WO2018005328A1 - Bictegravir deutérié - Google Patents

Bictegravir deutérié Download PDF

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Publication number
WO2018005328A1
WO2018005328A1 PCT/US2017/039207 US2017039207W WO2018005328A1 WO 2018005328 A1 WO2018005328 A1 WO 2018005328A1 US 2017039207 W US2017039207 W US 2017039207W WO 2018005328 A1 WO2018005328 A1 WO 2018005328A1
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compound
deuterium
hydrogen
pharmaceutically acceptable
formula
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PCT/US2017/039207
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English (en)
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WO2018005328A8 (fr
Inventor
Roger D. Tung
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Concert Pharmaceuticals, Inc.
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Publication of WO2018005328A1 publication Critical patent/WO2018005328A1/fr
Publication of WO2018005328A8 publication Critical patent/WO2018005328A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • ADME absorption, distribution, metabolism and/or excretion
  • ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites.
  • some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent.
  • modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.
  • a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly.
  • a drug that is cleared too rapidly.
  • the FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60).
  • CYP3A4 cytochrome P450 enzyme 3A4
  • Ritonavir causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs.
  • the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect.
  • Quinidine has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at www.accessdata.fda.gov).
  • a potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification.
  • Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability.
  • the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
  • This invention relates to deuterated forms of bictegravir, and pharmaceutically acceptable salts thereof.
  • the invention provides a compound of Formula I:
  • each of Y 1 , Y 2 , Y 3 , Y 4a , Y 4b , Y 5a , Y 5b , Y 6 , Y 7a , Y 7b , Y 8 , Y 9 , Y 10a , Y 10b , Y 11a , and Y 11b is independently hydrogen or deuterium; provided that if each Y 1 , Y 2 , Y 3 , Y 4a , Y 4b , Y 5a , Y 5b , Y 6 , Y 7a , Y 7b , Y 8 , Y 9 , Y 10a , Y 10b , and Y 11a is hydrogen, then Y 11b is deuterium.
  • This invention also provides compositions comprising a compound of this invention, including pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier.
  • This invention also provides the use of such compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a human immunodeficiency virus (HIV) integrase.
  • the invention provides a method of inhibiting human immunodeficiency virus (HIV) integrase activity in a cell, comprising contacting a cell with one or more compounds of Formula I herein, or a pharmaceutically acceptable salt thereof.
  • Some exemplary embodiments include a method of treating human
  • immunodeficiency virus that is beneficially treated by Formula I in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention.
  • Bictegravir also known by the chemical name (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N- (2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13- ,13a-octahydro-2,5- methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-0-carboxamide, and by the code names GS-9883 and GS-9883-001, is a potent HIV integrase inhibitor that causes a rapid reduction of HIV viral load in humans.
  • Bictegravir is currently in Phase III clinical trials for the treatment of HIV-1 infection, and is currently being tested for safety and efficacy in the antiretroviral treatment of HIV- infected adults as part of a fixed-dose combination with emtricitabine/tenofovir alafenamide.
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • a disease e.g., a disease or disorder delineated herein
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • the term“subject” includes humans and non-human mammals.
  • Non-limiting examples of non-human mammals include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, apes, pigs, cows, sheep, horses, etc.
  • alkyl refers to a monovalent saturated hydrocarbon group.
  • C 1 -C 6 alkyl is an alkyl having from 1 to 6 carbon atoms.
  • An alkyl may be linear or branched.
  • alkyl groups include methyl; ethyl; propyl, including n-propyl and isopropyl; butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl; pentyl, including, for example, n-pentyl, isopentyl, and neopentyl; and hexyl, including, for example, n-hexyl and 2-methylpentyl.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • the position is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% hydrogen.
  • a position when a position is designated specifically as“H” or“hydrogen”, the position incorporates ⁇ 10% deuterium, ⁇ 5% deuterium, ⁇ 4% deuterium, ⁇ 3% deuterium, ⁇ 2% deuterium, or ⁇ 1% deuterium. Also unless otherwise stated, when a position is designated specifically as“D” or“deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • each designated deuterium atom has deuterium incorporation of at least 52.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 60%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 67.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 75%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 82.5%.
  • each designated deuterium atom has deuterium incorporation of at least 90%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 95%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 97.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 99%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 99.5%. [24]
  • the term“isotopologue” refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.
  • a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure.
  • the relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.
  • the invention also provides salts of the compounds of the invention.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • the acid addition salt may be a deuterated acid addition salt.
  • A“pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • A“pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • A“pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionat
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • the acids commonly employed to form pharmaceutically acceptable salts include the above-listed inorganic acids, wherein at least one hydrogen is replaced with deuterium.
  • the pharmaceutically acceptable salt may also be a salt of a compound of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;
  • triethylamine mono-, bis-, or tris-(2-OH-(C 1 -C 6 )-alkylamine), such as N,N-dimethyl-N-(2- hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.
  • the pharmaceutically acceptable salt is a sodium salt.
  • the compounds of the present invention may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise.
  • compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers.
  • a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer.“Stereoisomer” refers to both enantiomers and diastereomers.
  • substantially free of other stereoisomers means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers are present.
  • Methods of obtaining or synthesizing an individual enantiomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.
  • stable compounds refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).
  • Substituted with deuterium refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
  • variable may be referred to generally (e.g., "each Y") or may be referred to specifically (e.g., Y 1 , Y 2 , Y 3 , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.
  • each of Y 1 , Y 2 , Y 3 , Y 4a , Y 4b , Y 5a , Y 5b , Y 6 , Y 7a , Y 7b , Y 8 , Y 9 , Y 10a , Y 10b , Y 11a , and Y 11b is independently hydrogen or deuterium; provided that if each Y 1 , Y 2 , Y 3 , Y 4a , Y 4b , Y 5a , Y 5b , Y 6 , Y 7a , Y 7b , Y 8 , Y 9 , Y 10a , Y 10b , and Y 11a is hydrogen, then Y 11b is deuterium.
  • At least one of Y 1 , Y 2 , Y 3 , Y 4a , Y 4b , Y 5a , Y 5b , Y 6 , Y 7a , Y 7b , Y 8 , Y 9 , Y 10a , Y 10b , Y 11a , and Y 11b is hydrogen.
  • At least one of Y 4a , Y 4b , Y 5a , Y 5b , Y 6 , Y 7a , Y 7b , Y 8 , Y 9 , Y 10a , Y 10b , Y 11a , and Y 11b is hydrogen.
  • Y 1 , Y 2 , and Y 3 are the same.
  • Y 1 , Y 2 , and Y 3 are hydrogen.
  • Y 1 , Y 2 , and Y 3 are deuterium.
  • the compound of Formula I has the structure of Formula 1A:
  • Y 4a and Y 4b are the same.
  • Y 4a and Y 4b are hydrogen.
  • Y 4a and Y 4b are deuterium.
  • Y 5a and Y 5b are the same.
  • Y 5a and Y 5b are hydrogen.
  • Y 5a and Y 5b are deuterium.
  • Y 4a , Y 4b , Y 5a , and Y 5b are the same.
  • Y 4a , Y 4b , Y 5a , and Y 5b are hydrogen.
  • Y 4a , Y 4b , Y 5a , and Y 5b are deuterium.
  • Y 4a and Y 4b are hydrogen and Y 5a and Y 5b are deuterium.
  • Y 4a and Y 4b are deuterium and Y 5a and Y 5b are hydrogen.
  • one of Y 4a and Y 4b is hydrogen and the other is deuterium; and one of Y 5a and Y 5b is hydrogen and the other is deuterium.
  • both of Y 4a and Y 4b are hydrogen; and one of Y 5a and Y 5b is hydrogen and the other is deuterium.
  • both of Y 4a and Y 4b are deuterium; and one of Y 5a and Y 5b is hydrogen and the other is deuterium.
  • both of Y 5a and Y 5b are hydrogen; and one of Y 4a and Y 4b is hydrogen and the other is deuterium.
  • both of Y 5a and Y 5b are deuterium; and one of Y 4a and Y 4b is hydrogen and the other is deuterium.
  • both of Y 5a and Y 5b are deuterium; and one of Y 4a and Y 4b is hydrogen and the other is deuterium.
  • Y 6 is hydrogen. Alternatively, Y 6 is deuterium.
  • Y 7a and Y 7b are the same. In one aspect, Y 7a and Y 7b are hydrogen. Alternatively, Y 7a and Y 7b are deuterium. In some embodiments, one of Y 7a and Y 7b is hydrogen the other is deuterium.
  • Y 8 is hydrogen.
  • Y 8 is deuterium.
  • Y 6 and Y 8 are the same.
  • Y 6 and Y 8 are hydrogen.
  • Y 6 and Y 8 are deuterium.
  • Y 6 is different than Y 8 .
  • Y 6 is hydrogen and Y 8 is deuterium.
  • Y 6 is deuterium and Y 8 is hydrogen.
  • Y 8 are the same. In one aspect, Y 6 7 7b 8 6 7 7b and Y 8 are deuterium.
  • Y 6 is hydrogen, Y 7a and Y 7b are hydrogen, and Y 8 is hydrogen.
  • Y 6 is hydrogen, Y 7a and Y 7b are hydrogen, and Y 8 is deuterium.
  • Y 6 is hydrogen, Y 7a and Y 7b are deuterium, and Y 8 is deuterium.
  • Y 6 is hydrogen, Y 7a and Y 7b are deuterium, and Y 8 is hydrogen.
  • Y 6 is deuterium, Y 7a and Y 7b are deuterium, and Y 8 is deuterium.
  • Y 6 is deuterium
  • Y 7a and Y 7b are deuterium
  • Y 8 is hydrogen
  • Y 6 is deuterium
  • Y 7a and Y 7b are hydrogen
  • Y 8 is deuterium
  • Y 6 is deuterium
  • Y 7a and Y 7b are hydrogen
  • Y 8 is hydrogen.
  • Y 9 is hydrogen.
  • Y 9 is deuterium.
  • Y 10a and Y 10b are hydrogen.
  • Y 10a and Y 10b are deuterium.
  • one of Y 10a and Y 10b is hydrogen, and the other is deuterium.
  • Y 9 is hydrogen and Y 10a and Y 10b are hydrogen.
  • Y 9 is hydrogen, Y 10a and Y 10b are deuterium.
  • Y 9 is deuterium, and Y 10a and Y 10b are hydrogen.
  • Y 9 is deuterium, and Y 10a and Y 10b are deuterium.
  • Y 11a and Y 11b are the same.
  • Y 11a and Y 11b are hydrogen.
  • Y 11a and Y 11b are deuterium.
  • one of Y 11a and Y 11b is hydrogen, and the other is deuterium.
  • the compound is a compound of Formula I, wherein Y , Y , and Y are hydrogen, and the compound is selected from any one of the compounds set forth in Table 1 below:
  • the compound is a compound of Formula I, wherein Y , Y , and Y are deuterium, and the compound is selected from any one of the compounds set forth in Table 2 below:
  • any atom not designated as deuterium is present at its natural isotopic abundance.
  • the level of deuterium incorporation at each Y 1 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 2 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 3 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 4a or Y 4b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 5a or Y 5b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 6 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 7a or Y 7b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 8 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 9 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 10a or Y 10b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 11a or Y 11b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • any atom not designated as deuterium in any of the embodiments set forth herein is present at its natural isotopic abundance.
  • deuterium incorporation at each designated deuterium atom is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • At least one of Y 1 , Y 2 , Y 3 , Y 4a , Y 4b , Y 5a , Y 5b , Y 6 , Y 7a , Y 7b , Y 8 , Y 9 , Y 10a , Y 10b , Y 11a , and Y 11b is hydrogen.
  • Deuterium-modified analogs of bictegravir can be synthesized by means known in the art of organic chemistry. For instance, using methods described in US Patent No.9,216,996 (Haolun J. et al., assigned to Gilead Sciences, Inc. and incorporated herein by reference), using deuterium-containing reagents provides the desired deuterated analogs.
  • Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.
  • deuterated intermediates 2a and 2b for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 2 below.
  • deuterated intermediates 4a-4d for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 3 below.
  • acetaldehyde is converted to alkylhalide 14a via reaction with chlorine gas and subsequent acetal protection with CaCl 2 in methanol.
  • Use of appropriately deuterated reagents allows deuterium incorporation at the Y 9 , Y 10a , and Y 10b positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y 9 , Y 10a , and/or Y 10b .
  • deuterated intermediates 9a-9d for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 4 below.
  • Cyclopentadiene-d 6 is prepared according to the procedure described in Cangoenuel, A. et. al. Inorg. Chem.2013, 52, 11859-11866.
  • the invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., including any of the formulae herein
  • the carrier(s) are“acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • Pharmaceutically acceptable carriers, adjuvants, excipients and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates (e.g., phosphate-buffered saline, etc.), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers e.g.,
  • the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art.
  • One method includes the use of lipid excipients in the formulation. See“Oral Lipid- Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and“Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples,” Kishor M. Wasan, ed. Wiley-Interscience, 2006.
  • Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL TM and PLURONIC TM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques).
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed.2000).
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.
  • Topically-transdermal patches and iontophoretic administration are also included in this invention.
  • compositions at the site of interest may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
  • the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
  • the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention.
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
  • the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.
  • composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
  • composition of this invention further comprises one or more additional therapeutic agents.
  • the additional therapeutic agent(s) may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as bictegravir.
  • Such agents include those indicated as being useful in combination with bictegravir, including but not limited to, lamivudine, zidovudine, lopinavir, ritonavir, abacavir, tenofovir disoproxil fumarate, emtricitabine, efavirenz, rilpivirine, elvitegravir, cobicistat, dolutegravir, atazanavir, darunavir, raltegravir, tenofovir alafenamide, tenofovir alafenamide fumarate, and any combination thereof.
  • the additional therapeutic agent is an agent useful in the treatment of Human Immunodeficiency Virus (HIV).
  • HIV Human Immunodeficiency Virus
  • the additional therapeutic agent is selected from emtricitabine and tenofovir alafenamide. In some embodiments, the additional therapeutic agent is a combination of emtricitabine and tenofovir alafenamide. In some embodiments, the additional therapeutic agent is a combination of 200 mg of emtricitabine and 25 mg of tenofovir alafenamide.
  • the pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, one or more additional therapeutic agents, and a pharmaceutically acceptable carrier in a single dosage form.
  • the single dosage form is a tablet.
  • the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described additional therapeutic agents, wherein the compound and additional therapeutic agent(s) are associated with one another.
  • the term“associated with one another” as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • the compound of the present invention is present in an effective amount.
  • the term“effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.
  • an effective amount of a compound of this invention can range from about 25 to 50 mg per day; 15 to 75 mg per day; 10 to 100 mg per day; 5 to 500 mg per day, or 2 to 1000 mg per day.
  • the effective amount can be dosed once or twice a day.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for bictegravir.
  • an effective amount of the additional therapeutic agent(s) is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent.
  • an effective amount is between about 70% and 100% of the normal
  • the invention provides a method of inhibiting human immunodeficiency virus (HIV) integrase activity in a cell, comprising contacting a cell with one or more compounds of Formula I herein, or a pharmaceutically acceptable salt thereof.
  • the cell is contacted in vitro.
  • the cell is contacted in vivo.
  • the cell is contacted ex vivo.
  • the invention provides a method of treating a disease that is beneficially treated by bictegravir in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention.
  • the subject is a patient in need of such treatment.
  • the subject is a human.
  • Such diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: human immunodeficiency virus (HIV) U.S. Patent Application No.2016016973, U.S. Patent Application No.2015366872, and U.S. Patent No.9,216,996.
  • the method of this invention is used to treat human immunodeficiency virus (HIV) in a subject in need thereof.
  • the invention provides a method of treating human immunodeficiency virus (HIV), the method comprising administering to a subject in need of such treatment an effective amount of a compound or a composition of this invention.
  • HIV human immunodeficiency virus
  • the HIV is HIV-1.
  • the subject is a patient in need of such treatment.
  • the subject is a human.
  • the subject is a virologically suppressed HIV-1-infected subject.
  • the subject is HIV-1 infected, antiretroviral treatment-naive subject.
  • Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • any of the above methods of treatment comprises the further step of co-administering to the subject in need thereof an effective amount of one or more additional therapeutic agents.
  • additional therapeutic agent may be made from any additional therapeutic agent known to be useful for co-administration with bictegravir.
  • additional therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of additional therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and an additional therapeutic agent.
  • the combination therapies of this invention include co-administering a compound of Formula I and one or more additional therapeutic agents to a subject in need thereof for treatment of human immunodeficiency virus (HIV).
  • HAV human immunodeficiency virus
  • co-administered means that the additional therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an additional therapeutic agent as described above) or as separate, multiple dosage forms.
  • the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention.
  • both the compounds of this invention and the additional therapeutic agent(s) are administered by conventional methods.
  • the administration of a composition of this invention, comprising both a compound of the invention and one or more additional therapeutic agents, to a subject does not preclude the separate administration of that same therapeutic agent, any other additional therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.
  • the effective amount of the compound of this invention is less than its effective amount would be where the additional therapeutic agent is not administered. In another embodiment, the effective amount of the additional therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
  • the invention provides the use of a compound of Formula I alone or together with one or more of the above-described additional therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment in a subject of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.
  • the invention provides a compound (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein alone or in combination with one or more of the above-described additional therapeutic agents for use in treating human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • the HIV is HIV-1.
  • the subject is a virologically suppressed HIV-1-infected subject.
  • the subject is HIV-1 infected, antiretroviral treatment-naive subject.
  • the compound or the pharmaceutical composition disclosed herein is used in combination with an effective amount of
  • Xenotech, LLC (Lenexa, KS).
  • ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl 2 ), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.
  • 7.5 mM stock solutions of test compounds are prepared in DMSO.
  • the 7.5 mM stock solutions are diluted to 12.5-50 ⁇ M in acetonitrile (ACN).
  • ACN acetonitrile
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl 2 .
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 ⁇ L aliquot of the 12.5-50 ⁇ M test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution.
  • the final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 ⁇ M test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl 2 .
  • the reaction mixtures are incubated at 37 °C, and 50 ⁇ L aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 ⁇ L of ice- cold ACN with internal standard to stop the reactions.
  • the plates are stored at 4 °C for 20 minutes after which 100 ⁇ L of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.

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Abstract

La présente invention concerne des formes deutériées de bictegravir, et ses sels pharmaceutiquement acceptables. Dans un aspect, l'invention prévoit un composé de Formule I : ou son sel pharmaceutiquement acceptable, chacun de Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, et Y11b étant indépendamment de l'hydrogène ou du deutérium ; à condition que si chacun de Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, et Y11 est l'hydrogène, alors Y11b est du deutérium.
PCT/US2017/039207 2016-06-27 2017-06-26 Bictegravir deutérié WO2018005328A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN110229174A (zh) * 2019-05-22 2019-09-13 博诺康源(北京)药业科技有限公司 Bictegravir原料药基因毒性杂质的合成方法
WO2020042841A1 (fr) * 2018-08-28 2020-03-05 重庆博腾制药科技股份有限公司 Procédé de préparation de (1r,3s)-3-amino-1-cyclopentanol et de ses sels
EP3653629A1 (fr) * 2018-11-16 2020-05-20 Sandoz AG Sels d'addition d'acide d'un inhibiteur de transfert de brins de l'intégrase
WO2021195403A1 (fr) 2020-03-26 2021-09-30 Cyclerion Therapeutics, Inc. Stimulateurs de sgc deutérés

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WO2015039348A1 (fr) * 2013-09-23 2015-03-26 Merck Sharp & Dohme Corp. Composés hétérocycliques tétracycliques utiles comme inhibiteurs de l'intégrase du vih
US20150291618A1 (en) * 2011-05-03 2015-10-15 Concert Pharmaceuticals Inc. Carbamoylpyridone derivatives

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US20150291618A1 (en) * 2011-05-03 2015-10-15 Concert Pharmaceuticals Inc. Carbamoylpyridone derivatives
US20140221356A1 (en) * 2012-12-21 2014-08-07 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2015039348A1 (fr) * 2013-09-23 2015-03-26 Merck Sharp & Dohme Corp. Composés hétérocycliques tétracycliques utiles comme inhibiteurs de l'intégrase du vih

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020042841A1 (fr) * 2018-08-28 2020-03-05 重庆博腾制药科技股份有限公司 Procédé de préparation de (1r,3s)-3-amino-1-cyclopentanol et de ses sels
JP2021532184A (ja) * 2018-08-28 2021-11-25 重慶博騰制薬科技股▲ふん▼有限公司 （１ｒ，３ｓ）−３−アミノ−１−シクロペンタノール及びその塩の調製方法
JP7174851B2 (ja) 2018-08-28 2022-11-17 重慶博騰制薬科技股▲ふん▼有限公司 （１ｒ，３ｓ）－３－アミノ－１－シクロペンタノール及びその塩の調製方法
EP3653629A1 (fr) * 2018-11-16 2020-05-20 Sandoz AG Sels d'addition d'acide d'un inhibiteur de transfert de brins de l'intégrase
CN110229174A (zh) * 2019-05-22 2019-09-13 博诺康源(北京)药业科技有限公司 Bictegravir原料药基因毒性杂质的合成方法
WO2021195403A1 (fr) 2020-03-26 2021-09-30 Cyclerion Therapeutics, Inc. Stimulateurs de sgc deutérés

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