 60°c, thereafter cooled to a temperature in the region of 20°C and filtered through sintered glass covered with Celite. The sintered glass is washed with dichloromethane (3x5 cc) and the filtrates are combined and then concentrated to dryness under reduced pressure 10 (2.7 kPa) at a temperature in the region of 40°C. The residue is treated with water (5 cc) and ethyl acetate (5 cc). The aqueous phase is separated after settling has taken place and then re-extracted with ethyl acetate (3x5 cc). The organic phases are combined, dried over 15 magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 4-Acetoxy-2a-benzoyloxy-5/3, 20-epoxy-l, 10/3-dihydroxy-7/S-[ (3-dimethylaminopropyl)carbamoyloxy]-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-2 0 phenylpropionate (9 mg) is obtained in the form of a white porous solid, the characteristics of which product are as follows:
- NMR spectrum (400 MHz; CDC13)
S (ppm) : 1.30 (2s, 3H each: -CH3 16 and 17); 1.36 (s, 9H: 25 -C(CH3)3); 1.82 (s, 3H: -CH3 18 or 19); 1.95 (s, 3H:
-CH3 18 or 19); 1.88 [m, 2H: -NHCH2CH2CH2N (CH3) 2] ; 2.2 to 2.70 [m, 15H: -CH2) - 6, -CH2- 14, -CH2N(CH3)2, -N(CH3)2, -COCH3] ; 3.15 and 3.3 [2m, 2H: -NHCH2CH2CH2N (CH3) 2] ; 4.0 (d, 1H: -H3);
? 4 3 5 4 8
4.2 and 4.38 (AB, 2H: -CH2-20) ; 4.68 (bs, 1H: -H2'); 4.96 (bd, 1H, J = 9 Hz: -H5) ; 5.3 (bs, 1H: -H3'); 5.40 (dd, 1H, J = 11 and 7: -H7); 5.5 [s + bs, 2H: -H10 and -NHCH2CH2CH2N(CH3)2]; 5.7 [d + bs, 2H: -H2 and -NHCOOC(CH3)3] ; 5 6.22 (bt, 1H: -H13); 7.2 to 7.4 (mt, 5H: -CgHj 3'); 7.53 [t, 2H, J = 7.5: -OCOC6H5 (-H3 and -H5) ] ; 7.65 [t, 1H: -OCOC6H5 (-H4)]; 8.12 [d, 2H: -OCOC6H5 -H2 and -H6) ] .
EXAMPLE 3
Using a procedure similar to that described in 10 Example 2, but starting with 4-acetoxy-2a-benzoyloxy-5)3,20-epoxy-l-hydroxy-9-oxo-7/?, 10/3-bis[ (2,2,2-trichloroethoxy)carbonyloxy]-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (6.95 g) and 3-(4-methylpiperazinyl)propylamine (0.94 g), 15 and after purification by high performance liquid chromatography with a methanol/ethanol/
hexane/dichloromethane (10:10:80:2 by volume) mixture as mobile phase, the following are obtained:
- 4-acetoxy-2a-benzoyloxy-5jS, 2 0-epoxy-l-hydroxy-10/?-{ [3- (4-20 methylpiperazinyl) propyl] carbamoyloxy}-9-oxo-7/3- (2,2,2-
trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate (1.37 g), in the form of a white porous solid,
- 4-acetoxy-2a-benzoyloxy-5/3,2 0-epoxy-l-hydroxy-7/3-{ [3- (4-25 methylpiperazinyl) propyl] carbamoyloxy}-9-oxo-10/3- (2 ,2,2-
trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate (2.17 g), in the form of a white porous solid.
243548
21
4-Acetoxy-2a-benzoyloxy-5/3,2 O-epoxy-l-hydroxy-10/3-{ [3- (4-methylpiperazinyl) propyl] carbamoyloxy}-9-oxo-7/3-(2,2,2-trichloroethoxy) carbonyloxy-ll-taxen-13a-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is 5 converted to 4-acetoxy-2a-benzoyloxy-5j8,2 0-epoxy-l,7/3-dihydroxy-10/3-{ [3-(4-methylpiperazinyl)propyl]-carbamoyloxy}-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate by the action of zinc in a mixture of methanol and acetic acid, as 10 described in Example 2 for 4-acetoxy-2a-benzoyloxy-5/3,20-epoxy-l-hydroxy-10/3- [ (3-dimethylamino-propyl) carbamoyloxy ] -9-OXO-7/3- (2,2, 2-trichloroethoxy) -carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate.
The product thereby obtained possesses the following characteristics:
- NMR spectrum (400 MHz; CDC13)
S (ppm) : 1.18 (s, 3H: -CH3 16 or 17); 1.27 (s, 3H: -CH3 16 or 17); 1.33 (s, 9H: -C(CH3)3); 1.7 (s, 3H: -CH3 19); 1.6 to 20 1.95 [mt, 3H: -OCONHCH2CH2CH2N= and -(CH)-H6]; 1.88 (s, 3H: -CH3 18); 2.2 to 2.7 [mt, 13H: -CH2N (CH2CH2) 2NCH3, -CH2- 14 and -(CH)- H6] ; 2.29 (s, 3H: =NCH3) ; 2.4 (s, 3H: -COCHj) ; 3.2 to 3.45 (mt, 2H: -OCONHCH2CH2CH2N=) ; 3.8 (d, 1H, J = 7: -H3); 4.18 and 4.31 (2d, 1H each, J = 8: -CH2- 20); 4.44 25 (dd, 1H, J = 11 and 7: -H7); 4.63 (unresolved peaks, 1H: -H2'); 4.97 (broad d, 1H, J = 10: -H5); 5.27 (broad d, 1H, J = 9.5: -H3') ; 5.4 [d, 1H, J = 9.5: -NHCOOC (CH3) 3] ; 5.67 (d, 1H, J = 7: -H2); 6.20 (s, 1H: -H10); 6.25 (mt, 1H:
22
243548
-H13); 7.0 (unresolved peaks, 1H: -NHCH2CH2CH2N=) ; 7.25 to 7.45 (mt, 5H: -0^3'); 7.51 [t, 2H, J = 8: -OCOC6H5(-H3 and -H5) ] ; 7.62 [t, 1H, J = 8: -OCOC6H5 (-H4)]; 8.13 [d, 2H, J = 8: -OCOC6H5 (-H2 and -H6) ] .
Distilled water (0.2 cc) is added to a solution of 4-acetoxy-2a-benzoyloxy-5i3, 2 0-epoxy-l, 7j8-dihydroxy-10/3-{[3-(4-methylpiperazinyl)propyl]carbamoyloxy}-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (5 mg), obtained above, in 0.1N aqueous 10 hydrochloric acid solution (0.1 cc), and the solution obtained is lyophilised. 4-Acetoxy-2a-benzoyloxy-5/?, 20-epoxy-l , 7/3-dihydroxy-10/?-{ [3-(4-methylpiperazinyl)propyl]-carbamoyloxy}-9-oxo-ll-taxen-13a-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate 15 dihydrochloride (5 mg) is thereby obtained, the characteristics of which product are as follows: - NMR spectrum (400 MHz; D20 + e CD3COOD)
S (ppm) : 0.88 (s, 3H: -CH3 16 or 17); 0.93 (s, 3H: -CH3 16 or 17); 1.09 (s, 9H: -C(CH3)3); 1.4 (s, 3H: -CH3 19); 1.4 to 20 1.9 (mt, 5H: -OCONHCH2CH2CH2N=, -CH2- 14 and -(CH)-H6); 1.66 (s, 3H: -CH3 18); 2.09 (s, 3H: -C0CH3) ; 2.32 (mt, 1H: -(CH)-Hfi) ; 2.81 (s, 3H: -NCH3) ; 2.9 to 3.2 and 3.4 to 3.55 (2 mt, respectively 4H and 9H: -OCONHCH2CH2CH2N (CH2CH2) 2NCH3 and -H3) ; 4.01 (mt, 3H: -CH2- 20 and -H7) ; 4.36 (d, 1H, J = 6.6 25 Hz: -H2'); 4.6 to 4.8 (-H3': signal cancelled out by presaturation of the solvent signal); 4.84 (broad d, 1H, J = 9: -H5): 5.34 (d, 1H, J = 7: -H2); 5.82 (t, 1H, J = 9: -H13) ; 6.01 (s, 1H: -H10) ; 7.03 [t, 1H, J = 8: -0^3'
2 435 4 8
23
(-H4)]; 7.13 [d, 2H, J = 8: -C^5 3' (-H2 and -H6)]; 7.2 [t, 2H, J = 8: 3' (-H3 and -H5)]; 7.38 [t, 2H, J = 8:
-OCOC6H5(-H3 and -H5) ] ; 7.51 [t, 1H, J = 8: -OCOC6H5 (-H4) ] ; 7.8 [d, 2H, J = 8: -OCOC6H5 (-H2 and -H6) ] . 5 4-Acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-
70-{ [3 -(4-methylpiperazinyl)propyl]carbamoyloxy}-9-oxo-10/3-(2,2,2-trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is converted to 4-acetoxy-2a-benzoyloxy-5/3, 20-epoxy-l, 10/3-10 dihydr oxy-7/3- { [ 3- (4-methylpiperaziny 1) propyl ] carbamoyloxy}-9-oxo-ll-taxen-13o:-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate by the action of zinc in a mixture of methanol and acetic acid, as described in Example 2 for 4-acetoxy-2a-benzoyloxy-5/3,20-epoxy-l-15 dihydroxy-10/3-[ (3-dimethylaminopropyl) carbamoyloxy ]-9-oxo-7/3- (2,2, 2-trichloroethoxy) carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
The product thereby obtained possesses the 20 following characteristics:
- optical rotation: [a]^0 = -14° (c = 0.41; methanol)
- NMR spectrum (4 00 MHz; CDC13)
6 (ppm) : 1.13 (s, 3H: -CH3 16 or 17); 1.24 (s, 3H: -CH3 16 or 17); 1.37 (s, 9H: -C(CH3)3); 1.6 to 2.0 [mt, 3H: 25 -OCONHCH2CH2CH2N= and -(CH)-H 6]; 1.84 (s, 3H: -CH3 19); 1.92 (S, 3H: -CH3 18); 2.3 (d, 2H, J = 8.5: -CH2- 14); 2.38 (s,
6H: =NCH3 and -COCH3) ; 2.3 to 2.8 [mt, 11H: -CH2N (CH2CH2) 2NCH3 and -(CH)-H 6]; 3.14 and 3.3 (2 mt, 1H each:
24 3 5 4 8
24
-OCONHCH2CH2CH2N=) ; 4.01 (d, 1H, J = 7: H3) ; 4.21 and 4.33 (2d, 1H each, J = 9: -CH2- 20); 4.63 (broad s, 1H: -H2'); 4.94 (broad d, 1H, J = 10: -H5); 5.27 (broad d, 1H, J =
9.5: -H3'); 5.38 (dd, 1H, J = 11 and 7: -H7) ; 5.44 [d, 1H, 5 J = 9.5: -NHCOOC(CH3)3] ; 5.51 (s, 1H: -H 10); 5.68 (d, 1H, J = 7: -H2) ; 6.09 (unresolved peaks, 1H: -NHCH2CH2CH2N=) ; 6.21 (broad t, 1H, J = 8.5: -H 13); 7.25 to 7.45 (mt, 5H: -C^ 3'); 7.50 [t, 2H, J = 8: -OCOC6H5(-H 3 and -H5) ] ; 7.62 [t, 1H, J = 8: -OCOC6H5 (-H4) ] ; 8.10 [d, 2H, J = 8: -OCOC6H5(-H2 10 and -H6)].
Distilled water (0.3 cc) is added to a solution of 4-acetoxy-2a-benzoyloxy-5/3, 20-epoxy-l, 10/3-dihydroxy-7/3-{[3-(4-methylpiperazinyl)propyl]carbamoyl-oxy}-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-15 3-phenylpropionate (5 mg) in 0.1N aqueous hydrochloric acid solution (0.1 cc), and the solution obtained is lyophilised. 4-Acetoxy-2a-benzoyloxy-5j8, 2 0-epoxy-l, 10/3-dihydroxy-7/3-{ [3 - (4-methylpiperazinyl) propyl] carbamoyloxy}-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-2 0 hydroxy-3-phenylpropionate dihydrochloride (5 mg) is thereby obtained, the characteristics of which product are as follows:
- NMR spectrum (400 MHz; D20 + eCD3COOD)
(ppm) : 0.82 (s, 3H: -CH3 16 or 17); 0.92 (s, 3H: -CH3 16 or 25 17); 1.1 (s, 9H: -C(CH3)3); 1.4 to 1.8 (mt, 5H:
-OCONHCH2CH2CH2N=, -CH2- 14 and -(CH)-H6); 1.48 (s, 3H: -CH3 19); 1.6 (s, 3H: -CH3 18); 2.1 (s, 3H, -COCH3) ; 2.28 (mt,
1H: - (CH) -H6) ; 2.78 (s, 3H:-NCH3); 2.8 to 3.1 and 3.42 (mt
? 4 3 5 4 8
and unresolved peaks, respectively 4H and 8H: -OCONHCH2CH2CH2N(CH2CH2)2NCH3) ; 3.57 (d, 1H, J = 7: -H3) ; 4.01 and 4.1 (2d 1H each, J = 8: -CH2- 20 and -H 7); 4.3 to 4.4 (-H 2': signal masked by the solvent band); 4.73 (d, 1H, J 5 = 7: -H 3'); 4.85 (broad d, 1H, J = 9: -H5); 5.02 (mt, 1H: -H7); 5.24 (s, 1H: -H10); 5.32 (d, 1H, J = 7: -H2) ; 5.82 (t, 1H, J = 9: -HI3) ; 7.02 [t, 1H, J = 8: -C,^ 3' (-fi4)]; 7.12 [d, 2H, J = 8: -C^j 3' (-H 2 and -H 6); 7.22 [t, 2H, J = 8: -C^ 3' (-H3 and -H 5)]; 7.41 [t, 2H, J = 8: -OCOC6H5(-10 H3 and -H5) ] ; 7.52 [t, 1H, J = 8 -OCOC6H5 (-H4)]; 7.8 [d,
2H, J = 8: -OCOC6H5 (-H2 and -H6) ] .
EXAMPLE 4
Using a procedure similar to that described in Example 2, but starting with 4-acetoxy-2a-benzoyloxy-5jS, 20-15 epoxy-l-hydroxy-9-oxo-7)3 ,10j3-bis [ (2,2,2-
trichloroethoxy)carbonyloxy]-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (6.95 g) and 3-morpholinopropylamine (0.88 cc), and after purification by high performance liquid chromatography with 20 a methanol/2-propanol/hexane (20:5:75 by volume) mixture as mobile phase, the following are obtained:
- 4-acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-10/3- [ (3-morpholinopropyl) carbamoyloxy] -9-OXO-7/3- (2, 2,2-trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-
butoxycarbonylamino-2-hydroxy-3-phenylpropionate (1.53 g),
in the form of a white porous solid,
- 4-acetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-7/3- [ (3-morpholinopropyl) carbamoyloxy] -9-oxo-10js- (2 , 2 , 2-
^435
26
trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R,3S) 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (1.35 g) , in the form a white porous solid.
4-Acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-5 10/3— [ (3-morpholinopropyl) carbamoyloxy] -9-oxo-7/S- (2,2,2-trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R, 3S)-3-tert-butoxycarbonylainino-2-hydroxy-3-phenylpropionate is converted to 4-acetoxy-2a-benzoyloxy-5/3,20-epoxy-l,7/8— dihydroxy-10/3-[ (3-morpholinopropyl) carbamoyloxy] -9-oxo-ll-10 taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-phenylpropionate by the action of zinc in a mixture of methanol and acetic acid, as described in Example 2 for 4-acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-10/3- [ (3-dimethylaminopropyl) carbamoyloxy] -9-oxo-7/3- (2,2,2-15 trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
The product thereby obtained possesses the following characteristics:
- NMR spectrum (400 MHz; CDC13)
fi(ppm): 1.15 (s, 3H: -CH3 16 or 17); 1.28 (s, 3H: -CH3 16 or 17); 1.35 (s, 9H: -C(CH3)3; 1.68 (s, 3H: -CHj 19); 1.65 to 1.9 (mt, 2H: -OCONHCH2CH2CH2N=) ; 1.88 (s, 3H: -CH3 18); 1.9 (mt, 1H: - (CH) -H6) ; 2.28 (mt, 2H: -CH2- 14); 2.4 (s, 3H: -C0CH3) ; 2.45 to 2.75 [mt, 7H: -CH2N(CH2CH2)20 and -(CH)- H 25 6]; 3.28 and 3.42 (2 mt, 1H each: -OCONHCH2CH2CH2N=) ; 3.8 [mt, 5H: -CH2N (CH2CH2) 20 and -H 3]; 4.18 and 4.31 (2d, 1H each, J = 8.5: -CH2- 20); 4.44 (dd, 1H, J = 11 and 7: -H 7); 4.63 (broad s, 1H: -H2'); 4.98 (broad d, 1H, J = 10: -
243548
27
H5); 5.27 (broad d, 1H, J = 9: -H3'); 5.41 [d, 1H, J = 9: -NHCOOC(CH3)3] ; 5.67 (d, 1H, J = 7: -H2); 6.21 (s, 1H: -H 10); 6.25 (mt, 1H: -H13); 6.58 (broad t, 1H, J = 5:
-NHCK2CH2CH2N=) ; 7.25 to 7.45 (mt, 5H: -CgHj 3'); 7.52 [t, 5 2H, J = 8: -OCOC6H5(-H 3 and -H 5); 7.62 [t, 1H, J = 8: -OCOC6H5 (-H4) ] ; 8.12 [d, 2H, J = 8: -OCOC6H5 (-H2 and -H6) ] .
4-Acetoxy-2-benzoyloxy-5/3,20-epoxy-l-hydroxy-7/3- [ (3-morpholinopropyl) carbamoyloxy]-9-oxo-10/3- (2 ,2,2-trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R, 3S)-3-10 tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is converted to 4-acetoxy-2-benzoyloxy-5/3,20-epoxy-l, 10/3-dihydroxy-7/3- [ (3-morpholinopropyl) carbamoyloxy] -9-oxo-ll-taxen-13a-yl (2R, 3S)-3-tert-butoxycarbonylamino-2-hydroxy-
3-phenylpropionate by the action of zinc in a mixture of 15 methanol and acetic acid, as described in Example 2 for
4-acetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-10/3- [ (3-dimethylaminopropyl) carbamoyloxy] -9-oxo-7/3- (2,2,2-trichloroethoxy) carbony loxy-ll-taxen-13ot-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
The product thereby obtained possesses the following characteristics:
- NMR spectrum (4 00 MHz; CDC13)
S (ppm) : 1.11 (s, 3H: -CH3 16 or 17); 1.24 (s, 3H: -CH3 16 or
17); 1.37 (s, 9H: -C(CH3)3); 1.6 to 1.9 (mt, 2H:
-OCONHCH2CH2CH2N=) ; 1.81 (s, 3H: -CH3 19); 1.93 (s, 3H: -CI^
18); 1.93 (mt, 1H: -(CH)-H6); 2.3 (d, 2H, J = 8: -CH2- 14); 2.4 (s, 3H: -C0CH3) ; 2.4 to 2.7 [mt, 7H: -CH2N(CH2CH2)20 and
- (CH) -H6 ] ; 3.12 and 3.31 (2 mt, 1H each: -OCONHCH2CH2CH2N=) ;
24 3 5 4 8
28
3.5 (unresolved peaks, 1H: -0H2'); 3.8 [unresolved peaks, 4H: -CH2N(CH2CH20] ; 4.0 (d, 1H, J = 7: -H3) ; 4.2 and 4.33 (2 d, 1H each, J = 8.5: -CH2-20) ; 4.64 (unresolved peaks, 1H: -H2'); 4.94 (broad d, 1H, J = 9.5: -H5); 5.28 (broad d, 1H, 5 J = 9: -H3'); 5.38 (dd, 1H, J = 10 and 7: -H7); 5.45 [broad d, 1H, J = 9: -NHCOOC(CH3)3] ; 5.51 (s, 1H; -H10); 5.68 (d, 1H, J = 7: -H2) ; 5.8 (t, 1H, J = 5: -NHCH2CH2CH2N=) ; 6.21 (t, 1H, J = 8: -HI3); 7.25 to 7.45 (mt, 5H: -CgHj 3'); 7.51 [t, 2H, J = 8: -OCOC6H5 (-H3 and -H5) ] ; 7.62 [t, 1H, J = 8: 10 -OCOC6H5 (-H4) ] ; 8.12 [d, 2H, J = 8: -OCOC6H5 (-H2 and -H6) ] . EXAMPLE 5
3-Dimethylaminopropylamine (0.31 cc) is added to a solution, maintained under an argon atmosphere, of 4-acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-9-oxo-7/3,10/3-15 bis[(2,2,2-trichloroethoxy)carbonyloxy]-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (0.29 g) in acetonitrile (100 cc). The reaction medium is heated with stirring for 3 hours to a temperature in the region of 60°C, then cooled to a 20 temperature in the region of 20°C and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. A white porous solid (0.32 g) is obtained, which product is purified by chromatography on alumina (0.12-0.15 mm) (3 0 g) contained in a column 1.5 cm in diameter [eluent: 25 dichloromethane/methanol (95:5 by volume)], collecting 10-cc fractions. Fractions 7 to 15 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 4-Acetoxy-2a-benzoyloxy-
243548
29
/3, 20-epoxy-l-hydroxy-7/?, 10/3-bis[ (3-dimethylaminopropyl) -carbamoyloxy]-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate (0.12 g) is thereby obtained in the form of a white porous solid, 5 the characteristics of which product are as follows:
- optical rotation: [a]" = -26° (c = 0.75; methanol)
- NMR spectrum (400 MHz; CDC13)
S (ppm) : 1.17 (s, 3H: -CH3 16 or 17); 1.20 (s, 3H: -CH3 16 or 17); 1.36 (s, 9H: C(CH3)3; 1.6 to 1.8 [mt, 4H: 10 -NHCH2CH2CH2N(CH3)2] ; 1.78 (s, 3H: -CH3 19); 1.83 (mt, 1H:
- (CH) -H6) ; 1.96 (s, 3H: -CH318) ; 2.26 [s, 6H: -N(CH3)2]; 2.36 (s, 3H: -COCH3) ; 2.2 to 2.6 [mt, 6H: -CH2 14 and -CH2N (CH3)2] ; 2.66 (mt, 1H: -(CH)-H6); 3.24 [mt, 4H: -NHCH2CH2CH2N(CH3)2] ; 3.92 (d, 1H, J = 7; -H3) ; 4.16 and 4.3
(2d, 1H each, J = 8: -CH2- 20); 4.62 (broad s, 1H: -H2');
4.93 (d, 1H, J = 9: -H5); 5.27 (mt, 1H: -H3'); 5.4 (mt, 1H; -H7) ; 5.48 and 5.76 [2 mt, 1H each: -NHCH2CH2CH2N (CH3) 2 ] ;
.55 [broad d, 1H: -NHCOOC (CH3) 3] ; 5.64 (d, 1H, J = 7: -H2); 6.16 (broad t, 1H, J = 9: -H13); 6.32 (s, 1H: -H10); 7.3 to 20 7.5 (mt, 5H: -CgHj 3'); 7.5 [t, 2H, J = 7.5: -OCOC6H5 (-H3
and -H5) ] ; 7.61 [t, 1H, J = 7.5; -OCOC6H5(-H4) ] ; 8.1 [d, 2H, J = 7.5: -OCOC6H5(-H2 and -H6) ] .
Distilled water (0.4 cc) is added to a solution of 4-acetoxy-2a-benzoyloxy-5j8,2 0-epoxy-l-hydroxy-7/3,10/3-25 bis[(3-dimethylaminopropyl)carbamoyloxy]-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (10.6 mg) in 0.1N aqueous hydrochloric acid solution (0.2 cc), and the solution obtained is
24 3 5 48
lyophilised.
4-Acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-7/3, 10/3-bis[(3-dimethylaminopropyl)carbamoyloxy]-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-5 phenylpropionate dihydrochloride (10 mg) is thereby obtained, the characteristics of which product are as follows:
- NMR spectrum (400 MHz; D20/CH3C00D, 90:10 by volume)
S (ppm: 0.85 (s, 3H: -CH3 16 or 17); 0.9 (s, 3H: -CH3 16 or 10 17); 1.10 (bs, 9H: -C(CH3)3); 1.5 (s, 3H: -CH3 19); 1.6 to 1.8 [m, 10H: -CH3 18, -NHCH2CH2CH2N (CH3) 2, -CH2, 14, -(CH)-H6]; 2.10 (s, 3H: -C0CH3) ; 2.3 (m, 1H: -(CH)- H6) ; 2.65 [2s, 6H each: -N(CH3)2]; 2.8 to 3.1 [vbm, 8H: -CH2N(CH3)2, -NHCH2CH2CH2N(CH3)2] ; 3.6 (bd, 1H: -H3) ; 4 and 4.15 (2d, AB, 15 2H: -CH2-20); 4.40 (bd, 1H: -H2'); 4.70 (vbs, 1H: -H3'); 4.90 (bd, 1H: -H5); 5.10 (bdd, 1H: -H7); 5.35 (bd, 1H: -H2); 5.8 (bt, 1H: -H13); 6.05 (s, 1H: -H 10); 7.0 to 7.25 (mt, 5H: -C£l53'); 7.4 [t, 2H, J = 7.5: -0C0C6H5(-H3 and -H5) ] ; 7.5 [t, 1H, J = 7.5: -OCOC6H5 (-H4) ] ; 7.80 [d, 2H, J = 20 7.5: -0C0C6H5 (-H2 and -H6) ] .
EXAMPLE 6
Using a procedure similar to that described in Example 5, but starting with 4-acetoxy-2a-benzoyloxy-5|3,20-epoxy-l-hydroxy-9-oxo-7/3,10/3-bis [ (2,2,2-25 trichloroethoxy)carbonyloxy]-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate (1.18 g) and 3-(4-methylpiperazinyl)propylamine (1.6 g), 4-acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-7/S, 10/3-
31
243548
bis{[3-(4-methylpiperazinyl)propyl]carbamoyloxy}-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (1.1 g) is obtained in the form of a white porous solid, the characteristics of which are as 5 follows:
- optical rotation: [a]^,0 = -22.9° (c = 0.51; methanol)
- NMR spectrum (4 00 MHz; CDCl3)
S (ppm) : 1.24 (s, 3H: -CH3 16 or 17); 1.28 (s, 3H: -CH3 16 or 17); 1.4 (s, 9H: -C(CH3)3) ; 1.6 to 1.85 (mt, 4H: 10 -OCONHCH2CH2Ch2N=) ; 1.83 (s, 3H: -CH3 19); 1.87 (ddd, 1H, J = 15, 11 and 2: -(CH)-H6); 2.01 (s, 3H: -CH3 18); 2.3 to 2.7 [mt, 31H: -CH2N(CH2CH2)2NCH3, -C0CH3 and -CH2- 14]; 2.7 (mt, 1H: - (CH) -H 6); 3.15 and 3.45 (mt, 4H: -OCONHCH2CH2CH2N=) ; 4.0 (d, 1H, J = 7: -H 3); 4.21 and 4.32 (2d, 1H each, J = 15 8: -CH2- 20); 4.66 (d, 1H, J = 2: -H2'); 4.98 (broad d, 1H, J = 9: -H 5); 5.28 (mt, 1H: -H3'); 5.4 to 5.5 [mt, 2H: -H 7 and -NHCOOC (CH3) 3] ; 5.7 (d, 1H, J = 7: = -H 2); 6.0 and 6.4 (2 unresolved peaks, 1H each; -NHCH2CH2CH2N=) ; 6.21 (t, 1H, J = 9: -H13) ; 6.4 (s, 1H: -H 10) ; 7.3 to 7.5 (mt, 5H: -C^ 20 3'); 7.51 [t, 2H, J = 7.5: -OCOC6H5 (-H3 and -H5) ] ; 7.64 [t, 1H, J = 7.5; -OCOC6H5(-H 4)]; 8.12 [d, 2H, J = 7.5: -OCOC6H5 (-H 2 and -H 6)] .
A solution of 4-acetoxy-2a-benzoyloxy-5jS, 20-epoxy-l-hydroxy-7j8,10|8-bis{ [3- (4-methyl-25 piperazinyl)propyl]carbamoyloxy}-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (0.35 g), obtained above, in 0.1N aqueous hydrochloric acid solution (12 cc) is lyophilised.
? 4 3 5 4 8
32
4-Acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-7j3,10/3— bis{[3-(4-methylpiperazinyl)propyl]carbamoyloxy}-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate tetrahydrochloride (0.365 g) is thereby 5 obtained, the characteristics of which product are as follows:
- optical rotation: [a]£° = -22° (c = 0.41; methanol)
- NMR spectrum (4 00 MHz; D20)
<S (ppm) : 1.1 (s, 3H: -CH3 16 or 17); 1.14 (s, 3H; -CH3 16 or 10 17); 1.36 (s, 9H: -C(CH3)3); 1.72 and 1.92 (2s, 3H each: -CH3 18 and -CH3 19); 1.65 to 2.05 (mt, 7H:
-OCONHCH2CH2CH2N=) , -CH2- 14 and -(CH)-H 6); 2.38 (s, 3H:
-COCH3) ; 2.55 (mt, 1H: -(CH)-H 6); 2.92 and 2.94 (2s, 6H: -NCH3) ; 3.0 to 3.7 (mt, 2 4H; -OCONHCH2CH2CH2N (CH2CH2) 2NCH3) ; 15 3.79 (d, 1H, J = 7: -H 3); 4.23 and 4.4 (2d, 1H each, J = 9: -CH2- 20); 4.67 (d, 1H, J = 7: -H2'); 4.98 (unresolved peaks, 1H: -H 3'); 5.16 (broad d, 1H, J = 9: -H 5); 5.33 (dd, 1H, J = 11 and 7: -H 7) ; 5.58 (d, 1H, J = 7: -H 2) ; 6.07 (t, 1H, J = 9: -H 13); 6.28 (s, 1H: -H 10); 7.27 [t, 20 1H, J = 7.5: -C& 3' (-H 4)]; 7.38 [d, 2H, J = 7.5: -C^ 3' (—H 2 and -H 6)]; 7.48 [t, 2H, J = 7.5: -C6H5 3' (-H 3 and -H 5)]; 7.67 [t, 2H, J = 7.5: -OCOC6H5 (-H 3 and -H 5) ] ; 7.78 [t, 1H, J = 7.5; -OCOC6H5 (-H 4)]; 8.18 [d, 2H, J = 7.5; -OCOC6H5 (-H 2 and -H 6)].
EXAMPLE 7
Using a procedure similar to that described in Example 5, but starting with 4-acetoxy-2a-benzoyloxy-5j3,20-epoxy-l-hydroxy-9-oxo-7j8,10j3-bis [2,2,2-
24 3 5 A 8
33
trichloroethoxy)carbonyloxy]-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (0.58 g) and 3-morpholinopropylamine (0.73 cc), 4-acetoxy-2a-benzoyloxy-5/3, 20-epoxy-l-hydroxy-7/S, 10/?-bis[ (3-5 morpholinopropyl)carbamoyloxy]-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (0.4 g) is obtained in the form of a white porous solid, the characteristics of which product are as follows:
- optical rotation: [a]^ = -24.7° (c = 0.52; methanol) - NMR spectrum (4 00 MHz; CDC13)
S (ppm) : 1.25 (s, 3H: -CH3 16 or 17); 1.28 (s, 3H: -CH3 16 or 17); 1.41 (s, 9H: -C(CH3)3; 1.6 to 1.85 (mt, 4H: -OCONHCH2CH2CH2N=) ; 1.81 (s, 3H: -CH3 19); 1.89 (ddd, 1H, J = 15 15, 11 and 2: -(CH)-H 6); 2.0 (s, 3H: -CH3 18); 2.36 (mt, 2H: -CH2- 14); 2.36 (s, 3H: -COCH3) ; 2.4 to 2.6 [mt, 12H: -CH2N(CH2)20] ; 2.7 (mt, 1H: -(CH)-H 6); 3.15 to 3.45 (mt, 4H: -OCONHCH2CH2CH2N=) ; 3.76 [mt, 8H: -CH2N (CH2CH2) 20] ; 3.98 (d, 1H, J = 7: -H 3); 4.20 and 4.31 [2d, 1H each, J = 8: -CH2-20 20); 4.65 (d, 1H, J = 2: -H 2'); 4.98 (broad d, 1H, J = 10: -H 5); 5.3 (broad d, 1H, J = 9: -H 3'); 5.4 [d, 1H, J = 9: -NHCOOC(CH3)3] ; 5.45 (mt, 1H: -H 7) ; 5.7 (d, 1H, J = 7: -H 2); 5.6 to 6.2 (unresolved peaks, 2H: -NHCH2CH2CH2N=) ; 6.22 (t, 1H, J = 9: -H 13); 6.38 (s, 1H: -H 10); 7.3 to 7.5 (mt, 25 5H: -CeHj 3')} 7.51 [t, 2H, J = 7.5; -OCOC6H5(-H 3 and -H
)]; 7.62 [t, 1H, J = 7.5: -OCOC6H5(-H 4)]; 8.11 [d, 2H, J = 7.5: -OCOC6H5(-H 2 and -H 6)].
Distilled water (0.4 cc) is added to a solution
24 35 4 8
34
of 4-acetoxy-2a-benzoyloxy-5/3, 2 0-epoxy-l-hydroxy-7/3,10/3-bis[(3-morpholinopropyl)carbamoyloxy]-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (11.5 mg), obtained above, in 0.1N aqueous 5 hydrochloric acid solution (0.2 cc), and the solution obtained is lyophilised. 4-Acetoxy-2a-benzoyloxy-5/3,20-epoxy-l-hydroxy-7/3,10/3-bis[ (3-
morpholinopropyl)carbamoyloxy]-9-oxo-ll-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-10 phenylpropionate dihydrochloride (12 mg) is thereby obtained, the characteristics of which product are as follows:
- NMR spectrum (400 MHz; D20/CH3C00D, 90:10 by volume)
S (ppm) : 0.85 (s, 3H: -CH3 16 or 17); 0.9 (s, 3H: -CH3 16 or 15 17); 1.1 (s, 9H: -C(CH3)3; 1.5 (s, 3H: -CH3 19); 1.6 to 1.8 (m, 10H: — CH3 18, -OCONHCH2CH2CH2N=, -CH2- 14, - (CH) -H 6); 2.1 (s, 3H: -C0CH3) ; 2.3 (m, 1H: -(CH)-H 6); 2.8 to 3.10 (vbm, 12H: -CH2N (CH2CH2) 20) ; 3.3 (bm, 4H: -OCONHCH2CH2CH2N=) ; 3.6 (bm, 4H: -CH2N (CH2CH2) 20) ; 3.85 (bm, 4H: -CH2N (CH2CH2) 20) ; 20 4 and 4.15 (bd, AB, 2H: -CH2- 20); 4.4 (bd, 1H: -H 2');
4.75 (bs, 1H: -H 3'); 4.9 (bd: 1H: -H 5); 5.1 (bdd, 1H: -H 7); 5.35 (bd, 1H: -H 2); 5.8 (bt, 1H: -H 13); 6.04 (s, 1H: -H 10); 7.0 to 7.25 (m, 5H: -C^ 3'); 7.4 [t, 2H, J = 7.5: -OCOC6H5 (-H 3 and -H 5)]; 7.52 [t, 1H, J = 7.5: -OCOC6H5 (-H 25 4)]; 7.8 [d, 2H, J = 7.5: -OCOC6H5 (-H 2 and -H 6)].
The new products of general formula (I) possess especially advantageous biological activities.
The new products of general formula (I)
24 35 4 8
manifest significant inhibitory activity towards abnormal cell proliferation, and possess therapeutic properties enabling patients having pathological conditions associated with abnormal cell proliferation to be treated. The 5 pathological conditions include the abnormal cell proliferation of malignant or non-malignant cells of various tissues and/or organs comprising, without implied limitation, muscle, bone or connective tissue, and the skin, brain, lungs, sex organs, lymphatic or renal system, 10 mammary or blood cells, liver, digestive system, pancreas and thyroid or adrenal glands. These pathological conditions can also include psoriasis, solid tumours,
cancer of the ovary, breast, brain, prostate, colon, stomach, kidney or testicles, Kaposi's sarcoma, 15 cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour, Hodgkin's disease, melanoma, multiple myeloma, chronic lymphocytic leukaemia and acute or chronic granulocytic lymphoma. The new products according to the invention are especially useful for the treatment of cancer 20 of the ovary. The products according to the invention may be used for preventing or delaying the appearance or reappearance of pathological conditions or for treating these pathological conditions.
The products according to the invention may be 25 administered to a patient according to various forms suited to the chosen administration route, which is preferably the parenteral route. Parenteral administration comprises intravenous, intraperitoneal, intramuscular or subcutaneous
24 35 48
36
administration. Intra-peritoneal or intravenous administration is more especially preferred.
The present invention also comprises pharmaceutical compositions containing at least one product 5 of general formula (I), in a sufficient amount suited to use in human or veterinary therapy. The compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants, vehicles or excipients. Suitable vehicles include diluents, sterile 10 aqueous media and various non-toxic solvents. Preferably, the compositions take the form of aqueous solutions or suspensions and of injectable solutions which can contain emulsifiers, colourings, preservatives or stabilisers.
The choice of adjuvants or excipients can be 15 determined by the solubility and the chemical properties of the product, the particular mode of administration and good pharmaceutical practice.
For parenteral administration, sterile, aqueous or non-aqueous solutions or suspensions are used. For the 20 preparation of non-aqueous solutions or suspensions,
natural vegetable oils such as olive oil, sesame oil or liquid paraffin, or injectable organic esters such as ethyl oleate, may be used. The sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt 2 5 dissolved in water. Aqueous solutions are suitable for intravenous administration provided the pH is suitably adjusted and the solution is made isotonic, e.g. with a sufficient amount of sodium chloride or glucose.
24 35 48
37
Sterilisation may be carried out by heating or by any other means which does not adversely affect the composition.
It is, of course, understood that all the products participating in the compositions according to the 5 invention must be pure and non-toxic in the amounts used.
The compositions can contain at least 0.01 % of therapeutically active product. The amount of active product in a composition is such that a suitable dosage can be prescribed. Preferably, the compositions are prepared in 10 such a way that a single dose contains from 0.01 to 1000 mg approximately of active product for parenteral administration.
The therapeutic treatment may be performed concurrently with other therapeutic treatments, including 15 antineoplastic drugs, monoclonal antibodies, immunotherapy or radiotherapy or agents that modify biological responses.
Agents that modify responses include, without implied limitation, lymphokines and cytokines such as inter leukins, interferons (a-, j3- or S-) and TNF. Other chemotherapeutic 20 agents which are useful in the treatment of disorders due to abnormal cell proliferation include, without implied limitation, alkylating agents such as nitrogen mustards, e.g. mechlorethamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulphonates such as busulphan,
2 5 nitrosoureas such as carmustine, lomustine, semustine and streptozocin, triazines such as dacarbazine, antimetabolites such as folic acid analogues, e.g.
methotrexate, pyrimidine analogues such as fluorouracil and
243548
38
cytarabine, purine analogues such as mercaptopurine and thioguanine, natural products such as vinca alkaloids, e.g. vinblastine, vincristine and vindesine, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as 5 dactinomycin, daunorubicin, doxorubicin, bleomycin,
plicamycin and mitomycin, enzymes such as L-asparaginase,
various agents such as coordination complexes of platinum, e.g. cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenal 10 cortex suppressants such as mitotane and aminoglutethimide, hormones and antagonists such as adrenocorticosteroids, e.g. prednisone, progestins, such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, oestrogens such as diethylstilboestrol and 15 ethinyloestradiol, oestrogen antagonists such as tamoxifen, and androgens such as testosterone propionate and fluoxymesterone.
The doses used to carry out the methods according to the invention are those which permit a 2 0 prophylactic treatment or a maximal therapeutic response. The doses vary according to the form of administration, the particular product selected and the distinctive characteristics of the subjects to be treated. In general, the doses are those which are therapeutically effective for 25 the treatment of disorders due to abnormal cell proliferation. The products according to the invention may be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond rapidly at
24 3 5 4 8
39
relatively high or low doses and may then require low or zero maintenance doses. In general, low doses will be used at the beginning of the treatment and, if necessary, increasingly stronger doses will be administered until an 5 optimal effect is obtained. For other patients, it may be necessary to administer maintenance doses 1 to 8 times a day, and preferably 1 to 4 times, depending on the physiological requirements of the patient in question. For some patients, it is also possible for it to be necessary 10 to use only one to two daily administrations.
In humans, the doses are generally between 0.01 and 200 mg/kg. Intraperitoneally, the doses will generally be between 0.1 and 100 mg/kg, preferably between 0.5 and 50 mg/kg and still more specifically between 1 and 15 10 mg/kg. Intravenously, the doses are generally between 0.1 and 50 mg/kg, preferably between 0.1 and 5 mg/kg and still more specifically between 1 and 2 mg/kg. It is understood that, in order to choose the most suitable dosage, the administration route, the patient's weight, 20 general state of health and age and all factors which may influence the efficacy of the treatment should be taken into account.
The example which follows illustrates the composition according to the invention.
EXAMPLE
The product obtained in Example 1 (40 mg) is dissolved in Emulphor EL 620 (1 cc) and ethanol (1 cc), and the solution is then diluted by adding physiological saline
24 3 5 4 8
40
(18 cc).
The composition is administered by introduction into a perfusion of a physiological solution for 1 hour.
41
Claims (8)
1. A taxol analogue of formula: 24 35 48 R-CONH o OCOC6H5 (I) in which: 5 Ar represents an aryl radical, R represents - a radical of formula: Rv0- (II) in which R7 represents a linear or branched alkyl radical 10 containing 1 to 8 carbon atoms, an alkenyl radical . containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicyclo-alkyl radical 15 containing 7 to 10 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains l to 4 carbon atoms, 20 piperidino or morpholino radicals, 1-piperazinyl radicals (optionally substituted at the 4-position with an alkyl 24 3 5 42 radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl, cyano and carboxyl radicals and alkyloxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, - or a phenyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms and alkyloxy radicals containing 1 to 4 carbon atoms, - or a saturated or unsaturated 4- or 6-membered nitrogenous heterocyclic radical optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms each, the said cycloalkyl, cycloalkenyl and bicycloalkyl radicals being optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms each, Rt and R2, which may be identical or different, represent a hydrogen atom or a radical of formula: t 1 FEBJ994, NCO (III) in which R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in a linear or branched chain, optionally 24 3 54 8 43 substituted: a) by a hydroxyl or carboxyl radical or an alkyloxy-carbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms and is optionally substituted by a phenyl 5 radical, or b) by a radical of formula: *5^ (IV) N R/ 6 in which R5 and Rj, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 10 to 4 carbon atoms in a linear or branched chain, or alternatively Rs and R^, together with the nitrogen atom to which they are linked, form a saturated or unsaturated 5-or 6-membered heterocycle optionally containing a second hetero atom chosen from nitrogen atoms (optionally 15 substituted by an alkyl radical containing 1 to 4 carbon atoms or a benzyl radical), oxygen atoms and sulphur atoms, or alternatively R3 and R4, together with the nitrogen atom to which they are linked, form a saturated or unsaturated 5- or 6-membered heterocycle optionally containing a sepdnd" if 20 hetero atom chosen from nitrogen atoms (optionally / 1 11 FEB 1994 £ substituted by an alkyl radical containing 1 to 4 carbon "V ^ // atoms or a benzyl radical), oxygen atoms and sulphur atorffe^,^ at least one of the symbols R, or R2 representing a radical of formula (III) , and, where they exist, its acid addition 25 salts.
2. A process for preparing a taxol analogue according to claim 1, which comprises reacting an amine of formula: r: NH (v) 5 in which R3 and R4 are as defined in claim 1, with a taxane derivative of formula: 10 ci3cch2ocoo_ r-conh o Ar'SA° oh 0 OCOOCH2CC)3 Vk (VI) ho "v 0C0CH3 OCOCgHj in which R and Ar are as defined in claim l, to obtain a product of formula: r-conh o (VII) 0C0CgH5 in which R and Ar are as defined above and and G2 each represent a radical of formula (III) where formula (III) is as defined in claim 1 or a protective group (CCl3CH2OCO-), provided that at least one of the radicals and G2 represents a radical of formula (III) as defined in claim 1, 15 followed, if necessary, by replacement of the protective group(s) (CCl3CH2OCO-) by a hydrogen atom, the products of formula - 45 - (I) are separated from the mixture thereof, and the separated product obtained is isolated, optionally in the form of a salt.
3. Process according to claim 2, wherein the amine 5 of formula (V) is reacted with the taxane derivative of formula (VI), in an inert organic solvent at a temperature between 0°C and the boiling point of the reaction mixture.
4. Process according to claim 3, wherein the inert organic solvent is a halogenated aliphatic hydrocarbon. 10
5. Process according to claim 3 or 4, wherein replacement of the protective 2,2,2-trichloroethoxy-carbonyl group by a hydrogen atom is performed using zinc in acetic acid, optionally in the presence of methanol, at a temperature of between 30 and 80°C. 15
6. Process for the preparation of a taxol analogue according to claim 1 substantially as described in any one of the Examples.
7. A taxol analogue according to claim 1 when produced by a process as claimed in any of claims 2 to 6. 20
8. A pharmaceutical composition which contains a taxol analogue according to claim 1 or 7, and one or more pharmaceutically acceptable, inert or pharmacologically active diluents or adjuvants. AaogjLJgriC, By the authorised agents A J PARK & SON
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9108937A FR2679230B1 (en) | 1991-07-16 | 1991-07-16 | NOVEL DERIVATIVES OF TAXOL ANALOGS, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ243548A true NZ243548A (en) | 1994-07-26 |
Family
ID=9415141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ24354892A NZ243548A (en) | 1991-07-16 | 1992-07-14 | Taxol analogues, preparation and pharmaceutical compositions |
Country Status (17)
| Country | Link |
|---|---|
| EP (2) | EP0596010A1 (en) |
| JP (1) | JPH06509107A (en) |
| AU (1) | AU2388092A (en) |
| CA (1) | CA2113074A1 (en) |
| CZ (1) | CZ9094A3 (en) |
| FI (1) | FI940191A0 (en) |
| FR (1) | FR2679230B1 (en) |
| HU (1) | HUT66600A (en) |
| IE (1) | IE922305A1 (en) |
| MX (1) | MX9204140A (en) |
| NO (1) | NO934723L (en) |
| NZ (1) | NZ243548A (en) |
| SK (1) | SK4894A3 (en) |
| TW (1) | TW201740B (en) |
| WO (1) | WO1993002065A1 (en) |
| YU (1) | YU69892A (en) |
| ZA (1) | ZA925245B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5646176A (en) * | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5654447A (en) * | 1991-09-23 | 1997-08-05 | Florida State University | Process for the preparation of 10-desacetoxybaccatin III |
| US5710287A (en) * | 1991-09-23 | 1998-01-20 | Florida State University | Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them |
| US5721268A (en) | 1991-09-23 | 1998-02-24 | Florida State University | C7 taxane derivatives and pharmaceutical compositions containing them |
| US6011056A (en) | 1991-09-23 | 2000-01-04 | Florida State University | C9 taxane derivatives and pharmaceutical compositions containing them |
| US5998656A (en) * | 1991-09-23 | 1999-12-07 | Florida State University | C10 tricyclic taxanes |
| US5714513A (en) * | 1991-09-23 | 1998-02-03 | Florida State University | C10 taxane derivatives and pharmaceutical compositions |
| US6028205A (en) * | 1991-09-23 | 2000-02-22 | Florida State University | C2 tricyclic taxanes |
| US5728725A (en) * | 1991-09-23 | 1998-03-17 | Florida State University | C2 taxane derivaties and pharmaceutical compositions containing them |
| US6018073A (en) * | 1991-09-23 | 2000-01-25 | Florida State University | Tricyclic taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
| US5489601A (en) * | 1991-09-23 | 1996-02-06 | Florida State University | Taxanes having a pyridyl substituted side-chain and pharmaceutical compositions containing them |
| US5739362A (en) * | 1991-09-23 | 1998-04-14 | Florida State University | Taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
| US5728850A (en) * | 1991-09-23 | 1998-03-17 | Florida State University | Taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
| US6794523B2 (en) | 1991-09-23 | 2004-09-21 | Florida State University | Taxanes having t-butoxycarbonyl substituted side-chains and pharmaceutical compositions containing them |
| US6335362B1 (en) | 1991-09-23 | 2002-01-01 | Florida State University | Taxanes having an alkyl substituted side-chain and pharmaceutical compositions containing them |
| US6005138A (en) * | 1991-09-23 | 1999-12-21 | Florida State University | Tricyclic taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
| US6495704B1 (en) | 1991-09-23 | 2002-12-17 | Florida State University | 9-desoxotaxanes and process for the preparation of 9-desoxotaxanes |
| US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5272171A (en) * | 1992-02-13 | 1993-12-21 | Bristol-Myers Squibb Company | Phosphonooxy and carbonate derivatives of taxol |
| US5294637A (en) * | 1992-07-01 | 1994-03-15 | Bristol-Myers Squibb Company | Fluoro taxols |
| US5614549A (en) * | 1992-08-21 | 1997-03-25 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| US5380751A (en) * | 1992-12-04 | 1995-01-10 | Bristol-Myers Squibb Company | 6,7-modified paclitaxels |
| US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5981568A (en) | 1993-01-28 | 1999-11-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| WO1994020485A1 (en) * | 1993-03-05 | 1994-09-15 | Florida State University | Process for the preparation of 9-desoxotaxanes |
| US6710191B2 (en) | 1993-03-05 | 2004-03-23 | Florida State University | 9β-hydroxytetracyclic taxanes |
| US5547981A (en) * | 1993-03-09 | 1996-08-20 | Enzon, Inc. | Taxol-7-carbazates |
| US5703247A (en) * | 1993-03-11 | 1997-12-30 | Virginia Tech Intellectual Properties, Inc. | 2-Debenzoyl-2-acyl taxol derivatives and methods for making same |
| DE69433146T2 (en) * | 1993-06-11 | 2004-06-09 | Pharmacia & Upjohn Co., Kalamazoo | Delta 6,7-taxol derivatives antineoplastic compounds and pharmaceutical compositions containing them |
| CA2129288C (en) * | 1993-08-17 | 2000-05-16 | Jerzy Golik | Phosphonooxymethyl esters of taxane derivatives |
| FR2711370B1 (en) * | 1993-10-18 | 1996-01-05 | Rhone Poulenc Rorer Sa | New taxoids, their preparation and the pharmaceutical compositions containing them. |
| US5965566A (en) * | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| AU8052194A (en) * | 1993-10-20 | 1995-05-08 | Enzon, Inc. | 2'- and/or 7- substituted taxoids |
| IL112412A (en) * | 1994-01-28 | 2000-02-29 | Upjohn Co | Delta 12,13-iso-taxol analogs and antineoplastic pharmaceutical compositions containing them |
| CA2253513A1 (en) | 1996-05-06 | 1997-11-13 | Florida State University | 1-deoxy baccatin iii, 1-deoxy taxol and 1-deoxy taxol analogs and method for the preparation thereof |
| BR9710366A (en) * | 1996-07-15 | 1999-08-17 | Yakult Honsha Kk | Taxane derivatives and drugs that contain them |
| GB9705903D0 (en) | 1997-03-21 | 1997-05-07 | Elliott Gillian D | VP22 Proteins and uses thereof |
| KR100551945B1 (en) * | 1997-12-19 | 2006-02-20 | 가부시키가이샤 야쿠루트 혼샤 | Taxane derivatives |
| AR030188A1 (en) | 2000-02-02 | 2003-08-13 | Univ Florida State Res Found | TAXANO COMPOUNDS REPLACED WITH ESTERS IN C7; PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND PROCESS TO TREAT A MAMMER SUBJECT THAT SUFFERS FROM A CONDITION THAT RESPONDS TO TAXANS |
| JP2003522173A (en) | 2000-02-02 | 2003-07-22 | フロリダ・ステイト・ユニバーシティ・リサーチ・ファウンデイション・インコーポレイテッド | C10 carbamoyloxy-substituted taxanes as antitumor agents |
| CZ20013521A3 (en) * | 2000-02-02 | 2002-03-13 | Florida State University Research Foundation, Inc. | C7 carbamoyloxy substituted taxanes functioning as antitumor substances |
| EP1451168A4 (en) | 2001-11-30 | 2005-08-24 | Bristol Myers Squibb Co | Paclitaxel solvates |
| WO2005035003A2 (en) * | 2003-09-22 | 2005-04-21 | Dihedron Corporation | Compositions and methods for increasing drug efficiency |
| PA8625301A1 (en) | 2004-03-05 | 2006-06-02 | Univ Florida State Res Found | TAXANOS WITH SUBSTITUTE LACTILOXILO IN C7 |
| CN104650012A (en) * | 2013-11-22 | 2015-05-27 | 天士力控股集团有限公司 | Taxane compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2601675B1 (en) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | TAXOL DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1991
- 1991-07-16 FR FR9108937A patent/FR2679230B1/en not_active Expired - Fee Related
-
1992
- 1992-07-14 NZ NZ24354892A patent/NZ243548A/en unknown
- 1992-07-14 TW TW081105531A patent/TW201740B/zh active
- 1992-07-14 ZA ZA925245A patent/ZA925245B/en unknown
- 1992-07-15 IE IE230592A patent/IE922305A1/en not_active Application Discontinuation
- 1992-07-15 MX MX9204140A patent/MX9204140A/en unknown
- 1992-07-15 YU YU69892A patent/YU69892A/en unknown
- 1992-07-16 SK SK48-94A patent/SK4894A3/en unknown
- 1992-07-16 CZ CS9490A patent/CZ9094A3/en unknown
- 1992-07-16 CA CA002113074A patent/CA2113074A1/en not_active Abandoned
- 1992-07-16 EP EP92916744A patent/EP0596010A1/en not_active Ceased
- 1992-07-16 HU HU9400113A patent/HUT66600A/en unknown
- 1992-07-16 JP JP5502629A patent/JPH06509107A/en active Pending
- 1992-07-16 AU AU23880/92A patent/AU2388092A/en not_active Abandoned
- 1992-07-16 WO PCT/FR1992/000687 patent/WO1993002065A1/en not_active Application Discontinuation
- 1992-07-16 EP EP92402046A patent/EP0524093A1/en active Pending
-
1993
- 1993-12-20 NO NO934723A patent/NO934723L/en unknown
-
1994
- 1994-01-14 FI FI940191A patent/FI940191A0/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5646176A (en) * | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
| US6455575B2 (en) | 1992-12-24 | 2002-09-24 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| NO934723D0 (en) | 1993-12-20 |
| CA2113074A1 (en) | 1993-02-04 |
| NO934723L (en) | 1993-12-20 |
| YU69892A (en) | 1995-10-03 |
| FR2679230A1 (en) | 1993-01-22 |
| FI940191A (en) | 1994-01-14 |
| CZ9094A3 (en) | 1994-06-15 |
| SK4894A3 (en) | 1994-12-07 |
| EP0524093A1 (en) | 1993-01-20 |
| FI940191A0 (en) | 1994-01-14 |
| HUT66600A (en) | 1994-12-28 |
| FR2679230B1 (en) | 1993-11-19 |
| ZA925245B (en) | 1993-04-28 |
| AU2388092A (en) | 1993-02-23 |
| TW201740B (en) | 1993-03-11 |
| JPH06509107A (en) | 1994-10-13 |
| HU9400113D0 (en) | 1994-05-30 |
| IE922305A1 (en) | 1993-01-27 |
| WO1993002065A1 (en) | 1993-02-04 |
| EP0596010A1 (en) | 1994-05-11 |
| MX9204140A (en) | 1993-01-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NZ243548A (en) | Taxol analogues, preparation and pharmaceutical compositions | |
| KR950006153B1 (en) | Taxol derivatives, their preparation and pharmaceutical compositions containing them | |
| AU704663B2 (en) | Taxoids, preparation thereof and pharmaceutical compositions containing same | |
| AP753A (en) | Novel taxoids, preparation thereof and pharmaceutical compositions containing same. | |
| KR100500351B1 (en) | Taxoid, preparation method thereof and pharmaceutical composition containing same | |
| US5847170A (en) | Taxoids, their preparation and pharmaceutical compositions containing them | |
| SK92794A3 (en) | Baccatine iii and 10-deacetyl baccatine iii derivatives, their preparation and pharmaceutical compositions containing same | |
| AU715228B2 (en) | Taxoids, preparation thereof and pharmaceutical compositions containing same | |
| US6372780B2 (en) | Methods of treating cell lines expressing multidrug resistance P-glycoprotein | |
| CZ287430B6 (en) | Taxoids, process of their preparation and pharmaceutical composition in which said taxoids are comprised | |
| US5840931A (en) | Taxoids, their preparation and pharmaceutical compositions containing them | |
| MXPA97007427A (en) | New taxoids, its preparation and the pharmaceutical compositions that contain them | |
| CZ285294A3 (en) | Novel derivatives of taxan, process of their preparation and pharmaceutical composition containing thereof | |
| US6232477B1 (en) | Methods of preparing new taxoids and pharmaceutical compositions containing them | |
| US6410756B1 (en) | Family of Canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof | |
| SK280950B6 (en) | Taxoids, preparation methods and pharmaceutical compositions containing them |