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PRODRUGS, ANALOGS OR DERIVATIVES OF ANTHOCYANIDIN AS ANTIVIRAL AGENTS

20220411409 · 2022-12-29

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to compounds which can inhibit host cell ACE2 receptor, viral spike S protein, Spike protein-ACE2 receptor interface, RNA-dependent RNA polymerase (RdRp), helicase and exoribonuclease activity. Particularly the invention relates to anthocyanidin analogs, derivatives and prodrugs as antiviral agents specific to Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or SARS-CoV-2 and SARS (Severe acute respiratory syndrome coronavirus).

    Claims

    1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof: ##STR00017## wherein the compound is anthocyanidin analog or a glycoside thereof, and wherein R.sub.1 is selected from group comprising—hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines; R.sub.2 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines; R1 and R2 are fused to form 1,3 dioxolane, R.sub.3 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines; R.sub.4 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines; R.sub.5 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines; R.sub.6 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines; R.sub.7 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines.

    2. The compound represented by Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R.sub.1-R.sub.7 comprises halogen, —OH, —SH, —NH.sub.2, —CN, —C(=0)OH, —C(=0)0(Ci-C.sub.4 alkyl), —C(=0)NH.sub.2, —C(=0)NH(C.sub.I-C.sub.4 alkyl), —C(=0)N(Ci-C.sub.4 alkyl).sub.2, C1-C4 alkyl, —S(Ci-C.sub.4 alkyl), C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocyclyl, —NH(C.sub.I-C.sub.4 alkyl), —N(C.sub.I-C.sub.4 alkyl).sub.2, phenyl, —C6H4OH, imidazole, and arginine.

    3. The compound represented by Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein at least one of R4, R5 or R7 is independently selected from —OR8, OR8R9R10, Wherein R8 is a glucose residue, and R8, R9 and R10 are independently selected from a glucose residue, a mannose residue, a galactose residue, a fucose residue, a rhamnose residue, an arabinose residue, a xylose residue, a fructose residue, a glucuronic acid residue, and an apiose.

    4. The compound represented by Formula (I) or a pharmaceutically acceptable salt as claimed in claim 1, wherein R.sub.1 is —OH, R2 is —OCH3, R.sub.3 is halogen, R.sub.4 is Cl, R.sub.5 is NO.sub.2, R.sub.6 is CN, and R.sub.7 is NH2.

    5. The compound represented by Formula (I) or a pharmaceutically acceptable salt as claimed in claim 1, selected from the compounds set forth below or a pharmaceutically acceptable salt thereof: TABLE-US-00002 1 embedded image 3,5,7-trihydroxy-2-(7- hydroxybenzo[d][1,3] dioxol-5- yl)chromenylium 2 embedded image 2-(benzo[d][1,3]dioxol- 5-yl)-3,5,7- trihydroxychromenylium 3 embedded image 3,5,7-trihydroxy-2-(4- hydroxy-3,5- dimethoxyphenyl) chromenylium 4 embedded image 3,5,7-trihydroxy-2-(4- hydroxy-3,5- dimethoxyphenyl) chromenylium 5 embedded image 2-(benzo[d]oxazol-5- yl)-3,5,7- trihydroxychromenylium 6 embedded image 2-(benzo[d]oxazol-5- yl)-3,5,6,7- tetrahydroxychromenylium 7 embedded image 5-(dimethylamino)-3,7- dihydroxy-2-(4- hydroxy-3,5- dimethoxyphenyl) chromenylium 8 embedded image 9-(dimethylamino)-7- hydroxy-6-(4-hydroxy- 3,5-dimethoxyphenyl)- [1,3]dioxolo[4,5-g] chromen-5-ium 9 embedded image 3,5,7-trihydroxy-2-(4- (hydroxymethyl)-3,5- dimethoxyphenyl) chromenylium 10 embedded image 1-(dimethylamino)- 2,3,7-trihydroxy-8- (hydroxymethyl) benzofuro[3,2-b] chromen-5-ium 11 embedded image 1-(dimethylamino)- 3,7-dihydroxy-8- (hydroxymethyl) benzofuro[3,2-b] chromen-5-ium 12 embedded image 1,3,8-trihydroxy-7- (trifluoromethoxy) benzofuro[3,2- b]chromen-5-ium 13 embedded image 3,8-dihydroxy-7,9- dimethoxy-1- (methylsulfonyl) benzofuro[3,2- b]chromen-5-ium 14 embedded image 1,3,7,9-tetrahydroxy- 8-(methylsulfonyl) benzofuro[3,2- b]chromen-5-ium

    6. The pharmaceutical composition, comprising a compound as claimed in claim 1 and a pharmaceutically accept able carrier or excipient.

    7. The pharmaceutical composition, comprising a compound as claimed in claim 1 wherein said composition is a food and drink.

    8. A method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds as claimed in claim 1, wherein the viral infection comprises infection by SARS-CoV or SARS-CoV2.

    Description

    DETAILED DESCRIPTION

    [0030] The present invention discloses in various embodiments compounds with antiviral activity. In one embodiment is disclosed a compound of Formula (I), or its or a pharmaceutically acceptable salt thereof.

    ##STR00016##

    [0031] Wherein the compound is an anthocyanidin analog or an glycoside thereof. In another embodiment the compound may comprise of salts, derivatives, esters, ethers prodrugs and analogs of the compound of Formula (I)

    [0032] In one embodiment R.sub.1 is selected from group comprising—hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines

    [0033] R.sub.2 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines.

    [0034] R.sub.3 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines.

    [0035] R.sub.4 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines.

    [0036] R.sub.5 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines.

    [0037] R.sub.6 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines.

    [0038] R.sub.7 is selected from group comprising hydrogen, alcohol, aryl, alkyl, alkoxy, acyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, hydroxyl, halogen, thiols, amides, amines.

    [0039] In another embodiment at least one of R4, R5 or R7 is independently selected from —OR8, OR8R9R10, Wherein R8 is a glucose residue, and R8, R9 and R10 are independently selected from a glucose residue, a mannose residue, a galactose residue, a fucose residue, a rhamnose residue, an arabinose residue, a xylose residue, a fructose residue, a glucuronic acid residue, and an apiose.

    [0040] In a particular embodiment, the compound of Formula (I) comprises R.sub.1 as —OH, R2 as —OCH3, R.sub.3 as halogen, R.sub.4 as Cl, R.sub.5 as NO.sub.2, R.sub.6 as CN, and R.sub.7 as NH2.

    [0041] In another embodiment of the present invention the composition is a pharmaceutical composition of comprising one or more dosage forms. The pharmaceutical composition comprises the compound of Formula (I) and a pharmaceutically acceptable carriers or excipients. In a particular embodiment the pharmaceutical dosage form is a dosage form for oral administration. Particular embodiment the dosage form is selected from food or a drink for oral administration.

    [0042] In another embodiment is disclosed a method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a combination of compounds as a dosage form, wherein the viral infection comprises infection by SARS-CoV or SARS-CoV2. The compounds represented by compound of Formula (I) show alleviation of viral diseases and improvement of symptoms of viral and infectious diseases, wherein the improvement in symptoms of viral and infectious diseases is due to modulation of ACE2 activity. Further the alleviation of symptoms of viral and infectious diseases is due to modulation of exoribonuclease, helicase and RdRp, RNA or DNA polymerase activity.