Claims for Patent: 5,385,907

Summary for Patent: 5,385,907

Title:	Ointments containing FK-506 or derivatives thereof
Abstract:	An ointment comprising a tricyclic compound such as FK 506 substance which is 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, or the like, a solubilizing and/or absorption-promoting agent and an ointment base, which is useful for treating various skin diseases.
Inventor(s):	Sotoo Asakura, Yoshio Murakami, Nobuto Kanagawa, Toshiomi Nakate
Assignee:	Astellas Pharma Inc
Application Number:	US08/062,330
Patent Claims:	1. An ointment consisting essentially of a tricyclic compound represented by the following formula (I): ##STR4## wherein each of adjacent pairs of R1 and R2, R3 and R4 or R5 and R6 independently is(a) two adjacent hydrogen atoms, or (b) may form another bond formed between the carbon atoms to which they are attached, and further, R2 is an alkyl group; R7 is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group, or an oxo group together with R1 ; R8 and R9 each is independently a hydrogen atom or a hydroxy group; R10 is a hydrogen atom, and alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups or an alkyl group substituted by an oxo group; X1 is a hydrogen atom or a hydroxy group; X2 is a hydrogen atom; or X1 and X2 may together represent an oxo group or --CH2 O--; Y1 is a hydrogen atom or a hydroxy group; Y2 is a hydrogen atom; or Y1 and Y2 may together represent an oxo group, ##STR5## R11 and R12 each is independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group; R13, R14, R15, R16, R17, R18, R19, R22 and R23 each is independently a hydrogen atom or an alkyl group; R20 and R21 each is an oxo group or independently (R20 a and a hydrogen atom) or (R21 a and a hydrogen atom) in which R20 a and R21 a each is a hydroxy group, an alkoxy group or a group represented by the formula --OCH2 OCH2 CH2 OCH3, or R21 a is a protected hydroxy group, or R2 a and R2 a may together represent an oxygen atom in an epoxide ring; n is an integer of 1, 2 or 3; in addition to their above definitions, four of Y1, Y2, R10 and R23, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkyl substituted by one or more hydroxy, an alkoxy, benzyl and a group of the formula --CH2 Se(C6 H5); or a pharmaceutically acceptable salt thereof, a solubilizing and/or absorption-promoting agent selected from the group consisting of a lower alkanediol, a lower alkylene carbonate, an alkane dicarboxylic ester, a higher alkane carboxylic glycerin ester, a higher alkene carboxylic glycerin ester, a higher alkane carboxylic alkyl ester, a higher unsaturated alcohol and an azacycloalkane, and an ointment based selected from the group consisting of oil and fat bases; in which the tricyclic compound (I) or a pharmaceutically acceptable salt thereof is contained therein in an amount of about 0.01 to 10% (w/w), and the solubilizing and/or absorption-promoting agent is contained therein in an amount of about 1 to 30% (w/w), where optionally is present one or more of the following ingredients selected from the group consisting of colorants, preservatives, and higher alkene carboxylic acids. 2. An ointment as claimed in claim 1 in which the solubilizing and/or absorption-promoting agent is a lower alkanediol, a lower alkylene carbonate or an alkane dicarboxylic ester. 3. An ointment as claimed in claim 1 in which the tricyclic compound (I) is the one wherein each of adjacent pairs of R3 and R4 or R5 and R6 independently may form another bond formed between the carbon atoms to which they are attached,R8 and R23 each is independently a hydrogen atom; R9 is a hydroxy group; R10 is methyl, ethyl, propyl or allyl; X1 is a hydrogen atom; X2 is a hydrogen atom; or X1 and X2 may together represent an oxo group; Y1 and Y2 may together represent an oxo group; R14, R15, R16, R17, R18, R19 and R22 each is independently methyl; R20 and R21 independently are (R20 a and a hydrogen atom) or (R21 a and a hydrogen atom) in which R20 a and R21 a each is a hydroxy group or an alkoxy group or R21 a is a protected hydroxy group; and n is an integer of 1 or 2. 4. An ointment as claimed in claim 3 in which the tricyclic compound (I) is the one wherein R7 is a hydrogen atom, a hydroxy group or a protected hydroxy group;X1 and X2 may together represent an oxo group; R20 a is methoxy; and R21 a is a hydroxy or protected hydroxy group. 5. An ointment as claimed in claim 4 in which the tricyclic compound (I) is 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. 6. An ointment as claimed in claim 4 in which the tricyclic compound (I) is 17-ethyl-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. 7. An ointment of claim 1, wherein at least one of said ingredients selected from the group consisting of perfumes, colorants, preservatives, and higher alkene carboxylic acids is present. 8. An ointment as claimed in claim 2 in which the tricyclic compound (I) is the one wherein each of adjacent pairs of R3 and R4 or R5 and R6 independently may form another bond formed between the carbon atoms to which they are attached,R8 and R23 each is independently a hydrogen atom; R9 is a hydroxy group; R10 is methyl, ethyl, propyl or allyl; X1 is a hydrogen atom; X2 is a hydrogen atom; or X1 and X2 may together represent an oxo group; Y1 and Y2 may together represent an oxo group; R14, R15, R16, R17, R18, R19 and R22 each is independently methyl; R20 and R21 independently are (R20 a and a hydrogen atom) or (R21 a and a hydrogen atom) in which R20 a and R21 a each is a hydroxy group or an alkoxy group or R21 a is a protected hydroxy group; and n is an integer of 1 or 2. 9. An ointment as claimed in claim 8 in which the tricyclic compound (I) is the one wherein R7 is a hydrogen atom, a hydroxy group or a protected hydroxy group;X1 and X2 may together represent an oxo group; R20 a is a methoxy; and R21 a is a hydroxy or protected hydroxy group. 10. An ointment as claimed in claim 9 in which the tricyclic compound (I) is 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. 11. An ointment as claimed in claim 9 in which the tricyclic compound (I) is 17-ethyl-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. 12. An ointment as claimed in claim 1 consisting of a tricyclic compound represented by the following formula (I): ##STR6## wherein each of adjacent pairs of R1 and R2, R3 and R4 or R5 and R6 independently is(a) two adjacent hydrogen atoms, or (b) may form another bond formed between the carbon atoms to which they are attached, and further, R2 is an alkyl group; R7 is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group, or an oxo group together with R1 ; R8 and R9 each is independently a hydrogen atom or a hydroxy group; R10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups or an alkyl group substituted by an oxo group; X1 is a hydrogen atom or a hydroxy group; X2 is a hydrogen atom; or X1 and X2 may together represent an oxo group or --CH2 O--; Y1 is a hydrogen atom or a hydroxy group; Y2 is a hydrogen atom; or Y1 and Y2 may together represent an oxo group, ##STR7## R11 and R12 each is independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group; R13 R14, R15, R16, R17, R18, R19, R22 and R23 each is independently a hydrogen atom or an alkyl group; R20 and R21 each is an oxo group or independently (R20 a and a hydrogen atom) or (R21 a and a hydrogen atom) in which R20 a and R21 a each is a hydroxy group, an alkoxy group or a group represented by the formula --OCH2 OCH2 CH2 OCH3, or R21 a is a protected hydroxy group, or R20 a and R21 a may together represent an oxygen atom in an epoxide ring; n is an integer of 1, 2 or 3; in addition to their above definitions, four of Y1, Y2, R10 and R23, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkyl substituted by one or more hydroxy, an alkoxy, benzyl and a group of the formula --CH2 Se(C6 H5); or a pharmaceutically acceptable salt thereof, a solubilizing and/or absorption-promoting agent selected from the group consisting of a lower alkanediol, a lower alkylene carbonate, an alkane dicarboxylic ester, a higher alkane carboxylic glycerin ester, a higher alkene carboxylic glycerin ester, a higher alkane carboxylic alkyl ester, a higher unsaturated alcohol and an azacycloalkane, and an ointment base selected from the group consisting of oil and fat bases; in which the tricyclic compound (I) or a pharmaceutically acceptable salt thereof is contained therein in an amount of about 0.01 to 10% (w/w), and the solubilizing and/or absorption-promoting agent is contained therein in an amount of about 1 to 30% (w/w). 13. An ointment as claimed in claim 1, wherein said oil and fat bases are selected from the group consisting of natural waxes, petroleum waxes, higher aliphatic acid glycerin esters, hydrocarbons, and mixtures thereof. 14. An ointment as claimed in claim 12, wherein said oil and fat bases are selected from the group consisting of natural waxes, petroleum waxes, higher aliphatic acid glycerin esters, hydrocarbons, and mixtures thereof. 15. An ointment as claimed in claim 1, wherein said ointment base consists of white petrolatum, solid paraffin, liquid paraffin and white beeswax and wherein said solubilizing and/or absorption-promoting agent is selected from the group consisting of propylene carbonate alone or in combination with diisopropyl adipate. 16. An ointment as claimed in claim 12, wherein said ointment base consists of white petrolatum, solid paraffin, liquid paraffin and white beeswax and wherein said solubilizing and/or absorption-promoting agent is selected from the group consisting of propylene carbonate alone or in combination with diisopropyl adipate. 17. An ointment as claimed in claim 1, in which the tricyclic compound represented by formula (I) is 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. 18. The ointment as claimed in claim 17, wherein said solubilizing and/or absorption-promoting agent is a lower alkylene carbonate. 19. The ointment as claimed in claim 18, wherein said lower alkylene carbonate is propylene carbonate. 20. An ointment as claimed in claim 12, in which the tricyclic compound represented by formula (I) is 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. 21. The ointment as claimed in claim 20, wherein said solubilizing and/or absorption-promoting agent is a lower alkylene carbonate. 22. The ointment as claimed in claim 21, wherein said lower alkylene carbonate is propylene carbonate. 23. An ointment as claimed in claim 15, wherein said solubilizing and/or absorption-promoting agent is propylene carbonate and wherein said tricyclic compound represented by formula (I) is 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. 24. An ointment as claimed in claim 16, wherein said solubilizing and/or absorption-promoting agent is propylene carbonate and wherein said tricyclic compound represented by formula (I) is 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.