CH676598A5 - - Google Patents

Description

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CH 676 598 A5

Description

The subject of the present invention is new derivatives of forskolin, the pharmaceutical compositions containing them as well as compounds for their preparation.

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

From the natural product, only certain products could be prepared (see for example J. Med. Chem. 26,436,1983 and J. Med. Chem. 26, 486 (1983) or the US patent USP 4,517,200).

Although the reconstruction of the C nucleus of forskolin derivatives no longer comprising a hy-droxy radical in positions 1.6 and 7 could have been carried out (J. Chem. Soc. Chem. Commun, 24.1987), attempts to certain functionalizations on the carbon at position 13 of forskolin and in particular the addition 1.4 to a dihydropyrone formed by the nucleus C have failed so far (J. Chem. Soc. Chem. Commun 1748,1985).

The licensee has developed a new reaction that provides access to interesting new derivatives from forskolin.

The present invention therefore has for first object the products of general formula (I):

in which Re and R? identical or different represent a hydrogen atom or an acyl radical, Ri represents:

- or a methyl radical optionally substituted by a halogenated hydroxyl radical, cyano, amino, phenyl, optionally esterified carboxyl, azido or carbamoyl optionally substituted by. an aIkyleCt-3 radical,

or an ethyl radical optionally substituted by a dimethylamino, trimethylammonium OH, or SH radical, each of these two radicals being optionally etherified, a vinyl or phenyl radical,

or a C3-4 alkyl radical optionally substituted by an OH or SH radical, each of these two radicals being optionally etherified,

- either a radical ctta chp-c

0h in which R 'represents a hydrogen atom or a methyl radical,

- be a radical r "

-ch = c in which either R 'and R' "each represent a hydrogen atom or a methyl radical, or else one represents a hydrogen atom and the other represents a methyl radical,

Either a radical CHO, CN, CO2H optionally esterified, CH = NOH or

-ch-cn. I

Oh

R2 represents:

- or a C1-3 alkyl radical,

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CH 676 598 A5

- thirsty for a radical

JP

2

/

-ch = c

^ "2

in which either R'2 and R "z each represent a hydrogen atom or else one represents a hydrogen atom and the other a C1-3 alkyl radical,

- or an ethynyl radical,

with the exception of products in which one of the substituents

Ri or R2 represents a beta-CH3 radical and the other represents an alpha-vinyl radical, CHO, CN, -CH = N-OH, C2-H5 or CH3.

In the general formula (I),

the acyl radical preferably represents an alkanoyl radical such as acetyl or propionyl; it can also represent an aroyl radical such as benzoyl,

the halogen radical preferably represents a chlorine or bromine atom, but it can also represent a fluorine or iodine atom;

- the C1-3 alkyl radical represents one of the following radicals:

methyl, ethyl, propyl, isopropyl, preferably linear radicals;

the esterified carboxy radical preferably represents an alkyloxy carbonyl radical such as methoxy carbonyl or ethoxy carbonyl;

the etherified OH or SH radicals are preferably the methoxy and methylthio, benzyloxy or benzylthio radicals;

- The C3-4 alkyl radicals represent a propyl, isopropyl, butyl, sec-butyl or tert-butyl radical, preferably linear radicals.

The subject of the invention is particularly the products of general formula (1) as defined above in which Re represents a hydrogen atom, R7 represents a hydrogen atom or an acetyl radical, Ri is chosen from the radicals following:

CH2OH, CHO, CO2H, optionally esterified in the form of a methyl or ethyl ester, -CH = NOH,

-ch-cn,

I

Oh

—CH2 — CH2 — N (GH3) 2, —OH2 — CH3, —CH — CHs, —OH2 — CH2 — CH3, —CH2 — CH2 — SCH3,

~ CH2-CH2 ~ S ^ ^

-CH2CI, -CHaBr, -CH2CO2H optionally esterified in the form of methyl or ethyl ester,

ch2-ch-ch3, ch2-c oh 0h

-CH = CH-CH3, -CH = Ç (CH3) 2, -CH2-CH2-OH and R2 is chosen from methyl, vinyl and ethynyl radicals.

A more particular subject of the invention is the products of general formula (1) as defined above in which the substituent Ri is chosen from the following radicals -CH2-OH, CO2H or -CH2-CO2H optionally esterified in the form of methyl or ethyl ester, -CH = CH2, -CH2-CH3, —CH2 — CH2 — CH3j — CH2 — CH2 — S — CH3,

-CH2-CH2-S-Q

-CH2-CH2-OH and especially:

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

A method of preparing the products of general formula I as defined above is also described, characterized in that a product of formula (II) is first treated:

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CH676 598A5

(II)

Ri in which R'i, R'6, R'7, R9 each represent a free or protected OH radical, or R'i and Rg on the one hand, R% and R'7 on the other hand together form radicals :

-oX ":

in which Ra and Rb, which are identical or different, represent a hydrogen atom or an alkyl or alkoxy radical having from 1 to 4 carbon atoms or Ra and Rb together form an oxygen atom and Ri represents a methyl radical

- Either by an oxidation reagent to obtain a product of formula (IIa) corresponding to a product of formula (II) in which Ri = CH2OH, product of formula (IIa) which can either be subjected to a new reagent of oxidation to obtain a product of formula (IIb), corresponding to a product of formula (11) in which Ri = CHO, or else to submit to a halogenation reagent to obtain a product of formula (lie) corresponding to a product of formula (11) in which Ri = CH2X, X representing a halogen atom, or else subject to an oxidizing agent to obtain a product of formula (Ito) corresponding to a product of formula (11) in which Ri = CO2H product which is optionally esterified, or alternatively the product of formula (Ife) in which Ri = CHO is subjected, where appropriate

i) to the action of hydroxylamine hydrochloride to obtain a product of formula (IIe) corresponding to a product of formula (11) in which Ri represents CH = NOH, or else it) to the action of hydrocyanic acid or acetone cyanohydrin to obtain a product of formula (IIf) corresponding to a product of formula (II) in which

R- = -CH-CN,

I

Ott or iii) the action of an oxidation reagent to obtain a product of formula (Ilei) previously described in which Ri = CO2H;

either with an oxidation reagent to directly obtain a product (IIb) in which Ri represents a CHO radical, which, if necessary, is treated as above,

- either with a halogenation reagent to directly obtain a product of formula (llG) previously described in which Ri = CHaX produced only if necessary, or else it is treated with a cyanide ion to obtain a product of formula (llg) corresponding to a product of formula (11) in which Ri = CH2-CN product of formula (llg) which is optionally treated with hydrogen peroxide to obtain a product of formula (Ilh) corresponding to a product of formula (11) in which Ri = CH2CONH2, or else a product of formula (llc) previously described is treated with an alkali metal azide to obtain a product of formula (Hi) corresponding to a product of formula (II) in which Ri = CH2N3 product of formula (Ili) which is optionally treated with triphenylphosphine to obtain a product of formula (11j) corresponding to a product of formula (II) in which Ri = CH2NH2,

- or by a product of formula CH2C = N® <, X ©] in which X © represents a halide ion or a carboxylate ion to obtain a product of formula (llk) corresponding to a product of formula (II) in which Ri = CH2-CH2-N (CH3) 2, product of formula (llk) which is optionally treated with a methyl halide to obtain a product of formula (III) corresponding to a product of formula (II)

in which Ri = -CH2-CH2-N® (CH3) 3, X ©, X © representing a halide ion and product of formula (III) which is optionally treated with a base to obtain a product of formula ( IIm) corresponding to a product of formula (11) in which Ri = -CH = CH2,

- Either a product of formula (II) is treated first with a strong base then, or else with a compound of formula RbX in which Rb represents a C1-3 alkyl radical, allyl or benzyl or with a compound of for -

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CH676 598 A5

mule R'bO (CH2) nX or R 'gS (CHz) nX formulas in which X represents a halogen atom or an arylsulfonate, R'b represents a hydrogen atom, an alkyl radical or a protecting group for the hydroxy radical or thiol and n represents an integer from 1 to 3, to obtain the products of formula (lini), (IIna). (Uns), (Ita) and (lln5) corresponding to the products of formula (II) in which Rt represents respectively an alkyl radical C2-4 (ni), a radical - (CH2) 2-CH = CH2 (n2), a radical - (CH2) 2® (n3), a radical - (CH2) 2-4 OR'b (n4) and (-CH2) 2-4 SR'b (n5),

or by an oxidizing agent to obtain a product of formula (IIa) previously cited corresponding to a product of formula (II) in which Ri = CH20H

or else by a halogenating agent to obtain a product of formula (Ile) previously cited corresponding to a product of formula (II) in which Ri = CH2X, X representing a halogen atom,

or by an agent for introducing the carboxy radical to obtain a product of formula (ll0) corresponding to a product of formula (II) in which Rt = CH2CQ2H, product which, if necessary, is esterified to obtain a product of formula (H'0),

or by an isocyanate of formula R0N = C = 0 in which R0 represents an alkyl radical having from 1 to 4 carbon atoms or a phenyl radical to obtain a product of formula (II "0) corresponding to a product of formula (II ) in which Ri = -CH2-CONH-R0 in which R0 has the previous meaning,

or by a reagent for introducing the aikoxy carbonyl radical to obtain a product of formula (ll'o) in which Ri = -CH2-C02-Alk, formula in which Alk represents an alkyl radical having from 1 to 4 carbon atoms , or by a product of formula

R \

^ C = 0 R * "

in which R "and R '" each represent a hydrogen atom or a methyl radical or else one represents a hydrogen atom and the other represents a methyl radical, to obtain a product of formula (llp) corresponding to a product of formula (II) in which i? "

/

"1 =" ch2> <

oh r "'

products of formula (llp) which are subjected if necessary to dehydration to obtain the products of formula (llq) corresponding to the products of formula (II) in which

R "

R1

= -CHsC ^

V "

or by a product of formula [CH2 = N® <, Xe] in which Xe has the meaning indicated above, to obtain a product of formula (llk) as defined above, then processes the products of formulas

(II), (Ha), (IIb), (He), (lld), (Ile), (llf), (Hg),

(llh), (Ili), (Ili), (llk), (III), (Ilm), (Ilm), (lina),

(Uns), (Un4), (Uns), (Ho), (H'o), (ll "o), (llp) and (Uq)

either with a reagent of formula R2 Cu, (R2) 2 Cu Li, R2 Rnt Cu Li, R2 Rnt Cu (CN) L12 or (R2) z Cu (CN) U2, formulas in which R2 has the values indicated above the exception of the ethynyl value and Rnt represents a non-transferable radical, either by a reagent of formula

(n Bu), Sn-CH = CH-Cu Li,

rnt then with lead tetracetate to obtain products of formula (I) in which R2 represents an ethynyl radical, then treats if desired the products of formula (la) in which Ri represents a radical

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CH676 598A5

CHaOH by an oxidizing agent to obtain the products of formulas (b) in which Ri represents a radical -CHO or the products of formula (ld) in which Ri represents a radical CO2H, then treats if necessary the products thus obtained in which one or more hydroxyl radicals are protected by a protective group, by a deprotection agent and treats, if desired or if necessary, the products obtained in which at least one of the radicals Re and R7 represents a hydroxyl radical by an acylating agent for obtain products of formula (i) in which Fun at least of the radicals Re and R? represents an acyloxy radical.

Among the protective groups that one or more of the substituents R'1, R'6, R'7 and Rg may include, there may be mentioned acyl radicals such as acetyl or propionyl. Preferably, the radicals Ri and R9 on the one hand and Re and R7 on the other hand, together form a radical

The different values that Ra and Rb can form are for example the values ethyl, ethoxy, propyl, propoxy.

If we start from a product in which the radicals R'1, Rg, R'6 and R'7 have not been modified compared to the natural product, the radicals R'1, Rg and R'6 represent a free OH radical and R'7 represents an acetyloxy radical.

a /, The reaction of transformation by oxidation of a product of formula (II) into product of formula (Ha) is carried out with selenium oxide SeOg in the presence of acetic anhydride and acetic acid to obtain the acetate allylic which is saponified by the usual methods, for example in the presence of a base such as sodium hydroxide.

The procedure for this reaction is described, for example, in the following publications: K.B. SHARPLESS, R.F. LAUER J. Am. Chem. Soc 94.7154 (1972) or VX BHALERAO, H. RAPOPORT J. Am. Chem. Soc 93.4835 (1971).

The direct transformation of the products of formula (II) into products of formula (Hb) is also carried out by SeO2. The reaction time can preferably be extended.

b /. The products of formula (IIa) can be oxidized to products of formula (IIb);

i) by a suspension of MnO2 in a hydrocarbon or in benzene according for example to the procedure 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 using latriethyfamine according to the publication A. MANCUSO, D SWERN Synthesis, 165 (1982),

Iii) or according to the method using a Crv | for example pyridium chlorochromate, method described for example in G. CAINELLI, G. CARDILLO, ehromium 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).

cf. The transformation of the products of formula (II) into products of formula (Ile) is preferably carried out using N-bromo or N-chloro succinimide. There is also a procedure for transforming the products of formula (11) into products of formula (Ile) in the references J. Chem. Research (M) 2314-2324 (1980) and Compt. Rend, Acad. Sci Paris 222.1441 (1946).

The transition from the products of formula (IIa) to the products of formula (Hc) is preferably carried out by the action of mesyl or tosyl chloride in the presence of a base such as latriethylamine or pyridine, then exchange of the sulfonate obtained in halide by the usual methods,

d /. The transformation of the products of formula IIb into products of formula IIa is preferably carried out with oxygen in the presence of a catalyst such as platinum. It is preferably carried out 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 transformation of the products of formula (IIa) into products of formula (III) can be carried out under the same conditions.

e /. The transformation of the products of formula (IIb) into products of formula (II) is carried out under the usual conditions using hydroxylamine hydrochloride.

f /. Likewise, the transformation of the products of formula (IIb) into products of formula (Hf) is carried out under conventional conditions, by the action of hydrocyanic acid or of cyanohydrin of acetone.

g /. The transformation of the products of formula (Ile) into products of formula (llg) is carried out in the presence of cyanide ions provided for example by sodium or potassium cyanide.

h /. The transformation of the products of formula (llg) into products of formula (11h) is preferably carried out in the presence of hydrogen peroxide in a slightly basic medium according to the process described by; K.B. WIBERG J. Am. Chem. Soc 75.3961 (1953) K.B. WIBERG J. Am. Chem. Soc 77.2519 (1955)

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CH 676 598 A5

i /. The transformation of the products of formula (li0) into products of formula (III) is preferably carried out in the presence of sodium azide.

d /. The transformation of the products of formula (Ili) into products of formula (11j) is carried out 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 products of formula (llk) is carried out by a “Mannich” type reaction by the action of a product of formula [CH2 = N® <, X ©], X © representing an ion halide or a carboxylate ion.

A description of a reaction of this type is found in the following references:

Y. JASOR, M. GAUDRY, M.J. LUCHE, A. MARQUEÎ Tétrahédron, 33. 295 (1977) and J.L. GRAS, Tet. Lett. 2111 (1978) and 2955 (1978).

I /. The transition from the products of formula (llk) to the products (III) is preferably carried out in the presence of methyl iodide.

m /. The elimination of the ammonium group from the products of formula (III) leading to the products of formula (llm) is carried out in the presence of a base or under the usual conditions.

The strong base in the presence of which a product of formula (II) is treated to obtain an anion on the methyl radical in position 13 is preferably chosen from diisopropyl lithium amide and any other metallic nitrogenous base such as lithiated hexamethyl disilazane , potash or soda.

not/. The action of the product of formula RbX on the anion formed as indicated above is carried out under the usual conditions.

have/. The transformation of the anion indicated above into a product of formula (IIIa) can be carried out:

i) in the presence of oxygen,

ii) in the presence of a peroxo mobyledene complex (MoOs, HMPT) according to the method described in the publication E. VEDEJS, D.A. ENGLER, Y.E. TELSCHOW J. Org. Chem. 43.188 (1978).

iii) in the presence of a derivative of formula according to the method described in the publication FA 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 (II0) can be carried out according to the usual methods using, for example, dry ice. If methyl or ethyl carbonate or methyl or ethyl chloroformate is used, an alkoxycarbonyl radical is introduced and a product of formula (Ilo) can thus be obtained directly in esterified form. The optional esterification of a product of formula (110) can be carried out according to the usual methods, preferably with dia-zomethane.

o ') The action on the anion indicates above an isocyanate of formula RoN = C = 0 in which R0 represents an alkyl radical C1-4 or a phenyie is carried out according to the usual methods.

p) The action on the anion obtained as indicated above of a product of formula which may in practice be gaseous depolymerized formaldehyde or acetaldehyde is preferably carried out in a solvent such as tetrahydrofuran or dimethoxy ethane.

q) The dehydration of the products of formula (llp) into products of formula (llq) is carried out according to the usual methods, either in basic medium or in acidic medium or in the presence of a Lewis acid.

ki) The transformation of the anion obtained as indicated above into the product of formula (llk) by the action of a product of formula [CH2 = N® <, X ©] where X © is a halide or carboxylate ion is carried out under the conditions described in the following references:

- S. DANISHEFSKY and coli J. Am. Chem. Soc. 98.6715 (1976)

-CD. POULTER and coli Tet. Let. 1621 (1977)

- N.L. HOLY, Y.F. WANG J. Am. Chem. Soc. 99, 944 (1977).

R "

R '"*

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CH676 598A5

The action of cuprates on the products of formulas (II) to (llq) is most preferably carried out on products whose hydroxyl functions in positions, 1.9 and 6.7 are protected.

Likewise, when the substituent Ri contains reactive functions such as the CHO, CO2H or -CH2OH functions, these functions are very preferably blocked. Usual blockages are then used, such as cyclic ketals or not, esters or ortho esters, groups protecting the hydroxyl function, such as, for example, ethers or acyls.

Preferably, the action on the products of formulas (lla) to (llq) of cuprates is carried out under the following conditions *.

The organocuprate is first formed according to known methods, then the products of formulas (lla) are added to (llq) and finally, the boron trifluoride etherate is added.

It is preferably carried out at low temperature (for example in the region of -78 ° C to -30 ° C), then the usual treatments are carried out after having allowed the reaction mixture to rise to room temperature.

As organocuprate, the following reagents can be used:

R2 Cu, (R2) z Cu Li, R2 Rnt Cu Li or R2 Rnt Cu (CN) Lia or (R2) 2 Cu (CN) Uz formulas in which R2 and Rnt have the previous values.

The use of the above-mentioned cuprates can be found in the literature on products having a function different from the dihydropyrone function.

We can, for example, cite the following references:

Use 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 radical Rnt preferably represents a thienyl radical:

-B.H. LIPSHUTZ Tet. Lett. 28, 945 (1987)

or a pentynyl radical C3H7-C = C-:

- E.J, COREY and D. BEAMES J. Am. Chem. Soc. 94: 7210 (1972)

or 3-methyl 3-methoxy 1-butynyl:

- E.J. COREY and coli J. Org. Chem. 43, 3418 (1978).

The reagents of formulas R2 Rnt Cu (CN) L12 or (R2) 2 Cu (CN) U2 are for example described in the reference-

-B.H. LIPSHUTZ Tétrahedron 40.5005, (1984).

The joint use of products of this type with boron trifluoride is written for example in the reference:

- B.H. LIPSHUTZ et al. Tet. Lett. 5959 (1984), but no product of this type had ever been used in the preparation of products comprising a dihydropyrone nucleus.

Among the aforementioned cuprates, the products of formula R2RNT Cu Li are preferred in which Rnt represents a thienyl or 1-pentynyl or 3-methyl 3-methoxy 1 -butynyie radical, for example.

The reaction of the products of formula

Cn Bu) 3Sn-CH = CH-Cu Li RNT

and the transformation of the products obtained into products in which R2 represents an ethynyl radical is carried out using lead tetracetate under the conditions indicated in the reference: - E.J. COREY, R.H. WOLLENBERG. J. Am. Chem. Soc. 96.5581 (1974).

Due to the use of lead tetracetate, it is also very preferable that the reaction be carried out on products in which the radicals R'1, Rg, R'6 and R'7 as well as the substituent R'1 when that -this includes a reactive function be protected.

The possible oxidation of the products of formula (la) corresponding to the products of formula (l) in which R1-CH2 OH into products of formulas (lt>) or (ld) in which Ri = CHO or CO2H is carried out under the same conditions than the possible transformations of the products of formula (II) into products of formulas (IIb) or (ild).

The deprotection agent for the products of formula (I) in which one or more hydroxyl radicals are protected by a protective group is chosen from known agents.

The acylating agent which can be used can for example be proplonic anhydride in the presence of pyridine at a temperature of the order of 0 ° C. under the conditions described in the reference J.C.S. 767,1982 or under the conditions described in American patent USP 4,517,200. The acetyl or propionyl radicals are preferred.

A method of preparing the products of general formula (I), as defined above, is also described, in which R 1 represents a methyl radical and R 2 represents an ethynyl radical, characterized in that a product of formula (III) is treated. :

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CH676 598A5

ch3 - • CHO

CIII)

in which R'i, R%, R'7 and Rg are defined as above, with a diazophosphonate of formula then treats if necessary the product of formula (le) thus obtained in which one or more hydroxyl radicals are protected by a protective group with a deprotection agent and treats, if desired or if necessary, the product of formula (I) thus obtained in which at least one of the radicals R6 and R7 represents a hydroxyl radical with an acylating agent to obtain a product of formula (I) in which at least one of the radicals Re and R7 represents an acyloxy radical.

The protective groups are preferably those which have been mentioned above.

The reaction with the diazophosphonate is preferably carried out in the presence of a base such as an alkaline alcoholate such as potassium terbutylate or an alkyilithium such as butyllithium, in a solvent such as tetrahydrofuran.

The operation is preferably carried out at low temperature, allowing it to gradually return to ambient temperature.

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

The deprotecting and acylating agents used are those which have been mentioned above.

The products of general formula (I) which are the subject of the present application have interesting pharmacological properties. Significant activation of the male rat hypocampal adenylate cyclase has thus been demonstrated for some of the products of formula (I) at concentrations of 1 to 100 micro-moles / l.

These properties make the products of general formula (I) suitable for use as medicaments in the cardiovascular field where they can have a positive inotropic effect or an antihypertensive or an anti-thrombotic effect. They can also be used in the treatment of glaucoma. The products of general formula (I) can also exhibit anti metastatic activity or be used as analgesics or bronchodilation agent.

Some of the products of formula (II) to (llq) are also capable of exhibiting similar properties.

A subject of the invention is therefore also, as medicaments, the compounds of general formula (I) which are pharmaceutically acceptable, that is to say non-toxic at the doses used.

A more particular subject of the invention is, as medicaments, the products of formula (I) in which the substituent Rt is chosen from the following radicals -CH2 OH, CO2H or -CH2 CO2H optionally esterified in the form of methyl ester or ethyl, -CH = CH2, -CH2-CH3, -CH2-CH2-GH3, - * GH2 - CH2 — S— ^ CH3,

N2CH-P- <0Me> 2

by operating in the presence of a base, to obtain a product of formula (le):

, ch3

'C == CH

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rr

CH676 598 A5

-ch2-ch2-s

-CH2-CH2 OH and especially:

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

The products of formula (I) can be used by the oral, rectal, transcutaneous or intravenous route. They can be prescribed in the form of tablets, coated tablets, cachets, capsules, granules, emulsions, suppositories, solutions and injectable suspensions.

The new products of formula (I), as defined above can be used to prepare pharmaceutical compositions containing, as active principle, at least one of said products.

The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

A subject of the invention is therefore pharmaceutical compositions containing as active principle at least one product of formula (I).

The subject of the invention is also, as new industrial products and in particular as new industrial products necessary for the preparation of the products of formula (I), the products of general formula (IIa):

in which R'1, R9, R% and R'7 have the meaning indicated above and Rai has the meaning indicated above for Ri except for the methyl value and it being understood that when Rai has a reactive function , said function can be in a protected form.

Among the functions which Ri may include and which can be protected, mention may be made of the functions indicated above and in particular the functions -CHO, CO2H, CH2OH. Examples of protective groups are also cited above.

The starting materials of formula (II) in which R 1 represents a methyl radical are described for example in the reference:

- A.K. SAKSENA and Coli J. Chem. Soc. Chem. Comm. 1748 (1985).

The starting materials of formula (III) can be obtained by ozonolysis of forskolin by operating in the presence of pyridine in the methylene chloride-methanol mixture.

The following examples illustrate the invention without, however, limiting it.

Example 1: Tétrahvdroxv 1 alpha. 6beta. 7beta. 9aloha nor-15 éooxv 8.13 labdane one-11.

Stage A: Tetrahydroxy 1 alpha, 6beta, 7beta, 9alpha epoxy-8,13 Iabdene-14one-11 bis acetonide 1.9: 6.7.

To a solution of forskolin (600 mg; 1.46 mmol) in 30 ml of CH2Cl2, add methoxy-2-propene (280 µl * 2.92 moles) and p-toluene sulfonic acid (a trace) then stirred for 15 hours at room temperature. Anhydrous K2CO3 is added, the mixture is stirred for 20 minutes, then NaHCO3 is added in saturated solution and extraction is carried out with CH2Cl2. It is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 0.65 g of white crystalline solid is obtained. A solution of sodium hydroxide (200 mg; 5 mmol) in 20 ml of water and 80 ml of methanol is added, followed by stirring for 48 hours. Extraction is carried out with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 0.60 g of white foam is obtained which is dissolved in 30 ml of CH2Cl2. Add 2-propene methoxy (280 µl; 2.92 mmol) and p-toluene sulfonic acid (a trace), then stir for 15 hours. 100 μl of 2-propene methoxy are added, then the mixture is stirred for 8 hours. The mixture is stirred with an excess of anhydrous K2CO3 for 15 minutes, then NaHCO3 is added in saturated solution and extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 0.69 g of slightly yellow solid is obtained which is purified by chromatography on silica (eluent CH2Cl2). 620 mg of expected product is obtained, white crystalline solid (94%). Mp 164 ° C.

] R (CHCI3): 1710 cm-1

SMl 448 (M +); 362

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Stage B: Tetrahvdroxv lalpha, 6beta, 7beta, 9alpha dinor-14.15 epoxy-8.13 labdene-12 one-11 bis acetonide 1.9: 6.7.

To a solution of product obtained in stage A (224 mg; 0.5 mm) in 10 ml of CCI4 and 10 ml of aceto-nitrile, 15 ml of water are added, sodium metaperiodate (481 mg; 2, 25 mmol) and ruthenium trichloride trihydrate (13 mg; 0.05 mm). The mixture is stirred vigorously at room temperature for 5 hours. Sodium metaperiodate (267 mg; 1.25 mm) is added, then the mixture is stirred vigorously for 2 hours. CH2Cl2 and water are added, then extracted with CH2GI2. Dried over Na2SO4, the solvent is evaporated off under reduced pressure, then the residue is taken up in ether and filtered. The solvent is evaporated off under reduced pressure to obtain 244 mg of brown solid. 150 μl of pyridine, 25 mg of cupric acetate and 4 ml of benzene are added, then the mixture is stirred for 1 hour 30 minutes at room temperature to obtain a green solution. Lead tetracetate (660 mg; -1.5 mm) is added. Stirred for 2 hours at room temperature, then heated to reflux for 1 hour. After cooling to room temperature, CH2Cl2 is added to the mixture, filtered through alumina which is first washed with 5 ml of methanol, then with CH2Cl2. The filtrate is washed with water and dried over Na2SO4. After evaporation of the solvent under reduced pressure, 240 mg of crude product are obtained which is purified by chromatography on silica (eluent: CH2Cl2). 160 mg of expected product, white crystalline solid, are obtained by trituration with ether (76%). Mp 123 ° C.

! B (CHCI3): 1666; 1619 UV (EtOH): X max 278 nm, s = 8500 M: 405 (M- + - CH3); 362; 347

Stage C: Tetrahvdroxv lalpha, 6beta, 7beta, 9alpha nor-15 epoxy-8,13 labdane one-11 bis acetonide 1.9: 6.7.

To a suspension of cuprous iodide (571 mg; 3 mmol) in 2 ml of dry ether stirred at 0 ° C under argon, a solution of methyllithium in ether is added until a gray solution of Me2CuLi is present a few yellow grains of (MeCu) n (6 ml; 0.37 M solution in Me2CuLi). 2.7 ml of this solution (1 mm) are added to a solution of product obtained in stage B (84 mg; 0.2 mm) in 4 ml of dry ether at -78 ° C under argon, then BF3-Et20 distilled (110 µl; 0.9 mm) and stirred for 1 hour at -78 ° C. The mixture is left to return to ambient temperature in 30 minutes, then the NH4Cl mixture in saturated solution -NH4OHC (9-1) is added. It is strongly stirred, then extracted with CH2Cl2. It is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 96 mg of crude product are obtained which are purified by chromatography on silica (eluent CH2Cl2). 77 mg of expected white crystalline solid product (85%) are obtained. Mp 151 ° C. B (CHCI3) 1709 MS: 436 (M-4); 350

Stage D: Tetrahvdroxv lalpha, 6beta, 7beta9alphanor-15 epoxy 8,13-Iabdane one-11.

To a solution of product obtained in stage C (24 mg; 0.055 mm 3) in 1.1 ml of THF, 0.8 ml of 7 N hydrochloric acid is added, then the mixture is stirred at room temperature for 29 hours. CH2CI2 and water are added and then extracted with CH2CI2. Washed with NaHCO3 in saturated solution, dried over Na2SO4, then the solvent is evaporated off under reduced pressure. 19 mg of crude product are obtained which are purified by chromatography on silica (eluent CH2Cl2 - ether 9: 1). 11 mg of expected product is obtained, giving white crystals by trituration with ethanol (56%).

MS: 356 (M +); 338; 300; 282

Example 2: Tétrahdroxv l alpha. 6beta. 7beta. 9alpha épi-13 époxv-8.13 labdane one-11 bis acetonide 1.9: 6.7.

Stage A: Tetrahvdroxv 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 μl; 1.1 mm 3) in 4 ml of dry THF stirred at 0 ° C. under argon, a solution of n-butyllithium in 1.5 M hexane (0.8 ml; 1.2 mm) and HMPT (191 μl; 1.1 mm), then cooled to -78 ° C and stirred for 10 minutes at -78 ° C. A solution of the product obtained in Example 1, stage B (420 mg; 1 mm) in 2 ml of THF (+ 0.2 ml to rinse) is added over 10 minutes, then the mixture is stirred for 25 minutes at -78 °. vs. Methyl iodide (65 µl; 1.05 mm) is added and allowed to warm to room temperature in 30 minutes, followed by further stirring for 10 minutes. Ether is added, washed with water and extracted with ether. It is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 442 mg of white solid are obtained, which is purified by chromatography on silica (eluent GH2Cl2). 432 mg of expected product is obtained, white crystalline solid (96%). Mp 173 ° C.

iE (CHCI3): 1663; 1613 UV (EtOH): X max 279 nm, e = 8700 SM: 419 (M- + - CHs); 376; 361 FD 434 (M +)

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Stage B: Tetrahvdroxv alpha, 6beta, 7beta, 9alpha epi-13 epoxy-8.13 labdane one-11 bis acetonide 1.9: 6.7.

To a suspension of cuprous iodide (571 mg; 3 mmol) in 2 ml of dry ether stirred at 0 ° C under argon, a solution of methyllithium in ether is added until a gray solution is obtained of MeaGuLi in the presence of a few yellow grains of (MeCu) n (4.5 ml; 0.44 M solution in MegCuU). 1.25 ml of this solution (0.55 mm) is added to a solution of product obtained in stage A (48 mg; 0.11 mm) in 2 ml of ether at -78 ° C under argon, then BF3- B2Ö distills (120 µl; 0.98 mm) and is stirred for 1 hour at -78 ° C. The mixture is left to return to ambient temperature in 30 minutes, then the NH4Cl mixture in saturated solution -NH4OH (9-1) is added. Extraction is carried out with CH2Cl2, dried over NaaSO4 and the solvent is evaporated off under reduced pressure. 47 mg of a slightly yellow crystalline solid are obtained which are purified by chromatography on silica (eluent CH2Cl2). 40 mg of expected product is obtained, white crystalline solid (80%), mp 190 ° C.

JR (GHCI3): 1707 SM: 450 (M- +)

Stage C: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha epi-13 epoxy-8.13 labdane one-11.

To a solution of product obtained in stage B (20 mg; 0.044 mm) in 1 ml of tetrahydrofuran, add 0.5 ml of 2N hydrochloric acid and 0.5 ml of concentrated hydrochloric acid, then stir for 48 hours at temperature ambient. CH2Cl2 and water are added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 21 mg of crude product are obtained which is purified by chromatography on silica (eluent CH2Cl2-Et20 9-1 then 8-2). 4.5 mg of expected product (27%) is obtained.

NMR 250 MHz fCDClaì:

Ethyl CHs: 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-5: 2.09 (d; J = 2.5); H-6: 4.49 (dd after exchange; J = 2.5 and 4); H-7; 4.07 (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 3: Tétrahvdroxv lalpha. 6beta. 7beta. 9alpha epoxv-8.13 labdene-14 one 11bis- acetonide 1.9: 6.7 and corresponding product 13-eoi.

To a solution of vinyltributyltin (817 mg; 2.5 mmol) in 4 ml of dry ether under argon, a solution of butyllithium in hexane 1.5 M (1.3 ml; 1.95 mmoie) is added, then stirred for 1 hour 10 minutes at room temperature. This solution is added to a suspension of pulverized copper iodide (229 mg; 1.2 mm) in 4 ml of ether, stirred at -60 ° C under argon and stirred from -40 ° C to -25 ° C for 3 hours (black suspension). Cool to -78 ° C, then add a solution of the product obtained in Example 1, stage B (84 mg; 0.2 mm) in 2 ml of ether (+0.2 ml to rinse) and BF3Et20 distilled (110 (il; 0.9 mmoie). The mixture is stirred for 1 hour at -78 ° G, then allowed to return to room temperature in 30 minutes, The NH4CI mixture is added in saturated NH4OH solution (9-1) and extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure, 976 mg of slightly yellow oil are obtained, which is purified by chromatography on silica (eluent CH2Cl2). First, 53 mg of expected product, crystalline solid is obtained. white (59%), then 13 mg of corresponding ear product, white crystalline solid (14%) Product 13 ear] R (CHCI3): 1711.1644 MS: 448 (M- +)

Example 4: Trihvdroxv-1 aloha. 6beta. 9alphaacetoxv-7beta nor-15 eooxv-8.13 labdane one-11.

To a solution of the product obtained in Example 1 (57.5 mg; 0.16 mmol) in 1.6 ml of pyridine, acetic anhydride (18 μl; 0.10 mm) is added and then stirred at room temperature for 17 hours. Acetic anhydride (9 (il; 0.095 mm)) is added and then stirred for 71 hours, CH2Cl2 and water are added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. white solid which is purified by chromatography on silica (eluent: CH2Cl2-Et) 20-1 then 8-2), 8.5 mg of diacetate-1.7 are obtained, white crystalline solid (12%), 36, 5 mg of monoacetate 7beta, white crystalline solid (57%).

IR (GHCI3): 3607,1743,1711,1246.

MS: 398 (M +); 380,342,324.43.

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CH676 598A5

Example 5: Tetrahvdroxv-1 alpha. 6beta. 7beta. 9alpha ethvl-15 epoxv-8.13 labdane one-11 and corresponding 13-ear product.

Stage A: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha ethyl-15 epoxy-8.13 labdane one-11 blsacetonide-1.9: 6.7 (isomer 1) and corresponding 13-epi product (isomer 2).

To a solution of cuprous iodide (105 mg; 0.55 mm) in 2.5 ml 40 of dry ether at -35 ° C under argon, a solution of 1.57 M n-butyllithium in hexane is added (0.64 ml; 1 mmoie) then stirred between -30 ° C and -32 ° C for 30 minutes (black suspension). The mixture is cooled to -78 ° C. and then a solution of the product obtained in Stage B of Example 1 (84 mg; 0.2 mm) in 2 ml of ether is added (rinsed with 0.2 ml of ether) and distilled boron trifluoride etherate (30 (il; 0.24 mm). The mixture is stirred for 1 hour at -78 ° C. and then allowed to return to room temperature in 30 minutes. A mixture of saturated NH4Cl-concentrated NhUOH is added ( 9-1), stirred vigorously for 20 minutes then extracted with CH2CÌ2, dried over Na2SÖ4 and evaporated the solvent under reduced pressure to obtain 102 mg of crude product which is purified by chromatography on silica (eluent: CH2Cl2). 61 mg of expected product 13-ear, colorless lacquer (61%) and 22.5 mg of the other isomer.

Stage B: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha ethyl-15 epoxy-8.13 labdane one-11 and corresponding 13-ear product.

17.5 mg of product obtained in stage A (isomer 2) are stirred in 0.84 ml of tetrahydrofuran and 0.6 ml of 7N hydrochloric acid at 20 ° C. After 18 hours, another 0.3 ml of 2N hydrochloric acid is added and stirring is continued for 56 hours. It is taken up in water and extracted with methylene chloride. After drying over sodium sulfate and evaporation under reduced pressure, the residue is chromatographed on silica (cyclohexane-ethyl acetate 4-1). 4.5 mg of expected product is obtained, a homogeneous white solid (Rent: 30%).

300 MHz NMR (CDCI ^:

CH of butyl: 0.91 (t; J = 7); CH3: 1.07 (s), 1.27 (3), 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.

By operating in a manner identical to that described above, starting from the isomer 1 obtained in stage A, the expected product is obtained.

Example 6: Tetrahvdroxv-1 alpha. 6beta. 7beta. 9aloha epoxv-8.13 labdvne-14 one-11.

Stage A: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha dinor-14.15 epoxy-8.13 labdane one-11 carboxaldehyde-13 acetonide-1.9 carbonate-6.7.

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

To a solution of 410 mg of forskolin (1.0 mm) in 20 ml of methylene chloride, stirred at 20 ° C., first add 0.14 ml of 2-methoxy propene (1.5 eq), then 0.1 ml of a 0.01 M solution of para-toluenesulfonic acid in methylene chloride. After 5 hours, the mixture is neutralized with stirring with approximately 100 mg of anhydrous potassium carbonate. It is then taken up in a saturated solution of sodium bicarbonate and extracted with methylene chloride. The organic phase is dried over sodium sulfate, then evaporated under reduced pressure. The residue is chromatographed on a silica column (CH2Cl2-AcOEt 9-1) to give 417 mg of expected product (yield 93%).

iE (CHCI3): 3605,1740,1714,1250.

MS: 450 (M- +); 432.43.

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

2.5 ml of 2N aqueous sodium hydroxide (4 eq) is added to the solution of 563 mg of product obtained in stage Ai (1.25 mm 3) in 28 ml of methanol, at 20 ° C., and the mixture is stirred overnight. The methanol is then evaporated under reduced pressure, at room temperature. The residue is taken up in water and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate. After evaporation to dryness under reduced pressure, 517 mg of expected product, white solid is obtained (Yield 100%).

Isomer 1

Product 13-ear: isomer 2

1B (CHCI3): 1707

SM 478 (M- *); 335,277,219

Jfì (CHCI3): 1707 SM: 335,277,219 FD: 478

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CH676 598A5

JR (CHCIa): 3588,3085,1713,1640,

MS: 408 (M- +); 390,350.

Stage A3: Tetrahydroxy-1 alpha, 6beta, 7beta 9alpha epoxy-8,13 labdene-14 one-11 acetonide-1,9 carbo-nate-6,7.

205 mg of product obtained in stage A2 (0.5 mm) are stirred in 10 ml of toluene with 163 mg of car bonyidiimidazole (2 eq), 5 hours at 60 ° C, then after subsequent addition of 50 mg of carbonyldiimidazole again 6 hours at reflux. After cooling, pour into water, extract with methylene chloride and dry over sodium sulfate. After evaporation under reduced pressure, 258 mg are obtained which are chromatographed on a silica column (CHaCfe-ethyl acetate 95-5) to provide 213 mg of the expected product (homogeneous white powder) (yield 98%).

300 MHz NMR (CDCI3):

CHa: 1.10 (8) 1.21 (s), 1.30 (s), 1.36 (s), 1.38 (s), 1.39 (s); 1.46 (s); H-1; 4.42 (dd; J = 2 and 3); H-5: 2.61 (d; 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-1 alpha, 6beta, 7beta, 9alpha, dinor-14.15 epoxy-8.13 labdane one-11 carboxal-dehyde-13 acetonide-1.9 carbonate-6.7.

A solution of 327 mg of product obtained in stage A3 (0.75 mm) in 10 ml of methylene chloride and 1.2 ml of pyridine (15 mmol) is cooled to -78 ° C., in an acetone-dry ice bath, before bubbling an oxygen-ozone mixture until a slight pale blue-gray coloration is obtained. A stream of nitrogen is then passed until discoloration and then another 10 minutes, before adding 0.05 ml of dimethylsulfide and allowing to rise to 20 ° C. The mixture is stirred for another 30 minutes, then poured into water and extracted with methylene chloride. After drying over sodium sulfate and evaporation under reduced pressure, the residue is chromatographed on a silica column (CH2CÌ2-ethyl acetate 95-5). 308 mg of expected product is thus obtained (white powder) (yield 94%).

IR (CHCI3): 2820,1802,1740,1726 MS: 436 (M- +); 421,407.43.

Stage B: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9a! Epoxy-8,13 labdyne-14 one-11 acetonide-1,9 carbonate-6,7.

To a solution of dimethyl diazomethylphosphonate (60 mg; 0.4 mm) in 3 ml of dry tetrahydrofuran at -78 ° C under nitrogen, a solution of 1.5M n-butyllithium in hexane (0, 27 ml; 0.4 mmol) (orange coloring) and then stirred for 10 minutes at -78 ° C. A solution of product obtained in Stage A (89 mg; 0.2 mm) is added in 3 ml of tetrahydrofuran, stirred for 30 minutes at -78 ° C and then allowed to return to room temperature in 30 minutes and stirred for 16 hours. CH2GI2 and water are added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 104 mg of yellow lacquer are obtained. To the aqueous phase (-50 ml), 5 ml of 2N sodium hydroxide is added, left for 4 hours, acidified with 5.5 ml of 2N hydrochloric acid and extracted with GH2Cl2. It is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 5 mg of yellow lacquer are thus obtained. The whole is purified by chromatography on silica (CH2Cl2-AcOEt 99-1 then 9-1 then 1-1 then AcEt). 22.5 mg of expected product is obtained, white crystalline solid (25%) and 19 mg of corresponding dihydroxy-6.7 product, yellow lacquer (23%).

Stage C: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha epoxy-8.13 labdyne-14 one-11 acetonide-1.9.

To a solution of product obtained in stage B (carbonate- 22.5 mg; 0.052 mm 3) in 2 ml of methanol, 0.2 ml of sodium hydroxide N is added and the mixture is stirred for 21 hours (formation of a white crystalline precipitate). 0.22 ml of sulfuric acid N is added and the mixture is stirred for 20 minutes, CH2CJ2 and water are added, then extracted with CH2GI2. It is dried over Na2SO * and the solvent is evaporated off under reduced pressure. 22 mg of expected product is obtained, colorless lacquer (100%).

Stage D: Tetrahvdroxv-1 alpha, 6beta, 7beta, 9alpha epoxy-8,13 labdyne-14 one-11.

To a solution of product obtained in stage C (45 mg; 0.11 mm) in 2 ml of tetrahydrofuran, 1.6 m are added! 2N hydrochloric acid and 0.4 ml of concentrated hydrochloric acid and then stirred for 16 hours at 20 ° C. CH2Cl2 and water are added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 43 mg of yellow lacquer are obtained which is purified by chromatography on silica (eluent: CH2Cl2-AcOËt 9-1 then 8-2). 27 mg of expected product is obtained, white crystalline solid (67%).

M (CHCI3): 3611.3306.1716 SM: 366 (M- + Ì: 348.

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Example 7: Tetrahvdroxv-1 alpha. 6beta. 7beta. 9alpha éooxv 8.13 labdvne-14 one-11 acétvl-7.

To a solution of the product obtained in Example 6 (38.5 mg; 0.105 mm) in 0.5 ml of pyridine, an acetic anhydride-pyridine mixture 1-9 (150 (it; 159 mm)) is added and then stirred for 17 hours at 20 ° C. Add 150 μl of acetic anhydride-pyridine mixture 1-9, stir for 9 hours, add CH2Cl2 and water and extract with CH & Gh. Dried over Na2SO4 and the solvent evaporated under reduced pressure 44 mg of colorless lacquer are obtained which is purified by chromatography on silica (eluent: CH2CÌ2-AcOEt 9-1 then 8-2). 29 mg of expected product is obtained, colorless lacquer crystallizing from CCI4 (67%).

jR (CHCI3): 3609.3478.3306,1744,1717,1371,1245.

MS: 408 (M- + Ì: 390.43.

Example 8: Tetrahvrdroxv-1 alpha. 6beta. 7beta. 9aloha ethvi-15 eooxv-8.13 labdane one-11.

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

0.33 ml (0.5 mmoie) of n-butyllithium (1.5 M in (hexane) is added to the suspension of 193 mg (0.5 mmoie) of n-propyltriphenylphosphonium bromide in 2.2 ml of tetrahydrofuran stirred at 0 ° C. After 30 minutes, the orange suspension obtained is placed in a bath at -78 ° C. and 56.3 mg of product obtained in Example 6, stage A4 (0.125 mm) is introduced in 2 minutes ) in solution in 2 ml of tetrahydrofuran. The temperature is then allowed to rise, with stirring, to be at 20 ° C. in 50 minutes and then a colorless medium is obtained. The mixture is stirred for another 1 hour 20 minutes, then taken up in methylene chloride and a phosphate buffer solution at pH 7. After extraction with CH2Cl2, drying over sodium sulphate, evaporation under reduced pressure, 240 mg of residue is obtained which is taken up in a little ethyl ether to remove the major part of triphenylphosphine oxide after filtration The ethereal solution gives after evaporation 107 mg of r residue which is chromatographed on a silica column (cyclohexane-ethyl acetate 9-1) then supply 34 mg of expected product (mixture of Z and E isomers) (yield 59%).

Stage B: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha ethyl-15 epoxy-8.13 labdane one-11.

A solution of product obtained in stage A (34 mg; 0.073 mm) in 5 ml of 96% ethanol is stirred in the presence of 20 mg of 5% palladium on activated carbon under a hydrogen atmosphere for 3 hours 30 minutes. The solvent is filtered and evaporated under reduced pressure. 34 mg of white solid are obtained which are dissolved in 3 ml of methanol. 0.3 ml of sodium hydroxide N is added and the mixture is stirred for 15 hours (formation of a white crystalline precipitate). 0.33 ml of N hydrochloric acid is added and the mixture is stirred for 30 minutes (dissolution). CH2Cl2 and water are added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 32 mg of colorless lacquer are obtained which is dissolved in 2 ml of tetrahydrofuran. 1.6 ml of 2N hydrochloric acid and 0.4 ml of concentrated hydrochloric acid are added and the mixture is stirred for 26 hours. CH2Cl2 and water are added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 30 mg of colorless lacquer are obtained which is purified by chromatography on silica (eluent: CH2Cl2-AcOEt 9-1). 25 mg of expected product is obtained, colorless lacquer, giving a white solid in the presence of cyclohexane (85%). 1

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

Example 9: Tetrahvdroxv-1 alpha. 6beta. 7beta. 9alpha éthvl-15 époXV-8.13 labdane one-11 acétvl-7.

To a solution of product obtained in Example 8 (24 mg; 0.06 mmoie) in 0.3 ml of pyridine, an acetic anhydride-pyridine mixture 1-9 (120 μl; 0.127 mmoie) is added and then stirred for 23 hours. CH2Cl2 and water are added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 24 mg of colorless lacquer are obtained which is purified by chromatography on silica (eluent: CH2CI2-AcOEt 9-1). 11.5 mg of expected product is obtained, a white crystalline solid (43%).

MS: 440 (M +); 422.43.

Example 10: Tetrahvdroxv-1 alpha. 6beta. 7beta. 9alpha epoxv-8.13 labdene-14 one-11 and corresponding 13-ear product.

Stage A: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha-8,13 epinor-14,15 labdene-12 one-11 acetonide-1,9 acetyl-7.

Stage Ai: Tetrahydroxy-1 alpha, 6beta, 7beta, 9alpha dinor-14.15 epoxy-8.13 labdane one-11 carboxalde-hyde-13 acetonide-1.9 acetyl-7.

A stream of oxygen and ozone is passed through the colorless solution of 406 mg of product obtained in Example 6, stage Ai (0.9 mm) in 10 ml of methylene chloride containing 0.5 ml of methanol and

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CH676 598A5

0.185 ml of pyridine (2.5 eq), stirred at -78 ° C until a pale blue-gray color is obtained. Then a stream of argon is bubbled for 15 minutes, then 0.1 ml of dimethylsulfide (1.36 mm) is added, before allowing to return to 20 ° C. It is then taken up in water, extracted with methylene chloride. After drying over sodium sulfate and evaporation under reduced pressure, 434 mg of white solid residue are obtained. After chromatography on a silica column (eluent: cyclohexane-ethyl acetate 4-1), 370 mg of the expected aldehyde are isolated (yield 91%) (white solid).

JR (CHCI3): 1724.

MS: 437.423.43.

FD: 452 (M), 423.

Stage A2: Tetrahydroxy-1 alpha, 6beta, 7beta, 9alpha-epoxy-8,13 dinorl 4,15 labdene-12 one-11 acetonide-1,9.

A solution of 340 mg of product obtained in stage Ai (0.75 mm 3) in 4.3 ml of pyridine is stirred with 63 mg (1.2 eq) of hydroxylamine hydrochloride for 2 hours 15 minutes at 20 ° C. Then poured into water and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated under reduced pressure, codistilizing with toluene to remove traces of pyridine. The oxime obtained (quantitative yield) is dissolved in 10 ml of methylene chloride. After addition of 244 mg of carbonyldiimidazole (2 eq), the mixture is brought to reflux for 3 hours 30 minutes. After cooling, it is taken up in water and extracted with methylene chloride. After drying over sodium sulfate and evaporation under reduced pressure, 341 mg of expected nitrile are obtained (quantitative yield).

NMR 250MHz (CDGI3):

GHs: 1, Û3 (s), 1.26 (8), 1.46 (s) (x2), 1.56 (s), 1.61 (s), l, 63 (s);

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 nitrite (0.62 mm 3) in 10 ml of methanol and 1 ml of 2N aqueous sodium hydroxide is stirred at 20 ° C overnight. Poured into water and extracted with methylene chloride. The organic phase is dried over sodium sulfate, then evaporated to dryness under reduced pressure to yield 230 mg of residue. After chromatography on a silica column (CHzClz-ethyl acetate 9-1), 214 mg of expected product is obtained (yield 90%) (white solid).

B (CHCI3): 3610.3591.16651.1621.

JLJV (EtOH): 280 nm; e = 9000.

SM: 365.322.307.

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

The procedure is analogous to that described in Example 9, starting with the product obtained in stage Az and obtaining the expected product.

Stage B: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha epoxy-8,13 labdene-14 one-11 and corresponding 13-spike product.

To a solution of vinyltributyltin (1.226 9; 3.75 mmol) in 6 ml of dry ether under argon, a solution of 1.6M n-butyilithium in hexane (1.875 ml; 3 mmol) is added and then stirred for 2 hours. This solution is added to a suspension of cuprous iodide (343 mg; 1.8 mm) in 6 ml of ether at -50 ° C under nitrogen (gray coloring) and then stirred from -45 ° C to -25 ° C in 2 hours 30 minutes (black suspension). Cool to -78 ° C, add distilled boron trifluoride etherate (165 μl; 1.34 mm) and a solution of product obtained in stage A (123 mg; 0.3 mm) in 20 ml of ether (rinse with 2 mi of ether). Stirred for 40 minutes at -78 ° C and then allowed to return to room temperature in 35 minutes. A saturated solution of sodium acid tartrate is added and the mixture is then stirred overnight (pale yellow precipitate). Extraction is carried out with AcOEt, dried over NazSO 4 the solvent is evaporated off under reduced pressure, the residue is taken up in CH2Cl2, filtered and the solvarit is evaporated under reduced pressure. 1.437 g of orange oil containing solid are obtained, which is treated as indicated in Stage D of Example 6. 1.410 g of orange oil containing solid is obtained, which is purified by chromatography on silica (eluent: CHaClz-EfeO 9-1 then 8-2), 4 mg of expected product is obtained, colorless lacquer (3.6%) and 25 mg of the other expected isomer (13-ear), white crystalline solid (22.5 %).

13-ear product:

] R (nujol): 3480,3365,3290,1706,1642.

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CH676598 A5

MS: 368 (M- +); 350.

Example 11: Tetrahvdroxv-1 alpha. 6beta. 7beta. 9alpha. 13-eoi epoxv-8.13 labdene-14 one-11 acetvl-7 and the corresponding 13-eoi isomer.

To a solution of the product obtained in Example 10 (isomer 13-ear: 20 mg; 0.054 mmoie) in 0.5 ml of pyridine, an acetic anhydride-pyridine mixture 1-9 (77 μl; 0.08 mmoie) is added ) then stir for 16 hours. 77 μl of the mixture are added and the mixture is stirred for 5 hours then 160 μl of the mixture are added and the mixture is stirred for 3 hours 45 minutes then 160 μl of the mixture is added and the mixture is stirred for 1 hour 30 minutes. CH2Cl2 and water are added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 19 mg of colorless lacquer are obtained which is purified by chromatography on silica (eluent: CH2Cl2-Et2O 9-1 then 8-2). 3 mg of diacetate 1.9 (12%) and 10.5 mg of expected product 13-ear, white crystalline solid (47%) are obtained.

SMi 410 (M- +); 392.43.

By following a procedure analogous to that described above starting from the other isomer obtained in Example 10, the expected product is obtained with an identical yield.

Example 12: Pentahvdroxv-1 alpha. 6beta. 7beta. 9aloha. 14 nor-15 epoxv-8.13 labdane one-11.

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

A solution of 3 ml of sodium hydroxide N in 9 ml of water and 48 ml of methanol is added to Forskolin (821 mg; 2 mmol) and then the mixture is stirred for 62 hours (rapid dissolution). Water is added, extracted with CH2Cl2, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 0.80 g of white crystalline solid is obtained which is purified by chromatography on silica (eluent: CH2Cl2-Et20 8-2). 750 mg of expected product is obtained, white crystalline solid (100%).

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

To a solution of product obtained in stage A (150 mg; 0.4 mm) in 10 ml of toluene, car-bonyldiimidazole (649 mg; 4 mmol) is added and then heated at 80-85 ° C for 6 hours. After cooling to room temperature, CH2Cl2 and water are added, extracted with ChfeCk, dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 0.18 g of white crystalline solid is obtained which is purified by chromatography on silica (eluent: GH2Cl2-Et2Q 98-2). 159 mg of expected product is obtained, white crystalline solid (94%).

Stage C: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9a! Pha dinor-14.15 epoxy-8.13 labdane one-11 carboxaldehyde-13 bis carbonate-1.9: 6.7.

An ozone-oxygen stream is passed through a solution of product obtained in stage B (149 mg; 0.35 mm) in 6 ml of CH2Cl2 and 4 ml of methanol at -78 ° C until a blue color is obtained clear. A stream of nitrogen is then passed for 20 minutes and then 260 μl of methyl sulfide are added. The mixture is left to return to ambient temperature and then stirred for 2 hours. CH2Cl2 and water are added, extracted with CH2Cl2, dried over NaaSO4 and the solvent is evaporated off under reduced pressure. 188 mg of colorless lacquer are obtained which is purified by chromatography on silica (eluent: CH2Cl2-Et20 9-1). 137 mg of expected product is obtained, a white crystalline solid (91%).

] R (CHCI3): 1835,1814,1765,1741,1691.

MS: 422 (M- +); 393.349.

FD: 422.393.

Stage D: Pentahvdroxv-1 alpha, 6beta, 7beta, 9alpha, 14 nor-15 epoxy-8,13 labdane one-11 bis carbonate-1,9: 6,7.

To a solution of product obtained in stage C (85 mg; 0.2 mmoie) in 5 ml of dry tetrahydrofuran, lithium triterbutoxyaluminohydride (56 mg; 0.22 mmoie) is added and then stirred for 1 hour 25 minutes. 5 mg of hydride are added and the mixture is stirred again for 45 minutes. A saturated solution of ammonium chloride is added, extracted with AcOEt, dried over Na2SO4, the solvent is evaporated off under reduced pressure, taken up in CH2Cl2, filtered and the solvent is evaporated off under reduced pressure. 92 mg of white solid are obtained which are purified by chromatography on silica (eluent: CH2Cl2-Et02 9-1 then 8-2). 57 mg of expected product, glassy solid (66%) are obtained.

Stage E: Pentahvdroxv-1 alpha, 6beta, 7beta, 9alpha, 14 nor-15 epoxy-8,13 labdane one-11.

To a suspension of product obtained in stage D (57 mg; 0.13 mm 3) in 5 ml of methanol, 1 ml of sodium hydroxide N is added and then stirred for 24 hours. Add 3 ml of water, stir for 48 hours, add 1 ml

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CH 676 598 A5

of water and stirred again for 24 hours. Extracted with AcOEt, dried over Na2SO4, the solvent evaporated under reduced pressure, taken up in CH2Cl2, filtered and the solvent evaporated under reduced pressure. 47.5 mg of expected product is obtained, white crystalline solid (95%).

] R (nujol): 3520.3447.3339.3188.1717.

MS: 372 (M- +); 354,341,336,323,305.

Example 13: Tetrahvdroxv-1 alpha. 6beta. 7beta. 9aloha dinor-14.15 epoxv-8.13 labdane one-11 carboxal-dehvde-13 bis acetonide-1.9: 6.7 and tetrahvdroxv-1 alpha. 6beta. 7beta. 9alpha dinor-14.15 epoxv-8.13 labdane one-11 carboxv-13 bis acetonide-1.9: 6.7.

An oxygen-ozone mixture is passed into a solution of 449 mg of product obtained in Stage A of Example 1 (1.0 mm) in 12 ml of methylene chloride and 0.4 ml of pyridine (5 eq), cooled to -78 ° C. Ozone saturation occurs after 10 minutes (pale blue-gray coloring) and the oxygen-ozone bubbling is continued for an additional 15 minutes.

A stream of nitrogen is then passed through for 20 minutes and 0.1 ml of dimethyl sulfide is added, before allowing to rise to 20 ° G. The mixture is stirred for another 30 minutes then taken up in water and extracted with methylene chloride. After drying over sodium sulfate and evaporation under reduced pressure, 483 mg of a slightly colored gum are obtained. After chromatography on a silica column (CHaCfe-ethyl acetate 95-5 / NEt3 1 °%, 160 mg of expected carboxaldehyde-13 product (35.5%) is obtained. Then eluting with CH2Cl2-CH3OH 85-15, obtains 198 mg of expected carboxy-13 product (yield 42.5%).

JR (CHGI3) carboxy-13 product: 3400,1769,1723.

Example 14: Tetrahvdroxv-1 alpha. 6beta. 7beta. 9alPha ethvl-15 epoxv-8.13 labdane one-11 bis acetonide-1.9: 6.7.

Stage A: Tetrahvdroxv-1 alpha, 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 mmoie) in 4.4 ml of dry tetrahydrofuran under argon at room temperature, a solution of 1.57M n-butyllithium in Phexane (0.63 ml; 1 mmoie) is added ) then stir for 30 minutes (orange solution * \ - 0.2M). 0.65 ml of this solution (0.13 mm) is added to a solution of carboxaldehyde-13 product obtained in Example 13 (54 mg; 0.12 mm) in 2 ml of tetrahydrofuran under argon and then stirred for 1 hour 20 minutes at room temperature. 0.25 ml of the ylide solution (0.05 mm) is added, the mixture is stirred again for 30 minutes, 0.3 ml of the ylide solution (0.06 mmoie) is added and the mixture is stirred again for 30 minutes. Ether and water are added, extracted with ether which is washed with water and dried over NaaSO *. The solvent is evaporated off under reduced pressure and 78 mg of slightly yellow lacquer is obtained which is purified by chromatography on silica (eluent: CH2Cl2) - 22 mg of expected product is obtained (mixture of E and Z isomers), colorless lacquer ( 38%).

Stage B: Tetrahvdroxv-1 alpha. 6beta, 7beta, 9alpha ethyl-15 epoxy-8.13 labdane one-11 bis acetonide-1.9: 6.7.

A solution of the product obtained in stage A (23 mg; 0.048 mm) is stirred in 3 ml of 96% ethanol in the presence of 10 mg of 5% palladium on carbon under a hydrogen atmosphere for 3 hours 15 minutes. The solvent is filtered and evaporated under reduced pressure. 23 mg of expected product is obtained, colorless lacquer (a. 100%).

PHARMACOLOGICAL STUDY

The products of the invention were tested with the aim of determining their activity on the adenyiate cycla-se "in vitro".

The enzyme is assayed in a homogenate of rat hippocampal tissue by measuring the formation of cyclic adenosine monophosphate from phosphorus-labeled adenosine triphosphate 32.

The percentage of stimulation of the enzyme was determined for each product tested at the concentration of 10-5M or 10-4M compared to the control without product (= 100%). The results are shown in the table below:

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Example product

% of stimulation lO ^ M

lO ^ M

6

7 9 11

196 517 167 230

322,863 296,403

Claims (8)

Claims 1. Compounds of general formula (I): -2 (I) OR6 in which Re and R7, which are identical or different, represent a hydrogen atom or an acyl radical, Ri represents: either a methyl radical optionally substituted by a hydroxyl, halogen, cyano, amino, phenyl, carboxyl radical optionally esterified, azido or carbamoyl optionally substituted by a C1-3 alkyl radical, either an ethyl radical optionally substituted by a dimethylamino, trimethylammonium, OH or SH radical, each of these two radicals being optionally etherified, a vinyl or phenyl radical, either a C3-4 alkyl radical optionally substituted by an OH or SH radical, each of these two radicals being optionally etherified, either a radical in which either R "and R '" each represent a hydrogen atom or a methyl radical, or else one represents a hydrogen atom and the other represents a methyl radical, - either a CHO, CN, optionally esterified CO2H radical, CH = NOH or in which R 'represents a hydrogen atom or a methyl radical, - or a radical -CH-CN 0H Hz represents: or a C1-3 alkyl radical, - be a radical 19 5 10 15 20 25 30 35 40 45 50 55 in CH 676 598 A5 in which either R'2 and R "2 each represent a hydrogen atom or else one represents a hydrogen atom and the other a C1-3 alkyl radical, either an ethynyl radical, with the exception of the products in which one of the substituents Ri to Ra represents a beta-CHa radical and the other represents an alpha-vinyl radical, CHO, CN, -CH = N-OH, C2H5 or CH3. 2, Compounds of general formula (I) as defined in claim i, in which Re represents a hydrogen atom and R7 represents a hydrogen atom or an acetyl radical, Ri is chosen from the following radicals; CH2OH, CHO, CO2H, optionally esterified in the form of a methyl or ethyl ester, -CH = NOH, -CH2CI, -CHaBr, -CH2CO2H optionally esterified in the form of methyl or ethyl ester, -CH = CH-CH3, -CH = C (CH3) 2, -CH2-CH2-OH and R2 is chosen from methyl, vinyl and ethynyl radicals. 3. Compounds of general formula (I) as defined in one of claims 1 or 2, in which the substituent Rt is chosen from the following radicals -CH2-OH, -CO2H or -CH2-CO2H optionally esterified in the form of 'methyl or ethyl ester, -CH = CH2, -CH2- CH3, -CH2-CH2-CH3, -CH2-CH2-S-CH3, -CH2-CH2 OH. 4. Compounds of general formula (I), as defined in claim 1 corresponding to the following nomenclature: trihydroxy-1 alpha, 6beta, 9alpha acetoxy-7beta epoxy-8,13 labdyne-14 one 11. 5. Compounds of formula (I), as defined in claim 1, pharmaceutically acceptable, as medicaments. 6. Compounds of formula (I), teile as defined in one of claims 2 to 4, pharmaceutically acceptable, as medicaments. 7. Pharmaceutical compositions containing, as active principle, at least one of the medicaments defined in one of claims 5 or 6. 8. Compounds of general formula (Ha): -ch-cn, I Oh -CH2-CH2-N (CHs) 2, -CH2-CH3, -CH = CH2, -CH2-CH2-CH3, -CH2-CH2-SCH3 20 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 676 598 A5 in which R'i, R'6, RV and R9 each represent a free or protected OH radical or R'i and R9 on the one hand, R'6 and R'7 on the other hand together form radicals in which Ra and Rb, identical or different, represent a hydrogen atom or an alkyl or alkoxy radical having from 1 to 4 carbon atoms or Ra and Rb together form an oxygen atom and Rai has the meaning indicated in claim 1 for Ri with the exception of the methyl radical, it being understood that when Rai comprises a reactive function, said function can be in a protected form, as products for the preparation of the compounds of formula (I), as defined in claim 1. 21