WO2017136375A1 - Tozadenant deutéré - Google Patents

Tozadenant deutéré Download PDF

Info

Publication number
WO2017136375A1
WO2017136375A1 PCT/US2017/015929 US2017015929W WO2017136375A1 WO 2017136375 A1 WO2017136375 A1 WO 2017136375A1 US 2017015929 W US2017015929 W US 2017015929W WO 2017136375 A1 WO2017136375 A1 WO 2017136375A1
Authority
WO
WIPO (PCT)
Prior art keywords
chs
cds
compound
deuterium
ring
Prior art date
Application number
PCT/US2017/015929
Other languages
English (en)
Inventor
I. Robert Silverman
Original Assignee
Concert Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Concert Pharmaceuticals, Inc. filed Critical Concert Pharmaceuticals, Inc.
Publication of WO2017136375A1 publication Critical patent/WO2017136375A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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.
  • 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 morpholinobenzo[d]thiazol-2-yl)-4- methylpiperidine-l-carboxamide compounds, and pharmaceutically acceptable salts thereof.
  • Certain as ects of the present invention provide a compound of Formula I:
  • R 1 is CH 3 or CD 3
  • R 2 is CH 3 or CD 3
  • Y 1 is H or D
  • Y 2 is H or D
  • Ring A is unsubstituted or substituted by 1-8 deuterium atoms
  • Ring B is unsubstituted or substituted by 1-8 deuterium atoms
  • R 1 is CD 3 .
  • 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 provide the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an adenosine A2A receptor antagonist. Some exemplary embodiments include a method of treating Parkinson's disease in a subject in need thereof comprising administering a compound or a pharmaceutical composition of the present invention.
  • Tozadenant also known as 4-hydroxy-N-(4-methoxy-7-(4- morpholinyl)benzo[d]thiazol-2-yl)-4-methylpiperidine-l-carboxamide or SYN115, is an adenosine A2A receptor antagonist.
  • the A2A receptor modulates the production of dopamine, glutamine and serotonin in several brain regions.
  • antagonism of the A2A receptor resulted in increases in dopamine levels, which gave rise to the reversal of motor deficits.
  • Tozadenant is currently phase III clinical trials for the treatment of Parkinson's disease as an adjunctive therapy with levodopa. It has also been explored for the treatment of cocaine dependency.
  • 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.
  • d-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 i-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.
  • a position is designated specifically as “H” or “hydrogen”
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • 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).
  • a compound of this invention has deuterium incorporation at each designated deuterium atom of least 52.5%. In some embodiments, a compound of this invention has deuterium incorporation at each designated deuterium atom of least 60%. In some embodiments, a compound of this invention has deuterium incorporation at each designated deuterium atom of least 67.5%. In some embodiments, a compound of this invention has deuterium incorporation at each designated deuterium atom of least 75%. In some embodiments, a compound of this invention has deuterium incorporation at each designated deuterium atom of least 82.5%. In some embodiments, a compound of this invention has deuterium incorporation at each designated deuterium atom of least 90%.
  • a compound of this invention has deuterium incorporation at each designated deuterium atom of least 95%. In some embodiments, a compound of this invention has deuterium incorporation at each designated deuterium atom of least 97.5%. In some embodiments, a compound of this invention has deuterium incorporation at each designated deuterium atom of least 99%. In some embodiments, a compound of this invention has deuterium incorporation at each designated deuterium atom of 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.
  • the acid addition salt may be a deuterated 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.
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite
  • 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.
  • a variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R 1 , R2 , 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 resent invention provides a compound of Formula (I):
  • R 1 is CH 3 or CD 3 ;
  • R 2 is CH 3 or CD 3 ;
  • Y 1 is H or D
  • Y 2 is H or D
  • Ring A is unsubstituted or substituted by 1-8 deuterium atoms
  • Ring B is unsubstituted or substituted by 1-8 deuterium atoms.
  • Ring A is unsubstituted and Ring B is
  • R 1 is CD 3 .
  • the compound is of Formula (I), R 1 is CH 3 , wherein the values for the remainder of the variables are as described in the first embodiment.
  • the compound is of Formula (I), R 1 is CD 3 , wherein the values for the remainder of the variables are as described in the first embodiment.
  • the compound is of Formula (I), R is CH 3 , wherein the values for the remainder of the variables are as described in the first, second or third embodiment.
  • the compound is of Formula (I), R is CD 3 , wherein the values for the remainder of the variables are as described in the first, second or third embodiment.
  • the compound is of Formula (I), Y 1 is H, wherein the values for the remainder of the variables are as described in the first, second, third, fourth or fifth embodiment.
  • the compound is of Formula (I), Y 1 is D, wherein the values for the remainder of the variables are as described in the first, second, third, fourth or fifth embodiment.
  • the compound is of Formula (I), Y is H, wherein the values for the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment. In one particular aspect of the eighth embodiment, both Y 1 and Y are hydrogen.
  • the compound is of Formula (I), Y is D, wherein the values for the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.
  • Y 1 and Y 2 are D, wherein the values for the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.
  • Y are deuterium.
  • the compound is of Formula (I), each carbon atom on ring A is bound to either two hydrogen or two deuterium, wherein the values for the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth or
  • A is selected from
  • the compound is of Formula (I), each carbon atom on ring B is bound to either two hydrogen or two deuterium, wherein the values for the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.
  • each carbon atom on ring B is bound to either two hydrogen or two deuterium, wherein the values for the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.
  • each carbon atom on ring A is bound to either two hydrogen or two deuterium
  • each carbon atom on ring B is bound to either two hydrogen or two deuterium
  • the compound is selected from any one of the compounds set forth in Table 1 (below):
  • a thirteenth embodiment is a deuterated intermediate useful for making the compounds of Formula I.
  • the deuterated intermediate is a compound having the structure of Formula II:
  • R 1 is CH 3 or CD 3 ;
  • Y 1 is H or D
  • Y 2 is H or D
  • Ring A is unsubstituted or substituted by 1-8 deuterium atoms
  • Ring A is substituted by at least one deuterium atom.
  • the compound is of Formula II, R 1 is CH 3 , wherein the values for the remainder of the variables are as described in the fourteenth embodiment.
  • the compound is of Formula II, R 1 is CD 3 , wherein the values for the remainder of the variables are as described in the fourteenth embodiment.
  • the compound is of Formula II, Y 1 is H, wherein the values for the remainder of the variables are as described in the fourteenth, fifteenth or sixteenth embodiment.
  • the compound is of Formula II, Y 1 is D, wherein the values for the remainder of the variables are as described in the fourteenth, fifteenth or sixteenth embodiment.
  • the compound is of Formula II, Y is H, wherein the values for the remainder of the variables are as described in the fourteenth, fifteenth, sixteenth, seventeenth or eighteenth embodiment.
  • Y 1 and Y 2 are hydrogen.
  • the compound is of Formula II, Y is D, wherein the values for the remainder of the variables are as described for the fourteenth, fifteenth, sixteenth, seventeenth or eighteenth embodiment.
  • Y 1 and Y 2 are deuterium.
  • the compound is of Formula II, each carbon atom on ring A is bound to either two hydrogen or two deuterium atoms, wherein the values for the remainder of the variables are as described in the fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.
  • Rin A is selected from
  • the deuterated intermediate is a compound of Formula III:
  • Ring B is unsubstituted or substituted by 1-8 deuterium atoms; wherein when R is CH 3 , Ring B is substituted by at least one deuterium atom.
  • the compound is of Formula III, R is CH 3 , wherein the values for the remainder of the variables are as described for the twenty- second embodiment.
  • the compound is of Formula III, R is CD 3 , wherein the values for the remainder of the variables are as described for the twenty- second embodiment.
  • each carbon atom on ring B is bound to either two hydrogen or two deuterium Ring B, wherein the values for the remainder of the variables are as described for the twenty- second, twenty- third, or twenty- fourth embodiment.
  • Ring B is selected from
  • any atom not designated as deuterium in any of the first through twenty- fifth embodiments set forth above is present at its natural isotopic abundance.
  • the level of deuterium incorporation at Y 1 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 2 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 R 1 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 R 2 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%.
  • Ring A comprises deuterium
  • the level of deuterium incorporation at Ring A 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%.
  • Ring B comprises deuterium
  • the level of deuterium incorporation at Ring B 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%.
  • At least one of Y 1 , R 1 , R2", Ring A, and Ring B comprises hydrogen.
  • the synthesis of compounds of Formula I 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 I and intermediates thereof are disclosed, for instance in US 7,368,446.
  • 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 intermediate (1) for use in the preparation of compounds of Formula I, according to Scheme 1 may be prepared from corresponding deuterated reagents exemplified in Scheme 2 below.
  • Reagents and conditions (a) K 3 P0 4 , (2-Biphenyl)dicyclohexylphosphine, Pd(OAc) 2 ; (b)H 2 , Pd-C; (c) benzoyl isothiocyanate; (d) NaOMe; (e) Br 2 .
  • deuterated intermediate (3) for use in the preparation of compounds of Formula I, according to Scheme 1 may be prepared from corresponding deuterated reagents exemplified in Scheme 3 below.
  • N-Boc-4-piperidone-2,2,3,3,5,5,6,6-d 8 (98 atom %D) (10b);
  • N-Boc-4-piperidinone-,2,2, 6,6-d 4 (96 atom %D) (lOd).
  • (10b), (10c) and (lOd) may be prepared according to a procedure described in WO 2010108103.
  • Methylmagnesium bromide-d3 (11a) may be prepared according to a procedure described by Al-Afyouni, M. et al., Journal of the American Chemical Society, 136(44), 15457-15460; 2014.
  • B-3, and B-4 positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any of R , B-2, B-3, and/or B-4.
  • deuterated intermediate (5) for use in the preparation of compounds of Formula I, according to Scheme 1 may be produced from corresponding deuterated reagents and as described in the references exemplified below.
  • Morpholine-dg (98 atom %D) (5b) is commercially available; morpholine-2,2,6,6-d4 intermediate (5c) may be prepared according to a procedure described in US8354557;
  • morpholine-3,3,5,5-d4 intermediate (5d) may be prepared according to a procedure described in WO2009023233.
  • 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 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 phosphat
  • 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.
  • 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,
  • 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.
  • 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, polycapro lactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluoro silicone, 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 a second therapeutic agent.
  • the second 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 tozadenant.
  • the second therapeutic agent is an agent useful in the treatment of Parkinson's disease.
  • the second therapeutic agent is an agent useful in treating cocaine addiction.
  • the second therapeutic agent is selected from levodopa; dopamine agonists, including, but not limited to, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride; monoamine oxidase inhibitors, including, but not limited to, selegiline and rasagiline; amantadine; anticholinergics, including, but not limited to atropine, benzatropine, biperiden, chlorpheniramine, dicyclomine, dimenhydrinate, diphenhydramine, doxylamine, glycopyrrolate, hydroxyzine, ipratropium, orphenadrine, oxitropium, oxybutynin, tolterodine, tiotropium, trihexyphenidyl, scopolamine, solifenacin, tropicamide, bupropion, dextromethorphan, doxacuri
  • the second therapeutic agent is levodopa.
  • the second therapeutic agent is an antagonist of the N-methyl- D-aspartate (NMDA) receptor.
  • the NMDA antagonist is selective for the NR2B subunit of the NMDA receptor.
  • the NR2B antagonist is selective over each of the other NMDA receptor subtypes NR2A, NR2C, and NR2D by a factor of at least 10, preferably 30 and ideally 100 or more.
  • adenosine A2A receptor antagonist e.g., tozadenant
  • the NMDA antagonist is selected from known NR2B antagonists including, but not limited to, MK-0657, Traxoprodil (CP-101,606), EVT-101, EVT-102, EVT-103, Radiprodil (RGH 896), RG-1, ED-1529, NeurOp, NeurOp-2, NeurOp-3, NeurOp- 4, TXT-0300, HON-0001, Ifenprodil, Safaprodil, and N- ⁇ (lS,3S)-3-[3-(4-Methylbenzyl)- l,2,4-oxadiazol-5-yl]cyclopentyl ⁇ -lH-pyr- azolo[3,4-d]pyrimidin-4-amine.
  • a preferred NR2B antagonist is selected from the group comprising
  • Radiprodil (RGH 896), EVT-101, EVT-102, EVT-103, Ifenprodil, MK-0657, Safaprodil or N- ⁇ (lS,3S)-3-[3-(4-Methylbenzyl)-l,2,4-oxadiazol-5-yl]cyclopentyl ⁇ -lH-pyr- azolo[3,4- d]pyrimidin-4-amine.
  • the NMDA antagonist is radiprodil.
  • the composition comprises a compound of Formula (I) and two or more second therapeutic agents.
  • Certain exemplary embodiments include a composition comprising a compound of Formula (I), radiprodil, and levodopa.
  • the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent 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).
  • Certain exemplary embodiments comprise separate dosage forms of a compound of Formula (I) and radiprodil.
  • Certain exemplary embodiments comprise separate dosage forms of a compound of Formula (I), radiprodil, and levodopa.
  • the compound of the present invention is present in an effective amount.
  • 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 120 mg to 240 mg; 24 mg to 480 mg; 12 mg to 1200 mg; and 0.12 mg to 2400 mg once or twice per day.
  • an effective amount of a compound of this invention is selected from 30 mg, 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, or 480 mg administered once or twice per day.
  • an effective daily amount of a compound of this invention is administered (once or twice per day) for a period of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks.
  • the subject to whom the compound of the invention is administered is suffering from Parkinson's disease.
  • 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 tozadenant.
  • an effective amount of the second therapeutic agent 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 monotherapeutic dose.
  • the normal monotherapeutic dosages of these second 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.
  • the ratio of doses between the compound of Formula (I) and the second therapeutic agent may vary from 30: 1 to 1:30, from 10: 1 to 1: 10, from 3: 1 to 1:3, or be about 1: 1.
  • the invention provides a method of modulating the activity of Adenosine A2A receptor (ADORA2A) in a cell, comprising contacting a cell with one or more compounds of Formula I herein, or a pharmaceutically acceptable salt thereof.
  • ADORA2A Adenosine A2A receptor
  • the invention provide a method of antagonizing the Adenosine A2A receptor in a cell, comprising contacting a cell with one or more compounds of Formula I herein, or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating a disease or condition that is beneficially treated by tozadenant 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 and conditions are well known in the art and are disclosed in, but not limited to the following patents and published applications: US 7,368,446.
  • Such diseases and conditions include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, conditions requiring neuroprotection, attention deficit hyperactivity disorder (ADHD), schizophrenia, anxiety, pain, respiration deficits, depression, drug addiction (such as addiction to one or more of amphetamine, cocaine, opioids, ethanol, nicotine, or cannabinoids), asthma, allergic responses, hypoxia, ischemia, seizure and substance abuse.
  • ADHD attention deficit hyperactivity disorder
  • the disease or condition is selected from Alzheimer's disease, depressive disorders, drug addiction, conditions requiring neuroprotection, Parkinson's disease and ADHD.
  • the method of this invention is used to treat a disease or condition selected from Parkinson'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).
  • any of the above methods of treatment comprises the further step of co -administering to the subject in need thereof one or more second therapeutic agents.
  • the choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with tozadenant.
  • the choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second 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 a second therapeutic agent.
  • the combination therapies of this invention include coadministering a compound of Formula I and levodopa (L-dopa) to a subject suffering from Parkinson's disease and in need of such treatment.
  • the combination therapies of this invention include coadministering a compound of Formula I and radiprodil to a subject suffering from
  • co- administered means that the second 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 second 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 second therapeutic agent(s) are administered by conventional methods.
  • the administration of a composition of this invention, comprising both a compound of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second 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 second therapeutic agent is not administered. In another embodiment, the effective amount of the second 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 second 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.
  • 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 ⁇ 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 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des formes deutérées de morpholinobenzo[d]thiazol-2-yl)-4-méthylpipéridine-1-carboxamide et des sels pharmaceutiquement acceptables de celles-ci. L'invention concerne également des compositions contenant un composé de cette invention et l'utilisation de ces compositions dans des procédés de traitement de maladies et d'affections pouvant être avantageusement traitées par l'administration d'un antagoniste de récepteur A2A.
PCT/US2017/015929 2016-02-05 2017-02-01 Tozadenant deutéré WO2017136375A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662291832P 2016-02-05 2016-02-05
US62/291,832 2016-02-05

Publications (1)

Publication Number Publication Date
WO2017136375A1 true WO2017136375A1 (fr) 2017-08-10

Family

ID=59499975

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/015929 WO2017136375A1 (fr) 2016-02-05 2017-02-01 Tozadenant deutéré

Country Status (1)

Country Link
WO (1) WO2017136375A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020021215A1 (fr) 2018-07-27 2020-01-30 Inventiva Derives deuteres du lanifibranor
WO2020020097A1 (fr) * 2018-07-23 2020-01-30 Beigene, Ltd. Dérivés de pyrazolotriazolopyrimidine en tant qu'antagoniste du récepteur a2a
WO2020146795A1 (fr) 2019-01-11 2020-07-16 Omeros Corporation Procédés et compositions pour le traitement du cancer
US11472811B2 (en) 2018-04-08 2022-10-18 Beigene, Ltd. Pyrazolotriazolopyrimidine derivatives as A2A receptor antagonist

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030153566A1 (en) * 2001-12-12 2003-08-14 Alexander Flohr 7-Amino-benzothiazole derivatives
US8168785B2 (en) * 2009-06-17 2012-05-01 Biotie Therapies, Inc. Benzothiazole derivatives
US20150157638A1 (en) * 2012-04-20 2015-06-11 Ucb Pharma, S.A. Methods for Treating Parkinson's Disease
WO2016204939A1 (fr) * 2015-06-19 2016-12-22 Biotie Therapies, Inc. Formulations de tozadénant à libération contrôlée

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030153566A1 (en) * 2001-12-12 2003-08-14 Alexander Flohr 7-Amino-benzothiazole derivatives
US8168785B2 (en) * 2009-06-17 2012-05-01 Biotie Therapies, Inc. Benzothiazole derivatives
US20150157638A1 (en) * 2012-04-20 2015-06-11 Ucb Pharma, S.A. Methods for Treating Parkinson's Disease
WO2016204939A1 (fr) * 2015-06-19 2016-12-22 Biotie Therapies, Inc. Formulations de tozadénant à libération contrôlée

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11472811B2 (en) 2018-04-08 2022-10-18 Beigene, Ltd. Pyrazolotriazolopyrimidine derivatives as A2A receptor antagonist
WO2020020097A1 (fr) * 2018-07-23 2020-01-30 Beigene, Ltd. Dérivés de pyrazolotriazolopyrimidine en tant qu'antagoniste du récepteur a2a
CN112469722A (zh) * 2018-07-23 2021-03-09 百济神州有限公司 作为a2a受体拮抗剂的吡唑并三唑并嘧啶衍生物
WO2020021215A1 (fr) 2018-07-27 2020-01-30 Inventiva Derives deuteres du lanifibranor
EP4331584A1 (fr) 2018-07-27 2024-03-06 Inventiva Derives deuteres du lanifibranor
WO2020146795A1 (fr) 2019-01-11 2020-07-16 Omeros Corporation Procédés et compositions pour le traitement du cancer

Similar Documents

Publication Publication Date Title
AU2014235462C1 (en) Deuterated palbociclib
WO2012151361A1 (fr) Dérivés de carbamoylpyridone
AU2014205472B2 (en) Deuterated momelotinib
EP2872159A2 (fr) Carfilzomib deutéré
WO2018106916A1 (fr) Composés de quinoxaline deutérés
WO2017136375A1 (fr) Tozadenant deutéré
WO2014100431A1 (fr) Inhibiteurs alk deutérés
WO2018005328A1 (fr) Bictegravir deutérié
US9676790B2 (en) Substituted thienotriazolodiazapines
AU2014237569B2 (en) Inhibitors of the enzyme UDP-glucose: N-acyl-sphingosine glucosyltransferase
US20190336494A1 (en) Deuterated morphinan compounds for treating agitation
WO2012119006A2 (fr) Dérivés de composés amino-hétéroaryles substitués par des pyrazoles
WO2011091035A1 (fr) Dérivés d'aminoquinoléine
WO2012129381A1 (fr) Preladenant deutéré
WO2017020002A1 (fr) Composés de morphinane deutéré utilisés pour le traitement de l'agitation
WO2015009889A1 (fr) Dérivés deutériés d'intédanib et leur utilisation pour le traitement de troubles prolifératifs
WO2014159511A1 (fr) Pacritinib deutérié
WO2016061488A1 (fr) Inhibiteurs de réabsorption d'amines
WO2020092604A1 (fr) Pitolisant deutéré
WO2018013686A1 (fr) Idalopirdine deutérée
WO2013109692A1 (fr) Acide deutérié alpha-lipoïque
WO2014150044A1 (fr) Inhibiteurs de réabsorption d'amines

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17748032

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17748032

Country of ref document: EP

Kind code of ref document: A1