Patent Application
20100009970
The invention relates to the treatment of diseases caused by a virus.
Diseases caused by viruses are major health problems worldwide, and include many potentially fatal or disabilitating illnesses. Viral diseases include diseases caused by single stranded RNA viruses, flaviviridae viruses, and hepatic viruses. In one example, viral hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E) can result in chronic or acute hepatitis. While vaccines protective against hepatitis A and hepatitis B exist, no cures for many viruses, including hepatitis B, C, D, or E, are available.
With regard to the hepatitis C virus (HCV), the Center for Disease Control estimates that 4.1 million Americans (1.6%) have been infected with this virus. Of those infected, 3.2 million are chronically infected, and HCV is the leading cause of death from liver disease in the United States. Hepatitis C is a major risk factor for developing liver cirrhosis and hepatocellular carcinoma, and the World Health Organization indicates that hepatitis C is responsible for two thirds of liver transplants. Worldwide, an estimated 180 million people, or about 3% of the world's population, are infected with HCV. No vaccine for hepatitis C is presently available, and the currently recommended therapy, a combination of pegylated interferon and ribavirin, is effective in only about 50% of those infected with HCV genotype 1. Further, both interferon and ribavirin have potentially serious side effects, which include seizures, acute heart or kidney failure, and anemia.
Given the lack of safe, efficacious treatments for many viral diseases, there exists a need for improved therapies.
Based on the results of our screen identifying compounds and combinations of compounds having antiviral activity, the present invention features compositions, methods, and kits for the treatment of viral disease (e.g., caused by the viruses described herein). In certain embodiments, the viral disease may be caused by a virus which is a member of one or more of the following groups: single stranded RNA viruses, flaviviridae viruses (e.g., a hepacivirus such as HCV, flavivirus, pestivirus, or hepatitis G virus), and hepatic viruses. HCV, for example, is a single stranded RNA virus, a flaviviridae virus, and a hepatic virus. In certain embodiments, the viral disease is caused by the hepatitis C virus. Additional exemplary viruses are described herein.
Accordingly in a first aspect, the invention features a composition including a first agent selected from the agents of Table 1, Table 2, and Table 3, or an analog thereof, and a second agent selected from the agents of Table 1, Table 2, Table 3, Table 4, and Table 5, or an analog thereof (e.g., Table 4 and Table 5, or excluding the combinations of Table 6). In certain embodiments, the first agent is sertraline, a sertraline analog, UK-416244, or a UK-4162244 analog (e.g., any of those described herein).
In another aspect, the invention features a composition including (a) sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; and (b) an HMG-CoA reductase inhibitor. The HMG-CoA reductase inhibitor may be fluvastatin, simvastatin, lovastatin, or rosuvastatin.
In another aspect, the invention features a composition including (a) sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; and (b) an antihistamine. The antihistamine may be hydroxyzine.
In another aspect, the invention features structural analogs of sertraline and UK-416244 (e.g., those described herein). In certain embodiments, the invention features a compound having the formula:
where R1 and R2 are independently selected from the group consisting of H, optionally substituted C1-6 alkyl (CH2)xCOOH, or CH2CHOH(CH2)x, (CH2)xN(CH3)2, where x is 1, 2, 3, 4, or 5, and optionally substituted C1-7 heteroalkyl; R3, R4, R5, and R6 are independently H or optionally substituted C1-6 alkyl; X and Y are each selected from the group consisting of H, F, Cl, Br, CF3, C1-6 alkoxy, and cyano; and W is NHCOPh, NHSO2Ph, NHCOcyclopentyl, NHSO2cyclopropyl, NHCOH, CONHPh,
C(S)NH2, NHC(S)CH3, CH2S(O)nR11, where n is 0, 1, or 2 and R11 is phenyl, C2-6 heterocyclyl, C4-8 unsubstituted alkyl, or C3-8 substituted alkyl. The compound may have a structure selected from the group consisting of those listed in Table 9, or the compound may have the formula:
where n is 0, 1, or 2; and R11 is phenyl, C2-6 heterocyclyl, C4-8 unsubstituted alkyl, or C3-8 substituted alkyl. The compound may be part of a composition along with a pharmaceutically acceptable carrier.
In another aspect, the invention features a compound having the formula:
where R1 is C1-6 alkyl and R2 is CH2CH(OH)R8, or CH2CH(R8)NR9R10, where R8, R9, and R10 are independently H or C1-6 alkyl; R3, R4, R5, and R6 are independently H or optionally substituted C1-6 alkyl; X and Y are each selected from the group consisting of H, F, Cl, Br, CF3, C1-6 alkoxy, and cyano; and W is selected from the group consisting of H, F, Cl, Br, CF3, C1-3 alkoxy, COOH, CH2CH2OH, NHCOH, NHCOCH3, CH2NH2, CH2S(O)nCH3, CONH2, CH2OH, NHCOPh, CH2NHS(O)nCH3, NHS(O)nPh, N(CH3)2, S(O)nNH2, NHCOBu, NHS(O)nCH3, NHCOcyclopropyl, NHCOcyclopentyl, CN, NHS(O)ncyclopropyl, NH2, NO2, I, SO2N(CH3)2, SO2NHMe, SO2NHCH2CH2OH, CO2Me, NHSO2Bu, CONHCH3, CH2NHCOCH3, CONHPh,
CONHcylopropyl, C(S)NH2, NHC(S)CH3, CONHCH2COOCH3, CONHCH2COOH, CONHCH2cyclopropyl, CON(CH3)cyclopropyl, CONHcyclobutyl, N(CH3)COCH3, and CH2S(O)nR11, where n is 0, 1, or 2 and R11 is phenyl, C2-6 heterocyclyl, or optionally substituted C1-8 alkyl (e.g., C4-8 unsubstituted alkyl such as Bu or C3-8 substituted alkyl), wherein said compound is not sertraline or an isomer thereof. In other embodiments, the compound has formula set forth herein (e.g., in the Examples).
The compound may have a formula selected from the group consisting of
or have the formula:
where R1 and R2 are independently H, C1-6 alkyl, CH2CH3N(CH3)2, (CH2)m(C3-6 cycloalkyl) where m is 0, 1, 2, or 3, or R1 and R2 together with the nitrogen to which they are attached form an azetidine ring; each R3 is independently H, I, Br, F, Cl, C1-6 alkyl, CF3, CN, OCF3, C1-4 alkylthio, C1-4 alkoxy, aryloxy, or CONR6R7; n is 1, 2, or 3; where one of R4 and R5 is A-X, where A is —CH═CH— or —(CH2)p— where p is 0, 1, or 2; X is H, F, Cl, Br, I, CONR6R7, SO2NR6R7, SO2NHC(═O)R6, OH, C1-4 alkoxy, NR8SO2R9, NO2, NR6R11, CN, CO2R10, CHO, SR10, S(O)R9 or SO2R10; R6, R7, R8 and R10 independently are H, C1-6 alkyl, C6-12 aryl optionally substituted independently by one or more R12, or C1-6 alkyl-aryl optionally substituted, and the other of R4 and R5 is SNHPh, SONHPh, or SO2NHPh, where the phenyl is optionally substituted by one or more R12; R9 is C1-6 alkyl optionally substituted independently by one or more R12; R11 is H, C1-6 alkyl optionally substituted independently by one or more R12, C(O)R6, CO2R9, C(O)NHR6, or SO2NR6R7; R12 is F (preferably up to 3), Br, OH, OCH3, CO2H, C3-6 cycloalkyl, NH2, CONH2, C1-6 alkoxy, C1-6 alkoxycarbonyl, or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R13; or R6 and R7, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclic ring optionally substituted independently by one or more R13; or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R13; where R13 is hydroxy, C1-4 alkoxy, F, C1-6 alkyl, haloalkyl, haloalkoxy, —NH2, —NH(C1-6 alkyl), or —N(C1-6 alkyl)2—. The UK-416244 analog may have a structure listed in Table 10 or Table 11 or described in the Examples.
In another aspect, the invention features a compound having the structure:
where R1 is H or C1-6 alkyl and R2 is C1-6 alkyl substituted with OH or is CH2XR14 or CH2CH2XR14, where X is N, O, or S, and R14 is H, C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or (CH2)q(C3-6 cycloalkyl) where q is 0, 1, 2, or 3, and R3 is independently H, I, Br, F, Cl, C1-6 alkyl, CF3, CN, OCF3, C1-4 alkylthio, C1-4 alkoxy, aryloxy, or CONR6R7; n is 1, 2, or 3; and R4 and R5 are independently A-X, where A is —CH═CH— or —(CH2)p— where p is 0, 1, or 2; X is H, F, Cl, Br, I, CONR6R7, SO2NR6R7, SO2NHC(═O)R6, OH, C1-4 alkoxy, NR8SO2R9, NO2, NR6R11, CN, CO2R10, CHO, SR10, S(O)R9, or SO2R10; R6, R7, R8, and R10 are independently H or C1-6 alkyl, C6-12 aryl optionally substituted independently by one or more R12, or C1-6 alkyl-aryl optionally substituted; R9 is C1-6 alkyl optionally substituted independently by one or more R12; R11 is H, C1-6 alkyl optionally substituted independently by one or more R12, C(O)R6, CO2R9, C(O)NHR6, or SO2NR6R7; R12 is F (preferably up to 3), OH, CO2H, C3-6 cycloalkyl, NH2, CONH2, C1-6 alkoxy, C1-6 alkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R13; or R6 and R7, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclic ring optionally substituted independently by one or more R13; or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R13; where R13 is hydroxy, C1-4 alkoxy, F, C1-6 alkyl, haloalkyl, haloalkoxy, —NH2, —NH(C1-6 alkyl) or —N(C1-6 alkyl)2. In certain embodiments, R1 is H, CH3, or CH2CH3 and R2 is CH2CH2OH, CH(OH)CH3, CH2CH2CH2OH, CH(CH2)CH2OH, and CH2CH2CH2CH2OH, CH(OH)CH2CH2CH3, CH2CH(OH)CH2CH3, and CH2CH2CH(OH)CH3. In particular embodiments, the compound has the structure:
where R1 is H or C1-6 alkyl and R2 is C1-6 alkyl substituted with OH (e.g., where R1 is H, CH3, or CH2CH3 and R2 is CH2CH2OH, CH(OH)CH3, CH2CH2CH2OH, CH(CH2)CH2OH, CH2CH2CH2CH2OH, CH(OH)CH2CH2CH3, CH2CH(OH)CH2CH3, or CH2CH2CH(OH)CH3. The compound may have the structure
In other embodiments, the UK-416244 analog has the structure:
where R3, R4 and R5 are as defined above and Z is CH2NR1R2 where R1 and R2 are as defined above, NH2, optionally substituted optional hetero C1-8 alkyl (e.g., with hydroxyl, NH2, NHC1-6 alkyl), or is selected from the group consisting of:
In certain embodiments, Z is CN, CH2CH(CH3)2, CH2OCH3, CH2N(CH3)CH2CH2OH, N(CH3)2, CH2N(CH3)2, COOH, CH2NHCH3, CH2OH, CH2NHCOCH3, CONHCH3, CH2NH(CH2)2N(CH3)2, CH2NH(CH2)3N(CH3)2, CHC(CH3)2, CH2N(CH3)(CH2)2N(CH3)2, CH2N(CH3)(CH2)3N(CH3)2, or CH2CH(CH3)2.
In yet another aspect, the invention features a composition including a pair of agents selected from the group consisting of amorolfine and sertraline; fluvastatin and sertraline; rosuvastatin and sertraline; fulvestrant and satraplatin; amorolfine and mebeverine; amorolfine and satraplatin; ifenprodil and sertraline; amorolfine and tolterodine; atorvastatin and sertraline; amorolfine and irinotecan; lovastatin and sertraline; cytarabine and triciribine; artesunate and wortmannin; sertraline and simvastatin hydroxy acid, ammonium salt; amorolfine and cytarabine; sertraline and simvastatin; octyl methoxycinnamate and suberohydroxamic acid; 1,5-bis(4-aminophenoxy)pentane and amorolfine; (S,S)—N-desmethyl sertraline and simvastatin; artemisinin and SB-202190; interferon alfa-2a and sirolimus; amorolfine and indocyanine green; TOFA and triciribine; 3,3′-(pentamethylenedioxy)dianiline and artemisinin; artemisinin and wortmannin; 3,3″-(pentamethylenedioxy)diacetanilide and artemisinin; amorolfine and benzamil; artemisinin and triciribine; 2,2′-(pentamethylenedioxy)dianiline and amorolfine; (s,s)-n-desmethyl sertraline and simvastatin; levothyroxine and wedelolactone; 1,5-bis(4-aminophenoxy)pentane and artemisinin; benzamil and dextrothyroxine; amorolfine and trifluperidol; artemisinin and indocyanine green; dihydroartemisinin and wortmannin; flupentixol and sertraline; benzamil and levothyroxine; amorolfine and meclizine; pravastatin and sertraline; 1,5-bis(4-aminophenoxy)pentane and indocyanine green; 2-hydroxyflavanone and amorolfine; ritonavir and vinorelbine; benoxinate and dehydroepiandrosterone; ifenprodil and indocyanine green; amorolfine and arbidol; 3,3′-(pentamethylenedioxy)dianiline and indocyanine green; fulvestrant and vinorelbine; amorolfine and ezetimibe; amorolfine and Evans blue; amorolfine and gefitinib; amorolfine and topotecan; 2′,2″-(pentamethylenedioxy)diacetanilide and artemisinin; amorolfine and wedelolactone; 3,3′-(pentamethylenedioxy)dianiline and amorolfine; simvastatin and rac-cis-n-desmethyl sertraline; adefovir dipivoxil and triciribine; cytarabine and Evans blue; artemisinin and Evans blue; fluphenazine and sertraline; benzamil and SB-202190; artemisinin and rifabutin; fluphenazine and tolterodine; interferon alfa-2a and melphalan; amorolfine and melphalan; artemisinin and fulvestrant; ifenprodil and quinacrine; simvastatin and rac-cis-n-desmethyl sertraline; flupentixol and tolterodine; triciribine and wortmannin; loratadine and vinorelbine; meclizine and sertraline; budesonide and vinorelbine; 2-hydroxyflavanone and indocyanine green; hydroxyzine and sertraline; 2,2′-(pentamethylenedioxy)dianiline and artemisinin; amorolfine and flupentixol; artemisinin and chlorophyllin; ezetimibe and fluphenazine; benzamil and fluphenazine; artemisinin and wedelolactone; cytarabine and dydrogesterone; artemisinin and benzamil; 3,3′-(pentamethylenedioxy)dianiline and artemether; tolterodine and trifluperidol; artesunate and fluvastatin; artemisinin and trifluridine; adefovir dipivoxil and amorolfine; interferon alfa-2a and trifluridine; fulvestrant and triciribine; artesunate and dydrogesterone; artesunate and LY 294002; mosapride citrate and TOFA; bromocriptine and wedelolactone; artemisinin and sodium fusidate; celgosivir and interferon alfa-2a; amorolfine and dextrothyroxine; andrographis and fulvestrant; 2′-c-methylcytidine and artemisinin; amorolfine and gemcitabine; oxeladin and sertraline; artemisinin and parthenolide; artemisinin and ribavirin; dehydroepiandrosterone and tyrphostin AG 1478; sertraline and toremifene; dihydroartemisinin and fulvestrant; 2-hydroxyflavanone and TOFA; artesunate and repaglinide; mofebutazone and wedelolactone; artesunate and simvastatin; 2,2′-(pentamethylenedioxy)dianiline and artesunate; artemisinin and gemcitabine; dihydroartemisinin and ezetimibe; chlorophyllin and cytarabine; interferon alfa-2a and sirolimus; suberohydroxamic acid and VX-497; artemisinin and VX-497; artesunate and VX-497; tolterodine and VX-950; artemisinin and HCV-796; artemisinin and NM-283; NM-283 and wedelolactone; artemisinin and SCH 503034; cytarabine and SCH 503034; SCH 503034 and triciribine; interferon alfa-2a and melphalan; benoxinate and VX-950; HCV-796 and sirolimus; benoxinate and SCH 503034; melphalan and VX-950; ritonavir and VX-950; VX-950 and VX-497; artemisinin and VX-950; triciribine and VX-950; suberohydroxamic acid and VX-950; HCV-796 and suberohydroxamic acid; sirolimus and VX-950; melphalan and SCH 503034; SCH 503034 and wortmannin; SCH 503034 and tolterodine; ritonavir and SCH 503034; ezetimibe and VX-950; HCV-796 and VX-497; chlorophyllin and VX-497; HCV-796 and melphalan; capsaicin and NM-283; SCH 503034 and sirolimus; LY 294002 and SCH 503034; adefovir dipivoxil and SCH 503034; interferon alfa-2a and trifluridine; HCV-796 and trifluridine; GW 5074 and NM-283; mosapride and VX-950; interferon alfa-2a and VX-497; NM-283 and trequinsin; cytarabine and HCV-796; adefovir dipivoxil and VX-950; cytarabine and VX-950; SCH 503034 and saquinavir; VX-950 and wortmannin; capsaicin and VX-950; 2-hydroxyflavanone and NM-283; bromhexine and VX-950; HCV-796 and wortmannin; artemisinin and ribavirin; VX-950 and verapamil; SCH 503034 and verapamil; SCH 503034 and topotecan; HCV-796 and topotecan; trifluperidol and VX-950; irinotecan and SCH 503034; artesunate and SCH 503034; repaglinide and SCH 503034; topotecan and VX-950; tepaglinide and VX-950; arbidol and VX-950; chlorophyllin and HCV-796; benzydamine and VX-950; NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 and phenazopyridine; NM-283 and trifluridine; and adefovir dipivoxil and HCV-796. In any of the pairs of agents above, the agent may be substituted with an analog of that agent (e.g., any analog described herein). In particular embodiments, sertraline is substituted with a sertraline analog, UK-416244, or a UK-416244 analog.
In certain embodiments, the combination is selected from group consisting of simvastatin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; fluvastatin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; fluphenazine and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; artesunate and simvastatin; artesunate and wortmannin; artemisinin and chlorophyllin; artemisinin and 3,3′-(pentamethylenedioxy)dianiline; amorolfine and meclizine; amorolfine and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; amorolfine and trifluridine; amorolfine and 2-hydroxyflavanone; amorolfine and ezetimibe; amorolfine and benzamil; amorolfine and trifluperidol; and octyl methoxycinnamate and suberohydroxamic acid.
In any of the above aspects, the two agents may be present in amounts that, when administered to a patient having a viral disease (e.g., any viral disease described herein), are effective to treat the patient. The composition may further include one or more (e.g., two, three, four, five, or six) additional agents selected from the agents of Table 1, Table 2, Table 3, Table 4, and Table 5 (e.g., where the agents are not a combination of agents selected from Table 7). The composition may be formulated, for example, for oral, systemic, parenteral, topical (e.g., ophthalmic, dermatologic), intravenous, or intramuscular administration.
In another aspect, the invention features a method for treating a patient having a viral disease. The method includes administering to the patient an agent selected from the agents of Table 1, or an analog thereof, in an amount effective to treat the patient. In certain embodiments, the agent is sertraline, a sertraline analog, UK-416244, or a UK-416244 analog (e.g., any of those described herein).
In another aspect, the invention features a method for treating a patient having hepatitis C. The method includes administering to the patient an agent selected from the agents of Table 1 and Table 2, or an analog thereof, in an amount effective to treat the patient. In certain embodiments, the agent is sertraline, a sertraline analog, UK-416244, or a UK-416244 analog (e.g., any of those described herein).
In another aspect, the invention features a method for treating a patient having a viral disease. The method includes administering to the patient a plurality of agents where the first agent is selected from the agents of Table 1, Table 2, and Table 3, or an analog thereof, and the second agent is selected from the agents of Table 1, Table 2, Table 3, Table 4, and Table 5 (e.g., Table 4 and Table 5), or an analog thereof, where the agents are administered within 28 days (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24 hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) of each other in amounts that together are effective to treat the patient.
In another aspect, the invention features a method for treating a patient having a viral disease. The method includes administering to the patient sertraline, a sertraline analog, UK-416244, or a UK-416244 analog, and an HMG-CoA reductase inhibitor, where the two agents are administered within 28 days of each other in amounts that together are effective to treat the patient. The HMG-CoA reductase inhibitor may be fluvastatin, simvastatin, lovastatin, or rosuvastatin.
In another aspect, the invention features a method for treating a patient having a viral disease. The method includes administering to the patient sertraline, a sertraline analog, UK-416244, or a UK-416244 analog, and an antihistamine where the two agents are administered within 28 days of each other in amounts that together are effective to treat the patient. The antihistamine may be hydroxyzine.
In yet another aspect, the invention features a method for treating a patient having a viral disease. The method includes administering to the patient a pair of agents selected from the group consisting of amorolfine and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; fluvastatin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; rosuvastatin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; fulvestrant and satraplatin; amorolfine and mebeverine; amorolfine and satraplatin; ifenprodil and sertraline; amorolfine and tolterodine; atorvastatin and sertraline; amorolfine and irinotecan; lovastatin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; cytarabine and triciribine; artesunate and wortmannin; sertraline, a sertraline analog, UK-416244, or a UK-416244 analog and simvastatin hydroxy acid, ammonium salt; amorolfine and cytarabine; sertraline, a sertraline analog, UK-416244, or a UK-416244 analog and simvastatin; octyl methoxycinnamate and suberohydroxamic acid; 1,5-bis(4-aminophenoxy)pentane and amorolfine; (S,S)—N-desmethyl sertraline and simvastatin; artemisinin and SB-202190; interferon alfa-2a and sirolimus; amorolfine and indocyanine green; TOFA and triciribine; 3,3′-(pentamethylenedioxy)dianiline and artemisinin; artemisinin and wortmannin; 3,3″-(pentamethylenedioxy)diacetanilide and artemisinin; amorolfine and benzamil; artemisinin and triciribine; 2,2′-(pentamethylenedioxy)dianiline and amorolfine; (s,s)-n-desmethyl sertraline and simvastatin; levothyroxine and wedelolactone; 1,5-bis(4-aminophenoxy)pentane and artemisinin; benzamil and dextrothyroxine; amorolfine and trifluperidol; artemisinin and indocyanine green; dihydroartemisinin and wortmannin; flupentixol and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; benzamil and levothyroxine; amorolfine and meclizine; pravastatin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; 1,5-bis(4-aminophenoxy)pentane and indocyanine green; 2-hydroxyflavanone and amorolfine; ritonavir and vinorelbine; benoxinate and dehydroepiandrosterone; ifenprodil and indocyanine green; amorolfine and arbidol; 3,3′-(pentamethylenedioxy)dianiline and indocyanine green; fulvestrant and vinorelbine; amorolfine and ezetimibe; amorolfine and Evans blue; amorolfine and gefitinib; amorolfine and topotecan; 2′,2″-(pentamethylenedioxy)diacetanilide and artemisinin; amorolfine and wedelolactone; 3,3′-(pentamethylenedioxy)dianiline and amorolfine; simvastatin and rac-cis-n-desmethyl sertraline; adefovir dipivoxil and triciribine; cytarabine and Evans blue; artemisinin and Evans blue; fluphenazine and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; benzamil and SB-202190; artemisinin and rifabutin; fluphenazine and tolterodine; interferon alfa-2a and melphalan; amorolfine and melphalan; artemisinin and fulvestrant; ifenprodil and quinacrine; simvastatin and rac-cis-n-desmethyl sertraline; flupentixol and tolterodine; triciribine and wortmannin; loratadine and vinorelbine; meclizine and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; budesonide and vinorelbine; 2-hydroxyflavanone and indocyanine green; hydroxyzine and sertraline; 2,2′-(pentamethylenedioxy)dianiline and artemisinin; amorolfine and flupentixol; artemisinin and chlorophyllin; ezetimibe and fluphenazine; benzamil and fluphenazine; artemisinin and wedelolactone; cytarabine and dydrogesterone; artemisinin and benzamil; 3,3′-(pentamethylenedioxy)dianiline and artemether; tolterodine and trifluperidol; artesunate and fluvastatin; artemisinin and trifluridine; adefovir dipivoxil and amorolfine; interferon alfa-2a and trifluridine; fulvestrant and triciribine; artesunate and dydrogesterone; artesunate and LY 294002; mosapride citrate and TOFA; bromocriptine and wedelolactone; artemisinin and sodium fusidate; celgosivir and interferon alfa-2a; amorolfine and dextrothyroxine; andrographis and fulvestrant; 2′-c-methylcytidine and artemisinin; amorolfine and gemcitabine; oxeladin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; artemisinin and parthenolide; artemisinin and ribavirin; dehydroepiandrosterone and tyrphostin AG 1478; sertraline, a sertraline analog, UK-416244, or a UK-416244 analog and toremifene; dihydroartemisinin and fulvestrant; 2-hydroxyflavanone and TOFA; artesunate and repaglinide; mofebutazone and wedelolactone; artesunate and simvastatin; 2,2′-(pentamethylenedioxy)dianiline and artesunate; artemisinin and gemcitabine; dihydroartemisinin and ezetimibe; chlorophyllin and cytarabine; interferon alfa-2a and sirolimus; suberohydroxamic acid and VX-497; artemisinin and VX-497; artesunate and VX-497; tolterodine and VX-950; artemisinin and HCV-796; artemisinin and NM-283; NM-283 and wedelolactone; artemisinin and SCH 503034; cytarabine and SCH 503034; SCH 503034 and triciribine; interferon alfa-2a and melphalan; benoxinate and VX-950; HCV-796 and sirolimus; benoxinate and SCH 503034; melphalan and VX-950; ritonavir and VX-950; VX-950 and VX-497; artemisinin and VX-950; triciribine and VX-950; suberohydroxamic acid and VX-950; HCV-796 and suberohydroxamic acid; sirolimus and VX-950; melphalan and SCH 503034; SCH 503034 and wortmannin; SCH 503034 and tolterodine; ritonavir and SCH 503034; ezetimibe and VX-950; HCV-796 and VX-497; chlorophyllin and VX-497; HCV-796 and melphalan; capsaicin and NM-283; SCH 503034 and sirolimus; LY 294002 and SCH 503034; adefovir dipivoxil and SCH 503034; interferon alfa-2a and trifluridine; HCV-796 and trifluridine; GW 5074 and NM-283; mosapride and VX-950; interferon alfa-2a and VX-497; NM-283 and trequinsin; cytarabine and HCV-796; adefovir dipivoxil and VX-950; cytarabine and VX-950; SCH 503034 and saquinavir; VX-950 and wortmannin; capsaicin and VX-950; 2-hydroxyflavanone and NM-283; bromhexine and VX-950; HCV-796 and wortmannin; artemisinin and ribavirin; VX-950 and verapamil; SCH 503034 and verapamil; SCH 503034 and topotecan; HCV-796 and topotecan; trifluperidol and VX-950; irinotecan and SCH 503034; artesunate and SCH 503034; repaglinide and SCH 503034; topotecan and VX-950; tepaglinide and VX-950; arbidol and VX-950; chlorophyllin and HCV-796; benzydamine and VX-950; NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 and phenazopyridine; NM-283 and trifluridine; and adefovir dipivoxil and HCV-796, where the agents are administered within 28 days of each other in amounts that together are effective to treat the patient.
In another aspect, the invention features a method for treating a patient having a viral disease. The method includes administering to the patient a pair of agents selected from the group consisting of simvastatin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; fluvastatin and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; fluphenazine and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; artesunate and simvastatin; artesunate and wortmannin; artemisinin and chlorophyllin; artemisinin and 3,3′-(pentamethylenedioxy)dianiline; amorolfine and meclizine; amorolfine and sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; amorolfine and trifluridine; amorolfine and 2-hydroxyflavanone; amorolfine and ezetimibe; amorolfine and benzamil; amorolfine and trifluperidol; and octyl methoxycinnamate and suberohydroxamic acid, where the two agents are administered within 28 days of each other in amounts that together are effective to treat the patient.
The methods of any of the above aspects may be performed in conjunction with administering to the patient an additional treatment (e.g., an antiviral therapy such as those agents listed in Table 4 and Table 5, or an analog thereof) for a viral disease, where the method and the additional treatment (e.g., not a combination of agents selected from Table 6 and Table 7) are administered within 6 months (e.g., within 3, 2, or 1 months; within 28, 21, 14, 10, 7, 5, 4, 3, 2, or 1 days; within 24, 12, 6, 3, 2, or 1 hours; or concomitantly) of each other. The agents may be administered to the patient by intravenous, intramuscular, inhalation, topical (e.g., ophthalmic, determatologic), or oral administration.
In certain embodiments of any of the above methods (e.g., methods including administration of an antidepressant agent such as an SSRI or a tricyclic antidepressant), the patient being treated has not been diagnosed with or does not suffer from depression, major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social anxiety disorder, generalized anxiety disorder, or premenstrual dysphoric disorder. In other embodiments, (e.g., methods including administration of an HMG-CoA reductase inhibitor), the patient being treated has not been diagnosed with or does not suffer from hypercholesteraolemia, primary familial hypercholesterolemia (heterozygous variant), mixed hyperlipidaemia (corresponding to type IIa and IIb of the Fredrickson classification), or coronary artery disease, or has not had a myocardial infarction, a cerebrovascular event, an coronary bypass surgery, or a translumen percutaneous coronary angioplasty.
In another aspect, the invention features a kit including an agent selected from any of the agents of Table 1, or an analog thereof; and instructions for administering the agent to a patient having a viral disease.
In another aspect, the invention features a kit including an agent selected from any of the agents of Table 1 and Table 2, or an analog thereof; and instructions for administering the agent to a patient having hepatitis C.
In another aspect, the invention features a kit including a composition including two or more (e.g., 3, 4, 5, 6, or 7) agents selected from any of the agents of Table 1, or an analog thereof, Table 2, and Table 3; and instructions for administering the composition to a patient having a viral disease.
In another aspect, the invention features a kit including a first agent selected from any of the agents of Table 1, Table 2, and Table 3, or an analog thereof; a second, different agent selected from any of the agents of Table 1, Table 2, and Table 3, or an analog thereof; and instructions for administering the first and second agents to a patient having a viral disease.
In another aspect, the invention features a kit including an agent selected from any one of the agents of Table 1, Table 2, and Table 3, or an analog thereof; and instructions for administering the agent with a second, different agent selected from any of the agents of Table 1, Table 2, and Table 3, or an analog thereof to a patient having a viral disease.
In another aspect, the invention features a kit including a composition including (i) a first agent selected from any one of the agents of Table 1, Table 2, and Table 3, or an analog thereof, and (ii) one or more agents of Table 4 and Table 5, or an analog thereof; and instructions for administering the composition to a patient having a viral disease.
In another aspect, the invention features a kit including (a) a first agent selected from any of the agents of Table 1, Table 2, and Table 3, or an analog thereof; (b) one or more agents of Table 4 and Table 5, or an analog thereof; and (c) instructions for administering (a) and (b) to a patient having a viral disease.
In another aspect, the invention features a kit including an agent selected from any of the agents of Table 1, or an analog thereof; and instructions for administering the agent and one or more agents of Table 4 or Table 5, or an analog thereof, to a patient having a viral disease.
In another aspect, the invention features a kit including an agent selected from any of the agents of Table 1 and Table 2, or an analog thereof; and instructions for administering the agent and one or more agents of Table 4 or Table 5, or an analog thereof, to a patient having hepatitis C.
In another aspect, the invention features a kit including (a) one or more agents of Table 4 and Table 5, or an analog thereof; and (b) instructions for administering the agent from (a) with any agent of Table 1, Table 2, and Table 3, or an analog thereof, to a patient having a viral disease.
In another aspect, the invention features a kit including a agent selected from the group consisting of sertraline, a sertraline analog, UK-416244, and a UK-416244 analog; an HMG-CoA reductase inhibitor (e.g., fluvastatin, simvastatin, lovastatin, or rosuvastatin); and instructions for administering the agent and the HMG-CoA reductase inhibitor to a patient having a viral disease.
In another aspect, the invention features a kit including a composition including sertraline, a sertraline analog, UK-416244, or a UK-416244 analog, and an HMG-CoA reductase inhibitor (e.g., fluvastatin, simvastatin, lovastatin, or rosuvastatin); and instructions for administering the composition to a patient having a viral disease.
In another aspect, the invention features a kit including sertraline, a sertraline analog, UK-416244, or a UK-416244 analog; an antihistamine (e.g., hydroxyzine); and instructions for administering the sertraline or sertraline analog and the antihistamine to a patient having a viral disease.
In another aspect, the invention features a kit including a composition including sertraline or UK-416244, and an antihistamine (e.g., hydroxyzine); and instructions for administering the composition to a patient having a viral disease.
In another aspect, the invention features a kit including (a) a pair of agents selected from the group consisting of amorolfine and sertraline; fluvastatin and sertraline; rosuvastatin and sertraline; fulvestrant and satraplatin; amorolfine and mebeverine; amorolfine and satraplatin; ifenprodil and sertraline; amorolfine and tolterodine; atorvastatin and sertraline; amorolfine and irinotecan; lovastatin and sertraline; cytarabine and triciribine; artesunate and wortmannin; sertraline and simvastatin hydroxy acid, ammonium salt; amorolfine and cytarabine; sertraline and simvastatin; octyl methoxycinnamate and suberohydroxamic acid; 1,5-bis(4-aminophenoxy)pentane and amorolfine; (S,S)—N-desmethyl sertraline and simvastatin; artemisinin and SB-202190; interferon alfa-2a and sirolimus; amorolfine and indocyanine green; TOFA and triciribine; 3,3′-(pentamethylenedioxy)dianiline and artemisinin; artemisinin and wortmannin; 3,3″-(pentamethylenedioxy)diacetanilide and artemisinin; amorolfine and benzamil; artemisinin and triciribine; 2,2′-(pentamethylenedioxy)dianiline and amorolfine; (S,S)-n-desmethyl sertraline and simvastatin; levothyroxine and wedelolactone; 1,5-bis(4-aminophenoxy)pentane and artemisinin; benzamil and dextrothyroxine; amorolfine and trifluperidol; artemisinin and indocyanine green; dihydroartemisinin and wortmannin; flupentixol and sertraline; benzamil and levothyroxine; amorolfine and meclizine; pravastatin and sertraline; 1,5-bis(4-aminophenoxy)pentane and indocyanine green; 2-hydroxyflavanone and amorolfine; ritonavir and vinorelbine; benoxinate and dehydroepiandrosterone; ifenprodil and indocyanine green; amorolfine and arbidol; 3,3′-(pentamethylenedioxy)dianiline and indocyanine green; fulvestrant and vinorelbine; amorolfine and ezetimibe; amorolfine and Evans blue; amorolfine and gefitinib; amorolfine and topotecan; 2′,2″-(pentamethylenedioxy)diacetanilide and artemisinin; amorolfine and wedelolactone; 3,3′-(pentamethylenedioxy)dianiline and amorolfine; simvastatin and rac-cis-n-desmethyl sertraline; adefovir dipivoxil and triciribine; cytarabine and Evans blue; artemisinin and Evans blue; fluphenazine and sertraline; benzamil and SB-202190; artemisinin and rifabutin; fluphenazine and tolterodine; interferon alfa-2a and melphalan; amorolfine and melphalan; artemisinin and fulvestrant; ifenprodil and quinacrine; simvastatin and rac-cis-n-desmethyl sertraline; flupentixol and tolterodine; triciribine and wortmannin; loratadine and vinorelbine; meclizine and sertraline; budesonide and vinorelbine; 2-hydroxyflavanone and indocyanine green; hydroxyzine and sertraline; 2,2′-(pentamethylenedioxy)dianiline and artemisinin; amorolfine and flupentixol; artemisinin and chlorophyllin; ezetimibe and fluphenazine; benzamil and fluphenazine; artemisinin and wedelolactone; cytarabine and dydrogesterone; artemisinin and benzamil; 3,3′-(pentamethylenedioxy)dianiline and artemether; tolterodine and trifluperidol; artesunate and fluvastatin; artemisinin and trifluridine; adefovir dipivoxil and amorolfine; interferon alfa-2a and trifluridine; fulvestrant and triciribine; artesunate and dydrogesterone; artesunate and LY 294002; mosapride citrate and TOFA; bromocriptine and wedelolactone; artemisinin and sodium fusidate; celgosivir and interferon alfa-2a; amorolfine and dextrothyroxine; andrographis and fulvestrant; 2′-c-methylcytidine and artemisinin; amorolfine and gemcitabine; oxeladin and sertraline; artemisinin and parthenolide; artemisinin and ribavirin; dehydroepiandrosterone and tyrphostin ag 1478; sertraline and toremifene; dihydroartemisinin and fulvestrant; 2-hydroxyflavanone and TOFA; artesunate and repaglinide; mofebutazone and wedelolactone; artesunate and simvastatin; 2,2′-(pentamethylenedioxy)dianiline and artesunate; artemisinin and gemcitabine; dihydroartemisinin and ezetimibe; chlorophyllin and cytarabine; interferon alfa-2a and sirolimus; suberohydroxamic acid and VX-497; artemisinin and VX-497; artesunate and VX-497; tolterodine and VX-950; artemisinin and HCV-796; artemisinin and NM-283; NM-283 and wedelolactone; artemisinin and SCH 503034; cytarabine and SCH 503034; SCH 503034 and triciribine; interferon alfa-2a and melphalan; benoxinate and VX-950; HCV-796 and sirolimus; benoxinate and SCH 503034; melphalan and VX-950; ritonavir and VX-950; VX-950 and VX-497; artemisinin and VX-950; triciribine and VX-950; suberohydroxamic acid and VX-950; HCV-796 and suberohydroxamic acid; sirolimus and VX-950; melphalan and SCH 503034; SCH 503034 and wortmannin; SCH 503034 and tolterodine; ritonavir and SCH 503034; ezetimibe and VX-950; HCV-796 and VX-497; chlorophyllin and VX-497; HCV-796 and melphalan; capsaicin and NM-283; SCH 503034 and sirolimus; LY 294002 and SCH 503034; adefovir dipivoxil and SCH 503034; interferon alfa-2a and trifluridine; HCV-796 and trifluridine; GW 5074 and NM-283; mosapride and VX-950; interferon alfa-2a and VX-497; NM-283 and trequinsin; cytarabine and HCV-796; adefovir dipivoxil and VX-950; cytarabine and VX-950; SCH 503034 and saquinavir; VX-950 and wortmannin; capsaicin and VX-950; 2-hydroxyflavanone and NM-283; bromhexine and VX-950; HCV-796 and wortmannin; artemisinin and ribavirin; VX-950 and verapamil; SCH 503034 and verapamil; SCH 503034 and topotecan; HCV-796 and topotecan; trifluperidol and VX-950; irinotecan and SCH 503034; artesunate and SCH 503034; repaglinide and SCH 503034; topotecan and VX-950; repaglinide and VX-950; arbidol and VX-950; chlorophyllin and HCV-796; benzydamine and VX-950; NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 and phenazopyridine; NM-283 and trifluridine; and adefovir dipivoxil and HCV-796; and (b) instructions for administering the pair of agents to a patient having a viral disease. The kit may include a composition including the pair of agents. In certain embodiments of the kit, sertraline is substituted for a sertraline analog, UK-416244, or a UK-416244 analog.
In another aspect, the invention features a kit including (a) a pair of agents selected from the group consisting of simvastatin and sertraline; fluvastatin and sertraline; fluphenazine and sertraline; artesunate and simvastatin; artesunate and wortmannin; artemisinin and chlorophyllin; artemisinin and 3,3′-(pentamethylenedioxy)dianiline; amorolfine and meclizine; amorolfine and sertraline; amorolfine and trifluridine; amorolfine and 2-hydroxyflavanone; amorolfine and ezetimibe; amorolfine and benzamil; amorolfine and trifluperidol; and octyl methoxycinnamate and suberohydroxamic acid; and (b) instructions for administering the pair of agents to a patient having a viral disease. The kit may include a composition including the pair of agents. In certain embodiments of the kit, sertraline is substituted for a sertraline analog, UK-416244, or a UK-416244 analog.
In another aspect, the invention features a method of identifying a combination that may be useful for the treatment of a patient having a viral disease, or the prevention or reduction of the viral disease. The method includes the steps of contacting cells including at least a portion of the genome of a virus with an agent selected from any one the agents of Table 1, Table 2, and Table 3 and a candidate compound, wherein the portion of the genome (e.g., of any virus described herein) is capable of replication in the cells; and determining whether the combination of the agent and the candidate compound inhibits the replication of the portion of the genome relative to cells contacted with the agent but not contacted with the candidate compound, where a reduction in replication identifies the combination as a combination useful for the treatment of a patient having a viral disease, or the prevention or reduction of a viral disease. The reduction in replication may be the result of a decreased rate of DNA or RNA replication, a decreased rate of RNA translation, or inhibition of a protein required for viral replication (e.g., a protein coded for by the viral genome or the host organism). If the at least portion of a genome is from the hepatitis C genome, the reduction in replication may also be due to a decreased rate of polyprotein processing. The cells may be mammalian cells (e.g., hepatic cells, for example, any of those described herein) such as human cells.
The viral disease referred to in any of the above aspects of the invention, including the methods of treatment of the invention, the compositions and kits of the invention, and methods of the invention for identifying combinations may be caused by a single stranded RNA virus, a flaviviridae virus (e.g., a hepacivirus such as HCV, flavivirus, pestivirus, or hepatitis G virus), or a hepatic virus (e.g., any hepatic virus described herein such as hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, non-ABCDE hepatitis, or hepatitis G). In certain embodiments, the viral disease is caused by a flavivirus which include without limitation Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, royal farm, Russian spring-summer encephalitis, Saboya, St. Louis encephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsbron, west Nile, Yaounde, yellow fever, and Zika viruses, or any of the viruses described in Chapter 31 of Fields Virology, Fields, B. N., Knipe, D. M., and Howley, P. M., eds. Lippincott-Raven Publishers, Philadelphia, Pa., 1996. In other embodiments, the viral disease is caused by a pestivirus, which include bovine viral diarrhea virus (“BVDV”), classical swine fever virus (“CSFV,” also called hog cholera virus), border disease virus (“BDV”) and any of those discussed in Chapter 33 of Fields Virology, supra. In other embodiments, the viral disease is caused by a virus such as hepatitis A, hepatitis B. hepatitis C (e.g., genotype 1 such as 1a or 1b; genotype 2 such as 2a, 2b, or 2c; genotype 3; genotype 4; genotype 5; genotype 6); hepatitis D; or hepatitis E. The viral hepatitis may further be a non-ABCDE viral hepatitis (e.g., hepatitis G).
Additional viral therapies are described in Table 4 and Table 5.
Additional hepatitis C therapies are described in Table 5.
Analogs of any of the compounds listed in Tables 1, 2, or 3 may be used in any of the compositions, methods, and kits of the invention. Such analogs include any agent from the same therapeutic class, having the same or related molecular targets, or from the same mechanistic class as those listed in Table 8. Exemplary analogs of these compounds are described throughout the specification.
Mycobacterium tuberculosis).
Andrographis paniculata
Diphyllobothrium latum
Giardia lamblia
regeli, is a DNA topoisomerase
Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs thereof, as well as racemic mixtures. Compounds useful in the invention may also be isotopically labeled compounds. Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl). Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically-labeled reagent in place of a non-isotopically-labeled reagent.
By “patient” is meant any animal (e.g., a mammal such as a human). Any animal can be treated using the methods, compositions, and kits of the invention.
To “treat” is meant to administer one or more agents to measurably slow or stop the replication of a virus in vitro or in vivo, to measurably decrease the load of a virus (e.g., any virus described herein including a hepatitis virus such as hepatitis A, B, C, D, or E) in a cell in vitro or in vivo, or to reduce at least one symptom (e.g., those described herein) associated with having a viral disease in a patient. Desirably, the slowing in replication or the decrease in viral load is at least 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 99%, as determined using a suitable assay (e.g., a replication assay described herein). Typically, a decrease in viral replication is accomplished by reducing the rate of DNA or RNA polymerization, RNA translation, polyprotein processing, or by reducing the activity of a protein involved in any step of viral replication (e.g., proteins coded by the genome of the virus or host protein important for viral replication).
By “an effective amount” is meant the amount of a compound, alone or in combination with another therapeutic regimen, required to treat a patient with a viral disease (e.g., any virus described herein including a hepatitis virus such as hepatitis A, B, C, D, or E) in a clinically relevant manner. A sufficient amount of an active compound used to practice the present invention for therapeutic treatment of conditions caused by a virus varies depending upon the manner of administration, the age, body weight, and general health of the patient. Ultimately, the prescribers will decide the appropriate amount and dosage regimen. Additionally, an effective amount may be an amount of compound in the combination of the invention that is safe and efficacious in the treatment of a patient having a viral disease over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug Administration).
By “more effective” is meant that a treatment exhibits greater efficacy, or is less toxic, safer, more convenient, or less expensive than another treatment with which it is being compared. Efficacy may be measured by a skilled practitioner using any standard method that is appropriate for a given indication.
By “hepatic virus” is meant a virus that can cause hepatitis. Such viruses include hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, non-ABCDE hepatitis, and hepatitis G.
By a “low dosage” is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition. For example, a low dosage of an agent that inhibits viral replication and that is formulated for administration by intravenous injection will differ from a low dosage of the same agent formulated for oral administration.
By a “high dosage” is meant at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) more than the highest standard recommended dosage of a particular compound for treatment of any human disease or condition.
By “hypercholesterolemia” is meant an total cholesterol level of at least 200 mg/dl. High risk groups include those with at least 240 mg/dl. Normal cholesterol levels are below 200 mg/dl. Hypercholesterolemia may also be defined by low density lipoprotein (LDL) levels. Less than 100 mg/dl is considered optimal; 100 to 129 mg/dl is considered near optimal/above optimal; 130 to 159 mg/dl borderline high; 160 to 189 mg/dl high; and 190 mg/dl and above is considered very high.
By a “candidate compound” is meant a chemical, be it naturally-occurring or artificially-derived. Candidate compounds may include, for example, peptides, polypeptides, synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components or derivatives thereof.
In the generic descriptions of compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 4 carbon atoms or C1-4 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alkyl group from 1 to 4 carbon atoms includes each of C1, C2, C3, and C4. A C1-12 heteroalkyl, for example, includes from 1 to 12 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms may be indicated in a similar manner.
As used herein, the terms “alkyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 12 ring carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
By “C1-4 alkyl” is meant a branched or unbranched hydrocarbon group having from 1 to 4 carbon atoms. A C1-4 alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C1-4 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl.
By “C2-4 alkenyl” is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 4 carbon atoms. A C2-4 alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The C2-4 alkenyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C2-4 alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.
By “C2-4 alkynyl” is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 4 carbon atoms. A C2-4 alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The C2-4 alkynyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C2-4 alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
By “C2-6 heterocyclyl” is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A nitrogen atom in the heterocycle may optionally be quaternized. Preferably when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
By “C6-12 aryl” is meant an aromatic group having a ring system comprised of carbon atoms with conjugated π electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group may be substituted or unsubstituted. Exemplary substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
By “C7-14 alkaryl” is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.
By “C3-10 alkheterocyclyl” is meant an alkyl substituted heterocyclic group having from 3 to 10 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).
By “C1-7 heteroalkyl” is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups. Examples of C1-7 heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.
By “halide” or “halogen” is meant bromine, chlorine, iodine, or fluorine.
By “fluoroalkyl” is meant an alkyl group that is substituted with a fluorine atom.
By “perfluoroalkyl” is meant an alkyl group consisting of only carbon and fluorine atoms.
By “carboxyalkyl” is meant a chemical moiety with the formula —(R) —COOH, wherein R is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl.
By “hydroxyalkyl” is meant a chemical moiety with the formula —(R) —OH, wherein R is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl.
By “alkoxy” is meant a chemical substituent of the formula —OR, wherein R is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl.
By “aryloxy” is meant a chemical substituent of the formula —OR, wherein R is a C6-12 aryl group.
By “alkylthio” is meant a chemical substituent of the formula —SR, wherein R is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl.
By “arylthio” is meant a chemical substituent of the formula —SR, wherein R is a C6-12 aryl group.
By “quaternary amino” is meant a chemical substituent of the formula —(R)—N(R′)(R″)(R′″)+, wherein R, R′, R″, and R′″ are each independently an alkyl, alkenyl, alkynyl, or aryl group. R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety. The nitrogen atom, N, is covalently attached to four carbon atoms of alkyl, heteroalkyl, heteroaryl, and/or aryl groups, resulting in a positive charge at the nitrogen atom.
Other features and advantages of the invention will be apparent from the following Detailed Description and the claims.
We have identified compounds that decrease replication of a hepatitis C(HCV) replicon in mammalian cells. Accordingly, the present invention provides compositions, methods, and kits useful in the treatment of viral diseases, which may be caused by a single stranded RNA virus, a flaviviridae virus, or a hepatic virus (e.g., described herein). In certain embodiments, the viral disease is viral hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E). The invention also features screening methods useful for the identification of novel compounds for the treatment of viral diseases. Compositions of the invention can include one or more agents selected from the agents of Table 1, Table 2, Table 3, Table 4, and Table 5. Treatment methods of the invention include administration of one or more agents selected from the agents of Table 1, Table 2, and Table 3, optionally along with an additional antiviral therapy (e.g., administration of one or more agents of Table 4 or Table 5) to a patient (e.g., a mammal such as a human). Optionally, functional or structural analogs (e.g., those described herein) of these agents or agents of the same therapeutic or mechanistic class as those described herein (see, e.g., Table 8) may be employed in the compositions, methods, and kits of the invention. The ability of a composition to reduce replication of a virus may be due to a decrease in RNA or DNA polymerization, RNA translation, RNA or DNA transcription, a decrease in posttranslational protein processing (e.g., polyprotein processing in hepatitis C), or a decrease in activity of a protein involved in viral replication (e.g., a protein coded for by the viral genome or a host protein required for viral replication). The compounds or combinations of compounds may also enhance the efficacy of the other therapeutic regimens such that the dosage, frequency, or duration of the other therapeutic regimen is lowered to achieve the same therapeutic benefit, thereby moderating any unwanted side effects.
In one particular example, the patient being treated is administered two agents listed in Table 1, Table 2 and/or Table 3 within 28 days of each other in amounts that together are sufficient to treat a patient having a viral disease. The two agents can be administered within 14 days of each other, within seven days of each other, within twenty-four hours of each other, or even simultaneously (i.e., concomitantly). If desired, either one of the two agents may be administered in low dosage.
The invention relates to the treatment of viral disease, which can be caused by any virus. Viruses include single stranded RNA viruses, flaviviridae viruses, and hepatic viruses. In particular, the flaviviridae family of viruses include hepacivirus (e.g., HCV); flaviviruses; pestiviruses, and hepatitis G virus.
Flaviviruses generally are discussed in Chapter 31 of Fields Virology, supra. Exemplary flaviviruses include Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, royal farm, Russian spring-summer encephalitis, Saboya, St. Louis encephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsbron, west Nile, Yaounde, yellow fever, and Zika viruses.
Pestiviruses generally are discussed in Chapter 33 of Fields Virology, supra. Specific pestiviruses include, without limitation: bovine viral diarrhea virus, classical swine fever virus (also called hog cholera virus), and border disease virus.
Viruses that can cause viral hepatitis include hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E. In addition, non-ABCDE cases of viral hepatitis have also been reported (see, for example, Rochling et al., Hepatology 25:478-483, 1997). Within each type of viral hepatitis, several subgroupings have been identified. Hepatitis C, for example, has at least six distinct genotypes (1, 2, 3, 4, 5, and 6), which have been further categorized into subtypes (e.g., 1a, 1b, 2a, 2b, 2c, 3a, 4a) (Simmonds, J. Gen. Virol. 85:3173-3188, 2004).
In the case of hepatitis C, acute symptoms can include jaundice, abdominal pain, fatigue, loss of appetite, nausea, vomiting, low-grade fever, pale or clay-colored stools, dark urine, generalized itching, ascites, and bleeding varices (dilated veins in the esophagus). Hepatitis C can become a chronic infection, which can lead to liver infection and scarring of the liver, which can, in turn, require the patient to undergo a liver transplant.
Hepatitis C is an RNA virus taken up specifically by hepatic cells. Once inside the cells, the RNA is translated into a polyprotein of about 3,000 amino acids. The protein is then processed into three structural and several non-structural proteins necessary for viral replication. Accordingly, HCV may be treated by reducing the rate any of the steps required for its replication or inhibiting any molecule involved in replication, including but not limited to, entry into a target cell, viral genome replication, translation of viral RNA, protolytic processing, and assembly and release from the target cell (e.g., using the agents described herein).
Certain compounds that may be employed in the methods, compositions, and kits of the present invention are discussed in greater detail below. It will be understood that analogs of any compound of Table 1, Table 2, or Table 3 can be used instead of the compound of Table 1, Table 2, or Table 3 in the methods, compositions, and kits of the present invention.
In certain embodiments, an HMG-CoA reductase inhibitor can be used in the compositions, methods, and kits of the invention. By an “HMG-CoA reductase inhibitor” is a compound that inhibits the enzymatic activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase by at least about 10%. HMG-CoA reductase inhibitors include but are not limited to simvastatin, lovastatin, mevastatin, pravastatin, monacolin M, monacolin X, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, fluindostatin, velostatin, compactin, dihydrocompactin, rivastatin, dalvastatin, pitavastatin, BAY102987, BAY X 2678, BB476, bervastatin, BMY21950, BMY22089, colestolone, CP83101, crilvastatin, DMP565, glenvastatin, L659699, L669262, P882222, P882284, PD134965, PD135022, RP61969, S2468, SC37111, SC45355, SQ33600, SR12813, SR45023A, U20685, and U88156, as well as pharmaceutically acceptable salts thereof (e.g., simvastatin sodium, lovastatin sodium, fluvastatin sodium, etc.). Additional HMG-CoA reductase inhibitors and analogs thereof useful in the methods and compositions of the present invention are described in U.S. Pat. Nos. 3,983,140; 4,231,938; 4,282,155; 4,293,496; 4,294,926; 4,319,039; 4,343,814; 4,346,227; 4,351,844; 4,361,515; 4,376,863; 4,444,784; 4,448,784; 4,448,979; 4,450,171; 4,503,072; 4,517,373; 4,661,483; 4,668,699; 4,681,893; 4,719,229; 4,738,982; 4,739,073; 4,766,145; 4,782,084; 4,804,770; 4,841,074; 4,847,306; 4,857,546; 4,857,547; 4,940,727; 4,946,864; 5,001,148; 5,006,530; 5,075,311; 5,112,857; 5,116,870; 5,120,848; 5,166,364; 5,173,487; 5,177,080; 5,273,995; 5,276,021; 5,369,123; 5,385,932; 5,502,199; 5,763,414; 5,877,208; and 6,541,511; and U.S. Pat. Application Publication Nos. 2002/0013334 A1; 2002/0028826 A1; 2002/0061901 A1; and 2002/0094977 A1.
In certain embodiments, clozapine or a clozapine analog can be used in the compositions, methods, and kits of the invention. Suitable clozapine analogs include acetophenazine maleate, alentemol hydrobromide, alpertine, azaperone, batelapine maleate, benperidol, benzindopyrine hydrochloride, brofoxine, bromperidol, bromperidol decanoate, butaclamol hydrochloride, butaperazine, butaperazine maleate, carphenazine maleate, carvotroline hydrochloride, chlorpromazine, chlorpromazine hydrochloride, chlorprothixene, cinperene: cintriamide, clomacran phosphate, clopenthixol, clopimozide, clopipazan mesylate, cloroperone hydrochloride, clothiapine, clothixamide maleate, cyclophenazine hydrochloride, droperidol, etazolate hydrochloride, fenimide, flucindole, flumezapine, fluphenazine decanoate, fluphenazine enanthate, fluphenazine hydrochloride, fluspiperone, fluspirilene, flutroline, gevotroline hydrochloride, halopemide, haloperidol, haloperidol decanoate, iloperidone, imidoline hydrochloride, lenperone, mazapertine succinate, mesoridazine, mesoridazine besylate, metiapine, milenperone, milipertine, molindone hydrochloride, naranol hydrochloride, neflumozide hydrochloride, ocaperidone, olanzapine, oxiperomide, penfluridol, pentiapine maleate, perphenazine, pimozide, pinoxepin hydrochloride, pipamperone, piperacetazine, pipotiazine palmitate, piquindone hydrochloride, prochlorperazine edisylate, prochlorperazine maleate, promazine hydrochloride, remoxipride, remoxipride hydrochloride, rimcazole hydrochloride, seperidol hydrochloride, sertindole, setoperone, spiperone, thioridazine, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, tioperidone hydrochloride, tiospirone hydrochloride, trifluoperazine hydrochloride, trifluperidol, triflupromazine, triflupromazine hydrochloride, and ziprasidone hydrochloride. Additional clozapine analogs are described in U.S. Pat. Nos. 2,519,886; 2,921,069, 3,084,161, 3,155,669, 3,155,670, 3,438,991, 3,161,644, 4,045,445, 4,308,207, 4,459,232, 4,460,508, 4,460,587, 4,507,311, 4,595,535, 4,192,803, 5,955,459, and 6,197,764.
Trifluperidol
In certain embodiments, trifluperidol or an analog thereof can be used in the compositions, methods, and kits of the invention. The structure of trifluperidol is:
Analogs of trifluperidol are described for example in U.S. Pat. No. 3,438,991 and have the general structure:
where Ar and Ar′ are monocyclic aryl rings, is 2 to 4, n is 1 or 2, m is 0, 1, or 2, and X is a hydrogen or a methyl group. Ar and Ar′ can represent halophenyls such as fluorophenyl, chlorophenyl, bromophenyl, and iodophenyl; alkoxyphenyls such as methoxyphenyl, ethoxyphenyl, dimethoxyphenyl, and trimethoxyphenyl; monocyclic aromatic hydrocarbon radicals such as phenyl, tolyl, xylyl, isopropylphenyl, and tertiary butyl phenyl; and a trifluoromethylphenyl radical. (CH2)p can represent a lower alkylene group, e.g., 2 to 4 carbon atoms such as ethylene, trimethylene, propylene, butylene, methylpropylene, and tetramethylene.
In certain embodiments, paclitaxel or a paclitaxel analog can be used in the compositions, methods, and kits of the invention. Paclitaxel is described in U.S. Pat. No. 4,814,470. Paclitaxel analogs include isoserine, taxol, taxotere, cephalomannine, 10-deacetylbaccatine III and those compounds described in U.S. Pat. Nos. 4,814,470, 4,857,653, 4,876,399, 4,924,011, 4,924,012, 4,942,184, 4,960,790, 5,015,744, 5,059,699, 5,136,060, 5,157,049, 5,192,796, 5,227,400, 5,243,045, 5,248,796, 5,250,683, 5,254,580, 5,271,268, 5,272,171, 5,283,253, 5,284,864, 5,290,957, 5,292,921, 5,294,637, 5,319,112, 5,336,684, 5,338,872, 5,350,866, 5,380,751, 5,380,916, 5,399,726, 5,430,160, 5,438,072, 5,470,866, 5,489,601, 5,508,447, 5,539,103, 5,547,981, 5,556,878, 5,574,156, 5,580,899, 5,580,998, 5,587,489, 5,587,493, 5,606,083, 5,622,986, 5,635,531, 5,646,176, 5,654,447, 5,677,470, 5,688,977, 5,693,666, 5,703,117, 5,710,287, 5,714,512, 5,714,513, 5,717,115, 5,721,268, 5,728,725, 5,728,850, 5,739,362, 5,750,562, 5,760,219, 5,773,464, 5,807,888, 5,821,363, 5,840,748, 5,840,929, 5,840,930, 5,854,278, 5,912,264, 5,919,815, 5,902,822, 5,965,739, 5,977,386, 5,990,325, 5,994,576, 5,998,656, 6,011,056, 6,017,935, 6,018,073, 6,028,205, 6,051,724, 6,066,747, 6,080,877, 6,107,332, 6,118,011, 6,124,481, 6,136,961, 6,147,234, 6,177,456, 6,307,064, 6,310,201, 6,350,886, 6,362,217, 6,455,575, 6,462,208, 6,482,963, 6,495,704, 6,515,151, 6,545,168, 6,710,191, 6,762,309, 6,794,523, 6,797,833, 6,878,834, 6,911,549, and 7,019,150.
In certain embodiments, an estrogenic compound can be used in the compositions, methods, and kits of the invention. Estrogenic compounds include estradiol (e.g., estradiol valerate, estradiol cypionate), colpormon, 2-methyoxyestradiol, conjugated estrogenic hormones, equilenin, equilin, dienestrol, ethinyl estradiol, estriol, mestranol, moxestrol, quinestradiol, quinestrol, estrone, estrone sulfate, equilin, diethylstilbestrol, broparoestrol, chlorotrianisine, fosfestrol, hexestrol, methestrol, and genistein. Estrogenic compounds are also described in U.S. Pat. Nos. 2,096,744, 2,465,505, 2,464,203, and 3,159,543.
In certain embodiments, an aminopyridine can be used in the composition, methods, and kits of the invention. By “aminopyridine” is meant any pyridine ring-containing compound in which the pyridine has one, two, or three amino group substituents. Other substituents may optionally be present. Exemplary aminopyridines include phenazopyridine, 4-aminopyridine, 3,4-diaminopyridine, 2,5-diamino-4-methylpyridine, 2,3,6-triaminopyridine, 2,4,6-triaminopyridine, and 2,6-diaminopyridine, the structures of which are depicted below. Phenazopyridine and derivatives thereof have been disclosed in U.S. Pat. Nos. 1,680,108 through 1,680,111. Modifications of di-amino(phenylazo)pyridines have been performed to improve solubility in water by reacting these compounds with alkylating agents (e.g., alkyl halides and alkyl sulphates) to produce quaternary pyridinium bases (see, e.g., U.S. Pat. No. 2,135,293). Heterocyclic azo derivatives and N-substituted diaminopyridines have also been described (U.S. Pat. Nos. 2,145,579 and 3,647,808).
In certain embodiments, an antiestrogen can be used in the methods, compositions, and kits of the invention. Antiestrogens include tamoxifen, 4-hydroxy tamoxifen, clomifene, raloxifene, faslodex, nafoxidine, fulvestrant, CI-680, CI-628, CN-55,956-27, MER-25, U-11,555A, U-11,100A, ICI-46,669, ICI-46,474, diphenolhydrochrysene, erythro-MEA, Parke Davis CN-35,945, allenolic acid, cyclofenil, ethamoxytriphetol, and triparanol and those compounds described in U.S. Pat. Nos. 5,384,332, 4,894,373, 4,536,516, 4,418,068, and 2,914,563.
In certain embodiments, a calcium channel inhibitor can be used in the compositions, methods, and kits of the invention. Calcium channel inhibitors include thapsigargin, verapamil, anipamil, bepridil, gallopamil, devapamil, falipamil, tiapamil, nifedipine, amlodipine, dazodipine, felodipine, isradipine, lanicardipine, nicardipine, nimodipine, nisoldipine, nitrendipine, ryosidie, diltiazem, cinnarizine, flunarizine, BAY-m 4786, and diperdipine.
Verapamil
In certain embodiments, verapamil or an analog thereof can be used in the compositions, methods, and kits of the invention. The structure of verapamil is:
Verapamil analogs are described, for example, in U.S. Pat. No. 3,261,859 and have the general formula:
where R is a lower aliphatic hydrocarbon radical; R1 is hydrogen, a lower alkyl radical, a saturated or unsaturated cyclic or bicyclic hydrocarbon radical, the benzyl radical, or the phenyl radical; R2, R3, R4, R5, R6, and R7 are hydrogen, halogen, lower alkyl radicals, lower alkoxy groups, or two of said substituents together forming the methylene dioxy group; n is an integer between 2 and 4; and m is an integer between 1 and 3.
In certain embodiments, a tricyclic compound can be used in the compositions, methods, and kits of the invention. By “tricyclic compound” is meant a compound having one the formulas (I), (II), (III), or (IV):
wherein each X is, independently, H, Cl, F, Br, I, CH3, CF3, OH, OCH3, CH2CH3, or OCH2CH3; Y is CH2, O, NH, S(O)0-2, (CH2)3, (CH)2, CH2O, CH2NH, CHN, or CH2S; Z is C or S; A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 3 and 6 carbons, inclusive; each B is, independently, H, Cl, F, Br, I, CX3, CH2CH3, OCX3, or OCX2CX3; and D is CH2, O, NH, or S(O)0-2. In preferred embodiments, each X is, independently, H, Cl, or F; Y is (CH2)2, Z is C; A is (CH2)3; and each B is, independently, H, Cl, or F. Other tricyclic compounds are described below. Tricyclic compounds include tricyclic antidepressants such as amoxapine, 8-hydroxyamoxapine, 7-hydroxyamoxapine, loxapine (e.g., loxapine succinate, loxapine hydrochloride), 8-hydroxyloxapine, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, and protriptyline, although compounds need not have antidepressant activities to be considered tricyclic compounds of the invention.
Tricyclic compounds that can be used in connection with the invention include amitriptyline, amoxapine, clomipramine, desipramine, dothiepin, doxepin, imipramine, lofepramine, maprotiline, mianserin, mirtazapine, nortriptyline, octriptyline, oxaprotiline, protriptyline, trimipramine, 10-(4-methylpiperazin-1-yl)pyrido(4,3-b)(1,4)benzothiazepine; 11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine; 5,10-dihydro-7-chloro-10-(2-(morpholino)ethyl)-11H-dibenzo(b,e)(1,4)diazepin-11-one; 2-(2-(7-hydroxy-4-dibenzo(b,f)(1,4)thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol; 2-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine; 4-(11H-dibenz(b,e)azepin-6-yl)piperazine; 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepin-2-ol; 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine monohydrochloride; (Z)-2-butenedioate 5H-dibenzo(b,e)(1,4)diazepine; adinazolam; amineptine; amitriptylinoxide; butriptyline; clothiapine; clozapine; demexiptiline; 11-(4-methyl-1-piperazinyl)-dibenz(b,f)(1,4)oxazepine; 11-(4-methyl-1-piperazinyl)-2-nitro-dibenz(b,f)(1,4)oxazepine; 2-chloro-11-(4-methyl-1-piperazinyl)-dibenz(b,f)(1,4)oxazepine monohydrochloride; dibenzepin; 11-(4-methyl-1-piperazinyl)-dibenzo(b,f)(1,4)thiazepine; dimetacrine; fluacizine; fluperlapine; imipramine N-oxide; iprindole; lofepramine; melitracen; metapramine; metiapine; metralindole; mianserin; mirtazapine; 8-chloro-6-(4-methyl-1-piperazinyl)-morphanthridine; N-acetylamoxapine; nomifensine; norclomipramine; norclozapine; noxiptilin; opipramol; oxaprotiline; perlapine; pizotyline; propizepine; quetiapine; quinupramine; tianeptine; tomoxetine; flupenthixol; clopenthixol; piflutixol; chlorprothixene; and thiothixene. Other tricyclic compounds are described in U.S. Pat. Nos. 2,554,736, 3,046,283, 3,058,979, 3,310,553, 3,177,209, 3,194,733, 3,205,264, 3,244,748, 3,271,451, 3,272,826, 3,282,930, 3,282,942, 3,299,139, 3,312,689, 3,389,139, 3,399,201, 3,409,640, 3,419,547, 3,438,981, 3,454,554, 3,467,650, 3,505,321, 3,527,766, 3,534,041, 3,539,573, 3,574,852, 3,622,565, 3,637,660, 3,663,696, 3,758,528, 3,922,305, 3,963,778, 3,978,121, 3,981,917, 4,017,542, 4,017,621, 4,020,096, 4,045,560, 4,045,580, 4,048,223, 4,062,848, 4,088,647, 4,128,641, 4,148,919, 4,153,629, 4,224,321, 4,224,344, 4,250,094, 4,284,559, 4,333,935, 4,358,620, 4,548,933, 4,691,040, 4,879,288, 5,238,959, 5,266,570, 5,399,568, 5,464,840, 5,455,246, 5,512,575, 5,550,136, 5,574,173, 5,681,840, 5,688,805, 5,916,889, 6,545,057, and 6,600,065, and phenothiazine compounds that fit Formula (I) of U.S. patent application Ser. Nos. 10/617,424 (published as U.S. 2004/0116407) or 60/504,310.
Sertraline and Analogs thereof.
In certain embodiments, sertraline or an analog thereof can be used in the compositions, methods, and kits of the invention. Sertraline has the structure:
Structural analogs of sertraline are those having the formula:
where R1 and R2 are independently selected from the group consisting of H, optionally substituted C1-6 alkyl (e.g., CH3, (CH2)xOH, cyclopropyl, (CH2)xCOOH, or CH2CHOH(CH2)x, (CH2)xN(CfH3)2, where x is 1, 2, 3, 4, or 5), and optionally substituted C1-7 heteroalkyl (e.g., CH2CH2N(CH3)2) or R1 and R2 together form a C3-8 cycloalkyl optionally heterocyclic, optionally substituted (e.g., forming a morpholine ring), R3, R4, R5, and R6 are independently H, Cl, F, Br, OH, or optionally substituted C1-6 alkyl; X and Y are each selected from the group consisting of H, F, Cl, Br, CF3, C1-6 alkoxy (e.g., OPh and OCH3), and cyano; and W is selected from the group consisting of H, F, Cl, Br, CF3, C1-3 alkoxy, COOH, CH2CH2OH, NHCOH, NHCOCH3, CH2S(O)nCH3, CH2NH2, CONH2, CH2OH, NHCOPh, CH2NHS(O)nCH3, NHS(O)nPh, N(CH3)2, S(O)nNH2, NHCOBu, NHS(O)nCH3, NHCOcyclopentyl, CN, NHS(O)ncyclopropyl, NH2, NO2, I, SO2N(CH3)2, SO2NHMe, SO2NHCH2CH2OH, CO2Me, NHSO2Bu, CONHCH3, CH2NHCOCH3, CONHPh,
CONHcylopropyl, C(S)NH2, NHC(S)CH3, CONHCH2COOCH3, CONHCH2COOH, CONHCH2cyclopropyl, CON(CH3)cyclopropyl, CONHcyclobutyl, NHCOcyclopropyl, NH(CH3)COCH3, N(CH3)COCH3, and CH2S(O)nR11, where n is 0, 1, or 2 and R11 is phenyl, C2-6 heterocyclyl, optionally substituted C1-8 alkyl (e.g., C4-8 unsubstituted alkyl such as Bu or C3-8 substituted alkyl). In certain embodiments, R1 is CH3 and R2 is CH3, CH2CH2OH, cyclopropyl, CH2COOH, CH2CH2NH2, CH2CH(OH)R8, or CH2CH(R8)NR9R10, where n is 0, 1, or 2 and R8, R9, and R10 are independently H or C1-6 alkyl. In certain embodiments, X is H and Y is p-OPh, p-OCF3, o-OCH3 m-OCH3, or p-OCH3. In certain embodiments of the above structure, the sertraline analog has the formula:
Other sertraline analogs have the formula:
where R3, R4, R5, R6, W, X, and Y are as defined above, and R7 is independently H, NH(CH2)mCH3, O(CH2)mCH3, OH, O(CH2)mCH3, ═O, C1-6 alkyl (e.g., isopropyl), or C1-6 alkyoxy, where m is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, R3, R4, R5, and R6 are H; X and Y are each Cl at the 3 and 4 positions of the benzyl ring. Exemplary analogs include:
Other sertraline analogs have the formula:
where R1, R2, R3, R4, R5, R6, X and Y are as defined above, and R7 is H or C1-6 optionally substituted alkyl.
Other sertraline analogs are described by the formula:
wherein R8, R9, and R10 are independently H, optionally substituted C1-6 alkyl (e.g., CH3, (CH2)xOH, cyclopropyl, (CH2)xCOOH, or CH2CHOH(CH2)x, (CH2)xN(CfH3)2, where x is 1, 2, 3, 4, or 5), and optionally substituted C1-7 heteroalkyl (e.g., CH2CH2N(CH3)2)
In certain embodiments, sertraline analogs are in the cis-isomeric configuration. The term “cis-isomeric” refers to the relative orientation of the NR1R2 and phenyl moieties on the cyclohexene ring (i.e., they are both oriented on the same side of the ring). Because both the 1- and 4-carbons are asymmetrically substituted, each cis-compound has two optically active enantiomeric forms denoted (with reference to the 1-carbon) as the cis-(1R) and cis-(1S) enantiomers. Sertraline analogs are also described in U.S. Pat. No. 4,536,518. Other related compounds include (S,S)—N-desmethylsertraline, rac-cis-N-desmethylsertraline, (1S,4S)-desmethyl sertraline, 1-des (methylamine)-1-oxo-2-(R,S)-hydroxy sertraline, (1R,4R)-desmethyl sertraline, sertraline sulfonamide, sertraline (reverse) methanesulfonamide, 1R,4R sertraline enantiomer, N,N-dimethyl sertraline, nitro sertraline, sertraline aniline, sertraline iodide, sertraline sulfonamide NH2, sertraline sulfonamide ethanol, sertraline nitrile, sertraline-CME, dimethyl sertraline reverse sulfonamide, sertraline reverse sulfonamide (CH2 linker), sertraline B-ring ortho methoxy, sertraline A-ring methyl ester, sertraline A-ring ethanol, sertraline N,N-dimethylsulfonamide, sertraline A-ring carboxylic acid, sertraline B-ring para-phenoxy, sertraline B-ring para-trifluoromethane, N,N-dimethyl sertraline B-Ring para-trifluoromethane, sertraline A-ring methyl sulfoxide (CH2 linker), sertraline A-ring carboxamide, sertraline A-ring reverse carboxamide, Sertraline A-ring methanamine, sertraline A-ring sulfonylmethane (CH2 linker), sertraline (reverse) methanesulfonamide, sertraline A-ring thiophene, reduced sulfur sertraline A-ring methyl sulfoxide (CH2 linker), and hetrocyclic substituted stertraline (reverse) methanesulfonamide. Structures of these analogs and others are shown in Table 9 below. Analogs are also described in Tables 19-24 below.
Particularly useful are the following compounds, in either the (1S)-enantiomeric or (1S)(1R) racemic forms, and their pharmaceutically acceptable salts: cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; cis-N-methyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; cis-N-methyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; cis-N-methyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; cis-N-methyl-4-(3-trifluoromethyl-4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; cis-N,N-dimethyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; cis-N,N-dimethyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; and cis-N-methyl-4-(4-chlorophenyl)-7-chloro-1,2,3,4-tetrahydro-1-naphthalenamine. Of interest also is the (1R)-enantiomer of cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine.
UK-416244 is an SSRI that is phenoxybenzylamine derivative. UK-416244 has the structure:
Structural analogs of UK-416244 are compounds having the formula:
where R1 and R2, independently, are H, C1-6 alkyl (e.g., CH3) or substituted heteroalkyl (e.g., CH2CH2N(CH3)2 and CH2OCH3), or (CH2)d(C3-6 cycloalkyl) where d is 0, 1, 2, or 3; or R1 and R2 together with the nitrogen to which they are attached form an azetidine ring; Z or Y is —S(O)nR3 and the other Z or Y is halogen or —R3; where R3 is independently C1-4 alkyl optionally substituted with fluorine (e.g., where R3 is or is not CF3) and n is 0, 1, or 2; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated, or aromatic, and where when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from O, S, and N; (e.g., with the proviso that when R5 is F and R2 is methyl then the fused ring is not 1,3-dioxolane and Z and Y together do not form a fused phenyl ring); R4 and R5 are, independently, A-X, where A is —CH═CH— or —(CH2)p— where p is 0, 1, or 2; X is H, F, Cl, Br, I, NH2, OH, CONR6R7, SO2NR6R7, SO2NHC(═O)R6, C1-4 alkoxy, NR8SO2R9, NO2, NR6R11 (e.g., N(CH3)2, CN, CO2R10 (e.g., COOH), CHO, SR10, S(O)R9 or SO2R10; R6, R7, R8 and R10 independently are H, C1-6 alkyl (e.g., CH3, (CH2)3CH3 or cyclopropyl), C6-12 aryl (e.g., phenyl) optionally substituted independently by one or more R12, or C1-6 alkyl-aryl optionally substituted (e.g., CH2Ph); R9 is C1-6 alkyl optionally substituted independently by one or more R12; R11 is H, C1-6 alkyl optionally substituted independently by one or more R12, C(O)R6, CO2R9, C(O)NHR6, or SO2NR6R7; R12 is F (preferably up to 3), Br, OCH3, OH, CO2H, C3-6 cycloalkyl, NH2, CONH2, C1-6 alkoxy, C1-6 alkoxycarbonyl, or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R13; or R6 and R7, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclic ring optionally substituted independently by one or more R13; or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R13; where R13 is hydroxy, C1-4 alkoxy, F, C1-6 alkyl, haloalkyl, haloalkoxy, —NH2, —NH(C1-6 alkyl), or —N(C1-6 alkyl)2—;
or compounds having the formula:
where R1 and R2 are independently H, C1-6 alkyl (e.g., CH3) or substituted heteroalkyl, (CH2)m(C3-6 cycloalkyl) where m is 0, 1, 2, or 3, or R1 and R2 together with the nitrogen to which they are attached form an azetidine ring; each R3 is independently H, I, Br, F, Cl, C1-6 alkyl (e.g., CH3), CF3, CN, OCF3, C1-4 alkylthio (e.g., SCH3), C1-4 alkoxy (e.g., OCH3), aryloxy (e.g., OPh), or CONR6R7; n is 1, 2, or 3; and R4 and R5 are independently A-X, where A is —CH═CH— or —(CH2)p— where p is 0, 1, or 2; X is H, F, Cl, Br, I, CONR6R7, SO2NR6R7, SO2NHC(═O)R6, OH, C1-4 alkoxy, NR8SO2R9, NO2, NR6R11, CN, CO2R10 (e.g., COOH), CHO, SR10, S(O)R9, or SO2R10; R6, R7, R8, and R10 are independently H or C1-6 alkyl (e.g., (CH2)3CH3 or cyclopropyl), C6-12 aryl (e.g., phenyl) optionally substituted independently by one or more R12, or C1-6 alkyl-aryl optionally substituted; R9 is C1-6 alkyl optionally substituted independently by one or more R12; R11 is H, C1-6 alkyl optionally substituted independently by one or more R12, C(O)R6, CO2R9, C(O)NHR6, or SO2NR6R7; R12 is F (preferably up to 3), OH, CO2H, C3-6 cycloalkyl, NH2, CONH2, C1-6 alkoxy, C1-6 alkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R13; or R6 and R7, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclic ring optionally substituted independently by one or more R13; or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R13; where R13 is hydroxy, C1-4 alkoxy, F, C1-6 alkyl, haloalkyl, haloalkoxy, —NH2, —NH(C1-6 alkyl) or —N(C1-6 alkyl)2 (e.g., where when R1 and R2 are methyl, R4 and R5 are hydrogen and n is 1, R3 is not a —SMe group para to the ether linkage linking rings A and B). In certain embodiments, n is 1 or 2, and the R3 group(s) is/are at positions 3 and/or 4 of the B ring, for example, are CH3, SCH3, OCH3, Br, or CF3. For either of the above structures, R4 or R5 can be SO2NHPh, SO2NHCH3, CN, H, Br, CONH2, COOH, SO2NHCH2Ph, SO2NHCOCH3, CH2NHSO2CH3 NH2, ORNO2, benzyl amide, acylsulfonamide, reverse sulfonamide, NHCH3, N(CH3)2, SO2NH2, CH2OH, NHSO2CH3, SO2NHCH2CCH2, CH2NH2, SO2NHBu, and SO2NHcyclopropyl. UK-416244 structural analogs are described in U.S. Pat. Nos. 6,448,293 and 6,610,747. UK-416244 analogs are described below.
Other analogs of UK-416244 can be described by the formula:
where are R3, R4, and R5 are as defined above and Z is CH2NR1R2 where R1 and R2 are as defined above, NH2, optionally substituted optionally hetero C1-8 alkyl (e.g., substituted with hydroxyl, NH2, NHC1-6 alkyl), or is selected from the group consisting of:
In certain embodiments, Z is CN, CH2CH(CH3)2, CH2OCH3, CH2N(CH3)CH2CH2OH, N(CH3)2, CH2N(CH3)2, COOH, CH2NHCH3, CH2OH, CH2NHCOCH3, CONHCH3, CH2NH(CH2)2N(CH3)2, CH2NH(CH2)3N(CH3)2, CHC(CH3)2, CH2N(CH3)(CH2)2N(CH3)2, CH2N(CH3)(CH2)3N(CH3)2, or CH2CH(CH3)2.
Other UK-416244 analogs are described by the formula.
where R1 is H, I, Br, F, Cl, C1-6 alkyl (e.g., CH3), CF3, CN, OCF3, C1-4 alkylthio (e.g., SCH3), C1-4 alkoxy (e.g., OCH3), aryloxy, or CONR2R3; n is 1, 2, or 3; R2 and R3 are independently H or C1-6 alkyl (e.g., (CH2)3CH3 or cyclopropyl), C6-12 aryl (e.g., phenyl) optionally substituted independently by one or more R4, or C1-6 alkyl-aryl optionally substituted; R4 is F (preferably up to 3), OH, CO2H, C3-6 cycloalkyl, NH2, CONH2, C1-6 alkoxy, C1-6 alkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R5; or R2 and R3, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclic ring optionally substituted independently by one or more R5; or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, and O optionally substituted independently by one or more R5; where R5 is hydroxy, C1-4 alkoxy, F, C1-6 alkyl, haloalkyl, haloalkoxy, —NH2, —NH(C1-6 alkyl) or —N(C1-6 alkyl)2. In certain embodiments, where R1 is Br, OMe, NO2, CO2Me, or CN. R1 may be at the ortho, meta, or para position)
Still other UK-416244 analogs are described by the formula:
where X is N, O, or S, and R1 is H, C1-6 alkyl or substituted heteroalkyl, (CH2)m(C3-6 cycloalkyl) where m is 0, 1, 2, or 3.
Additional compounds have the structure:
where R1 is H or C1-6 alkyl (e.g., CH3, CH2CH3) and R2 is C1-6 alkyl substituted with OH, such as CH2OH, CH2CH2OH, CH(OH)CH3, CH2CH2CH2OH, CH(CH2)CH2OH, and CH2CH2CH2CH2OH, CH(OH)CH2CH2CH3, CH2CH(OH)CH2CH3, and CH2CH2CH(OH)CH3) or is CH2XR14 or CH2CH2XR14, where X is N, O, or S, and R14 is H, C1-6 alkyl or substituted heteroalkyl, (CH2)q(C3-6 cycloalkyl) where q is 0, 1, 2, or 3, and where R3, R4, and R5 are as defined above. In certain embodiments, the compound has the structure,
where R1 is H or C1-6 alkyl (e.g., CH3, CH2CH3) and R2 is C1-6 alkyl substituted with OH, e.g., CH2OH, CH2CH2OH, CH(OH)CH3, CH2CH(OH)CH3, CH2CH2CH2OH, CH(CH2)CH2OH, and CH2CH2CH2CH2OH, CH(OH)CH2CH2CH3, CH2CH(OH)CH2CH3, and CH2CH2CH(OH)CH3). In particular embodiments, the compound is:
In any of the UK-416244 analogs, the bridge between the A and B rings may be replaced with an —NH— bridge (e.g., Compound 108).
Particular UK-416244 analogs include those of Table 10:
Other UK-416244 analogs include those of Table 11.
In certain embodiments, a corticosteroid can be used in the compositions, methods, and kits of the invention. If desired, one or more corticosteroid may be administered in a method of the invention or may be formulated with a tricyclic compound in a composition of the invention. Suitable corticosteroids include 11-alpha,17-alpha,21-trihydroxypregn-4-ene-3,20-dione; 11-beta,16-alpha,17,21-tetrahydroxypregn-4-ene-3,20-dione; 11-beta,16-alpha,17,21-tetrahydroxypregn-1,4-diene-3,20-dione; 11-beta,17-alpha,21-trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione; 11-dehydrocorticosterone; 11-deoxycortisol; 11-hydroxy-1,4-androstadiene-3,17-dione; 11-ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogesterone; 16-methylhydrocortisone; 17,21-dihydroxy-16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione; 17-alpha-hydroxypregn-4-ene-3,20-dione; 17-alpha-hydroxypregnenolone; 17-hydroxy-16-beta-methyl-5-beta-pregn-9(11)-ene-3,20-dione; 17-hydroxy-4,6,8(14)-pregnatriene-3,20-dione; 17-hydroxypregna-4,9(11)-diene-3,20-dione; 18-hydroxycorticosterone; 18-hydroxycortisone; 18-oxocortisol; 21-acetoxypregnenolone; 21-deoxyaldosterone; 21-deoxycortisone; 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17-alpha,20-beta,21-triol-3,11-dione; 6,17,20-trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycortisol; 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone 21-hemisuccinate sodium salt, 6-beta-hydroxycortisol, 6-alpha,9-alpha-difluoroprednisolone 21′-acetate 17-butyrate, 6-hydroxycorticosterone; 6-hydroxydexamethasone; 6-hydroxyprednisolone; 9-fluorocortisone; alclomethasone dipropionate; aldosterone; algestone; alphaderm; amadinone; amcinonide; anagestone; androstenedione; anecortave acetate; beclomethasone; beclomethasone dipropionate; betamethasone 17-valerate; betamethasone sodium acetate; betamethasone sodium phosphate; betamethasone valerate; bolasterone; budesonide (analogs described in U.S. Pat. No. 3,929,768); calusterone; chlormadinone; chloroprednisone; chloroprednisone acetate; cholesterol; ciclesonide; clobetasol; clobetasol propionate; clobetasone; clocortolone; clocortolone pivalate; clogestone; cloprednol; corticosterone; cortisol; cortisol acetate; cortisol butyrate; cortisol cypionate; cortisol octanoate; cortisol sodium phosphate; cortisol sodium succinate; cortisol valerate; cortisone; cortisone acetate; cortivazol; cortodoxone; daturaolone; deflazacort, 21-deoxycortisol, dehydroepiandrosterone; delmadinone; deoxycorticosterone; deprodone; descinolone; desonide; desoximethasone; dexafen; dexamethasone; dexamethasone 21-acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichlorisone; diflorasone; diflorasone diacetate; diflucortolone; difluprednate; dihydroelatericin a; domoprednate; doxibetasol; ecdysone; ecdysterone; emoxolone; endrysone; enoxolone; fluazacort; flucinolone; flucloronide; fludrocortisone; fludrocortisone acetate; flugestone; flumethasone; flumethasone pivalate; flumoxonide; flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide; fluocortin butyl; 9-fluorocortisone; fluocortolone; fluorohydroxyandrostenedione; fluorometholone; fluorometholone acetate; fluoxymesterone; fluperolone acetate; fluprednidene; fluprednisolone; flurandrenolide; fluticasone; fluticasone propionate; formebolone; formestane; formocortal; gestonorone; glyderinine; halcinonide; halobetasol propionate; halometasone; halopredone; haloprogesterone; hydrocortamate; hydrocortiosone cypionate; hydrocortisone; hydrocortisone 21-butyrate; hydrocortisone aceponate; hydrocortisone acetate; hydrocortisone buteprate; hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisuccinate; hydrocortisone probutate; hydrocortisone sodium phosphate; hydrocortisone sodium succinate; hydrocortisone valerate; hydroxyprogesterone; inokosterone; isoflupredone; isoflupredone acetate; isoprednidene; loteprednol etabonate; meclorisone; mecortolon; medrogestone; medroxyprogesterone; medrysone; megestrol; megestrol acetate; melengestrol; meprednisone; methandrostenolone; methylprednisolone; methylprednisolone aceponate; methylprednisolone acetate; methylprednisolone hemisuccinate; methylprednisolone sodium succinate; methyltestosterone; metribolone; mometasone (analogs described in 4,472,393); mometasone furoate; mometasone furoate monohydrate; nisone; nomegestrol; norgestomet; norvinisterone; oxymesterone; paramethasone; paramethasone acetate; ponasterone; prednicarbate; prednisolamate; prednisolone; prednisolone 21-diethylaminoacetate; prednisolone 21-hemisuccinate; prednisolone acetate; prednisolone farnesylate; prednisolone hemisuccinate; prednisolone-21(beta-D-glucuronide); prednisolone metasulphobenzoate; prednisolone sodium phosphate; prednisolone steaglate; prednisolone tebutate; prednisolone tetrahydrophthalate; prednisone; prednival; prednylidene; pregnenolone; procinonide; tralonide; progesterone; promegestone; rhapontisterone; rimexolone; roxibolone; rubrosterone; stizophyllin; tixocortol; topterone; triamcinolone; triamcinolone acetonide; triamcinolone acetonide 21-palmitate; triamcinolone benetonide; triamcinolone diacetate; triamcinolone hexacetonide; trimegestone; turkesterone; and wortmannin or derivatives thereof (see, e.g., U.S. Pat. No. 7,081,475).
Steroid Receptor Modulators
Steroid receptor modulators (e.g., antagonists and agonists) may be used as a substitute for or in addition to a corticosteroid in the compositions, methods, and kits of the invention.
Glucocorticoid receptor modulators that may used in the compositions, methods, and kits of the invention include compounds described in U.S. Pat. Nos. 6,380,207, 6,380,223, 6,448,405, 6,506,766, and 6,570,020, U.S. Pat. Application Publication Nos. 2003/0176478, 2003/0171585, 2003/0120081, 2003/0073703, 2002/015631, 2002/0147336, 2002/0107235, 2002/0103217, and 2001/0041802, and PCT Publication No. WO00/66522, each of which is hereby incorporated by reference. Other steroid receptor modulators may also be used in the methods, compositions, and kits of the invention are described in U.S. Pat. Nos. 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, 5,693,647, 5,693,646, 5,688,810, 5,688,808, and 5,696,130, each of which is hereby incorporated by reference.
In certain embodiments, bufexamac or a bufexamac analog can be used in the compositions, methods, and kits of the invention. By “bufexamac analog” is meant a compound having the formula (VI):
wherein R1 is
wherein R1A is and R1B is H, halo, CF3, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, or optionally substituted C1-6 thioalkoxy; each of R2 and R3 is, independently, H, C1-4 alkyl, or CF3; and R4 is optionally substituted C1-6 alkyl or optionally substituted C3-8 cycloalkyl.
In certain embodiments, an antiviral agent can be used in the compositions, methods, and kits of the invention. Suitable antiviral agents include, without limitation, abacavir, acemannan, acyclovir, adefovir, amantadine, amidinomycin, ampligen, amprenavir, aphidicolin, atevirdine, capravirine cidofovir, cytarabine, delavirdine, didanosine, dideoxyadenosine, n-docosanol, edoxudine, efavirenz, emtricitabine, famciclovir, floxuridine, fomivirsen, foscamet sodium, ganciclovir, idoxuridine, imiquimod, indinavir, inosine pranobex, interferon-α, interferon-β, kethoxal, lamivudine, lopinavir, lysozyme, madu, methisazone, moroxydine, nelfinavir, nevirapine, nitazoxanide, oseltamivir, palivizumab, penciclovir, enfuvirtide, pleconaril, podophyllotoxin, ribavirin, rimantadine, ritonavir, saquinavir, sorivudine, stallimycin, statolon, stavudine, tenofovir, tremacamra, triciribine, trifluridine, tromantadine, tunicamycin, valacyclovir, valganciclovir, vidarabine, zalcitabine, zanamivir, zidovudine, resiquimod, atazanavir, tipranavir, entecavir, fosamprenavir, merimepodib, docosanol, vx-950, and peg interferon. Additional antiviral agents are listed in Table 4 and Table 5.
Structural analogs of antiviral agents which may be used in the combinations of the invention include 9-((2-aminoethoxy)methyl)guanine, 8-hydroxyacyclovir, 2′-O-glycyl acyclovir, ganciclovir, PD 116124, valacyclovir, omaciclovir, valganciclovir, buciclovir, penciclovir, valmaciclovir, carbovir, theophylline, xanthine, 3-methylguanine, enprofylline, cafaminol, 7-methylxanthine, L 653180, BMS 181164, valomaciclovir stearate, deriphyllin, acyclovir monophosphate, acyclovir diphosphate dimyristoylglycerol, and etofylline.
Edoxudine analogs are described in U.S. Pat. No. 3,553,192. Efavirenz analogs are described in European Patent 582,455 and U.S. Pat. No. 5,519,021. Floxuridine analogs are described in U.S. Pat. Nos. 2,970,139 and 2,949,451. Nelfinavir analogs are described in U.S. Pat. No. 5,484,926. Aphidicolin analogs are described in U.S. Pat. No. 3,761,512. Trifluridine analogs are described in U.S. Pat. No. 3,201,387. Cytarabine analogs are described in U.S. Pat. No. 3,116,282. Triciribine analogs, including triciribine 5′-phosphate and triciribine-dimethylformamide, are described in U.S. Pat. No. 5,633,235. Nitazoxanide analogs are described in U.S. Pat. No. 3,950,391.
Ritonavir
Ritonavir is an antiviral used in treatment of HIV and has the structure:
Ritonavir analogs are described, for example, in U.S. Pat. No. 5,541,206 and have the general structure:
where R1 is monosubstituted thiazolyl, monosubstituted oxazolyl, monosubstituted isoxazolyl or monosubstituted isothiazolyl wherein the substituent is selected from (i) loweralkyl, (ii) loweralkenyl, (iii) cycloalkyl, (iv) cycloalkylalkyl, (v) cycloalkenyl, (vi) cycloalkenylalkyl, (vii) heterocyclic wherein the heterocyclic is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl and wherein the heterocyclic is unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy, (viii) (heterocyclic)alkyl wherein heterocyclic is defined as above, (ix) alkoxyalkyl, (x) thioalkoxyalkyl, (xi) alkylamino, (xii) dialkylamino, (xiii) phenyl wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy, (xiv) phenylalkyl wherein the phenyl ring is unsubstituted or substituted as defined above, (xv) dialkylaminoalkyl, (xvi) alkoxy and (xvii) thioalkoxy; n is 1, 2 or 3; R2 is hydrogen or loweralkyl; R3 is loweralkyl; R4 and R4a are independently selected from phenyl, thiazolyl and oxazolyl wherein the phenyl, thiazolyl or oxazolyl ring is unsubstituted or substituted with a substituent selected from (i) halo, (ii) loweralkyl, (iii) hydroxy, (iv) alkoxy and (v) thioalkoxy; R6 is hydrogen or loweralkyl; R7 is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl wherein the thiazolyl, oxazolyl, isoxazolyl or isothiazolyl ring is unsubstituted or substituted with loweralkyl; X is hydrogen and Y is —OH or X is —OH and Y is hydrogen, with the proviso that X is hydrogen and Y is —OH when Z is —N(R8)— and R7 is unsubstituted and with the proviso that X is hydrogen and Y is —OH when R3 is methyl and R7 is unsubstituted; and Z is absent, —O—, —S—, —CH2— or —N(R8)— wherein R8 is loweralkyl, cycloalkyl, —OH or —NHR8a wherein R8a is hydrogen, loweralkyl or an N-protecting group.
Saquinavir
In certain embodiments, saquinavir or its analogs can be used in the compositions, methods, and kits of the invention. Saquinavir is a protease inhibitor that is highly specific for the HIV-1 and HIV-2 proteases. The structure of saquinavir is:
Saquinavir analogs are described, for example, in U.S. Pat. No. 5,196,438 and have the general structure:
where R is benzyloxycarbonyl or 2-quinolylcarbonyl, and pharmaceutically acceptable acid addition salts thereof.
Adefovir Dipivoxil
In certain embodiments, adefovir dipivoxil or its analogs can be used in the compositions, methods, and kits of the invention. Analogs of adefovir dipivoxil are described, for example, in U.S. Pat. No. 4,808,716 and include compounds with the general structure:
wherein R1 is a hydrogen atom, an alkyl group containing one to three carbon atoms, or a hydroxymethyl group, and R2 is a methylene, ethylene, propylene, ethylidene, methoxyethylene, benzyloxyethylene, tetrahydropyran-2-yloxyethylene, (1-ethoxyethoxy)ethylene, or 1,2-O-isopropylidene-1,2-dihydroxypropylene group.
Celgosivir
In certain embodiments, celgosivir or an analog thereof can be used in the compositions, methods, and kits of the invention. Celgosivir is a prodrug of castanospermine, a natural product derived from the Australian Black Bean chestnut tree. It has antiviral (e.g., anti-HCV) activity, and acts as an inhibitor of α- and β-glucosidase. The structure of celgosivir is:
Analogs of celgosivir are described, for example, in PCT Publication No. WO 2006/096285 and have the general structure:
where R, R1 and R2 are independently hydrogen, C1-4 alkanoyl, C2-14 alkenoyl, cyclohexanecarbonyl, C1-8 alkoxyacetyl,
naphthalenecarbonyl optionally substituted by methyl or halogen; phenyl(C2-6 alkanoyl) wherein the phenyl is optionally substituted by methyl or halogen; cinnamoyl; pyridinecarbonyl optionally substituted by methyl or halogen; dihydropyridine carbonyl optionally substituted by C1-10 alkyl; thiophenecarbonyl optionally substituted by methyl or halogen; or furancarbonyl optionally substituted by methyl or halogen; Y is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, C1-4 alkylsulphonyl, C1-4 alkylmercapto, cyano or dimethylamino; Y′ is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen or it is combined with Y to give 3,4-methylenedioxy; Y″ is hydrogen, C1-4 alkyl, C1-4 alkoxy or halogen; and pharmaceutically acceptable salts thereof.
In certain embodiments, a nonsteroidal immunophilin-dependent immunosuppressant can be used in the compositions, methods, and kits of the invention. Suitable NsIDIs include cyclosporine, tacrolimus, rapamycin (sirolimus), everolimus, and pimecrolimus.
Cyclosporines
The cyclosporines are fungal metabolites that comprise a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporine A is a hydrophobic cyclic polypeptide consisting of eleven amino acids. It binds and forms a complex with the intracellular receptor cyclophilin. The cyclosporine/cyclophilin complex binds to and inhibits calcineurin, a Ca2+-calmodulin-dependent serine-threonine-specific protein phosphatase. Calcineurin mediates signal transduction events required for T-cell activation (reviewed in Schreiber et al., Cell 70:365-368, 1991). Cyclosporines and their functional and structural analogs suppress the T cell-dependent immune response by inhibiting antigen-triggered signal transduction. This inhibition decreases the expression of proinflammatory cytokines, such as IL-2.
Many different cyclosporines (e.g., cyclosporine A, B, C, D, E, F, G, H, and I) are produced by fungi. Cyclosporine A is a commercially available under the trade name NEORAL from Novartis. Cyclosporine A structural and functional analogs include cyclosporines having one or more fluorinated amino acids (described, e.g., in U.S. Pat. No. 5,227,467); cyclosporines having modified amino acids (described, e.g., in U.S. Pat. Nos. 5,122,511 and 4,798,823); and deuterated cyclosporines, such as ISAtx247 (described in U.S. Pat. Application Publication No. 2002/0132763 A1). Additional cyclosporine analogs are described in U.S. Pat. Nos. 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporine analogs include, but are not limited to, D-Sar (α-SMe)3 Val2-DH—Cs (209-825), Allo-Thr-2-Cs, Norvaline-2-Cs, D-Ala(3-acetylamino)-8-Cs, Thr-2-Cs, and D-MeSer-3-Cs, D-Ser(O—CH2CH2—OH)-8-Cs, and D-Ser-8-Cs, which are described in Cruz et al. (Antimicrob. Agents Chemother. 44:143-149, 2000).
Tacrolimus
Tacrolimus and tacrolimus analogs are described by Tanaka et al., (J. Am. Chem. Soc., 109:5031, 1987) and in U.S. Pat. Nos. 4,894,366, 4,929,611, and 4,956,352. FK506-related compounds, including FR-900520, FR-900523, and FR-900525, are described in U.S. Pat. No. 5,254,562; O-aryl, O-alkyl, O-alkenyl, and O-alkynylmacrolides are described in U.S. Pat. Nos. 5,250,678, 532,248, 5,693,648; amino O-aryl macrolides are described in U.S. Pat. No. 5,262,533; alkylidene macrolides are described in U.S. Pat. No. 5,284,840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, and N-alkynylheteroaryl macrolides are described in U.S. Pat. No. 5,208,241; aminomacrolides and derivatives thereof are described in U.S. Pat. No. 5,208,228; fluoromacrolides are described in U.S. Pat. No. 5,189,042; amino O-alkyl, O-alkenyl, and O-alkynylmacrolides are described in U.S. Pat. No. 5,162,334; and halomacrolides are described in U.S. Pat. No. 5,143,918.
Tacrolimus is extensively metabolized by the mixed-function oxidase system, in particular, by the cytochrome P-450 system. The primary mechanism of metabolism is demethylation and hydroxylation. While various tacrolimus metabolites are likely to exhibit immunosuppressive biological activity, the 13-demethyl metabolite is reported to have the same activity as tacrolimus.
Pimecrolimus
Pimecrolimus is the 33-epi-chloro derivative of the macrolactam ascomyin. Pimecrolimus structural and functional analogs are described in U.S. Pat. No. 6,384,073.
Rapamycin
Rapamycin structural and functional analogs include mono- and diacylated rapamycin derivatives (U.S. Pat. No. 4,316,885); rapamycin water-soluble prodrugs (U.S. Pat. No. 4,650,803); carboxylic acid esters (PCT Publication No. WO 92/05179); carbamates (U.S. Pat. No. 5,118,678); amide esters (U.S. Pat. No. 5,118,678); biotin esters (U.S. Pat. No. 5,504,091); fluorinated esters (U.S. Pat. No. 5,100,883); acetals (U.S. Pat. No. 5,151,413); silyl ethers (U.S. Pat. No. 5,120,842); bicyclic derivatives (U.S. Pat. No. 5,120,725); rapamycin dimers (U.S. Pat. No. 5,120,727); O-aryl, O-alkyl, O-alkyenyl and O-alkynyl derivatives (U.S. Pat. No. 5,258,389); and deuterated rapamycin (U.S. Pat. No. 6,503,921). Additional rapamycin analogs are described in U.S. Pat. Nos. 5,202,332 and 5,169,851.
Peptides, peptide mimetics, peptide fragments, either natural, synthetic or chemically modified, that impair the calcineurin-mediated dephosphorylation and nuclear translocation of NFAT are suitable for use in practicing the invention. Examples of peptides that act as calcineurin inhibitors by inhibiting the NFAT activation and the NFAT transcription factor are described, e.g., by Aramburu et al., Science 285:2129-2133, 1999) and Aramburu et al., Mol. Cell. 1:627-637, 1998). As a class of calcineurin inhibitors, these agents are useful in the methods of the invention.
In certain embodiments, an antihistamine or an antihistamine analog can be used in the compositions, methods, and kits of the invention. Antihistamines are compounds that block the action of histamine. Classes of antihistamines include:
(1) Ethanolamines (e.g., bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, diphenylpyraline, and doxylamine);
(2) Ethylenediamines (e.g., pheniramine, pyrilamine, tripelennamine, and triprolidine);
(3) Phenothiazines (e.g., diethazine, ethopropazine, methdilazine, promethazine, thiethylperazine, and trimeprazine);
(4) Alkylamines (e.g., acrivastine, brompheniramine, chlorpheniramine, desbrompheniramine, dexchlorpheniramine, pyrrobutamine, and triprolidine);
(5) piperazines (e.g., buclizine, cetirizine, chlorcyclizine, cyclizine, meclizine, hydroxyzine);
(6) Piperidines (e.g., astemizole, azatadine, cyproheptadine, desloratadine, fexofenadine, loratadine, ketotifen, olopatadine, phenindamine, and terfenadine);
(7) Atypical antihistamines (e.g., azelastine, levocabastine, methapyrilene, and phenyltoxamine).
In the compositions, methods, and kits of the invention, both non-sedating and sedating antihistamines may be employed. Non-sedating antihistamines include loratadine and desloratadine. Sedating antihistamines include azatadine, bromodiphenhydramine; chlorpheniramine; clemizole; cyproheptadine; dimenhydrinate; diphenhydramine; doxylamine; meclizine; promethazine; pyrilamine; thiethylperazine; and tripelennamine.
Other antihistamines suitable for use in the compositions, methods, and kits of the invention are acrivastine; ahistan; antazoline; astemizole; azelastine (e.g., azelsatine hydrochloride); bamipine; bepotastine; benztropine, bietanautine; brompheniramine (e.g., brompheniramine maleate); carbinoxamine (e.g., carbinoxamine maleate); cetirizine (e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine; chloropyramine; chlorothen; chlorphenoxamine; cinnarizine; clemastine (e.g., clemastine fumarate); clobenzepam; clobenztropine; clocinizine; cyclizine (e.g., cyclizine hydrochloride; cyclizine lactate); deptropine; dexchlorpheniramine; dexchlorpheniramine maleate; diphenylpyraline; doxepin; ebastine; embramine; emedastine (e.g., emedastine difumarate); epinastine; etymemazine hydrochloride; fexofenadine (e.g., fexofenadine hydrochloride); histapyrrodine; hydroxyzine (e.g., hydroxyzine hydrochloride; hydroxyzine pamoate); isopromethazine; isothipendyl; levocabastine (e.g., levocabastine hydrochloride); mebhydroline; mequitazine; methafurylene; methapyrilene; metron; mizolastine; olapatadine (e.g., olopatadine hydrochloride); orphenadrine; phenindamine (e.g., phenindamine tartrate); pheniramine; phenyltoloxamine; p-methyldiphenhydramine; pyrrobutamine; setastine; talastine; terfenadine; thenyldiamine; thiazinamium (e.g., thiazinamium methylsulfate); thonzylamine hydrochloride; tolpropamine; triprolidine; and tritoqualine.
Antihistamine analogs may also be used in according to the invention. Antihistamine analogs include 10-piperazinylpropylphenothiazine; 4-(3-(2-chlorophenothiazin-10-yl)propyl)-1-piperazineethanol dihydrochloride; 1-(10-(3-(4-methyl-1-piperazinyl)propyl)-10H-phenothiazin-2-yl)-(9CI) 1-propanone; 3-methoxycyproheptadine; 4-(3-(2-Chloro-10H-phenothiazin-10-yl)propyl)piperazine-1-ethanol hydrochloride; 10,11-dihydro-5-(3-(4-ethoxycarbonyl-4-phenylpiperidino)propylidene)-5H-dibenzo(a,d)cycloheptene; aceprometazine; acetophenazine; alimemazin (e.g., alimemazin hydrochloride); aminopromazine; benzimidazole; butaperazine; carfenazine; chlorfenethazine; chlormidazole; cinprazole; desmethylastemizole; desmethylcyproheptadine; diethazine (e.g., diethazine hydrochloride); ethopropazine (e.g., ethopropazine hydrochloride); 2-(p-bromophenyl-(p′-tolyl)methoxy)-N,N-dimethyl-ethylamine hydrochloride; N,N-dimethyl-2-(diphenylmethoxy)-ethylamine methylbromide; EX-10-542A; fenethazine; fuprazole; methyl 10-(3-(4-methyl-1-piperazinyl)propyl)phenothiazin-2-yl ketone; lerisetron; medrylamine; mesoridazine; methylpromazine; N-desmethylpromethazine; nilprazole; northioridazine; perphenazine (e.g., perphenazine enanthate); 10-(3-dimethylaminopropyl)-2-methylthio-phenothiazine; 4-(dibenzo(b,e)thiepin-6(11H)-ylidene)-1-methyl-piperidine hydrochloride; prochlorperazine; promazine; propiomazine (e.g., propiomazine hydrochloride); rotoxamine; rupatadine; SCH 37370; SCH 434; tecastemizole; thiazinamium; thiopropazate; thioridazine (e.g., thioridazine hydrochloride); and 3-(10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5-ylidene)-tropane.
Other compounds that are suitable for use in the invention are AD-0261; AHR-5333; alinastine; arpromidine; ATI-19000; bermastine; bilastin; Bron-12; carebastine; chlorphenamine; clofurenadine; corsym; DF-1105501; DF-11062; DF-1111301; EL-301; elbanizine; F-7946T; F-9505; HE-90481; HE-90512; hivenyl; HSR-609; icotidine; KAA-276; KY-234; lamiakast; LAS-36509; LAS-36674; levocetirizine; levoprotiline; metoclopramide; NIP-531; noberastine; oxatomide; PR-881-884A; quisultazine; rocastine; selenotifen; SK&F-94461; SODAS-HC; tagorizine; TAK-427; temelastine; UCB-34742; UCB-35440; VUF-K-8707; Wy-49051; and ZCR-2060.
Still other compounds that are suitable for use in the invention are described in U.S. Pat. Nos. 2,595,405, 2,709,169, 2,785,202, 2,899,436, 3,014,911, 3,813,384, 3,956,296, 4,254,129, 4,254,130, 4,282,833, 4,283,408, 4,362,736, 4,394,508, 4,285,957, 4,285,958, 4,440,933, 4,510,309, 4,550,116, 4,659,716, 4,692,456, 4,742,175, 4,833,138, 4,908,372, 5,204,249, 5,375,693, 5,578,610, 5,581,011, 5,589,487, 5,663,412, 5,994,549, 6,201,124, and 6,458,958.
Hydroxyzine
In certain embodiments, hydroxyzine or an analog thereof can be used in the compositions, methods, and kits of the invention. The structure of hydroxyzine is:
Analogs of hydroxyzine are described, for example, in U.S. Pat. No. 2,899,436 and have the general structure:
wherein R′ and R″ are a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, R′ and R″ being in ortho, meta, or para positions; R contains 2 to 11 carbon atoms and is alkyl, phenyl, alkyl substituted phenyl, aralkyl, cycloalkyl, hydroxyalkyl, hydroxycycloalkyl or —CH2—CH2—O—CH2—CH2—OH, and n is an integer from 1 to 6, inclusive. The compound may be in the form of a mineral acid salt or an organic acid salt.
In certain embodiments, irinotecan, topotecan, or their analogs can be used in the compositions, methods, and kits of the invention. Analogs of irinotecan are described, for example, in U.S. Pat. No. 4,604,463 and have the general structure:
where R1 is a hydrogen atom, a halogen atom, or a C1-4 alkyl, and X is a chlorine or —NR2R3, wherein R2 and R3 are the same or different and each represents a hydrogen atom, a C1-4 alkyl, or a substituted or unsubstituted carbocyclic or heterocyclic group, with the proviso that when both R2 and R3 are the substituted or unsubstituted alkyl groups, they may be combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with —O—, —S—, and/or >N—R4 in which R4 is a hydrogen atom, a substituted or unsubstituted C1-4 alkyl, or a substituted or unsubstituted phenyl group and where the grouping —O—CO—X is bonded to a carbon atom located in any of the 9-, 10-, and 11-positions in the ring A of camptothecin.
Analogs of topotecan are described, for example, in European Patent No. 321122 and include compounds with the general formula:
where X is hydroxy, hydrogen, cyano, —CH2NH2, or formyl; R is hydrogen when X is cyano, CH2NH2 or formyl or R is —CHO or —CH2R1 when X is hydrogen or hydroxy; R1 is —O—R2, —S—R2, —N—R2(R3); or —N+—R2—(R3)(R4), R2, R3, and R4 are the same or different and are selected from H, C1-6 alkyl, C2-6 hydroxyalkyl, C1-6 dialkyamino, C1-6-dialkylaminoC2-6alkyl, C1-6 alkyamino-C2-6 alkyl, C2-6 aminoalkyl, or a 3-7 member unsubstituted or substituted carbocyclic ring; and when R1 is —N—R2(R3), the R2 and R3 groups may be combined together to form a ring.
In certain embodiments, the anti-infective therapeutic agent is camptothecin, or an analogue or derivative thereof. Camptothecins have the following general structure.
In this structure, X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives. R1 is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C1-3 alkane. R2 is typically H or an amino containing group such as (CH3)2NHCH2, but may be other groups e.g., NO2, NH2, halogen (as disclosed in, e.g., U.S. Pat. No. 5,552,156) or a short alkane containing these groups. R3 is typically H or a short alkyl such as C2H5. R4 is typically H but may be other groups, e.g., a methylenedioxy group with R1.
Exemplary camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. Exemplary compounds have the structures:
Camptothecins have the five rings shown here. The ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity.
Camptothecins are believed to function as topoisomerase I inhibitors and/or DNA cleavage agents.
Disulfuram is used in the treatment of alcoholism; its mechanism of action is inhibition of alcohol dehydrogenase. The structure of disulfuram is:
Analogs of disulfuram are described in, for example, U.S. Pat. No. 1,796,977 and have the general structure:
wherein the R groups represent same of dissimilar organic groups (e.g., C1-4 alkyls).
Analogs include thiram. Disulfuram is a crystal, barely soluble in water, and is soluble in solvents such as alcohol, ether, acetone, and benzene. Disulfuram is available in tablet form, and is typically administered orally.
Auranofin is an anti-inflammatory agent and an antirheumatic. The structure of auranofin is:
Analogs of auranofin are described, for example, in U.S. Pat. No. 3,635,945, and can be represented by the general formulas:
where R represents acetyl or, when Z is oxygen, hydrogen; R1 represents a C1-4 alkyl; A represents a C2-5 alkylene chain, straight or branched; Y represents oxygen or sulfur; and Z represents oxygen or —NH—.
Auronfin is a white, odorless, crystalline powder and is insoluble in water. It is administered orally in tablet form.
In certain embodiments, an NSAID can be used in the compositions, methods, and kits of the invention. Suitable NSAIDs include A183827, ABT963, aceclofenac, acemetacin, acetyl salicylic acid, AHR10037, alclofenac, alminoprofen, ampiroxicam, amtolmetin guacil, apazone, aspirin, atliprofen methyl ester, AU8001, azelastine, benoxaprofen, benzydamine, benzydamine flufenamate, benzydamine hydrochloride, bermoprofen, bezpiperylon, BF388, BF389, BIRL790, BMS347070, bromfenac, bucloxic acid, butibufen, BW755C, C53, C73, C85, carprofen, CBS1108, celecoxib, CHF2003, chlorobiphenyl, choline magnesium trisalicylate, CHX108, cimicoxib, cinnoxicam, clidanac, CLX1205, CP331, CS502, CS706, D1367, curcumin, darbufelone, deracoxib, dexibuprofen, dexibuprofen lysine, dexketoprofen, DFP, DFU, diclofenac (e.g., diclofenac potassium, diclofenac sodium), diflunisal, DPI 55, DRF4367, E5110, E6087, eltenac, ER34122, esflurbiprofen, etoricoxib, F025, felbinac ethyl, fenbufen, fenclofenac, fenclozic acid, fenclozine, fenoprofen, fentiazac, feprazone, filenadol, flobufen, florifenine, flosulide, flubichin methanesulfonate, flufenamic acid, fluprofen, flurbiprofen, FPL62064, FR122047, FR123826, FR140423, FR188582, FS205397, furofenac, GR253035, GW406381, HAI105, HAI106, HCT2035, HCT6015, HGP12, HN3392, HP977, HX0835. HYAL AT2101, ibufenac, ibuprofen, ibuproxam-beta-cyclodextrin, icodulinum, IDEA070, iguratimod, imrecoxib, indomethacin, indoprofen, IP751, isoxepac, isoxicam, KC764, ketoprofen, L652343, L745337, L748731, L752860, L761066, L768277, L776967, L783003, L784520, L791456, L804600, L818571, LAS33815, LAS34475, licofelone, LM 4108, lobuprofen, lomoxicam, lumiracoxib, mabuprofen, meclofenamic acid, meclofenamate sodium, mefenamic acid, meloxicam, mercaptoethylguanidine, mesoporphyrin, metoxibutropate, miroprofen, mofebutazone, mofezolac, MX1094, nabumetone, naproxen sodium, naproxen-sodium/metoclopramide, NCX1101, NCX284, NCX285, NCX4016, NCX4215, NCX530, niflumic acid, nitric oxide-based COX-2 inhibitors and NSAIDs (NitroMed), nitrofenac, nitroflurbiprofen, nitronaproxen, NS398, ocimum sanctum oil, ONO3144, orpanoxin, oxaprozin, oxindanac, oxpinac, oxycodone/ibuprofen, oxyphenbutazone, P10294, P54, P8892, pamicogrel, parcetasal, parecoxib, PD138387, PD145246, PD164387, pelubiprofen, pemedolac, phenylbutazone, pirazolac, piroxicam, piroxicam beta-cyclodextrin, piroxicam pivalate, pirprofen, pranoprofen, resveratrol, R-ketoprofen, R-ketorolac, rofecoxib, RP66364, RU43526, RU54808, RWJ63556, S19812, S2474, S33516, salicylsalicylic acid, satigrel, SC236, SC57666, SC58125, SC58451, SFPP, SKF105809, SKF86002, sodium salicylate, sudoxicam, sulfasalazine, sulindac, suprofen, SVT2016, T3788, TA60, talmetacin, talniflumate, tazofelone, tebufelone, tenidap, tenoxican, tepoxalin, tiaprofenic acid, tilmacoxib, tilnoprofen arbamel, tinoridine, tiopinac, tioxaprofen, tolfenamic acid, tolmetin, triflusal, tropesin, TY10222, TY10246, TY10474, UR8962, ursolic acid, valdecoxib, WAY120739, WY28342, WY41770, ximoprofen, YS134, zaltoprofen, zidometacin, and zomepirac.
Other NSAIDs are described in U.S. Pat. Nos. 2,745,783, 3,318,905, 5,344,991, 5,380,738, 5,393,790, 5,401,765, 5,418,254, 5,420,287, 5,434,178, 5,466,823, 5,475,018, 5,474,995, 5,486,534, 5,504,215, 5,508,426, 5,510,368, 5,510,496, 5,516,907, 5,521,193, 5,521,207, 5,534,521, 5,565,482, 5,596,008, 5,616,601, 5,633,272, 5,639,777, 5,663,180, 5,668,161, 5,670,510, 5,672,626, 5,672,627 5,736,579, 5,739,166, 5,760,068, 5,756,529, 5,859,257, 5,886,016, 5,908,852, 5,916,905, 6,294,558, 6,476,042, 6,486,203, 6,492,411, 6,608,095, 6,649,645, 6,673,818, 6,689,805, 6,696,477, 6,727,268, 6,699,884, 6,727,238, 6,777,434, 6,846,818, 6,849,652, 6,949,536, 6,967,213, 7,019,144, and 7,041,694, PCT Publication Nos. WO94/13635, WO94/15932, WO94/20480, WO94/26731, WO96/03387, WO96/03388, WO96/09293, WO97/16435, WO98/03484, WO98/47890, WO96/06840, WO96/25405, WO95/15316, WO94/15932, WO94/27980, WO95/00501, and WO94/2673, and GB 839,057, GB 2,294,879, and EP 0745596.
Benzydamine
In certain embodiments, an NSAID such as benzydamine or an analog thereof can be used in the compositions, methods, and kits of the invention. The structure of benzydamine is:
Analogs of benzydamine are described, for example, in U.S. Pat. No. 3,318,905 and have the general structure:
wherein R is selected from the class consisting of hydrogen and chlorine; R′ is selected from the class consisting of lower alkyl and phenyl groups which latter may be substituted or not in their phenyl nucleus by halogen atoms or lower alkyl or lower alkoxy groups; R″ is a member selected from the class consisting of hydrogen and lower alkyl groups; R′″, which may be like or unlike, are lower alkyl residues; n is selected from the group consisting of 1 and 2.
In certain embodiments, an androgen such as testerone or a testosterone analog can be used in the compositions, methods, and kits of the invention. Androgens such as androstenols include 14-hydroxyandrost-4-ene-3,6,17-trione, 16-acetoxy-17-acetoxymethyl-11,17-dihydroxy-D-homoandrosta-1,4-diene-3,17-dione, 17beta-((1R)-1-hydroxy-2-propynyl)androst-4-en-3-one, 17beta-amino-3beta-methoxy-5-androstene, 17beta-hydroxy-17-(2-methylallyl)-9beta,10alpha-androst-4-en-3-one, 17-(cyclopropylamino)androst-5-en-3-ol, 17-acetamido-5-androsten-3-ol-4-bis(2-chloroethyl)aminophenylacetate, 17-beta-hydroxy-7alpha-methyl-androst-5-en-3-one, 17-ethynyl-(5a)-androst-2-ene-17-ol-17-nicotinate, 17-ethynylandrost-2-ene-17-ol-17-acetate, 17-hydroxy-17-methyl-3-oxospiro(androst-5-ene-4,1′-cyclopropane)-2-carbonitrile, 17-methyl-17-hydroxyandrosta-1,4,6-trien-3-one, 19-ethynyl-19-hydroxyandrost-4-en-17-one, 2,3,17,19-tetrahydroxyandrost-4-ene, 2-beta-hydroxy-19-oxo-4-androstene-3,17-dione, 3beta-methoxy-5-androsten-17-one, 3′-azido-3′-deoxy-5′-O-((11-hydroxy-3-oxo-17-androst-4-enyl)carbonyl)thymidine, 3,15,17-trihydroxy-5-androstene, 3,16,19-trihydroxy-5-androsten-17-one, 3,17-dihydroxy-7-(4-methoxyphenyl)-androst-5-ene 3,17-diacetate, 3-hydroxy-17-methyl-18-norandrost-13(17)-ene-16-one, 3-methoxy-17-aza-homoandrost-5-ene-17-one, 5alpha-androst-16-en-3beta-ol, 5-androstene-3,16,17-triol, 9-fluoro-11,16,17-trihydroxy-17-hydroxymethyl-D-homoandrosta-1,4-diene-3,17-dione, 9-fluoro-16-methyl-6,11,16-trihydroxy-1,4-androstadiene-3,17-dione, abiraterone, androst-16-en-3-ol, androst-16-en-3-ol sulfoconjugate, androst-5-en-3-ol, androst-5-ene-3,16,17-triol-3-sulfate, androsta-2,4-diene-17beta-ol, androsta-5,16-dien-3beta-ol, Androstenediols (e.g., 17-cyano-9,17-dihydroxyandrost-4-ene-3-one, 2-carbamoyl-4,5-epoxyandrost-2-ene-3,17-diol, 3beta,17 beta-dihydroxyandrost-5-en-16-one, 3,16-dihydroxyandrost-5-ene-17,19-dione, 4-androstene-3,17-diol, 4a,17-dimethyl-A-homo-B,19-dinor-3,4-secoandrost-9-ene-3,17-diol, androst-4-ene-3beta,17beta-diol dicyclopentylpropionate, androst-4-ene-3beta,17 beta-diol dienanthate, androstenediol, cortienic acid, delta (2,16)-5alpha-androstadiene-3,17-diol-3,17-diacetate, Fluoxymesterone, formyldienolone, Methandriol, and viridiol), azastene, cyanoketone (e.g., Win 19578), Dehydroepiandrosterone (e.g., 1-hydroxydehydroepiandrosterone, 15beta-carboxyethylmercaptodehydroepiandrosterone, 15-hydroxydehydroisoandrosterone, 16-hydroxydehydroepiandrosterone, 16-hydroxydehydroepiandrosterone sulfate, 7-hydroxydehydroepiandrosterone, 7-oxodehydroepiandrosterone, androst-5-en-17-one, dehydroepiandrosterone acetate, dehydroepiandrosterone enanthate, dehydroepiandrosterone sulfate, dehydroepiandrosterone-3-O-methylthiophosphonate, fluasterone, gonasterone, gynodian, OH 8356, and testosterone mustard), epostane, etiocholenic acid, methyl 14-hydroxy-1,7,17-trioxoandrost-8-ene-19-oate, mexrenoate potassium, nordinone, ratibol, RS 21314, RS 85095, stenbolone, stenbolone acetate, testosterone, and thiomesterone.
Testosterone derivatives include 11-ketotestosterone, 11-oxatestosterone, 15beta-carboxyethylmercaptotestosterone, 15-carboxymethyltestosterone, 17beta-aminocarbonyloxy-4-androsten-3-one, 17-bromoacetoxy-4-androsten-3-one, 17-ethinyl-11-oxa-testosterone, 19-O-carboxymethoxytestosterone, 4-(carboxymethylmercapto)testosterone, 6-dehydrotestosterone, 6-methylenetestosterone acetate, ablacton, androsta-3,5-diene-3,17-diol diacetate, bolasterone, boldenone undecylenate, climacterone, clostebol, D-4-chloro-17beta-hydroxy-3-oxo-17alpha-methylandrosta-1,4-diene, dehydrotestosterone, deladumone, dimeric testosterone, epitestosterone, estandron prolongatum, ethynodiol testosterone ester, gonasterone, hydroxytestosterones, metharmon F, methenolone, methyltestosterone, nichlotest, synovex-H, testosterone 17beta-carboxylic acid, testosterone 17beta-cypionate, testosterone 17-cyclohexanecarboxylate, testosterone 17-enanthate 3-benzilic acid hydrazone, testosterone 3-(O-dimethylaminopropyl)oxime, testosterone 4-n-butylcyclohexylcarboxylic acid, testosterone acetate, testosterone decanoate, testosterone enanthate, testosterone formate, testosterone glucuronate, testosterone isobutyrate, testosterone isocaproate, testosterone palmitate, testosterone pivalate, testosterone propionate, testosterone undecanoate, testosterone-17-succinate, testosterone-17-sulfate, testosterone-19-hemisuccinate, testosterone-3-(n-hexyl)cyclobutane carboxylate, testosterone-3-oxime, testosterone-4-n-pentylcyclohexyl carboxylate, testosterone-cysteamine-DANS, testosterone-DAH-fluorescein, testosterone-DAP-fluorescein, testosteronyl 4-dimethylaminobutyrate, testoviron-depot, topterone, trofodermin, and turinabol.
Androstanols include 1,2-seco-A-bis(norandrostan-17-ol)acetate, 1,3,5,6-tetrahydroxyandrostan-17-one, 1,3-trimethylene-2′,5-epoxyandrostane-3,17-diol 17-propionate, 11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one, 16,17-epoxyandrostan-3-ol, 17beta-(3-furyl)-5beta,14beta-androstane-3beta,14beta-diol, 17-(3′-thiophenyl)androstane-3,14-diol 3-glucopyranoside, 17-acetamido-5-androstan-3-ol-4-bis(2-chloroethyl)aminophenylacetate, 17-ethyl-17-hydroxyandrostane, 17-hydroxy-2,3-cyclopropanoandrostane, 17-methyl-17a-chloro-D-homoandrostan-3-ol, 2-(2-(3-hydroxy-12-(2-methyl-1-oxobutoxy)-5-androstan-17-yl)ethyl)tetrahydro-4-hydroxy-2H-pyran-6-one, 3beta-acetoxy-5,6beta-dichloromethylene-5beta-androstan-17-one, 3,3-difluoroandrostane-17-ol acetate, 3-acetoxy-7,15-oxido-16-oxaandrostan-17-one, 3-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene, 3-hydroxy-5-androstane-17-carbonitrile, 3-hydroxyetianic acid, 3-keto-5,10-epoxy-nor-19-methylandrostane-17-acetate, 4,5-epoxy-17-hydroxy-2-methylsulfonyl-3-androstanone, 5-bromo-3,6-dihydroxyandrostan-17-one-3-acetate, amafolone, androsol acetate, androstan-17-ol, androstan-3-ol, androstane-3,17-diol or derivatives thereof (e.g., 17-hydroxyandrostane-3-glucuronide, 17-methyl-D-homoandrostane-3,17-diol, 2,4-cycloandrostane-3,17-diol diacetate, 3-desacetylpipecuronium, 4-ethenylideneandrostane-3,17-diol, 4-ethenylideneandrostane-3,17-dione, androstane-2,3,17-triol, androstane-3,14-diol, androstane-3,16,17-triol, androstane-3,17-diol 17-sulfate, androstane-3,17-diol dipropionate, androstane-3,17-diol glucuronide, androstane-3,6,17-triol, androstane-3,7,17-triol, androstane-3,7-diol disulfate), androsterone or its derivatives (e.g., 11beta-hydroxyandrosterone, 11-ketoandrosterone, 16beta-hydroxyandrosterone, 16-bromoepiandrosterone, 17-hydroxy-6,6-ethylene-4-androsten-3-one, 19-hydroxy-4-androsten-17-one, 3-bromoacetoxyandrostan-17-one, 3-hydroxy-4-androsten-17-one, androsterone 3-benzoate, androsterone 3-palmitate, androsterone glucuronide, and androsterone sulfate), BOMT, CCI 22277, dihydrotestosterone or its derivatives (e.g., 11-fluoro-19-nor-dihydro-testosterone, 11-fluoro-dihydro-testosterone, 16-iodostanolone, 17-(2-iodoethenyl)androsta-4,6-dien-17-ol-3-one, 17-(2-iodoethynyl)androsta-4,6-dien-17-ol-3-one, 17-(2-iodovinyl)dihydrotestosterone, 17-hydroxyandrostan-19-ol-3-one, 17-hydroxyandrostan-3-one 17-sulfate, 17-ketotrilostane, 17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one, 17-N,N-diisopropylcarbamoyl-4-azaandrostan-3-one, 18-hydroxy-18-methyl-16,17-methylene-D-homoandrostane-3-one, 2,17-dimethyldihydrotestosterone, 2-bromo-5-dihydrotestosterone, 2-chloroethylnitrosocarbamoylalanine 17-dihydrotestosterone ester, 3-hydroxyandrostan-16-one, 4,17-dimethyltrilostane, 4,5-secodihydrotestosterone, 5-dihydrotestosterone 3,17-bromoacetate, androstan-3,17-diol-11-one, androstan-3-one, demalon, dihydrotestosterone 17-bromoacetate, dihydrotestosterone glucuronide, dihydrotestosterone heptanoate, dihydrotestosterone propionate, dihydrotestosterone-17-N-bis(2-chloroethyl)carbamate, mestanolone, mesterolone, nitrostanolone, stanolone benzoate, testiphenon, and trilostane), dromostanolone, dromostanolone propionate, epitiostanol, etiocholanolone or its derivatives (e.g., 11-ketoetiocholanolone, 3,7-dihydroxyandrostan-17-one, 3-hydroxyandrostane-7,17-dione, and androstane-3,17-dione), furazabol, mebolazine, mepitiostane, N-cyano-2-aza-A-norandrostan-17-ol acetate, nisterime acetate, ORG 9943, ORG 9991, Org NA 13, oxandrolone, oxymetholone or its derivatives (e.g., 17-hydroxy-2-(hydroxymethylene)androstan-3-one), Pancuronium or its derivative (e.g., (dideacetoxy)pancuronium, 2,16-dipiperidinoandrostane-3,17-diol dipivalate, 3alpha,17beta-dibutyryloxy-2beta,16beta-dipiperidino-5alpha-androstane dimethobromide, 3-(deacetoxy)pancuronium, 3-desacetylpancuronium, dacuronium, and Org 6368), RU 26988, rubrosterone, samanine, spiro-3-oxiranylandrostan-17-ol, stanozolol or its derivatives (e.g., 16-hydroxystanozolol and 4,16-dihydroxystanozolol), vecuronium bromide or its derivatives (e.g., (dideacetoxy)vecuronium, 17-deacetylvecuronium, 3,17-bis-deacetylvecuronium, 3-(deacetoxy)vecuronium, 3-deacetylvecuronium, Org 7617, Org 7678, Org 7684, Org 9273, and Org 9616).
Stanozolol analogs are described in U.S. Pat. No. 3,030,358. Mesterolone analogs are described in U.S. Pat. No. 3,361,773. Methyltestosterone analogs are described in U.S. Pat. No. 2,374,370.
In certain embodiments, a tyrophostin can be used in the compositions, methods, and kits of the invention. The tyrphostins are family of synthetic kinase inhibitors. Exemplary tyrphostins include 6,7-dimethoxy-2-phenylquinoxaline, AG 127, AG 183, AG 30, AG 494, AG 556, AG 879, RG 13022, RG 14620, RG 50810, RG 50864, tyrphostin 11, tyrphostin 23, tyrphostin 25, tyrphostin 8, tyrophostin 47, tyrphostin A46, tyrphostin A51, tyrphostin A9, tyrphostin AG 1024, tyrphostin AG 1112, tyrphostin AG 1296, tyrphostin AG 1478, tyrphostin AG 555, tyrphostin AG 568, tyrphostin AG-490, tyrphostin AG17, tyrphostin AG879, and tyrphostin AG957. Tyrphostins are described in U.S. Pat. Nos. 5,728,868 and 5,854,285.
Vitamin B12 and B12 analogs can be used in the compositions, methods, and kits of the invention. Vitamin B12, its derivatives, and its analogs are cofactors in folate enzymes and methionine synthase. 5-Deoxyadenosyl cobalamin is a cofactor required by the enzyme that converts L-methylmalonyl-CoA to succinyl-CoA. Other vitamin B12 analogs include 1,N(6)-ethenoadenosylcobalamin, 2′,5′-dideoxyadenosylcobalamin, 2-methyl-2-aminopropanol-B12, adeninylethylcobalamin, ambene, aminopropylcobalamin, aquacobalamin, biofer, Co-(carboxymethyl)cobalamin, cob(II) alamin, cobamides (e.g., (2-amino-5,6-dimethylbenzimidazolyl)cobamide, (2-hydroxy-5,6-dimethylbenzimidazolyl)cobamide, 2-methylsulfinyladenylcobamide, 2-methylsulfonyladenylcobamide, 4-cresolylcobamide, adenosylcobinamide methyl phosphate, coalpha-(alpha-5,6-dimethylbenzimidazolyl)-cobeta-cyanocobamide, cobamamide, cobamamide 5′-phosphate, cobinamide, phenolyl cobamide, thiobanzyme), cobyric acid, cobyrinic acid, cobyrinic acid hexamethyl ester f-nitrile, compound 102804, cyanocobalamin-b-monocarboxylic acid, cyanocobalamin-e-monocarboxylic acid, cysteinylcobalamin, factor A, factor III, ferribalamin, formylmethylcobalamin, FV 82, glutathionylcobalamin, hepavis, hydroxocobalamin (e.g., nitrosocobalamin and acetatocobalamin), Jectofer compound, mecobalamin, methylcobalamine chlorpalladate, nitritocobalamin, nitrosylcobalamin, proheparum, pseudovitamin B12, sulfitocobalamin, Transcobalamins, triredisol, and vitamin B12 factor B. Cobamamide analogs are described in U.S. Pat. No. 3,461,114.
Histone deacetylase inhibitors and their analogs may be used in the compositions, methods, and kits of the invention. Exemplary HDACs include CAY10433 and suberohydroxamic acid. Histone deacetylase inhibitors are used, for example, in cancer therapy, and in the treatment of inflammation and are a group of compounds that include, for example, cyclic peptides (e.g., depsipeptides such as FK228), short chain fatty acids (e.g., phenylbutyrate and valproic acid), benzamides (e.g., CI-994 and MS-27-275), and hydroxamic acids (e.g., suberoylanilide hydroxamic acid (SAHA)) as described in Richon and O'Brien ((2002) Clin. Canc. Res. 8, 662-664). Cyclic peptides and analogs useful in the invention are described, for example, in U.S. Pat. No. 6,403,555. Short chain fatty acid HDAC inhibitors are described in, for example, U.S. Pat. Nos. 6,888,027 and 5,369,108. Benzamides analogs are described, for example, in U.S. Pat. No. 5,137,918. Analogs of SAHA are described, for example, in U.S. Pat. No. 6,511,990. Other HDACs include anacardic acid, apicidin, histone deacetylase inhibitor I, histone deacetylase inhibitor II, histone deacetylase inhibitor III, ITSA1, oxamflatin, SBHA, scriptaid, sirtinol, splitomicin, trichostatin A, and valproic acid (e.g., sodium salt). Any of these compounds or other HDAC inhibitors may be used in the compositions, methods, or kits of the invention.
In certain embodiments, a platinum compound can be used in the compositions, methods, and kits of the invention. In general, suitable platinum complexes may be of Pt(II) or Pt(IV) and have this basic structure:
wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; R1 and R2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups. For Pt(II) complexes Z1 and Z2 are non-existent. For Pt(IV) Z1 and Z2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4,250,189.
Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Pat. Nos. 5,409,915 and 5,380,897. For example bisplatinum and triplatinum complexes of the type:
Exemplary platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin having the structures:
Other representative platinum compounds include (CPA)2Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), Cis-(PtCl2(4,7-H-5-methyl-7-oxo)1,2,4(triazolo(1,5-a)pyrimidine)2) (Navarro et al., J. Med. Chem. 41(3):332-338, 1998), (Pt(cis-1,4-DACH)(trans-Cl2)(CBDCA)).½MeOH cisplatin (Shamsuddin et al., Inorg. Chem. 36(25):5969-5971, 1997), 4-pyridoxate diammine hydroxy platinum (Tokunaga et al., Pharm. Sci. 3(7):353-356, 1997), Pt(II) . . . Pt(II) (Pt2(NHCHN(C(CH2)(CH3)))4) (Navarro et al., Inorg. Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al., Neurol. Res. 18(3):244-247, 1996), o-phenylenediamine ligand bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, cis-(Pt(OAc)2I2(en)) (Kratochwil et al., J. Med. Chem. 39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenediamine ligand (with sulfur-containing amino acids and glutathione) bearing cisplatin analogues (Bednarski, J. Inorg. Biochem. 62(1):75, 1996), cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et al., J. Inorg. Biochem. 61(4):291-301, 1996), 5′ orientational isomer of cis-(Pt(NH3)(4-aminoTEMP-O){d(GpG)}) (Dunham & Lippard, J. Am. Chem. Soc. 117(43):10702-12, 1995), chelating diamine-bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7):819-23, 1995), 1,2-diarylethyleneamine ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res. Clin. Oncol. 121(1):31-8, 1995), (ethylenediamine)platinum(II) complexes (Pasini et al., J. Chem. Soc., Dalton Trans. 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al., Int. J. Oncol. 5(3):597-602, 1994), cis-diaminedichloroplatinum(II) and its analogues cis-1,1-cyclobutanedicarbosylato(2R)-2-methyl-1,4-butanediamineplatinum(II) and cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg. Biochem. 26(4):257-67, 1986; Fan et al., Cancer Res. 48(11):3135-9, 1988; Heiger-Bernays et al., Biochemistry 29(36):8461-6, 1990; Kikkawa et al., J. Exp. Clin. Cancer Res. 12(4):233-40, 1993; Murray et al., Biochemistry 31(47):11812-17, 1992; Takahashi et al., Cancer Chemother. Pharmacol. 33(1):31-5, 1993), cis-amine-cyclohexylamine-dichloroplatinum(II) (Yoshida et al., Biochem. Pharmacol. 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues (FR 2683529), (meso-1,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine) dichloroplatinum(II) (Bednarski et al., J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et al., J. Am. Chem. Soc. 114(21):8292-3, 1992), platinum(II) polyamines (Siegmann et al., Inorg. Met.-Containing Polym. Mater., (Proc. Am. Chem. Soc. Int. Symp.), 335-61, 1990), cis-(3H)dichloro(ethylenediamine)platinum(II) (Eastman, Anal. Biochem. 197(2):311-15, 1991), trans-diamminedichloroplatinum(II) and cis-(Pt(NH3)2(N3-cytosine)Cl) (Bellon & Lippard, Biophys. Chem. 35(2-3):179-88, 1990), 3H-cis-1,2-diaminocyclohexanedichloroplatinum(II) and 3H-cis-1,2-diaminocyclohexane-malonatoplatinum (II) (Oswald et al., Res. Commun. Chem. Pathol. Pharmacol. 64(1):41-58, 1989), diaminocarboxylatoplatinum (EPA 296321), trans-(D,1)-1,2-diaminocyclohexane carrier ligand-bearing platinum analogues (Wyrick & Chaney, J. Labelled Compd. Radiopharm. 25(4):349-57, 1988), aminoalkylaminoanthraquinone-derived cisplatin analogues (Kitov et al., Eur. J. Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen et al., Eur. J. Cancer Clin. Oncol. 24(8):1309-12, 1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbell et al., Inorg. Chim. Acta 152(2):125-34, 1988), platinum(II), platinum(IV) (Liu & Wang, Shandong Yike Daxue Xuebao 24(1):35-41, 1986), cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(II) (carboplatin, JM8) and ethylenediammine-malonatoplatinum(II) (JM40) (Begg et al., Radiother. Oncol. 9(2):157-65, 1987), JM8 and JM9 cisplatin analogues (Harstrick et al., Int. J. Androl. 10(1); 139-45, 1987), (NPrn4)2((PtCL4).cis-(PtCl2—(NH2Me)2)) (Brammer et al., J. Chem. Soc., Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic acid platinum complexes (EPA 185225), and cis-dichloro(amino acid) (tert-butylamine)platinum(II) complexes (Pasini & Bersanetti, Inorg. Chim. Acta 107(4):259-67, 1985). Oxaliplatin analogs are described in U.S. Pat. Nos. 4,169,846, 5,290,961, 5,298,642, and 6,153,646. Satraplatin is described in Choy, Expert Rev. Anticancer Ther. 6(7):973-982, 2006). These compounds are thought to function by binding to DNA, i.e., acting as alkylating agents of DNA.
In certain embodiments, a flavanone can be used in the compositions, methods, and kits of the invention. Exemplary flavanones include 2-hydroxyflavanone, 137 L, 2′,3,5,7-tetrahydroxyflavanone, 3′-prenylnaringenin, 6-(1,1-dimethylallyl)naringenin, 7-hydroxyflavanone, 7-O-methyleriodictyol, 8-prenylnaringenin, baicalein, BE 14348D, carthamidin, desmal, eriodictyol, eriodictyol 7-glucuronide, flavanone, flemiphilippinin D, Hesperidin (e.g., Cirkan N. D., dehydro-sanol-tri, essaven, fleboplex, hesperetin, hesperetin 5-O-glucoside, hesperetin 7-O-lauryl ether, hesperidin methylchalcone, methyl hesperidin, neohesperidin dihydrochalcone, and S 5682), liquiritigenin, naringenin, naringenin-6-C-glucoside, naringin, pinobanksin, pinocembrin, plantagoside, scuteamoenin, scuteamoenoside, shinflavanone, uralenin, vexibinol, wogonin, and WS 7528.
In certain embodiments, amorolfine or an amorolfine derivative such as benzamil can be used in the compositions, methods, and kits of the invention. Amorolfine is an antifungal agent that is typically administered topically. The structure of amorolfine is:
Analogs of amorolfine are described, for example, in U.S. Pat. No. 4,202,894 and have the general structure:
wherein R is alkyl of 4 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, mono(lower alkyl)-substituted cycloalkyl of 4 to 7 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, phenyl or aryl-(lower alkyl) of 7 to 12 carbon atoms; R1, R2, and R3, independently, are hydrogen or alkyl of 1 to 8 carbon atoms; R4, R5, and R6, independently, are hydrogen or alkyl of 1 to 8 carbon atoms, and two of R4, R5, and R6 can each be bonded to the same carbon atom or together can form a fused alicyclic or aromatic 6-membered ring; provided that when R is tert.-butyl, at least one of R1 and R3 is alkyl of 2 to 8 carbon atoms or R2 is hydrogen or alkyl of 2 to 8 carbon atoms or at least one of R4, R5, and R6 is alkyl of 5 to 8 carbon atoms; X is methylene or an oxygen atom; z is zero or 1 and the dotted bonds can be hydrogenated, and acid addition salts of those compounds of formula I which are basic, where the term “lower alkyl” denotes a straight-chain or branched-chain hydrocarbon group of 1 to 4 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert.-butyl. Alkyl groups of 4 to 12 carbon atoms are straight-chain or branched-chain hydrocarbon groups, for example, butyl, isobutyl, tert.-butyl, neopentyl, 1,1-dimethylpropyl, 1,1-dimethylpentyl, 1,1-diethylpropyl, 1,1-dimethylbutyl, 1-isopropyl-3-methyl-but-1-yl, 1-ethyl-1-methylbutyl, dodecyl, and the like. Cycloalkylalkyls include, in particular, those groups in which the alkyl moiety is branched. The term “aryl-(lower alkyl)” includes not only groups which are mono- or di(lower alkyl)-substituted in the aryl ring but also groups which are mono- or di(lower alkyl)-substituted in the lower alkyl moiety. Exemplary of aryl(lower alkyl) groups are benzyl, phenylethyl, (lower alkyl)-benzyl, for example, methylbenzyl and dimethylbenzyl, naphthylmethyl, 2-phenyl-propan-2-yl, 1-phenyl-1-ethyl, or the like.
Amorolfine is a member of the morpholines, which include ((2-azido-4-benzyl)phenoxy)-N-ethylmorpholine, (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid, (morpholinyl-2-methoxy)-8-tetrahydro-1,2,3,4-quinoline, 1,1′-hexamethylenebis(3-cyclohexyl-3-((cyclohexylimino)(4-morpholinyl)methyl)urea), 1,4-bis(3′-morpholinopropyl-1′-yl-1′)benzene, 1,4-thiomorpholine-3,5-dicarboxylic acid, 1,4-thiomorpholine-3-carboxylic acid, 1-(morpholinomethyl)-4-phthalimidopiperidine-2,6-dione, 1-deoxy-1-morpholino-psicose, 1-deoxy-1-morpholinofructose, 1-phenyl-2,3-dimethyl-4-naphthalanmorpholinomethylpyrazolin-5-one, 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, 2,6-bis(carboxymethyl)-4,4-dimethylmorpholinium, 2,6-dimethylmorpholine, 2,6-dioxo-N-(carboxymethyl)morpholine, 2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine, 2-(3-trifluoromethyl)phenyltetrahydro-1,4-oxazine, 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate, 2-(4-morpholino-6-propyl-1,3,5-triazin-2-yl)aminoethanol, 2-(4-morpholinyl)-4H-1-benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, 2-(4-nitrophenyl)-4-isopropylmorpholine, 2-(morpholin-4-yl)benzo[h]chromen-4-one, 2-(N-methylmorpholinium)ethyl acetate, 2-(N-morpholino)ethanesulfonic acid, 2-benzylmorpholine, 2-hydroxy-4,4-dimethyl-2-(4-tolyl)morpholinium, 2-methyl-3-(2-methyl-2,3-diphenyl-4-morpholinyl)-1-phenyl-1-propanone, 2-morpholinomethyl-2′,3′,4′-trimethoxyacrylophenone, 2-n-pentyloxy-2-phenyl-4-methylmorpholine, 2-phenyl-5,5-dimethyltetrahydro-1,4-oxazine, 2-thiomorpholinoethylacrylamide, 3,5,5-trimethyl-2-morpholinon-3-yl radical dimer, 3-((benzyloxy)methyl)morpholine, 3-(beta-morpholinoethoxy)-1H-indazole, 3-cyano-2-morpholino-5-(pyrid-4-yl)pyridine, 3-thiomorpholinopropylacrylamide, 4,4′-dithiodimorpholine, 4,4-methylenedimorpholine, 4-(2-morpholinoethoxy)benzophenone, 4-(3,7,11,15-tetramethyl-6,10,14-hexadecatrienoyl)morpholine, 4-amino-5-chloro-2-ethoxy-N-((2-morpholinyl)methyl)benzamide, 4-amino-N-((4-benzyl-2-morpholinyl)methyl)-5-chloro-2-ethoxybenzamide, 4-amino-N-((4-benzyl-2-morpholinyl)methyl)-5-chloro-2-methoxybenzamide, 4-benzylphenoxy-N-ethylmorpholine, 4-cyclododecyl-2,6-dimethylmorpholine acetate, 4-methoxyphenyl-(5-methyl-6-(2-(4-morpholinyl)ethyl)-6H-thieno(2,3-b)pyrrol-4-yl)phenylmethanone, 4-methylmorpholine, 4-methylmorpholine N-oxide, 4-morpholinedithiocarbamate, 4-morpholinocarbonitrile, 5-pentyl-N-nitrosomorpholine, A 74273, AH 19437, aprepitant, AWD 140076, befol, BIBW 22, bis(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl), BW 175, cetethyl morpholinium, CGP 53437, C11033, ciclosidomine, CNK 6001, CNK 6004, CP 80794, CP 84364, CS 722, delmopinol, detensitral, Dextromoramide, di-beta-(morpholinoethyl)selenide, dimethomorph, dimethyl morpholinophosphoramidate, dimorpholamine, ES 6864, ES 8891, fenpropimorph, filenadol, FK 906, fominoben, FR 76830, Go 8288, GYKI 11679, indeloxazine, L 689502, L 742694, L 760735, landiolol, lateritin, M&B 16573, MDL 101146, MF 268, mofarotene, Molsidomine, morfolep, Moricizine, morlincain, moroxybrate, moroxydine, morpholine, morpholineoethylamino-3-benzocyclohepta(5,6-c)pyridazine, morpholinoamidine, morpholinophosphordichloridite, morpholinopropane sulfonic acid, morpholinosulfonic acid, morpholinylethoxy-3-methyl-4-(2′-naphthyl)-6-pyridazine, mosapride, N,N′-dicyclohexyl-4-morpholinecarboxamidine, N-((4-benzyl-2-morpholinyl)methyl)-5-chloro-4-(dimethylamino)-2-methoxybenzamide, N-(3,N′-morpholinopropyl)-2-(3-nitropyrrolo-(2,3-b)pyridine-1-yl)ethanoic acid amide, N-(3-nitro-4-quinoline)morpholino-4-carboxamidine, N-dodecylmorpholine, N-ethylmorpholine, N-hexylmorpholine-2′,5′-oligoadenylate, N-nitromorpholine, N-oxydiethylene-2-benzothiazole sulfenamide, O—(N-morpholinocarbonyl)-3-phenyllacetic acid, oxaflozane, oxymorphindole, P 1487, P 34081, PD 132002, phendimetrazine, Phenmetrazine, phenyl 2-(2-N-morpholinoethoxy)phenyl ether, pholcodine, phosphorodiamidate morpholino oligomer, pinaverium, pramoxine, proctofoam-HC, promolate, RE 102, reboxetine, Ro 12-5637, Ro 12-8095, RS 1893, RV 538, S 12024, S 14001, S-anisylformamidino-4-(N-methylisothioamide)morpholine, S-phenethylformamidino-4-(N-ethylisothioamide)morpholine, SC 46944, Seda-Miroton, silatiemonium iodide, SIN 1C, SR 121463A, Stymulen, sufoxazine, teomorfolin, theniloxazine, thiamorpholine, tiemonium iodide, tiemonium methylsulfate, tridemorph, trifenmorph, trimetozine, trimorfamid, trithiozine, TVX 2656, U 37883A, U 84569, U 86983, UP 614-04, Viloxazine, Win 55212-2, and YM 21095.
In certain embodiments, andrographis, or an extract or component thereof, can be used in the compositions, methods, and kits of the invention. Andographis paniculata is medicinal herb, which has been used as an antipyretic, an anti-inflammatory agent, and a liver protectant. It also is reported to have anticancer and antiviral (e.g., anti-HCV and anti-HIV) properties. The primary active agent in andrographis is andrographolide. The structure of andrographolide is:
Andrographolide analogs are described, for example, in U.S. Pat. Application Publication No. 2006/0223785 and have the general structure:
or its cis isomer, or its pharmaceutically acceptable salt, ester, salt of an ester or prodrug, wherein: B1, B2 and B3 are independently CR1R2, C(Y1), O, NR4, PR5, P(═Y2)R6, P(═Y3)2, S(═Y4)k, a spacer group or a covalent bond; and k can be 0, 1 or 2; and W1, W2 and W3 are independently CR7R8, CR9, C, C(Y5), O, NR10, PR11, P(═Y6)R12, P(═Y7)2, S(═Y8)f or a covalent bond; and f can be 0, 1 or 2; or B1—W1, B2—W2, and/or B3—W3 are independently CR3═CR9 or C≡C; and X1, X2 and X3 are independently hydrogen, CR18R19R20, C═R21R22, C≡R23, C≡N, C(═Y9)R24, OR25, NR26R27, N═NR28, P(═Y10)d(R29)V, S(═Y11)d(R30)i or NO2; and d can be 0, 1 or 2; and v can be 0, 1 or 2; and i can be independently 0 or 1; and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, and Y11 are independently O, S, or NZ; and Z can be independently hydrogen, R13, OR14, SR15 or NR16R17; and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, aldehyde, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfoxy, sulfinyl, sulfamoyl, hydroxyl, ester, carboxylic acid, amide, nitro, cyano, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, acid halide, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group; or alternatively, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, acyl, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfinyl, sulfamoyl, ester, amide, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group; and each carbon atom cannot be covalently bound to more than two heteroatoms; and wherein each B, W and X cannot be all heteroatom moieties unless B, W and X are all nitrogen based or B and X are independently O or N and W is PR11, POR12, PO2, S(Y4)m and m is 1 or 2; and wherein each B and W or W and X cannot both be of the general formula C(Y), POR12, PO2, S(═Y4)t and t is 1 or 2.
In one subembodiment of formula I, B1, B2, and B3 are independently CR1R2, C(Y1), O, or a covalent bond; W1, W2 and W3 are independently CR7R8, CR9, C, C(Y5), O, or a covalent bond; and X1, X2 and X3 are independently hydrogen, CR18R19R20, C═R21R22, C≡R23. In one subembodiment of formula I, at least one of B1, B2, and B3 and at least one W1, W2, and W3 is a covalent bond and at least one X1, X2, and X3 is hydrogen.
In another embodiment of the above formula, at least one R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, and R32 is selected from an aliphatic, saturated or unsaturated alkyl, alkenyl or alkynyl. In one subembodiment, the alkyl, alkenyl or alkynyl groups are substituted, and can be halogen substituted.
In one embodiment of the above formula, at least one R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 is selected from a carbonyl containing groups, including, but not limited to, aldehyde, ketone, carboxylic acid, ester, amide, enone, acyl chloride or anhydride.
In one embodiment of the above formula, at least one R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 is selected from an alkyl, aryl, heteroaryl or heteroaromatic ring.
In one embodiment of the above formula, at least one R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 is independently selected from alkyl, nitro, a phosphate, a sulfate, a thiol, and an amine.
In certain embodiments, arbidol or an analog thereof can be used in the compositions, methods, and kits of the invention. Arbidol is an antiviral that has anti-influenza activity and functions by inhibition of the fusion of influenza A and B viruses within endosomes. The structure of arbidol is:
Arbidol is typically administered orally.
In certain embodiments, artemisinin or an analog thereof can be used in the compositions, methods, and kits of the invention. The artemeisins are a family of compounds that include antimalarials such as artemisinin and artemether, a semi-synthetic derivative of artemisinin. The structure of artemisinin is:
The structure of artemether is:
The structure of artesunate is:
Other artemisinins include 3-hydroxydeoxyartemisinin, α-propoxycarbonyldihydroartemisine, arteannuin B, arteether, arteflene, artelinic acid, artemether, artemisic acid, artemisin, artemisinin B, artemisinine, artemisitene, artesunate, artesunic acid, deoxoartemisinin, deoxyartemisinin, and dihydroquinghaosu. The active metabolite of artemisinins is dihydroartemisinin.
In certain embodiments, procaine or a derivative thereof such as benoxiante can be used in the compositions, methods, and kits of the invention. Benoxinate is an anesthetic agent. The structure of benoxinate is:
Benoxinate is a procaine derivative. Other procaine derivatives include 4-bromoacetamidoprocaine, analgesin, aslavital, benoxinate, bivelin, Cardioplegin, celnovocaine, chloroprocaine, efatin, Fluress, Impletol, impletol depot Bayer, N,N-diethylaminoethyl(2-N-methyl)benzoate, N-acetylprocaine, nicotinoylprocaine, novdimal, Penicillin G, Procaine, procaine acryloyl polymer, procaine azide, procaine isothiocyanate, Renovaine, sulfocamphocaine, Tardomyocel compound, and turigeran.
In certain embodiments, amiloride or an analog thereof such as benzamil can be used in the compositions, methods, and kits of the invention. Amiloride is a diuretic agent. The structure of amiloride is:
The structure of benzamil is:
Amiloride derivatives are described, for example, in U.S. Pat. No. 3,313,813 and can be represented by the following formula:
where X represents hydrogen, a halogen or halogen-like radical, such as, chloro, bromo, iodo or trifluoromethyl, or a lower-alkyl, lower-cycloalkyl, mononuclear aryl, either unsubstituted or substituted, advantageously with a halogen especially a chloro or bromo substituent, amino, Z-thio or Z-sulfonyl wherein Z is lower alkyl or phenyl-lower alkyl; Y represents hydrogen, hydroxyl or mercapto, lower alkoxy or lower alkyl-thio, halogen, especially chlorine, lower-alkyl, lower-cycloalkyl, mononuclear aryl, especially phenyl or amino, advantageously having the structure NRR1, wherein R and R1 can be similar or dissimilar radicals and respectively represent hydrogen, amino or mono- or di-lower-alkylamino, (advantageously forming a hydrazino group at the 5-position carbon), lower alkoxy, Y represents substituted amino, —NRR1, where R and R1 represent lower alkyl either straight or branched chain or cyclic (3- to 6-membered rings) and either unsubstituted or containing one or more substituents such as hydroxyl, halogen (chlorine, bromine, fluorine and the like), a cycloalkyl substituent having 3 to 6 carbons in the cycloalkyl structure, an aryl substituent preferably phenyl or substituted phenyl such as lower-alkyl-phenyl and halophenyl as chlorophenyl, bromophenyl, fluorophenyl, and the like, or a heterocyclic substituent especially furyl, pyridyl, and (CH2)nN— wherein n is one of the numerals 4 through 6, or an amino substituent as the unsubstituted amino, or mono- or di4ower-alkyl amino, and when R and R1 each represents a lower alkyl, the lower alkyl groups can be linked together to form a cyclic structure with the nitrogen atom to which they are attached, particularly a 5- to 8-membered ring, advantageously forming with the nitrogen atom a 1-pyrrolidinyl, piperidino, hexahydro-1-azepinyl, or octahydro-1-azocinyl radical and the like, Y represents substituted amino, —NRR1, where R and R1 represent lower alkenyl, aryl, advantageously an unsubstituted or substituted phenyl, wherein the substituent(s) are preferably halogen (chlorine, bromine, fluorine) or lower alkyl (methyl, ethyl, propyl, iso-propyl) and the like, amidino or substituted amidino, especially an N,N-di-lower alkyl-imidino, such as N,N-dimethylamidino; X and Y, in addition, can be linked together to form a 4-membered carbon chain that can be either unsaturated or saturated and that can be unsubstituted or substituted, and if substituted the substituent advantageously is a halogen, especially a chloro-atom. R2 represents hydrogen and lower alkyl; R3 represents hydrogen, lower alkyl, either saturated or unsaturated and substituted or unsubstituted, the substituent group(s) preferably being hydroxyl, aryl, either mono- or di-nuclear aryl, as phenyl or naphthyl, and either unsubstituted or containing one or more substituents, especially selected from lower alkyl, definition of substituents, continued substituents on aryl moiety of aryl-alkyl group halogen, lower alkyl, lower alkoxy, or any combination of these substituent groups, mono- or di-lower-alkylamino, wherein the alkyl groups may be linked to form a hetero structure with the aminonitrogen to which they are attached such as to form an azacycloalkyl group, heterocyclic, and especially the pyridyl group, halogen, aryl or substituted aryl, the substituent group(s) preferably being halogen, and lower alkyl, heterocyclic, advantageously a pyridyl radical, alkylideneamino, and acyl; R4 represents hydrogen, lower alkyl, either saturated or unsaturated and substituted or unsubstituted as described above for R3 or R3 and R4 can be lower alkyl groups linked directly together or through a hetero atom, especially through oxygen or nitrogen to produce a 5 to 8 membered cyclic structure, thus forming with the nitrogen atom to which they are attached a 1-pyrrolidinyl, piperidino, 1-piperazinyl, especially a 4-lower alkyl-1-piperazinyl or morpholino, and the like radicals; and when R2 and R3 (or R4) each represents a lower alkyl, they can be linked together to form a cyclic structure with the nitrogen atoms to which they are attached, particularly to form a 2-(2-imidazolinyl) radical. The 3-position amino group can be an unsubstituted amino as well as mono- or di-substituted amino groups, the substituent(s) advantageously being lower alkyl and lower alkanoyl and also where the substituents are linked to form a heterocyclic structure with the amino nitrogen to which they are attached.
Amiloride derivatives include 2′,4′-dichlorobenzamil amiloride, 2′,4′-dimethylbenzamil, 2′-methoxy-5′-nitrobenzamil, 2-chlorobenzylamiloride, 3′,4′-dichlorobenzamil, 3,5-diamino-6-fluoro-2-pyrazinoylguanidine, 3,5-diamino-N-(aminoiminomethyl)-6-bromopyrazine-N-methylcarboxamide, 4-(((((3,5-diamino-6-chloropyrazinyl)carbonyl)amino)iminomethyl)amino)-2,2,6,6-tetramethyl-1-piperidinyloxy, 5,6-dichloroamiloride, 5-(ethylpropyl)amiloride, 5-(N,N-hexamethylene)amiloride, 5-(N-2′-(4″-azidosalicylamidino)ethyl-N′-isopropyl)amiloride, 5-(N-2′-aminoethyl-N′-isopropyl)amiloride-N-(4″-azidosalicylamide), 5-(N-4-chlorobenzyl)-N-(2′,4′-dimethyl)benzamil, 5-(N-butyl-N-methyl)amiloride, 5-(N-ethyl-(2′-methoxy-5′-nitrobenzyl))amiloride, 5-(N-methyl-N-isobutyl)amiloride, 5-(N-methyl-N-propyl)amiloride, 5-(N-propyl-N-butyl)-2′,4′-dichlorobenzamil amiloride, 5-(N-tert-butyl)amiloride, 5-diethylamiloride, 5-dimethylamiloride, 5-N-(3-aminophenyl)amiloride, 5H-amiloride, 6-bromoamiloride, 6-bromobenzamil, 6-chloro-3,5-diaminopyrazine-3-carboxamide, 6-iodoamiloride, alpha′,2′-benzobenzamil, amiloride caproate, benzamil, co-amilozide, Esmalorid, ethylisopropylamiloride, frumil, kalten, methylisopropylamiloride, moducrin, N(5)-piperazine-amiloride, N(5)-piperidine-amiloride, phenylamil, and uranidil A.
In certain embodiments, ergotamine alkaloids such as bromocriptine, can be used in the compositions, methods, and kits of the invention. Bromocriptin analogs are described, for example, in U.S. Pat. No. 4,145,549. Ergotamine alkaliods include 1-methylergotamine, 9,10-dihydroergosine, bellataminal, Bellergal, beta-ergoptine, Bromocriptine, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydroergotamine, dihydroergotoxine, ergosine, ergotamine, ergovaline, and neo-secatropin.
In certain embodiments, a chlorophyllide or an analog thereof can be used in the compositions, methods, and kits of the invention. Chlorophyllin is a derivative of chlorophyl, and a member of the chlorophyllides. Other chlorophyllides include chlorophyllide a, chlorophyllide b, methylchlorophyllide A, and methylchlorophyllide B.
In certain embodiments, cytarabine or an analog thereof can be used in the compositions, methods, and kits of the invention. Cytarabine is an antimetabolic and an antiviral agent. Cytarabine analogs are described in U.S. Pat. No. 3,116,282.
In certain embodiments, a thyroxine or derivative thereof can be used in the compositions, methods, and kits of the invention. Thyroxines are thyroid hormones and include levo thyroxine and dextrothyroxine, which has been used as antihyperlipidemic. The formula for dextrathyroxine is:
Dextrathyroxine can be administered orally and is typically provided in 2 mg or 4 mg tablets. Levothyroxine is used to increase the metabolic rate of cells.
In certain embodiments, a pregnadiene or an analog or derivative thereof such as dydrogesterone can be used in the compositions, methods, and kits of the invention. Dydrogesterone is a progesterone and used thus to treat progesterone deficiency. Pregnadienes include 12-hydroxy-3-oxo-1,4-pregnadiene-20-carboxylic acid, 17-benzoyloxy-11-hydroxy-3,20-dioxo-1,4-pregnadien-21-al hemiacetal, 20-carboxy-1,4-pregnadien-3-one, 20-succinamylpregna-1,4-dien-3-one, 21-hydroxypregna-1,4-diene-3,11,20-trione, 3alpha-hydroxy-5alpha-pregna-9(11),16-diene-20-one, 3-hydroxy-5,7-pregnadien-20-one, canrenoate potassium, canrenone, chlormadinone acetate, cymegesolate, cyproterone, danazol, domoprednate, fluocinolone acetonide, GR 2-1159, icometasone enbutate, medrogestone, megestrol, melengestrol acetate, nivazol, oxyma, pregnadienediols, pregnadienetriols, rimexolone, Ro 12-2503, Ro 14-9012, Ro 6-1963, and triamcinolone.
In certain embodiments, a azo dye such as Evans blue can be used in the compositions, methods, and kits of the invention. Evans blue is used in blood volume and cardiac output measurement by the dye dilution method. It is very soluble, strongly bound to plasma albumin. The structure of Evans blue is:
In certain embodiments, an azetidine or derivative thereof such as ezitamibe can be used in the compositions, methods, and kits of the invention. The structure of ezitamibe is:
Analogs of ezitamibe are described, for example, in U.S. Pat. No. 5,767,115 and are described by the formula:
where Ar1 and Ar2 are independently selected from the group consisting of aryl and R4-substituted aryl; Ar3 is aryl or R5-substituted aryl; X, Y and Z are independently selected from the group consisting of —CH2—, —CH(lower alkyl)- and —C(dilower alkyl)-; R and R2 are independently selected from the group consisting of —OR6, —O(CO)R6, —O(CO)OR9 and —O(CO)NR6R7; R1 and R3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5; R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6 (CO)NR7R8, —NR6 SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6, —CH═CH—COOR6, —CF3, —CN, —NO2 and halogen; R5 is 1-5 substituents independently selected from the group consisting of —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-0—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and —CH═CH—COOR6; R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R9 is lower alkyl, aryl or aryl-substituted lower alkyl. R4 is preferably 1-3 independently selected substituents, and R5 is preferably 1-3 independently selected substituents. Preferred are compounds of formula I wherein Ar1 is phenyl or R4-substituted phenyl, especially (4-R4)-substituted phenyl. Ar2 is preferably phenyl or R4-substituted phenyl, especially (4-R4)-substituted phenyl. Ar3 is preferably R5-substituted phenyl, especially (4-R5)-substituted phenyl. When Ar1 is (4-R4)-substituted phenyl, P4 is preferably a halogen. When Ar2 and Ar3 are R4- and R5-substituted phenyl, respectively, R4 is preferably halogen or —OR6 and R5 is preferably —OR6, wherein R6 is lower alkyl or hydrogen. Especially preferred are compounds wherein each of Ar1 and Ar2 is 4-fluorophenyl and Ar3 is 4-hydroxyphenyl or 4-methoxyphenyl.
Other azetidines include 1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone, 1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate, 1-methyl-2-(3-pyridyl)azetidine, 2-oxo-3-phenyl-1,3-oxazetidine, 2-tetradecylglycidyl-coenzyme A, 3-(2-oxopropylidene)azetidin-2-one, 3-aminonocardicinic acid, 3-phenyl-2-methylazetidine-3-ol, 4-((4-carboxyphenyl)oxy)-3,3-diethyl-1-(((phenylmethyl)amino)carbonyl)-2-azetidinone, 4-(3-amino-2-oxoazetidinonyl-1)methylbenzoic acid, 4-(3-amino-2-oxoazetidinonyl-1)methylcyclohexanecarboxylic acid, AHR 11748, azetidine, azetidine platinum(II), azetidinecarboxylic acid, azetidyl-2-carboxylic acid, azetirelin, BDF 9148, BMS-262084, E 4695, fluzinamide, L 652117, L 684248, N-(2-chloromethylphenyl)-3,3-difluoroazetidin-2-one, SCH 60663, SF 2185, tabtoxinine beta-lactam, tazadolene succinate, and ximelagatran.
In certain embodiments, thioxanthanes such as flupentixol can be used in the compositions, methods, and kits of the invention. Flupentixol is a antipsychotic that acts as a dopamine (D2 receptor) antagonist. Thioxanthane analogs are described, for example, in U.S. Pat. No. 3,951,961. Thioxanthane analogs include 2-(beta-diethylaminoethylamino)-3,4-cyclohexenothia-xanthone, 2-chlorothioxanthen-9-one, 2-thioxanthene, 3-carboxy-thioxanthone-10,10-dioxide, 4-(beta-diethylaminoethylamino)-1,2-cyclohexenothiaxanthone, 4-(bis(2′-chloroethyl)amino)propylamino-1,2-cyclohexenothioxanthone, 7-oxo-7-thiomethoxyxanthone-2-carboxylic acid, BW 616U76, chlorprothixene, clopenthixol, doxantrazole, flupenthixol, hycanthone, lucanthone, methixene, piflutixol, pimethixene, prothixene, quantacure QTX, spasmocanulase, teflutixol, thiothixene, and WIN 33377.
In certain embodiments, gemcitabine or an analog thereof can be used in the compositions, methods, and kits of the invention. Gemcitabine is a nucleoside with antineoplastic activity.
Analogs of gemcitabine are described, for example, in U.S. Pat. No. 4,808,614 and have the general structure:
wherein R is a base of one of the formulae:
wherein R1 is hydrogen, methyl, bromo, fluoro, chloro, or iodo; R2 is hydroxy or amino; R3 is hydrogen, bromo, chloro, or iodo.
In certain embodiments, GW 5074 or an analog thereof can be used in the compositions, methods, and kits of the invention. GW 5074 is a benzylidene-1,3-dihydro-indol-2-one derivative which acts as a receptor tyrosine kinase inhibitor (e.g., raf such as cRaf1). The structure of GW 5074 is:
Analogs of GW 5074 are described, for example, in U.S. Pat. No. 6,268,391 and have the general structure:
wherein R1 is H or optionally joined with R2 to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclyl rings having one to three heteroatoms where zero to three of said heteroatoms are N and zero to 1 of said heteroatoms are O or S and where said fused ring is optionally substituted by one to three of R9, where R2 and R9 are as defined below; R2 and R3 are independently H, HET, aryl, C1-12 aliphatic, CN, NO2, halogen, R10, —OR10, —SR10, —S(O)R10, —SO2R10, —NR10R11, —NR11R12, —NR12COR11, —NR12CO2R11, —NR12CONR11R12, —NR12SO2R11, —NR12C(NR12)NHR11, —COR11, —CO2R11, —CONR12R11, —SO2NR12R11, —OCONR12R11, C(NR12)NR12R11 where said C1-12 aliphatic optionally bears one or two insertions of one to two groups selected from C(O), O, S, S(O), SO2 or NR12; with said HET, aryl or C1-12 aliphatic being optionally substituted by one to three of R10; and where R2 is optionally joined with R3 to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclyl rings having zero to three heteroatoms where zero to three of said heteroatoms are N and zero to one of said heteroatoms are O or S and where said fused ring is optionally substituted by one to three of R9, where HET, R9, R10, R11 and R12 are as defined below; R4 is H, halogen, NO2 or CN; R5 is H or C1-12 aliphatic optionally substituted by one to three of halo, hydroxyl, heteroaryl, or aryl; R6 and R7 are independently halogen, CN, NO2, —CONR10R11, —SO2NR10R11, —NR10R11, or —OR11, where R10 and R11 are as defined below; R8 is OH, NHSO2R12 or NHCOCF3; R9 is each independently halogen, C1-12 aliphatic, CN, —NO2, R10, —OR11, —SR11, —S(O)R10, —SO2R10, —NR10R11, —N11R12, —NR12COR11, —NR12CO2R11, —NR12CONR11R12, —NR12SO2R11, —NR12C(NR12)NHR11, —CO2R11, —CONR12R11, —SO2NR12R11, —OCONR12R11 or C(NR12)NR12R11, where R10, R11 and R12 are as defined below; R10 is each independently H, halogen, C1-12 aliphatic, aryl or HET, where said C1-12 aliphatic optionally bears an inserted one to two groups selected from O, S, S(O), SO2 or NR12, where said C1-12 aliphatic, aryl or HET is optionally substituted by one to three of halo, another HET, aryl, CN, —SR12, —OR12, —N(R12)2, —S(O)R12, —SO2R12, —SO2N(R12)2, —NR12COR12, —NR12CO2R12, —NR12CON(R12)2, —NR12(NR12)NHR12, —CO2R12, —CON(R12)2, —NR12SO2R12, —OCON(R12)2, where HET and R12 are as defined below; R11 is H or R10; R12 is H, C1-12 aliphatic or HET, said C1-12 aliphatic optionally substituted by one to three of halogen or OH where HET is as defined below; and HET is a five to ten-membered saturated or unsaturated heterocyclic ring selected from the group consisting of benzofuran, benzoxazole, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, indole, indazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxiadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, quinazoline, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, and triazole; and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, solvates, hydrates, or prodrugs of the as defined above.
In certain embodiments, melphalan or an analog thereof can be used in the compositions, methods, and kits of the invention. Melphalan is an alkylating nitrogen mustard used as an antineoplastic in the form of the levo isomer, melphalan. The racemic mixture is merphalan, and the dextro isomer is medphalan. Melphalan analogs are described, for example, in U.S. Pat. No. 3,032,584.
In certain embodiments, mosapride or an analog thereof can be used in the compositions, methods, and kits of the invention. Mosapride is a benzamide that acts as a selective 5-HT4 receptor agonist and is used as a gastroprokinetic. The structure of mosparide is:
Analogs of mosparide are described, for example, in U.S. Pat. No. 4,870,074 and have the general structure:
wherein R is hydrogen, a C2-C5 alkoxycarbonyl, benzyloxycarbonyl, a heteroaryl(C1-C3)alkyl in which the heteroaryl is furyl, thienyl, pyridyl, or 1,2-benzisoxazolyl, a phenyl(C3-C5)alkenyl, or -T-(Y)p—R6 (wherein T is a single bond or a C1-C6 alkylene, Y is oxygen, sulfur or carbonyl, R6 is phenyl, a phenyl substituted by one to five members each independently selected from the group consisting of a halogen, a C1-C4 alkyl, trifluoromethyl, a C1-C4 alkoxy, nitro, cyano and amino, naphthyl, or diphenylmethyl, and p is 0 or 1, provided that when T is a single bond, p is 0), R1 is a halogen, hydroxy, a C1-C12 alkoxy, a C3-C6 cycloalkyloxy, a C3-C8 alkenyloxy, a C3-C8 alkynyloxy, a C2-C6 alkoxy interrupted by one or two oxygens or carbonyls, a C1-C4 alkylthio, amino, a monosubstituted amino in which the substituted is a C1-C8 alkyl, a phenyl(C1-C3)alkyl or a C3-C6 cycloalkyl, a C2-C6 alkoxy in which the carbon atom at any position other than the 1-position is substituted by one hydroxy or amino, or a substituted C1-C6 alkoxy in which the substituent is a halogen, cyano, a C2-C5 alkoxycarbonyl, phthalimido, a C3-C6 cycloalkyl, a phenyl optionally substituted by one halogen, a phenoxy optionally substituted by one halogen, or a benzoyl optionally substituted by one halogen, R2 is hydrogen, R3 is hydrogen, a halogen, amino, a C1-C4 alkylamino, a di(C1-C4 alkyl)amino, a C2-C5 alkanoylamino, or nitro, R4 is hydrogen, a halogen, nitro, sulfamoyl, a C1-C4 alkylsulfamoyl, or a di(C1-C4 alkyl)sulfamoyl, or any two adjacent groups of the R1, R2, R3 and R4 combine to form a C1-C3 alkylenedioxy, and the remaining two groups are each hydrogen, R5 is hydrogen or a C1-C4 alkyl, X is a C1-C3 alkylene, and m and n are each 1 or 2, provided that at least one of the groups R2, R3 and R4 is not hydrogen.
Mosapride is a benzamide. Other benzamides include 1-((4-fluorobenzoylamino)ethyl)-4-(7-methoxy-1-naphthyl)piperazine hydrochloride, 1-(3,4-dihydroxyphenyl)-2-(3-(4-carbamylphenyl)-1-methylpropylamino)ethanol, 1-nitrohydroxyphenyl-N-benzoylalanine, 2,2′-dithiobis(N-2-hydroxypropylbenzamide), 2,3-dimethoxy-5-iodo-N-((1-(4′-fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide, 2,3-dimethoxy-N-(1-(4-fluorobenzyl)piperidin-4-yl)benzamide, 2,3-dimethoxy-N-(9-(4-fluorobenzyl)-9-azabicyclo(3.3.1)nonan-3-yl)benzamide, 2,4-dichloro-6-nitrophenolamide, 2,6-dichlorobenzamide, 2,6-difluorobenzamide, 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide, 2-chlorobenzamide, 2-hexyloxybenzamide, 2-methoxy-4-fluoro-3-amino-N-((2-methylcyclopropylamino)ethyl)benzamide, 264 CP, 3,4,5-trimethoxybenzamide, 3,4-dichloro-N,N-di-sec-butylbenzamide, 3-(3-(dimethylamino)propyl)-4-hydroxy-N-(4-(4-pyridinyl)phenyl)benzamide, 3-(cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide, 3-(N-butyrylamino)benzamide, 3-acetamidobenzamide, 3-aminobenzamide, 3-carbamyl-(3′-picolyl)-4-methoxy-1-benzamide, 3-chloro-N-(4,6-dimethyl-2-pyridiny) benzamide, 3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide, 3-methoxybenzamide, 3-nitrosobenzamide, 4-((methylsulfonyl)amino)-N-((4-phenylpiperazin-2-yl)methyl)benzamide, 4-(1H-tetrazol-5-yl)-N-(4-(1H-tetrazol-5-yl)phenyl)benzamide, 4-(3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl)benzamide, 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide, 4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide, 4-(trifluoromethyl)benzamide, 4-amino-5-chloro-2-ethoxy-N-((2-morpholinyl)methyl)benzamide, 4-amino-N-((4-benzyl-2-morpholinyl)-methyl)-5-chloro-2-ethoxybenzamide, 4-amino-N-((4-benzyl-2-morpholinyl)methyl)-5-chloro-2-methoxybenzamide, 4-aminobenzamidopyridine, 4-azido-5-iodoclebopride, 4-chloro-N-(hydroxymethyl)benzamide, 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide, 4-dimethylamino-N-(4-(2-hydroxycarbamoylvinyl)benzyl)benzamide, 4-fluorobenzamide, 4-fluorobenzylamine, 4-hydroxybenzamide, 4-iodo-N-(2-(4-morpholinyl)ethyl)benzamide, 4-iodo-N-piperidinoethylbenzamide, 5-(aziridin-1-yl)-2-nitro-4-nitrosobenzamide, 5-bromo-2,3-dimethoxy-N-((1-(4-fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide, 5-bromo-2-ethoxybenzamide, 5-fluoropropylepidepride, 7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid, A 22700, AH 7921, aklomide, alloclamide, ameltolide, azapride, BA 74, befol, benodanil, benzamide, benzamide adenine nucleotide, benzcoprine, benzotripte, bis(2-(N-phenylcarboxamido)phenyl)diselenide, BRL 24682, BRL 32872, BRL 34778, bromadoline, bromtianide, brovanexine, BW 373U86, BWA 466C, BWA 728C, Card-Instenon, cinitapride, Cisapride, clebopride, cloxacepride, dazopride, DEET, dehydroxymethylepoxyquinomicin, desbenzylclebopride, Diethyltoluamide-20, dimetpramid, Dinitolmide, dobupride, ecabapide, EL 494, epidepride, ethamivan, ethyl 2-(4′-carboxybenzamido)-4-aminobenzoate, ethyl 2-(4′-carboxybenzamido)-4-propionamidobenzoate, FLA 981, flatoril, FLB 524, fluoroclebopride, fluphenacur, flurfamide, fomesafen, gentisamide, GGTI 297, GGTI 298, GR11665, GW 300, GW 532, GW 575, hexafluoron, Hippurates, HMR 1098, Indoramin, Instenon, iodopride, iofratol, isoxaben, itopride, L 1215, L 7063, LY 135114, LY 188544, LY 201409, meglitinide, Metoclopramide, Moclobemide, N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane, N,N-dimethylbenzamide, N-((4-benzyl-2-morpholinyl)methyl)-5-chloro-4-(dimethylamino)-2-methoxybenzamide, N-((4-methylphenyl)sulfonyl)-3-(2-quinolinylmethoxy)benzamide, N-(1′-benzyl-4′-piperidyl-N-oxide)-4-amino-5-chloro-2-methoxybenzamide, N-(2,6-dimethylphenyl)-4-(((diethylamino)acetyl)amino)benzamide, N-(2-(diethylamino)ethyl)-4-iodobenzamide, N-(2-(diethylamino)ethyl)benzamide, N-(2-aminocyclohexyl)-3,4-dichlorobenzamide, N-(2-aminoethyl)-2-anisamide, N-(2-aminophenyl)-4-(N-(pyridin-3-ylmethoxycarbonyl)aminomethyl)benzamide, N-(2-dimethylaminoethyl)-2-anisamide, N-(2-methylaminocyclohexyl)-3,4-dichlorobenzamide, N-(2-picolyl)-3,5-dimethylbenzamide, N-(3,4,5-trimethoxybenzoyloxy)-3,4,5-trimethoxybenzamide, N-(3-picolyl)-3,5-dimethylbenzamide, N-(4′-(delta-1′-piperidyl-N-oxide))-4-amino-5-chloro-2-methoxybenzamide, N-(4′-(N-hydroxypiperidyl))-4-amino-5-chloro-2-methoxybenzamide, N-(4,6-dimethyl-2-pyridinyl)benzamide, N-(4-(2-(dimethylamino)ethoxy)benzyl)-3,4-dimethoxybenzmide, N-(4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl)-N′-(2-nitrobenzoyl)urea, N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide monohydrate, N-(4-amino-1-butyl)-N-nitrosobenzamide, N-(4-chlorobenzoyl)-N-methyl-4-(4-dimethylaminomethylphenyl)cyclohexylamine, N-(acetoxymethyl)-4-chlorobenzamide, N-(exo-(hexahydro-1H-pyrrolizine-1-yl)methyl)-2-methoxy-4-amino-5-chlorobenzamide, N—(N-benzylpiperidin-4-yl)-4-iodobenzamide, N-2-fluorenylbenzamide, N-acetylbenzamide, N-butyrylbenzamide, N-demethylbromadoline, N-didemethylbromadoline, N-ethylbenzamide, N-formylbenzamide, N-hydroxymethyl-N-methylbenzamide, N-hydroxymethylbenzamide, N-isopropyl-4-hydroxymethylbenzamide, N-methyl-2,3-dihydroxybenzamide, N-methylbenzamide, N-octyl-3-nitro-2,4,6-trihydroxybenzamide, N-propionylbenzamide, N-pyrimidinobenzamide-2-carboxylic acid, nemonapride, nitromide, norcisapride, NP 101A, pancopride, parsalmide, Pellit, penfluoron, picobenzide, picobenzide N-oxide, Procainamide, Procarbazine, pronamide, Raclopride, rebemide, Remoxipride, renzapride, RG-4, RG-7, riparin, Ro 12-5637, Ro 12-8095, Ro 16-3177, Ro 16-6491, roflumilast, S 1688, SC 53116, sirtinol, SNC 121, spectramide, SR 48968, Sulpiride, T 0070907, teflubenzuron, tegalide, Tiapride, tonabersat, triflumuron, trimethobenzamide, WAY 100289, YM-08050, Z 338, and zacopride.
In certain embodiments, telaprevir or an analog thereof can be used in the compositions, methods, and kits of the invention. Octyl methoxycinnamate absorbs ultraviolet (UV) light and is used in sunscreens and other topical applications where UV protection is desired. The structure of octyl methoxycinnamte is:
Cinnamic acid derivatives are described, for example, in U.S. Pat. No. 5,457,226 and have the general structure:
wherein R1 signifies hydrogen or C1-8-alkyl and R2 signifies hydrogen, C1-10-alkyl, C1-10-hydroxyalkyl or C1-4-alkoxy-C1-10-alkyl. Cinnamic acid derivative include Other cinnmates include (4-(dimethylamino)cinnamoyl)imidazole, (N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N′-(3,4-dimethylphenyl)piperazine), 1,1-dimethylallyl-3′,4′-dihydroxycinnamic acid ester, 2,3-dihydroxycinnamic acid, 2-(4-amylcinnamoyl)amino-4-chlorobenzoic acid, 2-chlorocinnamic acid, 2-ethylhexyl-4-methoxycinnamate, 2-fluoro-p-hydroxycinnamate, 2-fluorocinnamic acid, 3,4,5-trimethoxycinnamic acid, 3,4-di(OH)-cinnamate, 3,4-dihydroxyhydrocinammic acid (1-aspartic acid dibenzyl ester) amide, 3,5-dihydroxycinnamic acid, 3,5-dimethoxycinnamic acid, 3,7-dimethyl-1,6-octadien-3-yl cinnamtae, 3-(3,4-dimethoxyphenyl)propenoic acid, 3-(4′-hydroxy-3′-adamantylbiphenyl-4-yl)acrylic acid, 3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid, 3-(4-methoxyphenyl)-2-propenoic acid 3-methylbutyl ester, 3-(trifluoromethyl)cinnamide, 3-bromocinnamamide, 3-bromocinnamic acid, 3-fluorocinnamic acid, 4-(3,3-dimethyl-1-triazeno)cinnamic acid, 4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid, 4-amidinophenyl 2-methylcinnamate, 4-amidinophenyl cinnamate, 4-amylcinnamoylanthranilic acid, 4-dimethylaminocinnamaldehyde, 4-fluorocinnamic acid, 4-hydroxy-3-methoxycinnamylpiperidine, 4-hydroxycinnamic acid (1-phenylalanine methyl ester) amide, 4-methoxycinnamate methyl ester, 4-methoxycinnamic acid, 5-(2-(methyl(2-phenethyl)amino)-2-oxoethyl)-2-(benzyloxy)cinnamic acid, A 25794, adamon, alpha-cyanocinnamate, alpha-methyl-2-hydroxy-4-diethylaminocinnamic acid, alpha-phenylcinnamate, aminocinnamonitrile, antithiamine factor, asarumin C, BM 42304, caffeic acids (e.g., 1,1-dimethylallyl caffeic acid ester, 2-S-glutathionylcaffeic acid, 3,4-dihydroxyphenylpropionic acid, 7-caffeoylloganin, caffeic acid, caffeic acid phenethyl ester, calceolarioside A, chicoric acid, crenatoside, dehydrodicaffeic acid dilactone, ethyl caffeate, ethyl ferulate, eugenol, fukinolic acid, methyl caffeate, myriceron caffeoyl ester, N-(3,4-diacetoxycinnamoyl)-2-pyrrolidone, N-caffeoyl-4-aminobutyric acid, octyl caffeate, petasiphenol, phenylethyl 3-methylcaffeate, salvianolic acid A, suspensaside, and swertiamacroside), caracasanamide, chlorogenic acid, cinametic acid, cinanserin or derivatives thereof (e.g., SQ 10631 and SQ 11447), cinnamic acid, cinnamic anhydride, cinnamoyl chloride, cinnamyl isobutyrate, cinromide, CKA 1303, clocinnamox, coniferin, coumaric acids (e.g., (3,4-disinapoyl)fructofuranosyl-(6-sinapoyl)glucopyranoside, (3-sinapoyl)fructofuranosyl-(6-sinapoyl)glucopyranoside, 1-(4-coumaroyl)alpha-rhamnopyranose, 2-hydroxycinnamic acid, 3-coumaric acid, 4-coumaric acid, 4-coumaric acid methyl ester, 4-hydroxycinnamoylmethane, 5-hydroxyferulic acid, 5-O-feruloylarabinose, alpha-cyano-3-hydroxycinnamate, alpha-cyano-4-hydroxycinnamate, angoroside C, asprellic acid A, coniferyl ferulate, cycloartenol ferulic acid ester, dihydro-3-coumaric acid, ferulic acid, feruloylputrescine, feruloyltyramine, karenin, methyl 5-O-feruloylarabinofuranoside, and sinapinic acid), cyclamen aldehyde, cyclamen aldehyde methyl anthranilate, diacetylcymarol, dimethylaminoethyl-alpha-phenylcinnamate, Dolo-Adamon, ethyl 2,5-dihydroxycinnamate, ethyl cinnamate, fagaramide, gagaminine, hordatine M, hygromycin A, igmesine, isoferulic acid, kutkin, linusitamarin, maxafil, methyl 2,5-dihydroxycinnamate, methyl 3-phenyl-2,3-epoxypropanoate, methyl 4-(dimethylamino)cinnamate, methyl cinnamate, N,N-dimethylhydrocinnamide, N-hydroxy-N-methyl-3-(2-(methylthio)phenyl)-2-propenamide, O-(alpha-(benzoylamino)-4-(phenylazo)cinnamoyl)-beta-phenyllactate, O-(alpha-(benzoylamino)cinnamoyl)-beta phenyllactate, octylmethoxycinnamate, ONO 8713, penupogenin, picroside I, picroside II, puromycin or derivative thereof (e.g., 2′-deoxypuromycin, 4-azidopuromycin, carbocyclic puromycin, cyclohexylpuromycin, cytidine-2′(3′)-P-5′-puromycin, methionylpuromycin, N-(2-nitro-4-azidobenzoyl)puromycin, N-acetylphenylalanylpuromycin, N-iodoacetylpuromycin, O-demethylpuromycin, puromycin aminonucleoside, and sparsopuromycin), Ro 03-6037, rosmarinic acid, S 8932, SC 1001A, sibirate, SQ 10624, ST 638, SU 1498, tolibut, trans-3-(2′-methylphenyl)-2-propene-1-carboxamide, vanicoside A, and vanicoside B.
In certain embodiments, oxeladin or an analog thereof can be used in the compositions, methods, and kits of the invention. Oxeladin is a used as an antitussive agent. The structure of oxeladin is:
Oxeladin derivates are described, for example, in U.S. Pat. No. 2,885,404 and have the general structure:
in which R1 and R2 are alkyl groups containing together not more than 12 carbon atoms, or together form a cyclic structure wherein —NR1R2 represents pyrrolidino, piperideino or piperidino. The groups R1 and R2 may be the same or different. Particular derivatives include 2-(β-diethylaminoethoxy)ethyl diethylphenylacetate, 2-(β-N-pyrrolidinoethoxy)ethyl diethylphenylacetate, 2-(β-N-piperidinoethoxy)ethyl diethylphenylacetate, 2-(β-N-Δ3-piperideinoethoxy)ethyl diethylphenylacetate, 2-(β-N-ethylmethylaminoethoxy)ethyl diethylphenylacetate, 2-(β-N-ethylpropylaminoethoxy)ethyl diethylphenylacetate, 2-(β-N-di-n-butylaminoethoxy)ethyl diethylphenylacetate and 2-(β-di-n-hexylaminoethoxy)ethyl diethylphenylacetate.
In certain embodiments, parthenolide or an analog thereof can be used in the compositions, methods, and kits of the invention. Parthenolide is a sesquiterpene lactone found in plants such as feverfew and Chrysanthemum parthenium. It has anti NFκB activity. The structure of parthenolide is:
Analogs of parthenolide are described, for example, in U.S. Pat. Application Publication No. 2005/0032886 and have the following structure.
wherein R1 and R2 may be the same or different; R1 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, carbamate, sulfonyl, sulfonamide and aryloxyalkyl, or OR1, wherein, O is an oxygen; R2 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, carbamate, sulfonyl, sulfonamide and aryloxyalkyl. In certain embodiments, R1 is hydrogen or optionally substituted lower alkyl; and R2 is optionally substituted lower alkyl. R1 and R2 can be each —CH3, or each —CH2CH3. R1 can be —CH2CH3 and R2 can be —CH3. R1 can be —CH2CH2CH3 and R2 can be —CH3. R1 can be —CH(CH3)2, and R2 can be —CH3. R1 and R2 also can combine with N to form a ring system. Examples of such combination include —CH2(CH2)nCH2—; where n is selected from 0 to 5. These ring systems can also have one or more substituents selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, carbamate, sulfonyl, sulfonamide, aryloxyalkyl and halogen as set forth above. This ring system can also be —CH2(CH2)nCH2Z-; where Z is O, S, Se, Si, P, —CO—, —SO—, —SO2—, —PO—; and —CH2(CH2)nCH2— are the groups as set forth above. Alternatively, this ring system can be —(CH2)a-Z-(CH2)b—; where a and b are the same or different and are from 1 to 4; and Z is O, N, S, Se, Si, P, —CO—, —SO—, —SO2— or —PO—. This ring system can also be a uracil ring and its derivatives with one or more substituents. These ring systems can also have one or more substituents connected to the carbon atom(s) and/or Z. The substituent is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, carbamate, sulfonyl, sulfonamide, aryloxyalkyl and halogen as set forth above. These ring systems can also be aromatic, such as pyrrole, imidazole, purine, and pyrazole and substituted derivative of these heterocyclics listed above with one or more substituents selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, carboxylate, carboxaldehyde, carboxamide, carbamate, hydroxy, alkoxy, isocyanate, isothiocyanate, nitro, nitroso, nitrate, sulfate, sulfonyl, sulfonamide, thiol, thioalkyl, aryloxyalkyl and halogen as set forth above. Any of the above ring systems comprising NR1R2 may optionally be fused with another ring to form an optionally substituted bicyclic or tricyclic ring system, each of the rings optionally comprising one or more heteroatoms. Preferred ring systems include aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, homopiperidyn-1-yl and heptamethyleneimin-1-yl, each being optionally substituted with one or more substituents as set forth above. Exemplary parthenolide derivatives include 11βH,13-Dimethylaminoparthenolide; 11βH,13-Diethylaminoparthenolide; 11βH,13-(tert-Butylamino)parthenolide; 11βH,13-(Pyrrolidin-1-yl)parthenolide; 11βH,13-(Piperidin-1-yl)parthenolide; 11βH,13-(Morpholin-1-yl)parthenolide; 11βH,13-(4-Methylpiperidin-1-yl)parthenolide; 11βH,13-(4-Methylpiperazin-1-yl)parthenolide; 11βH,13-(Homopiperidin-1-yl)parthenolide; 11βH,13-(Heptamethyleneimin-1-yl)parthenolide; 11βH,13-(Azetidin-1-yl)parthenolide; and 11βH,13-Diallylaminoparthenolide.
In certain embodiments, quinacrine or an analog thereof can be used in the compositions, methods, and kits of the invention. Quinacrine is an antiparasitic and an antiprotozoal (e.g., antimalarial) agent. The structure of quinacrine is:
Analogs of quincrine are described, for example, in U.S. Pat. No. 1,782,272 and have the following structure:
wherein R1 stands for hydrogen or alkyl, at least one R2 for the nitro group and another R2 for a basic residue, the remaining R2 representing hydrogen, halogen, or a nitro-, alkyl- or alkoxy group, where a “basic residue” is By the term “basic residue” is to be understood in the sense of the foregoing formula such groups contain at least one aliphatically bound N-atom and which may be linked to the acridine ring for instance through the medium of oxygen (in the manner of an ether), of nitrogen (in the manner of an amine), or of carbon (in the manner of a C—C linkage). Derivatives of quinacrine include acrisuxine, collagenan, dimethylquinacrine, Preparation ABP, quinacrine half mustard, and quinacrine mustard.
Quinacrine is an aminoacridine. Other aminoacridines include (((amino-2-ethyl)-2-aminomethyl)-2-pyridine-6-carboxylhistidyl-gamma-(2-amino-2-deoxyglucosyl)glutamylglycylamino)-4-phenyl-1-aminoacridine, (N-(2-((4-((2-((4-(9-acridinylamino)phenyl)amino)-2-oxoethyl)amino)-4-oxobutyl)amino)-1-(1H-imidazol-4-ylmethyl)-1-oxoethyl)-6-(((−2-aminoethyl)amino)methyl)-2-pyridinecarboxamidato) iron(1+), 1,2,3,4-tetrahydro-N-(3-iodophenyl-methyl)-9-acridinamine, 1,2,3,4-tetrahydro-N-(phenyl-methyl)-9-acridinamine, 1-nitro-9-(dimethylamino)acridine, 10-N-nonylacridinium orange, 2-(3,6-bis(dimethylamino)-10-acridinyl)ethyl-(2,3-di-O-palmitoylglycero)phosphate, 2-aminoacridone, 3,6-diamino-10-methylacridinium, 3,6-diamino-9-(4-(methylsulfonyl)aminophenyl)aminoacridine, 3-amino-6-methoxy-9-(2-hydroxyethylamino)acridine, 3-amino-6-methoxyacridine, 3-amino-7-methoxyacridine, 3-amino-9-(diethylaminoethylthio)acridine, 3-aminothioacridone, 3-dimethylamino-6-methoxyacridine, 4-(9-acridinylamino)-N-(4-(((4-amino-1-methylpyrrol-2-yl)carbonyl)amino)-1-methylpyrrol-2-carbonyl)glycylaniline, 4-(9-acridinylamino)-N-(glycyl-histidyl-lysyl-glycyl)aniline, 9-((6-(4-nitrobenzoyloxy)hexyl)amino)acridine, 9-(2-(2-nitro-1-imidazolyl)ethylamino)acridine, 9-(5-carboxypentylamino)acridine, 9-(6-(2-diazocyclopentadienylcarbonyloxy)hexylamino)acridine, 9-(6-(4-azidobenzamido)hexylamino)acridine, 9-amino-2-hydroxyacridine, 9-amino-3-azido-7-methoxyacridine, 9-amino-6-chloro-2-methoxyacridine, 9-amino-6-chloroacridine-2-phosphate, 9-aminoacridine-4-carboxamide, acridine mustard, acridine orange, acridine yellow, acriflavine, aminacrine, Amsacrine, C 1310, C 1311, C 325, C 829, coriphosphine, ethacridine, euchrysine, fluoroquinacrine, N-((2-dimethylamino)ethyl)-9-aminoacridine-4-carboxamide, N-((4-dimethylamino)butyl)-9-aminoacridine-4-carboxamide, N-(6-azido-2-methoxy-9-acridinyl)-N′-(9-acridinyl)octane-1,8-diamine, N-(9-acridinyl)bromoacetamide, Nitracrine, NLA 1, NSC 210733, proflavine, pyracrine phosphate, SDM, suronacrine, and tacrine.
In certain embodiments, repaglinide or an analog thereof can be used in the compositions, methods, and kits of the invention. Repaglinide is an antidiabetic agent which lowers glucose levels by closing potassium channels in the b-cell membrane. The structure of repaglinide is:
Analogs of repaglinide are described, for example, in U.S. Pat. No. 5,312,924 and can be represented as follows:
wherein R1 represents an unbranched alkyleneimino group with 4 to 6 carbon atoms optionally mono- or di-(alkyl of 1 to 3 carbon atoms)-substituted; R2 represents a hydrogen or halogen atom or a methyl or methoxy group; R3 represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a phenyl group optionally substituted by a halogen atom or a methyl or methoxy group, an alkyl group with 1 or 2 carbon atoms substituted by a hydroxy, alkoxy, alkanoyloxy, tetrahydrofuranyl, tetrahydropyranyl, cycloalkyl or phenyl group, in which the alkoxy part can contain from 1 to 3 carbon atoms, the alkanoyloxy part can contain 2 to 3 carbon atoms and the cycloalkyl part can contain 3 to 7 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 5 carbon atoms, a carboxy group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms; R4 represents a hydrogen atom, a methyl, ethyl or allyl group; and W represents a methyl, hydroxymethyl, formyl, carboxyl, alkoxycarbonyl, cyanomethyl, 2-cyano-ethyl, 2-cyano-ethenyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonylethenyl group, in which each alkoxy part can contain from 1 to 4 carbon atoms and can be substituted by a phenyl group; and when R3 is other then hydrogen and/or the radical R1 contains an optically active carbon atom, the enantiomeres and the diastereomeres thereof or their mixtures; when W is carboxyl, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the amino function in the R1-position.
In certain embodiments, a rifamycin such as rifabutin or an analog thereof can be used in the compositions, methods, and kits of the invention. Rifamycins are antibiotic compounds. The structure of rifabutin, an exemplary rifamycin, is:
Rifabutin analogs are described, for example, in U.S. Pat. No. 4,219,478, and have the general structure:
where R is selected from the group consisting of linear alkyl having 4 to 8 carbon atoms, branched alkyl having 4 to 8 carbon atoms, alkenyl having 3 or 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxyalkyl having 3 to 7 carbon atoms, alkyl-furyl having 5 or 6 carbon atoms, alkyl tetrahydrofuryl having 5 or 6 carbon atoms, alkanoyl having 5 or 6 carbon atoms, and monohaloalkanoyl having 2 to 6 carbon atoms, and Y is —H or —COCH3. Other rifamycins include 16,17-dihydro-17-hydroxyrifamycin S, 16,17-dihydrorifamycin S, 25-deacetoxy-25-hydroxyrifamycin S, 3-((dimethylhydrazono)methyl)rifamycin SV, 3-carbomethoxy rifamycin S, 3-formyl-25-desacetylrifamycin, 3-formylrifamycin SV, 31-homorifamycin W, 4-deoxy-3′-bromopyrido(1′,2′-1,2)imidazo[5,4-c]rifamycin S, AF 013, benzothiazole-rifamycin, C 27, CGP 27557, CGP 29861, CGP 4832, CGP 7040, FCE 22250, FCE 22807, halomicin B, kanglemycin A, KRM 1648, KRM 1657, KRM 1668, KRM 1671, protorifamycin I, R 761, reprimun, rifabutin derivatives (e.g., 17-(allylamino)-17-demethoxygeldanamycin, 25-desacetylrifabutin, and streptovaricin), rifamdin, rifamexil, rifamide, Rifampin or derivatives thereof (e.g., 18,19-dihydrorifampicin, 25-deacetylrifampicin, 25-desacetylrifapentine, CGP 43371, CGS 24565, dehydrorifampicin, DMB-rifampicin, rifampicin N-oxide, rifapentine, Rifaprim, Rifater, and rivicycline), rifamycin B, rifamycin L, rifamycin O, rifamycin P, rifamycin Q, rifamycin S, rifamycin SV, rifamycin Verde, rifaximin, rifazone-82, SPA-S 565, streptovaricin derivatives (e.g., damavaricin C, damavaricin Fc pentyl ether, protostreptovaricin, streptoval C, streptovaricin C, and streptovarone), tolypomycin Y, and tolypomycinone.
In certain embodiments, SB-202190 or an analog thereof can be used in the compositions, methods, and kits of the invention. SB-202190 is a pyridyl substituted imidazole with selective p38 MAP Kinase (MAPK) inhibitory activity. SB-202190 binds to the ATP binding site on active p38 MAPK. The structure of SB-202190 is:
Analogs of SB-202190 are described, for example, in U.S. Pat. No. 6,008,235 and have the structure:
wherein R1 is a mono- or di-substituted 4-quinolyl, 4-pyridyl, 1-imidazolyl, 1-benzimidazolyl, 4-pyrimidinyl wherein the substituent is independently selected from the group consisting of hydrogen, C1-4 alkyl, halo, O—C1-4 alkyl, S—C1-4 alkyl, or N(Ra)2; Ra is hydrogen, C1-6 alkyl, or Ra together with the nitrogen, may form a heterocyclic ring of 5 to 7 members, said ring optionally containing an additional heteroatom selected from the group consisting of oxygen, sulfur or nitrogen; R2 is mono- or di-substituted phenyl wherein the substituents are independently selected from the group consisting of hydrogen, halo, S(O)mR5, OR6, halo substituted C1-4 alkyl, C1-4 alkyl, or N(R12)2; R4 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, heterocyclic, heterocyclicalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl; R3 is (X)r-(Q)s-(Y)t; X is hydrogen, —(C(R10)2)n, —NR13, —O—, or S(O)m; r is a number having a value of 0 or 1; m is a number having a value of 0, 1 or 2; Q is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, heterocyclicalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; s is a number having a value of 0 or 1; Y is a substituent selected from the group consisting of hydrogen, C1-10 alkyl, halo-substituted C1-10 alkyl, halogen, —(C(R10)2)nOR8, —(C(R10)2)nNO2, —(C(R10)2)nS(O)m′R11, —(C(R10)2)nSR8, —(C(R10)2)nS(O)m′OR8, —(C(R10)2)nS(O)m′NR8R9, —Xa—P(Z)-(XaR13)2, —(C(R10)2)nNR8R9, —(C(R10)2)nCO2R8, —(C(R10)2)nOC(O)—R8, —(C(R10)2)nCN, —(C(R10)2)nCONR8R9, —(C(R10)2)nC(S)NR8R9, —(C(R10)2)nNR10C(O)R8, —(C(R10)2)nNR10C(S)R8, —(C(R10)2)nNR10C(Z)NR8R9, —(C(R10)2)nNR10S(O)mR11, —(C(R10)2)nNR10C(═NCN)—S—R11, —(C(R10)2)nNR10C(═NCN)—NR8R9, —(C(R10)2)nNR10C(O)C(O)—NR8R9, —(C(R10)2)nNR10C(O)C(O)—OR10, —(C(R10)2)nC(═NR10)—NR8R9, —(C(R10)2)n—C(═NR10)-ZR11, —(C(R10)2)n—OC(Z)-NR8R9, —(C(R10)2)nNR10S(O)mCF3, —(C(R10)2)nNR10C(O)OR10; t is an integer having a value of 0, 1, 2, or 3; Xa is independently —(C(R10)2)n, —NR8—, —O— or —S—; Z is oxygen or sulfur, m′ is an integer having a value of 1 or 2; n is an integer having a value of 0 to 10; R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, or N(R7)2; provided that when m is 1 or 2 then R5 is not hydrogen. R6 is hydrogen, C1-4 alkyl, halo substituted C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, or aryl; R7 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, aryl, or may form a heterocyclic ring of 5 to 7 members together with the nitrogen, said ring optionally containing an additional heteroatom selected from the group consisting of oxygen, sulfur or nitrogen; provided that when R5 is N(R7)2 then m is 1 or 2; R8 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, heterocyclic, heterocyclic alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl; R9 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl or R8 and R9 may together form a heterocyclic ring of 5 to 7 members together with the nitrogen, said ring optionally containing an additional heteroatom selected from the group consisting of oxygen, sulfur or nitrogen; R10 is hydrogen, or C1-4 alkyl; R11 is C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl; R12 is hydrogen, C1-4 alkyl, aryl, or may form a heterocyclic ring of 5 to 7 members together with the nitrogen; R13 is hydrogen, C1-10 alkyl, cycloalkyl, heterocylic, aryl, aryl alkyl, heteroaryl, or heteroaryl alkyl.
In certain embodiments, fusidic acid or a derivative thereof (e.g., sodium fusidate) can be used in the compositions, methods, and kits of the invention. The structure of fusidic acid is:
Fusidic acid derivatives are described in U.S. Pat. Nos. 3,352,854, 3,385,869, 3,376,324, 4,004,004, 4,060,606, 4,162,259, 4,315,004, 4,119,717, 6,103,884, and 6,593,319. Derivative include 11-monoketofusidic acid, 16-O-deacetylfusidic acid, 16-O-deacetylfusidic acid lactone, 3,11-diketofusidic acid, diethanolamine fusidate, helvolic acid, and tauro-24,25-dihydrofusidate.
In certain embodiments, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) or an analog thereof can be used in the compositions, methods, and kits of the invention. TOFA is an inhibitor of acetyl-CoA carboxylase. The structure of TOFA is:
Analogs of TOFA are described, for example, in U.S. Pat. No. 4,382,143 and have the general structure:
wherein X is selected from the group consisting of hydrogen, C3-C8 cycloalkyl, and substituted or unsubstituted aryl; A is a divalent radical selected from the group consisting of branched or unbranched C6-C19 alkylene, alkenylene, and alkynylene; Y is a 5- or 6-membered heteroaryl ring containing one or more nitrogen, sulfur, or oxygen atoms and optionally unsubstituted or substituted with one fluoro; and Z is selected from the group consisting of hydrogen, hydroxy, loweralkoxy, loweralkoxyloweralkoxy, diloweralkylaminoloweralkoxy, (mono- or polyhydroxy)loweralkoxy, (mono- or polycarboxy)loweralkoxy, (mono- or polycarboxy)hydroxyloweralkoxy, allyloxy, 2,3-epoxypropoxy, substituted or unsubstituted-(phenoxy, benzyloxy, or 3-pyridyloxy), pyridylmethoxy, tetrahydropyranyloxy, (mono- or polyhydroxy)alkylamino, allylamino, propargylamino, 2-sulfoethylamino, (mono- or polycarboxyl)loweralkylamino, loweralkanoylamino, (substituted or unsubstituted)aroylamino, loweralkanesulfonylamino, (substituted or unsubstituted)arenesulfonylamino, loweralkanylhydrazino, hydroxylamino, polymethyleneimino, and (4-carboxy- or 4-carboethoxy)thiazolidino; and the pharmaceutically acceptable acid-addition and cationic salts thereof.
In certain embodiments, tolterodine or an analog thereof can be used in the compositions, methods, and kits of the invention. Tolterodine is a competitive muscarinic receptor antagonist. The pharmacologically active agent is the 5-hydroxymethyl derivative. Cholinergic muscarinic receptors mediate urinary bladder contraction. Tolterodine is thus used to treat urinary incontinence. The structure of tolterodine is:
Analogs of tolterodine are described, for example, in U.S. Pat. No. 5,382,600 and have the general structure:
wherein R1 signifies hydrogen or methyl, R2, R3, and R4 independently signify hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphanoyl or halogen, and X represents a tertiary amino group (—NR5R6) wherein R5 and R6 signify non-aromatic hydrocarbol groups, which may be the same or different and which together contain at least three carbon atoms, preferably at least four or five carbon atoms, and where R5 and R6 may form a ring together with the amine nitrogen, said ring preferably having no other hetero atom that the amine nitrogen.
In certain embodiments, toremifene or an analog thereof can be used in the compositions, methods, and kits of the invention. Toremifene is antiestrogen and antineoplastic agent. The structure of toremifene is:
Analogs of toremifene are described, for example, in U.S. Pat. No. 4,696,949 have the general structure:
or the structure:
wherein n is 0 to 4, R1 and R2, which can be the same or different are H, OH, an alkoxy group of 1 to 4 carbon atoms, benzyloxy or methoxymethoxy; R3 is H, OH, halogen, alkoxy of 1 to 4 carbon atoms, benzyloxy, methoxymethoxy, 2,3-dihydroxypropoxy or —O(CH2)mCH2NR6R7 wherein m is 1 or 2, R6 and R7, which can be the same or different, are H or an alkyl group of 1 to 4 carbon atoms, or —NR6R7 can form an N-containing three-, four-, five- or six-membered heterocyclic ring; R4 is OH, F, Cl, Br, I, mesyloxy, tosyloxy, alkylcarbonyloxy of 1 to 4 carbon atoms, formyloxy or CH2R4 is replaced by CHO; R5 is H or OH; or R4 and R5 together form an —O— bridge between the carbon atoms to which they are attached.
In certain embodiments, trequinsin or an analog thereof can be used in the compositions, methods, and kits of the invention. Trequinsin is a platelet aggregation inhibitor. The structure of trequinsin is:
Trequinsin analogs are described, for example, in U.S. Pat. No. 5,141,936 and have the general structure:
in which R1, R4 and R5, which may be identical or different, may be hydrogen, hydroxyl, lower alkoxy, dialkylphosphinylalkoxy acyloxy or halogen, where two adjacent groups together may denote a methylenedioxy or ethylenedioxy group, and R2 and R3, which may be identical or different, may be hydrogen, hydroxyl, lower alkoxy, amino, alkylamino, dialkylamino, arylamino, alkyl, amino or alkyl substituted by a 5- or 6-membered carbon ring which may contain up to 3 heteroatoms from the group comprising N, O or S, cycloalkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl, haloalkyl, dialkylaminoalkyl, aralkyl, acyl and, optionally substituted, aryl, where aryl is in each case taken to mean an aromatic hydrocarbon having up to 10 carbon atoms, and R2 denotes an electron pair if R6 denotes one of the radicals indicated below and R2 and R3 together with the nitrogen atom to which they are bonded may denote a part of an optionally substituted nitrogen heterocycle which may contain a further nitrogen atom or an oxygen atom, and R6 stands for hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl, haloalkyl, dialkylaminoalkyl, aralkyl, heterocyclic-substituted alkyl, dialkylphosphinylalkyl, acyl and optionally substituted aryl, and also stands for an electron pair if R2 denotes one of the radicals indicated above, and their acid salts and quaternary ammonium salts.
In certain embodiments, vinorelbine or an analog thereof can be used in the compositions, methods, and kits of the invention. Vinorelbine is an antineoplastic agent that functions by binding microtubular proteins of the mitotic spindle, thereby inhibiting mitosis. The structure of vinorelbine is:
Analogs of vinorelbine are described, for example, in U.S. Pat. No. 4,307,100 and have the general structure:
wherein R′1 represents a hydrogen atom or an alkoxy, acyl, formyl or haloacyl radical; R12 represents a hydrogen atom or an alkyl radical; R′3 and R″3 which may be the same or different each represents a hydrogen atom or a hydroxyl radical or an alkanoyloxyl radical or together represent a carbonyl group, or R′3 and R′5 together represent an epoxy bridge or a double bond; R14 represent a hydrogen atom or an alkyloxycarbonyl, hydroxymethyl, alkanoyloxymethyl or acetamido radical; R′5 and R″5 which may be the same or different each represents a hydrogen atom or a hydroxyl, alkanoyloxyl, ethyl or 2-hydroxyethyl radical; R′6 represents a hydrogen atom or an ethyl, 2-hydroxyethyl or acetyl radical; R1 represents a hydrogen atom or an alkyl, formyl, or acyl radical; R2 represents a hydrogen atom or an alkoxy radical; R3 represents a hydrogen atom or a hydroxyl or alkanoyloxyl radical, or R3 and R4 together represent an epoxy bridge or a double bond; R4 represents a hydrogen atom or a hydroxyl or alkanoyloxyl radical, or R4 and R5 together represent an epoxy bridge; R6 represents an alkyloxycarbonyl, hydrazido, acetamido, hydroxymethyl or alkanyloxymethyl radical; and R5 and R7 represent a hydrogen atom or a hydroxyl or alkanoyloxyl radical. Vinorelbine is a member of the vinblastine compounds, which include 16-O-acetylvindoline, 3′,4′-anhydrovinblastine, 4′-deoxyvinblastine, 4-desacetylvinblastine, 4-desacetylvinblastine hydrazide, 4-O-deacetylvinblastine-3-oic acid, bis(N-ethylidene vindesine)disulfide, catharanthamine, catharinine, desacetylnavelbine, KAR 2, LY 266070, NAPAVIN, ViFuP protocol, vincathicine, vindoline, vindolinine, vinepidine, vinflunine, vinleucinol, vinorelbine, vintriptol, and vintriptol acid.
In certain embodiments, wedelolactone or an analog thereof can be used in the compositions, methods, and kits of the invention. Wedelolactone is IKKα and IKKβ kinase inhibitor and a IkB-α kinase inhibitor. The structure of wedelolactone is:
Wedelolactone is a member of the coumarins. Other coumarins include 11,12-dihydroxy-5-methylcoumestan, 11-desacetoxywortmannin, 2″,3″-dihydrogeiparvarin, 2-amino-3-(7-methoxy-4-coumaryl)propionic acid, 2-nitro-6H-dibenzo(b,d)pyran-6-one, 3′-angeloyloxy-4′-acetoxy-3′,4′-dihydroseselin, 3,4-dichloroisocoumarin, 3,4-dihydro-3,4-dibromo-6-bromomethylcoumarin, 3,4-dihydro-3-benzyl-6-chloromethylcoumarin, 3,4-dihydrocoumarin, 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one, 3-(2-(N,N-diethyl-N-methylammonium)ethyl)-7-methoxy-4-methylcoumarin, 3-acetylcoumarin, 3-carbethoxypyranocoumarin, 3-carboxylic acid-picumast, 3-cyano-7-ethoxycoumarin, 3-cyano-7-hydroxycoumarin, 3-hydroxy-(28-4-coumaroyloxy)lup-20(29)-en-27-oic acid, 3-hydroxymethyl-picumast, 3-nitro-6H-dibenzo(b,d)pyran-6-one, 3-phenyl-5,6-benzocoumarin, 3H-naphtho(2,1-b)pyran-3-one, 4′-hydroxyasperentin, 4-(diazomethyl)-7-(diethylamino)coumarin, 4-acetylisocoumarin, 4-bromomethyl-6,7-dimethoxycoumarin, 4-bromomethyl-6,7-methylenedioxycoumarin, 4-bromomethyl-7-acetoxycoumarin, 4-chloro-3-ethoxy-7-guanidinoisocoumarin, 4-methyl-7-diethylaminocoumarin, 4-methyl-7-ethoxycoumarin, 4-methyl-N-ethyl pyrrolo[3,2-g]coumarin, 4-nitro-6H-dibenzo(b,d)pyran-6-one, 4-phenyl-3-isocoumarinic acid, 4-phenyl-3-isocoumarinic acid allylamide, 4-trifluoromethylcoumarin phosphate, 5,6-benzocoumarin-3-carboxylic acid ethyl ester, 5,7-dihydroxy-4-imino-2-oxochroman, 5,7-dimethoxycoumarin, 5-iodo-6-amino-1,2-benzopyrone, 5-methyl-8-hydroxycoumarin, 5-methylcoumarin-4-cellobioside, 5-methylcoumarin-4-gentiobioside, 5H-(2)benzopyrano(3,4-g)(1,4)benzodioxin-5-one, 6′-feruloylnodakenin, 6,7-(4-methyl)coumaro-(2.2.2)cryptand, 6,8-dimethoxy-3-methyl-3,4-dihydroisocoumarin, 6-(7-beta-galactosylcoumarin-3-carboxamido)hexylamine, 6-amino-1,2-benzopyrone, 6-amino-4,4,5,7,8-pentamethyldihydrocoumarin, 6-chloro-3,4-dihydroxy-2H-1-benzopyran-2-one, 6-cyano-7-hydroxy-4,8-dimethylcoumarin, 6-hydroxymellein, 6-methoxy-8-hydroxy-3-methyl-3,4-dihydroisocoumarin, 6-methylcoumarin, 6-methylthionecoumarin, 6-nitroso-1,2-benzopyrone, 7,8-dimethoxycoumarin, 7-((N-tosylphenylalanyl)amino)-4-chloro-3-methoxyisocoumarin, 7-(alpha-glutamyl)-4-methylcoumarylamide, 7-(gamma-glutamyl)-4-methylcoumarylamide, 7-(N-benzyloxycarbonyl-beta-benzylaspartyl-prolyl-leucyl)amino-4-methylcoumarin, 7-(N-benzyloxycarbonylglycyl-glycyl-leucyl)amino-4-methylcoumarin, 7-amino-3-(2-bromoethoxy)-4-chloroisocoumarin, 7-amino-4-chloro-3-(3-isothiureidopropoxy)isocoumarin, 7-amino-4-methylcoumarin, 7-amino-4-methylcoumarin-3-acetic acid, 7-amino-4-trifluoromethylcoumarin, 7-aminocoumarin, 7-aminocoumarin-4-methanesulfonic acid, 7-anilino-4-methylcoumarin-3-acetic acid, 7-anilinocoumarin-4-acetic acid, 7-benzylcysteinyl-4-methylcoumarinylamide, 7-benzyloxy-4-trifluoromethylcoumarin, 7-beta-galactopyranosyl-oxycoumarin-4-acetic acid methyl ester, 7-beta-galactopyranosyloxycoumarin-4-acetic acid, 7-diethylamino-3-(4′-isothiocyanatophenyl)-4-methylcoumarin, 7-diethylaminocoumarin-3-carbohydrazide, 7-diethylaminocoumarin-3-carboxylic acid, 7-dimethylamino-4-methylcoumarin, 7-ethenyloxycoumarin, 7-ethoxy-4-trifluoromethylcoumarin, 7-ethoxycoumarin, 7-glycidoxycoumarin, 7-hydroxy-4-phenyl-3-(4-hydroxyphenyl)coumarin, 7-hydroxy-4-trifluoromethylcoumarin, 7-hydroxycoumarin-4-acetic acid, 7-leucylamido-4-methylcoumarin, 7-lysylalanyl-4-methylcoumarinamide, 7-succinylglycyl-prolyl-4-methylcoumaryl-7-amide, 8-(3-(4-phenyl-1-piperazinyl)propoxy)-7-methoxycoumarin, 8-hydroxy-4-methyl-3,4-dihydroxycoumarin, 8-hydroxycoumarin, 9-(3-diethylaminopropyloxy)-3H-naphtho(2,1-b)pyran-3-one, A 1062, Ac-aspartyl-glutamyl-valyl-aspartyl-aminomethylcoumarin, acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin, agrimonolide-6-O-glucopyranoside, AI 77B, alanyl-alanyl-phenylalanyl-7-amino-4-methylcoumarin, amicoumacin A, anomalin, arginine 4-methyl-7-coumarylamide, arnottin I, aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin, aurapten, baciphelacin, benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide, benzyloxycarbonylarginyl-arginine 4-methyloumarin-7-ylamide, bergaptol-O-glucopyranoside, Boc-leucyl-seryl-threonyl-arginine-4-methylcoumaryl-7-amide, byakangelicol, calanolide A, calanolide B, calophyllolid, carbobenzoxycoumarin, Cassella 7657, CGP 13143, chlorobiocic acid, Chromonar, CI 923, cladosporin, clausarin, clausindine, clausmarin, columbianadin, cordatolide A, coumachlor, coumarin, coumarin 3,4-epoxide, coumarin-3-carboxylic acid, coumarin-3-carboxylic acid succinimidyl ester, coumermycins, coumestrol, coumetarol, crenulatin, cytogenin, daphnoretin, dehydroindicolactone, demethylwedelolactone, dicurin, erythrocentaurin, Esculin, esuprone, F 1375, ferujol, ferulenol, folescutol, fraxetin, fraxin, galbanic acid, geiparvarin, gerberinside, glaupadiol, glisoflavone, glutaryl-alanyl-alanyl-phenylalanyl-amidomethylcoumarin, glutaryl-glycyl-arginine-4-methylcoumaryl-7-amide, glycyl-7-amino-4-methylcoumarin-3-acetic acid, glycylprolyl-4-methylcoumaryl-7-amide, GU 7, GUT-70, 4-hydroxycoumarins, hymecromone O,O-diethyl phosphorothioate, iliparcil, inophyllum B, isobyakangelicin angelate, isofraxidin, isorhamnetin 3-O-beta-(4′″-4-coumaroyl-alpha-rhamnosyl(1-6)galactoside), kaempferol-2,4-dicoumaroyl-3-O-glucoside, licopyranocoumarin, LL-N 313, mammein, mammeisin, maoyancaosu, marmesin, marmin, melilot, moellendorffiline, morocromen, moxicoumone, murayalactone, N-(2-(1-maleimidyl)ethyl)-7-(diethylamino)coumarin-3-carboxamide, N-(4-(7-(diethylamino)-4-methylcoumarin-3-yl))maleimide, N-(4-(7-diethylamino 4-methylcoumarin-3-yl)phenyl)iodoacetamide, N-(4-(7-diethylamino-4-methylcoumarin-3-yl)phenyl)maleimide, N-acetyl-alanyl-alanyl-prolyl-alanyl-amidomethylcoumarin, N-benzyloxycarbonylalanyl-arginyl-arginyl-4-trifluoromethyl-7-coumarylamide, N-benzyloxycarbonylglycyl-glycyl-arginine-4-methylcoumarinyl-7-amide, N-carbobenzoxyglycyl-prolyl-4-methylcoumarinyl amide, N-salicylidene-3-aminocoumarin, N-succinimidyl-7-dimethylaminocoumarin-4-acetate, necatorin, neoglycyrol, nitrofarin, nordentatin, notopterol, Ochratoxins, oosponol, oroselol, osthenol, osthol, oxamarine, pargyropyranone, PD 118717, peuarenine, peujaponiside, phebalosin, phellopterin, phyllodulcin, picumast, ponfolin, praeruptorin C, praeruptorin E, Psoralens, psoralidin, pterybinthinone, pteryxin, pyranocoumarins, qianhucoumarin A, qianhucoumarin B, qianhucoumarin C, reticulol, Ro7-AMCA, rubradiric acid A, rubradiric acid B, rubricauloside, sclerin, scoparone, scopolin, serine-7-amino-4-methylcoumarin carbamate, shijiaocaolactone A, soulattrolide, SP500263, succinyl-isoleucyl-isoleucyl-tryptophyl-methylcoumarinamide, succinyl-leucyl-leucyl-valyl-tyrosyl-methylcoumarinamide, succinyl-leucyl-tyrosyl-4-methyl-7-coumarylamide, succinylalanylalanyl-prolyl-phenylalanine-4-methylcoumaryl-7-amide, succinylglycyl-prolyl-leucyl-glycyl-prolyl-4-methylcoumaryl-7-amide, suksdorfin, sulfosuccinimidyl 7-amino-4-methylcoumarin-3-acetate, surangin B, tert-butyloxycarbonyl-leucyl-glycyl-arginine-4-trifluoromethylcoumarin-7-amide, tert-butyloxycarbonyl-norleucyl-glutaminyl-leucyl-glycyl-arginine-7-amino-4-methylcoumarin, tertiary butyloxycarbonylvalyl-leucyl-lysinyl-4-methylcoumarin-7-amide, tertiary-butyloxycarbonyl-isoleucyl-glutamyl-glycyl-arginyl-7-amino-4-methylcoumarin, tertiary-butyloxycarbonyl-phenylalanyl-seryl-arginyl-4-methylcoumarin-7-amide, tertiary-butyloxycarbonyl-valyl-prolyl-arginyl-7-amino-4-methylcoumarin, theo-esberiven, thunberginol A, thunberginol B, thunberginol D, tioclomarol, toddalolactone, tosyl-glycyl-prolyl-arginyl-4-methylcoumaryl-7-amide, ubiquitin C-terminal 7-amido-4-methylcoumarin, Umbelliferones, valyl-leucyl-lysyl-4-aminomethylcoumarin, valyl-leucyl-lysyl-7-amino-4-methylcoumarin, Venalot, W10294A, WS-5995 A, xanthalin, and xanthyletine.
In certain embodiments, telaprevir or an analog thereof can be used in the compositions, methods, and kits of the invention. Telaprevir (VX-950) is a hepatitis C therapy. The structure of telaprevir is:
Analogs of telaprevir are described, for example, in U.S. Pat. Application Publication No. 2005/0197299 and can be represented as follows:
wherein R0 is a bond or difluoromethylene; R1 is hydrogen, optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group; R2 and R9 are each independently optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group; R3, R5, and R7 are each independently (optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group) (optionally substituted methylene or optionally substituted ethylene), optionally substituted (1,1- or 1,2-)cycloalkylene or optionally substituted (1,1- or 1,2-)heterocyclylene; R4, R6, R8 and R10 are each independently hydrogen or optionally substituted aliphatic group;
is substituted monocyclic azaheterocyclyl or optionally substituted multicyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R9-L-N(R8)—R7—C(O)nN(R6)—R5—C(O)—N moiety and to which the —C(O)—N(R4)—R3—C(O)—C(O)NR2R1 moiety is attached; L is —C(O)—, —OC(O)—, —NR10C(O)—, —S(O)2—, or —NR10S(O)2—; and n is 0 or 1, or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug, provided when
is substituted
then L is —OC(O)— and R9 is optionally substituted aliphatic, or at least one of R3, R5 and R7 is (optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group) (optionally substituted ethanediyl), or R4 is optionally substituted aliphatic.
In certain embodiments, HCV-796 or an analog thereof can be used in the compositions, methods, and kits of the invention. HCV-796 is a non-nucleoside polymerase inhibitor. The structure of HCV-796 is:
Analogs of HCV-796 are described for example, in U.S. Pat. No. 7,265,152 and have the general structure:
wherein R1 represents a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano; R2 represents a radical selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, hydroxy, cycloalkyl, cycloalkyloxy, polyfluoroalkyl, polyfluoroalkoxy, halogen, amino, monoalkylamino, dialkylamino, cyano, a substituted or unsubstituted benzyloxy group, and a substituted or unsubstituted heterocyclic radical; R3 represents a radical selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, amino, a substituted or unsubstituted monoalkylamino, dialkylamino, cyano, amido, alkoxyamido, a substituted or unsubstituted heteroarylamino, acetylsulfonylamino, ureido, carboxamide, sulfonamide, a substituted sulfonamide, a substituted or unsubstituted heterocyclosulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstituted heterocyclic radical, and —O(CH2)—C(═O)—R7; R4 represents a radical selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy; R5 represents a radical selected from the group consisting of an alkyl (C1-C6) group, cycloalkyl, and cycloalkylalkyl; R6 represents a radical selected from the group consisting of a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; R7 represents a radical selected from the group consisting of dialkylamino, a substituted or unsubstituted arylamino, a substituted or unsubstituted heteroarylamino, and a substituted or unsubstituted aryl group, said monoalkylamino substituents being one or more radical(s) independently selected from the group consisting of cycloalkyl, hydroxy, alkoxy, and a substituted or unsubstituted heterocyclic radical; said arylamino substituents and said heteroarylamino substituents being one or more radical(s) independently selected from an alkyl group and an alkoxycarbonyl; said sulfonamide substituents being one or more radical(s) independently selected from the group consisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamide, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclosulfonyl substituents being one or more radical(s) independently selected from the group consisting of alkoxy and hydroxy; said alkyl radical substituents and said alkoxy group substituents being one or more radical(s) independently selected from the group consisting of alkenyl, amino, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, hydroxy, carboxyl, halogen, cyano, polyfluoroalkyl, polyfluoroalkoxy, sulfonamide, carboxamide, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, 2,2-dimethyl-4-oxo-4H-benzo[1,3]dioxinyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclic radical substituents being one or more radical(s) independently selected from the group consisting of alkyl, amino, amido, monoalkylamino, cycloalkyl-alkylamino, dialkylamino, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, carboxyl, carboxamide, halogen, haloalkyl, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, mercapto, oxo, a substituted or unsubstituted aryl group, arylalkyl, and a substituted or unsubstituted heteroaryl group; said heteroaryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, cycloalkyl, carboxyl, carboxamide, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, mercapto, and oxo; said benzyloxy group substituents being one or more radical(s) independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl; said aryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, acetylenyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amino, monoalkylamino, dialkylamino, aminoalkyl, alkoxyalkoxy, amido, amidoalkyl, carboxyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, and a heterocyclic radical; and pharmaceutically acceptable salts thereof;
In certain embodiments, merimepodib or an analog thereof can be used in the compositions, methods, and kits of the invention. Merimepodib is an inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH) and is used to treat HCV. The structure of merimepodib is:
Analogs of merimepodib are described for example, in U.S. Pat. No. 6,541,496 and have the general structure:
wherein A is selected from (C1-C6)-straight or branched alkyl, or (C2-C6)-straight or branched alkenyl or alkynyl; and A optionally comprises up to 2 substituents, wherein the first of said substituents, if present, is selected from R1 or R3, and the second of said substituents, if present, is R1; B is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, O, or S and selected from the formulae:
wherein each X is the number of hydrogen atoms necessary to complete proper valence; and B optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from R1, R2, R4 or R5, the second of said substituents, if present, is selected from R1 or R4, and the third of said substituents, if present, is R1; and D is selected from C(O), C(S), or S(O)2; wherein each R1 is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R6 or (CH2)n—Y; wherein n is 0, 1 or 2; and Y is selected from halogen, CN, NO2, CF3, OCF3, OH, SR6, S(O)R6, SO2R6, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6; each R2 is independently selected from (C1-C4)-straight or branched alkyl, or (C2-C4)-straight or branched alkenyl or alkynyl; and each R2 optionally comprises up to 2 substituents, wherein the first of said substituents, if present, is selected from R1, R4 and R5, and the second of said substituents, if present, is R1; R3 is selected from a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to any of said N, O, or S heteroatoms is optionally substituted with C(O); and each R3 optionally comprises up to 3 substituents, wherein the first of said substituents, if present, is selected from R1, R2, R4 or R5, the second of said substituents, if present, is selected from R1 or R4, and the third of said substituents, if present, is R1; each R4 is independently selected from OR5, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OP(O)(OR6)2, SR6, SR5, S(O)R6, S(O)R5, SO2R6, SO2R5, SO2N(R6)2, SO2NR5R6, SO3R6, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, NC(O)C(O)R6, NC(O)C(O)R5, NC(O)C(O)OR6, NC(O)C(O)N(R6)2, C(O)N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R5, C(NOR6)R6, C(NOR6)R5, N(R6)2, NR6C(O)R6, NR6C(O)R6, NR6C(O)R5, NR6C(O)OR6, NR6C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6SO2R6, NR6SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, N(OR6)R6, N(OR6)R5, P(O)(OR6)N(R6)2, and P(O)(OR6)2; each R5 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, O or S maybe substituted with C(O); and each R5 optionally comprises up to 3 substituents, each of which, if present, is R1; each R6 is independently selected from H, (C1-C4)-straight or branched alkyl, or (C2-C4) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7; R7 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, O or S maybe substituted with C(O); and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C4)-straight or branched alkyl, (C2-C4) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)n-Z; wherein n is 0, 1 or 2; and Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C4)-alkyl, SO(C1-C4)-alkyl, SO2(C1-C4)-alkyl, NH2, NH(C1-C4)-alkyl, N((C1-C4)-alkyl)2, N((C1-C4)-alkyl)R8, COOH, C(O)O(C1-C4)-alkyl or O(C1-C4)-alkyl; and R8 is an amino protecting group; and wherein any carbon atom in any A, R2 or R6 is optionally replaced by O, S, SO, SO2, NH, or N(C1-C4)-alkyl.
In certain embodiments, valopicitabine (NM-283) or an analog thereof can be used in the compositions, methods, and kits of the invention. Valopicitabine is a hepatitis C therapy that acts as a polymerase inhibitor. Valopicitabine is an orally available prodrug of 2′-C-methylcytidine. The structure of valopicitabine is:
Analogs of valopicitabine are described, for example, in U.S. Pat. Application Publication No. 2007/0015905, which is hereby incorporated by reference.
In certain embodiments, boceprevir (SCH 503034) or an analog thereof can be used in the compositions, methods, and kits of the invention. Boceprevir is a hepatitis C therapy that acts as a inhibitor of the NS3-serine protease. The structure of boceprevir is:
Analogs of boceprevir are described, for example, in U.S. Pat. Application Publication No. 2004/0254117 and have the general structure:
wherein Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y may be optionally substituted with X1 or X12; X11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X11 may be additionally optionally substituted with X12; X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X12; R1 is COR5 or B(OR)2, wherein R5 is H, OH, OR8, NR9R10, CF3, C2F5, C3F7, CF2R6, R6, or COR7 wherein R7 is H, OH, OR8, CHR9R10, or NR9R10, wherein R6, R8, R9 and R10 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R1′)]pCOOR11, [CH(R1′)]pCONR12R13, [CH(R1′)]pSO2R11, [CH(R1′)]pCOR11, [CH(R1′)]pCH(OH)R11, CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′)CON—R12R13, CH(R1′)CONHCH(R2′)R11, CH(R1′)CONHCH(R2′)CONHCH(R3′)COOR11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)COOR11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONR12R.-sup.13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH—(R5′)COOR11 and CH(R1′)CONHCH(R2′)CONHCH(R3′)CON—HCH(R4)CONHCH(R5′)CONR12R13, wherein R1′, R2′, R3′, R4′, R5′, R11, R12, R13, and R′ are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; Z is selected from O, N, CH or CR; W may be present or absent, and if W is present, W is selected from C═O, C═S, C(═N—CN), or SO2; Q may be present or absent, and when Q is present, Q is CH, N, P, (CH2)p, (CHR)p, (CRR′)p, O, NR, S, or SO2; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L; A is O, CH2, (CHR)p, (CHR—CHR′)p, (CRR′)p, NR, S, SO2 or a bond; E is CH, N, CR, or a double bond towards A, L or G; G may be present or absent, and when G is present, G is (CH2)p, (CHR)p, or (CRR′)p; and when G is absent, J is present and E is directly connected to the carbon atom in Formula I as G is linked to; J maybe present or absent, and when J is present, J is (CH2)p, (CHR)p, or (CRR′)p, SO2, NH, NR or O; and when J is absent, G is present and E is directly linked to N shown in Formula I as linked to J; L may be present or absent, and when L is present, L is CH, CR, O, S or NR; and when L is absent, then M may be present or absent; and if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E; M may be present or absent, and when M is present, M is O, NR, S, SO2, (CH2)p, (CHR)p(CHR—CHR′)p, or (CRR′)p; p is a number from 0 to 6; and R, R′, R2, R3 and R4 are independently selected from the group consisting of H; C1-C10 alkyl; C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate; further wherein said unit N—C-G-E-L-J-N represents a five-membered or six-membered cyclic ring structure with the proviso that when said unit N—C-G-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, G, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring.
In certain embodiments, an interferon or an analog thereof can be used in the compositions, methods, and kits of the invention. Intefereons includes interferon-α, interferon alfa-2a, interferon alfa-2b, interfereon alfa-2c, interferon alfacon-1, interferon alfa-n1, interferon alfa-n3, interferon-β, interferon β-1a, interferon β-1b, interferon-γ, interferon γ-1a, interferon γ-1b, and pegylated forms thereof.
Albendazole analogs are described in U.S. Pat. Nos. 5,468,765, 5,432,187, 4,299,837, 4,156,006, and 4,136,174. Amitraz analogs are described in U.S. Pat. No. 3,781,355. Betaxolol analogs are described in U.S. Pat. No. 4,252,984. Bromhexine analogs are described in U.S. Pat. Nos. 3,408,446 and 4,191,780 and Belgian patent BE625002. Bromocriptine analogs are described in U.S. Pat. No. 4,145,549. Capsaicin analogs are described in U.S. Pat. No. 4,812,446. Carbaryl analogs are described in U.S. Pat. No. 2,903,478. Chloroquine analogs are described in U.S. Pat. No. 2,233,970. Cladribine (2-chloro-2′-deoxyadenosine) analogs are described in U.S. Pat. Nos. 4,760,137, 5,208,327, 6,252,061, 6,596,858, and 6,884,880. Clomiphene analogs are described in U.S. Pat. No. 2,914,563. Cyclocytidine analogs are described in U.S. Pat. No. 3,463,850. Dibucaine analogs are described in U.S. Pat. No. 1,825,623. Dicyclomine analogs are described in U.S. Pat. No. 2,474,796. Dilazep analogs are described in U.S. Pat. No. 3,532,685. Diphenidol analogs are described in U.S. Pat. No. 2,411,664. Donepezil analogs are described in U.S. Pat. No. 4,895,841. Emetine analogs are described in U.S. Pat. No. 3,102,118. Exemestane analogs are described in U.S. Pat. No. 4,808,616. Ezetimibe analogs are described in U.S. Pat. No. 5,767,115. Fenbendazole analogs are described in U.S. Pat. No. 3,954,791. Fenretinide analogs are described in U.S. Pat. No. 4,190,594. Fenvalerate analogs are described in U.S. Pat. No. 3,996,244. Flubendazole analogs are described in U.S. Pat. No. 3,657,267 and German patent DE2029637. Fludarabine analogs are described in U.S. Pat. No. 5,034,518. Fluorouracil analogs are described in U.S. Pat. Nos. 2,802,005, 2,885,396, 4,092,313, and 4,080,455. Ifenprodil analogs are described in U.S. Pat. No. 3,509,164. Indocyanine green analogs are described in U.S. Pat. No. 2,895,955. Iophenoxic acid analogs are described in British patent GB726987. Isosulfan blue analogs include sulfan blue. Mycophenolic acid analogs are described in U.S. Pat. Nos. 3,705,894, 3,903,071, 4,686,234, 4,725,622, 4,727,069, 4,753,935, 4,786,637, 4,808,592, 4,861,776, 4,868,153, 4,948,793, 4,952,579, 4,959,387, 4,992,467, 5,247,083, 5,380,879, 5,441,953, 5,444,072, 5,493,030, 5,538,969, 5,512,568, 5,525,602, 5,554,612, 5,633,279, 6,399,773, 6,420,403, 6,624,184, 6,916,809, 6,919,335, 7,053,111, and U.S. patent application Ser. No. 07/927,260. Narasin analogs are described in U.S. Pat. Nos. 4,035,481, 4,038,384, 4,141,907, 4,174,404, 4,204,039, and 5,541,224. Oxeladin analogs are described in U.S. Pat. No. 2,885,404. Oxfendazole analogs are described in U.S. Pat. No. 3,929,821. Oxibendazole analogs are described in U.S. Pat. No. 3,574,845. Perospirone analogs are described in U.S. Pat. No. 4,745,117. Picotamide analogs are described in French patent FR2100850. Pramoxine analogs are described in U.S. Pat. No. 2,870,151. Quinacrine analogs are described in U.S. Pat. Nos. 2,113,357, 1,782,727, and 1,889,704. Repaglinide analogs are described in International Application Publication No. WO 93/00337. Rifaximin analogs are described in U.S. Pat. No. 4,341,785. Silver sulfadiazine analogs are described in U.S. Pat. Nos. 2,407,966 2,410,793. Terconazole analogs are described in U.S. Pat. Nos. 4,144,346 and 4,223,036. Tioxolone analogs are described in U.S. Pat. Nos. 2,332,418 and 2,886,488. Tirapazamine analogs are described in U.S. Pat. No. 3,868,371. Tiratricol analogs are described in British patent Nos. GB803149 GB805761. Toremifene analogs are described in U.S. Pat. No. 4,696,949. Vincristine analogs are described in U.S. Pat. No. 4,144,237. Zafirlukast analogs are described in U.S. Pat. No. 4,859,692.
If desired, the agents used in any of the combinations described herein may be covalently attached to one another to form a conjugate of formula I.
(A)-(L)-(B) (I)
In formula I, (A) is a drug listed on Table 1, Table 2, or Table 3 covalently tethered via a linker (L) to (B), a second drug listed on Table 1, Table 2, Table 3, Table 4, or Table 5.
Conjugates of the invention can be administered to a subject by any route and for the treatment of viral hepatitis (e.g., those described herein).
The conjugates of the invention can be prodrugs, releasing drug (A) and drug (B) upon, for example, cleavage of the conjugate by intracellular and extracellular enzymes (e.g., amidases, esterases, and phosphatases). The conjugates of the invention can also be designed to largely remain intact in vivo, resisting cleavage by intracellular and extracellular enzymes. The degradation of the conjugate in vivo can be controlled by the design of linker (L) and the covalent bonds formed with drug (A) and drug (B) during the synthesis of the conjugate.
Conjugates can be prepared using techniques familiar to those skilled in the art. For example, the conjugates can be prepared using the methods disclosed in G. Hermanson, Bioconjugate Techniques, Academic Press, Inc., 1996. The synthesis of conjugates may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of drug (A), the linker, and/or drug (B). For example, commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m-nitrophenyl. Other commonly used protecting groups for amines include amides, such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert-butylsulfonyl amides. Examples of commonly used protecting groups for carboxyls include esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl, 2-(trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho-esters, and halo-esters. Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy-trityls), and silyl ethers. Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls. In addition, sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides). Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule. The conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd Ed.), John Wiley & Sons, 1991 and P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below.
The linker component of the invention is, at its simplest, a bond between drug (A) and drug (B), but typically provides a linear, cyclic, or branched molecular skeleton having pendant groups covalently linking drug (A) to drug (B).
Thus, linking of drug (A) to drug (B) is achieved by covalent means, involving bond formation with one or more functional groups located on drug (A) and drug (B). Examples of chemically reactive functional groups which may be employed for this purpose include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups.
The covalent linking of drug (A) and drug (B) may be effected using a linker which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B). For example, an amine group of drug (A) may react with a carboxyl group of the linker, or an activated derivative thereof, resulting in the formation of an amide linking the two.
Examples of moieties capable of reaction with sulfhydryl groups include α-haloacetyl compounds of the type XCH2CO— (where X=Br, Cl, or I), which show particular reactivity for sulfhydryl groups, but which can also be used to modify imidazolyl, thioether, phenol, and amino groups as described by Gurd, Methods Enzymol. 11:532 (1967). N-Maleimide derivatives are also considered selective towards sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions. Reagents such as 2-iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through conversion of an amino group, may be considered as sulfhydryl reagents if linking occurs through the formation of disulfide bridges.
Examples of reactive moieties capable of reaction with amino groups include, for example, alkylating and acylating agents. Representative alkylating agents include:
(i) α-haloacetyl compounds, which show specificity towards amino groups in the absence of reactive thiol groups and are of the type XCH2CO— (where X=Br, Cl, or I), for example, as described by Wong Biochemistry 24:5337 (1979);
(ii) N-maleimide derivatives, which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group, for example, as described by Smyth et al., J. Am. Chem. Soc. 82:4600 (1960) and Biochem. J. 91:589 (1964);
(iii) aryl halides such as reactive nitrohaloaromatic compounds;
(iv) alkyl halides, as described, for example, by McKenzie et al., J. Protein Chem. 7:581 (1988);
(v) aldehydes and ketones capable of Schiff's base formation with amino groups, the adducts formed usually being stabilized through reduction to give a stable amine;
(vi) epoxide derivatives such as epichlorohydrin and bisoxiranes, which may react with amino, sulfhydryl, or phenolic hydroxyl groups;
(vii) chlorine-containing derivatives of s-triazines, which are very reactive towards nucleophiles such as amino, sufhydryl, and hydroxyl groups;
(viii) aziridines based on s-triazine compounds detailed above, e.g., as described by Ross, J. Adv. Cancer Res. 2:1 (1954), which react with nucleophiles such as amino groups by ring opening;
(ix) squaric acid diethyl esters as described by Tietze, Chem. Ber. 124:1215 (1991); and
(x) α-haloalkyl ethers, which are more reactive alkylating agents than normal alkyl halides because of the activation caused by the ether oxygen atom, as described by Benneche et al., Eur. J. Med. Chem. 28:463 (1993).
Representative amino-reactive acylating agents include:
(i) isocyanates and isothiocyanates, particularly aromatic derivatives, which form stable urea and thiourea derivatives respectively;
(ii) sulfonyl chlorides, which have been described by Herzig et al., Biopolymers 2:349 (1964);
(iii) acid halides;
(iv) active esters such as nitrophenylesters or N-hydroxysuccinimidyl esters;
(v) acid anhydrides such as mixed, symmetrical, or N-carboxyanhydrides;
(vi) other useful reagents for amide bond formation, for example, as described by M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, 1984;
(vii) acylazides, e.g., wherein the azide group is generated from a preformed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal. Biochem. 58:347 (1974); and
(viii) imidoesters, which form stable amidines on reaction with amino groups, for example, as described by Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962).
Aldehydes and ketones may be reacted with amines to form Schiff's bases, which may advantageously be stabilized through reductive amination. Alkoxylamino moieties readily react with ketones and aldehydes to produce stable alkoxamines, for example, as described by Webb et al., in Bioconjugate Chem. 1:96 (1990).
Examples of reactive moieties capable of reaction with carboxyl groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv. Protein Chem. 3:169 (1947). Carboxyl modifying reagents such as carbodiimides, which react through O-acylurea formation followed by amide bond formation, may also be employed.
It will be appreciated that functional groups in drug (A) and/or drug (B) may, if desired, be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity. Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as α-haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2-bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.
So-called zero-length linkers, involving direct covalent joining of a reactive chemical group of drug (A) with a reactive chemical group of drug (B) without introducing additional linking material may, if desired, be used in accordance with the invention.
More commonly, however, the linker will include two or more reactive moieties, as described above, connected by a spacer element. The presence of such a spacer permits bifunctional linkers to react with specific functional groups within drug (A) and drug (B), resulting in a covalent linkage between the two. The reactive moieties in a linker may be the same (homobifunctional linker) or different (heterobifunctional linker, or, where several dissimilar reactive moieties are present, heteromultifunctional linker), providing a diversity of potential reagents that may bring about covalent attachment between drug (A) and drug (B).
Spacer elements in the linker typically consist of linear or branched chains and may include a C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-10 heteroalkyl.
In some instances, the linker is described by formula (II):
G1-(Z1)o-(Y1)u-(Z2)s-(R30)-(Z3)t-(Y2)v-(Z4)p-G2 (II)
In formula (II), G1 is a bond between drug (A) and the linker; G2 is a bond between the linker and drug (B); Z1, Z2, Z3, and Z4 each, independently, is selected from O, S, and NR31; R31 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl; Y1 and Y2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; o, p, s, t, u, and v are each, independently, 0 or 1; and R30 is a C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-10 heteroalkyl, or a chemical bond linking G1-(Z1)o-(Y1)u-(Z2)s- to -(Z3)t—(Y2)v-(Z4)p-G2.
Examples of homobifunctional linkers useful in the preparation of conjugates of the invention include, without limitation, diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexanediol, and polycaprolactone diol.
The compositions, methods, and kits of the invention can include formulation(s) of compound(s) that, upon administration to a subject, result in a concentration of the compound(s) that treats a viral hepatitis infection. The compound(s) may be contained in any appropriate amount in any suitable carrier substance, and are generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously or intramuscularly), rectal, determatological, cutaneous, nasal, vaginal, inhalant, skin (patch), ocular, intrathecal, or intracranial administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A. R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
Pharmaceutical compositions according to the invention or used in the methods of the invention may be formulated to release the active compound immediately upon administration or at any predetermined time or time period after administration. The latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create substantially constant concentrations of the agent(s) of the invention within the body over an extended period of time; (ii) formulations that after a predetermined lag time create substantially constant concentrations of the agent(s) of the invention within the body over an extended period of time; (iii) formulations that sustain the agent(s) action during a predetermined time period by maintaining a relatively constant, effective level of the agent(s) in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the agent(s) (sawtooth kinetic pattern); (iv) formulations that localize action of agent(s), e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; (v) formulations that achieve convenience of dosing, e.g., administering the composition once per week or once every two weeks; and (vi) formulations that target the action of the agent(s) by using carriers or chemical derivatives to deliver the combination to a particular target cell type. Administration of compound(s) in the form of a controlled release formulation is especially preferred for compounds having a narrow absorption window in the gastro-intestinal tract or a relatively short biological half-life.
Any of a number of strategies can be pursued in order to obtain controlled release in which the rate of release outweighs the rate of metabolism of the compound in question. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Thus, the compound(s) are formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the compound(s) in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, molecular complexes, microspheres, nanoparticles, patches, and liposomes.
It is not intended that administration of compounds be limited to a single formulation and delivery method for all compounds of a combination. The combination can be administered using separate formulations and/or delivery methods for each compound of the combination using, for example, any of the above-described formulations and methods. In one example, a first agent is delivered orally, and a second agent is delivered intravenously.
The dosage of a compound or a combination of compounds depends on several factors, including: the administration method, the type of viral hepatitis to be treated, the severity of the infection, whether dosage is designed to treat or prevent a viral hepatitis infection, and the age, weight, and health of the patient to be treated.
For combinations that include an anti-viral agent in addition to a compound identified herein (e.g., a compound of Table 1, Table 2, or Table 3), the recommended dosage for the anti-viral agent is can be less than or equal to the recommended dose as given in the Physician's Desk Reference, 60th Edition (2006).
As described above, the compound in question may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories. Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound incorporated into liposomes. In cases where the compound in itself is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied. The correct dosage of a compound can be determined by examining the efficacy of the compound in viral replication assays, as well as its toxicity in humans.
An antiviral agent is usually given by the same route of administration that is known to be effective for delivering it as a monotherapy. For example, when used in combination therapy with a compound of Table 1, Table 2, or Table 3 according to the methods of this invention, an agent of Table 4 or Table 5 is dosed in amounts and frequencies equivalent to or less than those that result in its effective monotherapeutic use.
If desired, the compounds of the invention may be employed in mechanistic assays to determine whether other combinations, or single agents, are as effective as the combinations of the invention in inhibiting a viral disease (e.g., those described herein) using assays generally known in the art. For example, candidate compounds may be tested, alone or in combination (e.g., with an agent that inhibits viral replication, such as those described herein) and applied to cells (e.g., hepatic cells such as Huh7, Huh2, Huh 8, Sk-Hep-1, Huh7 lunet, HepG2, WRL-68, FCA-1, LX-1, and LX-2). After a suitable time, viral replication or load of these cells is examined. A decrease in viral replication or viral load identifies a candidate compound or combination of agents as an effective agent for treating a viral disease.
The agents of the invention are also useful tools in elucidating mechanistic information about the biological pathways involved in viral diseases. Such information can lead to the development of new combinations or single agents for treating, preventing, or reducing a viral disease. Methods known in the art to determine biological pathways can be used to determine the pathway, or network of pathways affected by contacting cells (e.g., hepatic cells) infected with a virus with the compounds of the invention. Such methods can include, analyzing cellular constituents that are expressed or repressed after contact with the compounds of the invention as compared to untreated, positive or negative control compounds, and/or new single agents and combinations, or analyzing some other activity of the cell or virus such as an enzymatic-activity, nutrient uptake, and proliferation. Cellular components analyzed can include gene transcripts, and protein expression. Suitable methods can include standard biochemistry techniques, radiolabeling the compounds of the invention (e.g., 14C or 3H labeling), and observing the compounds binding to proteins, e.g., using 2D gels, gene expression profiling. Once identified, such compounds can be used in in vivo models (e.g., knockout or transgenic mice) to further validate the tool or develop new agents or strategies to treat viral disease.
Peptide Moieties
Peptides, peptide mimetics, and peptide fragments (whether natural, synthetic or chemically modified) are suitable for use in the methods of the invention. Exemplary inhibitors include compounds that reduce the amount of a target protein or RNA levels (e.g., antisense compounds, dsRNA, ribozymes) and compounds that compete with viral reproduction machinery (e.g., dominant negative proteins or polynucleotides encoding the same).
Antisense Compounds
The biological activity of any protein that increases viral replication, viral RNA or DNA replication, viral RNA translation, viral protein processing or activity, or viral packaging can be reduced through the use of an antisense compound directed to RNA encoding the target protein. Antisense compounds can be identified using standard techniques. For example, accessible regions of the target the mRNA of the target enzyme can be predicted using an RNA secondary structure folding program such as MFOLD (M. Zuker, D. H. Mathews & D. H. Turner, Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide. In: RNA Biochemistry and Biotechnology, J. Barciszewski & B. F. C. Clark, eds., NATO ASI Series, Kluwer Academic Publishers, (1999)). Sub-optimal folds with a free energy value within 5% of the predicted most stable fold of the mRNA are predicted using a window of 200 bases within which a residue can find a complimentary base to form a base pair bond. Open regions that do not form a base pair are summed together with each suboptimal fold and areas that are predicted as open are considered more accessible to the binding to antisense nucleobase oligomers. Other methods for antisense design are described, for example, in U.S. Pat. No. 6,472,521, Antisense Nucleic Acid Drug Dev. 19977:439-444, Nucleic Acids Res. 28:2597-2604, 2000, and Nucleic Acids Res. 31:4989-4994, 2003.
RNA Interference
The biological activity of a molecule involved in a viral infection or viral replication can be reduced through the use of RNA interference (RNAi), employing, e.g., a double stranded RNA (dsRNA) or small interfering RNA (siRNA) directed to the signaling molecule in question (see, e.g., Miyamoto et al., Prog. Cell Cycle Res. 5:349-360, 2003; U.S. Pat. Application Publication No. 20030157030). Methods for designing such interfering RNAs are known in the art. For example, software for designing interfering RNA is available from Oligoengine (Seattle, Wash.).
One skilled in the art would know how to make dominant negative proteins to the molecules involved in a viral infection or viral replication. Such dominant negative proteins are described, for example, in Gupta et al., J. Exp. Med., 186:473-478, 1997; Maegawa et al., J. Biol. Chem. 274:30236-30243, 1999; Woodford-Thomas et al., J. Cell Biol. 117:401-414, 1992).
The following example is intended to illustrate rather than limit the invention. Unless stated otherwise, the data shown in the Examples was generated using the HCV replicon assay.
The HCV replicon assay enables screening of compounds with antiviral activity against HCV viral RNA replication. Huh7 cells expressing a subgenomic RNA replicon of Con1 (genotype 1b) sequence origin and expressing the reporter enzyme luciferase were obtained from ReBLikon, GmBH. In order to perform the assay, seed replicon cells on a 384-well plate at 4,000 cells/well in a total volume of 30 uL/well. The plated cells are incubated at 37° C., 5% CO2. Pre-diluted compounds are added at a 10× concentration to each well to achieve the desired final concentration. Plates are centrifuged at 900×g, 1 minute following the addition of compounds. Incubate cells an additional 48 hours or 72 hours at 37° C., 5% CO2. Remove plates from the incubator 30 minutes to 1 hour prior to the addition of 25 μL/well of SteadyLite luciferase assay reagent from Perkin Elmer in order to equilibrate plates to room temperature. Following the addition of SteadyLite reagent, allow cells to incubate for 10 minutes prior to collecting data with a luminometer. Antiviral activity is quantified by the inhibition of luciferase activity.
In order to confirm that a decrease in luciferase activity correlates with inhibition of HCV replicon replication and not an increase in cell death, a counter screen is run in tandem. Huh7 parental cells which do not express HCV replicon RNA are treated similarly to the above replicon cells; briefly, seed cells on a 384-well plate at 4,000 cells/well as described above. Compounds are added the following day and, after a subsequent 48-hour incubation at 37° C., 5% CO2, 15 μl/well of ATPlite (Perkin Elmer) is added after plates have been equilibrated at room temperature. The ATPlite assay provides a quantitative measure of the levels of ATP in the cell cultures in each well, where higher levels of ATP correlate with greater cellular viability. Thus, a compound with antiviral activity is expected to inhibit the levels of luciferase measured by the SteadyLite assay without any or minimal effect on the ATP levels measured by the ATPlite assay.
Using the screen described above or a similar screen, we identified the agents listed in Tables 1, 2, and 3 and the combinations of agents listed in Table 9. For screens involving a combination of compounds, a synergy score was calculated by the formula s=log fX log fYΣIdata(Idata−ILoewe), summed over all non-single-agent concentration pairs, and where log fX,Y are the natural logarithm of the dilution factors used for each single agent. This effectively calculates a volume between the measured and Loewe additive response surfaces, weighted towards high inhibition and corrected for varying dilution factors. The synergy score indicates that the combination of the two agents provides greater antiviral activity than would be expected based on the protection provided by each agent of the combination individually. The following ranges of concentrations of agents were used to generate the synergy scores in Table 12: sertraline (0.105-13 μM); simvastatin (0.175-22 μM); fluvastatin (0.22-28 μM); lovastatin (0.06-7.9 μM); rosuvastatin (0.19-24 μM); and hydroxyzine (0.21-27 μM). These data were generated following a 48-hour cell incubation.
Synergy scores were also identified for the following combination of compounds (Tables 13 and 14). These data were also generated after a 48-hour cell incubation.
Synergy scores and were also determined for combinations of sertraline analogs with simvastatin (Table 15). IC50, Maximal effect, CC50 and the therapeutic index (TI) (CC50/IC50) for the sertraline analogs are shown in Table 16. These data were generated after a 48-hour cell incubation.
Activity data for sertraline analogs was also generated following a 72-hour cell incubation, as shown in Table 17.
Monocytes purified from blood mononuclear cell preparation were differentiated to macrophages (14 days) in 5% autologous serum. Macrophages were then infected with an A/VN/3212/04 (H5N1) virus at a MOI of two. Cells were incubated with the combination, one hour prior to the infection. During the infection, the drug was washed off for 30 minutes and reintroduced for 3 hours. RT-PCR analysis of mRNA in virus infected macrophages was carried out for the following cytokines: TNF-alpha, IFN-beta, IP-10, IL-6, IL-8, H5N1 matrix gene (Lee et. al., J. Virol., 79:10147-10154, 2005). Cytotoxicity was evaluated visually and by Beta-actin gene expression. Fifteen combinations of agents were tested at three concentrations each.
From these experiments, the RT-PCR data was analyzed and calculated as a percentage inhibition versus a DMSO-treated control. The percent inhibition data is show in Table 18 below.
We also tested the effectiveness of sertraline and combinations containing sertraline in an influenza mouse model. Mouse adapted influenza A/PR/8/34 was procured from American Type Culture Collection (ATCC) and propagated in Madin-Darby Canine Kidney (MDCK) cells. The virus stock was titrated in MDCK cells to give a 108TCID50/mL, prior to use in mice. The virus stock was diluted in phosphate buffered saline (PBS) such that the working concentration was 104.5 TCID50 of virus per 50 μL.
Specific pathogen free, male C57/BL6 mice weighing 20-25 g were procured from Biological Resource Centre (BRC) and housed in groups of 3, in cages with Corncob bedding (Harlan-Teklad, U.K.). Experiments were conducted in Animal Bio-safety level 3 (ABSL-3) rooms. Cages were placed in isolator maintained at −100 pa pressure and supply of HEPA filtered air. Mice were provided with commercial rodent diet (Harlan-Teklad, U.K.) and distilled water ad libitum.
Mice were orally administered with respective treatments starting 4 hours before virus inoculation daily for five days. At the time of virus inoculation mice were anesthetized with Ketamine (75 mg/kg)+Xylazine (50 mg/kg). 50 μL of 104.5 TCID50 virus suspension was administered intranasally to each mouse. Previous experiments have shown that 104.5 TCID50/mouse of virus is lethal and produces 100% mortality in C57/BL6 mice (data not shown). Mice were weighed daily, and the weights were used for dose adjustment. Sertraline and prednisolone were suspended in 0.5% HPMC and administered once daily while oseltamivir was dissolved in distilled water and administered twice daily. Sertraline, sertraline+prednisolone combination, oseltamivir, and vehicle were orally administered for 5 days starting 4 hr before virus inoculation. The survival rate of animals was monitored for 10 days after infection.
From these experiments, vehicle treated mice began to die on day 7 and their survival rate on day 9 was 0%. The survival rate of mice receiving sertraline at a dose of 30 mg/kg/day was 22.2% on day 10. In mice treated with sertraline at 100 mg/kg/day, the survival rate was 55.5% on day 8, 44.4% on day 9, and 22.2% on day 10. Thus, sertraline shows dose dependant increase in survival rate by day 9 by which vehicle treated group shows 100% mortality (
Mice treated with a combination of sertraline 30 mg/kg/day and prednisolone 0.1 mg/kgday showed 30% survival on day 10. Oseltamivir was used as a positive control and the survival rates for 30 mg/kg/day and 100 mg/kg/day were 33.3% and 100% respectively on day 10. Sertraline alone or in combination with prednisolone improves survival rate of C57/BL6 mice infected with lethal dose of influenza A/8/PR/34.
Characterization of sertraline, UK-416244, and analoges thereof is shown in Table 19.
Characterization of additional sertraline analogs of the formula,
is shown in Table 20 below. Sertraline is shown in bold.
H
4.23
2.75
Characterization of sertraline analogs of the formula:
is shown in Table 21. Sertraline is shown in bold.
3,4-di-Cl
4.23
2.75
Characterization of sertraline analogs of the formula:
are shown in Table 22. Sertraline is noted in bold.
NHMe
4.23
2.75
Characterization of sertraline analogs of the formula:
is shown in Table 23. Sertraline is shown in bold.
H
4.23
2.75
Characterization of additional sertraline analogs is shown in Table 24. Sertraline is in bold.
Sertraline HCL
4.22 ± 1.05
11.7 ± 2.03
2.77
14
Characterization of analogs of UK-416244 having the formula:
is shown in Table 25. UK-416244 is shown in bold.
SO
2
NH
2
1.41
>35
6.17
Characterization of analogs of UK-416244 having the formula:
is shown in Table 26. UK-416244 is shown in bold.
SO
2
NH
2
3-Me, 4-SMe
1.41
>35
6.17
Characterization of analogs of UK-416244 having the formula:
is shown in Table 27. UK-416244 is shown in bold.
CH
2
NMe
2
1.41
>35
6.17
Characterization of additional UK-416244 analogs is described in Table 28.
Additional characterization of sertraline and UK-416244 analogs is provided in Tables 29-32 below.
Additional characterization of sertraline analogs is provided in Table 31.
Additional characterization of UK-416244 analogs is provided in Table 32.
Synthesis of exemplary sertraline analogs is described in Examples 7-64 below. Other sertraline analogs can be made using the methods described in Welch et al., J. Med. Chem. 27:1508-1515, 1984, and PCT Publication Nos. WO 00/51972 WO 02/18333, and WO 01/72687. In the Examples below, the starting materials were purchased from Aldrich, Tee Hai, and Atomax. Merck silica gel 60 (230-400 mesh) was used for chromatography. 1H NMR spectra were recorded on Bruker 400 MHz spectrometers. MS was obtained on Agilent 1200 LC/MS system. The HPLC separations were achieved on shimadzu HPLC system.
The following abbreviations are used in the Examples below. 6 chemical shift; Ac: acetyl; Ar: aromatic; Boc: t-Butoxycarbonyl; d: doublet; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: Dimethylsulfoxide; HATU: 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium; HPLC: High pressure liquid chromatography; LAH: lithium aluminum hydride; Me: methyl; MS: mass spectrum; NMP: N-methylmorpholine; NMR: nuclear magnetic resonance; m/z: mass spectrum peak; Pd/C: palladium on activated charcoal, 10% Pd; q: quartet; s: singlet; t: triplet; TBAI: tetrabutylammonium Iodide; TEA: triethyl amine; THF: tetrahydrofuran;
A mixture of 3-cyano-4-fluorobenzene-1-sulfonyl chloride (1 g, 4.55 mmol) and aniline (4.1 ml, 45.5 mmol) in methanol (15 ml) was stirred at room temperature for 15 min. The mixture was quenched with 2N HCl. pH was adjusted to 1. The mixture was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue (1.25 g) was directly used for the next step. 1H NMR (CD3OD, 400 Mhz) generated the following peaks: δ 8.10 (dd, 1H), 7.99-8.03 (m, 1H), 7.47 (t, 1H), 7.23-7.27 (m, 2H), 7.07-7.13 (m, 3H).
A mixture of 3-cyano-4-fluoro-N-phenylbenzenesulfonamide (1.25 g, 4.55 mmol), 3-methyl-4-(methylthio)phenol (772 mg, 5.00 mmol) and K2CO3 (660 mg, 4.78 mmol) in DMF (20 ml) was stirred in an 100° C. oil bath for 4 hours. The mixture was then cooled to 0° C. and acidified to pH 1 using 2 N HCl. The mixture was extracted 3 times with diethyl ether. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:Hexane (30-50%) to yield 1.4 g of the desired product, 3-cyano-4-(3-methyl-4-(methylthio)phenoxy)-N-phenylbenzenesulfonamide. 1H NMR (CD3OD, 400 Mhz) generated the following peaks: δ 8.04 (d, 1H), 7.83 (dd, 1H), 7.23-7.30 (m, 3H), 7.07-7.11 (m, 3H), 6.97-6.99 (m, 2H), 6.85 (d, 1H), 2.47 (s, 3H), 2.30 (s, 3H).
3-cyano-4-(3-methyl-4-(methylthio)phenoxy)-N-phenylbenzenesulfonamide (200 mg, 0.48 mmol) was dissolved in 3 ml anhydrous THF and cooled to 0° C., followed by drop-wise addition of 2 ml of LAH (1.0 M in THF). The mixture was then warmed to room temperature and stirred overnight. The mixture was quenched by addition of 2 N NaOH, water, and 10% Rochelle's salt solution. The mixture was extracted 3 times with ethyl acetate. The resulting organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with MeOH:DCM (1-10%) to yield 100 mg of the desired product, 3-(aminomethyl)-4-(3-methyl-4-(methylthio)phenoxy)-N-phenylbenzenesulfonamide. 1H NMR (CD3OD, 400 Mhz) generated the following peaks: δ 7.81 (d, 1H), 7.55 (dd, 1H), 7.18-7.26 (m, 3H), 7.01-7.10 (m, 3H), 6.88-6.89 (m, 2H), 6.71 (d, 1H), 3.86 (s, 2H), 2.44 (s, 3H), 2.29 (s, 3H). Mass spectrometry showed m/z=415.0 (M+H+).
3-(aminomethyl)-4-(3-methyl-4-(methylthio)phenoxy)-N-phenylbenzenesulfonamide (100 mg, 0.24 mmol) was dissolved in 3 ml THF and was added to 37% formaldehyde (27 μl, 0.36 mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of NaHB(OAc)3 (153 mg, 0.72 mmol). The mixture was then stirred overnight, quenched by addition of saturated sodium bicarbonate solution, and extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:DCM (1-5%) twice to yield 18 mg of the desired product, 3-((dimethylamino)methyl)-4-(3-methyl-4-(methylthio)phenoxy)-N-phenylbenzenesulfonamide. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.96 (d, 1H), 7.54 (dd, 1H), 7.15-7.26 (m, 3H), 7.07-7.09 (m, 3H), 6.78-6.81 (m, 2H), 6.67 (d, 1H), 3.58 (s, 2H), 2.45 (s, 3H), 2.31 (s, 3H), 2.25 (s, 6H). Mass spectrometry showed m/z=443.1 (M+H+).
This compound was prepared a manner analogous to 3-((dimethylamino)methyl)-4-(3-methyl-4-(methylthio)phenoxy)-N-phenylbenzenesulfonamide, as described in Example 7. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 8.01 (d, 1H), 7.66 (dd, 1H), 7.23-7.30 (m, 3H), 7.18-7.20 (m, 3H), 6.81-6.84 (m, 3H), 4.16 (s, 2H), 3.58 (s, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 2.30 (s, 6H). Mass spectrometry showed m/z=457.1 (M+H+)
Magnesium (80 mg, 3.28 mmol), 2-bromopropane (0.324 ml, 3.46 mmol) and THF (5 ml) were added to a flame-dried round bottom flask. The mixture was stirred for 30 minutes until all of the magnesium was consumed. 4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one (503 mg, 1.73 mmol) in 5 ml THF was then added to the mixture at 0° C. After stirring for two hours, the reaction mixture was diluted using saturated NH4Cl. The mixture was extracted 3 times with diethyl ether. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:Hexane (10%) to yield 174 mg (cis+trans) of the desired product, 4-(3,4-dichlorophenyl)-1-isopropyl-1,2,3,4-tetrahydronaphthalen-1-ol.
4-(3,4-dichlorophenyl)-1-isopropyl-1,2,3,4-tetrahydronaphthalen-1-ol (174 mg, 0.52 mmol) was dissolved in 20 ml 1.0 M HCl in diethyl ether and the mixture was stirred overnight. The mixture was concentrated in vacuo, resulting in a yellow residue. The residue was purified by flash chromatography eluted with hexane to yield 80.4 mg of the desired product, 1-(3,4-dichlorophenyl)-4-isopropyl-1,2-dihydronaphthalene. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.42 (d, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.22 (d, 1H), 7.14 (t, 1H), 6.98 (dd, 1H), 6.89 (d, 1H), 5.74 (t, 1H), 3.98 (t, 1H), 2.98-3.02 (m, 1H), 2.45-2.67 (m, 2H), 1.16 (d, 6H).
1-(3,4-dichlorophenyl)-4-isopropyl-1,2-dihydronaphthalene (80.4 mg, 0.25 mmol) was dissolved in 5 ml ethanol. The mixture was purged with N2 before 150 mg Pd/C was added. H2 then was allowed to bubble through the solution until all of the starting material was consumed. The mixture was passed through Celite and concentrated in vacuo, resulting in a yellow residue. The residue was purified by flash chromatography eluted with hexane to yield 53.3 mg of the desired product, 1-(3,4-dichlorophenyl)-4-isopropyl-1,2,3,4-tetrahydronaphthalene. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.32 (d, 1H), 7.25-7.27 (m, 1H), 7.14-7.20 (m, 2H), 7.06-7.08 (m, 2H), 6.86-6.89 (m, 1H), 4.09-4.17 (m, 1H), 2.67-2.74 (m, 1H), 2.31-2.37 (m, 1H), 2.03-2.08 (m, 2H), 1.61-1.71 (m, 2H), 1.04 (d, 3H), 0.80 (d, 3H).
Magnesium (323 mg, 13.28 mmol), 4-bromo-1,2-dichlorobenzene (3 g, 13.28 mmol), and THF (10 ml) were added to a flame-dried round bottom flask. The mixture was allowed to stir until all of magnesium was consumed. Then 4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one (1.11 g, 7.3 mmol) in 4 ml THF was added to the mixture at 0° C. After stirring for two hours, the reaction mixture was diluted with saturated NH4Cl. The mixture was then extracted 3 times with diethyl ether. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:hexane (4-7%) to yield 1.5 g of the desired product, 4-(3,4-dichlorophenyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.50 (d, 1H), 7.36 (d, 1H), 7.14 (dd, 1H), 7.07 (d, 1H), 6.59 (d, 1H), 2.84-2.97 (m, 2H), 1.86-2.17 (m, 4H).
4-(3,4-dichlorophenyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol (1.5 g, 5.01 mmol) was dissolved in acetone/H2O (170.6 ml/3.5 ml) and KMnO4 (11.88 g, 75.2 nmol) was added to the solution. The mixture was heated in a 60° C. oil bath overnight. The mixture was passed through Celite and concentrated in vacuo, resulting in a yellow residue. The residue was dissolved in ethyl Acetate\H2O mixture. The aqueous layer was extracted twice using ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with Ethyl Acetate:Hexane (20%) to yield 225 mg of the desired product, 4-(3,4-dichlorophenyl)-4-hydroxy-5,6-dihydrobenzo[b]thiophen-7(4H)-one. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.69 (d, 1H), 7.51 (d, 1H), 7.41 (d, 1H), 7.11 (dd, 1H), 6.87 (d, 1H), 2.88-2.91 (m, 1H), 2.42-2.56 (m, 3H).
4-(3,4-dichlorophenyl)-4-hydroxy-5,6-dihydrobenzo[b]thiophen-7(4H)-one (225 mg, 0.72 mmol) was dissolved in 1 ml THF, and 5.4 ml 2 M MeNH2 in THF was added to the solution. The mixture was placed in an ice bath, and TiCl4 (144 mg, 0.43 mmol) was slowly added. After stirring for 3 hours, the mixture was passed through Celite and concentrated in vacuo, generating a white foam. The foam was dissolved in 3 ml anhydrous methanol and followed by addition of NaBH4 (54 mg, 1.44 mmol). The mixture was stirred for 1 hour, diluted with ethyl acetate, and washed using water and brine. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with DCM:methanol:NH3 (90:10:1) to yield 200 mg of the desired product, 4-(3,4-dichlorophenyl)-7-(methylamino)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.52 (d, 1H), 7.37 (d, 1H), 7.13-7.16 (m, 2H), 6.55 (d, 1H), 3.88-3.91 (m, 1H), 2.60 (s, 3H), 2.17-2.27 (m, 2H), 1.82-2.00 (m, 2H).
4-(3,4-dichlorophenyl)-7-(methylamino)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol (200 mg, 0.61 mmol) was dissolved in 3 ml 10% methanol in DCM. 5 ml 2.0 M HCl in diethyl ether was added to the solution. The mixture was then stirred for 1 hour, concentrated in vacuo, and basified with saturated sodium bicarbonate solution. The mixture was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo to give 180 mg of brown oil. The residue was dissolved in 10 ml ethanol. N2 was used to purge the mixture prior to adding 200 mg Pd/C. H2 then was allowed to bubble through the solution until all of the starting material was consumed. The mixture was passed through Celite and concentrated in vacuo to give yellow residue, which was purified by flash chromatography eluted with ethyl acetate:hexane:triethylamine (40:60:1) to yield 84.8 mg of the desired product, 4-(3,4-dichlorophenyl)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-7-amine. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.32-7.36 (m, 1H), 7.18-7.21 (m, 1H), 7.11-7.16 (m, 1H), 6.91-6.96 (m, 1H), 6.43-6.51 (m, 1H), 3.85-3.97 (m, 2H), 2.57 (d, 3H), 1.73-2.29 (m, 4H). Mass spectrometry showed m/z=312.0 (M+H+).
Triethyl amine (2.87 ml, 20.52 mmol) was added to sertraline (3 g, 9.80 mmol) in DCM (40 ml), followed addition of methyl bromoacetate (1.1 ml, 11.75 mmol) at 0° C. The mixture was stirred overnight and then washed with water. The aqueous layer was extracted 3 times with DCM. The organic layer was separated, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with ethyl acetate:hexane (5%-10%) to yield 1.38 g of the desired product, methyl 2-(((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)amino)acetate. 1H NMR (CDCl3, 400 MHz) generated the following peaks: δ 7.81 (d, 1H), 7.32 (d, 1H), 7.26 (t, 1H), 7.12-7.17 (m, 2H), 6.89 (d, 1H), 6.81 (dd, 1H), 4.07-4.14 (m, 1H), 3.93-3.97 (m, 1H), 3.31 (q, 2H), 2.41 (s, 3H), 2.02-2.14 (m, 2H), 1.62-1.76 (m, 2H).
1 M LAH (5 ml) in THF was added to methyl 2-(((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)amino) acetate (0.28 g, 0.74 mmol) in THF (5 ml) at 0° C. The mixture was stirred overnight and was quenched with water. The aqueous layer was extracted 3 times with ethyl acetate. The organic layer was then separated, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:hexane (10%-30%) to yield 150 mg of the desired product, 2-(((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)amino)ethanol. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.70 (d, 1H), 7.32 (d, 1H), 7.28 (t, 1H), 7.16 (t, 1H), 7.11 (d, 1H), 6.91 (d, 1H), 6.82 (dd, 1H), 4.11-4.14 (m, 1H), 3.93 (t, 1H), 3.64-3.67 (m, 2H), 2.71 (t, 2H), 2.41 (s, 3H), 1.99-2.24 (m, 2H), 1.68-1.73 (m, 2H). Mass spectrometry revealed m/z=350.1 (M+H+).
Lithium hydroxide (64 mg, 2.69 mmol) was added to (5S,8S)-methyl 8-(tert-butoxycarbonyl(methyl)amino)-5-(3,4-dichlorophenyl)-5,6,7,8-tetra-hydronaphthalene-2-carboxylate (Preparation 1 (Example 23), 250 mg, 0.538 mmol) in 10 ml MeOH/H2O (9:1). The mixture was stirred at room temperature overnight and then acidified using 1 N HCl to pH 3-4. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with MeOH:DCM (5%-20%) to yield 200 mg of the desired product, (5S,8S)-8-(tert-butoxycarbonyl(methyl)amino)-5-(3,4-dichlorophenyl)-5,6,7,8-tetrahydrona-phthalene-2-carboxylic acid.
To (5S,8S)-8-(tert-butoxycarbonyl(methyl)amino)-5-(3,4-dichlorophenyl)-5,6,7,8-tetrahydrona-phthalene-2-carboxylic acid (120 mg, 0.27 mmol) in 2 ml DMF/DCM (1:1) was added HATU (0.186 g, 0.49 mmol), followed by cyclopropylamine (33 μl, 0.49 mmol) and 4-methyl morpholine (0.14 ml, 1.33 mmol). The mixture was stirred over night and diluted with water. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with ethyl acetate:hexane (20%) to yield 100 mg desired product, tert-butyl (1S,4S)-7-(cyclopropylcarbamoyl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-1-yl(methyl)carbamate. Mass spectrometry resulted in m/z=511.1 (M+Na+).
Trifluoroacetic acid (0.5 ml) was added to (5S,8S)-8-(tert-butoxycarbonyl(methyl)amino)-5-(3,4-dichlorophenyl)-5,6,7,8-tetrahydrona-phthalene-2-carboxylic acid (100 mg, 0.20 mmol) in 2 ml DCM. The mixture was stirred for 1 hour, diluted with DCM, and washed using saturated sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:DCM:triethyl amine (2:98:1 to 10:90:1) to yield 25 mg of the desired product, (5S,8S)—N-cyclopropyl-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxamide. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.77 (d, 1H), 7.45 (dd, 1H), 7.34 (d, 1H), 7.20 (d, 1H), 6.93 (dd, 1H), 6.85 (d, 1H), 6.23 (s, 1H), 3.99 (t, 1H), 3.74-3.76 (m, 1H), 2.87-2.92 (m, 1H), 2.54 (s, 3H), 1.99-2.08 (m, 2H), 1.79-1.85 (m, 2H), 0.85-0.90 (m, 2H), 0.60-0.64 (m, 2H). Mass spectrometry showed m/z=389.0 (M+H+).
This compound was prepared in an analogous fashion to (5S,8S)—N-cyclopropyl-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxamide, as described in example 12. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.94 (d, 2H), 7.64-7.66 (m, 3H), 7.35-7.39 (m, 3H), 7.23 (d, 1H), 7.15 (t, 1H), 6.91-6.97 (m, 2H), 4.01 (t, 1H), 3.79-3.81 (m, 1H), 2.56 (s, 3H), 1.87-2.10 (m, 4H). Mass spectrometry showed m/z=425.0 (M+H+).
This compound was prepared in an analogous fashion to (5S,8S)—N-cyclopropyl-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxamide, as described in example 12. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 8.61 (s, 1H), 8.39 (d, 1H), 8.30-8.32 (m, 1H), 7.97 (d, 1H), 7.74-7.79 (m, 1H), 7.67 (dd, 1H), 7.37 (d, 1H), 7.24 (d, 1H), 7.07-7.10 (m, 1H), 6.93-6.97 (m, 2H), 4.00-4.04 (m, 1H), 3.77-3.79 (m, 1H), 2.56 (s, 3H), 1.85-2.12 (m, 4H). Mass spectrometry showed m/z=426.0 (M+H+).
To (5S,8S)-5-(3,4-dichlorophenyl)-8-(dimethylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (made from N,N-dimethyl sertraline; see PCT Publication No. WO 00/51972 for details, 100 mg, 0.27 mmol) in 2 ml DMF/DCM (1:1) was added HATU (163 mg, 0.43 mmol), followed by cyclobutylamine (36 μl, 0.43 mmol) and 4-methyl morpholine (0.18 ml, 1.65 mmol). The mixture was stirred overnight and diluted with water. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with ethyl acetate:hexane (20%) to yield 100 mg desired product, (5S,8S)—N-cyclobutyl-5-(3,4-dichlorophenyl)-8-(dimethylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxamide. 1H NMR (CDCl3, 300 Mhz) generated the following peaks: δ 8.06 (s, 1H), 7.60 (d, 1H), 7.31 (d, 1H), 7.08 (s, 1H), 6.96 (d, 1H), 6.81 (d, 1H), 6.31 (b, 1H), 4.51-4.62 (m, 1H), 4.11-4.14 (m, 1H), 3.75-3.80 (t, 1H), 2.42-2.48 (m, 2H), 2.30 (s, 6H), 1.95-2.11 (m, 4H), 1.56-1.82 (m, 4H). Mass spectrometry showed m/z=417.1 (M+H+).
This compound was prepared in an analogous fashion to (5S,8S)—N-cyclobutyl-5-(3,4-dichlorophenyl)-8-(dimethylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxamide, as described in example 15. 1H NMR (CDCl3, 300 Mhz) generated the following peaks: δ 8.03 (s, 1H), 7.61 (d, 1H), 7.31 (d, 1H), 7.07 (s, 1H), 6.96 (d, 1H), 6.80 (d, 1H), 6.34 (b, 1H), 4.11-4.14 (m, 1H), 3.75-3.80 (t, 1H), 2.89-2.93 (m, 1H), 2.29 (s, 6H), 2.00-2.14 (m, 2H), 1.69-1.73 (m, 2H), 0.84-0.95 (m, 2H), 0.55-0.64 (m, 2H). Mass spectrometry showed m/z 403.1 (M+H+).
This compound was prepared in an analogous fashion to (5S,8S)—N-cyclobutyl-5-(3,4-dichlorophenyl)-8-(dimethylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxamide, as described in example 15. 1H NMR (CDCl3, 300 Mhz) generated the following peaks: δ 8.01 (s, 1H), 7.62 (d, 1H), 7.32 (d, 1H), 7.09 (s, 1H), 6.97 (d, 1H), 6.82 (d, 1H), 6.31 (b, 1H), 4.09-4.16 (m, 1H), 3.77-3.82 (t, 1H), 3.30-3.36 (m, 2H), 2.31 (s, 6H), 2.04-2.14 (m, 2H), 1.68-1.73 (m, 2H), 1.04-1.14 (m, 1H), 0.55-0.65 (m, 2H), 0.24-0.34 (m, 2H). Mass spectrometry showed m/z=417.0 (M+H+).
To tert-butyl (1S,4S)-7-amino-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl) carbamate (see PCT Publication No. WO 00/51972 for details, 100 mg, 0.24 mmol) in 5 ml THF was added benzoyl chloride (48 μl, 0.47 mmol) and triethyl amine (99 μl, 0.71 mmol). The mixture was stirred at room temperature overnight and diluted with water. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:hexane (5-20%) to yield 121 mg of the desired product, tert-butyl (1S,4S)-7-benzamido-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydrona-phthalen-1-yl(methyl)carbamate. Mass spectrometry showed m/z=547.1 (M+Na+).
Trifluoroacetic acid (0.25 ml) was added to tert-butyl (1S,4S)-7-benzamido-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydrona-phthalen-1-yl(methyl)carbamate (121 mg, 0.23 mmol) in 2 ml DCM, and the mixture was stirred for 3 hours. The mixture was then diluted with DCM and washed with saturated sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with methanol:DCM (6%) to yield 85.4 mg of the desired product, N-((5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)benzamide. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.85-7.87 (m, 3H), 7.76 (d, 1H), 7.48-7.55 (m, 3H), 7.33-7.36 (m, 2H), 7.24 (d, 1H), 6.97 (d, 1H), 6.81 (d, 1H), 3.96-4.00 (m, 1H), 3.74-3.76 (m, 1H), 2.55 (s, 3H), 1.83-2.04 (m, 4H). Mass spectrometry showed m/z=425.0 (M+H+).
This compound was prepared in fashion analogous to that of (5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-N-(pyridin-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Example 18). 1H NMR (MeOH-d4, 400 Mhz) generated the following peaks: δ 7.62 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 7.25 (dd, 1H), 7.13 (dd, 1H), 6.72 (d, 1H), 4.02 (t, 1H), 3.76-3.78 (m, 1H), 2.76-2.80 (m, 1H), 2.51 (s, 3H), 1.77-2.04 (m, 10H), 1.62-1.65 (m, 2H). Mass spectrometry showed m/z=417.1 (M+H+)
(5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-N-(pyridin-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (85.4 mg, 0.20 mmol), produced as described in Example 18, was dissolved in 1 ml DCM and was added 37% formaldehyde (14.7 μl, 0.18 mmol). The mixture was stirred at room temperature for 60 minutes, followed by addition of NaHB(OAc)3 (153 mg, 0.72 mmol). The mixture was stirred overnight, quenched by addition of saturated sodium bicarbonate solution, and was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with ethyl acetate:hexane (20-50%) to yield 25 mg of the desired product, N-((5S,8S)-5-(3,4-dichlorophenyl)-8-(dimethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)benzamide. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.87-7.89 (m, 3H), 7.79 (dd, 1H), 7.71 (d, 1H), 7.47-7.58 (m, 3H), 7.31 (d, 1H), 7.13 (d, 1H), 6.93 (d, 1H), 6.84 (dd, 1H), 4.09-4.14 (m, 1H), 3.78-3.82 (m, 1H), 2.32 (s, 6H), 1.62-2.14 (m, 4H). Mass spectrometry showed m/z=439.0 (M+H+).
1-methyl-1H-imidazole-4-sulfonyl chloride (186 μl, 1.43 mmol) and triethyl amine (298 μl, 2.14 mmol) was added to tert-butyl (1S,4S)-7-amino-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl) carbamate (150 mg, 0.36 mmol, see PCT Publication No. WO 00/51972 for details) in 6 ml THF. The mixture was stirred at room temperature overnight and diluted with water, which was then extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified using flash chromatography eluted with ethyl acetate:hexane (40-60%) to yield 181 mg of the desired product, tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-sulfonamido)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate. Mass spectrometry showed m/z=587.0 (M+Na+).
Trifluoroacetic acid (0.4 ml) was added to tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-sulfonamido)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate (181 mg, 0.32 mmol) in 5 ml DCM. The mixture was stirred for 3 hours, diluted with DCM, and washed with saturated sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:ethyl acetate (20%) to yield 93 mg of the desired product, N-((5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-methyl-1H-imidazole-4-sulfonamide. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.52 (d, 1H), 7.29-7.35 (m, 3H), 7.13 (dd, 1H), 7.02 (dd, 1H), 6.91 (dd, 1H), 6.63 (d, 1H), 3.88 (t, 1H), 3.65-3.67 (m, 4H), 2.44 (s, 3H), 1.79-1.99 (m, 4H). Mass spectrometry showed m/z=465.0 (M+H+).
This compound was prepared in a manner analogous to N-((5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl)-1-methyl-1H-imidazole-4-sulfonamide, as described in Example 21. 1H NMR (MeOH-d4, 400 Mhz) generated the following peaks: δ 8.50 (s, 1H), 7.78 (dd, 2H), 7.57 (t, 1H), 7.44-7.50 (m, 3H), 7.33 (dd, 2H), 7.13 (dd, 1H), 6.96 (dd, 1H), 6.74 (d, 1H), 4.30 (t, 1H), 4.06-4.10 (m, 1H), 2.71 (s, 3H), 1.83-2.21 (m, 4H). Mass spectrometry showed m/z=461.0 (M+H+).
This compound was prepared in a manner analogous to N-((5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl)-1-methyl-1H-imidazole-4-sulfonamide, as described in Example 21. 1H NMR (MeOH-d4, 400 Mhz) generated the following peaks: δ 8.33 (s, 1H), 7.40 (d, 1H), 7.28 (d, 2H), 7.13 (d, 1H), 7.03 (d, 1H), 6.89 (d, 1H), 4.28-4.30 (m, 1H), 4.08-4.10 (m, 1H), 2.71 (s, 3H), 2.51-2.59 (m, 1H), 1.80-2.10 (m, 4H), 0.92-0.94 (m, 4H). Mass spectrometry showed m/z=425.0 (M+H+).
(5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1 g, 3.01 mmol, described in PCT Publication No. WO 00/51972) was added to 20 ml concentrated HCl and the mixture was stirred in a 60° C. oil bath for 2-3 hours. The mixture was then cooled to room temperature and treated with sodium bicarbonate in an ice bath. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH: DCM (10-20%) to yield 404 mg of the desired product, (5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydro-naphthalene-2-carboxamide. 1H NMR (MeOH-d4, 400 Mhz) generated the following peaks: δ 7.92 (d, 1H), 7.64 (dd, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.15 (dd, 1H), 6.89 (d, 1H), 4.12 (t, 1H), 3.91-3.94 (m, 1H), 2.56 (s, 3H), 1.91-2.16 (m, 4H). Mass spectrometry showed m/z=349.0 (M+H+).
Lawesson's reagent (76 mg, 0.18 mmol) was added to (5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydro-naphthalene-2-carbox-amide (65 mg, 0.19 mmol) in 3 ml THF. The mixture was stirred in a 55° C. oil bath for 6 hours. After being cooled to room temperature, the mixture was diluted with water, and the resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography and was eluted with MeOH:DCM (5-10%) to yield 20 mg of product which was further purified by HPLC (33% acetonitrile with 0.1% formic acid). The resulting formic acid salt was treated with NaOH and was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous MgSO4, and concentrated in vacuo, resulting in 8 mg of the desired product, (5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carbothioamide. 1H NMR (MeOH-d4, 400 Mhz) generated the following peaks: δ 7.93 (d, 1H), 7.65 (dd, 1H), 7.44 (d, 1H), 7.39 (d, 1H), 7.15 (dd, 1H), 6.81 (d, 1H), 4.08 (t, 1H), 3.81-3.83 (m, 1H), 2.52 (s, 3H), 1.88-2.12 (m, 4H). Mass spectrometry showed m/z=365.0 (M+H+).
1.0 M LAH solution (1.26 ml, 1.26 mmol) was added to (5S,8S)-methyl 8-(tert-butoxycarbonyl(methyl)amino)-5-(3,4-dichlorophenyl)-5,6,7,8-tetra-hydronaphthalene-2-carboxylate (Preparation 1 (Example 23), 450 mg, 0.969 mmol) in 10 ml THF. The mixture was stirred at room temperature overnight and then quenched by Rochelle solution and 1 N NaOH. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with ethyl acetate:hexane (30-40%) to yield 350 mg of the desired product, tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl (methyl)carbamate. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.32 (d, 1H), 7.19 (d, 2H), 7.08 (s, 1H), 6.95 (d, 1H), 6.82 (d, 1H), 5.28-5.50 (m, 1H), 4.69 (d, 2H), 4.16-4.18 (m, 1H), 2.62 (s, 3H), 1.73-2.27 (m, 4H), 1.52 (s, 9H).
Triethyl amine (0.56 ml, 4.01 mmol) was added to tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl (methyl)carbamate (350 mg, 0.80 mmol) in 15 ml DCM. The mixture was stirred at room temperature for 10 minutes and thionyl chloride (0.13 ml, 1.60 mmol) was added at 0° C. After being stirred at room temperature for 2 hours, the reaction mixture was quenched by saturated sodium bicarbonate solution. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:hexane (5-20%) to yield 250 mg of the desired product, tert-butyl (1S,4S)-7-(chloromethyl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.33 (d, 1H), 7.21 (d, 2H), 7.09 (s, 1H), 6.95 (d, 1H), 6.80 (d, 1H), 5.28-5.50 (m, 1H), 4.58 (s, 2H), 4.16-4.18 (m, 1H), 2.62 (s, 3H), 1.73-2.27 (m, 4H), 1.52 (s, 9H).
Benzenesulfinic sodium salt (72 mg, 0.44 mmol), potassium iodide (37 mg, 0.22 mmol) and TBAI (16 mg, 0.044 mmol) was added to tert-butyl (1S,4S)-7-(chloromethyl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate (100 mg, 0.22 mmol) in 6 ml DMF was added. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then diluted with water. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:hexane (10-40%) to yield 50 mg of the desired product, tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-7-(phenylsulfonylmethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl(methyl)carbamate. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.59-7.69 (m, 3H), 7.46-7.52 (m, 2H), 7.35 (d, 1H), 6.81-6.95 (m, 5H), 5.15-5.35 (m, 1H), 4.30 (s, 2H), 4.14-4.16 (m, 1H), 2.45 (d, 3H), 1.63-2.27 (m, 4H), 1.51 (d, 9H).
Trifluoroacetic acid (0.8 ml) was added to tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-7-(phenylsulfonylmethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl(methyl)carbamate (50 mg, 0.089 mmol) in 3 ml DCM. The mixtures was stirred for 1 hour in an ice bath, diluted with DCM, and washed with saturated sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:DCM (4%) to yield 22 mg of the desired product, (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-7-(phenylsulfonylmethyl)-1,2,3,4-tetrahydro-naphthalen-1-amine. 1H NMR (CDCl3, 400 Mhz) generated the following peaks: δ 7.59-7.67 (m, 3H), 7.46-7.50 (m, 2H), 7.35 (d, 1H), 7.15-7.17 (m, 2H), 6.96 (dd, 1H), 6.84 (dd, 1H), 6.71 (d, 1H), 4.27 (s, 2H), 3.93-3.97 (m, 1H), 3.72 (b, 1H), 2.47 (d, 3H), 1.80-2.01 (m, 4H). Mass spectrometry showed m/z=460.0 (M+H+).
(5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.50 g, 4.53 mmol, described in PCT Publication No. WO 00/51972) was dissolved in acetone (37 ml). A solution of KMnO4 (1.22 g, 7.70 mmol) in 37 ml water was added dropwise over 20 minutes. After stirring for 1 hour, the solids were filtered off and washed thoroughly with acetone and EA. The filtrate was concentrated in vacuo and brought to pH 1 using concentrated HCl. The mixture was warmed on a steam bath for 45 minutes. The cooled suspension was extracted 2 times with chloroform. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with EA: Hexane (10-20%) to yield 910 mg of the desired product, (S)-5-(3,4-dichlorophenyl)-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. 1H NMR (CDCl3, 400 MHz) generated the following peaks: δ 8.41 (d, 1H), 7.70 (dd, 1H), 7.44 (d, 1H), 7.21 (d, 1H), 7.09 (d, 1H), 6.93 (dd, 1H), 4.30 (m, 1H), 2.65-2.82 (m, 2H), 2.47-2.52 (m, 1H), 2.26-2.32 (m, 1H).
(S)-5-(3,4-dichlorophenyl)-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (910 mg, 2.88 mmol) was dissolved in concentrated H2SO4 (29.5 ml) and heated at 100° C. for 70 minutes. The cooled reaction was poured into water and neutralized with 2 N NaOH solution until pH 7. The mixture was extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in a little MeOH and filtered to yield 700 mg of the desired product, (S)-5-(3,4-dichlorophenyl)-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxamide. 1H NMR ((CD3)2SO, 300 MHz) generated the following peaks: δ 8.46 (s, 1H), 8.15 (s, 1H), 8.99 (d, 1H), 7.61 (d, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.15 (d, 1H), 6.99 (d, 1H), 4.50 (t, 1H), 2.32-2.68 (m, 4H).
A small amount of 2-bromopropane (1.97 ml, 20.95 mmol), in anhydrous THF (10 ml) was stirred with magnesium (458 mg, 18.85 mmol) at 55° C. until a reaction is started. The rest of the solution was added and stirred for 1 hour at 55° C. under nitrogen atmosphere until all the magnesium was consumed. A solution of (S)-5-(3,4-dichlorophenyl)-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxamide (700 mg, 2.09 mmol) in anhydrous THF (10 ml) was slowly added to the Grignard preparation at 0° C. The mixture was warmed to room temperature and stirred for 3 hours under nitrogen atmosphere. The mixture was diluted with water and 10% NH4Cl and extracted 3 times with diethyl ether. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (20-40%) to yield 150 mg of the desired product, (5S)-5-(3,4-dichlorophenyl)-8-hydroxy-8-isopropyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide.
(5S)-5-(3,4-dichlorophenyl)-8-hydroxy-8-isopropyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide (150 mg, 0.40 mmol) was dissolved in 20 ml of 1 M HCl in diethyl ether. The mixture was stirred overnight. The mixture was diluted with NaHCO3 and extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (30-50%) to yield 92 mg of the desired product, (S)-5-(3,4-dichlorophenyl)-8-isopropyl-5,6-dihydronaphthalene-2-carboxamide. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 7.91 (s, 1H), 7.51 (dd, 1H), 7.34 (d, 1H), 7.20 (d, 1H), 6.97 (d, 2H), 5.82 (t, 1H), 4.03 (t, 1H), 3.04-3.14 (m, 1H), 2.52-2.72 (m, 2H), 1.17 (d, 6H). Mass spectrometry showed m/z=360.1 (M+H+).
N-(5-(3,4-dichlorophenyl)-8-isopropyl-5,6-dihydronaphthalen-2-yl)acetamide (87 mg, 0.24 mmol) was dissolved in methanol. The reaction vessel was purged with nitrogen before Pd/C (200 mg) was added. Hydrogen gas was allowed to bubble through the solution for 2 hours. The mixture was filtered over celite and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (50%) to yield 36 mg of the desired product, (S)-5-(3,4-dichlorophenyl)-8-isopropyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide. 1H NMR (CDCl3, 400 MHz) generated the following peaks: δ 7.82 (s, 1H), 7.44 (dd, 1H), 7.18-7.30 (m, 3H), 7.04 (dd, 2H), 6.99 (d, 1H), 4.17 (t, 1H), 2.72-2.75 (m, 1H), 2.37-2.39 (m, 1H), 2.00-2.08 (m, 2H), 1.70-1.74 (m, 2H), 1.05 (d, 3H), 0.84 (d, 3H).
A solution of 4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one (5.00 g, 17.17 mmol) in TFA (52.5 ml) was cooled to 0° C. Trifluoromethanesulfonic acid (5.25 ml) was added followed by potassium nitrate (1.73 g, 17.17 mmol). The mixture was stirred for 1.5 hours under nitrogen atmosphere. The reaction was poured into a mixture of ice and ammonia solution. The mixture was extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with EA:Hexane (10%) to yield 1.70 g of the desired product, 4-(3,4-dichlorophenyl)-7-nitro-3,4-dihydronaphthalen-1(2H)-one. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 7.53 (d, 1H), 6.81-6.93 (m, 4H), 6.32 (d, 1H), 3.72-3.77 (m, 1H), 2.05-2.09 (m, 2H), 1.87-1.95 (m, 1H), 1.63-1.72 (m, 1H).
4-(3,4-dichlorophenyl)-7-nitro-3,4-dihydronaphthalen-1(2H)-one (1.64 g, 4.88 mmol) was dissolved in 35 ml of 85% ethanol. Fe powder (2.45 g, 43.91 mmol) and CaCl2 (271 mg, 2.44 mmol) were added and the mixture was reflux at 90° C. overnight under nitrogen atmosphere. The reaction was cooled and filtered over celite. The filtrate was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (10-25%) to yield 1.09 g of the desired product, 7-amino-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 8.11 (d, 1H), 7.35-7.50 (m, 2H), 7.01 (d, 1H), 6.66 (d, 1H), 6.34 (d, 1H), 4.13-4.16 (m, 1H), 2.21-2.77 (m, 4H).
To a solution of 7-amino-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one (1.09 g, 3.56 mmol) in DCM (15 ml) was added triethylamine (2.5 ml) followed by acetic anhydride (1.3 ml). The mixture was stirred for 2 days. The mixture was diluted with water and extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (30%) to yield 900 mg of the desired product, N-(5-(3,4-dichlorophenyl)-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 8.28 (s, 1H), 8.12 (d, 1H), 7.69 (s, 1H), 7.36-7.50 (m, 2H), 6.97 (d, 1H), 6.86 (d, 1H), 4.27-4.31 (m, 1H), 2.24-2.77 (m, 4H), 2.24 (s, 3H). Mass spectrometry showed m/z=348.0 (M+H+).
A small amount of 2-bromopropane (809 ul, 8.62 mmol), in anhydrous THF (8 ml) was stirred with magnesium (188 mg, 7.75 mmol) at 35° C. until a reaction is started. The rest of the solution was added and stirred for 30 minutes at 55° C. under nitrogen atmosphere until all the magnesium was consumed. A solution of N-(5-(3,4-dichlorophenyl)-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (300 mg, 0.86 mmol) in anhydrous THF (8 ml) was slowly added to the Grignard preparation at 0° C. The mixture was warmed to room temperature and stirred for 3 hours under nitrogen atmosphere. The mixture was diluted with water and 10% NH4Cl and extracted 3 times with diethyl ether. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (20-40%) to yield 60 mg of the desired product, N-(5-(3,4-dichlorophenyl)-8-hydroxy-8-isopropyl-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide.
N-(5-(3,4-dichlorophenyl)-8-hydroxy-8-isopropyl-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (60 mg, 0.15 mmol) was dissolved in 10 ml of 1 M HCl in diethyl ether. The mixture was stirred overnight. The mixture was diluted with NaHCO3 and extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (15-30%) to yield 20 mg of the desired product, N-(5-(3,4-dichlorophenyl)-8-isopropyl-5,6-dihydronaphthalen-2-yl)acetamide. Mass spectrometry showed m/z=374.1 (M+H+).
N-(5-(3,4-dichlorophenyl)-8-isopropyl-5,6-dihydronaphthalen-2-yl)acetamide (20 mg, 0.05 mmol) was dissolved in methanol. The reaction vessel was purged with nitrogen before Pd/C (150 mg) was added. Hydrogen gas was allowed to bubble through the solution for 2 hours. The mixture was filtered over celite and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (30%) to yield 8 mg of the desired product, N-(5-(3,4-dichlorophenyl)-8-isopropyl-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide. 1H NMR (CDCl3, 400 MHz) generated the following peaks: δ 7.46 (d, 1H), 7.15-7.31 (m, 2H), 7.05-7.09 (m, 2H), 6.91 (d, 1H), 6.80 (d, 1H), 4.11-4.14 (m, 1H), 2.68-2.70 (m, 1H), 2.31-2.33 (m, 1H), 2.14 (s, 3H), 1.95-2.09 (m, 2H), 1.67-1.71 (m, 2H), 1.04 (d, 3H), 0.82 (d, 3H).
N-(5-(3,4-dichlorophenyl)-8-((2-hydroethyl)(methyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (43.5 mg, 0.12 mmol, described in PCT Publication No. WO 00/51972) in methanol (1 mL) was mixed with (tert-butyldimethylsilyloxy)acetaldehyde (15.8 μL, 0.083 mmol). The reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added to the mixture, and it was allowed to stir overnight at room temperature. The mixture was concentrated in vacuo before subsequent dilution with dichloromethane and extraction with water. The organic fractions were washed with brine and dried over anhydrous MgSO4. The product was purified by silica gel flash chromatography using 10% ethyl acetate in hexane to yield 33 mg of the desired product. Mass spectrometry showed m/z=521.2 (M+H+).
N-((5S,8S)-8-((2-(tert butyldimethylsilyloxy)ethyl)(methyl)amino)-5-(3,4-dichloro-phenyl)-5,6,7,8-tetrahydronaphthalen-2 yl)acetamide (33 mg, 0.063 mmol) in THF (0.5 mL) was added to 1M tetrabutylammonium fluoride in THF (0.095 mL, 0.095 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic fractions were washed with brine and dried over anhydrous MgSO4. The product was purified by silica gel flash chromatography using 65% ethyl acetate in hexane to yield 9.9 mg of the desired product. 1H NMR (MeOD, 400 MHz) δ 7.90 (d, 1H), 7.40 (dd, 1H), 7.13 (d, 1H), 6.94 (dd, 1H), 6.85 (d, 1H), 4.16 (t, 1H), 3.88 (s, 1H), 3.69-3.65 (m, 2H), 2.71-2.58 (m, 2H), 2.31 (s, 3H), 2.15-2.11 (m, 4H), 2.04-2.00 (m, 1H), 1.74-1.60 (m, 2H). Mass spectrometry showed m/z=407.1 (M+H+).
This compound was prepared in a manner analogous to N-((5S,8S)-5-(3,4-dichlorophenyl)-8-((2-hydroxyethyl)(methyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, as described in Example 28. 1H NMR (MeOH-d4, 400 Mhz) generated the following peaks: δ 7.84 (s, 1H), 7.39 (d, 1H), 7.14-7.17 (m, 2H), 6.94 (dd, 2H), 4.13-4.21 (m, 2H), 3.99-4.04 (m, 2H), 3.67 (t, 2H), 2.62-2.70 (m, 2H), 2.58 (s, 3H), 2.35 (s, 3H), 1.98-2.06 (m, 2H), 1.64-1.77 (m, 2H). Mass spectrometry showed m/z=426.1 (M+H+).
(5S,8S)-5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (2.1 g, 6.34 mmol, WO 00/51972) was added to 40 ml concentrated HCl and the mixture was refluxed overnight. After being cooled to room temperature white solid was filtered, washed with cold water, and dried in vacuum. The white solid was dissolved in methanol (60 ml), to which 2 ml of concentrated H2SO4 was added. The mixture was refluxed overnight and then the reaction was quenched by sodium bicarbonate in ice bath. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:hexane (50%) to yield 1.5 g desired product, (5S,8S)-methyl 5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxylate. Mass spectrometry showed m/z=364.0 (M+H+).
DIPEA (1.12 ml, 8.24 mmol) was added to (5S,8S)-methyl 5-(3,4-dichlorophenyl)-8-(methylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (1.5 g, 4.12 mmol) in DCM (30 ml) and followed by addition of Boc2O (1.35 g, 6.18 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours, diluted with DCM, and washed with water and brine. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography and eluted with ethyl acetate:hexane (10%-40%) to yield 1.86 g desired product, (5S,8S)-methyl 8-(tert-butoxycarbonyl(methyl)amino)-5-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate. Mass spectrometry showed m/z=364.0 (M+H+-Boc).
To 2-fluoro-5-sulfamoylbenzoic acid (250 mg, 1.14 mmol) in 3 mL DMF/DCM (1:1) was added HATU (542 mg, 1.42 mmol) and followed by Glycine methyl ester, hydrochloride (179 mg, 1.42 mmol) and 4-methyl morpholine (0.627mL, 5.70 mmol). The mixture was stirred at room temperature for 2 hours and diluted with water. The resulting mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with Ethyl Acetate:Hexane (40%) to yield 280 mg desired product, methyl 2-(2-fluoro-5-sulfamoylbenzamido)acetate.
A mixture of methyl 2-(2-fluoro-5-sulfamoylbenzamido)acetate (280 mg, 0.96 mmol), 3-methyl-4-(methylthio)phenol (164 mg, 1.06 mmol) and K2CO3 (160 mg, 1.15 mmol) in DMF (4 ml) was allowed to stir at 100° C. oil bath for 2 hours. Then the mixture was cooled to 0° C. then acidified to pH=1 by 2N HCl. The mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:Hexane (50%) to yield 267 mg desired product, Methyl 2-(2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzamido)acetate. Mass spectrometry showed m/z=425.0 (M+H+).
Methyl 2-(2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzamido)acetate (247 mg, 0.58 mmol) was dissolved in 5 mL of anhydrous THF and cooled to 0° C., followed by dropwise addition of 17.5 mL of Borane THF complex (1.0M in THF). Then the mixture was warmed to room temperature and then refluxed for two days. The mixture was quenched by addition of 10N HCl (1.75 mL), and the mixture was refluxed for 1 hour. Then the solution was basified by K2CO3 until pH=9-10. The mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH: DCM (10%) to yield 77.5 mg desired product, 3-((2-hydroxyethylamino)methyl)-4-(3-methyl-4-(methylthio)phenoxy)benzenesulfon-amide. 1H NMR (DMSO-d6, 400 MHz) generated the following peaks: δ 7.98 (d, 1H), 7.66 (dd, 1H), 7.24-7.28 (m, 3H), 6.85-6.95 (m, 3H), 4.59 (b, 1H), 3.86 (s, 2H), 3.48-3.53 (m, 2H), 2.66 (t, 2H), 2.46 (s, 3H), 2.25 (s, 3H). Mass spectrometry showed m/z=383.1 (M+H+).
3-((2-hydroxyethylamino)methyl)-4-(3-methyl-4-(methylthio)phenoxy)benzenesulfon-amide (Example 29, 67 mg, 0.17 mmol) was dissolved in 1 mL MeOH and was added to 37% formaldehyde (12.8 uL, 0.16 mmol). The mixture was stirred at room temperature for 1 hour and followed by addition of NaHB(OAc)3 (148 mg, 0.70 mmol). Then the mixture was stirred for 4 hours. The mixture was quenched by addition of water. The mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with ethyl acetate:Hexane (80%) and ethyl acetate:Hexane:triethylamine (90:10:1) to yield 16.7 mg desired product, 3-(((2-hydroxyethyl)(methyl)amino)methyl)-4-(3-methyl-4-(methylthio)phenoxy)benzenesul-fonamide. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 8.02 (d, 1H), 7.74 (dd, 1H), 7.18 (d, 1H), 6.83-6.86 (m, 3H), 3.73 (s, 2H), 3.64 (t, 2H), 2.66 (t, 2H), 2.46 (s, 3H), 2.33 (d, 6H). Mass spectrometry showed m/z=397.1 (M+H+).
2-fluoro-5-sulfamoyl benzoic acid (3.5 g, 16 mmol) in anhydrous DMF (30 mL) were added to iodomethane (1.09 mL, 17.6 mmol) and potassium carbonate (2.65 g, 19.2 mmol). The reaction was then stirred overnight at room temperature and quenched with water. The organic layer was separated, the aqueous fraction was extracted with ethyl acetate, and the organic layers were combined and dried with anhydrous MgSO4. The desired product (2.57 g) was purified by silica gel flash chromatography using 50% ethyl acetate in hexanes. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 8.53 (dd, 1H), 8.05-8.11 (m, 1H), 7.31 (d, 1H), 5.14 (s, 2H), 3.96 (s, 3H).
Methyl 2-fluoro-5-sulfamoylbenzoate (2.57 g, 11 mmol) in anhydrous DMF (15 mL) were added to 3-methyl-4-(methylthio)phenol (1.87 g, 12.1 mmol) and potassium carbonate (1.82 g, 13.2 mmol). The reaction was then stirred overnight at 100° C. and acidified with 1M HCl to pH 1. The organic layer was separated, the aqueous fraction was extracted with ethyl acetate, and the organic layers were combined and dried with anhydrous MgSO4. The desired product (2.00 g) was purified by silica gel flash chromatography using 50% ethyl acetate in hexane. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 8.45 (d, 1H), 7.91 (dd, 1H), 7.20 (d, 1H), 6.88-6.93 (m, 3H), 4.88 (s, 2H), 3.91 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H).
Methyl 2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzoate (2.00 g, 5.44 mmol) in 10% H2O in methanol was added to lithium hydroxide (1.96 g, 81.6 mmol). The reaction was then stirred overnight at room temperature and quenched with 0.1N HCl. The organic layer was separated. The aqueous fraction was extracted with ethyl acetate and the organic layers were combined and dried with anhydrous MgSO4. The desire product (1.36 g) was purified by silica gel flash chromatography using 20% methanol in ethyl acetate. 1H NMR (CD3OD, 300 MHz) generated the following peaks: δ 8.16 (d, 1H), 7.78 (dd, 1H), 7.24 (d, 1H), 6.87-6.91 (m, 3H), 2.43 (s, 3H), 2.29 (s, 3H); Mass spectrometry showed m/z=354.2 (M+H+).
To a mixture of 2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzoic acid (100 mg, 0.28 mmol, Preparation 2) and HATU (161 mg, 0.42 mmol) in 1:1 anhydrous DCM: DMF (3 ml) was added to (S)-1-aminopropan-2-ol (25 ul, 0.31 mmol) and 4-methylmorpholine (124 ul, 1.13 mmol). The mixture was stirred overnight. The mixture was diluted with water and extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:DCM (2%) to yield 96 mg of the desired product, (S)—N-(2-hydroxypropyl)-2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzamide. Mass spectrometry showed m/z=411.0 (M+H+).
A solution of (S)—N-(2-hydroxypropyl)-2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzamide (96 mg, 0.23 mmol) in THF (3 ml) was treated with 1 M BH3.THF complex (935 ul, 0.94 mmol) at room temperature. The mixture was refluxed at 100° C. for 5 hours. The mixture was then cooled to room temperature and treated cautiously with 6 M HCl solution (2 ml). The resulting mixture was refluxed at 100 for 30 minutes. The mixture was cooled to room temperature, diluted with water and basified by the cautious addition of K2CO3 to pH 9. The mixture was extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:EA (0-10%) to yield 50 mg of the desired product, (S)-3-((2-hydroxypropylamino)methyl)-4-(3-methyl-4-(methylthio)phenoxy)benzenesulfonamide. 1H NMR (CD3OD, 300 MHz) generated the following peaks: δ 7.95 (d, 1H), 7.74 (dd, 1H), 7.29 (d, 1H), 6.84-6.94 (m, 3H), 3.86-3.40 (m, 3H), 2.55-2.61 (m, 2H), 2.46 (s, 3H), 2.32 (s, 3H), 1.15 (d, 3H). Mass spectrometry showed m/z=397.1 (M+H+).
Example 35-57 (Table 33) were prepared in a manner analogous to (S)-3-((2-hydroxypropylamino)methyl)-4-(3-methyl-4-(methylthio)phenoxy)benzenesulfonamide, as described in Example 34.
Example 58-61 (Table 34) were prepared in a manner analogous to 3-(((2-hydroxyethyl)(methyl)amino)methyl)-4-(3-methyl-4-(methylthio) phenoxy)benzenesulfonamide, as described in Example 32.
A solution of 2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzoic acid (500 mg, 1.41 mmol, Preparation 2) in MeOH (40 ml) and concentrated sulfuric acid (0.5 ml) was refluxed at 80° C. overnight. The mixture was concentrated in vacuo. The residue was purified by flash chromatography eluted with EA:Hexane (30-50%) to yield 500 mg of the desired product, methyl 2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzoate.
Methyl 2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzoate (500 mg, 1.36 mmol) was dissolved in anhydrous THF (10 ml) and cooled to 0° C., followed by drop-wise addition of 1 M LAH in THF (2.7 ml). The mixture was then warmed to room temperature and stirred for 2 hours under nitrogen atmosphere. The mixture was quenched by addition of water at 0° C., and then acidified to pH 1 using 2% HCl solution. The aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (50%) to yield 400 mg of the desired product, 3-(hydroxymethyl)-4-(3-methyl-4-(methylthio)phenoxy)benzene-sulfonamide.
To a solution of 3-(hydroxymethyl)-4-(3-methyl-4-(methylthio)phenoxy)benzenesul-fonamide (400 mg, 1.18 mmol) in DCM (10 ml) was added Dess-Martin periodinane (600 mg, 1.41 mmol). The mixture was stirred for 2 hours. The mixture was diluted with 10% sodium thiosulfate and saturated NaHCO3. The aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (20-60%) to yield 324 mg of the desired product, 3-formyl-4-(3-methyl-4-(methylthio)phenoxy)benzenesulfonamide.
To a solution of 3-formyl-4-(3-methyl-4-(methylthio)phenoxy)benzenesulfonamide (324 mg, 0.96 mmol) in DCM (10 ml) was added di-tert-butyl dicarbonate (241 mg, 1.10 mmol), triethylamine (147 ul, 1.06 mmol) and DMAP (12 mg, 0.10 mmol). The mixture was stirred overnight. The mixture was diluted with water and extracted 3 times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (30-60%) to yield 305 mg of the desired product, tert-butyl 3-formyl-4-(3-methyl-4-(methylthio)phenoxy)phenylsulfonylcarbamate.
A small amount of 2-bromopropane (655 ul, 6.97 mmol), in anhydrous THF (8 ml) was stirred with magnesium (136 mg, 5.58 mmol) at 35° C. until a reaction is started. The rest of the solution was added and stirred for 30 minutes at 35° C. under nitrogen atmosphere until all the magnesium was consumed. A solution of tert-butyl 3-formyl-4-(3-methyl-4-(methylthio)phenoxy)phenylsulfonylcarbamate (305 mg, 0.70 mmol) in anhydrous THF (8 ml) was slowly added to the Grignard preparation at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes under nitrogen atmosphere. The mixture was diluted with water and 10% NH4Cl and extracted 3 times with diethyl ether. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (30%) to yield 90 mg of the desired product, tert-butyl 3-(1-hydroxy-2-methylpropyl)-4-(3-methyl-4-(methylthio)phenoxy)phenylsulfonylcarbamate. 1H NMR (CDCl3, 400 MHz) generated the following peaks: δ 8.11 (d, 1H), 7.81 (dd, 1H), 7.20 (d, 1H), 6.78-6.91 (m, 3H), 4.87 (d, 1H), 2.48 (s, 3H), 2.35 (s, 3H), 2.15 (m, 2H), 1.40 (s, 9H), 0.96 (dd, 6H).
To a solution of tert-butyl 3-(1-hydroxy-2-methylpropyl)-4-(3-methyl-4-(methylthio) phenoxy)phenylsulfonylcarbamate (90 mg, 0.19 mmol) in DCM (3 ml) was added Dess-Martin periodinane (95 mg, 0.22 mmol). The mixture was stirred for 2 hours. The mixture was diluted with 10% sodium thiosulfate and saturated NaHCO3. The aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (20-30%) to yield 62 mg of the desired product, tert-butyl 3-isobutyryl-4-(3-methyl-4-(methylthio)phenoxy)phenylsulfonyl-carbamate. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 8.22 (d, 1H), 7.98 (dd, 1H), 7.22 (d, 1H), 6.88-6.94 (m, 3H), 3.51 (m, 1H), 2.49 (s, 3H), 2.36 (s, 3H), 1.42 (s, 9H), 1.20 (d, 6H).
A mixture of zinc (169 mg, 2.59 mmol), mercury(II) chloride, concentrated HCl (1 drop) and water (1 ml) was stirred for 5 minutes. The solution was decanted and to it was added water (2.4 ml), concentrated HCl (0.6 ml), tert-butyl 3-isobutyryl-4-(3-methyl-4-(methylthio)phenoxy)phenylsulfonylcarbamate (62 mg, 0.13 mmol) in toluene (0.9 ml) and glacial acetic acid (1 drop) sequentially. The mixture was heated at 100° C. overnight. The reaction was diluted with water and extracted 3 times with diethyl ether. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with EA:Hexane (10-30%) to yield 10 mg of a mixture of products. The crude product was further purified using reverse phase HPLC to yield 5 mg of the desired product, 3-isobutyl-4-(3-methyl-4-(methylthio)phenoxy)benzenesulfonamide. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 7.77 (d, 1H), 7.65 (dd, 1H), 7.19 (d, 1H), 6.80-6.84 (m, 3H), 4.77 (s, 2H), 2.61 (d, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 2.01 (m, 1H), 0.94 (d, 6H). Mass spectrometry showed m/z=366.1 (M+H+).
5 mg of a side product, 4-(3-methyl-4-(methylthio)phenoxy)-3-(2-methylprop-1-enyl)benzenesulfonamide was obtained. 1H NMR (CDCl3, 300 MHz) generated the following peaks: δ 7.84 (d, 1H), 7.66 (dd, 1H), 7.18 (d, 1H), 6.82-6.85 (m, 3H), 6.30 (s, 1H), 4.78 (s, 2H), 2.46 (s, 3H), 2.34 (s, 3H), 1.88 (d, 6H). Mass spectrometry showed m/z=364.0 (M+H+).
To a mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (108 mg, 0.47 mmol) and TBTU (163 mg, 0.51 mmol) in DMF (2 ml) was added 4-(3-methyl-4-(methylthio)phenoxy)-3-((methylamino)methyl)benzenesulfonamide (149 mg, 0.42 mmol, WO 00/51972) and N-ethyl-N-isopropylpropan-2-amine (295 ul, 1.69 mmol). The mixture was stirred overnight. The mixture was diluted with water and extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with EA:Hexane (50-100%) to yield 120 mg of the desired product, (2R,4R)-tert-butyl 4-hydroxy-2-(methyl(2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzyl)carbamoyl)pyrrolidine-1-carboxylate.
To a solution of (2R,4R)-4-hydroxy-N-methyl-N-(2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzyl)pyrrolidine-2-carboxamide (120 mg, 0.21 mmol) in DCM (3 ml) was added TFA (3 ml). The mixture was stirred for 30 minutes. The mixture was concentrated in vacuo. Te residue was diluted with saturated NaHCO3 and neutralized with NH4Cl to pH 8. The mixture was extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:EA (8-20%) to yield 75 mg of the desired product, (2R,4R)-4-hydroxy-N-methyl-N-(2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzyl)pyrrolidine-2-carboxamide. Mass spectrometry showed m/z=466.1 (M+H+).
A solution of (2R,4R)-4-hydroxy-N-methyl-N-(2-(3-methyl-4-(methylthio)phenoxy)-5-sulfamoylbenzyl)pyrrolidine-2-carboxamide (75 mg, 0.16 mmol) in THF (2 ml) was treated with 1 M BH3.THF complex (1.6 ml, 1.61 mmol) at room temperature. The mixture was refluxed at 100° C. for 5 hours. The mixture was then cooled to room temperature and treated cautiously with 6 M HCl solution (2 ml). The resulting mixture was refluxed at 100 for 30 minutes. The mixture was cooled to room temperature, diluted with water and basified by the cautious addition of K2CO3 to pH 9. The mixture was extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:DCM (5-20%) to yield 20 mg of the desired product, 3-(((((2R,4R)-4-hydroxypyrrolidin-2-yl)methyl)(methyl)amino)methyl)-4-(3-methyl-4-(methylthio)phenoxy)benzenesulfonamide. 1H NMR ((CD3)2SO, 400 MHz) generated the following peaks: δ 7.98 (d, 1H), 7.67 (dd, 1H), 7.28 (s, 2H), 7.24 (d, 1H), 6.85-6.92 (m, 3H), 4.92 (s, 1H), 4.23 (s, 1H), 4.10 (s, 1H), 3.31 (s, 4H), 3.06 (dd, 1H), 2.76 (d, 1H), 2.44 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 1.78-1.82 (m, 1H), 1.48-1.51 (m, 1H). Mass spectrometry showed m/z=452.1 (M+H+).
2 M Ammonia in ethanol (54 ml) was added to 3-cyano-4-fluorobenzenesulfonyl chloride (4.70 g, 21.40 mmol). The suspension was stirred for 15 minutes under nitrogen atmosphere. The mixture was diluted with 2 N HCl solution and extracted 3 times with diethyl ether. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with EA:Hexane (50%) to yield 3.00 g of the desired product, 3-cyano-4-fluorobenzenesulfonamide. 1H NMR ((CD3)2SO, 300 MHz) generated the following peaks: δ 8.32 (dd, 1H), 8.16-8.20 (m, 1H), 7.76 (t, 1H), 7.62 (s, 2H).
To a solution of 3-cyano-4-fluorobenzenesulfonamide (1.00 g, 5.00 mmol) in anhydrous DCM (20 ml) was added di-tert-butyl dicarbonate (1.25 g, 5.74 mmol), triethylamine (766 ul, 5.49 mmol) and DMAP (61 mg, 0.50 mmol). The mixture was stirred for 5 hours. The mixture was diluted with water and extracted 3 times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with MeOH:DCM (2-10%) to yield 1.27 g of the desired product, tert-butyl 3-cyano-4-fluorophenylsulfonylcarbamate. 1H NMR ((CD3)2SO, 400 MHz) generated the following peaks: δ 8.16 (dd, 1H), 8.07-8.11 (m, 1H), 7.61 (t, 1H), 1.23 (s, 9H).
The prepared aniline (367 mg, 2.40 mmol) was added to potassium tert-butoxide (1.12 g, 9.99 mmol) in anhydrous DMSO (8 ml). The mixture was stirred for 10 minutes and cooled to 0° C. tert-butyl 3-cyano-4-fluorophenylsulfonylcarbamate (600 mg, 2.00 mmol) was added and the mixture stirred overnight at room temperature under nitrogen atmosphere. The mixture was diluted with saturated NH4Cl solution and extracted 3 times with diethyl ether. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography and eluted with MeOH:DCM (2-10%) to yield 400 mg of the desired product, tert-butyl 3-cyano-4-(3-methyl-4-(methylthio)phenylamino)phenylsulfonyl-carbamate, contaminated with a side product. Sufficient clean fractions were obtained for 1H NMR (CDCl3, 400 MHz) which generated the following peaks: δ 8.13 (d, 1H), 7.88 (dd, 1H), 7.20 (d, 1H), 7.01-7.10 (m, 3H), 6.74 (s, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 1.43 (s, 9H).
To a solution of impure tert-butyl 3-cyano-4-(3-methyl-4-(methylthio)phenylamino) phenylsulfonylcarbamate (400 mg, 0.92 mmol) in DCM (15 ml) was added TFA (5 ml). The mixture was stirred for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by flash chromatography eluted with EA:Hexane (40%) to yield 190 mg of the desired product, 3-cyano-4-(3-methyl-4-(methylthio)phenylamino)benzene-sulfonamide. 1H NMR (CD3OD, 400 MHz) generated the following peaks: δ 7.99 (d, 1H), 7.79 (dd, 1H), 7.26 (d, 1H), 7.06-7.12 (m, 3H), 2.46 (s, 3H), 2.32 (s, 3H).
A solution of 3-cyano-4-(3-methyl-4-(methylthio)phenylamino)benzenesulfonamide (190 mg, 0.57 mmol) in THF (4 ml) was treated with 1 M BH3.THF complex (5.7 ml) at room temperature. The mixture was refluxed at 100° C. for 5 hours. The mixture was then cooled to room temperature and treated cautiously with MeOH (5.7 ml). The mixture was concentrated in vacuo. The residue was treated with 6 M HCl solution (5.7 ml) and the resulting mixture was refluxed at 100 for 1 hour. The mixture was cooled to room temperature, diluted with water and basified with 2 N NaOH solution until pH 9 was reached. The mixture was extracted 3 times with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with MeOH:EA (0-5%) to yield 140 mg of the desired product, 3-(aminomethyl)-4-(3-methyl-4-(methylthio)phenylamino)benzenesulfonamide. 1H NMR (CD3OD, 400 MHz) generated the following peaks: δ 7.74 (d, 1H), 7.61 (dd, 1H), 7.18-7.23 (m, 2H), 6.97-6.99 (m, 2H), 3.90 (s, 2H), 2.41 (s, 3H), 2.31 (s, 3H).
37% Formaldehyde in MeOH (10 ul, 0.13 mmol) was added to 3-(aminomethyl)-4-(3-methyl-4-(methylthio)phenylamino)benzenesulfonamide (50 mg, 0.15 mmol) in anhydrous DCM (3 ml) and stirred for 30 minutes. NaHB(OAc)3 (126 mg, 0.59 mmol) was added and the mixture stirred overnight. Another portion of formaldehyde and NaHB(OAc)3 were added and the mixture stirred for another 5 hours. The mixture was basified with saturated NaHCO3 and extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluted with EA:Hexane (30-80%) to yield 10 mg of the desired product, 3-methyl-1-(3-methyl-4-(methylthio)phenyl)-1,2,3,4-tetrahydroquinazoline-6-sulfonamide. 1H NMR (CDCl3, 400 MHz) generated the following peaks: δ 7.49 (m, 2H), 7.20 (d, 1H), 7.00-7.06 (m, 2H), 6.59 (d, 1H), 4.62 (s, 2H), 4.38 (s, 2H), 3.99 (s, 2H), 2.55 (s, 3H), 2.49 (s, 3H), 2.34 (s, 3H). Mass spectrometry showed m/z=364.1 (M+H+).
10 mg of side product, 3-((dimethylamino)methyl)-4-(3-methyl-4-(methylthio)phenyl-amino)benzenesulfonamide was also obtained. 1H NMR (CDCl3, 400 MHz) generated the following peaks: δ 9.19 (s, 1H), 7.66 (dd, 1H), 7.61 (d, 1H), 7.20 (m, 2H), 6.97 (m, 2H), 4.65 (s, 2H), 3.52 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.26 (s, 6H). Mass spectrometry showed m/z=366.1 (M+H+).
All publications, patent applications, including U.S. Provisional Application Nos. 60/844,463, filed Sep. 14, 2006, 60/874,061 filed Dec. 11, 2006, and 61/069,917, filed Mar. 19, 2008, 61/070,047, filed Mar. 19, 2008, and U.S. patent application Ser. No. 11/900,893, filed Sep. 13, 2007, and patents mentioned in this specification are herein incorporated by reference.
Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific desired embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the fields of molecular biology, medicine, immunology, pharmacology, virology, or related fields are intended to be within the scope of the invention.
This application claims the benefit of U.S. Provisional Application No. 61/070,047, filed Mar. 19, 2008 and U.S. Provisional Application No. 61/089,850, filed Aug. 18, 2008, each of which is hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61070047 | Mar 2008 | US | |
| 61089850 | Aug 2008 | US |
