Heteroatoms-containing tricyclic compounds

Claim 2

A compound of formula I wherein R, is acyloxy or optionally protected hydroxy; R 2 is optionally protected hydroxy or is absent, whereby, when R 3 is cyclopropylmethyl or methylcyclopropylmethyl, R 2 additionally can be hydrogen; R 3 is methyl, ethyl, n-propyl, allyl, cyclopropylmethyl or methylcyclopropylmethyl; either R 4 is hydrogen, optionally protected hydroxy, acyloxy or is absent; and R 5 is unprotected hydroxy, halogen of atomic number of from 9 to 53 or is absent; or R 4 and R 5 together form a group -OC(=O)O- or -OC(=S)O-; and Rs is hydrogen or, when R 4 and R 5 together form a group -OC(=O)O-, is hydrogen or methoxy; or R 4 and R 5 6 together form a group oxo; and R 5 is unprotected hydroxy or halogen of atomic number of from 9 to 53 or is absent; R 7 is unprotected hydroxy or methoxy; and n is 1 or 2, with the provisos that a) at least one of R 1 , R 2 , R 4 and R 5 is other than unprotected hydroxy; b) when R 4 and R 6 together form a group oxo, then either R 3 is cyclopropylmethyl or methylcyclopropylmethyl; or R 5 is halogen of atomic number of from 9 to 53 or is absent; and c) when R 1 is acyloxy, then either R 4 and Rs are other than together a group oxo; or R 4 and R 6 together form a group oxo and Rs is halogen of atomic number of from 9 to 53 or is absent.

Claim 3

A compound according to claim 1 of formula I wherein R 1 is acetoxy or optionally protected hydroxy; R 2 is optionally protected hydroxy or is absent; R 3 is methyl, ethyl, n-propyl or allyl; either R 4 is hydrogen, optionally protected hydroxy, acetoxy or is absent; and Rs is unprotected hydroxy or halogen of atomic number of from 9 to 53 or is absent; or R 4 and R 5 together form a group -OC( = 0)0- or -OC( = S)O-; and R 6 is hydrogen or, when R 4 and Rs together form a group -OC(=0)0-, is hydrogen or methoxy; or R 4 and R 6 together form a group oxo; and R 5 is unprotected hydroxy or halogen of atomic number of from 9 to 53 or is absent; R 7 is methoxy; and n is 1 or 2, with the provisos that a) at least one of R 1 , R 2 , R 4 and Rs is other than unprotected hydroxy; b) when R 4 and R 5 together form a group oxo, then R 5 is halogen of atomic number of from 9 to 53 or is absent; and c) when R 1 is acetoxy, then either R 4 and R 6 are other than together a group oxo; or R 4 and R 6 together form a group oxo and R 5 is halogen of atomic number of from 9 to 53 or is absent.

Claim 4

A compound according to claim 1 of formula I wherein R 1 is acetoxy or optionally protected hydroxy; R 2 is hydrogen or optionally protected hydroxy; R 3 is cyclopropylmethyl or methylcyclopropylmethyl; either R 4 and R 5 are unprotected hydroxy; and R 6 is hydrogen; or R 4 and Rs together form a group oxo; and Rs is unprotected hydroxy; R 7 is methoxy; and n is 2, with the provisos that a) at least one of Ri, R 2 , R 4 and R 5 is other than unprotected hydroxy; b) when R 1 is acetoxy, then R4 and R 5 are other than together a group oxo.

Claim 5

A compound according to claim 1 of formula I wherein R 1 is alkylcarbonyloxy of altogether 2 to 6 carbon atoms, benzoyloxy monosubstituted by halogen of atomic number of from 9 to 53 or hydroxy optionally protected by tert-butyldimethylsilyl; R 2 is hydroxy optionally protected by tert-butyldimethylsilyl or is absent; R 3 is ethyl, allyl, cyclopropylmethyl or methylcyclopropylmethyl; either R 4 is hydrogen, unprotected hydroxy, acetoxy or is absent; R 5 is unprotected hydroxy, halogen of atomic number of from 9 to 53 or is absent; or R 4 and R 5 together form a group -OC( = 0)0- or -OC( = S)O-; and R 6 is hydrogen or, when R 4 and R 5 together form a group -OC(=0)0-, is hydrogen or methoxy; or R 4 and R 6 together form a group oxo; and R 5 is unprotected hydroxy, halogen of atomic number of from 9 to 53 or is absent; R 7 is methoxy; and n is 2, with the provisos that a) at least one of R 1 , R 2 , R 4 and R s is other than unprotected hydroxy; b) when R 4 and R 6 together form a group oxo, then either R 3 is cyclopropylmethyl or methylcyclopropylmethyl; or R 5 is halogen of atomic number of from 9 to 53 or is absent; and c) when R 1 is alkylcarbonyloxy or benzoyloxy as defined in this claim, then either R 4 and R 6 are other than together a group oxo; or R 4 and R 6 together form a group oxo and R 5 is halogen of atomic number of from 9 to 53 or is absent.

Claim 6

A compound of formula I according to claim 1 selected from - 9(R)-dihydro-10-desoxy-Δ 10,11 -FK506 (compound of Example 11); - 33-acetoxy-9(S)-dihydro-FK506-9,10-carbonate (compound of Example 20); - 33-pivaloyloxy-9(S)-dihydro-FR520 (compound of Example 25); - 9(R)-dihydro-10-desoxy-Δ 10,11 -FR520 (compound of Example 30); - 21-desallyl-21-cyclopropylmethyl-FK506 (compound of Example 61); and - 21-desallyl-21-methylcyclopropylmethyl-FK506 (compound of Example 65).

Claim 7

A process for the preparation of a compound according to claim 1 comprising a) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that R 4 is unprotected hydroxy and R 6 is hydrogen (i.e. a compound la), reducing a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that R 4 and R 6 together form a group oxo (i.e. a compound Ib); b) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that at least one of R 1 , R 2 and R 4 is unprotected hydroxy (i.e. a compound lc), deprotecting a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that at least one of Ri, R 2 and R 4 is protected hydroxy (i.e. a compound ld); c) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that at least one of R, and R 4 is acyloxy (i.e. a compound le), acylating a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that at least one of R, and R 4 is unprotected hydroxy (i.e. a compound If); d) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that R 4 and R 5 together form a group -OC( = O)O- or -OC( = S)O- and R 6 is hydrogen (i.e. a compound lg), reacting with N,N -carbonyl- or N,N'-thiocarbonyldiimidazol a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that R 4 and R s are unprotected hydroxy and R 6 is hydrogen (i.e. a compound Ih); e) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that R 5 is halogen of atomic number of from 9 to 53 (i.e. a compound li), halogenating a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that R 5 is unprotected hydroxy (i.e. a compound Ij); f) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that Rs is absent and there is a double bond in position 10,11 (i.e. a compound Ik), splitting off hydrogen halide from a corresponding compound li; g) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that R 4 and R 5 together form a group -OC( = 0)0- and R 6 is methoxy (i.e. a compound lm), reacting with a hydrogen carbonate a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that R 4 and Rs together form a group oxo and R 5 is halogen of atomic number of from 9 to 53 (i.e. a compound In); h) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that R 4 and R 5 are absent (i.e. a compound lo), reacting with tributyl tin hydride a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that R 4 and R 5 together form a group -OC(=S)O-(i.e. a compound lp); i) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that R 2 and R 5 are absent and there is a double bond in positions 10,11 and 23,24 (i.e. a compound lq), dehydrating a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that R 2 and Rs are unprotected hydroxy (i.e. a compound lr); or j) for the preparation of a compound of formula I as defined in claim 1 under formula I with the further proviso that R 3 is cyclopropylmethyl or methylcyclopropylmethyl and there is a single bond in position 9,10 (i.e. a compound Is), reacting with diazomethane or -ethane a corresponding compound of formula I as defined in claim 1 under formula I with the further proviso that R 3 is allyl and there is a single bond in position 9,10 (i.e. a compound It), whereby in the above process variants reactive groups which are not meant to take part in a reaction may be transiently protected and the protecting group(s) split off after completion of the reaction.

Claim 8

A pharmaceutical composition comprising a compound according to claim 1 in association with at least one pharmaceutically acceptable carrier or diluent.

Claim 9

A compound according to claim 1 for use as a pharmaceutical.

Claim 10

A compound according to claim 1 for use as an immunosuppressant or antiinflammatory agent.

Claim 11

A method of treatment comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need of such treatment.