FR2614891A1 - NOVEL FORSKOLINE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF, THEIR USE AS MEDICAMENTS, THE PHARMACEUTICAL COMPOSITIONS COMPRISING THEM, AND THE INTERMEDIATES OF THEIR PREPARATION PROCESS - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS PRODUCTS OF FORMULA: (CF DRAWING IN BOPI) IN WHICH: R AND R H OR ACYL. A: IN PARTICULAR METHYL POSSIBLE SUBSTITUTE, ETHYL POSSIBLE SUBSTITUTE, CHO, COH, C NOH OR -CH-CN. OR R: ALKYL C-, -CHC R ETR H OR ALK C OR ETHYNYL, THEIR PROCESS OF PREPARATION, THEIR APPLICATION AS MEDICINAL PRODUCTS, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THE INTERMEDIARIES OF THEIR PROCESS OF PREPARATION.

Description

The present invention relates to novel derivatives of Forskolin,

  Their preparation process, their application as medicaments, the pharmaceutical compositions containing them as well as

intermediates in their process.

  Forskolin is a diterpene, isolated from the roots of the Indian plant "CoLeus Forskohlii", which has been assigned

  Pharmaceuticals of Interest (J.C.S. Perkin I, 767 (1982) and Tet.

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 C1983) or US Pat. No. 4,517,200).

  Although the reconstruction of the core C of Forskolin derivatives having no hydroxy radical at the 1, 6 and 7 positions could be carried out (J. Chem Soc Chem Common, 24, 1987), the attempts at certain functionalizations on the carbon at the 13-position of Forskolin and in particular the 1,4-addition on a dihydropyrone formed by the ring C have failed so far (J. Chem Soc Chem Common 1748,

1985).

  The plaintiff has developed a new reaction which allows

  to access, from the Forskoline, interesting new derivatives.

  The present invention therefore firstly relates to the products of general formula I: R -43 R o <R am R

- I

  In which R6 and R7, which are identical or different, represent a hydrogen atom or an acyl radical, R1 represents: either a methyl radical optionally substituted by a halogenated hydroxyl radical, cyano, amino or carbamoyl, optionally substituted by an alkyl radical; C1_3 or a phenyl radical, optionally esterified carboxyl or azido, - is an ethyl radical optionally substituted with a dimethylamino radical, trimethylammonium, OH, or SH each of these two radicals being optionally etherified, a vinyl or phenyl radical, - or an alkyl radical C3_4 possibly substituted by a radical

261'4891

  OH or SH, each of these two radicals being optionally etherified, 1 CH3 - is a radical CH2-C in which R 'represents a hydrogen atom H' R 'or a methyl radical, R "- is a radical -CH = Wherein R "and R" "R1 'each represent a hydrogen atom or a methyl radical, or one represents a hydrogen atom and the other represents a methyl radical, or a CHO radical; , Optionally esterified CO2, CH = NOH or

- H-CN.

  R 2 represents: - either an alkyl radical C1_3, R '_ / 2 - or a radical -CH = C in which either R'2 and R "2

\ R-'2

  each represents a hydrogen atom or 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 R 1 or R 2 represents a beta-CH 3 radical and the other represents a

  alpha-vinyl radical, CHO, CN, -CH = N-OH or C2-H5.

  In the general formula I, the acyl radical is preferably an alkanoyl radical such as acetyl or propionyl. he can

  also represent an aroyl radical such as benzoyl.

  - The halogen radical preferably represents a chlorine atom or

  bromine, but it can also represent a fluorine or iodine atom.

  - The alkyl radical C1_3 represents one of the following radicals: methyl, ethyl, propyl, isopropyl, preferably linear radicals. The esterified carboxy radical preferably represents a radical

  alkyloxycarbonyl such as methoxycarbonyl or ethoxycarbonyl.

  - The etherified OH or SH radicals are preferably the radicals

  methoxy and methylthio, benzyloxy or benzylthio.

  The C3-4 alkyl radicals represent a propyl-isopropyl radical;

  butyl, sec-butyl or tert-butyl, preferably linear radicals.

  The subject of the invention is particularly the products of general formula I as defined above in which R 6 represents a hydrogen atom and R 7 represents a hydrogen atom and R 7

  represents a hydrogen atom or an acethyl radical.

  R1 is chosen from the following radicals CH20H, CHO, -CO2H, optionally esterified in the form of methyl or ethyl ester, - CH = NOH, -CH-CN, -CH2-CH2-N (CH3) 2, OH

  -CH2-CH3, -CH = CH2, -CH2-CH2-CH3, -CH2-CH2-SCH3;

-CH2-CH2-S--;

  -CH 2 Cl, -CH 2 Br, -CH 2 CO 2 H optionally esterified to form CH 3 of methyl or ethyl ester, CH 2 -CH-CH 3, CH 2 -,

OH OH CH3

  -CH = CH-CH3, -CH = C (CH3) 2, -CH2-CH2-OH

  R2 is selected from methyl, vinyl or ethynyl.

  The invention more particularly relates to the products of the general formula I as defined above in which the substituent R 1 is chosen from the following radicals -CH 2 OH, CO2H or -CH 2 CO 2 H optionally esterified in the form of methyl or ethyl ester. , CH = CH2, -CH2-CH3, -CH2-CH2-CH3,

  -CH 2 -CH 2 -S-CH 3, -CH 2 -CH 2 -S->, -CH 2 -CH 2 OH.

  Among the preferred products, mention may be made of the product corresponding to the following nomenclature: -tetrahydroxy 1 alpha, 6 beta, 7 beta, 9 alpha nor15-epoxy 8.13 labdane

one It.

  The subject of the invention is also a process for preparing the products of general formula I as defined above, characterized in that a product of formula II is first treated: R6 in which R'1, R'6, R'7, R9 each represent a free or protected OH radical, or R'1 and R9 on the one hand, R'6 and R'7 on the other hand together form radicals: - Ra -OXRb in which Ra and Rb identical or different represent a hydrogen atom, or an alkyl or alkoxy radical having 1 to 4 carbon atoms or Ra and Rb together form an oxygen atom and R1 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 R1 = CH20H, a product of formula IIa which may be subjected to a new reagent of oxidation to obtain a product of formula IIb, corresponding to a product of formula II in which R1 = CHO, or subject to a halogenating reagent to obtain a product of formula IIc corresponding to a product of formula II in which R1 = CH2X , X represents a halogen atom, or subject to an oxidation agent for o obtain a product of formula IId corresponding to a product of formula II in which R1 = CO2H is produced which is optionally esterified, or the product of formula IIb in which R1 = CHO i) is optionally subjected to the action of hydroxylamine hydrochloride to obtain a product of formula IIe corresponding to a product of formula II in which

R1 = CH = NOH.

  ii) the action of hydrocyanic acid or cyanohydrin of acetone to obtain a product of formula IIf corresponding to a product of formula II in which R1 = -CH-CN OH iii) to the action of an oxidation reagent to obtain a product of formula IId previously described wherein R1 = CO2H, or by an oxidation reagent to obtain a product IIb in which R1 represents a radical CHO: - or by a halogenation reagent to obtain a product of formula IIc previously described in which R1 = CH2X, which product may optionally be treated with a cyanide ion to obtain a product of formula IIg corresponding to a product of formula II in which R1 = CH2- CN product of formula IIg which can optionally be treated with hydrogen peroxide to obtain a product of formula IIb corresponding to a product of formula II in which R1 = CH2CONH2, or a product of formula IIc described above is treated by an azi alkali hardstock to obtain a product of formula II in which formula IIl is optionally treated with triphenylphosphine to give a product of formula IIj corresponding to a product of formula II in formula (II); R1 = CH2 NH2, or a product of the formula CH2C = N <X wherein X represents a halide ion or a carboxylate ion to give a product of formula I1k corresponding to a product of formula II in which R1 = CH2 -CH 2 -N (CH 3) 2, a product of formula IIk which may optionally be treated with a methyl halide to give a product of formula III corresponding to a product of formula II in which R 1 = -CH 2 -CH 2 -N (CH 3) 3 X, X representing a halogen atom and a product of formula I 11 which may optionally be treated with a base to obtain a product of formula IIm corresponding to a product of formula II in which R 1 = -CH = CH 2, - or treat a product of formula II firstly with a strong base and then with an RBX radical in which RB represents a C 1-3 alkyl, an allyl, benzyl or a radical R'BO (CH 2) nX or R'BS (CH 2) wherein X represents a halogen atom or arylsulfonate, R'B represents a hydrogen atom, an alkyl radical or a protecting group of the hydroxyl or thiol radical and n represents an integer of 1 to 3 to obtain IInl IIn2 IIn3 IIn4 and IIn5 corresponding to the products of formula II in which R1

  represents respectively an alkyl radical C2_4 (n1), a radical -

  (CH2) 2-CH = CH2 (n3) a radical - (CH2) 2 (n3), a radical -

  (CH2? 2-4 OR'B (n4) and - (CH2) 24 SR'B (n5), or by an oxidizing agent to obtain a previously mentioned product of formula IIa corresponding to a product of formula II in which

R1 = CH20H,

  or by a halogenating agent to obtain a product of formula IIc previously mentioned corresponding to a product of formula II in which R 1 = CH 2 X, X representing a halogen atom, or else by a carboxy radical introducing agent for to obtain a product of formula IIo corresponding to a product of formula II in which R1 = CH2CO2H, product which may optionally be esterified to obtain a product of formula II'O or of an isocyonate of formula RoN = C = O in which Ro represents an alkyl radical having from 1 to 4 carbon atoms or a phenyl radical to obtain a product of formula II "o corresponding to a product of formula II in which R 1 = CH 2 -CO-NH-Ro in which Ro has the the preceding meaning, or else by a reagent for introducing the alkoxycarbonyl radical to obtain a product of formula II'o in which R1 = CH2-CO2 Alk, in which formula Alk represents an alkyl radical having from 1 to 4 carbon atoms, R or by a product of formula wherein R "and R" R 1 "each represent a hydrogen atom or a methyl radical or one represents a hydrogen atom and the other represents a methyl radical to obtain a product of formula IIp corresponding to an R "

  product of formula II in which R1 = -CH2-

OH'- R '"

  products of formula IIp which are optionally subjected to dehydration to obtain the products of formula IIq corresponding R "to the products of formula II in which R1 = -CH = C

- \ R '"

  or by a product of formula ECH2 = N4, X] in which X has the meaning indicated above to obtain a product of formula IIk as defined above and then processes the products of formulas II, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, IIi, IIj, IIk, IIl, IIm, IInl, IIn2, IIn3, IIn4, IIn5, IIo, II'o, IIp and IIq, or by a reagent of formula R2 Cu, ( R 2) 2 Cu Li, R 2 RNT Cu Li, R 2 RNT Cu (CN) Li 2 or (R 2) 2 Cu (CN) Li 2, formulas in which R 2 has the values indicated above with the exception of ethynyl and RNT represents a non-transferable radical, either by a reagent of formula (n Bu) 3 Sn-CH = CH-, u Li., then by the RNT lead tetracetate to obtain a product in which R2 represents an ethynyl radical, and then treated if desired products of formula Ia wherein R1 represents a CH20H radical by an oxidizing agent to obtain the products of formulas Ib in which R1 represents a radical -CHO or the products of formula Id in laq R1 represents a radical C02H, then treats the products if necessary.

2 6 1 4891

  thus obtained in which one or more hydroxyl radicals are protected by a protecting group by a deprotection agent and treat if desired or necessary if the products obtained in which at least one of the radicals R6 and R7 represents a hydroxyl radical by a d acylation to give a product of formula I in which one

  at least one of R6 and R7 represents an acyloxy radical.

  Protecting groups that one or more substituents R'1, R'6, R'7 and R9 may include, include acyl radicals such as acetyl or propionyl. Preferably, the radicals R1 and R9 on the one hand and R6 and R7 on the other hand, form

together a radical X or C = O.

  The different values that Ra and Rb can form are

  example: the ethyl, ethoxy, propyl, propoxy values.

  If we start from a product in which the radicals R'1, R9, R'6 and R'7 have not been modified, relative to the natural product, the radicals R'1, R9 and R'6 represent a free OH radical

  and R'7 represents an acetyloxy radical.

  at/. The reaction of oxidation of a product of formula II to a product of formula Ia is carried out by selenium oxide SeO 2 in the presence of acetic anhydride and acetic acid to obtain the allylic acetate which is saponified by the usual methods, by

  example in the presence of a base such as sodium hydroxide.

  The procedure of this reaction is described, for example, 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 conversion of the products of formula II to products of formula IIb is also carried out by SeO2. We can preferably

lengthen the reaction time.

  b /. The oxidation of the products of formula IIa to products of formula IIb can be carried out: i) by a suspension of MnO 2 in a hydrocarbon or in benzene according to, for example, the procedure described in the publication AJ FATIADI Synthesis 65 (1976), ii or according to the so-called "Swern" method in methylene chloride or chloroform and using triethylamine according to the publication A. MANCUSO, D SWERN Synthesis, 165 (1982), chlorochromate, method described for example in 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) 2314-2344 (1980).

  c /. Transformation of the products of formula II into products of formula IIc is preferably carried out using N-bromo or N-chloro succinimide. There is also a procedure for converting the products of formula II into products of formula IIc in the reference

  J. Chem. Research (M) 2314-2324 (1980).

  Compt. Makes. Acad. Sci Paris 222, 1441 (1946).

  The passage of the products of formula IIa to products of formula IIc is preferably carried out by the action of mesyl or tosyl chloride in the presence of a base such as triethylamine or pyridine,

  then exchange of the sulfonate obtained in the halide by the usual methods.

  d /. The conversion of the products of formula IIb into products of formula IId is preferably carried out by oxygen in the presence of a catalyst such as platinum. The operation 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).

  Direct processing of formula IIa products into products

  of formula IId can be carried out under the same conditions.

  e /. The products of formula IIb are converted into products of formula IIe under the usual conditions using hydroxylamine hydrochloride. f /. Likewise, the conversion of the products of formula IIb into products of formula IIf is carried out in standard conditions, by action.

  of hydrogen cyanide or cyanohydrin of acetone.

  g /. The conversion of the products of formula IIc into products of formula IIg is carried out in the presence of cyanide ions provided for example by

  sodium cyanide or potassium cyanide.

  h /. The conversion of the products of formula IIg into products of formula IIh is preferably carried out in the presence of hydrogen peroxide in a slightly basic medium according to the method described by K. B. WIBERG J. Am. Chem. Soc. 75, 3961 (1953)

"77, 2519 (1955)

  i /. The processing of formula IIc products into products of

  formula IIij is preferably carried out in the presence of sodium azide.

  j /. The transformation of the products of formula II into products of formula IIj is carried out in the presence of triphenyl phosphine according to the method described in the publication N. KNOUZI, M. VAULTIER, R. CARRIE

261 4891

Bull Soc. Chim. Fr. 815 (1985).

  k /. The conversion of the products of formula II to products of formula IIk is carried out by a reaction of the "Mannich" type by the action of a - +, _ e_ product of formula [CH2 = N <, X], X representing a halide ion

  representing a halide ion or a carboxylate ion.

  A description of a reaction of this type is found in

  following references: Y. JASOR, M. GAUDRY, M.J. LUCHE, A. MARQUET Tetrahedron, 33, 295 (1977)

  and J. L. GRAS, Tet. Lett. 2111 (1978) and 2955 (1978).

  l /. The transition from products of formula IIk to products IIl is

  preferably carried out in the presence of methyl iodide.

  m /. The elimination of the ammonium group of the products of formula III leading to the products of formula IIm is carried out in the presence of a

  base or under the reaction conditions.

  The strong base in the presence of which a product of formula II is treated in order to obtain an anion on the methyl radical in position 13 is preferably chosen from lithium diisopropyl amide or any other metallised 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 performed under the usual conditions.

  al /. The transformation of the anion indicated above into a product of formula IIa can be carried out i) in the presence of oxygen, ii) in the presence of a peroxo complex of mobyledene (Mo05, HMPT) according to the process described in publication E VEDEJS, DA ENGLER,

  Y.E. TELSCHOW J. Org. Chem. 43, 188 (1978).

  CH-9 iii) in the presence of a derivative of formula N so2-o according to the method described in the publication F.A. DAVIS, L.C. VISHWAKARMA,

  J. M. BILLMERS, J. FINN J. Org. Chem. 49, 3241 (1984).

  o) The transformation of the anion indicated above into a product of formula IIo can be effected according to the usual methods using, for example, dry ice. If methyl or ethyl carbonate or a methyl or ethyl chloroformate is used, an alkoxycarbonyl radical is introduced and it is thus possible to obtain directly a product of

& n fmrmirra c TT, _t.t ç_1 ..

  product of formula IIo can be carried out according to the usual methods,

  preferably with diazomethane.

  o ") The action on the anion indicated above of an isocyanate of formula RoN = C = O in which Ro represents a C 1-4 alkyl radical or a phenyl is carried out according to the usual methods. on the anion obtained as indicated above a product of formula R "C = O which may be in practice depolymerized formaldehyde R, gaseous or acetaldehyde is preferably carried out in a solvent such

  than tetrahydrofuran or dimethoxy ethane.

  q) The dehydration of the products of formula IIp into products of formula IIq is carried out according to the usual methods, either in a basic medium,

  either in an acid medium or in the presence of a Lewis acid.

  k1) The transformation of the anion obtained as indicated above into a product of formula IIk by the action of a product of formula ## STR4 ## is a halide or carboxylate ion carried out under the conditions described in the following references: S. DANISHEFSKY et al J. Am Chem Chem Soc 98, 6715 (1976) CD POULTER et al Tet, 1621 (1977)

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

  The action of cuprates on the products of formulas II to IIq is carried out very preferentially on products whose functions

  hydroxyls in positions 1, 9 and 6, 7 are protected.

  Likewise, when the substituent R 1 comprises reactive functions such as the CHO, CO 2 H or -CH 2 OH functions, these functions are very preferably blocked. The usual functions, such as cyclic or non-cyclic ketals, esters or ortho esters, and protective groups of the hydroxyl function, for example, are used.

  as for example ethers or acyls.

  Preferably, the action on the formula products

  IIa to IIq, cuprates are made under the following conditions.

  The organocuprate is first formed according to the known methods, then the products of formulas IIa to IIq are added and finally, one adds

  boron trifluoride etherate.

  It is preferably carried out at low temperature (for example in the region of 78nC at -30mC), then the usual treatments are carried out after

  let the reaction mixture rise to room temperature.

  As organocuprate, the following reagents R.sub.2 Cu, (R.sub.2) .sub.2 Cu Li, R.sup.2 RNT Cu Li or R.sup.2 RNT Cu (CN) Li.sup.2 or (R.sub.2) .sub.2 Cu (CN) Li.sub.2 may be used, in which R.sup.2 and RNT,

having the previous values.

  The use of the aforementioned cuprates on products having a function different from the dihydropyrone function will be found in the literature.

  For example, the following references may be cited.

  Use of R2 Cu and (R2) 2 Cu Li reagents 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 pentenyl radical C3H7-C = C-: E.J. COREY and D. BEAMES J. Am. Chem. Soc. 94: 7210 (1972) or 3-methyl-3-methoxy-butynyl E.J. COREY et al., J. Org. Chem.

43, 3418 (1978).

  The reactants of the formula RNT R 2 (Cu) CN (Li 2) or (R 2) 2 Cu (CN) Li 2 are for example described in the reference:

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

  The joint use of products of this type with boron trifluoride is described for example in the reference: - 8H. LIPSHUTZ et al. Tet. Lett. 5959 (1984), but never any such product had been used in the preparation of products

a dihydropyrone ring. -

  Among the cuprates mentioned above, the products of formula

  R2RNT Cu Li in which RNT represents a thienyl radical or 1-

  pentynyl or 3-methyl-3-methoxy-1-butynyl, for example.

  The reaction of the products of formula (n Bu) 3 Si-CH = CH-u Li

-RNT

  and the conversion of the products obtained into products in which R2 represents an ethynyl radical is carried out using lead tetraacetate under the conditions indicated in the reference:

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

  Because of the use of lead tetraacetate, it is also very preferable for the reaction to be carried out on products in which the radicals R'1, R9, R'6 and R'7 as well as the substituent

  R'1 when it includes a reactive function are protected.

  The possible oxidation of the products of formula Ia corresponding

  Al Y nrndilitQ HP fnrcmii [T riAnq lAnlil IP ... -

12 2614891

  formulas Ib or Id in which R1 = CHO or CO2H is carried out under the same conditions as the possible transformations of the products of formula II into products of formula II into products of formulas IIb

Yes D.

  The deprotection agent of the products of formula I in which one or more hydroxyl radicals are protected by a group

  protector is selected from known agents.

  The acylating agent that can be used can be, for example, propionic anhydride in the presence of pyridine at a temperature of the order of O'C under the conditions described in J.C.S. 767 '1982'

  or under the conditions described in USP 4, 517, 200.

  Acetyl or propionyl radicals are preferred.

  The products of general formula I, objects of the present application have interesting pharmacological properties. Significant activation of male ritonaval hypocampal adenylate cyclase has thus been demonstrated for some of the products of formula I at low doses.

micromolar to 100 micromolar.

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

  analgesics or bronchodilating agent.

  Some of the products of formula II to IIq are also

  likely to have similar properties.

  The subject of the invention is therefore also, as medicaments,

  the compounds of general formula I pharmaceutically acceptable, that is,

  ie non-toxic at the doses used.

  The subject of the invention is more particularly, as medicaments, the products of formula I in which the substituent R 1 is chosen from the following radicals -CH 2 OH, CO2H or -CH 2 CO2H, optionally esterified in the form of methyl or ethyl ester,

-CH = CH2, -CH2-CH3, -CH2-CH2-CH3,

  CH-CH 2 -SH 2 -CH 3, -CH 2 -CH 2 -S-, -CH 2 -CH 2 OH.

  Even more particularly, the subject of the invention is, as a medicament, the product corresponding to the following nomenclature: tetrahydroxy 1 alpha, 6 beta, 7 beta, 9 alpha nor-15-epoxy 8,13 labdane

one 11.

  The products of formula (I) can be used orally, rectally, transcutaneously or intravenously. They may be prescribed in the form of tablets, coated tablets, cachets, capsules, granules, emulsions, suppositories, solutes and injectable suspensions. The new products of formula (I), as defined above, can be used to prepare pharmaceutical compositions

  containing, as active ingredient, at least one of said products.

  The active ingredient (s) can be incorporated into the excipients usually employed in these pharmaceutical composites, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles. , fats of animal or vegetable origin, paraffinic derivatives, glycols,

  various wetting, dispersing or emulsifying agents, preservatives.

  The subject of the invention is therefore pharmaceutical compositions

  containing as active ingredient at least one product of formula CI).

  The subject of the invention is also, as new industrial products and especially as new industrial products necessary for the preparation of the products of formula I, the products of general formula IIA Ri R 5 Rai IA

X '' R '

R

  in which R'1, R9, R'6 and R'7 have the meaning indicated above and RA1 has the meaning indicated above for R1 with the exception of the methyl value and it being understood that when RA1 has a function responsive, said function can be in a form

protected. -

  Among the functions that may comprise R1 and which can be protected include the functions indicated above and in particular the functions -CHO, C02H, CH20H. Examples of groupings

  protectors are also mentioned 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 Col J. Chem. Soc. Chem. Comm. 1748 (1985).

  The following examples illustrate the invention without however the iii :: | Example 1: Tetrahydroxy 1-6lpha, 6-beta, 7-beta, 9-alpha nor-epoxy 8,13-laabdane one-11 Step A: tetrahydroxy-1L-alpha, 6-beta, 7-beta, 9-alpha

  epoxy 8,13-labdene 14-one 11-bis-acetonide 1.9: 6.7.

  To a solution of forskolin (600 mg, 1.46 mmol) in 30 ml of CH 2 Cl 2 was added methoxy-2-propene (280 °, 2.92 moles) and p-toluenesulfonic acid (spatula tip). ) and then stirred for 15 hours at room temperature. Anhydrous K 2 CO 3 was added, stirred for 20 minutes, then saturated NaHCO 3 was added and extracted with CH 2 Cl 2. It is dried over Na 2 SO 4 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. Extracted with CH 2 Cl 2, dried over Na 2 SO 4 and the solvent evaporated under reduced pressure. 0.60 g of white foam is obtained which is dissolved in 30 ml of CH 2 Cl 2. Methoxy 2-propene (280 μl, 2.92 mmol) and p-toluenesulfonic acid (a spatula tip) are added, followed by stirring for 15 hours. 100 μl of methoxy-2-propene are added, followed by stirring for 8 hours. It is stirred with an excess of anhydrous K 2 CO 3 for 15 minutes, then saturated NaHCO 3 is added and extracted with CH 2 Cl 2. It is dried over Na 2 SO 4 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 CH 2 Cl 2). 620 mg of expected product is obtained, white crystalline solid

(94%).

IR (CHCl 3): 1710 cm -1

MS: 448 (M +); 362

  Stage B: tetrahydroxy 1-alpha, 6-beta, 7-beta 9-alpha dinor

  14,15-epoxy 8,13-labdene 12-one 11-bis-acetonide 1, 9: 6.7.

  To a solution of product obtained in Step A (224 mg, 0.5 mmol) in 10 ml of CCl4 and 10 ml of acetonitrile was added 15 ml of water, sodium metaperiodate (481 mg, 2.25 mmol). ) and ruthenium trichloride trihydrate (13 mg, 0.05 mmol). The mixture is stirred vigorously at room temperature for 5 hours. Sodium metaperiodate (267 mg, 1.25 mmol) is added, followed by vigorous shaking for 2 minutes.

  hours. CH 2 Cl 2 and water are added and then extracted with CH 2 Cl 2.

  It is dried over Na 2 SO 4, the solvent is evaporated under reduced pressure and the residue is taken up in ether and filtered through Celite. The solvent is evaporated under reduced pressure to give 244 mg of brown solid. 150 μl of pyridine, 25 mg of cupric acetate and 4 ml of benzene are added, followed by stirring for 1 hour 30 minutes at room temperature to increase the concentration of olombenate. (660 mg;

26 1 4 89 1

  1.5 mmol). Stirred for 2 hours at room temperature, then heated at reflux for 1 hour. After cooling to room temperature, CH 2 Cl 2 is added to the mixture, filtered through a little alumina which is washed first with 5 ml of methanol and then with CH 2 Cl 2. The filtrate is washed with water and dried over Na 2 SO 4. After evaporation of the solvent under reduced pressure, 240 mg of green lacquer are obtained which is purified by chromatography on silica (eluent: CH 2 Cl 2). A lacquer giving 160 mg of expected product is obtained, white crystalline solid by trituration

with ether (76%).

  IR (CHCl 3): 1666; 1619 UV (EtOH): max 278 nm, = 8500

MS: 405 (M- + -CH3); 362; 347

  Stage C: tetrahydroxy 1-alpha, 6-beta, 7-beta, 9-alpha nor

  epoxide 8.13-labdane on 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 Me 2 CuLi in the presence of a few yellow grains of (MeCu) n (6 ml, 0.37M solution in Me 2 CuLi). 2.7 ml of this solution (1 mmol) is added to a solution of product obtained in Stage B (84 mg, 0.2 mmol) in 4 ml of dry ether at -78 ° C. under argon, and then distilled BF 3 -Et 2 ( 0.9 mmol) and stirred for 1 hour at -78 ° C. Allowed to warm to room temperature in minutes, then saturated NH4Cl -NH40Hc 9: 1 was added. The mixture was stirred vigorously and then extracted with CH2CL2. It is dried over Na 2 SO 4 and the solvent is evaporated off under reduced pressure. 96 mg of lacquer are obtained

  colorless, which is purified by chromatography on silica (CH 2 Cl 2 eluent).

  77 mg of expected white crystalline solid product (85%) is obtained.

IR (CHCl3) 1709

MS: 436 (M +); 350

  Stage D: tetrahydroxy 1-alpha, 6-beta, 7-beta 9-alpha nor

epoxide 8.13-labdane one-11.

  To a solution of product obtained in Stage C (24 mg, 0.055 mmol) in 1.1 ml of THF, 0.8 ml of 7 N hydrochloric acid is added, followed by stirring at room temperature for 29 hours. CH 2 Cl 2 and water are added and then extracted with CH 2 Cl 2. Wash with saturated NaHCO 3, dry over Na 2 SO 4 and then evaporate the solvent under reduced pressure. 19 mg of colorless lacquer are obtained which are purified by chromatography on silica (eluent CH 2 Cl 2 ether 9: 1). 11 mg of expected product is obtained, colorless lacquer giving white crystals by trituration with

ethanol (56%).

  Example 2 Tetrahydroxy 1-alpha, 6-beta, 7-beta, 9-alpha epi 13-epoxy

  8,13-labdane one-11 bis acetonide 1.9: 6.7.

  Stage A: Tetrahydroxy 1-alpha, 6-beta, 7-beta, 9-alpha

  nor 16-epoxy 8,13-labdene 12-one 11-bis-acetonide 1.9: 6.7.

  To a solution of diisopropylamine (154 μl, 1.1 mmol) 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; 2 mmol) and HMPT (191, μL, 1.1 mmol), then cooled to -78 ° C. and stirred for 10 minutes at -7 ° C. A solution of product obtained in Example 1, Stage B (420 mg, 1 mmol) in 2 ml of THF (+ 0.2 ml for rinsing) is added over 10 minutes and then stirred for 25 minutes at -78 ° C. Methyl iodide (65 → 1.05 mmol) was added and allowed to warm to room temperature over 30 minutes, followed by further stirring for 10 minutes. Ether is added, washed with water and extracted with ether. It is dried over Na 2 SO 4 and the solvent is evaporated off under reduced pressure. 442 mg of white solid are obtained which are purified by chromatography on silica (eluent CH 2 Cl 2). We obtain

  432 mg of expected product, white crystalline solid (96%).

  IR (CHCl 3): 1663; 1613 UV (EtOH): max 279 nm, = 8,700

MS: 419 (M + - CH3); 376; 361

FD 434 (M +)

  Stage B: Tetrahydroxy 1-alpha, 6-beta, 7-beta, 9-alpha spike

  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 of Me 2 Cu / Li 2 is obtained. in the presence of some yellow grains of (MeCu) n (4.5 ml, 0.44 M solution in Me2CuLi). 1.25 ml of this solution (0.55 mmol) are added to a solution of product obtained in Step A (48 mg, 0.11 mmol) in 2 ml of ether at -78 ° C. under argon, and then distilled BF3-Et2O. (120ul, 0.98 mmol) and stirred for 1 hour at -78mC. Allowed to warm to room temperature in 30 minutes, then saturated NH4Cl -NH40Hc 9: 1 is added. Extracted with CH2Cl2, dried over Na2SO4 and the solvent evaporated under reduced pressure. 47 mg of slightly yellow crystalline solid are obtained which are purified by chromatography on silica (eluent CH 2 Cl 2). We obtain 40 mg of expected product, solid

white crystalline (80%).

IR (CHCl3: 1707

* SM: 450 (M- +)

  Example 3: Tetrahydroxy 1-alpha, 6-beta, 7-beta, 9-alpha epoxy

2 614891

  8.13-Labdene 14-one 11-bis acetonide 1.6: 6.7 and corresponding 13-epi product. To a solution of vinyltributyltin (817 mg, 2.5 mmol) in 4 mL of dry ether under argon was added a solution of butyllithium in 1.5M hexane (1.3 mL, 1.95 mmol), then stirred for 1 hour 10 minutes at room temperature. This solution is added to a suspension of pulverized cuprous iodide (229 mg, 1.2 mmol) in 4 ml of ether, stirred at -60 ° C. under argon and shaken from -40 ° C. to -25 ° C. for 3 hours (suspension black). It is cooled to -78 ° C. and a solution of product obtained in Example 1, Stage B (84 mg, 0.2 mmol) in 2 ml of ether (+ 0.2 ml for rinsing) and BF3-Et2O is then added. distilled (110 μl, 0.9 mmol). It is stirred for 1 hour at -78 ° C. and then allowed to come to room temperature in 30 minutes. Saturated NH4Cl-NH4 HCl 9: 1 was added and extracted with CH2Cl2. It is dried over Na 2 SO 4 and the solvent is evaporated off under reduced pressure. 976 mg of slightly yellow oil are obtained which are purified by chromatography on silica (eluent CH 2 Cl 2). 53 mg of expected product is first obtained, white crystalline solid (59%),

  then 13 mg of corresponding epi product, white crystalline solid (14 0).

Product 13 ear:

IR (CHCl3): 1711, 1644

SM: 448 (M '+)

Claims (8)

  1 /. The products of general formula I: ## STR2 ## wherein R 6 and R 7, which are identical or different, represent an atom hydrogen or an acyl radical ,.   R1 represents: - a methyl radical optionally substituted by a hydroxyl radical) halogen, cyano, amino, carbamoyl, optionally substituted by a C1-3 alkyl radical or a phenyl radical, optionally esterified carboxyl or azido, - or an ethyl radical optionally substituted by a radical dimethylamino, trimethylammonium, OH, or SH each of these two radicals being optionally etherified, a vinyl or phenyl radical, - is a C3-4 alkyl radical optionally substituted by an OH or SH radical, each of these two radicals being optionally etherified, CH3 - or a CH2-C radical in which R 'represents an R. OH R '   of hydrogen or a methyl radical, or a radical -CH = C in which either R "and R '" RI' $ each represent a hydrogen atom or a methyl radical, or one represents a hydrogen atom and the other represents a methyl radical, or a radical CHO, CO2 optionally esterified, CH = NOH or -CH-CN.   R 2 represents: - either an alkyl radical C1_3, R'2 - or a radical CH = C in which either R'2 and R "2 R" 2 each represent a hydrogen atom or one represents an atom hydrogen and the other a C1_3 alkyl radical, or an ethynyl radical.   With the exception of products in which one of the substituents R 1 or R 2 represents a beta-CH 3 radical and the other represents a   alpha-vinyl radical, CHO, CN, -CH = N-OH or C2-H5.   2 /. The products of general formula I as defined in claim 1 in which R 6 represents a hydrogen atom and R 7 represents a hydrogen atom and R 7 represents a hydrogen atom or an acetyl radical.   R1 is selected from the following radicals: CH20H, CHO, CO2H, optionally esterified as methyl or ethyl ester, CH = NOH, -CH-CN, -CH2-CH2-N (CH3) 2, OH   -CH2-CH3, -CH = CH2, -CH2-CH2-CH3, -CH2-CH2-SCH3; -CH2-CH2-S-Q   -CH2Cl, -CH2Br, -CH2CO2H optionally esterified in the form CH3   methyl or ethyl ester, CH2-CH-CH3, CH2-C OH OH CH3   -CH = CH-CH3, -CH = C (CH3) 2, -CH2-CH2-OH   R2 is selected from methyl, vinyl or ethynyl.   3 /. Products of general formula I as defined in one of the   claim 1 or 2, wherein the substituent R 1 is selected from   the following radicals -CH 2 OH, CO2H or -CH 2 CO2H optionally esterified in the form of methyl or ethyl ester, -CH = CH 2, -CH2-CH3, -CH2-CH2-CH3,   -CH2-CH2-S-CH3, -CH2-CH2-S-O, -CH2-CH2OH.   4 /. Products of general formula I as defined in   claim 1 corresponding to the following nomenclature: -tetrahydroxy 1 alpha, 6 beta, 7 beta, 9 alpha nor-15-epoxy 8.13 labdane one 11.   /. Process for the preparation of the products of formula I as defined in claim 1, characterized in that a product of formula II is first treated: <II   XR6 in which R'1, R'6, R'7, R9 each represent a free or protected OH radical, or R'1 and R9 on the one hand, R'6 and R'7 on the other hand together form radicals: -O Ra -O Rb in which Ra and Rb identical or different represent a hydrogen atom, or an alkyl or alkoxy radical having 1 to 4 carbon atoms or Ra and Rb together form an oxygen atom and R1 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 R1 = CH20H, a product of formula IIa, which may either be subjected to a new reagent of oxidation to obtain a product of formula IIb, corresponding to a product of formula II wherein R1 = CHO, or subject to a halogenating reagent to obtain a product of formula IIc corresponding to a product of formula II wherein R1 = CH2X, X representing a halogen atom, or subject to an oxidation agent for o obtain a product of formula IId corresponding to a product of formula II in which R 1 = CO 2 H product which is optionally esterified, or the product of formula IIb wherein R1 = CHO.   i) the action of hydroxylamine hydrochloride to obtain a product of formula IIe corresponding to a product of formula II in which R1 = CH = NOH.   ii) the action of hydrocyanic acid or cyanohydrin of acetone to obtain a product of formula IIf corresponding to a product of formula II in which R1 = -CH-CN OH iii) to the action of an oxidation reagent to obtain a product of formula IId previously described in which R1 = CO2H, or by an oxidation reagent to obtain a product IIh in which R1 represents a radical CHO: - or by a halogenation reagent to obtain a product of formula IIc previously described in which R1 = CH2X produces that one can Z614891   optionally, or treat with a cyanide ion to obtain a product of formula IIg corresponding to a product of formula II in whichR1 = CH2-CN product of formula IIg that can optionally be treated with hydrogen peroxide.to obtain a product product of formula IIh corresponding to a product of formula II in which R1 = CH2CONH2, or else treating a product of formula IIc previously described by an alkaline azide to obtain a product of formula IIi corresponding to a product of formula II in which R1 = CH2N3 product of formula IIi which is optionally treated with triphenylphosphine to obtain a product of formula IIj corresponding to a product of formula II in which R1 = CH2 NH2, - - or by a product of formula [H2C = N <, X] wherein X represents a halide ion or a carboxylate ion to give a product of formula IIk corresponding to a product of formula II wherein R1 = CH2-CH2-N (CH3) 2, a product of formula II which can optionally be treated with a methyl halide to obtain a product of formula IIl corresponding to a product of formula II in which R1 = -CH2-CH2-N (CH3) 3 X, X representing an atom of halogen and a product of formula III which can optionally be treated with a base to obtain a product of formula IIm corresponding to a product of formula II in which R1 = -CH = CH2, or a product of formula Firstly with a strong base and then with a linear RBX in which RB represents a C1-3 alkyl, an allyl, benzyl or a radical R'B0 (CH2) nX or R'BS (CH2) nX where X represents a halogen atom or an arylsulfonate, R'I represents a hydrogen atom, an alkyl radical or a protecting group for the hydroxyl or thiol radical and n represents an integer of 1 to 3 to obtain IInl IIn2 IIn3 IIn4 and IIn5 corresponding to the products of formula II in which R 1 represents respectively an alkyl radical C2-4 (n1), a radical - (C2) 2-Cn = CH2 (n3) a racial - (CH) 20 (n3) a radical - (CH2) 2_4 OR'B (n4) and (CH2t) - 4 SR '(nS), or with an oxidizing agent to obtain a product of formula IIa previously mentioned corresponding to a product of formula II in which R1 = CHkOH, or else by a halogenating agent to obtain a product of formula IIc previously cited corresponding to a product of formula II in ? 614891   Which R1 = CH2X, X represents a halogen atom, or else an agent for introducing the carboxy radical to obtain a product of formula IIo corresponding to a product of formula II in which R1 = CH2CO2H, product that can be optionally esterifying to obtain a product of formula II'o, or else an isocyanate of formula RoN = C = O in which Ro represents an alkyl radical having from 1 to 4 carbon atoms or a phenyl radical to obtain a product of formula II corresponding to a product of formula II in which R 1 = CH 2 -CO-NH-Ro in which Ro has the above meaning, or else by a reagent for introducing the alkoxycarbonyl radical to obtain a product of formula II'o in which R 1 = CH 2 -CO 2 Alk, in which formula Alk represents an alkyl radical having from 1 to 4 carbon atoms, R " '   or by a product of formula C = O in which R "and R" "R" "each represent a hydrogen atom or a methyl radical or one represents a hydrogen atom and the other represents a hydrogen atom. methyl radical to obtain a product of formula IIp corresponding to a R "product of formula II in which R1 = -CH2-C OH R "'   products of formula IIp which are optionally subjected to dehydration to obtain the products of formula Iq corresponding to the products of formula II in which R1 = -CH = C, R "J to the products of formula [I in which R1 = -CH = C or a product of formula ECH2 = N /, X] in which X has the meaning indicated above to obtain a product of formula IIk as defined above and then treated the products of formulas II, IIa, Ib , IIc, IId, IIe, If, IIg, IIh, IIi, IIj, Ik, II, Im, IIn2In, IIn4, IIn5, IIo, IIo, IIp and IIq, or by a reagent of formula R2 Cu, (R2) 2 Cu Li, R2 RNT Cu Li;   R2 RNT Cu (CN) Li2 or (R2) 2 Cu (CN) Li2, formulas   in which R2 has the values indicated in claim 1 except the ethynyl value and RNT represents a non-radical 23 2614891   transferable, either by a reagent of formula (n Bu) 3 Sn-CH = CH-Cu Li, then by the RNT pLomb tetracetate to obtain a product in which R2 represents an ethynyl radical, and then if desired treat the products of formula Ia in which R1 represents a CH20H radical with an oxidation agent to obtain the products of formulas Ib in which R1 represents a -CHO radical or the products of formula Id in which R1 represents a CO2H radical, and then, if necessary, treat the products thus obtained in which one or more hydroxyl radicals are protected by a protective group by a deprotection agent and treat if desired or necessary if the products obtained in which at least one of the radicals R6 and R7 represents a hydroxyl radical by an acylating agent to obtain a product of formula I in which one   at least one of R6 and R7 represents an acyloxy radical.   6 /. As medicaments, the products of formula I as defined in   Pharmaceutically acceptable claim 1.   7 /. As medicaments, the products of formula I as defined in   one of claims 2 to 4 pharmaceutically acceptable.   8 /. Pharmaceutical compositions containing, as a principle   active, at least one of the drugs-defined in one of the claims 6 or 7.   9 /. A product of new industrial products The products of the general formula IIA: wherein R'1, R9, R'6 and R'7 have the meaning indicated in claim 5 and RA1 has the meaning indicated in the claim 1 for R1 with the exception of the methyl value and it being understood that when RA1 comprises a reactive function, said function   may be in a protected form.