US2011152276A1PendingUtilityA1
Substituted pyrrolo[2,3-d]pyrimidines as antifolates
Est. expiryJan 19, 2027(~0.5 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 37/00A61P 35/00A61P 35/02A61P 9/10A61P 27/02A61P 29/00C07D 487/04A61P 19/02A61P 17/06A61P 11/06A61K 31/519
44
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Claims
Abstract
The present invention is directed to antifolate compounds having the structure wherein: X is CHR 9 or NR 9 ; Y 1 , Y 2 , and Y 3 independently are O or S; V 1 and V 2 independently are O, S, or NZ; Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; R 1 and R 2 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; as well as pharmaceutically acceptable esters, amides, salts, solvates, and prodrugs thereof. The compounds are useful in pharmaceutical compositions and in methods of treating multiple conditions, including abnormal cell proliferation, inflammatory diseases, asthma, and arthritis.
Claims
exact text as granted — not AI-modified1 . A method for treating a condition selected from the group consisting of abnormal cell proliferation, inflammation, asthma, and arthritis, the method comprising administering to a patient in need of treatment for the condition a compound according to the following formula
wherein:
X is CHR 9 or NR 9 ;
Y 1 , Y 2 , and Y 3 independently are O or S;
V 1 and V 2 independently are O, S, or NZ;
Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 1 and R 2 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and
R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; or
a pharmaceutically acceptable ester, amide, salt, or enantiomer thereof
2 . The method of claim 1 , wherein the condition is arthritis.
3 . The method of claim 1 , wherein the condition is rheumatoid arthritis.
4 . The method of claim 1 , wherein the condition is psoriatic arthritis.
5 . The method of claim 1 , wherein the condition is psoriasis.
6 . The method of claim 1 , wherein the condition is a disease of the eye.
7 . The method of claim 1 , wherein the condition is an inflammatory bowel disease.
8 . The method of claim 1 , wherein the condition is lupus.
9 . The method of claim 1 , wherein the condition is multiple sclerosis.
10 . The method of claim 1 , wherein the condition is asthma.
11 . The method of claim 1 , wherein the condition is a disorder of the cardiovascular system.
12 . The method of claim 1 , wherein the condition is atherosclerosis.
13 . The method of claim 1 , wherein the condition is a cancerous condition selected from the group consisting of hemangioma, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuroma, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipoma, leiomyoma, mesothelioma, teratoma, myxoma, nodular regenerative hyperplasia, trachoma, pyogenic granuloma, sarcoma, carcinoma, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder cancer, pancreatic cancer, rectal cancer, parathyroid cancer, thyroid cancer, adrenal cancer, neural tissue cancer, colon cancer, stomach cancer, bronchial cancer, kidney cancer, basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, reticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuroma, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma, malignant hypercalcemia, renal cell tumor, polycythemia vera, adenocarcinoma, glioblastoma multiforma, leukemia, lymphoma, malignant melanoma, and epidermoid carcinoma.
14 . The method according to claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.
15 . The method according to claim 14 , wherein the compound is in the form of an alkali metal salt.
16 . The method according to claim 15 , wherein the compound is in the form of a disodium salt.
17 . The method according to claim 14 , wherein one or both of R 1 and R 2 are replaced by a salt-forming cation.
18 . The method according to claim 17 , wherein the salt-forming cation comprises an alkali metal cation.
19 . The method according to claim 14 , wherein V 1 and V 2 are O, and R 1 and R 2 are both independently replaced by a salt-forming cation.
20 . The method according to claim 19 , wherein the salt-forming cation comprises an alkali metal cation.
21 . The method of claim 1 , wherein the compound has the following formula
wherein:
X is CHR 9 or NR 9 ;
R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and
R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; or
a pharmaceutically acceptable ester, amide, salt, or enantiomer thereof.
22 . The method of claim 21 , wherein the compound is in the form of a pharmaceutically acceptable salt.
23 . The method of claim 22 , wherein the compound is in the form of an alkali metal salt.
24 . The method of claim 23 , wherein the compound is in the form of a disodium salt.
25 . The method of claim 1 , wherein the compound has the following formula
wherein:
X is CHR 9 or NR 9 ;
Y 1 , Y 2 , and Y 3 independently are O or S;
V 1 and V 2 independently are O, S, or NZ;
Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 1 and R 2 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and
R 9 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; or
a pharmaceutically acceptable ester, amide, salt, or enantiomer thereof.
26 . The method of claim 25 , wherein the compound is in the form of a pharmaceutically acceptable salt.
27 . The method of claim 26 , wherein the compound is in the form of an alkali metal salt.
28 . The method of claim 27 , wherein the compound is in the form of a disodium salt.
29 . The method of claim 25 , wherein one both of R 1 and R 2 are replaced by a salt-forming cation.
30 . The method of claim 29 , wherein the salt-forming cation comprises an alkali metal cation.
31 . The method of claim 25 , wherein V 1 and V 2 are O, and R 1 and R 2 are both independently replaced by a salt-forming cation.
32 . The method of claim 31 , wherein the salt-forming cation comprises an alkali metal cation.
33 . The method of claim 1 , wherein the compound has the following formula
or a pharmaceutically acceptable ester, amide, salt, or enantiomer thereof.
34 . The method of claim 33 , wherein the compound is in the form of a pharmaceutically acceptable salt.
35 . The method of claim 34 , wherein the compound is in the form of an alkali metal salt.
36 . The method of claim 34 , wherein the compound is in the form of a disodium salt.
37 . The method of claim 33 , wherein the compound is enantiomerically pure for the (S) enantiomer.
38 . The method of claim 37 , wherein the compound has an enantiomeric purity of at least about 80%.
39 . The method of claim 37 , wherein the compound has an enantiomeric purity of at least about 95%.
40 . The method of claim 33 , wherein the compound is enantiomerically pure for the (R) enantiomer.
41 . The method of claim 40 , wherein the compound has an enantiomeric purity of at least about 80%.
42 . The method of claim 40 , wherein the compound has an enantiomeric purity of at least about 95%.
43 . The method of claim 36 , wherein the compound is enantiomerically pure for the (S) enantiomer.
44 . The method of claim 43 , wherein the compound has an enantiomeric purity of at least about 80%.
45 . The method of claim 43 , wherein the compound has an enantiomeric purity of at least about 95%.
46 . The method of claim 36 , wherein the compound is enantiomerically pure for the (R) enantiomer.
47 . The method of claim 46 , wherein the compound has an enantiomeric purity of at least about 80%.
48 . The method of claim 46 , wherein the compound has an enantiomeric purity of at least about 95%.
49 . The method of claim 1 , wherein the compound has the following formula
or an enantiomer thereof.
50 . The method of claim 1 , wherein the compound is administered as a component of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
51 . The method of claim 1 , wherein the compound is administered in combination with one or more further active agents.
52 . The method of claim 51 , wherein the compound and the one or more further active agents are administered in separate pharmaceutical compositions, each pharmaceutical composition comprising a pharmaceutically acceptable carrier.
53 . The method of claim 51 , wherein the one or more further active agents comprises methotrexate.
54 . A method for treating a condition responsive to inhibition of dihydrofolate reductase (DHFR), the method comprising administering to a patient in need of treatment for the condition an amount of a compound according to the following formula therapeutically effective to inhibit DHFR,
wherein:
X is CHR 9 or NR 9 ;
Y 1 , Y 2 , and Y 3 independently are O or S;
V 1 and V 2 independently are O, S, or NZ;
Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 1 and R 2 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and
R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; or
a pharmaceutically acceptable ester, amide, salt, or enantiomer thereof
55 . The method of claim 54 , wherein the inhibition of DHFR is selective.
56 . The method of claim 55 , wherein the selective inhibition of DHFR comprises inhibition of DHFR without inhibition of TS or GARFT.
57 . The method of claim 54 , wherein the compound is administered as a component of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
58 . The method of claim 54 , wherein the compound is administered in combination with one or more further active agents.
59 . The method of claim 58 , wherein the compound and the one or more further active agents are administered in separate pharmaceutical compositions, each pharmaceutical composition comprising a pharmaceutically acceptable carrier.
60 . The method of claim 58 , wherein the one or more further active agents comprises methotrexate.Join the waitlist — get patent alerts
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