WO2006137772A1 - Nouvelle forme physique d'oxabispidines n,n-disubstituees - Google Patents

Nouvelle forme physique d'oxabispidines n,n-disubstituees Download PDF

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Publication number
WO2006137772A1
WO2006137772A1 PCT/SE2006/000692 SE2006000692W WO2006137772A1 WO 2006137772 A1 WO2006137772 A1 WO 2006137772A1 SE 2006000692 W SE2006000692 W SE 2006000692W WO 2006137772 A1 WO2006137772 A1 WO 2006137772A1
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Prior art keywords
crystalline material
alkyl
compound
formula
alkylene
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PCT/SE2006/000692
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English (en)
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Anne Juppo
Gerald Steele
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Astrazeneca Ab
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Publication of WO2006137772A1 publication Critical patent/WO2006137772A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the invention relates to a new physical form of ⁇ iV'-disubstituted oxabispidines in which one substituent is a N-(alkoxycarbonylamino)alkyl moiety, as well as to a process for preparing such compounds in that new form.
  • the physical form of a drug substance can be a key issue when placing a drug on the open market.
  • the drug substance when the drug substance is prepared and formulated (e.g. in oral dosage forms such as tablets) on a large scale, its physical form can determine how easy it is to handle and process. Ease of handling can affect both the cost and the efficiency of manufacture.
  • a drug substance is incorporated into its final , formulation should, ideally, be free of characteristics that represent a hindrance to consumer acceptance (e.g. unpalatable aroma or taste).
  • the crystalline materials described in, for example, WO 02/083688 and WO 2004/035592 have a surface area (as determined by BET adsorption) of greater than 0.7 m 2 g '1 .
  • the handling characteristics of the crystalline drug substances disclosed therein might be improved by decreasing the surface area (i.e. increasing the average particle size) of those materials.
  • a crystalline material consisting essentially of a compound of formula I,
  • D represents optionally branched C 2-6 alkylene
  • R 1 represents C 1-6 alkyl (optionally substituted by one or more substituents selected from -OH, halo, cyano, nitro and aryl) or aryl,
  • R 5 represents H 5 C 1-6 alkyl, -E-aryl, -E-Het 1 , -C(O)R 8a , -C(0)0R 8b or
  • R 6 represents H, C 1-6 alkyl, -E-aryl, -E-Het 1 , -C(O)R 8 Y -C(O)OR 8b ,-S(O) 2 R 8 °, -[C(O)] p N(R 9a )R 9b or -C(NH)NH 2 ;
  • R 7 represents H, C 1-6 alkyl, -E-aryl or -C(0)R 8d ;
  • R 8a to R 8d independently represent, at each occurrence when used herein,
  • Ci_ 6 alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het 2 ), aryl, Het 3 , or R 8a and R 8d independently represent H; R a and R independently represent, at each occurrence when used herein, H or
  • C 1-6 alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het ), aryl, Het 5 , or together represent C 3-6 alkylene, optionally interrupted by an O atom;
  • E represents, at each occurrence when used herein, a direct bond or C 1-4 alkylene; p represents 1 or 2;
  • A represents a direct bond, -J-, -J-N(R 1Oa )-, -J-S(O) 2 N(R 10b )-, -J-N(R 100 ) S(O) 2 - or
  • B represents -Z- ⁇ [C(O)] a C(H)(R lla ) ⁇ b -, -Z-[C(O)] C N(R 1 lb )-, -Z-N(R llc )S(O) 2 -,, -Z-S(O) 2 N(R 1 ld )-, -Z-S(O) n -, -Z-O- (in which latter six groups, Z is attached to the carbon atom bearing R 2 and R 3 ), -N(R lle )-Z-, -N(R llf )S(O) 2 -Z-, -S(O) 2 N(R 1 lg )-Z- or -N(R llh )C(O)O-Z- (in which latter four groups, Z is attached to the R 4 group);
  • J represents C 1-6 alkylene optionally interrupted by -S(O) 2 N(R 10d )- or
  • Z represents a direct bond or C 1-4 alkylene, optionally interrupted by
  • a, b and c independently represent O or 1 ; n represents 0, 1 or 2; R a to R 1Oe independently represent, at each occurrence when used herein, H or
  • R lla represents H or, together with a single ort/z ⁇ -substituent on the R 4 group (ortho- relative to the position at which the B group is attached), R lla represents C 2-4 alkylene optionally interrupted or terminated by O, S, N(H) OrN(C 1-6 alkyl); R llb represents H, C 1-6 alkyl or, together with a single ortAo-substituent on the R 4 group (ortho- relative to the position at which the B group is attached), R llb represents C 2-4 alkylene;
  • R llc to R llj independently represent, at each occurrence when used herein, H or C 1-6 alkyl
  • R 4 represents phenyl or pyridyl, both of which groups are optionally substituted by one or more substituents selected from -OH, cyano, halo, nitro, C 1-6 alkyl (optionally terminated by -N(H)C(0)0R 12a ), C 1-6 alkoxy, -N(R 13a )R 13b , -C(O)R 13c , -C(O)OR 13d , -C(O)N(R 13e )R 13f , -N(R 13g )C(O)R 13h , -N(R 13i )C(O)N(R 13j )R 13k , -N(R 13m )S(O) 2 R 12b , -S(O) 2 N(R 13n )R 13 °, -S(O) 2 R 12c , -QS(O) 2 R 12d and/or aryl; and an ortAo-sub
  • R lla together with R lla , represent C 2-4 alkylene optionally interrupted or terminated by O, S, N(H) OrN(Ci -6 alkyl), or (ii) together with R llb , represent C 2-4 alkylene;
  • R 12a to R 12d independently represent Ci -6 alkyl
  • R 13a and R 13b independently represent H, C 1-6 alkyl or together represent C 3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring;
  • R 13c to R 130 independently represent H or C 1-6 alkyl;
  • R 14a to R 141 independently represent C 1-6 alkyl, aryl or R 14a to R 14k independently represent H;
  • D does not represent 1,1-C 2-6 alkylene
  • J does not represent C 1 alkylene or 1,1-C 2-6 alkylene; and (ii) B does not represent -N(R 1 lb )-, -N(R llc )S(O) 2 - 5 -S(OV, -0-, -N(R lle )-Z-, -N(R llf )S(O) 2 -Z- or -N(R llh )C(O)O-Z-; and
  • A does not represent a direct bond, -J-N(R 1Oa )-, -J-S(O) 2 N(R 12b )- or
  • B does not represent -N(R llb )-, -N(R llc )S(O) 2 -, -S(O) n -, -O-,
  • the crystalline material of the invention which material is hereinafter referred to as "the crystalline material of the invention".
  • all surface areas (of crystalline materials) mentioned herein are those as determined by nitrogen gas adsorption measurements that have been interpreted using Brunauer, Emmett and Teller (BET) adsorption isotherm. Specific methods of performing such measurements include those detailed below.
  • the surface area of the crystalline material of the invention is less than 0.6 m 2 g "1 , such as less than 0.5, 0.45, 0.4, 0.35, 0.3 or, particularly, 0.25 m 2 g '1 .
  • Preferred ranges of surface area for the crystalline material of the invention include from 0.05 to 0.7 or 0.6 m 2 g "1 , such as from 0.1 to 0.5 m 2 g -1 (e.g. from 0.1 to 0.45, 0.4, 0.35, 0.3 or, particularly, 0.25 mV 1 )-
  • alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain, and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl and alkoxy groups may also be part cyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkyl and alkoxy groups may also be substituted by one or more halo, and especially fiuoro, atoms.
  • alkylene groups as defined herein may be straight- chain or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be branched-chain. Such alkylene chains may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkylene groups may also be substituted by one or more halo atoms.
  • aryl when used herein, includes C 6-13 aryl (e.g. C 6-10 ) groups. Such groups may be monocyclic, bicyclic or tricylic and, when polycyclic, be either wholly or partly aromatic.
  • C 6-13 aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, fluorenyl and the like.
  • the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.
  • aryloxy when used herein includes C 6-13 aryloxy groups such as phenoxy, naphthoxy, fluorenoxy and the like. For the avoidance of doubt, aryloxy groups referred to herein are attached to the rest of the molecule via the 0-atom of the oxy-group.
  • aryl and aryloxy groups may be substituted by one or more substituents selected from -OH, cyano, halo, nitro, C 1-6 alkyl, C 1-6 alkoxy, -N(R 13a )R 13b , -C(O)R 130 , -C(O)OR 13d , -C(O)N(R 13e )R 13f , -N(R 13g )C(O)R 13h , -N(R 13m )S(O) 2 R 12b , -S(O) 2 N(R 13n )(R 13 °), -S(O) 2 R 120 and/or -OS(O) 2 R 12d , (wherein R 12b to R 12d and R 13a to R 13 ° are as hereinbefore defined).
  • aryl and aryloxy groups are preferably substituted by between one and three substituents. For the avoidance of doubt, the point of attachment
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • Het (Het 1 , Her 2 , Her 3 , Her 4 and Het 5 ) groups that may be mentioned include those containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system are between five
  • Het (Het 1 , Het 2 , Het 3 , Het 4 and Het 5 ) groups may be fully saturated, wholly aromatic, partly aromatic and/or bicyclic in character.
  • Heterocyclic groups that may be mentioned include l-azabicyclo[2.2.2]octanyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazinonyl, benzoxazolidinyl, benzoxazolyl, benzopyrazolyl, benzo[e]pyrimidine, 2,1,3- benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, chromanyl, chromenyl, cinnolinyl, 2,
  • Substituents on Het (Het 1 , Het 2 , Het 3 , Het 4 and Het 5 ) groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of Het (Het 1 , Het 2 , Het 3 , Het 4 and Het 5 ) groups may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Het (Het 1 , Het 2 , Het 3 , Het 4 and Het 5 ) groups may also be in the N- or S-oxidised form.
  • compositions of the compound of formula I include salts and solvates. Salts which may be mentioned include acid addition salts.
  • compositions of formula I also include, at the oxabispidine or (when R 4 represents pyridyl) pyridyl nitrogens, C 1-4 alkyl quaternary ammonium salts and N-oxides, provided that when a N-oxide is present:
  • a crystalline material of the invention may consist essentially of a compound of formula I in any of its tautomeric forms, or in a mixture of any such forms.
  • Preferred crystalline materials of the invention include those that consist essentially of a compound of formula I in which:
  • D represents -(CHi) 2 -;
  • R 1 represents C 1-6 alkyl and, particularly saturated C 1-6 alkyl;
  • R 2 represents H, halo, C 1-3 alkyl, -OR 5 , -N(H)R 6 or, together with R 3 , represents
  • R 5 represents H, C 1-6 alkyl, -E-(optionally substituted phenyl) or -E-Het 1 ;
  • R 6 represents H, C 1-6 alkyl, -E-(o ⁇ tionally substituted phenyl), -C(O)R 8a ,
  • R 8a to R 8c independently represent C 1-6 alkyl, or R 8a represents H;
  • R 9a and R 9b independently represent H or C 1-4 alkyl
  • E represents, at each occurrence when used herein, a direct bond or C 1-2 alkylene;
  • A represents -J-, -J-N(R 1Oa )- or -J-O-;
  • B represents -Z-, -Z-N(R llb )-, -Z-S(O) n - or -Z-O-;
  • J represents C 1-4 alkylene
  • Z represents a direct bond or C 1-3 alkylene
  • R 1Oa and R llb independently represent H or C 1-4 alkyl; n represents O or 2;
  • R 4 represents phenyl or pyridyl, both of which groups are optionally substituted by one or more substituents selected from cyano, halo, nitro, C 1-6 alkyl, C 1-6 alkoxy,
  • R represents C 1-3 alkyl
  • R 13e to R 13m independently represent, at each occurrence when used herein, H or C 1-4 alkyl
  • R 14a to R 14d independently represent H, C 1-4 alkyl or aryl; optional substituents on aryl and aryloxy groups, are unless otherwise stated, one or more substituents selected from cyano, halo, nitro, C 1-4 alkyl and C 1-4 alkoxy.
  • More preferred crystalline materials of the invention include those that consist essentially of a compound of formula I in which: R 1 represents C 3-5 alkyl and, particularly, saturated C 4 alkyl;
  • R 2 represents H, methyl, -OR 5 or -N(H)R 6 ;
  • R 3 represents H or methyl
  • R 5 represents H, C 1-2 alkyl or phenyl (which phenyl group is optionally substituted by one or more substituents selected from cyano and C 1-4 alkoxy);
  • R 6 represents H, C 1-2 alkyl, phenyl (which phenyl group is optionally substituted by one or more substituents selected from cyano, halo, nitro, C 1-4 alkyl and
  • R 8a and R 8b independently represent C 1-6 alkyl
  • A represents C 1-4 alkylene
  • B represents -Z-, -Z-N(R 1 lb )-, -Z-S(O) 2 - or -Z-O-;
  • R llb represents H or methyl
  • R 4 represents pyridyl or phenyl, which latter group is optionally substituted by one to three substituents selected from cyano, nitro, C 1-2 alkoxy, NH 2 and
  • crystalline materials of the invention include those that consist essentially of a compound of formula I in which: R 2 represents H 5 -OR 5 or -N(H)R 6 ;
  • R 5 represents H or phenyl (optionally substituted by one or more substituents selected from cyano and C 1-2 alkoxy); .
  • R 6 represents H, phenyl (optionally substituted by one or more cyano groups) or
  • A represents C 1-3 alkylene
  • B represents -Z-, -Z-N(H)-, -Z-S(O) 2 - or -Z-O-;
  • R 4 represents phenyl, substituted by cyano in the ortho- and/or, in particular, the
  • Especially preferred crystalline materials of the invention include those that consist essentially of a compound of formula I in which:
  • R 1 represents terf-butyl
  • R 2 represents H or -OH
  • R 3 represents H
  • A represents CH 2 ;
  • B represents -Z-, -Z-N(H)- or -Z-O;
  • Z represents a direct bond or C 1-2 alkylene
  • R 4 represents p ⁇ r ⁇ -cyanophenyl.
  • Especially preferred crystalline materials of the invention include those that consist essentially of a compound of formula I in which the structural fragment of formula Ia,
  • compositions of the invention include those that consist essentially of a compound of formula Ib:
  • R 1 is as hereinbefore defined.
  • R 1 represents optionally branched C 2 . 5 alkyl (e.g. branched C 3-4 alkyl, such as isopropyl or, particularly, tert-bv ⁇ yl); the structural fragment
  • Preferred crystalline materials consisting essentially of a compound of formula I (or Ib) include those that are neither salts nor solvates.
  • the crystalline material of the invention includes less than 0.2% (e.g. less than 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11 or, particularly, 0.1%) by weight of solvent (which solvent may, in particular, be a dialkyl ether such as diisopropyl ether).
  • solvent which solvent may, in particular, be a dialkyl ether such as diisopropyl ether.
  • the surface area of a crystalline material is indirectly proportional to the average size of the particles in that material.
  • the crystalline materials of the invention comprise particles of an inherently larger average size than those of the corresponding crystalline materials disclosed in the prior art (e.g. in WO 02/083688, WO 02/083690 and WO 2004/035592).
  • the particles of the crystalline materials of the invention have a 90% fractile (as determined by laser diffraction measurements) of at least 70 ⁇ m and a median particle size of at least 35 ⁇ m.
  • the crystalline materials of the invention have a bulk density of over 0.25 g/mL (e.g. over 0.27 or, particularly, 0.3 g/mL). Ranges of bulk density that may be mentioned include any of the above-mentioned lower limits to 0.5, 0.47 or, particularly, 0.45 g/mL.
  • the crystalline materials of the invention are advantageously (and efficiently) prepared by "ripening" crystalline materials having a surface area of greater than 0.7 m 2 g "1 in a solvent system that is saturated with the relevant compound of formula I.
  • the crystalline materials employed in this process preferably consist essentially of the compounds of formula I (and Ib) identified hereinbefore.
  • step (a) above may be prepared according to or by analogy with methods described in the prior art (e.g. in WO 02/083688 or, particularly, WO 02/083690 and WO 2004/035592).
  • step (b) of the above process involves contacting the crystalline material with a solvent system capable of recrystallising it
  • the crystalline material provided in step (a) is not, in step (b), fully dissolved in that solvent system (i.e. that at least part of the material remains in crystalline form, thereby providing the mixture of solvent and crystalline material described in step (c) above).
  • saturated takes its normal definition, i.e. a saturated solution of a compound of formula I refers to a solution of a compound of formula I that, at the given temperature and pressure, is incapable of dissolving any more of that compound.
  • near-saturated?' should be interpreted accordingly, i.e. as referring to a concentration that, at the given temperature and pressure, is 50% or more (e.g. 60, 75 or, particularly, 90% or more) of the saturation concentration.
  • the solvent system employed in the process according to the second aspect of the invention may be any single solvent, or a mixture of two or more solvents, that is capable of recrystallising the compound of formula I.
  • the solvent system preferably comprises a mixture of diisopropyl ether and isopropanol, such as a mixture consisting essentially of diisopropyl ether, isopropanol and no more that 10% v/v (e.g. no more than 5, 4, 3, 2, 1 or, particularly, 0.5% v/v) of other solvent(s).
  • Other solvents that may be mentioned in this respect include water and organic solvents such as aromatic hydrocarbons (e.g. toluene) and/or, particularly, C 1-6 alkyl alcohols (e.g. 4-methyl-2-pentanol).
  • the volumetric ratio of diisopropyl ether to isopropanol is preferably in the range from 20:1 to 1:2, such as from 15:1 to 2:1 (e.g. from 6:1 to 4:1, such as about 5:1).
  • the mixture of solvent and crystalline material in step (c) is prepared by partially dissolving a larger body of crystalline material.
  • a process for preparing the crystalline material according to the first aspect of the invention which process comprises:
  • partial dissolution is used to reflect the fact that only part of the crystalline material provided in step (A) is dissolved through contact with the solvent system mentioned in step (B), thereby leaving at least part of the original material in crystalline form (albeit having particles of a reduced average size).
  • step (B) comprises:
  • step (i) fully dissolving the crystalline material (i.e. that provided in step (A) above) in a solvent system that is capable of recrystallising that compound;
  • step (iii) crystallising the compound of formula I from that solution, thereby providing a mixture in which a crystalline material consisting essentially of a compound of formula I is in contact with a solvent system that is capable of recrystallising that compound.
  • dissolution of the crystalline material may be effected by warming the solvent system (or mixture of crystalline material and solvent system) to elevated temperature (e.g. to a temperature above 25°C, such as to any temperature from 40 to 90, 50 to 80 or, particularly, 60 to 7O 0 C).
  • the solution may be maintained at that elevated temperature for a short period of time, such as any period from 5 to 90 minutes (e.g. 10, 30 or 60 minutes). Further, when filtration is performed (i.e. optional step (ii) above), it is preferably performed upon a solution that is at elevated temperature (e.g. at any temperature
  • step (iii) above may be performed by cooling the resulting solution to sub-ambient or, preferably, ambient temperature (e.g. about 25 0 C). This cooling may take place at any rate, but preferably at a rate below 1, 0.8 or, particularly, 0.6 0 C per minute. Preferred ranges of cooling rates include from 0.1 to 1.0°C per minute, such as 0.3 to 0.6 0 C per minute or, particularly, from 0.4 to 0.5 0 C per minute.
  • step (iii) seeding with a crystal of the compounds of formula I may, if desired, be employed (e.g. in order to accelerate the crystallisation process).
  • the partial dissolution of step (C) above may be effected by warming the solvent system contacting the crystalline material to above ambient temperature, such as to a temperature of from 3O 0 C to reflux.
  • the solvent system is warmed to a temperature of from 30 to 6O 0 C.
  • the partial dissolution of step (C) is effected by warming the solvent system to a temperature of from 35 to 45°C (e.g. to about 4O 0 C).
  • the warming may take place at any rate, but preferably at a rate below 1, 0.75 or, particularly, 0.5°C per minute.
  • Preferred ranges of warming rates include 0.01 °C per minute to any of the above-mentioned upper limits, such as from 0.05 to 0.5, 0.4, 0.3, 0.2 or, particularly, 0.15 0 C per minute (e.g. about 0.1 0 C per minute).
  • the resulting mixture is optionally held at elevated temperature for a short period (e.g. a time period of anywhere from 2 minutes to 3 hours, such as from 5 to 15 minutes or, particularly, about 10 minutes).
  • Step (c) of the process according to the second aspect of the invention and step (D) of the process according to the third aspect of the invention both involve cooling of a mixture of crystalline material and solvent. This is preferably effected by cooling the mixture to ambient or, when elevated temperature is employed in the previous step, sub-ambient temperature. In any event, the cooling may take place at any rate, but preferably at a rate below 1, 0.75 or, particularly, 0.5°C per minute. Preferred ranges of cooling rates include 0.01 °C per minute to any of the above-mentioned upper limits, such as from 0.05 to 0.5, 0.4, 0.3, 0.2 or, particularly, 0.15 0 C per minute (e.g. about 0.1 or about 0.2°C per minute).
  • the mixture of crystalline material and solvent is optionally maintained at the temperature to which it was cooled for a short period (e.g. a time period of anywhere from 2 minutes to 3 hours, such as from 5 to 15 minutes or, particularly, about 10 minutes).
  • the total quantity of solvent employed in step (b) of the process according to the second aspect of the invention or step (B) of the process according to the third aspect of the invention may be anything from 5 to 25 (e.g. from 8 to 16, such as about 12) relative volumes. If a crystalline material according to the first aspect of the invention with a particularly low surface area is required, then that material may be prepared by a process according to the third aspect of the invention in which steps (C) and (D) are repeated one or more times (optional step (E) above). Preferred numbers of repetitions of steps (C) and (D) include 1 to 6 or, particularly, 2 to 4 (making a total of 2 to 7 or, particularly, 3 to 5 times that steps (C) and (D) are performed).
  • the mixture of solvent and crystalline material may be cooled to sub-ambient temperature, such as any temperature from 0 to 15°C (e.g. from 2 to 8°C, such as about 5°C).
  • the rate of cooling to this temperature may be anything from 0.1 to I 0 C per minute (e.g. about 0.6°C per minute).
  • the product may be isolated at step (d) or step (F) using conditions known to those skilled in the art, for example by filtration and/or evaporation of solvent.
  • the crystalline material of the invention may be washed with any of the solvent systems identified above with respect to the second and third aspects of the invention.
  • the solvent system employed to wash the product may, for convenience, be pre-cooled to, for example, between 0 and 15°C (e.g. about 5°C), but this pre-cooling is not essential.
  • the processes of the second and third aspects of the invention are most advantageously employed to prepare a crystalline material according to the first aspect of the invention, which material consists essentially of a compound of formula Ib, as hereinbefore defined.
  • the solvent system utilised in such processes most preferably comprises a mixture of diisopropyl ether and isopropanol.
  • a solvent system comprising a mixture of diisopropyl ether and isopropanol in a method of decreasing the surface area of a crystalline material consisting essentially of a compound of formula Ib, as hereinbefore defined, which method comprises either:
  • preferences relating to the compound of formula Ib, the solvent system comprising diisopropyl ether and isopropanol, effecting partial dissolution, warming of the solvent system and cooling of the mixture of solvent and crystalline material are as described above with respect to the first to third aspects of the invention.
  • step (I) of method (2) above may, in one particular embodiment, be performed by first recrystallising the compound of formula I in the mixture of diisopropyl ether and isopropanol (and optionally filtering the solution obtained when that compound is folly dissolved).
  • step (B) of the process according to the third aspect of the invention apply equally to this aspect of the invention.
  • the crystalline materials of the invention have the advantage that they are effective against cardiac arrhythmias.
  • the crystalline materials of the invention are indicated as pharmaceuticals.
  • the crystalline materials of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or via inhalation, in the form of a pharmaceutical preparation comprising the crystalline materials of the invention in a pharmaceutically acceptable dosage form.
  • the crystalline materials of the invention may be administered at varying doses.
  • a pharmaceutical formulation including a crystalline material of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • crystalline material of the invention which is employed in such a formulation will depend on the condition, and patient, to be treated, as well as the compound(s) which is/are employed.
  • a method of treatment of an arrhythmia which method includes administering a therapeutically effective amount of a crystalline material of the invention to a patient in need of such treatment.
  • treatment we include the therapeutic treatment, as well as the prophylaxis, of a condition.
  • the crystalline materials of the invention may also be combined with any other drugs useful in the treatment of cardiovascular conditions.
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Such combination products provide for the administration of crystalline materials of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises crystalline material of the invention and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including crystalline material of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a crystalline material of the invention, as hereinbefore defined, or solvate and/or a pharmaceutically- acceptable salt thereof, an anticoagulant, and a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • an anticoagulant includes references to one a substance selected from the group consisting of aspirin, warfarin, enoxaparin, heparin, low molecular weight heparin, cilostazol, clopidogrel, ticlopidine, tirofiban, abciximab, dipyridamole, plasma protein fraction, human albumin, low molecular weight dextran, hetastarch, reteplase, alteplase, streptokinase, urokinase, dalteparin, filgrastin, immunoglogulin, ginkolide B, hirudins, foropafant, rocepafant, bivalirudin, dermatan sulfate mediolanum, eptilibatide, tirofiban, thrombomodulin, abcxmab, low molecular weight dermatan sulfate- opocrin
  • anticoagulants include aspirin and warfarin.
  • an anticoagulant also includes references to thrombin inhibitors.
  • thrombin inhibitors that may be mentioned include low molecular weight thrombin inhibitors.
  • low molecular weight thrombin inhibitors will be understood by those skilled in the art, and includes references to any composition of matter (e.g. chemical compound) that inhibits thrombin to an experimentally determinable degree (as determined by in vivo and/or in vitro tests), and which possesses a molecular weight of below about 2,000, preferably below about 1,000.
  • Preferred low molecular weight thrombin inhibitors include low molecular weight peptide-based, amino acid-based, and/or peptide analogue-based, thrombin inhibitors, as well as derivatives thereof.
  • low molecular weight peptide-based, amino acid-based, and/or peptide analogue-based, thrombin inhibitors will be well understood by one skilled in the art to include references to low molecular weight thrombin inhibitors with one to four peptide linkages, and includes those described in the review paper by Claesson in Blood Coagul. Fibrin.
  • derivatives of thrombin inhibitors include chemical modifications, such as esters, prodrugs and metabolites, whether active or inactive, and pharmaceutically acceptable salts and solvates, such as hydrates, of any of these, and solvates of any such salt.
  • Preferred low molecular weight peptide-based thrombin inhibitors include those known collectively as the "gatrans". Particular gatrans which may be mentioned include HOOC-CH 2 -(R)Cha-Pic-Nag-H (known as inogatran) and HOOC-CH 2 - (R)Cgl-Aze-Pab-H (known as melagatran) (see International Patent Application WO 93/11152 and WO 94/29336, respectively, and the lists of abbreviations contained therein).
  • R a OOC-CH 2 -(R)Cgl-Aze-Pab-R b wherein R a represents H, benzyl or C 1-1O alkyl, R b (which replaces one of the hydrogen atoms in the amidino unit of Pab-H) represents OH, OC(O)R 0 or C(O)OR , R c represents C 1-17 alkyl, phenyl or 2-naphthyl and R represents C 1-12 alkyl, phenyl, C 1-3 alkylphenyl, or 2-naphthyl.
  • Preferred compounds include R a OOC-CH 2 -(R)Cgl-Aze-Pab-OH, wherein R a represents benzyl or C 1-10 alkyl, e.g. ethyl or isopropyl, especially EtOOC-CH 2 -(R)Cgl-Aze-Pab-OH.
  • R a represents benzyl or C 1-10 alkyl, e.g. ethyl or isopropyl, especially EtOOC-CH 2 -(R)Cgl-Aze-Pab-OH.
  • the active thrombin inhibitors themselves are disclosed in WO 94/29336.
  • thrombin inhibitors include those disclosed in WO 02/44145, such as compounds of the following general formula,
  • R c represents -OH or -CH 2 OH
  • R 1 represents at least one optional halo substituent
  • R 2 represents one or two C 1-3 alkoxy substituents, the alkyl parts of which substituents are themselves substituted with one or more fluoro substituents (i.e.
  • R 2 represents one or two 1IuOrOaUcOXy(C 1-3 ) groups
  • Y represents -CH 2 - or -(CH 2 ) 2 -;
  • R 3 represents a structural fragment of formula I(i) or I(ii):
  • R 4 represents H or one or more fluoro substituents
  • R 5 represents H, OR 6 or C(O)OR 7 ;
  • R 6 represents H, C 1-10 alkyl, C 1-3 alkylaryl or C 1-3 alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents);
  • R 7 represents C 1-10 alkyl (which latter group is optionally interrupted by one or more oxygen atoms), or C 1-3 alkylaryl or C 1-3 alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents); and one or two of X
  • R 2 represents -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F or -OCH 2 CHF 2 ;
  • R 5 represents H or OR 6 ; and
  • R 6 represents methyl, ethyl, n-propyl, /-propyl or cyclobutyl.
  • Crystalline materials of the invention may have the advantage that they are in a form that provides for improved ease of handling (e.g. improved characteristics during granulation) compared to the corresponding crystalline materials of the prior art. Further, crystalline materials of the invention may also have the advantage that they are in a form that includes fewer impurities, has higher chemical and/or solid state stability, has improved in vivo characteristics, has a longer "shelf-life" and/or has a higher average bulk density compared to the corresponding crystalline materials of the prior art.
  • crystalline materials of the invention may have levels of volatile and/or malodorous components such as diisopropyl ether that are reproducibly and consistently lower than the average levels in materials prepared by prior art methods (thereby promoting consumer acceptability and improving the safety of handling large quantities of material).
  • volatile and/or malodorous components such as diisopropyl ether
  • Crystalline materials of the invention may also have the advantage that they may be produced in good yields, in a higher purity, more conveniently and at lower cost than the corresponding crystalline materials of the prior art.
  • relative volume refers to the volume (in millilitres) per gram of reagent/material employed.
  • Weight percentage of diisopropyl ether was determined by gas chromatography.
  • the mixture was hydrogenated under 2.5 bar of hydrogen pressure and was simultaneously heated to 55°C (temperature overshot to 73 0 C). Gas uptake measurement showed the reaction to be complete after 1 hour. After cooling to 47 0 C the catalyst was removed by filtration through a glass fibre filter paper. The catalyst was washed on the filter with IPA (75 mL) and the combined filtrate and washings used in the next step.
  • Aqueous sodium carbonate solution (1 M, 133 mL) was added, followed by a warm (4O 0 C) solution of 4-[(2 ⁇ S)-oxiranylmethoxy]benzonitrile (44.4 g) in IPA (75 mL) and toluene (75. mL).
  • the solution was rinsed into the reaction flask with IPA (37 mL) and toluene (37 mL).
  • the reaction was heated to 78 0 C for 4 hours and then left to stir at ambient temperature overnight.
  • Toluene was added (1050 mL) and solvent was distilled (600 mL). The mixture was then allowed to cool to 26°C.
  • Aqueous sodium hydroxide (1 M, 450 mL) was added.
  • the mixture was stirred for 5 minutes and then the phases were separated.
  • the aqueous phase was discarded and the toluene phase washed with aqueous citric acid (10% w/v, 450 mL).
  • the toluene phase was discarded.
  • 4-Methyl-2-pentanol (MIBC; 600 mL) and aqueous sodium hydroxide (5 M, 450 mL) were added to the citric acid phase. After stirring for 5 minutes the phases were separated and the aqueous phase discarded.
  • the MIBC phase was washed with aqueous sodium chloride (20% w/v, 150 mL) and the phases separated.
  • the MIBC solution was then left to stir overnight (this overnight stir is unnecessary but in this example was carried out for convenience).
  • the MIBC phase was concentrated under reduced pressure (78 mL of solvent was collected).
  • the solution was filtered to a clean vessel, washing through with MIBC (150 mL).
  • Solvent (437 mL) was distilled under reduced pressure at ⁇ 70°C.
  • Diisopropyl ether (IPE; 900 mL) was added at 55°C and the temperature fell to 40 0 C.
  • the solution was re-heated to 58 0 C and then allowed to cool naturally to ambient temperature (at 28°C a precipitate forms).
  • the mixture was stirred overnight at ambient temperature.
  • the mixture was cooled to 5°C and the solid collected by filtration.
  • the filter cake was washed by displacement with IPE (300 mL) and dried by suction on the filter. Further drying in vacuo at 70 0 C gave the title compound as a white solid (97.3 g, 82% over
  • the mixture was hydrogenated under 3.5 bar of hydrogen pressure and was simultaneously heated to 55°C (temperature overshot to 68°C). Gas uptake measurement showed the reaction to be complete after 3.5 hours.
  • the reaction was filtered directly to the next reaction vessel at the appropriate point detailed below.
  • the catalyst was washed with IPA (50 mL) and the wash added directly to the next reaction vessel at the appropriate point detailed below.
  • Solvent was removed (236 mL) by distillation under reduced pressure (approximately 2.5 volumes of solvent need to be distilled to ensure removal of IPA). Toluene (400 mL) and aqueous sodium hydroxide (3 M, 100 mL) were added and the mixture stirred for 5 minutes. The phases were separated at 27 0 C and the lower aqueous phase discarded. Aqueous citric acid (10% w/v, 300 mL) was added to the remaining toluene phase. After stirring for 5 minutes the phases were separated and the upper toluene phase discarded.
  • MIBC 4-Methyl-2-pentanol
  • an aqueous solution of sodium hydroxide 5 M, 450 mL
  • sodium chloride at 10% w/v
  • the MIBC phase was washed with aqueous sodium chloride (20% w/v, 10 mL) and after 5 minutes stirring the phases separated.
  • the MIBC solution was then left to stand overnight (this overnight stand is unnecessary but in this example was carried out for convenience).
  • the MIBC phase was concentrated under vacuum at a temperature of less than 44°C (maximum temperature that can be reached at this part of the process is 7O 0 C); solvent was collected (water 18 mL: MIBC 35 mL). The solution was filtered to a clean vessel, washing through with MIBC (50 mL). Solvent (240 mL) was distilled under vacuum at less than 7O 0 C. Diisopropyl ether (IPE; 600 mL) was added and the solution was re-heated to 64°C. The solution was stirred at 250 rpm and allowed to cool naturally. After 2 hours stirring, the temperature had fallen to 28 0 C and precipitation of product had started. After stirring for a further 90 minutes, the temperature had fallen to 21 0 C.
  • IPE isopropyl ether
  • reaction mixture was then cooled to -1O 0 C 5 over approximately five minutes, after which trimethylamine hydrochloride (1.4 g) was added, followed by a solution of para- toluenesulfonyl chloride (14.6 g), dissolved in 4-methylpenatan-2-one (80 mL). During the addition, the reaction temperature was maintained at -10 0 C ⁇ .5 0 C. When the addition was complete, the reaction mixture was warmed to 2O 0 C. Water (60 mL) was added and the reaction mixture was heated to 75°C, at which temperature the layers were separated and the lower (aqueous) layer was discarded.
  • the catalyst was removed by filtration and was washed with isopropanol (150 mL). The organic filtrate and the isopropanol catalyst washings were combined. To this was added 2-(4-cyano-2-fluorophenoxy)ethyl toluene-4-sulfonate (175.5 g; see step (i) above) and a solution of sodium carbonate (315 g) dissolved in water (930 mL). The reaction mixture was heated to 75°C, at which temperature it was held for twelve hours before being cooled to 20 0 C. The reaction mixture was reduced in volume by reduced pressure distillation (at less than 5O 0 C), and approximately 650 mL of solvent was removed.
  • Diisopropyl ether isopropanol (10: 2 v/v; 300 mL) was added to tert-butyl (2- ⁇ 7- [(25 ⁇ -3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3- yl ⁇ ethylcarbamate having a surface area of above 0.7 m 2 g "1 (25.01 g, 56 mmol; see WO 2004/035592 or Comparative Example B above). The mixture was heated to 65°C over 90 minutes in order to form a solution and was then held at 65°C for 10 minutes.
  • the mixture was held at 25°C for 10 minutes before the same heating/cooling procedure was repeated twice more.
  • the mixture was then cooled to 5 0 C over 30 minutes.
  • the product was isolated by filtration, and the filter cake washed by displacement with diisopropyl ether (50 mL).
  • the filter cake (low surface area, crystalline material) was dried as much as possible by suction on the filter before being dried in vacuo for 24 hours at 55°C. This gave 21.20 g (85%) of a crystalline, white solid.
  • Diisopropyl ether isopropanol (10: 2 v/v; 536.1 kg) was added to tert-butyl (2- ⁇ 7- [(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclb[3.3.1]non-3- yl ⁇ ethylcarbamate having a surface area of above 0.7 m 2 g "1 (61.4 kg; see WO 2004/035592 or Comparative Example B above). The mixture was heated to 65°C ⁇ 3°C over 3 hours in order to form a solution.
  • the resulting mixture of solvent and crystalline material was then warmed to 40 0 C + 3 0 C at 0.FC per minute, maintained for 10 minutes at 4O 0 C ⁇ 3 0 C, and then cooled to 23°C ⁇ 3°C at a rate of 0.1 0 C per minute. The mixture was then held at 23 0 C + 3 0 C for 30 minutes before the same heating/cooling procedure was repeated twice more. The mixture was then cooled to 5°C over 90 minutes. The product was isolated by filtration, and the filter cake washed by displacement with cold (5 0 C), filtered, diisopropyl ether (89.2 kg).
  • the filter cake (low surface area, crystalline material) was as dried to constant weight on the filter, in vacuo for 106 hours (for convenience; other batches at this scale were dried for less than 48 hours) at 3O 0 C, to 55.46 kg (91%) of a crystalline, white solid.
  • the mixture was then cooled to 5 0 C over 30 minutes.
  • the product was isolated by filtration, and the filter cake washed by displacement with diisopropyl ether (50 mL).
  • the filter cake (low surface area, crystalline material) was dried as much as possible on the filter before being dried in vacuo for 5 days at 55 0 C. This gave 21.33 g (85%) of a crystalline, white solid.
  • Diisopropyl ether isopropyl alcohol (10: 2 v/v; 300 mL) was added to tert-butyl (2- ⁇ 7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]- non-3-yl ⁇ ethyl)carbamate having a surface area of above 0.7 m 2 g "! (25.07 g, 56.14 mmol). The mixture was heated to 65 0 C ⁇ 5°C over 90 mins in order to form a solution and held at 65°C ⁇ 5 0 C for 10 mins (hot filtration to clarify the solution can be carried out at this point if necessary).
  • reaction mixture was cooled back to 25°C ⁇ 3°C over 1 hour 30 minutes.
  • a seed (approx. 25 mg) of pure tert-hx ⁇ yl (2- ⁇ 7-[(2 ⁇ S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7- diazabicyclop.S.lJnon-S-yllethyrj-carbarnate was added once the temperature had reached 45°C during the cool down.
  • the mixture was seeded, this caused immediate crystallisation.
  • the mixture was heated to 4O 0 C over forty minutes.
  • the mixture was cooled to 2O 0 C over one hour and forty minutes.
  • the mixture was heated to 40 0 C over forty minutes.
  • the mixture was cooled to 2O 0 C over one hour and forty minutes.
  • the mixture was heated to 40 0 C over forty minutes.
  • the mixture was cooled to 20 0 C over one hour and forty minutes.
  • the mixture was held 20 0 C, for approximately 10 hours.
  • the mixture was cooled to 5 0 C over thirty minutes.
  • the mixture was held at 5 0 C for five minutes before being filtered and washed with cold diisopropyl ether (50 mL, 5°C).
  • the damp solid was dried in vacuo at 35 0 C, for approximately twenty-four hours to give the crystallised title compound a white crystalline solid (21 g, 84%).
  • the compounds of the invention have a surface area (as determined by BET measurements) of less than 0.7 m ⁇ g "1 .
  • corresponding crystalline materials of the prior art e.g. those obtained by the procedures outlined in WO 2004/035592
  • surface areas of greater than this value as do the same prior art materials that have been subjected to a recrystallisation procedure, such as that outlined in WO 02/083688.
  • the compounds of the invention in a preferred embodiment, have a diisopropyl ether content of less than 0.15% (w/w). This value is reproducibly and consistently lower than the average levels in corresponding prior art crystalline materials (e.g. those obtained by the procedures outlined in WO 2004/035592), including those that have been subjected to a recrystallisation procedure, such as that outlined in WO 02/083688. Specific results are detailed in the table below.
  • n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

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Abstract

L'invention concerne un matériau cristallin consistant essentiellement en un composé de formule I, dans lequel R1 à R4, A, B et D ont les significations données dans la description, ledit matériau cristallin étant caractérisé en ce qu'il présente une aire de surface inférieure à 0,7 m2g-1. L'invention concerne également des procédés de préparation de tels matériaux cristallins.
PCT/SE2006/000692 2005-06-20 2006-06-12 Nouvelle forme physique d'oxabispidines n,n-disubstituees WO2006137772A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase

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WO2001028992A2 (fr) * 1999-10-18 2001-04-26 Astrazeneca Ab Nouveaux composes d'oxabispidine utiles dans le traitement d'arythmies cardiaques
WO2002028863A1 (fr) * 2000-10-02 2002-04-11 Astrazeneca Ab Nouveau compose d'oxabispidine utile pour traiter les arythmies cardiaques
WO2002083690A1 (fr) * 2001-04-12 2002-10-24 Astrazeneca Ab Preparation d'oxabispidines
WO2002083688A1 (fr) * 2001-04-12 2002-10-24 Astrazeneca Ab Formulations 3,7-diazabicyclo [3.3.1] en tant que composes antiarythmiques
WO2003092720A1 (fr) * 2002-05-06 2003-11-13 Astrazeneca Ab Produit mixte contenant un anticoagulant et des oxabispidines anti-arythmisantes
WO2003101956A1 (fr) * 2002-05-31 2003-12-11 Astrazeneca Ab Combinaison pharmaceutique
WO2004035592A1 (fr) * 2002-10-14 2004-04-29 Astrazeneca Ab Intermediaire chimique

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Publication number Priority date Publication date Assignee Title
WO2001028992A2 (fr) * 1999-10-18 2001-04-26 Astrazeneca Ab Nouveaux composes d'oxabispidine utiles dans le traitement d'arythmies cardiaques
WO2002028863A1 (fr) * 2000-10-02 2002-04-11 Astrazeneca Ab Nouveau compose d'oxabispidine utile pour traiter les arythmies cardiaques
WO2002083690A1 (fr) * 2001-04-12 2002-10-24 Astrazeneca Ab Preparation d'oxabispidines
WO2002083688A1 (fr) * 2001-04-12 2002-10-24 Astrazeneca Ab Formulations 3,7-diazabicyclo [3.3.1] en tant que composes antiarythmiques
WO2003092720A1 (fr) * 2002-05-06 2003-11-13 Astrazeneca Ab Produit mixte contenant un anticoagulant et des oxabispidines anti-arythmisantes
WO2003101956A1 (fr) * 2002-05-31 2003-12-11 Astrazeneca Ab Combinaison pharmaceutique
WO2004035592A1 (fr) * 2002-10-14 2004-04-29 Astrazeneca Ab Intermediaire chimique

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11858939B2 (en) 2015-07-06 2024-01-02 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10519149B2 (en) 2017-01-11 2019-12-31 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10696673B2 (en) 2017-01-11 2020-06-30 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10793567B2 (en) 2017-01-11 2020-10-06 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11225479B2 (en) 2017-01-11 2022-01-18 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11286256B2 (en) 2017-01-11 2022-03-29 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11987580B2 (en) 2017-01-11 2024-05-21 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11912702B2 (en) 2017-08-07 2024-02-27 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase

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