US2009176745A1PendingUtilityA1
Triarylmethane analogs and their use in treating cancers
Est. expiryDec 31, 2027(~1.4 yrs left)· nominal 20-yr term from priority
Inventors:Jack L. Arbiser
A61P 35/00A61P 43/00A61P 33/00A61P 33/02A61P 35/02A61P 35/04A61P 33/06A61K 31/136C07D 215/26A61K 31/353A61K 31/428A61P 27/02C07F 9/4056C07D 215/46C07D 275/06A61K 31/55C07D 279/28A61P 27/12C07D 223/28A61K 31/4706A61K 31/662A61K 31/553A61K 31/14A61P 27/00C07D 263/32A61P 27/06A61K 31/422C07D 311/36A61K 31/4709A61K 9/127C07D 223/26A61K 31/404A61K 31/47C07F 9/4059A61K 31/54A61P 27/14Y02A50/30
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Claims
Abstract
Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are triphenyl methane analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers, inflammatory, degenerative and vascular diseases, including various ocular diseases, and parasitic infections. Representative triphenyl methane analogs include triphenyl methane analogues of various dyes, hormones, sugars, peptides, oligonucleotides, amino acids, nucleotides, nucleosides, and polyols. The compounds are believed to function by inhibiting tNOX expression, the effects of ROS, and/or the production of HIF2. Thus, the compounds are novel therapeutic agents for a variety of cancers and other diseases.
Claims
exact text as granted — not AI-modified1 . A method for treating a cancer in a mammal having cancer cells that express tNOX, comprising administering to the mammal a therapeutically effective amount of a composition comprising a triarylmethane therapeutic agent in an amount sufficient to inhibit a therapeutically significant amount of tNOX expression, such that the growth of the tumor is at least partially inhibited.
2 . The method of claim 1 wherein the mammal is a human.
3 . The method of claim 1 wherein the cancer is selected from a group consisting of hemangioma, melanoma, rectal carcinoma, colon carcinoma, breast carcinoma, ovarian carcinoma, small cell lung carcinoma, colon carcinoma, chronic lymphocytic carcinoma, hairy cell leukemia, osophogeal carcinoma, prostate carcinoma, breast cancer, myeloma, and lymphoma.
4 . The method of claim 1 , wherein the cancer is a metastasized cancer.
5 . The method of claim 1 wherein the human is immunosuppressed by reason of having undergone anti-cancer therapy prior to administration of the composition.
6 . The method of claim 1 , wherein the cancer is manifested in the form of a solid tumor having cells that express tNOX.
7 . The method of claim 6 , wherein the tumor is a tumor of epithelial tissue, lymphoid tissue, connective tissue, bone, or the central nervous system.
8 . The method of claim 1 , wherein the compounds are administered parenterally, orally, or directly into the tumor.
9 . The method of claim 1 , wherein the compounds are administered via an implanted device.
10 . The method of claim 1 , wherein the administration is provided using a sustained release formulation.
11 . The method of claim 1 , wherein compound has one of the following formulas:
and counterparts to Formula 4 that include the heteroaryl rings in Formulas 2 and 3,
wherein
J represents a direct linkage between the two aryl rings, O, S, Se, NR, or (CR 2 ) n
n=0-4,
E is CH, C bonded to a substituent Z, as defined herein, or N,
R═H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl,
X═H, amine, hydroxy, ether, thiol, or thiol ether,
Y═O, S, or NR 2 , where an amine can optionally link back to the ring in an ortho position via an alkyl, alkenyl, alkynyl, alkylaryl, or arylalkyl moiety,
Z=an optional substituent, a cyclic ring attached to the aryl ring, or a second aryl or heteroaryl ring attached to the benzene ring or cyclohexadiene ring,
wherein the aryl or heteroaryl rings can be substituted at any free position with H or a substituent, Z, as described herein, and
substituents defined by Z are selected from the group consisting of C 1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl.
12 . The method of claim 11 , wherein X is selected from the group consisting of amine, hydroxy, ether, thiol, and thiol ether.
13 . The method of claim 1 , wherein the compound has the following formula:
wherein
Z, X, and J are as defined above in claim 11 ,
X′ is O, S, NR, or NR 2 + ,
T is selected from the group consisting of —C(O)—, —C(O)—O—, —C(O)—S—, —C(O)—NR—, —O—C(O)—, —S—C(O)—, —NR—C(O)—, NR, O, S, (—CR 2 ) n , (—CR 2 ) n —NR—, (—CR 2 ) n —O—, and (—CR 2 ) n —S—; and
U is selected from the group consisting of —C(O)—, NR, S, O, and (—CR 2 ) n .
14 . The method of claim 13 , wherein the tricyclic rings including the U and T substituents are selected from the group consisting of:
wherein X, Z, and R are as defined above in claim 11 .
15 . The method of claim 13 , wherein the tricyclic rings including the U and T substituents are selected from the group consisting of:
16 . The method of claim 11 , wherein the compounds have the following formulas:
wherein X, Z, J, and R are as defined in claim 11 .
17 . The method of claim 11 , wherein the compounds have the following formulas:
wherein X, Z, J, and R are as defined in claim 11 .
18 . A method for treating an ocular disorder, comprising administering to a mammal a triarylmethane-containing compound in an amount sufficient to treat the ocular disorder.
19 . The method of claim 18 , wherein the amount of the triarylmethane-containing compound is sufficient to inhibit a therapeutically significant amount of NADPH oxidase.
20 . The method of claim 18 , wherein the mammal is a human.
21 . The method of claim 18 , wherein the ocular disorder is selected from the group consisting of wet or dry age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, neovascular glaucoma, retinal vasculitis, uveitis, such as posterior uveitis, conjunctivitis, retinitis secondary to glaucoma, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, cataract, ocular inflammation following ocular surgery, ocular inflammation resulting from physical eye trauma, ocular allergy, and dry eye.
22 . The method of claim 18 , wherein the ocular disorder is selected from the group consisting of glaucoma and cataract.
23 . The method of claim 18 , wherein the compound is administered by topical administration in the form of eye drops or other suitable topical formulations for direct administration to the eye.
24 . The method of claim 18 , wherein the compound is administered by subconjunctival injection, periocular injection, or intravitreal injection.
25 . The method of claim 18 , wherein the compound is administered by surgical implant.
26 . The method of claim 18 , wherein the compound is administered by systemic administration or by iontophoresis.
27 . The method of claim 18 , wherein the administration is provided using a sustained release formulation.
28 . The method of claim 18 , wherein compound has one of the following formulas:
and counterparts to Formula 4 that include the heteroaryl rings in Formulas 2 and 3,
wherein
J represents a direct linkage between the two aryl rings, O, S, Se, NR, or (CR 2 ) n
n=0-4,
E is CH, C bonded to a substituent Z, as defined herein, or N,
R═H or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl,
X═H, amine, hydroxy, ether, thiol, or thiol ether,
Y═O, S, or NR 2 , where an amine can optionally link back to the ring in an ortho position via an alkyl, alkenyl, alkynyl, alkylaryl, or arylalkyl moiety; and
Z is selected from the group consisting of hydrogen, C 1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)O R″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, wherein the aryl or heteroaryl rings can be substituted at any free position with Z.
29 . The method of claim 18 , wherein the compound has the formula:
wherein
X═H, amine, hydroxy, ether, thiol, or thiol ether,
X′═O, S, NR or NR 2 (+) , where an amine can optionally link back to the ring in an ortho position via an alkyl, alkenyl, alkynyl, alkylaryl, or arylalkyl moiety; and
Z is selected from the group consisting of hydrogen, C 1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, wherein the aryl or heteroaryl rings can be substituted at any free position with Z,
T is selected from the group consisting of —C(O)—, —C(O)—O—, —C(O)—S—, —C(O)—NR—, —O—C(O)—, —S—C(O)—, —NR—C(O)—, NR, O, S, (—CR 2 ) n , (—CR 2 ) n —NR—, (—CR 2 ) n —O—, and (—CR 2 ) n —S—; and
U is selected from the group consisting of —C(O)—, NR, S, O, and (—CR 2 ) n .
30 . The method of claim 29 , wherein the tricyclic rings including the U and T substituents are selected from the group consisting of:
wherein X, Z, and R are as defined above in claim 28 .
31 . The method of claim 29 , wherein the tricyclic rings including the U and T substituents are selected from the group consisting of:
32 . The method of claim 21 , wherein the compounds have the following formulas:
wherein X, Z, J, and R are as defined in claim 28 .
33 . The method of claim 18 , wherein the compounds have the following formulas:
wherein X, Z, J, and R are as defined in claim 28 .
34 . A compound having the formula:
wherein
J represents a direct linkage between the two aryl rings, O, S, Se, NR, or (CR 2 ) n
n=0-4,
E is CH, C bonded to a substituent Z, as defined herein, or N,
R═H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl,
X═H, amine, hydroxy, ether, thiol, or thiol ether, and is preferably selected from amine, hydroxy, ether, thiol, and thiol ether,
Y═O, S, or NR 2 , where an amine can optionally link back to the ring in an ortho position via an alkyl, alkenyl, alkynyl, alkylaryl, or arylalkyl moiety,
Z=an optional substituent, a cyclic ring attached to the aryl ring, or a second aryl or heteroaryl ring attached to the benzene ring or cyclohexadiene ring,
wherein the aryl or heteroaryl rings can be substituted at any free position with H or a substituent, Z, as described herein, and
substituents defined by Z are selected from the group consisting of C 1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR′, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl.
X′ is O, S, NR, or NR 2 + ,
T is selected from the group consisting of —C(O)—, —C(O)—O—, —C(O)—S—, —C(O)—NR—, —O—C(O)—, —S—C(O)—, —NR—C(O)—, NR, O, S, (—CR 2 ) n , (—CR 2 ) n —NR—, (—CR 2 ) n —O—, and (—CR 2 ) n —S—; and
U is selected from the group consisting of —C(O)—, NR, S, O, and (—CR 2 ) n .
35 . The compound of claim 34 , wherein the tricyclic rings including the U and T substituents are selected from the group consisting of:
wherein X, Z, and R are as defined above in claim 34 .
36 . The compound of claim 34 , wherein the compounds have the following formulas:
wherein X, Z, J, and R are as defined in claim 34 .
37 . The compound of claim 34 , wherein the compound has the following formula:
wherein X, Z, J, and R are as defined in claim 34 .
38 . A method for treating parasitic infections in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound comprising a triarylmethane therapeutic agent in an amount sufficient to treat the disorder.
39 . The method of claim 38 , wherein the amount of the triphenyl methane therapeutic agent is sufficient to inhibit a therapeutically significant amount of NADPH oxidase.
40 . The method of claim 38 wherein the mammal is a human.
41 . The method of claim 38 wherein the parasitic infection is selected from the group consisting of malaria, trypanosomiasis, and leishmaniasis.
42 . The method of claim 38 , wherein the administration is provided using a sustained release formulation.
43 . The method of claim 38 , wherein compound has one of the following formulas:
and counterparts to Formula 4 that include the heteroaryl rings in Formulas 2 and 3,
wherein
J represents a direct linkage between the two aryl rings, O, S, Se, NR, or (CR 2 ) n
n=0-4,
E is CH, C bonded to a substituent Z, as defined herein, or N,
R═H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl,
X═H, amine, hydroxy, ether, thiol, or thiol ether, and is preferably selected from amine, hydroxy, ether, thiol, and thiol ether,
Y═O, S, or NR 2 , where an amine can optionally link back to the ring in an ortho position via an alkyl, alkenyl, alkynyl, alkylaryl, or arylalkyl moiety,
Z=an optional substituent, a cyclic ring attached to the aryl ring, or a second aryl or heteroaryl ring attached to the benzene ring or cyclohexadiene ring,
wherein the aryl or heteroaryl rings can be substituted at any free position with H or a substituent, Z, as described herein, and
substituents defined by Z are selected from the group consisting of C 1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl.
44 . The method of claim 43 , wherein the compound has the formula:
wherein
Z, X, and J are as defined above in claim 34 ,
X′ is O, S, NR, or NR 2 + ,
T is selected from the group consisting of —C(O)—, —C(O)—O—, —C(O)—S—, —C(O)—NR—, —O—C(O)—, —S—C(O)—, —NR—C(O)—, NR, O, S, (—CR 2 ) n , (—CR 2 ) n —NR—, (—CR 2 ) n —O—, and (—CR 2 ) n —S—; and
U is selected from the group consisting of —C(O)—, NR, S, O, and (—CR 2 ) n .
45 . The method of claim 44 , wherein the tricyclic rings including the U and T substituents are selected from the group consisting of:
wherein X, Z, and R are as defined above in claim 44 .
46 . The method of claim 44 , wherein the compounds have the following formulas:
wherein X, Z, J, and R are as defined in claim 44 .
47 . A compound having the formula:
wherein
J represents a direct linkage between the two aryl rings, O, S, Se, NR, or (CR 2 ) n
n=0-4,
E is CH, C bonded to a substituent Z, as defined herein, or N,
R═H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl,
X═H, amine, hydroxy, ether, thiol, or thiol ether, and is preferably selected from amine, hydroxy, ether, thiol, and thiol ether,
Y═O, S, or NR 2 , where an amine can optionally link back to the ring in an ortho position via an alkyl, alkenyl, alkynyl, alkylaryl, or arylalkyl moiety,
Z=an optional substituent, a cyclic ring attached to the aryl ring, or a second aryl or heteroaryl ring attached to the benzene ring or cyclohexadiene ring,
wherein the aryl or heteroaryl rings can be substituted at any free position with H or a substituent, Z, as described herein, and
substituents defined by Z are selected from the group consisting of C 1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl.
X′is O, S, NR, or NR 2 + ,
T is selected from the group consisting of —C(O)—, —C(O)—O—, —C(O)—S—, —C(O)—NR—, —O—C(O)—, —S—C(O)—, —NR—C(O)—, NR, O, S, (—CR 2 ) n , (—CR 2 ) n —NR—, (—CR 2 ) n —O—, and (—CR 2 ) n —S—; and
U is selected from the group consisting of —C(O)—, NR, S, O, and (—CR 2 ) n .
48 . The compound of claim 47 , wherein the tricyclic rings including the U and T substituents are selected from the group consisting of:
wherein X, Z, and R are as defined above in claim 4 .
49 . The compound of claim 47 , wherein the tricyclic rings including the U and T substituents are selected from the group consisting of:
wherein X, Z, and R are as defined above in claim 47 .
50 . The compound of claim 47 , wherein the compounds have the following formulas:
where J and X are as defined above in claim 47 .
51 . The compound of claim 40 , wherein the compounds have the following formula:
wherein J and X are as defined above in claim 47 .Join the waitlist — get patent alerts
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