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US20170129916A1 - Novel betulinic proline imidazole derivatives as hiv inhibitors - Google Patents

Novel betulinic proline imidazole derivatives as hiv inhibitors Download PDF

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Publication number
US20170129916A1
US20170129916A1 US15/321,970 US201515321970A US2017129916A1 US 20170129916 A1 US20170129916 A1 US 20170129916A1 US 201515321970 A US201515321970 A US 201515321970A US 2017129916 A1 US2017129916 A1 US 2017129916A1
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carbonyl
pyrrolidine
icosahydro
cyclopenta
chrysen
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Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Gazula Levi DAVID KRUPADANAM
Adulla PANDURANGA REDDY
Bammidi ESWARA RAO
Ranga Reddy
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Hetero Labs Ltd
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Hetero Research Foundation
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Priority claimed from PCT/IB2015/054784 external-priority patent/WO2015198263A2/fr
Publication of US20170129916A1 publication Critical patent/US20170129916A1/en
Assigned to HETERO RESEARCH FOUNDATION reassignment HETERO RESEARCH FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAMMIDI, Eswara Rao, BANDI, Parthasaradhi Reddy, GAZULA LEVI, David Krupadanam, KURA, Rathnakar Reddy, LANKA, Vl Subrahmanyam, REDDY, RANGA, ADULLA, Panduranga Reddy
Assigned to HETERO LABS LIMITED reassignment HETERO LABS LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HETERO DRUGS LIMITED, HETERO RESEARCH FOUNDATION
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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 the compounds of the formula (1):
  • R 2 can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aminoacids, substituted or unsubstituted alkoxy or substituted or unsubstituted cycloalkyl;
  • X can be absent, O, S, CH 2 or NR a (wherein Ra can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or Ra can be with their adjacent N and Carbon together form N-contained heterocycle (Preferably, pyrrolidine, piperdine, piperzine, or morpholine);
  • R 5 , R 7 and R 8 can be independently selected from H, CO 2 R d (wherein R d can be H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl;
  • R 3 and R 4 can be independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or substituted or unsubstituted aminoacids and preferably amino acids are substituted by to substituted or unsubstituted alkyl, phosphoric acid, or phosphorus prodrugs or R 3 and R 4 can be together with their adjacent carbons to form a bond or R 3 and R 4 can be together with their adjacent carbons to form cyclopropyl or R 3 and R 4 can be together with their adjacent carbons to form epoxide;
  • prodrugs of the compounds of the formula (1A), including ester prodrugs are also contemplated.
  • 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 cause that infection, specifically in the form of a pharmaceutical composition.
  • the 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 an retroviral infection genetically related to AIDS.
  • aryl refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • 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.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • R 6 is more specifically isopropyl, t-butyl, substituted or unsubstituted phenyl, pyridine, and thiophene
  • P can be a protecting group more specifically BOC, benzyl, MOM chloride (chloromethyl methyl ether), tosyl, TBDMS, p-methoxy phenyl (PMP), CBZ chloride, THP, dimethyl acetol, allyl ether, t-butyl ether or phthalimide can be prepared as described in Scheme 1.
  • the acetyl compounds of formula 1 can be converted to bromo compounds of formula 2 in the presence of bromine, N-bromosuccinimide, or the like in the solvents such as THF, diethyl ether, or the like.
  • the bromo compounds of formula 2 can be coupled with BOC protected proline compounds of formula 3 to get the compound of prolinated compounds of formula 4 in the presence of suitable coupling agents such as DIPEA, TEA, potassium carbonate or the like in the solvents such as N,N-Dimethylformamide, dichloromethane, dichloroethane, or the like.
  • the C-3 acetyl (C-28 acid) compounds of formula 8 can be couple with substituted proline compounds of formula 9 (synthesized as described in Scheme 1) to give the C-28 cyclic amide compounds of formula 10 in the presence of oxylylchloride, TEA or the like in the presence of solvents such as DCM, or the like.
  • the C-28 cyclic amide (C-3 ester) compounds of formula 10 can be hydrolysed to give C-3 hydroxy compounds of formula 11 in the presence of bases such as potassium carbonate, sodium hydroxide, ammonia or the like in the solvents such as methanol:THF, methanol:water, 1,4-dioxane, methanol or the like.
  • bases such as potassium carbonate, sodium hydroxide, ammonia or the like
  • solvents such as methanol:THF, methanol:water, 1,4-dioxane, methanol or the like.
  • Step 1 Synthesis of 2-bromo-1-(pyridin-2-yl) ethanone
  • Step 3 Synthesis of 2-(2-(4-(benzyloxy)phenyl)-2-oxoethyl) 1-(tert-butyl) (S)-pyrrolidine-1,2-dicarboxylate
  • Step 7 Synthesis of (S)-5-(4-(2-methoxyethoxy)phenyl)-2-(pyrrolidin-2-yl)-1H-imidazole
  • Step 3 Synthesis of tert-butyl (S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
  • Step 2 Synthesis of 1-(tert-butyl) 2-(2-oxo-2-(4-(trifluoromethyl) phenyl)ethyl) (S)-pyrrolidine-1,2-dicarboxylate
  • Step 3 Synthesis of tert-butyl (S)-2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
  • reaction mixture was poured into ice cold water, the solution pH was adjusted to 2 to 3 by addition of 4N HCl (Note: the temperature of reaction mixture should be 5-10° C.).
  • the aqueous layer was extracted with ethyl acetate (2 ⁇ 500 ml), combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and solvent was evaporated under reduced pressure to provide title compound (wt: 85.0 g, yield: 96%).
  • step 1 A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (step 1, 20.0 g, 86.9 mmol) in DMF (200 ml) was treated with sodium hydride (8.43 g, 347.8 mmol) at 0° C. After stirring about 15 minutes at 0° C., 1-bromo-2-methoxyethane (24.2 g, 174.0 mmol) was added and stirred at ambient temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C., then 400 ml water was added slowly over 30 minutes and stirred at room temperature for about 4 hours.
  • Step 3 Synthesis of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-(2-methoxyethoxy) pyrrolidine-1,2-dicarboxylate
  • step 4 To a solution of (2S,4R)-tert-butyl 4-(2-methoxyethoxy)-2-(4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (step 4, 4.0 g, 10.36 mmol) in DCM (40 ml) was added trifluoroacetic acid (10 ml) and stirred at room temperature for about 4 hours. After completion of the reaction, solvents were evaporated and aqueous sodium bicarbonate was added to the residue. The product was extracted with dichloromethane (2 ⁇ 100 ml), washed with brine, dried over Na 2 SO 4 and filtered.
  • Step 1 Synthesis of (2S,4R)-1-tert-butyl 2-(2-(3-fluorophenyl)-2-oxoethyl) 4-(2-methoxy ethoxy)pyrrolidine-1,2-dicarboxylate
  • step 1 To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-(4-fluorophenyl)-2-oxoethyl) 4-(2-methoxyethoxy)pyrrolidine-1,2-dicarboxylate (step 1, 4.5 g, 10.58 mmol) in toluene (60 ml), ammonium acetate (8.15 g, 105.8 mmol) was added at room temperature and refluxed for about 18 hours. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (200 ml) and the organic layer was washed with 1N HCl (2 ⁇ 200 ml).
  • Step 3 Synthesis of 4-(4-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate
  • step 1 To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-oxo-2-(pyridin-3-yl)ethyl) 4-(2-methoxyethoxy)pyrrolidine-1,2-dicarboxylate (step 1, 16.0 g, 39.21 mmol) in toluene (100 ml), ammonium acetate (24.15 g, 313.72 mmol) was added at room temperature and refluxed for about 24 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (200 ml) and the organic layer was washed with 1N HCl (2 ⁇ 150 ml).
  • Step 3 Synthesis of(S)-Benzyl 2-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate
  • Step 1 Synthesis of (S)-1-benzyl 2-(2-oxo-2-phenylethyl) pyrrolidine-1,2-dicarboxylate
  • step 1 To a stirred solution of (S)-1-benzyl 2-(2-oxo-2-phenylethyl) pyrrolidine-1,2-dicarboxylate (step 1, 12.0 g, 32.69 mmol) in acetic acid (150 ml), ammonium acetate (37.7 g, 490.3 mmol) was added at room temperature and heated at 120° C. for about 6 hours. Cooled to room temperature, the reaction mixture was concentrated, the residue was dissolved in dichloromethane (500 ml) and the organic layer was washed with aq. NaHCO 3 solution and brine. The organic layer was dried over Na 2 SO 4 , filtered and solvent was is evaporated.
  • Step 2 Synthesis of (S)-tert-butyl 2-(4-tert-butyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
  • step 1 To a stirred solution of (S)-tert-butyl 2-(3,3-dimethyl-2-oxobutylcarbamoyl) pyrrolidine-1-carboxylate (step 1, 11.3 g, 36.33 mmol) in xylene (130 ml), ammonium acetate (56.0 g, 726.6 mmol) was added at room temperature and heated at 140° C. for about 48 hours. The reaction mixture was cooled to room temperature, the pH was adjusted (pH ⁇ 7-8) with aq. NaHCO 3 solution and extracted with ethyl acetate (2 ⁇ 300 ml).
  • Step 2 Synthesis of tert-butyl (S)-2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
  • Step 3 Synthesis of tert-butyl (S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate
  • step 2 To a stirred solution of 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid (step 2, 15.0 g, 65.42 mmol, 1.0 eq) in CH 2 Cl 2 (150 ml) was added DIPEA (17.08 gr, 130.84 mmol) and 2-bromoacetophenone (13.02 gr, 65.42 mmol). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water. The aqueous layer was extracted with EtOAc (2 ⁇ 250 ml).
  • Step 4 Synthesis of tert-butyl 4-(5-phenyl-H-imidazol-2-yl)piperidine-1-carboxylate
  • step 4 To a stirred solution of tert-butyl 4-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate (step 4, 2.2 g, 6.72 mmol, 1.0 eq) in CH 2 Cl 2 (22 ml) was added 4M HCl in dioxane (20 mL). The reaction mixture was stirred at room temperature for 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated under reduced pressure to get the residue (1.52 gr) and used directly for next step without further purification.
  • step 1 To a stirred solution of 1-benzylpiperidin-4-one oxime (step 1, 3.3 g, 16.17 mmol, 1.0 eq) in methanol (15 ml) was added Raney Nickel (0.5 g) and 7N Methanolic ammonia solution (30 ml). The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through a pad of celite and washed with methanol (50 ml). The filtrate was evaporated under reduced pressure to obtain the desired product (2.9 g, 96% yield) as colourless oil.
  • Step 5 Synthesis of tert-butyl-2-(5-phenyl-4H-1, 2, 4-triazole)pyrrolidine-1-carboxylate
  • the reaction mixture was diluted with dichloromethane (200 ml), washed with water, saturated brine, dried over Na 2 SO 4 , filtered and the organic layer was concentrated under reduced pressure to afford the title compound (crude 7.5 g, 97%).
  • the crude product was used in the next step without further purification.
  • step 1 To a stirred solution of (S)-1-tert-butyl 2-(2-(3-fluoro-4-methoxyphenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (step 1, 7.5 g, 19.68 mmol) in toluene (60 ml), ammonium acetate (15.15 g, 196.8 mmol) was added at room temperature and refluxed for about 18 hours. Cooled to room temperature, the reaction mixture was diluted with ethyl acetate (200 ml) and the organic layer was washed with 1 N HCl (2 ⁇ 100 ml).
  • Step 3 Synthesis of tert-butyl (S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
  • reaction mixture was diluted with DCM, washed with water, saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude was proceeded to next step without further purification (wt: 18.0 g).
  • Step 2 Synthesis of 1-(tert-butyl) 2-(2-(2-fluorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate
  • reaction mixture was diluted with DCM, washed with water, saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude was proceeded to next step without further purification (wt: 18.0 g).
  • Step 3 Synthesis of tert-butyl (S)-2-(5-(2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
  • Step 1 Synthesis of (S)-1-tert-butyl 2-(2-(3-chlorophenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate
  • Step 1 Synthesis of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-hydroxypyrrolidine-1,2-dicarboxylate
  • Step 2 Synthesis of (2S,4R)-tert-butyl 4-hydroxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
  • step 1 To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-hydroxy pyrrolidine-1,2-dicarboxylate (step 1, 20.0 g, 57.5 mmol) in toluene (200 ml), ammonium acetate (44.25 g, 575.0 mmol) was added at room temperature and resulting reaction mixture was refluxed for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (2 ⁇ 250 ml) and the organic layer was washed with 1N HCl (2 ⁇ 200 ml).
  • step 2 To a solution of (2S,4R)-tert-butyl 4-hydroxy-2-(4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (step 2, 2.0 g, 6.1 mmol) in DCM (20 ml) was added trifluoroacetic acid (4.6 ml, 61.60 mmol) and stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford the title compound (2.0 g, yield: 100%) as a TFA salt.
  • step 1 To a stirred solution (2S,4R)-1-(tert-butoxycarbonyl)-4-isopropoxypyrrolidine-2-carboxylic acid (step 1, 10.0 g, 36.6 mmol) in DCM (100 ml) at 0° C. was added triethyl amine (11.1 g, 109.9 mmol) and after stirring about 10 minutes, 2-bromo-1-phenylethanone (8.74 g, 43.9 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), water was added to the reaction mixture and extracted with dichloromethane (200 ml).
  • Step 3 Synthesis of (2S,4R)-tert-butyl 4-isopropoxy-2-(4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate
  • Step 2 Synthesis of (2S,4R)-tert-butyl 2-(4-tert-butyl-1H-imidazol-2-yl)-4-(2-methoxyethoxy) pyrrolidine-1-carboxylate
  • reaction mixture was diluted with dichloromethane (200 ml), washed with water (200 ml), saturated brine (100 ml), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified on silica gel column (100-200 mesh, eluted in 20-25% ethyl acetate/hexane) to afford the title compound (6.80 g, yield: 77%).
  • Step 1 Synthesis of (2S,4R)-1-tert-butyl 2-(2-(3-fluorophenyl)-2-oxoethyl) 4-methoxy pyrrolidine-1,2-dicarboxylate
  • step 1 To a solution of (S)-tert-butyl 2-(4,5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 1, 3.70 g, 14.01 mmol) in DCM (40 ml) was added trifluoroacetic acid (20 ml) and stirred at room temperature for about 5 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford title compound (3.80 g) as a TFA salt.
  • Step 1 Synthesis of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate
  • the reaction mixture was heated FOR overnight at 90° C. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was evaporated under reduced pressure and diluted with water.
  • the aqueous layer was extracted with CH 2 Cl 2 (2 ⁇ 50 ml), the DCM layer was washed with 1N HCl, followed by water and brine solution.
  • the organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • the crude residue was purified by silicagel column chromatography by using 1.5% methanol: dichloromethane as an eluent to obtain the title compound (0.5 g) as a white solid.
  • Example 3 Preparation of (1R,3S)-2,2-dimethyl-3(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl) 3a-((S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid
  • Example 6 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(4-(trifluoromethyl) phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl icosahydro-1H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl cyclobutane-1-carboxylic acid
  • Example 7 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11R,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy)-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 8 Preparation of (1R,3S)-3-((((R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 11 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl) cyclobutane-1-carboxylic acid
  • Example 12 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)oxazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxycarbonyl)-2,2-dimethylyclobutane-1-carboxylic acid
  • Example 13 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11a,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-methyl-4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid
  • Example 14 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-isopropyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid
  • Example 15 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyloxazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid
  • Example 20 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid
  • Example 24 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl) cyclobutane-1-carboxylic acid
  • Example 25 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(3-fluoro-4-methoxyphenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl-5a,5b,8, 8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 28 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(3-chlorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl-5a 5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 31 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(tert-butyl)-1H-imidazol-2-yl)-4(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 34 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-55b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidin-1-carbonyl)-icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid
  • Example 35 Preparation of (1R,3S)-3-((((((1R,3aS,5aR,5bR,7a,9S,11a,11bR,13aR,13bR)-3a-((S)-2-(4, 5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid
  • Example 36 Preparation of (1R,3S)-3-((((13aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxycarbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 37 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl oxy)carbonyl)-2,2-dimethylcycobutane-1-carboxylic acid
  • Example 38 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo(3.2.1 octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • reaction mixture was diluted with EtOAc, washed with water followed by 1N HCl, water and brine solution. The residue was dried over Na 2 SO 4 , the solvent was evaporated under vacuum and purified by silica gel column (100-200 mesh, elution 5% MeOH/DCM) to afford the title compound (wt: 0.120 g) as an off white solid.
  • Example 40 Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
  • Example 42 Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bS)-1-(1,2-dihydroxypropan-2-yl)-5a,5b,8,8,11a-pentamethyl-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid
  • Example 43 Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy-2-(4-phenyl-1-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
  • Example 48 Preparation of 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carbonyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid
  • Example 50 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,1 aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Step 1 Synthesis of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate
  • Step 2 Synthesis of ((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl) ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8, 1a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)methanone
  • Step 3 Synthesis of 1-benzyl 3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) (1R,3S)-2,2-dimethylcyclobutane-1,3-dicarboxylate
  • the reaction mixture was heated for overnight at 90° C. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was evaporated under reduced pressure and diluted with water.
  • the aqueous layer was extracted with CH 2 Cl 2 (2 ⁇ 50 ml), the DCM layer was washed with 1N HCl, followed by water and brine solution.
  • the organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • the crude residue was purified by silicagel column chromatography by using 1.5% methanol: dichloromethane as an eluent to afford the title compound (wt: 0.3 g) as a white solid.
  • Step 4 Synthesis of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid
  • Example 51 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid
  • Example 52 Preparation of (1R,3S)-3-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 54 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 55 Preparation of (1R,3S)-3-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a 5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 58 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 59 Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(trifluoro methyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl icosahydro-1H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)cyclobutane-1-carboxylic acid
  • Example 60 Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a 5b,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid
  • Example 62 Preparation of 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) butanoic acid
  • Step 1 Synthesis of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate
  • Step 3 2, 2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,1 aR,11bR,13aR,13bR)-5a,5b,8,8, 11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl) icosahydro-H-cyclopenta[a]chrysen-9-yl)oxy) butanoic acid
  • reaction mixture was diluted with EtOAc, washed with water followed by 1N HCl, water and brine solution. The residue was dried over Na 2 SO 4 , the solvent was evaporated under vacuum and purified by silica gel column (100-200 mesh, elution 5% MeOH/DCM) to afford the title compound (wt: 0.15 g) as an off white solid.
  • Example 63 Preparation of 3,3-dimethyl-5-oxo-5-(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S-2-(5-pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) pentanoic acid
  • Example 64 Preparation of 5-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid
  • Example 65 Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid
  • Example 69 Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid
  • Example 70 Preparation of 5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxo
  • Example 71 Preparation of 4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
  • Example 72 Preparation of 5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a 5b,8,8,11a-pentamethyl-1-(-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid
  • the compounds described herein can be tested for their antiviral activity following procedures known to a person of ordinary skill in the art. For example, the following protocols can be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.

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US9868758B2 (en) 2014-06-30 2018-01-16 Hetero Labs Limited Betulinic proline imidazole 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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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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