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WO2018106916A1 - Composés de quinoxaline deutérés - Google Patents

Composés de quinoxaline deutérés Download PDF

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Publication number
WO2018106916A1
WO2018106916A1 PCT/US2017/065111 US2017065111W WO2018106916A1 WO 2018106916 A1 WO2018106916 A1 WO 2018106916A1 US 2017065111 W US2017065111 W US 2017065111W WO 2018106916 A1 WO2018106916 A1 WO 2018106916A1
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WIPO (PCT)
Prior art keywords
compound
hydrogen
same
deuterium
composition
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PCT/US2017/065111
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English (en)
Inventor
Roger D. Tung
Julie F. Liu
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Concert Pharmaceuticals, Inc.
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Publication date
Application filed by Concert Pharmaceuticals, Inc. filed Critical Concert Pharmaceuticals, Inc.
Publication of WO2018106916A1 publication Critical patent/WO2018106916A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

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 novel 2,3,6b,7,8,9,10,10a-octahydro-lH- pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalines, and pharmaceutically acceptable salts thereof. Certain aspects of the present invention are directed to compounds of Formula III:
  • R is CH3, CH 2 D, CHD 2 or CD3;
  • R 2 is hydrogen, deuterium, or C(0)-C 1-21 alkyl;
  • Y 8a , Y ®> , and Y 14 are each deuterium;
  • Y 12a and Y 12b are each hydrogen;
  • Y 13a and Y 13b are each hydrogen; and
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 711 , Y 9 , and Y 10 are independently selected from hydrogen and deuterium.
  • compositions comprising a compound of this invention, including pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier. Certain aspects of the present invention also provide the use of such compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a serotonergic, dopaminergic, and glutamatergic modulator. Some exemplary embodiments include a method of treating a disease or condition selected from schizophrenia, depression, bipolar disorder, agitation, insomnia, dementia, and Alzheimer's Disease, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.
  • ITI-007 (CAS Registry numbers 1187020-80-9, 313368-91-1) also known as rn-722 and l-(4-fluorophenyl)-4-[(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a- octahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl]butan-l-one tosylate, modulates the serotonergic, dopaminergic, and glutamatergic systems.
  • ITI-007 is currently in phase III clinical trials for the treatment of
  • phase II clinical trials for the treatment of insomnia phase Ib/II clinical trials for the treatment of dementia, including Alzheimer's disease; and is currently being tested for safety and efficacy in patients with an acute exacerbation of the aforementioned diseases.
  • ITI-007 is metabolized into two active metabolites, IC200131 and IC200161.
  • IC200131 (CAS Registry number 1469343-42-7) is also known as (6bR,10aS)- -(4-fluorophenyl)- 2,3,6b,9,10,10a-hexahydro-3-methyl-lH-Pyrido[3',4':4,5]pyrrolo[l,2,3- de]quinoxaline-8(7H)-butanol.
  • IC200131 is reported to be a serotonin-2A (5-HT2A) receptor antagonist and inhibitor of serotonin reuptake with roughly equal potency at each of these two targets.
  • IC200131 is reported to have a longer plasma half-life than IT1-007 or IC200161.
  • IC200131 is reported to be able to undergo back- conversion into IT1-007. The metabolism of ⁇ -007 is also discussed in
  • 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.
  • 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 has at least 80%, 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 ⁇ " or “hydrogen”, the position incorporates ⁇ 20% deuterium, ⁇ 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%.
  • 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%. In some embodiments, in a compound of this invention, 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%.
  • 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%.
  • 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.
  • pharmaceutically acceptable 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.
  • 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.
  • 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-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylprop
  • 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 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.
  • substantially free of other stereoisomers as used herein 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.
  • 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 R") or may be referred to specifically (e.g., R 1 , R 2 , R 3 , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.
  • the present invention in one embodiment provides a compound of Formula III:
  • R is CH 3 , CH 2 D, CHD 2 or CD 3 ;
  • R 2 is hydrogen, deuterium, or C(0)-d- 21 alkyl
  • Y 8a , Y 8b , and Y 14 are each deuterium
  • Y 1a Y 1b Y 2a Y 2b Y 3a Y 3b Y 4a Y 4b Y 5a Y 5 ' 5 Y 6a Y 6b Y 7a Y 7 * 5 Y 9 Y 10 Y 11a Y 11b , Y 11c , Y 12a , Y 12b , Y 13a , and Y 13b are independently selected from hydrogen and deuterium.
  • the compound of formula III is a compound of Formula Ilia:
  • R, R 2 , Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y a , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9 , Y 10 , Y 11a , Y 11b , Y 11c , Y 12a , Y 12b , Y 13a , Y 13b , and Y 14 are as defined herein.
  • the compound of formula III is a compound of Formula Illb:
  • R, R 2 , Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9 , Y 10 , Y 11a , Y 11b , Y 11c , Y 12a , Y 12b , Y 13a , Y 13b , and Y 14 are as defined herein.
  • R is CH 3 .
  • R is CD3. 11 [43] In some embodiments of any one of Formulae III, Ilia and Illb, Y 1a and Y 1b are the same. In some aspects of these embodiments, Y 1a and Y 1b are each hydrogen.
  • Y 1a and Y 1b are each deuterium.
  • Y 2a and Y 2b are the same. In some aspects of these embodiments, Y 2a and Y 2b are each hydrogen.
  • Y 2a and Y 2b are each deuterium.
  • Y 1a , Y 1b , Y 2a and Y 2b are the same.
  • Y 1a , Y 1b , Y 2a and Y 2b are each hydrogen.
  • Y 1a , Y 1b , Y 2a and Y 2b are each deuterium.
  • Y 1a and Y 1b are each hydrogen; and Y 2a and Y 2b are each deuterium. In other embodiments, Y 1a and Y 1b are each deuterium; and Y 2a and Y 2b are each hydrogen.
  • Ilia and Illb are the same. In some aspects of these embodiments, Y 3a and Y 3b are each hydrogen.
  • Y 3a and Y 3b are each deuterium.
  • Y 4a and Y 4b are the same. In some aspects of these embodiments, Y 4a and Y 4b are each hydrogen.
  • Y 4a and Y 4b are each deuterium.
  • Ilia and Illb are the same. In some aspects of these embodiments, Y 5a and Y* are each hydrogen.
  • Y 5a and Y 5b are each deuterium.
  • Y 4b , Y 5a and Y 5b are the same. In some aspects of these embodiments, Y 3a , Y 3b , Y 4a ,
  • Y 4b , Y 5a and Y 5b are each hydrogen. In other aspects of these embodiments, Y 3a , Y 3b ,
  • Y 4a , Y 4b , Y 5a and Y 5b are each deuterium.
  • Ilia and Illb, Y 3a , Y 3b , Y 5a and ⁇ ⁇ are each hydrogen; and Y 4a and Y 4b are each deuterium.
  • Y 3a , Y 3b , Y 5a and Y 5b are each deuterium; and Y 4a and Y 4b are each hydrogen.
  • Ilia and Illb, Y 6a and Y 6b are the same. In some aspects of these embodiments, Y 6a and Y* are each hydrogen. In other aspects of these embodiments, Y 6a and Y 6b are each deuterium. [53] In some embodiments of any one of Formulae III, Ilia and Illb, Y 7a and Y 711 are the same. In some aspects of these embodiments, Y 7a and Y 715 are each hydrogen. In other aspects of these embodiments, Y 7a and Y 711 are each deuterium.
  • Ilia and Illb, Y 6a , Y*, Y 7a , and Y 711 are the same.
  • Y 6a , Y a , Y 7a , and Y 711 are each hydrogen.
  • Y 6a , Y 6b , Y 7a , and Y 715 are each deuterium.
  • Y 7a and Y 711 are each hydrogen; and Y 6a and Y 6b are each deuterium. In other embodiments, Y 7a and Y 711 are each deuterium; and Y 6a and Y 6b are each hydrogen.
  • Y 11a , Y 11b , Y 11 c Y i2a yi2b ; yi3a md yi3b each hydrogen.
  • Y 11a , Y 11b , Y 11c , Y 12a , Y 12b , Y 13a , and Y 13b are each deuterium.
  • R 2 is hydrogen
  • R 2 is deuterium
  • R 2 is C(0)-C 1- 21 alkyl. In some embodiments, R 2 is C(0)-Cs- 1 9 alkyl. In some embodiments, R 2 is C(0)-C9-n alkyl. In some embodiments, R 2 is C(0)-C 1 5 alkyl. In some embodiments, R 2 is palmitoyl.
  • Y 9 is hydrogen
  • Y 9 is deuterium.
  • Y 10 is hydrogen
  • Y 10 is deuterium.
  • Ilia and Illb, Y 9 and Y 10 are each hydrogen.
  • Ilia and Illb, Y 9 and Y 10 are each deuterium.
  • Ilia and Illb, Y 11a , Y 11b and Y 11c are each hydrogen.
  • Ilia and Illb, Y 11a , Y 11b and Y 11c are each deuterium.
  • Ilia and Illb, Y 12a and Y 12b are each hydrogen.
  • Ilia and Illb, Y 12a and Y 12b are each deuterium.
  • Ilia and Illb, Y 13a and Y 13b are each hydrogen.
  • Ilia and Illb, Y 13a and Y 13b are each deuterium.
  • R is CD 3 ;
  • R 2 is hydrogen; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; Y 6a and Y 6b are the same; Y 7a and Y 711 are the same; Y 9 is hydrogen;
  • Y 10 is hydrogen; Y 11a , Y 11b and Y 11c are each hydrogen; Y 12a and Y 12b are each hydrogen; Y 13a and Y 13b are each hydrogen; and the compound of Formula III is selected from any one of the compounds (Cmpd) set forth in Table la (below):
  • R is CH3;
  • R 2 is hydrogen; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; Y 6a and Y 6b are the same; Y 7a and Y 711 are the same; Y 9 is hydrogen;
  • Y 10 is hydrogen; Y 11a , Y 11b and Y 11c are each hydrogen; Y 12a and Y 12b are each hydrogen; Y 13a and Y 13b are each hydrogen; and the compound of Formula III is selected from any one of the compounds (Cmpd) set forth in Table lb (below):
  • R is CD 3 ;
  • R 2 is palmitoyl;
  • Y 1a and Y 1b are the same;
  • Y 2a and Y 2b are the same;
  • Y 3a and Y 3b are the same;
  • Y 4a and Y 4b are the same;
  • Y 5a and Y 5b are the same;
  • Y 6a and Y 6b are the same;
  • Y 7a and Y 711 are the same;
  • Y 9 is hydrogen;
  • Y 10 is hydrogen;
  • Y 11a , Y 11b and Y 11c are each hydrogen;
  • Y 12a and Y 12b are each hydrogen;
  • Y 13a and Y 13b are each hydrogen; and
  • the compound of Formula III is selected from any one of the compounds (Cmpd) set forth in Table lc (below):
  • R is CH 3 ;
  • R 2 is palmitoyl;
  • Y 1a and Y 1b are the same;
  • Y 2a and Y 2b are the same;
  • Y 3a and Y 3b are the same;
  • Y 4a and Y 4b are the same;
  • Y 5a and Y 5b are the same;
  • Y 6a and Y 6b are the same;
  • Y 7a and Y 711 are the same;
  • Y 9 is hydrogen;
  • Y 10 is hydrogen;
  • Y 11a , Y 11b and Y 11c are each hydrogen;
  • Y 12a and Y 12b are each hydrogen;
  • Y 13a and Y 13b are each hydrogen; and
  • the compound of Formula III is selected from any one of the compounds (Cmpd) set forth in Table Id (below):
  • R is CD3;
  • R 2 is hydrogen;
  • Y 1a and Y 1b are the same;
  • Y 2a and Y 2b are the same;
  • Y 3a and Y 3b are the same;
  • Y 4a and Y 4b are the same;
  • Y 5a and Y 5b are the same;
  • Y 6a and Y 6b are the same;
  • Y 7a and Y 711 are the same;
  • Y 9 is hydrogen;
  • Y 10 is hydrogen;
  • Y 11a , Y 11b and Y 11c are each hydrogen;
  • Y 12a and Y 12b are each hydrogen;
  • Y 13a and Y 13b are each hydrogen; and
  • the compound of Formula Ilia is selected from any one of the compounds (Cmpd) set forth in Table 2a (below):
  • R is CH 3 ;
  • R 2 is hydrogen; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; Y 6a and Y 6b are the same; Y 7a and Y 711 are the same; Y 9 is hydrogen;
  • Y 10 is hydrogen; Y 11a , Y 11b and Y 11c are each hydrogen; Y 12a and Y 12b are each hydrogen; Y 13a and Y 13b are each hydrogen; and the compound of Formula Ilia is selected from any one of the compounds (Cmpd) set forth in Table 2b (below):
  • R is CD 3 ;
  • R 2 is palmitoyl;
  • Y 1a and Y 1b are the same;
  • Y 2a and Y 2b are the same;
  • Y 3a and Y 3b are the same;
  • Y 4a and Y 4b are the same;
  • Y 5a and Y 5b are the same;
  • Y 6a and Y 6b are the same;
  • Y 7a and Y 711 are the same;
  • Y 9 is hydrogen;
  • Y 10 is hydrogen;
  • Y 11a , Y 11b and Y 11c are each hydrogen;
  • Y 12a and Y 12b are each hydrogen;
  • Y 13a and Y 13b are each hydrogen; and
  • the compound of Formula Ilia is selected from any one of the compounds (Cmpd) set forth in Table 2c (below):
  • R is CH3; R 2 is palmitoyl; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; Y 6a and Y 6b are the same; Y 7a and Y 711 are the same; Y 9 is hydrogen; Y 10 is hydrogen; Y 11a , Y 11b and Y 11c are each hydrogen; Y 12a and Y 12b are each hydrogen; Y 13a and Y 13b are each hydrogen; and the compound of Formula Ilia is selected from any one of the compounds (Cmpd) set forth in Table 2d (below):
  • R is CD 3 ;
  • R 2 is hydrogen; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; Y 6a and Y 6b are the same; Y 7a and Y 711 are the same; Y 9 is hydrogen;
  • Y 10 is hydrogen; Y 11a , Y 11b and Y 11c are each hydrogen; Y 12a and Y 12b are each hydrogen; Y 13a and Y 13b are each hydrogen; and the compound of Formula Illb is selected from any one of the compounds (Cmpd) set forth in Table 3a (below):
  • R is CH 3 ;
  • R 2 is hydrogen; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; Y 6a and Y 6b are the same; Y 7a and Y 711 are the same; Y 9 is hydrogen;
  • Y 10 is hydrogen; Y 11a , Y 11b and Y 11c are each hydrogen; Y 12a and Y 12b are each hydrogen; Y 13a and Y 13b are each hydrogen; and the compound of Formula Illb is selected from any one of the compounds (Cmpd) set forth in Table 3b (below):
  • R is CD3; R 2 is palmitoyl; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; Y 6a and Y 6b are the same; Y 7a and Y 711 are the same; Y 9 is hydrogen; Y 10 is hydrogen; Y 11a , Y 11b and Y 11c are each hydrogen; Y 12a and Y 12b are each hydrogen; Y 13a and Y 13b are each hydrogen; and the compound of Formula Illb is selected from any one of the compounds (Cmpd) set forth in Table 3c (below):
  • R is CH 3 ;
  • R 2 is palmitoyl;
  • Y 1a and Y 1b are the same;
  • Y 2a and Y 2b are the same;
  • Y 3a and Y 3b are the same;
  • Y 4a and Y 4b are the same;
  • Y 5a and Y 5b are the same;
  • Y 6a and Y 6b are the same;
  • Y 7a and Y 711 are the same;
  • Y 9 is hydrogen;
  • Y 10 is hydrogen;
  • Y 11a , Y 11b and Y 11c are each hydrogen;
  • Y 12a and Y 12b are each hydrogen;
  • Y 13a and Y 13b are each hydrogen; and
  • the compound of Formula Illb is selected from any one of the compounds (Cmpd) set forth in Table 3d (below):
  • the level of deuterium incorporation at each Y 1a or Y 1b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 2a or Y 2b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 3a or Y 3b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is 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%, is 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%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 6a or Y 6b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 7a or Y 711 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 8a or Y 8b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at Y 9 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at Y 10 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 11a , Y 11b , or Y 11c is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 12a or Y 12b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 13a or Y 13b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • 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%.
  • Y 13b is hydrogen.
  • Y 6a , Y a , Y 7a , Y 7b , Y 8a , Y 8b , and Y 14 are as described hereinabove.
  • any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
  • the synthesis of compounds of Formula III may be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis and Examples disclosed herein. Relevant procedures analogous to those of use for the preparation of compounds of Formula III and intermediates thereof are disclosed, for instance in PCT application No. PCT/US2008/003340 (published as
  • 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.
  • R, R 2 , Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y a , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9 , Y 10 and Y 14 are as described hereinabove.
  • a compound of Formula III, Ilia and/or Illb may be prepared as shown in Scheme 1 (which illustrates an exemplary embodiment wherein Y 11a , Y 11b , Y 11c , Y 12a , Y 12b , Y 13a , and Y 13b are each hydrogen).
  • Scheme 1 which illustrates an exemplary embodiment wherein Y 11a , Y 11b , Y 11c , Y 12a , Y 12b , Y 13a , and Y 13b are each hydrogen.
  • appropriately deuterated c/s-indoline intermediate (1) is treated with appropriately deuterated alkyl halide intermediate (2), in the presence of a base such as potassium carbonate or sodium hydride to produce appropriately deuterated alkylated c/s-indoline intermediate (3) which is reduced with an appropriately deuterated reducing agent such as Borane-d3, to produce appropriately deuterated ethyl ester protected c/s-indoline intermediate (4).
  • Intermediate (4) is then treated with a base such as potassium hydroxide to remove the ethoxycarbonyl protection, furnishing appropriately deuterated free amino c/s-indoline intermediate (5).
  • Intermediate (5) is alkylated with appropriately deuterated intermediate (21), prepared as shown in Scheme 5 below, under basic conditions to produce an appropriately deuterated compound of Formula III.
  • appropriately deuterated intermediate (21) is first resolved into its enantiomers, as shown in Scheme 5, and alkylation of intermediate (5) with the desired enantiomer of (21) provides the corresponding optical isomer of Formula III, that is, a compound of Formula Ilia or Formula Illb.
  • compounds of Formula III, Ilia and/or Illb can be prepared with greater than 90% or greater than 95% deuterium incorporation at each position designated as D (see below for details).
  • deuterated intermediate (1) for use in the preparation of compounds of Formula III (or Ilia or Illb) according to Scheme 1 may be prepared from corresponding deuterated reagents exemplified in Scheme 2.
  • Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 9 and Y 10 are as described hereinabove.
  • Reagents and conditions (a) NaN0 2 , HOAc; (b) Zn, HOAc; (c) HOAc, HC1; (d) NaBD 3 CN, d-TFA, NH 4 OH, NaOH or NaBH 3 CN, TFA, NH4OH, NaOH; (e) chiral resolution
  • compounds of Formula III can be prepared with greater than 90% or greater than 95% (e.g., up to 98% or 99.5 %) deuterium incorporation at some or all of Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 9 and Y 10 in Formula III (or Ilia or Illb).
  • deuterated intermediate (8) for use in the preparation of intermediate (1), and hence of compounds of Formula III (or Ilia or Illb) according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 3.
  • Reagents and conditions (a) N 2 0 5 , Bismuth triflate; (b) EtN(Pr-i) 2 , KF,18-Crown-6; (c) H 2 , Pd.
  • Intermediate 16 is commercially available. Using such commercially available reagents and deuterated reagents that can be readily prepared by known methods, compounds of Formula III (or Ilia or Illb) can be prepared with greater than 90% or greater than 95% (e.g., up to 98% or 99%) deuterium incorporation at Y 2a and/or Y 2b in Formula III (or Ilia or Illb).
  • compounds of Formula III can be prepared with greater than 90% or greater than 95% (e.g., up to 98% or 99%) deuterium incorporation at Y 2a and/or Y 2b .
  • Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b are as described hereinabove; and Y 3aa and Y 3bb are selected from hydrogen and deuterium.
  • Reagents and conditions (a) 1) HQ or TFA, 2) Ethyl chloroformate, Et3N.
  • deuterated intermediates (20) are commercially available: N- Boc-4-Piperidone-2,2,3,3,5,5,6,6-ds (98 atom % D) (20a), [2,6- 2 H 4 ]-N-Boc-4- Piperidinone (98 atom % D) (20b), N-Boc-4-Piperidone-3,3,5,5-d 4 (98 atom % D) (20c).
  • appropriately deuterated (20a), (20b), and (20c) may be prepared as described in WO 2010/108103.
  • compounds of Formula III can be prepared with greater than 90% or greater than 95% (e.g., up to 98% or 99%)deuterium incorporation at some or all of Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , and or Y a in Formula III (or Ilia or Illb).
  • deuterated intermediate (21) for use in the preparation of compounds of Formula III (or Ilia or Illb) according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 5.
  • Reagents and conditions (a) reduction with BD3 or other D source, (b) (optional) chiral resolution
  • deuterated intermediate (6) for use in the preparation of intermediate (21), in turn used in the preparation of compounds of Formula III (or Ilia or Illb) according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 6.
  • compounds of Formula III can be prepared with greater than 90% or greater than 95% (e.g., up to 98% or 99%) deuterium incorporation at some or all of Y 6a , Y 6b , Y 7a , Y 7 *, Y 8a Y* Y 9 , Y 10 and/or ⁇ 14
  • the invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula III (e.g., including any of the formulae herein, such as Formula Ilia or Illb), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • a compound of Formula III e.g., including any of the formulae herein, such as Formula Ilia or Illb
  • a pharmaceutically acceptable carrier e.g., including any of the formulae herein, such as Formula Ilia or Illb
  • 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 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, 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 alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphate
  • 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 LUTROLTM and PLURONICTM (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.
  • 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.
  • the compound is administered orally.
  • 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 nonaqueous 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.
  • the acceptable 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.
  • R 2 is C(0)-C 1-21 alkyl. In some embodiments, R 2 is C(0)-C5-!9 alkyl. In some embodiments, R 2 is C(0)-C9-n alkyl. In some embodiments, R 2 is C(0)-Cis alkyl. In some embodiments, R 2 is palmitoyl.
  • 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 bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
  • 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.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • 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.
  • a composition of this invention further comprises one or more additional therapeutic agents.
  • the additional therapeutic agent 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 ITI-007.
  • Such agents include those indicated as being useful in combination with ITI-007, including but not limited to, those described in PCT application No. PCT/US2008/009357 (published as WO2009/017836).
  • the additional therapeutic agent is selected from selective serotonin re-uptake inhibitor (SSRI) (e.g. citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital); dapoxetine (Priligy); escitalopram (Lexapro, Cipralex, Seroplex, Esertia); fluoxetine (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, Lactose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)); fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox); indalpine (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax, Derox
  • SSRI selective
  • cholinesterase inhibitor e.g., acetylcholinesterase inhibitor
  • Tacrine rivastigmine
  • donepezil Aricept
  • galantamine Razadyne, formerly called Reminyl
  • NMD A N-Methyl D- Asparate receptor antagonist
  • memantine combination of agents useful for the prophylaxis or treatment of Alzheimer's disease (donepezil and memantine), anti-depressant, anti-psychotic, other hypnotic agents, agents use to treat Parkinson's disease or mood disorders, compounds that modulate GABA activity (e.g.
  • doxepin doxepin
  • alprazolam bromazepam, clobazam
  • clonazepam clorazepate
  • diazepam flunitrazepam
  • fiurazepam lorazepam
  • midazolam nitrazepam
  • oxazepam temazapam
  • triazolam indiplon, zopiclone, eszopiclone, zaleplon
  • Zolpidem gabaxadol
  • vigabatrin tiagabine
  • EVT 201 Euvotec Pharmaceuticals
  • estazolam a GABA-B agonist
  • 5-HT modulator e.g.
  • a 5-HT 2 A agonist e.g. ketanserin, risperidone, eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907 (SanofiAventis, France), HY 10275 (Eli Lilly), APD 125 (Arena),
  • a 5-HT 2 A inverse agonist etc.
  • a melatonin agonist e.g. melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan)
  • VEC-162 Vehicle-to-live
  • PD-6735 Phase II Discovery
  • agomelatine an ion channel modulator
  • SARI antagonist/reuptake inhibitor
  • Org 50081 Organon -Netherlands
  • ritanserin nefazodone
  • serzone or trazodone
  • an orexin receptor antagonist e.g. orexin, a 1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK
  • H3 agonist or antagonist an H3 agonist or antagonist, a noradrenergic agonist or antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin- 1 drug (e.g. Casopitant), an anti-depressant (e.g.
  • amitriptyline amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitaloprame, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine sulfate, protiptyline, sertraline, tranylcypromine, trazodone, trimipramine, and velafaxine), and an antipsychotic agent (e.g.
  • chlorpromazine haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molidone, pe ⁇ henazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiparazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone), an atypical antipsychotic agent (e.g.
  • 5HTLA agonist e.g. repinotan, sarizotan, eptapirone, buspirone or MN-305
  • anti-Parkinson's agent e.g.
  • L- dopa co-careldopa, duodopa, stalova, Symmetrel, benzotropine, biperiden, bromocryiptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline or tolcapone), levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, anticholinergics (e.g. levodopa), atypical stimulant (e.g. modafinil, adrafinil, or armodafinil), antidepressant (e.g.
  • SSRJs selective serotonin reuptake inhibitors
  • SNRJs serotonin-norepinephrine reuptake inhibitors
  • tricyclic antidepressants antihistamine agents
  • 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 are associated with one another.
  • association with one another 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 is a pharmaceutical composition of the invention.
  • an “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 be 20 mg per dose. In one embodiment, an effective amount of a compound of this invention can be 30 mg per dose. In one embodiment, an effective amount of a compound of this invention can be 40 mg per dose. In one embodiment, an effective amount of a compound of this invention can be 60 mg per dose. In one embodiment, an effective amount of a compound of this invention can range from about 20 mg to about 60 mg per dose. In one embodiment, an effective amount of a compound of this invention can range from about 4 mg to about 120 mg per dose. In one embodiment, an effective amount of a compound of this invention can range from about 2 mg to about 300 mg per dose.
  • an effective amount of a compound of this invention can range from about 0.2 mg to about 600 mg per dose. In one embodiment, the dose is administered twice daily. In one embodiment, the dose is administered once daily. In some embodiments, a dose of the injectable compositions of the present invention may be administered once a week, once every two weeks, or once a month.
  • 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 ITI-007.
  • an effective amount of the additional therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose.
  • the normal monotherapeutic dosages of these additional therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.
  • Some of the additional therapeutic agents referenced above may act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the additional therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the additional therapeutic agent of a compound of this invention, synergistically improving efficacy, improving ease of administration or use and/or reduced overall expense of compound preparation or formulation.
  • the invention provides a method of modulating the activity of serotonin, glutamate, and dopamine receptors in a cell (in vivo or in vitro), comprising contacting a cell with one or more compounds of Formula III herein (e.g., Formula Ilia or Illb), 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 modulating the activity of a 5-hydroxytryptamine (5-HT) receptor.
  • the method comprises contacting a 5-hydroxytryptamine (5-HT) receptor in a cell, in vivo or in vitro, such that activity of the 5-hydroxytryptamine (5-HT) receptor is modulated (e.g., increased or decreased).
  • the invention provides a method of modulating the activity of 5-HT 2 A receptor.
  • the invention provides a method of antagonizing the activity of 5-HT 2 A receptor.
  • the invention provides a method of modulating the activity of a serotonin transporter (SERT).
  • SERT serotonin transporter
  • the method comprises contacting a serotonin transporter in a cell, in vivo or in vitro, such that activity of the serotonin transporter is modulated (e.g., increased or decreased).
  • the invention provides a method of inhibiting a serotonin transporter.
  • the invention provides a method of modulating the activity of a dopamine (e.g. D 2 ) receptor.
  • the method comprises contacting a dopamine receptor in a cell, in vivo or in vitro, such that activity of the dopamine receptor is modulated (e.g., increased or decreased).
  • the invention provides a method of antagonizing a postsynaptic D2 receptor.
  • the invention provides a method of partially agonizing a presynaptic striatal D2 receptor.
  • the invention provides a method of modulating the activity of GluN2B-type N-methyl-D-aspartate (NMD A) receptor.
  • the method comprises contacting a GluN2B-type N-methyl-D-aspartate receptor in a cell, in vivo or in vitro, such that activity of the GluN2B-type N-methyl-D-aspartate receptor is modulated (e.g., increased or decreased).
  • the invention provides a method of indirectly modulating glutamatergic
  • N-methyl-D- aspartate (NMD A) receptor GluN2B-type N-methyl-D- aspartate
  • the invention provides a method of treating a disease that is beneficially treated by ITI-007 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.
  • diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: PCT application No. PCT/US2008/003340 (published as WO2008112280); PCT application No. PCT/US2009/001608 (published as WO2009114181); PCT application No. PCT/US2000/016373 (published as WO2000077010); PCT application No.
  • PCT/US2014/029914 published asWO2014145192
  • PCT application No. PCT/US2013/036515 published as WO2013155506
  • PCT application No. PCT/US2013/036512 published as WO2013155504;
  • Such diseases include, but are not limited to, addictive behavior (e.g. behavior associated with and or caused by physical and/or psychological dependence on narcotics, opiates, analgesics, painkillers, amphetamines, cocaine, heroin, opium, marijuana, alcohol, smoking, nicotine, gambling or eating), affective disorders, aggressive and assaultive behavior, aggressive behavior, agitation, agitation in Alzheimer's disease, agitation in autism and/or related autistic disorders, agitation in dementia (e.g. agitation in Alzheimer's disease), Alzheimer's disease, amyotrophic lateral sclerosis, anger, anorexia, anxiety, assaultive behavior, attention deficit disorder, attention deficit hyperactivity disorder, behavioral disturbances in patients with dementia (e.g.
  • addictive behavior e.g. behavior associated with and or caused by physical and/or psychological dependence on narcotics, opiates, analgesics, painkillers, amphetamines, cocaine, heroin, opium, marijuana, alcohol, smoking, nicotine, gambling or
  • agitation and irritability e.g. agitation irritation
  • bipolar depression e.g. depression
  • bipolar disorder e.g. depression
  • brain spinal cord trauma e.g. bulemia
  • cancer e.g., cancer
  • central nervous system disorders e.g., central nervous system disorders
  • cephalic pain e.g., cognition associated with schizophrenia, conditions associated with cephalic pain, corticobasal degenerations, dementia, dementia with Lewy bodies, dementing illnesses (e.g. senile dementia, Alzheimer's disease, Pick' s disease, frontotemporal dementia,
  • Parkinson's disease e.g. schizophrenia
  • depression e.g. refractory depression, co-morbid depression, MDD
  • depression in a patient suffering from psychosis e.g. schizophrenia
  • psychosis e.g. schizophrenia
  • Down syndrome dyskinesia, elderly depression, excessive sleepiness, fatigue in conditions such as Parkinson's disease, frontotemporal dementia, gastrointestinal disorders, gastrointestinal disorders (e.g. dysfunction of the gastrointestinal tract motility), Huntington's disease, impulse control disorder, impulse control disorder or intermittent explosive disorder in patients suffering from psychosis (e.g. schizophrenia), intermittent explosive disorder, irritation, major depressive disorder, migraine, mild cognition impairment, mood disorders associated with Parkinson's disease, mood disorders associated with psychosis (e.g.
  • schizophrenia multiple sclerosis, neurodegenerative diseases, obesity, obsessive-compulsive disorder, other psychiatric or neurological diseases, paraminenculear palsy, Parkinson's disease, physical or emotional outbursts, Pick's disease, post-traumatic stress disorder, prion disease, psychosis, schizophrenia, senile dementia, sexual disorders, sleep disorder (e.g. maintenance insomnia, frequent awakenings, waking up feeling unrefreshed, insomnia, narcolepsy, sleep apnea), sleep disorders (particularly sleep disorders associated with schizophrenia), sleep disorders associated with Parkinson's disease, sleep disorders associated with psychosis (e.g. schizophrenia), sleep disorders in patients suffering from dementia (e.g. Alzheimer's disease), social phobias, traumatic conditions, vascular dementia, Wemicke- Korsakoffs syndrome..
  • dementia e.g. Alzheimer's disease
  • social phobias traumatic conditions
  • vascular dementia Wemicke- Korsakoffs syndrome.
  • the method of this invention is used to treat a disease or condition selected from schizophrenia, schizophrenia having an acute exacerbation of psychosis, acute exacerbation of psychosis, depression, bipolar disorder, agitation, insomnia, dementia, and Alzheimer's Disease, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound or a composition of the present invention.
  • the method of this invention is used to treat a disease or condition selected from schizophrenia, schizophrenia having an acute exacerbation of psychosis, acute exacerbation of psychosis, and Alzheimer's Disease in a subject in need thereof.
  • 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).
  • the method comprises administering to a subject an injectable composition comprising a compound disclosed herein once a week.
  • the method comprises administering to a subject an injectable composition comprising a compound disclosed herein once every two weeks.
  • the method comprises administering to a subject an injectable composition comprising a compound disclosed herein once every three weeks. [181] In some embodiments, the method comprises administering to a subject an injectable composition comprising a compound disclosed herein twice a month.
  • the method comprises administering to a subject an injectable composition comprising a compound disclosed herein once a month.
  • R 2 is C(0)-C 1-21 alkyl.
  • R 2 is C(0)-Cs-i9 alkyl.
  • R 2 is C(O)- C9-n alkyl.
  • R 2 is C(0)-C 1 5 alkyl.
  • R 2 is palmitoyl.
  • any of the above methods of treatment comprises the further step of co-administering to the subject in need thereof 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 ITI-007.
  • 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.
  • 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. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the additional therapeutic agent(s) are administered by conventional methods.
  • composition of this invention comprising both a compound of the invention and an additional therapeutic agent, 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 III 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 III for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.
  • Microsomal Assay Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCh), 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 ⁇ 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 MgCh.
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 ⁇ , aliquot of the 12.5-50 ⁇ 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 ⁇ 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 ⁇ , aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow- well 96- well plates which contain 50 ⁇ , of ice-cold ACN with internal standard to stop the reactions.
  • the plates are stored at 4 °C for 20 minutes after which 100 ⁇ , of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux 2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines et leurs sels pharmaceutiquement acceptables. L'invention concerne également des compositions comprenant un composé selon l'invention, et l'utilisation de telles compositions dans des procédés de traitement de maladies et d'états pathologiques qui sont traités avantageusement par l'administration d'un modulateur sérotonergique, dopaminergique et/ou glutamatergique.
PCT/US2017/065111 2016-12-07 2017-12-07 Composés de quinoxaline deutérés WO2018106916A1 (fr)

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US10960009B2 (en) 2013-12-03 2021-03-30 Intra-Cellular Therapies, Inc. Methods of treating schizophrenia and depression
US11052084B2 (en) 2018-08-31 2021-07-06 Intra-Cellular Therapies, Inc. Pharmaceutical capsule compositions comprising lumateperone mono-tosylate
US11331316B2 (en) 2016-10-12 2022-05-17 Intra-Cellular Therapies, Inc. Amorphous solid dispersions
US11957791B2 (en) 2018-08-31 2024-04-16 Intra-Cellular Therapies, Inc. Methods
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US11723909B2 (en) 2016-03-25 2023-08-15 Intra-Cellular Therapies, Inc. Organic compounds
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US11826367B2 (en) 2016-10-12 2023-11-28 Intra-Cellular Therapies, Inc. Amorphous solid dispersions
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US10716786B2 (en) 2017-03-24 2020-07-21 Intra-Cellular Therapies, Inc. Transmucosal and subcutaneous compositions
US12268686B2 (en) 2017-03-24 2025-04-08 Intra-Cellular Therapies, Inc. Transmucosal methods for treating psychiatric and neurological conditions
US11052083B2 (en) 2017-03-24 2021-07-06 Intra-Cellular Therapies, Inc. Transmucosal methods for treating psychiatric and neurological conditions
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US12195464B2 (en) 2018-06-06 2025-01-14 Intra-Cellular Therapies, Inc. Lumateperone bis-tosylate salts and crystals and methods for manufacture thereof
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US11806348B2 (en) 2018-08-31 2023-11-07 Intra-Cellular Therapies, Inc. Methods of treatment using pharmaceutical capsule compositions comprising lumateperone mono-tosylate
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US11052084B2 (en) 2018-08-31 2021-07-06 Intra-Cellular Therapies, Inc. Pharmaceutical capsule compositions comprising lumateperone mono-tosylate
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