WO2018029610A1 - Nouvelle triterpénone en c-3 avec des dérivés de n-amide en c-17 en tant qu'inhibiteurs du vih - Google Patents

Nouvelle triterpénone en c-3 avec des dérivés de n-amide en c-17 en tant qu'inhibiteurs du vih Download PDF

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WO2018029610A1
WO2018029610A1 PCT/IB2017/054858 IB2017054858W WO2018029610A1 WO 2018029610 A1 WO2018029610 A1 WO 2018029610A1 IB 2017054858 W IB2017054858 W IB 2017054858W WO 2018029610 A1 WO2018029610 A1 WO 2018029610A1
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substituted
unsubstituted
oxo
formula
pentamethyl
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PCT/IB2017/054858
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English (en)
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Parthasaradhi Reddy BANDI
Rathnakar Reddy KURA
David Krupadanam GAZULA LEVI
Bhaskar Reddy KASIREDDY
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Hetero Labs Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • the present invention relates to C-3 novel triterpenone with C-17 N-amide derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immunodeficiency Syndrome
  • AIDS is characterized by the destruction of the immune system, particularly of CD4+T-cells.
  • HIV is a retrovirus, and the HIV life cycle encompasses several crucial steps, starting from the attachment of the virus to the host cell membrane and finishing with the release of progeny virons from the cell.
  • betulinic acid isolated from Syzygium clavifolium and several other plant species was found to possess anti-HIV activity. Chemical modifications were undertaken by several research groups in an attempt to identify potent anti-HIV agents by making semi- synthetic analogs of betulinic acid, leading to the discovery of Bevirimat as a compound with a novel mechanism of action (J. Nat. Prod. 1994, 57(2): 243-7; J. Med. Chem. 1996, 39(5), 1016). Further studies shown that Bevirimat acts by disrupting Gag processing (Proc. Natl. Acad. Sci. USA 2003, 100(23): 13555-60; Antimicrob. Agents. Chemother. 2001, 45(4), 1225-30; J. Virol.
  • WO 2007/141383 describes betulin derivatives as antifeedants for plant pests
  • US 6670345 describes use of betulinic acid and its derivatives for inhibiting cancer growth and process for the manufacture of betulinic acid
  • WO 2002/091858 describes anxiolytic marcgraviaceae compositions containing betulinic acid, betulinic acid derivatives, and methods of preparation and use
  • WO 2000/046235 describes preparation of novel betulinic acid derivatives for use as cancer growth inhibitors
  • WO 2007/141392 describes cosmetic and pharmaceutical compositions comprising betulonic acid and betulin derivatives
  • Pharmaceutical Chemistry Journal, 2002, 36(9), 29-32 describes synthesis and anti-inflammatory activity of new acylated betulin derivatives.
  • the present invention relates to the compounds of the formula (I):
  • R 2 is hydrogen, substituted or unsubstituted Q-C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
  • R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, haloalkyl, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted amine, substituted or unsubstituted C 3 -C 8 cycloalkyl; or R3 and R 4 are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, epoxide, oxetane, or azetidine;
  • R5 and R 6 are independently selected from hydrogen, Ci-C 6 alkyl, substituted or unsubstituted C 6 -Ci 2 aryl, substituted or unsubstituted C 6 -Ci 2 arylalkyl, substituted or unsubstituted C 3 -C8 cycloalkyl, substituted or unsubstituted 4-15 membered heterocyclyl, substituted or unsubstituted 4-15 membered heteroaryl; or R5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted 3-8 membered heterocyclyl; wherein the substituents are independently selected from one or more R m ;
  • R m at each occurrence is independently selected from alkyl, halo, alkoxy, alkoxylalkoxy, substituted or unsubstituted heterocyclyl, -0(CH 2 ) n -heterocyclyl, or substituted or unsubstituted heteroaryl; wherein the substituent is alkyl;
  • 'X' is absent or (CR e Rf) m ;
  • R e and R f are independently selected from hydrogen, or substituted or unsubstituted alkyl
  • 'n' is an integer selected from 0-3, and
  • 'm' is an integer selected from 1-3, or
  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising C-3 novel triterpenone with C-17 N-amide derivatives and related compounds of formula (I) and processes for preparing thereof.
  • the present invention relates to C-3 novel triterpenone with C- 17 N-amide derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
  • the present invention relates to C-3 novel triterpenone with C-17 N-amide derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
  • the present invention relates to compounds of formula (I):
  • R 2 is hydrogen, substituted or unsubstituted Q-C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
  • R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, haloalkyl, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted amine, substituted or unsubstituted C 3 -C 8 cycloalkyl; or R3 and R 4 are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, epoxide, oxetane, or azetidine;
  • R5 and R 6 are independently selected from hydrogen, Ci-C 6 alkyl, substituted or unsubstituted C 6 -Ci 2 aryl, substituted or unsubstituted C 6 -Ci 2 arylalkyl, substituted or unsubstituted C 3 -C8 cycloalkyl, substituted or unsubstituted 4-15 membered heterocyclyl, substituted or unsubstituted 4-15 membered heteroaryl; or R5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted 3-8 membered heterocyclyl; wherein the substituents are independently selected from one or more R m ;
  • R m at each occurrence is independently selected from alkyl, halo, alkoxy, alkoxylalkoxy, substituted or unsubstituted heterocyclyl, -0(CH 2 ) n -heterocyclyl, or substituted or unsubstituted heteroaryl; wherein the substituent is alkyl;
  • 'X' is absent or (CR e R f ) m ;
  • R e and R f are independently selected from hydrogen or substituted or unsubstituted alkyl
  • 'n' is an integer selected from 0-3, and
  • 'm' is an integer selected from 1-3;
  • the present invention relates to compounds of formula (IA):
  • R 2 is hydrogen, substituted or unsubstituted Q-C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
  • R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, haloalkyl, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted amine, substituted or unsubstituted C 3 -C 8 cycloalkyl; or R3 and R 4 are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, epoxide, oxetane, or azetidine;
  • R5 and R 6 are independently selected from hydrogen, Ci-C 6 alkyl, substituted or unsubstituted C 6 -Ci 2 aryl, substituted or unsubstituted C 6 -Ci 2 arylalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 4-15 membered heterocyclyl, substituted or unsubstituted 4-15 membered heteroaryl; or R5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted 3-8 membered heterocyclyl; wherein the substituents are independently selected from one or more R m ;
  • R m at each occurrence is independently selected from alkyl, halo, alkoxy, alkoxylalkoxy, substituted or unsubstituted heterocyclyl, -0(CH 2 ) n -heterocyclyl, or substituted or unsubstituted heteroaryl; wherein the substituent is alkyl;
  • 'X' is absent or (CR e R f ) m ;
  • R e and R f are independently selected from hydrogen or substituted or unsubstituted alkyl
  • 'n' is an integer selected from 0-3, and
  • 'm' is an integer selected from 1-3;
  • the present invention relates to compounds of formula
  • R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, haloalkyl, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted amine, substituted or unsubstituted C 3 -C 8 cycloalkyl; or R 3 and R 4 are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, epoxide, oxetane, or azetidine;
  • R5 and R 6 are independently selected from hydrogen, Ci-C 6 alkyl, substituted or unsubstituted C 6 -Ci 2 aryl, substituted or unsubstituted C 6 -Ci 2 arylalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 4-15 membered heterocyclyl, substituted or unsubstituted 4-15 membered heteroaryl; or R5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted 3-8 membered heterocyclyl; wherein the substituents are independently selected from one or more R m ;
  • R m at each occurrence is independently selected from alkyl, halo, alkoxy, alkoxylalkoxy, substituted or unsubstituted heterocyclyl, -0(CH 2 ) n -heterocyclyl, or substituted or unsubstituted heteroaryl; wherein the substituent is alkyl, and
  • 'n' is an integer selected from 0-3, or
  • the present invention relates to compounds of formula
  • R5 and R 6 are independently selected from hydrogen, Ci-C 6 alkyl, substituted or unsubstituted C 6 -Ci 2 aryl, substituted or unsubstituted C 6 -Ci 2 arylalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-15 membered heterocyclyl, substituted or unsubstituted 4-15 membered heteroaryl; or R5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted 3-8 membered heterocyclyl; wherein the substituents are independently selected from one or more R m ;
  • R m at each occurrence is independently selected from alkyl, halo, alkoxy, alkoxylalkoxy, substituted or unsubstituted heterocyclyl, -0(CH 2 ) n -heterocyclyl, or substituted or unsubstituted heteroaryl; wherein the substituent is alkyl; and
  • 'n' is an integer selected from 0-3, or
  • prodrugs of the compounds of the formula (I) includes esters of the compounds.
  • a compound of formula (I) wherein R5 and R 6 taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted 3-8 membered heterocyclyl.
  • a compound of formula (I) wherein the above said heterocyclyl is morpholine, piperidine and piperazine.
  • the compounds of formula (I) can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic formula (I).
  • H isotopic forms of hydrogen
  • protium 1H
  • deuterium 2 H
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds of formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • a compound of formula (I) has one or more of its hydrogen atoms replaced with deuterium.
  • the compounds of formula (I) structurally encompasses all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the general formula (I) described herein.
  • the absolute configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1 % of the other isomers.
  • the prodrugs of present invention are the compounds of formula (I) and its pharmaceutically acceptable salts, stereoisomers, solvates thereof containing an hydroxyl group; wherein hydrogen atom of the hydroxyl group are replaced with (Ci-C 6 )alkanoyloxymethyl, l-((Ci-C 6 )alkanoyloxy)ethyl, 1 -methyl- l-((Ci- C 6 )alkanoyloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonyl aminomethyl, succinoyl, (Ci-C 6 )alkanoyl, a-amino(Ci-C 4 )alkyl, a-amino(Ci-C 4 )alkylene- aryl, arylacyl and a-aminoacyl, where each a -aminoacyl group is independently selected from
  • the prodrugs of present invention are the compounds of formula (I) and its pharmaceutically acceptable salts, stereoisomers, hydrates, solvates thereof containing an amine group; wherein one or more hydrogen atoms of the amine group is replaced with (Ci-C 6 )alkylcarbonyl, (Ci-C 6 )alkoxycarbonyl, aminocarbonyl, (C3-C 6 )cycloalkylcarbonyl, benzylcarbonyl and the like.
  • the present invention also provides a pharmaceutical composition that includes at least one compound according to formula (I) and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound according to formula (I).
  • the compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, or other container.
  • the compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections.
  • the present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject one or more compounds described herein in a therapeutically effective amount to treat that infection, specifically in the form of a pharmaceutical composition.
  • the present invention relates to combinations comprising a compound of the formula (I) and a second therapeutic agent that is an anti-HIV agent, an anti-HCV agent or anti-TB agents.
  • the present invention relates to pharmaceutical compositions comprising the compound of formula (I) and one or more second anti-HIV agents and their pharmaceutically acceptable salts and stereoisomers thereof.
  • the present invention relates to combinations comprising a compound of the formula (I) and one or more second anti-HIV agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.
  • second anti-HIV agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.
  • the present invention relates to methods of treatment of HIV infection, AIDS, and AIDS-related conditions by administering to a subject a compound of formula (I) and one or more second therapeutic agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.
  • the present invention relates to combinations comprising a compound of the formula (I) and one or more second anti-HIV agents wherein the second anti-HIV agent is Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir disoproxil Fumarate, Tenofovir Alafenamide Fumarate, Elasulfavirine, Zidovudine, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Ritonavir, Cobicistat, Saquinavir, Tipranavir, Enfuvirtide, Maraviroc, Fostemsavir, Dolutegravir, Elvitegravir, Raltegravir, Bictegravir, Cabotegravir or a combination thereof.
  • the second anti-HIV agent is Abacavir, Didanosine, Emtric
  • the present invention provides a method for preventing; ameliorating or treating a HIV mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method, wherein the HIV mediated disease, disorder or syndrome is like AIDS, AIDS related complex, or a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss, or a retroviral infection genetically related to AIDS.
  • Anti HIV inhibitory potential of the compounds of present invention may be demonstrated by any one or more methodologies known in the art, such as by using the assays described in Mossman T, December 1983, Journal of immunological methods, 65 (1- 2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.
  • halogen or halo includes fluorine, chlorine, bromine, or iodine.
  • hydroxyl refers to -OH.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • alkoxy refers to a straight or branched hydrocarbon chain with oxygen radical consisting carbon and hydrogen atoms, containing saturation or unsaturation, having from one to eight carbon atoms, and which is attached through oxygen atom to the rest of the molecule by a single bond, e.g., methyloxy, ethyloxy, n-propyloxy, 1-methylethyloxy (isopropyloxy), n-butyloxy, n-pentyloxy, and 1,1-dimethylethyloxy (t-butyloxy).
  • alkoxylalkoxy refers to a straight or branched hydrocarbon chain with oxygen radical consisting carbon atom, hydrogen atom and alkoxy groups, containing saturation or unsaturation, having from one to eight carbon atoms, and which is attached through oxygen atom to the rest of the molecule by a single bond, e.g., 2- (methyloxy)ethyloxy, 2-(ethyloxy)ethyloxy, 2-(n-propyloxy)ethyloxy, and 3- (isopropyloxy)butyloxy.
  • amine refers to an organic compounds and functional groups that contain a basic nitrogen atom with a lone pair.
  • Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group these may respectively be called alkylamines and arylamines; amines in which both types of substituent are attached to one nitrogen atom may be called alkylarylamines.
  • Important amines include amino acids, trimethylamine, and aniline.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups, e.g., bicyclo [2.2.1] heptane and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
  • aryl refers to an aromatic radical having from 6 to 14 ring carbon atoms. In certain embodiments the term “aryl” refers to an partially unsaturated 6 to 14 membered ring. In preferred embodiments the aryl ring can be monocyclic, bicyclic and tricyclic, when aryl is bicyclic or tricyclic ring, one or more of the rings can be saturated or partially saturated. Exemplary compounds of aryl are not limited to phenyl, naphthyl, indeneyl, indanyl, tetrahydronapthyl, indanyl, biphenyl, 9H-fluorenyl and 2,3-dihydro-lH-indenyl and the like.
  • haloalkyl refers to alkyl group (as defined above) is substituted with one or more halogens.
  • a monohaloalkyl radical for example, may have a chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms.
  • haloalkyl examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoro chloromethyl, dichloro fluoromethyl, difluoroethyl, difluoropropyl and the like.
  • heterocyclyl and “heterocyclic ring” refer to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxetane, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxasolidinyl, morpholinyl, tetrahydrofuranyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidin
  • heteroaryl refers to an aromatic heterocyclic ring radical or partially saturated ring radical.
  • the heteroaryl ring can be monocyclic, bicyclic and tricyclic, when heteroaryl ring is bicyclic or tricyclic ring, one or more of the rings can be saturated or partially saturated rings.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems.
  • heteroaryl rings include, but are not limited to lH-benzo[d]imidazolyl, pyridinyl, pyrazolyl, lH-indolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, benzo[d][l,3]dioxolyl, 2,3- dihydrobenzo[b][l,4]dioxinyl, 1,3,4-thiadiazolyl, lH-l,2,4-triazolyl, thiazolyl, imidazolyl, thiophenyl, and quinoxalinyl.
  • arylalkyl or “aralkyl” refers to a aryl ring radical directly bonded to an alkyl group.
  • the arylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereo centers. Stereoisomers include enantiomers and diastereomers.
  • regioisomer or “positional isomer” refer to that have the same carbon skeleton and the same functional groups but differ from each other in the location of the functional groups on or in the carbon chain.
  • prodrug denotes a derivative of a compound, which derivative, when administered to warm -blooded animals, e.g. humans, is converted into the compound (drug).
  • the enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
  • a carboxylic acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester.
  • an ester When an ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group.
  • An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
  • moieties e.g., acyloxymethyl esters
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • treating or “treatment” of a state, disease, disorder or condition includes:
  • the benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
  • the compounds of the present invention may form salts.
  • Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of the present invention are capable of existing in stereoisomeric forms (e.g., diastereomers, enantiomers, racemates, and combinations thereof). With respect to the overall compounds described by the Formula (I), the present invention extends to these stereoisomeric forms and to mixtures thereof.
  • solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • compositions provided in the present invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to treat viral infection in a subject.
  • the subjects contemplated include, for example, a living cell and a mammal, including human.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
  • the carrier or diluent may include a sustained release material, such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • a sustained release material such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick-, sustained-, or delayed-release of the active ingredient after administration to the subject by employing procedures known in the art.
  • compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampule, capsule, or sachet.
  • the carrier serves as a diluent, it may be a solid, semi- solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is specifically suitable.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Exemplary carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tableting techniques.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions specifically aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections.
  • the connection between therapeutic effect and antiviral is illustrated.
  • the present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • Diseases, conditions, and/or disorders that are mediated by viral infections are believed to include, but are not limited to, FHV infection, HBV, HCV, a retroviral infection genetically related to HIV, AIDS, inflammatory disease, respiratory disorders (including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), multiple sclerosis, rheumatoid arthritis, graft rejection (in particular but not limited to kidney and lung allografts), endometriosis, type I diabetes, renal diseases, chronic pancreatitis, inflammatory lung conditions, chronic heart failure and bacterial infections (in particular but not limited to tuberculosis).
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • chronic obstructive pulmonary disease
  • the compounds of the present invention may obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the available drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than antiviral can be avoided or declined.
  • the compounds described herein may be prepared by techniques known in the art.
  • the compounds described herein may be prepared by following the reaction sequence as depicted in below schemes. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereoisomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • Betulin Key intermediates required for synthesizing analogues are either commercially available or can be prepared by the methods published in the literature. For example, the key intermediates in the present invention were prepared by modifying the procedures published in Journal of organic chemistry 2010, 75, 1285-1288; Journal of organic chemistry 2000, 65, 3934-3940; Tetrahedron: asymmetry 2008, 19, 302-308; or Tetrahedron: asymmetry 2003, 14, 217-223.
  • Another embodiment of the present invention provides process for preparation of the compounds of general formula (I) are set forth in the below generalized schemes.
  • One of skill in the art will recognize that below generalised schemes can be adapted to produce the compounds of general formula (I) and pharmaceutically acceptable salts of compounds of general formula (I) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated.
  • a suitable ester forming reagents such as anhydrides, acid halides or mixed anhydrides or the like in the presence of base such as triethylamine (TEA) or N,N- diisopropylethylamine (DIPEA) or pyridine or the like in solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or toluene or the like with or without addition of catalyst such as 4-(Dimethylamino)pyridine (DMAP) under heating conditions or the like to give the C-3 & C-28 di hydroxy protected compounds of formula (2) (Pi and P 2 are protecting groups such as acetyl, benzyl or the like).
  • base such as triethylamine (TEA) or N,N- diisopropylethylamine (DIPEA) or pyridine or the like
  • solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or
  • the compounds of formula (2) can be converted to the ring-E ene compounds of formula (3) in the presence of hydrogen bromide (HBr) in acetic acid (AcOH), acetic acid (AcOH) and acetic anhydride (Ac 2 0) in solvents such as toluene or benzene or xylene or the like.
  • HBr hydrogen bromide
  • AcOH acetic acid
  • AcOH acetic acid
  • Ac 2 0 acetic anhydride
  • the ring-E ene compounds of formula (3) can be converted to the ring-E enone compounds of formula (4) in the presence of sodium dichromate dihydrate (Na 2 Cr 2 0 7 .2H 2 0), sodium acetate (NaOAc), acetic acid (AcOH) and acetic anhydride (Ac 2 0) in solvents such as toluene or benzene or the like.
  • the ring-E enone compounds of formula (4) can be selectively deprotected at C-28 to give the C-28 hydroxy compounds of formula (5) in the presence of potassium hydroxide (KOH) or the like in the combination of solvents such as toluene: ethanol (EtOH) (1: 1) or with reagent like Aluminium isopropoxide [Al(OCH(CH 3 )2)3] in a solvent such as 2-propanol or the like.
  • KOH potassium hydroxide
  • EtOH ethanol
  • the C-28 hydroxy compounds of formula (5) can be converted to the C-28 acid compounds of formula (6) in the presence of oxidizing agents such as 2,2,6,6-Tetramethylpiperidine-l-oxyl (TEMPO), sodium chlorite (NaC10 2 ), 10% sodium hypochlorite solution (10% NaOCl), buffer such as Sodium dihydrogen phosphate (NaH 2 P0 4 ) and inorganic bases such as sodium bicarbonate or the like in the combination of solvents such as tert-butanol (t-BuOH) and water (H 2 0) or the like.
  • oxidizing agents such as 2,2,6,6-Tetramethylpiperidine-l-oxyl (TEMPO), sodium chlorite (NaC10 2 ), 10% sodium hypochlorite solution (10% NaOCl), buffer such as Sodium dihydrogen phosphate (NaH 2 P0 4 ) and inorganic bases such as sodium bicarbonate or the like in the combination of solvents such as tert-but
  • the C-28 acid compounds of formula (6) can be converted to the C-17 carbamate compounds of formula (7) by using the reagent like diphenylphosphoryl azide (DPPA) or combination of ethylchloroformate and sodium azide (NaN 3 ) in the presence of bases such as triethylamine (TEA) or ⁇ , ⁇ -Diisopropylethylamine (DIPEA) or the like in the solvents such as 1,2-DCE or Toluene or the like in the presence of alcohol such as 4-methoxybenzyl alcohol (PMBOH) or the like.
  • DPPA diphenylphosphoryl azide
  • NaN 3 sodium azide
  • bases such as triethylamine (TEA) or ⁇ , ⁇ -Diisopropylethylamine (DIPEA) or the like
  • solvents such as 1,2-DCE or Toluene or the like
  • alcohol such as 4-methoxybenzyl alcohol (PMBOH) or
  • the C-3 hydroxy compounds of formula (8) can be achieved by deprotection at C-3 of compounds of formula (7) in the presence of aqueous solution of inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as methanol (MeOH): tetrahydrofuran (THF): water (H 2 0) (4:2: 1) or 1,4- dioxane: water (H 2 0) (4: 1) or the like.
  • the C-3 hydroxy compounds of formula (8) can be coupled with the acid of compounds of formula (9) to give the C-3 ester compounds of formula (10) in different ways like
  • the C-17 amine compounds of formula (11) can be coupled with the acid compounds of formula (12) in the presence of coupling reagents such as 0-(7-Azabenzotriazol-l-yl)-N,N,N ,N -tetramethyluronium hexafluorophosphate (HATU) or 0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or combination of l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) and 1-Hydroxybenzotriazole hydrate (HOBt) or the like in the presence of bases such as triethylamine (TEA) or N,N-Diisopropylethylamine (DIPEA) or the like in the solvents such as 1,2-dichloroethane (1,2-DCE) or N,N- dimethylform
  • the compounds of formula (13) containing the ester group can be deprotected to the acid of compounds of formula (14) in the presence of acid medium such as trifluoroacetic acid (TFA) or HCl/l,4-dioxane or the like in the solvents such as dichloromethane (DCM) or chloroform (CHCI 3 ) or the like.
  • acid medium such as trifluoroacetic acid (TFA) or HCl/l,4-dioxane or the like
  • solvents such as dichloromethane (DCM) or chloroform (CHCI 3 ) or the like.
  • the compounds of formula (14) can be coupled with the compounds of formula (15) in the presence of coupling reagents such as 0-(7-Azabenzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluroniumhexafluorophosphate (HATU) or O-(Benzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluroniumhexafluorophosphate (HBTU) or combination of l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) and 1-Hydroxybenzotriazole hydrate (HOBt) or the like in the presence of bases such as triethylamine (TEA) or N,N-Diisopropylethylamine (DIPEA) or the like in the solvents such as 1,2-dichloroethane (1,2-DCE) or N,N- dimethylformamide (DMF)
  • the compounds of formula (16) containing the ester group can be hydrolyzed to the acid of compounds of formula (I) in the presence of aqueous solution of inorganic bases such as Lithium hydroxide (LiOH) or sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as tetrahydrofuran (THF): methanol (MeOH) (1:1) or the like.
  • inorganic bases such as Lithium hydroxide (LiOH) or sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as tetrahydrofuran (THF): methanol (MeOH) (1:1) or the like.
  • DIPEA ⁇ , ⁇ -Diisopropylethylamine
  • °C degree Celsius
  • ⁇ delta
  • ppm parts per million
  • % percentage
  • DMSO-d 6 Deuterated DMSO
  • d Doublet
  • dd Doublet of doublet
  • EtOH Ethanol
  • g or gr gram(s)
  • H or H 2 Hydrogen
  • HC1 Hydrochloric acid
  • h or hr hour(s)
  • HATU (0-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate); Hz (Hertz); HPLC (High-performance liquid chromatography); mol (mole(s)); mmol (Millimole); N (Normal); ml (Mill
  • reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layers were washed with water (500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-1% methanol in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (22.0 g, yield: 72.84%) as a colourless oil.
  • step 1 To a stirred solution of 4-methoxybenzyl 3-hydroxy-2,2-dimethylpropanoate (step 1, 22.0 g, 92.328 mmol, 1.0 eq) in THF (220 mL) at room temperature was added TEMPO ( 1.44 g, 9.232 mmol, 0.1 eq), stirred for 10 minutes, then NaH 2 P0 4 (38.221 g, 276.985 mmol, 3.0 eq) dissolved in water (330 mL) was added followed by NaHC0 3 (15.51 g, 184.656 mmol, 2.0 eq) was added and stirred for 10 minutes.
  • TEMPO 1.44 g, 9.232 mmol, 0.1 eq
  • Step 1 Synthesis of ((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-acetoxy-
  • Step 2 Synthesis of ((3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl- 5a,5b, 8,8, 11 a-pentamethyl-2, 3,4,5, 5a,5b,6, 7,7a,8,9, 10, 11,11 a,l lb, 12, 13,13a-octadecahydro- 3aH-cyclopenta[a]chrysen-3 -yl)methyl acetate:
  • HBr in acetic acid 400 mL, 33%), was added to a suspension of ((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l la-pentamethyl-l- (prop-l-en-2-yl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate (step 1, 200 g, 379.65 mmol, 1.0 eq) in toluene (400 mL), Ac 2 0 (400 mL) and acetic acid (400 mL) previously heated at 105 °C.
  • the reaction mixture was stirred and heated at this temperature for 1.5 hours. After cooling down to room temperature, quenched with sodium acetate (240 g). The resulting reaction mixture was evaporated to dryness. The residue was taken up in CH 2 C1 2 (600 mL) and the organic phase was washed with water (2x250 mL). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized over 95% ethanol and CH 2 C1 2 gave the desired product (135 g, yield: 67.5%) as a white solid.
  • Step 3 Synthesis of ((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl- 5 a, 5b, 8,8,11a -pentamethyl-2-oxo -2,3,4,5, 5 a, 5b, 6, 7, 7a, 8, 9, 10,11,1 la, lib, 12, 13, 13 a- octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate:
  • reaction mixture was stirred and heated at 60 °C for 14 hours. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (1000 mL). The organic phase was washed successively with saturated solution of sodium carbonate (1x500 mL) and brine solution (2x200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with methanol, precipitates formed were collected by filtration and dried under vacuum to obtain the desired product (100 g, yield: 72.2%) as a white solid.
  • Step 4 Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(hydroxymethyl)-l- isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo-
  • reaction mixture was stirred vigorously at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with aqueous IN HC1 and evaporated to dryness. The obtained residue was taken up in water (300 mL) and a small amount of acetone (30 mL). The precipitates formed were collected by filtration, washed with water (50 mL) and dried in vacuo to obtain the desired product (75 g, yield: 81.32%) as an off-white solid.
  • Step 5 Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl- 5 a, 5b, 8,8,11a -pentamethyl-2-oxo -2,3,4,5, 5 a, 5b, 6, 7, 7a, 8, 9, 10,11,1 la, lib, 12, 13, 13 a- octadecahydro-3aH-cyclopenta[a ] chrysene-3a-carboxylic acid:
  • NaC10 2 (40.6 g, 451.12 mmol, 3.0 eq) was added slowly portion wise over a period of 30 minutes and stirred for another 10 minutes.
  • the reaction mixture was cooled to 0-5 °C and added 10% bleach solution (112.5 mL) over a period of 30 minutes and stirred at the same temperature for 30 minutes.
  • the reaction mixture was allowed to stir at room temperature for 3 hours.
  • IN HC1 solution 300 mL
  • Ethyl acetate 750 mL was added to the reaction mixture and stirred for 30 minutes.
  • Step 6 Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-l-isopropyl-3a-((((4- methoxybenzyl)oxy)carbonyl)amino)-5a,5b,8,8,lla-pentamethyl-2-oxo-
  • Step 7 Synthesis of 4-methoxybenzyl ((3aR,5aR,5bR, 7aR,9S,l laR,l lbR,l 3aS)-9-hydroxy-l - isopropylSa, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 2,3,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-3aH-cyclopenta[a]chrysen- 3a-yl)carbamate:
  • the reaction mixture was removed from the ice bath and was stirred at room temperature for overnight. After completion of the reaction (monitored by TLC), the organic phase was evaporated under reduced pressure and diluted with water (100 mL). The mixture was cooled to 0 °C, neutralized with IN HCl and extracted with DCM (3x400 mL). The combined organic extracts were washed with water (200 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (42.0 g, yield: 97.65%) as an off-white solid.
  • Step 8 Synthesis of 1-benzyl 3-((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-l-isopropyl-3a- (((( 4-methoxybenzyl )oxy )carbonyl )amino ) -5 a, 5b, 8,8,11a -pentamethyl-2 -oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl) ( lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • reaction mixture was stirred at room temperature for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (400 mL) and extracted with DCM (3x500 mL). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (53.0 g, yield: 89.93%) as an off-white solid.
  • Step 9 Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-amino-l-isopropyl- 5 a, 5b, 8,8,11a -pentamethyl-2-oxo -3,3 a, 4, 5, 5 a, 5b, 6,7, 7a, 8, 9, 10,11,1 la, lib, 12, 13, 13 a- octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2-dimethylcyclobutane- 1,3-dicarboxylate:
  • reaction mixture was allowed to stir at room temperature for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure and diluted with water (200 mL). The mixture was cooled to 0 °C, ptl adjusted to 8.0 with saturated sodium bicarbonate solution and extracted with DCM (3x500 mL). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was triturated with acetonitrile (400 mL) and stirred at room temperature for 1 hour.
  • Step 10 Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-3a-(3- ((4-methoxybenzyl)oxy)-2,2-dimethyl-3-oxopropanamido)-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl) ( lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • Step 11 Synthesis of 3-(((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-(((lS,3R)-3- ((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l -carbonyl)oxy)-l -isopropyl-5a,5b,8, 8,11a- pentamethyl-2-oxo-2, 3,4,5, 5a,5b,6,7,7a,8,9, 10, 11,11 a,l lb, 12, 13,13a-octadecahydro-3aH- cyclopenta[a]chrysen-3a-yl)amino)-2,2-dimethyl-3-oxopropanoic acid:
  • reaction mixture was allowed to stir at room temperature for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure, triturated with MTBE (200 mL) and stirred at room temperature for 30 minutes. The precipitates formed were collected by filtration, washed with MTBE (20 mL) and dried under vacuum for 10 minutes to obtain the title compound (10.0 g, yield: 76.92%) as a white solid.
  • Example 1 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2,2- dimethyl-3-morpholino-3-oxopropanamido)-l-isopropyl-5a,5b,8,8 J la-pen tamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10, l l,l la,l lb,12,13,13a-octadecahvdro-2H-cvclopentaralchrysen- 9-yl)oxy)carbonyl)-2,2-dimethylcvclobutane- 1-carboxylic acid:
  • Step 1 Synthesis of 1 -benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2,2-dimethyl-3- morpholino-3-oxopropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl) ( lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • Step 2 Synthesis of ⁇ lR,3S)-3- ⁇ 3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a- ⁇ 2,2-dimethyl-3- morpholino-3-oxopropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-
  • reaction mixture was stirred at room temperature for overnight. After completion of the reaction (monitored by TLC), the organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (20 mL), cooled to 0 °C, ptl adjusted to 5.0 with IN HC1 and extracted with DCM (3x50 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography by using 0-5% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure.
  • Example 3 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(3- (cyclohexylamino)-2,2-dimethyl-3-oxopropanamido)-l-isopropyl-5a,5b,8,8 J la-pentamethyl- 2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H- cvclopentaralchrvsen-9-yl)oxy)carbonyl)-2,2-dimethylcvclobutane-l-carboxylic acid:
  • HOOCT " 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (lR,3S)-3-
  • MT2 cells were infected with HIV-1 strain 92HT599 (15TCID 50/ 30000 cells).
  • the infected cells were plated at the concentration of -30 000 cells per well in 96 well plate.
  • Test compound was added to the micro plate in defined format with the final concentration of DMSO (vehicle) is not more than 1%.
  • Assay was carried out with and without human serum/human serum albumin (HSA 45 mg/ml) for the serum shift. Incubation was carried out in C02 incubator for - 96 hours for viral infection. At the end of incubation period an aliquot from each well was taken for p24 estimation. The quantitation of p24 is an index for antiviral activity of the compound. Percent inhibition was calculated with reference to control values (vehicle controls).
  • the compounds described herein have an a IC 50 value of less than 10 nM, represented herein as "A".
  • A refers to an IC 50 value of less than 50 nM
  • B refers to IC 50 value greater than 50 nM.
  • the IC 50 (nM) values are set forth in Table- 1.
  • HIV-1 p24 antigen capture assay enzyme immunoassay for detection of Human immunodeficiency Virus Type 1 (HIV-1) p24 in tissue culture media - Advanced bio science laboratories, Inc kit procedure.

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Abstract

La présente invention concerne un nouveau triterpénone en C-3 avec des composés de N-amide en C-17 de formule (I); et des sels pharmaceutiquement acceptables de celui-ci, dans laquelle R1, R2, R3, R4, R5, R6 et 'X' sont tels que définis dans la formule (I). La présente invention concerne également des composés de formule (I) et leurs composés apparentés, et des compositions pharmaceutiques utiles dans le traitement thérapeutique de maladies virales et en particulier de maladies induites par le VIH.
PCT/IB2017/054858 2016-08-09 2017-08-09 Nouvelle triterpénone en c-3 avec des dérivés de n-amide en c-17 en tant qu'inhibiteurs du vih WO2018029610A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10370405B2 (en) * 2015-03-16 2019-08-06 Hetero Labs Limited C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors
US10533035B2 (en) 2015-02-09 2020-01-14 Hetero Labs Ltd. C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors

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WO2008057420A2 (fr) * 2006-11-03 2008-05-15 Panacos Pharmaceuticals, Inc. Dérivés de triterpène étendus
WO2009082819A1 (fr) * 2008-01-03 2009-07-09 Virochem Pharma Inc. Nouveaux dérivés de lupane
WO2013117137A1 (fr) * 2012-02-08 2013-08-15 Jiangxi Qingfeng Pharmaceutical Inc. Dérivés de triterpénoïdes de lupane et leur utilisation pharmaceutique

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2008057420A2 (fr) * 2006-11-03 2008-05-15 Panacos Pharmaceuticals, Inc. Dérivés de triterpène étendus
WO2009082819A1 (fr) * 2008-01-03 2009-07-09 Virochem Pharma Inc. Nouveaux dérivés de lupane
WO2013117137A1 (fr) * 2012-02-08 2013-08-15 Jiangxi Qingfeng Pharmaceutical Inc. Dérivés de triterpénoïdes de lupane et leur utilisation pharmaceutique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10533035B2 (en) 2015-02-09 2020-01-14 Hetero Labs Ltd. C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
US11034718B2 (en) 2015-02-09 2021-06-15 Hetero Labs Limited C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
US10370405B2 (en) * 2015-03-16 2019-08-06 Hetero Labs Limited C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors

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