EP2334297A1 - Énantiomères de lofexidine en vue d'une utilisation en tant que traitement de maladie et de pathologies du système nerveux central et sa synthèse chirale - Google Patents

Énantiomères de lofexidine en vue d'une utilisation en tant que traitement de maladie et de pathologies du système nerveux central et sa synthèse chirale

Info

Publication number
EP2334297A1
EP2334297A1 EP08782677A EP08782677A EP2334297A1 EP 2334297 A1 EP2334297 A1 EP 2334297A1 EP 08782677 A EP08782677 A EP 08782677A EP 08782677 A EP08782677 A EP 08782677A EP 2334297 A1 EP2334297 A1 EP 2334297A1
Authority
EP
European Patent Office
Prior art keywords
lofexidine
enantiomers
treatment
opioid
salt
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP08782677A
Other languages
German (de)
English (en)
Inventor
George A. Digenis
Peter Crooks
Abeer Alghananeem
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Agean LLC
Original Assignee
Agean LLC
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 Agean LLC filed Critical Agean LLC
Publication of EP2334297A1 publication Critical patent/EP2334297A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/22—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to methods for treatment of CNS disease and pathologies.
  • the invention relates to methods for the treatment of CNS disease and pathologies by administering Lofexidine enantiomers.
  • the invention relates to methods of treatment of CNS disease, such as opioid detoxification, with less undesirable side effects than conventional treatments.
  • This invention also relates to a novel chiral synthesis of Lofexidine enantiomers.
  • Heroin has been reported to be the most prominent illicit drug of abuse among admissions at public! ⁇ -funded substance abuse treatment facilities in the US.
  • about 2.4 million people have used heroin; in 1997, there were 81 ,000 new heroin users of whom 87% were less than 26 years of age.
  • Hospital emergency room episodes from 21 metropolitan areas show that 14% of drug-related emergency room episodes involved heroin, and such episodes increased more than 2-fold from 1991 to 1996.
  • prescription opioid abuse escalates; the number of people addicted to prescription pain relievers is 3 -fold higher than those addicted to heroin. For example, from 1999 to 2001, the non-medical use of OxyContin ® increased 4-fold, and its use continues to escalate.
  • opioid addiction has been associated with high morbidity and mortality, with a 15-20 fold increase in risk of death for intravenous drug users compared with their same age peers.
  • opioid addiction has been associated with high morbidity and mortality, with a 15-20 fold increase in risk of death for intravenous drug users compared with their same age peers.
  • the medical and social importance of the development of effective treatments for opioid addiction is well recognized. Surprisingly, few treatment options for opioid addiction are available.
  • methadone Due to the abuse liability of methadone and its consequent Schedule II classification by the Drug Enforcement Administration (DEA), methadone has additional disadvantages with respect to its prescription requirements, the carefully controlled conditions under which it is dispensed, and the annoyance experienced by patients who must frequently visit the dispensing unit to obtain their methadone dosages.
  • DEA Drug Enforcement Administration
  • BritLofexTM (Lofexidine hydrochloride 0.2 mg tablet), an ⁇ 2 -adrenergic agonist, is used as a non-opioid medication for opioid detoxification in the United Kingdom (UK).
  • FDA Food and Drug Administration
  • the only medications currently approved by the FDA for opioid detoxification are methadone and buprenorphine, both opioid receptor agonists and both associated with abuse liability.
  • Clonidine an 01 2 -adrenergic agonist, is often used "off-label" for this indication in the U.S.
  • clonidine has not been approved by the FDA for this indication.
  • the use of clonidine is limited by its side-effect profile, i.e., significant hypotension at doses effective in alleviating opioid withdrawal symptoms.
  • Lofexidine HCl is the only non-opiate, non-addictive treatment approved for use in the UK to manage withdrawal symptoms in patients undergoing opiate detoxification.
  • Lofexidine has been found to be effective in reducing the symptoms associated with heroin withdrawal such as chills, vomiting, sweating, stomach cramps, diarrhea, muscle pain, and runny nose and eyes.
  • the treatment is responsible for approximately 20,000 detoxifications per year.
  • the drug's proven level of safety permits its use in an outpatient situation. This is of great importance to patients in the US who are located in parts of the country where treatment clinics are not readily available.
  • naltrexone, methadone and more recently buprenorphine are FDA approved in the treatment of opioid addiction, these opioid treatments are associated with high relapse rates. Furthermore, there is currently insufficient availability of methadone and buprenorphine treatment for patients who abuse opioids. A significant number of these patients are undergoing detoxification treatments. However, the great risk of abuse and several other existing restrictions, such as medical prescribing and pharmaceutical dispensing, limit the use of methadone and buprenorphine for outpatient detoxification. In addition, the unapproved status of clonidine, its side effects, such as the lowering of blood pressure, and moderate efficacy limit its use.
  • (-)-lofexidine and (+)- lofexidine can be used in the treatment of opioid addiction and other related drug addictions.
  • non-racemic mixtures of (-)-lofexidine and (+)-lofexidine i.e. mixtures where the molar ratio of one enantiomer is greater than, or less than, that of the other
  • (-)-Lofexidine is more potent than (+)-lofexidine at brain adrenergic receptors involved in the mechanism of opioid detoxification.
  • (+)-lofexidine may also have advantages over ( ⁇ )-Lofexidine as an opioid detoxification agent since it has practically no effect on reducing blood pressure or bradycardiac activity.
  • the (+)-lofexidine enantiomer can be combined with a small proportion of the centrally active (-)-lofexidine to afford a product formulation with a lower effective dose with reduced undesirable side effects.
  • This invention also relates to a physical separation and a synthetic procedure for producing large quantities of either enantiomer by a preparative manufacturing-scale procedure.
  • ( ⁇ )-lofexidine's action as a medication for opioid detoxification may have therapeutic benefits in the treatment of opioid addiction.
  • the use of both (-)-lofexidine and (+)-lofexidine in the treatment of opioid addiction and other related drug addictions may offer additional benefits over the use of racemic ( ⁇ )-lofexidine.
  • the use of mixtures of (-)-lofexidine and (+)-lofexidine that are in a molar ratio of greater than, or less than one, but not equimolar i.e. a racemic mixture
  • this invention is directed at a physical separation and a synthetic procedure for producing large quantities of either lofexidine enantiomer by a preparative manufacturing-scale procedure.
  • (-)-Lofexidine is a more suitable therapeutic agent than ( ⁇ )-lofexidine because it is more potent than (+)-lofexidine at brain adrenergic receptors involved in the mechanism of opioid detoxification.
  • lower doses of (-)-lofexidine can be used, compared to those used for ( ⁇ ) Lofexidine, reducing unwanted peripheral pressor effects of ( ⁇ )-lofexidine given at higher doses.
  • (+)-lofexidine also has advantages over ( ⁇ )-Lofexidine as an opioid detoxification agent since it has practically no effect on reducing blood pressure, and is only four times less potent than (-)-lofexidine at oti -adrenergic receptors in rat brain membranes, and nine times less potent than (-)-lofexidine at ⁇ , 2 -adrenergic receptors in rat brain membranes.
  • the dose of (+)-lofexidine compared to ( ⁇ )-lofexidine may need to be increased due to this reduced affinity for the CNS receptors, the (+)-enantiomer exhibits considerably lower peripheral side effects on blood pressure.
  • (+)-lofexidine enantiomer can be combined with a small proportion of the centrally active (-)-lofexidine to afford a product formulation with a lower effective dose with reduced undesirable side effects.
  • the amount of the more active (-)-lofexidine in the optimal non-racemic mixture should be of such amount that it will not activate peripheral adrenergic receptors causing undesirable side effects such as, blood pressure lowering, bradycardiac activity etc.
  • the use of the individual (+)- lofexidine and (-)- lofexidine enantiomers, and also non-racemic mixtures of these two enantiomers will produce less undesirable peripheral side effects than the use of a racemic mixture.
  • This invention relates to novel uses of (-)-lofexidine, (+)-lofexidine, and a non- racemic mixture of lofexidine enantiomers as a treatment to relieve symptoms in patients undergoing opiate detoxification, to decrease stress-induced reinstatement of seeking addictive materials, to treat cardiovascular complications in patients with obstructive sleep apnea, to treat chronic pelvic pain in females as well as pain management in general such as migraine and neuropathic pain, to treat behavioral disorders (i.e.
  • ADHD attention-deficit/hyperactivity disorder
  • NMDA N-methyl-D-aspartate
  • NMDA schizophrenia-associated receptor hypofunction
  • IOP intraocular pressure
  • This invention further relates to novel use of (-)-lofexidine and (+)-lofexidine as growth-enhancing agent in livestock feeds.
  • the present invention also relates to processes for the stereo specific synthesis and a physical separation process of resolution of (-)-lofexidine and (+)-lofexidine.
  • This novel process for preparing (-)-lofexidine and (+)-lofexidine comprises:
  • (+) and (-)-enantiomers of lofexidine comprising the following steps:
  • Figure 1 shows the synthesis of R-; or (-)-lofexidine enantiomer starting with pure chiral form of
  • a chiral chromatographic matrix was used to separate a racemic mixture of lofexidine into its component enantiomers by a process of HPLC to obtain optically pure (-)- lofexidine and optically pure (+)-lofexidine.
  • the separation was performed using a chiral stationary phase consisted of D-glucose cyclodextran complex (Cyclobond HP-RSP) from Astec
  • the method comprised the following steps: [0032] A racemic form of lofexidine (10 mmol) was placed in ethanol (100 mL), and the chiral acid (+)-Di-p-toluoyl-D-tartaric acid was added in order to form a mixture of the (+)(-) and (+)(+) diastereomeric lofexidine salts.
  • the diastereomeric salts i.e.: (+)(-) lofexidine Di-p- toluoyl-D-tartarate salt was separated from the (+)(+) lofexidine Di-p-toluoyl-D-tartarate salt by a process of fractional crystallization.
  • (+)(-) lofexidine Di-p-toluoyl-D-tartarate salt or the(+)(+) lofexidine Di-p-toluoyl-D-tartarate salt obtained was treated with a base such as 0.1 N sodium carbonate to liberate (-)-lofexidine and (+)-lofexidine.
  • the resulting enantiomerically pure free base of (-)-lofexidine and (+)-lofexidine was converted to lofexidine hydrochloride salt.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur des procédés de traitement d'une maladie et de pathologies du système nerveux central à l'aide de mélanges non racémiques d'énantiomères de lofexidine. L'invention porte également sur des procédés de fabrication d'énantiomères de lofexidine de pureté chirale.
EP08782677A 2008-08-08 2008-08-08 Énantiomères de lofexidine en vue d'une utilisation en tant que traitement de maladie et de pathologies du système nerveux central et sa synthèse chirale Withdrawn EP2334297A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2008/072570 WO2010016844A1 (fr) 2008-08-08 2008-08-08 Énantiomères de lofexidine en vue d'une utilisation en tant que traitement de maladie et de pathologies du système nerveux central et sa synthèse chirale

Publications (1)

Publication Number Publication Date
EP2334297A1 true EP2334297A1 (fr) 2011-06-22

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EP08782677A Withdrawn EP2334297A1 (fr) 2008-08-08 2008-08-08 Énantiomères de lofexidine en vue d'une utilisation en tant que traitement de maladie et de pathologies du système nerveux central et sa synthèse chirale

Country Status (3)

Country Link
EP (1) EP2334297A1 (fr)
JP (1) JP2011530504A (fr)
WO (1) WO2010016844A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8101779B2 (en) * 2008-10-06 2012-01-24 University Of Kentucky Research Foundation Enantioselective synthesis of (+) and (–)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene
IT201900009777A1 (it) * 2019-06-21 2020-12-21 Procos Spa Processo per la sintesi di lofexidina

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4382946A (en) * 1981-12-14 1983-05-10 Merrell Dow Pharmaceuticals Inc. Method of alleviating withdrawal symptoms
US4575510A (en) * 1983-02-17 1986-03-11 Merrell Dow Pharmaceuticals Inc. Method of alleviating withdrawal symptoms
US4800209A (en) * 1981-12-14 1989-01-24 Merrell Dow Pharmaceuticals Inc. Method of alleviating withdrawal symptoms
WO1997049396A1 (fr) * 1996-06-25 1997-12-31 Britannia Pharmaceuticals Limited Utilisation de lofexidine dans la fabrication d'un medicament permettant de traiter l'hyperactivite avec deficit de l'attention
WO1998016226A1 (fr) * 1996-10-17 1998-04-23 Arnsten Amy F T Utilisation de lofexidine dans le traitement de troubles du comportement
US20020068754A1 (en) * 1998-02-25 2002-06-06 Olney John W. Combination of adrenergic agonist and aryl-cyclo-alkanolamine for relieving chronic pain without adverse side effects

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3149010A1 (de) * 1981-12-10 1983-07-07 A. Nattermann & Cie GmbH, 5000 Köln (+)-2-(1-(2,6-dichlorphenoxy)-ethyl)-1,3- diazacyclopent-2-en, dessen herstellung und seine verwendung in pharamazeutischen praeparaten
DE3149009A1 (de) * 1981-12-10 1983-06-23 A. Nattermann & Cie GmbH, 5000 Köln (-)-2-(1-(2,6-dichlorphenoxy)-ethyl)-1,3-diazacyclopent-2-en, dessen herstellung und seine verwendung in pharmazeutischen praeparaten
PL1762239T3 (pl) * 2005-09-08 2010-12-31 Texcontor Ets Lofeksydyna do podawania dordzeniowego

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4382946A (en) * 1981-12-14 1983-05-10 Merrell Dow Pharmaceuticals Inc. Method of alleviating withdrawal symptoms
US4800209A (en) * 1981-12-14 1989-01-24 Merrell Dow Pharmaceuticals Inc. Method of alleviating withdrawal symptoms
US4575510A (en) * 1983-02-17 1986-03-11 Merrell Dow Pharmaceuticals Inc. Method of alleviating withdrawal symptoms
WO1997049396A1 (fr) * 1996-06-25 1997-12-31 Britannia Pharmaceuticals Limited Utilisation de lofexidine dans la fabrication d'un medicament permettant de traiter l'hyperactivite avec deficit de l'attention
WO1998016226A1 (fr) * 1996-10-17 1998-04-23 Arnsten Amy F T Utilisation de lofexidine dans le traitement de troubles du comportement
US20020068754A1 (en) * 1998-02-25 2002-06-06 Olney John W. Combination of adrenergic agonist and aryl-cyclo-alkanolamine for relieving chronic pain without adverse side effects

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GILBERTO GERRA ET AL: "Lofexidine versus clonidine in rapid opiate detoxification", JOURNAL OF SUBSTANCE ABUSE TREATMENT, vol. 21, no. 1, 1 July 2001 (2001-07-01), pages 11 - 17, XP055071700, ISSN: 0740-5472, DOI: 10.1016/S0740-5472(01)00178-7 *
See also references of WO2010016844A1 *
STRANG J ET AL: "Lofexidine for opiate detoxification: Review of recent randomised and open controlled trials", AMERICAN JOURNAL ON ADDICTIONS 199909 US, vol. 8, no. 4, September 1999 (1999-09-01), pages 337 - 348, ISSN: 1055-0496 *

Also Published As

Publication number Publication date
JP2011530504A (ja) 2011-12-22
WO2010016844A1 (fr) 2010-02-11

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