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GB2245561A - Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same - Google Patents

Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same Download PDF

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Publication number
GB2245561A
GB2245561A GB9014880A GB9014880A GB2245561A GB 2245561 A GB2245561 A GB 2245561A GB 9014880 A GB9014880 A GB 9014880A GB 9014880 A GB9014880 A GB 9014880A GB 2245561 A GB2245561 A GB 2245561A
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Prior art keywords
alkyl
represent
independently
substituted
hydroxy
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GB9014880A
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GB9014880D0 (en
Inventor
Chiyoshi Kasahara
Takehiko Ohkawa
Masashi Hashimoto
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Priority to GB9014880A priority Critical patent/GB2245561A/en
Publication of GB9014880D0 publication Critical patent/GB9014880D0/en
Publication of GB2245561A publication Critical patent/GB2245561A/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of the formula: <IMAGE> [wherein each vicinal pair of substituents [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; additionally R<2> may represent an alkyl group; R<7> represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R<1> it may represent =O; R<8> and R<9> independently are H or OH; R<10> is H, alkyl (optionally substituted by one or more hydroxyl), alkenyl (optionally substituted by one or more hydroxyl), or alkyl substituted by =O; X represents O, (H, OH), (H, H) or -CH2O-; Y represents protected carbonyl; R<14>, R<15>, R<16>, R<17>, R<18>, R<19>, R<22> and R<23> independently are H or alkyl; R<20> and R<21> independently are O, or they may independently represent R<20>a, H) and (R<21>a, H) respectively; R<20>a and R<21>a independently are OH, O-alkyl or OCH2OCH2CH2OCH3 or R<21>a is protected hydroxy; in addition, R<20>a and R<21>a may together represent an oxygen atom in an epoxide ring; n is 1, 2 or 3; in addition to their significances above, Y, R<10> and R<23>, 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 hydroxy, alkyl (optionally substituted by one or more hydroxyl groups), O-alkyl, benzyl and -CH2Se(C6H5)] and salts thereof possess immunosuppressive and antimicrobial activities. A process for the production of these compounds is also described, together with pharmaceutical compositions containing them.

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], tR5 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, R 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; 10 R 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; X represents 0, (H,OH), (H,H) or -CH2O-;; Y represents protected carbonyl; R14 R15 R16 R17 18 19 22 23 independently represent H or alkyl; 20 and 21 R20 and R21 independently represent 0, or they may independently represent (R20a,H) and (R21a,H) respectively; R20a and R21a independently represent OH, O-alkyl or OCH2OCH2CH2OCH3 or R a represents protected hydroxy; in addition, R a and R a may together represent an oxygen atom in an epoxide ring; 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); and pharmaceutically acceptable derivatives thereof.
with respect to the tricyclo compounds (I) of this invention, it is to be understood that there may be one or more conformerEs) or stereoisomeric pairs such as optical and geometrical isomers due to asymmetric carbon atom(s) and double bond(s), and such isomers and also included within a scope of this invention.
According to this invention, the object tricyclo compounds (I) can be prepared by the following process.
Process
or a salt thereof
Introduction of the carbonyl protective group
or a salt thereof in which R1 to R10 R14 to R23, X, Y and n 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 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 "protected hydroxy" may include l-(lower alkylthio)(lower)alkyl, trisubstituted silyl and acyl as exemplified in European Patent Publication No. 0184162.
Suitable "5- or 6-membered N-, S- or 0- containing heterocyclic ring" may include pyrrolyl, tetrahydrofuryl, and the like.
Suitable "protected carbonyl" may be a carbonyl group protected by a conventional protective group which is used in the field of organic chemistry and may include a group represented by the formula
in which R24 and R25 may include each hydrogen, alkyl such as lower alkyl (e.g. methyl, ethyl, propyl, hexyl, etc.), aryl (e.g. phenyl, tolyl, naphthyl, etc.), acyl (e.g.
acetyl, benzoyl, etc.), and the like; or R24 and R25 are combined, which may include a group to form alkylene such as lower alkylene (e.g. methylene, ethylene, trimethylene, etc.), haloalkylene (e.g. dichloromethylene, etc.), and the like.
Preferred embodiments of the Symbols R1 to R10, R14 to R23, 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; 7 R is hydrogen, hydroxy, O-lower alkyl such as methoxy or protected hydroxy; R8 is hydrogen; R9 is hydroxy; R10 is methyl, ethyl, propyl or allyl, R14 R15 R16 R17 R18 and R19 are each methyl, R20 is oxo or [R20a,H], wherein R20a is hydroxy or methoxy; R21 is [R21a,H), wherein R21a is hydroxy or protected hydroxy such as tri(lower)alkylsilyloxy (e.g.
trimethylsilyloxy, t-butyldimethylsilyloxy, etc.); R23 is hydrogen; X is oxo, (H,OH) or (H,H); Y is protected carbonyl; and n is 1 or 2.
Salts of the tricyclo compounds (I) of the present invention and the starting compound (II) include all pharmaceutically acceptable salts without limitation.
The process for production of tricyclo compounds (I) of this invention are explained in detail in the following.
The compound (I) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to introduction reaction of the carbonyl protective group.
Suitable introducing agent of the carbonyl protective group used in this reaction may be a conventional one such as alcohol (e.g. methanol, ethanol, etc.), orthoester (e.g. trimethylorthoformate, triethylorthoformate, triphenylorthoformate, etc.), glycol derivatives (e.g.
methylene glycol, ethylene glycol, dichloromethylene glycol, etc.), and the like.
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, benzene, 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 heating.
This process includes, within a scope thereof, the case that other parts is reacted within the object compounds of the formula (I) during the reaction or at the post-treating step of the present process, and the preferred embodiments thereof are shown in the following working examples.
Further, in case that the compound (I), wherein R21 is protected hydroxy, can also be prepared by introducing the hydroxy-protective group into the compound (I), wherein R21 is hydroxy, in a conventional manner.
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, and the like.
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 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 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 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 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 To a solution of l-hydroxy-12-[2-(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 (100 mg) in benzene (3 ml) were added ethylene clycol (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-l2-2-(4- hydroxy-3-methoxycyclohexyl) -1-methylvinyl) -23,25- dimethOxy-13,19,21,27-tetramethyl-11,28-dioxa-17-propyl-4- azatricyclo22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone- 16-ethylene acetal (55 mg).
FAB-MS : m/z 857 (M+Na+l) Example 2 To a solution of 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.l.04,9)octacos-18-ene-2,3,l0,l6-tetraone- 16-ethylene acetal (3.65 g) in dimethylformamide (36.5 ml) were added t-butyldimethylsilyl chloride (0.859 g) and imidazole (0.388 g) successively. The mixture was stirred at ambient temperature for 2 hours and poured into diethyl ether (200 ml). The solution was washed with brine, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (diethyl ether-n-hexane : 1-2, V/V) to give 12-[2-(4-t-butyl dimethylsiloxy-3-methoxycyclohexyl) -1-methylvinyl) -1- hydroxy-23 , 25-dimethoxy-l3 ,19,21, 27-tetramethyl-ll , 28- dioxa-l7-propyl-4-azatricyclo(22.3 .l.04,9)octacos-l8-ene- 2,3,10,16-tetraone-16-ethylene acetal (3.90 g).
FAB-MS : m/z 971 (M+Na+l) Example 3 17-Allyl-l-hydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl) -1-methylvinyl) -23, 25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1. , 9)octacos-l4 , l8-diene-2 ,3,10, 16-tetraone-l6- ethylene acetal (111 mg) was obtained by subjecting 17-allyl-1-hydroxy-12-[2-(4-hydroxy-3-methoxycycloheXyl)- 1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-14,18-diene- 2,3,10,16-tetraone (200 mg) to a similar manner to that of Example 1.
FAB-MS : m/z 852 (M+Na) Example 4 To a solution of 17-allyl-l-hydroxy-l2-[2-(4-hydroxy- 3-methoxycyclohexyl)-1-methylvinyl] -23, 25-dimethoxy- 13,19,21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo- [22.3.l.04,9)octacos-14,18-diene-2,3,10,l6-tetraone-16- ethylene acetal (100 mg) in ethyl acetate (2 ml) was added 10% palladium on carbon (10 mg) and the mixture was stirred under hydrogen atmosphere at ambient temperature for 6 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate-n-hexane : 1.5-1, V/V) to afford l-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11, 28-dioxa-l7-propyl-4-azatricyclo [22.3.1.04,9] octacos- 14,18-diene-2,3,10,16-tetraone-16-ethylene acetal (46 mg).
FAB-MS : m/z 854 (M+Na)

Claims (5)

  1. What we claim is 1. A compound of the 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 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; X represents 0, (H,OH), (H,H) or -CH2O-; Y represents protected carbonyl;;
    14 15 R16 R17 R18, R19, R22 and R independently represent H or alkyl; R20 and R21 independently represent 0, or they may independently represent (R20a,H) and (R21a,H) respectively; R20a and R21a independently represent OH, O-alkyl or OCH2OCH2CH < OCH3 or R21a represents protected hydroxy; in addition, R20a and R21a may together represent an oxygen atom in an epoxide ring; 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); and salts thereof.
  2. 2. A process for preparing a compound of the formula
    wherein each vicinal pair of substituents [ 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 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; X represents 0, (H,OH), (H,H) or -CH2O-;; Y represents protected carbonyl; R14 R15 R16 R17 R18 R19 R22 and R2 independently represent H or alkyl; R20 and R21 independently represent 0, or they may independently represent (R20a,H) and (R21a,H) respectively; R20a and R21a independently represent OH, O-alkyl or OCH2OCH2CH2OCH3 or R21a represents protected hydroxy; in addition, R20a and R21a may together represent an oxygen atom in an epoxide ring; 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); or a salt thereof, which comprises subjecting a compound of the formula:
    wherein R1 to R10 R14 to R23, X and n are each as defined above, or a salt thereof, to introduction of the carbonyl protective group.
  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.
GB9014880A 1990-07-05 1990-07-05 Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same Withdrawn GB2245561A (en)

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GB9014880A GB2245561A (en) 1990-07-05 1990-07-05 Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same

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Application Number Priority Date Filing Date Title
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GB9014880D0 GB9014880D0 (en) 1990-08-22
GB2245561A true GB2245561A (en) 1992-01-08

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989005304A1 (en) * 1987-12-09 1989-06-15 Fisons Plc Macrocyclic compounds
EP0413532A2 (en) * 1989-08-18 1991-02-20 FISONS plc Macrocyclic compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989005304A1 (en) * 1987-12-09 1989-06-15 Fisons Plc Macrocyclic compounds
EP0413532A2 (en) * 1989-08-18 1991-02-20 FISONS plc Macrocyclic compounds

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