GB2205564A

GB2205564A - Forskoline derivatives

Info

Publication number: GB2205564A
Application number: GB08810463A
Authority: GB
Inventors: Bernard Delpech; Robert Lett
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1987-05-04
Filing date: 1988-05-04
Publication date: 1988-12-14
Also published as: NL8801174A; JPS63284169A; DE3815213A1; FR2614891B1; IT1219567B; CH676598A5; FR2614891A1; IT8847912A0; GB8810463D0

Description

7 2 P, - DITERPENE DERIVATIVES The present invention has as its subject

new derivatives of Forskoline, their process of preparation, their use as medicines, the pharmaceutical compositions containing them as well as some intermediates in that process.

Forskoline is a diterpene, isolated from the roots of the Indian plant "Coleus Forskohlii", to which interesting pharmaceutical properties have been attributed (for example J.C.S. Perkin 1, 767 (1982) and Tet. Let. 1669, 1977).

Starting from the natural product, only certain products have been able to be prepared (see for example J.

Med. Chem., 26, 436, 1983 and J. Med. Chem., 26, 486 (1983) or the American Patent USP 4 517,200).

Although it has been possible to achieve the reconstruction of the C ring of derivatives of Forskoline no longer containing the hydroxy radical at positions 1, 6 and 7 (J. Chem. Soc. Chem. Commun., 24, 198'17), attempts to introduce certain functions on the carbon atom at position 13 in Forskoline and specifically the 1,4 addition on a dihydropyrone formed by the C ring have failed up till now (J. Chem. Soc. Chem. Commun. 1748, 1985).

The Applicants have developed a new reaction which 2 makes it possible to gain access, starting from Forskoline, to interesting new derivatives.

The present invention thus has as its main objective products of general formula (I):

0 ORC in which R6 and R7, which may be the same or different, represent a hydrogen atom or an acYl radical, R, represents:

- either a methyl radical optionally substituted by an hydroxyl, halogen, cyano, amino, phenyl, optionally esterified carboxyl, azido or carbamoyl radical, the latter optionally substituted by an Cl-3 alkyl radical, - or an ethyl radical optionally substituted by a dimethylamino, trimethylammonium OH, or SH radical, each of the two latter radicals being optionally etherified, or a vinyl or phenyl radical, -2r a C3_4 alkyl radical optionally substituted by an OH or SH radical, each of these two latter radicals being optionally etherified, - or a-CHi- C radical in which R' represents 1 "- 1 R UM an hydrogen atom or a methyl radical, - or a - CH= C radical in which either W' and 9 - - 3 - R" each represents an hydrogen atom or a methyl radical, or one of them represents an hydrogen atom and the other represents a methyl radical, or a CHO, -CN, optionally esterif ied -C02H, -CH=NOH or - CH-CN 1 OW radical, R2 represents:

- either a Cl-3 alkyl radical, 2_ --.2r a radical in which either W2 and P"'2 21 each represents an hydrogen atom or one of them represents an hydrogen atom and the other represents a Cl-3 alkyl radical, - or an ethynyl radical, with- the exception of the products in which one of the R, or R2 substituents represents a beta-CH3 radical and the other represents an alpha-vinyl, -CHO, -CN, -CH=N-OH, -C2H 5 or CH 3 radical.

In the general formula (I), the acyl radical preferably represents an alkanoyl radical such as acetyl or propionyl; it can equally represent an aroyl radical such as benzoyl, - the halogen radical preferably represents an atom of chlorine or bromine, but it can equally represent an atom of fluorine or iodine; - the C1-3 alkyl radical represents one of the following radicals:

methyl, ethyl, propyl, isopropyl, preferably the straight chain radicals; - the esterified carboxy radical preferably represents an alkyloxy carbonyl radical such as methoxy carbonyl or ethoxy R0 carbonyl; - the etherified 011 or SH radicals are preferably methoxy and methylthio, benzyloxy or benzylthio radicals; 4 the C3-4 alkyl radicals represent a propyl, isopropyl, butyl, sec-butyl or tert- butyl radical, preferably straight- chain radicals.

The invention has particularly as its subject the products of general formula (I) as defined above in which R6 represents an hydrogen atom, R 7 represents an hydrogen atom or an acetyl radical, R, is selected from amongst the following radicals:

CH20H, CHO, C02H, optionally esterified in the form of a methyl or ethyl ester, -CH=NOH, -CH-CN, -CH2-CH2-N (CH3)2, -CH2-CH3, -CH=CHI, -CH2-CH CH 2-CH31 2-C112-S-CH31 2 CH2 Cl, -CH2Br, -CH2CO2H optionally esterified in the form of the methyl or ethyl ester, - C#, Cl -C13, -C92 -C A ' 1 1.

OW 0 M 3 -CH=CH-CH31 -CH=C(CH3)2, -CH2-CH2-OH and R2 is selected from amongst methyl, vinyl and ethynyl radicals.

The invention more especially has as its subject the products of general formula (I) as defined above in which the R, substituent is selected from amongst the following radicals -CH2-0% -C02H or -CH2-CO2H optionally esterified in the form of the methyl or ethyl ester, -CH=CH2, -CH2-CH3 ' CH2-CH2-CH3, -CH2-CH2-S-CH3, CP2 -(,g CH -CH -011 and most C3 2 2 particularly:

2c,- trihydroxy-lalpha, 6beta, 9alpha acetoxy-7beta nor-15 epoxy 8,13 labdane one-11 and trihydroxy-lalpha, 6beta, galpha acetoxy-7beta expoxy-8,13 labdyne-14 one-11.

The invention equally has as its subject a process for the preparation of the products of general formula (I) as defined above, characterizd in that one first treats a product of formula (II):

9 R'( in whIch R',, R'6, R'79 R9 each represents a free or protected OH radical, or R', and R9 on the one hand and V6 and W7 on the other hand together form the radicals:

-0 >< Ra.

in which R. and Rbl which may be the same or different, represent an hydrogen atom or an alkyl or alkoxy radical having from 1 to 4 carbon atoms or R. and Rb together form an oxygen atom and R, represents a methyl radical - either with an oxidizing reagent so as to obtain a product of formula (,,a) corresponding to a product of formula (II) is in which R, = -CH20H, which product of formula (IIa) one can either subject to a new oxidizing reagent so as to obtain a product of formula (I,b), corresponding to a product of formula (II) in which R, = C110, or subject to a halogenating reagent so as to obtain a product of formula (IIC) corresponding to a product of formula (II) in which R, = CH2X, X representing an halogen atom, or subjects to an oxidizing agent so as to obtain a product of formula (IId) corresponding to a product of formula (II) in which R, = CO H 1 2 6 which product one optionally esterifies, or if appropriate one submits the product of formula (I,b) in which R, = -CHO, i) to the action of hydroxylamine-hydrochloride so as to obtain a product of formula (II e) corresponding to a product of formula (II) in which R, represents -CH=NOH, or alternatively ii) to the action of hydrocyanic acid or of acetone cyanhydrin so as to obtain a product of formula (IIf) corresponding to a product of formula (II) in which R, = -CH CN, or alternatively iii) to the action of an oxidizing reagent so as to obtain a product of formula (I,d) previously described in which R, = -C02H; - or with an oxidizing reagent directly to obtain a product (I,b) in which R, represents a -CHO radical, which if appropriate one treats as above, - or with a halogenation reagent so as directly to obtain the previously described product of formula (IIC) in which R, = - CH2X, which product if appropriate either one treats with cyanide ion to obtain a product of formula (11 9 corresponding to a product of formula (II) in which R, = CH2-CN which product of formula (11 9) one treats if appropriate with hydrogen peroxide so as to obtain a product of formula (,,h) corresponding to a product of formula (II) in which R, = CH2CONH.1, or one treats the previously described product of formula (IIC) with an alkali azide so as to obtain a product of formula (IIi) corresponding to a product of formula (II) in which R, = -CH2N3 which product of f o r m u 1 a (I1j) one treats if appropriate w i t h triphenylphosphine so as to obtain a product of formula (II j) corresponding to product of formula (II) in which R, = -CH2 NH 2P ED 4D - or with a product of formula [H2C = N <,X 1 in which X0 represents a halide ion or a carboxylate ion so as to obtain a product of formula Mk) corresponding to a product of 7 f ormula (II) in which R -CH 1 2-CH2-N(CH3)2, which product of formula (I,k) one treats if appropriate with a methyl halide so as to obtain a product of formula (II1) corresponding to a product of formula (II) in which R, = -CH2-CH2-N(CH3)31 X4 X0representing a halide ion and which product of formula (II1) one treats if appropriate with a base so as to obtain a product of formula (II.) corresponding to a product of formula (II) in which R, = -CII=CH21 - or one treats a product of formula (II) first with a strong base-and then either with a compound of formula RBX in which RB represents a Cl-3 alkyl, allyl or benzyl radical or with a compound of formula R'Bo (CH2)n-X or WBS (CH2)n_Xl in which formulae X represents an halogen atom or an aryl sulphonate, R'B represents an hydrogen atom, an alkyl radical or a protective group for the hydroxy or thiol radical and n represents an integer from 1 to 3, so as to obtain the products of formulae (IInl)l (IIn2), (IIn3), (IIn4) and (IInS) corresponding to products of formula (II) in which R, represents respectively a C2-4 alkyl radical (nl), a -(CH2)2 CH=C112 radical (n2), a -(CH2)3 radical (n3), a -(CH2)2-4 OR'B radical (n4) and a _(CM2-4SR'B radical (n5), either with an oxidation agent so as obtain the previously mentioned product of formula (II.) corresponding to a product of formula (II) in which R, -CH20H, or with a halogenation agent so as to obtain the previously mentioned product of formula (IIc) corresponding to a product of formula (II) in which R1 = -CH2X, X representing an halogen atom, or with an agent for the introduction of the carboxy radical so as to obtain a product of formula (II.) corresponding to a product of formula (II) in which R, = -CH2CO2H, which product if appropriate one esterifies to obtain a product of formula or with an isocyanate of formula R.N=C=0 in which R.

represents an alkyl radical having from 1 to 4 carbon atoms or a phenyl radical so as to obtain a product of formula 4 9 _ - 8 - ) corresponding to a product of formula (II) in which R, aill 0 - -CH2-CO-NH-R, in which Ro has the previous meaning, or with a reagent for the introduction of the alkoxy carbonyl radical so as to obtain a product of formula (IV.) in which R, = -CH., -Alk, in which formula Alk represents an alkyl 4.-C02 radical having from 1 to 4 carbon atoms, IC= 0 in which W' nr with a product of formula and R each represents an hydrogen atom or a methyl radical or one of them represents an hydrogen atom and the other represents a methyl radical, so as to obtain a product of formula (II) corresponding to a product of formula (II) in p 11 OR 11 which R, 12 2 which products of its formula (II p) one subjects if appropriate to dehydration so as to obtain the products of formula Mq) corresponding to it the products of formula (II) in which R, C lit %.,R (D a (E) or with a product of formula [CH2=N< X 1 in which X has the previously indicated meaning, so as to obtain a product of formula (I,k) as defined above, then treats the products of formulae (II), (,,a), (IIb), (,,c), (I,d), (IIe), (,If), (Iig), (,,h), (I1i), (IIj), Mk), (II1), (,,m), (IInl), (IIn2), (IIn3), (IIn4), (IIn5), (IIo), (II'o), GV? 0), (11 p and (I,q), or with a reagent of formula R2 Cu, (R2)2 Cu Li, R2 RNT Cu Li, R2 RNT Cu (CN) L'2 or (R2)2 Cu (CN) L'2, in which formulae R2 has the significations indicated above with the exception of the signification ethynyl and RNT represents a non-transferable radical, or with a reagent of formula (n Bu)3 Sn-CH=CH-Cu Li, then X HT 9 with lead tetraacetate so as to obtain products of formula (I) in which R represents an ethynyl radical, then if 2 desired treats the products of formulae (,a) in which R, represents a -CH20H radical with an oxidization agent so as to obtain the products of formulae (Ib) in which R, represents a -CHO radical or the products of formulae (IC) in which R, represents a -C02H radical, then if necessary treats the products thus obtained in which one or more of the hydoxyl radicals are protected by a protective grouping with a deprotection agent and if desired or if necessary treats the products obtained in which at least one of the radicals R6 and R7 represents an hydroxyl radical with an acylation agent so as to obtain the products of formula (I) in which at least one of the radicals R6 and R7 represents an acyloxy radical.

Amongst the protective groupings which one or more of the substituents R',, V6, V7 and R9 can include there can specifically be mentioned acyl radicals such as acetyl or propionyl. As a matter of preference, the radicals R, and R9 on the one hand and R6 and R7 on the other hand together form 0 P3 radical.

a or a The different significations that Ra and Rb can take are for example ethyl, ethoxy, propyl, propoxy.

If one starts from a product in which the radicals R',, R9, R'6 and W7 have not been modified with respect to the natural product, the radicals R',, R9 and W6 represent a free 011 radical and M7 represents an acetyloxy radical.

a/. The transformation reaction by oxidation of a product of formula (II) into a product of formula (,,a) is effected by selenium oxide Se02 in the presence of acetic anhydride and acetic acid so as to obtain the allyl acetate which one saponifies by conventional methods, for example in the presence of a base such as sodium hydroxide.

The method of performance of this reaction is for example described in the following publications:

K.B. SHARPLESS, R.F. LAUER J. Am. Chem. Soc., 94, 7154 (1972) or V.T. BHALERAO, H. RAPOPORT, J. Am. Chem. Soc., 93, 4835 (1971).

The direct transformation of the products of formula (II) into products of formula (IIb) is equally effected by Se02' The duration of the reaction can preferably be prolonged.

b/. The oxidation of the products of formula (,,a) into products of formula (IIb) can be effected:

i) by a suspension of Mn02 in a hydrocarbon or in benzene for example according to the method of performance described in the publication A.J. FATIADI Synthesis 65 (1976), ii) or according to the so-called "Swern" method in methylene chloride or chloroform and employing triethylamine according to the publication A. MANCUSO, D SWERN Synthesis, 165 (1982), iii) or according to the method employing a CrV, for example pyridinium chlorochromate, this method being described for example by G. CAINELLI, G. CARDILLO, Chromium Oxidations in Organic Chemistry - Springer 1984.

iv) or finally according to the method indicated in the publication T. BUGGY, G.P. ELLIS, J. Chem. Research (M) 2314 2324 (1980).

c/. The transformation of the products of formula (II) into products of formula (IIC) is preferably effected employing N bromo or N-chloro succinimide. Equally a method of performance for transforming the products of formula (II) W into products of formula (IId can be found in the references J. Chem. Research (M) 2314-2324 (1980) and Compt. Rend. Acad.

Sci. Paris, 222, 1441 (1946).

The conversion of the products of formula (,,a) into products of the formula (IIc) is preferably effected by the action of mesyl or tosyl chloride in the presence of a base such as triethylamine or pyridine, then exchange of the sulphonate obtained into haloginide by conventional methods.

V. The transformation of the products of formula Ib into products of formula IId is preferably effected by oxygen in the presence of a catalyst such as platinium. One operates preferably in the presence of an aqueous solution. Such a reaction is described for example in the publication K.

HEYNS, H. PAULSEN, Angew. Chem., 69, 600 (1957).

The direct transformltion of the products of formula (,,a) into products of formula (I,d) can be effected under the same conditions.

e/. The transformation of the products of formula (I,b) into products of formula (I,e) is effected under the usual conditions with the aid of hydroxylamine hydrochloride.

f/. Similarly, the transformation of the products of formula (I,b) into products of formula (IIf) is effected under classical conditions, by the action of hydrocyanic acid or acetone cyanhydran.

g/. The transformation of the products of formula (IIC) into products of formula (11 9) is effected in the presence of cyanide ions introduced for example by sodium or potassium cyanide.

h/. The transformation of the products of formula (11 9) into products of formula M0 is effected preferably in the presence of hydrogen peroxide in a slightly basic medium according to the procedure described by:

K.B. WIBERC J. Am. Chem. Soc., 75, 3961 (1953) 11 11 11 It 77, 2519 (1955).

V. The transformation of the products of formula (IIc) into products of formula (IIi) is preferably effected in the presence of sodium azide.

jl. The transformation of the products of formula (IIi) into products of formula (II j) is effected in the presence of triphenyl phosphine according to the method described in the publication N. KNOUZI, M. VAULTIER, R. CARRIE, Bull. Soc.

Chim. Fr., 815 (1985).

k/. The transformation of the products of formula (II) into 12 products of formula (,Ik) is effected by a "Mannich" type reaction by the action of a product of formula [CH2 = NQ;<P XO], ion or a carboxylate ion.

X representing a halogen A description of a reaction of this type is to be found in the following references:

Y. JASOR, M. GAUDRY, M.J. LUCHE, A. MARQUET, Tetrahedron, 33, 295 (1977) and J.L. GRAS, Tet. Lett. 2.111 (1978) and 2955 (1978).

l/. The conversion of the products of formula (IIk) into products (IIj) is preferably effected in the presence of methyl iodide.

m/. The elimination of the ammonium grouping of the products of formula (II1) leading to the products of formula (IIm) is effected in the presence of a base or under the usual conditions.

The strong base in the presence of which one treats a product of formula (II) to obtain an anion upon the methyl radical at position 13 is preferably selected from amongst lithium diisopropyl amide and all other metallic nitrogen bases such as lithium, potassium or sodium hexamethyl disilazane.

n/. The action of the product of formula RBX upon the anion formed as indicated above is effected under conventional conditions.

a,/. The transformation of the anion indicated above into the product of formula (,,a) can be effected:

i) in the presence of oxygen, ii) in the presence of a molybdenum peroxo complex (Mo05HMPT) according to the procedure described in the publication E. VEDEJS, D.A. ENGLER, Y.E. TELSCHOW, J. Org.

Chem., 43, 188 (1978). 1 0' ill) in the presence of a derviative of formula according to the procedure described in the publication F.A.

13 DAVIS, L.C. VISHWAKARMA, J.M. BILLMERS, J. FINN, J. Org.

Chem., 49, 3241 (1984).

o) The transformation of the anion indicated above into the product of formula (II.) can be effected according to the usual methods with the aid for example of dry ice. If one employs methyl or ethyl carbonate or methyl or ethyl chloroformate, one introduces an alkoxy carbonyl radical and one can thus directly obtain a product of formula (II'o) in esterified form. The optional esterification of a product of formula (110) can be effected according to conventional methods, preferably with diazomethane.

o') The action on the anion indicated above of an isocyanate of formula R,N=C=O in which Ro represents a Cl-4 alkyl radical or phenyl is effected according to conventional i9 methods.

p) The action on the anion obtained as indicated above of a product of formula C=O which can in practice be - R gaseous depolymerized formaldehyde or acetaldehyde is preferably effected in a solvent such as tetrahydrofuran or dimethoxyethane.

q) The dehydration of the products of formula (II p) into products of formula GIq) is effected according to conventional methods, either in a basic medium or in an acid medium or in the presence of a Lewis acid.

kl) The transformation of the anion obtained as indicated above into a product of formula Mk) by the action of a X(:EL product of formula [CH2 = N <. X where a halide or carboxylate ion is effected under the conditions described in the following references:

- S. DANISHEFSKY et coll., J. Am. Chem. Soc., 98, 6715 (1976) - C.D. POULTER et coll., Tet. Let., 1621 (1977) - N.L. HOLY, Y.F. WANG, J. Am. Chem. Soc., 99, 944 (1977).

The action of cuprates on the products of formulae (II) to (II q very preferably takes place upon products whose I I - 14 - hydroxyl functions at positions 1, 9 and 6, 7 are protected.

Similarly when the R, substituent includes reactive functions such as -CHO, _C02H or -CH2011 functions, these functions are very preferably blocked. One then employs the usual blockages such as respectively those of cyclic or non cyclic ketals, esters or orthoesters, and protective groupings for the hydroxyl function such as for example ethers or acyl groupings.

As a matter of preference, the action upon the products of formulae (,,a) to (IIq) of cuprates is effected under the following conditions:

- One first forms the organo cuprate according to known methods, then adds the products of formulae (,,a) to (IIq) and finally one adds boron trifluoride etherate.

-One preferably operates at low temperatures (for example in the region of -780C to -300C), then one performs the usual treatments after having allowed the reaction mixture to recover to ambient temperature.

As organo cuprate one can employ the following reagents: R2 Cu, (R2)2 Cu Li, R2 RNT Cu Li or R2 RNT Cu (CN) L'2 or (R2)2 Cu (CN) L'2 in which formulae R2 and RNT have the previous significations.

The employment of the above-cited cuprates on products possessing a different function from the dihydropyrone 25- function will be found in the literature.

One can for instance cite the following references:

Employment of reagents of the R2 Cu and (R2)2 Cu Li type in the presence of boron trifluoride etherate:

- Y, YAMAMOTO, Angew. Chem. Int. Ed. Engl., 25, 947 (1986).

The RNT radical preferably represents a thienyl radical:

- B.H. LIPSHUTZ, Tet. Lett., 28, 945 (1987) or a 1 pentynyl C3H7_C Cradical:

- E.J. COREY and D. BEAMES, J. Am. Chem. Soc., 94: 7210 (1972) or 3-methyl 3-methoxy 1-butynyl:

E.J. COREY et coll., J. Org. Chem., 43, 3418 (1978).

The reagents of formulae R2 RN or (R T Cu (CN) L'2 2)2 Cu (CN) L'2 are described for example in the reference:

- B.H. LIPSHUTZ, Tetrahedron, 40, 5005, (1984).

9 The combined use of products of this type with boron trifluoride is described for example in the reference:

- B.H. LIPSHUTZ et coll., Tet. Lett., 5959 (1984), but no product of this type has ever been employed in the preparation of products including a dihydropyrone nucleus.

Amongst the previously-cited cuprates, one prefers products of formula R2RNT Cu Li in which RNT represents for e.xmaple a thienyl or 1-pentynyl or 3-methyl 3-methoxy 1 butynyl radical.

The reaction of products of the formula (n Bu)3Sn- CH=CH-Cu Li and the transformation of the products thus I %-r obtained into products in which R2 represents an ethynyl radical is effected with the aid of lead tetraacetate under the conditions indicated in the reference:

- E.J. COREY, R.H. WOLLENBERG, J. Am. Chem. Soc., 96, 5581 (1974).

In view of the use of lead tetraacetate, it is equally very preferable that the reaction should be carried out on products in which the radicals R'l. R99 R'6 and R'7 are protected as well as the substituent R'l when this includes a reactive function.

The optional oxidation of the products of formula (,a) corresponding to products of formula (I) in which R, = -CH2 OR into products of formulae (Ib) or (Id) in which R, =-CHO or -C0211 is carried out under the same conditions as the optional transformations of the products of formula (II) into products of formulae (IIb) or (,Id)' The deprotection agent for the products of formula (I) in which one or more hydroxyl radicals are protected by a protective grouping is selected from amongst the known agents.

16 The acylation agent which one can employ may for example be propionic anhydride in the presence of pyridine at a temperature of the order of OOC under the conditions described in the reference J.C.S., 767, 1982 or under the conditions described in the American Patent USP 4,517,200.

The acetyl or propionyl radicals are preferred.

The invention equally has as its subject a process for the preparation of products of general formula (I), as defined previously, in which R, represents a methyl radical and R2 represents an ethynyl radical, characterized in that one treats a product of formula (III):

i"., nr 0 R' in which R',, W6, W7 and R9 are defined 19 as previously, with -P- operating in a diazophosphonate of formula NeCR (OM c) 2 the presence of a base, so as to obtain a product of formula (Ie):

PC- = C (Ie) -1 P,- 1 17 then if necessary treats the product of formula (Ie) thus obtained in which one or more hydroxyl radicals are protected by a protective grouping with a deprotection agent and, if desired or if necessary, treats the product of formula (I) thus obtained in which at least one of the R6 and R7 radicals represents an hydroxyl radical with an acylation agent so as to obtain a product of formula (I) in which at least one of the R6 and R7 radicals represents an acyloxy radical.

The protective groupings are preferably those which have been cited earlier.

-The reaction with diazophosphonate is effected preferably in the presence of a base such as an alkali alcoholate such as potassium terbutylate or an alkyllithium such as butyllithium, in the presence of a solvent such as tetrahydrofuran.

One operates preferably at low temperature allowing this to return progressively to ambient temperature.

The conditions of the reaction are for example those described by J.C. GILBERT et al., J. Org. Chem., 1982, 47, 1837-1845.

The deprotection and acylation agents employed are those which have been mentioned earlier.

The products of general formula (I), the subject of the present applica.tion, possess interesting pharmacological Z5 properties. Evidence has been found of a notable stimulation of the cyclase adenylate of the hippocamp of the male rat by certain of the products of formula (I) at concentrations of 1 to 100 micromoles per litre.

These properLies make the products of general formula (1) suitable for use as medicines in the cardio-vascular field where they can display a positive inotropic effect or an anti-hypertensive effect or an anti-thrombotic effect.

They can equally be used in the treatment of glaucoma. The products of general formula (I) can also display an anti metastatic activity or can be employed as analgesics or bronchodilation agents.

- 18 Certain of the products of formula (II) to (IIq) are equally capable of displaying analogous properties.

The invention therefore equally has as its subject, in their capacity as medicines, the pharmaceutical ly-acceptable compounds of general formula (I), that is to say those which are non-toxic at the dosage levels employed.

More especially the invention has as its subject, in their capacity as medicines, the products of formula (I) in which the substituent R, is selected from amongst the following radicals -CH2-0H, -C02H or -CH2-CO2H optionally esterified in the form of methyl or ethyl ester, CH=CH21 -CH,-CH -CH,)-CH -CH -CH,)-CH9-S-CH -CH 3, 2 39 3, 2-CHn-S- -CH2-CH2-OH and most especially:

trihydroxy-lalpha, 6beta, 9alpha acetoxy-7beta epoxy-8,13 labdyne-14 one-11.

The invention provides a pharmaceutical composition comprising at least one of the present compounds together with a pharmaceutically acceptable excipient.

The compositions can be administered by buccal, rectal, transcutaneous or intravenous routes. The compositions can be solid or liquid and can be presented in the pharmaceutical forms currently used in human medicine such as plain or sugar-coated compressed tablets, cachets, capsules, granules, emulsions, suppositories, or injectable solutions or suspensions. The pharmaceutical forms can be prepared by the usual methods.

The active principle is usually employed in admixture with apharmaceutical ly acceptable excipient, which may be an excipient known for use in the formulation of pharmaceutical compositions. Such excipients may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gum - 19 arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. The active principle may be compounded with one or more wetting, dispersing or emulsifying agents and/or one or more preservatives.

The invention equally has as its subject, in their capacity as new industrial products and especially as new industrial products needed for the preparation of the products of formula (I), the products of general formula MA):

R i - P. A.1 n-W A) in which R',, R9, R'6 and R7 have the meanings given above and RA, has the meaning indicated above for R, with the exception of the signification methyl and it being understood is that when RA1 contains a reactive function the said function can be in a protected form.

Amongst the functions which R, can include and which can be protected one can mention the functions indicated above and specifically the -CHO, -C02H and -CH20H functions.

Examples of protective groupings are equally mentioned above.

The starting products of formula (II) in which R, represents a methyl radical are described for example in the reference:

- A.K. SAKSENA et coll., J. Chem. Soc. Chem. Comm., 1748 (1985).

The starting products of formula (III) can be obtained by ozonolysis of Forskoline operating in the presence of pyridine in methylene chloride/methanol mixture.

The following Examples illustrate the invention without limiting it in any way.

1 - 20 - 1 Ebcwple 1. Tetrahydroxy 1 alpha, 6beta, 7beta, 9alpha nor-1 5 epoxy 8,13 Labdane one-11 Stage A: tetrahydroxy lalpha, 6beta, 7beta, 9alpha epoxy-8,13 labdene-14 one-11 bis acetonide 1,9: 6,7.

Methoxy 2-propene (280 111; 2.92 mmoles) and p-toluene sulphonic acid (a trace are added to a solution of forskoline (600 mg; 1.46 mmoles), then one agitates for 15 hours at ambient temperature. One adds anhydrous K2CX)3, agitates for minutes, then one adds NaHC03 in saturated solution and one extracts with CH2C12. One dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 0.65 g of white crystalline solid. One adds a solution of sodium hydroxide (200 mg; 5 mmoles) in 20 ml of water and 80 ml of methanol, then one agitates for 48 hours.

One extracts with CH2C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 0.60 g of white paste which one dissolves in 30 m' of CH2C12. One adds methoxy 2-propene (280 pl; 2.92 mmoles) and p-toluene sulphonic acid (a trace), then agitates for 15 hours. One adds another 100 ul of methoxy 2-propene, then agitates for 8 hours. One agitates with an excess of anhydrous K20D3 for 15 minutes, then adds NaHC03 in saturates solution and extracts with CH2C12. One dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 0.69 g of a slightly yellow solid which one purifies by chromatography over silica (eluent CH2C12), One obtains 620 mg of expected product (white crystaline solid) (94%). m.pt- = 164"C IR (CHC13): 1 710 cm-1 SM 448 (M+); 362 Stage B: Tetrahydroxy l alpha, 6beta, 7beta, 9alpha dinor 14,15 epoxy-8,13 labdene-12 one-11 bis acetonide 1,9: 6,7.

To a solution of the product obtained from Stage A (224 mg 0.51nmoles) in 10 ml Of CC14 and 10 ml of acetonitrile, one adds 15 ml of water, sodium metaperiodate (481 mg; 2.25 mmoles) and r-uthenium trihydrate trichloride (13 mg; 0.05 21 mmoles). One agitates the mixture strongly at ambient temperature for 5 hours. One adds more sodium metaperiodate (267 mg; 1.25 mmole), then agitates strongly again for 2 haws. One adds CHIC12 and water, then extracts with CH2C12.

One dries over Na2S04, evaporates off the solvent under reduced pressure, then takes up the residue with ether and f 11 ters. One evaporates off the solvent under reduced pressure so as to obtain 244 mg of che s tnutcoloured solid.

One adds 150 ul of pyridine, 25 mg of cupric acetate and 4 ml of benzene, then one agitates for 1 hour 30 minutes at ambient temperature so as to obtain a green solution. One adds lead tetracetate (660 mg; 1.5 mmole). One agitates for 2 hours at ambient temperature, then heats to reflux for 1 hour. After cooling to ambient temperature, one adds CH2C12 to the mixture, filters aver alumina which one washes first 5 ml of methanol, then with CH2C12. The filtrate is washed with water and dried over Na2S04. After evaporaticn of the solvent under reduced pressure, cne obtains 240 mg of crude product which one purifies by chromatography over silica (eluent: CH2C12), One obtains 160 mg of the expected product, white crystilline solid, by trituration with ether (76%). MPT 123C.

IR (CHC13) 1666; 1619 UV (EtOH):max 278 rim, (-c = 8500 SM: 405 (W±CH3; 362;347 Staqe C Tetrahydroxy lalpha, 6beta, 7beta, 9alpha nor-15 epoxy-8,13 (labdane one-11 bis acetonide 1,9: 6,7.

To a suspension of cupric iodide (571 mg; 3 mmoles) in 2 ml of dry ether agitated at CC under argon, one adds a solution of methyllithium in ether until one has a grey solution of Me2C11L' in the prescence of some yellow grains of (MeCu)n (6 ml; 0.37 M solution of Me2CuLi). On adds 2.7 ml of this solution (1 mmole) to a solution of the product obtained in Stage B (84 mg; 0.2 mmoles) in 4 ml of dry ether at -78C under argon, then distilled W3-Et20 (110 ul; 09 mmoles) and one agitates for 1 hour at -78C. One allows it 22 to recover to ambient temperature in 30 minutes, then one adds a mixture of NH4C1 in saturated -NH40H. solution (9-1).

One agitates strongly, then one extracts with CH2C12. One dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 96 mg of crude product which one purifies by chromatography over silica (eluent CH2C12), One obtains 77 mg of the expected product white crystalline solid (85%). MPT = 151 "C.

IR (CHC13) 1709 SM: 436 (M+); 350 Stage D: Tetrahydroxy 1 alpha, 6beta, 7beta, 9alpha nor-1 5 epoxy 8,13-labdane one-11.

To a solution of the product obtained from Stage C (24mg; 0.055 mmole) in 1.1 ml of THF, one adds 0.8 ml of 7 N, hydrochloric acid, then one agitates at ambient temperature for 29 hours. One adds CH2C12 and water then extracts with CH2C12. One washes with NaM03 in saturated solution, dries over Na2S04, then evaporates the solvent under reduced pressure. One obtains 19 mg of crude product which one purifies by chromatography over silica (eluent CH2C12 - ether 9: 1). One obtains 11 mg of the expected product, yielding white crystals by trituration with ethanol (56%).

SM: 356 (M+); 338; 300; 282 Example 2: Tetrahydroxy lalpha, 6beta, 7beta, 9alpha epi-13 epoxy-8,13 labdane one-11 bis acetonide 1,9: 6,7 Stage A: Tetrahydroxy lalpha, 6beta, 7beta, 9alpha nor-16 epoxy-8,13 labdene-12 one-11 bis acetonide 1,9: 6,7.

To a solution of diisopropylamine (154 ul.; 1.1 mmole) in 4 ml of dry THF agitated at CC under argon, one adds a solution 1.5 M of n-butyllithium in hexane (0.8 ml; 1.2 mmole) and of HMPT (191 ul; 1.1 mmole), then one cools to - 7CC and agitates for 10 minutes at -780C. Over the course of 10 minutes one adds a solution of the product obtained in Example 1, Stage B (420 mg; 1 mmole) in 2 ml of THF (+0.2 ml for rinsing), then one agitates for 25 minutes at -78"C_ One 23 adds methyliodide (65 ul 1.05 mmole) and allows to recxner to ambient temperature in the course of 30 minutes, then one agitates again for 10 minutes. One adds ether, washes with water and extracts with ether. One dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 442 mg of a white solid which one purifies by chromatography over silica (eluentCH2C12). One obtains 432 mg of the expected product, white crystalline solid (96%).

MPT = 17 3'C IR (CHC11): 1663; 1613 uv (Et OH) max 279 rim, 8 700 SM: 419 (M±W13); 376; 361 FD 4 3 4 (M+) Stage B: Tetrahydroxy 1 alpha, 6beta, 7beta, 9alpha epi 13 epoxy-8,13 labdane ane-11 bis acetonide 1,9: 6,7.

Th a suspension of cupric iodide (571 mg; 3 mmoles) in 2 ml of dry ether agitated at OOC under argon, one adds a soluticn of methyllithium in ether until there is obtained a grey solution of Me2CuLi in the presence of some yellow grains (MeCu)n (4.5 ml; 0.44 M solution in Me2CuLi). One addsl.25 ml of this solution (0.55 mmole) to a solution of the product obtained in Stage A (48 mg; 0.11 mmole) in 2 ml of ether at -78C under argon, then distilled W3-Et20 (120 pl; 0.98 mmole) and cne agitates for one hour at -78OC- One allows to recover to ambient temperature in the cv=e of 30 minutes, and then cne adds a mixture of NH4C1 in saturated - NH4011 solution (9-1). One extracts with CH2C12,dries over Na2S04 and evaporates off the solvent under reduced pressure.

One obtains 47 mg of slightly yellow crystalline solid which one purifies by chromatography over silica (eluent CH2C12).

One obtains 40 mg of the expected product, white crystalline solid (80%). MPT = 1 9CC.

IR (CHC13): 1707 SM: 450 (M+) Staqe C Tetrahydroxy 1 alpha, 6beta, 7beta, 9alpha epi-1 3 24 epoxy-8,13 labdane one-11.

To a solution of the product obtained from Stage B (20 mg; 0.044 mmole) in 1 ml of tetrahydrofuranne, one adds 0.5 ml of 2N hydrochloric acid and 0.5 ml of concentrated hydrochloric acid, then agitates for 48 hours at ambient temperature. One adds CH2C12 and water, extracts with CH2C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 21 mg of crude product which one purifies by chromatography over silica (eluent CH2C12-Et20 9-1 then 8-2). One obtains 4.5 mg of expected product- solids (2-$'%.).

M 250 MHz (CDC'3):

CH 3 of ethyl: 0.93 (t; J=7.5); CH3: 1.07 (s), 1.27 (s), 1.35 (s), 1.39 (s), 1.59 (s); H-1: 4.69 (m); H-S: 2.09 (d; J=2.5); H-6: 4.49 (dd after exchange; J=2.5 and 4); H-7: 4.07 (d after exchange; J=4); CH2-12: 2.47 and 2.95 (d; J=17.5); OH:

2.25 (s), 2.34 - (d; J=3); 2.41 (d; J=3.5), 6.67 (s).

Example: Tetrahydroxy lalpha, 6beta, 7beta. 9alpha epoxy 8,13 labdene-14 one 11-bis acetonide 1,9: 6,7 and correspondinq 13-eni product- To a solution of vinyltributyletain (817 mg; 2.5 mmoles) in 4 ml of dry ether under argon, one adds a 1.5 M solution of butyllithium in hexane (1.3 ml; 1.95 mmole), then one agitates for 1 hour 10 minutes at ambient temperature. One adds this solution to a suspension of powdered cupric iodide (229 mg; 1.2 mmole) in 4 ml of ether, agitated at -600C under argon and one agitates from -40C to -25'C for 3 hours (black suspension). One cools again to -78% then one adds a solution of the product obtained in Example 1, Stage B (84 mg; 0.2 mmole) in 2 ml of ether (+0.2 ml for rinsing) and distilled BF3 Et20 110 U'; 0.9 mmole).

One agitates for 1 hour at -78% then allows to recover to ambient temperature during the course of 30 minutes. One adds a mixture of NH4C1 in a saturated solution (9-1) and extracts with CH2C12. One dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 976 mg of slightly yellow oil which one purifies by chromatography over silica (eluent CH2C12), One first obtains 53 mg of the expected product, white crystalline solid (59%), then 13 mg of the corresponding epi product, white crystalline solid (14%).

13 epi Product M (CHC'3): 1711r 1644 SM: 448 (M+) Example 4: Trihydroxy-1 alpha, 6betai 9alpha acetoxy-7beta nor-15 epoxy-8,13 labdane one-11.

To a solution of the product obtained from Example 1 (57.5 mg, 0.16 mmole) in 1.6 ml of pyridine, one adds acetic anhydride (18 ul; 0.10 mmole) then agitates at ambient temperature for 17 hours. One adds more acetic anhydride (9 ul; 0.095 mmole) then agitates for 71 hours. One adds CH2C12 and water, extracts with CH2C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 58 mg of white solid which one purifies by chromatography over silica (eluent: CH2C12-Et20 9-1 then 8 2). One obtains 8.5 mg of 1,7-diacetateg, white crystalline solid (12%), 36.5 mg of 7beta monoacetate,, white crystalline solid (57%).

IR (CHC13: 3607, 1743, 1711, 1246.

SM: 398 (M+); 380r342324,43.

Eample: Tetrahydroxy-1 alpha, 6beta, 7beta, 9alpha eLhyl epoU-8,13 labdane one-11 and corresponding 13-epi product.

StaSLe A: Tetrahydroxy-1 alpha, 6beta, 7betap 9alpha ethyl-15 epoxy-8,13 labdane one-11 bisacetanide-1,9:6,7 (isomer 1) and corresponding 13-epi product (isomer 2).

To a solution of cupric iodide (105 mg; 0.55 mmole) in 2.5 ml of dry ether at -35C under argon, one adds a 1.57 M solution of n-butyllithium in hexane (0.64 ml; 1 mmole) then agitates between -30C and -32'C for 30 minutes (black suspension). One cools again to -7CC then adds a solution 26 of the product obtained in Stage B of Example 1 (84 mg; 0.2 mmole) in 2 ml of ether (one rinses with 0.2 ml of ether) and distilled boron trif louride etherate (30 ul; 0.24 mmole).

One agitates f or 1 hour at -78C then allows to recover to ambient temperature in the course of 30 minutes. One adds a mixture of saturated NH4C1 - concentrated NH40H (9-1), agitates strongly for 20 minutes, then extracts with CH2C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 102 mg of crude product which one purifies by chromatography over silica (eluent CH2C12), One obtains 61 mg of the expected 13-epi product, colourless lake (61 %) and 22.5 mg of the other isomer.

Isemer 1 13epi product _: isomer 2 IR (CHC'3); 1707. IR (CHC'3: 1707.

SM,,'M'+); 335, 277, 219. SM: 335, 277f 219.

FD: 478.

Stage B: Tetrahydroxy-1 alpha, 6beta, 7beta, 9alpha ethyl-15 epoxy-8,13 labdane one-11 and corresponding 13-epi product.

One agitates 17.5 mg of the product obtained in Stage A (isomer 2) in 0.84 ml of tetrahydrofuran and 0.6 ml of 7N hydrochloric acid at 20'C_ After 18 hours one adds a further 0.3 ml of 2N hydrochloric acid and continues to agitate for 56 hours. One takes it up again in water and extracts with pethylene chloride. After drying over sodium sulphate and evaporation under reduced pressure, the residue is chromatographed aver silica (cyclohexane - ethyl acetate 4 1). One obtains 4.5 ml of solid expected product - -(Yield:30%).

NMR 300 MHz (CDC12):

ch3 of butyl: 0.91 (t;J=7); CH3: 1.07 (s), 1.27 (s), 1.36 (s), 1.39 (s), 1.59 (s); H-1: 4.69 (t after exchange; J=3); H-5: 2.09 (d; J=2.5); H-6: 4.49 (dd after exchange; J=2.5 and 4); H-7: 4.07 (d after exchange; J=4); CH2-12: 2.48 and 2.95 (d; J=17.5); OH: 2.24, 2.32, 2.39, 6.66.

Operating in a manner identical to that described above, starting from isomer 1 obtained in Stage A, one -27 obtained the expected product.

Example. Tetrahydroxy-1 alpha, 6beta, 7betar 9alpha epoxy 8,13 labdyne-14 one-11.

Stage A Tetrahydroxy-1 alpha, 6beta, 7beta, 9alpha. dinor 14,15 epcDry-8,13 labdane one-11 carboxaldehyde-13 acetonide 1r9 carbonate-6,7.

Stage A,: Tetrahydroxy-1 alpha, 6beta, 7beta, 9alpha epoxy 8,13 labdene-14 one-11 acetonide-1,9 acetyl-7.

To a solution of 410 mg of forskoline (1.0 mmole) in 20 ml of methylene chloride, agitated at 20"C, one adds first 0.14 ml of 2-methoxy propene (approx. 1.5 eq), then 0.1 ml of a 0.01 M solution of paratoluenesulphonic acid in methylene chloride. After 5 hours, one neutralises by agitating with about 100 mg of anhydrous potassium carbonate. One then takes it up with a saturated solution of sodium bicarbonate and extracts with methylene chloride. The organic phase is dried aver sodium sulphate, then evaporated off under reduced pressure. the residue is chromatographed on a column of silica (CH2C12-AcOET 9-1) to give 417 mg of the expected product (yield 93%).

IR (CHC'3): 3605,1740, 1714, 1250 SIM: 450 (M+); 32, 43.

Stage A2: Tetrahydroxy-1 alpha, 6beta, 7beta, 9alpha epoxy 8,13 labdene-14 one-11 acetonide-1,9.

One adds 2.5 ml of 2N aqueous solution of sodium hydroxide (4eq) to a solution of 563 mg of the product obtained in Stage A, (1.25 mmole) in 28 ml of methanol, at 20% and one agitates over night. The methanol is then evaporated off under reduced pressure. at ambient temperature. One takes up the remainder with water and extracts with methylene chloride. The organic phase is washed with water, dried over sodium sulphate. Af ter evaporation to dry this under reduced pressure, one obtains 517 mg of the expected product, white solid (Yield 100%).

'R (CHC13): 3588r 3085r 17130 1640.

1 -25 SM: 408 (M +); 390, 350.

Stage A 3: Tetrahydroxy-lalpha, -beta, 7beta, 9alpha zpoxy-8,13 labdene14 one-11 acetonide-1,9 carbonate-6,7.

205 mg of the product obtained in stage A 2 (0.5 moles) are agitated in 10 mI of toluene with 163 mg of carbonyldiimidazole (2eq), for 5 hours at 60% of ca then after a further addition of 50 mgV,-a-g-a-lrlnQ-TnElo ou"rclreflux.

g After coolnig 2 1 down, one pours into water, extracts with methylene chloride and dries over sodium sulphate. After evaporation off under reduced pressure, one obtains 258 mg which are chromatographed on a silica column (CH2C12-ethyl acetate 95 5) to provide 213 mg of the expected product (homogenous white powder) (Yield 98%).

NMR 300 MHz (CDC11), CH3: 1.10 (s) 1.21 (s), 1.30 (s), 1.36 (s), 1.38 (s), 1.39 (s); 1j46 (S); H-1: 4.42 (dd; J=2 and 3); H-5: 2.61 (d; to J=3.5); H-6: 5.11 (dd; J=3.5 and 6.5); H-7: 4.84 (d; J=6.5); CH2-12: 2..70 and 3.06 (d; J=19); H-14: 6.03 (dd; J=10.5 and 17); CH2-15: 5.00 (dd; J=1 and 10,5) and 5.22 (dd; J=1 and 17).

Stage A4: Tetrahydroxy-lalpha, 6beta, 7beta, galpha, dinor 14,15 epoxy-8,13 labdane one-11 carboxaldehyde-13 acetonide- 1,9 carbonate-6,7.

A solution of 327 mg of the product obtained in Stage A3 (0.75 mmoles) in 10 ml of methylene chloride and 1.2 ml of pyridine (15 mmoles) is cooled down to -781C, in an acetone/dry ice bath before bubbling through an oxygen-ozone mixture until there is obtained a slight blue-pale grey colouration. One then passes through a stream of nitrogen until decolouration is achieved and then for another 10 minutes, before adding 0.05 ol of dimethylsulphide and leaving to recover to 201C. one agitates for a further 30 minutes, then pours into water and extracts with methylene chloride. After drying over sodium sulphate and evaporation off under reduced pressure, the residue is chromatographed on a silica column (CH2C12-ethyl acetate 95-5). on thus obtains 30308 mg of the expected product (white powder) (Yield 94%) Af.t 1 IR (CHC13: 2820 9 740, 1726 SM: 436 (M+); 421, 407, 43.

11 Stage B: Tetrahydroxy-lalpha, 6beta, 7beta, galpha epoxy-8,13 labdyne-14 one-11 acetonide-1,9 carbonate-6,7.

To a solution of dimethyl diazomethylphosphonate (60 mg, 0.4 mmole) in 3 m! of dry tetrahydrafuran-at -78C under nitrogen, one adds a 1.5M solution of n-butyllithium in hexane ( 0.27 ml; 0.4 maole) (orange colouration) then one agitates for 10 minutes at -7CC.. One adds a solution of the product- obtained in Stage A (89 ag; 0.2 mmole) in 3 al of tetrahydrofuran, agitates for 30 minutes at -780C then allows to recover to ambient temperature in the course of 30 minutes and agitates for 16 hours. One adds CH2C12 and water, extracts with CH2C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 104 mg of yellow lake. To the aqueous phase (approx. 50 al), one adds ml of 2N Sodium hydroxide, allows to stand for 4 hours, acidifies with 5.5 ml of.IN hydrochloric acid and extracts with CH2C12. One dries over Na2S04 and evaporates off the solvent under reduced pressure. One thus recovers 5 mg of yellow lake. One purifies the lot by chromatography over silica (CH2C12-ACOEt 99-1 then 9-1 then 1-1 then AcEt). One obtains 22.5 mg of the expected product, white crystalline solid (25%) and 19 mg of the corresponding dihydroxy-6,7 product, yellow lake (23).

Stage C: Tetrahydroxy-lalpha, 6beta, 7beta, galpha epoxy-8,13 labdyne-14 one-11 acetonide-1,9.

To a solution of the product obtained from Stage B (carbonate- 22.5 mg; 0.052 mmole) in 2 ml of methanol, one adds 0.2 ml of N sodium hydroxide solution, and agitates for 330 21 hours (formation of a crystalline white precipitate). One 1 3i adds 0.22 ml of N sulphuric acid and agitates for 20 minutes, adds CH2C12 and water then extracts with CH2C12. one dries over M2S04 and evaporates off the solvent under reduced pressure. one obtains 22 mg of the expected product colourless lake (approx. 100%).

Stage D,: Tetrahydroxy-lalpha, 6betaI"-,9beta epoxy.,8,13 labdgne-14 one-11.

To a solution of the product obtained from Stage C (45 mg; 0.11 mmole) in 2 ml of tetrahydrofuran, one adds 1. 6 ml of 2N hydrochloric acid and 0.4 ml of concentrated hydrochloric acid then agitates for 16 hours at 201C. One adds CH2C12and water extracts with CH2C12, dries over Na2504 and evaporates off the solvent under reduced pressure. One obtains 43 mg of yellow lake which one purifies by chromatography over silica (cluant: CH2C12-Ac5OEt9-1 then 8- 2). One obtains 27 mg of the expected product, white crystalline solid (67%).

IR (CHC13)' 3611, 3306, 1716 SM: 366 (M.'); 348.

Example 7: Tetrahydroxy -1alpha, 6beta, 7beta, galpha epoxy-8,13 labdyne-14 one-11 acetyl-7.

To a solution of the product obtained in Example 6 (38.5 mg; 0.105 mmole) in 0.5 ml of pyridine, one adds an acetic anhydride-pyridine mixture 1-9 (150lil; 159 mmole) then one agitates for 17 hours at 201C. One adds a further 150 pl of the acetic anhydride-pyridine mixture 1-9, agitates for 9 hours, adds CH2C12 and water and extracts with CH2C12.

One dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 44 mg of colourless lake which one purifies by chromatography over silica (eluant: CH2C12- AcOEt 9-1 then 82). One obtains 29 mg of the expected product, colourless lake crystallising in CCL4 (67%).

IR (OHC-13): 3609, 3478, 3306, 1744, 1717, 1371, 1245.

SM: 408 (M"); 390, 43.

Example 8: Tetrahydroxy-lalpha, 6beta, 7beta, galpha ethyl- epoxy-8,13 labdane one-11.

Stage A: Tetrahydroxy-lalpha, 6beta, 7beta, 9alpha ethyl-15 epoxy-8,13 labdene-14 one-11 acetonide-1,9 carbonate-6,7.

One adds 0.33 ml (0.5 mmole) of n-butyllithiuia (1.5M in hexane) to the.;uspensi"f 193 mg (0.5 amole) of n-propyl- /in 2,2 ml of tetrahdrofuran/ triphenylphosphonium broml-a-eVeLgitated at WC. After 30 minutes, the orange-coloured suspension obtained is placed in a 'bath at -78C and over the course of 2 minutes one introduces 56.3 mg of the product obtained in Example 6, Stage A4 (0.125 mmole) in solution in 2 M1 of tetrahydrofuran. one then allows the temperature to climb while agitating so as to reach 200C over 50 minutes and to obtain then a colourless medium. One agitates again for 1 hour 20 minutes, then takes up with methylene chloride and a phosphate buffer solution at pH 7. After extraction with CH2C12, drying over sodium sulphate, evaporation under reduced pressure, one obtains 240 mg of residue which one takes up with a little ethyl ether to eliminate the major part of triphenylphosphine oxide after filtration. The etheral solution after evaporation gives 107 mg of residue which is chromatographed on a silica column (cyclohexane ethyl acetate 9-1) so as to provide 34 mg of expected product (mixtures of Z and E isomers) (Yield 59%).

Staqe B: Tetrahydroxy-lalpha, 6beta, 7beta, 9alpha ethyl-15 epoxy-8,13 labdane one-11.

One agitates a solution of the product obtained in Stage A (34 mg; 0.073 maole) in 5 ml of 96% ethanol in the presence of 20 mg of 5% palladium on active charcoal under a hydrogen atmosphere for 3 hours 30 minutes. One filters and evaporates the solvent under reduced pressure. One obtains 34 mg of a white solid which one dissolves in 3 C of methanol. One adds 0.3 ml of N sodium hydroxide and agitates for 15 hours (formation of a white crystalline precipitate).

One adds 0.33 ml of N hydrochloric acid and agitates for 30 minutes (dissolution). One adds CH2C12 and water, extracts with C22C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 32 mg of colourless lake which one dissolves In 2 ml of totrehydrofuran. one obtains 1.6 ml of 2N hyrochloric acid and 0.4 ml of concentrated hydrochloric acid then agitates for 26 hours. one adds CH2C12 and water, extracts with CH2C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 30 mg of colourless lake which one purifies by chromatography over silica (cluent: CH2C12-AC0Ecg-1). One obtains 25 mg of the expected product, colourless lake, giving a white solid In the presence of cyclobexane (85%).

SM: 398 (M.+); 380, 365, 324.

Example 9:, Tetrahydroxy- 1 alpha, 6beta, 7beta, 9alpha6thyl-15 epoxy 8,13 labdane one-11 acetyl-7 To a solution of the product obtained in Example 8 (24 ag; 0.06 mmole) in 0.3 ml of pyridine, one adds an acetic anhydride pyridine mixture 1-9 (120 pl; 0.127 mmole) then agitates for 23 hours. One adds CH2C12 and water, extracts with CH2C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. One obtains 24 mg of colourless lake which is purified by chromatography over silica (eluant:

CH2C12-AcOEt 9-1). One obtains 11.5 mg of the expected product, white crystalline solid (43%).

SM: 440 (M.+); 422, 43 Example-10: Tetrehydroxy-lalpha, 6beta, 7beta, galpha epoxy 8,13 labdene-14 one11 and corresponding 13-epi product.

Stage A: Tetrahydroxy-lalpha, 6beta, 7beta, galpha epoxy- 8,13 dinor-14,15 labdene-12 one-11 acetonide-1,9 acetyl-7.

Stage A,: Tetrahydroxy-lalpha, 6beta, 7beta, 9alpha dinor 14,15 epoxy-8,13 labdane one-11 carboxaldehyde-13 acetonide 1,9 acetyl-7.

One causes a stream of oxygen and ozone to pass into the colourless solution of 406 mg of products obtained in Example 6, Stage A, (0.9 mmole) in 10 ml of methylene chloride containing 0.5 l of methanol and 0.185 ml of pyridine (2.5 eq), agitated at -780C until there is obtained a blue pale grey colouration. One then bubbles thtough a stream of_ argon for 15 minutes, then adds 0.1 ml of dimethylsulphide (1.36 mmole), before allowing it to return to 20 C, One takes up with water, extracts with methylene chloride. After drying over sodium sulphate and evaporation under reduced pressure, one obtains 434 mg of a white solid residue. After chromatography over a silica column (eluent:

cyclohexane-ethyl acetate 4-1), one isolates 370 mg of expected aldehyde (yield 91%) (white solid).

IR (CHC13): 1724.

SM: 437, 423, 43.

FD: 452 (M), 423.

Stage A2:Tetrahydroxy-lalpha, 6beta, 7beta, galphe epoxy-8,13 dinor-14,15 labdene-12 one-11 acetonide-1,9.

A solution of 340 mg of tte product obtained at stage A, (0.75 maole) in 4.3 ml of pyridine is agitated with 63 mg (1.2 eq) of hydroxylamine hydrochloride for 2 hours 15 minutes at 200C. one then pours into water and extracts with methylene chloride. The organic phase is dried over sodium sulphate and evaporated off under reduced pressure, co distilling with toluene to eliminate traces of pyridine. The oxime obtained (quantitative yield) is put into solution in al of methylene chloride. After addition of 244 mg of ls carbonyldlimidazole (2 eq), one takes to reflux for 3 hours minutes. After cooling, one takes up with water and extracts with methylene chloride. After drying over sodium sulphate and evaporating off under reduced pressure, one obtains 341 mg of the expected nitrile (quantitative yield).

NMR 250 MHz (CDC13):

CH3: 1.03 (s), 1.26 (s), 1.46 (s) (x2), 1.56 (s), 1.61 (s), 1.63 (s); CH3-C.' 2.16 (s); H-1: 4.35 (M); H-5:2.26 (d; J=2); H-6: 4.48 (dd; J=2 and 3.5); H-7: 5.26 (d; J=3.5); CH212: 2.79 and 3.15 (d; J=20).

A solution of 280 mg of nitrile (0.62 mmole) in 10 ml of methanol and 1 ml of 2N aqueous solution of sodium hydroxide is agitated to 200C for one night. One pours into water and extracts with methylene chloride. The organic phase is dried 1 3(0 over sodium sulphate, then evaporated to dryness under reduced pressure in order to obtain 230 mg of residue. Afterchromatography on a silica column (CH2C12 - ethyl acetate g 1), one obtains 2.14 mg of the expected product (Yield 90%) (white solid).

IR (CHC13): 3610, 3591, 1665, 1621.

UV (Et OH): 280 nm; E = 9000.

SM: 365, 322, 307.

Stage A3: Tetrahydroxy-lalpha, 6beta, 7beta, galpha, epoxy- 8,13 dinor 14,15 labdene-12 one-11 acetonide-1,9 acetyl-7.

one operates in a manner analogous to that described in Example 9, employing at the start the product obtained in Stage A2 and obtains the expected product.

Stage B: Tetrahydroxy-lalpha, 6beta, 7beta, galpha epoxy-8,13 151 labdene-14 one-11 and the corresponding 13-epi product.

To a solution of vinyltributyletain (1.226 g; 3.75 mmoles) in 6 ml of dry ether under argon, one adds a 1.6M solution of n-butyllithium in hexane (1.875 mi; 3 mmoles) then one agitates for 2 hours. one adds the solution to a tuspension of cupric iodide (343 mg; 1.8 mmole) in 6 ml of ether at -50%C under nitrogen (grey colouration) then agitates at from -450C to -250C in the course of 2 hours 30 minutes (black suspension). one cools to -78'C, adds distilled baron triflouride etherate (165 pl; 1.34 mmole) and a solution of the product obtained from stage A (123 mg; 0.3 mmole) in 20 ml of ether (one rinses with 2 ml of ether).

One agitates for 40 minutes at -78'C then allows to recover to ambient temperature over 35 minutes. one adds saturated solution of sodium acid tartrate then one agitates over night (pale yellow precipitate). One extracts with AcCEt, dries over M2S04, evaporates off the solvent under reduced pressure, takes up in CH2C12, filters and evaporates off the solvent under reduced pressure. One obtains 1.437 g of orange oil containing a solid which one treats as indicated in Stage D of Example 6. One obtains 1.410 g of orange oil containing a solid which one purifies by chromatography over silica (cluent: CH2C12-Et20 9-1 then 8-2). one obtains 4 mg of the expected product, colourless lake (3.6%) and 25 %g of the other expected isomer (13-epi), white crystalline solid (22.5%).

13-epi Product:

IR (nujol): 3480, 3365, 3290, 1706, 1642.

SM: 368 (M.+); 350 Example 11: Tetrahydroxy- 1 alpha, 6beta, 7beta, galphaVepoxy 8,13 labdene-14 one-11 acetyl-7 and corresponding 13-epi isomer.

To a solution of the product obtained from Example 10 (13-epi isomer: 20 mg; 0.054 mmole) in 0.5 ml of pyridine, one adds an acetic anyhydride pyridine mixture 1-9 (77 pl; 0.08 mmole) the one agitates for 16 hours. one adds a further 77 P1 of the mixture and agitates for 5 hours then adds a still further 160pl of the mixture and agitates for 3 hours 45 minutes and then adds yet a further 160 pl of the mixture and agitates for 1 hour 30 minutes. One adds CH2C12 and water, extracts with CH2C12, dries over N62S04 and evaporates off the solvent under reduced pressure. one obtains 19 mg of colourless lake which one purifies by chromatography over silica (eluent: CH2C12-Et20 9-1 then 8 2). One obtains 3 mg of 1,9=diacetate (12%) and 10.5 mg of -381 the expected 13-epi product, white crystalline solid (47%).

SM: 410 (M.'); 392, 43. -.

Operating in a manner analogous to that described above starting from the other isomer obtained from Example 10, one obtains the expected product in identical yield.

1 Example 12: Pentahydroxy-lalpha, 6beta, 7beta, galpha, 14 nor-15 epoxy-8,13 labdane one-11.

Stage A:. Tetrahydroxy-lalpha, 6beta, 7beta, galpha epoxy-8, 13 labdene-14 one-11.

One adds a solution of 3 ml of N sodium hydroxide solution in 9 ml of water and 48 al of methanol to Forskoline (821 mg;; 2 mmoles) then one agitates for 62 hours (rapid dissolution). One adds water, extracts with CH2C12 dries over Na2S04 and evaporates off the solvent under reduced pressure. one obtains 0.80 g of white crystalline solid hich one purifies by chromatography over silica (eluent:

H2C12-EtIO -98-2). One obtains 750 mg of the expected product, white crystalline solid (100%).

Stage B: Tetrahydroxy-lalpha, 6beta, 7beta, galpha epoxy-8,13 labdene-14 one-11 bis carbonate-1,9:6,7.

To a solution of the product obtained from stage A (150 mg; 0.4 mmole) in 10 M1 of toluene, one adds carbonyldiimidazole (649 mg; 4 mmoles) then one heats to SO 850C for 6 hours. After cooling down to ambient temperature, one adds CH2C12 and water, extracts with CH2C12, dries over N12S04 and evaporates off the solvent under reduced pressure.

one obtains 0.18 g of white crystalline solid which one purifies by chromatography over silica (eluent: CH2C12 98-2).

Et20 one obtains 159 mg of the expected product, white crystalline 36-7 solid (94%).

Stage C: Tetrahydroxy-lalpha, 6beta, 7beta, 9alpha dinor 14,15 epoxy-8,13 labdene one-11 carboxaldehyde-13 bis carbonate-1,9:6,7.

one passes a stream of ozone-oxygen into a solution of the product obtained from Stage B (149 mg; 0.35 amole) in 6 ml of CH2C12 and 4 ml of methanol at -78C until a clear blue colouration is obtained. One then passes In a stream of nitrogen for 20 minutes then adds 260 pl of methyl sulphide.

One allows to recover to ambient temperature then agitates for 2 hours. one adds CH2C1 2 and water, extracts with CH2C12, dries over Na2S04 and evaporates off the solvent under reduced pressure. one obtains 188 mg of colourless lake which one purifies by chromatography over silica (eluent: CH2C12-Et20 9-1). One obtains 137 mg of the expected product, white crystalline solid (91%).

IR (CHC13): 1835, 1814, 1765, 1741, 1691.

SM: 422 (M-'); 393,349.

irD: 422, 393.

tage D: Pentahydroxy-lalpha, 6beta, 7beta, galpha, 14 nor-15 epoxy-8,13 labdane one-11 bis cartonate-1,9:6,7.

* To a solution of the product obtained f rom Stage C (85 g; 0.2 moole) in 5 ml of dry tetrahydrofuran, one adds :ithium triterbutoxyaluminohydride (56 mg; 0.22 mmole) then one agitates for 1 hour 25 minutes. one adds a further 5 mg of hydride and agitates again for 45 minutes. One adds a saturated ammonium chloride solution, extracts with ACOEt, dries over Na2S04, evaporates off the solvent under reduced pressure takes up with CH2C12, filters and evaporates off the solvent under reduced pressure. one obtains 92 mg of white solid which one purifies by chromatography over silica (eluent: CH2C12 - Et20 9-1 then 8-2). One obtains 57 mg of the expected product, vitreous solid (66%).

Stage E: Pentahydroxy-lalpha, 6beta, 7beta, 9alpha, 14 nor-15 epoxy-8,13 labdane one-11.

To a suspension of the product obtained in Stage D (57 ag; 0.13 amole) in 5 al of methanol, one adds 1 al of N sodium hydroxide solution then agitates for 24 hours. One adds 3-al of water, agitates for 48 hours, adds a further 1 1G l of water and agitates again for 24 hours. One extracts with AcOEt, dries over Na2S04, evaporates off the solvent under reduced pressure, takes up with CH2C12, filters and evaporates off the solvent under reduced pressure. One obtains 47.5 mg of the expected product, white crystalline solid (95%).

IR (nujol): 3520, 3447, 3339, 3188, 1714.

SM: 372 (M-'); 354, 341, 336, 323, 305.

Example 13: Tetrahydroxy-lalpha, 6beta, 7beta, 9alpha dinor 14,15 epoxy-8,13 labdant one-11 carboxaldehyde-13 bis acetonide-1,9:6,7 and tetrahydroxy-lalpha, 6beta, 7beta, galpha dinor-14,15 epoxy-8,13 labdane one-11 carboxy-13 bis acetonide-1,9:6,7.

One passes an oxygen-ozone mixture into a solution of 449 mg of the product obtained from Stage A of Example 1 (1.0 mmole) in 12 ml of methylene chloride and 0.4 ml of pyridine (5 eq), cools down to -781C. There is saturation of ozone after 10 minutes (pale bluegrey colouration) and one continues the bubbling in of oxygen-ozone for 15 minutes more. One then causes a stream of nitrogen to pass in for 20 At minutes and adds 0.1 ml of dimethylsulphide, before allowing to climb back to 200C. One agitates another 30 minutes then takes in water and extracts with methylene chloride. After drying over sodium sulphate and evaporation off under reduced pressure, one obtains 483 mg of a slightly coloured gum.

1 After chromatography on a silica column (CH2C12 - ethyl acetate 95-5/NEt3 10/0), one obtains 160 mg of the expected 13-carboxaldehyde product (35.5%). On then cluting with CH2C12. Ch30H 85-15, one obtains 198 mg of the expected 13 carboxy product (Yield 42.5%).

IR (CHC13 13-carboxy product: 3400, 1769, 1723.

Example 14: Tetrahydroxy-lalpha, 6beta, 7beta, galphe ethyl epoxy-8,13 labdane one-11 bis acetonide-1,9:6,7.

Stage A: Tetrahydroxy-lalpha, 6beta, 7beta, 9alpha ethyl-15 epoxy-8,13 labdene-14 one-11 bis acetonide-1,9:6,7.

To a suspension of n-propyltriphenylphosphonium bromide (385 mg; 1 mmole) in 4.4 C of dry tetrahyorofuran under argon at ambient temperature, one adds a 1.57M solution of n butyllithium in hexane (0.63 ml; 1 mmole) then one' agitates for 30 minutes (orange solution 0.2M). One adds 0.65 &l of this solution (0.13 mmole) to a solution of the 13 carboxaldehyde product obtained from Example 13 (54mg; 0.12 amole) in 2 ml of tetrahydrofuran under argon then agitates for 1 hour 20 minutes at ambient temperature. one adds a further 0.25 mI of the ylure solution (0.05 mmole), agitates again for 30 minutes, adds a further 0.3 ml of the ylure solution (0.06 mmole) and agitates again for 30 minutes. One adds ether and water, extracts into the ether which one washed with water and dries over Na2S04. One evaporates off the solvent under reduced pressure and obtains 78 mg of slightly yellow lake which one purifies by chromatography over silica (eluent: CH2C12). one obtains 22 mg of the expected product (mixture of isomers E and Z), colourless lake (38%).

Stage B: Tetrahydroxy-lalpha, 6beta, 7beta, galpha ethyl-15 epoxy-8,13 labdane one-11 bis acetonide-1,9:6,7.

One agitates a solution of the product obtained from Stage A (23 mg; 0.048 mmole) In 3 ml of 96% ethanol in the presence of 10 mg of 51 palladium on charcoal under an atmosphere of hydrogen for 3 hours 15 minutes. one filters and evaporates off the solvent under reduced pressure. One obtains 23 mg of the expected product, colourless lake (approx. 100%).

PHARMACOLOGICAL STUDY The products of the invention have been tested with the object of determining their activity "in vitro" on cyclase adenylate.

The enzyme is treated in a homogenate of rat hippocamp tissue while measuring the formation of cyclic monophosphate adenosine starting from adenosine triphosphate labelled with Phoshorous 32.

The percentage stimulation of the enzyme has been evaluated for each product tested at a concentration of 10-SM 21-, or 10-4M by comparison with a control absent product (=100%).

The results appear in the table below:

Product of Example stimulation 10-5m 10-4M 6 196 322 7 517 863 9 167 296 11 230 403 Ak Z- 1

Claims

1 1. A compound of general formula (I):

R -i 1.1 0 11 g 1, (I) a,, 0 0" 1 R OR, 0 R c.

in which R6 and R7 which may be the same or different represent an atom of hydrogen or an acyl radical, R, represents:

- either a methyl radical optionally substituted by an hydroxyl, halogen, cyano. amino, phenyl, optionally esterified carboxyl, azido or carbamoyl radical the last mentioned optionally substituted with a Cl-3 alkyl radical, - or an ethyl radical optionally substituted by a dimethylamino, trimethylamino, optionally etherified OH or SH, vinyl or phenyl radical, or a C3-4 alkyl radical optionally substituted by an optionally etherified OH or SH radical, CH3 - or a -CH2-C/ radical in which R' represents \R' OH an hydrogen atom or a methyl radical, 11 - or a -CH=C radical in which either W' and \R" ilLS7 R" each represents an hydrogen atom or a methyl radical, or one of them represents an hydrogen atom and the other represents a methyl radical, - or a -CHO, -CN, optionally esterified -C02H, -CH=NOH or - CH-M radical., R2 represents:

- either a %, alkyl radical, L-J / RT 2 radical in which either - or a CH=C \IZII 2 M2 and W'2 each represents an hydrogen atom or one of them represents an hydrogen atom and the other represents a Cl-3 alkyl radical, - or an ethynyl radical, with the exception of the compounds in which one of the substituents R, and R2 represents a beta-CH3 radical and the other represents an alpha-vinyl, -CHO, -CN, -CH=N-OH, -C2H5 or CH3 radical.

2. A compound according to claim 1 wherein R6 represents an hydrogen atom, R7 represents an hydrogen atom or an acetyl radical, R1 is selected from the following radicals:

-CH20H, -CHO, -C02H optionally esterified in the form of the methyl or ethyl ester, -CH=NOH, -CH-CN, 1 OH -CH2-CH2-N(CH3)2, -CH2-CH3, -CH=CH2, -CH2-CH2-CH3.

-CH2-CH2-SCH3, -CH2-CH2-S-'/\ -CH2C11 -CH2Br, -CH2CO2H optionally esterified in the f orm of the methyl CH3 or ethyl ester, -CH,)-CH-CH3, -CH,)-C 1 \CH3 OH OH -CH=CH-CH3, -CH=C(CH92, and -CH2-CH2-0% and R2 is selected from methyl, vinyl and ethynyl radicals.

3. A compound according to claim 1 or 2 wherein the substituent R, is selected from the following radicals -CH2-0H, -C02H or -CH2-CO2H optionally esterified in the form of the methyl or ethyl esters, -CH--CH21 -CH2-CH3, -CH2-CH2-CH3, -CH2-CH2-S-CH3, -CHq-CH9-S and -CH2-CH2-0H.

4. A compound according to claim 1 substantially as described herein.

5. A compound according to claim 1 which is specifically named herein.

6. 1-Alpha,6-beta,9-alpha-trihydroxy-7-beta-acetoxy-8,13-epoxy-14-labdyne-11-one.

7. A process for the preparation of a compound claimed in any one of the preceding claims, wherein one optionally first treats a product of formula (II):

in which R',, R6, R7 and R9 each represents a free or protected OH radical, or R', and R9 on the one hand or W6 and W7 on the other hand together f orm a radical:

-0 >< Ra -0 Rb in which Ra and Rb which may be the same or different represent an hydrogen atom or an alkyl or alkoxy radical having 1 to 4 carbon atoms pr Ra and Rb together form an oxygen atom and R, represents a methyl radical - either with an oxidation reagent so as to obtain a product of formula (,,a) corresponding to a product of formula (II) in which R, represents CH20H, which product of formula (,,a) one can either subject again to an oxidation reagent so as to obtain a product of formula Mb)g corresponding to a product of formula (II) in which R, represents -CHO, or subject to a halogenation reagent so as to obtain a product of formula (IIC) corresponding to a product of formula (II) in which R, represents -CH2X, X representing an halogen atom, or subject to an oxidation agent so as to obtain a product of formula (I,d) corresponding to a product of formula (II) in which R, represents -C02H which product can optionally be esterified, and one if appropriate subjects the product of formula Mb) in which R, represents -CHO i) to the action of hydroxylamine hydrochloride so as to obtain a product of formula Me) corresponding to a product of formula (II) in which R, represents -CH=NOH, or alternatively ii) to the action of hydrocyanic acid or acetone cyanhydrin so as to obtain a product of formula (IIf) corresponding to a product of formula (II) in which.Rl represents -CH-CN, or alternatively 1 Uti iii) to the action of an oxidation reagent so as to obtain the previously described product of formula (I,d) 41 in which R, represents -C02H which product can optionally be esterified; - or with an oxidation reagent so as directly to obtain a product (I,b) in which R, represents a -CHO radical, which if appropriate, one treats as above, - or with a halogenation reagent so as directly to obtain the previously described product of formula (IIC) in which R, represents -CH2X. and if appropriate either the product of formula (II.) prepared in this way or as above one treats with cyanide ion to obtain a product of formula (11 9) corresponding to a product of formula (II) in which R, represents -CH2-CN which product of formula (11 9) one treats if appropriate with hydrogen peroxide so as to obtain a product of formula (,,h) corresponding to a product of formula (II) in which R, represents -CH2CONH2. or this product of formula (IIC) one treats with an alkali azide so as to obtain a product of formula (IIi) corresponding to a product of formula (II) in which R, represents -CH2N3 which product of formula (IIi) one treats if appropriate with triphenylphosphine so as to obtain a product of formula (II j) corresponding to a product of formula (II) in which R, represents CH2-NH2, 2CNPXG in which X0 - or with a product of formula [H 9 represents a halide ion or a carboxylate ion so as to obtain a product of formula Mk) corresponding to a product of formula (II) in which R, represents -CH2-CH2-N(CH3)2, which product of formula (I,k) one treats if appropriate with a methyl halide so as to obtain a product of formula (II1) corresponding to a product of f ormula (II) in which R, represents I -CH -CH e ' CH Halq Halg representing a halide ion, 2 2-W' 3)3 and which product of formula (II1) one treats if appropriate with a base so as to obtain a product of formula (IIm) corresponding to a product of formula (II) in which R, represents -CH=CH2, -or one optionally first treats a product of formula (II) with a strong base and then, either with a compound of formula RBX in which RB represents a C1-3 alkyl radical or an allyl or benzyl radical or with a reagent of formula R'Bo (CH2)nX or MBS (CH2)nX in which formulae X represents an halogen atom or an arylsulphonate, VB represents an hydrogen atom, an alkyl radical or a protective grouping for the hydroxy or thiol radical, and n represents an integer from 1 to 3, so as to obtain a product of formula (IInl), (IIn2), (IIn3), (IIn4) or (IIn5) corresponding to a product of formula (I1) in which R, represents respectively a C2-4 alkyl radical (nl), a -(CH2)2-CH=CH2 radical (n2), a -(CH2)2 radical (n3), a -(CH2)2-4 OR'B radical (n4) or a -(CH2)2-4 SR'B radical (n5), or with an oxidation agent so as to obtain the previously mentioned product of formula (,,a) corresponding to a product of formula (II) in which R 1 represents -CH20H, which if appropriate one treats as above, or with a halogenation agent so as to obtain the previously mentioned product of formula (IIc) corresponding to a product of formula (II) in which R, represents -CH2X, X representing an halogen atom, which if appropriate one treats as above, or with an agent for the introduction of the carboxy radical so as to obtain a product of formula (110) corresponding to a product of formula (II) in which R, represents -CH2CO2H, which product if appropriate one esterifies so as to obtain a product of formula (IVO), or with an isocyanate of formula RON=C=0 in which Ro represents an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical so as to obtain a product of formula (IV'0) corresponding to a product of formula (II) in which R, represents -CH2-CO-NH-Ro in which Ro has the previous meaning, S-0.

or with a reagent for the introduction of the alkoxycarbonyl radical so as to obtain a product of formula (IV.) in which R, represents -CH2-CO2-Alk, in which formula Alk represents an alkyl radical having f rom 1 to 4 carbon atoms, or with a product of formtla C=0 in which W' R" / and R" each represents an hydrogen atom or a methyl radical or one of them represents an hydrogen atom and the other represents a methyl radical, so as to obtain a product of formula (II p) corresponding to a product of f ormula (II) in which R /), 11 represents -CH 2-C which product of formula R" OH (II p) one subjects if appropriate to dehydration so as to obtain a product '. of formula Wq) corresponding to a product of formula (II) in which R, represents - C H = C"' W' p \R?? 1 or with a product of formula [CH2=N0<13l in which X0 has the meaning defined above, so as to obtain the above-defined product of formula (II01 THEN treats the product of formula (II), (,,a), (I,b), (IIdy (IId), (I,e), (,If), (,,g), (,,h), (I,i), Wj), (IIk)g (II1), (,,m), (IInl), (iin2), (IIn3), (IIn4), (IIn5), Mo), (,,'o), (II"o), (,,p) or (II q) either with a reagent of formula R2Cul (R2)2 Cu Li.

R2RNT Cu Li, R2RNT Cu (CN) L'2 or (R2)2 CU (CN) L'21 in which tormulae R has the sianifications attributed 2 0 in claim 1 except for the signification ethynyl and RN IT represents a non-transferable radical, so as to obtain a product of formula (X):

R a j R.

2 0 (X) P;' VA R' 1,7 A R' 6 in which R 1, R'6, R'7, R, and R9 are as defined above and R2 has the significations attributed in claim 1 except for the signification ethynyl, or with a reagent of formula (n Bu)3 Sn-CH=CH-Cu Li, 1 R NT then with lead tetraacetate so as to obtain a product of formula (X) in which R2 represents an ethynyl radical, AND THEN if desired treats the product of formula (,a) corresponding to the product of formula (X) in which R, represents a -CH20H radical with an oxidation agent so as to obtain the corresponding product of formula (Ib) in which R, represents a -CHO radical or the corresponding product of formula (Id) in which R, represents a -C02H radical, then if necessary treats the product thus obtained in which one or more hydroxyl radicals are protected by a protective grouping with a deprotection agent and treats if desired or if necessary the compound of formula (I) obtained in which at least one of the radicals R6 and R7 represents an hydroxyl radical with an acylation agent so as to obtain a compound of formula (I) in which at least one of the radicals R6 and R7 represents an acyl radical.

8. Process for the preparation of a compound claimed in 52 any one of claims 1-6, wherein one treats the product of formula (II), (I,a)v (IIb)y Mc), Md), (I,e), (,If), (Iig), (I,h)y (I,i)g (I,j), (IIk), (,,l) (,,m), (IInl), (IIn2), (IIn3), (IIn4), (IIn5)g (I,o), (,,'o)g M"ds (11 p) or (I,q) as defined in claim 8 either with a reagent of formula R2Cu, (R2)2 Cu Li, R2RNT Cu Li, R2RNT Cu (CN) L'2 or (R 2)2 Cu (CN) Li 2' in which formulae R2 has the significations atributed in claim 1 except for the signification ethynyl and RNT rep resents a non-transferable radical, so as to obtain a product of formula (X):

Ri 0 R2.

P P5' FA R(X) P (0 in which R',, R'6, R'7Y R, and R9 are as defined in claim 8 and R2 has the significations attributed in claim 1 except for the signification ethynyl, or with a reagent of formula (n Bu)3 Sn-CH=CH-Cu Li, 1 R NT then with lead tetraacetate so as to obtain a product of formula (X) in which R2 represents an ethynyl radical, and then if desired treats the product of formula (I a) corresponding to the product of formula (X) in which R, represents a -CH20H radical with an oxidation agent so as to obtain the corresponding product of formulae (Ib) in which R, represents a -CHO radical or the corresponding product of formula (Id in which R, represents a -C02H radical, then if necessary treats the product thus obtainedin which one or more hydroxyl radicals are protected by a protective grouping with a deprotection agent and treats if desired or if necessary the compound of formula (I) obtainedin which at least 53 one of the radicals R6 and R7 represents an hydroxyl radical with an acylation agent so as to obtain a compound of formula (I) in which at least one of the radicals R6 and R7 represents an axyl radical.

9. A process for the preparation of a compound claimed in any one of claims 1-6in which R, represents a methyl radical and R2 represents an ethynyl radical, wherein one treats a product of formula (III):

CH 1= R 1 : 5 ' Cm 0 2 (m) 11/ h R _+ in which R'p W6, W7 and R9 are as def ined in claim 7, 0 with a diazophosphonate of formula N2CHP(OMe)2 operating in the presence of a base, so as to obtain a product of formula (Ie):

CIA 3 (Ie) W1.

then treats if necessary the product of formula (Ie) thus obtained in which one or more hydroxyl radicals are protected with a protective grouping with a deprotection agent and, if desired or if necessary, treats the compound of formula (I) thus obtained in which at least one of the radicals R6 and R7 represents an hydroxyl radical with an acylation agent so as to obtain a compound of formula (I) in which at least one of the radicals R6 and R7 represents an acyl radical.

10. A process for the preparation of a compound claimed in any one of claims 1-6, which process is performed substantially as described herein.

11. A process for the preparation of a compound claimed in any one of clams 1-6, which process is performed substantially as described herein in any one of the Examples.

12. A compound claimed in any one of claims 1-6 prepared by a process claimed in any one of claims 7-11.

13. A pharmaceutical composition comprising a compound claimed in any one of claims 1-6 and 12 together with a pharmaceutically acceptable excipient.

14. A pharmaceutical composition according to claim 13 which is substantially as described herein.

15. A compound claimed in any one of claims 1-6 and 12, or a composition claimed in claim 13 or 14 for use in a method of treatment of the human or animal body by therapy.

16. The chemical of formula (,,A):

j O P, -i A) in which Rl, R99 R6 and R'7 are as defined in claim 7 and RAl is as defined in claim 1 for R, with the exception of methyl and with the variant that when RAl includes a reactive function the said function can be in a protected form.

17. A chemical according to claim 16 substantially as described herein.

18. A chemical according to claim 16 which is specifically named herein.

19. A process for preparing a chemical claimedin any one of claims 16-18 which process is performed substantially as described herein.

20. A process for preparing a chemical claimedin any one of claims 16-18, which process is performed substantially as described herein in any one of the Examples.

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