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WO2009111540A1 - Procédés pour préparer des carbolines substituées par pyridyléthyle - Google Patents

Procédés pour préparer des carbolines substituées par pyridyléthyle Download PDF

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Publication number
WO2009111540A1
WO2009111540A1 PCT/US2009/035992 US2009035992W WO2009111540A1 WO 2009111540 A1 WO2009111540 A1 WO 2009111540A1 US 2009035992 W US2009035992 W US 2009035992W WO 2009111540 A1 WO2009111540 A1 WO 2009111540A1
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Prior art keywords
dimebon
carboline
mvp
compound
ppm
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Susan Wollowitz
Erik W. Kataisto
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Medivation Neurology Inc
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Medivation Neurology Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the methods described herein address one or more of the existing drawbacks to using MVP in the synthesis of pyridy lethyl- substituted carbolines such as dimebon (2,8- dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-lH-pyrido[4,3-b]indole). Additionally, new solid forms of dimebon and methods of preparing those solid forms are disclosed.
  • the invention relates to new methods for the synthesis of pyridy lethyl- substituted carbolines using MVP.
  • a pyridy lethyl- substituted carboline is prepared under reaction conditions that use fewer molar equivalents of MVP to produce the pyridy lethyl- substituted carboline as compared to reported methods of preparing pyridy lethyl- substituted carbolines using MVP.
  • a pyridy lethyl- substituted carboline is prepared using non-commercial MVP, wherein the MVP is either generated in situ in the preparation of a pyridy lethyl- substituted carboline or is prepared just prior to use in the preparation of a pyridy lethyl- substituted carboline.
  • a pyridylethyl- substituted carboline is prepared both (1) under reaction conditions that use fewer molar equivalents of MVP to produce the pyridylethyl- substituted carboline as compared to reported methods of preparing pyridylethyl- substituted carbolines using MVP, and (2) the MVP used is non-commercial MVP, wherein the MVP is either generated in situ in the preparation of a pyridylethyl- substituted carboline or is prepared just prior to use in the preparation of a pyridylethyl- substituted carboline.
  • the methods detailed herein may be used in the preparation of various pyridylethyl- substituted carbolines and salts thereof and solvates of the foregoing.
  • the invention specifically embraces methods of making dimebon (2,8- dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro- lH-pyrido[4,3-b]indole) and salts thereof and solvates of all of the foregoing.
  • a method of preparing dimebon dihydrochloride dihydrate (dimebon • 2HCl • 2H 2 O) is provided.
  • the invention relates to synthesis of, and alternate solid forms of, pyridylethyl- substituted carbolines and related compounds of the formula:
  • Ri is Me, Et or PhCH 2
  • R 2 is H, PhCH 2 or 6-Me-3-Py-(CH 2 ) 2 ;
  • R 3 is H, Me or Br, and salts, hydrates, or combined salt-hydrates.
  • the invention relates to synthesis of, and alternate solid forms of, compounds where the compound is of formula I and:
  • the invention relates to synthesis of, and alternate solid forms of, the following pyridylethyl-substituted carbolines: 2,8-dimethyl-5-[2-(6- methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-lH-pyrido[ 4,3-b]indole; or 2-methyl-5-[2-(6- methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-lH-pyrido[4,3-b ]indole; or salts, hydrates, or combined salt-hydrates thereof.
  • the invention embraces a method of making a pyridylethyl-substituted carboline and related compounds, comprising reacting a carboline compound of the formula:
  • Ri and R 3 are as defined above for compound (I), or salts, hydrates, or combined salt-hydrates thereof, with a vinyl pyridine compound of the formula:
  • salts, hydrates, or combined salt-hydrates thereof in a yield of about 60% or greater. If the free base is formed, salts, hydrates, or combined salt-hydrates can be formed by further treatment as described herein. If the dihydrochloride dihydrate is formed, alternate salts, hydrates, or combined salt-hydrates can be formed by further treatment as described herein.
  • the reaction above is of the form: base
  • the yield of pyridylethyl-substituted carboline compound (IV) is about 60% or greater. In another embodiment, the yield of pyridylethyl-substituted carboline compound (IV) is about 65% or greater. In another embodiment, the yield of pyridylethyl-substituted carboline compound (IV) is about 70% or greater. In another embodiment, the yield of pyridylethyl-substituted carboline compound (IV) is about 75% or greater. In another embodiment, the yield of pyridylethyl-substituted carboline compound (IV) is about 80% or greater. In another embodiment, the yield of pyridylethyl-substituted carboline compound (IV) is about 85% or greater.
  • the yield of pyridylethyl-substituted carboline compound (IV) is about 90% or greater. In another embodiment, the yield of pyridylethyl-substituted carboline compound (IV) is about 95% or greater.
  • the carboline (II) is selected from the group consisting of
  • the carboline compound (II) is 2,8-dimethyl-2,3,4,5- tetrahydro-lH-pyrido[4,3-b]indole, or salts, hydrates, or combined salt-hydrates thereof.
  • the carboline compound (II) is 2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole, or salts, hydrates, or combined salt-hydrates thereof, and the pyridylethyl-substituted carboline compound (IV) is dimebon, or salts, hydrates, or combined salt-hydrates thereof.
  • the carboline compound (II) is 2,8-dimethyl-
  • about 4 or less than about 4 equivalents of vinyl pyridine compound (III) per equivalent of carboline compound (II) are used for the reaction.
  • about 3 or less than about 3 equivalents of vinyl pyridine compound (III) per equivalent of carboline compound (II) are used for the reaction.
  • about 2 or less than about 2 equivalents of vinyl pyridine compound (III) per equivalent of carboline compound (II) are used for the reaction.
  • about 1.5 to about 2 equivalents of vinyl pyridine compound (III) per equivalent of carboline compound (II) are used for the reaction.
  • about 1.7 equivalents of vinyl pyridine compound (III) per equivalent of carboline compound (II) are used for the reaction.
  • the solvent for the reaction is selected from the group consisting of N-methyl pyrrolidone (NMP), dimethyl acetamide (DMAC), and diglyme (bis(2-methoxy ethyl ether).
  • NMP N-methyl pyrrolidone
  • DMAC dimethyl acetamide
  • diglyme bis(2-methoxy ethyl ether).
  • the reaction is carried out in the presence of a base, preferably a base having a potassium ion as cation; the base can be selected from the group consisting of KOH, K 3 PO 4 , tBuOK, tBuONa, tBuOLi, EtOK, EtONa, EtOLi, MeOK, and MeONa.
  • the base can be selected from the group consisting of KOH, K 3 PO 4 , tBuOK,
  • the reaction of the carboline compound (II) with the vinyl pyridine compound (III) is carried out at a temperature of about 80 0 C to about 130 0 C. In another embodiment, the reaction of the carboline compound (II) with the vinyl pyridine compound (III) is carried out at a temperature of about 100 0 C to about 120 0 C. In one embodiment, the vinyl pyridine compound (III) is added as the last reagent, after the carboline compound (II) and base in the solvent have reached the desired reaction temperature.
  • the reaction is performed for about 8 hours to about 26 hours. In another embodiment, the reaction is performed from about 16 hours to about 26 hours.
  • the water content of the solvent is about 5 wt.% or less.
  • the water content of the solvent is about 1 wt.% to about 5 wt.%.
  • the water content of the solvent is about 1 wt.% or less.
  • the solvents are degassed prior to use.
  • the solvents are degassed and then sparged with an inert gas, such as nitrogen or argon, prior to use.
  • the reaction vessels used are purged with inert gas, such as nitrogen or argon, prior to use.
  • the reaction is performed under an inert gas atmosphere, such as nitrogen or argon, for example, in a reaction vessel purged with inert gas such as nitrogen or argon prior to use.
  • carboline compound (II) is 2,8-dimethyl-
  • DMAC or diglyme are reacted at about 100 0 C - about 12O 0 C for about 8 hours.
  • 2,3,4,5,-tetrahydro-lH-pyrido[4,3-b]indole and the vinyl pyridine compound (III) is 2- methyl-5-vinylpyridine (MVP), about 1.75 equivalent MVP, about 1 equivalent 2,8-dimethyl- 2,3,4,5,-tetrahydro-lH-pyrido[4,3-b]indole free base, and about 1.8 equivalent K 3 PO 4 in DMAC are reacted at about 120 0 C for about 18 hours.
  • MVP 2- methyl-5-vinylpyridine
  • the invention embraces a method of preparing a pyridylethyl- substituted carboline, comprising reacting a hydrazino compound of the formula:
  • about 4 or less than about 4 equivalents of vinyl pyridine compound (III) per equivalent of hydrazino compound (V) are used for the reaction. In one embodiment, about 3 or less than about 3 equivalents of vinyl pyridine compound (III) per equivalent of hydrazino compound (V) are used for the reaction. In one embodiment, about 2 or less than about 2 equivalents of vinyl pyridine compound (III) per equivalent of hydrazino compound (V) are used for the reaction. In one embodiment, about 1.5 to about 2 equivalents of vinyl pyridine compound (III) per equivalent of hydrazino compound (V) are used for the reaction.
  • the hydrazino compound (V) is p-tolylhydrazine.
  • the 4-piperidinone compound is l-methyl-4-piperidinone (N-methyl-4- piperidinone).
  • the hydrazino compound (V) is p-tolylhydrazine, the 4-piperidinone compound (VII) is l-methyl-4-piperidinone (N-methyl-4-piperidinone), and the pyridylethyl-substituted carboline compound (IV) is dimebon, or salts, hydrates, or combined salt-hydrates thereof.
  • the solvent for the reactions is selected from the group consisting of N-methyl pyrrolidone (NMP), dimethyl acetamide (DMAC), and diglyme (bis(2-methoxy ethyl ether).
  • NMP N-methyl pyrrolidone
  • DMAC dimethyl acetamide
  • diglyme bis(2-methoxy ethyl ether).
  • the reaction of the hydrazino compound with the vinylpyridine compound is carried out in the presence of a base; the base is selected from the group consisting of KOH, K 3 PO 4 , tBuOK, tBuONa, tBuOLi, EtOK, EtONa, EtOLi, MeOK, and MeONa.
  • the base is selected from the group consisting of KOH, K 3 PO 4 , tBuOK, EtOK, and MeOK.
  • pyridylethyl-substituted carboline (IV) when pyridylethyl-substituted carboline (IV) is prepared as the free base, it can be converted to the dihydrochloride dihydrate form by a method comprising: mixing dimebon free base with acetone; optionally heating the solution to about 3O 0 C to about 6O 0 C, about 4O 0 C to about 5O 0 C, or about 45 0 C; adding hydrochloric acid aqueous solution, optionally mixed with additional acetone (such as 37 wt% HCl mixed with acetone); and, if heated, cooling the solution to about O 0 C to about 25 0 C or about room temperature, or about 5 0 C to about 2O 0 C, or about 1O 0 C to about 15 0 C, and recovering the pyridylethyl-substituted carboline (IV) dihydrochloride dihydrate.
  • the product can be isolated by adding water and isolating the pyridylethyl- substituted carboline (IV) from the resultant slurry.
  • the product can be isolated by adding water and a small amount of water-immiscible solvent (for example, about 5% to about 25% of the volume of water added) to the reaction mixture, and isolating the pyridylethyl-substituted carboline (IV) from the resultant slurry.
  • the product can be isolated by adding water and a large amount of water-immiscible solvent (for example, about 25% to about 200% of the volume of water added) to the reaction mixture, where the pyridylethyl-substituted carboline (IV) is highly soluble in the water- immiscible solvent, followed by separating the water immiscible solvent from the aqueous layer and isolating the product by crystallization from the water-immiscible solvent; in this embodiment, the water can be extracted with additional portions (e.g., one, two, three, or more portions) of water-immiscible solvent, all portions of the water- immiscible solvent can be combined and optionally concentrated before isolating the product by crystallization.
  • additional portions e.g., one, two, three, or more portions
  • the pyridylethyl- substituted carboline (IV) is further purified by recrystallization prior to use or conversion to a salt.
  • the pyridylethyl-substituted carboline (IV) can be dimebon.
  • dimebon dihydrochloride anhydrous Form A, Form B hemi-hydrate, Form C monohydrate, Form D dihydrate, Form F trihydrate, and amorphous dimebon dihydrochloride.
  • the invention embraces anhydrous dimebon dihydrochloride (Form A). This form is characterized by having carbon solid state NMR peaks at about 147.1, about 124.0, about 111.1, and about 21.6 ppm, referenced to an external sample of solid phase adamantane at 29.5 ppm. In another embodiment, the chemical shifts are within ⁇ 0.2 ppm of the values indicated.
  • Form A can also be characterized by the following PXRD peaks having the indicated intensity at the specified angle: about 54.6% at about angle (°2-theta) 8.8; about 42.9% at about angle (°2-theta) 11.9; about 31.1% at about angle (°2-theta) 17.8; and about 100% at about angle (°2-theta) 24.9.
  • the values of intensities and angles can vary by + 5%.
  • the invention comprises a method of making anhydrous dimebon dihydrochloride (Form A), comprising stirring or otherwise agitating dimebon dihydrochloride dihydrate in toluene for at least one day, e.g., 1 to 10 days, optionally evaporating the toluene and replacing with fresh toluene one, two, three, or more times, optionally at elevated temperature of about 30-120 0 C, about 80-100 0 C, or about 85- 95 0 C.
  • Form A anhydrous dimebon dihydrochloride
  • the method can further comprise removal of the solvent and subjecting the resulting material to a vacuum of about 500 mbar or higher, about 300 mbar or higher, about 200 mbar or higher, about 100 mbar or higher, about 50 mbar or higher, or about 10 mbar or higher (where "higher vacuum” signifies a lower pressure, e.g., 50 mbar is a higher vacuum than 100 mbar).
  • the invention embraces dimebon dihydrochloride hemi-hydrate (Form B).
  • Form B dimebon dihydrochloride hemi-hydrate
  • This form is characterized by having carbon solid state NMR peaks at about 148.5, about 133.8, about 117.0, and about 17.6 ppm, referenced to an external sample of solid phase adamantane at 29.5 ppm.
  • the chemical shifts are within ⁇ 0.2 ppm of the values indicated.
  • Form B can also be characterized by the following PXRD peaks having the indicated intensity at the specified angle: about 45.1% at about angle (°2-theta) 9.0; about
  • the values of intensities and angles can vary by ⁇ 5%.
  • the invention embraces a method of making dimebon dihydrochloride hemi-hydrate (Form B), comprising stirring or otherwise agitating dimebon dihydrochloride dihydrate in ethanol for at least about 5 days or about 5 to about 10 days, e.g., about 7 days, under ambient conditions, isolating the solid (e.g., by filtration such as centrifugal filtration), drying in a vacuum oven at a temperature between about 45-65 0 C, e.g., about 55 0 C, for at least about 30 minutes, e.g., approximately 30 to 90 minutes, or about 45 minutes.
  • Form B dimebon dihydrochloride hemi-hydrate
  • the invention embraces a method of making dimebon dihydrochloride hemi-hydrate (Form B), comprising stirring or otherwise agitating dimebon dihydrochloride dihydrate in acetonitrile for at least about 15 days or about 15 to about 30 days, e.g., about 23 days, under ambient conditions, isolating the solid (e.g., by filtration such as centrifugal filtration), drying in a vacuum oven at a temperature between about 45-65 0 C, e.g., about 55 0 C, for at least about 30 minutes, e.g., approximately 30 to 90 minutes or about
  • Form B dimebon dihydrochloride hemi-hydrate
  • the invention embraces dimebon dihydrochloride monohydrate (Form C). This form is characterized by having carbon solid state NMR peaks at about 152.9, about 118.7, about 113.4, about 38.4, and about 30.2 ppm, referenced to an external sample of solid phase adamantane at 29.5 ppm.
  • the chemical shifts are within ⁇ 0.2 ppm of the values indicated.
  • Form C can also be characterized by the following PXRD peaks having the indicated intensity at the specified angle: about 100% at about angle (°2-theta) 6.7; about
  • the values of intensities and angles can vary by ⁇ 5%.
  • the invention embraces a method of making dimebon dihydrochloride monohydrate (Form C), comprising stirring or otherwise agitating dimebon dihydrochloride in IPA under ambient conditions for at least about 8 days, or about 8 to about 20 days, such as 13 days, isolating the solid (e.g., by filtration) and drying in a vacuum dessicator for about 20 to 60 minutes, e.g., approximately 30 minutes.
  • Dimebon dihydrochloride dihydrate (Form D). This form is characterized by having carbon solid state NMR peaks at about 149.9, about 132.9, about 22.5, and about 17.5ppm, referenced to an external sample of solid phase adamantane at 29.5 ppm. In another embodiment, the chemical shifts are within + 0.2 ppm of the values indicated.
  • Form D can also be characterized by the following PXRD peaks having the indicated intensity at the specified angle: about 100% at about angle (°2-theta) 8.6; about
  • the values of intensities and angles can vary by + 5%.
  • a method of making dimebon dihydrochloride dihydrate comprising stirring or otherwise agitating dimebon free base in acetone, heating the solution to about 35 0 C to 6O 0 C, e.g. about 45 0 C, optionally filtering the solution, and adding HCl solution (e.g., 37 wt% HCl with about 0.25 volumes or more acetone, such as about 0.48 volumes). The addition can be done at elevated temperature of about 45 0 C to
  • the material can then be cooled, for example to 10-15 0 C, and optionally filtered.
  • the material can be dried at room temperature under vacuum with a nitrogen stream for about 3 hours to 12 hours, e.g., for about 6 hours.
  • the invention embraces dimebon dihydrochloride trihydrate (Form F). This form is characterized by having carbon solid state NMR peaks at about 147.5, about 130.6, about 123.7, and about 44.7 ppm, referenced to an external sample of solid phase adamantane at 29.5 ppm. In another embodiment, the chemical shifts are within ⁇ 0.2 ppm of the values indicated.
  • Form F can also be characterized by the following PXRD peaks having the indicated intensity at the specified angle: about 47.0% at about angle (°2-theta) 7.7; about
  • the values of intensities and angles can vary by ⁇ 5%.
  • the invention embraces a method of making dimebon dihydrochloride trihydrate (Form F), comprising adding methanol slowly (such as dropwise) to dimebon dihydrochloride dihydrate until the solid dissolves, and allowing the solution to evaporate.
  • the solution can be optionally ground with a mortar during evaporation (in order to pulverize precipitating material).
  • the invention embraces amorphous dimebon dihydrochloride. This form is characterized by having carbon solid state NMR peaks at about 151.5, about 125.0, about 111.3, and about 21.3 ppm, referenced to an external sample of solid phase adamantane at 29.5 ppm. In another embodiment, the chemical shifts are within ⁇ 0.2 ppm of the values indicated.
  • the invention embraces a method of making amorphous dimebon dihydrochloride, comprising dissolving dimebon dihydrochloride dihydrate in methanol, and evaporating the solvent at elevated temperature above about 35 0 C, such as between about 35 0 C and 75 0 C, or about approximately 55 0 C, which under a vacuum of about 500 mbar or higher, about 300 mbar or higher, about 200 mbar or higher, about 100 mbar or higher, about 50 mbar or higher, or about 10 mbar or higher (where "higher vacuum” signifies a lower pressure, e.g., 50 mbar is a higher vacuum than 100 mbar).
  • the vacuum used for any of the above methods may be about 500 mbar or higher, about 300 mbar or higher, about 200 mbar or higher, about 100 mbar or higher, about 50 mbar or higher, or about 10 mbar or higher (where "higher vacuum” signifies a lower pressure, e.g., 50 mbar is a higher vacuum than 100 mbar).
  • the invention also embraces a composition comprising one or more of any of the anhydrous Form A, Form B hemi-hydrate, Form C monohydrate, Form F trihydrate, and amorphous dimebon dihydrochloride and a pharmaceutically acceptable carrier.
  • the invention also embraces a composition comprising any individual solid form of dimebon and a pharmaceutically acceptable carrier.
  • the invention also embraces a composition comprising a mixture of two or more solid forms of anhydrous Form A, Form B hemi- hydrate, Form C monohydrate, Form D dihydrate, Form F trihydrate, and amorphous dimebon dihydrochloride in any proportion.
  • the invention also embraces a composition comprising a mixture of two or more solid forms of dimebon in any proportion, additionally comprising a pharmaceutically acceptable carrier.
  • the compound and/or composition can comprise the compound and/or composition indicated, consist essentially of the compound and/or composition indicated, or consist of the compound and/or composition indicated.
  • the method can comprise the method steps indicated, consist essentially of the method steps indicated, or consist of the method steps indicated.
  • Figure 1 depicts, from bottom to top, a comparison of the proton decoupled
  • 13 C CPMAS spectra of dimebon dihydrochloride A. anhydrous Form A; B. Form B hemi- hydrate; C. Form C monohydrate; D. Form D dihydrate; F. Form F trihydrate; and E. amorphous. 13 C CPMAS spectra were taken at 1O 0 C, with sealed cap, spinning at 15.0 kHZ, referenced to adamantane at 29.5 ppm.
  • Figure 2 depicts, from bottom to top, a comparison of the 0-70 ppm region of the proton decoupled 13 C CPMAS spectra of dimebon dihydrochloride: A. anhydrous Form A; B. Form B hemi-hydrate; C. Form C monohydrate; D. Form D dihydrate; F. Form F trihydrate; and E. amorphous. Peaks included in the unique peak set for each form are noted with arrows. 13 C CPMAS spectra were taken at 1O 0 C, with sealed cap, spinning at 15.0 kHZ, referenced to adamantane at 29.5 ppm.
  • Figure 3 depicts, from bottom to top, a comparison of the 90-160 ppm region of the proton decoupled 13 C CPMAS spectra of dimebon dihydrochloride A. anhydrous Form A; B. Form B hemi-hydrate; C. Form C monohydrate; D. Form D dihydrate; F. Form F trihydrate; and E. amorphous. Peaks included in the unique peak set for each form are noted with arrows. 13 C CPMAS spectra were taken at 1O 0 C, with sealed cap, spinning at 15.0 kHZ, referenced to adamantane at 29.5 ppm.
  • Figure 4 depicts the powder x-ray diffraction pattern of dimebon dihydrochloride anhydrous Form A.
  • Figure 5 depicts the ssNMR carbon spectrum of dimebon dihydrochloride anhydrous Form A.
  • Figure 6 depicts the powder x-ray diffraction pattern of dimebon dihydrochloride Form B hemi-hydrate.
  • Figure 7 depicts the ssNMR carbon spectrum of dimebon dihydrochloride
  • Figure 8 depicts the powder x-ray diffraction pattern of dimebon dihydrochloride Form C monohydrate.
  • Figure 9 depicts the ssNMR carbon spectrum of dimebon dihydrochloride
  • Figure 10 depicts the powder x-ray diffraction pattern of dimebon dihydrochloride Form D dihydrate
  • Figure 11 depicts the ssNMR carbon spectrum of dimebon dihydrochloride
  • Figure 12 depicts the powder x-ray diffraction pattern of amorphous dimebon dihydrochloride.
  • Figure 13 depicts the ssNMR carbon spectrum of amorphous dimebon dihydrochloride. The peaks marked by asterisks are spinning sidebands.
  • Figure 14 depicts the powder x-ray diffraction pattern of dimebon dihydrochloride Form F trihydrate
  • Figure 15 depicts the ssNMR carbon spectrum of dimebon dihydrochloride
  • Form F trihydrate The peaks marked by asterisks are spinning sidebands.
  • Non-commercial MVP refers to MVP that is not obtained directly from a commercial source and is not purified from commercially available MVP.
  • Non-commercial MVP may be produced in situ from an MVP precursor or can be prepared just prior to use from an MVP precursor by a variety of methods, such as but not limited to those shown in Scheme 1 below.
  • X and Y halo or pseudohalo group (e.g., a triflate); the X or Y that is not a halo or pseudohalo group is a metal such as tributyltin or boric acid.
  • an MVP precursor 5-(l-chloroethyl)-2- methylpyridine (3)
  • l-(6-methylpyridin-3-yl)ethanol (1) in any form (e.g., can be a salt form such as by addition of maleic acid (2)), under appropriate reaction conditions and can generate MVP under appropriate reaction conditions, such as in the presence of KOH or NaOH and a THF or NMP solvent.
  • reaction (II) of Scheme 1 dehydration of an MVP precursor, l-(6-methylpyridin-3-yl)ethanol (1) or 2-(6- methylpyridin-3-yl)ethanol (5), under appropriate reaction conditions provides MVP (4) (2- methyl-5-vinylpyridine, 5-ethenyl-2-methyl-pyridine, or 5-vinyl-2-picoline).
  • reaction (III) of Scheme 1 e.g., 5-halo-2-methylpyridine or a like compound is coupled under appropriate reaction conditions to an appropriately substituted vinyl group to provide MVP (4). Other methods for production are possible.
  • an MVP precursor may be converted to MVP in a batch-wise or continuous process and the resultant product mixture may be reacted directly with a carboline to provide a pyridylethyl- substituted carboline. If desired, purification or removal of impurities from the reaction product mixture may be conducted. However, MVP can be used without isolation and storage beyond typical processing times.
  • MVP that is prepared in the presence of a carboline or carboline precursor is prepared in situ. For instance, if an MVP precursor and a carboline or carboline precursor are in the same reaction vessel and MVP is generated from the MVP precursor and is available for reaction with the carboline or carboline precursor in the same reaction vessel, the MVP is deemed generated in situ. However, if MVP is prepared from an MVP precursor not in the presence of a carboline or carboline precursor, such as when MVP is prepared in one reaction vessel and is then added to a different reaction vessel for reaction with a carboline or carboline precursor or a carboline or carboline precursor is added to the reaction vessel containing the MVP so produced, the MVP is said to be prepared just prior to use.
  • MVP in situ generation of MVP or preparation of MVP just prior to use
  • a carboline such as a tetrahydro-gamma-carboline
  • Carbolines and carboline precursors may be obtained commercially or prepared according to existing synthetic methods or those detailed herein.
  • a particular carboline used in the preparation of dimebon and salts and solvates thereof is 2,8-dimethyl-2,3,4,5,-tetrahydro-lH-pyrido[4,3-b]indole shown in Scheme 2 below as compound (8).
  • the carboline (8) is prepared by reaction of p- tolylhydrazine with l-methyl-4-piperidone. Alternative methods may also be used.
  • Preparations of pyridylethyl- substituted carbolines are exemplified by the preparation of dimebon.
  • Alkylation of carboline (8) with MVP obtained commercially, generated in situ, or generated just prior to use provides dimebon as a free base (treatment of a free base of dimebon with HCl in acetone provides dimebon dihydrochloride in the dihydrate form; see Example 7 below).
  • Carboline»HCl can be converted to the free base for reaction with MVP, or additional base can be added to the reaction mixture to avoid the additional step of converting the carboline to the free base.
  • Improved methods of making pyridylethyl- substituted carbolines under reaction conditions that use fewer molar equivalents of MVP to produce the pyridylethyl- substituted carboline as compared to reported methods of preparing pyridylethyl-substituted carbolines using MVP are provided by this invention.
  • the improved process preferably achieves a similar yield to that reported in the literature, but uses fewer equivalents of MVP, preferably about 4 equivalents of MVP or fewer than 4 equivalents of MVP, more preferably about 3 equivalents of MVP or fewer than about 3 equivalents of MVP, still more preferably about 2 equivalents of MVP or fewer than about 2 equivalents of MVP.
  • the improved processes of this invention are characterized primarily by careful matching of solvent and base for the addition of vinylpyridines to carbolines.
  • the new methods of synthesis detailed herein use lower amounts of base, such as 1.3 to 2, 1.5 to 2, or 1.5 to 3 equivalents of bases such as KOH and K 3 PO 4 while also reducing the number of equivalents of MVP needed for the reaction.
  • This process works with MVP, including MVP obtained from commercial sources, or with non-commercial MVP, such as MVP that has been prepared just prior to use.
  • Examples of compatible solvents, bases, and temperatures, and the resulting reduced amount of MVP required for reaction are given in the following table.
  • the invention also encompasses salts of the compounds generated by the methods detailed herein.
  • the invention embraces a method of preparing dimebon or a salt thereof, including but not limited to the dimebon dihydrochloride salt.
  • Other salts are also embraced by the invention, such as a monophosphate salt of dimebon.
  • Solvates, in particular hydrates, of the compounds and salts thereof are also embraced.
  • the invention embraces a method of preparing dimebon, a dimebon salt or a solvate of the foregoing, such as the monohydrate, dihydrate or trihydrate.
  • a method of preparing the dihydrate of dimebon dihydrochloride is provided. Dimebon dihydrochloride dihydrate is thus embraced by this invention, as are methods of making and using it.
  • dosage forms of compounds prepared by the methods detailed herein are contemplated, including unit dosage forms prepared with a therapeutically effective amount of compound.
  • unit dosage form refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.
  • the dosages can be formulated as controlled release formulations.
  • Controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a "controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool.
  • the term encompasses depot formulations designed to gradually release the drug compound over an extended period of time.
  • Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).
  • any of the compounds disclosed herein, or combinations thereof, can also be combined with a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, pharmacologically acceptable carrier or pharmacologically acceptable excipient.
  • pharmaceutically acceptable carrier pharmaceutically acceptable excipient
  • pharmaceutically acceptable carrier pharmaceutically acceptable excipient
  • pharmaceutically acceptable carrier pharmaceutically acceptable carrier
  • pharmaceutically acceptable excipient pharmaceutically acceptable carrier
  • pharmaceutically acceptable excipient have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • any of the compounds disclosed herein, or combinations thereof, can also be formulated as a pharmaceutically acceptable salt or salts.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
  • a pharmaceutically acceptable salt intends ionic interactions and not a covalent bond. As such, an N-oxide is not considered a salt.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Further examples of pharmaceutically acceptable salts include those listed in Berge et al, Pharmaceutical Salts, J. Pharm. ScL 1977 Jan;66(l):l-19.
  • Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • carrier or "excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • carrier or excipient including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • Compounds prepared by the methods detailed herein may find use in the treatment and/or prevention of a neurodegenerative or other disease or may find use as an antihistamine.
  • dimebon and salts thereof and hydrates of the foregoing prepared by the methods detailed herein may be used in the treatment and/or prevention of Alzheimer's disease, Huntington's disease, canine cognitive dysfunction syndrome, ALS, schizophrenia, ischemia/reperfusion injury of the brain, mild cognitive impairment and in methods of slowing aging in a mammal or methods of slowing the aging of a cell, tissue, or organ. They may be administered alone or in combination with other active agents.
  • the examples provided below illustrate but are not intended to limit the invention. Various modifications to the experimental conditions reported below may be made. For example, the reactions may proceed with different reactant ratios, solvents, temperature, etc. In addition, the invention embraces modifications to the reaction conditions that accompany scale-up to production quantities of drug.
  • WBu 3 MgLi was prepared by treating ⁇ Bu 2 Mg (1 equiv.) in THF (2 vol.) with wBuLi (0.5 equiv.) at 0 0 C. 3-bromopicoline in THF (2 vol.) was then added, maintaining temperature between -10 and 0 0 C, and allowed to stir for 30 minutes forming the "ate" complex. Acetaldehyde (5 or preferably 3 equiv.) in THF (2 vol.) was added to the "ate” complex and the reaction was complete within one hour. The reaction was quenched with a base such as 2N NaOH and partially concentrated under reduced pressure.
  • a base such as 2N NaOH
  • 1-Pyridylethanol in any suitable form such as but not limited to a salt such maleic acid salt, was extracted with isopropyl acetate (IPAC) and azeotropically dried prior to the addition of maleic acid in methanol.
  • IPAC isopropyl acetate
  • the solution was heated to 40 0 C for 1 hour and diluted with IPAC.
  • the maleate salt was filtered and washed with IPAC to give the maleate salt in 55% yield and in high purity by 1 H-NMR.
  • the active magnesate species may be further modified by using wBuMgCl (1 equiv) and MeLi (2 equiv) to give «BuMe2MgLi, which increased yield to 80-85% and gave a colorless maleate salt.
  • IPAC solution was concentrated under reduced pressure, azeotropically removing water, and re-diluted to 2.5 volumes.
  • the 1-pyridylethanol solution was slowly added to a mixture of SOCl 2 (1.5 equiv) in IPAC (2.5 vol.).
  • the reaction was diluted with 2N NaOH, phases separated, and the chloride in IPAC is solvent swapped into NMP (4.2 vol.) and 3.5 equiv. of KOH was added.
  • the elimination to MVP was complete. MVP was obtained in high yield and purity by 1 H-NMR.
  • Reaction completion for the MVP formation is preferably driven to >99% to avoid reaction by-product in subsequent steps via reaction of the intermediate chloride with a carboline, which by-products can be purged via crystallization.
  • Example 3 Preparation of 2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole hydrochloride (8)
  • IPA (20 vol.) at 40 0 C provided the hydrazone intermediate within 1 hour.
  • the solution was treated with HCl and the Carboline «HCl (8) precipitates.
  • the salt was filtered and washed with IPA/MTBE.
  • Carboline»HCl (8) was obtained in good yield with > 99% AUC purity.
  • Carboline free base (10) and K 3 PO 4 (5 mol equiv, 2.6 wt. equiv) were charged to a reactor and purged with nitrogen. Then, DMAC (5 vol, 3.749 wt. equiv) followed by MVP (1.75 mol. equiv, 1.04 wt. equiv) were added and the resulting slurry was stirred at 100 0 C for 24h. The temperature was then adjusted to 40-60 0 C and water (23.5 vol, 23.5 wt. equiv) was slowly added over Ih. The mixture was cooled to RT and stirred for 2 hours. The slurry was filtered off and the resulting solid was washed with water (5 vol, 5 wt. equiv), dried in the oven at 5O 0 C under vacuum for 16h. Dimebon free base is obtained in 80% isolated yield.
  • Example 8 Various coupling conditions for carboline and methylvinylpyridine [00106] The coupling reaction of carboline with methylvinylpyridine was run under various conditions of solvent and temperature, using different bases and equivalents of MVP as indicated in the following table.
  • Table 1 compares carbon chemical shifts (ppm, referenced to external sample of solid phase adamantane at 29.5 ppm) observed for Dimebon Dihydrochloride anhydrous Form A, Form B hemi-hydrate, Form C monohydrate, Form D dihydrate, Form F trihydrate, and amorphous. Characteristic sets of peaks for each form which can be used to distinguish each form from the remaining forms are listed in bold italics. An asterisk (*) next to a chemical shift indicates a peak shoulder.
  • Table 2 lists sets of carbon chemical shifts (ppm, referenced to external sample of solid phase adamantane at 29.5 ppm) to uniquely ( ⁇ 0.2 ppm) define dimebon dihydrochloride anhydrous Form A, Form B hemi-hydrate, Form C monohydrate, Form D dihydrate, Form F trihydrate, and amorphous.
  • Example 1OA Preparation, powder x-ray diffraction, and ssNMR of anhydrous
  • Solid-state NMR Instrument Method Approximately 80 mg of sample were tightly packed into a 4 mm ZrO 2 rotor. A rotor cap fitted with O-rings was used to seal the rotor. Spectra were collected at ambient pressure on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide -bore Bruker-Biospin Avance DSX 500 MHz ( 1 H frequency) NMR spectrometer. The sample was cooled with a direct stream of nitrogen onto the rotor having an output temperature of 10°C at a flow rate of 1200 liters/hour. The packed rotor was oriented at the magic angle and spun at 15.0 kHz.
  • the 13 C solid state spectrum was collected using a proton decoupled cross-polarization magic angle spinning experiment (CPMAS).
  • CPMAS proton decoupled cross-polarization magic angle spinning experiment
  • the cross-polarization contact time was set to 2.0 ms.
  • a proton decoupling field of approximately 85 kHz was applied.
  • 28,672 scans were collected with recycle delay of 3.25 seconds.
  • the carbon spectrum ( Figure 5) was referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm; see Table 5 below.
  • Example 1OB Preparation, powder x-ray diffraction, and ssNMR for Dimebon
  • Method 1 Approximately 60 mg of dimebon dihydrochloride dihydrate was placed in a 4 mL glass scintillation vial. 2 mL of ethanol was added and solution was capped and stirred. All solid dissolved therefore more solid was added until solution was saturated. Solution was capped and stirred for 7 days under ambient conditions. Solid was recovered from solution using centrifugal filtration in microcentrifuge tubes equipped with 0.45 ⁇ m nylon filter membrane inserts. Filtrand was dried in a 55 0 C vacuum oven for approximately 45 minutes. Solid was analyzed using PXRD and was form B. Filtrate was returned to glass vial and approximately 30 to 75 mg more dimebon dihydrochloride was added. Solution was capped and stirred under ambient conditions for 23 days. Solid was collected using vacuum filtration on a 0.45 ⁇ m PTFE membrane filter. Sample was identified as Form B using PXRD.
  • Solid-state NMR Instrument Method Approximately 80 mg of sample were tightly packed into a 4 mm ZrO 2 rotor. A rotor cap fitted with O-rings was used to seal the rotor. Spectra were collected at ambient pressure on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide -bore Bruker-Biospin Avance DSX 500 MHz ( 1 H frequency) NMR spectrometer. The sample was cooled with a direct stream of nitrogen onto the rotor having an output temperature of 10°C at a flow rate of 1200 liters/hour. The packed rotor was oriented at the magic angle and spun at 15.0 kHz.
  • the 13 C solid state spectrum was collected using a proton decoupled cross-polarization magic angle spinning experiment (CPMAS).
  • CPMAS proton decoupled cross-polarization magic angle spinning experiment
  • the cross-polarization contact time was set to 2.0 ms.
  • a proton decoupling field of approximately 85 kHz was applied.
  • 5,120 scans were collected with recycle delay of 4.0 seconds.
  • the carbon spectrum ( Figure 7 and Table 8) was referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm.
  • Solid-state NMR Instrument Method Approximately 80 mg of sample were tightly packed into a 4 mm ZrO 2 rotor. A rotor cap fitted with O-rings was used to seal the rotor. Spectra were collected at ambient pressure on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide -bore Bruker-Biospin Avance DSX 500 MHz ( 1 H frequency) NMR spectrometer. The sample was cooled with a direct stream of nitrogen onto the rotor having an output temperature of 10°C at a flow rate of 1200 liters/hour. The packed rotor was oriented at the magic angle and spun at 15.0 kHz.
  • the 13 C solid state spectrum was collected using a proton decoupled cross-polarization magic angle spinning experiment (CPMAS).
  • CPMAS proton decoupled cross-polarization magic angle spinning experiment
  • the cross-polarization contact time was set to 2.0 ms.
  • a proton decoupling field of approximately 85 kHz was applied.
  • 4,352 scans were collected with recycle delay of 9.7 seconds.
  • the carbon spectrum ( Figure 9 and Table 11) was referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm.
  • Example 10D Preparation, powder x-ray diffraction, and ssNMR for Dimebon
  • Solid-state NMR Instrument Method Approximately 80 mg of sample were tightly packed into a 4 mm ZrO 2 rotor. A rotor cap fitted with O-rings was used to seal the rotor. Spectra were collected at ambient pressure on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide -bore Bruker-Biospin Avance DSX 500 MHz ( 1 H frequency) NMR spectrometer. The sample was cooled with a direct stream of nitrogen onto the rotor having an output temperature of 10°C at a flow rate of 1200 liters/hour. The packed rotor was oriented at the magic angle and spun at 15.0 kHz.
  • the 13 C solid state spectrum was collected using a proton decoupled cross-polarization magic angle spinning experiment (CPMAS).
  • CPMAS proton decoupled cross-polarization magic angle spinning experiment
  • the cross-polarization contact time was set to 2.0 ms.
  • a proton decoupling field of approximately 85 kHz was applied.
  • 5,120 scans were collected with recycle delay of 4.2 seconds.
  • the carbon spectrum ( Figure 11 and Table 14) was referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm.
  • Example 1OE Preparation, powder x-ray diffraction, and ssNMR for amorphous
  • Example 1OF Preparation, powder x-ray diffraction, and ssNMR for Dimebon
  • Solid-state NMR Instrument Method Approximately 80 mg of sample were tightly packed into a 4 mm ZrO 2 rotor. A rotor cap fitted with O-rings was used to seal the rotor. Spectra were collected at ambient pressure on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide -bore Bruker-Biospin Avance DSX 500 MHz ( 1 H frequency) NMR spectrometer. The sample was cooled with a direct stream of nitrogen onto the rotor having an output temperature of 10°C at a flow rate of 1200 liters/hour. The packed rotor was oriented at the magic angle and spun at 15.0 kHz.
  • the 13 C solid state spectrum was collected using a proton decoupled cross-polarization magic angle spinning experiment (CPMAS).
  • CPMAS proton decoupled cross-polarization magic angle spinning experiment
  • the cross-polarization contact time was set to 2.0 ms.
  • a proton decoupling field of approximately 85 kHz was applied.
  • 4,352 scans were collected with recycle delay of 2.0 seconds.
  • the carbon spectrum ( Figure 15 and Table 18) was referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm. Table 16.

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Abstract

L'invention concerne des procédés de préparation de carbolines substituées par pyridyléthyle dans des conditions de réaction qui utilisent moins d'équivalents molaires de MVP pour produire la carboline substituée par pyridyléthyle par comparaison aux procédés cités consistant à préparer des carbolines substituées par pyridyléthyle utilisant MVP. L'invention concerne également des procédés de préparation de carboline substituée par pyridyléthyle utilisant du MVP non commercial.
PCT/US2009/035992 2008-03-04 2009-03-04 Procédés pour préparer des carbolines substituées par pyridyléthyle Ceased WO2009111540A1 (fr)

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