GB2244991A - Tricyclo compounds - Google Patents

Abstract

Compounds of the formula: <IMAGE> wherein R<1> is hydrogen or acyl, R<2> is hydrogen, hydroxy or acyloxy, R<3> is methyl, ethyl, propyl or allyl, R<4> is hydroxy or alkoxy, A is methylene or carbonyl, n is an integer of 1 or 2, and the symbol of a line and dotted line is a single bond or a double bond, and salts thereof are useful for the treatment or prevention of, for example, resistance to transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases and infectious diseases. Corresponding 16-ethylene acetal intermediates are also novel compounds.

Description

TRICYCLO COMPOUNDS, A PROCESS FOR THEIR PRODUCTION AND A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME This invention relates to novel tricyclo compounds having pharmacological activities, to a process for their production and to a pharmaceutical composition containing the same.

More particularly, it relates to novel tricyclo compounds, which have pharmacological activities such as immunosuppressive activity, antimicrobial activity, and the like, to a process for their 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 the novel tricyclo compounds, which are useful for treatment and prevention of resistance to transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases, infectious diseases, and the like.

smother object of this invention is to provide a process for production of the tricyclo compounds by synthetic process.

A further object of this invention is to provide a pharmaceutical composition containing, as active ingredients, the tricyclo compounds.

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

The new tricyclo compounds of this invention can be represented by the following general formula

wherein R1 is hydrogen or acyl, R2 is hydrogen, hydroxy or acyloxy, R3 is methyl, ethyl, propyl or allyl, R is hydroxy or alkoxy, A is methylene or carbonyl, n is an integer of 1 or 2, and the symbol of a line and dotted line is a single bond or a double bond.

With respect to the tricyclo compounds (I) of this invention, it is to be understood that there may be one or more conformer(s) or 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 scope of this invention.

According to this invention, the object tricyclo compounds (I) can be prepared by the following processes.

Process 1

or a salt thereof

Elimination of the carbonyl protective group

or a salt thereof Process 2

or its reactive derivative at the hydroxy group or a salt thereof

Introduction of Ra group

or a salt thereof in which R1, R2, R31 R4, A and n are each as defined above, Ra is acyl, and the symbol of a line and dotted line is a single bond or a double bond.

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 carbon atoms, unless otherwise indicated.

Suitable "acyl" and acyl group in the "acyloxy" may include 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 substituent(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, protected carboxy and hydroxy for example, carboxy(lower)alkylcarbamoyl (e.g. carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), protected carboxy(lower)alkylcarbamoyl such as tri(Iower) alkylsilyl (lower) alkoxycarbonyl ( lower) alkylcarbamoyl (e.g.

trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsi lylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsi lylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbam etc.), hydroxy(lower)alkylcarbamoyl (e.g. - hydroxymethylcarbamoyl, hydroxyethylcarbamoyl, hydroxypropylcarbamoyl, hydroxybutylcarbamoyl, hydroxypentylcarbamoyl, hydroxyhexylcarbamoyl, 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.), arylcarbamoyl which may have one or more suitable substituent(s) such as halogen (e.g. phenylcarbamoyl, fluorophenylcarbamoyl, chlorophenylcarbamoyl, etc.), and the like.

The heterocyclic acyl may include heterocyclic carbonyl (e.g. furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, morpholinocarbonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group 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-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenylacetyl, etc.), and the like.

The more preferred acyl group thus defined may be C1-C4alkanoyl which may have carboxy, cyclo(C5-C6)alkyloxy(C1-C4)alkanoyl having two (C1-C4)alkyl groups on the cycloalkyl moiety, camphorsulfonyl, carboxy(C1-C4)alkylcarbamoyl, hydroxy(C1-C4)alkylcarbamoyl, tri(C1-C4)alkylsilyl(Cl-C4)alkoxyzarbonyl(Cl-C4)alkyl- carbamoyl, haloarylcarbamoyl, benzoyl which may have one or two nitro, benzenesulfonyl having halogen, phenyl(C1-C4)alkanoyl having C1-C4alkoxy and trihalo(C1-C4)alkyl, morpholinocarbonyl, and the most preferred one may be acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, hydroxypropylcarbamoyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl, phenylcarbamoyl, fluorophenylcarbamoyl, chlorophenylcarbamoyl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl and morpholinocarbonyl.

Suitable alkoxy may be lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy and the like, in which the preferred one is C1-C 4alkoxy.

The processes for production of tricyclo compounds (I) of this invention are explained in detail in the following.

Process 1 The compound (Ia) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to elimination reaction of carbonyl protective group.

The reaction may be carried out in a conventional manner, and preferably it may be carried out in the presence of acid(s).

Suitable acid used in this Process may be e.g. an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfonic acid; an organic acid such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; and an acidic ion-exchange resin.

This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, pyridine, acetone, ethyl acetate, N,N-dimethylformamide, dichloromethane, or a mixture thereof.

The reaction temperature of this reaction is not critical and the reaction is usually conducted under from cooling to warming.

Process 2 The compound (Ib) or a salt thereof can be prepared by introducing R1 group into the compound (Ia) or a salt thereof.

Suitable introducing agent of R1 group used in this reaction may be a conventional one such as acylating agent which is capable of introducing the acyl group as mentioned before such as carboxylic acid, sulfonic acid, carbamic acid and their reactive derivative, for example, an acid halide, an acid anhydride, an activated amide, an activated ester, isocyanate, and the like. Preferable example of such reactive derivative may include acid chloride, acid bromide, a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g.

dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g. methyl carbonate, ethyl carbonate, propyl carbonate, etc.), alphatic carboxylic acid (e.g.

pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trifluoroacetic acid, etc.) aromatic carboxylic acid (e.g. benzoic acid, etc.), a symmetrical acid anbydride, an activated acid amide with a heterocyclic compound containing imino function such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole and tetrazole, an activated ester (e.g.

p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine, l-hydroxy-2- ( lH) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxybenzotriazole, l-hydroxy-6-chlorobenzotriazole, etc.), isocyanate, and the like.

The reaction is preferably conducted in the presence of an organic or inorganic base such as alkali metal (e.g.

lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine (e.g. triethylamine, etc.), pyridine compound (e.g.

pyridine, lutidine, picoline, 4-N ,N-dimethylaminopyridine, etc.), quinoline, and the like.

In case that the acylating agent is used in a free form or its salt in this reaction, the reaction is preferably conducted in the presence of a conventional condensing agent such as a carbodiimide compound [e.g.

N,N' -dicyclohexylcarbodiimide, N-cyclohexyl-N' - (4- diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N' - (3 -dimethylaminopropyl ) carbodiimide, etc.], a ketenimine compound (e.g. N,N'-carbonylbis (2-methylimidazole), pentamethyleneketene N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ether compounds (e.g.

ethoxyacetylene, 8-cyclovinylethyl ether), a sulfonic acid ester of N-hydroxybenzotraizole derivative [e.g.

1- ( 4-chlorobenzenesulfonyloxy) -6-chloro-lH-benzotriazole, etc.], and the like.

The reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g.

methanol, ethanol, etc.), tetrahydrofuran, pyridine, benzene, N,N-dimethylformamide, etc., or a mixture thereof, and further in case that the base or the introducing agent of the acyl group is in liquid, it can also be used as a solvent.

The reaction temperature is not critical and the reaction is usually conducted under from cooling to heating.

This process includes, within a scope thereof, a case that during the reaction, the hydroxy group for R of the compound (Ia) may occasionally be transformed into the corresponding acyloxy group in the object compound (Ib).

The object tricyclo compounds (I) obtained according to the process as explained above can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, an the like.

Suitable salts of the compounds (I), (Ia), (Ib) and (II) may include pharmaceutically acceptable salts such as basic salts, for example, alkali metal salt (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), ammonium salt, amine salt (e.g. triethylamine salt, N-benzyl-N-methylamine salt, etc.) and other conventional organic salts.

With respect to the tricyclo compounds ( I) of this invention, it is to be understood that there may be one or more conformer(s) or 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 scope of this invention.

The starting compound (II) in the process mentioned above is also a novel compound, and can be prepared by the following procedure.

or a salt thereof

acetalation

or a salt thereof

oxidation

or a salt thereof

dehydrogenation

or a salt thereof

dehydrogenation

or a salt thereof in which R3, Rt, A and n are each as defined above, and the symbol of a line and dotted line is a single bond or a double bond.

Each step of the above-mentioned procedure can be carried out in a same manner to that of the preparations in the present specification.

PHARMACOLOGICAL ACTIVITIES OF THE TRICYCLO COMPOUNDS The tricyclo compounds (I) possess pharmacological activities such as immunosuppressive activity, antimicrobial activity, and the like, and therefore are useful for the treatment and prevention of the resistance by transplantation of organs or tissues such as heart, kidney, liver, medulla ossium, skin, cornea 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, uveitis such as Behcet's disease, etc., vernal keratoconjunctivitis, infectious diseases caused by pathogenic microorganisms, and the like.

And further, the tricyclo compounds (I) are also useful in the topical administration for the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angoiedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus and Alopecia areata.

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 tricyclo compounds (I), as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, 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, creme 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 an coloring agents and perfumes may be used. Particularly, as a solubilizing agnet, there may be exemplified water-soluble cellulose polymer (i.e. hydroxypropyl methylcellulose, 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 or enteral administration. While the dosage of therapeutically effective amount of the tricyclo compound (I) 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 C.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.

Preparation 1 To a solution of l-hydroxy-12-l2-(4-hydroxy-3- methoxycyclohexyl) -1-methylvinyl) -23, 25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-17-propyl-4- azatricyclor22.3.1. O4, 9oc;tacos-18-ene-2,3,10,16-tetraone (100 mg) in benzene (3 ml) were added ethylene glycol (100 mg) and p-toluenesulfonic acid (3 ml) successively and the mixture was heated at reflux azeotropically for 8 hours.

The solution was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate-n-hexane : 1-1, V/V) to give l-hydroxy-12-[2-(4 hydroxy-3-methoxycyclohexyl) -1-methylvinyl) -23,25- dimethOxy-13,19,21,27-tetramethyl-11,28-dioxa-17-propyl-4- azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone- 16-ethylene acetal (55 mg).

FAB-MS : m/z 857 (M+Na+l) Preparation 2 To a solution of l-hydroxy-12-l2-(4-hydroxy-3- methOxycyclohexyl)-l-methylvinyl]-23,25-dimethOxy- 13,19,21,27-tetramethyl-11,28-dioxa-17-propyl-4- azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16- tetraone-16-ethylene acetal (0.68 g) in dimethylformamide (15 ml) was added pyridinium dichlomate (1.1 g) and the mixture was stirred at ambient temperature for 12 hours.

The solution was poured into ethyl acetate and purified by florisil column chromatography eluted with ethyl acetate.

The combined fractions were concentrated under reduced pressure and the residue was dissolved in diethyl ether.

The solution was washed with aqueous 1N hydrochloric acid solution and brine successively, dried, and evaporated under reduced pressure to afford l-hydroxy-23,25-dimethoxy-12-l2-(3-methoxy-4- oxocyclohexyl)-1-methylvinyl)-13,19,21,27-tetramethyl- 11,28-dioxa-17-propyl-4-azatricyclo[22.3.1.04,9)- octacos-18-ene-2,3,10,16-tetraone-16-ethylene acetal (0.64 g).

FAB-MS : m/z 855 (M+Na+l) Preparation 3 To a solution of l-hydroxy-23,25-dimethoxy 12-12-(3-methoxy-4-oxocyclohexyl)-1-methylvinyl]- 13,19,21,27-tetramethyl-11,28-dioxa-17-propyl-4- azatricyclot22.3.l.04,9)octacos-18-ene-2,3,10,l6- tetraone-16-ethylene acetal (82 mg) and triethylamine (0.16 ml) in dichloromethane (2 ml) was added trimethylsilyl trifluoromethanesulfonate (0.06 ml) at 0 C and the mixture was stirred at the same temperature for 10 minutes. The solvent was removed off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate-n-hexane : 1-1, V/V).

The oily material was dissolved in acetonitrile (1 ml) and Palladium(II) acetate (50 mg) was added. The mixture was stirred for 10 hours and concentrated after filtration under reduced pressure. The residue was purified by silica gel cholumn chromatography (ethyl acetate-n-hexane: 2-1, V/V) and successively by preparative thin layer chromatography (ethyl acetate-n-hexane : 1-1, V/V) to give l-hydroxy-23 ,25-dimethoxy-12-[2-( 5-methoxy-4-oxo-2- cyclohexen-1-yl)-1-methylvinyl)-13,19,21,27-tetramethyl- 11,28-dioxa-17-propyl-4-azatricyclot22.3.1.04'9]octacos- 18-ene-2,3,10,16-tetraone-16-ethylene acetal (31 mg).

FAB-MS : m/z 853 (M+Na+l) Preparation 4 To a solution of l-hydroxy-23,25-dimethoxy-12-L2-(5- methoxy-4-oxo-2-cyclohexen-l-yl) -1-methylvinyl) - 13,19,21,27-tetramethyl-11,28-dioxa-17-propyl-4- azatricyclo[22.3.1.04,9)octacos-18-ene-2,3,10,16- tetraone-16-ethylene acetal (40 mg) and triethylamine (0.08 ml) in dichloromethane (1 ml) was added trimethtlsilyl trifluoromethanesulfonate (0.032 ml) at 0CC and the mixture was stirred at the same temperature for 30 minutes. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (diethyl ether-n-hexane : 1-1, V/V). The oily material which resulted was dissolved in acetonitrile (1 ml) and Palladium(II) acetate (40 mg) was added.The mixture was stirred for 2 days and concentrated after filtration under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate-n-hexane : 1-1, V/V) to give 1-hydroxy-12-f2-(4-hydroxy-3-methoxyphenyl)- l-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11,28-dioxa-17-propyl-4-azatricyclo[22.3.1.04'9]octacos- 18-ene-2,3,10,16-tetraone 16-ethylene acetal (4.0 mg).

FAB-MS : m/z 850 (M+Na) Example 1 l-Hydroxy-12-L2-(4-hydroxy-3-methoxyphenyl)-1- methylvinyl)-23,25-dimethoxy-13,19,21,27-tetramethyl- 11,28-dioxa-17-propyl-4-azatricyclot22.3.1.04'9]octacos- 18-ene-2,3,10,16-tetraone-16-ethylene acetal (4 mg) was dissolved in a mixture of acetone (0.5 ml) and aqueous 1N hydrochloric acid (0.1 ml) and the solution was allowed to stand at ambient temperature for 2 days. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to afford l-hydroxy-12-t2-(4-hydroxy-3-methoxyphenyl)-1- methylvinyl)-23,25-dimethoxy-13,19,21,27-tetramethyl- 11,28-dioxa-17-propyl-4-azatricyclo[22.3.1.04,9)octacos- 18-ene-2,3,10,16-tetraone (1.5 mg).

FAB-MS : m/z 806 (M+Na)

Claims (5)

1. What we claim is A compound of the formula

   wherein R1 is hydrogen or acyl, R2 R2 is hydrogen, hydroxy or acyloxy, 3 R is methyl, ethyl, propyl or allyl, R4is hydroxy or alkoxy, A is methylene or carbonyl, n is an integer of 1 or 2, and the symbol of a line and dotted line is a single bond or a double bond, and salts thereof.
2. 2. A process for preparing a compound of the formula

   wherein R1 is hydrogen or acyl, R2 is hydrogen, hydroxy or acyloxy, R3 is methyl, ethyl, propyl or allyl, R4 is hydroxy or alkoxy, A is methylene or carbonyl, n is an integer of 1 or 2, and the symbol of a line and dotted line is a single bond or a double bond, or a salt thereof, which comprises (a) subjecting a compound of the formula

   wherein R2, R3, R4, A and n are each as defined above, and the symbol of a line and dotted line is a single bond or a double bond, or a salt thereof, to elimination reaction of the carbonyl protective group, to give a compound of the formula

   wherein R2, R3, R4, A and n are each as defined above, and the symbol of a line and dotted line is a single bond or a double bond, or a salt thereof, or (b) subjecting a compound of the formula

   wherein R2, R3, R4, A and n are each as defined above, and the symbol of a line and dotted line is a single bond or a double bond, or its reactive derivative at the hydroxy group or a salt thereof, to introduction reaction of Ra group, to give a compound of the formula

   wherein R2, R3, R4, A and n are each as defined above, Ra is acyl, and the symbol of a line and dotted line is a single bond or a double bond, or a salt thereof.
3. 3. A pharmaceutical composition containing tricyclo compounds of claim 1, as active ingredients, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
4. 4. A use of tricyclo compounds of claim 1 as a medicament.
5. 5. A method for treating or preventing resistance to transplantation, graft-versus-host diseases by medulla ossium, autoimmune diseases and infectious diseases which comprises administering a compound of claim 1 to human or animal.