JPS61277685A - Novel indolizidine derivative, production thereof and composition containing said derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is H, hydroxy, cyano, halogen, acyloxy, etc.; R<2> is hydroxy or acyloxy; R<3> is H, hydroxy, acyloxy or halogen; R<4> is lower alkyl; Y is halogen; n is 0 or 1, etc.). EXAMPLE:1alpha,2alpha,8beta-Tribenzoyloxy-8alphabeta-indolizidine. USE:An immunological regulator. PREPARATION:A compound expressed by formula II is reacted with an acylating agent, e.g. aliphatic carboxylic acid or aromatic carboxylic acid, preferably in the presence of a base in a solvent, e.g. dimethyl sulfoxide, under mild conditions such as while cooling, at room temperature or while warming to afford the aimed compound expressed by formula I.

Description

[Detailed description of the invention] This invention relates to novel intrizidine derivatives.

More particularly, the present invention relates to novel intrizidine conductors and pharmaceutically acceptable salts thereof having immunomodulatory activity, as well as processes for their preparation and compositions containing them.

The novel intrizidine derivative of this invention is represented by the following general formula.

R'R'Ye)n (wherein R3 is hydrogen, hydroxy group, cyano group, halogen, acyloxy group, amino group or alkoxy group;
R2 is a hydroxy group or an acyloxy group; R1 is hydrogen, a hydroxy group, an acyloxy group, or a halogen; R4
is a lower alkyl V group;
.

When R'' and IN are both hydroxy groups, n is an integer l, and when R1 and R8 are both acetoxy groups and n is an integer zero, R1 is a cyano group, a halogen or an acetoxy group excluding acetoxy).

Details and preferred examples of the definitions of the gods described above and below will be explained below.

As used in this specification, "low grade" and "high grade" mean
Unless otherwise specified, radicals having 1 to 6 carbon atoms and 7 to 20 carbon atoms, respectively, are meant.

(1) R', R2, R1%RA, Be, R> and gc
Regarding the acyl moiety of the vavvoxy group: Examples of the acyl group include an aliphatic acyl group, an aromatic acyl group, and a heterocyclic acyl group, and examples of such acyl groups are as follows.

Preferred examples of the aliphatic acyl group include lower alkanoyl groups such as acetyl, propionyl, tertiary butyryl, and piparoyl; higher alkanoyl groups such as t-bamyristoyl, valmitoyl, and stearoya; Globansulfonyl, iso1
Examples include lower alkanesulfonyl V groups such as 0-(ns Vhonyl) and butanesulfonyl.

Aromatic acyl group means a large acyl group derived from an acid having an aryl group such as phenyV group, and preferred examples thereof include aroyl groups such as benzoyl, toluoyl, etc., such as phenylacetyl, phenylacetyl, phenyl aryloxy(lower)alkanoyl groups such as phenoxyacetyv2 phenoxypropionyl, e.g. penylsulfonyl,
Examples include an allenthyl group such as Toshi V.

The multicyclic acyl group means an acyl group derived from an acid or a thioic acid having a heterocyclic group containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. is, for example, a heterocyclic Vbonyl group or a heterocyclic thiocarbonyl group having a 5- to 6-membered heterocyclic ring such as thenoyl, furoyl, imitasol V carboni V, imidazolylthiocarbonyl, etc., such as a 5- to 6-membered heterocyclic thiocarbonyl group such as Chenya acetyl. Examples include a heterocyclic (lower) alkanoyl group having a heterocyclic ring.

(2) R”, R”, RA, Rlt, R9,a
>YohiyOhaa Regarding Ken: Preferred examples of halogen are chlorine, fluorine, alkyl moiety and lower alkyl of R4: Alkyl groups include lower and higher alkyl groups.

Preferred examples of lower alkyl groups include methyl, ethyl V
, butyl, bench V, hexy V, etc.

Preferred examples of the higher alkyl V group include heptyV, octyv1dodytv, benzydenyl, hexadecyl, octadecyV, and the like.

(4) Regarding the hydroxy protecting group for R'': Preferred examples of the Rb hydroxy protecting group include conventional groups that protect adjacent hydroxy groups such as isopropylidene, benzylidene and the like.

(5) Regarding pharmaceutically acceptable salts of compound (1): Preferred examples of pharmaceutically acceptable salts of compound (1) include manic acid, fumaric acid, tartaric acid, citric acid, acetic acid, benzoic acid, and hydrochloric acid. , sulfuric acid, nitric acid, phosphoric acid, etc., and salts with organic or inorganic acids.

In this specification, the target intrizidine derivative (1) is named as follows in the sixth position representing this stereoisomer, taking into consideration the presence of asymmetric carbon atoms at the 1st, 2nd and 8th positions of the intrizidine ring. They were named stereochemically using the method.

(R' ye) n That is, in the above formula, if the direction of addition of the substituent represented by R1, R2 or R8 is below the plane of the intrizidine ring, it is called α-configuration; If it is above the plane of the ring, it is named β-configuration.

Compound (1) of the present invention and its pharmaceutically acceptable salts can be produced by various methods described below.

(1) Manufacturing method 1 (1) (1”) (2) Manufacturing method 2 (Ib) (1”) (3) Manufacturing method 3 Blunt (1 > (4) Manufacturing method 4 (■c) iId ) (5) Manufacturing method 6 side 'on CIl on (IC)
(1) (7) Manufacturing method 7 (8) Manufacturing method 8 Fu (1) (Ig) (9) Manufacturing method 9 (Ih) (Hei (10) Manufacturing method 10 (厘) (1')
(11) Manufacturing method 11 (Yama (Ik)) (12) Manufacturing method 12 陀 (ff) (11) (18) Manufacturing method 13 (Im) (1”) (14) Manufacturing method 14 (Ma) (1') (In the above formula, RAR2 and R: are each an acyloxy group, RA and RA are each different from a halogen,
(Vano, halogen, acyloxy, hydrogen, amino, alkoxy, R and S mean halogen and R'H hydroxy protecting group, respectively).

(1) Production method 1 The salt of compound ([a)] can be produced by reacting compound (1) or a salt thereof with an acylating agent.

Preferred examples of the salts of compounds (Ia) and (Ia) include the same salts as those of compound (1).

In the compound (1) to be used as a raw material compound in this production method, 8aβ-intridizine-1α, 2α, 8β
-Trio-V is a known compound, for example, published in the Austrian Journal og Chemistry (Australian Journal of Chemistry).
lian Journal of Ch@m1slry
) Vol. 82, pp. 2257-2264, 1979.

The acylating agent used in this production method is Organic Power V
Examples include organic acids such as bonic acids and the corresponding thio acids, but more particularly, aliphatic carboxylic acids, aromatic carboxylic acids or heterocyclic carboxylic acids and the corresponding thioacids.
Included are bonic acids and their reactive derivatives.

Reactive derivatives include acid halides, acid anhydrides,
Examples include activated amides and activated esters.

The above-mentioned reactive derivatives are selected depending on the type of acid to be used.

If a free acid is used as the acylating agent in this reaction, the process is preferably carried out in the presence of a conventional condensing agent.

The reaction is usually carried out using dimethyVA/poxide, methylene chloride,
It is carried out in a solvent such as tetrahydrofuran, pyridine, chloroform, dichloroethane, dimethylformamide, etc.

This reaction is preferably carried out in the presence of a conventional organic or inorganic base used in acylation reactions.

The reaction is preferably carried out under somewhat mild conditions, such as under cooling, at room temperature, or under heating.

(2) Production method 2 Compound ([a) or its salt can be produced by reacting compound (Ib) or its salt with an acylating agent.

Preferred examples of the salts of compound (Ib) include compound (Ib);
The same things as 1) and salts can be mentioned.

The compound (Ib
), the compound in which RH and RH are each an acetoxy group is a known compound, for example, Australian Journal V. Og Chemistry (Au-stralia
n Joutnal of Chemistry) No. 8
2, pp. 2257-2264, 1979.

The reaction in this production method is carried out substantially in accordance with Production Method 1.

(3) Production method 8 Compound (IC) or a salt thereof can be produced by reacting compound (Ib) or a salt thereof with a halogenating agent.

Preferred examples of salts of compound (■0) include compound (
The same salts as 1) can be mentioned.

Preferred examples of halogenating agents to be used in this production method include halogens such as chlorine and bromine, thionyl halides such as thiodiV chloride, e.g. sodium chloride,
Iodide), alkali halides such as lithium chloride, alkylammonium halides such as tertiary-n-buty-V ammonium fluoride, and the like.

The reaction is usually carried out in a solvent such as dimethyM sulfoxide, 1-y-dine chloride, tetrahydrofuran, chloroform, benzene, and the like.

This reaction can be carried out using organic or W-free
Preferably, the reaction is carried out in the presence of a base.

The reaction is preferably carried out under mild conditions, such as under cooling, at room temperature, or under warm conditions.

In the present invention, the case where the H configuration at the 8-position of the intrizidine ring changes during the reaction of compound (Ib) with the halogenating agent is also included within the scope of the present invention.

(4) Production method 4 Compound (1d) or a salt thereof can be produced by reacting compound (IC) or a salt thereof with a cyanating agent.

Preferred examples of the salts of compound (Id) include compound (Id);
The same things as 1) and salts can be mentioned.

Preferred examples of the cyanating agent used in this production method include anchor metal cyanides such as sodium cyanide and potassium cyanide;
Dialkyl V aminium cyanides such as ammium and the like can be mentioned.

The reaction is usually carried out in a solvent such as water, an alcohol such as methano-V, ethanol, propano-M, etc., dimethysulfoxide, methylene chloride, tetrahydrofuran, and the like.

This reaction is preferably carried out under somewhat mild conditions, such as under cooling and heating in chamber A and M6.

In this reaction, a case where a change in configuration occurs at the 08-position of the intrizidine ring during the reaction of compound (1') with the cyanating agent is also included within the scope of the present invention.

(5) Production method 5 Compound (1'') or a salt thereof can be produced by reacting with compound (1) or its at-acyl M-forming agent.

Preferred examples of salts of compound (1e) include compound (1e).
) are listed as the same salts.

Preferred examples of the alkylating agent used in this production method include lower alkyl halides such as methyl chloride, methyl bromide, and ethyl iodide.

The reactions in this process are usually carried out in a solvent such as water, alcohols such as methanol, ethanol, globanol, dimethyV sulfoxide, tetrahydrofuran, and the like.

This reaction is preferably carried out in the presence of organic or inorganic bases commonly used in alkylation reactions.

The reaction is preferably carried out under somewhat mild conditions, such as under cooling, at room temperature, or under heating.

(6) Production method 6 Compound (Ia') or a salt thereof can be produced by subjecting compound (IC) or a salt thereof to a halogen exchange reaction.

Examples of the halogenating agent used in this production method include halogens such as chlorine, bromine, and iodine, sodium chloride,
Examples include alkali halides such as sodium iodide.

The reaction is usually carried out using alcohols such as methano-V, ethanol, and globanol, dimethyl-V! It is carried out in solvents such as refoxide, methylene chloride, tetrahydrofuran, chloroform, methifrethyl ketone, and the like.

This reaction is preferably carried out under somewhat mild conditions, such as under cooling, at room temperature, or under heating.

(7) Production method 7 Compound (Ih) and (, h/ ) or salts thereof can be produced by reacting compound (If) or a salt thereof with an acylating agent.

Preferred examples of the salts of the compound (among them, (1'')) include the same salts as the compound 0).

The reactions of this production method are carried out substantially in the same manner as in Production Method I. Acyl groups are in the 1st and 2nd positions of the intrizidine ring
The chemotactic compounds (Ih) and (1'') introduced into one of the hydroxyl groups can be obtained by selecting appropriate reaction conditions from those described in the explanation of the production method 1 above.

The generated compounds (Ih) and (Ih') are each
It can be separated from the reaction mixture by conventional separation methods such as chromatography.

(8) Production method 8 Compound (Ig) or fc can be produced by reacting compound (Ih) or a salt thereof with an acylating agent.

Preferred examples of salts of compound (tg) include compound (tg).
The same salts can be mentioned in summer).

The reactions in this production method are carried out in substantially the same manner as in Production Method I.

(9) Production method 9 Compound (If) or fcFi, its salt is compound (Ih)
It can be produced by subjecting a hydroxyl group or a salt thereof to an elimination reaction of a hydroxyl group.

Preferred examples of salts of compound (It) include compound (It);
The same salts as 1) can be mentioned.

The elimination reaction is carried out by a conventional method such as a method in which a group to be eliminated is introduced into compound (Ih) and then the resulting compound is reduced.

Suitable leaving groups to be introduced into the hydroxy group include lower alkanesulfonyl groups such as mesyl and trifluoromethane Mhonyl, allenesulfonyl groups such as tosyl, and heterocyclic-thiocarbonyl groups such as imidazolyl-thiocarbonyl. V Motogo is an example.

Examples of reagents used for introducing the leaving group include acids corresponding to the acyl V of the leaving group and reactive derivatives thereof. Reactive derivatives include acid halides,
Examples include acid anhydrides.

The introduction reaction is water, alcohol, dimethyV sulfoxide,
It is preferable to carry out the reaction in a solvent such as dichloromethane or chloroform that does not adversely affect the una reaction, and under somewhat mild conditions such as cooling, room temperature, or heating.

Subsequent reductions (e.g. hydrogenation) +7- n-
This is carried out by conventional methods such as chemical reduction using alkyltin hydrides such as butyltin, eg metal hydrides such as lithium aluminum hydride.

This reduction can be carried out in a somewhat milder environment, such as under cooling, room temperature, or heating, in a solvent that does not adversely affect the reaction, such as water, methanol, ethanol, l-luene, chloroform, ether hydrofuran, etc. It is preferable to carry out under the following conditions.

(10) Production method 10 Compound (If) t Takeso salt can be produced by subjecting compound (1) or a salt thereof to a hydroxy protecting group elimination reaction.

Preferred examples of salts of compound (lI) include compound (lI);
The same salts as 1) can be mentioned.

The elimination reaction in this production method is carried out by conventional methods such as hydrolysis and reduction, and the details thereof will be explained below.

(10-1) Hydrolysis Hydrolysis is preferably carried out in the presence of an acid or a base.

Preferred examples of acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, for example formic acid, acetic acid, trifluoroacetic acid,
Examples include organic acids such as propionic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

Preferred examples of the base include sodium hydroxide,
Alkali powders such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, calcium hydroxide, etc.
Inorganic bases such as potassium metal hydroxides or corresponding carbonates or acid hydrogen salts, ammonium hydroxide, etc.; alkoxides or phenoxides of the above metals such as sodium ethoxide, sodium methoxide, etc.; For example, methylamine, ethylamine, N,N-dimethyV-1
, 3-fluorobandiamine, trimethylamine, triethylamine, etc., di- or trier V-amines, and the like.

Hydrolysis can be carried out in a solvent such as water 1, an alcohol such as methanol, ethanol, propano-V, dimethyl sulfoxide, methylene chloride, tetrahydrofuran, etc. that does not adversely affect the reaction, under cooling, or under heating. It is preferable to carry out the reaction under somewhat mild conditions. The liquid acids and bases mentioned above can also be used as solvents.

(10-2) Reduction Reduction includes chemical reduction and catalytic reduction, and is carried out by conventional methods.

Preferred examples of reducing agents used in the chemical reduction are metals such as tin, zinc, iron, or such metals and/or metal compounds such as chromium chloride, chromium acetate, etc. with formic acid, acetic acid, propionic acid, etc. , trifluoroacetic acid, p-) IV ence V It is a combination with an organic or inorganic acid such as fonic acid or hydrochloric acid.

Preferred examples of catalysts used for catalytic reduction include platinum plates, platinum sponges, platinum black, and colloidal platinum.

Conventional catalysts such as platinum catalysts such as platinum oxide, such as palladium sponges, palladium black, palladium oxide, palladium catalysts such as palladium-carbon dicolloid palladium, and the like.

Reduction is usually carried out in a solvent such as water, alcohols such as methanol, ethanol, tetrahydrofuran, and the like.

The reduction is preferably carried out under somewhat mild conditions, such as under cooling, at room temperature, or under heating.

By subjecting the salt to a deacylation reaction, 11! ! For the preparation, the same salts as compound (1) can be mentioned.

The reactions in this production method are carried out in substantially the same manner as in Production Method 10.

(12) Production method 12 Compound (1) or a salt thereof can be produced by reducing compound OF) or a salt thereof.

Preferred examples of the salts of compounds (1) and (ff) include the same salts as those of compound (1).

The reduction in this production method is carried out substantially in the same manner as in production method (10-2).

(18) Production method 13 Compound (1'') or a salt thereof can be produced by reacting compound (P) or a salt thereof with a halogenating agent.

Preferred examples of the salts of compounds (1'') and (In) include the same salts as those for compound (summer).

The reaction in this production method is carried out in substantially the same manner as in Production Method 3.

In this production method, by introducing a group that leaves the 2-hydroxy group in the β-configuration or Lα-configuration in the compound (In) prior to halogenation, the halogen of the kaji can be changed to α-configuration or Lα-configuration. Compound (1'') having the β-configuration can be selectively obtained.

For suitable leaving groups and methods of introducing such leaving groups, reference may be made to the explanation 'f: given in Production Method 9.

(I4) Production method 14 Compound (10) or a salt thereof can be produced by isomerizing compound (Ma) or a salt thereof.

Preferred examples of the salts of compounds (1'') and (ma) include the same salts as those of compound (1).

In this reaction, an aqueous solution of the compound (7') is
For example, by leaving a solution in an organic solvent such as chloroform at room temperature, the 8β-halogen-6β,7β-dihydroxyintrizidine compound (10) isomerized and the 8β-
A mixture of halogen-6β,7β-dihydroxyintrizidine compounds and 8β-halogen-1α,2α-dihydroxyintrizidine compounds is produced.

The target 8β-halogen-1α,2α-dihydroquine intrizidine compound (I0) is obtained from the resulting mixture,
They can be separated by conventional separation procedures such as chromatography.

Among the compounds used as starting materials in this invention, compounds (1), (IV) and (ma) are each new compounds, and can be produced, for example, by the production examples described below and methods similar thereto.

(4) Manufacturing method A (1) (I a) Φ) Manufacturing method B OIa) (■b) 0 Manufacturing method C (Seal a)
(Rin C) ■) Manufacturing method D @) It! Manufacturing method E (la) (ma) prompt) Manufacturing method F G) Manufacturing method G (1") (ma b) (In the above formula, H, Hj, , R3 and R5 each have the same meaning as before, (abbreviation means alkoxy group)
.

The method for producing the starting material of this invention will be explained below.

Compound (m''), (sulfur b), (m'), (wd), (
xs), (w'') Preferred examples of the salts of oyohi (ma b) include the same salts of the compound (ri).

The compound (Natsu) or its salt can be produced by subjecting the compound (Natsu) to a reaction of introducing a hydroxy protecting group for R6.

The reaction of this production method converts compound (1) into the formula: R1'<1
ω) (wherein R6 has the same meaning as before and A means a lower alkoxy group or a halogen), which is carried out by a conventional method for introducing a hydroxy protecting group.

The reaction between compound (summer) and compound (W) is carried out by a conventional method.

It can be produced by subjecting a salt of 2 to a hydroxyl group elimination reaction.

The reaction in this production method is carried out substantially in the same manner as in Production Method 9.

Dll1l Production Method c Compound (1'') or a salt thereof can be produced by reacting compound (1'') or a salt thereof with an alkylating agent.

Preferred examples of the alkylating agent used in this production method include alkyl halides such as methyl iodide and n-hexadecyl bromide.

The reactions in this process are carried out by conventional methods.

I) Production method D i) Compound (ld) or a salt thereof can be produced by reacting compound (Ia) or a salt thereof with an azide compound.

Preferred examples of azide compounds include metal azides such as sodium azide.

The reactions in this process are carried out by conventional methods.

In this production method, prior to the reaction with the azide compound, a group that leaves the β-configured 8-hydroxy group of compound (Ia) as described in Production Method 9 is introduced, Compounds in which the 8-azido group is in the β-configuration (I
d') can be obtained selectively.

Production Method E Compound (ma) or a salt thereof can be produced by reacting compound (1'') or a salt thereof with a halogenating agent.

The reaction in this production method can be carried out in substantially the same manner as in Production Method 8.

In this regard, in this production method, prior to halogenation, the β-configuration or α-configuration of compound (1'') or
By introducing a leaving group into the 8- and droxy group in the - configuration as described in Production Method 9, the 8-halo group becomes α
It is possible to selectively obtain a compound (ma) having the -configuration or the β-configuration.

Production method F Compound (1e) or fcFi can be produced by reacting compound (1'') or a salt thereof with an acyl V-forming agent.

The reaction in this production method can be carried out in substantially the same manner as in Production Method 1.

(2) Production method G Compound (ma b) or its salt can be produced by subjecting compound (ma) or its salt to an elimination reaction of the hydroxy protecting group.

The reaction in this production method can be carried out in substantially the same manner as in Production Method 10.

The target compound (1) contains one or more stereoisomers based on asymmetric carbon atoms in the molecule, and all such isomers are included within the scope of the present invention.

The novel intrizidine derivatives and their pharmaceutically acceptable salts have immunomodulatory activity such as restoration of decreased immunity and immunity for the pharmacotherapy of diseases due to (or accompanied by) decreased immune activity. Useful as a regulator.

In order to demonstrate the usefulness of the target compound (1), pharmacological test data of representative compounds of this invention are shown below.

Test method for competitive effect of target compound (1) on immunosuppressive factors obtained from serum of tumor-bearing mice 1) Preparation of immunosuppressive factors from serum of tumor-bearing mice Mice 28-week-old ICR/JCL female mice was obtained from Itoma Mouse Cooperative.

Tumor: Sarcoma 180 (S-180), which was maintained intraperitoneally in ICR mice, was used in the experiment.

Preparation of Immunosuppressive Factors 0.2 wt of S-180 suspension (cell count: 5 x 106 cells/m1) was intraperitoneally transplanted into ICR mice. S-180f
: Blood was collected with a sterile syringe under mild anesthesia from 8 days after transplantation, and serum was prepared.

Immunosuppressive factors were extracted from the serum of S-180 tumor-bearing mice according to the method described by Sek-Yung OH and F, L, Modu M-Tung (Jana V. Immunology 127, pp. 2800-2307, 1981).
＃した. 4% phosphotungstic acid 1/1 in serum (50%)
0 volume and 1/40 volume of 2M magnesium chloride were added, the lipids were removed, and the mixture was centrifuged at 6000XG for 10 minutes. Excess phosphotungstic acid and magnesium ions were removed by dialysis against phosphate buffered saline (PBS: 0.15 M chloride l-U ram and OIM phosphoric acid slow rr solution, pH 7.4).

Partial membrane lipid serum was then precipitated with ammonium sulfate at 50% saturation. The supernatant was removed by centrifugation at 20,000×G for 80 minutes. Redissolve the precipitate in a small amount of water and
Dialyzed against BI overnight at 4°C. The dialysis solution was subjected to column chromatography on Sephadex G-200 in PBS.

The immunosuppressive activity of each eluate (15 g/) was assayed.

2) Immunosuppressive activity assay method Immunosuppressive activity was measured by mitogen-induced mouse pancreatic cell proliferation inhibition assay.

8) Mitogen-induced mice III by immunosuppressive factors in vitro! It! j! Inhibition of cell proliferation and its recovery by the target compound (summer) Mitogenic activity against mouse pancreatic cells in vitro: (a) Mice: 8-week-old BALB/C female mice were used.

Φ) Tissue culture medium: Fi as the tissue culture medium used
A complete medium devised at Roswell Park Memorial Institute 1-(RPMI)-1640 was used. All media used were penicillin G100.
units/ml and streptomycin sulfate 100μf
/ml and 5% fetal bovine serum.

(C) Preparation of splenic cells: The pancreas was excised under sterile conditions, washed with Hank's solution, and then placed in am culture medium. Cells were suspended in tissue culture medium to a concentration of 5 x 10'' cells/ml.

(d) Culture conditions: Multi-dish for tissue culture ()
0.1 gt of the above mouse spleen cell suspension and a compound solution of a predetermined concentration were added to each well of the Alcon Ifx B 040 ).
．． 1 ml and/or 0.1 ml of the immunosuppressive factor solution at a predetermined concentration was dispensed. Furthermore, concanavalin At
-M was added at a final concentration of lμf//ml for cell stimulation.

Cultures were placed in a carbon dioxide cell culture incubator (95% air).

Co, 5%) and cultured at 37°C for 48 hours.

(,) Assay of mitogen-induced murine u*m cell proliferation: Mitogen-induced murine pancreatic cell proliferation was assayed by incorporation of tritium-labeled thymidine ("H-thymidine").
)/wl of H-thymidine was added to each well containing the 48-hour culture medium of the mouse pancreatic cells described above.The cells were then cultured for 24 hours, and after feeding, m-thymidine was added to filter paper, Whatman GF
88) and wash sequentially with brine and 596) 17 chloroacetic acid. The filter paper was dried and placed in a scintillator (toluene III containing 0.1 f of p-bis-(5-phenyloxazole)benzene and 4 f of H-2,5-diphenylated oxazole) to detect the 8H- Thymidine was measured.

Results Immunosuppressive factors prepared from tumor-bearing mouse serum significantly inhibited mitogen-induced promotion of 8H-thymidine uptake by mouse pancreatic cells.

The minimum effective concentration of the target compound (1) against immunosuppressive factors was determined, and the results are shown in Table 1.

Table 1 Test compound (Example Todoroki) Minimum effective concentration (μf/m
l ) 1 0.0022〉2 8 0.0024
0.0025
0.0026
0.0087〉2 6 0, 0029
0.0810
0.1811
0.00212 0
．． 08-0.0618
0,00414-1) 0.24
-4) 0.04815
0.0617
0.1221
0.016 Urinary recovery rate of Compound (1) Compound (1) T-The urinary recovery rate (compound of Example 1) when administered orally to mice was compared with that of the control compound (8aβ-intrididine-1α, 2α, 8β- Compare with that of Triol).

Compound (1) and control compound were administered to 5-week-old dd7 mice.
1@I administration fi10!51/&9 was administered orally to five mice of the strain. Urine samples were collected 4 hours post-dose, ie, from hour 0 to hour 4. The total urine volume was measured, and the immunosuppressive factor obtained from the serum of tumor-bearing mice was
<The amount of the substance in urine was biologically assayed based on the recovery activity from inhibition of phosphorus A-induced murine cell proliferation.

The test results are shown in Table 2.

Table 2 Test compound Urinary excretion (n=5) (10m!
1//&g) Example 1 75% Control compound 38% The immunomodulator of the invention can be prepared by mixing the active substance of the invention with an organic or inorganic carrier or excipient suitable for topical, oral or parenteral administration. The solid or semi-solid substances contained in the liquid can be used in the form of liquid preparations.

The active ingredient is, for example, a tablet, pellet, turnip V, suppository,
It can be used as a solution, suspension, or usually mixed with a non-toxic pharmaceutically acceptable carrier to form a suitable dosage form. The carriers herein include water, glucose, lactose, gum arabic, gelatin, mannide-vl starch paste, magnesium trisilicate, Merck, corn starch, keratin, colloidal silica, potato starch, urea and solid, semisolid, or liquid Other carriers suitable for use in preparing the formulations may also be used, such as auxiliaries, stabilizers, thickening and dotting agents, and perfumes.

The immunomodulator may also contain preservatives or bacteriostatic agents to maintain stable activity of the active ingredient in the desired formulation. The amount of effective target compound contained in the immunomodulatory agent is an amount sufficient to exert the desired therapeutic effect on the disease process and condition.

When applying this immunomodulator to humans, intravenously.

Preference is given to application by intramuscular or oral administration.

The dosage or therapeutically effective amount of the subject compounds of this invention will vary depending on the age and condition of the individual patient being treated, but will generally be about 0.1 of the daily dose of active ingredient for large animals. ~100ml/'j is administered therapeutically, usually about 5011y, 100Wv, 25
0q, 500 capes are administered.

The proportion of the combination drug to be used varies depending on the type of disease, the type of drug, etc., but in general, it is appropriate to use 0.001 to 10 of the drug to be used in combination with 0 of the target compound.

The invention will be explained by way of examples.

Production Example 1 8aβ-intridizine-1α, 2α, 8β-triol (846 Misaki), 2,2-dimethoxypropane (L2
4F) and p-toluenesulfuric acid--hydrate (
A mixture of 400#) in N,N-dimethylformamide (4G) is stirred at room temperature overnight. Add water to this solution (<5ml)
and the mixture was diluted with a saturated aqueous solution of sodium bicarbonate.
Adjust to H8 and then evaporate to dryness. The residue is extracted with chloroform, and the extract is washed with a saturated aqueous solution of sodium IF chloride. The solvent was distilled off under reduced pressure and the residue was crystallized from n-hexane to give 1α,2α-isopropylidene dioxane.
-8β-hydroxyV-8aβ-isotrizidine<aOO
Da) is obtained as pale yellow needle crystals.

mp7 109-111℃ IR: 3290, 138G, 125
0.1200.1140.1120°1060al-' NMRgCDCI, δ): 1.31 (3H, s),
1.4-14 (78, m).

1.47 (3H, s), 2.98 (IH, m), 3
．． 12 (IH, dd.

J-11H2, IH Ri, 3.84 (IH, In),
4.65(2)Lff1) Production Example 2 1α,2α-isopropylidenedioxy-8β-hydroxy-8aβ-isotrizidine (600q) and 1-17ium hydride (81#) in dry N,N-dimethylformamide (15 g/) The mixture is stirred at room temperature for 1 hour and then cooled in a water bath. Add methyl iodide (4
11 g of 8U) are added dropwise and the mixture is stirred for 1 hour in a water bath and then for 2 hours at room temperature.

Acetic acid (0.6 tl) is added to the reaction mixture and the solvent is distilled off under reduced pressure. Chloroform (50+w/) and saturated aqueous sodium chloride solution (80 g/) are added to the residue, and the solution is adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. Satoshi Ariiso is separated and the aqueous phase is extracted with chloroform (50tt). The combined organic extracts are washed with a saturated aqueous solution of 17 um, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The oily residue was subjected to column chromatography using silica gel (80F) and eluted with chloroform-methanol (80:1) to give % 2a-
Isopropylidene dioxy-8β-methoxyτ8aβ-
Intrizidine (8091F) is obtained as a pale yellow oil.

IR (Film): 2990.1485.1400
．． 1230.1175°1125cm-' NMR (CDCI, δ): 1.32 (3H, 83,
1,47 (3F1.8).

1.2-14 (?H, m), 3.03 (2H, m)
, 3.42 (3H,a).

3.42 (IH, m), 4.62 (2H, ff+) Production method 3 The following compound is obtained in the same manner as in Example 2.

1) la%2α-yne 10pylidenedioxy-8β-n
-hexyVoxy-8aβ-intridizine.

IR (pure substance): 2930.1460.1375.
1205,1150.1125゜1095as-' NMR (CDCI δ): 0.90(3)L m)
, 1.33 (3H,S).

, 1.51 (3H, s), 1.2-1.9 (12H,
m) + 2.0-2.3 (3H, m), 3.01 (2
H, m), 3.58 (3H, m) 464 (2βm) 2) 1α, 2a-iso10pylidenedioxy-8β-n
-HexadecyVoxy-8aβ-intridizine.

IR (Stripe 1-L): 1260.1205.115
0.1125.1095ω″″1NMR (CDCI
J)? 0.88 (3H, m), 1.1-2.3 (4
1H, m).

2.95 (2H, m), 3.56 (3H, m), 4
．． 61(2H,m) Production Example 4 lα,2α-isopropylidenedioxy-8β-hydroxy-8aβ-intridizine (107q) and 4-dimethyV-aminopyridine (78#) in dichloroethane (5
To the mixture in st) is added a solution of valmitic anhydride (297w of dichloroethane C:dsl) and the mixture is stirred at room temperature for 4 hours. The reaction mixture was dichloroethane (30g
/) and the solution was sequentially diluted with sodium bicarbonate saturated water f
4, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel (8f/)'fr-, and eluted with chloroform to obtain 1α, 2α-
￥10 Pylidenedioxy-8β-palmitoyloxy-8aβ-isotrizidine (198Mg) e[Obtained as a colored oil.

IR (pure substance): 2'l10.1730.1460
, 1375.1205°1150c11-' NMR (CDCIsa): 0.86 (3H, m),
1.1-1.9 (35H, m).

1.46 (3H, s), 2.23 (4H, m), 3
．． 00(1)1. m).

3.17 (IH, d, J-12H2), 4.58 (
2H, ITI) Production Example 5 The following compound was obtained in the same manner as in Production Example 4.

1α,2a-iso10pylidenedioxy-8β-benzoyloxy-8aβ-indo “fzidine.

mp: 81-83℃ IR (31di*-At): 1705, 1315.1
270.1120.710cm-'NMR (CDCI,
a): 1.25(31(,s), 1.49(3)
(, a).

1.3-2.4(7H,m>, 3.12(2T(,m
), 4.66 (IH, m).

4.9-5.4 (2H, m), 7.50 (3H, m
), 8.07 (2H,m)φν construction example 61) 1α,2α-isopropylidenedioxy-8β-
Hydroxy-8aβ-isotrizidine (50Mg) and 1
, 1'-thioka V poni v diimidazole (188 Da) in 1,2-dichloroethane Ca5t) is refluxed for 6 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography using silicage/L' (2.5 g) and eluted with chloroform to obtain 1α
, 2α-isopropylidenedioxy-8β-(1-imidazolyl-thiocaVboni/L/)oxy-8aβ-intridizine (46■) is obtained as a tan oil.

IR (Film): 1330.1310.1255
．． 1240Ro1HMR (CDCI δ): 1.32
(3H,s), 1.53(3)1. s).

1.4-2-8 (7H, m), 3.07 (IH, m)
.

3.24 (IH, d, J-11HI), 4.64 (
2H, m).

5.55 (IH, m), 7.06 (IH, In),
7.54 (IH, m).

8.33 (IH, m) (2) While refluxing a solution of tri-n-butyltin hydride (1st) in toluene C1ot) in a nitrogen atmosphere, 1α,2α-iso10pylidenedioxy-8β-
(1-imidazolyl-thiocarbonyl)oxy-8aβ
-isotrizidine (290wg) toluene (15m/
) Add the solution dropwise over 15 minutes.

The mixture is heated to reflux for a further 2 hours and the solvent is removed under reduced pressure. The oily residue was dissolved in 7M acetonitrile (80+wt), washed with n-hexane (30 ml) to separate acetonitrile, and the solvent was distilled off under reduced pressure.

The residue was subjected to column chromatography using silica gel (15F) and eluted with chloroform to obtain lα, 2
α-isopropylideneoxy-8aβ-isotrizidine (1641!y) is obtained as a light brown oil.

IR (Film): 2950, 1515.1460
,1445.1380.1240゜1210,1115
．． 1080 Country-1 HMR (CDCI, a): 1.2-2.3 (9H,
m), t34 (3H, s).

1.54 (3H, 8), 3.16 (IH, d, J-
11H2).

3.78 (IH, t, J-5H, 4.33 (
IH, dd, J-IHL6IU), 4.56 (
IH, m) Production Example 7 (1) 1α,2α-isopropylidenedioxy-8
β-hydroxy-8aβ-intridizine (87011
g) To the nohyridine (lh/) solution is added methanesulfonyl chloride (0,27 g/t) at 5°C and the mixture is stirred in a water bath for 4 hours. The solvent is evaporated under reduced pressure and the residue is dissolved in chloroform (50 g/t). The chloroform solution is sequentially diluted with hydrogen carbonate), washed with a saturated aqueous solution of IJ and then dried over magnesium sulfate.The solvent is distilled off under reduced pressure, and the residue is dissolved in silica gel (
Subjected to column chromatography using 15F),
Elution with chloroform gave 1α,2a-isopropylidenedioxy-8β-methanesulfinyloxy-8aβ-intridizine (293°5%) as a pale yellow oil.

IR (Pure Substance Month 2930.2800.1350.12
05.11B5.1150°960, 930 (11-' NMR (CDCI, a): 1.30 (3H, @),
1.50 (3H, S).

1.4-2.6 (7H, rn), 3.09 (3H
, 8), 2.9-3.2 (2H, m), 4.6
9 (3H,m)(2)lα,2α-isopropylidenedioxy-8β-methane Ilephonyloxy-8aβ-
Intrizidine (4,18f) and sodium amide (
9,29) with N,N-dimethylformamide (100
m+/) Heat the warm mixture to 100°C for 5 hours. Molten g
is distilled off under reduced pressure and the residue is dissolved in ethyl acetate (200 mg/ml). The solution is washed successively with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate.

The solvent was distilled off under reduced pressure, and the residue was washed with silicage 1v (100F
) and column chromatography using chloroform.

1α,2α-isopropylidenedioxy-8β-azido-8aβ-intridizine is eluted first and is obtained as a pale yellow oil (590111').

IR (pure substance): 2930.2780, 20913
,1370.1260.1200゜1145,1120
0m-' NMR (CDCI, a): 1.21 (IH, m),
1.31 (3H, a).

1.48 (3H, s), 1.6-1.9 (4H, m)
, 2.14 (IH, d, d.

111m3H2 and 11Hz), 2.14(IH, m
), 3.01 (IH, m).

3゜13 (IH, d, J-11Hz), 3.24C
IH, m).

4.63 (2H, m) Next, 6β,7β-iso10pylidenedioxy-8β-azido-8aβ-isotrizidine is eluted and obtained as a pale yellow oil (2,056f).

IR (pure substance): 2930, 2090, 1380.
1220.101055a'NMR (CDC1, δ):
1.39 (3H, s), 1.54 (3H, s).

1.54 (IH, m), 1.83 (2H, rn),
115 (IH, m)-120 (IH, d, d, J-9H
z and 11.5H! ).

2.29 (tH, q, J-s, sHz), 2.4
3 (IH, d, t.

J-10H2 and 7H, 2.97 (IH, m), 3
．． 08(1)L d, d.

J-6,5H! and 11.5H, 3.25(IH,
d, d, J-10H2 and 5Hz), 4.34 (IH
, d, d, d, J-sHz and 6.5H! and 9H
! ), 4.41 (IH, t, J-5H2) Production Example 8 (1) 1α,2α-isopropylidenedioxy-8
β-Hydroxy-8aβ-Intrizidine (90011
To a solution of g) in pyridine (25 liters) is added p-) IV chloride (1,of), and the mixture is stirred at room temperature for 70 hours. The solvent is distilled off under reduced pressure and the residue is dissolved in chloroform (80 t/). The chloroform solution is sequentially diluted with hydrogen carbonate, washed with an aqueous rum solution and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel (45 g).
1α,2α-isopropylidenedioxy-8β-p-toluenes Vhonyloxy-8aβ-
Intrizidine (4801q) is obtained as yellow-brown needles.

mp: 116-118℃ IR (line 1-l): 1170.970,930,
830.805011-'NMR (CDCI, a):
1.04 (3H, s), 1.23 (31 (, ri.

1.2-1.9 (6H, m), 2.08 (IH, d, d
, J-11HI and 4H! 3.143 (3H, fi)
, 2.94 (IH, m), 3.05 (IH, d.

J = 11Hz), 4.38 (3H, ml, 7.28 (2
H, d, J-8Hz).

7.84(2H,d,J-8H2) N(2) 1α,2α-Iso10Bilidegoxy-8
β-p-t/L'enesulfonyloxy-8aβ-indolizidine (480wv) and lithium chloride (275η)
70° medium temperature mixture of dimethyls M phosphate (10d) with
Heat to C for 4 hours. The mixture was diluted with chloroform (50te
diluted with water (30t/2 times)
and chloride) and dried over magnesium sulfate. 6β obtained by distilling off the solvent under reduced pressure,
7β-isopropylidenedioxy-8β-chloro-8a
The pale yellow oil of β-intridizine (461W) is used in the next step without further purification.

IR (pure substance): 2920, 1365.1140.
1030cm'NMR (CDCI, J: 1.3
4 (3H, II), 1.50 (forceps, S).

1.5-2.4 (7H, m), 3.00 (IH, m
), 3.12 (IH, d.

J-1oHz), 4.00 (IH, m), 4.62 (2
H, m) Production Example 9 Crude 6β,7β-inpropylidenedioxy-8β-chloro-8aβ-intridizine (15111F) 75
% trifluoroacetic acid in water & (10 g/) solution is stirred at room temperature overnight and the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography using Amberphyto IRA400 (OH-type) (5 g/) and the column was eluted with water (20 g/). The eluate was evaporated to dryness under reduced pressure and the residue was subjected to column chromatography using silica gel (8f) and eluted with chloroform-methanol-V-water (65:25:4) to obtain 8β-chloro -8aβ-intridizine-6
β,7β-dio-v (3011F) is obtained as white crystals.

mp: 73-75℃ IR (null): 336G, 1215, 114
0,1130.1100°1085,760am-' NMR (CDCI, J) = 1.4-2.1 (5H,
m), 2.2-2.6 (2αm).

3.04 (2H, m), 3.35 (IH, m), 4
．． 10 (2H, m).

4.31 (2H, m) Example 1 8aβ-intridizine-1α, 2α, 8β-trio-
To a solution of v(aOq) in pyridine (OJxtl), bency chloride v(904) is added dropwise under stirring at 0″C and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into dilute aqueous sodium bicarbonate solution. Extract with chloroform. The chloroform extract is washed with water, dried, and the solvent is distilled off to obtain an oily substance that is purified by column chromatography using silica gel.

Elute with chloroform t, -'c, tα%2α, 8β-
Tribenzoyloxy-8aβ-intridizine (68
Mg) is obtained.

IR(CHCI,) = 3020.2950.2800
．． 1720.1285.1272゜7033-' NMRCCDCl, )a: &00-7.00(15H
, m), 5.82 (IH, dd.

J-5, 6H, 560 (IH, ddd, J-1, 5,
6,8H2).

5.35 (IH, ddd, J-5, 11, IIH,
3.35 (IH, dd.

J-1,5,11Hz), 3.22-1.10 (
8H, m) Example 2 Examples 1 and 5i! In a qualitatively similar manner, 1α, 2α, 8
β-tribalmitoyl salt 8aβ-intridizine (104 wg) is obtained.

IR(CHCl, ): 2930.2850.1730
．． 1180 am-'NMR (CDCI, ) δ: 5.
67-4.73 (3H, m), 3.30-2.00 (
12H,m), 2.00-0.8 (901(,m)) Example 8 Substantially as in Example 1, 8aβ-intrizidine-1α,2α,8β-triol (30 capes) and phenoxy chloride From aceti7L/(1001B5'), 1
α,2α,8β-Triphenoxyacetoxy-8aβ-
Intrizidine (74 capes) is obtained.

IR(CHCI,): 3030.2950.2800
．． 1760.1195.1180゜685011-' NMR (CDCI,) a: 7.4-6.67 (15
H, m), 5.60-4.83 (3) (, m).

4.60 (2H, S), 4.53 (2H, s), 4.5
o(2H,s).

3.30-1.43 (8H, m) Example 4 Substantially similar to Example 1, from 8aβ-intridizine-1α,2α,8β-triol (30 Da) and phenylacetyl chloride (1001q) , lα, 2α
, 8β-triphenylacetoxy-8aβ-intridizine (7011Iy) t-obtained.

IR(CHCI,) = 2960.2830.1740
．． 1160.700cm-'NMR (CDCI, )a
: 7.5o-7,0(15H,m), s, 6-4
．． 8 (3H, m).

3.50 (6H, I), 3.30-1.40 (9H, 1
Example 5 In substantially the same manner as in Example 1, 1α, 2α, 8β was prepared from 8aβ-intridizine-1α, 2α, 8β-triol (80 ml) and 2-thenoyl chloride (100 wg).
-(tri-2-thiophenekaVbonyloxy)-8aβ
- Obtain Intrizidine (66#).

rR(CHCI,): 2960.2800.1?20
．． 1280.1100a++-'NMR (CDCI, )
δ: 7.67-6.73 (9H, m), 6.70-
5.00 (3H, m), 3.50-1.53 (9H,
I'n) Example 6 Substantially similar to Example 1, 1
α, 2α, 8β-(tri-2-thienyV acetoxy)-
8aβ-intridizine (69■) is obtained.

IR(CHCI,): 2950.2800.1740
．． 1175.695am-'NMR (CDCI,) δ:
7.5-6.8 (9H, m), 5.67-4.76
(3I(,m).

3.80 (6H, a), 3.40-1.40 (9H,
m) Example 7 8&β-intridizine-1α, 2α, 8β-trio-
Methyl iodide (100 ~) is added to a suspension of V (80 Tq) and sodium bicarbonate (801 q) in methanol/L/(10 jIF) at room temperature under stirring. The mixture is stirred at the same temperature for 1 hour and then filtered. Concentrate the filtrate and
-MethiA/-8aβ-Intrizidine-1α, 2α, 8
β-Trio-V iodide (40 capes) is obtained.

fR (nuji-ru): 3420.2925.2B5
0.1160.1140.1115°1090, 107
0.9703-' NMR (CDCI, )δ: 4.1-4.5 (2H
, m), 3.5-3.9 (3H, m).

3.37 (3)L II), 1.33-2.67
(7H,m) Example 8 1α,2α-diacetoxy-8aβ-intridizine-
8β-ol (30#) and thioca Vbonyldiimidazole (150q) in tetrahydrofuran (20gt)
The solution is refluxed for 8 hours. The oil obtained by evaporation of the solvent under reduced pressure is subjected to chromatography on silica gel. Elution with chloroform gives 1α,2α-diacetoxy-8β-(1,3-imidazolyVthiocaVbonyloxy)-8aβ-intridizine (80 capes).

IR(CHCI,): 2950.2800.1745
．． 13QO, 1345, 1285゜1250-1000
aa-' NMR (CDCI, ) a: 8.27 (IH, m
), 7.53 (IH, m).

F, 03 (IH, m), 5.93-5.13 (3H
, m), 3.33-186(2)1. m), 2.8
0-1.50 (7H, m), 2.05 (6H, S) Example 9 1α% 2α-Diacetoxy 8a β-Intrizidine-
8β-ohA/(2251!V) and pyridine (0.2m
Thionyl chloride (0,2 g/) is added to a mixture of 12 g/l) in methylene chloride (10 g/) at 0° C. under stirring. This mixture is stirred at the same temperature for 3 hours. The reaction mixture is successively washed with aqueous rum solution and water, dried, and the solvent is distilled off to obtain an oily residue. Chromatography using the oily residue afV+1 Kagel and eluting with chloroform yielded 8α-chloro-1α,2α-diacetoxy-8
'aβ-Intrizidine (8011y) is obtained.

IR(CHCI,): 2920.2800.1740
．． 1365.1240-1200゜1045a11-' NMR (CDCI,) a: 5.5? (11(,m)
, 5.05 (IH, m), 3.77 (IH, m),
3.3-1.4 (9H, m), 2.17 (3H,
s).

2.0 (3H, II) Example 10 8α-chloro-1α,2α-diacetoxy-8aβ-intridizine (15 g/) and sodium cyanide (20
A mixture of 1q) and dimethyzyl, zIvhokisz)' (5 am/) is heated to 110° C. for 2 hours under stirring.

The mixture is poured into water (20d) and extracted with chloroborm. The extract is washed with water, dried, and the solvent is distilled off to obtain an oily residue. The oily residue is subjected to cuff chromatography on silica gel and eluted with chloroform to give 8β-anor 1α,2α-diacetoxy-8aβ-intridizine (8q).

IRCCHCI, ): 2920.2800.2170
．． 1740.1370°1240cm-' Example 11 1α,2α-diacetoxy-8aβ-intridizine-
Balmitoyl chloride (120q) is added to a solution of 8β-OA/(2614) in viridiy (1 m/).

The resulting solution is left at room temperature overnight. Pyridine is distilled off under reduced pressure, and the residue is poured into an aqueous solution of hydrogen carbonate. The mixture is stirred at room temperature for 1 hour and extracted with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure to obtain a residue. The residue was purified by preparative thin chromatography, eluting with a mixture of ethyl acetate, M-chloroform (1:9) to give lα,2(1-diacetoxy-8β-valmitoyloxy-8aβ-intridizine (39 μl). ) get it.

IR(CHCI,): 2930.2B50.1735
．． 126[+3-'NMR (CDCI, δ)75.6-
4.8 (3H, ff1), 3.3-3.0C2H, m
).

2.8-1.1 (35H, m), 2.1 (3H, 8),
2.06 (3H, S).

0.95 (3H, t, J-7H2) Example 12 8α-chloro-1α, 2α-diacetoxy-88β-intridizine (100 da), sodium iodide A (129 w
Iy) and MethiV! f /l/keto7 (24d)
Heat the mixture to 90° C. for 24 hours. Methyl V ethyl ketone is distilled off under reduced pressure and the residue is triturated with methi M acetate.

The solid produced is removed from the oven, and the PR is sequentially washed with an aqueous solution of sodium bicarbonate and water, and then dried. Methyl acetate V is distilled off to obtain a residue. The residue was purified by preparative thin layer chromatography, eluting with a mixture of ether-carbon tetrachloride (1:1) to give 1α,2α-diacetoxy-8β-iobi-8aβ-intridizine (58 μm).

IR(CHCI,): 2930.2810.1740
．． 124001-'NMR (CDCI, δ) 75.6-
4.9 (2H, m), 4.0 (IH, dd.

J-11,3H! 3.3.3. -1.5 (9H, m)
, λ2. (3H, 8).

2.0 (3H, 8) Example 18 A solution of 1α,2α-isopropylidenedioxy-8β-baMidoyloxy-8aβ-intridizine (170 Cape) in 75% aqueous trif-V oroacetic acid (10 ml) at room temperature. Stir for days. The solvent is distilled off under reduced pressure and the residue is dissolved in chloroform (800 txl). The solution was sequentially diluted with hydrogen carbonate) + 7 um saturated aqueous solution and sulfur chloride l-+
Wash with 7um saturated aqueous solution and dry with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in silica gel (10 g
) was subjected to column chromatography using poppy, chloroform, then chloroform methanol 7L' (50:
1) Elute with a mixture of 8β-passimitoioxy-8
aβ-intridizine-1α,2α-dio-v (67■
, 48.5%) as a white powder.

rnp: 52-55°C IR (X Geel): 3410, 1730.126
0-1210.1175-1110am-'NMR(C
DCI, J): 0.88 (3H, rrl), 1.
1-2.6 (35H, m).

3.03 (2H, m), 4.00 (IH, d, d, J-
3Hz and 6)(ri.

4.32 (IH, m), 4.85 (IH, m) Example 14 In the same manner as in Example 18, the following compound is obtained.

(1) 8β-methoxy-8aβ-intridizine-1α
, 2α-diol.

rnp: 91-92℃ IR (nuji! l-ru): 3300, 1335, 1
315.1150.1135.1110am-'NMR
(Parrot OD a) 70.9-1.2 (IH, m), 1.
37 (4H, m).

2.1-15 (2)L m), 2.90 (2H
, m), 3.34 (IH, m).

3.44 (3H, 11), 4.16 (2H, nl
) (2) 8β-n-hexyloxy-8aβ-intridizine-1α,2α-diol.

mp: 61-62℃ rR (Nuji plexus-k): 3360I3Q8G, 133
511315.1150.1140°1115dl-' NMR (CDC1, J): 0.88 (3H, m),
1.1-2.0 (13H, m).

2.0-2.6 (2K m), 3.02 (2H, m
), 3.50(2)L 8).

3.54 (3)! , m), 4.23 (2H, m) (8
) 8β-n-hexadecyloxy-8aβ-intridizine-1α,2α-dio-v611p: 49-5
0℃ IR (Nugitaire): 3450.3390,115
0.1135,1120.109010201805c
71% NMR (CDCI* J) = 1.87 (3'H,
m), 1. l-2-5 (35H, m).

2J5 (2H, m), 3.12 (2H, 8), 3.50
(3H, m).

4.19 (2H, m) (4) 8aβ-intridizine-1α,2α-dio-A
/.

1M': T1-74℃ IR (null): 3350.1245.112
0,1065.102G.

890 ■-1 NMR (CD OD a) = 1.2-2.2 (
8H, m), 2.36 (IH, d, d.

J-10Hz, 6Hz), 2.98 (2H, m),
3.97 (IH, d, d.

J-7H2, 4H1), 4.24 (IH, d, d
, d, J-2HL 4H2,6Hri(5) 8β
-benzoyloxy-8aβ-intridizine-1α,
2α-diol.

mp: 185-186℃ IR (line 1-l): 340G, 3190.170
5.1280,1270.1110°715cm-' NMR (CDCI, a): T3-2.6(
71(,m), 3.01(21(,m).

4.09 (2H, m), 5.07 (IH, m), 7
．． 05 (3H, m).

8, oH2H, m) (6) 8β-amino-8aβ-intridizine-1
α,2α-Geo-A/6 mp: 13B-139°C (decomp) fR(X
J*-Jtt month 3300.16QO-1145,1(
195'NMR (D, Oυ: 1.0-2.2 (6H
, ITI), 2.3-3.2<4H, m).

4.28 (2H, m) σ) 8β-chloro-8aβ-intridizine-1α,
2α-diol.

mp: 114-117℃ IR (line 1-l): 3350.3420,116
11.1080.930°770ao-' Example 15 8aβ-intridizine-1α, 2α-8β-triol (84611 #g), 4-dimethylaminopyridine (
A mixture of 80111F) and bipaloyv (2,5-) chloride in pyridine (1(h+/)) is heated to 70°C for 10 hours. The reaction mixture is dissolved in a saturated aqueous solution of Sourium bicarbonate (20 m/) Pour the solution into ethyl acetate (80g
/.

Extract twice). The organic solution was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel (2[')?
The column chromatography used was eluted with a chloroform-carbon tetrachloride (1:1) mixture to obtain 1α, 2
α,8β-Tripiparoyloxy-8aβ-intridizine (8089) is obtained as a brown oil.

IR (pure substance: 297 (1,1725, f4g0
．． 1280.1160tx-'NMR (CDC: 1.δ
): 1.17 (18 ls), 1.26 (9H, s)
.

1.5-1.9 (3H, m), 1o-16 (4H,
m), 2.94 (2F, m).

4.80 (IH, m), 5.34 (2H, m) Example 16 8β-benzoyloxy-8aβ-intridizine-1
Pyridine (15 g/
) to the mixture in dichloromethane (8 g/) was added dropwise at -10"C, and the mixture was stirred in a water bath for 2 hours. The solvent was evaporated and the residue was dissolved in chloroform (50 g/ ).The chloroform solution is sequentially dissolved in a saturated aqueous solution of sodium bicarbonate, l-If chloride.
Wash with a saturated aqueous solution of magnesium and dry with magnesium sulfate. The solvent is evaporated and the residue is subjected to color chromatography using silica ty'v<4oy) with chloroform.

First, 2α,8β-dibenzoyloxy-8aβ-indolizidine-1α-V was eluted, and a colorless oil (6
6019,60,1%).

IR (Film): 3400.1715,1705
,1445.1310.1275゜1110,1075
．． 101025a'NMR (CDCI, δ): 1.
36-2.54 (71 (, m), 3.08 (2Hjm
).

4.48(11(,m), 5.19-5.502H,
m), ? , 4o(6)T, m).

7.88 (4H, m) Then 1α,8β-dibenzoyloxy-8aβ-intridizin-2α-ol was converted into a colorless oil (198W)
It is eluted as

IR (FJ/A): 3460.1710,13
10.1265.1110,1065°1020aa' NMR (CDCI, J): 1.25-2.81 (7
1(,m), 3.11(1)T,m).

3.36 (IH, d, d, J-2Hz, 10Hz
), 4.40 (IH, m).

5.04(,52(2H,m), 7.41(6H,m
)-8,04 (4H, m) Example 17 A 28% methanol solution of sodium methoxide (20 da) was added to a methano-v (LOwl) solution of 1α,8β-dibenzoyloxy-8aβ-intridizine (150 da).
was added and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography using silica gel (8f) to obtain chloroform-methanol-V-
Elution with water (65:25:4) gives 8aβ-intridizine-1α,8β-diol (451119) as pale yellow crystals.

mp: 144-146 (disassembly) IR (nujiru): 3360, 1425.111
5.1065,1020,1000°890Q11-' NMR (CDρD a): 1.0-2.3 (9H, m
), 3.04 (2H, m).

3.75 (IH, m), 4.38 (IH, m) Example 1
8 A mixture solution of 1α,2α-isopropylidenedioxy-8β-azido-8aβ-intrizidine (1,00f) in detohydrofuran (25 at/l) and IN hydrochloric acid (25 l) was added to 10% palladium- Hydrogenation is carried out at room temperature and medium pressure (2 atm) in the presence of carbon (100q). The catalyst is removed from the furnace and the p liquid is concentrated to about 25 ml.

Concentrated hydrochloric acid <7.5*t) is added to this solution and the solution is stirred at room temperature overnight. The solution was evaporated to dryness under reduced pressure and the residue fyinverly) IRA400 (OH- form) (100+/)
The column is eluted with water (300+t). The eluate was concentrated under reduced pressure, and the residue was solidified with ether.
8β-amino-8 & β-intridizine-1α, 2α-
Geo-v (57011 g) is obtained as a light tan powder.

ml): 136-139°C (decomposition) IR (medium 1-
): 3300.1600.1145.10109
5a'NMR (D!Oδ): 1.0-2.2 (6
H, m), 2.3-3.2 (4H, m).

4.28 (2H, m) Example 19 (1) A solution of 8aβ-intridizine-1α, 2α, 8β-trio-V in pyridine (8zl) was cooled in a water bath,
A solution of p-tVenesulfoniM chloride (191!q) in dichloromethane (8 zl) is added dropwise and the mixture is stirred at room temperature overnight. The solvent is evaporated under reduced pressure, and the residue is dissolved in chloroform (20 kg/ml), washed successively with an aqueous solution of sodium bicarbonate+7um and a saturated aqueous solution of I−+7um chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using Silicage V (8f) and chloroform-methanol (40:1).
Elute with 2α-p-toluenesulfonyloxy-8
aβ-intridizine-1α,8β-diol (108
4) is obtained as pale red crystals.

ml): 126-128°C IR (X diva-k): 3370, 2950, 13
60.11B0,1100°1070(!l-' NMR (CDC1,a): 1.74(5H,m),
2.24 (3H, S).

2.25 (2H, m), 2.9HIH, m), 3.
1HIH, d, d.

J-2Hz, 12Hz), 3.83 (IH, m), 4.
33 (IIL d, d.

J-6HL 4Hz), 4.90 (IH, m), 7
．． 32 (2H, d.

J-8H Ri, 7.84 (2H, d, J-8H Ri, (2)
2α-p-toluenesulfonyloxy-8aβ-intridizine-1α,8β-dio-V (28711g)
and lithium chloride (220 caps) in dimethyM sulfoxide (6 zl) is heated to 100° C. for 4 hours. The solution was evaporated to dryness under reduced pressure and the residue was dissolved in chloroform (50
Extract with m/). The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel (15F) and eluted with chloroform-methanol/L/(50:1) to obtain 2β-chloro-8aβ-intridizine- 1
α, 8β-Geo-7! / (56,4 Hz) as a tan powder.

r! D): 126-128℃ IR (X Joe Nori: 3390, 1255.110
5.1065.1025a! l-'NMR (CDCI,
δ): 1.2-2.2 (6M, m), 2.3
0(IH, d, d.

J-a6H1 and 9H2>, 2.91 (IH, m),
3.63 (2H, m).

3.68 (2H, m), 4.06 (IH, d, d, J-
8H2 and 7Hz).

4.29 (IH, d, J-4Hz) Intrizidin-2α-ol (19811 g) and 1.
1'-thiocarbonyldiimidazole (220 liters)
．． The mixture in 2-dichloroethane (10+wl) is refluxed for 7 hours under nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography using silica gel (1([')) and eluting with chloroform to obtain 1α, 8β-
dibenzoyloxy-2α-(1-imidazolyluthiovinyl)oxy-8aβ-indolizidine (246
11!1J) t- Obtained as a pale yellow oil.

IR (Film): 2950.1?35.1390
,1290.1270,1130°755,715am
'NMR (CDCI, δ): 1.2-2.7 (6
H, m), 2.82 (IH, d, d.

J-11HL 6Hri, 3.11 (IH, m), 3
．． 47 (IH, d, d.

J-11H1, IH2), 5.29 (IH, m),
5.95(2)L m).

6.83 (IH, m), 7.40 (7H, m), 7
．． 87 (4H, m).

8.13 (IH, lli(2) trin-1 tyltin hydride (0.86ml
) in refluxing toluene (50 ml) in a nitrogen atmosphere,
A solution of α,8β-dibenzoyloxy-2α-(l-imidazolyl-thiocarbonyl)oxy-8aβ-intridizine (220 Wv) in toluene (10 g/) is added dropwise and the mixture is heated under reflux for 4 hours. The solvent is evaporated under reduced pressure and the residue is subjected to column chromatography using silica gel/l/(10 exposures), eluting with charcoal tetrachloride and then chloroform. Both desired fractions are collected and the solvent is distilled off under reduced pressure. The oily residue is crystallized from n-hexane to give 1α,8β-dibenzoinoleoxy-8aβ-intridizine (168JIg) as white needles.

mlP: 86-87℃ IR (yt di! l-le): 172B, 1280,1
125,760,720ts-'NMR(CDCIjδ
): 1.2-2.6 (9H, m), 3.20 (2Hj
m).

5.2-5.6 (2H, m), 7.24 (6H, m
), 7.92 (4H, m) Example 21 8β-chloro-8aβ-intoridicin-6β,7β-
Diol 1α, 2α-dihydroxy-8β-chloro-
Isomerization to 8aβ-intridizine occurs in chloroform at room temperature. These two isomers are separated by chromatography using a silica gel column, eluting with chloroform-methanol (40:1).

The raw material compound 8β-chloro-8aβ-intridizine-6β,7β-diol was first eluted as the main component, and the target compound 8β-chloro-8aβ-intrididine-1α,2α-diol was then eluted as white crystals. Ru.

mV 114-117℃ IR (Nuji-ru): 3350, 3420, 116
0,1080,930°770al-' NMR (CDCI,,a): 1.5-2
．． 1 (3H, m), 2.2-2.8 (4H, m)
.

3.00 (2H, m), 3. a-4,2 (3H, m)
, 4.07(2H,S)Mass: m/e 191

Claims (1)

[Claims] General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is hydrogen, hydroxy group, cyano group, halogen, acyloxy group, amino group or alkoxy group;
R^2 is a hydroxy group or an acyloxy group; R^3 is hydrogen, a hydroxy group, an acyloxy group, or a halogen;
R^4 is a lower alkyl group; Y is a halogen; n means an integer 0 or 1, and when R^1 is a hydroxy group and R^2 and R^3 are both hydroxy groups, n is an integer 1, and when R^2 and R^3 are both acetoxy groups and n is an integer zero, R^1
means an acyloxy group excluding a cyano group, halogen or acetoxy group).