US2011144074A1PendingUtilityA1
Caspase inhibitors and uses thereof
Est. expiryMay 23, 2021(expired)· nominal 20-yr term from priority
A61P 37/02A61P 3/06A61P 3/10A61P 39/02A61P 9/10A61P 37/00A61P 37/04A61P 7/06A61P 9/00A61P 37/08A61P 37/06A61P 43/00A61P 7/00A61P 9/04A61P 5/14A61P 7/04A61P 31/18A61P 3/00A61P 35/00A61P 31/00A61P 25/14A61P 25/32A61P 29/00A61P 31/04A61P 25/00A61P 25/28A61P 35/02A61P 25/08A61P 27/00A61P 31/12A61P 31/20A61P 25/16A61K 31/435A61K 31/5025A61P 1/00A61P 13/00A61P 1/18A61K 31/407A61P 17/00A61K 31/498A61K 31/55A61P 1/10A61P 1/16A61K 31/45A61P 11/06A61P 19/02A61K 31/538A61P 11/00A61P 19/08A61K 31/4015A61P 13/12A61P 17/14A61P 19/10A61P 19/00A61P 1/04A61P 17/02A61K 31/54A61P 17/06A61P 21/00A61K 31/403A61P 21/04Y02A50/30
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Claims
Abstract
This invention provides caspase inhibitors of formula I: wherein Z is oxygen or sulfur; R 1 is hydrogen, —CHN 2 , R, CH 2 OR, CH 2 SR, or —CH 2 Y; between R 3 and R 4 represents a single or double bond; Y is an electronegative leaving group; R 2 is CO 2 H, CH 2 CO 2 H, or esters, amides or isosteres thereof; R 3 is a group capable of fitting into the S2 subsite of a caspase enzyme; R 4 is a hydrogen or C 1-6 alkyl or R 3 and R 4 taken together form a ring; Ring A and Ring B are each heterocyclic rings, and R and R 5 are as described in the specification. The compounds are effective inhibitors of apoptosis and IL-1β secretion.
Claims
exact text as granted — not AI-modified1 . A method of treating a disease in a patient that is alleviated by treatment with a caspase inhibitor, comprising administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I:
or a pharmaceutically-acceptable derivative thereof,
wherein:
next to R 3 represents a single or double bond;
Z is oxygen or sulfur;
R 1 is hydrogen, —CHN 2 , —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
R is a C 1-12 aliphatic, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;
Y is an electronegative leaving group;
R 2 is CO 2 H, CH 2 CO 2 H, or esters, amides or isosteres thereof;
R 3 is a group capable of fitting into the S2 sub-site of a caspase;
R 4 is hydrogen or a C 1-6 aliphatic group that is optionally interrupted by —O—, —S—, —SO 2 —, —CO—, —NH—, or —N(C 1-4 alkyl)-, or R 3 and R 4 taken together with their intervening atoms optionally form a 3-7 membered ring having 0-2 heteroatoms selected from nitrogen, oxygen or sulfur;
Ring A is a nitrogen-containing mono-, bi- or tricyclic ring system having 0-5 additional ring heteroatoms selected from nitrogen, oxygen or sulfur;
Ring B is a nitrogen-containing 5-7 membered ring having 0-2 additional ring heteroatoms selected from nitrogen, oxygen or sulfur;
R 5 is R 6 , (CH 2 ) n R 6 , COR E , CO 2 R 6 , SO 2 R 6 , CON(R 6 ) 2 , or SO 2 N(R 6 ) 2 ;
n is one to three; and
each R 6 is independently selected from hydrogen, an optionally substituted C 1-4 aliphatic group, an optionally substituted C 6-10 aryl group, or a mono- or bicyclic heteroaryl group having 5-10 ring atoms.
2 . The method of claim 1 where next to R 3 represents a single bond and Z is oxygen.
3 . The method of claim 2 wherein the compound is a compound of formula Ia.
4 . The method of claim 3 wherein the compound has one or more of the following features:
(i) R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
(ii) R 2 is CO 2 H or an ester, amide or isostere thereof;
(iii) R 3 is a group having a molecular weight up to 140 Daltons;
(iv) R 4 is hydrogen or C 1-6 alkyl; and
(v) Ring A is a monocyclic, bicyclic or tricyclic ring system wherein each ring of the system has 5-7 ring atoms.
5 . The method of claim 4 wherein the compound has the following features:
(i) R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
(ii) R 2 is CO 2 H or an ester, amide or isosteres thereof;
(iii) R 3 is a group having a molecular weight up to 140 Daltons;
(iv) R 4 is hydrogen or C 1-6 alkyl; and
(v) Ring A is a monocyclic, bicyclic or tricyclic heterocyclic or heteroaryl ring system wherein each ring of the system has 5-7 ring atoms.
6 . The method of claim 5 wherein R 1 is —CH 2 Y.
7 . The method of claim 6 wherein R 1 is —CH 2 F.
8 . The method of claim 7 wherein R 3 is a C 1-4 alkyl group.
9 . The method of claim 8 wherein Ring A is a tricyclic heterocyclic or heteroaryl ring system wherein each ring of the system has 5-7 ring atoms.
10 . The method of claim 9 wherein the middle ring of the tricyclic ring system is a five- or six-membered ring.
11 . The method of claim 4 wherein Ring A is selected from indole, isoindole, indoline, indazole, purine, dihydropyridine, benzimidazole, imidazole, imidazoline, pyrrole, pyrrolidine, pyrroline, pyrazole, pyrazoline, pyrazolidine, triazole, piperidine, morpholine, thiomorpholine, piperazine, carbazole, iminostilbene, phenothiazine, phenoxazine, dihydrophenazine, dihydrocinnoline, dihydroquinoxaline, tetrahydroquinoline, tetrahydroisoquinoline, dihydronaphthyridine, tetrahydronaphthyridine, dihydroacridine, β-carboline, pyrido[4,3-b]indole, 2,3,9-triazafluorene, 9-thia-2,10-diazaanthracene, 3,6,9-triazafluorene, thieno[3,2-b]pyrrole, or dihydrophenanthridine.
12 . The method of claim 5 wherein Ring A is selected from indole, isoindole, indoline, indazole, purine, dihydropyridine, benzimidazole, imidazole, imidazoline, pyrrole, pyrrolidine, pyrroline, pyrazole, pyrazoline, pyrazolidine, triazole, piperidine, morpholine, thiomorpholine, piperazine, carbazole, iminostilbene, phenothiazine, phenoxazine, dihydrophenazine, dihydrocinnoline, dihydroquinoxaline, tetrahydroquinoline, tetrahydroisoquinoline, dihydronaphthyridine, tetrahydronaphthyridine, dihydroacridine, β-carboline, pyrido[4,3-b]indole, 2,3,9-triazafluorene, 9-thia-2,10-diazaanthracene, 3,6,9-triazafluorene, thieno[3,2-b]pyrrole, or dihydrophenanthridine.
13 . The method of claim 12 wherein Ring A is selected from carbazole, phenothiazine, β-carboline, pyrido[4,3-b]indole, 2,3,9-triazafluorene, 9-thia-2,10-diazaanthracene, 3,6,9-triazafluorene, phenoxazine, dibenzoazepine, dihydro-dibenzoazepine, dihydrophenazine, dihydroacridine, or dihydrophenanthridine.
14 . The method of claim 1 wherein the compound is selected from the following Table 1 compounds
No.
Structure
Ia-1
Ia-2
Ia-3
Ia-4
Ia-5
Ia-6
Ia-7
Ia-8
Ia-9
Ia-10
Ia-11
Ia-12
Ia-13
Ia-14
Ia-15
Ia-16
Ia-17
Ia-18
Ia-19
Ia-20
Ia-21
Ia-22
Ia-23
Ia-24
Ia-25
Ia-26
Ia-27
Ia-28
Ia-29
Ia-30
Ia-31
Ia-32
Ia-33
Ia-34
Ia-35
Ia-36
Ia-37
Ia-38
Ia-39
Ia-40
Ia-41
Ia-42
Ia-43
Ia-44
15 . The method of claim 2 wherein the compound is a compound of formula Ib.
16 . The method of claim 15 wherein the compound has one or more of the following features:
(i) R 1 is —CH 2 OR, —CH 2 SR, or —CH 2 Y;
(ii) R 2 is CO 2 H or an ester, amide or isostere thereof;
(iii) R 3 is a group having a molecular weight up to about 140 Daltons;
(iv) Ring B is a nitrogen-containing five to seven membered ring having 0-1 additional ring heteroatoms selected from nitrogen, oxygen or sulfur; and
(v) R 5 is an optionally substituted C 1-6 aliphatic group, an optionally substituted phenyl or an optionally substituted benzyl group.
17 . The method of claim 16 wherein the compound has the following features:
(i) R 1 is —CH 2 OR, —CH 2 SR, or —CH 2 Y;
(ii) R 2 is CO 2 H or an ester, amide or isostere thereof;
(iii) R 3 is a group having a molecular weight up to about 140 Daltons;
(iv) Ring B is a nitrogen-containing five to seven membered ring having 0-1 additional ring heteroatoms selected from nitrogen, oxygen or sulfur; and
(v) R 5 is an optionally substituted C 1-6 aliphatic group, an optionally substituted phenyl or an optionally substituted benzyl group.
18 . The method of claim 17 wherein R 1 is —CH 2 Y.
19 . The method of claim 18 wherein R 1 is —CH 2 F.
20 . The method of claim 19 wherein R 3 is a C 1-4 alkyl group.
21 . The method of claim 2 wherein the compound is selected from the following compounds
22 . The method according to claim 1 wherein the disease is selected from an IL-1 mediated disease, an apoptosis mediated disease, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a disease associated with cell death, an excess dietary alcohol intake disease, a viral mediated disease, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, graft vs host disease, organ transplant rejection, osteoporosis, leukemias and related disorders, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, haemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy's disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, coronary artery bypass graft, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue fever, or Japanese encephalitis, various forms of liver disease including alcoholic hepatitis, renal disease, polyaptic kidney disease, H. pylori -associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, and meningitis.
23 . The method according to claim 1 wherein the compound is used for the preservation of cells, said method comprising the step of bathing the cells in a solution of the compound or a pharmaceutically acceptable derivative thereof.
24 . The method according to claim 1 wherein the compound or a pharmaceutically acceptable derivative thereof is used for an organ transplant or for preserving blood products.
25 . The method according to claim 1 wherein the compound is used as a component of immunotherapy for the treatment of cancer.
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