Conjugates of pharmaceutically useful proteins

Claim 2

A conjugate comprising a pharmaceutically useful protein linked to at least one water-soluble polymer by means of a reversible linking group.

Claim 3

A conjugate according to claim 1 in which the pharmaceutically useful protein is a fibrinolytic enzyme or pro-enzyme thereof.

Claim 4

A conjugate according to claim 1 or 2 of formula (II): where X is a pharmaceutically useful protein and the NH moiety is derived from a protein amino group in X; and either: (i) R l and R 2 are each a non-polymeric organic group or a group of formula -R 3 -P wherein P is a water-soluble polymer and R 3 is a bridging group; or (ii) R l and R 2 together are C 3 - 5 polymethylene to complete a 5- to 7-membered alicyclic ring or together complete an aromatic ring, wherein the alicyclic or aromatic ring is substituted by groups R 4 and R 5 which are each a non-polymeric organic group or a group of formula -R 3 -P; provided that at least one of R l and R 2 or of R 4 and R 5 is a group -R 3 -P.

Claim 5

A conjugate according to claim 3, wherein one of R 1 and R 2 is a group P-CH 2 - and the other is methyl.

Claim 6

A conjugate according to any preceding claim, wherein the water soluble polymer is methoxypolyethylene glycol.

Claim 7

A conjugate according to any preceding claim, wherein the pharmaceutically useful protein is tissue plasminogen activator or urokinase.

Claim 8

2-[ω-Methoxypolyethyleneglycoxymethylene]-3-methylmaleyl-human serum albumin, 2-methyl-3-[ω-methoxypolyethyleneglycoxy-methylene] -maleyl-human serum albumin, 2-[ω-methoxypolyethyleneglycoxymethylene]-3-methylmaleyl-urokinase, 2-methyl-3-[ω-methoxypolyethyleneglycoxy-methylene] -maleyl-urokinase, 2-[ω-methoxypolyethyleneglycoxymethylene]-3- methylmaleyl-tissue plasminogen activator or 2-methyl-3-[ω-methoxypolyethyleneglycoxy-methylene]-maleyl-tissue plasminogen activator.

Claim 9

2-[ω-Methoxypolyethyleneglycoxymethylene]-3-methylmaleyl-human serum albumin, 2-methyl-3-[ω-methoxypolyethyleneglycoxy-methylene] -maleyl-human serum albumin, 2-[ω-methoxypolyethyleneglycoxymethylene]-3-methylmaleyl-urokinase, 2-methyl-3-[ω-methoxypolyethyleneglycoxy-methylene] -maleyl-urokinase, 2-[ω-methoxypolyethyleneglycoxymethylene]-3- methylmaleyl-tissue plasminogen activator or 2-methyl-3-[ω-methoxypolyethyleneglycoxy-methylene]-maleyl-tissue plasminogen activator.

Claim 10

A process for preparing a conjugate according to any one of the preceding claims which process comprises reacting a pharmaceutically useful protein with a water-soluble polymer-containing reagent comprising a group which is capable of reacting with a protein amino group or derivative thereof, to form a reversible linking group.

Claim 11

A pharmaceutical composition comprising a conjugate according to any of claims 1 to 6 in combination with a pharmaceutically acceptable carrier.

Claim 12

A water-soluble polymer-containing reagent comprising a group which is capable of reacting with a protein amino group or derivative thereof, to form a reversible linking group.

Claim 13

A water-soluble polymer-containing reagent comprising a group which is capable of reacting with a protein amino group or derivative thereof, to form a reversible linking group.

Claim 14

A reagent according to claim 10 of formula (IV): wherein R l and R 2 are as defined in claim 3.

Claim 15

2-[Methoxypolyethylene (5000) glycoxymethylene] -3-methyl maleic anhydride.

Claim 16

2-[Methoxypolyethylene (5000) glycoxymethylene] -3-methyl maleic anhydride.

Claim 17

A conjugate according to any of claims 1 to 7 for use as an active therapeutic substance.

Claim 18

A conjugate according to claim 2 or any claim appendant thereto, for use in the treatment of thrombotic diseases.