WO1992013862A1

WO1992013862A1 - Lactone compounds

Info

Publication number: WO1992013862A1
Application number: PCT/JP1992/000091
Authority: WO
Inventors: Yoshihiro Namiki; Noriaki Kihara
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1991-02-05
Filing date: 1992-01-30
Publication date: 1992-08-20

Abstract

A compound of formula (I), and two other lactone compounds are disclosed. In formula (I) R?1 and R2¿ are independently O, (H, OH), (H, protected hydroxy), or (H, alkoxy), R3 is hydrogen, hydroxy, alkoxy or protected hydroxy, R4 is alkyl or alkenyl, and the symbol of a line and a dotted line is a single bond or a double bond. And processes for their production, composition containing them, and their use as an immunosuppressive agent are also described.

Description

862 - l -

DESCRIPTION

LACTONE CO.MPOUNDS

This invention relates to a novel lactone compound having pharmacological activities, to a process for its production and to a pharmaceutical composition containing the same.

More particularly, it relates to a novel lactone compound, which has pharmacological activities such as i munosuppressive activity, antimicrobial activity, and the like, to a process for its production, to a pharmaceutical composition containing the same and to a use thereof as a medicament.

Accordingly, one object of this invention is to provide a novel lactone compound, which is useful as an i munosuppressant and an antimicrobial agent.

Another object of this invention is to provide a process for production of a novel lactone compound.

(continued to the next page)

A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, a novel lactone compound.

Still further object of this invention is to provide a use of a lactone compound as a medicament for treating and preventing immune-mediated diseases such as resistance to transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases and the like, and further infectious diseases.

The novel lactone compound of this invention can be represented by the following general formula :

CH₃0 OCH.

in which R 1 and R2 are independently O, (H, OH), (H, protected hydroxy) , or (H, alkoxy), 3 R is hydrogen, hydroxy, alkoxy or protected hydroxy, 4 R is alkyl or alkenyl, and the symbol of a line and a dotted line is a single bond or a double bond. With respect to the lactone compound (I) of this invention, it is to be understood that there may be one o more stereoisomeric pairs such as optical and geometrical isomers due to asymmetric carbon atom(s) and double bond(s), and such isomers are also included within a scop of this invention.

According to this invention, the object lactone compound (I) can be prepared by the following process.

Process

OCH., OCH.

or a salt thereof

Photolysis

CH₃0 OCE.

or a salt thereof

in which R 1, R2, R3_/ R4 and the symbol of a line and a dotted line are each as defined above.

Particulars of the above definitions and the preferred .embodiments thereof are explained in detail as follows.

The term "lower" used in the specification is intended to mean 1 to 6, preferably 1 to 4 carbon atoms, unless otherwise indicated.

Suitable "alkyl" may include a straight or branched alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, octyl, nonyl, and the like, in •which the preferred one is lower alkyl and the most preferred one is methyl, ethyl and propyl.

Suitable "alkoxy" may include a straight or branched alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, he.xyloxy, octyloxy, nonyloxy, and the like, in which the preferred one is lower alkoxy and the most preferred one is methoxy.

Suitable "alkenyl" may include a straight or branched alkenyl such as vinyl, allyl, butenyl, pentenyl, hexenyl, octenyl, nonenyl, and the like, in which the preferred one is lower alkenyl and the most preferred one is allyl.

Suitable hydroxy-protective group in the "protected hydroxy" may include :

l-(lower alkylthio) (lower)alkyl such as lower alkylthiomethyl (e.g. methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethy1, isobutylthiomethyl, hexylthio ethyl, etc.), and the like, in which the preferred one may be C₁~C₄alkylthiomethyl and the most preferred one may be methylthiomethyl;

trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl-dimethylsilyl, tri-tert-butylsilyl, etc.), lower alkyl-diarylsilyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsilyl, propyl-diphenylsilyl, tert-butyl-diphenylsilyl, etc.), and the like, in which the preferred one may be tri(C, -C.Jalkylsilyl and C₁-C₄alkyl-diphenylsilyl, and the most preferred one may be tert-butyl-dimethylsilyl and tert-butyl-diphenylsilyl;

acyl such as aliphatic acyl, aromatic acyl and aliphatic acyl substituted with aromatic group, which are derived from carboxylic, sulfonic and carbamic acids; and the like. The aliphatic acyl may include lower alkanoyl which may have one or more suitable subs ituent(s) such as carboxy (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc. ) , cyclo(lower)alkyloxy(lower)- alkanoyl which may have one or more suitable substituent(s) such as lower alkyl (e.g. cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxyheptanoyl, menthyloxyhexanoyl, etc. ) , camphorsulfonyl, lower alkylcarbamoyl having one or more suitable substituent(s) such as carboxy and a protected carboxy, for example, carboxy(lower)alkylcarbamoyl (e.g. carboxymethylcarbamoyl, carbo.xyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc. ) , protected carboxy(lower)alkylcarbamoyl such as tri(lower)- alkylsilyl(lower)alkoxycarbonyl(lower)alkylcarbamoyl (e.g. trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl, etc.), and the like.

The aromatic acyl may include aroyl which may have one or more suitable substituent(s) such as nitro (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc.), arenesulfonyl which may have one or more suitable substituent(s) such as halogen (e.g. benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group

» 5 may include ar(lower)alkanoyl which may have one or more suitable substituent(s) such as lower alkoxy and trihalo(lower)alkyl (e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethoxy-2-trifluoromethyl-2-phen lacetyl, 10 2-trifluoromethyl-2-propoxy-2-phenylacetyl, etc.), and the like.

The more preferred acyl group thus defined may be C--C₄alkanoyl which may have carbcxy,

15 cyclo(C₅-Cg)alkyloxy(C₁-C₄)alkanoyl having two (C₁~C₄)alkyl groups on the cycloalkyl moiety, camphorsulfonyl, carboxy(C.-C₄)alkylcarbamoyl, tri(C,-C₄)alkylsilyl( C. - . )alkoxycarbonyl( - -C₄)alkyl¬ carbamoyl, benzoyl which may have one or two nitro,

20 benzenesulfonyl having halogen; phenyl(C₁-C₄)alkanoyl having C..-C₄alkoxy and trihalo(C.,-C₄)alkyl, and the most preferred one may be acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and

25 2-trifluoromethyl-2-metho.xy-2-phenylacetγl.

The process for production of the lactone compound (I) of this invention is explained in detail in the following.

30

»

The compound (I) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof tc photolysis.

35 The starting compound (II) used in this process is known and described, for example, European Patent Publication Nos. 0 184 162 and 0 323 042. Among these compounds, the FR-900506 and FR-900525 substances can be produced by fermentation of Streptomyces tsukubaensis No. 9993 (FERM BP-927), and the FR-900523 substance can be produced by fermentation of Streptomyces hygroscopicus subsp. yakushimaensis No. 7238 (FERM BP-928), and further the FR-900520 substance can be produced by fermentation of both microorganisms.

The FR-900506 substance possesses the following chemical structure.

FR-900506 substance

The photolysis can be carried out by a conventional manner, for example, exposure to light, preferably intense light such as 30,000 luxes.

This photolysis can be carried out in the absence or the presence of a solvent which does not adversely influence the reaction such as alkanol (e.g. ethanol, etc.), and the like. Further, this reaction can also be carried out in a suspension, for example, in water.

The reaction temperature is not restrictive, and the reaction is usually carried out at ambient temperature.

Further, this invention relates to a novel compound selected from the compounds of the following chemical formulae :

or a salt thereof,

15 or a salt thereof, and

30 OCH₃ OCH₃

or a salt thereof,

m which R 1, R2, R3, R4 and the symbol of a line and a

35 dotted line are each as defined above. The compound (III) or a salt thereof can be prepared by heating the compound (II-l) or a salt thereof in the absence or the presence of a solvent such as alcohols (e.g. ethanol, etc.), and the like.

This process can be represented by the following reaction scheme.

OCH₃ OCH or a salt thereof

or a salt thereof, in which R 1, R 2, R Δ, R 4 and the symbol of a line and a dotted line are each as defined above.

Also, the compounds (IV) and (V) or their salts can be prepared by reacting the compound (II-2) or a salt thereof in a polar solvent such as water, alcohols (e.g. ethanol, etc.), and the like.

This process can be represented by the following

10 reaction schemes.

OCH₃ OCH₃ D

or a salt thereof

in a polar solvent

or a salt thereof or a salt thereof

1 O *5 A in which R , R , R , R and the symbol of a line and a dotted line are each as defined above.

Suitable salt of the compounds (I) to (V) may be a conventional pharmaceutically acceptable salt such as basic or acidic salt.

The lactone compounds (I), (III), (IV) and (V) or the salts possess pharmacological activities such as immunosuppressive activity, antimicrobial activity, and th like, and therefore are useful for the treatment and prevention of immune-mediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nervus, etc.; graft-versus-host diseases by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, and the like; and further infectious diseases caused by pathogenic microorganisms. Further, the lactone compounds (I), (III), (IV) and (V or their salts are also useful for the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of 5 immunologically- ediated illnesses, such as, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis. Lichen planus, Pemphigus, bullαus Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides,. erythemas, 0 cutaneous eosinophilias. Lupus erythematosus, acne and Alopecia areata; various eye diseases such as autoimmune diseases and so on (e.g. keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic 5 keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus. Mooren's ulcer, Scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.); reversible obstructive airways disease, which includes o conditions such as asthma ( e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma ) , particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness) , bronchitis and the like; inflammation of ucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, leukotriene B.-mediated diseases; intestinal inflammations/allergies such as Coeliac disease, proctitis, eosnophilic gastroenteritis, mastocytosiε, Crohn's disease and ulcerative colitis; food related allergic diseases which have symptomatic manifestation remote from the gastro-intestinal tract, for — ID —

example migraine, rhinitis and eczema; renal diseases such as interstitial nephritis,

Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple yositis,

Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and

Basedow's disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia a anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin diseases such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity a cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa a myocardosis; collagen diseases such as scleroderma, egener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesion of gingiva, periodontiu alveolar bone, substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern alopecia or alopecia senilis; muscular dystrophy;

Pyoderma and Sezary's syndrome;

Addison's disease; active oxgen- ediated diseases, for example, organ injury 862

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such as ischemia-reperfusion injury of organs (e.g. heart, liver, kidney, digestive tract) which occurs o preservation, transplantation or ischemic diseases (e.g. thrombosis, cardiac infarction) : intestinal diseases such a endotoxin-shock, pseudomembranous colitis, colitis caused b drug or radiation: renal diseases such as ischemic acute renal insufficiency, chronic renal insufficiency: pulmonary diseases such as toxinosis caused by lung-oxygen or drug (e.g. paracort,bleomycins) , lung cancer, pulmonary emphysema: ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn: dermatitis such as erythema multiforme, linear IgA ballous dermatitis, cement dermatitis: and others such as gingvatis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution(e.g. air pollution), aging, carcinogenis, metastasis of carcinoma, hypobaropathy; diseases caused by histamine or leukotriene C. release;

Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also the one which affects oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney; and so on.

And further, the lactone compounds (I), (III), (IV) and (v) or their salts have liver regenerating activity and/or activities of stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis) , partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis, cirrhosis (e.g. alcoholic cirrhosis) and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on-chronic" liver failure (acute liver failure on chronic liver diseases) .

And further, the lactone compounds (I), (III), (IV) an (V) or their salts are useful for various diseases because of their useful pharmaceutical activity such as augmenting activity of chemotherapeutic effect, preventing or treating activity of cytomegalovirus infection, anti-inflammatory activity, and so on.

As an example for showing such pharmacological activities, the pharmacological test data of the object compounds of the present invention are illustrated in the following-.

Test 1

Suppression of in vitro Mixed Lymphocyte Reaction (MLR)

The MLR test was performed in microtiter plates, with each well containing 5 x 10 C57BL/6 responder cells (H-2b), 5 x 105 mitomycin C treated (25 ug/ml mitomycin C at 37°C for 30 minutes and washed three times with RPMI 1640 medium) BALB/C stimulator cells (H-2 ) in 0.2 ml RPMI

1640 medium supplemented with 10% fetal calf serum, 2 mM sodium bicarbonate, penicillin (50 unit/ml) and streptomycin (50 μg/ml) . The cells were i cubated at 37°C in humidified atmosphere of 5% carbon dioxide and 95% of

3 air for 68 hours and pulsed with H-thymidine (0.5 μCi) ■ hours before the cells were collected. The object compound of this invention were dissolved in ethanol and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of 100 nM or less.

The I ₅₀ value (mol concentration to suppress 50% of

MLR) was calculated by a conventional method.

The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the compounds (I), (III), (IV) or (V) or their salts, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external (topical), enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, cream and any other form suitable for use. ^■ The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes may be used. Particularly, as a solubilizing agent, there may be exemplified water-soluble cellulose polymer (i.e. hydroxypropyl ethylcellulose, etc.), water-soluble glycol (i.e. propylene glycol, etc.), etc.

The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases. For applying this composition to human, it is preferable to apply it by parenteral, enternal or external administration. While the dosage of therapeutically effective amount of the compounds (I), (III), (IV) or (V) varies from and also depends upon the age and condition of each individual patient to be treated, a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg, of the active ingredient is generally given for treating diseases, and an average single dose of about 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered.

The following examples are given for the purpose of illustrating the present invention.

Example 1

FR-900506 Substance (1 g) was dissolved in absolute ethanol (100 ml) and the solution was exposed to light (30000 Luxes) with stirring for 10 days. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in absolute ethanol (20 ml), and the resultant solution was subjected to high-pressure liquid chromatography (HPLC) . The first HPLC procedure used COSMOSIL _I C_{T O} (column 20 mm i.d. x 15 cm, NACALAI TESQUE INC.) with water:isopropanol:isopropyl ether

(20:12:1) as an eluent (flow rate: 8 ml/minute) . The product having retention time of nine minutes was collected, lyophilized and then dissolved in a small amount of n-hexane, isopropanol and chloroform. The second HPLC step was used twice to be further purified the product. Elution was carried out using TSKgel 120-OH (4.6 mm i.d. x 25 cm, TOSOH Co., Ltd.) with n-hexane:isopropanol (9:1) as a mobile phase (flow rate: 1 ml/minute). The fraction which contained the product was combined, and the solvent was removed on a rotary evaporator to yield the chromatographycally pure material, which is considered to have the following chemical structure.

CH₃0 OCH.

FAB-Mass : 826 (M+Na)^T ¹³C-NMR : 9.22, 14.41, 16.09, 16.72, 18.78, 19.85, ^•26.05, 26.65, 30.61,-31.14, 32.33, 33.42, 34.27, 34.56, 34.72, 34.91, 35.27, 40.54, 44.91, 47.51, 51.96, 52.85, 55.96, 56.53, 57.04, 69.58, 72.59, 73.43, 73.95, 76.86, 78.08, 80.22, 84.06, 86.05, 97.55, 116.45, 123.07, 129.66, 131.78, 135.50, 140.06, 166.51, 169.47, 211.09

Example 2

A solution containing FR-900506 substance (400 mg) , polyoxyethylene hydrogenated caster oil 60 (HCO-60) (16000 mg) and absolute ethanol (40 ml) was allowed to stand at 80°C for 14 days. The reaction mixture was subjected to HPLC. The first HPLC procedure used μ-Bondasphere 5 y o

C-18 100A (column 19 mm i.d. x 15 cm. Waters) with water:isopropanol:isopropyl ether (20:12:1) as a mobile phase (flow rate : 7 ml/minute) . The product having retention time of 27 minutes was collected and lyophilized. The second preparative HPLC step was used to be further purified the product. In this step, the product in chloroform was injected onto a TSKgel 120-OH (4.6 mm i.d. x 25 cm, TOSOH Co., Ltd.) with n-hexane:isopropanol (9:1) as a mobile phase (flow rate: 1 ml/minute). The fraction which contained the product was combined, and the solvent was removed on a rotary evaporator to yield the chromatographycally pure material having the following physical properties.

F.AB-Mass : 826 (M+Na)⁺ ¹³C-NMR : 15.36, 16.13, 17.30, 17.58, 18.29, 20.76,

24.85, 25.72, 26.29, 26.81, 29.82, 30.82, 32.66, 33.68, 34.63, 35.59, 37.88, 39.07, 43.95, 44.89, 49.38, 52.14, 52.48, 56.21, 56.31, 57.64, 71.33, 71.56, 73.48, 73.69, 75.74, 80.57, 84.33, 98.30, 116.49, 123.36, 127.94, 133.47, 135.56, 139.30, 165.91, 168.87, 197.06, 212.14

13 From the FAB-Mass data and C-NMR data, this compound is considered to have the following chemical structure.

Example 3

Water (100 ml) was added to a solution of FR-900506 substance (1 g) in ethanol (100 ml). The resultant solution was allowed to stand at ambient temperature for an hour. To the reaction mixture were added water and isopropanol, and then the mixture was lyophilized.

Half of this lyophilized residue was dissolved in a small amount of n-hexane:tetrahydrofuran (2:1) and subjected to HPLC using TSKgel 120-OH (column 4.6 mm i.d. X 25 cm) with n-hexane:tetrahydrof ran (2:1) as a mobile phase (flow rate :₍1 ml/minute). The fraction having retention time of 16 minutes was combined, and the solvent was removed on a rotary evaporator to yield the pure material having the following 13C-NMR data. ¹³C-NMR : 9.97, 14.42, 15.94, 16.04, 18.71, 22.33,

25.86, 27.06, 27.36, 29.92, 31.89, 33.18, 34.22, 35.49, 36.06, 36.65, 40.41, 42.68, 44.23, 44.60, 48.65, 51.50, 54.16, 56.32, 57.00, 57.15, 71.88, 74.30, 74.30, 74.99, 76.84, 77.31, 85.46, 98.23, .115.61, 122.53, 129.81, 134.16, 137.62, 141.35,

166.04, 169.52, 199.07, 210.47

From the 13C-NMR data, this product is considered to have the following chemical structure.

0CH₃ OCH The remaining half of the lyophilized residue was dissolved in a small amount of chloroform and subjected to HPLC using TSKgel 120-OH (column 4.6 mm i.d. X 25 cm) with n-hexane:l,2-dichloroethane:acetonitrile (6:3:1) as a mobile phase (flow rate : 1 ml/minute). The fraction having retention time of 13 minutes was combined, and the solvent was removed on a rotary evaporator to yield the pure material having the following C-NMR data.

¹³C-NMR : 9.71, 12.79, 16.60, 16.68, 19.71, 20.76,

24.41, 26.43, 27.49, 30.46, 31.21, 34.57, 34.79, 34.92, 35.08, 38.15, 38.86, 39.32, 40.51, 44.14, 47.73, 52.45, 53.85, 56.50, 57.43, 57.73, 69.64, 73.50, 73.61, 76.53, 77.62, 78.26, 84.12, 98.25, 116.62, 123.61, 131.59, 132.59, 135.45, 138.68, 166.92, 170.06, 210.36, 210.80

13 From the C-NMR data, this product is considered to have the following chemical structure.

Claims

1. A compound, which is selected from the group consistin of a compound of the formula (I) :

, a compound of the formula (IV) :

and a compound of the formula (V)

OCH₃ OCH₃

1 2 in which and are independently 0, (H, OH). (H, protected hydroxy), or (H, alkoxy),

R is hhyyddrrooggeenn, hydroxy, alkoxy or protected hydroxy,

R is alkyl or alkenyl, and the symbol of a line and a dotted line is a single bond or a double bond, or a pharmaceutically acceptable salt thereof.

2. The compound in claim 1, in which R is (H, OH), R²

3 3 ((HH,, aallkkooxxyy)) ,, RR iiss hhyyddrrooxxyy,, aa:nd the symbol of a line and a dotted line is a single bond.

A process for production of a compound of the formula (I) as defined in claim 1 or a salt thereof, which comprises subjecting a compound of the formula :

OCH₃ OCH₃

1 2 3 4 in which R , R , R , R and the symbol of a line and a dotted line are each as defined in claim 1, or a salt thereof to photolysis.

4 A process for production of a compound of the formula (IV) or (V) as defined in claim 1 or a salt thereof, which comprises reacting a compound of the formula (II-2) :

OCH, OCH.

in which R 1, R2, R3, R4 and the symbol of a line and a dotted line are each as defined in claim 1, or a salt thereof with water.

5. A pharmaceutical composition containing the compound o the formula (I), (IV) or (V) as defined in claim 1, or a salt thereof.

6. A use of the compound of the formula (I), (IV) or (V) as defined in claim 1, or a salt thereof as a medicament.

7. A method for treating or preventing rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases and infectious diseases which comprises administering the compound of the formula (I), (IV) or (V) as defined in claim 1, or a salt thereof to human or animal.