# US 7,410,956 B2 · Caspase inhibitor prodrugs

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 7,410,956 B2
- Document ID: US7410956B2
- Status: Granted
- Kind: B2
- Application number: 10/366,192
- Filed: 2003-02-11
- Published: 2004-01-29
- Granted: 2008-08-12
- Earliest claimed: 2002-02-11
- Assignees: Vertex Pharmaceuticals Incorporated
- Inventors: Michael Mortimore; Julian M. C. Golec
- Web page: https://patentgrep.com/patent/US7410956B2

## CPC

- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07C 235/52: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 271/28: to a carbon atom of a non-condensed six-membered aromatic ring
- C07D 209/26: with an acyl radical attached to the ring nitrogen atom
- C07D 209/86: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
- C07D 209/94: containing carbocyclic rings other than six-membered
- C07D 211/34: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 239/90: with acyclic radicals attached in position 2 or 3
- C07F 9/10: Phosphatides, e.g. lecithin
- C07F 9/5728: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07K 5/0202: {containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to compounds of formula I which are prodrugs of caspase inhibitors and pharmaceutically acceptable salts thereof. This invention further relates to the release of caspase inhibitors from these compounds through selective bond cleavage. This invention further relates to pharmaceutical compositions comprising these compounds, which are particularly well-suited for treatment of caspase-mediated diseases, including inflammatory and degenerative diseases. This invention further relates to methods for preparing compounds of this invention.

## Claims

### Claim 1

A compound of the formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a saturated or unsaturated, straight-chain or branched, unsubstituted hydrocarbon chain;
R2 is choline;
X is a direct covalent bond; and
Y is a residue of a caspase inhibitor selected from a structure in Table 1 below:
TABLE 1
Structures of Selected Caspase Inhibitors
Comp.
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

### Claim 2 (depends on 1)

The compound of claim 1, wherein the R1 hydrocarbon chain has from 2 to 30 carbon atoms.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the R1 hydrocarbon chain has from 2 to 24 carbon atoms.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Y is a reversible caspase inhibitor.

### Claim 5 (depends on 1)

The compound of claim 1, wherein Y is an irreversible caspase inhibitor.

### Claim 6 (depends on 1, 2, 3, 4, 5)

A pharmaceutical composition comprising: a) a compound according to any one of claims 1-3 or 4-5; and b) a pharmaceutically acceptable carrier.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

A method for treating a disease selected from the group consisting of osteoarthritis, pancreatitis, rheumatoid arthritis, chronic active hepatitis, inflammatory bowel disease, Crohn's disease, psoriasis, organ transplant rejection, sepsis, septic shock, cerebral ischemia, myocardial ischemia, myocardial infarction, amyotrophic lateral sclerosis, multiple sclerosis, neurological damage due to stroke, hepatitis-B, hepatitis-C, hepatitis-G and liver disease, in a mammal comprising administering to said mammal a compound according to any one of claims 1-3 or 4-5 or a composition according to claim 6.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6)

A method for treating complications associated with coronary artery bypass grafts in a mammal comprising administering to said mammal a compound according to any one of claims 1-3 or 4-5 or a composition according to claim 6.

### Claim 9 (depends on 7, 8)

The method according to any one of claims 7 or 8, wherein said mammal is a human.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6)

A method for preserving cells in vitro comprising treating the cells with a solution comprising an effective amount of a compound according to any one of claims 1-5 or a composition according to claim 6.

### Claim 11 (depends on 10)

The method according to claim 10, wherein said compound or composition is used for an organ transplant or for preserving blood products.

### Claim 12 (depends on 7, 8)

The method according to any one of claims 7 or 8, wherein said compound or composition is administered with an additional therapeutic agent.

### Claim 13 (depends on 12)

The method according to claim 12, wherein said additional therapeutic agent is a thrombolytic agent.

### Claim 14 (depends on 13)

The method according to claim 13, wherein said thrombolytic agent is selected from the group consisting of tissue plasminogen activator and streptokinase.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6)

A method for decreasing IGIF or IFN-γ production in a mammal in need thereof comprising administering to said mammal a compound according to any one of claims 1-5 or a composition according to claim 6, wherein the method is used to treat a disease selected from the group consisting of osteoarthritis, pancreatitis, rheumatoid arthritis, chronic active hepatitis, inflammatory bowel disease, Crohn's disease, psoriasis, organ transplant rejection, sepsis, septic shock, cerebral ischemia, myocardial ischemia, myocardial infarction, amyotrophic lateral sclerosis, multiple sclerosis, neurological damage due to stroke, hepatitis-B, hepatitis-C, hepatitis-G, and liver disease.