US20130197031A1 - Deuterated analogs of pridopidine useful as dopaminergic stabilizers - Google Patents

Deuterated analogs of pridopidine useful as dopaminergic stabilizers Download PDF

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Publication number
US20130197031A1
US20130197031A1 US13/820,024 US201113820024A US2013197031A1 US 20130197031 A1 US20130197031 A1 US 20130197031A1 US 201113820024 A US201113820024 A US 201113820024A US 2013197031 A1 US2013197031 A1 US 2013197031A1
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pharmaceutically acceptable
deuterium
acceptable salt
deuterated analog
represent hydrogen
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US13/820,024
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Clas Sonesson
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Teva Pharmaceuticals International GmbH
NSAB Filial af Neurosearch Sweden AB
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Ivax International GmbH
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Assigned to IVAX International GmbH reassignment IVAX International GmbH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NSAB, FILIAL AF NEUROSEARCH SWEDEN AB, SVERIGE
Assigned to NSAB, FILIAL AF NEUROSEARCH SWEDEN AB, SVERIGE reassignment NSAB, FILIAL AF NEUROSEARCH SWEDEN AB, SVERIGE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SONESSON, CLAS
Publication of US20130197031A1 publication Critical patent/US20130197031A1/en
Assigned to TEVA PHARMACEUTICALS INTERNATIONAL GMBH reassignment TEVA PHARMACEUTICALS INTERNATIONAL GMBH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: IVAX International GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/24—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Definitions

  • the present invention provides novel deuterated analogs of Pridopidine, i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine.
  • Pridopidine is a drug substance currently in clinical development for the treatment of Huntington's disease.
  • the invention relates to pharmaceutical compositions comprising a deuterated analog of Pridopidine of the invention, and to therapeutic applications of these analogs.
  • Deuterium also called “heavy hydrogen” is a stable isotope of hydrogen with a natural abundance in the oceans of Earth of approximately one atom in 6,500 of hydrogen ( ⁇ 154 ppm). Deuterium thus accounts for approximately 0.0154% (alternately, on a mass basis: 0.0308%) of all naturally occurring hydrogen in the oceans on Earth.
  • the nucleus of deuterium called a deuteron, contains one proton and one neutron, whereas the hydrogen nucleus contains no neutron.
  • Deuterium forms bonds with carbon that vibrate at a lower frequency and are thus stronger than C—H bonds. Therefore “heavy hydrogen” versions of drugs may be more stable towards degradation and last longer in the organism. Incorporating deuterium in place of hydrogen thus may improve the pharmacodynamic and pharmacokinetic profiles of drugs, thus modifying the metabolic fate, while retaining the pharmacologic activity and selectivity of physiologically active compounds. Deuterated drugs thus may positively impact safety, efficacy and/or tolerability.
  • Pridopidine i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, a dopaminergic stabilizer currently in clinical development for the treatment of Huntington's disease.
  • the compound is described in e.g. WO 01/46145, and in e.g. WO 2006/040155 an alternative method for its synthesis is described.
  • the object of the present invention is to provide analogs of Pridopidine with improved pharmacodynamic and pharmacokinetic profiles.
  • the invention provides a partially or fully deuterated analog of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine as represented by Formula 1, below.
  • the invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a deuterated analog of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.
  • the invention relates to the use of the deuterated analog of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine of the invention as a medicament, or for the manufacture of a medicament.
  • the invention provides a method for treatment, prevention or alleviation of a dopamine mediated disorder of a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a deuterated analog of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine according to the invention, or a pharmaceutically acceptable salt thereof.
  • the present invention provides deuterated analogs of Pridopidine.
  • the deuterated analog of the invention may be a fully or partially deuterium substituted derivative.
  • the deuterated analog of the invention may in particular be characterised by Formula I
  • R 1 -R 23 represents deuterium (D).
  • R 1 -R 23 represent hydrogen (H).
  • the abundance of deuterium at that position is at least 3340 times greater (i.e. at least 50.1% incorporation of deuterium) than the natural abundance of deuterium.
  • the abundance of deuterium at that position is at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • the deuterated analog of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein
  • R 1 -R 2 represent deuterium (D);
  • R 3 -R 23 represent hydrogen (H).
  • the deuterated analog of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein
  • R 1 -R 7 represents deuterium (D).
  • R 1 -R 23 represent hydrogen (H).
  • the deuterated analog of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein
  • R 1 -R 7 represent deuterium (D).
  • R 8 -R 23 represent hydrogen (H).
  • the deuterated analog of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein
  • R 8 , R 9 , R 10 and R 11 represent deuterium (D);
  • R 1 -R 7 and R 12 -R 23 represent hydrogen (H).
  • the deuterated analog of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein
  • R 12 represents deuterium (D).
  • R 1 -R 11 and R 13 -R 23 represent hydrogen (H).
  • the deuterated analog of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein
  • R 17 -R 20 represent deuterium (D).
  • R 1 -R 16 and R 21 -R 23 represent hydrogen (H).
  • the deuterated analog of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the deuterated analog of the invention.
  • salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like.
  • Such salts may be formed by procedures well known and described in the art.
  • acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a deuterated analog of the invention and its pharmaceutically acceptable acid addition salt.
  • Examples of pharmaceutically acceptable cationic salts of a deuterated analog of the invention include, without limitation, the sodium, the potassium, the calcium, the magnesium, the zinc, the aluminium, the lithium, the choline, the lysinium, and the ammonium salt, and the like, of a deuterated analog of the invention containing an anionic group.
  • Such cationic salts may be formed by procedures well known and described in the art.
  • the deuterated analog of the invention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvent such as water, ethanol, and the like.
  • Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
  • the deuterated analog of the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples.
  • the starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
  • one compound of the invention may be converted to another compound of the invention using conventional methods.
  • the end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
  • WO 01/46145, WO 01/46146, WO 2005/121087, WO 2007/042295 WO 2008/127188 and WO 2008/155357 all describe substituted 4-phenyl-N-alkyl-piperazines and 4-phenyl-N-alkyl-piperidines, reported to be modulators of dopamine neurotransmission, and to be useful in treatment of symptoms of various disorders of the central nervous system.
  • the deuterated analog of the invention is considered useful for the same medical indications as described in these publications, and these publications therefore are incorporated by reference.
  • Neurological indications contemplated according to these publications include the treatment of Huntington's disease and other movement disorders, as well as movement disorders induced by drugs.
  • the invention relates to the use of the deuterated analog of the invention for use as a medicament for the treatment of Huntington's disease.
  • the invention provides deuterated analogs for use as medicaments. Therefore, in another aspect, the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the compound of the invention.
  • a deuterated analog of the invention for use in therapy may be administered in the form of the raw compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • compositions of the invention may in particular be formulated as described in WO 01/46145.
  • the dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
  • compositions containing of from about 1 to about 500 mg of active ingredient per individual dose, preferably of from about 10 to about 100 mg, most preferred of from about 25 to about 50 mg, are suitable for therapeutic treatments.
  • the daily dose will preferably be administered in individual dosages 1 to 4 times daily.
  • the invention provides a method for the treatment, prevention or alleviation of a dopamine mediated disorder of a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of the deuterated analog of the invention.
  • the dopamine mediated disorder is Huntington's disease.
US13/820,024 2010-09-03 2011-08-31 Deuterated analogs of pridopidine useful as dopaminergic stabilizers Abandoned US20130197031A1 (en)

Applications Claiming Priority (3)

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DKPA201070385 2010-09-03
DKPA201070385 2010-09-03
PCT/EP2011/064954 WO2012028635A1 (en) 2010-09-03 2011-08-31 Deuterated analogs of pridopidine useful as dopaminergic stabilizers

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US14/968,522 Continuation US20160166559A1 (en) 2010-09-03 2015-12-14 Deuterated analogs of pridopidine useful as dopaminergic stabilizers
US14/968,510 Continuation US20160095847A1 (en) 2010-09-03 2015-12-14 Deuterated analogs of pridopidine useful as dopaminergic stabilizers

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US13/820,024 Abandoned US20130197031A1 (en) 2010-09-03 2011-08-31 Deuterated analogs of pridopidine useful as dopaminergic stabilizers
US14/968,510 Abandoned US20160095847A1 (en) 2010-09-03 2015-12-14 Deuterated analogs of pridopidine useful as dopaminergic stabilizers
US14/968,522 Abandoned US20160166559A1 (en) 2010-09-03 2015-12-14 Deuterated analogs of pridopidine useful as dopaminergic stabilizers
US15/960,041 Abandoned US20180235950A1 (en) 2010-09-03 2018-04-23 Deuterated analogs of pridopidine useful as dopaminergic stabilizers
US16/133,192 Active US10799492B2 (en) 2010-09-03 2018-09-17 Deuterated analogs of pridopidine useful as dopaminergic stabilizers

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US14/968,510 Abandoned US20160095847A1 (en) 2010-09-03 2015-12-14 Deuterated analogs of pridopidine useful as dopaminergic stabilizers
US14/968,522 Abandoned US20160166559A1 (en) 2010-09-03 2015-12-14 Deuterated analogs of pridopidine useful as dopaminergic stabilizers
US15/960,041 Abandoned US20180235950A1 (en) 2010-09-03 2018-04-23 Deuterated analogs of pridopidine useful as dopaminergic stabilizers
US16/133,192 Active US10799492B2 (en) 2010-09-03 2018-09-17 Deuterated analogs of pridopidine useful as dopaminergic stabilizers

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US (5) US20130197031A1 (es)
EP (1) EP2611759A1 (es)
JP (1) JP2013536825A (es)
KR (1) KR20140008297A (es)
CN (1) CN103249697B (es)
AU (2) AU2011298382A1 (es)
BR (1) BR112013005125A2 (es)
CA (1) CA2810092A1 (es)
CL (1) CL2013000604A1 (es)
EA (1) EA201390332A1 (es)
IL (1) IL224776A (es)
MX (1) MX2013002453A (es)
NZ (1) NZ608120A (es)
PE (1) PE20140105A1 (es)
SG (2) SG10201506761XA (es)
WO (1) WO2012028635A1 (es)
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US10322119B2 (en) 2013-06-21 2019-06-18 Prilenia Therapeutics Development Ltd. Use of pridopidine for treating Huntington's disease
US10959996B2 (en) 2015-03-06 2021-03-30 Auspex Pharmaceuticals, Inc. Methods for the treatment of abnormal involuntary movement disorders
US11090297B2 (en) 2013-06-21 2021-08-17 Prilenia Neurotherapeutics Ltd. Pridopidine for treating huntington's disease
US11207310B2 (en) 2016-08-24 2021-12-28 Prilenia Neurotherapeutics Ltd. Use of pridopidine for treating functional decline
US11207308B2 (en) 2012-04-04 2021-12-28 Prilenia Neurotherapeutics Ltd. Pharmaceutical compositions for combination therapy
US11471449B2 (en) 2015-02-25 2022-10-18 Prilenia Neurotherapeutics Ltd. Use of pridopidine to improve cognitive function and for treating Alzheimer's disease
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US11738012B2 (en) 2016-02-24 2023-08-29 Prilenia Neurotherapeutics Ltd. Treatment of neurodegenerative eye disease using pridopidine
US11826361B2 (en) 2016-08-24 2023-11-28 Prilenia Neurotherapeutics Ltd Use of pridopidine for treating dystonias

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