FI79845B - PHARMACOLOGICAL ACTIVE 2,5,5,8A-TETRAMETHYL-1,2,3,4,4A, 5,6,7,8,8A--DECAHYDRONAPHTHALEN-1-SPIRO-2 '- (2', 3'-DIHYDROBENSOFURAN) -DERIVAT. - Google Patents

Description

79345

Method for the determination of pharmacologically active 2,5,5,8a-tetramethyl-1,2,3,4,43,5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (2', 3'-dihydro -benzofuran) derivatives for the preparation of pharmacologically active 2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 ' - (2 ', 3'-dihydrobenzofuran) derivatives

The invention relates to a process for the preparation of new sesquiterpene derivatives, i.e. 2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (2 To prepare ', 3'-dihydrobenzofuran) derivatives of the formula RVN ^ VCH3 (I) R CKa Ch'3 and pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and R which may be the same or different represent a formyl, hydroxymethyl, hydroxyl, carboxyl, lower alkanoyloxymethyl group, or a group of the formula -CH = Cr7r8, wherein R? and R 1, which may be the same or different, represent a hydrogen atom, a cyano, lower alkoxycarbonyl, or carboxyl group, or R 1 and R 2 may together form a lactone ring of the formula R 9 o 'ff -CH-OC-, wherein R 1 represents hydrogen atom 2 79345 or a hydroxyl group, R4 and R6, which may be the same or different, denote a hydroxyl group or a lower alkanoyloxy group, R5 represents a hydrogen atom, R4 and R4 may together form an oxo group (= O) and R4 and R4 may together form a lower alkylidenedioxy.

According to the invention, it is also possible to prepare acceptable salts of the sesquiterpene derivatives of the general formula I by reacting these sesquiterpene derivatives with the appropriate basic compounds.

The new compounds I can be prepared chemically by converting the compound 6,7-dibydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a, which is the subject of the present application FI 781517 of this application. -decahydronaphthalene-1-spiro-2 '- (6', 7'-diformyl-4'-hydroxy-2 ', 3'-dihydrobenzofuran) of the formula H ° yyvcr; 3 (Ia) C »3 CH3 and according to the application of the strain is prepared by culturing a microorganism belonging to the species Stachybotrys species Stachybotrys alter-Mans IFO 9355, Stachybotrys chariarum IFO 5369, Stachybotrys chatrarum IFO 7222, Stachybotrys cylindrospora 8858, Stachybotrys ryssound25, Stachybotrys echinata nov. mp. K-76, Stachybotrys complement! nov. T-789 or Stachybotrys (Memmoniella) echinata var. T-791 aerobically in a medium containing assimilable nitrogen sources, carbon sources, inorganic salts and trace elements, at a pH of about 3.5 to 11.5, at a temperature of about 15 to 35 ° C, and recovered as a product 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (6 ', 7'-diformyl-4'-hydroxy-2', 3'-dihydrobenzofuran) and, if desired, converting the compound into a pharmaceutically acceptable salt thereof.

3,79845

The new compounds have an inhibitory effect on the complement system of animals (anti-complement effect) and an anti-tumor effect.

The compounds according to the invention can be used as effective components in pharmaceutical compositions which act against autoimmune diseases, nephritis, rheumatism, collagen diseases, allergic diseases, cancers, etc. The compounds can also be used as intermediates to prepare such effective components.

The phrase "complement" refers to a complex group of proteins in body fluids. These protetins interact with antibodies or other factors to play an important role in mediating immune, allergic, immunochemical and / or immunopathological reactions. Reactions in which complement is involved occur in blood serum or other body fluids and are therefore considered humoral or fluid reactions.

The complement system has been suggested to be involved in inflammatory, coagulation, fibrinolytic, antibody-antigen reactions, and other metabolic events (cf. U.S. Patent 4,021,544, Bull. World Health Org., 39, 935-938). (1968), Scientific American, 929 (No. 5) 54-66 (1973), Medical World News, October 11, 53-58, 64-66 (1974), Harvey Lectures, 66 75-104 (1972), The New England Journal of Medicine, 287, 489-495, 545-549, 592-596, 642-646 (1972), The Johns Hopkins Med. J. 128, 57-74 (1971), and Federation Proceedings, 32, 134- 137 (1973)).

Many compounds are known to have complementary activity, including ethylenediaminetetraacetic acid (EDTA), Saldox, floricin (Borsos, J. Immunol. 94, (4), 629 (1964)), hydroxybenzene derivatives (Shir Mayer, Biochemistry NY , 73003 (1968)), guanidines and phenoxyacetamides (BR Baker, J. Med. Chem., 12, 408 (1968)), phosphonate esters (EL Becker, BBA, 147, 289 (1967)), chlorophyllin, glycyrrhizin , etc. However, these compounds are not suitable for practical purposes because they are highly toxic or have a low anti-complement effect. To the best of our knowledge, no anti-complement compound or substance is currently commercially available.

The compounds (I) prepared according to the invention and their pharmaceutically acceptable salts can be used in pharmaceutical compositions containing a therapeutically effective amount of these compounds so as to obtain an anti-complement effect in animals. The compounds of formula (I) can be used in particular for the treatment of inflammatory diseases of the kidneys in animals by administering a medicament mixture to an animal suffering from such a disease.

The accompanying figures show in more detail the compounds according to the invention.

Figure 1 shows the nuclear magnetic resonance spectrum of the starting compound (Ia).

Figures 2 to 4 show the nuclear magnetic resonance spectrum of the compound (Ib) prepared according to Example 5 in different solvents.

Figure 5 shows the nuclear magnetic resonance spectrum of the compound prepared according to Example 9.

Lower alkyl groups represented by the symbol R1 include straight-chain or branched alkyl groups having 1 to 4 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert. butyl.

Lower alkanoyl groups represented by the symbol include straight-chain or branched alkanoyl groups having 2 to 4 carbon atoms, e.g. acetyl, propionyl, butyryl and isobutyryl.

Lower alkanoyloxymethyl groups represented by R 1 and R 2 * include oxymethyl groups substituted with the lower alkanoyl groups described above, e.g., acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, and isobutyryloxymethyl.

5,79845 methyl, butyryloxymethyl and isobutyryloxymethyl groups.

Lower alkoxycarbonyl groups represented by R7 and R® include straight-chain or branched alkoxycarbonyl groups having a total of 2 to 5 carbon atoms / e.g. methoxycarbonyl, ethoxycarbonyl / n-propoxycarbonyl / n-butoxycarbonyl and tert-butoxy.

Lower alkanoyloxy groups represented by the symbols R 1 and R 10 include straight-chain or branched alkanoyloxy groups having 2 to 4 carbon atoms / e.g. acetyloxy, propionyloxy / butyryloxy and isobutyryloxy groups.

Lower alkylideneoxy groups represented by R 1 and R 10 include straight or branched alkylidene groups having 1 to 4 carbon atoms / substituted with two oxygen atoms (e.g. methylidenedioxy / ethylidenedioxy) isopropylenedioxy and butylidenedioxy.

In general, the nomenclature of compounds is based on the position numbers in the above general formula (I). Those compounds of general formula (I) / in which R 1 and R 10 form a lactone ring together with the two carbon atoms to which they are attached are designated by the position numbers in general formula (I ').

«- ** mc * ·) lr- / · jJ / iSpCTj __0" tr BU r ** CHj CMj 6 79845 (7) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1,2,3 , 4,4a, 5,6,7,8,8a, - decahydronaphthalene-1-spiro-2 * - (6,7,7'-di- (2-carboxyvinyl) -4'-hydroxy-2 ', 3' -dihydrobenzofuran_7 (8) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro- 21- (6'-carboxy-7'-hydroxyethyl-4 * -hydroxy-21,31-dihydrobenzofuran) (9) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1,2,3, 4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- ^' 61,7'-di (2,2-dietcksikarbonyyli-vinyl) -41-hydroxy-21,31- dihydrobenzofuran_7 (10) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- N, 61,7'-di- (2,2-butoxycarbonyl-vinyl) -4 * -hydroxy-2 ', 3 * -dihydrobenzofuran_7 (11) 6,7-Dihydroxy-2,5,5,8a-tetramethyl -1,2,3,4,4a, 3,6,7,8,8a-decahydronaphthalene-1-spiro-2 · - (6} 7 1, dihydroxymethyl-4 '»hydroxy-21.3 (-dihydrobenzofuran) (12) 6,7-Dihydroxy-2,5,5,8a-tetraraethyl-1,2,3,4,4a, 5,6,7,8,8a- Deca-hydronaphthalene-1-spiro-2 '- (61,7'-dihydroxymethyl-4'-methoxy-21,31-dihydrobenzofuran) (13) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1 , 2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- (71-carboxy-61-formyl-4 * -hydroxy-21,3'-dihydrobenzofuran ) (14) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 ' - (6'-carboxy-7 * -formyl-4 * -hydroxy-2 ', 3'-dihydrobenzofuran) (15) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1,2,3, 4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (71-carboxy-6 * -formyl-4'-methoxy-21.31-dihydrobenzofuran) (16) 6.7 -Dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21 - [“61,7 ' -di- (2,2-dicyanovinyl) -41-ethoxy-2 ', 3 * -dihydrobenzofuran ^ (17) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4 , 4α, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- (6,7'-di- (2-cyano-2-carboxyvinyl) -41-propoxy-2 ', 3'-dihydrobenzofuran_7 (18) 6,7-Dihydroxy-2,5,5,8a, tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydronaphthalene-1-spiro-2 '- (7'-carboxy-61- (2,2-dicyanovinyl) -4'-hydroxy-2 *, 3'-dihydrobenzofuran) (19) 6,7-Dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2l- N-71-carboxy-61- (2-cyano-2-carboxyvinyl) -4'-ethoxy-21,31-dihydrobenzofuran_7 (20) 6,7-Dipropionyloxy-2,5,5,8a-tetramethyl-1 , 2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- (61,71-diformyl-4'-propionyl-cyclo-21,5'-dihydrobenzofuran) 7 79845 (21) 6,7-Diacetyloxy-2,5,5,8a-tetraroethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 * - ^ ” 6 ', 7' - (2,2-dicyanovinyl) -4'-acetyloxy-21,3'-dihydrobenzofuran (22) 6,7-Dibutyryloxy, 2,5,5,8a, tetramethyl-1,2 , 3,4,4a-5,6,7,8,8a-1-spiro-2'6 *, 7'-di- (2-cyano-2-ethoxycarbonylvinyl) -4'-butyryloxy-2,3- dihydrobenzofuran_7 (23) 6,7-diacetyloxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2'- 6 ', 7'-di- (2-cyano-2-carboxyvinyl) -4 * -acetyloxy-21,3'-dihydrogen obenzofuran_7 (24) 6,7-Diacetyloxy-2,5,5,58a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 · - ^ “6 ', 7'-Di- (2,2-diethoxycarbonyl-vinyl) -4'-acetyloxy-21,3'-dihydrobenzofuran_7 (25) 6,7-Diacetyloxy-2,5,5,8a-tetramethyl-1 , 2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2, - (6 ', 7'-diacetyloxymethyl-N-acetyloxy-21,3'-dihydrobenzofuran) (26 ) 7-Acetyloxy-6-hydroxy-2,5,5,8a-tetracetyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- (6 *, 7'-diacetyloxymethyl-4'-acetyloxy-2 ', 3'-dihydrobenzofuran) (27) 6,7-Diacetyloxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydronaphthalene-1-spiro-21- (71-carboxy-61-formyl-4'-acetyloxy-21,3 * -dihydrobenzofuran) (28) 6,7- Dipropionyloxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spyro-21- (71-carboxy-61-f oryl-41-methoxy-21,31-dihydrobenzofuran) (29) 6,7-Diacetyl oxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8, 8a-decahydronaphthalene-1-spiro 2 * - {6 ', 7'τ ^ ΐ- (2,2-dicyanovinyl) -4 * -ethoxy-21,31-dihydrobenzofuran_7 (30) 6,7-Diisobutyryloxy-2-5-5- 8α-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '-? 6', 7'-di- (2-cyano-2- carboxyvinyl) -4, -propoxy-2H, 3'-dihydrobenzofuran_7 (31) 6,7-Diacetyloxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7 , 8,8a-decahydronaphthalene-1-spiro-21 - [', 7'-carboxy-6' - (2,2-dicyanovinyl) -4'-acetyloxy-2 ', 3 * -dihydrobenzofuran ^ (32) 6 , 7-Isopropylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (61,71-diformyl -41-hydroxy-21,3'-dihydrobenzofuran) (33) 6,7-Isopropylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,

8,8a-Decahydronaphthalene-1-spiro-2 * - [6 ', 71-di- (2,2-dicyanovinyl) 4'-hydroxy-2', 3'-dihydrobenzofuran J

(34) 6,7-Ethylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2'-£ 61 , 7'-di- (2-cyano-2-ethoxycarbonylvinyl) -41-hydroxy-21,3'-dihydrobenzofuran 7e 79845 (35) 6,7-Isopropylidenedioxy-2,5,5,8a-tetranethyl- 1,2,3,4,4a, 5,6,7,8,8a-Decahydronaphthalene-1-spiro-21- [61,7'-di- (2-cyano-2-isopropoxycarbonylvinyl) -4'- acetyloxy-2 *, 3'-dihydrobenzofuran_7 (36) 6,7-Methylenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a- decahydronaphthalene-1-spiro-2 '- (6', 7'-di- (2-cyano-2-carboxyvinyl) -4, -hydroxy-2,3,3'-dihydxobenzofuran_7 (37) 6,7- Isopropylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- "" 6', 7 ' -di- (2,2-dicyanovinyl) -4 * -acetyloxy-2 ', 31-dihydrobenzofuran_7 (38) 6,7-propylidene diiodo-2,5,5,8a-tetramethyl-1,2,3,4 , 4α, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (6', 71-di- (2-carboxyvinyl) 4'-hydroxy-21,31-dihydrobenzofuran_7 (39) 6 , 7-isopropylidenedioxy-2,5,5,8a-tetrahydro- methyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (6', 7'-di- (2,2-diethoxycarbonylvinyl) -4'-hydroxy-21,3'-dihydrobenzofuran_7 (40) 6,7-Isopropylenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a -decahydronaphthalene-1-spiro-2 '- (6', 7 * -dihydroxymethyl-4'-hydroxy-2 ', 31-dihydrobenzofuran) (41) 6,7-Isopropylidenedioxy-2,3,5,8a-tetraine style -1,2,3,4,5,6,7,8,8a-Decahydronaphthalene-1-spiro-2 '- (6', 7'-diacetyloxymethyl-4'-acetyloxy-2 ', 3'-dihydrobenzofuran ) (42) 6,7-Isopropylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a-5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- ( 6 *, 7'-dihydroxymethyl-4'-methoxy-2 ', 3'-dihydrobenzofuran) (43) 6,7-Isopropylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydronaphthalene-1-spiro-2 '- (7 * -carboxy-6'-formyl-4'-hydroxy-2', 3'-dihydrobenzofuran) (44) 6,7- Propylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a-5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (7 * -carboxy-6'- formyl-4'-acetyloxy-2 ', 31 -dihydrobenzofurazine) (45) 6,7-Butylidenedioxy-2,3,5,8a-tetranethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (7'-carboxy-6'-forroyl-4'-methoxy] -2', 3'-dihydrobenzofuran) (46) 6,7-Isopropylidenedioxy-2,5,5,8a-tetramethyl-1,2,3, 4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (6', 7 * -di- (2,2-dicyanovinyl) -4'-ethoxy-2 *, 3'- dihydrobenzofuran_7 (47) 6,7-Isopropylidenedioxy-2,5,5,8a-tetraraethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- "6 ', 7'-di- (2-cyano-2-carboxyvinyl) -4'-acetyloxy-2', 31-dihydrobenzofuran 7979345 (48) 6,7-Isopropylidenedioxy-2,5,5,8a -tetramethyl-1,2,3,4 ·, 4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2,7-carboxy-6 '- (2-cyano-2- * carboxyvinyl) -4, -hydroxy-2 ', 3'-dihydrobenzofuran_7 (49) 7-Acetyloxy-6-oko-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6 , 7,8,8a-Decahydronaphthalene-1-spiro-2 '- (6', 7'-diaethyloxymethyl-41-acetyloxy-2 ', 3'-dihydrobenzofuran) (50) 7-Acetylxix-6-oxo- 2.5 »5,8a-tetramethyl-1,2, 3,4,4a, 5,6,7,8,8a-Decahydronaphthalene-1-spiro-2 '-?', 6 ', 7'-di- (2,2-dicyanovinyl) -4'-acetyloxy-2' 1,3'-dihydrobenzofuran_7 (51) 7-acetyloxy-6-oxo-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1- Epiro-2 '- [' 6 ', 7'-di- (2-cyano-2-ethoxycarbonylvinyl) -4 * -acetyloxy-2', 3'-dihydrobenzofuran_7 (52) 7-Acetyloxy-6-oxo- 2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- /' 6 ', 7'-di- ( 2-cyano-2-isopropoxyxarbonylvinyl) -4'-methoxy-2 ', 3'-dihydrobenzofuran-7 (53) 7-propionyloxy-6-oxo-2,5,5,8a-tetraraethyl-1,2,3, 4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- [1,7,7'-di- (2,2-butoxycarbonylvinyl) -4'-propionyloxy-2', 3 * -dihydrobenzofuran_7 (54) 7-Acetyloxy-6-oxo-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1 - spiro-21- [6 ', 7'-di- (2-cyano-2-carboxyvinyl) -4'-propoxy-2', 3'-dihydrobenzofuran_7 (55) 4-hydroxy-8-oxo-2, 3,6,8-Tetrahydro-furo - [3,4-g] benzofuran-2-spiro-1 '- (6', 7 '-dihydroxy-2', 5 ', 5', 8'a-tetramethyl-1 ^ 2 ^ 3% 4 ^ 4 ^, 5 ^ 6 ^ 71.8 *, 8 * α-decahydronaphthalene) (5 6) 4 ., 6-Dihydroxy-8-oxo-2,3,6,8-tetrahydro-furo- [3,4-g] -7-benzofuran-2-spiro-1 '- (6', 7'- dihydroxy-2 ', 5', 5 ', 8a'-tetramethyl-1', 2 ', 3', 4 ', 4', 4 ', 5', 6 ' isopropoxy-8-oxo-2,3,6,8-tetrahydro-furo - / '3,4-gj-benzofuran-2-spiro-1' - (6 *, 7 f-dihydroxy-2 ', 5', 51 , 8α'-tetramethyl-1β, 3,3,4,4,4a, 5 *, 6 ', 7', 8 ', 8 · α-decahydronaphthalene) (58) 4-Propionyloxy-8-oxo-2 , 3,6,8-tetrahydro-furo- [3,4-g] -7-benzofuran-2-spiro-11- (6 *, 7, -di-propionyloxy-2 ', 5', 5 ', 8'a -tetraethyl-11,2 ', 3', 4 ', 4'a, 5', 6 ', 7', 8 *, 8'a-decahydronaphthalene) (59) 4-Acetyloxy-6-hydroxy-8-oxo -2,3,6,8-tetrahydro-furo - [3,4-g] N-benzofuran-2-spiro-1 '- (61,7, -diacetyloxy-2f, 5', 5 ', 8'a -tetranethyl-1 ', 2', 3 ', 4', 4'a, 5 ', 6', 7 ', 8', 8'a-decahydronaphthalene (60) 4-Butyryloxy-6-hydroxy-8-oxo -2,3,6,8-tetrahydro-furo - / '3,4-G7-benzofuran-2-spiro-1' - (7 -butyryylioksi-6-hydroxy-2 · 5 ', 5', 8'a-tetranethyl-1 ', 2', 3 ', 4', 4'a, 5 ', 6', 7 ', 8', 8'a-decahydronaphthalene) (61) 6 -Hydroxy-4-propoxy-8-oxo-2,3,6,8-tetrahydro-furo- [3,4-g] -benzofuran-2-spiro-1 '- (6', 7'- propionyloxy-2f, 5 ', 5', 8'a-tetramethyl-1 ', 2', 3 ', 4', 4 ', 5', 6 ', 7', 8 ', 8'a-decahydronaphthalene) ( 62) 4-Hydroxy-8-oxo-2,3,6,8-tetrahydro-furo-3,4-g-7-benzofuran-2-spiro-1 '- (6', 7'-isopropylidenedioxy-2 ', 5', 5 ', 8'a-tetramethyl-1', 2 *, 3 ', 4', 4'a, 5 ', 6', 7 ', 8', 8'a-decahydronaphthalene) (63 ) 4,6-Dihydroxy-8-oxo-2,3,6,8-tetrahydro-furo - [[3,4-g] -7-benzofuran-2-spiro-1 '- (6 *, 7 '-isopropylidenedioxy-2', 5 ', 5', 8'a-tetramethyl-'i', 2 ', 3', 4 ', 4'a, 5', 6 ', 7', 8 ', 8' α-decahydronaphthalene) (64) 6-Hydroxy-4-isopropoxy-8-oxo-2,3,6,8-tetrahydro-furo- [3,4-g] -7-benzofuran-2-spiro-1 '- ( 6 ·, 7 * -propylidenedioxy-2 ', 5', 5 ', 8'a-tetramethyl-1', 2 ', 3', 4 ', 4'a, 5', 6 *, 7 ', 8' , 8'a-decahydronaphthalene) (65) 6-Hyaroxy-4-acetyloxy-8-oxo-2'-t3,6,8-tetrahydro-phyto- [3,4-g] benzofuran-2-spiro-1 '- (6 *, 7'-isopropylidene enidioxy-2 ', 5', 5 ', 81α-tetramethyl-1', 2 ', 3', 4 ', 4'a, 5', 6 ', 7', 8 ', 8 * α-decahydronaphthalene ) (66) 4-Hydroxy-8-oxo-2,3,6,8-tetrahydro-furo-3,4-g-7-benzofuran-2-spiro-1 ', (7'-acetyloxy-6 '-oxo-2', 5 ', 5' -8 'α-tetramethyl-1', 2 ', 3', 4 ', 4'a, 5', 6 ', 7', 8 ', 8 (α-decahydronaphthalene) (67) Disodium 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydxonaphthalene-1- spiro-2 '- (5 * -carboxylate-7 1-formyl-4'-oxide-2', 3'-dihydrobenzofuran)

The noise level of the above compounds is based on the station numbers in the above general formula (i). Those compounds of general formula (I) in which E and R form a lactone ring together with the two carbon atoms to which they are attached are designated by the position numbers in the following general formula (I ').

A

di Ig 1 * £ _k (I,) 7 '8'a 2' 6 '4'a 3' n 79845 I. Production of starting material of general formula (Ia) by micro-organisms of the genus Stachybotrys

The preparation of the substance of the general formula (Ia) by means of microorganisms belonging to the genus Stachybotrys is carried out as described in more detail in the parent application FI 781517 of this application. Briefly, the production is carried out as follows.

The microorganisms are first cultured on a medium containing common food sources, nitrogen sources, and carbon sources, as well as various additives. The culture can be performed in a conventional aqueous medium containing the above-mentioned substrates, using either a surface culture technique or a liquid culture technique with aeration and mixing. Liquid cultivation with aeration and scaling is recommended. Cultivation can be advantageously carried out at a temperature of 15 to 35 ° C, preferably 20 to 32 ° C, for approximately 3 to 7 days under normal aeration conditions, maintaining the pH of the culture medium at about 3.5 to 11.5 , the best is pH 4.5 ... 9.5.

The material formed after culturing is obtained from the culture broth. The recovery method is not particularly limited, and many different methods can be applied using the physicochemical properties of the recovered substances, such as differences in dissolution of products and impurities, or differences in adsorption strength and affinity of common adsorbents, differences in partition coefficients, 781517 is explained in more detail.

II. Preparation of compounds of general formula (I).

The sesquiterpene derivatives of the general formula (I) of the invention can be prepared from the starting material of the formula (Ia) as defined in the claims according to the methods 12,79845 described below, or by combining two or more of these methods. The reactions of these methods and the compounds formed are explained below.

(A) Method (1)

Compounds of general formula (i) wherein R and R, one or both, represent a carboxyl group (hereinafter referred to as compounds (13) V may be prepared by oxidation of compounds of formula (I) wherein one or both of R and R represent formyl) a group (hereinafter referred to as compounds (IA)), for example compound (Ia).

The oxidation reaction can be carried out according to conventional methods to obtain aromatic carboxylic acids from aromatic aldehyde compounds. Examples of useful oxidation methods are the following: a method utilizing an oxidizing agent, a method using light radiation without a catalyst, a contact oxidation method in the presence of a coxalite using air or oxygen, an electrolytic oxidation method in the presence of a copper compound or sulfuric acid, and an oxidizing agent. If the simplicity of operation, etc., the ease of separation and purification of the reaction products, the amount of product, etc. are checked, the method using an oxidizing agent and the contact oxidizing method using air or oxygen are favorable.

There is no particular restriction on the choice of oxidizing agent if the oxidizing agent method is used. Any inorganic or organic oxidizing agent can be used. Typical examples of useful inorganic oxidizing agents are permanganate salts, manganese oxide, manganese pyrophosphate, chromic acid, chromate salts, silver oxide, silver nitrate, Tollens reagent, peroxoal acid, peroxide, gold oxide, nickel peroxide, selenium dioxide, chlorine, and salts of perhalonic acids, nitric acid, nitric acid, nitric oxide nitric oxide, cobalt salts such as cobalt silicate or cobalt acetate, cerium salts such as cerium sulfate, cerium oxide and cerium perchlorate, hydrogen peroxide and ozone. Useful organic oxidizing agents include, for example, N-bromosuccin track, N-chlorosuccinimide, sodium N-chloro-p-toluenesulfonamide, sodium N-chlorobenzenesulfonamide, azo compounds such as ethyl azodicarboxylate and 4-phenyl-1,2,4-trinol 79845 3,5-dione and percarboxylic acids such as perforic acid, peracetic acid, monoperphthalic acid, trifluoroperacetic acid, perbenzoic acid and m-chloroperbenzoic acid.

Of these oxidizing agents, permanganate salts, silver oxide, hydrogen peroxide, chromic acid, peracetic acid and perbenzoic acid are recommended, and permanganate salts and silver oxide are especially recommended.

Our oxidation using a scaffold oxidant is best performed in a suitable solvent. Suitable useful solvents are, for example, water and dry or wet organic solvents, for example alcohols such as methanol and ethanol, pyridine, ethers such as dioxane, tetrahydrofuran and diethyl ether, ketones such as acetone and methyl ethyl ketone, carboxylic acids such as acetic acid and propionic acid, propionic acid, aromatic hydrocarbons such as benzene or chlorobenzene, hexamethylphosphoramide, dimethylformamide, and dimethyl sulfoxide. A suitable amount of oxidizing agent is about 1 to 10 equivalents, preferably 1 to 2 equivalents, per formyl group of the starting material (IA). The reaction can be carried out at temperatures of about -10 ...

100 ° C, 0-50 ° C is recommended, from about 30 minutes to about 24 hours.

The coractation oxidation process using an oxygen-containing gas such as air or oxygen can be carried out, for example, by bubbling oxygen or air through an aqueous solution of sodium hydroxide or potassium hydroxide without a catalyst, or by bubbling air or oxygen through an aqueous solution in the presence of a catalyst using an inorganic salt such as cobol in the presence of a radical initiator such as benzoyl peroxide or using light radiation. The most preferred of these methods is the contact-self-oxidation method, in which air or oxygen bubbles without a catalyst through a basic aqueous solution. This reaction can be completed by stirring the reaction mixture at a temperature that can be about 1 ...

100 ° C, 40-50 ° Cf is recommended for about 30 minutes to about 24 hours, usually 30 minutes to 2 hours.

After the above oxidation reaction, the oxidizing agent, if used, is decomposed with a reducing agent, and then inorganic by-products are removed by filtration, neutralization, vacuum distillation, etc. If air, etc. is bubbled through the reaction mixture, it is recommended that the reaction mixture be treated with activated carbon and then acidified with chlorine. with hydrochloric acid to accompany the crystals. The reaction mixture is extracted with an organic i4 79845 solvent such as ethyl acetate and then treated by a conventional separation-purification granular method such as column chromatography or fractional crystallization. Thus, the desired compound (13) can be isolated.

Of the compounds obtained in the above-mentioned manner, a compound in which one of the groups R and R represents a fornyl group and the other a carboxyl group (this compound is hereinafter referred to as the compound (ib)) has a structure (Ib) having a lactone ring in crystalline form. In the solvent, especially the alkaline solvent, the compound (Ib) is present in an equilibrium mixture of the compound (Ib1) and its tautomer, the monocarboxylic acid compound (Ib-) shown below. c

HO ^ T

/ TT

CH- / j HO H

"IT -— 0 H °" 'Tl 0H5 ho -

'' 'K' ^ Π LI

tl

ΗΟ-Χ ^ γ. COOi i ^ X ~ CHO

CH, / I (Ib2 ^ HO CHj ch5 ch5 15 79845

The above structures show examples of a compound of formula (I) wherein R 1 and R 5 represent a hydrogen atom, R 2 represents a formyl group, R represents a carboxyl group, and R 1 and R 2 represent a hydroxyl group.

This structure was confirmed by dissolving the compound (Ib ^ (crystalline) in dimethyl sulfoxide and measuring its MLR (nuclear magnetic resonance) spectrum over time. Twenty minutes after dissolution, a peak was observed at 9.89 ppm, a characteristic sign of aldehyde proton (-CH0), another The integrated ratio between the previous and subsequent peaks was about 73: about 27. Two hours after dissolution, the peak of 9.89 ppm increased slightly and the integrated ratio was about 70. This integrated ratio, obtained two hours after dissolution, did not change immediately thereafter, indicating that compounds (Ib ^ and (^ 2) were present in the above solvent as a 7: 3 molar equilibrium mixture. When methanol or pyridine was used as a solvent, a similar spectroscopic analysis did not detect compound (^ 2), which is a tautomer of compound (Ib ^).

(B) Method (2)

O

Compounds of general formula (I) in which at least one of R and E? means a hydroxymethyl group (hereinafter referred to as compound (IC)) can be prepared by (1) reducing the formyl or carboxyl group of compounds (IA) or (IB) or (2) reducing compounds of general formula (I) 2 3 wherein R and together form a lactone qq a ring of the formula R 2, wherein R 2 represents a hydrogen atom

I II

-CH-O-C- or hydroxyl group (hereinafter referred to as compounds (ID)).

The above reduction can be performed using the following two methods.

The reduction of the formyl groups can be carried out according to a number of conventional methods in which aromatic aldehydes are reduced to aromatic alcohols, for example by using a reducing agent, by a catalytic reduction method, or by an electrolytic reduction method.

If a reducing agent method is used, suitable useful reducing agents include, for example, aluminum hydride compounds such as lithium aluminum hydride, sodium alarine hydride, sodium ethoxyaluminum dihydride and sodium diis (2-methoxyethoxy) sodium dihydride, aluminum hydride, aluminum hydride, organic tin hydrides such as tri-n-butyltin hydride, diphenyltin hydride and triethyltin hydride, and hydrosilanes such as dimethylphenylsilane and triethylsilane.

Catalyst Reduction Method Many different conventional catalysts can be used in the process. Suitable catalysts that can be used include, for example, palladium black, palladium on carbon, Raney nickel, and platinum oxide. A suitable amount of catalyst ranges from about 1 to 50 masses, preferably from 5 to 15 mass masses, based on the mass of the starting compounds, the starting compounds being compounds of general formulas (IA), (13) or (ID).

The electrolyte reduction method can be carried out using, for example, mercury, lead, platinum, zinc, nickel, palladium, graphite, etc. as the cathode, and by conducting a direct current with a voltage of 2 .. .12 V, 4 ... 6 V, a neutral or alkaline solution is recommended. containing the compound in question.

Of the above-mentioned reduction methods, the method using a reducing agent is most preferable because the method is simple and relatively inexpensive. The most popular of the reducing agents is sodium borohydride. More specifically, this process is carried out in a neutral solvent, for example an aqueous solution of a base such as sodium hydroxide or potassium hydroxide, water, a lower alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxane, or a mixture of these solvents. A suitable amount of reducing agent is generally considered to be at least 1 equivalent, preferably 1 to 8 equivalents, based on the formyl groups of the starting material to be reduced. The reaction temperature is usually about 0 to 60 ° C, 5 to 25 ° C is recommended. The reaction is usually complete in 30 minutes ... 10 hours.

When compound (Ib) is used as a starting material in the reduction reaction, a basic substance must be added to the reaction system in order to open the lactol ring. This is because the compound (Ib) under neutral or acidic conditions forms a lactol compound, of which 17 79845 the above-mentioned compound having the structure (Ib ^) is typical, and this compound is very stable and not easily reduced. It follows that the above-mentioned reducing agents, solvents and reaction conditions should be used in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogen carbonate. A suitable amount of the basic substance is about 1 mole / or more per mole of the starting material of the general formula (Ib). It is preferable to heat the above starting material in the presence of a basic substance with stirring to about 0 to 80 ° C, preferably 40 to 60 ° C for 1 to 8 hours in combination with sodium borohydride, which acts as a reducing agent, and in an amount should be at least 4 equivalents, preferably 4 to 16 equivalents. The entire system is maintained in a common neutral solvent such as water, methanol, ethanol, tetrahydrofuran and dioxane, either in a single solvent or in a solvent.

The reduction of the carboxyl groups of the compound (IB) or the compound (IC) obtained in the above manner, wherein one group R and R represents a hydroxymethyl group and the other a carboxyl group and together form a lactone ring (hereinafter referred to as compound (Id)), can be performed in the following manner. The compound (Id) is reacted with lithium aluminum hydride, which acts as a reducing agent and is at least 1 equivalent, preferably 1 to 8 equivalents per equivalent of the compound (Id), in a common neutral solvent such as dioxane or diethyl ether at a temperature of about 0 to ... 60 ° C, recommended 5. # .25 ° C, 30 minutes ... between 10 hours.

(C) Method (3)

Compounds of formula (i) wherein R and together form a lactone ring of formula 0 (hereinafter referred to as

- C ^ -O- C

to compounds (Id)) can be readily prepared by subjecting the ring closure by water separation in the compounds of formula (IC) obtained by the above-mentioned method, wherein one of the groups 9xo -2 R and R- 'represents a hydroxymethyl group and the other of the groups R and R · means a carboxyl group in the absence of a solvent or in the presence of a suitable solvent.

The above-mentioned ring-closing reaction in which water is released can be carried out directly by heating the starting materials, which are the capped compounds of formula (IC) i.e. 79845, to a temperature of 100 to 200 ° C. Alternatively, the starting material is dissolved in a suitable neutral solvent and heated in the presence of an acidic substance to require a catalytic amount (about 0.01 to 50 wt.%, Preferably 0.01 to 10 wt.% By weight of the starting material) at a temperature of about 0. .200 ° C, 60 to 150 ° C is recommended for about 10 minutes to 24 hours, usually 2 to 10 hours. Suitable useful solvents include, for example, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, ethers such as dimethyl ether, tetrahydrofuran and dioxane, glycols such as ethylene glycol and ethanols, and the former alcohols.

Suitable useful acidic compounds include, for example, chlorohydrogen, hydrochloric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, perchloric acid, trichloromethanesulfonic acid, trifluoroacetic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, benzene sulfonic acid,

(D) Method (4) O 7

Compounds of general formula (I) in which one of the groups R and one or both represent a group of the formula -CH 3 * CR 2 R 8 in which R 'and R have the same meaning as above (hereinafter referred to as compounds (IE)) may be prepared by dehydrocondensation of the compounds (ia) active methylene compounds of general formula (II); Λ

H 2 O (R) 7 R 8 wherein R 'and R are as defined above in the presence of a catalyst.

The dehydrocondensation reaction can be performed without a solvent. However, the dehydrocondensation reaction can be better carried out with a tertiary amine of a conventional neutral solvent such as a basic aqueous solution such as sodium hydroxide solution, water, an alcohol such as methanol or ethanol, an ether such as dioxane or tetrahydrofuran, an aromatic hydrocarbon such as benzene or toluene, pyridine in the presence of triethylamine, or a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride.

If an alkaline aqueous solution, pyridine or triethylamine are used as a solvent, they can also act as catalysts, and thus it is not necessary to add another catalyst. If other solvents are used, a catalyst must be used, for example an amino acid such as β-alanine, a 19,79845 cyclic mine such as piperidine or morpholine, ammonia, an amine such as ethylamine, diethylamine or butylamine, acetate salts of these amines or alkali metal acetate, alkali metal acetate, such as an alkali metal alcoholate such as sodium ethylate or sodium methylate. The amount of catalyst should be from 0.01% by weight to excess, preferably from 0.05 to 30% by weight, based on the weight of the starting compound (IA).

The solvent used determines the temperature and length of the reaction. If a non-polar solvent such as benzene or chloroform is used, the reaction is generally carried out by heating the reaction system close to the boiling point of the solvent and since the water formed in the reaction separates as an azeotrope, the reaction is continued until the theoretical amount of water has separated. If a solvent which is completely miscible with water such as ethanol, pyridine or dioxane is used, the reaction can generally be carried out at room temperature to 120 ° C, 30 ...

60 ° C, about i., For 30 hours, usually i ... 3 hours, without separating the water formed in the reaction.

The amount of the active methylene compound of the general formula (II) used in the above-mentioned dehydrocondensation reaction is at least 1 equivalent, preferably 1 to 2 equivalents, relative to the fornyl groups of the starting material (IA).

(E) Method (5)

Compounds of general formula (i) in which one or both of R and R are hydroxyl groups (hereinafter referred to as compounds (IF)) can be easily prepared by reacting compounds (IA) with peroxides in an inert solvent.

Useful suitable inert solvents include, for example, aqueous solutions of alkali hydroxides such as sodium hydroxide and potassium hydroxide, water, pyridine, methanol, ethanol, acetic acid, propionic acid, chloroform, methylene chloride, methyl acetate, ethyl acetate, benzene. Suitable useful peroxides include organic or inorganic peroxides such as hydrogen peroxide, peracetic acid, trifluoro-per-acetic acid, m-chloroperbenzoic acid, per-benzoic acid and perfumaric acid.

The reaction temperature is usually about 0 to 100 ° C, 79845 to 50 to 50 ° C is recommended, and the reaction is completed by stirring the reaction system for about 1 to 24 hours. The amount of peroxide should be at least about 2 moles, preferably 2 to 3 moles, per mole of starting material (IA).

When the reaction is complete, a suitable neutralizing agent is added, and the mixture is concentrated under reduced pressure. The residue is mixed with ice water and the precipitated coarse crystals are collected by filtration, washed with water and dried.

The dried coarse crystals are dissolved in a suitable solvent such as chloroform and separated by column chromatography. The desired compound (I?) Is usually obtained in the methanol-eluted fraction.

(?) Method (6) o 7

Compounds of general formula (I) in which the groups R and both represent a lower alkanoyloxymethyl group (hereinafter referred to as compounds (IG)) can be prepared by acylation of compounds (IC) obtained in the above-mentioned process (2).

As the acylating agent in this reaction, for example, a lower alkanoyl acid such as acetic acid, propionic acid, butyric acid, iso-butyric acid, etc., an anhydride of these acids or a halide of these acids such as acetyl chloride, propionyl bromide, butyryl bromide, butyryl bromide, isobutyl, isobutyl, can be used. halides. The acylating reaction can be carried out without a solvent or in the presence of a common neutral solvent in the presence of a basic compound. Suitable neutral solvents include, for example, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, dioxane or tetrahydrofuran, halogenated hydrocarbons such as chloroform and methylene chloride, tertiary amines such as pyridine and triethylamine, dimethylamine, dimethyl. Useful basic compounds include, for example, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and tertiary amines such as pyridine, quinoline, N, N-dimethylaniline or triethylamine. A suitable amount of the basic compound is at least 1 mole, 1 to 2 moles are recommended, per mole of starting material (IC) when an acid halide is used as the acylating agent and about 0.01 to 10% by weight, 1 to 5% by weight is recommended % by weight of starting material (IC) when acid anhydride is used as the acylating agent.

2i 79845

The reaction can be carried out at a temperature of about -60 to 150 ° C, 0 to 100 ° C is recommended, and the reaction is completed in about 1 to 20 hours.

The amount of acylating agent is at least 1 equivalent, usually about 1.10 equivalents, relative to the hydroxyl groups of the starting material (IC).

When a compound of formula (I?) Is used as a starting material in this acylating reaction, wherein both R and R · 'and nvös represent at least one of -OR, and R ° represents a hydroxyl group, one or others of the hydroxyl groups may also be acylated depending on the acylation conditions and in particular depending on the choice of reaction temperature or the amount of acylating agent. If the starting material has more than one hydroxyl group, and it is desired that only R and R be acylated, one or other hydroxyl groups may be protected using appropriate conventional procedures prior to the reaction, and when R and R are acylated, the protecting groups are removed.

(G) Method (7)

The capped compounds of formulas (IA) ... (IG) obtained by the above methods wherein R 1 represents an lower alkyl group can be prepared by reacting vasxalizing compounds wherein R 1 represents a hydrogen atom with known alkylating agents.

Suitable alkylating agents. Examples of those which may be used are alkyl halides such as methyl iodide, ethyl bromide, propyl bromide, isopropyl bromide, butyl iodide and tert-butyl bromide, dialkyl sulphates such as dimethyl sulphate or diethyl sulphate, and diazoalkanes such as diateomethane or diazoethane.

The alkylation reaction can be carried out at about room temperature to 100 ° C, preferably 50 to 70 ° C, in a common neutral solvent such as ketones such as acetone or methyl ethyl ketone, an ether such as tetrahydrofuran or dioxane, or a lower alcohol such as methanol or ethanol, in the presence of a basic compound, for example potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide in an amount of about 1 to 10 moles, 1 to 2 moles per mole of alkylating agent is recommended. The reaction is usually completed in about 1 to Θ hours. The amount of alkylating agent used is at least about 1 mole, usually about 1 to 5 moles, per mole of element (IA) ... (IG). If diazoalkanes are used as the alkylating agent, the basic agent may be omitted.

22 79845 (H) Method (B)

Compounds of formulas (1A) to (IG) in which R 1 represents a lower alkanoyl group may be prepared by reacting the corresponding compounds in which R represents a hydrogen atom with known acylating agents.

The acylation reaction can be carried out according to the above-mentioned method (6).

If compounds of general formula (I) having a hydroxyl group other than the 4 'position are used as a starting material, it is likely that such a hydroxyl group is acylated under the acylation conditions of the above-mentioned method (6). When acylating such a starting material, it is therefore recommended that the hydroxyl group other than the 4'-position be protected in a conventional manner with a suitable protecting group.

(I) Method (9)

Compounds of general formulas (IA) ... (IG) in which R 1 and R 2 represent a lower alkanoyloxy group can be prepared by acylation of the corresponding compounds in which R 1 "and R 2 represent a hydroxyl group. The same acylation ratios, protection and subsequent deprotection can also be used in this reaction. removal as explained in method (6).

(J) Method (10)

Compounds of general formulas (IA) ... (IS) in which R1 and R6 represent a lower alkylidenedioxy group may be prepared by reacting ag corresponding compounds in which R and R represent a hydroxyl group with aldehydes or ketones of general formula (III): R10 C * 0 (III) R11 ^ 10 11 wherein R and R, which may be the same or different, represent a hydrogen atom or a lower alkyl group, or with acetals or ketals having the general formula (IV): 23 79845 R10. ^ OCH, 11 c -__ (IV) R ^ OCH3

Where R10 and R11, which may be saunas or different, have the same meaning as above (III).

Here, the reaction can be carried out in the presence of a catalyst, without a solvent or in the presence of a suitable solvent. Useful suitable solvents include, for example, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl and dioxar, halogenated hydrocarbons such as chloroform and methylene chloride, and ketones such as acetone and methyl ethyl ketone. Useful suitable catalysts include, for example, hydrogen halides such as hydrogen chloride and hydrogen bromide, sulfuric acid,

Lewis acids, anhydrous alunine chloride, anhydrous zinc chloride and boron trifluoride, and p-toluenesulfonic acid. A suitable amount of catalyst is about 0.1 to 20% by weight, preferably 5 to 10% by weight, based on the weight of the starting material (IA) ... (IG). If compounds of general formulas (III) and (IV) are used in the reaction, they are generally used in excess of the compounds of general formulas (IA) ... (IG) because they also act as solvents. A suitable reaction temperature is about -30 ° C to 70 ° C, 0 ° C to room temperature is recommended. Under these conditions, the reaction is completed in about 30 minutes ... 6 hours.

• (K) Method (11)

Compounds of general formulas (IA) ... (IG) in which R 1 and R 2 both represent an oxo group (-O) can be prepared by oxidizing the corresponding compounds in which a hydroxyl group and R 1 represent a hydrogen atom.

The oxidation reaction can be carried out using a number of known oxidizing agents used in the oxidation of secondary alcohols to oxo groups. Useful suitable oxidizing agents include, for example, chromic acid, bichromic acid, salts of these acids with metals such as sodium and potassium, nitric acid, halogens such as bromine or chlorine, Oppenauer oxidizing agent and Jones' reagent.

The reaction is best carried out in a suitable solvent. Suitable solvents are, for example, water, alcohols such as methanol and ethanol, ethers such as dioxane, tetrahydrofuran and diethyl ether, ketones such as acetone and methyl ethyl ketone, organic acids such as acetic acid and propionic acid, esters such as ethyl acetate and aromatic hydrocarbons, aromatic hydrocarbons chlorobenzene, halogenated hydrocarbons such as dichloromethane and dichloroethane, dimethylformamide, dimethyl sulfoxide and pyridine.

The amount of oxidizing agent can be selected to suit the purpose within wide limits. An excess of oxidizing agent is usually used.

The reaction can be carried out at a temperature of about -10 ° C to 100 ° C, preferably 0 ° C to room temperature, for about 30 minutes to 6 hours. If starting materials having groups which are readily oxidized in the oxidation reaction such as formyl or hydroxyl groups are used in the above oxidation reaction, it is recommended that these groups be protected with suitable protecting groups in a conventional manner as described in Method (6). Deprotection after the reaction can be easily carried out in a conventional manner.

The sesquiterpenes of the general formula (i) of the present invention can be prepared using one or more of the above methods (1) ... (11) in suitable series, and, if desired, by protecting reactive targets followed by deprotection and using various separation and cleaning methods.

Those compounds of the sesquiterpene derivatives of the general formula (I) of the present invention which contain an acid group, for example, a phenolic hydroxide group and / or a carboxyl group, can react with basic compounds and thus easily form salts thereof. Also included in this invention are salts of sesquiterpene derivatives of general formula (I).

Non-basic compounds which can be used in the preparation of the salts of the sesquiterpene derivatives of the general formula (i) include, for example, alkali metal and alkaline earth metal hydroxides and carbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen. Organic amides such as methylamine, ethylamine, isopropylamine, morpholine, piperazine, piperidine and 3,4-dimethoxyphenethylamine can also be used as basic compounds.

25 79845

Salt formation using basic compounds can be readily performed in a suitable solvent using conventional salt formation techniques. Suitable solvents include, for example, water, lower alcohols such as methanol, ethanol and propanol, ethers such as dioxane and tetrahydrofuran, acetone, benzene, ethyl acetate, dimethyl sulfoxide, dimethylformamide, methylene chloride and chloroform. The salt formation can be carried out at a temperature from room temperature ... to about 100 ° C, suitably from room temperature to ... 50 ° C, for about 5 minutes to about 6 hours, usually open to air or in an oxygen-free state, an atmosphere in which is a neutral gas such as nitrogen or argon. The amount of the basic compound used is not particularly limited, but usually a suitable amount is at least about 1 equivalent, suitably 1 to 2 equivalents, based on the acid groups of the starting material (I).

When the above reactions are complete, the desired final compound can be easily isolated and purified using known conventional separation methods. For example, solvent distillation, solvent extraction, precipitation, recrystallization, column chromatography, and preparative chromatography can be used as separation methods.

III. Therapeutic Agents The sesquiterpene derivatives of the general formula (I) of the present invention and their salts are useful as a treatment agent for nephritis, and when thus used, they have been added to pharmaceutical compositions together with customary pharmaceutically acceptable carriers. Suitable carriers include, for example, diluents and additives such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and lubricants commonly used in the preparation of such drugs, depending on the dosage form.

Depending on the purpose of the treatment, different dosage forms of the therapeutic agent in the treatment of nephritis can be selected. Typical dosage forms that can be used include tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, and injectable preparations (solutions, suspensions, etc.).

In preparing a pharmaceutical composition comprising a sesquiterpene derivative of the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient in the form of a tablet, a wide variety of such known carriers can be used. Suitable carriers are, for example, excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, pure syrup, glucose, starch gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone, dispersing agents such as dried starch, sodium alginate, agarpulveri, laminaariapulveri, sodium hydrogen carbonate, calcium carbonate, Tween, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose, hajotusinhibiittorit such as white sugar, stearic acid glyceryl esters, cacao butter and cured oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, wetting agents such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as detergents talc, stearic acid salts, boric acid powder, Macrogol (trade name of a polyethylene glycol manufactured by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycol.

A wide variety of conventional carriers can be used to prepare a pharmaceutical composition in tablet form. Suitable carriers include excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminar and agar. If desired, tablets may be coated and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or tablets coated with two or more layers.

A wide variety of conventional carriers can be used to prepare a pharmaceutical composition in the form of a suppository. Suitable carriers are, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and semisynthetic glycerides.

If the pharmaceutical composition is to be injected, the resulting solution and suspension are recommended to be sterilized and must be isotonic with blood. When the pharmaceutical composition is made into a solution or suspension, all the usual diluents can be used for this purpose. Suitable diluents include, for example, water, ethyl alcohol 79845 27 propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol may be added to the therapeutic agent, for example a nephritis treatment agent, in sufficient amounts to form isotonic solutions. The therapeutic agent may further contain conventional solubilizing agents, buffers, analgesics and preservatives, and optionally colorants, perfumes, spices, sweeteners and other drugs.

The amount of the compound of the general formula (I) of the present invention and its pharmaceutically acceptable salts as an active ingredient that can be added to a pharmaceutical composition useful as a treatment for nephritis is not particularly limited, and can vary within wide limits. A suitable therapeutically effective amount of a compound of general formula (I) of this invention, or a pharmaceutically acceptable salt thereof, is usually about 1 to 70% by weight, preferably 5 to 50% by weight based on the total weight of the mixture.

There is no particular restriction on the use of the therapeutic agent as a treatment agent for nephritis, and the therapeutic agent may be administered by suitable means depending on the particular form of the therapeutic agent. For example, tablets, pills, liquid preparations, suspensions, emulsions, granules and capsules are administered orally. Syringes are administered into a blood vessel either alone or with a common excipient such as glucose and amino acids. In addition, if required, the therapeutic agent may be administered intramuscularly, intradermally, subcutaneously, or intraperitoneally. A suppository is administered rectally.

The dose of the nephritis treatment agent is appropriately selected according to the intended use, the symptoms, etc. Generally, a suitable dose of the compound of this invention is about 0.5 to 20 mg / kg of body weight per day in single or multiple doses.

The compounds of this invention have anti-complement activity and are also useful as therapeutic agents in the treatment of autoimmune diseases, collagen diseases and rheumatic diseases, each of which includes a complement system.

The following are the results of experiments on the pharmacological efficacy of the compounds of general formula (I) of this invention and their pharmaceutically acceptable salts.

28 79845 (1) Test Compounds The compounds representative of the present invention shown above and in Table 1 were tested. The compounds are further indicated with reference to general formula (I), in which its various substituents are also shown in Table 1 below, for example R 10 R 2 is R 1 -— CH, * kXj R, CrY CH 4; OH, R5 = 'h and R6 * -OH.

table 1

Compound no_R ^ __ R2 ___ R ^ ___

(1) -k -CHO -CHO

(67) -Na -COONa -CHO

(2) -H -OH -OH

.CN CN

(3) -K -CH.CY -CH «C ^

^ CH ^ ~ CN

CH. CN

(4) -H -CH = C

^ 00002 ^ 00002 ^

CN ___CN

(6) -K -CH = C ^ -CH * C

^ COOH COOH

(7) -H -CH-CHCOOH -CH = CHC00H

(8) -H -COOH -CH2OH

(11) -H -CH 2 OH -CH 2 OH

(12) -CH 3 -CH 2 OH -CH 2 OH

79845 29

Compound no (25) has the following structure:

0 S

CHjCO ch2occh3

CH ~ OCC'rU

CH, / I ° 0 1 ° CHjCO S ^ N- ch5 οκ3οο 0 ch5 ch5

Compound no (62) has the following structure: 0 HO - ΛΛ / 0 3H7 0

CH3 cv / VX ^ C-CH

CH3 ^ Οϊζ ^ CH5 (2) Complementary effect

The anti-Xomplement effect was measured and determined according to the method described in Meneki Kagaku (Immuno-Chemistry). Yuichi Yamamura et al., Ed. pages 830 ... 834, Asakura Shoten, Tokyo, Japan (1973). Specifically, 0.5 ml of an aqueous dispersion of each test compound, 0.5 ml of photosensitive red cells (EA) as a solution containing 1 x 10® cells / ml, 1 ml of a five-fold diluted solution of Veronal buffer containing gelatin, Ca ++ and Mg ** (GVB), and 0.5 ml of complement serum (guinea pig complement) diluted 150-fold in GVB **. The mixture was treated hot at 37 ° C for 60 minutes. 5 ml of ice-cold physiological saline was then added, and the mixture was centrifuged. The absorbance of the obtained supernatant was measured in 0D ^ 13, and the extent to which the test compound inhibited the hemolysis of photosensitive red blood cells was determined. The brain (y / ml) of the effect of 5 096 inhibition of hemolysis, measured for each test compound according to the above 30 7 9 8 4 5 method, is shown in Table 2 below.

(3) Acute toxicity

The LD50 values (mg / kg) of the test compounds when administered intravenously to mice were measured, and these results are also shown in Table 2 below.

Table 2

Value of anti-complement LD, -q

Compound no activity value (y / ml) Ug / kg) (1) 10 40 (67) 60 500 (2) 80 150 (3) 40 200 (4) 80 200 (6) 40 250 (7) 80 150 (8 ) 125 (11) 500 (12) 250 (25) 600 (62) 450

Chlorophyllin 40 (4) Therapeutic effect on nephrotoxin-type nephritis

Rat nephrotoxin (abbreviated "NT") was obtained as follows. The rat renal cortex was homogenized with the same amount of physiological saline. The homogenized mixture was mixed with "Freund's complete excipient" (product of Difco Company) in a volume ratio of 1: 1. Two milliliters of this solution was injected into the rabbit muscle (body weight 3,100 g to immune the rabbit. After 1.5 months, blood was taken from the rabbit heart to obtain serum. This serum was inactivated at 56 ° C for 30 minutes, then desalted with 40% saturated arammonium sulfate). aqueous solution, and fractionated, the γ-globulin fraction (igG) was collected to obtain NT.

The evaluation was performed using male Wietar rats weighing 150-160 g using three replicates of each test compound. The test compound was administered intraperitoneally once every 24 hours for seven days. One hour after administration of test compound 3i 79845, NT was administered on the third day. 1 ml of NT was injected into the tail vein of each rat. Chlorophyllin (CP) was used as a reference solution and physiological saline was used as a control.

The amount of protein in the urine (total amount of urine excreted in 24 hours) was measured using nephelometry and control serum albumin with sulfosalicylic acid.

The results obtained are shown in Table 3 below.

Table 3

Compound Dose Parallel (mg rat sample No. Daily reading *) 1 4 7 10

Compound No. 1 2.5 ** 1.5 0.8 8 (1) (starting 3 2 4.3 2.1 1.8 10 substance) 3 1.7 1.1 0.9 7 average 2.8 1.6 1.2 8 1 2.7 1.8 0.7 9

Compound No. 5 2 4.1 2.0 1.5 12 (67) 3 2.3 1.3 1.2 7 average 3.0 1.7 1.1 9 1 2.1 1.9 0.8 13

Compound No. 5 2 1.5 1.2 0.9 7 (6) 3 3.7 2.3 1.4 9 average 2.5 1.8 1.0 10 1 2.41.50.99

Chlorophyllin 5 2 4.4 2.6 1.7 8 3 3.2 2.1 3.5 6 average 3.4 2.1 2.0 8 1 13 16 21 29 (control) - 2 19 23 25 35 3 11 18 24 40 average 14 19 23 35 * The daily reading in Table 3 is calculated from the time the test compound was administered, which was 1 hour before NT administration ** The amount of protein urea is expressed in mg / day 32 79845

The protein urea level in a healthy rat is 0.5 to 5 mg / day.

When the protein urea level exceeds this limit, especially when the protein urea level is higher than 10 mg / day, it can be said with certainty that nephritis occurs. From the results in Table 3, it is noted that nephritis was present in the control batch and that in the batches of compounds of formula I and chlorophyllin, the amount of protein urea was approximately the same as in a healthy rat 10 days after NT administration. Thus, it can be considered that the administration of the compounds of formula I inhibits primary and secondary immune reactions.

When the same experiment was performed with compounds Nos. 3, 4, 5, 7, 8, 11, 12, 25, and 62 prepared according to the present invention, it was found that all of these compounds inhibited the primary reaction of nephrotoxin-type nephritis.

(5) Therapeutic effects on Heymann-type nephritis

Male Wistar rats weighing 180-200 g were used in the experiment. The rat renal cortex was extracted and homogenized with the same volume of physiological saline. The homogenized solution was centrifuged at 1500 G for 1 hour. The supernatant solution was purified according to the method of T.S. Edgington et al., Journal of Experimental Medicine, 127, 555 (1968), and mixed with Freund's complete excipient 37 Ra (product of Difco Company) in a volume ratio of 0.4: 1. The resulting mixture was injected intraperitoneally into isological rats, 0.5 ml per rat. Thereafter, the same amount of excipient was administered every other week until the protein urea level exceeded 100 mg / day. (This period was about 6 to 8 weeks).

The results are shown in Table 4.

Il 33 79845

Table 4 Number of days

Dose of Compound Parallel Dose Number mg / Rat Sampling _ _ ^ _ _ _1_ _4_ _7_ 14 21

Compound (1) 1 95 90 47 17 9 10 starting material 3 2 132 125 65 35 15 12 3 121 120 70 27 10 9 average 116 111 61 26 11 10 1 117 109 59 23 13 9

Compound (67) 5 2 152 127 67 41 17 13 3 105 114 51 25 11 12 average 118 117 59 30 14 11 1 98 113 48 36 18 8

Compound (6) 5 2 127 121 63 47 21 15 3 139 116 57 29 13 14 average 121 116 56 37 17 12 (1 123 116 72 32 16 ~ 10

Chlorophyllin. 2 117 108 63 29 12 8 (Comparison) 3 129 121 52 22 15 13 average 123 115 62 28 14 10 1 135 127 132 135 114 126 control '2 121 105 121 103 105 109 3 137 117 135 121 109 132 midbrain 131 116 12g 119 109 122 34 79845

Each test compound in Table 4 was administered intraperitoneally to rats suffering from Heymann-type nephritis (weighing 300-350 g) once daily for 7 days, after which the amount of protein urea (mg / day) was measured with the above-mentioned pill. . CP was used as a reference compound and physiological saline was used as a control. Three parallel experiments were performed on each co-compound. The results obtained are shown in Table 4.

At 2 to .3 weeks after the start of the experiment, the rats gained body weight to 400 to .500 g, and normal protein urea levels were likely to be 5 to 15 mg / day. As can be seen from the results in Table 4, the compounds of formula I can ameliorate Heymann-type kidney disease. When the same experiments were performed with the compounds 3, 4, 5, 7, 8, 11, 12, 25 and 62 prepared according to the present invention, it was found that these compounds also had considerable healing effects on Heymann-type nephritis.

IV Examples

To illustrate this invention in more detail, the preparation of the compounds of general formula (I) of the present invention is set forth in the following Reference Examples and Examples. Unless otherwise stated, all parts, percentages, ratios, etc. are by weight and the term room temperature as used herein means 15 ... 25 °.

RE 35 79845 REFERENCE EXAMPLE A 1,500 ml Sakaguchi flask was charged with 100 ml of medium according to the following composition, and Stachybotrys sp. K-76 was cultured at 28 ° C and pH: 6.4 for 4 days with shaking.

Medium composition%

Glycerol 0.5 Starch 1.0

Lactose 0.2

Soy flour 0.5

Yeast extract 0.1

Malt extract 0.2

CaCO 3 0.3

MgSO 4 0.05 A 30 liter fermentation flask was charged with 20 liters of medium according to the above composition, and one flask of the obtained inoculum was cultured in medium at 28 ° C for 5 days with stirring at 400 rpm and aeration of 1 liter of medium per minute. The resulting culture broth was centrifuged at 8,000 rpm to remove microbial cells. To the supernatant solution was added 5 liters of methanol, and the mixture was stirred, after which the mixture was allowed to stand for 3 hours. The mixture was centrifuged and the solid removed. The supernatant was extracted with an equal volume of ethyl acetate. The solvent of the ethyl acetate layer was distilled off under reduced pressure. The precipitate was dissolved in methanol, and passed through a column of active vinyl. The eluate was concentrated to dryness under reduced pressure. The dry mass was dissolved in a mixture of chloroform and ethyl acetate (1: 1 v / v) and gel filtered through a Sephadex 1H-20 column. The filtrate was subjected to thin-layer chromatography (using a mixture of ethyl acetate, chloroform and acetic acid (50: 50: 2 by volume) as the developing solution), and the fraction having an anti-complement effect corresponding to Rf * 0.34 was collected. Alternatively, the filtrate was subjected to thin-layer chromatography. ia (using a mixture of benzene, butanol and acetic acid (60:15:15 by volume) as developing solution) and a fraction with an anti-complement effect corresponding to Rf 0.58 was recovered, and 2.0 g of the solvent was evaporated, 7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (6', 7'-dichloromethyl) 4'-hydroxy-2 ', 3'-dihydrobenzofuran), as a pale yellow, slightly acidic substance with anti-complement activity, the formation of which was confirmed by the following physicochemical properties 11a.

36 79845 (1) ^ "cx_7p °" 4-8 ° (C <2.5, methanol) (2) Elemental analysis values for C2H2O2O8

Calculated (%): C 68.84, H 7.51

Found (50): C 68.58, H 7.55 (3) Ultraviolet absorption spectral analysis (UV) ethanol * 246 nm (ε = 16474) λ max = 307 nm (ε * 6659) (4) Nuclear Magnetic Resonance Spectrum Analysis (NKR) NI1R- The analysis was performed using pyridine-N, N-sodium 2,2-dimethyl-2-silapentane-5-sulionate (DSS) as the internal standard_7 · The NMR result obtained is shown in Figure 5. The conditions for NMR measurement were as follows:

Spectral range: 4 x 100 filter 0.1 sec

RF power 0.5 mG

sweep time 5 minutes sweep width 10 ppm sweep limit 0 ppm REFERENCE EXAMPLE A 2,500 ml Sakaguchi flask was charged with 100 ml of medium according to the following composition, and a known Stachybotrys chart Arum IFO 5369 species was cultured in medium at 28 ° C for 4 days at pH 6 for 6 days.

Medium composition% glycerol 0.5 starch 1.0 lactose 0.2 soy flour 0.5 yeast extract 0.1 malt extract 0.2

CaCO3 0.3

MgSO 4 0.05 20 liters of medium according to the above composition was placed in a 30 liter fermentation flask, and two flasks of the obtained inoculum were cultured in medium at 28 ° C for five days with stirring at 37,798,445 rpm and 1 liter of aeration per liter of medium per minute. The resulting broth was centrifuged at 8,000 rpm to remove microbial cells. To the supernatant solution was added 5 liters of methanol, and the mixture was stirred and allowed to stand for 3 hours. The mixture was centrifuged and the solid removed. The supernatant was extracted with an equal volume of ethyl acetate. The solvent of the ethyl acetate layer was removed under reduced pressure and concentrated to dryness.

The precipitate was dissolved in methanol and passed through a column of activated carbon. The eluate was concentrated to dryness under reduced pressure, dissolved in a mixture of chloroform and ethyl acetate (1: 1, v / v), and gel filtered through a Sephadex LH-20 column. Fractions with peaks corresponding to the Rf values of the thin layer chromatography described in Example 1 were collected. Evaporation of the solvent gave 2.2 g of (6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro- 21- (6 *, 7'-diformyl-41-hydroxy-21,31-dihydrobenzofuran a), as a pale yellow, slightly acidic substance with anti-complement activity, which had the same physical properties as in Example 1. , and these properties confirmed the formation of this compound.

REFERENCE EXAMPLE 3

Stachybotrys sp, T-789 was cultured and purified in the same manner as described in Example 1, except that the composition of the medium was as follows and the pH was 7.5 and the culture temperature was 32 ° C.

Media composition% glycerol 0.5 glucose 1.2 maize leachate 0.5 dried yeast 0.1 malt extract 0.2

MgSO 4 0.05

NaCl 0.3 There was thus obtained 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 ' - (6 *, 7'-diformyl-4'-hydroxy-2 *, 3'-dihydrobenzofuran), as a pale yellow slightly acidic substance with anti-complement effect. The physicochemical properties of this compound correspond to the values of the compound isolated and purified in Example 1.

38 79345 REFERENCE EXAMPLE 4

Stachybotrys sp. T-791 was cultured and purified in the same manner as in Example 1 except that the composition of the medium was as follows, the pH was 5.5, and the culture temperature used was 25 ° C.

Medium composition glycerol 0.5 starch 1.0 sucrose 0.2 soy flour 0.5 peptone 0.1 malt extract 0.2

Mg 3 O 0.3 HCl 0.05 There was thus obtained 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1 -spiro-2 '- (6', 7 * -diphenyl-4'-hydroxy-2 ', 31-dihydrobenzofuran), as a pale yellow slightly acidic substance with anti-complement effect. The physicochemical properties of this compound correspond to the values of the compound isolated in Example 1.

The following are examples of processes according to the invention for the preparation of compounds of formula (I).

The numbering of the manufacturing examples has followed the numbering extended from the reference examples.

Example 5

Silver nitrate (2.1 g) was dissolved in 1 ml of water, and 39,798,4.5 ml of an aqueous solution of sodium hydroxide having a concentration of 5.8 was added.

The mixture was stirred at room temperature for 20 minutes. 1.0 g of the compound obtained in Example 1, 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro- 2 * - (6 ·, 7'-diformyl-4'-hydroxy-2 ', 3'-dihydrobenzofuran) in 2 ml of ethanol was added to the mixture. The reaction agent was stirred at room temperature for 1.5 hours, and the pH was adjusted to about 2 with 2N hydrochloric acid. The reaction mixture was extracted with the same volume of ethyl acetate, and the solvent of the extract was distilled off under reduced pressure. The precipitate was purified by silica gel column chromatography (silica gel "Wako C-200", product of Wako Junyaku Kabushiki Kaisha, chloroform / ethyl acetate / acetic acid (100: 50: 2 by volume) as eluent). Fraction corresponding to TLC Rf * 0.37 (using a mixture of ethyl acetate, chloroform and acetic acid in a volume ratio of 50: 50: 2 as developing solution) or fraction corresponding to TLC Rf = 0.71 (using developing mixture containing benzene, butanol and acetic acid in a volume ratio of 60: 15: 5) was recovered, and the solvent was evaporated to give 700 mg of 4, N-dihydroxy-6-oxo-2,3,6,8-tetrahydro-furo-3,4- gis-7-benzofuran-2-spiro-1 '- (61,7'-dihydroxy-2', 51,5 ', 8'a-tetramethyl-11,2', 3 ', 4', 4'a, 5 ', 6 ', V, 6', 8 'α-decahydronaphthalene) as pale yellow amorphous crystals. The compound had the following physicochemical properties, and the formation of this compound was confirmed on the basis of these properties.

O) (Cs 0.9, methanol) (2) Elemental analysis values for C23H30 ° 7

Calculated (%): C 66.03 H 7.18

Found (%): C 65.93 H 7.21 (3) Nuclear Magnetic Resonance Spectrum Analysis (NMR) (i) NMR analysis was performed using CD 1 OD (DS 3) as solvent, and the NMR result obtained is shown in Figure 6.

(ii) NMR analysis was performed using pyridine-D 2 (DSS) as solvent, and the obtained NMR result is shown in Fig. 7.

(iii) Dimethyl sulfoxide-d 2 was used as a solvent, and NMR analyzes were performed 2 hours and 63 hours after dissolution. The NMR result obtained is shown in Figure 8 (NMR results at 2 hours and 63 hours after dissolution were similar).

The measurement conditions were as follows when these NKR spectra were obtained.

40 79845

Figure 6 Figure 7 Figure 8

Spectral range 9x100 5x100 8x100

Filter 0.1 sec. 0.1 sec. 0.1 sec.

RE power 0.05 mG 0.05 mG 0.05 mG

Sweep time 5 min 5 min 5 min

Scanning width 10 ppm 10 ppm 10 ppm

Sweep limit 0 0 0

Example 6

Silver oxide (0.64- g) was suspended in 1N aqueous sodium hydroxide solution, and 1 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7 g was added at room temperature. , 8,8a-decahydronaphthalene-1-spiro-2 '- (6 *, 7 * -dimethyl-4'-hydroxy-2', 3'-cihydrobenzofuran) with stirring. The mixture was stirred at the same temperature for 1 hour, and the precipitate was washed with 10 ml of water 5 times. The washings and filtrate were combined and concentrated hydrochloric acid (36) was added to adjust the pH to about 2-3, after which the solution was cooled to 0-10 ° C.

The precipitated crystals were collected by filtration, washed with 10 ml of ice water 5 times and dried. The dried powdery crystals were dissolved in 50 ml of ethyl acetate, and the insoluble matter was separated by filtration. The filtrate was concentrated to a volume of 5 ml under reduced pressure. Concentrate in-tyyr. to the solution was added 50 ml of ligroin, and the mixture was stirred well and cooled to 0-10 ° C. The precipitated crystals were collected by filtration, washed twice with 20 ml of ligroin, and dried to give 1.01 g of 4,8-dihydroxy-6-oxo-2,3,6,8-tetrahydrofuro [3,4-g] 'oenzofuran-2-spiro-1' - (6 ', 7, -dihydroxy-2', 5 ', 6', 8'a-tetramethyl-1 ', 2 *, 3', 4 · *, 4'a , 5 *, 6 *, 7 ', 8', 8 'α-decahydronaphthalene).

The physicochemical properties of this compound were in agreement with those of Example 5.

Example 7 1.0 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahyaronaphthalene-1-spiro-2 ( 6 *, 7 * -diformyl-4'-hydroxy-2 ', 3'-dihydroenzofuran) was dissolved in 50 ml of 10% aqueous sodium hydroxide solution, and the solution was stirred by letting air bubble through the solution at 50 ° C for 30 minutes. The solution was acidified with hydrochloric acid to a pH of about 2-3, and the precipitated crystals were collected by filtration. The crystals were washed in 10 ml of cold water 10 times and dried. The crystals were dissolved in 50 ml of ethyl acetate, and the insoluble matter was separated by filtration. The filtrate was treated with activated carbon, and concentrated to a volume of 5 ml under reduced pressure. To the concentrated solution was added 50 ml of naphtha with vigorous stirring. The precipitated crystals were collected by filtration, washed with naphtha and dried to give 0.72 g of 4,8-dihydroxy-6-oxo-2,3,6,8-79845 41 tetrahydrofuro [3,4-g] 7-benzofuran-2 -spiro-1 '- (6', 7'-dihydroxy-2 ^ 5 ^ 5 ^ 81 a-tetraraethyl-1 ^ 2 ^ 3 ^ 4 ^ 4 ^, 5 ^ 6 ^ 7 ^ 8 ^ 81 α-decahydro- naphthalene). The physicochemical properties of this compound were in agreement with those of Example 5.

Example 8 1.0 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,4,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- (6 ', 7'-Dimethyl-41-hydroxy-2', 3'-dihydrohenzofuran) was dissolved in 25 ml of 1N aqueous potassium hydroxide solution, and 50 ml of an aqueous solution containing 0.578 g of potassium permanganate was gradually added with stirring. When the color of the potassium permanganate disappeared, stirring was stopped. The precipitate was removed by filtration using celite as a filter aid. The filtrate was acidified with hydrochloric acid to a pH of about 2-3. The precipitated crystals were collected by filtration, washed three times with 10 ml of water and then dried. The dried crystals were dissolved in 30 ml of ethyl acetate. The insoluble matter was separated by filtration, and the filtrate was decolorized with activated carbon and concentrated under reduced pressure. To the concentrated solution was added 50 ml of naphtha, and the mixture was stirred. The precipitated crystals were collected by filtration, washed with naphtha and dried at 60 ° C under reduced pressure to give 0.9 g of 4β-dihydroxy-6-oxo-2,3,6,8-tetrahydrofuro [3,4-g] benzofuran. -2-spiro-1 '- (6', 7 * -dihydroxy-2 ', 5', 5 ', 8'a-tetramethyl-11,2', 3 ', 4', 4 'a, 5', 6 ', 7', 8 ', 8'a-decahydronaphthalene). The physicochemical properties of this compound agree with those of the compound obtained in Example 5.

Example 9 418 mg of 4,6-dihydroxy-6-oxo-2,3,6,8-tetrahydro-furo [3,4-g] -7-benzofuran-2-spiro-1 '- (6', 7, -dihydroxy -2 ', 5' (51,8'a-tetramethyl-1 ', 2', 3 ', 4', 4'a, 5 ', 6', 7 ', 8', 8 * α-decahydronaphthalene) was added 5 to 1 ml of a 0.4N aqueous solution of sodium hydroxide and to 5 ml of ethanol. The mixture was stirred under a stream of nitrogen at 30-40 ° C for 30 minutes.

After the reaction, the solvent was distilled off under reduced pressure. The precipitate was dried, and 10 ml of acetone was added. The acetone-soluble portion was removed by filtration. The remaining crude crystals were recrystallized from water / acetone solution by adding dropwise acetone to the aqueous solution until crystals precipitated to give disodium 6,7-dihydroxy-2,5,5,8a-tetranethyl-1,2,3,4, 4α, 5,6,7,8,8a-Decahydronaphthalene-1-spiro-2 '- (e'-carboxylate-β'-formyl-β-oxides *, 3β-dihydrobenzofuran) 342 g, as pale yellow amorphous crystals. This compound had the following physicochemical properties, and the formation of this compound was confirmed on the basis of these properties.

42 79345 0) r * jl ° = -44.2 ° (C = 1.25, H 2 O) (2) Elemental analysis values for C 2 H 2 SO 2 Na 2

Calculated ($ 6): C 59 * 74 H 6.10

Found (> ό) * C 59.48 H 5.91 (5) Ultraviolet absorption spectral analysis (UV)

HpO = 252 nm (C = 20500) λ max = 330 nm (U 45900) (4) Nuclear Magnetic Resonance Spectrum Analysis (NMR) NMR analysis was performed using L 2 O (DSS) as solvent.

The NHR result obtained is shown in Figure 9. The NKR measurement conditions were as follows:

Spectral width 9 x 100

Filter 0.1 sec.

RP power 0.05 mG

Sweep time 5 min

Scanning width 10 ppm

Sweep limit 0 ppm

Example 10 418 mg of 4,8-dihydroxy-6-oxo-2,3,6,8-tetrahydro-furo-3,4-g-7-benzofuran-2-spiro-1 '- (6 *, 71-dihydroxy- 2 ', 5 *, 5', 8 • α-tetranethyl-1 ', 2', 3 ', 4', 4'a, 5 ', 6', 7 ', 8', 6'a-decahydronaphthalene) were dissolved To 10 ml of ethyl acetate, and with stirring, 0.33 mol of sodium hydroxide as a 6N aqueous solution was added thereto. The mixture was stirred under a stream of nitrogen at room temperature for 10 minutes. The precipitated crystals were collected by filtration, washed three times with ethyl acetate and dried. There was thus obtained 390 mg of disodium 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8a-decahydronaphthalene-1-spiro-21 - ( ξ * -carboxylate-7'-formyl-4'-oxide (4 ', 3'-dihydrobenzofuran) as pale yellow amorphous crystals. The physicochemical properties of this compound are the same as those of the compound obtained in Example 9.

Example 11 4.02 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro 2 * - (6 *, 71-difformyl-4 * -hydroxy-2 *, 3 * - * dihydrobenzofuran) was dissolved in 1N aqueous sodium hydroxide solution, and 14.2 g of a 3 # aqueous solution of hydrogen peroxide was added. The mixture was stirred at 50 ° C for 18 hours. Acetic acid was then added to bring the pH to 3-4. The precipitated crystals were collected by filtration, washed with water and dried.

79845 43 The crude crystals thus obtained were chromatographed on a column of silica gel using a mixture of chloroform and methanol (9: 1 by volume) as eluent. The resulting eluate was collected and concentrated to dryness under reduced pressure. Water was added to the precipitate, and the formed crystals were collected by filtration, after which they were washed with water and dried. There was thus obtained 0.80 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 ' - (4 ', 6', 7, -trihydroxy-2 ', 3'-dihydrobenzofuran) as brown amorphous crystals. When the melting point of this compound was measured, it was found that it gradually decomposed at a temperature of about 250 ° C. This compound had the following physicochemical properties, and the formation of this compound was confirmed on the basis of these properties.

(1) Melting point: Gradual decomposition at about 250 ° C, no actual melting point was observed.

(2) Elemental analysis values for C21H30 ° 6

Calculated (i): C 66.64 H 7.99

Found (td): C 66.43 H 8.13 (3) Ultraviolet absorption spectral analysis (UV) methanol = 219 nm (i * 8700) λ max * 260 nm (i »2300) (4) Infrared absorption spectral analysis (IR) Ä 1

The compound had the following ^ („(cm ') values when using the KBr max tablet method.

350 (b), 2980 (s), 2980 (sh), 1640 (m), 1480 (m), H00 (w), 1330 (w), 1260 (W), 1220 (w), 1140 (w), 1120 (w), 1060 (w), 1010 (w), 910 (w), 890 (w), 760 (w).

(s means strong absorption; m medium absorption; w weak absorption, and sh shoulder. These abbreviations have the same meaning below).

Example 12 2.01 g of 6,7-dihydroxy-2,5,5,8a, tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 ' - (6 ', 7'-diformyl-4'-hydroxy-21,3 * -dihydrobenzofuran) was dissolved in 50 ml of ethanol and 1.45 g of malonitrile and a drop of piperidine was added as a catalyst.

The mixture was stirred at 50 ° C for 30 minutes. After the reaction, the reaction mixture was concentrated to a volume of 10 ml under reduced pressure, and allowed to cool. The precipitated crystals were collected by filtration, and washed with ice-cold ethanol. The obtained crude crystals were dissolved in 50 ml of 1N aqueous sodium hydroxide solution and treated with activated carbon. Using ice-cooling, hydrochloric acid 44 79845 was added to change the pH of the solution to 2-3. The precipitated crystals were collected by filtration, washed thoroughly with water, and dried. There was thus obtained 1.02 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-s-pyro-2 '- [? 6', 7'-di (2,2-dicyanovinyl) -4 * -hydroxy-2 ', 3'-dihydrobenzofuran_7 as yellow amorphous crystals. The formation of this compound was confirmed by the following physicochemical properties.

(1) Melting point: Gradual decomposition at about 230 ° C and no actual melting point was observed.

(2) Elemental analysis values for C29H3044N4

Calculated (ft): C 69.86 H 6.07 N 11.24

Found (#): C 69.58 H 6.32 N 11.09 (3) Infrared absorption spectral analysis (IR)

The compound had the following values when using the KBr max tablet method: 3450 (s), 2980 (s), 2900 (s), 2210 (s), 1720 (w), 1660 (s), 1640 (s), 1580 (s) ), 1520 (w), 1470 (m), 1400 (m), 1380 (m), 1360 (m), 1340 (m), 1260 (m), 1200 (w), 1110 (w), 1050 (m ), 1020 (w), 1000 (w), 980 (w), 960 (w), 940 (w), 900 (w), 840 (w), 760 (w).

Example 13 2.01 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- (61,7 * -diformyl-4 * -hydroxy-21,3'-dihydrobenzofuran) was dissolved in 50 ml of ethanol, and 3 ml of ethyl cyanoacetate was added. In addition, three drops of piperidine were added as a catalyst, and the mixture was stirred at 60 ° C for 2 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The precipitate was washed with a small amount of dilute hydrochloric acid (IN), then with water and dried to form crude crystals. The crude crystals were dissolved in 50 ml of a methanol-water mixture (1: 1 by volume), and treated with activated carbon. The same volume of water was added to precipitate crystals. The crystals were collected by filtration, washed with water and dried. There was thus obtained 1.89 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydro-naphthalene-1-spiro- 21- [61,71-di- (2-cyano-2-ethoxycarbonylvinyl) -4'-hydroxy-2 ', 3'-dihydrobenzofuran] as pale amorphous crystals. The formation of this compound was confirmed by the following physico-cerebral properties.

(1) Melting point: 161.0-167.0 ° C

45 79845 (2) Elemental analysis values for C35H4008N2

Calculated (%): C 66.87 H 6.80 K 4.73

Found (%): C 66.63, H 7.02 N 4.51 (3) Infrared absorption spectral analysis (IR)

The compound had the following (c® "1) values when using the KBr tablet method: 3450 (s), 2970 (sh), 2950 (m), 2900 (sh), 2240 (w), 1740 (s), 1630 (s). ), 1470 (e), 1460 (sh), 1400 (w), 1300 (w), 1250 (e), 1100 (m), 1050 (m), 1030 (h), 1020 (sh), 970 (w) ), 950 (sh), 940 (w), 900 (sh), 890 (w), 860 (w).

Example 14 3.00 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6f7, S, 8a-decahydronaphthalene-1-spiro-2 '- ( 61,7 * -Diphornyl-4'-hydroxy-2f, 3'-dihydrobenzofuran) was dissolved in 20 nl of pyridine, and 10 g of cyanoacetic acid and a drop of piperidine were added as a catalyst. The mixture was stirred for 5 hours at 50 ° C. After the reaction, the reaction mixture was concentrated to dryness. 50 ml of water was added to the precipitate to obtain crystals from the precipitate. The crystals were collected by filtration, washed with water, then with dilute hydrochloric acid (11!) And again with water. The crude crystals were dissolved in 100 ml of a 10 'aqueous solution of sodium bicarbonate. The insoluble matter was separated by filtration, and the ice-cooled filtrate was acidified to pH 2-3 with hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to give 1.1 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6, 7,8,8a-Decahydronaphthalene-1-spiro-2 '- (6', 6,7-di- (2-cyano-2-carboxyvinyl) -4'-hydroxy-2 ', 3'-dihydrobenzofuran_7 as pale yellow amorphous crystals. The formation of this compound was confirmed by the following physicochemical properties.

(1) Melting point: 217-223 ° C

(2) 1 \ μl * -23.2 ° (C »0.8, methanol) (3) Elemental analysis values for G29H32N2 ° 8

Calculated ($ *): C 64.91 H 6.01 N 5.22

Found (#): C 64.63 H 6.23 N 5.01 46 79345 (4) Infrared absorption spectral analysis (IR)

The compound had the following values when using the Or t ab1et t method: 3450 (s), 2950 (m), 28? 0 (sh), 2240 (w), 1710 (a), 1660 (h), 1610 (a) , 1580 (h), 1460 (h), 1440 (h), 1400 (h), 1300 (h), 1250 (h), 1200 (sh), 1120 (w), 1100 (w), 1040 (w) .880 (w).

Example 15 1.0 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- ( 6 ', 7'-diformyl-4'-hydroxy-2', 3'-dihydrobenzofuran) was dissolved in 10 ml of pyridine, and 1.0 g of malonic acid and 3 drops of piperidine as catalyst were added. The mixture was heated to reflux for 4 hours. After the reaction, 200 ml of water was added to the reaction mixture, and the mixture was acidified to pH 2-3 with hydrochloric acid and allowed to cool. The precipitated tar was collected, washed with water, dissolved in 100 ml of methanol, treated with activated carbon, and concentrated to dryness under reduced pressure. The precipitate was recrystallized from a mixture of methanol and water (1: 1 by volume) to give 0.58 g of 6,7-dihydroxy-2,5,5,8a-tetrane-1,2,3,4,4a, 5,6,7,8,8a-Decahydronaphthalene-1-spiro-2'-C6 ', 7 * -di- (2-carboxyvinyl) -4'-hydroxy-2', 31-dihydrobenzofuran as light brown amorphous crystals. The formation of this compound was confirmed by the following physicochemical properties.

(1) Melting point: 190-196 ° C

(2) Elemental analysis values for C27H34 ° 8

Calculated (%): C 66.65 H 7.04

Found (^): c 66.36 H 7.31 (3) Infrared absorption spectral analysis (IR) Λ

The compound had the following values when using the KBr tablet method: 3450 (s), 2970 (m), 2950 (m), 2890 (sh), 1690 (e), 1620 (s), 1470 (a), 1390 (a) , 1350 (h), 1330 (h), 1290 (w), 1260 (h), 1200 (w), 1120 (w), 1070 (w), 1050 (h), 960 (w), 950 (h) .

Example 16 1.0 g of sodium borohydride was dissolved in 20 ml of 0.1 N aqueous sodium hydroxide solution. 0.9 g of 4,6-dihydroxy-6-oxo-2,3,6,8-tetrahydro-furo [3,4-g] benzofuran-2-spiro-1 - ((6 ·, 7'-dihydroxy) ', 5', 5 ', 8'a-tetramethyl-1', 2 ', 3', 4 ', 4 * a, 5', 6 ·, 7 ', 8', 8'a-decahydronaphthalene) 47 79845 was added in 10 ml of 1% aqueous sodium hydroxide solution. The mixture was stirred at 60 ° C for 18 hours, cooled on ice to about 2-5 ° C, and acidified with hydrochloric acid (1N). The solution was concentrated to dryness under reduced pressure, and the precipitate was dissolved in 50 ml of ethyl acetate. The insoluble matter was separated by filtration. The filtrate was washed with water, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the precipitate was concentrated to dryness under reduced pressure. The precipitate was recrystallized from 10 ml of a methanol-water mixture (1: 1 by volume) to give 0.28 g of 6,7-cHydroxy-2,5,5,8a-tetramethyl-1,2,3,4, 4a, 5 , 6,7,8,8a-decahydronaphthalene-1-spiro-2 '- (6'-carboxy-7'-hydroxymethyl-4'-hydroxy-2', 5'-dihydrohenzofuran) as colorless amorphous crystals. The formation of this compound was confirmed by the following physicochemical properties.

(1) Melting point: 212-216 ° C

(2) Elemental analysis values for G23 ^ 32 ^ 7

Calculated (%): C 65.71 H 7.62

Found (%): C 65.74 H 7.47 (3) Infrared Absorption Spectrum Analysis (IR)

The compound had the following ^ (cm -1) values when using the KBr max tablet method.

3450 (s), 2950 (sh), 2920 (m), 2900 (sh), 1740 (s), 1620 (m), 1475U), 1400 (w), 1360 (w), 1340 (m), 1260 ( w), 1140 (w), 1080 (a), 1050 (w), 1030 (w), 960 (sh), 950 (m), 780 (w).

Example 17 4.02 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2, - (6 ', 7, -diformyl-4, -hydroxy-2 ·, 3' 'dihydrohenzofuran) was dissolved in 100 ml of benzene by heating (to a temperature of about 60-70 ° C). Then 10 ml of diethyl malonate and a drop of piperidine as catalyst were added. Water was removed by azeotropic distillation. Distillation was continued for 4 hours, and after almost the theoretical amount of water had been removed, the mixture was concentrated under reduced pressure. The residual tar was washed with diethyl ether, and the ether-insoluble matter was collected by filtration, dried and recrystallized from diethyl ether-water (1: 2 by volume). There was thus obtained 1.32 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro- 21- [6 ', 7'-di- (2,2-diethoxycarbonylvinyl) -4'-hydroxy-2', 3'-dihydrohenzofuran] as colorless, amorphous crystals. The formation of this 46,79345 compound was confirmed by the following physicochemical properties.

(1) Melting point: 138-142 ° C

(2) C ^ H ^ qO · ^ * 11 a-^ substance as a 1-y value

Calculated (96): C 64.70 H 7.34

Found (96); C 64.43 H 7.59 (3) Infrared absorption spectral analysis (IR)

The compound had the following values when using the KBr tablet method.

3450 (a), 2980 (sh), 2900 (s), 2880 (sh), 1730 (s), 1680 (m), 1630 (sh), 1600 (s), 1470 (m), H40 (m), 1400 (m), 1320 (m), 1250 (s), 1120 (w), 1100 (w), 1080 (w), 1050 (w), 1020 (w), 970 (w), 950 (w), 890 (w), 7b0 (m).

Example 18 1.0 g of sodium borohydride was dissolved in 50 ml of 1N aqueous sodium hydroxide solution, and 4.02 g of 6,7-dihydroxy-2,5,5,8a-tetranethyl-1,2,3,4,4a, 5.6 g were added at room temperature. , 7,8,8a-decahydronaphthalene-1-spiro-21- (6 *, 7'-diformyl-41-hydroxy-2 ', 3'-dihydrobenzofuran; dissolved in 20 ml of 1N aqueous sodium hydroxide solution, stirred for 3 hours. After the reaction, the reaction mixture was acidified with hydrochloric acid to pH 2 to 3 under ice-cooling (about 2 to 5 ° C), and the precipitated crystals were collected by filtration, washed with water and dried, and the crude crystals were recrystallized from 50 ml. methanol-water (1: 5 by volume) to give 2.51 g of 6,7-dihydroxy-2,5,5,8a-tetracetyl-1,2,3,4,4a, 5,6,7,8, 3α-Decahydronaphthalene-1-spiro-2β (6β, 7'-dihydroxymethyl-4'-hydroxy-2 ', 3'-dihydro-benzofuran) as light brown, amorphous crystals. .

(1) Melting point: Gradual decomposition at about 270 ° G, and no actual melting point was observed.

(2) ^ 23 ^ 34 ^ 6 ^ elemental analysis values

Calculated (96); C 67.95 H 8.43

Found (96); C 67.71 H 8.66 (3) Infrared absorption spectral analysis (IR)

The compound had the following Ό (cm ”1) values using the KBr cix tablet method.

49 79845 3450 (s), 2920 (m), 2880 (m), 1620 (m), 1600 (sh), 1440 (ra), 1390 (w), 1320 (w), 1260 (m), 1200 (w ), 1100 (in) f 1040 (w), 1000 (w), 980 (w), 940 (w), 830 (w).

Example 19 1.00 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- ( 6 ·, 7'-Dihydroxymethyl-4'-hydroxy-2 ·, 31-dihydrobenzofuran) was dissolved in 50 methanol. The solution was added dropwise to any freshly prepared diethyl ether solution containing 1.0 g of diazomethane via addition funnel at room temperature. The mixture was stirred at room temperature for 2 hours, then cooled with ice (2 to 5 ° C). Hydrogen chloride gas was bubbled into the mixture to decompose the excess diazomethane. 100 ml of water were then added and the mixture was concentrated to dryness under reduced pressure. To the residue was added 10 ml of 0.1N aqueous sodium hydroxide solution, and the insoluble matter was collected by filtration and dried. There was thus obtained 0.87 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydro-naphthalene-1-spiro- 2 '- (6', 7'-dihydroxymethyl-4'-methoxy-2 ', 3 dihydrobenzofuran) as colorless amorphous crystals. The formation of this compound was confirmed by the following physicochemical properties.

(1) Melting point: 107. *. 115 ° C

(2) Elemental analysis values for C24H36 ^ 6

Calculated (%): C 68.54 H 8.63

Found (#): C 68.31 H 8.90 (3) Infrared Absorption Spectrum Analysis (IR)

The compound had the following? Nax (C? D ”^) values using KBr table 11 et seq · 3320 (s), 2920 (m), 2880 (m), 1720 (w), 1620 (m), 1600 (s ), 1500 (sh), 1450 (m), 1420 (m), 1390 (w), 1320 (m), 1230 (m), 1200 (w), 1120 (s), 1040 (m), 1000 (m ), 940 (w), 820 (w).

Example 20 2.0 g of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- (6 · -Carboxy-7'-hydroxymethyl-4'-hydroxy-2 ', 3'-dihydrobenzofuran) was dissolved in 50 ml of ethyl acetate, and 10 mg of p-toluenesulfonic acid was added to the solution.

The mixture was boiled using reflux. After completion of the reaction, the mixture was cooled to room temperature, washed with 10 ml of 1N aqueous sodium hydroxide solution, thoroughly with water and dried over anhydrous sodium sulfate. Sodium sulfate was filtered off, and the residue was distilled to dryness under reduced pressure. There was thus obtained 1.45 g of 4-hydroxy-6-oxo-2,3,6,8-tetrahydrofuro [3,4-g] benzofuran-2-spiro-1 '- (6 *, 7'-dihydroxy-2 *, 5 ', 5', 8'a-tetramethyl-1 ', 2', 3 ', 4', 4'a-5 ', 6', 7 ', 8', 8 * α-decahydronaphthalene) as colorless amorphous crystals. The preparation of this compound was confirmed based on the following physicochemical properties.

(1) Melting point: 187-193 ° C

(2) Characteristic analytical values of C 2 H 2 O 2 g

Calculated (%): C 68.63 H 7.51

Found {%) C 68.47 H 7.70 (3) Infrared absorption spectral analysis (IR)

The compound had the following 0 (cm -1) values when K3r was used

m SIX

Number of tablets: 3280 (s), 2950 (m), 2890 (m), 1730 (s), 1610 (m), H60 (s), 1330 (s), 1240 (w), 1130 (w), 1080 (m ), 1040 (w), 1000 (w), 940 (m), 750 (m).

Example 21 100 mg of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 '- ( 61,7'-Dihydroxymethyl-4'-hydroxy-2 *, 3'-dihydrobenzofuran) was dissolved in 2 ml of dry pyridine and 1 ml of acetic anhydride was added. The mixture was allowed to stand overnight at room temperature. Ice water was added to the reaction mixture. The precipitate was collected by filtration, and ethyl acetates were recrystallized from n-hexane, whereupon n-hexane was added portionwise to the ethyl acetate solution until crystals precipitated. There was thus obtained 105 mg of 7-acetyloxy-6-hydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-21- (61,7'-diacetyloxymethyl-4, -acetyloxy-2 ', 3'-dihydrobenzofuran) as white crystals.

The formation of this compound was confirmed by the following physicochemical properties:

(1) Melting point: 78-83 ° C

(2) Specific analytical values for C 31 H 42 ° 10

Calculated (%): C 64.79 H 7.37

Found (%): C 64.51 H 7.19 (3) Infrared absorption spectral analysis (IR)

The compound had the following? Raax (cnf ^) values using the KBr tablet method: 5i 79845 3430 (w), 2900 (m), 2860 (sh), 1763 (sh), 1730 (b), 1715 (sh), 1620 ( m), 1600 (m), H65 (sh), 1447 (sh), H30 (s), 1378 (sh), 1364 (s), 1302 (m), 1250 (sh), 1220 (e), 1195 ( s), 1160 (sh), 1126 (m), 1096 (b), 1020 (b), 1000 (sh), 980 (m), 950 (m), 915 (sh), 895 (sh), 865 (sh) sh), 830 (sh), 810 (sh), 763 (w), 690 (sh), 592 (w).

Example 22 100 mg of 6,7-dihydroxy, 2,5,5,8a, tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2'- ( 6 ', 7 * -dihydroxymethyl-4 * -hydroxy-2 *, 3'-dihydrohydrofuran) was dissolved in 2 ml of dry pyridine and 1 ml of acetic anhydride was added. The mixture was heated to 100 ° C for 2 hours. Ice water was added to the reaction mixture. The precipitated precipitate was collected by filtration, and recrystallized from a mixture of ethyl acetate and n-hexane, whereby n-hexane was added portionwise to the ethyl acetate solution until crystals precipitated. There was thus obtained 115 mg of 6,7-diacetyloxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 - ( 6 (71'acetyl oxymethyl-4'-acetyloxy-2 ·, 3'-dihydrobenzofuran) as white crystals.

The formation of this compound was confirmed by the following physicochemical properties.

(1) Melting point: 76-80 ° C

(2) Eigenvalue analysis values of 0., -,

Estimated (c / o): G 64.27 H 7.19

Found (c / o): C 64.12 H 7.03 (3) Infrared absorption spectral analysis (IR)

The compound had the following νΏ3χ (οιη) values when using the KBr tablet method: 2920 (m), 2880 (sh), 1760 (sh), 1750 (sh), 1730 (e), 1624 (sh), 1603 (m), 1473 (sh), 1457 (sh), 1447 (sh), 1428 (s), 1376 (sh), 1363 (b), 1300 (s), 1260 (sh), 1220 (s), 1195 (b), 1150 (sh), 112p (w), 1095 (b), 1035 (sh), 1020 (s), 980 (sh), 953 (s), 915 (no), 895 (sh), 870 (sh), 820 (w), 765 (w), 715 (w), 686 (w), 657 (w), 618 (ah), 596 (m), 583 (m).

Example 23 100 mg of 7-acetyl-6-hydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 * - (6 *, 7'-diacetyloxymethyl-4'-acetyloxy-2 ', 5'-dihydrobenzofuran) was dissolved in 5 ml of acetone, and 0.1 ml of Jones reagent was added dropwise thereto under ice-cooling. The mixture was stirred for 1 hour. Isopropanol was added dropwise to the reaction mixture to decompose excess Jones reagent.

52 79345

Ice water was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off. The precipitate was recrystallized from a mixture of acetone and n-hexane so that n-hexane was added portionwise to the acetone solution until crystals precipitated. There was thus obtained 72 mg of 7-acetyloxy-6-oxo-2,5,5,8a-tetrarcetyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 ' - (61,7'-diacetyloxymethyl-4'-acetyloxy-2 ', 3'-dihydrobenzofuran) as white crystals. The preparation of this compound was confirmed based on the following physicochemical properties.

(1) Melting point: 140-143 ° C. j (2) Characteristic adysis values of C ^ H ^ QO-jgin

Estimated (ft): C 65.02 H 7.04

Found (ft): C 65, H H 7.13 (3) Infrared absorption spectral analysis (IR)

The compound had the following ^ _ev (cm -1) values when KBr max t ab le 11 imeiEt e Imaa 2900 (m), 2880 (sh), 1766 (sh), 1750 (s), 1720 (s), 1628 (m ), 1600 (m), 1456 (s), 1427 (a), 1380 (sh), 1363 (a), 1340 (sh), 1300 (s), I265 (ah), 1220 (s), 1185 (s) ), 1120 (m), 1083 (a), 1070 (sh), 1030 (e), 1013 (sh), 1000 (sh), 970 (m), 950 (s), 936 (sh), 926 (sh) ), 905 (a), 895 (a), 870 (m), 854 (sh), 827 (w), 780 (w), 766 (w), 738 (w), 712 (w), 666 (w ), 610 (w), 588 (w).

Example 24 100 mg of 4-hydroxy-6-oxo-2,3,6,8-tetrahydrofuro [3,4-g] benzofuran-2-spiro-1 '- (6', 7, -dihydroxy-2 ', 5 ', 5', 8'a-tetramethyl-1 ', 2', 3 ', 4', 4'a, 5 ', 6', 71,8 '(e'a-decahydronaphthalene) were dissolved in 2 ml dry acetone, and 1 ml of 2,2-dimethoxypropane was added followed by 5 mg of anhydrous p-toluenesulfonic acid. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with water. The solvent was evaporated, and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 83 mg of 4-hydroxy-6-oxo-2,3,6,8-tetrahydrofuro [3,4-g] benzofuran-2-spiro-1'- (6 *, 7'-isopropylidenedioxy-2 ', 5', 5 ', 8'a-tetramethyl-1', 2 ', 3', 4 ', 4 *, 5', 6 ', 7', 8 *, 8'a-decahydronaphthalene) as white crystals. The formation of this compound was confirmed by the following physicochemical properties.

(1) Melting point: 142-150 ° C

53 79845 (2) Characteristic analytical values for C26H33 ° 6

Estimated (56): C 70.73 H 7.33

Found (%): C 70.51 H 7.38 (3) Infrared Absorption Spectrum Analysis (IR)

The compound had the following? Raax (cm ”) values using the KBr tablet method: 3280 (w), 2920 (m), 2880 (sh), 1760 (sh), 1733 (a), 1620 (sh), 1608 (m) , H63 (s), 1387 (sh), 1368 (m), 1354 (s), 1330 (s), 1300 (sh), I255 (sh), 1238 (m), 1216 (a), 1178 (w) (1153 (w), 1124 (w), 1106 (w), 1080 (m), 1060 (m), 1043 (a), 1016 (m), 1005 (ah), 985 (sh), 950 (m)) , 923 (w), 895 (w), 870 (sh), 858 (m), 784 (sh), 768 (sh), 753 (m).

Example 25 100 mg of 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2'- ( 6 ', 7'-Dihydroxymethyl-41-hydroxy-2', 3'-dihydrobenzofuran) was dissolved in 2% of dry acetone and 1 ml of 2,2-dimethoxypropane and 5 mg of anhydrous p-toluenesulfonic acid were added. The mixture was stirred at room temperature for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and then with water, and the solvent was distilled off. The residue was purified by silica gel column chromatography and re-extracted from a mixture of ethyl acetate and n-hexane by adding n-hexane portionwise to the ethyl acetate solution until crystals precipitated. There was thus obtained 21 mg of 6,7-isopropylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2 * - (6 ', 7'-dihydroxymethyl-41-hydroxy-2', 3'-dihydrobenzofuran) as white crystals. The preparation of this compound was confirmed based on the following physicochemical properties.

(1) Melting point: Gradual decomposition at a temperature of about 200 ° C, at which point the compound became colored, and no actual melting point was observed.

(2) Assay values for C26H38 ^ 6

Estimated (> o): C 69.93 H 8.58

Found (5i): C 69.71, H 8.39 (3) Infrared absorption spectral analysis (I)

The compound had the following max (cm-1) pounds using the KBr tablet method: 54,798,445,360 (m), 304O (m), 2920 (m), 2880 (sh), 1735 (w), 1700 (w), 1618 (m), H58 (sh), 1440 (s), 1386 (sh), 1368 (e), 1346 (m), 1313 (m), 1253 (®) »1237 (m), 1215 (d), 1180 (w), 1150 (w), 1106 (s), 1083 (m), 1052 (sh), 1047 (a), 1026 (d), 1000 (s), 974 (a), 952 (d), 920 (w), 895 (w), 870 (sh), 857 (m). 837 (m), 785 (w), 765 (sh), 700 (w), 670 (w).

Example 26 100 mg of 4-hydroxy-6 · oxo-2,3,6,8-tetrahydrofuro [3,4-g] -7-benzo [uranium-2-spiro-1 * - (6 ', 7, -isopropylideneoxy) 2 ', 5', 5 ', 8'a-tetramethyl-1 ^ 2 ^ 3 ^ 4 ^ 4 ^, 5 ^ 6 ^ 7 ^ 81,8'a-decahydronaphthalene) was dissolved in 5 lanes of dry diethyl ether, and on ice under cooling, 5 mg of lithium aluminum hydride was added. The mixture was stirred for 1 hour. Ice water was added to the reaction mixture, and the solution was weakly acidified (pH 3 ··· 5) with 1K hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off. The residue was recrystallized from a mixture of ethyl acetate and n-hexane by adding n-hexane portionwise to the ethyl acetate solution until crystals precipitated. There was thus obtained 75 mg of 6,7-isopropylidenedioxy-2,5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydronaphthalene-1-spiro-2'- (61,71-dihydroxymethyl-4'-hydroxy-2 ', 3'-dihydrohentofuran) as white crystals. The physicochemical properties of this compound are the same as those of the compound obtained in Example 25.

Il

Claims (2)

1. Menetelmä uusien pharmacologistesti activist sesquiterpeeni-johdarinaist or 2,5,5 / 8a-tetramethyl-1,2,3,4,4a, 5,6,7,8,8a-de-cahydronaphthalene-1-spiro-2 ' - (2 ', 3'-dihydrobentsofuraani) -johdannaisten valmistamiseksi, joiden kaava on JUXj ___o (I) R, t CH3 CH3 l secäiden yes R3, jotka voivat olla samat tai erilaiset tarkoittavat formyyli-, hydroxymethyl-, hydroxyyl-, carboxyyl-, alempaa alkanoyylioksimethylyliryhmää, tai kaavan -CH = CR? R® mukaista ryhmää, jossa R? yes R®, jotka voivat olla samat tai erilaiset, tarkoittavat vatyatomia, syano-, alempaa alkoksicarbonyyli-, tai carboxyylyliryhmää, tai R2 yes R3 voivat yhdessä muodostaa kaavan R9 0 t H -CH-OC- mukaisen ,, R4, R6, jotka voivat olla samat tai erilaiset, tarkoittavat hydroxyyliryhmää tai alempaa alkanoyyli-oksiryhmää, R5 tarkoittaa vetyatomia, R4 ja R5 voivat yhdessä muodostaa oksoryhmän (= 0) a) kaavan (Ia) 56 79845 ho - ^^^ - cho - / Ύ ~ (Ia) /0 / V ^ ch3 6h3 mucaine 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3 , 4,4a, 5,6, -7,8,8a-decahydronaphthalene-1-spiro-2 '- (6', 7'-diformyyl-4'-hydroxy-2 ', 3'-dihydrobentsofurani) hapethane yleiskaavan (I) mukaiseksi yhdisteeksi (IB), jossa R2, R2 tai molemmat tarkoittavat carboxyyliryhmää, ja kaikki muut symbolit tarkoittavat same kuin noble on merit tti, tai b) kaavan (Ia) tai kaavan (IB) muka inen yhdiste taikka kaavan (ID) mukainen yhdiste, jossa R2 and R2 yhdessä muodostavat kaavan R9 0 / Il -CH-OC- mukaisen lactonirenkaan, jossa R9 IC) mukaiseksi yhdisteeksi, jossa R2, R2 tai molemmat tarkoittavat hydroxy-methyliryhmää ja kaikki muut symbolit tarkoittavat samea kuin edellä on määritetty, tai c) kaavan (IC) mukainen yhdiste, jossa toinen ryhmistä muut symbolit tarkoittavat samea kuin edellä on määritetty, cyclicisoidaan veden erottumisella kaavan (ID) mukaiseksi yhdisteeksi, jossa R2 yes R2 yhdessä muodostavat kaavan R9 0 t H -CH-OC- mukaisen lactonirenkaan, jossa R9 tarka d) kaavan (Ia) mukainen yhdiste dehydrocondensoidaan yleis a caravan (II). R7 H2C ^^ (II) mukaisen activivisen metyleeniyhdisteen kanssa, jossa R? yes tarkoittavat same kuin noble on meritetty, catalysatorin readnäessless kaavan (IE) mukaiseksi yhdisteeksi, jossa R2, R3 tai molemmat tarkoittavat kaavan -CH = CR ^ R® mukaista ryhmää ja kaikki muut symboli tarkoittavat kaai Ia) mukainen yhdiste saatetaan reagoimaan peroxidin kanssa inertissä liuottimessa kaavan (IF) mukaiseksi yhdisteeksi, jossa R2, R3 tai molemmat tarkoittavat hydroksyyliryhmää ja kaikki 'muut symbolit tarkoittavat samea kuin yhdiste asyloidaan kaavan (IG) mukaiseksi yhdisteeksi, jossa R ), (IF) tai (IG) mukainen yhdiste, jossa R1 tarkoittaa vetyatomia ja kaikki muut symbolit tarkoittavat samea kuin nobelä on määritetty, haluttaessa alkyloidaan vastaavaksi kaavan (I) mukaiseksi yhdisteeks i, jossa R1 tarkoittaa alempaa alkyyliryhmää, tai h) kaavan (Ia), (IB), (IC), (ID), (IE), (IF) tai (IG) mukainen yhdiste, jossa R * tarkoittaa vetyatomia ja kaikki muut symbolit tarkoittavat samaa kuin edellä on määritetty, haluttaessa asyloidaan vastaavaksi kaavan (I) mukaiseksi yhdisteeksi, jossa R1 tarkoittaa alkanoyyliryhmää, tai 2 2 kaavan (Ia), (IB), (IC), (ID), (IE) tai (IG) mukainen yhdiste, jossa R4 and R6 tarkoittavat hydroxyyliryhmää ja kaikki 58 79845 muut symbolit tarkoittavat samea kuin (Ia), (IB), (IC), (ID) * (IE), (IF) tai (IG) mukainen yhdiste, jossa R4 ja R® tarkoittavat hydroxylyliryhmää ja kaikki muut symbolit tarkoittavat same kuin noble on meritetty, haluttaessa saatetaan reagoimaan yleisen kaavan (III) R10 C = 0 (III) R11 V) r! ^ ^ And3 (IV) R11 * "^^^ 0CH3 mukaisen acetalin tai ketonin kanssa, joissa kaavoissa R * 0 ja rH voivat olla samat tai erilaiset ja tarkoittavat vetyatomia tai alempaa alkyyliryhmää, vastaavaksi kaeksi (I) mu yhdisteeksi, jossa R4 ja R® tarkoittavat alempaa alkylideeni-dioxiryhmää, tai k) kaavan (Ia), (IB), (IC), (ID), (IE), (IF) tai (IG) mukainen yhdiste, jossa R4 on hydroxylyliryhmä ja R® on vetyatomi haluttaessa, hapetetaan vastaavaksi kaavan (I) mukaiseksi yhdisteeksi, jossa R4 ja R5 yhdessä tarkoittavat oksoryhmää (= 0), tai 1 saatu kajana 5 9 798 45 A process for the preparation of novel pharmacologically active sesqui terpene derivatives, ie. 2, 5,5,8a-tetramethyl-1,2,3,4,4a, 5,6,7,8, -8a-decahydronaphthalene-1-spiro-2 '- (2', 3'-dihydrobenzofuran) - derivatives having the formula R 1 -S 2 S-R 2 R3, which may be the same or different, represents a formyl, hydroxymethyl, hydroxyl, carboxyl, lower alkanoyloxymethyl group or a group of the formula -CH = CR7R8, where R7 and R8, which may be the same or different, represent a hydrogen atom , cyano, lower alkoxycarbonyl, or carboxyl group, or R 2 and R 3 may together form a lactone ring of the formula R9 O / t -CH-OC-, where R different, represents a hydroxyl group or a lower alkanoyloxy group, R5 represents a hydrogen atom, R4 and R8 may together form an oxo group (= O) and R4 and R8 may together form a lower alkylidene dioxide group known as a) 6,7-dihydroxy-2,5,5,8a-tetramethyl-1,2,3,4,48,5,6,7,8,8a-deca-hydronaphthalen-1-spiro 2 '- (6', 7'-diformyl-4'-hydroxy-2 ', 3'-dihydro-robensofuran) of formula (Ia) HO-j to a compound (IB) of the general formula (I), wherein R 2, R 3 or each represent a carboxyl group and all the other symbols denote the same son as defined above, or b) a compound of formula (Ia) or formula (IB), or a compound of formula (ID) wherein R 2 and R 3 together form a lactone ring of formula R 9 wherein W is -CH-O-C is reduced to a compound of formula (IC) wherein R 2, R 3 or each represent a hydroxymethyl group and all the other symbols denote the same as defined above, or c) a compound of formula (IC) wherein one of groups R 2 and R 3 represents one hydroxymethyl group and the other represents a carboxyl group and all the other symbols denote the same as defined above, are cyclized under decomposition of water to a compound of formula (ID), wherein R 2 and R 3 together form a lactone ring of formula R 9 - II -CH-OC-, where R 9 a hydrogen atom or a hydroxyl group, and all the other symbols denote the same as defined above, or e) a compound of Form In (Ia) is dehydro-condensed with an active methylene compound of general formula (II) H 2 Cl 2 (II) where R ? and R 2 represents the same as defined above, in the presence of a catalyst for a compound of formula (IU) wherein R 2, R 3 or each represent a group of the formula -CH = CR 2 and all other symbols denote the same as defined above. or e) reacting a compound of formula (Ia) with a peroxide in an inert solvent to a compound of formula (IF) wherein R 2, R 3 or each represent a hydroxyl group and all the other symbols are the same as defined above; or f) a compound of formula (IC) or of formula (IF) is acylated to a compound of formula (IG) wherein R 2, R 3 or each denote an alkanoyloxymethyl group and all the other symbols denote the same as defined above, or g) a compound of formula (Ia), (IB), (IC), (ID), (IE), (IF) or (IG), wherein R * represents a hydrogen atom and all the other symbols denote the same as defined above, are alkylated , if desired, to a corresponding compound of formula (I), where R * is lower alkyl group, or h) a compound of formula (Ia), (IB), (IC), (ID), (IE), (IF) or (IG), where R * represents a hydrogen atom and all the other symbols represents the same as defined above, acylated, if desired, to a corresponding compound of formula (I), wherein R 1 represents alkanoyl group, or 62 79845 i) a compound of formula (Ia), (IB), (IC), (ID) ), (IE), (IF) or (IG), where R4 and r6 represent a hydroxyl group and all the other symbols denote seamen as defined above are acylated, if desired, to a corresponding compound of formula (I), where R 4 and R 6 represent a lower alkanoyloxy group, or, j) a compound of formula (Ia), (IB), (IC), (ID), (IE), (IF) or (IG), where R 4 and R 6 represent a hydroxyl group and all the other symbols denoting the amine as defined above are reacted, if desired, with an aldehyde or ketone of the general formula (III) R 10 J c = o (m) R acetal or a ketone with the general in which formulas R10 and R11 may be the same or different, and denotes a hydrogen atom or a lower alkyl group, to a corresponding compound of formula (I), wherein R 4 and R 6 represent a lower alkylidene dioxide group or k) a compound of formula (Ia), (IB), (IC), (ID), (IE), (IF) or (IG) where R 4 is a hydroxyl group and R 5 is a hydrogen atom is oxidized, if desired, to a corresponding compound of formula (I), where R 4 and R 2 together represent an oxo group (= 0), or 1 k a highly obtained compound of formula (I) is reacted if is desired, with a basic compound to prepare its site.