Title of Invention

"NOVEL ARTEMISININE DERIVATIVES AND USES THEREOF FOR TREATING MALARIA"

Abstract A subject of the present invention is new artemisinin derivatives, of following general formula (I): In which: - a and b represent a single or a double bond, - n1 and n2 represent 0 or 1, - R1 represents a fluoroalkyl group or a fluoroaryl group, - R2 represents a hydrogen atom, or a halogen atom, or a group, if appropriate ionisable, making it possible to render said compounds of formula (I) water-soluble, - R3 represents a group, if appropriate ionisable, making it possible to render said compounds of formula (I) water-soluble, - R4 represents H or OH. The invention also relates to the process by which they are obtained, and their uses in pharmaceutical compositions intended for the treatment of malaria. (no drawing)
Full Text A subject of the present invention is new derivatives of artemisinin, a process for obtaining them, and their uses in pharmaceutical compositions intended for the treatment of malaria.
The rapid development of the phenomenon of resistance to anti-malarial drugs is particularly alarming because of its considerable consequences in Africa and South-East Asia. New medicaments must urgently be discovered for the treatment of malaria from multi-drug resistant Plasmodium falciparum.
In addition to the current need for effective malarial therapies, are added the mandatory costs linked with the localization of the epidemic in poorer countries. Artemisinin is a natural, inexpensive compound, extracted from a plant Artemisia annua, used in traditional Chinese medicine against malaria.
Artemisinin (ART) has appeared to be a promising medicament against these resistant strains; its effectiveness is however limited by a very short plasmatic half-life, and low activity by oral route.
By taking into account the specific properties provided by the presence of fluorinated groups (Rf), the Inventors have conceived and prepared fluorinated analogues of dihydroartemisinin (DHA) by hemisynthesis, by introducing a fluoroalkyl group on the strategic C-10 carbon, in order to slow down the various processes of the metabolism (oxidation, hydrolysis and glucuronidation) which take place on this site and thus to prolong the duration of the action of the compounds (Truong Thi Thanh Nga et al., 1998, J. Med. Chem., 41, 4101-4108). These fluoro artemisinins (F-ART) are more active than artemisinin and artesunate in vivo in mice. The survival rate is 100 %. The preliminary results of pharmacokinetic studies seem to validate the hypothesis on the extension of the plasmatic half-life of an artemisinin derivative by the introduction of a fluorinated substituent on the C-10 site.
The problem of the insolubility in water of these compounds which limits the effectiveness of administration by oral route remains to be solved. A new generation of fluorinated derivatives of artemisinin had to be envisaged and synthesis found


allowing the presence of a fluoroalkyl group in C-10 and the introduction of a function, which is if appropriate ionisable (amine, acid etc.), making it possible to render these compounds water-soluble.
The present invention follows on from the highlighting by the Inventors, that it is possible to prepare new artemisinin derivatives, substituted both by a fluoroalkyl group in C-10, which has proved to extend the period of action of artemisinin, and by a function, if appropriate ionisable, on the carbon in position 10 or 16, which allows solubility in water and therefore easy administration by oral route.
The present invention has consisted of finding a chemical means of introducing an ionisable function on artemisinin derivatives fluorinated in C-10. Difficulties in synthesis have resided in the following facts: i) The starting products have few anchorage points allowing the introduction of new functions without harming activity; ii) The presence of fluorine in the molecules considerably alters its chemical reactivity.
The inventors have been able to resolve the problem, by preparing allylic bromide in C-9, a key product which allows the introduction of any other function, and thus by using inexpensive chemical reagents. Compounds which are water-soluble allow administration by oral route, which*facilitates the treatment of malaria.
The invention relates to compounds of following general formula (I):
(Formula Removed)
In which:
- a and b represent a single or a double bond, provided that a and b can not both represent a double bond,
- nl and n2, independently from one another, represent 0 or 1, provided that when a represents a double bond then nl=n2=0 and when b represents a double bond then nl=0,
- R1 represents:
- A fluoroalkyl group of approximately 1 to approximately 5 carbon atoms, and comprising at least two fluorine atoms, such as the following perfluoroalkyl groups: CF3, C2F5, C3F7, C4F9, and C5F11,
- Or a fluoroaryl group comprising at least two fluorine atoms, such as the C6F5 perfluoroaryl group,
- Or a CF2 group when b represents a double bond and n1=0,

- R2 represents a hydrogen atom, or a halogen atom, such as Br, or a group, if appropriate ionisable, making it possible to render said compounds of formula (I) water-soluble, such as the groups derived from piperazine, morpholine, alkylamine, alkoxy, ester or diester, acid or diacid, thioalkyl, alkylhydroxyl, or glycosyl,
- R3 represents a group, if appropriate ionisable, making it possible to render said compounds of formula (I) water-soluble, such as:
. An OR group in which R represents H, or an alkyl group of approximately 1 to 10 carbon atoms, if appropriate substituted, in particular a group of formula -(CH2)n-R5 in which n represents an integer from 1 to 5, and R5 represents: CF3, OH, -CH=CH2, COOH, COH, CHOH-CH2OH, or a phenyl group, if appropriate substituted, in particular by CH2OH,
. NH2, or a NH-R6 group in which R6 represents an alkyl or alkoxy group of 1 to 5 carbon atoms, or an arylalkyl or arylalkoxy group, such as the -NH-C6H5-OCH3,
- R4 represents H or OH.
A more particular subject of the invention is compounds of general formula (Ia) corresponding to abovementioned formula (I) in which a represents a double bond, b represents a single bond, and nl=n2=0, namely compounds of following formula:
(Formula Removed)
In which:
- R1 represents:
- A fluoroalkyl group of approximately 1 to approximately 5 carbon atoms, and comprising at least two fluorine atoms, such as fee following perfluoroalkyl groups: CF3, C2F5, C3F7, C4F9, and C5Fn,
- Or a fluoroaryl group comprising at least two fluorine atoms, such as the perfluoroaryl group C6F5,
- R2 represents a halogen atom, such as Br, or a group, if appropriate ionisable,
making it possible to render said compounds of formula (I) water-soluble, such as the
groups derived from piperazine, morpholine, alkylamine, alkoxy, ester or diester, acid
or diacid, thioalkyl, alkylhydroxyl, or glycosyl,
A subject of the invention is also the compounds of formula (Ia-bis), corresponding to the abovementioned compounds of formula (I) in which R2 represents a group, if appropriate ionisable, making it possible to render said compounds water-soluble.
A more particular subject of the invention is the compounds of formula (Ia-bis) in which R2 represents:
- A group derived from piperazine, if appropriate substituted by an amine, alcohol,
or acid function, such as the piperazine ethanol group of formula,
(Formula Removed)
- Or a morpholino group of formula,
(Formula Removed)
- Or an alkylamine group of approximately 1 to approximately 10 carbon atoms, if
appropriate substituted by a hydroxyl, such as the ethylamine group of formula -NH-
CH2-CH3, or the -NH-CH2-CH2-OH group,
- Or an alkoxy group of approximately 1 to approximately 10 carbon atoms, if appropriate substituted by a hydroxyl or amine function, such as the ethoxy group of formula -O-CH2-CH3, the -O-CH2-CH2-OH group, or the -O-CH2-CH2-NHR group in which R represents an alkyl group of 1 to 5 carbon atoms,
- Or an alkyl group of approximately 1 to approximately 10 carbon atoms, substituted by one or more -COOR functions in which R represents H or an alkyl,
alkylamine, or alkylhydroxy group, of approximately 1 to approximately 4 carbon atoms, such as the group of formula
(Formula Removed)
in which Ra and Rb represent H or CH3,
- or a thioalkyl group of approximately 1 to approximately 6 carbon atoms, such as the group of formula -S-CH2-CH3,
- or an alkylhydroxyl group of approximately 1 to approximately 10 carbon atoms,
- or a glycosyl group such as glucuronic acid or other nonasaccharides.
The invention more particularly relates to the abovementioned compounds, of formula (I) or (Ia) in which R1 represents CF3, C2F5, C3F7, or C6F5.
A more particular subject of the invention is the abovementioned compounds of formula (Ia), corresponding to the following formulae:
(Formula Removed)
The invention also relates to compounds, of general formula (Ib) corresponding to formula (I) in which a and b represent a single bond, and nl=n2=l, namely compounds of following formula:
(Formula Removed)
In which:
- R1 represents:
- A fluoroalkyl group of approximately 1 to approximately 5 carbon atoms, and comprising at least two fluorine atoms, such as the following perfluoroalkyl groups: CF3, C2F5, C3F7, C4F9, and C5F11,
- Or a fluoroaryl group comprising at least two fluorine atoms, such as the perfluoroaryl group C6F5,
- R2 represents a hydrogen atom, or a halogen atom, such as Br, or a group, if
appropriate ionisable, making it possible to render said compounds of formula (I) water-
soluble, such as the groups derived from piperazine, morpholine, alkylamine, alkoxy,
ester or diester, acid or diacid, thioalkyl, alkylhydroxyl, or glycosyl,
- R3 represents:
. An OR group in which R represents H, or an alkyl group of approximately 1 to 10 carbon atoms, if appropriate substituted, in particular a group of formula -(CH2)n-R5 in which n represents an integer from 1 to 5, and R5 represents: CF3, OH, -CH=CH2, COOH, COH, CHOH-CH2OH, or a phenyl group, if appropriate substituted, in particular by CH2OH,
. NH2, or a NH-R5 group in which R5 represents an alkyl or alkoxy group of 1 to 5 carbon atoms, or an arylalkyl or arylalkoxy group, such as the -NH-C6H5-OCH3,
- R4 represents H or OH.
A more particular subject of the invention is compounds of abovementioned general formula (Ib) in which R1 represents CF3, R2 and R4 represent a hydrogen atom, and R3 is such as defined above, namely compounds of following formula:

(Formula Removed)
The invention more particularly relates to compounds of abovementioned formula (Ib), corresponding to following formulae:
(Formula Removed)
A subject of the invention is also compounds of general formula (Ic) corresponding to abovementioned formula (I), in which a represents a single bond, b represents a double bond, nl=0, n2=l, namely compounds of following formula:
(Formula Removed)
In which:
- R1 represents a CF2 group,
- R2 represents a hydrogen atom, or a halogen atom, such as Br, or a group, if appropriate ionisable, making it possible to render said compounds of formula (I) water-soluble, such as the groups derived from piperazine, morpholine, alkylamine, alkoxy, ester or diester, acid or diacid, thioalkyl, alkylhydroxyl, or glycosyl,
- R4 represents H or OH.
A more particular subject of the invention is the compound of abovementioned formula (Ic), of following formula:
(Formula Removed)
The invention also relates to any pharmaceutical composition characterized in that it comprises at least one compound of formula (Ia) defined above, and more particularly of formulae (Ia-bis), (Ib), and (Ic), combined with a pharmaceutically acceptable vehicle.
The pharmaceutical compositions of the invention are advantageously presented in a form intended for administration by oral, injectable, or rectal route.
Preferably, the pharmaceutical compositions of the invention are characterized in that the unit dose of compounds of formula (I) as active ingredient of said compositions, is approximately 5 mg, to approximately 5 g, for a dosage of approximately 1 mg/kg/day to approximately 100 mg/kg/day.
The invention also relates to any pharmaceutical composition as defined above, characterized in that it also comprises one or more other anti-malarial compounds chosen in particular from pyrimethamine, sulfadoxine, quinine, lumefantrine, mefloquine.
A subject of the invention is also the use of a compound of formula (I) defined above, and more particularly of abovementioned formulae (Ia-bis), (Ib), and (Ic), for the preparation of a medicament intended for the treatment of malaria, and more particularly malaria caused by strains of Plasmodium falciparum resistant to
chloroquine.
The invention also relates to the products comprising:
- At least one compound of formula (I) defined above, and more particularly of abovementioned formulae (Ia-bis), (Ib), and (Ic),
- And at least one other anti-malarial compound chosen in particular from those listed above,
as a combined preparation for simultaneous, separate or sequential use in the treatment of malaria.
The invention also relates to a process for the preparation of compounds of formula (Ia) defined above, characterized in that it comprises the following stages:
-Treatment of artemisinin with a fluoroalkylating or fluoroarylating agent as defined above in the scope of the definition of R1, such as a trimethylsilane in the presence of fluoride ions, or an organolithium, which leads to the obtaining of the compound of the following formula:
(Formula Removed)
In which R1 is as defined above,
-Dehydration of the compound obtained in the previous stage, in particular by treatment with SOCl2 in pyridine, which leads to the obtaining of the following compound of formula (I):
(Formula Removed)
in which R1 is as defined above,
-Treatment of the compound obtained in the previous stage with a halogen, such as bromine, which leads to the obtaining of the following compound of formula (la):

(Formula Removed)
In which Rx represents a halogen atom, and R1 is as defined above,
-Substitution of the Rx halogen by a group, if appropriate ionisable, allowing
solubility in water as defined above, which leads to the obtaining of a compound of the
following formula (Ia-bis):
(Formula Removed)
In which R1 and R2 are as defined above.
The invention also relates to the compounds used as synthesis intermediates within the scope of the abovementioned preparation process, and corresponding to the following formulae:
(Formula Removed)
In which R1 is as defined above,
(Formula Removed)
In which Rx represents a halogen atom, and R1 is as defined above.
A subject of the invention is also a process for the preparation of compounds of formulae (Ib) and (Ic), characterized in that it comprises the treatment of the compound of following formula:
(Formula Removed)
-With the nucleophile of formula HO-R, in which R is as defined above, in the case where one wishes to obtain a compound of formula (Ib) in which R3 represents OR, or with acetonitrile in the case where one wishes to obtain a compound of formula (Ib) in which R3 represents NH2, or with NH2-R6 in which R6 is as defined above, in the case where one wishes to obtain a compound of formula (lb) in which R3 represents -NHR6, agitation at room temperature, followed by treatment of the reaction mixture with an aqueous solution of sodium bicarbonate, drying,, in particular over magnesium sulphate, and solvent evaporation, which leads to the obtaining of the compound of following formula (lb):
(Formula Removed)
In which R3 is as defined above,

-With methyllithium at 78°C under agitation, then at room temperature, followed by hydrolysis, which leads to the obtaining of compound of following formula (Ic):
(Formula Removed)
The invention will be further illustrated using the detailed description of new artemisinin derivatives, and their properties.
I Compounds of formula (Ia)
The compounds of formula (Ia) are prepared from 10-CF3 hydroartemisinin, already described by the Inventors (Truong Thi Thanh Nga et al., 1998, mentioned above), which has the following formula:
(Formula Removed)
The latter is dehydrated and the enol ether obtained reacts with Br2 in order to produce an allylic bromide which is the key intermediate being able to be substituted by various functions.
Preparation of methyl-9, CF3-10 hydroartemisinin
(Formula Removed)
Hemiketal (100mg, 2.8X10-4 mol) dissolved in pyridine (1 ml) (distilled and stored on KOH) is introduced into a flask under argon. SOCl2( 1.5 eq, 0.032 ml) is added dropwise at 0°C. The reaction mixture is agitated for 1 hour. A solution of 3N hydrochloric acid HC1 is added (5 ml), and extraction is carried out with dichloromethane. The organic solution is washed with a sodium chloride saturated solution and dried over MgSO4. Olefin is obtained in a mixture with the chlorinated derivative in a 90/10 ratio. Silica gel chromatography (petrol ether/ ethyl acetate: 95/5) leads to pure olefin in the form of white crystals (82 mg, 78%).
19F NMR 5 (ppm) -65.2 (qd, 5JFH=2.5 Hz,6 JFH=1.5 Hz, 3 F, CF3)
1H (ppm) 1.01(d, 3JH15.H6, 3 H, H15), 1.18 (m, 1 H, H7ax), 1.24 (qd, 2J = 3JH8ax-H7ax = 3JH8aX-H8a= 13 Hz, 3JH8ax-H7eq= 3 Hz 1 H, H8aX), 1.44 (s, 3 H, H14and m, 1 H, H5l), 1.45 (m, 1 H, H5), 1.46 (m, 1 H, H6)1.73 (dq, 2J =13 Hz, 3JH7eq.H6ax = 3JH7eq-H8eq = 3JH7eq-Hsax = 3 Hz, 1 H, H7eq), 1.82 (m, 1 H, H8a), 1.83 (q, 5JHF = 2.5 Hz, 3 H, H16), 1.95 (m, 1 H, H5), 2.03 (m, 1 H, H8eq), 2.05 (ddd, 2J = 14.5 Hz, 3JH4eq-H5ax = 3 Hz, 3JH4eq-H5eq = 4.5 Hz, 1 H, H4eq) 2.41 (ddd, 2J =14.5 Hz, 3JH4ax-H5ax =13 Hz, 3JH4ax. H5eq = 4 Hz, 1 H, H4ax), 5.7 (s, 1 H, H12).
13C δ (ppm) 15.5 (C16), 20.2 (C15), 24.5 (C5), 25.7 (C14), 28.9 (C8), 34.2 (C7), 36.2 (C4), 37.7 (C6), 47.5 (C8a), 50.8 (C5a), 78.5 (C12a), 90.5 (Cl2), 105.0 (C3), 112.1 (m, C9), 135 (m,C10).
MP =118 °C(EP/AcOEt)
[α] D = - 42.6° ( c= 0.54 , MeOH)
Elementary analysis C16H23F3O4 % Calculated C 57.14 6.89
% Found H 57.46 6.33
Preparation of allylic bromide
(Formula Removed)
Olefin (100mg, 3 10-4 mol) dissolved in 5 ml of carbon tetrachloride CC14 is introduced into a flask under argon at 0°C. A solution of dibromine in carbon tetrachloride (5%, 0.4 ml) is added dropwise. The reaction medium is agitated for approximately 2 hours. After washing with a solution of 38% sodium hydrogen-sulphite and extraction with diethyl ether, the solvent is evaporated, then the residue is purified by chromatography on a silica column (petrol ether/ethyl acetate: 90/10) in order to produce allylic bromide in the form of pale yellow crystals (105 mg, 88%).
19F δ (ppm) -65.8 (s, 3F, CF3)
lH 8 (ppm) 0.99 (d, 3JH15-*H6 = 6 Hz, 1 H, H15), 1.16 (ddd, 3J H7axH7eq = 13.5 Hz,
3J H7axH8ax = 11.5 Hz, 3J H7axH8eq = 3.5 nZ, 1 H, H7ax ), 1.3 (qd, J = 3J H8axH7ax = 3JH8axH8a = 13.5 HZ, 3J H8axH7eq =
3.5 Hz, 1 H, H8ax), 1.4 (m, 1 H, H6), 1.41 (s, 1 H, H16), 1.5 (m, 2 H, H5 and H5a), 1.72 (dq, 2J = 13 Hz, VH7eqH8ax = 3JH7eq = 3JH7eqH6=3.5 Hz, 1 H, H7eq), 1.96 (m, 1 H, H5), 2.04 (ddd, 2J = 15 Hz, 3JH4eqH5ax = 4.5 Hz, JH4eqH5eq = 3 Hz, 1 H, H4eq), 2.11 (dtd, 2J = 13.5 Hz, 3JH8eqH7eq = 3JH8eqH7ax = 3.5 Hz, 3JH8eqH8a = 4.5 Hz, 1 H, H8eq), 2.19 (ddd, 3JH8aH8ax = 12.5 Hz, 3JH8aH8eq = 4.4 H, 4JCF3H8 = 1.5 Hz, 1 H, H8a), 2.4 (td, 2J H4axH5ax = 3J H4axH5ax = 13.5 Hz, 3J H4axH5eq = 4 Hz, 1 H, H4aX), 4.0 (dq, 2J HaHb = 11 Hz, 5JHaCF3 = 1.5 Hz 1 H, Ha), 4.28 (dq,2J=11 Hz,5JHbCF3 = 1Hz, 1 H, Hb), 5.7 (s, 1 H, H12).
13C 5 (ppm) 20 (C15), 24.2 (C5), 25.5 (C14), 29. (CH2Br and C8), 34 (C7), 36 (C4), 37.5 (C6), 44.0 (C8a), 50.5 (C5a), 77(C12a), 91 (C12), 105 (C3), 112 (C9), 139
(C10).
MP = 119.5 oC(EP/Et2O).
Elementary analysis C16H22O4F3Br % Calculated C, 46.28 H, 5.34
% Found C, 46.17 H, 5.10
Substitution by piperazine ethanol
(Formula Removed)
Allylic bromide (100 mg, 2.4 10-4 mol) in 8 ml of THF is introduced into a flask under argon and at 0°C, then piperazine ethanol is added dropwise (126 mg, 2 eq). The mixture is agitated whilst allowing the temperature to rise. The evolution of the reaction is followed by CCM. After 5 hours, the medium is taken up with a sodium chloride saturated solution. The aqueous phase is extracted with Et2O ( 3x10 ml), then the organic phase is dried over MgS04 and the compound (110 mg) is obtained in the form of light brown crystals with a yield of 98% and with >95% purity. The compound is recrystallized in a petrol ether/AcOEt mixture.
NMR 19F δ (ppm) -63.1(s, 3F, CF3)
1H δ (ppm) 0.97 (d, 3JH15H6 = 5.5 Hz, 3 H, H 15), 1.4 (s, 3 H, H14), 1.98 (td, 3JH4axH5ax = 2J = 13.5 Hz, 3JH4axH5eq = 3.5 Hz, 1 H, H4ax), 2.51 (m, 8 H), 2.84 (s br, 1 HOH), 3.05 (s br, 2 H), 3.58 (t, 3JH22H21 = 5.5 Hz, 2 H, H22), 5.69 (s, 1 H, H12).
13C δ (ppm) 20.1 (C15); 24.4 (C5); 25.5 (CI4); 28.7 (C8); 33.9 (C7); 36.0 (C4); 37.5 (C6); 42.0 (C8a); 42.9 (C16), 50.3 (C5a); 52.5, 54.1, 57.7, 59.2, 77.9 (C12a); 90.8 (C12); 104.9 (C3); 113.5 (C9); 138 (C10), CF3 not observed. Melting point (EP/AcOEt) = 126 °C Elementary analysis C22 H 35 O5 F3 N2
% Calculated C, 56.88 H, 7.59 N, 6.03
% Found C, 56.08 H, 7.21 N, 5.27
Hydrochloride: Melting point: 158°C
Solubility in water greater than 50 mg/ml NMR 19F δ (ppm) -63.1(s, 3F, CF3)
Substitution by morpholine
(Formula Removed)
Morpholine (126 mg, 2 eq) is added dropwise, under argon, at 0 °C, to a solution of allylic bromide (500 mg, 0.1 mmol) in THF (50 mL). The reaction mixture is agitated whilst allowing the temperature to rise. The evolution of the reaction is followed by CCM. After 7 hours, the reaction medium is hydrolysed with a NaCl saturated solution. After extraction with Et2O (3x20 mL), the organic phase is then dried over MgS04. After evaporation of the solvent, the compound is purified by silica gel chromatography (EP/AcOEt: 30/70) so as to produce an orange brown solid with morpholine (400mg, 79%).
19F δ (ppm) - 63.0 (s, 3 F, CF3)
1H δ (ppm) 0.98 (d, 3JH15-H6 = 5.5 Hz, 3 H, CH3-15), 1.4 (s, 3 H, CH3-14), 2.3 (m, 2 H), 2.5 (m, 6 H), 3.04 (m , 3J = 13.5 Hz, 5J CH2-CF3 = 2 Hz, 2 H), 3.65 (m,4H),5.7(s, 1 H, H-12).
13C δ (ppm) 20.0 (C-15), 24.3 (C-5), 25.4 (C-14), 28.6 (C-8), 33.9 (C7), 37.5 (C-4 and C-6), 41.9 (C-8a), 42.9 (C-16), 53.0, 54.4, 67.1, 50.3 (C-5a), 77.8 (C-12a), 90.8 (C-12), 104.8 (C-3), 113.1 (C-9), 137.6 (q, 2J C-F = 34 Hz, C-10), CF3 not observed.
[α]33D= + 67.4 (c = 0.9, MeOH). Elementary analysis C20H30O5 F3 N
% Calculated C, 56.99 H, 7.17 N, 3.32
% Found C, 55.42 H, 6.72 N, 3.09
Hydrochloride: Melting point: 110°C
Solubility in water greater than 20 mg/ml 19F δ(ppm) -63.0(s, 3 F, CF3)
Substitution by ethylamine
(Formula Removed)
A solution of 2 M ethylamine (0.36 mL, 3eq) in THF is added slowly at 0°C to a solution of allylic bromide (100 mg, 0.25 mmol) in THF (5 mL). The mixture is agitated whilst allowing the temperature to rise. The evolution of the reaction is followed by CCM. The solution is agitated for 8 hours then hydrolyzed with a sodium chloride saturated solution. After extraction in E^O (4x5 mL), the organic phase is dried over MgS04. After evaporation of die solvent, the compound is purified by silica gel chromatography (EP/AcOEt: 50/50) so as to produce a yellow oil (64 mg, 68%).
19F δ (ppm) - 63.2 (s, 3F, CF3)
1H δ (ppm) 0.97 (d, 3J H15-H6 = 5.5 Hz, 3 H, CH3-15), 1.1 (t, 3J CH3-CH2 = 7 Hz, 3 H, CH3), 1.4 (s, 3 H, CH3-14), 2.3 (m, 2 H), 3.25 (d, 2JHa-Hb = 13.5 Hz, 1 H, Ha), 3.5 (d,2Ja = 13.5 Hz, Hb), 5.7 (s, 1 H, H-12).
13C δ (ppm) 14.5 (C-18), 20.0 (C-15), 24.3 (C-5), 25.5 (C-14), 28.9 (C-8), 33.8 (C-7), 36 (C-4), 37.5 (C-6), 42.5 (C-16), 42.6 (C-8a), 43.0, 50.2 (C-5a), 77.8 (C-12a), 90.9 (C-12), 105.0 (C-3), 114.2 (C-9), C-10 and CF3 not observed.
[α]33D= + 55.6° (c = 0.9, MeOH).
Elementary analysis C18H28O4F3N:
% Theoretical C, 56.98 H, 7.43 N, 3.69
% Experimental C, 55.25 H, 6.81 N, 2.99
19Fδ(ppm)-63.1(s, 3 F, CF3)
Substitution by ethanol FC 487
(Formula Removed)
Allylic bromide (100 mg, leq, 0.24 mmol) and 10 % (4 mg) of KI are added at 0°C to a solution of sodium ethylate in THF prepared under argon from ethanol (0.03 ml, 2 eq, 0.5 mmol) and NaH (2 eq, 20 mg) in 10 ml of THF. The mixture is agitated for approximately 17 hours at ambient temperature then hydrolysed with a NaCl saturated solution. After extraction with Et2O, the organic phase is dried over MgSO4. After evaporation of the solvent, the residue is purified by rapid filtration on silica gel (EP/AcOEt: 95/5) in order to produce a white solid (85 mg, 95 %).
19Pδ (ppm) - 64.06 ppm ( s, 3F, CF3)
1H δ (ppm) 0.98 (d, 3J H15-H6 = 5.5 Hz, 3 H, CH3-15), 1.18 (t, 3JCH3-H2= 7 Hz, 3H, CH3), 1.4 (s, 3 H, CH3-14), 3.3 (qd, 3JHa-H3 = 7 Hz, 2JHa-Hb = 9 Hz, 1 H, Ha), 3.5 ( qd, 3JHb-CH3 = 7 Hz, 2J = 9 Hz, 1 H, Hb), 4.1 (s, 2 H, CH2, 5.7 (s, 1 H, H-12).
I3C δ (ppm) 15.1 (CH3), 20.2 (C-15), 24.4 (C-5), 25.5 (C-14), 28.9 (C-8), 9 (C-7), 35.9 ( C-4), 37.5 (C-6), 42.2 (C-8a), 50.4 (C-5a), 64.3 (OCHj), 65.0 (C-16), 77.7 (C-12a), 90.9 (C-12), 104.9 (C-3), 113.1 (C-9), CF3and C-10 not observed.
Melting point (EP/Et2O) = 52 °C.
α33D= + 103.5° ( c = 0.8, MeOH).
Elementary analysis C18 H 27 O5 F3 % Calculated C, 56.83 H, 7.15
% Found C, 56.97 H, 6.98
Substitution by methyl malonate
(Formula Removed)
Methyl malonate (0.36 ml, 1.5 eq, 3 mmol) and NaH (3 eq, 140 mg) are placed under argon in 8 ml of THF at 0°C. Allylic bromide (800 mg, leq, 1.9 mmol) is then added. The mixture is agitated for 4 hours 30 minutes at ambient temperature then hydrolysed with an NaCl saturated solution. The aqueous phase is extracted with Etp, then the organic phase is dried over MgSO4. After evaporation of the solvent, the compound is purified by silica gel chromatography (EP/AcOEt: 90/10) in order to produce a white solid (810 mg) with a yield of 90 %.
19F δ (ppm) - 66.14ppm (s, 3F, CF3)
1H 6 (ppm) 0.94 (d, 3JH15-H6 = 5.5 Hz, 3 H, CH3-15), 1.35 (s, 3 H, CH3-14), 2.5 (ddq, 2JHb-Ha = 14.5 Hz, 3J Hb-CH = 6 Hz, 5J Hb-CF3 = 2 HZ 1 H, Hb), 3.0 ( ddq, 2J Ha-Hb = 14.5 Hz, 3J Ha-CH = 6 Hz, 5J Ha-CF3 = 1.5 Hz, 1 H, Ha), 3.5 (dd, 3J CH-Ha = 3JCH-Hb = 6 Hz, 1H, CH), 3.7 (s, 3 H, CH3), 3.71 (s, 3 H, CH3), 5.6 (s, 1 H, H-12).
13C δ (ppm) 19.9 (C-15), 25.4 (CH2), 25.5 (C-14), 28.7 (C-8), 33.9 (C-7), 35.9 (C-4), 37.5 (C-6), 42.1 (C-8a), 45.1 (CH), 50.2 (C-5a), 77.7 (C-12a), 90.5 (C-12), 104.8 (C-3), 112.3 (C-9), 136.8 (C-10), 168.9 (CO), 169.5 (CO), CF3 not observed.
Melting point (EP/Et2O) = 84 °C.
α26 D= + 70.7° ( c= 0.9, MeOH).
Elementary analysis C21 H 29 O8 F3 % Calculated C, 54.43 H, 6.31
% Found C, 53.90 H, 5.88
Hydrolysis to diacid
(Formula Removed)
A solution of lithium hydroxide (17 rag, 3.3eq, 0.7 mmol) in 1 mL of water is added to a solution of diester (100 mg, 0.2 mmol) in 1 mL of acetonitrile. The mixture is agitated for 5 hours at ambient temperature, then acidified with a solution of HC1 until an acid pH is obtained. After extraction with an Et2O/AcOEt mixture (2:1) and washing with a NaCl saturated solution, the organic phase is dried over MgSO4. After evaporation of the solvent, the compound is purified by silica gel chromatography (EP/AcOEt: 30/70) in order to produce a slightly ecru foam (40 mg) with a yield of 40 % (this diacid contains 8 % of diester, it has not been purified).
19F δ (ppm) -66.8 ppm (s, 3 F, CF3)
1H δ (ppm) 0.97 (d, 3JH15-H6 = 4.5 Hz, 3 H, H-15), 1.24 (s, 3 H, H-14), 2.1 (ddq, 2JHb-Ha = 15.5 Hz, 3JHb-CH = 7 Hz, 5JHb-CF3 = 1 Hz 1 H, Hb), 3.0 (ddq, 2J Ha-Hb = 15.5 Hz, 3J Ha-CH = 7 Hz, 5JHb-CF3 = 1 Hz, 1 H, Ha), 3.5 (m 3JCH-Ha, = 3JCH-Hb = 6.5 Hz, 1 H), 5.7 (s, 1 H, H-12), 8.8 (s br, 2 H, COOH).
13C δ (ppm) 19.8 (C-15), 24.2 (C-16), 25.3 (C-14), 28.7 (C-8), 33.8 (C-7), 35.8 (C-4), 37.5 (C-6), 45.3 (C-8a), 50.1 (C-17), 51.2 (C-5a), 77.5 (C-12a), 90.5 (C-12), 105 (C-3), 112 (C-9), 120.1 (q, 7= 278, CF3), 137.5 (q, 2J= 34.5, C-10), 173 (CO), 173.1 (CO), 120.1 (CF3).
Substitution by ethanethiol
(Formula Removed)
Ethanethiol (0.02 ml, 1.2 eq, 0.3 mmol) and NaH (1.2 eq, 12 mg) are placed, under argon in 10 ml of THF. Allylic bromide (100 mg, leq, 0.24 mmol) is added to the mixture. The reaction medium is agitated for 1 hour 30 minutes at ambient temperature then hydrolysed with a NaCl saturated solution. The aqueous phase is extracted with Et2O then the organic phase is dried over MgSO4. After evaporation of the solvent, the compound is purified by silica gel chromatography (EP/AcOEt: 95/5) in order to produce a colourless oil (30 mg) with a yield of 31 %. 19F δ (ppm) - 64.14ppm (s, 3 F, CF3)
lH δ (ppm) 0.99 (d, 3J H15-H6 = 6.5 Hz, 3 H, CH3-15), 1.1 (m, 1 H, H-7), 1.22 (t, 3JCH3-CH2 = 7.3 Hz, 3 H, CH3), 1.3 (m, 1 H, H-8), 1.41 (s, 3 H, CH3-14), 1.5 (m, 1 H, H-6), 1.55 (m, 1 H, H-5a), 1.7 (dq, 7 = 13 Hz, 3JH7-H8 = 3JH7-H8.= 3JH7-H6 = 3 Hz,l H, H-7'), 1.95 (m, 1 H, H-5'), 2.0 (m, 1 H, H-8'), 2.05 (m, 1 H, H-4'), 2.4 (m, 1 H, H-4), 2.49 (q, 37CH2-CH3 = 7 Hz, 2 H, CH2, 2.53 (dd, 7H8a-Hg = 7 Hz, 3JH8a-H8, = 5 Hz, 1 H, H-8a), 2.98 (dq, V = 14.5 Hz, 5JHa-CF3 = 2 Hz, 1 H, Ha), 3.74 (dq, V = 14.5 Hz, 5JHb-CF3 = 1 Hz, 1 H, Hb), 5.7 (s, 1 H, H-12)'
13C δ (ppm) 14.2 (CH3), 20.0 (C-15), 24.2 (C-5), 24.3 (CH2), 25.5 (C-14), 28.7 (C-8), 29.12 (q, J = 3 Hz, CH2-S), 33.9 (C-7), 35.9 (C-4), 37.5 (C-6), 42.5 (C-8a), 50.2 (C-5a), 77.6 (C-12a), 90.8 (C-12), 104.9 (C3), 112.5 (J=2 Hz, C-9), 120.5 (q, J = 275 Hz, CF3), 136.9 (q, J = 34 Hz, C-10). [α]33D= + 33.6° ( c = 1.1, MeOH)
II Compounds of formulae (Ib) and (Ic)
(Formula Removed)
The C-10 brominated starting compound is described in Organic Letters 2002, 4 (5), 757-759.
RMN(CDCl3): δ(ppm)
1H 0.98 (qd, 2J H7ax-H7eq = 3J H7ax-H8ax = 3J H7ax-H6 = 13.5 Hz, 3J H7ax-H8eq = 3.5 Hz, 1H, H-7ax),
1.0 (d, 3JH15-H6 = 6 Hz, 3H, CH3-15), 1.15 (d, 3JH16-H9 = 7 Hz, 3H, CH3-16), 1.35
(td, 3J H5a-H5ax = 3J H5a-H6 = 11 Hz , 3J H5a-H5eq = 6.5 HZ,1H, H-5a), 1.42 (m, 1H, H-6), 1.43 (S, 3H, CH3-14), 1.55 (tdd, 2JH5ax-H5eq, = 3JH5ax-H4ax = 13.5 Hz, 3JH5ax-H4eq= 5 Hz, 3JH5ax-H5a = 11 Hz, 1H, H-5ax), 1.68 (td, 3J H8a-H9 = 3J H8a-H8eq = 4.5 Hz, 3J H8a-H8ax = 14 Hz, 1H, H-8a), 1.78 (dq, 2J H7eq-H7ax = 13 Hz, 3J H7eq-H8ax = 3J H7eq-H8eq = 3J H7eq-H6 = 3.5 Hz, 1H, H-7eq), 1.86 (dq, 2JH8eq-H8ax = 14 Hz, 3J H8eq-H7ax = 3J H8eq-H7eq = 3J H8eq-H8a = 3.5 HZ, 1H, H-8eq), 1.95 (dddd, 2JH5eq-H5ax = 14 Hz, 3J H5eq-H5a = 6 Hz, 3J H5eq-H4ax = 4 Hz, 3J H5eq-H4eq = 3 Hz, , 1H, H-5eq ), 2.1 ( ddd, 2J H4eq-H4ax = 14.5 Hz, 3J H4eq-H5ax = 5 Hz, 3JH4eq-H5eq = 3 Hz, 1H, H-4eq), 2.29 (qd, 2J H8ax-H8eq = 3J H8ax-H7ax = 3J H8ax-H8a = 14 Hz, 3JH8ax-H7eq= 3.5 Hz, 1H, H-8ax), 2.4 (td, 2J H4ax-H4eq = 3J H4ax-H5ax = 14 Hz, 3J H4ax-H5eq = 4
Hz, 1H, H-4ax), 2.95 (qd, 3JH9-H16 = 7 Hz, 3JH9-H8a = 5.5 Hz, 1H, H-9), 5.55 (s, 1H, H-12)
13C 15.6 (C-16), 20.5 (C-15), 23 (C-8), 25 (C-5), 26 (C-14), 33.2 (C-9), 34.9 (C-7),
36.2 (C-4), 37.8 (C-6), 47 (C-8a), 52.7 (C-5a), 80 (C-12 a), 92 (C-12), 101 (C-10), 106 (C-3), CF3 not observed.
19F -77.9 (s, 3 F, CF3)
Elementary analysis for C16H22F3O4 (415.25 g.mol-1)
% Calculated C 46.30% H 5.34%
% Found C 46.24% H 5.37%
TMeltmg =116°C
[α]D = +182(0.9;MeOH)
General operating mode:
The C-10 brominated compound (415mg; 1mmol) is dissolved in dichloromethane (5mL). Hexafluoroisopropanol (520µL; 5mmol) and then the nucleophile (10mmol) are added to this solution. The reaction mixture is treated with an aqueous solution of sodium bicarbonate after 12 hours agitation at room temperature, it is dried over magnesium sulphate, and the solvent is evaporated. The product is then obtained by silica gel purification.
Substitution by methanol

(Formula Removed)
This compound is synthesised according to the general operating mode. After purification on silica gel (petrol ether/ethyl acetate 9/1) 238 mg (65%) of white crystals are obtained.
RMN(CDCl3): δ(ppm)
1H 0.92 (1H7); 0.95 (3H15; d; J15-6 = 6.2Hz); 0.98 (3H16; dq; J16-9 = 7.2Hz; J16-F =
1.2Hz); 1.25 (lH5a); 1-3 (2H6); 1.42 (3H14; s); 1.5 (lH8a); 1.5 (1H5); 1.65 (H7); 1.65 (1H8); 1.78 (1H8); 1.9 (H5); 2.03 (H4eq; ddd; J4eq-4ax = 14.6Hz; J4eq-5ax = 3.0Hz;
J4eq-5eq = 5.1Hz); 2.37 (H4ax; ddd; J4ax-4eq = 14.6Hz; J4ax-5a = 13.4Hz; J4ax-5eq = 4.1Hz); 2.83 (H9; dq; J9-16 = 7.2Hz; J9-8a = 4.9); 3.43 (3H17; q; J17-CF3 = 1.8Hz); 5.3 (H,2, s)
13C 11.9 (C16); 20.0 (C15); 23.4 (C8); 24.6 (C5); 25.6 (C14); 29.5 (C9); 34.5 (C7); 36.1 (C4); 37.4 (C6); 46.0 (C8a); 49.9 (Cl7); 52.0 (C5a); 79.8 (C12a); 89.1 (C12); 98,6 (C10; q; 2JC-F = 29Hz); 104.3 (C3); 122.5 (CF3; q; 1J C-F = 293Hz)
19F -75.5 (s, 3 F, CF3)
Elementary analysis for C17H25F3O5 (366.38 g.mol-1 )
% Calculated C 55.73% H 6.88%
% Found C 55.62% H 6.79%
TMelting = 82°C
[α]D = +135.6 (0.45; MeOH) Substitution by ethanol
(Formula Removed)
This compound is synthesised according to the general operating mode. After purification on silica gel (petrol ether/ ethyl acetate 9/1) 266 mg (70%) of white crystals are obtained.
RMN(CDCl3): δ (ppm)
1H 0.91 (3H15; d; J15-6 = 5.5Hz); 0.96 (3H,6; d; J16-9 = 7.0Hz); 1.15 (3H18; t; J18-17 =
7.1Hz); 1.35 (3H,4; s); 2.31 (1H4; m); 2.76 (H9; m); 3.61 (1H17; m); 3.84 (1H17; m); 5.27 (1H,2; s) .
13C 11.9 (C16); 15.1 (C18);19.9 (C15); 23.3 (C8); 24.5 (C5); 25.5 (C14); 29.5 (C9,); 34.5 (C7); 36.0 (C4); 37.4 (C6); 46.0 (C8a); 50.0 (C5a); 58.2 (C17); 79.8 (C12a); 89.0 (C12); 98.4 (C10; q; 2JC-F = 29Hz); 104.2 (C3); 122.4 (CF3; q; 1JC-F = 293Hz)
19F -75.7(s,3F,CF3)
Elementary analysis for C18H27F3O5 (380.41 g.mol-1)
% Calculated C 56.83% H 7.15%
% Found C 56.72% H 7.23%
TMelting = 94°C
[α]D = +106.7 (0.52; MeOH)
Substitution by trifluoroethanol
(Formula Removed)
The C-10 brominated compound (1.3g; 3.1mmol) is dissolved in trifluoroethanol (5mL), then triethylatnine (316mg; 3.1mmol) is added to this solution. The reaction mixture is diluted in ether after 12 hours agitation at room temperature, then the organic phase is washed with an aqueous solution of sodium bicarbonate, dried over magnesium
sulphate, and the solvent is evaporated. After silica gel purification (petrol ether/ethyl acetate 95/5) 458mg (34%) of white crystals are obtained.
RMN(CDCl3): δ(ppm)
1H 0.90 (lH7ax); 0.96 (3Hi5; d; J15-6= 5.9Hz); 1.04 (3H16; dq; J16-9 = 7.2Hz;
J16-CF3 = 0.9Hz); 1.30 (1H6); 1.40 (1H5); 1.42 (3H14; s); 1.55 (lH8a); 1.63 (H8); 1.69 (lH7eq; dq; J7eq-7ax = 12.9; J7eq-6 = J7eq-8ax = J7eq-8eq = 3.4Hz); 1.82 (1H8); 1.90 (H5); 2.04
(1H4eq; ddd; J4eq-4ax = 14.6Hz; J4eq-5ax = 4.5Hz; J4eq-5eq = 5.0Hz); 2.38 (1H4ax; ddd; J4ax-4eq
= 14.6Hz; J4ax-5ax = 13.6Hz; J4ax-5eq, = 4.0Hz); 2.92 (1H9; m); 3.90 (1H17; qd; J17-CF3 = 8.5Hz; J17.17 = 8.5Hz); 4.35 (1H17; qd; J17-CF3 = 8.5Hz; J,7.17 = 8.5Hz); 5.4 (1H,2, s)
13C 12.0 (C16); 20.2 (C,5); 22.9 (C8); 24.7 (C5); 25.7 (C14); 29.3 (C9); 34.7 (C7);
36.2 (C4); 37.6 (C6); 45.7 (C8a); 52.1 (C5a); 60.3 (C17; q; 1JC-F = 36Hz); 79.9 (C12a); 89.4 (C12); 99.0 (C,o; q; 2JC-F = 30Hz); 104.8 (C3); (CF3; q; 1JC-F = 291Hz); (CF3; q; 1JC-F = 277Hz)
19F -74.3 (3F; t;1JF-H = 8.5Hz); -75.9 (s, 3 F, CF3)
Elementary analysis for C18H24F6O5 (434.38 g.mol-1)
% Calculated C 49.77% H 5.57%
% Found C 49.81% H 5.61%
TMelting= 104°C
[α]D = +97.5 (0.44; MeOH)
Substitution by ethylene glycol
(Formula Removed)
The C-10 brominated compound (1.939g; 4.7mmol) is dissolved in a 1/1 mixture of THF and ethylene glycol (8mL), then triethylamine (472mg; 4.7mmol) is added to this solution. The reaction mixture is diluted by ether after 12 hours agitation at room temperature, then the organic phase is washed with an aqueous solution of sodium chloride, dried over magnesium sulphate, and the solvent is evaporated. After silica gel purification (petrol ether/ethyl acetate 9/1) 637mg (37%) of pale yellow crystals are obtained.
RMN(CDCl3): S(ppm)
1H 0.95 (3H,5; d; J15-6 = 5.8Hz); 1.01 (3Hi6; d; J16-9 = 7.3Hz); 1.42 (3H14; s); 2.37
(1H4; m); 2.86 (H9; m); 3.75 (3H; m); 3.98 (1H); 5.5 (H12)
13C 12.0 (C16); 20.1 (C15); 23.1 (C8); 24.6 (C5); 25.6 (C14); 29.6 (C9); 34.6 (C7); 36.2 (C4); 37.3 (C6); 46.0 (C8a); 52.1 (C5a); 61.6 (C17 ou 18 ); 64.4 (C17 ou 18); 80.1 (C12a); 89.1 (C12); 98.6 (C10; q; 2JC-F = 29Hz); 104.4 (C3); 122.5 (CF3; q;lJC-F = 293Hz)
19F -76.0 (s, 3 F, CF3)
Elementary analysis for C18H17F3O6 (396.41 g./nol-1;
% Calculated C 54.54% H 6.87%
% Found C 54.51 H 6.87
TMelting ~ 92°C
[α]D = +109.6 (0.44; MeOH) Substitution by acetonitrile
(Formula Removed)
The C-10 brominated compound (538g; 1.3mmol) is dissolved in acetonitrile (10mL), then succinic acid (3g; 26mmol) and triethylamine (655mg; 6.5mmol) are added to this solution. After two days agitation at room temperature, the reaction mixture is diluted with ethyl acetate and the organic phase is washed with an aqueous solution of sodium chloride, it is dried over magnesium sulphate, and the solvent is evaporated. After silica gel purification (petrol ether/ethyl acetate 5/5) 114mg (25%) of white crystals are obtained.
RMN(CDCUl3: δ(ppm)
1H 0.89 (3H15; d; J15-6 = 4.3Hz); 1.02 (3H16; d; J16-9 = 7.4Hz); 1.34 (3H14; s); 2.93 (H9; m); 5.37 (NH; s large); 5.69 (H12; s broad)
13C 12.3 (C16); 19.9 (C15); 22.9 (C8); 24.4 (C5); 25.5 (C14); 29.6 (C9); 34.3 (C7); 36.0 (C4); 37.2 (C6); 45.9 (Cga); 51.9 (C5a); 79.4 (CI2a); 89.2 (C12); 98.6 (C10; q; 2JC-F = 29Hz); 104.5 (C3); 123.1 (CF3; q; 1JC-F = Hz)
19F -79.6 (s, 3 F, CF3)
Elementary analysis for C16H24F3NO4 (351.37 g.mol-1)
%Calculated C 54.69% H6.88% N 3.99%
% Found C 53.30% H6.52% N 3.02%
TMelting = 145°C
[α]D = +134.8 (0.18; MeOH) Substitution by succinic acid
(Formula Removed)
The C-10 brominated compound (456g; l.lmmol) is dissolved in a 1/1 mixture of dichloromethane and hexafluoroisopropanol (8mL), then succinic acid (1.3g; llmmol) and triethylamine (555mg; 5.5mmol) are added to this solution. After 12 hours agitation at room temperature, the reaction mixture is diluted with ethyl acetate, then the organic phase is washed with an aqueous solution of sodium chloride, drying is performed over magnesium sulphate, and solvent is evaporated. After silica gel purification (petrol ether/ethyle acetate 8/2 then AcOEt alone) 328mg (66%) of a beige foam is obtained.
RMN(CDCl3): δ(ppm)
1H 0.94 (3H15; d; J15-6 = 5.5Hz); 1.05 (3H16; d; J16-9 - 6.9Hz); 1.40 (3H14; s);
2.34 (1H4; m); 2.62 (2H18 et 2H19; m); 2.88 (H9; m); 5.54 (H12; s); 8.39 (COOH; s broad)
13C 11.95 (C16); 20.0 (C,5); 23.0 (C8); 24.3 (C5); 25.5 (C14); 28.5 (C18; m); 29.9 (C19); 30.1 (C9); 34.4 (C7); 36.0 (C4); 37.1 (C6); 45.6 (C8a); 51.8 (C5a); 79.5 (C12a); 90.4
(C12); 102.1 (C10; q; 2JC-F = 32Hz); 104.7 (C3); 121.5 (CF3; q; 1JC-F = 289Hz); 168.5 (C17); 177.4 (C20)
19F -77.2 (s, 3 F, CF3)
Elementary analysis for C20H27F3O8 (452.43 g.mol-1)
% Calculated C 53.10% H 6.02%
% Found C 52.49% H 6.04%
Substitution by anisidine
(Formula Removed)
This compound is synthesised according to the general operating mode. After silica gel purification (petrol ether/ethyl acetate 9/1) 114mg (25%) of an orange foam is obtained.
RMN(CDCl3): δ(ppm)
1H 0.95 (3H15; d; J15-6 = 5.4Hz); 1.11 (3H16; d; J16-9 = 7.3Hz); 1.47 (3H14; s);
2.39 (1H4; m); 3.05 (H9; m); 3.63 (NH; s broad); 3.75 (3H21; s); 5.56 (H12; s); 6.81
(2HAr ;m);7.04(2HAr ;m)
l3C 12.6 (C16); 20.0 (C15); 23.5 (C8); 24.5 (C5); 25.7 (C,4); 30.1 (C9); 34.3 (C7); 36.2 (C4); 37.2 (C6); 46.3 (C8a); 52.2 (C5a); 55.2 (C21); 80.1 (C12a); 88.3 (C10; q; 2JC-F = 28Hz); 90.0 (C12); 104.3 (C3); 114.2 (C18); 119.2 (C19); 123.8 (CF3; q; 1JC-F = 294Hz); 136.4 (C17); 154.0 (C20)
19F -75.5 (s, 3 F, CF3)
Elementary analysis for C23H30F3NO5 (457.49 g.mol-1)
% Calculated C 60.38% H6.61% N3.06%
% Found C 60.22% H6.65% N2.97%
[α]D = +93.6 (0.34; MeOH)
Substitution by allylic alcohol
(Formula Removed)
This compound is synthesised according to the general operating mode. After silica gel purification (petrol ether/acetate d'ethyle 9/1) 255mg (65%) of a light yellow oil is obtained.
RMN(CDCl3): δ(ppm)
1H 0.94 (3H15; d; J15-6 = 5.8Hz); 1.01 (3Hi6; dq; J16-9 = 7.2Hz; 5JH-F = 1.3Hz); 1.41
(3H14; s); 2.37 (1H4; m); 2.85 (H9); 4.15 (1H17; dm; J17-17 = 12,8Hz); 4.35 (1H17; dd; J17-17 = 12.8Hz; J17-18 = 5.8Hz); 5.15 (lH19; dq; J19-18 = 10.3Hz; J19-19 = J19-17 = 1.6Hz); 5.28 (1H|9; dq; J19-18 = 17.3Hz; J19-19 = J19-17 = 1.6Hz); 5.31 (H12; s); 5.89 (H18; m)
13C 12.2 (C16); 20.2 (C15); 23.5 (C8); 24.7 (C5); 25.8 (C14); 29.7 (C9); 34.7 (C7); 36.2 (C4); 37.6 (C6); 46.1 (Cta); 52.1 (C5a); 63.9 (C17); 80.1 (C12a); 89.3 (Cl2); 98.7 (C10; q; 2JC-F = 29Hz); 104.5 (C3); 116.6 (C19); 122.6 (CF3; q; lJc-F = 293Hz); 134.0 (C18)
19F -75.9 (s, 3 F, CF3)
Elementary analysis for C19H27F3O5 (392.42 g.moV1)
% Calculated C 58.16% H 6.94%
% Found C % H %
Fluoride elimination
(Formula Removed)
The C-10 compound (1.223g; 2.9mmol) is dissolved in anhydrous THF (20mL), then methyl-lithium (3.7mL; 1.6M; 5.9mmol) is added at -78°C under argon. After 2 hours at low temperature agitation is performed 1 more hour at room temperature, then hydrolysis is performed with a saturated ammonium chloride solution. After silica gel purification (petrol ether /ethyle-acetate 9/1) 575mg (62%) of a pale yellow oil is ohtained.
RMN(CDCl3): δ(ppm)
1H 0.93 (3H15; dm; J15-6 = 5.7Hz); 1.06 (3H,6; t; J16-9 = 4JH-F = 7.0Hz); 1.41 (3H14;
d; JH-F = 1.4Hz); 2.35 (1H4; m); 3.23 (H9; m); 5.3 (H12)
13C 12.9 (C16; d; 4JC-F = 9.4Hz); 19.9 (C15); 21.9 (C8); 24.6 (C5); 25.5 (C14); 28.5
(C9; d; 3JC-F = 3.9Hz); 33.6 (C7); 35.8 (C4); 37.1 (C6); 46.2 (C8a; 4JC-F = 2.3Hz); 51.3 (C5a); 80.7 (C12a); 93.6 (C12; dd; 4JC-F = 2.3Hz; 4JC-F = 1.1Hz); 104.4 (C3); 114.5 (C10; dd; 2JC-F = 35Hz; 2JC-F = 14Hz); 1549 (CF2; dd; 1JC-F = 286Hz; 5JC-F = 282Hz)
19F -117.0 (1F; dm; 1JF-F= 80Hz); -98.9 (1F; dm; 1JF.F = 80Hz)
Elementary analysis for C16H22F2O4 (316.35 g.mol1)
% Calculated C 60.75% H 7.01%
% Found C 60.12% H 7.10%
Oxidation to acid
(Formula Removed)
The abovementioned allylic compound (595mg; 1.5mmol) is dissolved in a tertiary mixture of carbon tetrachloride (3mL), acetonitrile (3mL) and water (5mL). Sodium periodate (1.6g; 7.6mmol) and ruthenium trichloride (8mg; 0.03mmol) are then added to this solution. After one night the reaction mixture is diluted with ethyl acetate and the organic phase is washed with an aqueous solution of sodium bisulfite. After silica gel purification (petrol ether/ethyl acetate 7/3) 299mg (48%) of a colourless foam is obtained.
RMN(CDCl3): δ(ppm)
1H 0.91 (3H15; d; J15-6 = 5.7Hz); 1.00 (3H,6; d; J16-9 = 7.1Hz); 1.37 (3H14; s); 2.30
(1H4; m); 2.84 (H9; m); 4.18 (1H17; d; Jl7-17 = 16.4Hz); 4.62 (1H17; d; Jl7-17 = 16.4Hz); 5.44 (H12; s); 8.55 (COOH broad)
13C 12.1 (C16); 20.2 (C15); 22.8 (C8); 24.7 (C5); 25.7 (C14); 29.5 (C9); 34.7 (C7); 36.2 (C4); 37.3 (C6); 45.9 (C8a); 52.1 (C5a); 60.7 (C,7); 80.2 (C12a); 89.6 (C,2); 98.9 (C10; q; 2JC-F = 29Hz); 104.7 (C3); 122.4 (CF3; q;1 JC-F = 292Hz); 175.5 (C18)
19F -76.1(s,3F,CF3)
Elementary analysis for C18H25F3O7 (410.39g.mol-1)
% Calculated C 52.68% H 6.14%
% Found C 52.75% H 6.31%
[α]D = +71.2 (0.80; MeOH)
IR: v (cm-1) 1728 (CO); 3200 broad (COOH)
Oxidation to aldehyde
(Formula Removed)
This compound is obtained as an intermediate product of the latter reaction. Thus, operating conditions have not been optimised to obtain it as a unique compound.
RMN(CDCl3): δ(ppm)
1H 0.94 (3H,5; d; J15-6 = 5.5Hz); 1.04 (3H16; d; J16-9 = 7.1Hz); 1.39 (3H14; s); 2.35 (1H4; m); 2.88 (H9; m); 4.35 (lHn; dm; J17-17 - 18.4Hz); 4.54 (lHn; d; J17-17 = 18.4Hz); 5.28 (H12; s); 9.6 (H18)
13C 12.0 (C16); 20.1 (C15); 23.1 (C8); 24.5 (C5); 25.6 (C14); 29.4 (C9); 34.5 (C7); 36.0 (C4); 37.3 (C6); 45.6 (C8a); 51.8 (C5a); 68.4 (C17); 79.9 (C12a); 89.4 (C12); 98.8 (C10; q; 2JC-F = 29Hz); 104.6 (C3); 122.2 (CF3; q; 1JC-F = 292Hz); 197.8 (C18)
19F -76.3 (s, 3 F, CF3)
Elementary analysis for C18H25F3O6 (394.39 g.mol-1)
% Calculated C 54.82% H 6.39%
% Found C 54.71% H6.47%
[α]D =+94.0 (0.32; MeOH)
Substitution by HPU (Hydrogen Peroxide Urea)
(Formula Removed)
The C-10 brominated compound (92mg; 0.22mmol) is dissolved in dichloromethane (2mL). A solution of the hydrogen peroxide-urea complex (208mg; 2.2mmol) is then added to it in hexafluoroisopropanol (2mL). After 12 hours agitation at room temperature excess HPU is precipitated by adding diethylic ether, then filtration over silica is performed. The solvent is then cautiously evaporated. After silica gel purification (petrol ether/ethyl acetate 9/1) 59mg'(73%) of white crystals is obtained.
RMN(CDCl3): δ(ppm)
1H 0.90 (3H15; d; J15-6 = Hz); 0.94 (3H,6; d; J16_9 = 8.0Hz); 1.38 (3H14; s); 2.32
(1H4; m); 2.95 (H9; m); 5.53 (H12; s); 8.83 (OH; s)
13C 11.6 (C16); 20.0 (C15); 24.0 (C8); 24.6 (C5); 25.6 (C14); 30.1 (C9); 34.3 (C7); 36.1 (C4); 37.4 (C6); 45.4 (C8a); 51.9 (C5a); 79.9 (C12a); 89.7 (C12); (C10; q; 2JC-F = Hz); 105.0 (C3); 116.6 (C,9); 121.6 (CF3; q; 1JC-F = 290Hz)
19F -74.6 (s, 3 F, CF3)
Elementary analysis for C16H23F3O6 (368.35 g.mol-1)
% Calculated C 52.17% H 6.29%
% Found C 51.28% H 6.66%
Oxidation to diol
(Formula Removed)
The abovementioned allylic compound (396mg; l.0mmol) is dissolved in a terbutanol (20mL) water (2mL) mixture. N-oxide morpholine (150mg; l.lmmol) and osmium tetraoxide (13mg; 0.05mmol) are then added to this solution. After 3 hours, the reaction mixture is diluted with ethyl acetate, then the organic phase is washed successively with a sodium bisulfite aqueous solution, a sodium bicarbonate solution, and a sodium chloride solution. After silica gel purification (petrol ether/ethyl acetate 8/2) 257mg (60%) of a colourless foam is obtained.
RMN (CDCl3): δ(ppm)
1H 0.94 (3Hl5; d; J15-6 = 5.8Hz); 1.00 (3Hl6; d; J16-9 = 7.3Hz); 1.41 (3H14; s); 2.37
(1H4; m); 2.86 (1H9); 3.41-4.05 (5H; m); 5.48 (H12 mino); 5.55 (H12 majo)
13C 11.7 (C16); 19.7 (Cl5); 22.6 (C8); 22.8 (C8); 24.3 (C5); 25.2 (Cl4); 29.3 (C9);
34.4 (C7); 35.8 (C4); 36.85 (C6); 36.90 (C6); 45.6 (C8a); 45.7 (C8a); 51.8 (C5a); 63.3 (C19); 63.5 (C19); 63.6 (C,7); 64.2 (C,7); 70.6 (C,8); 71.0 (CI8); 79.7 (C12,); 79.8 (C12a); 88.7 (C12); 88.8 (C12); 98.22 (C10; q; 2JC-F = 29Hz); 98.25 (C10; q; 2JC-F = 29Hz); 104.0 (C3); 122.2 (CF3q;1JC-F= 293Hz)
19F -76.1 (40%); -76.2 (60%)
Elementary analysis for C19H29F3O7 (426.43 g.mol-1)
% Calculated C 53.52% H 6.85%
% Found C 53.81% ■ H6.58%
Olefin to diol oxidation
(Formula Removed)
The abovementioned olefin (100mg; 0.3mmol) is dissolved in a carbon tetrachloride (ImL), acetonitrile (lmL) and water (1.5mL) mixture. Sodium periodate (1.5eq) and then ruthenium trichloride (0.02eq) are added to this solution. After overnight reaction the reaction mixture is diluted with ethyl acetate, then the organic phase is successively washed with a sodium bisulfite aqueous solution, a sodium bicarbonate solution, and a sodium chloride solution. After silica gel purification (petrol ether /ethyl acetate 9/1) 66mg (65%) of white crystals are obtained (diastereoisomer mixture 65/35).
RMN(CDCl3): δ(ppm)
lH 0.96 (3H15; d; J 15-6= 5.9Hz); 1.00 (H7ax); 1.30 (1H6); 1.32 (H5a); 1.36 (3H16; s); 1.44 (3H14; s); 1.50 (1H8); 1.53 (1H5); 1.66 (H7eq; dq; J7eq-7ax = 13.1; J7eq-6 = J7eq-8ax = J7eq-8eq = 3.3Hz); 1.76 (H8a; dd; J8a-8ax = 12.0Hz; J8a-8eq = 5.7Hz); 1.90 (1H8); 1.92 (1H5); 2.08 (H4eq; ddd; J4eq-4ax= 14.6Hz; J4eq-5ax = 4.8Hz; J4eq-5eq = 3.0Hz); 2.37 (H4ax; ddd; J4ax. 4eq = 14.6Hz; J4ax-5ax = 13.8Hz; J4ax-5eq = 4.2Hz); 3.21 (OH10; s); 4.66 (OH9; s); 5.61 (H12, s)
13C 20.2 (C15); 22.6 (C16; q; 4JC-F = 3.1Hz); 24.5 (C8); 25.5 (C5); 25.6 (C14); 34.3 (C7); 36.1 (C4); 37.6 (C6); 52.0 (C5a); 52.1 (C8a; q; 4JC-F = 1.6Hz); 72.1 (C9;
q; 3JC-F = 1.2Hz); 83.0 (C12a); 88.9 (C12); 98.8 (C10; q; 2JC-F = 29Hz); 104.8 (C3); 116.6 (C19); 122.5 (CF3; q; lJC-F = 289Hz)
19F -79.3 (s, 3 F, CF3)
Elementary analysis for C16H23F3O6 (368.35 g.mol-1)
% Calculated C 52.17% H6.29%
% Found C 52.24% H 6.36%
Substitution by dimethanol benzene
(Formula Removed)
This compound is synthesised according to the general operating mode with monoacetylated dimethanoi benzene as a nucleophile. The corresponding ester is then dissolved in methanol (3mL) and potassium carbonate (2eq) is added to it. After silica gel purification (petrol ether/ethyl acetate 9/1) 25% of white crystals is obtained.
RMN(CDCl3): δ(ppm)
1H 0.91 (3H15; d; J15-6 = 5.9Hz); 1.05 (3H16; d; J16-9 = 7.3Hz); 1.44 (3H14; s); 2.38
(1H4; m); 2.90 (1H9; m); 4.69 (2H18; s); 4.72 (1H17; d; J17-17 = 11.7Hz); 4.83 (1H17; d; J17.-7= 11.7Hz); 5.37 (H12;s)
13C 12.2 (C16; m); 20.1 (C15); 23.4 (C8); 24.6 (C5); 25.8 (C14); 29.7 (C9); 34.5 (C7);
36.2 (C4); 37.5 (C6); 45.9 (C8a); 52.0 (C5a); 64.7 (Cn; q; 4JC-F = 2.0Hz); 65.0 (C18): 79.7 (C12a); 80.0 (C12a); 89.4 (C,2); 88.8 (C12); 98.9 (C10; q; 2JC-F = 29Hz); 104.6 (C3); 122.6 (CF3; q; 1JC-F = 293Hz); 127.0 (CAr); 127.7 (CAr); 136.9 (CAr); 140.3 (CAr)
19F -75.4 (s, 3F,CF3)
Elementary analysis for C24H31F3O6 (472.51 g.mol-1)
% Calculated C 61.01% H6.61%
% Found C % H %
III Biological activities
The above products have proved to be active on P. Falciparum, equally well on resistant as non-resistant strains, as well as in vivo in the Peters test on mice infected by Plasmodium berghei.
Thus, by way of an example, the compound substituted by piperazine ethanol has nanomolar IC50 values of 17 and of 3 respectively vis-a-vis sensitive and resistant (W2) strains of P. falciparum respectively. The same compound provides the mice with protection, all the mice survive in the Peters test after 20 days with a daily dose of 50 mg/Kg for 4 days.
The dosages used for the compounds of the invention are thus comparable to those used for artemether, or artesunate.



We Claim
1. Artemisinin derivates of following general formula (I):
(FORMULA REMOVED)
In which:
- a and b represent a single or a double bond, provided that a and b can not both
represent a double bond,
- nl and n2, independently from one another, represent 0 or 1, provided that when a
represents a double bond then nl=n2=0 and when b represents a double bond then nl=0,
- R1 represents:
- A fluoroalkyl group of approximately 1 to approximately 5 carbon atoms,
and comprising at least two fluorine atoms, such as the following perfluoroalkyl
groups: CF3, C2F5, C3F7, C4F9, and C5F11,
- Or a fluoroary] group comprising at least two fluorine atoms, such as the
perfluoroaryl group C6F5,
- Or a CF2 group when b represents a double bond and n 1=0,
-R2 represents a hydrogen atom, or a halogen atom, such as Br, or a group, if appropriate ionisable, making it possible to render said compounds of formula (I) water-soluble, such as the groups derived from piperazine, morpholine, alkylamine. alkoxy, ester or diester, acid or diacid, thioalkyl, alkylhydroxyl, or glycosyl,
-R3 represents a group, if appropriate ionisable, making it possible to render said compounds of formula (1) water-soluble, such as:
. An OR group in which R represents H, or an alkyl group of approximately 1 to 10 carbon atoms, if appropriate substituted, in particular a group of formula - (CH2)n-R5 in which n represents an integer from 1 to 5, and R5 represents:
CF3, OH, -CH=CH2, COOH, COH, CHOH-CH2OH, or a phenyl group, if appropriate substituted, in particular by CH2OH,
. NH2, or a NH-R6 group in which R6 represents an alkyl or alkoxy
group of 1 to 5 carbon atoms, or an arylalkyl or arylalkoxy group, such as the -NH-
C6H5-OCH3
- R4 represents H or OH.
2. Artemisinin derivatives as claimed in claim 1, of general formula (Ia)
corresponding to formula (I) in which a represents a double bond, b represents a single
bond, and nl=n2=0, namely compounds of following formula:
(FORMULA REMOVED)
In which:
- R1 represents:
- A fluoroalkyl group of approximately 1 to approximately 5 carbon atoms, and comprising at least two fluorine atoms, such as the following perfluoroalkyl groups: CF3, C2F5, C3F7, C4F9, and C5F11,
- Or a fluoroaryl group comprising at least two fluorine atoms, such as the perfluoroaryl group C6F5,
- R2 represents a halogen atom, such as Br, or a group, if appropriate ionisable,
making it possible to render said compounds of formula (I) water-soluble, such as the
groups derived from piperazine, morpholine, alkylamine, alkoxy, ester or diester, acid or
diacid, thioalkyl, alkylhydroxyl, or glycosyl.
3. Artemisinin derivatives as claimed in claim 1 or 2, of formula (Ia) in which R2
represents a group, if appropriate ionisable, making possible to render said compounds
water-soluble.
4. Artemisinin derivatives as claimed in any one of claims 1 to 3, of formula (Ia)
in which R2 represents:
- A group derived from piperazine, if appropriate substituted by an amine, alcohol,
or acid function, such as the piperazine ethanol group of formula,
(FORMULA REMOVED)
- Or a morpholino group of formula,
(FORMULA REMOVED)
- Or an alkylamine group of approximately 1 to approximately 10 carbon atoms, if
appropriate substituted by a hydroxyl, such as the ethylamine group of formula -NH-
CH2-CH3, or the -NH-CH2-CH2-OH group,
-Or an alkoxy group of approximately 1 to approximately 10 carbon atoms, if appropriate substituted by a hydroxyl or amine function, such as the ethoxy group of formula -O-CH2-CH3 the -O-CH2-CH2-OH group, or the -O-CH2-CH2-NHR group in which R represents an alkyl group of 1 to 5 carbon atoms,
-Or an alkyl group of approximately 1 to approximately 10 carbon atoms, substituted by one or more -COOR functions in which R represents H or an alkyl, alkylamine, or alkylhydroxy group of approximately 1 to approximately 4 carbon atoms, such as the group of formula
(FORMULA REMOVED)
in which Ra and Rb represent H or CH3,
- or a thioalkyl group of approximately 1 to approximately 6 carbon atoms, such as
the group of formula -S-CH2-CH3,
-or an alkylhydroxyl group of approximately 1 to approximately 10 carbon atoms,
- or a glycosyl group such as glucuronic acid or other nonasaccharides.
5. Artemisinin derivatives as claimed in any one of claims 1 to 4, of formula (la) in
which R1 represents CF3, C2F5, O2F5, C3F7, or C6 F5.
6. Artemisinin derivatives of formula (Ia) as claimed in any one of claims 1 to 5, corresponding to the following formulae:
(FORMULA REMOVED)
7. Artemisinin derivatives as claimed in claim 1, of general formula (lb) corresponding to formula (I) in which a and b represent a single bond, and nl=n2=l, namely compounds of following formula:in which: - Ri represents
(FORMULA REMOVED)
- A fluoroalkyl group of approximately 1 to approximately 5 carbon atoms, and
comprising at least two fluorine atoms, such as the following perfluoroalkyl groups: CF3
C2F5, C3F7, C4F9, and C5F11,
-Or a fluoroaryl group comprising at least two fluorine atoms, such as the perfluoroaryl group C6F5,
- R2 represents a hydrogen atom, or a halogen atom, such as Br, or a group, if
appropriate ionisable, making it possible to render said compounds of formula (I) water-
soluble, such as the groups derived from piperazine, morpholine, alkylamine, alkoxy, ester
or diester, acid or diacid, thioalkyl, alkylhydroxyl, or glycosyl,
- R3 represents:
. An OR group in which R represents H, or an alkyl group of approximately 1 to 10 carbon atoms, if appropriate substituted, in particular a group of formula - (CH2) n-R5 in which n represents an integer from 1 to 5, and R5 represents: CF3, OH, -CH=CH2, COOH, COH, CHOH-CH2OH, or a phenyl group, if appropriate substituted, in particular by CH2OH,
. NH2, or a NH-R6 group in which R6 represents an alkyl or alkoxy group of 1 to 5 carbon atoms, or an arylalkyl or arylalkoxy group, such as the -NH-C6H5-OCH3,
- R4 represents H or OH.
8. Artemisinin derivatives as claimed in claims 1 or 7, of general formula (lb) in
which R1 represents CF3, R2 and R4 represent a hydrogen atom, and R3 is such as defined
in claim 1 or 7, namely compounds of following formula:
(FORMULA REMOVED)
9. Artemisinin derivatives of formula (Ib) as claimed in claim 8, corresponding to
following formulae:
(FORMULA REMOVED)
10. Artemisinin derivatives as claimed in claim 1, of general formula (Ic)
corresponding to formula (I) in which a represents a single bond, b represents a double
bond, nl=0, n2=l, namely compounds of following formula:
In which:
(FORMULA REMOVED)
- R1 represents a CF2 group,
- R2 represents a hydrogen atom, or a halogen atom, such as Br, or a group, if appropriate ionisable, making it possible to render said compounds of formula (I) water-soluble, such as the groups derived from piperazine, morpholine, alkylamine, alkoxy, ester or diester, acid or diacid, thioalkyl, alkylhydroxyl, or glycosyl,
- R4 represents H or OH.
11. Artemisinin derivatives of formula (Ic) as claimed in claim 10, of following
formula:
(FORMULA REMOVED)
12. Artemisinin derivatives as claimed in any of the preceding claims as and when
used in the preparation of a medicament for the treatment of malaria.
13. Process for the preparation of compounds as claimed in any one of claims 1 to
6, characterized in that it comprises the following stages:
-Treatment of ailemisinin with a fluoroalkylating or fluoroarylating agent as defined in claim 2 in the scope of the definition of R1, such as a trimelhylsilane in the presence of fluoride ions, or an organolithium, which leads to the obtaining of the compound of the following formula:
(FORMULA REMOVED)
In which R1 is as defined in claim 2,
-Dehydration of the compound obtained, in the previous stage, in particular by treatment with SOCl2 in pyridine, which leads to the obtaining of the compound of the following formula:
(FORMULA REMOVED)
In which R1 is as defined in claim 2,
-Treatment of the compound obtained in the previous stage with a halogen, such as bromine, which leads to the obtaining of the compound of the following formula:
(FORMULA REMOVED)
In which Rx represents a halogen atom, and R1 is as defined in claim 2, -Substitution of the Rx halogen by a group, if appropriate ionisable, allowing
solubility in water, as defined in claim 2, which leads to the obtaining of a compound of
the following formula:
(FORMULA REMOVED)
In which R1 is as defined in claim 2, and R2 is as defined in claim 3.
14. Process for the preparation of compounds as claimed in any one of claims 1, 7 to 11, characterized in that it comprises the treatment of the compound of following formula:
(FORMULA REMOVED)
With the nucleophile of formula HO-R, in which R is as defined in claim 1, in the case where one wishes to obtain a compound of formula (lb) in which R3 represents , OR, or with acetonitrile in .the case where one wishes to obtain a compound of formula (lb) in which R3 represents NH2, or with NH2-R6 in which R6 is as defined in claim 1, in the case where one wishes to obtain a compound of formula (lb) in which R3 represents -NHR6, agitated at room temperature, followed by the treatment of the reaction mixture with an aqueous solution of sodium bicarbonate, drying, in particular over magnesium sulphate, and solvent evaporation, which leads to the obtaining of the compound of following formula (lb); (FORMULA REMOVED)
In which R3 is as defined in claim 1,
- With methyllithium at -78°C under agitation, then at room temperature, followed by hydrolysis, which leads to the obtaining of compound of following formula (Ic):
- (FORMULA REMOVED)

Documents:

905-DELNP-2004-Abstract-(25-03-2011).pdf

905-delnp-2004-abstract.pdf

905-DELNP-2004-Claims (06-07-2011).pdf

905-DELNP-2004-Claims-(06-07-2011).pdf

905-DELNP-2004-Claims-(25-03-2011).pdf

905-DELNP-2004-Claims-(28-03-2011).pdf

905-delnp-2004-claims.pdf

905-delnp-2004-Correspondence Others-(06-07-2011).pdf

905-DELNP-2004-Correspondence Others-(25-03-2011).pdf

905-DELNP-2004-Correspondence-others (06-07-2011).pdf

905-DELNP-2004-Correspondence-Others-(28-03-2011).pdf

905-delnp-2004-correspondence-others.pdf

905-DELNP-2004-Description (Compete)-(25-03-2011).pdf

905-delnp-2004-description (complete).pdf

905-delnp-2004-form-1.pdf

905-delnp-2004-form-2.pdf

905-delnp-2004-form-26.pdf

905-delnp-2004-form-3.pdf

905-delnp-2004-form-5.pdf

905-DELNP-2004-From-3-(25-03-2011).pdf

905-delnp-2004-gpa (06-07-2011).pdf

905-delnp-2004-GPA-(06-07-2011).pdf

905-delnp-2004-pct-210.pdf

905-DELNP-2004-Petition 137-(25-03-2011).pdf

905-DELNP-2004-Petition 138-(25-03-2011).pdf

abstract.jpg


Patent Number 248383
Indian Patent Application Number 905/DELNP/2004
PG Journal Number 28/2011
Publication Date 15-Jul-2011
Grant Date 08-Jul-2011
Date of Filing 07-Apr-2004
Name of Patentee CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
Applicant Address 3, RUE MICHEL-ANGE F-75794 CEDEX 16, FRANCE
Inventors:
# Inventor's Name Inventor's Address
1 GRELLEPOIS FABIENNE 1, ALLEE JULIETTE RECAMIER, F-92296 CHATENAY-MALABRY, FRANCE
2 OUREVITCH MICHELE 14, AVENUE PAULINE, F-94000 CRETEIL, FRANCE
3 BEGUE JEAN-PIERRE 15, RUE DE LA LANCETTE, F-75012, PARIS, FRANCE
4 BONNET-DELPON DANIELE 125, RUE DE LA REUNION, F-75020 PARIS, FRANCE
5 CROUSSE BENOIT 3, RUE DES VERGERS, F-91370 VERRIERES LE BUISSON, FRANCE
6 CHORKI FATIMA 11, RUE DES SABLONS, F-91310 LINAS, FRANCE
7 MAGUEUR GUILLAUME 52, RUE DU MOULIN FIDEL, F-92350 LE PLESSIS-ROBINSON, FRANCE
PCT International Classification Number C07D
PCT International Application Number PCT/FR02/03675
PCT International Filing date 2002-10-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 01/13869 2001-10-26 France