TRICYCLO COMPOUNDS, A PROCESS FOR THEIR PRODUCTION AND A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME

Abstract: Compounds of formula (I) are disclosed and pharmaceutically acceptable salts thereof. And processes for their production, and a 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 a.. 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 (FΞRM 3?-927) and Streotomyces hvσroscopicus subsp. vakushimaensis No. 7238 (FΞRM 3P-928). Such macrolides are particularly numbered FR-900506, FR-90Q52Q, 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 [R 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; 2 in addition to its significance above, R may represent an alkyl group; 7 R represents H, OH, protected hydroxy or O-alkvl, or in conjunction with R 1 i.t may represent =0; 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 =0; Y represents 0, (H,0H) , (H,H) , N-NR 1L R 12 or N-OR 13 ; R 11 and R12 independently represent H, alkyl, aryl or tOΞVl" R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 and R 23 independently represent H or alkyl; R 20 and R21 independently represent 0, or they may independently represent (R 20a,H) and (R21a,H) respectively; R 20a and R21a independently represent OH, 0-alkyl or OCH-OCH-CH OCH-, 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, 0-alkyl, benzyl and -CH 0 Se(C c H ; R24 δ 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, isobutyi, 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, hexenyi, and the like. Suitable "aryl" may include phenyl, tolyl, xylyi, cumenyl, mesityl, naphthyl, and the like. Suitable "protected hydroxy" may include l-(lower alkylthio) (lower)alkyl, trisubstitute 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. "* i n - A Preferred embodiments of the Symbols R 1 to , '^ 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 and R are combined to form a second bond; R is hydrogen; R is hydrogen; 9 R is hydroxyl; R is propyl; R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are each methyl; R is [R a,H], wherein R a is methoxy,- R 21 is [R21a,H], wherein R21a is hydroxy; R 22 is methyl; R 23 is hydrogen; 94 R~ 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 R" -NH-AS. CR-- ) ( III ) or a salt thereof wherein R 1 to R10, R14 to R24, Y and n are each as defined above, and R ,25 i,s 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 b^ reacting the compound (II) or a salt thereof with the compound ( III ) . The compound (III) can be prepared by reacting the compound R -NH with AS,(R ), 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 ossiu 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- ediated illnesses, suc as, psoriasis, atopical dermatitis, contact dermatitis an further ecze atous 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 leuko a, 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-ure ic 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 lu and idiopathic interstitial pneumonia; skin diseases selected from dermatomyositis , leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity a cutaneous T cell lymphoma; circulatory diseases selected from arteriosclerosis, atherosclerosis, aortitis syndrome, polvarteritis nodosa an 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, the are useful for the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. chronic autoimmune liver diseases selected from the group consisti 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 fo 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, 10 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 2 o and perfumes may be used. Particularly, as a solubilizing agent, there may be exemplified water-soluble cellulose polymer (i.e. hydroxypropyl methylcelluloεe, etc.), water-soluble glycol. (i.e. propylene glycol, etc.), etc. The active object compound is included in the 25 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 5 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 g and more preferably 0.5-100 mg, of the active ingredient is generally given for treating diseases, and an average single dose of about 10 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 cf illustrating the present invention. 15 Example 1 A solution of l-hydroxy-12-[2-(4-hγdroxy-3- ethoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 20 13,19,21,27-tetramethyl-17-propyl-ll,28-dioxa-4- 4 9 azatricyclo[22.3.1.0 ' ]octacos-18-ene-2,3,10,16-tetraone (100 mg) and dimethylaluminum benzylamide (0.28 mol) , which had been prepared from benzylamine (29 mg) and trimethylaluminum (0.11 ml; 2.6M n-hexane solution) in ' 25 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 HC1 and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and 30 concentrated to afford crude product, which was purified by silica gel column chromatography to give 2-(benzylimino)-l-hγdroxy-12-[2-(4-hydrαxy-3- methoxycyclohexy1)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-17-propyl-ll,28-dioxa-4- 35 azatricyclo[22.3.1.0 ' ]octacos-18-ene-3,10,16- trione (38 mg) . FAB MS : m/z 901 (M+Na) Example 2 l-Hydroxγ-12-[2-(4-hγdroxy-3-methoxγcyclohexyl)-l- methylvinyl]-2-[ (3-hydroxypropyl)imino]-23,25-dimethoxy- 13,19,21,27-tetramethγl-17-propyl-ll,28-dioxa-4- azatricyclo[22.3.1.0 4'9]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 l-Hγdroxγ-12-[2-(4-hydroxy-3-methoxycyclohexγl)-1- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 2-(propylimino)-17-propyl-ll,28-dioxa-4-azatricyclo- [22.3.1.0 4'9]octacos-18-ene-3,10,16-trione was obtained in 25.7% yield in substantially the same manner as that of Example 1. p : 64-67°C 13 C-NMR (CDC1 3 , δ) : 211.5 (C χ6 ), 170.3 (C 1Q ), 164.7, 164.5 (C 1 , C 2 ) - - - EMI^ Λ INTERNATIONAL FORM BUDAPEST TREATY ON THE INTERNA¬ TIONAL RECOGNITION OF THE DEPOSIT OF MICROORGANISMS FOR THE PURPOSES D2SE©HB£W#!T OF PATENT PROCEDURE RECEIPT IN THE CASE OF AN ORIGINAL TUSHBSΦSE^K: -a τfflfl i j 7. l it - DEPOSIT issued pursuant to Rule 7. 1 by the INTERNA¬ c \~ ^ T © giEfϊE TIONAL DEPOSITARY AUTHORITY identified at the bottom of this page. m. • t.l * T £, ΛKrøisβBT TS 3 « mm iςimlm m D f ^tøϊ£ πi. δSδRtfgfE IflO røP 1-3, Higashi 1 chome Yatabe-machi Tsukuba-gun Ibaraki-ken 305, JAPAN u 60 -f ( 1985 ) 10^19 B EϋlliJ INTERNATIONAL FORM BUDAPEST TREATY ON THE INTERNA¬ TIONAL RECOGNITION OF THE DEPOSIT OF MICROORGANISMS FOR THE PURPOSES OF PATENT PROCEDURE F m ι >.-<ϊ.'τ®M7. ι * vt*. χ RECEIPT IN THE CASE OF AN ORIGINAL DEPOSIT issued pursuant to Rule 7. 1 by the INTERNA¬ TIONAL DEPOSITARY AUTHORITY identified at the bottom of this page. 93 &I0F£3?Sf5 9 27 (Streptomyces tsukubaensis No. 9993) (FERM BP- 9 2 7 π . ® Mi H. Vi*®-£±<D tøE I Jffl©i» -:tøιιc(± f &©TO£iΞ τι t< ÷OTi^fitE^i±, il ' Sfπ 59 ^ 10 Α 5 B (HI?ifcB )lcg£iL;fc Ifflfl©$K tøι£ 1-3, Higashi 1 chome Yatabe-machi Tsukuba-gun Ibaraki-ken 305, JAPAN πSfP 60 ^ ( 1985) 10 ^19 B

Claims: CLAIMS : A compound of the formula wherein each vicinal pair of substituents [R and R 2 ], [R 3 and R 4 ], tn ~ 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, ~. ~ may represent an alkyl group; 7 R represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R it may represent =0; 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 lkyl substituted by =0; Y represents O, (H,OH) , (H,H) , N- R X1 R 12 or R 11 and R12 i.ndependently represent H, alkyl, aryl or tosyl; R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 and R 23 independently represent H or alkyl; R 20 and R21 i.ndependently represent O, or they may independently represent (R a,H) and (R a,H) respectively; R 20a and R21a independently represent OH, O-alkyl or OCH 2 OCH 2 CH-OCH 3 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 -CH 9 Se(C-H c ) ; 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 [R and R ], [R and R 3, [R and R ] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached; 2 in addition to its significance above, R may represent an alkyl group; 7 R represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R it may represent =0; 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 =0; Y represents 0, (H,OH) , (H,H) , N-NR^R 12 or R 11 and R12 independently represent H, alkyl, aryl or tosyl; R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 and R 23 independently represent H or alkyl; R 20 and R21 i.ndependently represent 0, or they may independently represent and (R21a,H) respectively; R 20a and R21a independently represent OH, O-alkyl or 0CH 2 0CH 2 CH 2 0CH 3 or R 21 a 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 R" , 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 -CH Se(C f -H c -) ; 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, 14 to R23, Y and n are each as defined above, or a salt thereof, with a compound of the formula : 24 25 R -NH-AMR ) - 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.

Inventors: HASHIMOTO MASASHI, KASAHARA CHIYOSHI, OHKAWA TAKEHIKO, HASHIMOTO, MASASHI, KASAHARA, CHIYOSHI, OHKAWA, TAKEHIKO
Applicants: FUJISAWA PHARMACEUTICAL CO, FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P37, C07D498, C07H19