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Indole antiviral compositions and methods

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Indole antiviral compositions and methods


The present invention provides novel chemical compounds, and methods for their use. In particular, the present invention provides indole derivatives (e.g. as shown in Formula (I)) and related compounds and methods of using indole derivatives and related compounds as therapeutic agents to treat a number of conditions, including those associated with viral infection and cardiovascular diseases.
Related Terms: Indole Indole Derivatives Viral Infection

Browse recent The Regents Of The University Of Michigan patents - Ann Arbor, MI, US
Inventors: Leroy B. Townsend, John C. Drach
USPTO Applicaton #: #20120270827 - Class: 514 43 (USPTO) - 10/25/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >O-glycoside >Nitrogen Containing Hetero Ring

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The Patent Description & Claims data below is from USPTO Patent Application 20120270827, Indole antiviral compositions and methods.

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CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation allowed U.S. patent application Ser. No. 13,077,538, filed Mar. 31, 2011 (which will issue on Jun. 19, 2012 as U.S. Pat. No. 8,202,844), which is a Continuation of allowed U.S. patent application Ser. No. 12/500,311, filed Jul. 9, 2009 (now U.S. Pat. No. 7,928,080), which is a Continuation of allowed U.S. patent application Ser. No. 12/038,919, filed Feb. 28, 2008 (now U.S. Pat. No. 7,625,871), which is a Continuation of allowed U.S. patent application Ser. No. 10/959,885, filed Oct. 6, 2004 (now U.S. Pat. No. 7,419,963), which claims priority to expired U.S. Provisional Application No. 60/509,412, filed Oct. 7, 2003, all of which are incorporated hereby by reference in their entireties.

STATEMENT OF FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under grant numbers AI31718 and AI46390 awarded by the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The government has certain rights in this invention.

FIELD OF THE INVENTION

The present invention relates to novel chemical compounds, and methods for their use. In particular, the present invention provides indole derivatives (e.g. as shown in Formula (I)) and related compounds and methods of using indole derivatives and related compounds as therapeutic agents to treat a number of conditions, including those associated with viral infection and cardiovascular diseases.

BACKGROUND OF THE INVENTION

The herpesviruses comprise a large family of double stranded DNA viruses. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans. Several of these viruses are important human pathogens. HSV-1 is estimated to affect 100 million people in the U.S. Primary infection of HSV-1 usually occurs between the ages of one and four. Cold sores, the visible symptom, typically appear at a later age, with 20-45% of the population over the age of fifteen affected (see, Whitley, Clin. Intect. Dis., 26:541-555, 1998, herein incorporated by reference). Genital herpes (HSV-2) is the second most common sexually transmitted disease, with approximately 22% of the U.S. population infected with this virus. VZV is the causative agent of chicken pox upon primary infection and can recur in adults as zoster. EBV results in approximately two million cases of infectious mononucleosis in the U.S. each year. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt\'s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. Infection with HCMV often occurs during childhood and is typically asymptomatic except in immunocompriomised patients where it causes significant morbidity and mortality. HHV-6 is the causitive agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi\'s sarcoma, body cavity based lymphomas, and multiple myeloma.

These viruses are capable of residing in a latent state within the host. Reactivation of latent virus results from response to environmental stimuli (ex. UV exposure, stress, etc.). Infections or recurrence can be life threatening in immunocompromised patients such as AIDS or transplant patients where HCMV can result in retinitis, pneumonia, and gastrointestinal disease. What is needed, therefore, are compounds capable of treating and/or preventing infection with one or more of these viruses.

SUMMARY

OF THE INVENTION

The present invention provides novel chemical compounds, and methods for their therapeutic use. In particular, the present invention provides indole derivatives and related compounds and methods of using indole derivatives and related compounds as therapeutic agents to treat a number of conditions associated with viral infection and cardiovascular disease.

In some embodiments, the present invention provides compositions comprising a compound as depicted in formula (I), wherein formula (I) is as follows:

and wherein: R1 is alkyl, alkenyl, aralkyl, polyhydroxyalkyl, or carbohydrate; R2 is halogen, —N, R9, —O—R10, or —S—R11; R3 is CN, C═NR12, CXNH2, COR, CH2COR—COR13, halogen, exocyclic heterocycle, or NO2; and R4, R5, R6, R7 are hydrogen, halogen, nitro, or azido (R9-R13 and remaining R groups described in examples below). In particular embodiments, R3 is not CHO, CN, or CONH2. It is noted that Formula I is not limited to any particular stereochemistry, unless otherwise indicated.

In certain embodiments, R1 is alkyl C1-10; alkenyl C1-10; aryl C1-10, including heteroaryl; hydroxyethoxymethoxy (HEM), dihydroxypropoxymethyl (DHPM); pentofuranosyl and pentopyranosyl (D or L) (α or β), tetrafuranosyl (D or L) (α or β); R2 is —NR8R9 where R8 and R9 may be different or the same and selected from alkyl (C1-10), alkenyl (C1-10), aryl, heteroaryl, arylalkyl; halogen (e.g., chloro, bromo), cyano, mercaptan, alkylmercaptan, (C1-10), alkoxy (C1-10; R3 is cyano, C═NR12 where R12 may be alkyl, alkylamine, urea, thiourea; —CXNH2 where X may be ═S, ═O, ═NH, ═N—NH2, ═NOH, ═N—NHR; —RC═O where R may be H, alkyl (C1-10); —CH2—C—R where R may be H, alkyl (C1-10); heterocycle, e.g., thiophine, furan, imidazole, tetrazole, imidazolidine, thiazole, triazole; or nitro; and R4-R7 are halogen (chloro, bromo, fluoro, iodo) where R4-R7 may be the same or different halo groups or hydrogen; R4-R7 may be nitro groups or azido group with halogens in different juxtapositions, or R4-R7 may also represent different alkyl (C1-6) groups in with the halogens, nitro and azido groups.

In other embodiments, R1 is D or L-ribose, D or L-xylose, D or L-arabinose, D or L-lyxose, D or L-erythrose, D or L threose; also the 2-deoxy, 3-deoxy, 5-deoxy and 2,3-dideoxy derivatives of the above, also the α or β-anomers of both categories described above; alkyl (C1-10) e.g., methyl, ethyl, propyl; aralkyl, e.g., benzyl, phenethyl, substituted benzyl, substituted phenethyl; heteroaryl, e.g., picolylmethyl; HEM (hydroxyethoxymethoxy), DHPM (dihydroxypropoxymethyl), or structural variations of HEM & DHPM; R2 is NR8R9 where R8═R9H, CH3, C2H5 isopropyl, cyclopropyl; halogen, chloro, bromo; —O—R10 where R10═CH3, C2H5, CH2C6H5; —S—R11 where R11═CH3, C2H5, or CH2C6H5; R3 is cyano; C═NR12 where R12 urea, substituted urea, thiourea, substituted thiourea; —CXNH2 where X is ═O, ═S, ═NOH, ═N—NH2; —CR═O where R is H, CH3, C2H5, C3H7; —CH2—RC═O where R is H, CH3, C2H5, C3H7; or exocyclic heterocycles; and R4-R7 are selected variations of substitution using the halo groups Cl, Br, F or I and the nitro and azido groups.

In certain embodiments, R1 is D-ribofuranosyl, 2′-deoxy-D-ribofuranosyl, 5′-O-acetyl-D-ribofuranosyl, 5′-O-acetyl-2′-deoxy-D-ribofuranosyl, 2′,3′,5′-tri-O-acetyl-D-ribofuranosyl, 3′-5′-di-O-acetyl-2′-deoxy-D-ribofuranosyl; or 5′-deoxy-D-ribofuranosyl, 2′,3′-di-O-acetyl-5′-deoxy-D-ribofuranosyl; R2 is —NR8R9 where R8═R9═H, CH3, C2H5, R8═H R9=isopropyl or cyclopropyl; where R2═Cl, Br; R3 is Cyano; C═NR12 where R12=urea, thiourea; —CXNH2 where X is ═O, ═S, ═NOH, ═N—HN—R; —RC═O where R═H, CH3, C2H5, C3H7; thienyl, or furyl; and R4-R7 are exocyclic groups selected from chloro, bromo, hydrogen or nitro groups.

In some embodiments, the compound is selected from the group consisting of compound 4.33, compound 4.46, compound 4.97, compound 4.117, compound 4.122, compound 4.137, compound 4.140, and compound 4.143. In certain embodiments, the compound is selected from compounds 4.6-4.143. In other embodiments, the compound has antiviral activity. In particular embodiments, the selectivity index (calculated by dividing the CC50 by the IC50) of the compound (against viruses) is at least 85 (e.g. at least 85, at least 90, at least 95, at least 100, at least 110, at least 125, at least 150, at least 170, at least 190). In further embodiments, the selectivity index (calculated by dividing the CC50 by the IC50) is between 85 and 195 (e.g. 85-195, 95-175, 100-150, or other ranges). In certain embodiments, the composition further comprises a pharmaceutically acceptable carrier or a pharmaceutically acceptable derivative.

In some embodiments, the present invention provides a prodrug of a compound as depicted in formula (I), wherein formula (I) is as follows:

and wherein: R1 is alkyl, alkenyl, aralkyl, polyhydroxyalkyl, or carbohydrate; R2 is halogen, —N, R9, —O—R10, or —S—R11; R3 is CN, C═NR12, CXNH2, COR CH2COR—COR13, halogen, exocyclic heterocycle, or NO2; and R4, R5, R6, R7 are hydrogen, halogen, nitro, or azido. It is noted that Formula I is not limited to any particular stereochemistry, unless otherwise indicated.

In other embodiments, the present invention provides methods comprising; a) providing; i) a patient with symptoms of viral or retroviral infection; and ii) a composition comprising a compound as depicted in formula (I), wherein formula (I) is as follows:

and wherein: R1 is alkyl, alkenyl, aralkyl, polyhydroxyalkyl, or carbohydrate; R2 is halogen, —N, R9, —O—R10, or —S—R11; R3 is CN, C═NR12, CXNH2, COR CH2COR—COR13, halogen, exocyclic heterocycle, or NO2; and R4, R5, R6, R7 are hydrogen, halogen, nitro, or azido, and b) administering the composition to the patient under conditions such that at least one of the symptoms of viral or retroviral infection is reduced or eliminated.

In other embodiments, the viral infection is selected from the group consisting of herpes virus infection, pox virus infection, and hepatitis virus infection. In some embodiments, the viral infection is selected from the group consisting of cytomegalovirus infection, hepatitis B virus infection, herpes simplex virus type 1 infection, herpes simplex virus type 2 infection, varicella zoster virus infection, Epstein Barr virus infection, human herpes virus 6 infection, human herpes virus 7 infection, human herpes virus 8 infection, and hepatitis C virus infection.

In particular embodiments, the present invention provides methods comprising; a) providing; i) a patient with symptoms of cardiovascular disease (e.g., restenosis); and ii) a composition comprising a compound as depicted in formula (I), wherein formula (I) comprises:

and wherein: R1 is alkyl, alkenyl, aralkyl, polyhydroxyalkyl, or carbohydrate; R2 is halogen, —N, R9, —O—R10, or —S—R11; R3 is CN, C═NR12, CXNH2, COR CH2COR—COR13, halogen, exocyclic heterocycle, or NO2; and R4, R5, R6, R7 are hydrogen, halogen, nitro, or azido, and b) administering the composition to the patient under conditions such that at least one of the symptoms of the cardiovascular disease (e.g., restenosis) is reduced or eliminated.

In certain embodiments, the administering is conducted after a surgical procedure has been performed on the patient. In further embodiments, the administering is conducted following angioplasty in the patient. In certain embodiments, the present invention provides one or more stents (e.g. for cardiovascular procedures) comprising a compound of Formula (I) (e.g. a stent coated with the compound of Formula (I)). The further embodiments, the indole compounds of the present invention (e.g. as shown in Formula (I)) can be packaged into a kit, which may include instructions for administering the compounds to a subject.

In some embodiments, the present invention provides a compound as shown in Formula I as a medicament. In certain embodiments, the present invention provides a method of treating viral or retroviral infection, or cardiovascular disease in a subject, where the method comprises administering the subject an effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof. In other embodiments, the present invention provides the use of compounds of Formula I in the manufacture of a medicament for the treatment of viral, retroviral, or cardiovascular diseases. In some embodiments, the present invention provides a pharmaceutical for the treatment of viral, retroviral or cardiovascular disease characterized in that it contains compounds of Formula I as an active substance. In particular embodiments, the present invention provides a compound of Formula I for the preparation of a composition for the treatment of viral, retroviral or cardiovascular disease.

DESCRIPTION OF THE FIGURES

FIG. 1A shows TCRB and structurally related nucleosides, and FIG. 1B shows modifications of indole nucleosides.

FIG. 2 shows synthesis of 2-dialkylamine-substituted indole nucleosides.

FIG. 3A shows synthesis of 2-monoalkylamine-substituted nucleosides, and FIG. 3B shows synthesis of 2-thiomethyl derivatives and synthesis of 2-methoxy derivatives.

FIG. 4 shows synthesis of 3-modified indole nucleosides: condensation of 3-aldehyde.

FIG. 5 shows synthesis of 3-modified indole nucleosides: condensation of 3-nitrile.

FIG. 6A shows synthesis of 3-modified indole nucleosides: 3-acyl indoles, and

FIG. 6B shows synthesis of 3-modified indole nucleoside precursors: 2,5,6-trichloro-3-methylindole.

FIG. 7 shows synthesis of 3-modified indole nucleosides: glycosylation of 2,5,6-tricholoro-3-methylindole.



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stats Patent Info
Application #
US 20120270827 A1
Publish Date
10/25/2012
Document #
13492983
File Date
06/11/2012
USPTO Class
514 43
Other USPTO Classes
536 271
International Class
/
Drawings
18


Indole
Indole Derivatives
Viral Infection


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