EP0537354A1 - Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same - Google Patents

Abstract

The invention relates to compounds represented by formula (I), as well as to pharmaceutically acceptable salts of these compounds. Methods for producing these compounds and a pharmaceutical composition containing these compounds 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 immunoεupprεssive 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 by 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 by 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 macrocvclic compounds isolated from microorganisms belonging to genus Streotomyces such as Streptomvces tsukubaensis No. 9993 (FERM 3?-927) and Streotomyces hvσroscopicus subsp.

vakushimaensis No. 7238 (FERM 3P-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 macrocvclic 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, R² may

represent an alkyl group;

R⁷ represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R ¹ i.t may represent =O;

R ⁸ 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 =O;

Y represents O, (H,OH), (H,H), N-N^R11R¹² or N-OR¹³; R ¹¹ 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 R²¹ independently represent O, or they may independently represent (R 20a,H) and (R21a,H) respectively;

R ²⁰a and R²¹a independently represent OH, O-alkyl or OCH₂OCH₂CH₂OCH₂, or R ²¹a 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 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 alkyl, hydroxyl, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and

-CH₂Se(C₆H₅);

R²⁴ is lower alkyl which may be substituted by

suitable substituent(s); and pharmaceutically acceptable derivatives thereof.

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, xylyi, 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.

Suitable "lower alkyl which may be substituted by suitable substituents" may include aforementioned lower alkyl, which may be substituted by one or more, preferably one or two suitable substituents such as hydroxyl, aryl as mentioned above, and the like.

Preferred embodiments of the Symbols R¹ to R¹⁰, R¹⁴ to R ²³, X, Y and n are as follows.

R ¹ and R² are each hydrogen;

R ³ and R⁴ are combined to form a second bond;

R ⁵ and R ⁶ are combined to form a second bond;

R ⁷ is hydrogen;

R ⁸ is hydrogen;

R ⁹ is hydroxyl;

R ¹⁰ is propyl; R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are each methyl;

R²⁰ is [R²⁰a,H], wherein R²⁰a is methoxy;

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

R ²² is methyl;

R ²³ is hydrogen;

R²⁴ is propyl, 3-hydroxypropyl or benzyl;

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.

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

Process

or a salt thereof wherein R ¹ to R¹⁰, R¹⁴ to R²⁴, Y and n are each as defined above, and

R²⁵ is lower alkyl, preferably methyl.

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

following.

Process :

The compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound ( III ) .

The compound (III) can be prepared by reacting the compound R²⁴-NH₂ with AS,(R²⁵)₃ in a conventional solvent at the temperature of cooling to warming.

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 warming 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, and the like.

Suitable salts of the compounds (I) 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 compounds (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 compounds (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 compounds 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 immune-mediated diseases controlled by a immunσsuppressant such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossiurα, 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 the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous

manifestations of immunolσgically-mediated illnesses, suc as, psoriasis, atopical dermatitis, contact dermatitis an further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolys bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alooecia 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-Barrέ syndrome, Meniere'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, polvarteritis nodosa and myocardosis;

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

adiposis;

eosinophilic fasciitis;

periodontal disease;

nephrotic syndrome such as glomerulonephritis;

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 immunogenic 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- 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 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.

(continued on the next page) 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 compounds (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

A solution of 1-hydroxy-12-[2-(4-hγdroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-17-propyl-11,28-dioxa-4- azatricyclo[22.3.1.0^4,9]octacos-18-ene-2,3,10,16-tetraone

(100 mg) and dimethylaluminum benzylamide (0.28 mmol), which had been prepared from benzylamine (29 mg) and trimethylaluminum (0.11 ml; 2.6M n-hexane solution) in dichloromethane (5 ml), was heated under reflux for 3 hours and additional stirring for 16 hours was carried out at room temperature. The resulting mixture was carefully quenched with IN HCl and extracted with dichloromethane.

The organic layer was dried over magnesium sulfate and concentrated to afford crude product, which was purified by silica gel column chromatography to give

2-(benzylimino)-1-hγdroxy-12-[2-(4-hydrαxy-3- methoxycyclohexy1)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-17-propyl-11,28-dioxa-4- azatricyclo[22.3.1.0^4,9]octacos-18-ene-3,10,16- t1ione (38 mg).

FAB MS : m/z 901 (M+Na)

Example 2

1-Hydroxγ-12-[2-(4-hγdroxy-3-methoxγcyclohexyl)-1- methylvinyl]-2-[(3-hydroxypropyl)imino]-23,25-dimethoxy-13,19,21,27-tetramethγl-17-propyl-11,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-3,10,16-trione was obtained in 33.6% yield in substantially the same manner as that of Example 1.

FAB MS : m/z 869 (M+Na)

Example 3

1-Hγdroxγ-12-[2-(4-hydroxy-3-methoxycyclohexγl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 2-(propylimino)-17-propyl-11,28-dioxa-4-azatricyclo-[22.3.1.04'9]octacos-18-ene-3,10,16-trione was obtained in

25.7% yield in substantially the same manner as that of

Example 1.

mp : 64-67°C

¹³C-NMR (CDCl₃, δ) : 211.5 (C₁₆), 170.3 (C₁₀),

164.7, 164.5 (C₁, C₂)

Claims

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

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;

7

R represents H, OH, protected hydroxy or

O-alkyl, or in conjunction with R¹ it may represent

=O;

R 8 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 =O; Y represents O, (H,OH), (H,H), N-NR¹¹R¹² or

N-OR ¹³;

R ¹¹ 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 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 OCH₂OCH₂CH-OCH₃ or R ²¹a 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 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 alkyl, hydroxyl, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH₂Se(C₆H₅);

R ²⁴ is lower alkyl which may be substitut°ed by suitable substituent(s);

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], [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;

R ⁸ 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

R ¹¹ 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 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 R²¹a represents protected hydroxy;

m 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-, 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, hydroxyl, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH₂Se(C₆H₅);

R ²⁴ is lower alkyl which may be substituted by suitable substituent( s);

or a salt thereof, which comprises reacting

a compound of the formula :

wherein R¹ to R¹⁰, R¹⁴ to R²³, Y and n are

each as defined above,

or a salt thereof, with a compound of the formula : R²⁴-NH-Aℓ(R²⁵) ₂ wherein R ²⁴ is as defined above, and

R ²⁵ is lower alkyl.

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 by

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 Claim 1 for

manufacturing a medicament for treating or preventing resistance by 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 Claim 1 with a pharmaceutically acceptable carrier or excipient.