WO1998022110A1 - Promedicaments pour l'inhibition selective de la monoamine oxydase-b - Google Patents

Promedicaments pour l'inhibition selective de la monoamine oxydase-b Download PDF

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Publication number
WO1998022110A1
WO1998022110A1 PCT/US1997/021230 US9721230W WO9822110A1 WO 1998022110 A1 WO1998022110 A1 WO 1998022110A1 US 9721230 W US9721230 W US 9721230W WO 9822110 A1 WO9822110 A1 WO 9822110A1
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WO
WIPO (PCT)
Prior art keywords
mao
prodrug
activity
methyl
chemical structure
Prior art date
Application number
PCT/US1997/021230
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English (en)
Inventor
Neal Castagnoli, Jr.
Patrick Flaherty
Kay Castagnoli
You-Xiong Wang
Original Assignee
Virginia Tech Intellectual Properties, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Virginia Tech Intellectual Properties, Inc. filed Critical Virginia Tech Intellectual Properties, Inc.
Publication of WO1998022110A1 publication Critical patent/WO1998022110A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

Definitions

  • the present invention is generally related to pharmaceuticals used in central nervous system applications, and, more particularly to prodrugs targeted to the brain
  • the excellent monoamine oxidase-B (MAO-B) substrate properties of the Parkinsonian inducing cyclic tertiary allylamine l-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (1VLPTP) (Identified as 1 in Reaction Scheme 1 below) have led to extensive structure-enzyme substrate activity studies on a variety of related tetrahydropyridine derivatives
  • the reaction pathway involves initial -carbon oxidation to yield the dihydropyridinium species MPDP+ (2) which, following subsequent oxidation, is converted to the neurotoxic l-methyl-4-phenylpyridinium species MPP+ (3) (Scheme 1, path a)
  • the 4- phenoxy analog, l-methyl-4-phenoxy-l,2,3,6-tetrahydropyridine (Identified as 4 in Scheme 1 below), proved to be a better MAO-B substrate than MPTP, but was not toxic in vivo, presumably because the intermediary dihydropyridinium
  • Reaction scheme 3 shows the bioactivation pathway for tetrahydropyridyl carbamates.
  • a carbamate linkage (13) is employed to circumvent the hydrolytic instability of the enamine functionality that results from direct attachment of the amino group and the tetrahydropyridyl carrier.
  • the MAO catalyzed oxidation of (13) generates the dihydropyridinium intermediate (14) which, following 1,4-hydrolytic cleavage and decarboxylation of the resulting carbamic acid (15), releases the amine drug (12).
  • novel tetrahydropyridyl derivatives of chiral drugs have been synthesized. These drugs fall into two classes.
  • the first class includes tetrahydropyridyl carbamate derivatives where the nitrogen is a primary or secondary amine containing an alkyl moiety with a chiral center.
  • the tetrahydropyridyl carbamate derivative of nordeprenyl has been synthesized.
  • Experiments have demonstrated that under some circumstances the (R)- enantiomer is as effective as (R)-de ⁇ renyl in inhibiting brain MAO-B activity with complete retention of the brain MAO- A activity.
  • the (R)-carbamate provided neuroprotection against MPTP toxicity.
  • the second class includes tetrahydropyridyl phosphorodiamidates. These compounds were shown to be stable in the presence of MAO-B, but proved to be MAO-A substrates, which makes them useful for the selective release of phosphoramide mustards in certain applications (e.g., anti-tumor agents).
  • Figure la is a graph showing the linear relationship between the absorbance at 420 nm and the concentration of the synthetic l-methyl-4-(l- methyl-2-pyrryl)-2, 3 -dihydropyridinium perchlorate;
  • Figure lb is a graph showing the linear production over time of 1- methyl-4-(l-methyl-2-pyrryl)-2,3-dihydropyridinium metabolite following a thirty minute pre-incubation at 37 °C in the presence of mouse brain mitochondrial membranes.
  • one embodiment of the invention is directed to a novel prodrug which is a tetrahydropyridyl carbamate derivative
  • THP refers to the l-methyl-4-(l,2,3,6- tetrahydropyridyl) group.
  • R deprenyl
  • PD Parkinson's disease
  • the prodrug approach of this invention involving the selective release of the active agent in the central nervous system might help to circumvent mortality problems encountered in PD patients.
  • the (S)-tetrahydropyridyl carbamate derivative (S)-( 16) of (S)-nordeprenyl ((S)- 17) has also been synthesized and has been used to demonstrate the effect the configuration has on the interactions of the prodrug with MAO-A and MAO-B.
  • the nitrogen can be a primary or secondary amine and where at least one of R, and R 2 is an organic moiety containing at least one chiral center
  • R, and R 2 is an organic moiety containing at least one chiral center
  • the nitrogen is a primary amine
  • one of R, and R 2 is a hydrogen
  • R, or R 2 can very widely depending on the drug which is to be delivered
  • the drug could include ethers, esters, amino groups, thio groups, halogens, etc
  • R, and R 2 can be connected by an alkyl, heteroalkyl, aryl, or heteroaryl moiety which encompasses both R, and R 2 and the nitrogen atom
  • Examples of certain drugs within the class contemplated by this invention include those specified in Formula Set 2
  • a second embodiment of this invention contemplates the formation and use of certain chiral tetrahydropyridyl phosphorodiamidates. These compounds are defined by the structure:
  • R, and R 2 are amino groups.
  • Rj is N(CH 2 CH 2 C1) 2 and R 2 is either NH 2 or NHCH 2 C 6 H 5 .
  • THP l-methyl-4-(l,2,3,6- tetrahydrophyridinyl) group
  • the THP provides for targeted delivery to tissues rich in MAO, including the brain, the spinal chord, tumors, etc.
  • the Examples below describe the synthesis, enzymatic testing, and in vivo neuroprotection afforded by these compounds.
  • the compounds of this invention can be incorporated into sterile solutions or dispersions for delivery by injection or oral routes, or be incorporated into a powder for preparation of sterile solutions.
  • the compounds may be formulated for aerosol delivery as a dry powder or in combination with suitable CFC or HFC propellants.
  • transdermal and transmucosal and other delivery routes may also be employed.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, or oils (e.g., vegetable oils).
  • the prevention of the action of microorganisms can be achieved using various antibacterial and antifungal agents, for example, parabens, chlorobuntanol, phenol, sorbic acid, thimerosal, and the like. In some cases isotonic agents could be included such as sugars and sodium chloride.
  • the compounds of this invention can be combined with any "pharmaceutically acceptable carrier" including any and all solvents, dispersion media, coatings, antibacteria and antifungal agents, buffers, isotonic agents, and the like. Except insofar as any conventional media or agent is incompatible with the active ingredient (e.g., the THP derivative), its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • GC-EIMS Gas chromatography electron-ionization mass spectrometry
  • HP Hewlett-Packard
  • HP-1 fused silica capillary column (12 m x 0.2 mm, 0.33 ⁇ m film thickness) connected to an HP 5870 mass selective detector.
  • Data were acquired on an HP 5970 ChemStation.
  • Helium was employed as the carrier gas (40 mL/min) and oven parameters were 100°C for one minute followed by
  • High resolution chemical ionization mass spectrometry was performed on a VG 7070 HF instrument. Melting points were determined with a Thomas-Hoover melting point apparatus and are uncorrected. Elemental analyses, performed by Atlantic Microlabs of Norcross, GA, were within 0.4% of the theoretical values calculated for C, H and N.
  • Reaction Scheme 4 sets forth the synthetic route used to synthesize the tetrahydropyridyl carbamates (R)-(16) and (S)-(16). It should be understood by those skilled in the art that the prodrug (R)-(16) of this invention could be made by other synthetic pathways, and that the quantities of reactants used in the synthesis procedures set forth below are for laboratory purposes, and can vary considerably depending on production scale-up or the like.
  • MAO-A and MAO-B were prepared from human placenta and bovine liver, respectively, according to the method of Salach (Salach, Meth. in Enzymol, 142 627-637 (1987)) with the following variations
  • the phospholipase A was obtained commercially (Sigma, St Louis, MO) rather than from the crude venom
  • the MAO-A preparation was not subjected to the sephadex purification step and the MAO-B preparation was not subjected to the gradient purification step
  • mice 25-35 g, Harlan, Dublin, VA were housed 1-6 per cage in the Laboratory Animal Resource facility at 21-23 °C with free access to standard laboratory chow and tap water on a 12 hour day/night cycle. All compounds were dissolved in sterile saline and injections were administered intraperitoneally in a volume of 100 ⁇ L.
  • (S)-Tetrahydropyridyl Carbamate Studies were performed in a volume of 100 ⁇ L.
  • the MAO-A and MAO-B substrate properties of the (R)- and (S)-carbamates at 1 mM were examined spectrophotometrically by recording repeated scans (500 to 250 ran) over a 120 minute incubation period. No new chromophore was detected during the incubations with MAO-B. This behavior is consistent with previous results showing the lack of MAO-B substrate properties of related tetrahydropyridyl carbamates (see, Zhao et al, J. Med. Chem. 35:4473-4478(1992)).
  • the prodrug configuration of the present invention which utilizes host systems to release (R)-nordeprenyl, may have enhanced utility in the treatment of Parkinson's disease or other disorders in the central nervous system and avoid mortality problems encountered with (R)- deprenyl
  • the prodrug properties observed with the R-carbamate will lead to the selective inhibition of brain MAO-B activity with a sparing of peripheral MAO-B activity
  • the (R)-(l 6) carbamate can be administered by a variety of routes including i.v , i.p., subcutaneous, i.m , oral, sublingual, suppository, etc , and can be combined with a variety of carrier fluids such as saline, oils, elixirs, emulsions, etc., or solids such as lactose, lozenges, etc.
  • carrier fluids such as saline, oils, elixirs, emulsions, etc., or solids such as lactose, lozenges, etc
  • the Parkinson disease patient, or other patient that would benefit from selective inhibition of MAO-B would be administered a quantity of (R)-( 16) sufficient to selectively inhibit brain MAO-B activity for a desired period of time EXAMPLE 2
  • DA Dopamine
  • mice C57BL/6 male retired breeder mice (25 - 35 g; Harlan/Sprague Dawley) were housed 1/cage in the Laboratory Animal Resource Facility at 21-23° C with free access to standard laboratory chow and tap water on a 12 h day/night cycle. All compounds were dissolved in sterile saline, and injections were administered intraperitoneally in a volume of 0.15,
  • Prodrug groups Animals received one injection of the (R)- carbamate as the oxalate salt (5mgKg, 15 mg/Kg, 30 mg/Kg, or 50 mg/Kg) on days 1, 2 and 3, followed on day 3 at 1 h post treatment with MPTP-HCl (40 mg/Kg); MPTP only group (M): Animals received sterile saline days 1, 2 and 3, followed on day 3 at 1 h post treatment with MPTP-HCl (40 mg/Kg); Control Animals (C): Control animals received sterile saline only. Seven days post MPTP treatment, animals were sacrificed by cervical dislocation and the striata were dissected on ice. Ten ⁇ L IS in 5% trichloroacetic acid was added per mg striata.
  • Tetrahydropyridyl phosphorodiamidates are synthesized according to the general synthesis scheme 6:
  • R, and R 2 are substituted amine moieties and can be either pnmary or secondary amines
  • One compound according this aspect of the invention has R j as N(CH 2 CH 2 C1) 2 and R 2 as NHCH 2 C 6 H 5 The synthesis of this compound is set forth below

Abstract

La présente invention relate l'identification de cellules ciblant des promédicaments riches en monoamine oxydase (MAO) telles que celles trouvées dans le système nerveux central. Ces composés sont des médicaments chiraux ou des produits cytotoxiques qui ont été dérivatisés avec un groupe 1-méthyl-4-(1,2,3,6-tétrahydropyridinyle)(THP). Des essais ont montré que certains composés de la classe présentent une inhibition sélective de la monoamine-oxydase-B mitochondriale du cerveau.
PCT/US1997/021230 1996-11-20 1997-11-19 Promedicaments pour l'inhibition selective de la monoamine oxydase-b WO1998022110A1 (fr)

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US3143996P 1996-11-20 1996-11-20
US60/031,439 1996-11-20

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1178034A1 (fr) * 2000-08-01 2002-02-06 Warner-Lambert Company Dérivés alkyle d'aminoacides comme agents thérapeutiques
WO2005019163A2 (fr) 2003-08-20 2005-03-03 Xenoport, Inc. Prodrogues a base de carbamate d'alkyle acyle, procede de synthese et utilisation
EP1906952A1 (fr) * 2005-07-01 2008-04-09 Jenrin Discovery Inhibiteurs mao-b utiles dans le traitement de l obésité
EP2354120A1 (fr) 2003-08-20 2011-08-10 XenoPort, Inc. Synthèse de promédicaments a base de carbamate d'acyloxyalkyle et leurs intermédiaires
WO2013151584A1 (fr) * 2011-10-31 2013-10-10 The Methodist Hospital Research Institute Composé comprenant un fragment de ciblage/recherche de mao pour le traitement de gliomes humains
US20220298150A1 (en) * 2021-03-18 2022-09-22 Supernus Pharmaceuticals, Inc. Derivatives of substituted morpholines and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4251538A (en) * 1978-06-24 1981-02-17 Merck Patent Gesellschaft Mit Beschrankter Haftung Indolealkylamines and processes for their preparation
US4301168A (en) * 1978-09-09 1981-11-17 Beecham Group Limited Tetrahydropyridyl derivatives of clavulanic acid, a process for their preparation and their use
US4338445A (en) * 1979-08-31 1982-07-06 Canadian Patents & Development Limited N-(Carbonylamino)-tetrahydropyridyl derivatives
US5627169A (en) * 1994-07-20 1997-05-06 The Regents Of The University Of California Selective antagonists for GABArho receptor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4251538A (en) * 1978-06-24 1981-02-17 Merck Patent Gesellschaft Mit Beschrankter Haftung Indolealkylamines and processes for their preparation
US4301168A (en) * 1978-09-09 1981-11-17 Beecham Group Limited Tetrahydropyridyl derivatives of clavulanic acid, a process for their preparation and their use
US4338445A (en) * 1979-08-31 1982-07-06 Canadian Patents & Development Limited N-(Carbonylamino)-tetrahydropyridyl derivatives
US5627169A (en) * 1994-07-20 1997-05-06 The Regents Of The University Of California Selective antagonists for GABArho receptor

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1178034A1 (fr) * 2000-08-01 2002-02-06 Warner-Lambert Company Dérivés alkyle d'aminoacides comme agents thérapeutiques
US9944592B2 (en) 2003-08-20 2018-04-17 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
US7300956B2 (en) 2003-08-20 2007-11-27 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
WO2005019163A2 (fr) 2003-08-20 2005-03-03 Xenoport, Inc. Prodrogues a base de carbamate d'alkyle acyle, procede de synthese et utilisation
EP2354120A1 (fr) 2003-08-20 2011-08-10 XenoPort, Inc. Synthèse de promédicaments a base de carbamate d'acyloxyalkyle et leurs intermédiaires
US7572830B2 (en) 2003-08-20 2009-08-11 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
US7109239B2 (en) 2003-08-20 2006-09-19 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
EP1906952A4 (fr) * 2005-07-01 2010-04-14 Jenrin Discovery Inhibiteurs mao-b utiles dans le traitement de l obésité
US7956220B2 (en) 2005-07-01 2011-06-07 Jenrin Discovery MAO-B inhibitors useful for treating obesity
EP1906952A1 (fr) * 2005-07-01 2008-04-09 Jenrin Discovery Inhibiteurs mao-b utiles dans le traitement de l obésité
CN104136026B (zh) * 2011-10-31 2018-03-02 卫理公会医院研究所 包含mao靶向/探寻器部分的人神经胶质瘤治疗用化合物
CN104136026A (zh) * 2011-10-31 2014-11-05 卫理公会医院研究所 包含mao靶向/探寻器部分的人神经胶质瘤治疗用化合物
WO2013151584A1 (fr) * 2011-10-31 2013-10-10 The Methodist Hospital Research Institute Composé comprenant un fragment de ciblage/recherche de mao pour le traitement de gliomes humains
US10555936B2 (en) 2011-10-31 2020-02-11 The Methodist Hospital Chemotherapeutic compositions and methods for treating human gliomas
EP3815685A3 (fr) * 2011-10-31 2021-10-13 The Methodist Hospital Research Institute Composé comprenant un fragment de ciblage/recherche de mao pour le traitement de gliomes humains
US20220298150A1 (en) * 2021-03-18 2022-09-22 Supernus Pharmaceuticals, Inc. Derivatives of substituted morpholines and uses thereof
US11634415B2 (en) * 2021-03-18 2023-04-25 Supernus Pharmaceuticals, Inc. Derivatives of substituted morpholines and uses thereof
US11919889B2 (en) 2021-03-18 2024-03-05 Supernus Pharmaceuticals, Inc. Derivatives of substituted morpholines and uses thereof

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