WO2023208867A1 - NOVEL 1,2,3,4,4a,5,8,9,10,10a-DECAHYDROBENZO[G]QUINOLIN-6(7H)-ONE COMPOUNDS AND USES THEREOF - Google Patents
NOVEL 1,2,3,4,4a,5,8,9,10,10a-DECAHYDROBENZO[G]QUINOLIN-6(7H)-ONE COMPOUNDS AND USES THEREOF Download PDFInfo
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- WO2023208867A1 WO2023208867A1 PCT/EP2023/060700 EP2023060700W WO2023208867A1 WO 2023208867 A1 WO2023208867 A1 WO 2023208867A1 EP 2023060700 W EP2023060700 W EP 2023060700W WO 2023208867 A1 WO2023208867 A1 WO 2023208867A1
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Classifications
-
- 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
-
- 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
Definitions
- the present disclosure relates to novel 1 ,2, 3, 4, 4a, 5, 8, 9, 10, 10a- decahydrobenzo[g]quinolin-6(7H)-one compounds, a method for preparing said compounds, a pharmaceutical composition comprising said compounds and to uses of said compounds.
- 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 D1 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 D1 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 at least partly 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. 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.
- 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-1H-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 N- (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 designated as (4aR,10aR)-1-propyl- 1 ,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (also named Compound 10) was found to be an active metabolite functioning as a potent agonist at both the D1 and D2 receptors in vitro and possessing a superior profile as a dopamine agonist in vivo.
- the compound designated as (4aR,10aR)-n-1-propyl- 2,3,4,4a,5,7,8,9,10,10a-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.
- TL 333 (named as trans-N-ethyl-6,7-dihydroxyoctahydrobenzo[g]-quinoline) stimulates both D1 and D2 dopamine receptors.
- WO 2001/078713 discloses maleate salts of the two enantiomers of the compound designated as 1-propyl-f/'ans-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. More specifically, it is stated that the invention relates to new prodrug derivatives of the compound titled as (4aR,10aR)-1-n-propyl-1 ,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- 1 -propyl- 1 ,2, 3, 4, 4a, 5, 10, 10a-octahydro-benzo[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-1-propyl- 1 ,2, 3, 4, 4a, 5, 10, 10a-octahydro-benzo[g]quinoline-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 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,11-octahydro-[1 ,3]dioxolo[4’.5’.5.6]benzo[1 ,2- gjquinoline and (4aR,10aR)-1-n-propyl-1 ,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline- 6,7-diol. It is stated that the compounds are for use in the treatment of neurodegenerative diseases such as Parkinson’s disease.
- WO 2020/234274, WO 2020/234275, WO 2020/234276, and WO 2020/234277 disclose different prodrugs of the catecholamine (4aR,10aR)-1-n-propyl-1 ,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.
- 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.
- Ri is methyl or ethyl.
- the present disclosure also provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable amount of a compound of Formula I 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 use of a compound of Formula I 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 of (i) a compound of Formula I 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 Example 1 (Ex 1), i.e. a compound of Formula lb.
- the synthetic intermediates in Fig.1 named P1 to P5 are abbreviations of Preparation 1 to Preparation 5.
- Fig. 2 shows effects on locomotor activity for the prior art compound according to Preparation 6 when said compound was administered subcutaneously.
- Fig. 3 shows effects on locomotor activity for the compound of the present disclosure according to Example 1 when said compound was administered subcutaneously.
- Fig. 4 shows effects on gene expression (mRNA) of Arc in different brain regions by the prior art compound according to Preparation 6.
- Fig. 5 shows effects on gene expression (mRNA) of Arc in different brain regions by the compound according to Example 1.
- the present disclosure provides a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein carbon 4a and carbon 10a both have R configuration, and
- R 1 is methyl or ethyl.
- R 1 of the compounds described herein may be methyl, or ethyl.
- R 1 is methyl.
- R 1 is ethyl.
- the stereochemistry of the tricyclic system is as depicted herein, i.e. the ring containing the nitrogen atom exhibits trans configuration.
- the compound of Formula I may have R configuration at carbon atoms 4a and 10a, respectively. The numbering of the carbon atoms for the compound of Formula I is shown below.
- nitrogen atom of the compounds disclosed herein may be provided in oxidized form such as a compound of Formula 11 .
- 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 present disclosure provides a compound of Formula la wherein R 1 is methyl as shown below.
- the chemical name of the compound of Formula la may be (4aR, 1 OaR)- 1 -methyl-1 ,2, 3, 4, 4a, 5, 8, 9, 10, 10a-decahydrobenzo[g]quinolin-6(7H)-one.
- the present disclosure provides a pharmaceutically acceptable salt of the compound(s) described herein, such as the compounds of Formula I, Formula II, Formula la and Formula lb.
- the compounds described herein, or a pharmaceutically acceptable salt thereof may exist in solid form, i.e. they may be provided as a solid.
- the compound(s) or pharmaceutically acceptable salt(s) thereof may be amorphous, crystalline or a mixture thereof.
- the compounds, or pharmaceutically acceptable salt thereof, described herein 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 I 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 I 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 which 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.
- a compound of Formula I as described herein such as a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use as a medicament.
- 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 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 use of a compound of Formula I 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, an effective amount, i.e. a therapeutically effective amount, of (i) a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition 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 non-motor 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/or dementia such as Parkinson’s disease dementia.
- the treatment of Parkinson's disease described herein may take place without or substantially without inducing side effects such as nausea or vomiting.
- the treatment may be associated with no or mild side effects such as nausea and/or vomiting.
- the treatment described herein may comprise or consist of treatment of non-motor symptoms associated with Parkinson's disease.
- non-motor symptoms include cognitive functional decline, depression, anxiety and/or Parkinson's disease dementia.
- cognitive functional decline include problems with memory, language, thinking, learning and/or judgment.
- compositions of the present disclosure may be provided in the form of a pharmaceutically acceptable salt.
- pharmaceutically acceptable salt includes salt prepared from a pharmaceutically acceptable non-toxic acid, i.e. pharmaceutically acceptable acid addition salts.
- the pharmaceutically acceptable salt may be formed by combining a compound as described herein with an organic acid or inorganic acid in a desired ratio using e.g. methods known in the art.
- the pharmaceutically acceptable salt may be a combination of the compound of Formula I and an acid such as a combination of the compound of Formula I and an acid in a ratio of 1 :1 or 2:1.
- salts include, without limitation, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulphate, formate, acetate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate, and the like.
- non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulphate, formate, acetate, ascorbate, benzenesulphonate
- 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.
- the compounds of the present disclosure may be used in their labelled or unlabelled form.
- the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- the labelling may allow easy quantitative detection of said compound.
- 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 present disclosure provides a compound as described herein which is labelled with one or more isotopes such as deuterium.
- the compounds labelled with an isotope as described herein may be combined with an acid as described herein thereby providing a salt such as a pharmaceutically acceptable salt as described herein.
- 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 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.
- 3-(4-Methoxyphenyl)propanoyl chloride 3-(4-Methoxyphenyl)propionic acid (50.0 g, 272 mmol) was dissolved in DCM (500 mL) and to the formed solution was added thionylchloride (49.3 mL, 680 mmol). The mixture was heated to reflux for 6 h, allowed to cool to room temperature and then evaporated to dryness using a rotary evaporator. The crude acid chloride (52.8 g, 98%) was used in the next step without further purification.
- 3-(4-Methoxyphenyl)propanoyl chloride (23.9 g, 120 mmol) was dissolved in dry THF (30 mL) and the formed solution was slowly added to an ice-cold mixture of ethylamine (2 M in THF, 150 mL, 300 mmol) and triethylamine (20 mL, 144 mmol) in THF (80 mL). The reaction mixture was stirred at room temperature for one hour and then diluted with aqueous sodium carbonate (10%). The mixture was extracted several times with EtOAc, and the combined organic solutions were washed with brine and dried over sodium sulphate.
- the product was purified (and the two stereoisomers were separated) by silica-gel chromatography using EtOAc/MeOH (gradient, 0-10% MeOH) as eluent. There was obtained 4.66 g of the first eluting cis isomer and then 0.51 g of the trans isomer, respectively.
- the cis isomer was then converted into the desired trans isomer by dissolving 4.66 g in ethanolic KOH (1%, 470 mL), stirring the formed solution at room temperature for four days under a nitrogen atmosphere and the flask covered with aluminium foil.
- the reaction mixture was stirred with cooling for 4 h and then for 18 h at room temperature. After cooling with an ice-bath, water (120 mL) was added, and the product was extracted several times with diethyl ether. The organic solutions were successively washed with aqueous LiCI (5%, 75 mL) and brine, dried over sodium sulphate and concentrated to dryness on a rotary evaporator. The residue, which consisted of a mixture of the desired ethyl ester and the corresponding tert-butyl ester as a by-product, was dissolved in ethanol (50 mL) together with concentrated sulfuric acid (1 mL). The mixture was heated to reflux for 18 h and then allowed to cool to room temperature.
- the HCI-salt of (4aR,10aR)-1-propyl-1 ,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.
- Behavioral activity was measured using eight Digiscan activity monitors (RXYZM (16) TAO, Omnitech Electronics, Columbus, OH, USA), connected to an Omnitech Digiscan analyzer and an Apple Macintosh computer equipped with a digital interface board (NB DIO-24, National Instruments, USA).
- a rat was put in a transparent acrylic cage (WxLxH, 40x40x30 cm) which in turn was placed in the activity monitor.
- Each activity monitor was equipped with three rows of infrared photo beam sensors, each row consisting of 16 sensors.
- the computer software was written using object-oriented programming (LabVIEWTM, National instruments, Austin, TX, USA).
- Behavioral data from each activity monitor representing the position (horizontal center of gravity and vertical activity) of the animal at each time, were recorded at a sampling frequency of 25 Hz and collected using a custom written LABViewTM application. The data from each recording session were stored and analyzed with respect to distance traveled. Each behavioral recording session lasted 180 min, starting approximately 5 min after the injection of test compound.
- Fig. 2 shows the means of distance travelled after administration of either 0.3 pmol/kg of the prior art compound according to Preparation 6 (4aR,10aR)-1-propyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one 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 bar).
- Fig 3 shows the means of distance travelled after administration of either two doses (3 pmol/kg and 9 pmol/kg) of the compound according to Example 1 (4aR,10aR)-1-ethyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one 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 bars) and for the group of animals that obtained the drug [light filled bars (3 pmol/kg) and filled bars (9 pmol/kg)].
- both of the two compounds being tested do affect motor activity patterns in normal, non-pre-treated, rats.
- the prior art compound is more potent as a dopamine agonist as compared to the inventive compound according to Example 1 which is reflected in the higher doses needed of the compound according to Example 1 (3 pmol/kg and 9 pmol/kg) in order to effectively affect motor activity.
- the prior art compound according to Preparation 6 as well as the compound according to Example 1 do induce hyperactivity and that desired effect is lasting for at least 180 min for both of the two compounds showing that both of the two compounds do have a long duration of action.
- a difference between the two compounds is that the on-set of action, i.e.
- the brains were dissected into a left and a right part.
- the left part was analyzed for gene expression and dissected into 4 different areas:
- Limbic system (containing nucleus accumbens, most parts of the olfactory tubercle, ventral pallidum and amygdala), striatum, frontal cortex, and hippocampus.
- Total RNA was prepared by RNeasy Plus Universal Tissue Mini Kit (Qiagen).
- RNA pellets were dissolved in RNAse-free water and stored at -80°C. The sample concentration was determined spectrophotometrically by a NanoDrop ND-1000.
- RNAse-free water 1 pl was reversed transcribed with 5 pl 2X RT Reaction Mix, 1 pl RT Enzyme and the mix volume was adjusted to 10 pl with RNAse-free water. The samples was incubated at 25°C for 10 min, 50°C for 30 min and finally 85°C for 5 min. 1 U of E.coli RNase H was added following incubation at 37°C for 20 min and 85°C for 5 minutes. The cDNA solution was diluted 40 times in Tris EDTA buffer solution pH8 (Merck) and stored at -20°C.
- the real-time PCR reaction consisted of 10 pl Sso Advanced Universal Probes Supermix, 1 pl primer/probe, 1 pl reference gene or 1 pl MQ water and
- EGR-1 Error growth response qRnoCEP0022872
- HPRT hypoxanthine phosphoribosyltransferase qRnoCEP0050840.
- Npas4 neurovascular PAS domain protein4 qRnoCEP0029461 was analyzed in singleplex.
- the reference gene Ppia (cyclophilin A peptidyl-propyl cis-trans isomerase qRnoCIP0050815) was also analyzed in order to quantify gene expression for genes of interest.
- Fig. 4 illustrates the effects on tissue levels of Arc mRNA in four different regions of the brain (limbic regions, striatum, frontal cortex and hippocampus) after subcutaneous administration of the prior art compound according to Preparation 6 (4aR,10aR)-1-propyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one.
- the effects on tissue levels of Arc were measured at two different doses (0.3 pmol/kg and 1 pmol/kg) and the effects are presented as percent of control means ⁇ SEM. Statistical significance was assessed using Student’s t-test (2 tailed) vs controls.
- Fig. 5 illustrates the effects on tissue levels of Arc mRNA in four different regions of the brain (limbic regions, striatum, frontal cortex and hippocampus) after subcutaneous administration of the compound according to Example 1 (4aR,10aR)-1-ethyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one.
- the effects on tissue levels of Arc were measured at two different doses (3 pmol/kg and 9 pmol/kg) and the effects are presented as percent of control means ⁇ SEM. Statistical significance was assessed using Student’s t-test (2 tailed) vs controls.
- arcL stands for Arc mRNA in the limbic regions
- arcs stands for Arc mRNA in striatum
- arcF stands for Arc mRNA in the frontal cortex
- arcH stands for Arc mRNA in hippocampus.
- both of the two compounds dose- dependently increase tissue levels of Arc in the frontal cortex, which sometimes is observed for a dopamine receptor agonist.
- the compound according to Example 1 dose-dependently increases the tissue levels of Arc in the limbic regions which is a property that the prior art compound according to Preparation 6 does not have.
- Arc is a biomarker of synaptic activity
- this attribute of the compound according to Example 1 allows for providing a unique therapeutic profile such as for instance improvements related to emotion, behavior, and/or long-term memory.
- the compound according to Example 1 increases tissue levels of other genes in the limbic regions such as for instance egr-1 and Npas4. The compound does so to a greater extent as compared to that of the prior art compound according to Preparation 6 and these observed effects allow for an improved therapy for the patients with neurodegenerative diseases and/or neurological disorders.
- the primer and probe sequences are as follows for measuring of arc:
- Antisense 5’- CCA CAT ACA GTG TCT GGT A -3’ (SEQ ID NO:2) Probe: CCG CTT ACG CCA GAG GAA CT (SEQ ID NO:3)
- Antisense 5’- CTG CTA GTT CTT TAC TGG C -3’ (SEQ ID NO:5)
- Cyclophilin A (cyclo) (accession number M19533)
- Antisense 5’- ATG CCT TCT TTC ACC TTC -3’ (SEQ ID NO:8) Probe: TTG CCA TCC AGC CAC TCA GT (SEQ ID NO:9)
Abstract
There is disclosed a compound of Formula (I), a method of manufacturing thereof as well as uses thereof.
Description
NOVEL 1 ,2, 3, 4, 4a, 5, 8, 9,10,1 Oa-DECAHYDROBENZO[G]QUINOLIN-6(7H)-ONE COMPOUNDS AND USES THEREOF
TECHNICAL FIELD
The present disclosure relates to novel 1 ,2, 3, 4, 4a, 5, 8, 9, 10, 10a- decahydrobenzo[g]quinolin-6(7H)-one compounds, a method for preparing said compounds, a pharmaceutical composition comprising said compounds and to uses of said compounds.
BACKGROUND
Neurodegenerative diseases and neurological disorders are becoming increasingly prevalent with the growing number of aging populations worldwide. One of the most common of these diseases and disorders is 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.
Currently there is no known cure for Parkinson's disease. Instead, the treatment of Parkinson's disease is focused on providing symptom relief.
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 D1 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 D1 and/or D2 dopamine receptors. However, therapies involving L-dopa or apomorphine are associated with drawbacks. For instance, L-dopa has low and variable bioavailability which at least partly 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. 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. By introducing protecting groups at the hydroxyl and/or the amino functions of the compound, 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-1H-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 N- (n-propyl)-6,7-di-OH-benzo[g]quinoline (also named Compound 3).
Bioorganic & Medicinal Chemistry, 16 (2008), 3438-3444, discloses a synthesis and pharmacological evaluation of a compound titled as racemic trans- 1-propyl- 1 ,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (also named Compound 4), which is believed to be the active form of its enone prodrug. It is stated that the catechol moiety of this compound is decisive for the low bioavailability observed. Further, it is stated that the high efficiency of the compound results in the possibility of administering low dose, which could make it a candidate for the treatment of Parkinson's disease.
WO 2010/097092 describes compounds for treating dyskinesia related disorders, such as Parkinson's disease. The compound designated as (4aR,10aR)-1-propyl- 1 ,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (also named Compound 10) was found to be an active metabolite functioning as a potent agonist at both the D1 and D2 receptors in vitro and possessing a superior profile as a dopamine agonist in vivo. It is also described that the compound designated as (4aR,10aR)-n-1-propyl- 2,3,4,4a,5,7,8,9,10,10a-benzo[g]quinolin-6-one (also named Compound 12) 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.
European Journal of Pharmacology, 108 (1985), 99-101 , states that TL 333 (named as trans-N-ethyl-6,7-dihydroxyoctahydrobenzo[g]-quinoline) stimulates both D1 and D2 dopamine receptors.
WO 2001/078713 discloses maleate salts of the two enantiomers of the compound designated as 1-propyl-f/'ans-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. More specifically, it is stated that the invention relates to new prodrug derivatives of the compound titled as (4aR,10aR)-1-n-propyl-1 ,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- 1 -propyl- 1 ,2, 3, 4, 4a, 5, 10, 10a-octahydro-benzo[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-1-propyl- 1 ,2, 3, 4, 4a, 5, 10, 10a-octahydro-benzo[g]quinoline-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 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,11-octahydro-[1 ,3]dioxolo[4’.5’.5.6]benzo[1 ,2- gjquinoline and (4aR,10aR)-1-n-propyl-1 ,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline- 6,7-diol. It is stated that the compounds are for use in the treatment of neurodegenerative diseases such as Parkinson’s disease.
WO 2020/234274, WO 2020/234275, WO 2020/234276, and WO 2020/234277 disclose different prodrugs of the catecholamine (4aR,10aR)-1-n-propyl-1 ,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.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
The prior art compound 1-propyl-f/'ans-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H- benzo[g]quinolin-6-one (hereinafter named as 1 -propyl-frans-
1 H,2H,3H,4H,4aH,5H,6H,7H,8H,9H, 10H, 10aH-cyclohexa[g]quinolin-6-one or (4aR, 1 OaR)- 1-propyl-1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one), either as the racemate or as its (4aR,10aR)-enantiomer, is as mentioned above a prodrug of an extremely potent orally active dopamine receptor agonist. However, 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.
Furthermore, in 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.
There is a need for novel therapeutic agents allowing for treatment of CNS diseases, disorders and/or conditions such as Parkinson's disease. In particular, there is a need for a therapeutic agent that is potent, has a long duration of action and/or has few side effects. Further, there is also a need for a novel therapeutic agent allowing for treating non-motor symptoms associated with Parkinson's disease.
SUMMARY
It is an object of the present disclosure 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 a novel therapeutic agent allowing for treating non-motor symptoms associated with Parkinson's disease. It is also an object of the present disclosure to provide aspects and/or advantages not provided by hitherto known techniques.
Formula I or a pharmaceutically acceptable salt thereof, wherein carbon 4a and carbon 10a both have R configuration, and
Ri is methyl or ethyl.
The present disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
Further, there is also provided a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use as a medicament.
There is also provided a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein 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 use of a compound of Formula I 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 of (i) a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition as described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a reaction scheme for the preparation of Example 1 (Ex 1), i.e. a compound of Formula lb. The synthetic intermediates in Fig.1 named P1 to P5 are abbreviations of Preparation 1 to Preparation 5.
Fig. 2 shows effects on locomotor activity for the prior art compound according to Preparation 6 when said compound was administered subcutaneously.
Fig. 3 shows effects on locomotor activity for the compound of the present disclosure according to Example 1 when said compound was administered subcutaneously.
Fig. 4 shows effects on gene expression (mRNA) of Arc in different brain regions by the prior art compound according to Preparation 6.
Fig. 5 shows effects on gene expression (mRNA) of Arc in different brain regions by the compound according to Example 1.
DESCRIPTION
The present disclosure provides a compound of Formula I:
Formula I or a pharmaceutically acceptable salt thereof, wherein carbon 4a and carbon 10a both have R configuration, and
R1 is methyl or ethyl.
Thus, R1 of the compounds described herein may be methyl, or ethyl. In an example, R1 is methyl. In a further example, R1 is ethyl.
For the compounds of Formula I, the stereochemistry of the tricyclic system is as depicted herein, i.e. the ring containing the nitrogen atom exhibits trans configuration. Moreover, the compound of Formula I may have R configuration at carbon atoms 4a and 10a, respectively. The numbering of the carbon atoms for the compound of Formula I is shown below.
Formula I
It will be appreciated that the nitrogen atom of the compounds disclosed herein may be provided in oxidized form such as a compound of Formula 11 . 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 present disclosure provides a compound of Formula la wherein R1 is methyl as shown below. The chemical name of the compound of Formula la may be (4aR, 1 OaR)- 1 -methyl-1 ,2, 3, 4, 4a, 5, 8, 9, 10, 10a-decahydrobenzo[g]quinolin-6(7H)-one.
Formula la
In a further example, there is provided a compound of Formula lb, wherein R1 is ethyl.
The chemical name of the compound of Formula lb may be
Formula lb
The present disclosure provides a pharmaceutically acceptable salt of the compound(s) described herein, such as the compounds of Formula I, Formula II, Formula la and Formula lb.
The compounds described herein, or a pharmaceutically acceptable salt thereof, may exist in solid form, i.e. they may be provided as a solid. For example, the compound(s) or pharmaceutically acceptable salt(s) thereof may be amorphous, crystalline or a mixture thereof. Further, the compounds, or pharmaceutically acceptable salt thereof, described herein 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 I described herein or a pharmaceutically acceptable salt thereof, may be included in a pharmaceutical composition. Thus, there is provided a pharmaceutical composition comprising a therapeutically acceptable amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable carrier, excipient and/or diluent. As used herein, the expression “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 which 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. In an example, the parenteral administration may be intravenous, intramuscular or subcutaneous administration. Further, 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. Alternatively, the pharmaceutical composition may be provided in liquid form such as in the form of one or more emulsions, solutions, suspensions and/or syrups.
There is also provided a compound of Formula I as described herein, such as a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use as a medicament.
There is also provided a compound of Formula I as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein 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. For instance, the treatment may comprise or consist of treatment of Parkinson's disease. In a further example, the treatment may comprise or consist of treatment of Huntington's disease or Restless leg syndrome. In still a further example, the treatment may comprise or consist of treatment of Alzheimer's disease or schizophrenia. In yet an example, the treatment may comprise or consist of treatment of attention deficit hyperactivity disorder (ADHD) or drug addiction.
As used herein, 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. For instance, the treatment may be therapeutic treatment and/or palliative treatment. Additionally or alternatively, the treatment may be treatment reducing worsening or the development of a disorder or disease as described herein.
The present disclosure also provides use of a compound of Formula I 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. For instance, the treatment may comprise or consist of treatment of Parkinson's disease. In a further example, the treatment may comprise or consist of treatment of Huntington's disease or Restless leg syndrome. In still a further example, the treatment may comprise or consist of treatment of Alzheimer's disease or schizophrenia. In yet an example, the treatment may comprise or consist of treatment of attention deficit hyperactivity disorder (ADHD) or 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, i.e. a therapeutically effective amount, of (i) a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition described herein. For instance, the treatment may comprise or consist of treatment of Parkinson's disease. In a further example, the treatment may comprise or consist of treatment of Huntington's disease or Restless leg syndrome. In still a further example, the treatment may comprise or consist of treatment of Alzheimer's disease or schizophrenia. In yet an example, the treatment may comprise or consist of treatment of attention deficit hyperactivity disorder (ADHD) or drug addiction.
As used herein, Parkinson's disease includes motor symptoms with or without non-motor 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/or dementia such as Parkinson’s disease dementia.
The treatment of Parkinson's disease described herein may take place without or substantially without inducing side effects such as nausea or vomiting. Thus, the treatment may be associated with no or mild side effects such as nausea and/or vomiting. Additionally or alternatively, the treatment described herein may comprise or consist of treatment of non-motor symptoms associated with Parkinson's disease. Examples of non-
motor symptoms include cognitive functional decline, depression, anxiety and/or Parkinson's disease dementia. Examples of cognitive functional decline include problems with memory, language, thinking, learning and/or judgment.
Pharmaceutically Acceptable Salts
Compounds of the present disclosure may be provided in the form of a pharmaceutically acceptable salt. As used herein “pharmaceutically acceptable salt”, where such salt is possible, includes salt prepared from a pharmaceutically acceptable non-toxic acid, i.e. pharmaceutically acceptable acid addition salts. The pharmaceutically acceptable salt may be formed by combining a compound as described herein with an organic acid or inorganic acid in a desired ratio using e.g. methods known in the art. Thus, the pharmaceutically acceptable salt may be a combination of the compound of Formula I and an acid such as a combination of the compound of Formula I and an acid in a ratio of 1 :1 or 2:1.
Examples of pharmaceutically acceptable salts include, without limitation, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulphate, formate, acetate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate, and the like.
Other 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.
Solvates
It is to be understood that compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may exist in solvated form. Alternatively, the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may exist in nonsolvated forms. The term “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). The term “hydrate” is employed when the solvent is
water. Thus, solvated forms may include hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like.
Polymorphs
The compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, 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.
Labelled Compounds
The compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may be used in their labelled or unlabelled form. In the context of this present disclosure the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The labelling may allow easy quantitative detection of said compound.
For example, there is provided a compound as described herein which is labelled with one or more isotopes, such as for example tritium (3H), deuterium (2H), or carbon-14 (14C). In an example, 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.
Thus, the present disclosure provides a compound as described herein which is labelled with one or more isotopes such as deuterium. The compounds labelled with an isotope as described herein may be combined with an acid as described herein thereby providing a salt such as a pharmaceutically acceptable salt as described herein.
Dosage
It will be appreciated that the compounds described herein may be administered in a therapeutically acceptable amount. For example, 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.
Methods of Preparation
Compounds of the present disclosure may be prepared as described herein. For instance, the compounds of the present disclosure may be prepared as shown in Fig. 1.
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.
Persons skilled in the art will appreciate that, in order to obtain compounds of the present disclosure the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction).
The disclosure is illustrated in the following non-limitative Examples.
EXAMPLES
The naming of the compounds (preferred IUPAC name) as disclosed herein was made using ChemDraw Ultra, version 12.0.2. 1076. In this document, if the chemical name and the chemical structure are inconsistent the chemical structure should be considered to be the correct structure.
General methods
The following general experimental procedures were used:
For flash chromatography, Biotage Isolera Vers 1 .2 with Star Silica HC D columns were used. Low resolution mass spectra were recorded on a HP 5970A instrument operating at an ionization potential of 70 eV. The mass detector was interfaced with a HP5700 gas chromatograph equipped with a HP-5MS Ul GO column (15m, 0.25mm, 0.25pm) with helium gas flow 40 cm/s.
Liquid chromatography-mass spectra (LC MS) were acquired using a HP-Agilent 1100 MSD system using an aqueous solution of acetic acid as mobile phase (0.03% acetic acid).
NMR experiments were run on an Oxford 800 magnet, Bruker Avance III HD spectrometer with 4 channels, 5 mm TXO cold probe and ASTM 13C S/N 3300 or, using a Varian Mercury 400 MHz spectrometer.
Melting points were determined by a Buchi B-545 and are uncorrected.
For flash chromatography, Biotage Isolera Vers 1.2 with SNAP Cartridge KP-Sil, mobile phase gradient mixtures of isooctane/ethyl acetate/methanol was used.
Evaporation of solvents was performed using a Laborota 4000 connected to a Vario PC2001 vacuum pump.
Abbreviations
AP anterior posterior
ARC activity-regulated cytoskeleton-related protein
CNS Central Nervous System
Ctrl Control d doublet dd doublet of doublets
DCM dichloromethane
DEA diethylamine
DMF dimethylformamide
DMSO dimethsulphoxide egr-1 early growth response protein 1
EtOAc ethyl acetate
EtOH ethanol g gram(s)
GC Gas Chromatography mg milligram(s) kg kilogram(s) i.p. intraperitoneal
IP intraperitoneal
IPA 2-propanol
HPLC High Performance Liquid Chromatography
HPRT Hypoxanthine-guanine phosphoribosyltransferase
IUPAC International Union of Pure and Applied Chemistry
LC MS Liquid Chromatography Mass Spectroscopy
M molar, i.e. mole(s)/ liter
MeOH methanol mM millimolar, i.e. millimole(s)/liter
ML medial lateral
MS(ESI+) Mass Spectroscopy Electrospray Ionization min. minute(s) mg milligram(s) mL millilitre(s) mol mole mmol(e) millimole
MS Mass Spectrometry
NMR Nuclear Magnetic Resonance
Npas4 Neuronal PAS Domain Protein 4
PCR Polymerase Chain Reaction
PO perorally
RT Reverse transcriptase
SEM standard error of the mean
SC subcutaneously td triplet of doublets
THF Tetrahydrofurane
UV ultraviolet
V ventral
A Angstrom
Preparation 1
3-(4-Methoxyphenyl)propanoyl chloride
3-(4-Methoxyphenyl)propionic acid (50.0 g, 272 mmol) was dissolved in DCM (500 mL) and to the formed solution was added thionylchloride (49.3 mL, 680 mmol). The mixture was heated to reflux for 6 h, allowed to cool to room temperature and then evaporated to dryness using a rotary evaporator. The crude acid chloride (52.8 g, 98%) was used in the next step without further purification.
Preparation 2
3-(4-Methoxyphenyl)propanoyl chloride (23.9 g, 120 mmol) was dissolved in dry THF (30 mL) and the formed solution was slowly added to an ice-cold mixture of ethylamine (2 M in THF, 150 mL, 300 mmol) and triethylamine (20 mL, 144 mmol) in THF (80 mL). The reaction mixture was stirred at room temperature for one hour and then diluted with aqueous sodium carbonate (10%). The mixture was extracted several times with EtOAc, and the combined organic solutions were washed with brine and dried over sodium sulphate. The solvent was removed by evaporation and there was obtained 19.0 g (76%) of the desired amide which was used in the next step without further purification. GC MS m/z (relative intensity, 70 eV) 208 (10), 207 (71), 135 (23), 134 (79), 122 (9), 121 (bp), 119 (9), 108 (9), 91 (19), 78 (11), 77 (14).
Preparation 3
/V-ethyl-3-(4-methoxyphenyl)propenamide (19.0 g, 91.7 mmol) was dissolved in dry THF (150 mL) and the formed solution was added dropwise to a mixture of LiAIH (6.96 g, 183 mmol) in THF (120 mL). The reaction mixture was heated to reflux for 3.5 h, cooled with an ice-bath and then diluted with THF (150 mL). After successively quenching with water (7 mL), aqueous NaOH (15%, 7 mL) and finally with water (21 mL), the mixture was stirred for 15 min and then the solids were removed by filtration. The filter cake was washed with EtOH (3x20 mL) and the filtrate was evaporated to dryness using a rotary
evaporator. Water (50 mL) was added to the residue and the mixture was extracted several times with EtOAc. The combined organic solutions were washed with brine and then dried over sodium sulphate. The solvent was removed by evaporation and there was obtained 16.8 g (95%) of the desired amine that was used in the next step without further purification. GC MS m/z (relative intensity, 70 eV) 193 (38), 148 (51), 147 (20), 134 (7), 121 (30), 117 (7), 91 (15), 78 (11), 77 (13), 70 (7), 58 (bp).
/V-Ethyl-3-(4-methoxyphenyl)propan-1 -amine (16.8 g, 87.0 mmol) was dissolved in dry THF (180 mL) in a three necked round bottom flask and the solution was flushed with nitrogen for several minutes before f-butanol (16 mL, 192 mmol) was added. The solution was cooled to -60°C and then anhydrous ammonia was added via the gas inlet with continues cooling until the volume of the reaction mixture had increased by 180 mL. Metallic lithium (2.35 g, 295 mmol) was slowly added in small portions and the mixture was stirred at -60°C for 4 h. A mixture of MeOH and saturated aqueous ammonium chloride (1 :1 , 62 mL) was added to the mixture which then was allowed to warm to room temperature. After carefully heating with a water bath until most of the ammonia had been evaporated from the flask, the pH was adjusted to about 1 by the addition of concentrated hydrochloric acid. The mixture was stirred at room temperature for 18 h and then the pH was adjusted to above 9 at a temperature below 15°C by the addition of aqueous 4 M NaOH. After extracting the basic mixture several times with DCM, the combined organic solutions were washed with brine and then dried over sodium sulphate. After the solvent was removed by evaporation, the product was purified (and the two stereoisomers were separated) by silica-gel chromatography using EtOAc/MeOH (gradient, 0-10% MeOH) as eluent. There was obtained 4.66 g of the first eluting cis isomer and then 0.51 g of the trans isomer, respectively. The cis isomer was then converted into the desired trans isomer by dissolving 4.66 g in ethanolic KOH (1%, 470 mL), stirring the formed solution at room temperature for four days under a nitrogen atmosphere and the flask covered with aluminium foil. After performing a similar work-up and separation procedures as described above, there was obtained 3.25 g (20%) in total of the racemic trans isomer. GC MS m/z
(relative intensity, 70 eV) 181 (14), 166 (7), 125 (10), 124 (bp), 111 (6), 110 (6), 96 (13), 56 (4), 55 (4). 1H NMR (800 MHz, CDCI3) 6 2.94 (dq, 1 H), 2.81 (m, 1 H), 2.78 (m, 1 H), 2.53 (dq, 1 H), 2.37 (m, 2H), 2.26 (t, 1 H), 2.20 (td, 1 H), 2.09 (ddd,1 H), 1.90 (ddt, 1 H), 1.81 (dt, 1 H), 1.71 (m, 2H), 1.62 (ddd, 1 H), 1.36 (tdd, 1 H), 1.05 (m, 1 H), 0.99 (t, 3H).
Preparation 5
[3-(Ethoxycarbonyl)propyl]triphenylphosphonium bromide (16.7 g, 35.9 mmol) was dissolved in dry DMF (55 mL) and the formed solution was added dropwise to a cooled (0°C) solution of potassium tert-butoxide (4.1 g, 35.9 mmol) in DMF (6 mL) under a nitrogen atmosphere. The mixture was stirred with cooling for 30 min. and then a solution of (4aR,8aR)-1-ethyloctahydroquinolin-7(1 H)-one (3.25 g, 17.9 mmol) in DMF (7 mL) was added dropwise at 0°C. The reaction mixture was stirred with cooling for 4 h and then for 18 h at room temperature. After cooling with an ice-bath, water (120 mL) was added, and the product was extracted several times with diethyl ether. The organic solutions were successively washed with aqueous LiCI (5%, 75 mL) and brine, dried over sodium sulphate and concentrated to dryness on a rotary evaporator. The residue, which consisted of a mixture of the desired ethyl ester and the corresponding tert-butyl ester as a by-product, was dissolved in ethanol (50 mL) together with concentrated sulfuric acid (1 mL). The mixture was heated to reflux for 18 h and then allowed to cool to room temperature. The solvent was removed by evaporation and the residue diluted with water. The pH was adjusted to over 10 by the addition of saturated aqueous Na2CO3 and then the mixture was extracted several times with EtOAc. The combined organic solutions were washed with brine, dried over sodium sulphate, and then evaporated. The product was purified by silica-gel chromatography using isooctane/EtOAc/MeOH (gradient, 0- 100% EtOAc and then 0-100% MeOH) as eluent. There was obtained 4.68 g (93%) of the desired ethyl ester as an oil. GC MS m/z (relative intensity, 70 eV) 279 (4), 234 (5), 125 (10), 124 (bp), 111 (2), 110 (2), 96 (5), 91 (2), 79 (2).
Preparation 6
(4aR,10aR)-1-propyl-1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[q1quinolin-6(7H)-one hydrochloride salt (HCI-salt of prior art compound)
(E)-ethyl 4-(f/'ans-1-propyloctahydroquinolin-7(1 H)-ylidene)butanoate (4.0 g, 13.7 mmol), which had been obtained in a similar fashion as in Preparations 2-5 but using propylamine rather than ethylamine, was mixed with Eaton’s reagent (phosphorus pentoxide, 7.7 wt. % in methanesulfonic acid, 21.1 g) and the mixture was heated at 80°C for 3 h. The reaction mixture was carefully added dropwise to an ice-cooled aqueous solution of NaHCO3 (10%). After extracting three times with DCM, the organic solution was dried over Na2SO , filtered, and evaporated. The residue was purified by silica-gel chromatography using isooctane/EtOAc/MeOH (gradient, 0-100% EtOAc and then 0-100% MeOH) as eluent. There was obtained 1 .4 g of the racemic intermediate and the two enantiomers were thereafter separated on a chiral column (Chiralpak IG, 10mmx250mm) using heptane, EtOH and DEA (90:10:0.1) as eluent. Approximately 25 mg of the racemate was each time loaded on the column and the isomer that eluted last from the column was collected. After pooling the desired fractions, the product was again purified by silica-gel chromatography using isooctane/EtOAc/MeOH as eluent (gradient, 0-100% EtOAc and then 0-100% MeOH). There was obtained 0.35 g of (4aR,10aR)-1-propyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one in its non-salt form as an oil. [a]20 D= -215,6 (c, 0.010 g/mL, MeOH). 1H NMR (800 MHz, CDCI3): 5 0.88 (t, 3H), 1.04 (m, 1H), 1.38 (m, 1 H), 1.49 (m, 2H), 1.62 (m, 1 H), 1.68 (m, 2H), 1.84 (m, 1 H), 1.98 (m, 3H), 2.16 (m, 2H), 2.26 (m, 2H), 2.35 (m, 2H), 2.42 (m, 1H), 2.52 (m, 2H), 2.67 (m, 1 H), 2.97 (m, 1 H).
The HCI-salt of (4aR,10aR)-1-propyl-1 ,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. [a]20 D= -199,6 (c, 0.010 g/mL, MeOH). 1H NMR (800 MHz, methanol-c/4): 6 1.07 (t, 3H), 1.40 (m, 1 H), 1.77 (m, 1 H), 1.86 (m, 3H), 1.9-2.1 (m, 4H), 2.4-2.5 (m, 4H), 2.56 (m, 1 H), 2.68 (m, 1 H), 2.92 (m, 1 H), 3.10 (m, 2H), 3.23 (m, 1 H), 3.32 (m, 1 H), 3.62 (m, 1 H).
Preparation 7
(E)-ethyl 4-(f/'ans-1-methyloctahydroquinolin-7(1H)-ylidene)butanoate was synthesized in a similar fashion as in Preparation 2 to Preparation 5 but using methylamine rather than ethylamine as starting material. Starting with 22 g (111 mmol) of 3-(4- methoxyphenyl)propanoyl chloride and 150 mL of methylamine in THF (2M, 300 mmol) afforded 3.6 g (6%) of (E)-ethyl 4-(f/'ans-1-methyloctahydroquinolin-7(1 H)- ylidene)butanoate as an oil.
Example 1
Synthesis of the hydrochloride salt of (4aR,10aR)-1-ethyl-1 ,2,3,4,4a,5,8,9,10,10a- decahydrobenzo[q1quinolin-6(7H)-one
(E)-ethyl 4-(f/'ans-1-ethyloctahydroquinolin-7(1 H)-ylidene)butanoate from Preparation 5 (4.67 g, 16.7 mmol) was mixed with Eaton’s reagent (18 mL, Phosphorus pentoxide in methanesulfonic acid, 7.7%). The reaction mixture was stirred overnight at 70°C, allowed to cool to room temperature, and then carefully poured into aqueous Na2CO3 (10%, 300 mL). After extracting the basic mixture several times with DCM, the combined organic solutions were washed with brine, dried over sodium sulphate, and then concentrated to dryness using a rotary evaporator. The residue was purified by silica-gel chromatography
using EtOAc/MeOH (gradient, 0-30% MeOH) as eluent and there was obtained 1 .86 g (48%) of the racemic product as an oil. Separating the two enantiomers by repetitive chiral chromatography (Chiralpak® IG, 250x20 mm) using heptane, IPA and DEA (60:40:0.1) as eluent afforded the (+)-enantiomer as the first eluting isomer and the (-)-enantiomer as the last eluting isomer, respectively (approximately 45 mg of the racemic mixture was injected on the column each time). In total, there was obtained 808 mg of the desired (-)-isomer of f/'ans-1-ethyl-1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one in its non-salt form as an oil consisting of 99.5% of the (-)-isomer and 0.5% of the (+)-isomer as determined by analytical chiral chromatography. Also, there was obtained 795 mg of the (+)-isomer of said compound in its non-salt form as an oil. A fraction of the (-)-isomer (80 mg, 0.34 mmol) was dissolved in an ethanolic solution of HCI (1 .25 M, 3 ml_). The solution was evaporated and then co-evaporated twice with ethanol. Dropwise to the residue was added diethyl ether and the formed solid was eventually collected by filtration. After drying in an oven at 70°C for two hours there was obtained 45 mg of the (-)-isomer of trans-1- ethyl-1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one as the hydrochloric acid salt.
Data for the (-)-isomer of trans- 1 -ethyl-1 , 2, 3, 4, 4a, 5, 8, 9, 10, 10a- decahydrobenzo[g]quinolin-6(7H)-one in its non-salt form: MS (ESI+) m/z 234 [M+H]+. [C(]D25 = -199° (c=0.05, methanol). 1H NMR (800 MHz, CDCI3) 6 2.95 (m, 1 H), 2.87 (m, 1 H), 2.53 (m, 3H), 2.42 (m, 1 H), 2.36 (m, 1 H), 2.26 (m, 2H), 2.18 (m, 2H), 2.05 (td,1 H), 1.97 (m, 2H), 1.85 (m, 1 H), 1.68 (m, 3H), 1.41 (m, 1 H), 1.05 (m, 4H).
Data for the corresponding HCI-salt: Melting point: 228.4°C. MS (ESI+) m/z 234 [M+H]+. 1H NMR (800 MHz, methanol-d4) 6 3.59 (m, 1 H), 3.48 (m, 1 H), 3.25 (m, 2H), 3.09 (td, 1 H), 2.91 (dd, 1H), 2.69 (m, 1 H), 2.54 (m, 1 H), 2.41 (m, 4H), 2.03 (m, 4H), 1.95 (m, 1 H), 1.85 (m, 2H), 1.42 (m, 1 H), 1.38 (t, 3H).
The absolute configuration of the two enantiomers was not determined by X-ray crystallography but by comparing the sign of optical rotation as well as elution order for the isomers on the chiral column with that of the isomers of the propyl analogue, which has a known absolute configuration (Preparation 6). Thus, it was concluded that the (-)- isomer of the title compound has the (4aR,10aR)-configuration and the (+)-isomer has the (4aS,10aS)-configuration.
Example 2
The (-)-isomer of f/'ans-1-methyl-1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin- 6(7H)-one was synthesized in a similar fashion as in Example 1 but using (E)-ethyl 4- (frans-1-methyloctahydroquinolin-7(1 H)-ylidene)butanoate from Preparation 7 rather than (E)-ethyl 4-(f/'ans-1-ethyloctahydroquinolin-7(1 H)-ylidene)butanoate. Starting with 3.2 g (12 mmol) of Preparation 7 afforded 0.53 g (20%) of the (-)-isomer of frans-l-methyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one_as an oil.
MS (ESI+) m/z 220 [M+H]+. [a]D 25 = -244° (c=0.05, methanol). 1H NMR (800 MHz, CDCI3) 5 2.88 (m, 1 H), 2.53 (m, 3H), 2.42 (m, 1 H), 2.36 (m, 1 H), 2.27 (m, 2H), 2.14 (m, 2H), 1.97 (m, 2H), 1.85 (m, 1 H), 1.74 (m, 1 H), 1.6-1.7 (m, 3H), 1.40 (m, 1 H), 1.06 (m, 1 H).
The absolute configuration of the two enantiomers was not determined by x-ray crystallography comparing the sign of optical rotation as well as elution order for the isomers on the chiral column with that of the isomers of the propyl analogue, which has a known absolute configuration (Preparation 6). Thus, it was concluded that the (-)-isomer of the title compound has the (4aR,10aR)-configuration and the (+)-isomer has the (4aS,10aS)-configuration.
Example 3
Locomotor activity:
Behavioral activity was measured using eight Digiscan activity monitors (RXYZM (16) TAO, Omnitech Electronics, Columbus, OH, USA), connected to an Omnitech Digiscan analyzer and an Apple Macintosh computer equipped with a digital interface board (NB DIO-24, National Instruments, USA). Each activity monitor consisted of a quadratic metal frame (W x L=40cm x 40cm) equipped with photo beam sensors. During measurements of behavioral activity, a rat was put in a transparent acrylic cage (WxLxH, 40x40x30 cm) which in turn was placed in the activity monitor. Each activity monitor was equipped with three rows of infrared photo beam sensors, each row consisting of 16 sensors. Two rows were placed along the front and the side of the floor of the cage, at a 90° angle, and the third row was placed 10 cm above the floor to measure vertical activity. Photo beam
sensors were spaced 2.5 cm apart. Each activity monitor was fitted in an identical sound and light attenuating box containing a weak house light and a fan.
The computer software was written using object-oriented programming (LabVIEW™, National instruments, Austin, TX, USA).
Behavioral data from each activity monitor, representing the position (horizontal center of gravity and vertical activity) of the animal at each time, were recorded at a sampling frequency of 25 Hz and collected using a custom written LABView™ application. The data from each recording session were stored and analyzed with respect to distance traveled. Each behavioral recording session lasted 180 min, starting approximately 5 min after the injection of test compound.
Compounds disclosed herein have been tested for effects on spontaneous locomotor activity in non-pre-treated Sprague-Dawley rats (based on accumulated distance travelled 0-180 min post dosing), and with the single dose of 0.3 pmol/kg (n=5, SC) compared to a control group of animals (n=5) that obtained saline (SC). The unit of the distance travelled is an arbitrary unit. Further, for the compound according to Example 1 doses of 3 pmol/kg and 9 pmol/kg, respectively, were tested as described herein.
Fig. 2 shows the means of distance travelled after administration of either 0.3 pmol/kg of the prior art compound according to Preparation 6 (4aR,10aR)-1-propyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one 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 bar).
Fig 3 shows the means of distance travelled after administration of either two doses (3 pmol/kg and 9 pmol/kg) of the compound according to Example 1 (4aR,10aR)-1-ethyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one 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 bars) and for the group of animals that obtained the drug [light filled bars (3 pmol/kg) and filled bars (9 pmol/kg)].
As shown in Fig. 2 and Fig. 3, both of the two compounds being tested do affect motor activity patterns in normal, non-pre-treated, rats. The prior art compound is more potent as a dopamine agonist as compared to the inventive compound according to Example 1 which is reflected in the higher doses needed of the compound according to Example 1 (3 pmol/kg and 9 pmol/kg) in order to effectively affect motor activity. Nevertheless, the prior art compound according to Preparation 6 as well as the compound according to Example 1 do induce hyperactivity and that desired effect is lasting for at least 180 min for both of the two compounds showing that both of the two compounds do have a long duration of action. However, a difference between the two compounds is that the on-set of action, i.e. that the distance travelled increases after the initial decrease in distance travelled taking place immediately after administration, for the prior art compound is faster (20-25 min) as compared to the compound according to Example 1 (30-45 min). A further difference is that the immediate effect on motor activity for the prior art compound is steeper with a long distance travelled already within 20-45 min. These data taken together show that the compound according to Example 1 is having a slower on-set of action as compared to that of the prior art compound. Consequently, the compound according to Example 1 is associated with no or a low-risk for the patients to obtain a peak plasma concentration of the active species resulting from the administered drug producing side effects such as nausea and/or vomiting as compared to the prior art compound.
Example 4 m-RNA analysis:
Animals were killed 60 min after the injection of the drugs by decapitation.
The brains were dissected into a left and a right part. The left part was analyzed for gene expression and dissected into 4 different areas:
Limbic system (containing nucleus accumbens, most parts of the olfactory tubercle, ventral pallidum and amygdala), striatum, frontal cortex, and hippocampus.
Total RNA was prepared by RNeasy Plus Universal Tissue Mini Kit (Qiagen).
RNA pellets were dissolved in RNAse-free water and stored at -80°C. The sample concentration was determined spectrophotometrically by a NanoDrop ND-1000.
A two-step reversed transcription was performed by using a Superscript III kit (Invitrogen). 1 pg of total RNA was reversed transcribed with 5 pl 2X RT Reaction Mix, 1 pl RT Enzyme and the mix volume was adjusted to 10 pl with RNAse-free water. The samples was incubated at 25°C for 10 min, 50°C for 30 min and finally 85°C for 5 min. 1 U of E.coli RNase H was added following incubation at 37°C for 20 min and 85°C for 5 minutes. The
cDNA solution was diluted 40 times in Tris EDTA buffer solution pH8 (Merck) and stored at -20°C.
Three sequences (arc and two reference genes) were amplified together in a triplex PCR- reaction. For real-time PCR measurements: 5 pl of the cDNA reaction was amplified in a 20 pl reaction mixture containing 10 pl PerfeCTa Multiplex qPCR SuperMix (Quantabio), 3.5 pl RNAse-free water, 0.15 pM of each primer and 0.1 pM of each probe. Real-time PCR was measured on CFX96 (Bio-Rad) using the following settings for all genes: 3 min pre-incubation at 95°C followed by 40 cycles of denaturation at 95°C for 15s, annealing and elongation at 60°C for 1 min. Reference genes are HPRT and cyclophilin.
TaqMan single and duplex PCR for analysis of EGR-1 and Npas4
The real-time PCR reaction consisted of 10 pl Sso Advanced Universal Probes Supermix, 1 pl primer/probe, 1 pl reference gene or 1 pl MQ water and
8 pl of cDNA (diluted 40 times from RT-PCR). Real-time PCR reactions were performed in a CFX96 Real-Time PCR Detector (Bio-Rad) with the following cycling conditions: initial denaturation at 95°C for 2 min followed by 40 cycles of 95°C for 5 s and 60°C for 30 s.
All genes of interest were labelled with the fluorophore FAM on the 5' end and reference genes (HPRT and ppia (also named cyclophilin)) were labelled with HEX. TaqMan primers and probes were synthesized by Bio-rad (Coralville, Iowa, USA) and used according to the manufacturing protocol.
EGR-1 (Early growth response qRnoCEP0022872) was analyzed in duplex with the reference gene HPRT (hypoxanthine phosphoribosyltransferase qRnoCEP0050840). Npas4 (neuronal PAS domain protein4 qRnoCEP0029461) was analyzed in singleplex.
The reference gene Ppia (cyclophilin A peptidyl-propyl cis-trans isomerase qRnoCIP0050815) was also analyzed in order to quantify gene expression for genes of interest.
Fig. 4 illustrates the effects on tissue levels of Arc mRNA in four different regions of the brain (limbic regions, striatum, frontal cortex and hippocampus) after subcutaneous administration of the prior art compound according to Preparation 6 (4aR,10aR)-1-propyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one. The effects on tissue levels of Arc were measured at two different doses (0.3 pmol/kg and 1 pmol/kg) and the
effects are presented as percent of control means ± SEM. Statistical significance was assessed using Student’s t-test (2 tailed) vs controls.
Fig. 5 illustrates the effects on tissue levels of Arc mRNA in four different regions of the brain (limbic regions, striatum, frontal cortex and hippocampus) after subcutaneous administration of the compound according to Example 1 (4aR,10aR)-1-ethyl- 1 ,2,3,4,4a,5,8,9,10,10a-decahydrobenzo[g]quinolin-6(7H)-one. The effects on tissue levels of Arc were measured at two different doses (3 pmol/kg and 9 pmol/kg) and the effects are presented as percent of control means ± SEM. Statistical significance was assessed using Student’s t-test (2 tailed) vs controls.
In Fig. 4 and Fig. 5 arcL stands for Arc mRNA in the limbic regions, arcs stands for Arc mRNA in striatum, arcF stands for Arc mRNA in the frontal cortex and arcH stands for Arc mRNA in hippocampus.
As shown in the diagrams of Fig. 4 and Fig. 5, both of the two compounds dose- dependently increase tissue levels of Arc in the frontal cortex, which sometimes is observed for a dopamine receptor agonist. Also shown in the diagrams is that the compound according to Example 1 dose-dependently increases the tissue levels of Arc in the limbic regions which is a property that the prior art compound according to Preparation 6 does not have. As Arc is a biomarker of synaptic activity, this attribute of the compound according to Example 1 allows for providing a unique therapeutic profile such as for instance improvements related to emotion, behavior, and/or long-term memory. Furthermore, the compound according to Example 1 increases tissue levels of other genes in the limbic regions such as for instance egr-1 and Npas4. The compound does so to a greater extent as compared to that of the prior art compound according to Preparation 6 and these observed effects allow for an improved therapy for the patients with neurodegenerative diseases and/or neurological disorders.
SEQUENCE LISTING
The primer and probe sequences are as follows for measuring of arc:
Activity-regulated gene (Arc) (accession number U19866)
Sense:5’- GGA GTT CAA GAA GGA GTT TC-3’ (SEQ ID NO:1)
Antisense: 5’- CCA CAT ACA GTG TCT GGT A -3’ (SEQ ID NO:2)
Probe: CCG CTT ACG CCA GAG GAA CT (SEQ ID NO:3)
Dye: 5'FAM Quencher: 3'BHQ1
Product size: 149 Hypoxantine phosphoribosyl transferase (HPRT) (accession number AF001282)
Sense: 5’- AGG GAT TTG AAT CAT GTT TG -3’ (SEQ ID NO:4)
Antisense: 5’- CTG CTA GTT CTT TAC TGG C -3’ (SEQ ID NO:5)
Probe: TGT AGA TTC AAC TTG CCG CTG TC (SEQ ID NO:6)
Dye: 5'HEX Quencher: 3'BHQ1 Product size: 121
Cyclophilin A (cyclo) (accession number M19533)
Sense: 5’- CTG GAC CAA ACA CAA ATG-3’ (SEQ ID NO:7)
Antisense: 5’- ATG CCT TCT TTC ACC TTC -3’ (SEQ ID NO:8) Probe: TTG CCA TCC AGC CAC TCA GT (SEQ ID NO:9)
Dye: 5'Texas red Quencher: 3'BHQ2
Product size: 100
References
1. Liu et al., ’’Extremely Potent Orally Active Benzo[g]quinoline Analogue of the Dopaminergic Prodrug: 6-(N,N-Di-n-propyl)amino-3,4,5,6,7,8-hexahydro-2H- naphtalen-1-one”, J. Med. Chem., 2006, 49, 1494-1498 (The title of this article was soon afterwards corrected to ’’Extremely Potent Orally Active Benzo[g]quinoline Analogue of the Dopaminergic Prodrug: 1-Propyl-trans-2,3,4,4a,5,7,8,9,10,10a- decahydro-1 H-benzo[g]quinoline-6-one”, J. Med. Chem., 2006, 49, 6930)
2. Liu et al., ”A novel synthesis and pharmacological evaluation of a potential dopamine D1/D2 agonist: 1-Propyl 1 ,2, 3, 4, 4a, 5, 10, 10a- octahydrobenzo[g]quinoline-6,7-diol ’’Bioorganic & Medicinal Chemistry, 16 (2008), 3438-3444
3. WO 2010/097092
4. Itoh et al., ”TL333, A Benzhydro[G]quinoline, Stimulates Both D-1 and D-2 Dopamine Receptors: Implications for the Selectivity of LY 141865 Towards the D- 2 Receptor”, European Journal of Pharmacology, 108 (1985), 99-101
5. WO 2019/101917
6. WO 2020/234270
7. WO 2020/234271
8. WO 2020/234272
9. WO 2020/234273
10. WO 2020/234274
11 . WO 2020/234275
12. WO 2020/234276
13. WO 2020/234277
14. WO 2001/078713
Claims
Formula I or a pharmaceutically acceptable salt thereof, wherein carbon 4a and carbon 10a both have R configuration, and R1 is methyl or ethyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Formula la
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Formula lb
4. A pharmaceutically acceptable salt of the compound according to any one of the preceding claims.
5. The compound according to any one of claims 1-3, or the pharmaceutically acceptable salt according to any one of claims 1-4, which is in solid form.
6. The compound according to any one of claims 1-3 or 5, or the pharmaceutically acceptable salt according to any one of claims 1-5, which is in crystalline form.
7. A pharmaceutical composition comprising a therapeutically acceptable amount of the compound according to any one of claims 1-3 or 5, or the pharmaceutically acceptable salt according to any one of claims 1-6, in admixture with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
8. The compound according to any one of claims 1-3 or 5, or the pharmaceutically acceptable salt according to any one of claims 1-6, or the pharmaceutical composition according to claim 7 for use as a medicament.
9. The compound according to any one of claims 1-3 or 5, or the pharmaceutically acceptable salt according to any one of claims 1-6, or the pharmaceutical composition according to claim 7 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.
10. The compound for use according to claim 9, or the pharmaceutically acceptable salt for use according to claim 9, or the pharmaceutical composition for use according to claim 9 wherein the treatment comprises or consists of treatment of Parkinson's disease.
11 . The compound for use according to claim 9 or 10, or the pharmaceutically acceptable salt for use according to claim 9 or 10, or the pharmaceutical composition for use according to claim 9 or 10
wherein the treatment is associated with no or mild side effect(s).
12. The compound for use according to claim 11 , or the pharmaceutically acceptable salt for use according to claim 11 , or the pharmaceutical composition for use according to claim 11 wherein the mild side effect(s) comprise(s) or consist(s) of nausea and/or vomiting.
13. The compound for use according to any one of claims 9-12, or the pharmaceutically acceptable salt for use according to any one of claims 9-12, or the pharmaceutical composition for use according to any one of claims 9-12 wherein the treatment further comprises treatment of non-motor symptom(s) associated with Parkinson's disease.
14. The compound for use according to claim 13, or the pharmaceutically acceptable salt for use according to claim 13, or the pharmaceutical composition for use according to claim 13 wherein the non-motor symptom(s) associated with Parkinson's disease comprise(s) or consist(s) of one or more of the following: cognitive functional decline, depression, anxiety, apathy, Parkinson's disease dementia.
15. Use of a compound according to any one of claims 1 -3 or 5, or a pharmaceutically acceptable salt according to any one of claims 1-6, or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for use in the treatment of Parkinson's disease, Huntington's disease, Restless leg syndrome, Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, drug addiction.
16. The use according to claim 15, wherein the treatment comprises or consists of treatment of Parkinson's disease.
17. The use according to claim 15 or 16, wherein the treatment is associated with no or mild side effect(s).
18. The use according to claim 17, wherein the mild side effect(s) comprise(s) or consist(s) of nausea and/or vomiting.
19. The use according to any one of claims 15-18, wherein the treatment further comprises treatment of non-motor symptom(s) associated with Parkinson's disease.
20. The use according to claim 19, wherein the non-motor symptom(s) associated with Parkinson's disease comprise(s) or consist(s) of one or more of the following: cognitive functional decline, depression, anxiety, apathy, Parkinson's disease dementia.
21. 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 comprising administering to a mammal in need thereof, a therapeutically effective amount of: a compound according to any one of claims 1-3 or 5, or a pharmaceutically acceptable salt according to any one of claims 1-6, or a pharmaceutical composition according to claim 7.
22. The method according to claim 21 , wherein the mammal is a human and/or an animal.
23. The method according to claim 21 or 22, wherein the treatment comprises or consists of treatment of Parkinson's disease.
24. The method according to any one of claims 21-23, wherein the treatment is associated with no or mild side effect(s).
25. The method according to claim 24, wherein the mild side effect(s) comprise(s) or consist(s) of nausea and/or vomiting.
26. The method according to any one of claims 21-25, wherein the treatment further comprises treatment of non-motor symptom(s) associated with Parkinson's
disease. The method according to claim 26, wherein the non-motor symptom(s) associated with Parkinson's disease comprise(s) or consist(s) of one or more of the following: cognitive functional decline, depression, anxiety, apathy, Parkinson's disease dementia.
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