GB2245891A

GB2245891A - Tricyclo compounds

Info

Publication number: GB2245891A
Application number: GB9015098A
Authority: GB
Inventors: Chiyoshi Kasahara; Takehiko Ohkawa; Masashi Hashimoto
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1990-07-09
Filing date: 1990-07-09
Publication date: 1992-01-15
Also published as: GB9015098D0

Abstract

Tricyclo compounds have the formula: <IMAGE> wherein each vicinal pair of substituted [R<1> and R<2>], [R<3> and R<4>], [R<5> and R<6>] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached; in addition to its significance above, R<2> may represent an alkyl group; A represents -O- or -S-; R<21> represents ar(lower)alkyl or heterocyclic group; n is 1, 2 or 3; and R<25> is hydrogen, or R<25> and R<9> are combined to form a second bond; or are pharmaceutically acceptable salts thereof, the remaining symbols having various defined meanings. The compounds possess immunosuppressive and antimicrobial activities.

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.

Another 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 each vicinal pair of substituents [R1 and R2), [R3 and R4), [R5 and R6] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached; in addition to its significance above, R2 may represent an alkyl group; R7 represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R1 it may represent =0; R8 and R independently represent H or OH; R10 represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =O; A represents -0- or -S-;; X represents 0, (H,OH), (H,H), -C1120- or (H,oR24); 24 R represents acyl; Y represents O, (H,OH), (H,H), N-NR11R12 or N-OR13; R11 and R12 independently represent H, alkyl, aryl or tosyl; R13 R14 R15 R16 R17 R18 R19 R22 and R23 independently represent H or alkyl; R20 represents 0, (R20a,H); R20a represents OH, O-alkyl or OCH2OCH2CH2OCH3; R21 represents ar(lower)alkyl or heterocyclic group; n is 1, 2 or 3;; in addition to their significances above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or O- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH2Se(C6H5); 25 R is hydrogen, or R25 and R9 are combined to form a second bond; and a pharmaceutically acceptable salt thereof.

According to this invention, the object tricyclo compounds (I) can be prepared by the following processes Process 1

or a salt thereof

R21-OH (III) or its reactive derivative at the hydroxy group

or a salt thereof Process 2

or a salt thereof

R21-SH (IV) or its reactive derivative at the mercapto group

or a salt thereof Process 3

or a salt thereof

Reduction

or a salt thereof Process 4

or a salt thereof

Acylation

or a salt thereof Process 5

or a salt thereof

Reduction

or a salt thereof in h R1 to R10 R14 to R25, X, Y and n are each as defined above, and R24 is aryloxythiocarbonyl.

a 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, and preferably 1 to 4 carbon atoms, unless otherwise indicated.

Suitable "alkyl" means straight or branched saturated aliphatic hydrocarbon residue and may include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, and the like.

Suitable "alkenyl" means straight or branched unsaturated aliphatic hydrocarbon residue having one double bond and may include lower alkenyl such as vinyl, propenyl, butenyl, methylpropenyl, pentenyl, hexenyl, and the like.

Suitable "aryl" may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like.

Suitable "protected hydroxy" may include l-(lower alkylthio)(lower)alkyl, trisubstituted silyl and acyl as exemplified in European Patent Publication No. 0184162.

Suitable "ar(lower)alkyl" means afore-mentioned lower alkyl, which is substituted by aryl as mentioned above, wherein more preferred example may be phenyl(C1-C4)alkyl, and the most preferred one may be benzyl.

Suitable "5- or 6-membered N-, S- or O-containing heterocyclic ring" may include pyrrolyl, tetrahydrofuryl, and the like.

Suitable "heterocyclic group" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.

Preferred heterocyclic group may be heterocyclic group such as -unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3triazolyl, etc.) tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.; -saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, etc.;; -unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotraizolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[ l,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc.; -unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; -saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.; ; -unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; -unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl), etc.; -saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; -unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.;; -unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc., and the like; wherein more preferred example may be unsaturated condensed heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s).

Suitable "leaving group" may include an acid residue and the like, and suitable examples of "acid residue" may be halogen (e.g. chlorine, bromine, iodine, etc.), sulfonyloxy (e.g. methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.

Suitable "acyl" may include carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carboxylic, thiocarboxylic, carbonic, sulfonic and carbamic acids.

The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, isoporpylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g.

methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.

vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group(s) may include aryloxycarbonyl (e.g. phenoxycarbonyl, etc.), aryloxythiocarbonyl (e.g. phenoxythiocarbonyl, etc.), ar(lower)alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.

These acyl groups may be further substituted with one or more suitable substituent(s) such as nitro, and the like, and preferable acyl having such substituent(s) may be nitroar(lower)alkoxycarbonyl (e.g.

nitrobenzyloxycarbonyl, etc.), and the like.

Preferred examples of the acyl group thus defined may be aryloxythiocarbonyl and the most preferred one may be phenoxythiocarbonyl.

Preferred embodiments of the Symbols R1 to R10, R14 to R23, R25, X, Y and n are as follows.

R1 and R2 are each hydrogen or combined to form a second bond; R3 and R4 are combined to form a second bond; R5 and R6 are combined to form a second bond; R7 is hydrogen; R8 is hydrogen; R9 is hydroxy and R25 is hydrogen, or R9 and R25 are combined to form a second bond; R10 is propyl or allyl; R14 R15 R16I R17 R18 R19 and R22 are each methyl; R20 is [R20 a,H], wherein R20 a is methoxy; R21 is benzyl or 2-benzothiazolyl; R23 is hydrogen; X is oxo, (H,OH), (H,H) or

Y is oxo; and n is 2.

With respect to the tricyclo compounds (I) of this invention, it is to be understood that there may be one or more conformers or stereoisomeric pairs such as optical and geometrical isomers due to asymmetric carbon atoms and double bond, and such isomers are also included within the scope of the present invention.

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 reacting the compound (II) or a salt thereof with the compound (III) or its reactive derivative at the hydroxy group.

Suitable reactive derivative at the hydroxy group of compound (III) may include halide (e.g. bromide, chloride, iodide, etc.), (lower)alkanesulfonate (e.g. mesylate, ethanesulfonate, etc.), ar(lower)alkyl sulfonate (e.g.

tosylate, etc.), (lower)alkanimidate which may have additional halogen (e.g. formimidate, acetimidate, trichloroacetimidate, etc.), and the like.

This reaction is preferably carried out under acidic condition (e.g. in the presence of catalytic amount of trifluoromethanesulfonic acid, etc.).

This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, pyridine, ethyl acetate, N, N-dimethylformamide, dichloromethane, ethyl ether, isopropyl ether, 1,4-dioxane, hexane, 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 reacting the compound (II) or a salt thereof with the compound (IV) or its reactive derivative at the mercapto group.

Suitable reactive derivative at the mercapto group of compound (IV) may include the same reactive derivative as mentioned for the compound (III) and a dimer thereof.

In case that the suitable reactive derivative of the compound (IV) is a dimer, this reaction is preferably carried out in the presence of tri(lower)alkylphosphine (e.g. triethylphosphine, tributylphosphine, etc.), and the like.

In case that R9 is hydroxy and R25 is hydrogen, both the hydroxy and the hydrogen may be eliminated during the reaction to form a second bond.

This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, pyridine, ethyl acetate, N,N-dimethylformamide, dichloromethane, ethyl ether, isopropyl ether, 1,4-dioxane, benzene, toluene, xylene, or a mixture thereof.

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

Process 3 The compound (Id) or a salt thereof can be prepared by reducing the compound (Ic) or a salt thereof.

The reduction method applicable to this reaction is a conventional one which is capable of reducing the oxo group of compound (Ic) into hydroxy group and may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a chrome compound (e.g.

chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.); rhodium on alumina powder, sodium borohydride, a combination of tri(lower)alkylborane and sodium borohydride, diisobutylaluminum hydride, a combination of tri(lower alkyl)tin hydride (e.g. tributyltin hydride, etc.) and an initiator for free radical reaction such as 2,2'-azobisisobutyronitrile, and the like.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), benzene, toluene, xylene, and the like, or a mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.

Process 4 The compound (Ie) or a salt thereof can be prepared by acylating the compound (Id) or a salt thereof.

Suitable acylating agent used in this reaction may include conventional ones which can introduce the acyl group as mentioned above into the compound (tod), and preferred acylating agents may be aryloxythiocarboxylic acid or its reactive derivative such as acid halide (e.g.

phenyl chlorothionoformate, etc.), acid anhydride, and the like.

When the acylating agent is used in a free acid form or its salt form in this reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as carbodiimide compound [e.g.

N,N' -diethylcarbodlimide, N,N' -diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N' - morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N' - ( 3-dimethyl- aminopropyl) carbodiimide, etc.);N,N' -carbonyldiimidazole, N,N'-carbonylbis(2-methylimidazole); keteneimine compound (e.g. pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); ethoxyacetylene; l-alkoxy-l-chloroethylene; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalyl chloride; a combination of triphenylphosphine and carbon tetrachloride or diazenedicarboxylate; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; l-(p-chloro benzenesulfonyloxy)-6-chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.; and the like.

This reaction can preferably be carried out in the presence of an organic or inorganic base such as lower alkylalkalimetal (e.g. methyllithium, butyllithium, etc.), 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 rnethoxide, 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-dimethylamino)pyridine, etc.), quinoline, and the like, preferably 4-(N,N-dimethylamino)pyridine.

The reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as acetone, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridine, benzene, acetonitrile, N,N-dimethylformamide, hexane, ethyl ether, isopropyl ether, 1,4-dioxane, etc., or a mixture thereof.

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

Process 5 The compound (Ig) or a salt thereof can be prepared by reducing the compound (If) or a salt thereof.

The reduction method applicable for this reaction is a conventional one which is capable of hydrogenating the aryloxythiocarbonyloxy group of compound (If) into hydrogen, and may include, for example, reduction by using a combination of tri(lower alkyl)tin hydride (e.g.

tirbutyltin hydride, etc.) and an initiator for free radical reaction such as 2,2'-azobisisobutyronitrile, and the like.

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

Suitable salts of the compounds (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) 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 compound (II) 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 contains known and novel compounds, and the known compounds are disclosed, for example, in European Patent Publication Nos. 184162 and 323042 and the new compound can be prepared by a conventional manner.

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 hy 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 scleroiss, 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 phrmaceutical prepare'.ior.; 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 and coloring agents and perfumes may be used.

Particularly, as a solubilizing agent, 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 0.5-100 mg, of the active ingredient is generally given for treating diseases, and an average single dose of about 2.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg 250 mg arsd 500 mg is generally administered.

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

Example 1 To a solution of l-hydroxy-12-12-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-17-propyl-11,28-dioxa-4- azatricyclo22.3.l.04,9)octacos-l8-ene-2,3,10,l6-tetraone (155 mg) and benzyl trichloroacetimidate (100 mg) in diethyl ether (5 ml) was added catalytic amount of trifluoromethanesulfonic acid at room temperature. The reaction mixture was stirred for 2 hours and worked up in the usual manner, and the product was purified by preparative thin layer chromatography to give 12-[2-(4-benzyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1- hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-17-propyl- 11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene- 2,3,10,16-tetraone (40 mg).

FAB MS : m/z 902 (M+Na) Example 2 l7-Allyl-12- 2- ( 4-benzylox -3-methoxycyclohexyl) -1- methylvinyl]-1-hydroxy-23,25-dimethoxy-l3,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.l.04,9)octacos- 14,18-diene-2,3,10,16-tetraone was obtained in 44.8% yield in substantially the same manner as that of Example 1.

FAB MS : m/z 898 (M+Na) Example 3-1) 17-Allyl-1-hydroxy-12-12-(4-hydroxy-3- methOxycyclohexyl)-l-methylvinyl]-23,25-dimethOxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1.04,9)octacos-18-ene-2,3,10,16-tetraone (788 mg) was dissolved in toluene (23 ml) and 2,2'-dibenzothiazolyl disulfide (998 mg) and tributylphosphine (607 mg) were added successively. The solution was heated at reflux for 40 minutes.Evaporation of the solvents in vacuo and purification of the residue by a silica gel column chromatography (eluent;ether-hexane = 3:2) and subsequent silica gel column chromatography (eluent;ethyl acetate-hexane = 2:5) gave pure 17-allyl-12-{2-t4-(2-benzothiazolylthio)-3-methOxy- cyclohexyl)-1-methylvinyl)-23,25-dimethoxy-13,19,21,27- tetrametnyl-11,28-dioxa-4-azatricyclo22.3. l.04,9)octacos- 18,27-diene-2,3,10,16-tetraone (305 mg).

MS : 941 (M +Na) Example 3-2) A solution of 17-allyl-12-(2-r4-(2- benzothiazolylthio) -3-methoxycyclohexyl) -1-methylvinyl) - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4- azatricyclo 22.3.1. 04,9)octacos-l8, 27-diene-2 ,3,10,16- tetraone (305 mg) in benzene (9 ml) containing 2,2'azobisisobutyronitrile (catalytic amount) was treated with tributyltin hydride (0.27 ml).The reaction mixture was heated at reflux for 3.5 hours and concentrated in vauo, and the residue was purified by a silica gel column chromatography (eluent;ethyl acetate-hexane = 1:3) to give pure 17-allyl-12-{2-[4-(2-benzothiazolylthio)-3- methoxycyclohexyl)-1-methylvinyl)-2-hydroxy-23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4- azatricyclol22.3.1.O4,9]octacos-18,27-diene-3,10,16- trione (300 mg).

MS : 943 (M +Na) Example 3-3) Phenyl chlorothionoformate (0.14 ml) and 4-dimethylaminopyridine (199 mg) were added to a solution of 17-allyl-12-{2-[4-(2-benzothiazolylthio)-3- methOxycyclohexyl]-l-methylvinyl}-2-hydroxy-23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4- azatricyclo22.3.1.,4,9octacos-18,27-diene-3,10,16- trione (300 mg) in acetonitrile (13 ml). The reaction mixture was stirred for 3 hours at ambient temperature.

Following the successive addition of 4-dimethylaminopyridine (199 mg) and dichloromethane (10 ml), the reaction mixture was stirred for an additional 1 hour at the same temperature. The solution was poured into 1N aqueous hydrochloric acid and extracted with ether, and the extracts were washed with brine and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo, and the residue was purified by a silica gel column chromatography (eluent;ether-hexane = 1:1), to give 17-allyl-12-{2-[4-(2-benzothiazolylthio)-3-methOxyCyclo- hexyl)-1-methylvinyl}-23,25-dimethoxy-13,19,21,27-tetra- methyl-2- (phenoxythiocarbonyloxy) -11, 28-dioxa-4-azatricyclo- [22.3.1.04,9]octacos-18,27-diene-3,10,16-trione (256 mg).

1H-NMR (CDC13, 6) : 7.06-7.47 (7H, m), 7.75 (1H, d, J=lOHz), 7.86 (lH, d, J=lOHz) Example 3-4) i7-Allyl-12-(2-[4-(2-benzothiazolylthio)-3-methOxy- cycloheXyl]-l-methylvinyl}-23,25-dimethoxy-13,19,21,27- tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18,27-diene-3,10,16-trione (73 mg) was obtained by reducing 17-allyl-12-{2-[4-(2-benzothiazolylthio)-3-methOxyCyclo- hexyl)-1-methylvinyl)-23,25-dimethoxy-13,19,21,27-tetra- methyl-2- (phenoxythiocarbonyloxy) -11, 28-dioxa-4-azatricyclo- [22.3.1.04,9]octacos-18,27-diene-3,10,16-trione (250 mg) in substantially the same manner as that of Example 3-2).

MS : 927 (M++Na) Example 4 17-Allyl-12-{2-[4-(2-benzothiazolylthio)-3-methOxy- cycloheXyl]-l-methylvinyl}-23,25-dimethoxy-13,19,21,27- tetramethyl-ll,2B-dioxa-4-azatricyclo[22.3 .1.0 4,9)octacos- 14,18,27-triene-2,3,10,16-tetraone was obtained in 81.3% yield in substantially the same manner as that of Example 3-1).

MS : 917 (M++1)

Claims

What is claimed is 1 A compound of the formula

wherein each vicinal pair of substituents I and R27 [R3 and R4), [R5 and R6] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vieinal carbon atoms to which they are attached; in addition to its significance above, R2 may represent an alkyl group; R7 represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R1 it may represent =0; R8 and R9 independently represent H or OH; R10 represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =O; A represents -0- or -S-;; X represents 0, (H,OH), (H,H), -CH2O- or (H,OR24 R24 represents acyl; Y represents O, (H,OH), (H,H), N-NR11R12 or N-OR13 R11 and R12 independently represent H, alkyl, aryl or tosyl; R13 R14 R15, R16, R17, R18, R19, R22 and R23 independently represent H or alkyl; R20 represents 0, (R20a,H); R20a represents OH, O-alkyl or OCH2OCH2CH2OCH3; R21 represents arElower)alkyl or heterocyclic group; n is 1, 2 or 3;; in addition to their significances above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or 0- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH2Se(C6H5); R25 is hydrogen, or R25 and R9 are combined to form a second bond; or a pharmaceutically acceptable salt thereof.
2. A process for the preparation of a compound of the formula

wherein each vicinal pair of substituents R1 and R2), tR3 and R4), IR5 and R6) independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached; in addition to its significance above, R2 may represent an alkyl group; R7 represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R1 it may represent =0; R8 and R9 independently represent H or OH; R10 represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =O; A represents -0- or -S-;; X represents 0, (H,OH), (H,H), -CH2O- or (H,OR24); g24 represents acyl; Y represents 0, (H,OH), (H,H), N-NR11R12 or N-OR13; R11 and R12 independently represent H, alkyl, aryl or tosyl; R13,R14,R15,R16, R17, R181 R19, R22 and R23 independently represent H or alkyl; 20 R20 represents O, (R a,H); R20a represents OH, O-alkyl or OCH2OCH2CH2OCH3; R represents ar(lower)alkyl or heterocyclic group; n is 1, 2 or 3;; in addition to their significances above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or 0- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH2Se(C6H5); 25 R is hydrogen, or R25 and R9 are combined to form a second bond;; or a salt thereof, which comprises (a) reacting a compound of the formula

wherein R to R10, R14 to R23 R25 X, Y and n are each as defined above, or a salt thereof, with acompound of the formula R21 -OH (III) wherein R21 is as defined above, or its reactive derivative at the hydroxy group, to give a compound of the formula

wherein R1 to R10 R14 to R23, R25, X, Y and n are each as defined above, or a salt thereof; or (b) reacting the compound of formula (II) or a salt thereof with a compound of the formula R21-SH (TV) wherein R21 is as defined above, or its reactive derivative at the mercapto group, to give a compound of the formula

wherein R to R10, R14 to R23, R25 X, Y and n are each as defined above, or a salt thereof or (c) reducing a compound of the formula

wherein R1 to R10 R14 to R23, R25, Y and n are each as defined above, or a salt thereof, to give a compound of the formula

wherein R1 to R10 R14 to R23, R25, Y and n are each as defined above, or a salt thereof; or (d) acylating the compound of formula (Id) or a salt thereof to give a compound of the formula

wherein R1 to R10 R14 to R25, Y and n are each as defined above, or a salt thereof; or (e) reducing a compound of the formula

wherein R1 to R10 R14 to R23, R25, Y and n are each as defined above, and R24 is aryloxythiocarbonyl, a or a salt thereof, to give a compound of the formula:

wherein R1 to R10 R14 to R23 R25, Y and n are each as defined above, or a salt thereof.
3. A pharmaceutical composition containing tricyclo compounds of Claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
4. A use of tricyclo compounds of Claim 1 as a medicament.
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.
6. A tricyclo compound of Claim 1 for use as a medicament.
7. A use of a tricyclo compound of Calim 1 for manufacturing a medicament for treating or preventing resistance to transplantation, graft-versus host diseases by medulla ossium, autoimmune diseases and infectious diseases.
8. A process for preparing a pharmaceutical composition which comprises admixing a tricyclo compound of Calim 1 with a pharmaceutically acceptable carrier or excipient.