JPS63284169A - Novel derivative of forskoline, manufacture and intermediate, use as medicine and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention is directed to forskolin (Forsk) as its subject matter.
ol 1ne), a process for their preparation, their use as a medicament, pharmaceutical compositions containing them, as well as certain intermediates in this process.

[Prior Art] Forskolin is a plant native to India [Coleus F.
orskohlii) J (D) is a salercyterpene isolated from the root [e.g. J, C, S, Perkin, Vol.
See page 767 (1982) and Tetrahedron Letters, page 1669 (1977)].

Only a few compounds of the species could be prepared starting from natural substances [e.g. Journal Radical Chemistry, Vol. 26, p. 436 (1983)].
) and Journal Medical Chemistry, No. 26
Vol. 486 (1983) or U.S. Pat. No. 45172
See No. 00].

It was also possible to rearrange the C ring of a derivative of forskolin that no longer has hydroxyl groups at positions 1.6 and 7 [Journal Chemical Society Chemistry Communications, Vol. 24, (1987)].
, attempts to introduce a species function at the carbon atom in position 13 in phtruscholine and 1,4 addition to the dihydropyrone formed by the C ring have so far failed [Journal Chemical Society. Chemistry φ Communication, p. 1748 (19
85) l.

Now, a novel reaction has been developed that allows us to start from forskolin and arrive at interesting new derivatives.

[Summary of the Invention] Therefore, the main subject of the present invention is to solve the general formula (
I): [wherein R6 and R7 may be the same or different and represent a hydrogen atom or an acyl group, and R1 is an appropriately hydroxyl, halogen, cyanide, amine, phenyl, appropriately esterified carboxyl, azide or carbamoimo group ( a methyl group, optionally substituted by a C1-3 alkyl group), or an optionally dimethylamino, trimethylamino, OH or SH group (each of these two groups optionally optionally esterified) , an ethyme group substituted by a vinyl group or a phenyl group, or a C3-4 alkyl group optionally substituted by an OH or SH group (each of these groups being appropriately substituted), or a CH3 group -Ct-12-C IR'il (where R' represents a hydrogen atom or a methyl group), or a group -CH-C'R'' (where R11 and R'' each represent a hydrogen atom or a methyl group, or one of these represents a hydrogen atom and the other represents a methyl group), or -CO2H, -CH=NOl-1 or 10H- as appropriate
Represents either CH00 or CN substituted by an ON group: R2 is a C1-3 alkyl group, or R'2 group -CH=C group 2 (wherein each of R'2 and R"2 is represents a hydrogen atom, or one of these represents a hydrogen atom and the other represents a C1
-3 alkyl group) or ethynyl group, provided that one of substituted WR1 or R2 represents a β-C83 group and the other represents α-vinyl, -CH
o, -CN.

A compound exhibiting CH-N-OH, -C2R5, or CH3 group is provided.

In the general formula (I), an acyl group preferably denotes an alkanoyl group, such as, for example, acetyl or propionyl, which can equivalently denote an aroyl group, such as, for example, benzoyl; a halogen group preferably denotes a chlorine or bromine group. atom, which can equally represent a fluorine or iodine atom; a C1-3 alkyl group represents one of the following: methyl, ethyl, propyl, isoisopropyl, preferably a straight-chain group: esterification The carboxy group preferably represents an alkyloxycarbonyl group, such as methoxycarbonyl or ethoxycarbonyl;
or SH groups are preferably methoxy and methylthio,
It is a benzyloxy or benzylthio group: The C3-4 alkyl group represents a propyl, isopropyl, butyl, 5ec-butyl or tert-butyl group, preferably a straight chain group.

The present invention particularly focuses on the general formula (I>) in which R6 represents a hydrogen atom, R7 represents a hydrogen atom or an acetyl group, and R1 represents CH2-OH, CHO, CO2.
H (which is optionally esterified in the form of methyl or ethyl ester) -CH=CH2-1, -CH-CN
.

-OH2-CH2-N (CI-13)2, -CI
-12-CI-fa, -CH=CH2, -CH2-C
I-1z-CI-13, -CH2-CI-12-3-Cto13, -CH2-CH
2-5-(L-CH2Ce.

-CH2Br, -CH2CO20 (which is optionally esterified in the form of methyl or ethyl ester), -Ct-f2-CH-CH3, OH.

OH3 -CH2-C (CHa OH -CH-CH-CHa, -CH-C(CH3)2, -
It relates to compounds selected from the group consisting of CI-12-CH2-OH and R2 selected from methyl, vinyl and ethynyl groups.

In particular, the subject matter of the present invention is that in general formula (I), the substituent R1 is -CH2-OH.

-CO2H or -CH2-CO2H (which is optionally esterified in the form of methyl or ethyl ester), -CH=C) (2, -CH2-CH3, -CH2
Regarding compounds selected from the group consisting of -CH2-CH3, -CH2-CH2-3-CH3, -CI-12-CH2-OH, in particular compounds , 9α-trihydroxy-7β-acetoxy-8,13-epoxy-14-ravudin-11-one.

The present invention likewise provides as its subject a process for the preparation of a compound having the above general formula (I), which process comprises firstly preparing a compound having the formula (■): [wherein R'1, R'e , Each of R'7 and R'9 is free or 1. denotes a protected OH group, or R'1 and R'9 on the one hand and R'e on the other hand.
and R'7 together represent a group (in this formula, Ra and Rb may be the same or different and represent a hydrogen atom or an alkyl or alkoxy group having 1 to 4 carbon atoms, or Ra and Rb together form an oxygen atom) and R1 represents a methyl group] is treated with an oxidizing agent to form a compound of formula (R8) corresponding to a compound of formula (II> which is R1-CH20H) A compound of this formula (R
The compound of formula (IIb) corresponding to the compound of formula (■) where R1=-CHO is obtained by adding 1q of the compound of formula (IIb) by applying the compound of 8) again to an oxidizing reagent, or by applying a halogenating reagent to obtain R1=-CH
Corresponds to a compound of formula (II) in which R1 = -CO21-1 by applying a compound of formula (IIo) to (q or an oxidizing agent) A compound of formula (nd) is obtained, and this compound is suitably esterified, or if necessary, a compound of formula (nb) in which R1=-CHO is subjected to the action of (i>hydroxylamine hydrochloride) to form R1.
= -CH-NOH, or (ii) upon the action of hydrocyanic acid or acetone cyanohydrin, a compound of formula (R1 = -CH-CN) is obtained, obtain a compound of formula (I[f) corresponding to the amount of compound OH in II), or (ii
i) by the action of an oxidizing reagent to obtain the compound of formula (IId) in which R1=-CO2H: or by treatment with an oxidizing reagent directly to obtain the compound of formula (■b) in which R1 represents a -CHO group; or treated with a halogenating reagent directly to obtain the compound of formula (IIo> in which R1=-CH2X), which was optionally treated with cyanide ions to form
A compound of formula (■.) corresponding to the compound of formula (II> which is --CH2-CN) was obtained, and this compound of formula (■.) was optionally treated with hydrogen peroxide to R1--CI- 120O
Formula (■h) corresponding to the compound of formula (II) which is NH2
or by treating the compound of the formula (II.) with an alkali azide to form a compound of the formula (II.
A compound of formula (ni) corresponding to the compound of formula (II) is obtained, and this compound of formula (Ili) is optionally treated with triphenylphosphine to obtain a compound of formula (1) which is R1--CH2-NH2.
) corresponding to the compound of formula (Ilj>): or treated with a compound of the formula [112c=NO1X○] [wherein XO represents a halogen ion or a carboxyl ion] to form -N (CH3)
A compound of formula (■k) corresponding to the compound of formula (If) which is 2 is obtained, and this compound of formula (I[k) is optionally treated with methyl halide to obtain R1--CH2-CH2-NΦ
-(CH3)3XO [Here, XQ represents a halogen ion] A compound of formula (■,) corresponding to the compound of formula (II) was obtained, and the compound of formula (R2) was optionally treated with a base. to obtain a compound of formula (■□) corresponding to the compound of formula (II) where R1--CH=CH2; or a compound of formula (I[
) is first treated with a strong acid and then treated with a compound of the formula RBX [c:c:TERBhac1 37/L/indicating a kill group, allyl or benzyl group] or with a compound of the formula R'BO (CH2 ). X or R'BS (C
H2) nX [In the formula, e, Indicates an integer "g]
R1 is a C2-4 alkyl group (nl), -(CH2)2 -CH=CH2 group (n2), -
(CH2)2φ group (n3), -(CH2)2-4 OR'B group (ni) and -(CH
2>2-4 Formula (■.1), (I[), (I ) corresponding to the compound of formula (n) showing SR'Bi (nb)
, (■n4) and n2 n3 (■n5): Or treated with an oxidizing agent to obtain compounds of the formula (n
) or treated with a halogenating agent to obtain the compound of formula (II) corresponding to the compound of Rt-10H2X [where X represents a halogen atom]. Said compound of formula (IIo) is obtained: or treated with a reagent for introducing a carboxy group to form R1
= -CH2CO2H A compound of formula (Ro) corresponding to the compound of formula (II) is obtained, and this compound is optionally esterified to obtain a compound of formula (■'o))q: or formula RN=C=O [wherein Ro does not represent an alkyl group having 1 to 4 carbon atoms or a phenyl group] to form Rt = -CH2-GO-N+-1-R8 [where Ro
is 1 having the above meaning to obtain a compound of formula (■''o) corresponding to the compound of formula (II); or treated with a reagent that introduces an alkoxyl carbonyl group to form R1=-CH2-
GO2-Ae k [L.

During the ceremony, A! gives a compound of formula (■'o) which is 1 representing an alkyl group having 1 to 4 carbon atoms; or formula >C=O [where R" and R"' are each R"' hydrogen atom or a methyl group, or one of these represents a hydrogen atom and the other represents a methyl group] to form a compound of the formula [Ma'R1=-CH2-Cg1R'''H A compound of formula (1,) corresponding to the compound of (II) is obtained, and this compound of formula (I[,) is optionally dehydrated to obtain a compound of formula (II) where II Rt -CH=CxR''' A compound of formula (■.) corresponding to the compound is obtained: or treated with a compound of formula [CH2-N■,xO] [wherein compound of formula (II>, (R8), (■b), (IFo>, (IF
d＞.

(no>, (I[f), (II,), (I[fi>, (
I[i), (I[j>, (IIk>, (■,), (II
>, (II), (■n2), (II03),
m "11 (II), (II), (II), (It'
. >, R4R50 (II” >, (II) and (■.), Op 2R2Cu, (R2, > 2 Cu I-i, R2RN
-[Cu I-i, R2RN-[-Cu (CN)Li2 or (R2)
2 CLI (CN)Li2 [In these formulas, R2 has the meaning as defined in claim 1 except for ethynyl, and RNT represents a non-mobile group]; or a reagent of the formula % formula % and then treated with tetraacetic acid r11 lead to obtain a compound of formula (I) in which R2 represents an ethynyl group, and then optionally treated with an oxidizing agent to a compound of formula (I.) in which R1 represents -CH20H. to obtain a compound of formula (from) in which R1 represents a -CH0 group or a compound of formula (■b) in which R1 represents a 1002 H group, and then, if necessary, one or more hydroxyl groups are protected. The resulting compound protected by the groups is treated with a deprotecting agent and, if desired, the groups 6 and R
It is characterized in that the resulting compound in which at least one of groups R6 and R7 represents an acyloxy group is treated with an acylating agent to obtain a compound of formula (I>) in which at least one of the groups R6 and R7 represents an acyloxy group.

As protective groups which one or more of the substituents R'1, R'e, R'7 and R9 may carry, mention may be made in particular of acyl groups, such as for example acetyl or propionyl. Preferably, the groups R1 and R on the one hand
9 and R6 and R7 on the other hand can form a group.

The different meanings that R and Rb can have are, for example, a Ethyl, di[1-oxy, propyl, propoxy.

If the radicals R'1, R9, R'6 and R'7 start from unmodified substances with respect to natural substances, the radicals IR'1, R9
and R' e represents free OHI and 1 ('7 represents an acetyloxy group).

(a) The oxidative conversion reaction from the compound of formula (II> to the compound of formula (R8) is carried out with selenium oxide SeO2 in the presence of acetic anhydride and acetic acid to obtain allyl acetate,
This is saponified in a conventional manner in the presence of a base such as sodium hydroxide.

Methods for carrying out this reaction are described, for example, in the following publications: B. Sharpless, R.F. Lauer, Journal of the American Chemical Society, Vol. 94, No. 7.
154 (1972) or V. T., Barrerao, H. Labobot, Journal American Chemical Society, Vol. 93, p. 4835 (1971).

The direct conversion of compounds of formula (n) to compounds of formula (IIb) is likewise carried out with SeO2.

Preferably, the time of the reaction can be extended.

(b) Oxidation of a compound of formula (ffa) to a compound of formula <1 [b) can be carried out as follows (i)
For example, Circular A, J, Fatiazi, Synthesis, No. 6
(ii) by a suspension of MnO2 in hydrocarbons or benzene according to the practice described in p. by the so-called "Swern" method using triethylamine in methylene or chloroform, or (iii) for example G. Cainelli, G. Calcillo, [
Organic Chemistry (Chromium Oxidation in Organic Chemistry), Springer Publishing (1)
984) or by methods using Cr Vl, such as pyridinium chlorochromate, or by methods using CrVl, such as pyridinium chlorochromate, or by methods using (deceased) publications T. Pugy, G., P. Ellis, Journal Chemical Research (M), No. 2314- According to the method described on page 2324 (1980).

(C) The conversion of compounds of formula (II) to compounds of formula (IIo) is preferably carried out using N-bromo or N-chlorosuccinimide.

Similarly, methods of carrying out the conversion of compounds of formula (II) to compounds of formula (IIo) are described in the publication Journal Chemical Research (M), pages 2314-2324 (19
80) and C01lIpt, Rend, ^cad, s
ci, Paris.

222, p. 1441 (1946).

The conversion of the compound of formula (II) to the compound of formula (■o) is preferably carried out by the action of mesyl or tosyl chloride in the presence of a base such as triethylamine or pyridine, and then the sulfonate obtained is converted into a halogen The exchange to a compound is carried out using the usual method.

(d) The conversion of compounds of formula (IIb> to compounds of formula (IId>) is preferably carried out with oxygen in the presence of a catalyst such as platinum. Preferably it is operated in the presence of an aqueous solution. Species reactions are described, for example, in publications such as Hayles, H., Poulsen, Angewande Hemie.
1, Vol. 69, p. 600 (1957).

Direct conversion of compounds of formula (R8) to compounds of formula (■d) can be carried out under the same conditions.

(e) Conversion of compounds of formula (I(b)) to compounds of formula (ffo) is carried out using hydroxylamine hydrochloride under conventional conditions.

(f) Similarly, from a compound of formula (IIb>), a compound of formula (Il
The conversion to compounds f> is carried out under classical conditions by the action of hydrocyanic acid or acetone cyanohydrin.

(Q) The conversion of the compound of formula (TI) to the compound of formula (■.) is carried out in the presence of cyanide ions introduced by, for example, sodium or potassium cyanide.

(h) The conversion of a compound of formula (■.) to a compound of formula (II 11) is preferably carried out in the publication: B. Biebel, Journal of the American Chemical Society, Vol. 75, p. 3961. (1953) and the same, No. 77
Vol. 2519 (1955) in the presence of hydrogen peroxide in a slightly basic medium.

(i> The conversion of the compound of formula (1) to the compound of formula (IIi) is preferably carried out in the presence of strionic azide.

(j) Conversion of compounds of formula (II.) to compounds of formula (I[j>
France, p. 815 (1985), in the presence of triphenylphosphine.

(k) From the compound of formula (I[) to the compound of formula (I[k)] (7) Conversion of the formula [CH2=N,Xo] [where xO represents a halogen ion or a carboxyl ion] The action of the compound is carried out by a "Mannich" type reaction.

Descriptions of reactions of this type can be found in: Y., Jasour, M., Galadry, M.J., Ruchiko, A.
, Marquette, Tetrahet [1, Vol. 33, No. 29
5 (1977) and J. L. Glass, Tetrahedron Letters, pages 2111 (197B> and 2955)
Page (1978).

(j) The conversion of the compound of formula (IIk) to the compound of formula (■, ) is preferably carried out in the presence of methyl iodide.

(m) The reaction of removing the ammonium group of the compound of formula (■,) to produce the compound of formula (■,) is carried out in the presence of a base or under normal conditions.

The strong base present for treating the compound of formula (n) to obtain an anion for the methyl group in position 13 is preferably lithium diisopropylamide as well as all other metal nitrogen bases such as lithium, potassium or sodium hexamethyl. selected from disilazane.

(n> The action of the compound of formula RBX on the anion formed as described above is carried out under customary conditions.

(al) The conversion of the above anion to a compound of formula (R8) can be carried out as follows: (i) in the presence of oxygen; (it) Publication E, Bedeis, D.A., Engler; Y
Molybdenum peroxo complexes (Mo05
, t-IMPT), (iii) Publications F, A
of derivatives of formula 0g1 according to the method described in Davis, L.C., Bishiwakarma, J.M., Billmers, J., Finn, Journal Organic Chemistry, Vol. 49, p. 3241 (1984). In the presence of 802-φ (0) The above anion can be converted to the compound of formula (no) according to a conventional method using, for example, dry ice. By using methyl or ethyl carbonate or methyl or ethyl chloride, the compound of formula (■'o) can be directly obtained in an esterified form by introducing an alkoxycarbonyl group. Any esterification of the compound of formula (no) can be carried out according to conventional methods, preferably with diazomethane.

(0') Formula RN, ==C=O [Here, R8 is C1-
The action of the isocyanate [representing an alkyl group or phenyl group] on the above-mentioned anion is carried out in accordance with a conventional method.

(p) As mentioned above, a compound of the formula 〉C=0 with R″ on the q anion (which in fact R″′ can be gaseous depolymerized formadehyde or acetaldehyde) The action is preferably carried out in a solvent such as, for example, tetrahydrofuran or dimethoxyethane.
The dehydration of the compound of formula (■.) to the compound of formula (■.) is carried out in a conventional manner either in a basic or acidic medium or in the presence of a Lewis acid.

(kl) From the anion obtained as above, the formula [CH
The conversion to the compound of formula (IIk) by the action of a compound of 2=N, : S. Daniszewski et al., Journal American Chemical Society, Volume 98, Page 6715 (19
7B>, C. D. Boulter et al., Tetrahedron Letters, p. 1621 (1977), N. L., Holley, Y. F., Wamp, Journal American Chemical Society, Vol. 99, p. 944 (
1977).

The action of copper salts on compounds of formulas (If) to (R6) is
Most preferably it is carried out on compounds in which the hydroxyl groups in positions 1.9 and 6.7 are protected.

Similarly, if the JA group at R1 has a reactive function, such as a --CH01-C02 or 10H2O3 group, these groups are very preferably protected. Customary protections, such as, for example, cyclic or acyclic ketals, Nisdel or otole esters, respectively, and protecting groups for the hydroxyl groups, such as, for example, ether or acyl groups, are then used.

Preferably, the action of copper salts on the compounds of formulas (I[) to (■.) is carried out under the following conditions: first the organic copper salts are formed according to known methods and then
) to (■.) are added, and finally boron trifluoride ether is added.

Preferably at low temperature (e.g. in the range of -78 to -30°C)
The reaction mixture is then allowed to warm to room temperature before being worked up as usual.

The following reagents can be used as organic copper salts: R2Cu, (R2)2CuLi or R2RN-1-Cut-i or The use of the above copper salts for compounds can be found in the literature.

For example, the following document may be mentioned: R2CLJ and (R2)2 in the presence of boron trifluoride etherides.
Regarding the use of CuLi type reagents: Y. Yamamoto, Angewante Hemi International Edition, English edition, Volume 25, Page 947 (
1986).

Preferably the RNT group represents a chenyl group: B, H. Lipschutz, Tetrahedro Letters, Vol. 28, No. 94
5 (1987) or 1-pentynyl C387-C=C
-Group: E, J, Kore and Tori, Beames, Journal・
American Chemical Society, Volume 94, No. 72
10 (1972) or 3-methyl-3-methoxy-1-butynyl: E, J
, Collet et al., Journal Organic Chemistry, vol. 43, p. 3418 (1978).

Formula R2RNl・Cu (CN)I i2 or (R2
)2 CU (CN)L i2 reagents are described, for example, in the following documents: B, T1. Lipschutz, Tetrahedron, Volume 40,
No. 5005 (1984).

The use of compounds of this type in combination with boron trifluoride is described, for example, in the following literature: B.H., Lipschutz et al., Tetrahedron Letters;
No. 5959 (1984). However, no compounds of this type have hitherto been used for the preparation of compounds having a dihydropyrone nucleus.

As the above-mentioned copper salt, RNT may be, for example, chenyl, 1-pentynyl or 3-methyl-3-medoxy 1
Preference is given to compounds of the formula R2RNTCuLi, which exhibit a -butynyl group.

Formula (n-Bu)a 5n-CI-1=cl-1-CuL
The reaction of the compound of il NT and the conversion of the obtained compound into a compound in which R2 represents an ethynyl group is carried out using lead tetraacetate under the conditions given in the following references: E, J, Collet 1R,
G1. Borenberg, Journal of the American Chemical Society, Volume 96, Page 5581 (1974)
.

Concerning the use of lead tetraacetate, it is likewise very preferable to protect compounds in which the reactive groups R'1, R9, R'6 and R'7 are protected, as well as the substituent R'1 (if this carries a reactive group). This should be done for all compounds that have been tested.

Any compound of formula (I.) corresponding to a compound of formula (1) which is R1--CH2-OH to a compound of formula (1b) or (Id) which is R1--CHO or -CO2H. The oxidation is carried out under the same conditions as in any conversion of a compound of formula (n) to a compound of formula (■b) or (I[d).

Deprotecting agents for compounds of formula (I) in which one or more hydroxyl groups are protected by a protecting group are selected from known reagents.

The acylating agents used are, for example, those described in Documents J, C, S,
, p. 767 (1982) or under the conditions described in U.S. Pat. No. 4,517,20 (1@) in the presence of lysine at a temperature of around 0° It can be an acid, preferably an acetyl group or a propionyl group.

Similarly, the present invention also relates, as its subject matter, to a method for producing a compound having the above general formula (1) in which R1 represents a methyl group and R2 represents an ethynyl group, which method comprises the formula (■): [in the formula , R'1, R'e, R'7 and R9 have the above meanings in the formula % formula % -91! ! to obtain a compound of formula (Io): and then, if necessary, the compound of formula (Io) in which one or more hydroxyl groups thus obtained is protected with a protecting group is treated with a deprotecting agent. and, if necessary, the thus obtained compound of formula (I) in which at least one of the groups R6 and R7 represents a hydroxyl group is treated with an acylating agent so that at least one of the groups R6 and R7 represents an acyloxy group. It is characterized by obtaining a compound of formula (I>) representing a group.

Preferably, the protecting group is a group as described above.

The reaction with the diazophosphonate is preferably carried out with an alkali alcohol, such as potassium t-butyralate.
or in the presence of a base such as an alkyllithium such as butyllithium and in the presence of a solvent such as tetrahydrofuran.

Preferably, it is operated at low temperature, allowing it to gradually return to room temperature.

The reaction conditions are described, for example, by J. C. Gilbert et al., Journal Organic Chemistry (1982) No. 47.
Vol., pages 1837-1845.

The deprotecting agents and acylating agents used are the reagents described above.

The compounds of the general formula (I), which are the subject of the present invention, have interesting pharmacological properties. Evidence was obtained for significant stimulation of cyclase adenylate.

These properties make the compounds of general formula (I) suitable for use as medicaments in the cardiovascular field, where they exhibit active muscle contractile or antihypertensive or antithrombotic effects. Equivalently, they can also be used to treat intracranial conditions. In addition, the compounds of general formula (I) also exhibit anti-tumor metastasis activity or can be used as analgesics or bronchodilators.

The compounds of formulas (I[) to (R1) can exhibit similar properties as well.

The present invention therefore furthermore relates as its subject to pharmaceutically acceptable compounds having the general formula (I>) as medicaments, ie compounds which are non-toxic at the doses used.

In particular, the present invention has as its subject matter a substituent R as a medicament.
1 is a group -CH2-0H1-CO2H or -CH esterified as a methyl or ethyl ester as appropriate
2-CO2H.

-CI-1=cH2, -CH2-CI-13, -C)-
12-CH2-CH3, -OH2-CI-12-5-CI-13, -Cti2-
Compounds with formula (I> selected from CH2-3-@ -CH2-CH2-OH, in particular: ゛Trihydroxy-1α.

6β,9α-acetoxy-7β-epoxy-8゜13-
Ravudin-14-one-11 is provided.

Compounds of formula (I) can be administered by buccal, enteral, transdermal or intravenous routes. They can be supplied as tablets, coated tablets, capsules, granules, emulsions, suppositories and injectable solutions and suspensions.

As mentioned above, the novel compounds of formula (I) can be used to prepare pharmaceutical compositions containing at least one of said compounds as active ingredient.

Active ingredients include, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin,
It can be formulated with excipients commonly used in pharmaceutical compositions such as paraffin derivatives, glycols, various wetting agents, dispersing agents or emulsifying agents, and preservatives.

The present invention therefore also provides as its subject a pharmaceutical composition containing as active ingredient at least one compound of formula (I>).

The present invention likewise has as its subject matter new industrial products, in particular new industrial products required for the production of compounds of formula (I), of the general formula [wherein R'1, R9,
R'6 and R'7 have the meanings given above, and RAl has the meanings given above for R1 except for methyl, and roughly RA
If l has a reactive group, this reactive group can be present in protected form.

Groups that R1 includes and can be protected include the groups mentioned above, especially -CHol-CO2t-1 and -CH20
Mention may be made of the H group. Examples of protecting groups are also those mentioned above.

Starting materials of the formula (I [>) in which R1 represents a methyl group are described, for example, in the following literature: A., Saxena et al., Journal Chemical Competition Society φ Chemical Communications, p. 1748 (
1985).

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

[Example] The invention will now be explained by way of non-limiting examples.

Step A: 1α, 6β, 7β, 9α-tetrahydroxy-
8,13-Evo' Nizi-14-Rabten-11-one-
1,9:6.7-bisacetonide.

2-Metho4nidipropene (280 μ5: 2.92 mmol) and p-toluenesulfonic acid (a swig) were added to a solution of filskolin (600 mg; 1.46 mmol) and then stirred at room temperature for 15 hours. Anhydrous 2
Add CO3, stir for 20 min, then Na1-1
．． A saturated solution of CO3 was added and extracted with CH2G (12). Dry over Na2SO4 and the solvent was evaporated under reduced pressure. 0.65 tJ of white crystalline solid was obtained. 20 d of water
and sodium hydroxide in methanol 80In1 (
200n+c+: 5 mmol) was added and then stirred for 48 hours. Extracted with CH2Cl12, Na
Dry over 2SO4 and evaporate the solvent under reduced pressure. 0.
60 g of white paste was obtained, which was dissolved in 30 nrll of CH2 (, l.2-methoxypropene (2
80 μe; 2°92 mmol) and p-toluenesulfonic acid (trace amounts) were added and then stirred for 15 hours. 100 μe of 2-methoxypropene was added to the colander and then stirred for 8 hours. The excess of anhydrous was stirred with 2CO3 for 15 min and then a saturated solution of Nal-1cO3 was added and extracted with Ct-12 (12). Dry over Na2SO4 and evaporate the solvent under reduced pressure. A yellow solid was obtained which was purified by chromatography on silica (eluent CH2Cl12). 620 mg of the desired product (white crystalline solid) were obtained (94%).

m, p, = 164℃.

Soil R (CHCa): 1710cm-15M 4
48 (M”+): 362°J: 1 (r,
6β,7B,9(X-tetrahydroxy-14,15-
dinor-8,13-epoxy-12-lapden-11-
On-1,9:6,7-bisacetonide.

Step A in CCjalO- and acetonitrile 17
To a solution of the product obtained from (224 mg; 0.5 mmol) in water, sodium metaperiodate (181 mg; 2.25 mmol) and ruthenium trichloride trihydrate jQ (13 mg; 0.05 mmol) ) was added.

The mixture was stirred vigorously for 511 i at room temperature. Sodium metaperiodate (267mg: 1.
25 mmol) and then stirred vigorously again for 2 hours. Add CH2Cj2 and water, then CH2C
Extracted with l12. Dry over Na2SO4, evaporate the solvent under reduced pressure, then dissolve the residue in ether and filter. The solvent was evaporated under reduced pressure to give 244 mg of a maroon solid. 150 Iij of pyridine, 25 mg of cupric acetate and 4 ml of benzene were added and then stirred at room temperature for 1.5 hours to obtain a green solution. Lead tetraacetate (66
0 mU: 1.5 mmol) was added. Stir at room temperature for 2 hours, then heat to reflux for 1 hour.

After cooling to room temperature, 082 C12 was added to the mixture and filtered through alumina, washing first with 5IrIi methanol and then with CH2Ch. Wash the filtrate with water and
Dehydrated with a2SO4. After evaporating the solvent under reduced pressure,
240 mg of crude product was obtained, which was purified by chroma I-graphy on silica (eluent: C1-12C112).

160 mg of the desired product, a white crystalline solid, was obtained by tritylation with ether (76%),
p, = 123°C.

IR(CHCea):1666:1619UV(E
tOH):λrn a X 278nllll, ε=
8500SM: 405 (M”-Ct-13:
362; 347° Engineering IQ: 1 α, 68.7
B, 9α-tetrahydroxy-15-true 8,13-
Epoxy-labdan-11-one-1,9:6,7-bisacetonide.

A solution of methyllithium in ether is added to a suspension of cupric iodide (571111!11:3 mmol) in dry ether 2d that is stirred at 0 °C under argon to form a gray solution of Me2Cu1-i. until a solution is obtained (M
eCu)n (6m: 0.31M solution of Me2CuLi)
of yellow particles. 2.7 ml (1 mmol) of the above solution were added to a solution of the product obtained in step B (84 mg; 0.2 mmol) in dry ether 4d at -78° C. under argon and then distilled B F3
-Et20 (110 μj: 0.9 mmol) was added and stirred for 1 hour at -78°C.

This was brought to room temperature over 30 minutes and then saturated with -N
JUG to H40Hc solution N+-14Ce (9-1
F, by adding a mixture of ). Stir vigorously, then CH2
Extracted with Cj2. It was dried over Na2SO4 and the solvent was evaporated under reduced pressure. 96n+g of crude product was obtained,
This was chromatographed on silica (eluent CH2
Ce2).

77 mg of the desired product were obtained as a white crystalline solid (85%).

m, p, = 151°C.

IR (CHCj3) 1709 SM: 436 (M”+): 350 process D=1
α,6β,7β,9α-Tetrahydroxy-15-true 8,13-epoxy-labdan-11-one.

The product obtained from step C (24 m
g; 0.055 mmol) to a solution of 0.8+! of 7N hydrochloric acid and then at room temperature 291R)[:old i
I stirred it.

Add CH2Cj2 and water, then wash with Cl12C (extracted with !2, Na1-ICOs saturated) solution, and
Dry over 2SO4 and then evaporate the solvent under reduced pressure.

19 mg of crude product was obtained, which was chromatographed on silica (eluent CH2C12z-ether, 9
:1). 11 mg of the desired product were obtained, and tritylation with ether gave white crystals (5
6%).

SM: 356 (M”): 338: 3
00: 282゜Dan$: 1 α, 68.7B, 9 (2-tetrahydroxy-16-true 8,13-epoxy-12-rbutine-
11-one-1,9: 6.7-bisacetonide Hexane (0.8 d : 1.2 mmol) and HMPT (191 mmol) in
1.1 mmol) of a 1.5 M solution of
Cool to 8°C and stir at -78°C for 10 minutes. 1
211 dl of 1-HF over 0 minutes (10.2 tons to the rinsing river)
The product obtained in step B of Example 1 in <420
mg ; 1 mmol) solution, then -18
Stirred at ℃ for 25 minutes. Methyl iodide (65 μl: 1.
05 mmol) was added and allowed to warm to room temperature over 30 minutes, then stirred again for 10 minutes. Ether was added, washed with water and extracted with ether. It was dried over Na2SO4 and the solvent was evaporated under reduced pressure. 442 mg of a white solid was obtained, which was purified by chromatography on silica (eluent CH2Cl12). 432mg
96% of the desired product was obtained as a white crystalline solid.
).

m, p, = 173°C.

Dish (CH013): 1663: 1613UV
(E tOH> : λ m a x 27
9nm, ε = 87005M: 419(M
"+-CH3'): 376: 361F[)
: 434 (M”) ■Procedure B: 1α, 6β, 7β, 9α-tetrahydroxy-
13-■P8,13-■Poxylabdan-11-one-1,9:6.7-bisacetonide.

A solution of methyllithium in ether in the presence of yellow particles (MeCu) is added to a suspension of cupric iodide (571+nc+: 3 mmol) in dry ether 2d stirred at 0° C. under argon. Gray solution of Me2CuLi (,4,5d; 0 in Me2Cu-1-i,
44M solution) was obtained. Product obtained in step A in ether 2d (48111 g: 0
．． The above solution (0°55 mmol > 1.251r11) was added to a solution of 11 mmol) at -78°C under argon and then distilled BF3-Et20 (12011 (: 0
．． 98 mmol) was added and then stirred at -78°C for 1 hour. Return to room temperature for 30 minutes, then saturated N
A mixture of N1-140+2 (9
-1> was added.

Extracted with Cl-12 (12), dried over Na2SO4 and evaporated the solvent under reduced pressure. 47 mg of a slightly yellow crystalline solid was obtained, which was purified on silica with C paste [171-granoy (eluent CH20e2)]. Purified with 40mg
The desired product was obtained as a white crystalline solid (80%
).

m, p, = 190℃.

IR (CHCja): 1707 5M: 4!10 (lvl'+) Process C: 1α
, 6β, 7β, 9α-tetrahydroxy-13-shrimp-
8,13-epoxy-labdane-11-71.

Adding 0.5 d of 2N hydrochloric acid and 0.5 m of concentrated hydrochloric acid to a solution of the product obtained from step B <20 ma: 0.044 mmol) in 1 rnl of tetrahydrofuran;
The mixture was then stirred at room temperature for 48 hours. CH2Cl12 and water were added, extracted with CH2Cff12, dried over Na25O9 and the solvent was evaporated under reduced pressure. A crude product of 21m (1) was obtained which was purified by chromatography on silica (eluent CH2C122-Et20.9-1 then 8-2).4.5 mg of the desired product solid was obtained. (27%)

NMR250Mt-IZ (CDCe3): Ethyl C
H3: 0.93 (t:J=7.5);C
H3: 1.07 (S), 1°27 (s>, 1.
35(S>, 1.39(S), 1.59(S):
H-1: 4.69 (m): H-5: 2. o
9 (d:J=2.5):1-1-5:4
．． 49 (dd after exchange: J=2.5 and 4); H-
7: 4.07 (d:J=4 after exchange): CH2
-12: 2.47 and 2.95 (d: J=1
7.5) :OH: 2.25 (s), 2.34
(d ; J-3) ;.

2.41 (d: J-3,5>, 6.67 (s).

A solution of vinyl tributyletheine (817 mg: 2.5 mmol) in 4 d of dry ether under argon was mixed with a 1.5 M solution of butylridium in bexane (1.3 m
g: 1.95 mmol) and then stirred at room temperature for 1 hour and 10 minutes. Apply this solution to needle 4 me.
powdered cupric iodide (229 mg; 1.2 mmol) was added to a suspension of powdered cupric iodide (229 mg; 1.2 mmol), stirred at -60°C under argon, and stirred for 3 hours at -4()°C to -25°C. (black suspension). Cooled again to -78° C. and then a solution of the product obtained in step B of Example 1 (84 mg; 0.2 mmol) in 2 ether (+0.2 d for rinsing) was added. BF3E'j20 (11
0.9 mmol) was added to 011. The mixture was stirred at −78° C. for 1 hour and then returned to room temperature over 30 minutes. A mixture of a saturated solution of N1-f4c2 (9-1>) was added and extracted with CH2Cl12.

It was dried over Na2SO4, and the solvent was removed under reduced pressure under light.

976 mg of a slightly yellow oil were obtained, which was chromatographed on silica (eluent CF-12C (1
2). Initially the desired product of 53 ma was obtained as a white crystalline solid (95%), then 13 mC
The corresponding shrimp compound of 1 was obtained as a white crystalline solid (
14%).

±1 Nie [Kamigane Enjo R (CHCJ3): 1711.16445M:
448(M”+) Product obtained in Example 1 in pyridine 1.6d (57
, 5 mg; 0.16 mmol) of acetic anhydride (
18 composition: 0.10 mmol) was added and then stirred at room temperature for 17 hours. Furthermore, acetic anhydride (9μe:0,
095 mmol) was added and then stirred for 11 hours.

CH2Cl12 and water were added, extracted with CH2Cl12, dried over Na2SOs and the solvent was evaporated under reduced pressure. 58flIg of a white solid was obtained, which was chromatographed on silica (eluent: CH2C112-E
t20.9-1 and then purified by 8-2). 8.5
1,7-diacetate was obtained as a white crystalline solid (12%) and 36.5 mg of 7β-monoacetate was obtained as a white crystalline solid (57%).

IR(CHCe3): 3607.1743.1
711.12465M: 398(M”):
380.342.324.43゜2 [culm Δ: 1α,
6β,7β,9α-LatrahydroE]oxy-15-1del-8,13-epoxy-labdan-11-one-1,
9:6.7-bisacetonide (isomer 1) and the corresponding 13-shrimp compound (isomer 2).

1.57 M of n-butyllithium in hexane (0.64d: 1 mmol) to a solution of cupric iodide (105111CI: 0.55 mmol) in dry ether 2.5i at 35 °C under argon (black suspension) and then stirred for 30 minutes at -30 to -32°C. Cool again to -78°C, then add 2 m of ether.
A solution of the product obtained in step B of Example 1 (84119: 0.2 mmol) in (rinsing with 0.2 ad! of ether) is added and warm boron trifluoride etherate (
30 composition: 0.24 mmol) was added. -78℃
Stir at room temperature for 1 hour, then return to room temperature over 30 minutes. Saturation N1-1. tcj-In thickness NH40f-I (9
-1> mixture and stirred vigorously for 20 minutes, then CH2G! 2, dried over Na2SO4 and the solvent was removed under reduced pressure and light.

1q of 1021+11J of crude product was obtained, which was purified by chromatography on silica (eluent CH2Cl2). 61 mg of the desired 13-shrimp compound was obtained as a colorless lake (61%), and 22.5 mg of the isomer was also obtained.

! Explosive Meiyu 1dan (CHCj3): 1707 5M 478 (M”): 335.277.21
9゜1 Unitechnical raw food seal two 1st place 2 1st (CHCla): 1707 5M: 335.277.219 1" (): 478゜Process step: 1a, 6β, 7β, 9α-tetrahydroxy-15- Ethyl-8,13-epoxy-labdane-11
-one and the corresponding 13-shrimp compound.

Tetrahydroxyfuran 0.84d and 7N hydrochloric acid 0.6
The product obtained in step A in gl1 (isomer 2 >
17.5119 was stirred at 20°C. After 18 hours, an additional 0.3 d of 2N hydrochloric acid was added and stirring continued for 56 hours. This was redissolved in water and extracted with methylene chloride. After drying over sodium sulfate and evaporating under reduced pressure, the residue was chromatographed on silica (
The eluent was cyclohexane-ethyl acetate (4-1). 4.5 ■ of the desired solid product was obtained (yield 30%).
).

NMR300MHz (CDCj3) Nibutyl CH3
: 0.91 (t :J=7) :CH3:
1.07 (S), 1.21° (s>, 1.36 (
S>, 1.39 (s), 1.59 (S): H-1
:4.69 (t after exchange: J=3) :H
-5: 2.09 (d: J-2,5): H-
6: 4.49 (dd after exchange: J=2.5 and 4): H-7: 4.07 (d after exchange:
J-4): CH2-12: 2.48 and 2.
95 (d: J=17.5): OH: 2
．． 24.2.32.2.39, 6.66.

Using the same procedure as above, starting from isomer 1 obtained in step A, the desired product was obtained.

11-one Step A: 1α, 6β, 7β, 9α-detrahydride I'xy-14,15-dinol-8,13-conihoxy 14-
Labdan-11-one-13-carboxaldehyde
1,9-acetonide-6,7-carbonate.

Step ΔL: 1a, 6/3.7B, 9a-tetrahydroxy-8,13-epoxy-14-laban-11-one-1,9-acetonide-7-acetyl.

Forskolin 41011 in methylene chloride 20d
(II) (1,0 mmol) was first added with stirring at 20°C 0.14 m 2-methoxypropene (approx. 0.17 of a 0.01 M solution was added. After 5 hours, it was neutralized by stirring In with about 100 mg of anhydrous potassium carbonate. This was then dissolved with a saturated solution of sodium bicarbonate and extracted with menlene chloride. The organic phase was washed with sodium sulfate and then evaporated under reduced pressure. The residue was chromatographed on a silica column (eluent: (]-12Ce2-AcOET, 9-
1), 417+ng of the desired product was obtained (yield 93%).
).

IR(CHCL3): 3605.1740.17
14.12505M: 450(M”):
432.43° Step A2: 1α, 6β, 7β, 9α-tetrahydroxy-8,13-epoxy-14-laban-11-one-1,9-acetonide.

To a solution of 563 m 0 (1.25 mmol) of the product obtained in step A1 in 28 d of methanol at 20° C., 2.5 d of a 2N aqueous solution of sodium hydroxide (4 eq.) were added and stirred overnight. Methanol was then evaporated off under reduced pressure at room temperature. The residue was dissolved in water and extracted with methylene chloride. The organic phase was washed with water and dried over sodium sulfate. After evaporating this to dryness under reduced pressure, 517+++ g of the desired product were obtained as a white solid (100% yield).

1dan (CI-IC+f!3): 3588.3085
．． 1713.1640th day M: 408 (M”>
: 390.350゜■ Culm A3: 1α, 6β, 7β
, 9α-tetrahuman Nikki 8.13-■Boxi 14
-Rabten-11-one-1,9-acetonide-6,7
- Carbonate.

■Product obtained from culm A2 205ng (0,!!t
mol) to 163rIIi of carbonyldiimidazole (
The mixture was stirred at 60° C. for 5 hours in 10 ml of toluene containing 2.5 g of carbonyl diimidazole, and then 50 Bg of carbonyldiimidazole was added thereto, followed by refluxing again for 6 hours. After cooling, it was poured into water, extracted with methylene chloride and dried over sodium sulfate. After evaporation under reduced pressure, 258r
RQ was obtained, which was chromatographed on a silica column (eluent CH2Cjz-ethyl acetate, 95-5).
The desired product of 2131G was obtained (homogeneous white powder) (98% yield).

MR300M)-1z (CDC13):CH3:
1.10 (S> 1.217(S), 1.3
0(S), 1.36(S), 1.38(S), 1
．． 39(S): 1.4B(S):l-
1=1: 4°/12 (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): Cf-12-12:2.70
and 3.06 (d: J=19): H-14
:6.03 (d d : J = 10.5 and 17
): CH2-15:5.00 (dd:J=
1 and 10.5) and 5,22 (dd: J=1 and 1
7).

■Procedure A4: 1α, 6β, 7β, 9α-tetrahydroxy-14,15-dinol-8,13-epoxy-labdan-11-one-13-power! Levoxyaldehyde 1,9
-acetonide-6,7-carbonate.

327 mg (0
, 75 mmol) was cooled to -78 DEG C. in an acetone/dry ice bath and then bubbled into the oxygen-osine mixture until a slight blue-gray coloration was obtained. It was then passed through a stream of nitrogen until decolorization was obtained, then after approximately 10 minutes 0.05 rIII of dimethyl sulfide was added and the temperature was returned to 20°C. It was stirred roughly for 30 minutes, then poured into water and extracted with methylene chloride. After drying over sodium sulphate and evaporating under reduced pressure, the residue was chromatographed on a silica column (eluent Cl-12cj!2-ethyl acetate,
95-9λ Thus, 305 mg of the desired product (white powder) is 1 q (yield 94%).

IR(CHCj3:1820.1802.1740.
17265M: 43B(M"+'); 42
1.407.43゜Process date: 'I a, 6β, 7β,
9a-tetrahydroxy-8,13-epoxy-14-
Rabutin-11-one-1,9-acetonide-6,7-
Carbonate.

Dimethyldiazomethylphosphonate (60B) in dry tetrahydroxyfuran 3Id at -18 °C under nitrogen
g: 0.4 mmol) in a 1.5 M solution of n-butyllithium in hexane (0.24 d; (), 4
mmol) (orange color) and then at -78°C.
Stirred for 0 minutes. A solution of the product obtained in step A (89 mg: 0.2 mmol) in 3 tnl of 1-rabidroxyfuran was added and stirred for 3 () minutes at -78 °C, then warmed to room temperature over 30 minutes. The mixture was returned to the C and then stirred for 16 hours. Add CH2Ce2 and water, CH2C4
'2, dried over Na2SO4 and the solvent was evaporated under reduced pressure. , 1041 Kl of yellow lake was obtained. To the aqueous phase (approximately 50 d) was added 5 d of 2N sodium hydroxide solution, allowed to stand for 4 hours, acidified with 5.5 mi of 2N hydrochloric acid and extracted with CH2C12. Na2SO4
and the solvent was evaporated off under reduced pressure. 5I11g
of yellow rake was recovered. This was chromatographed on silica (eluent CH2Cl2-AcOEt199
-1, then 9-1, then 1-1, then ACOEt
(only). 22.5 mo of the desired product was obtained as a white crystalline solid (25%) and i 9 mg of the corresponding 6,7-hydroxy product was obtained as a yellow lake.
q (23%).

■Culm C: 1α, 6β, 7β, 9α-detrahydroxy-
8,13・〜■Poxy 14-Lovedine-11-On-
1,9-acetonide.

Adding 0.2 Id of N sodium hydroxide solution to a solution of the product obtained from step B (22.5 mg of carbonate: 0.052 mmol) in 2 mi of methanol;
and stirred for 211 ti (formation of a crystalline white precipitate).

Add 0.22 d of N sulfuric acid and stir for 20 minutes, C
H2(,2z) and water were added and then extracted with CH2Ce. Dried over Na2SO4 and the solvent was evaporated off under reduced pressure. 22 mg of the desired product were obtained as a colorless lake (approx. 100%).

Process fi: 1 cx, 6β, 7β, 9ff-
Tetrahydroxy-8,13-epoxy-14-rabutin-11-one.

The product obtained in step C in tetrahydrofuran 2d (
45 mg: 0.11 mmol) was added 1.6 d of 2N@acid and 0.4 ml of concentrated hydrochloric acid, and then heated to 20°C.
The mixture was stirred for 16 hours. Cl-120!2 and water were added, extracted with CH2Cl12, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. A yellow lake of 3 mg/l was obtained which was chromatographed on silica (eluent Cf-12C (12-AcOEt, 9-1,
Then, it was purified by 8-2). 27 mg of the desired product was obtained as a white crystalline solid as C1q (67%).

l R(CI-ICj2a): 3611.330
6.11165M: 366 (M”):
The product obtained in Example 6 in 0.5 d of 348° lysine (
38.5 mg; 0.105 mmol) of the acetic anhydride-pyridine mixture 1-9 (150 composition: 15
9 mmol) and then stirred at 20° C. for 11 hours. To the colander was added 1501 Ill of acetic anhydride-pyridine mixture (1-9>), stirred for 9 hours, added CH2Ce2 and water, and extracted with C82C12.

It was dried over Na2SO4 and the solvent was evaporated under reduced pressure. 44+ng of a colorless lake was obtained, which was chromatographed on silica (eluent: CH2CI!2-AC
Of=t, 9-1 and then purified by 8-2).

29mQ of the desired product is obtained as a colorless lake, which crystallizes in CCL4 (67%).

IR (CI-1ce3): 3609.3478.33
06.1744.1717.1371.1245 5M: (M”): 390.43° Process A: 1
α,6β,7β,9α-tetrahydroxy-15-ethyl-8,13-epoxy-14-laban-11-one-1,9-acetonide-6,7-carbonate.

2.2r of tetrahydroxyfuran being stirred at 0°C
to a suspension of 193 mg (0.5 mmol) of n-propyltriphenylphosphonium bromide in Idt.
33 m (0.5 mmol) of n-butylridium (
1.5M in hexane) was added. After 30 minutes, the resulting orange suspension was placed in a bath at -78° C. and the product obtained in step A4 of Example 6, 56 as a solution, was poured into tetrahydroxyfuran 2d for 2 minutes. .3111g (
0.125 mmol) was introduced. The temperature was then increased with stirring over 50 minutes until reaching 20°C,
A colorless medium was thus obtained. The mixture was stirred again for 1 hour and 2 minutes, and then dissolved in methylene chloride and a phosphate buffer solution of pH 7. After extraction with CH2C, drying over sodium sulfate and evaporation under reduced pressure, 240 mg of residue were obtained, which was dissolved in a small amount of ethyl ether to remove most of the triphenylphosphine oxide. was removed after filtration.

The ether solution after evaporation gave 107 mg of a residue, which was chromatographed on a silica column (eluent cyclohexane-ethyl acetate, 9-1) to give 34 mg of the desired product (mixture of Z and E isomers). (yield 5
9%).

■Procedure B: 1α, 6β, 7β, 9α-tetrahydroxy-
15-ethyl-8,13-epoxy-labdane-11-
on.

A solution of the product obtained in step A (34 mg: 0.073 mmol) in 96% ethanol 5 d was stirred for 3.5 h under an atmosphere of hydrogen in the presence of 20 mg of 5% palladium on activated carbon. . It was filtered and the solvent was evaporated under reduced pressure. 34 mg of white solid was obtained, which was dissolved in 3-methanol. 0.3 d of N sodium hydroxide solution was added and stirred for 15 hours (formation of white crystalline precipitate). Added 0.337N hydrochloric acid and stirred for 30 minutes (dissolution).

CH2Ce2 and water were added, extracted with CH2Cl12, dried over Na2SO4 and the solvent was evaporated under reduced pressure. 1q of 32 mg of colorless lake was taken and dissolved in 2d of tetrahydroxyfuran.

1.6-2N1! Add acid and 0.4 d of concentrated hydrochloric acid,
The mixture was then stirred for 26 hours. CH2Ce2 and water were added, extracted with CH2CH2, dried over Na2s04 and the solvent was evaporated under reduced pressure. 30 mg of a colorless lake was obtained, which was purified by chromatography on silica (eluent: CH2Ce2-ACOEt, 9-1). 25 mg of the desired product was obtained as a colorless lake, which in the presence of cyclohekirin gave a white solid (
85%).

SM: 398 (M”): 380.3
In Example 8 in 65.324°Pyridine 0.3Irt1 (q product (24 mg: 0.06 mmol)
Add anhydrous W# acid-resistant-lysine mixture (1-9> (
120IiIl: 0.127 mmol),
The mixture was then stirred for 23 hours.

CH2Cff12 and water were added, extracted with CH2Ce2, dried over Na2SO4 and the solvent was evaporated under reduced pressure. A colorless lake of 24m(J) was obtained which was chromatographed on silica (eluent: CH2C112-
It was purified with ACOEt, 9-1).

11.5111 g of the desired product were obtained as a white crystalline solid (43%).

SM: 440 (M”+): 422.4
3゜lj;: ”l α, 68.7B, 9 (X-Te1~
Rahid culm A: 1α, 6β, 7β, 9α-tetrahydroxy-8,13-epoxy-12-laban-11-one-1,9-acetonide-7-acetyl.

Step A1: 1α, 6β, 7β, 9α-tetrahydroxy-14,15-dinol-8,13-epoxy-14-
Labdan-11-one-13-carboxyacetamide
1,9-acetonide-7-acetyl.

The oxygen and ozone stream was mixed with 0.5 ml of methanol and 0.
．． Passed through a colorless solution of 406,111 g (0,9 mmol) of the product obtained in step A1 of Example 6 in 10 d of methylene chloride containing 185 rltl of pyridine (2,5 eq.), giving a blue-light gray coloration. 178 until
Stir at ℃. Then bubble 1 for 15 minutes in an argon stream.
then 0.17 dimethyl sulfide (1
, 36 mmol), the temperature was returned to 20'C.

Dissolved in water and extracted with methylene chloride.

After dehydration over sodium sulfate and evaporation under reduced pressure, 43
4 mg of white solid was obtained. After chromatography on a silica column (eluent dichlorohekirin-ethyl acetate, 4-1), 370 mg of the desired aldehyde (white solid) were isolated (yield 91%).

IR (CI-ICj3): 1724°SM: 437.
423.43° FD: 452 (M), 423° Process ΔL: 1a, 68.7/3,9α-tetrahydroxy-8,13-epoxy-14,15-dinol-12
- Labuan-11-one-1,9-acetonide.

Product obtained in step A in pyridine 4.3d 34
63 mg of a solution of 001G (0.75 mmol)
(1,2 eq.) of hydroxyxylamine hydrochloride for 2 hours and 15 minutes at 20°C. It was then poured into water and extracted with methylene chloride. The organic phase was dried over sodium sulfate, evaporated under reduced pressure and heated with toluene to remove traces of pyridine. The obtained oxime (quantitative yield) was dissolved in 10 ml of methylene chloride. 24dma carbonyldiimidazole (
2 equivalents) was added and then refluxed for 3.5 hours. After cooling, it was dissolved in water and extracted with methylene chloride. After drying over sodium sulfate and evaporation under reduced pressure, the required nitrile (quantitative yield) of 341+1 (l) was obtained.

NMR250MHz (CDCj3): CHa:
1.03 (S), 1.26 (s), 1.46
(s>(x2>, 1.56(s), 1.61 (S
), 1.63 (S): CH3-C: 2.16 (s): H-1:
4.35 (m); H-5: 2.26 (
d: J-2): G1-6: 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).

Methanol led and 2N aqueous solution of sodium hydroxide 1
Nitrile 280ffllJ (0,62
(mmol) solution was stirred at 20° C. overnight. Poured into water and extracted with methylene chloride. The organic phase was dried over 1 to 2 sulfuric acid and then evaporated to dryness under reduced pressure.
30 mg of residue was obtained. (7) on a silica column
? After l'' Craffy (eluent: Cl-120g 2-ethyl acetate, 9-1), 214+ng of the desired product were obtained (90% yield) (white solid).

IR (CHCja): 3610.3591.166
5.1621゜UV (E, -t0+-1): 2
80nm: 5 = 90000SM: 365.322
．． 307° Step A3: 1α, 6β, 7β, 9α-tetrahydroxy-8,13-epoxy-14,15-dinol-12-labdan-11-one-1,9-acetonide 7-acetyl.

Working as described in Example 9, using the product obtained in Step A2 as the starting point, the desired product was obtained.

Step B: 1α, 6β, 7β, 9α-tetrahydroxy-
8,13-Epoxy-14-lapden-11-one and the corresponding 13-shrimp compounds.

Vinyltributyletheine (1,226 g: 3.75 mmol) in dry ether 6d under argon
A 1.6M solution of n-butyllithium in hexane (1,875d: 3 mmol) was added to the solution and then stirred for 2 to 14 hours. This solution was added to a suspension of cupric iodide (34311 (J: 1.8 mmol) in 6 ml of ether at -50°C under nitrogen (gray color) and then heated from -45°C to -25°C. and stirred for 2.5 hours (black suspension). Cool to −78° C., add warm boron trifluoride etherate (165 tIIl: 1.34 mmol) and add the product obtained from step A (123
A solution of 111 (II: 0.3 mmol) was added.

Stir at -78°C for 40 minutes, then return to room temperature over 35 minutes. A saturated solution of sodium acid tartrate was added and then stirred overnight (pale yellow precipitate).

Extracted with ACOEt, dried over Na2SO4, the solvent was evaporated under reduced pressure, dissolved in CH2Cl12, filtered and the solvent was evaporated under reduced pressure. 1 containing solids;
4371;l of an orange oil was obtained, which was treated analogously in the process of Example 6. 1,43 containing solids
7 g of an orange oil were obtained, which was chromatographed on silica (eluent: CH2C112-Et20.9
-1, then +1+'F8-2>. 4mg of the desired product as a colorless lake is 1! I received (3.6%);
and 25 mg of the other desired isomer (13-shrimp compound)
was obtained as a white crystalline solid (22.5%).

Industrial eclipse: IR (Nudiol): 3480.3365.329
Product obtained from Example 10 (13
- shrimp isomer: 20 mg; 6.054 mmol) of acetic anhydride-pyridine mixture 1-9 (77/J
:0.08 mmol) and stirred for 16 hours. Added a further 77 mixture and stirred for 5 hours, then added 160Iiε mixture to the colander and added 4 hours for 3 hours.
Stir for 5 minutes, then add 160μ2 of the mixture to the colander for 1.5115 minutes. CI-! 2cf
22 and water, extracted with Cf-12c (!z, and extracted with N
It was dried over a2SO4 and the solvent was evaporated off under reduced pressure.

19 mg of colorless lake was obtained, which was chromatographed on silica (eluent: CH2Ge2-Et20,
9-1 and then 8-2>. 3 mg of 1,
9-diacetate (12%) was obtained and 10.5 m
The desired 13-shrimp compound was obtained as a white crystalline solid (47%).

SM: 410 (M”+): 392.4
3. Starting from the other isomer obtained from Example 10, the same procedure as above gave the desired product in the same yield.

1 hill Δ: 1 α, 6β, 78.9 (2-tetrahydroxy-8,13-epoxy-14-laban-11-one.

Water 9rI! Forskolin (821 m
g:2d> and then stirred for 62 hours (rapid dissolution). Add water, extract with CH2Ce2, Na2SO
4 and the solvent was evaporated off under reduced pressure. 0.80
A white crystalline fixation of g was obtained, which was chromatographed on silica (eluent: CH2Cl2-Et2o, 9
8-2>.

The desired product was obtained as a white crystalline solid (100%).

Step B: 1α, 6β, 7β, 9α-tetrahydroxy-
8,13-epoxy-14-lapden-11-one-1
, 9:6,7-Scarbonate.

Product obtained from step A in toluene 10d (1
Carbonyldiimidazole (649 mg; 4 mmol) was added to a solution of 50 mg (0.4 mmol) and then heated to 80-85° C. for 6 hours. After cooling to room temperature, CH2Cl12 and water were added and CH2
It was extracted with Oj2, dried over Na25Oa and the solvent was evaporated under reduced pressure. 0.18 (l of white crystalline solid is 4 [
1, paste this on silica [17 tog 7 fi (I
Eject: CH2C(12-Et20)F Purified. 159
mg of the desired product was obtained as a white crystalline solid (9
4%).

Engineering ffc: 1α, 6β, 7β, 9α-tetrahydroxy-dinol-8,13-epoxylabden-11-one-13-carboxaldehyde-1,9:6,7-biscarbonate.

Into a solution of the product obtained in step B (149 mg: 0.35 mmol) in 126 d of CH2Cl and 4 d of methanol was passed through a stream of ozone-oxygen until a clear blue coloration was obtained at -78 °C. I let it happen. A stream of nitrogen was then applied for 20 minutes and then 260111 methyl sulfide was added. The mixture was allowed to warm to room temperature and then stirred for 2 hours. CH20j2 and water were added, extracted with CH2CR2, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. 188,111 g of a colorless lake was obtained, which was chromatographed on silica (-(1 solvent: CH2Ce2-
It was purified with Et20°9-1). 137 mg of the desired product was obtained as a white crystalline solid (91%).

IR (CHCI13): 1835.1814.17
65.1741.1691゜SM: 422 (M'10): 393.3
49°F [): 422.393° Step D: 1α, 6β, 7β, 9α, 14-pentahydroxyxy-15-true 8,13-epoxy-labdan-11-one-1,9:6.7- Biscarbonate.

A solution of the product obtained from step C (85 mmol: 0.2 mmol) in dry tetrahydrofuran was added with lithium trit-t-butoxyaluminohydride (56 mmol).
g: 0.22 mmol) and then for 1 hour 2
Stirred for 5 minutes. 5 mg of hydride was added to the colander and stirred again for 45 minutes. Saturated ammonium chloride solution was added, extracted with Ac0Et, dried over Na2SO4, the solvent was evaporated off under reduced pressure, dissolved in CH2Cl2, filtered and the solvent was evaporated off under reduced pressure. 92m
g of a white solid was obtained, which was chromatographed on silica (eluent: Ct-12Ce2-Et20.9
-1, then 'r''8-2). 57 mg of the desired product was obtained as a glassy solid (66%).
.

Step E: 1α, 6β, 7β, 9α, 14-pentahydroxy-15-true 8,13-epoxy-labdan-1
1-on.

1 d to a suspension of the product obtained in the step (57 m (1: 0.13 mmol) in methanol 5f111
of N sodium hydroxide solution was added and then stirred for 24 hours. Added 3I111 of water and stirred for 48 hours, added 11R1 of water to a colander and stirred again for 24 hours.

Extracted with ACOEt, dried over Na2SO4, evaporated the solvent under reduced pressure, dissolved in CH20f12, filtered and evaporated the solvent under reduced pressure. 47.5 mg of the desired product was obtained as a white crystalline solid. IR (nudiol): 3520.3447.3339.3188.171
4゜SM: 372 (M”): 35/l,
341,336,323.305° 449 mg of product obtained from step A of Example 1 in methylene chloride 12rR1 and 0.4 m (5 equivalents) of pyridine
(1,049 mol) was passed through an oxygen-ozone mixture and cooled to -78°C. After 10 minutes, the ozone became saturated (pale blue-gray coloration), and then bubbling in oxygen-osine was continued for an additional 15 minutes.

A stream of nitrogen was then passed through for 20 minutes and 0.1 d of dimethyl sulfide was added before returning to 20°C.

Stirred for a further 30 minutes, then dissolved in water and extracted with methylene chloride. After dehydration of the sulfuric acid to thulium and evaporation under reduced pressure, 483 mg of a slightly discolored gummy material were obtained. Chromatography on a silica column (eluent: Cl-120e2-ethyl acetate, 95
-5/NEt31%), then 160 m (13
-Carboxaldehyde product- product was obtained (35.5
%). Then CH2Cl2-CH30H (85-15
) to give the desired 13-carboxy product of 198m (1) (42.5% yield).

IR (CHC113) 13-carboxy product: 340
0.1769.1723゜■ Degree A: 1α, 6β, 7β, 9α-tetrahydroxy-
15-Ethyl-8,13-epoxy-14-lapden-11-one-1,9:6.7-bisacetonide.

Dry tetrahydrofuran under argon at room temperature 4.4
A suspension of n-propyltriphenylphosphonium bromide (38 ml; 1 mmol) in d was added with a 1.57 M solution of ]-butylridium in hexane (0.
63d: 1 ml) was added and then stirred for 30 minutes (orange solution 0.2M>. This solution 0.65
d (0.13 milliliters) in tetrahydrofuran 2r
To a solution of the 13-carboxaldehyde product obtained from Example 13 (54 mg; 0.12 mmol) in nl was added under argon and then incubated at room temperature for 1 hour 20
Stir for 1 minute. Another 0.25 m of the same solution (0.05 mmol) was added, stirred again for 30 minutes, and the
The same solution of d (0.06 mmol) was added and stirred again for 30 minutes. Ether and water were added and extracted into ether, which was washed with water and dried over Na2SO4. The solvent was evaporated off under reduced pressure to give 78 mg of a slightly yellow lake, which was purified by chromatography on silica (eluent: CH2C (12). 22 mg of the desired product (isomers E and Z) (38%) was obtained as a colorless lake.

] Two hands'ii [3:1α, 6β, 7β, 9α-tetrahydroxy-15-ethyl-8,13-epoxy-labdan-11-one-1,9:6.7-bisacetonide.

A solution of the product obtained from step A (23n+g: 0.048 mmol) in 3 Wdl of 96% ethanol was stirred for 3 hours 15 minutes under an atmosphere of hydrogen in the presence of 10 mg of 5% palladium on activated carbon. It was filtered and the solvent was evaporated off under reduced pressure. 23 mg of the desired product was obtained as a colorless lake (approximately 100%).

Compounds of the present invention were added to cyclase adenylate.
was tested to determine its introductory activity.

The enzyme was treated with homogenized rat hippocampal tissue and the production of cyclic adenosine phosphate was measured starting from 7 denosine triphosphate labeled with phosphorus 32.

The % stimulation of the enzyme was evaluated by testing each product at a concentration of 1o-5 or 10-4M and compared to the comparison compound (=
100%). The results are shown in the table below:

Claims (10)

[Claims] (1) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_6 and R_7 may be the same or different and represent a hydrogen atom or an acyl group, and R_1 is a hydroxyl or halogen as appropriate. , cyano, amino, phenyl, a methyl group optionally substituted by an esterified carboxyl, azide or carbamoimo group (which is optionally substituted by a C_1_-_3 alkyl group), or a dimethylamino group, a trimethylamino group, an OH or by an ethime group substituted by a SH group (each of these two groups may be optionally esterified), a vinyl group or a phenyl group, or an OH or SH group (each of these groups optionally substituted) Substituted C_3_-_4 alkyl group, or group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R' represents a hydrogen atom or methyl group), or groups ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (here each of R'' and R'' represents a hydrogen atom or a methyl group, or one of them represents a hydrogen atom and the other represents a methyl group), or -CO_2H, -CH=NOH or ▲ formula, as appropriate. There are chemical formulas, tables, etc. ▼ Indicates either -CHO or CN substituted by a group; R_2 is a C_1_-_3 alkyl group or a group ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (Here, R'_2 and R Each of ``_2 represents a hydrogen atom, or one of these represents a hydrogen atom and the other represents a C_1_-_3 alkyl group), or an ethynyl group, provided that the substituent R_1 or R_2
One of them shows β-CH_3 group and the other one shows α-vinyl,
-CHO, -CN, CH=N-OH, -C_2H_5 or CH_3 group is excluded]. (2) R_6 represents a hydrogen atom, R_7 represents a hydrogen atom or an acetyl group, and R_1 represents -CH_2-OH, -
CHO, -CO_2H (which is optionally esterified in the form of methyl or ethyl ester), -CH=NO
H, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -CH_2-CH_2-N(CH_3)_2, -CH_
2-CH_3, -CH=CH_2, -CH_2-CH_
2-CH_3, -CH_2-CH_2-SCH_3, ▲Mathematical formulas, chemical formulas, tables, etc.▼, -CH_2Cl, -CH_2Br, -CH_2CO_2O (which is suitably esterified in the form of methyl or ethyl ester) ▲Mathematical formulas, chemical formulas , there are tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -CH=CH-CH_3, -CH=C(CH_3)_2
, -CH_2-CH_2-OH, and R_2 is selected from methyl, vinyl and ethynyl groups. (3) Substituent R_1 is -CH_2-OH, -CO_2H or -CH_2-CO_2H (which is suitably esterified in the form of methyl or ethyl ester), -CH=CH_2, -CH_2-CH_3, -CH_2-CH_2 -CH_
3. -CH_2-CH_2-S-CH_3, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -CH_2-CH_2-OH is selected from the group consisting of the general formula (I) according to claim 1 or 2. Compounds with (4) 1α,6β,9α-trihydroxy-7β-acetoxy-8,13-
Claim 1: Epoxy-14-ravudin-11-one
A compound having the general formula (I) as described. (5) First, formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, each of R'_1, R'_6, R'_7, and R'_9 is free or protected. or R'_1 and R'_9 on the one hand and R'_9 on the other hand.
'_6 and R'_7 together represent the group ▲mathematical formula, chemical formula,
There are tables, etc.▼ (In this formula, R_a and R_b may be the same or different and represent a hydrogen atom or an alkyl or alkoxy group having 1 to 4 carbon atoms, or R_a and R_b may be used together. forming an oxygen atom) and R_1 represents a methyl group] is treated with an oxidizing agent to form a compound of formula (II) where R_1=CH_2OH
A compound of formula (II_a) corresponding to the compound of
A compound of formula (II_b) corresponding to a compound of formula (II) which is HO is obtained or applied to a halogenating reagent to obtain R_1=
A compound of formula (II_c) corresponding to a compound of -CH_2X (where X represents a halogen atom) is obtained, or a compound of formula (II_d) corresponding to a compound of formula (II) where R_1=-CO_2H is obtained by applying an oxidizing agent. This compound is esterified as required, or R_1=-CH
The compound of formula (II_b) which is O is subjected to the action of (i) hydroxylamine hydrochloride to form R_1
A compound of formula (II_e) corresponding to the compound of formula (II) where =-CH=NOH is obtained, or (ii) by the action of hydrocyanic acid or acetone cyanohydrin ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or (ii
i) through the action of an oxidizing reagent to obtain the compound of formula (II_d) in which R_1 = -CO_2H; or directly by treatment with an oxidizing reagent to obtain a compound of formula (II_b) in which R_1 represents a -CHO group; If necessary, treat in the same manner as above; or treat with a halogenating reagent to directly obtain the compound of formula (II_c) where R_1=-CH_2X, and optionally treat this compound with cyanide ions to give R_1= A compound of formula (II_g) corresponding to the compound of formula (II) which is -CH_2-CN is obtained, and this compound of formula (II_g) is optionally treated with hydrogen peroxide to R_1=-C
Either obtain a compound of formula (II_h) corresponding to the compound of formula (II) which is H_2CONH_2 or treat the compound of formula (II_c) with an alkali azide to obtain R_1=-CH_2
Formula (II_i) corresponding to the compound of formula (II) which is N_3
This compound of formula (II_i) is optionally treated with triphenylphosphine to obtain R_1=-CH_2
-NH_2 corresponding to the compound of formula (II)
j); or treated with a compound of the formula [H_2C=N^■, A compound of formula (II_k) corresponding to the compound of formula (II) which is (CH_3)_2 is obtained, and this compound of formula (II_k) is optionally treated with methyl halide to R_1=-CH_2-CH_2-N
^■-(CH_3)_3X^■ [Here, to obtain a compound of formula (II_m) corresponding to a compound of formula (II) where R_1 = -CH=CH_2; or a compound of formula (II) is first treated with a strong acid and then treated with a compound of the formula R_BX [where R_B represents a C_1_-_3 alkyl group, allyl or benzyl group] or a compound of the formula R'_BO(CH_2)_nX or R'_B
S(CH_2)_nX [wherein, X represents a halogen atom or an arylsulfonate, R'_B represents a hydrogen atom,
represents a protecting group for an alkyl group or a hydroxyl or diol group, and n represents an integer of 1 to 3], and R_1 is a C_2_-_4 alkyl group (n_1), -(CH_2)_2-CH= CH_2 group (n_2), -(CH_2)_2φ group (n_3), -(CH_2)_2_-_4OR'_B group (n_4) and -(CH_2)_2_-_4SR'_B group (n_5)
Formula (II_n__1) corresponding to the compound of formula (II) showing
, (II_n___2), (II_n___3), (II_n___
4) and (II_n__5); or treated with an oxidizing agent to obtain the compound of formula (II_a) corresponding to the compound of formula (II) in which R_1=-CH_2OH; or treated with a halogenating agent. to obtain the compound of formula (II_c) corresponding to the compound of formula (II) where R_1=-CH_2X [where X represents a halogen atom]; or treated with a reagent for introducing a carboxy group to obtain R_
Obtain a compound of formula (II_o) corresponding to the compound of formula (II) where 1=-CH_2CO_2H, and optionally esterify this compound to obtain a compound of formula (II'_o); or formula R_oN=C=O [where R_o represents an alkyl group or phenyl group having 1 to 4 carbon atoms] is treated with an isocyanate of R_1=-CH_2-CO-NH-R_o [where R_
o has the meaning given above] to obtain a compound of formula (II″_o) corresponding to a compound of formula (II) where R_1=-CH
_2-CO_2-Alk [In this formula, Alk represents an alkyl group having 1 to 4 carbon atoms]
_o) Obtain a compound of the formula ▲ Numerical formula, chemical formula, table, etc. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ to obtain a compound of formula (II_p) corresponding to the compound of formula (II), which represents a methyl group, and to obtain a compound of formula (II_p) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ to obtain a compound of formula (II_q) corresponding to the compound of formula (II); DeX^■
has the meaning given above] to form a compound of formula (II_k
), and then formula (II), (II_a), (
II_b), (II_c), (II_d), (II_e), (I
I_f), (II_g), (II_h), (II_i), (II
＿j), (II_k), (II_l), (II_m), (II_
n___1), (II_n___2), (II_n___3), (
II_n___4), (II_n___5), (II_o), (I
I′_o), (II″_o), (II_p) and (II_q)
A compound of the formula R_2Cu, (R_2)_2CuLi, R_2R_N_TCuLi, R_2R_N_TCu(CN)Li_2 or (R_
2)_2Cu(CN)Li_2 [In these formulas, R_2 has the meaning as defined in claim 1 except for ethynyl, and R_N_
T represents an immobile group]; or treated with a reagent of the formula ▲ Mathematical formula, chemical formula, table, etc. ▼ and then treated with lead tetraacetate to form the formula ( A compound of the formula (I_a) in which R_1 is -CH_2OH is obtained as desired, and then a compound of the formula (I_a) in which R_1 is -CH_2OH is treated with an oxidizing agent to obtain a compound of the formula (I_a) in which R_1 is -CHO group.
I_b) or a compound of formula (I_b) in which R_1 represents a -CO_2H group, and then optionally deprotecting the resulting compound in which one or more hydroxyl groups are protected by a protecting group. and optionally the resulting compound in which at least one of the groups R_6 and R_7 represents a hydroxyl group is treated with an acylating agent to form a compound of formula (I) in which at least one of the groups R_6 and R_7 represents an acyloxy group. A method for producing a compound having formula (I) according to claim 1, characterized in that the compound is obtained. (6) When producing a compound having the formula (I) according to claim 1, in which R_1 represents a methyl group and R_2 represents an ethynyl group, formula (III): ▲Mathematical formula, chemical formula, table, etc.▼(III ) [In the formula, R'_1, R'_6, R'_7 and R_9 have the above meanings] In the diazophosphonate of the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ in which the compound of the formula is operated in the presence of a base. By processing, one obtains a compound of the formula (I _e): ▲Formula, chemical formula, table, etc.▼(I _e), and then, if necessary, one or more hydroxyl groups thus obtained are protected. The compound of the formula (I_e) protected by the group is treated with a deprotecting agent, and if necessary, the compound of the formula (I_e) in which at least one of the groups R_6 and R_7 thus obtained is a hydroxyl group is prepared.
I) is treated with an acylating agent to form a compound of the formula (I) in which at least one of the groups R_6 and R_7 is an acyloxy group.
A method for producing a compound having the above formula (I), which comprises obtaining a compound of formula (I). (7) A pharmaceutically acceptable compound having the formula (I) according to claim 1 as a medicament. (8) A pharmaceutically acceptable compound having the formula (I) according to any one of claims 2 to 4 for use as a medicament. (9) A pharmaceutical composition containing at least one medicament according to claim 7 or 8 as an active ingredient. (10) General formula (II_A) as a new industrial product ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II_A) [In the formula, R'_1, R_9, R'_6 and R'_7 have the above meanings. And R_A__1 is R_ other than methyl
1 has the above-mentioned meaning, and if R_A__1 has a reactive function, this function can be of a protected type].