GB2246350A - Tricyclo compounds - Google Patents
Tricyclo compounds Download PDFInfo
- Publication number
- GB2246350A GB2246350A GB9016115A GB9016115A GB2246350A GB 2246350 A GB2246350 A GB 2246350A GB 9016115 A GB9016115 A GB 9016115A GB 9016115 A GB9016115 A GB 9016115A GB 2246350 A GB2246350 A GB 2246350A
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- United Kingdom
- Prior art keywords
- alkyl
- represent
- formula
- independently represent
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
- C07D498/18—Bridged systems
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: in addition to its significance above, R<2> may represent an alkyl group; Y represents O, (H,OH), (H,H), N-NR<11>R<12> or N-OR<13.>, X represents a group of the formula: <IMAGE> or a group of the formula: <IMAGE>
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 IR1 and R2), tR3 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, 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 represents 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;;
Y represents 0, (HsOH), (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 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 R21a
OCH2OCH2CH2OCH3 or 20 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;
X represents a group of the formula
or a group of the formula
in which R17 and R18 are each the same definitions as
R13 and
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 conformer(s) 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
Rearrangement
or a salt thereof
or a salt thereof wherein R1 to RB, R10 R14 to R23, 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 "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 "5- or 6-membered N-, S- or 0- containing heterocyclic ring" may include pyrrolyl, tetrahydrofuryl, and the like.
Preferred embodiments of the Symbols R1 to R8, R10,
R14 to R23, 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
R7 is hydrogen, hydroxy, O-lower alkyl such as methoxy or protected hydroxy;
R8 is hydrogen;
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; 21 37 21
R21 is tR a,H), wherein R a is hydroxy or protected hydroxy;
R is hydrogen;
Y is oxo; and
n is 1 or 2.
Salts of the tricyclo compounds of the present invention include all pharmaceutically acceptable salts without limitation.
The process for production of tricyclo compounds (I) of this invention is explained in the following.
The compound (I-a) or a salt thereof and the compound (I-b) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to rearrangement.
The reaction may be carried out in a conventional manner using base, and the like, which is explained in detail in the below example.
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.
The reaction temperature is not critical and the reaction is usually conducted under from cooling to heating.
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.
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 example is given for the purpose of illustrating the present invention.
Example 1
To a solution of l-hydroxy-l2-2-(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 (300 mg) in tetrahydrofuran (9 ml) was added p-toluenesulfonamide sodium salt (81 mg) at room temperature. Then to this suspension was added dimethylsulfoxide (2 ml) and stirred for 4 hours. The reaction mixture was diluted with diethyl ether and washed with water and brine, and dried over magnesium sulfate.
The solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane 3:1, V/V) to give l-hydroxy-ll-[2-(4- hydroxy-3 -methoxycyclohexyl) -1-methylvinyl) -22,24- dimethOxy-12,18,20,26-tetramethyl-10,28-dioxa-16-propyl-3- azatricyclol21,4.1.03' 81,,tacos-17-ene-2,9,15,27- tetraone, which can be represented by the following formula (A), (55 mg) and 16,20-dihydroxy-4-12-(4- hydroxy-3-methoxycyclohexyl) -1-methylvinyl) -15,17- dimethoxy-5,11,13,19-tetramethyl-3-oxa-9-propyl-23- azatricyclo[18.7.0.01,23]heptacos-10-ene-2,8,21,22- tetraone, which can be represented by the following formula (B), (25 mg).
(A)
FAB MS : m/z 812 (M + Na) 13C-NMR (CDC13, 6) : 73.3, 73.4, 74.8, 79.6, 79.8, 84.0,
96.6, 124.1, 131.0, 131.4, 137.6, 169.7, 170.0,
210.6, 211.2,
FAB MS : m/z 812 (M + Na) 13C-NMR (CDC13, 6) : 72.2! 73.3, 76.6, 78.1, 78.9, 83.9,
85.9, 124.6, 131.1, 134.5, 138.8, 164.3, 169.9, 202.5, 210.6.
Claims (5)
1. A compound of the formula
wherein each vicinal pair of substituents TR1 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 R it may represent =0; R8 represents 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;
Y represents 0, (H,OH), (H,H), N-NR11R12 or 13
N-OR ;; R1l and R12 independently represent H, alkyl, aryl or tosyl; 13 R14 R15 R16 R17 R18 R19 R22 and R23 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 R21 a represents protected hydroxy;
in addition, R20a and R21a may together represent an oxygen atom in an epoxide ring;
n is 1, 2 or 3;;
X represents a group of the formula
or a group of the formula
in addition to their significances above, Y, R10 and
and , 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. A process for preparing a compound of the formula
wherein each vicinal pair of substituents [ and2), [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 =O; 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;;
Y represents 0, (H,OH), (H,H), N-NR11R12 or or
N-OR
11
R and R12 independently represent H, alkyl, aryl or tosyl;
13 14 R15 R16 R17 R18, R19, R22 and R independently represent H or -alkyl; R20 and R21 independently represent 0, or they 20 21 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;;
X represents a group of the formula
or a group of the formula
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(CsH5); or a salt thereof, which comprises subjecting a compound of the formula: :
wherein R1 to R8 R10, R14 to R23, Y and n are
each as defined above, or a salt thereof, to rearrangement, to give a compound of the formula
of a salt thereof and a compound of the formula
or a salt thereof
wherein R1 to R8, R10, R14 to R23, Y and n are each
as defined above.
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. 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9016115A GB2246350A (en) | 1990-07-23 | 1990-07-23 | Tricyclo compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9016115A GB2246350A (en) | 1990-07-23 | 1990-07-23 | Tricyclo compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9016115D0 GB9016115D0 (en) | 1990-09-05 |
| GB2246350A true GB2246350A (en) | 1992-01-29 |
Family
ID=10679498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9016115A Withdrawn GB2246350A (en) | 1990-07-23 | 1990-07-23 | Tricyclo compounds |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2246350A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0552031A1 (en) * | 1992-01-16 | 1993-07-21 | American Home Products Corporation | Oxepane isomers of rapamycin useful as immunosuppressive agents |
| US5514685A (en) * | 1992-05-07 | 1996-05-07 | Sandoz Ltd. | Heteroatom-containing tricyclic compounds |
| US5686424A (en) * | 1992-04-08 | 1997-11-11 | Miles Inc. | 2-oxoethyl derivatives as immunosuppressants |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
| GB2225576A (en) * | 1988-11-29 | 1990-06-06 | Sandoz Ltd | Substituted azatricyclo derivatives and metabolites |
-
1990
- 1990-07-23 GB GB9016115A patent/GB2246350A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
| GB2225576A (en) * | 1988-11-29 | 1990-06-06 | Sandoz Ltd | Substituted azatricyclo derivatives and metabolites |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0552031A1 (en) * | 1992-01-16 | 1993-07-21 | American Home Products Corporation | Oxepane isomers of rapamycin useful as immunosuppressive agents |
| US5686424A (en) * | 1992-04-08 | 1997-11-11 | Miles Inc. | 2-oxoethyl derivatives as immunosuppressants |
| US5514685A (en) * | 1992-05-07 | 1996-05-07 | Sandoz Ltd. | Heteroatom-containing tricyclic compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9016115D0 (en) | 1990-09-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |