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WO2025078571A1 - Nouveaux carbonates et carbamates de composés 1,2,3,4,4a,5,6,7,8,9,10,10a-dodécahydrobenzo[g]quinolin-6-ol et leurs utilisations - Google Patents

Nouveaux carbonates et carbamates de composés 1,2,3,4,4a,5,6,7,8,9,10,10a-dodécahydrobenzo[g]quinolin-6-ol et leurs utilisations Download PDF

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Publication number
WO2025078571A1
WO2025078571A1 PCT/EP2024/078645 EP2024078645W WO2025078571A1 WO 2025078571 A1 WO2025078571 A1 WO 2025078571A1 EP 2024078645 W EP2024078645 W EP 2024078645W WO 2025078571 A1 WO2025078571 A1 WO 2025078571A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
propyl
acceptable salt
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Henrik GRADÉN
David BLIMAN
Sverker Von Unge
Clas Sonesson
Johan Kajanus
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Integrative Research Laboratories Sweden AB
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Integrative Research Laboratories Sweden AB
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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/08—Aza-anthracenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • Parkinson 's disease which is characterized by tremors, motor disturbances and coordination defects. Parkinson 's disease is believed to be caused by deterioration of dopamine-producing neurons of the brain, in particular the substantia nigra neurons.
  • Parkinson 's disease Currently there is no known cure for Parkinson 's disease. Instead, the treatment of Parkinson 's disease is focused on providing symptom relief.
  • L-dopa or apomorphine The state of the art treatment of Parkinson 's disease involves administering to the patient L-dopa or apomorphine. These compounds are known to exert their action by being agonists of the DI and/or D2 dopamine receptors. In the case of L-dopa, it is its active metabolite dopamine that is the species that interacts at the DI and/or D2 dopamine receptors.
  • therapies involving L-dopa or apomorphine are associated with drawbacks. For instance, L-dopa has low and variable bioavailability which depends on protein intake. Further, use of L-dopa may result in long term complications such as dyskinesias.
  • Apomorphine has a very short duration of action and a patient therefore has to take multiple injections per day.
  • Apomorphine is also extensively metabolized and cannot be administered orally or intravenously. In fact, apomorphine only allows for subcutaneous administration such as via injection or infusion.
  • the low oral bioavailability of L-dopa and apomorphine is associated with the presence of a catechol moiety in these compounds.
  • a catechol moiety In order to reach the bloodstream and enable transport to the brain most of the pharmaceutical drug has to pass through the gastrointestinal tract and the liver, where most catecholamines are subjected to rapid biotransformation.
  • the oral bioavailability can be increased by e.g. slowing down the transformation into the active metabolite and/or allowing the protected drug to function as a prodrug which may release the drug by removal of the protective group by cleavage.
  • One such a prodrug of dopamine is for instance docarpamine wherein the two hydroxyl groups of dopamine are protected as ethyl carbonate esters and its amino group is protected with an acetyl methionine moiety.
  • J. Med . Chem 2006, 49, 1494-1498 describes enone prodrugs of dopaminergic catecholamines in the research area of dopamine receptor agonists. It is disclosed that the (-)-enantiomer of the trans-isomer of the compound designated as 1-propyl- 2,3,4,4a,5,7,8,9,10,10a-decahydro-lH-benzo[g]quinolin-6-one (also named Compound 4) acts as an enone prodrug of a dopamine receptor agonist. It is suggested that said enone compound is converted in vivo to the corresponding catechol compound designated as /V-(n-propyl)-6,7-di-OH-benzo[g]quinoline (also named Compound 3).
  • WO 2010/097092 describes compounds for treating dyskinesia related disorders, such as Parkinson 's disease.
  • the compound (4aR,10aR)-l-propyl-l,2,3,4,4a,5,10,10a- octahydrobenzo[g]quinoline-6,7-diol also named Compound 10.
  • Compound 10 was found to be an active metabolite functioning as a potent agonist at both the DI and D2 receptors in vitro and possessing a superior profile as a dopamine agonist in vivo.
  • the compound designated as (4aR,10aR)-n-l-propyl- 2,3,4,4a,5,7,8,9,10,10a-decahydro-lH-benzo[g]quinolin-6-one may be used for preparing the aforementioned metabolite as well as in the preparation of a medicament for treating Parkinson 's disease while maintaining a low dyskinesia induction profile.
  • WO 2001/078713 discloses maleate salts of the two enantiomers of the compound designated as l-propyl-trans-2,3,4,4a,5,7,8,9,10,10a-decahydrobenzo[g]quinoline-6- one.
  • WO 2019/101917 discloses catecholamine prodrugs for use in the treatment in Parkinson 's disease.
  • the invention relates to new prodrug derivatives of the compound (4aR,10aR)-l-n-Propyl-l,2,3,4,4a,5,10,10a- octahydro-benzo[g]quinoline-6,7-diol, and it is reported that glucuronide conjugates and sulfate conjugates of this compound are orally active prodrugs of this compound.
  • WO 2020/234270 and WO 2020/234271 both disclose processes for the manufacture of the catecholamine prodrug (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7- hydroxy-l-propyl-l,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6- yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid. It is stated that said catecholamine prodrug is for use in the treatment of neurodegenerative diseases and disorders such as Parkinson's disease.
  • WO 2020/234272 discloses a new solid form of the catecholamine prodrug (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-l-propyl-
  • catecholamine prodrug is for use in the treatment of neurodegenerative diseases such as Parkinson's disease.
  • WO 2020/234273 discloses a process for the manufacture of the two compounds (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro-
  • WO 2020/234274, WO 2020/234275, WO 2020/234276, and WO 2020/234277 disclose different prodrugs of the catecholamine (4aR,10aR)-l-propyl- l,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol.
  • the compounds are for use in the treatment of neurodegenerative or neuropsychiatric diseases such as Parkinson's disease.
  • PCT/EP2023/060703 relates to esters of 1, 2, 3, 4, 4a, 5, 6, 7, 8, 9, 10, 10a- dodecahydrobenzo[g]quinolin-6-ol compounds.
  • the compounds are for use in the treatment of one or more of the following: Parkinson 's disease, Huntington 's disease, Restless leg syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction.
  • the prior art compound l-propyl-trans-2,3,4,4a,5,7,8,9,10,10a-decahydro-lH- benzo[g]quinolin-6-one (hereinafter named as (4aR,10aR)-l-propyl- l,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one), either as the racemate or as its (4a/?,10a/?)-enantiomer, is as mentioned above an orally active prodrug of an extremely potent dopamine receptor agonist.
  • administration of these compounds is associated with a risk for quickly obtaining high peak plasma concentrations and/or emergent side effects such as nausea and vomiting.
  • Parkinson's disease degeneration of the nigro-striatal dopamine pathways is associated with the core motor symptoms. This deficit is addressed by available dopamine receptor agonists. However, there is also a degeneration of other dopaminergic pathways of the brain. In particular, degeneration of the mesolimbic dopamine pathways is associated with important non-motor symptoms such as depression and apathy in Parkinson's disease.
  • a further object is to provide novel therapeutically active compounds that at least partly overcome or mitigate some of the drawbacks of the aforementioned compounds.
  • a further object is to provide novel therapeutically active compounds useful in the treatment of a CNS disease, disorder and/or condition such as Parkinson 's disease.
  • Still a further object of the present disclosure is to provide novel therapeutically active compounds that are potent, have a long duration of action and/or have few side effects, such as nausea and vomiting, when used in the treatment of a CNS disease, disorder and/or condition such as Parkinson 's disease.
  • It is also an object of the present disclosure to provide aspects and/or advantages not provided by hitherto known techniques.
  • X is O or NR 3 ,
  • R 1 is methyl, ethyl or n-propyl
  • R 2 is Ci-C4alkyl
  • R 3 is Ci-C4alkyl, and m is 0 or 1.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically acceptable amount of a compound of Formula III as described herein, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
  • Parkinson 's disease Huntington 's disease, Restless leg syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction.
  • the present disclosure also provides the use of a compound of Formula III as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for the manufacture of a medicament for use in the treatment of one or more of the following: Parkinson 's disease, Huntington 's disease, Restless leg syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction.
  • the present disclosure also provides a method for treatment of one or more of the following: Parkinson 's disease, Huntington 's disease, Restless leg syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction, said method comprising administering to a mammal, such as a human or an animal, in need thereof, an effective amount such as a therapeutically effective amount of (i) a compound of Formula III as described herein, or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition as described herein.
  • Fig. 1 shows a reaction scheme for the preparation of compounds of Formula II and Formula III, respectively.
  • Fig. 2 shows a chromatogram for the 6S and 6R epimers of (4a/?,10a/?)-l-propyl- 1, 2, 3, 4, 4a, 5, 6, 7, 8, 9, 10, 10a -dodeca hyd robenzo[g]qu inolin -6-ol.
  • Fig. 4 shows effects on locomotor activity for the compound of the present disclosure according to Example 5 when said compound was administered perorally.
  • X is O or NR 3 ,
  • R 2 is Ci-C4alkyl
  • R 3 is Ci-C4alkyl, and m is 0 or 1.
  • Ci-C4alkyl denotes a straight or branched alkyl group of one to four carbon atoms such as methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, 2- methylpropyl, or tert-butyl.
  • C2-C4alkene denotes a straight or branched alkene group comprising from two to four carbons.
  • Examples of C2-C4alkene include vinyl, allyl, isopropenyl, 1- propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, or 3-butenyl.
  • halide may be Cl, Br or I.
  • R 1 substituent of the compounds described herein may be methyl, ethyl or n-propyl.
  • R 1 may be ethyl or n-propyl.
  • R 1 is ethyl.
  • R 1 is n-propyl.
  • the R 2 substituent may be Ci-C4alkyl, Cs-Cecycloalkyl, C2-C4alkene or (CH2) m phenyl, said phenyl being substituted with 0, 1, 2 or 3 Ci-C4alkyl groups. It will be appreciated that when the phenyl ring is substituted with two or three Ci-C4alkyl groups these may be the same or different.
  • the R 2 substituent is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, or benzyl wherein the phenyl ring is substituted with 0, 1, 2 or three methyl groups.
  • R 2 is methyl, ethyl, /so-butyl or benzyl.
  • X may be O thereby providing a compound of Formula IV:
  • X may be NR 3 thereby providing a compound of Formula V:
  • R 2 and X for the compounds of Formula Illa and Formula Illb, respectively, may be as described herein.
  • X may be oxygen thereby providing a compound of Formula IVa or Formula IVb:
  • X may be NR 3 thereby providing a compound of Formula Va or Formula Vb:
  • the compounds of Formula Illa and Formula Illb are epimers that differ in configuration on carbon 6 (i.e. the carbon linked to the OC(O)XR 2 group).
  • the compound of Formula Illa is the 6R epimer while the compound of Formula Illb is the 6S epimer.
  • the stereochemistry of the tricyclic system is as depicted herein, i.e. the ring containing the nitrogen carrying the R 1 substituent exhibits trans configuration wherein the carbon 4a has /? configuration and the carbon 10a has /? configuration.
  • the numbering of the carbon atoms for the compounds of Formula III, Formula Illa and Formula Illb is shown below.
  • the compound of the present disclosure is a compound of Formula Illa.
  • the compound of the present disclosure is a compound of Formula Illb.
  • the compound of Formula III is a mixture of the compound of Formula Illa and the compound of the Formula Illb, such as a 1 : 1 mixture of the compound of Formula Illa and the compound of Formula Illb.
  • nitrogen atom carrying the R 1 substituent of the compounds disclosed herein may be provided in oxidized form thereby providing a compound of Formula III2.
  • Persons skilled in the art will understand that such compounds may be administered to a patient or formed in vivo after administration to a patient.
  • the compounds described herein may be provided as a single diastereomer such as a diastereomer essentially free of any other diastereomer.
  • the single diastereomer may have /? configuration at carbon 6, and have /? configuration both at carbon 4a and at carbon 10a.
  • the single diastereomer may have S configuration at carbon 6, and have /? configuration both at carbon 4a and at carbon 10a.
  • the single diastereomer may be provided in a diastereomeric excess equal to or above 90%, such as equal to or above 95%, or such as equal to or above 99%.
  • the diastereomeric excess equals the percentage of the major diastereomer minus the percentage of the minor diastereomer. For instance, a mixture composed of 95% of the major diastereomer and 5% of the minor diastereomer has a diastereomeric excess of 90%.
  • the present disclosure provides a pharmaceutically acceptable salt of the compound(s) described herein, such as the compounds of Formula III, Formula Illa, Formula Illb and/or Formula III2.
  • the pharmaceutically acceptable salt of the compounds described herein may be provided as a combination of a compound of Formula III as described herein and an organic acid. Further, the pharmaceutically acceptable salt of the compounds described herein may be provided as a combination of a compound of Formula III as described herein and an organic acid in a ratio of 1 : 1 or 2: 1. In an example, the ratio is 1 : 1. In a further example, the ratio is 2: 1.
  • the organic acid may be D-tartaric acid.
  • the compound of Formula III may be one or more of the following: ethyl ((4a/?,6R,10a/?)-l-propyl-l,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrobenzo[g] quinol in -6-yl) carbonate, methyl ((4aR,6R,10aR)-l-propyl-l,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrobenzo[g] quinol in -6-yl) carbonate, isobutyl ((4a/?,6/?,10a/?)-l-propyl-l,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrobenzo[g] quinol in -6-yl) carbonate, propyl-l,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quino
  • the compounds of the present disclosure may exist in solid form, i.e. they may be provided as a solid.
  • the compounds described herein, or a pharmaceutically acceptable salt thereof may be amorphous, crystalline or a mixture thereof.
  • the compounds described herein, or a pharmaceutically acceptable salt thereof may exist in crystalline form, i.e. they may be provided as crystal(s).
  • the degree of crystallinity may be equal to or above 80 %, 85%, 90%, 95% or 99%.
  • the compound of Formula III described herein, or a pharmaceutically acceptable salt thereof may be included in a pharmaceutical composition.
  • a pharmaceutical composition comprising a therapeutically acceptable amount of a compound of Formula III as described herein, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
  • therapeutically effective amount means an amount of a compound as disclosed herein that is sufficient to induce the desired therapeutic effect in a patient to whom the compound is administered.
  • the pharmaceutical composition may be for oral administration. Additionally or alternatively, the pharmaceutical composition may be for rectal, intracisternal, intravaginal, intraperitoneal and/or parenteral administration.
  • parenteral administration may be intravenous, intramuscular or subcutaneous administration.
  • the pharmaceutical composition may be provided in solid form such as in the form of one or more capsules, tablets, pills, powders and/or granules.
  • the pharmaceutical composition may be provided in liquid form such as in the form of one or more emulsions, solutions, suspensions and/or syrups.
  • Parkinson 's disease Huntington 's disease, Restless leg syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction.
  • the treatment and may comprise or consist of treatment of Parkinson 's disease.
  • the treatment may comprise or consist of treatment of Huntington 's disease or Restless leg syndrome.
  • the treatment may comprise or consist of treatment of Alzheimer's disease or schizophrenia.
  • the treatment may comprise or consist of treatment of attention deficit hyperactivity disorder (ADHD) or drug addiction.
  • ADHD attention deficit hyperactivity disorder
  • the term treatment may involve one or more of the following: therapeutic treatment, palliative treatment, treatment reducing worsening or the development of a disorder or disease as described herein.
  • the treatment may be therapeutic treatment and/or palliative treatment.
  • the treatment may be treatment reducing worsening or the development of a disorder or disease as described herein.
  • the present disclosure also provides the use of a compound of Formula III as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for the manufacture of a medicament for use in the treatment of one or more of the following: Parkinson 's disease, Huntington 's disease, Restless leg syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction.
  • the treatment may comprise or consist of treatment of Parkinson 's disease.
  • the treatment may comprise or consist of treatment of Huntington 's disease or Restless leg syndrome.
  • the treatment may comprise or consist of treatment of Alzheimer's disease or schizophrenia.
  • the treatment may comprise or consist of treatment of attention deficit hyperactivity disorder (ADHD) or drug addiction.
  • ADHD attention deficit hyperactivity disorder
  • the present disclosure also provides a method for treatment of one or more of the following: Parkinson 's disease, Huntington 's disease, Restless leg syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction, said method comprising administering to a mammal, such as a human or an animal, in need thereof, a therapeutically effective amount of (i) a compound of Formula III as described herein, or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition described herein.
  • the disease, condition and/or disorder may involve Parkinson 's disease.
  • a method for treatment of Parkinson 's disease comprising administering to a mammal, such as a human or an animal, in need thereof, a therapeutically effective amount of (i) a compound of Formula III as described herein, or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition as described herein.
  • the treatment may comprise or consist of treatment of Parkinson 's disease.
  • the treatment may comprise or consist of treatment of Huntington 's disease or Restless leg syndrome.
  • the treatment may comprise or consist of treatment of Alzheimer's disease or schizophrenia.
  • the treatment may comprise or consist of treatment of attention deficit hyperactivity disorder (ADHD) or drug addiction.
  • ADHD attention deficit hyperactivity disorder
  • Parkinson 's disease includes motor symptoms with or without nonmotor symptoms.
  • the main motor symptoms include tremor, rigidity, slowness of movement and difficulty in walking. Collectively, these main motor symptoms are known as “parkinsonism” or “parkinsonian syndrome”.
  • Non-motor symptoms include cognitive functional decline, depression, anxiety, apathy and dementia.
  • Y is a halide such as chloro
  • Y is a halide such as chloro
  • R 1 is as described herein, optionally in the presence of a solvent such as dichloromethane thereby forming a compound of Formula VIII:
  • Formula IX optionally in the presence of a solvent such as dichloromethane wherein R 2 and R 3 are as defined herein thereby forming the compound of Formula V, c) optionally separating the compound of Formula V, into a compound of Formula Va and a compound of Formula Vb as described herein, and d) optionally combining the compound of Formula V of step a), or the compound of Formula Va or IVb of step b), with a pharmaceutically acceptable acid thereby providing a pharmaceutically acceptable salt of the compound of Formula V, Va or Vb.
  • a solvent such as dichloromethane wherein R 2 and R 3 are as defined herein
  • the pharmaceutically acceptable acid in the methods for preparing the compounds of Formula IV and Formula V, respectively may be a pharmaceutically acceptable acid as described herein.
  • the pharmaceutically acceptable acid may comprise or consist of D-tartaric acid.
  • the compound of Formula II in step a) in the aforementioned methods may be a compound of Formula Ila or Formula lib.
  • the para-nitrophenoxy moiety in the compound of Formula VII may be exchanged for another leaving group.
  • This leaving group which may be abbreviated LG, may have the same or substantially the same leaving group properties as the para-nitrophenoxy moiety.
  • the leaving group may be less reactive towards alcohols, such as an alcohol of Formula II, than the Y moiety of the compound of Formula VII. Accordingly, the present disclosure provides a compound of Formula VIII wherein the leaving group LG and the Y moiety are as described herein.
  • the compound of Formula II used in the method for preparing a compound of Formula IV, or pharmaceutically acceptable salt thereof, or the method for preparing a compound of Formula V, or pharmaceutically acceptable salt thereof, described herein may comprise a compound of Formula Ila and/or Formula lib.
  • the compound of Formula II is provided as a mixture of the compound of Formula Ila and the compound of Formula lib such as a 1: 1 mixture.
  • the compound of Formula II may be provided as a compound of Formula Ila or a compound of Formula lib.
  • R 1 for the compounds of Formula Ila and Formula lib may be as described herein. Further, it is understood that the compounds of Formula Ila and Formula lib are epimers that differ in configuration on carbon 6 (i.e. the carbon linked to the OH group).
  • the compound of Formula Ila is the 6R epimer while the compound of Formula lib is the 6S epimer.
  • R 1 group of the compounds of Formula II, Formula Ila and Formula lib may be n- propyl thereby providing a compound of Formula III, Formula Hal and/or Formula Ilbl.
  • the chemical name of the compound of Formula III may be (4a/?,10a/?)-l-propyl- l,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol.
  • the chemical name of the compound of Formula Hal may be (4a/?,6/?,10a/?)-l-propyl- l,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-ol.
  • the chemical name of the compound of Formula Ilbl may be (4a/?,6S,10a/?)-l-propyl- l,2,3,4,4a,5,6,7,8,9,10,10a-dodecahyd robenzo[g]quinolin-6-ol.
  • the compound of Formula II may be prepared from a compound of Formula I by selective reduction of the carbonyl moiety into a hydroxyl group.
  • the compounds of Formula I and Formula II such as the compounds of Formula II and Formula III corresponding to compounds of Formula I and Formula II wherein R 1 is n- propyl, may be prepared as shown in Figure 1, as known in the art and/or as described in this document.
  • acids such as oxalic acid, may be useful in the preparation of salts useful as intermediates in obtaining a compound of the present disclosure and its pharmaceutically acceptable acid addition salt.
  • solvated forms may exist in solvated form.
  • the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof may exist in nonsolvated forms.
  • solvate is used herein to describe a molecular complex comprising a compound of the present disclosure and one or more pharmaceutically acceptable solvent molecule(s).
  • hydrate is employed when the solvent is water.
  • solvated forms may include hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like.
  • the compounds of the present disclosure may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. Thus, it is to be understood that the compounds of the present disclosure may be in the form of a polymorph.
  • a compound as described herein which is labelled with one or more isotopes, such as for example tritium ( 3 H), deuterium ( 2 H), or carbon-14 ( 14 C).
  • the compound is labelled with one or more deuterium atoms. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.
  • the compounds described herein may be administered in a therapeutically acceptable amount.
  • the dose may be from about 0.0001 mg/kg bodyweight to about 5 mg/kg bodyweight, such as from 0.001 mg/kg bodyweight to about 1 mg/kg bodyweight.
  • the exact dosages will depend upon the frequency and mode of administration, the sex, the age, the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and/or other factors known to those skilled in the art.
  • the compounds of the present disclosure may be prepared as described herein. Further, intermediates of the compounds of the present disclosure may be prepared as described herein. For example, the compounds of Formula II and Formula III may be prepared as depicted in Fig. 1 and/or in the examples section as described herein.
  • the end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallization, distillation, chromatography, etc.
  • the compounds of the present disclosure may be prepared in chemically pure form, i.e. they are substantially free from reactants, solvents, impurities etc. Further, the compounds of the present disclosure may be prepared in substantially stereochemically pure form.
  • the compound of Formula III may contain the compound of Formula Illa and the compound of Formula Illb in a ratio equal to or above 95:5, 96:4, 97:3, 98:2 or 99: 1.
  • the compound of Formula III may contain the compound of Formula Illb and the compound of Formula Illa in a ratio equal to or above 95:5, 96:4, 97:3, 98:2 or 99: 1.
  • Analyses were performed by using either an ACE 3 C8 (3.0 x 50 mm) column with a 10-97 % gradient of acetonitrile in 0.1 % aqueous TEA over 3 min and a flow of 1 mL/min, or an Xbridge C18 (3.0 x 50 mm) column with a 10-97 % gradient of acetonitrile in 10 mM ammonium bicarbonate over 3 min and a flow of 1 mL/min and UV detection.
  • a 10-100% gradient of acetonitrile in 0.03% acetic acid was used as eluent.
  • Low resolution mass spectra were recorded on a HP 5970A instrument operating at an ionization potential of 70 eV.
  • the phases were separated using a phase separator and the organic phase was concentrated giving 247 mg of a brown oil.
  • the crude product was purified by flash chromatography on silica gel using a gradient of 0 to 20% MeOH in EtOAc as eluent. Product fractions were pooled and concentrated giving 206 mg of the carbonate as a brown oil.
  • the oil was purified a second time by flash chromatography using EtOAc as eluent followed by a gradient of 0 to 20% MeOH in EtOAc. Evaporation of the solvents gave 86 mg of the title compound in its non-salt form as a colourless oil.
  • the oil was dissolved in EtOAc (7 mL) in a 50 mL round bottomed flask.
  • the D-tartaric acid salt of ethyl ((4a/?,6/?,10a/?)-l-propyl- l,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl) carbonate is provided as a combination of ethyl ((4a/?,6/?,10a/?)-l-propyl-l,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrobenzo[g]quinolin-6-yl) carbonate and D-tartaric acid taken in a ratio of 1 : 1.
  • the mixture was stirred at 40 °C in order to promote the dissolution of tartaric acid.
  • the mixture was stirred at room temperature with the flask open to the air through a connecting adapter leading to a very slow evaporation of the solvent. After five days, a sticky semi-solid material was obtained on the bottom of the flask.
  • the mixture was heated to 40 °C and then also ultrasonicated for a few minutes leading to that some white solid material could be detected visually. After stirring for additional three days at room temperature, a white precipitate was collected.
  • the solid material was washed with EtOAc and dried under reduced pressure at 40 °C for 3 h. There was obtained 18 mg (21%) of the desired D-tartrate as a white solid.
  • the D-tartaric acid salt of methyl ((4a/?,6/?,10a/?)-l-propyl- l,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl) carbonate is provided as a combination of methyl ((4a/?,6/?,10a/?)-l-propyl-l,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrobenzo[g]quinolin-6-yl) carbonate and D-tartaric acid taken in a ratio of 1: 1.
  • 6-ol obtained in a similar fashion as in Preparation 2, (204 mg, 0.82 mmol) was dissolved in DCM (4 mL) together with pyridine (0.26 mL, 3.2 mmol). The solution was cooled with an ice-bath and then 4-nitrophenyl chloroformate (250 mg, 1.2 mmol) was added. The reaction mixture was stirred at 0 °C for 90 min giving an orange slurry. A solution of dimethylamine (2.0 M in THE, 4 mL, 8.0 mmol) was added with further cooling. The reaction mixture was allowed to slowly reach room temperature overnight and then an additional portion of dimethylamine (2.0 M in THE, 1 mL, 2.0 mmol) was added.
  • the D-tartaric acid salt of (4aR, 6/?,10a/?)-l- propyl-l,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl dimethylcarbamate is provided as a combination of (4a/?,6/?,10a/?)-l-propyl- l,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydrobenzo[g]quinolin-6-yl dimethylcarbamate and D-tartaric acid taken in a ratio of 1 : 1.
  • the D-tartaric acid salt of (4a/?,6R,10a/?)-l-propyl-l,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrobenzo[g]quinolin-6-yl ethyl(methyl)carbamate is provided as a combination of ((4a/?,6/?,10a/?)-l-propyl-l,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrobenzo[g]quinolin-6-yl ethyl(methyl)carbamate and D-tartaric acid taken in a ratio of 1: 1.
  • the HCI-salt of (4a/?,10a/?)-l-propyl-l,2,3,4,4a,5,8,9,10,10a- decahydrobenzo[g]quinolin-6(7H)-one was prepared by mixing 518 mg (2.1 mmol) of its non-salt form (synthesized in a similar fashion as above) with HCI in ethanol (1.25 M, 4 mL) and then concentrating the formed solution on a rotavapor. The residue was co-evaporated with ethanol and then crystallized from ethanol/diethyl ether. There was obtained 355 mg (60%) of the title compound as a white powder. Melting point: 220.7 °C.
  • epimer 1 can also be named as (4aR,6R,10aR)-l-propyl-l,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrobenzo[g]quinolin-6-ol.
  • Fig. 3 shows the means of distance travelled after peroral administration of either 0.3 pmol/kg or 1.0 pmol/kg of the prior art compound according to Preparation 1, i.e. ((4a/?,10a/?)-l-propyl-l,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one as HCI-salt), or administration of saline (control experiment) to drug-naive rats.
  • the animals were placed in the motility meters immediately after administration and locomotor activity was recorded for 180 minutes. Results are presented as distance travelled for the control group (empty bar) and for the group of animals that obtained the drug (filled bars, grey or black).
  • both of the two compounds being tested do affect motor activity patterns in normal, non-pre-treated, rats.
  • a dose of 1.0 pmol/kg the prior art compound according to Preparation 1 as well as the compound according to Example 5 induce hyperactivity.
  • the desired effect is lasting for at least 180 min for both of the two compounds showing that the two compounds do have a long duration of action.
  • an even more pronounced difference between the two compounds is that the on-set of action, i.e.

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Abstract

L'invention concerne un composé de formule (III), son procédé de fabrication ainsi que ses utilisations.
PCT/EP2024/078645 2023-10-12 2024-10-11 Nouveaux carbonates et carbamates de composés 1,2,3,4,4a,5,6,7,8,9,10,10a-dodécahydrobenzo[g]quinolin-6-ol et leurs utilisations Pending WO2025078571A1 (fr)

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