US20080221141A1 - Spirocyclic Cyclohexane Compounds Useful To Treat Substance Dependency - Google Patents

Spirocyclic Cyclohexane Compounds Useful To Treat Substance Dependency Download PDF

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US20080221141A1
US20080221141A1 US11/870,051 US87005107A US2008221141A1 US 20080221141 A1 US20080221141 A1 US 20080221141A1 US 87005107 A US87005107 A US 87005107A US 2008221141 A1 US2008221141 A1 US 2008221141A1
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dimethylamino
tetrahydro
diazafluorene
phenylpentamethylene
pentamethylene
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Elmar Friderichs
Babette-Yvonne Koegel
Klaus Linz
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Gruenenthal GmbH
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Gruenenthal GmbH
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Assigned to GRUENENTHAL GMBH reassignment GRUENENTHAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRIDERICHS, ELMAR, KOEGEL, BABETTE-YVONNE, LINZ, KLAUS
Publication of US20080221141A1 publication Critical patent/US20080221141A1/en
Priority to US12/939,274 priority Critical patent/US8034936B2/en
Priority to US14/310,690 priority patent/US20140303125A1/en
Priority to US15/168,906 priority patent/US20160271107A1/en
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/30—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
    • A61P25/36—Opioid-abuse

Definitions

  • Opiate dependency is a major medical and social problem, which requires intensive medical care.
  • a standard treatment is opiate substitution by a specially suitable ⁇ -opioid.
  • Clinically established substances for the substitution therapy of opiate dependency are:
  • methadone (racemate, in rare cases levomethadone)
  • LAAM ( ⁇ -acetylmethadol)
  • substitution therapeutic agents must have the following properties:
  • the object of the present invention was to provide a new method of treating substance dependence with substitution therapeutic agents.
  • Another object of the invention is to provide a method of treating opioid dependency which has advantages compared to the standard therapies.
  • the term salt is understood to denote any form of the active constituent according to the invention in which this adopts an ionic form or is charged, and is coupled to a counter-ion (a cation or anion) and/or is present in solution.
  • the term is also understood to include complexes of the active constituent with other molecules and ions, in particular complexes which are complexed via ionic interactions.
  • the term is understood to include (and this is also a preferred embodiment of the present invention) physiologically compatible salts, in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or also a salt formed with a physiologically compatible acid or with a physiologically compatible cation.
  • salt formed with a physiologically compatible acid is understood within the context of the present invention to denote salts of the respective active constituent with inorganic or organic acids, which are physiologically compatible—especially when used in humans and/or mammals.
  • the hydrochloride and citrate are particularly preferred.
  • physiologically compatible acids are: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutanic acid, 1,1-dioxo-1,2-dihydrol ⁇ 6 -benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric acid and/or aspartic acid.
  • C 1-3 -alkyl “C 1-5 -alkyl”, “C 1-7 -alkyl” and “C 1-4 -alkyl” include acyclic saturated or unsaturated hydrocarbon radicals, which may be branched or straight-chain, with respectively 1, 2 or 3 C atoms, 1, 2, 3, 4 or 5 C atoms, 1, 2, 3, 4, 5, 6 or 7 C atoms or 1, 2, 3 or 4 C atoms.
  • Unsaturated compounds have at least one C—C double bond or at least one C—C triple bond.
  • alkyl is advantageously selected, which includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl; ethylenyl (vinyl), ethinyl, propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )—CH 3 ), propinyl (—CH—C ⁇ CH, —C ⁇ C—CH 3 ), 1,1-dimethylethyl, 1,1-dimethylpropyl, butenyl, butinyl, pentenyl and pentinyl.
  • C 5-6 -cycloalkyl denotes cyclic hydrocarbons with 5 or 6 Carbon atoms, wherein the hydrocarbons may be saturated or unsaturated (but not aromatic). From the above group C 5-6 -cycloalkyl is advantageously selected, which includes cyclopentyl and cyclohexyl.
  • heteroaryl denotes a 5-, 6- or 7-membered cyclic aromatic radical, which contains at least 1, but possibly also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are identical or different and the heterocycle may be unsubstituted or singly or multiply substituted; in the case of substitution in the heterocycle, the substituents may be identical or different and in any arbitrary and possible position of the heteroaryl.
  • Preferred heteroatoms are nitrogen, oxygen and sulphur.
  • heteroaryl radical from the group comprising pyrrolyl, furyl (furanyl), benzofuranyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, or carbazolyl, wherein the bonding to the compounds of the general structure I can be effected by any arbitrary and possible ring member of the heteroaryl radical.
  • Pyridyl and thienyl are particularly preferred.
  • Pyrazolyl and furyl are also particularly preferred.
  • the compounds according to the invention have on account of the ORL1 active component additional properties which the standard substances such as methadone, LAAM or buprenorphine do not possess and which improve the treatment.
  • the ORL1 active component In withdrawal jumping in mice it was shown that in the case of mice that had been treated with combined ⁇ -/ORL1 agonists, as in Example 1, Example 3 or Example 4, no, or only a minimal, withdrawal behaviour is triggered by naloxone. This confirms that the withdrawal symptoms are suppressed by the ORL1 component. This results in a significant advantage if these substances are used in the treatment of withdrawal symptoms, since the occurrence of withdrawal symptoms is one of the most important side effects of this treatment and often leads to non-compliance.
  • the ORL1/ ⁇ -affinity should be 0.3 or greater. It is preferred if the ORL1/ ⁇ -affinity ratio is ⁇ 1, particularly preferably ⁇ 1.7.
  • the substance dependency is opiate dependency, for example dependency on alfentanil, buprenorphine, butorphanol, codeine, dextromoramide, dextropropoxyphene, dezocin, dihydrocodeine, diphenoxylate, ethylmorphine, hydrocodone, hydromorphone, ketobemidone, LAAM, levorphanol, meptazinol, oxycodon, oxymorphone, fentanyl, morphine, heroin, pethidine, sufentanil or tilidin, preferably morphine, methadone or heroin.
  • opiate dependency for example dependency on alfentanil, buprenorphine, butorphanol, codeine, dextromoramide, dextropropoxyphene, dezocin, dihydrocodeine, diphenoxylate, ethylmorphine, hydrocodone, hydromorphone, ketobemidone, LAAM, levorphanol, mept
  • the spirocyclic cyclohexane derivatives according to the invention can also be used in combination with an opioid receptor antagonist, preferably with naloxone.
  • Spirocyclic cyclohexane derivatives in which R 3 denotes heteroaryl are preferred in the context of the present invention. Also preferred in the context of the present invention are spirocyclic cyclohexane derivatives in which R 3 denotes phenyl, unsubstituted or singly or multiply substituted with F, OH, Cl or OCH 3 , or denotes benzyl.
  • R 1 and R 2 denote CH 3 or H, in which case R 1 and R 2 do not simultaneously denote H.
  • spirocyclic cyclohexane derivatives selected from the group:
  • Particularly preferred compounds are selected from the group consisting of:
  • spirocyclic cyclohexane derivatives in which W denotes NR 4 and X denotes 0 are likewise particularly preferred. Accordingly, in the context of the present invention spirocyclic cyclohexane derivatives in which W denotes NR 4 and X denotes 0 are preferred. It is particularly preferred to use compounds selected from the group consisting of:
  • solvent for example methanol/ethyl acetate was used in a ratio of 1:1, 2:1, 3:1 or 4:1, preferably 3:1, or methanol/conc. ammonia solution 99.5:0.5 or methanol/ethyl acetate/conc. ammonia solution in a ratio of 66:33:0.5.
  • compositions of the invention optionally contain, besides at least one compound according to the invention, suitable additives and/or auxiliary substances, including carrier materials, fillers, solvents, diluents, coloring agents and/or binders, and may be administered as liquid medicament forms in the form of injection solutions, drops or ointments, as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols.
  • suitable additives and/or auxiliary substances including carrier materials, fillers, solvents, diluents, coloring agents and/or binders, and may be administered as liquid medicament forms in the form of injection solutions, drops or ointments, as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols.
  • suitable additives and/or auxiliary substances including carrier materials, fillers, solvents, diluents, coloring agents and/or binders
  • suitable preparations are in the form of tablets, coated tablets, capsules, granules, drops, ointments and syrups, while for parenteral, topical and inhalative application suitable forms are solutions, suspensions, readily reconstitutable dry preparations, as well as sprays.
  • Spirocyclic cyclohexane derivatives according to the invention in depot form, in dissolved form or in a plaster form, optionally with the addition of agents promoting penetration of the skin, are suitable percutaneous application preparations.
  • Orally or percutaneously usable preparation forms can provide for the delayed release of the compounds according to the invention.
  • the compounds according to the invention can also be employed in parenteral long-term depot forms, such as for example implants or implanted pumps. In principle other active constituents known to the person skilled in the art can be added to the medicaments according to the invention.
  • the amount of active constituent to be administered to the patient varies depending on the patient's weight, form of application, medical implications and the severity of the illness. Normally 0.00005 to 1 mg/kg, preferably 0.0001 to 0.05 mg/kg of at least one spirocyclic cyclohexane derivative according to the invention is applied.
  • All the aforementioned forms of the medicaments according to the invention also may contain, in addition to at least one compound according to the invention, a further active constituent, in particular an opioid antagonist, preferably naloxone.
  • a further active constituent in particular an opioid antagonist, preferably naloxone.
  • levomethadone which has no significant ORL1 component
  • Levomethadone which is one of the standard therapeutic agents used in substitution therapy, likewise induced withdrawal jumping.
  • compounds described in US 2006/004034 A1 and US 2005/066183 A1 are a number of substances with a slight ORL1 component.
  • Two typical members with a slight ORL1 component (compounds m and n) were likewise tested in the withdrawal jumping test and induced withdrawal jumping. This shows the importance of the ORL1 component as regards the suitability of a substance for substitution therapy within the group of compounds described in US 2006/004034 A1 and US 2005/066183 A1.
  • the compounds according to the invention show significantly reduced cardiovascular side effects compared to methadone and LAAM.
  • the cardiovascular side effects are attributed to a delayed cardiac repolarisation (manifested as a QTc extension in the outside ECG), which is caused by the blockade of a special potassium channel (HERG) (Kornick et al. Pain 2003, 105, 499-506).
  • HERG special potassium channel
  • Both methadone and LAAM exhibit interactions with the HERG channel (Jiesheng et al., Eur. J. Pharmacol. 2003, 458, 25-29; Katchman et al., J. Pharmacol. Exp. Ther. 2002, 303, 688-694).
  • the cyclohexane derivatives of the general formula I were investigated in a receptor binding assay with 3 H-nociceptin/orphanin FQ with membranes of recombinant CHO—ORL1 cells.
  • This test system was implemented according to the method proposed by Ardati et al. (Mol. Pharmacol., 51, 1997, pp. 816-824).
  • the concentration of 3H-nociceptin/orphanin FQ in these tests was 0.5 nM.
  • the binding assays were carried out with 20 ⁇ g of membrane protein per 200 ⁇ l of batch in 50 mM Hepes, pH 7.4, 10 mM MgCl 2 and 1 mM EDTA.
  • the binding to the ORL1 receptor was determined using in each case 1 mg WGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubating the batch for one hour at room temperature followed by measurement in a Trilux scintillation counter (Wallac, Finland).
  • the receptor affinity for the human ⁇ -opiate receptor was determined in a homogeneous batch in mikrotiter plates. For this purpose dilution series of the respective substituted cyclohexyl-1,4-diamine derivatives to be tested were incubated with a receptor membrane preparation (15-40 ⁇ g protein per 250 ⁇ l incubation batch) of CHO—K1 cells which express the human ⁇ -opiate receptor (RB-HOM receptor membrane preparation obtained from the NEN company, Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand [3H]-naloxone (NET719, NEN company, Zaventem, Belgium) as well as of 1 mg WGA-SPA beads (wheat germ agglutinin SPA Beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 ⁇ l for 90 minutes at room temperature.
  • a receptor membrane preparation 15-40 ⁇ g protein per 250 ⁇ l incubation batch
  • the percentage displacement of the radioactive ligand from its binding to the human ⁇ -opiate receptor at a concentration of the test substances of 1 ⁇ mol/l was determined and given as the percentage inhibition (% inhibition) of the specific binding.
  • IC 50 inhibition concentrations which effect a 50% displacement of the radioactive ligand were calculated on the basis of the percentage displacement by different concentration of the compounds of the general formula I to be tested. Ki values for the test substances were obtained by conversion using the Cheng-Prusoff relationship.
  • test substances were applied intraperitoneally a total of seven times over two days. Five applications were made on the first day at 9:00, 10:00, 11:00, 13:00 and 15:00 hours, and on the second day at 9:00 and 11:00 hours. The first three applications were made in increasing dosages (dosage scheme), the further applications being at the dosage of the third application.
  • the withdrawal symptoms were triggered with 30 mg/kg naloxone (i.p.) two hours after the last substance application. Immediately following this the animals were placed individually in transparent observation cages (height 40 cm, diameter 15 cm) and the jumping reactions were counted over 15 minutes in 5-minute periods in each case. Morphine was administered in a dosage as comparison/standard.
  • the withdrawal symptoms were quantified by counting the number of jumps over 0 to 10 minutes after application of naloxone. The number of animals per group exhibiting more than 10 jumps/10 minutes was determined and recorded as “% positive animals”. The average jumping frequency in the group was also calculated. Twelve animals were used per group.
  • FIG. 1 is a graph of the mice jumping test results for levomethadone
  • FIG. 2 is a graph of the jumping test results for compound m
  • FIG. 3 is a graph of the jumping test results for compound n
  • FIG. 4 is a graph of the jumping test results according to Example 1.
  • FIG. 5 is a graph of the jumping test results according to Example 3.
  • FIG. 6 is a graph of the jumping test results according to Example 4.
  • the electrocardiogram measurement was carried out as a bipolar limb lead according to Einthoven (lead II).
  • the Beagle dogs were placed in a special hammock-like holder (Animal sling, Havard Instruments, ZAK, Tidenfeld, Germany) and loosely secured.
  • a measurement electrode was applied to each of the left and right front limbs, and a reference electrode was also applied to the rear limb. All electrodes were plate electrodes, which were fixed to the shaved skin by rubber collars.
  • the plate electrodes were connected to a ECG pre-amplifier and the signals were continuously digitised by means of a computer-controlled data receiving and archiving system (PO-NE-MAH, Gould-Instrument Systems, USA) (digitising frequency: 2 kHz).
  • PO-NE-MAH Gould-Instrument Systems, USA
  • the mean values of the following parameters were determined from 10 successive ECG intervals per measurement time: RR interval, PR interval, QRS interval and QT interval.
  • the frequency correction of the QT interval was made according to the correction formula of Van de Water et al. (1989).
  • Each of the test substances was administered as an i.v. short infusion (15 minutes) via the V. cephalica antibrachii.
  • the changes in the ECG parameters over a period of 60 minutes after administration of the substance were recorded relative to the base value before administration of the substance.
  • the statistical evaluation was carried out by means of variance analysis (ANOVA) compared to synchronous vehicle control measurements. (Van de Water A, Verheyen J, Xhonneux R, Reneman R S. An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. J Pharmacol Methods. 1989 November; 22(3):207-17).
  • the IC 50 value for LAAM is 2 ⁇ m (interactions of LAAM/HERG channel, see Jiesheng et al., Eur. J. Pharmacol. 2003, 458, 25-29), the IC 50 value for methadone is 9.8 ⁇ M (see Katchman et al., J. Pharmacol. Exp. Ther. 2002, 303, 688-694).

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US12/939,274 US8034936B2 (en) 2005-04-11 2010-11-04 Spirocyclic cyclohexane compounds useful to treat substance dependency
US14/310,690 US20140303125A1 (en) 2005-04-11 2014-06-20 Spirocyclic Cyclohexane Compounds Useful To Treat Substance Dependency
US15/168,906 US20160271107A1 (en) 2005-04-11 2016-05-31 Spirocyclic Cyclohexane Compounds Useful To Treat Substance Dependency

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DE102005016460A DE102005016460A1 (de) 2005-04-11 2005-04-11 Spriocyclische Cyclohexanderivate zur Behandlung von Substanzabhängigkeit
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PCT/EP2006/003176 WO2006108565A1 (de) 2005-04-11 2006-04-07 Spirocyclishe cyclohexanderivate zur behandlung von substanzabhängigkeit

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Cited By (22)

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US20090156593A1 (en) * 2006-07-18 2009-06-18 Grunenthal Gmbh Spirocyclic Azaindole Derivatives
US20090247561A1 (en) * 2008-03-27 2009-10-01 Grunenthal Gmbh Substituted spirocyclic cyclohexane derivatives
US20090247591A1 (en) * 2008-03-27 2009-10-01 Grunenthal Gmbh Substituted cyclohexyldiamines
US20090247505A1 (en) * 2008-03-27 2009-10-01 Grunenthal Gmbh Spiro(5.5)undecane derivatives
US20090275590A1 (en) * 2008-01-11 2009-11-05 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US20100048553A1 (en) * 2007-02-22 2010-02-25 Gruenenthal Gmbh Spirocyclic Cyclohexane Compounds
US20100048554A1 (en) * 2007-02-22 2010-02-25 Gruenenthal Gmbh Spirocyclic Cyclohexane Compounds
US20100240897A1 (en) * 2002-11-11 2010-09-23 Gruenenthal Gmbh Spirocyclic Cyclohexane Compounds
US20110003737A1 (en) * 2009-07-01 2011-01-06 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof
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US20140303125A1 (en) 2014-10-09
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US20160271107A1 (en) 2016-09-22
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US8034936B2 (en) 2011-10-11
US20110053970A1 (en) 2011-03-03
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