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

Claim 2

A compound of the formula: wherein R 1 is hydroxy or protected hydroxy, R 2 is hydrogen, hydroxy or protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, n is an integer of 1 or 2, and the symbol of a line and dotted line is a single bond or a double bond, and salt thereof.

Claim 3

A compound of claim 1, which can be represented by the following formula: wherein R is hydroxy or protected hydroxy, R 2 is hydroxy or protected hydroxy, and R 3 is methyl, ethyl, propyl or allyl.

Claim 4

A compound of claim 2, wherein R 3 is allyl.

Claim 5

A compound of claim 3, wherein R 1 is hydroxy, 1-(lower alkylthio)(lower)alkoxy, trisubstituted silyloxy or acyloxy.

Claim 6

A compound of claim 4, wherein R 1 is hydroxy, lower alkylthiomethoxy, tri(lower)alkylsilyloxy, lower alkyl-diarylsilyloxy, lower alkanoyloxy which may have carboxy, cyclo(lower)alkoxy(lower)alkanoyloxy which may have two lower alkyl groups on the cycloalkyl moiety, camphorsulfonyloxy, aroyloxy which may have one or two nitro, arenesulfonyloxy which may have halogen or ar(lower)alkanoyloxy which may have lower alkoxy and trihao(lower)alkyl, and R 2 is hydroxy or lower alkanoyloxy.

Claim 7

A compound of claim 5, 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-[22.3.1.0 4,9 ]octacos-18-ene-2,3,10,16-tetraone.

Claim 8

A compound of claim 5, wherein R 1 is lower alkanoyloxy and R 2 is hydroxy or lower alkanoyloxy.

Claim 9

A compound of claim 7, which is 12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0 4,9 ]-octacos-18-ene-2,3,10,16-tetraone.

Claim 10

A compound of claim 7, which is 14-acetoxy-12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-l-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 4 ' 9 ]octacos-18-ene-2,3,10,16-tetraone.

Claim 11

A compound of claim 2, which is 17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1.0 4,9 ]octacos-18-ene-2,3,10,16-tetraone.

Claim 12

A compound of claim 2, which is 1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,17,21,27-pentamethyl-11,28-dioxa-4-azatricyclo[22.3.1.0 4,9 )-octacos-18-ene-2,3,10,16-tetraone.

Claim 13

A compound of claim 1, wherein R 1 is hydroxy, lower alkylthiomethoxy, lower alkanoyloxy or arenesulfonyloxy which may have halogen, R 2 is hydrogen or hydroxy, n is an integer of 2 and the symbol of a line and dotted line is a double bond.

Claim 14

A compound of claim 1, which is 16-allyl-1,13-dihydroxy-11-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-22,24-dimethoxy-12,18,20,26-tetraramethyl-10,27-dioxa-4-azatricyclo-[21.3.1.0 4,8 )heptacos-17-ene-2,3,9,15-tetraone.

Claim 15

A process for production of the compound of the formula:

Claim 16

A process for production of the compound of the formula:

Claim 17

wherein R 1 is hydroxy or protected hydroxy, R is hydrogen, hydroxy or protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, n is an integer of 1 or 2, and the symbol of a line and dotted line is a single bond or a double bond, and salt thereof, which comprises (a) culturing a FR-900506, FR-900520 and/or FR-900525 substance(s)-producing strain belonging to the genus Streptomyces in a nutrient medium and recovering the FR-900506, FR-900520 and/or FR-900525 substance(s) to give the FR-900506, FR-900520 and/or FR-900525 substance(s); (b) culturing a FR-900520 and/or FR-900523 substance(s)-producing strain belonging to the genus Streptomyces in a nutrient medium and recovering the FR-900520 and/or FR-900523 substance(s) to give the FR-900520 and/or FR-900523 substance(s); (c) introducing a hydroxy-protective group into a compound of the formula: wherein R 2 , R 3 , n and the symbol of a line and dotted line are each as defined above, to give a compound of the formula: wherein R 2 , R 3 , n and the symbol of a line and dotted line are each as defiend above, and R 1 a is protected hydroxy, or a salt thereof; (d) introducing a hydroxy-protective group into a compound of the formula: wherein R 1 , R 3 , n and the symbol of a line and the dotted line are each as defined above, or a salt thereof, to give a compound of the formula: wherein R 1 , R 3 , n and the symbol of a line and dotted line are each as defined above, and R 2 a is protected hydroxy, or a salt thereof; (e) reacting a compound of the formula: wherein R 1 , R 3 and n are each as defined above, and R 2 b is a leaving group, or a salt thereof, with a base, to give a compound of the formula: wherein R 1 , R 3 and n are each as defined above, or a salt thereof; (f) oxidizing a compound of the formula: wherein R 1 , R 3 and n are each as defined above, or a salt thereof, to give a compound of the formula: wherein R 1 , R 3 and n are each as defiend above, or a salt thereof; and (g) reducing a compound of the formula: wherein R 1 , R 2 , n and the symbol of a line and dotted line are each as defined above, or a salt thereof, to give a compound of the formula: wherein R 1 , R 2 , n and the symbol of a line and dotted line are each as defined above, or a salt thereof.

Claim 18

wherein R 1 is hydroxy or protected hydroxy, R is hydrogen, hydroxy or protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, n is an integer of 1 or 2, and the symbol of a line and dotted line is a single bond or a double bond, and salt thereof, which comprises (a) culturing a FR-900506, FR-900520 and/or FR-900525 substance(s)-producing strain belonging to the genus Streptomyces in a nutrient medium and recovering the FR-900506, FR-900520 and/or FR-900525 substance(s) to give the FR-900506, FR-900520 and/or FR-900525 substance(s); (b) culturing a FR-900520 and/or FR-900523 substance(s)-producing strain belonging to the genus Streptomyces in a nutrient medium and recovering the FR-900520 and/or FR-900523 substance(s) to give the FR-900520 and/or FR-900523 substance(s); (c) introducing a hydroxy-protective group into a compound of the formula: wherein R 2 , R 3 , n and the symbol of a line and dotted line are each as defined above, to give a compound of the formula: wherein R 2 , R 3 , n and the symbol of a line and dotted line are each as defiend above, and R 1 a is protected hydroxy, or a salt thereof; (d) introducing a hydroxy-protective group into a compound of the formula: wherein R 1 , R 3 , n and the symbol of a line and the dotted line are each as defined above, or a salt thereof, to give a compound of the formula: wherein R 1 , R 3 , n and the symbol of a line and dotted line are each as defined above, and R 2 a is protected hydroxy, or a salt thereof; (e) reacting a compound of the formula: wherein R 1 , R 3 and n are each as defined above, and R 2 b is a leaving group, or a salt thereof, with a base, to give a compound of the formula: wherein R 1 , R 3 and n are each as defined above, or a salt thereof; (f) oxidizing a compound of the formula: wherein R 1 , R 3 and n are each as defined above, or a salt thereof, to give a compound of the formula: wherein R 1 , R 3 and n are each as defiend above, or a salt thereof; and (g) reducing a compound of the formula: wherein R 1 , R 2 , n and the symbol of a line and dotted line are each as defined above, or a salt thereof, to give a compound of the formula: wherein R 1 , R 2 , n and the symbol of a line and dotted line are each as defined above, or a salt thereof.

Claim 19

A pharmaceutical composition containing tricyclo compounds of claim 1, as active ingredients, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

Claim 20

A use of tricyclo compounds of claim 1 for manufacture of medicament for treating or preventing resistance by transplantation, autoimmune diseases and infectious diseases.

Claim 21

17 . Use of compounds of claim 1 as a medicament.

Claim 22

Use of compounds of claim 1 in treating or preventing resistance by transplantation, autoimmune diseases and infectious diseases.

Claim 23

A biologically pure culture of the microorganism Streptomyces tsukubacnsis No. 9993.

Claim 24

A biologically pure culture of the microorganism Streptomyces tsukubacnsis No. 9993.

Claim 25

A biologically pure culture of the microorganisms Streptomyces hygroscopicus subsp. yakushimaensis No. 7238.

Claim 26

A biologically pure culture of the microorganisms Streptomyces hygroscopicus subsp. yakushimaensis No. 7238.