Methods for the treatment of cysteamine sensitive disorders
AssigneeThiogenesis Therapeutics, Inc.
InventorsVincent P. STANTON, Jr., Patrice P. RIOUX, Piotr BARSKI, Dariusz WITT
Life of this patent
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Abstract
The invention features methods for the treatment of cystinosis and other cysteamine sensitive disorders in a subject including administration of a disulfide convertible to cysteamine in vivo. The methods can include the separate administration of a reducing agent to the subject to increase the bioavailablity and extend the plasma pharmacokinetic profile of the cysteamine produced following administration of the disulfide. The methods permit sustained cysteamine plasma concentrations in a subject.
Claims105
A method for treating a cysteamine sensitive disorder in a subject comprising administering to the subject a dose of from 50 to 150 milligrams per kilogram of body weight (mg/kg) of compound 1:
- or a pharmaceutically acceptable salt thereof, one or more times daily.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising a reducing agent;
- and
- (iii) instructions for administering the second pharmaceutical composition at least two hours after the first pharmaceutical composition is administered to a subject for the treatment of a cysteamine sensitive disorder.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising a pantetheinase inducing agent;
- and
- (iii) instructions for administering the first pharmaceutical composition and the second pharmaceutical composition to a subject for the treatment of a cysteamine sensitive disorder.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising cystamine, or a pharmaceutically acceptable salt thereof;
- and
- (iii) instructions for administering the second pharmaceutical composition within 30 minutes of administration of the first pharmaceutical composition to a subject for the treatment of a cysteamine sensitive disorder.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising compound 3, or a pharmaceutically acceptable salt thereof;
- and
- (iii) instructions for administering the second pharmaceutical composition within 30 minutes of administration of the first pharmaceutical composition to a subject for the treatment of a cysteamine sensitive disorder.
A method for treating a cysteamine sensitive disorder in a subject comprising administering to the subject a dose of from 50 to 150 milligrams per kilogram of body weight (mg/kg) of compound 2:
- or a pharmaceutically acceptable salt thereof, one or more times daily.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 2, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising a reducing agent;
- and
- (iii) instructions for administering the second pharmaceutical composition at least two hours after the first pharmaceutical composition is administered to a subject for the treatment of a cysteamine sensitive disorder.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 2, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising a pantetheinase inducing agent;
- and
- (iii) instructions for administering the first pharmaceutical composition and the second pharmaceutical composition to a subject for the treatment of a cysteamine sensitive disorder.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 2, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising cystamine, or a pharmaceutically acceptable salt thereof;
- and
- (iii) instructions for administering the second pharmaceutical composition within 30 minutes of administration of the first pharmaceutical composition to a subject for the treatment of a cysteamine sensitive disorder.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 2, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising compound 3, or a pharmaceutically acceptable salt thereof;
- and
- (iii) instructions for administering the second pharmaceutical composition within 30 minutes of administration of the first pharmaceutical composition to a subject for the treatment of a cysteamine sensitive disorder.
The kit of any one of claims 36-39, wherein the instructions are for performing the method of any one of claims 21-55.
A pharmaceutical composition comprising compound 3:
- or a pharmaceutically acceptable salt thereof.
A method for treating a cysteamine sensitive disorder in a subject comprising administering to the subject a dose of from 50 to 150 milligrams per kilogram of body weight (mg/kg) of compound 3:
- or a pharmaceutically acceptable salt thereof, one or more times daily.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 3, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising a reducing agent;
- and
- (iii) instructions for administering the second pharmaceutical composition at least two hours after the first pharmaceutical composition is administered to a subject for the treatment of a cysteamine sensitive disorder.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 3, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising a pantetheinase inducing agent;
- and
- (iii) instructions for administering the first pharmaceutical composition and the second pharmaceutical composition to a subject for the treatment of a cysteamine sensitive disorder.
A kit comprising:
- (i) a first pharmaceutical composition comprising compound 3, or a pharmaceutically acceptable salt thereof;
- (ii) a second pharmaceutical composition comprising cystamine, or a pharmaceutically acceptable salt thereof;
- and
- (iii) instructions for administering the second pharmaceutical composition within 30 minutes of administration of the first pharmaceutical composition to a subject for the treatment of a cysteamine sensitive disorder.
An acid addition salt of compound 1, wherein the acid is hydrochloric acid, acetic acid, trifluoroacetic acid, or tartaric acid.
A method of synthesizing an asymmetric disulfide, said method comprising combining:
- (a) 1 molar equivalent of an organic carboxylic acid, or a salt thereof;
- (b) from 2 to 4 molar equivalents of cystamine, or a salt thereof;
- and
- (c) an amide coupling reagent,
- to form a mixture comprising greater than 90% of the organic carboxylic acid, or a salt thereof, is converted to the asymmetric disulfide of formula (A) and less than 10% organic carboxylic acid remains unreacted or is converted into the symmetric disulfide of formula (B):
- wherein R is an organic radical.
A method of synthesizing an asymmetric disulfide, said method comprising combining in an organic solvent:
- (a) from 2 to 4 molar equivalents of a thiol selected from cysteamine, N-acetylcysteamine, cysteine, N-acetylcysteine, N-acetylcysteine amide, or salts thereof;
- and
- (b) 1 molar equivalent of a disulfide selected from cystamine, pantethine, or salts thereof.
Dependencies are inferred from the claim text.