WO1992000980A1

WO1992000980A1 - Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same

Info

Publication number: WO1992000980A1
Application number: PCT/JP1991/000899
Authority: WO
Inventors: Chiyoshi Kasahara; Takehiko Ohkawa; Masashi Hashimoto
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1990-07-05
Filing date: 1991-07-03
Publication date: 1992-01-23
Also published as: GB9014881D0; EP0537353A1; JPH06501923A

Abstract

Compounds of formula (I) are disclosed, and pharmaceutically acceptable salts thereof, and processes for their production, and pharmaceutical composition containing them are also described.

Description

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 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.

European Patent Application 184162 (Fujisawa

Pharmaceutical Co. Ltd.) discloses a number of macrocyclic compounds isolated from microorganisms belonging to genus Streptomyces such as Streptomyces tsukubaensis No. 9993 (FERM BP-927) and Streptomyces hygroscopicus subsp.

yakushimaensis No. 7238 (FERM BP-928). Such macrolides are particularly numbered FR-900506, FR-900520,

FR-900523 and FR-900525. And the preparation of some their derivatives is also described. International Patent Application WO 89/05304,

European Patent Application Nos. 353678, 349049, 349061, 356399, 402931, etc also disclose a number of macrocyclic immunosuppressive compounds.

We have now found a novel group of compounds which possess certain advantageous properties over those disclosed previously.

Thus, according to the invention, we provide a new compound of the following 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, R ² may

represent an alkyl group;

R⁷ represents H, OH, protected hydroxy or 0-alkγl, or in conjunction with R¹ it may represent =0;

R⁸ and R⁹ independently represent H or OH;

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 =0;

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 and R²¹ independently represent O, or they may independently represent (R²⁰a,H) and (R²¹a,H)

respectively;

R ²⁰a and R²¹a independently represent OH, O-alkyl or OCH₂OCH₂CH₂OCH₃ or R ²¹a 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, R 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 wherein R¹ to 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 1-(lower alkylthio)(lower) alkyl, trisubstituted silyl and acyl as exemplified in European Patent Publication No. 0184162.

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

Preferred embodiments of the Symbols R¹ to R¹⁰, R¹⁴ to R ²³, 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, 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;

R ²¹ is [R²¹a,H], wherein R²¹a is hydroxy or protected hydroxy;

R²³ 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) 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 Grignard reagent, and the like, which is explained in detail in the below example.

The reaction can also be carried out in the presence of Lewis acid.

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 immune-mediated diseases controlled by a immunosuppressant such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nervus, etc.; graft-versus-host diseases by medulla ossium

transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, and the like; and further infectious diseases caused by pathogenic microorganisms.

Further, the tricyclo compounds (I) are also useful fo 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, angioedemas, vasculitidas, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata;

various eye diseases such as autoimmune diseases and so on (e.g. keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer,

Scleritis, Graves' ophthalmopathy, etc.);

reversible obstructive airways disease, which includes conditions such as asthma ( e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma ), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness), bronchitis and the like;

inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, leukotriene B₄-mediated diseases;

intestinal inflammations/allergies such as Coeliac disease, proctitis, eosnophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food related allergic diseases which have symptomatic manifestation remote from the gastro-intestinal tract, for example migraine, rhinitis and eczema;

renal diseases selected from interstitial nephritis,

Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy;

nervous diseases selected from multiple myositis,

Guillain-Barré syndrome, Ménière's disease and

radiculopathy;

endocrine diseases selected from hyperthyroidism and

Basedow's disease;

hematic diseases selected from pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic

thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia;

bone diseases such as osteoporosis;

respiratory diseases selected from sarcoidosis, fibroid lung and idiopathic interstitial pneumonia;

skin diseases selected from dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma;

circulatory diseases selected from arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis;

collagen diseases selected from scleroderma, Wegener's granuloma and S jogren ' s syndrome;

adiposis;

eosinophilic fasciitis;

periodontal disease;

nephrotic syndrome such as gloraerulonephritis;

hemolytic-uremic syndrome;

photoallergic sensitivity;

male pattern alopecia or alopecia senilis; and so on. And further, the tricyclo compounds (I) have liver regenerating activity and/or activities of stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the treatment and prevention of hepatic diseases such as immunogeniσ diseases (e.g. chronic

autoimmune liver diseases selected from the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis and cirrhosis. And further, the tricyclo compounds (I) are useful for various diseases because of its useful pharmaceutical activity such as augmenting activity of chemotherapeutic effect. 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 suspension of magnesium (1.21 g) in anhydrous tetrahydrofuran (100 ml) were added a catalitic amount of iodine and iodomethane (7.07 g) successively in ice-water cooling bath and the mixture was stirred for 1 hour at ambient temperature. The resultant white suspension (60 ml) was added to a solution of 17-allyl-1,14-dihydroxy- 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-18-ene-2,3,10,16- tetraone (1.0 g) in anhydrous tetrahydrofuran (20 ml). The mixture was stirred at ambient temperature for 1 hour and then heated under reflux for 1 hour, and quenched by an aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give

16-allyl-1,13-dihydroxy-11-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-22,24-dimethoxy-12,18,20,26-tetramethyl-10,28-dioxa-3-azatricyclo[21.3.2.0 ^3,8]octacos- 17-ene-2,9,27-trione (218 mg).

FAB-MS : m/z 826 (M+Na)

Claims

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

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 =0; 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 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 OCH₂-OCH₂CH₂OCH₃ or R²¹a represents

protected hydroxy;

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 salts thereof.

2. A process for preparing 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

=O;

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;

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;

R ²⁰ and R ²¹ independently represent O, or they may independently represent (R²⁰a,H) and (R²¹a,H) respectively;

R ²⁰a and R²¹a independently represent OH,

O-alkyl or OCH₂OCH₂CH₂OCH₃ or R²¹a represents

protected hydroxy;

in addition, R 20a 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, R ¹⁰ and R²³, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-,

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, Y and n are each as defined above,

or a salt thereof, to rearrangement.

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.