WO2020070099A1

WO2020070099A1 - Administration of catecholamine prodrugs in combination with a 5-ht2b antagonist

Info

Publication number: WO2020070099A1
Application number: PCT/EP2019/076529
Authority: WO
Inventors: Peter FLAGSTAD; Nathalie BREYSSE; Claus Tornby CHRISTOFFERSEN; Morten JØRGENSEN
Original assignee: H. Lundbeck A/S
Priority date: 2018-10-02
Filing date: 2019-10-01
Publication date: 2020-04-09

Abstract

The present invention provides combinations comprising treatment with compounds that are prodrugs of the dopamine agonist (4aR,10aR)-1-n-Propyl-1,2,3,4,4a,5,10,10a- octahydro-benzo[g]quinoline-6,7-diol, in particular compounds of formula (Ia) below or a pharmaceutically acceptable salt thereof, together with a 5-HT2B antagonist. R1 and R2 are selected independently from the group consisting of H, C_1-6 alkyl and saturated monocyclic C_3-6 cycloalkyl, or one of R1 and R2 is H and the other is phenyl, or R1 and R2 are connected to form a saturated monocyclic _3-6 cycloalkyl.Especially, the invention is directed to the combined use of said compounds in the treatment of Parkinson's disease and/or other conditions for which treatment with a dopamine agonist is therapeutically beneficial. The present invention also provides pharmaceutical compositions comprising said compounds and a 5-HT2B antagonist. In a separate aspect, the invention relates to new compounds that are prodrugs of (4aR,10aR)-1-n-Propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol wherein R1 and R2 are individually selected from the group consisting of H, C_1-6 alkyl and saturated monocyclic C_3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof; with the proviso that both R1 and R2 cannot be H at the same time.

Description

Administration of catecholamine prodrugs in combination with a 5-HT2B antagonist.

FIELD OF THE INVENTION

The present invention provides combinations comprising treatment with compounds that are prodrugs of the dopamine agonist (4aR,10aR)-l-n-Propyl-l,2,3,4,4a,5,10,10a- octahydro-benzo[g]quinoline-6,7-diol together with a 5-HT2B antagonist. Especially, the invention is directed to the combined use of said compounds in the treatment of

Parkinson's disease and/or other conditions for which treatment with a dopamine agonist is therapeutically beneficial. The present invention also provides pharmaceutical compositions comprising said compounds and a 5-HT2B antagonist.

In a separate aspect, the invention relates to new compounds that are prodrugs of (4aR,10aR)-l-n-Propyl-l,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol.

BACKGROUND OF THE INVENTION

Parkinson's disease (PD) is a common neurodegenerative disorder that becomes increasingly prevalent with age and affects an estimated seven to ten million people worldwide. Parkinson's disease is a multi-faceted disease characterized by both motor and non-motor symptoms. Motor symptoms include resting tremor (shaking),

bradykinesia/akinesia (slowness and poverty of movements), muscular rigidity, postural instability and gait dysfunction; whereas non-motor symptoms include neuropsychiatric disorders (e.g. depression, psychotic symptoms, anxiety, apathy, mild-cognitive impairment and dementia) as well as autonomic dysfunctions and sleep disturbances (Poewe et al., (2017), Nature Review, vol 3 article 17013 for review).

A key hallmark of Parkinson's disease pathophysiology is the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta that provides dopaminergic innervation to the striatum and other brain areas. Such progressive neurodegeneration leads to the decrease in dopamine striatal levels which ultimately results in a series of changes in the basal ganglia circuitry, ultimately ending up in the occurrence of the four cardinal motor features of Parkinson's disease. The main target of dopamine in the striatum consists of medium spiny GABAergic neurons (MSNs) selectively expressing D1 or D2 receptors pending topographical projections. GABAergic-MSN projecting to the external pallidum, also called striato-pa I lida I 'indirect pathway' express D2 receptors (MSN-2);

whereas GABAergic-MSN projecting to the substantia nigra pars reticulata and internal pallidum, also called striato-nigral 'direct pathway' express D1 receptors (MSN-1). Depletion of dopamine because of neuronal loss results in an imbalanced activity of the two pathways, resulting in a marked reduction of thalamic and cortical output activities and ultimately motor dysfunctions (Gerfen et a I, (1990) Science 250: 1429-32; Delong, (1990) Trends in Neuroscience 13: 281-5; Alexander et Crutcher, (1990) Trends in Neuroscience 13: 266-71; and for review Poewe et al., (2017) Nature Review, vol. 3 article 17013).

The most effective therapeutic strategies available to patients suffering from

Parkinson's disease, and aiming at controlling motor symptoms are primarily indirect and direct dopamine agonists. The classic and gold standard treatment regimen includes chronic oral intake of L-3,4-di hydroxy phenylalanine (L-DOPA) which is decarboxylated in the brain to form dopamine. Other approaches consist in the administration of dopamine receptor agonists such as apomorphine which acts both on the D1 and D2 receptors subtypes, or pramipexole, ropinirole and others which are exclusively directed towards D2 receptors subtypes. Optimal motor relief is obtained with use of both L-DOPA and apomorphine due to their activation of both D1 and D2 receptor subtypes and holistic re-equilibrium of the indirect-direct pathways (i.e. while D2 agonists only reverse the indirect pathway

dysfunction).

L-DOPA and apomorphine with the structures depicted below are currently the most efficacious PD drugs in clinical use.

L-DOPA is a prodrug of dopamine and remains the most efficacious drug in the treatment of motor Parkinson's disease. However, after several years of treatment (i.e. honeymoon period), complications arise due the inherent progression of the disease (i.e. sustained loss of dopaminergic neurons) as well as poor pharmacokinetic (PK) profile of L- DOPA. Those complications include ¹¹ dyskinesia which are abnormal involuntary

movements occurring during the optimal 'on-time effect' of the drug; and ²⁾ off fluctuations, period during which the L-DOPA positive effect wears off and symptoms re-emerge or worsen (Sprenger and Poewe, (2013), CNS Drugs, 27: 259-272).

Direct dopamine receptor agonists are able to activate the dopamine autoreceptors as well as the postsynaptic dopamine receptors located on the medium spiny neurons MSN- 1 and MSN-2. Apomorphine belongs to a class of dopamine agonists with a 1,2- dihydroxybenzene (catechol) moiety, which are generally known to possess low or no oral bioavailability. Apomorphine is used clinically in PD therapy albeit by non-oral delivery (typically intermittent subcutaneous administration or daytime continuous parenteral infusion via a pump). The poor oral bioavailability of catecholamines has prevented their clinical use as oral drugs. For apomorphine, animal studies have shown that transdermal delivery or implants may provide possible forms of administration. However, when the delivery of apomorphine from implants was studied in monkeys (Bibbiani et al., Chase Experimental Neurology (2005), 192, 73-78) it was found that in most cases the animals had to be treated with the immunosuppressant Dexamethasone to prevent local irritation and other complications following the implantation surgery. Alternative delivery strategies for apomorphine therapy in PD such as inhalation and sublingual formulations have been extensively explored (see e.g. Grosset et al. (2013), 128:166-171 and Hauser et al.,

Movement Disorders (2016), Vol. 32 (9): 1367-1372). However, these efforts are yet not in clinical use for the treatment of PD.

An alternative to the non-oral formulations of the catecholamines involves the use of a prodrug masking the free catechol hydroxy groups to enable oral administration.

However, a known problem associated with the development of prodrugs for clinical use is the difficulties associated with predicting conversion to the parent compound in humans.

The compound (4aR,10aR)-l-n-Propyl-l,2,3,4,4a,5,10,10a-octahydro- benzo[g]quinoline-6,7-diol depicted as compound (I) below is a catecholamine known for example from Liu et al., J. Med. Chem. (2006), 49: 1494-1498.

Compound (I) is a dopamine agonist with mixed D1 and D2 activity.

WO 2009/026934 discloses a methylene-di-oxy (MDO) acetal derivative of compound (I) with the formula (la-i) below:

(la-i)

Compound (la-i) has been demonstrated to be a prodrug of compound (I). The conversion of compound (la-i) to compound (I) in rat and human hepatocytes has been disclosed in WO 2010/097092. Furthermore, the in vivo pharmacology of compound (la-i) as well as the active "parent compound" (I) has been tested in various animal models relevant for Parkinson's Disease (WO 2010/097092). Both compound (I) and compound (la-i) were found to be effective, indicating that compound (la-i) is converted in vivo to compound (I). Compound (la-i) was reported to have a duration of action that was longer than observed for L-dopa and apomorphine.

Despite the long-standing interest in the field, there is evidently still an unmet need as regards developing efficient, well-tolerated treatments with orally active drugs for Parkinson's Disease. SUMMARY OF THE INVENTION

The present invention relates to new combinations for treatment of Parkinson's Disease and/or other conditions for which treatment with a dopamine agonist is

therapeutically beneficial. More particularly, the invention relates to combined

administration of prodrugs of compound (I) and a 5-HT2B antagonist. Accordingly, the present invention relates to:

1) A first compound of formula (la)

wherein R1 and R2 are selected independently from the group consisting of H, Ci-e alkyl and saturated monocyclic C3-6 cycloalkyl, or one of R1 and R2 is H and the other is phenyl, or R1 and R2 are connected to form a saturated monocyclic 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof; and

2) a second compound which is a 5-HT2B antagonist; or a pharmaceutically acceptable salt thereof; wherein 1) and 2) are for combined use in therapy.

In one embodiment, the invention relates to a first compound of formula (la) or a pharmaceutically acceptable salt thereof; and a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; wherein said first and second compound are for combined use in the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

In one embodiment, the invention relates to a method for the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; which method comprises the administration of a therapeutically effective amount of a first compound of formula (la) or a pharmaceutically acceptable salt thereof; and a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; to a patient in need thereof.

In one embodiment, the invention relates to a pharmaceutical composition comprising

1) a therapeutically effective amount of a first compound of formula (la) or a

pharmaceutically acceptable salt thereof; and

2) a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, diluents and excipients. A separate aspect of the invention relates to a compound of formula (la'),

wherein R1 and R2 are selected independently from the group consisting of H, Ci-e alkyl and saturated monocyclic C3-6 cycloalkyl, or one of R1 and R2 is H and the other is phenyl, or R1 and R2 are connected to form a saturated monocyclic 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof; with the proviso that both R1 and R2 cannot be H at the same time. DEFINITIONS

Compounds of formula (la)

In the context of the invention, compounds of formula (la) represent compound (la-i) and substituted derivatives of compound (la-i). Compounds of formula (la') represents substituted derivatives of compound (la-i). Thus, compounds of formula (la') are

encompassed by the scope of formula (la). The term "substituted derivatives" in the context of the present invention indicates compounds of formula (la) wherein R1 and R2 are selected independently from the group consisting of H, Ci-e alkyl and saturated monocyclic C3-6 cycloalkyl, or one of R1 and R2 is H and the other is phenyl, or R1 and R2 are connected to form a saturated monocyclic 3-6 cycloalkyl; with the proviso that both R1 and R2 cannot be H at the same time. Reference to compounds of formula (la) includes the free substance (zwitter ion) of the compounds, pharmaceutically acceptable salts of the compounds, such as acid addition salts or base addition salts, and polymorphic and amorphic forms of compounds of the compounds and of pharmaceutically acceptable salts thereof. Furthermore, the compounds of formula (la) and pharmaceutically acceptable salts thereof may potentially exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Both solvated and unsolvated forms are encompassed by the present invention.

Substituents

The term "Ci-e alkyl" refers to a linear (i.e. unbranched) or branched saturated hydrocarbon having from one up to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl- 2-propyl, 2-methyl-l-butyl and n-hexyl

The term "saturated monocyclic C3-6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Pharmaceutically acceptable salts

The combinations of the present invention also comprise pharmaceutically acceptable salts of the compounds of formula (la) and pharmaceutically acceptable salts of 5-HT2B inhibitors. Pharmaceutically acceptable salts in the present context is intended to indicate non-toxic, i.e. physiologically acceptable salts.

The term "pharmaceutically acceptable salts" include salts formed with inorganic and/or organic acids. Said acids may be selected from for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid, saccharin, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid.

The term "pharmaceutically acceptable salts" also includes salts formed with inorganic and/or organic bases. Said bases may be selected from for example alkali metal bases, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, alkaline earth bases, such as calcium hydroxide and magnesium hydroxide, and organic bases, such as trimethylamine and trimethylamine.

Additional examples of useful acids and bases to form pharmaceutically acceptable salts can be found e.g. in Stahl and Wermuth (Eds) "Handbook of Pharmaceutical salts. Properties, selection, and use", Wiley-VCH, 2008.

Prodrug

In the present context, the terms "prodrug" or "prodrug derivative" indicates a compound that, after administration to a living subject, such as a mammal, preferably a human; is converted within the body into a pharmacologically active moiety. The conversion preferably takes place within a mammal, such as in a mouse, rat, dog, minipig, rabbit, monkey and/or human. In the present context a "prodrug of the compound (4aR,10aR)-l-n- Propyl-l,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol" or "a prodrug of the compound of formula (I)" is understood to be a compound that, after administration, is converted within the body into the compound (4aR,10aR)-l-n-Propyl-l,2,3,4,4a,5,10,10a- octahydro-benzo[g]quinoline-6,7-diol. Said administration may be by any conventional route of administration of pharmaceutical compositions known in the art, preferably by oral administration.

In the present context, the terms "parent compound" and "parent molecule" indicate the pharmacologically active moiety obtained upon conversion of a corresponding prodrug. For example, the "parent compound" of a compound of formula (la) is understood to be the compound of formula (I).

Pharmacokinetic definitions and abbreviations

As used herein, a "PK profile" is an abbreviation of "pharmacokinetic profile".

Pharmacokinetic profiles and pharmacokinetic parameters described herein are based on the plasma concentration-time data obtained for the compound of formula (I) after oral dosing of a compound of the invention, using non-compartmental modelling. Abbreviated PK parameters are Cmax (maximum concentration) ; tmax (time to Cmax ); t_½ (half-life); AUCo- (area under the curve from time of dosing to infinity). Therapeutically effective amount

In the present context, the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, arrest, partly arrest, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage of a compound of formula (la) may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

In the context of the present invention, a "therapeutically effective amount" of a compound of formula (la) indicates an amount of said compound of formula (la) that is able to provide an amount of the compound of formula (I) which is sufficient to alleviate, arrest, partly arrest, remove or delay the clinical manifestations of a given disease and its complications when said compound of formula (la) is administered, preferably by the oral route, to a mammal, preferably a human.

Treatment and treating

In the present context, "treatment" or "treating" is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting, removing or delaying progress of the clinical manifestation of the disease. The patient to be treated is preferably a mammal, in particular a human being.

Conditions for treatment

The compound of formula (la) or a pharmaceutically acceptable salt thereof is intended for treatment of neurodegenerative diseases and disorders such as Parkinson's disease and/or other conditions for which treatment with a dopamine agonist is

therapeutically beneficial.

Therapeutic indications include a variety of central nervous system disorders characterized by motor and/or non-motor disturbances and for which part of the underlying pathophysiology is a dysfunction of the striatal-mediated circuitry. Such functional disturbances can be seen in neurodegenerative diseases such as but not limited to

Parkinson's disease (PD), Restless leg syndrome, Huntington's disease, and Alzheimer's disease but also neuropsychiatric diseases such as, but not limited to schizophrenia, attention deficit hyperactivity disorder and drug addiction.

In addition to neurodegenerative diseases and disorders, other conditions in which an increase in dopaminergic turnover may be beneficial are in the improvement of mental functions including various aspects of cognition. It may also have a positive effect in depressed patients, and it may also be used in the treatment of obesity as an anorectic agent and in the treatment of drug addiction. It may improve minimal brain dysfunction (MBD), narcolepsy, attention deficit hyperactivity disorder and potentially the negative, the positive as well as the cognitive symptoms of schizophrenia.

Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are alternative indications, which are clinically treated with dopamine agonists. In addition, impotence, erectile dysfunction, SSRI induced sexual dysfunction, ovarian hyperstimulation syndrome (OHSS) and certain pituitary tumors (prolactinoma) are also likely to be improved by treatment with dopamine agonists. Dopamine is involved in regulation of the

cardiovascular and renal systems, and accordingly, renal failure and hypertension can be considered alternative indications for the compounds of the invention.

The invention encompasses use of the compound of formula (la) in combination with a 5-HT2B antagonist for treatment of all diseases and disorders listed above.

Combinations

The terms "combined use", "in combination with" and "a combination of" and the like as used herein in the context of the method of the invention comprising the combined administration of therapeutically effective amounts of 1) a first compound of formula (la) or a pharmaceutically acceptable salt thereof, and 2) a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; is intended to mean the administration of a compound of formula (la) simultaneously or sequentially, in any order, together with a 5-HT2B antagonist. The two compounds may be administered simultaneously or with a time gap between the administrations of the two compounds. The two compounds may be administered either as part of the same pharmaceutical formulation or composition, or in separate pharmaceutical formulations or compositions. The two compounds may be administered on the same day or on different days. They may be administered by the same route, such as by oral administration, or by depot, or by intramuscular or intra peritoneal injection, or by intravenous injection; or by different routes wherein one compound is for example administered orally or placed by depot and the other compound is injected, or wherein one compound is for example placed by depot and the other is administered orally or injected. The two compounds may be administered by the same dosage regime or interval, such as once or twice daily, weekly, or monthly; or by different dosage regimes for example wherein one is administered once daily and the other is administered twice daily, weekly or monthly.

5-HT2B antagonists

In the context of the present invention, a compound is considered to be a 5-HT2B antagonist if the pKi of the compound at the 5-HT2B receptor is 5 or more, such as 6 or more, preferably 7 or more.

Representative examples of 5-HT2B antagonists in the context of the present invention are selected from, but not limited to amisulpride, agomelatine, tegaserod, naluzotan, PRX-3140, BW-723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER-082, BF-1, lisuride, SB-200646A, vabicaserin, SB-221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

Preferably, said 5-HT2B antagonist is administered in an amount that is at least sufficient to antagonize or outcompete the 5-HT2B agonism caused by the compound of formula (la). It will be understood that determining an appropriate dosage of a 5-HT2B antagonist in the context of the present invention, may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician. Administration routes

The pharmaceutical compositions comprising a compound of formula (la) or a pharmaceutically acceptable salt thereof and/or a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof, may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, buccal, sublingual, pulmonal, transdermal and parenteral (e.g. subcutaneous, intramuscular, and intravenous) route. In the context of the present invention the oral route is the preferred route of administration.

It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.

Pharmaceutical formulations and excipients

In the following, the term, "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients including, but not limited to, fillers, antiadherents, binders, coatings, colours, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.

The present invention also provides a pharmaceutical composition comprising 1) a first compound of formula (la) or a pharmaceutical acceptable salt thereof; and 2) a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable excipients in accordance with conventional techniques such as those disclosed in Remington, "The Science and Practice of Pharmacy", 22^th edition (2012), Edited by Allen, Loyd V., Jr.

Pharmaceutical compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups as well as powders and granules to be dissolved or suspended in an appropriate liquid.

Solid oral dosage forms may be presented as discrete units (e.g. tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient, and preferably one or more suitable excipients. Where appropriate, the solid dosage forms may be prepared with coatings such as enteric coatings or they may be formulated so as to provide modified release of the active ingredient such as delayed or extended release according to methods well known in the art. Where appropriate, the solid dosage form may be a dosage form disintegrating in the saliva, such as for example an orodispersible tablet.

Examples of excipients suitable for solid oral formulation include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatin, pectin, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Similarly, the solid formulation may include excipients for delayed or extended release formulations known in the art, such as glyceryl monostearate or hypromellose. If solid material is used for oral administration, the formulation may for example be prepared by mixing the active ingredient with solid excipients and subsequently compressing the mixture in a conventional tableting machine; or the formulation may for example be placed in a hard capsule e.g. in powder, pellet or mini tablet form. The amount of solid excipient will vary widely but will typically range from about 25 mg to about 1 g per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs, syrups, oral drops or a liquid filled capsule. Liquid oral dosage forms may also be presented as powders for a solution or suspension in an aqueous or non-aqueous liquid. Examples of excipients suitable for liquid oral formulation include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol, poly-sorbate, mono and di-glycerides,

cyclodextrins, coconut oil, palm oil, and water. Liquid oral dosage forms may for example be prepared by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations, such as colourings, flavourings and preservatives etc.

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion as well as sterile powders to be reconstituted in sterile solutions or dispersions for injection or infusion prior to use. Examples of excipients suitable for parenteral formulation include, but are not limited to water, coconut oil, palm oil and solutions of cyclodextrins. Aqueous formulations should be suitably buffered if necessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, dermal patches, implants and formulations for buccal or sublingual administration.

It is requisite that the excipients used for any pharmaceutical formulation comply with the intended route of administration and are compatible with the active ingredients.

Doses

In one embodiment, the compound of formula (la) or a pharmaceutically acceptable salt thereof is administered in an amount from about 0.0001 mg/kg body weight to about 5 mg/kg body weight per day. In particular, daily dosages may be in the range of 0.001 mg/kg body weight to about 1 mg/kg body weight per day. 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 other factors known to those skilled in the art.

A typical oral dosage of a compound of formula (I) will be in the range of 0.01-100 mg/day of a compound of the present invention, such as 0.05-50 mg/day, such as 0.1-10 mg/day or 0.1-5 mg/day. Conveniently, the compounds of the invention are administered in a unit dosage form containing said compounds in an amount of about 0.01 to 50 mg, such as 0.05 mg, 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg or up to 50 mg of a compound of the present invention.

The second compound used in the present invention, which is a 5-HT2B antagonist is preferably dosed in an amount sufficient to outcompete the agonistic effect of the compound of formula (la) at the 5-HT2B receptor. BRIEF DESCRIPTION OF FIGURES

Figure 1: PK profile in Wistar rats obtained after oral dosing of compound (la-i) according to Example 3 (n=3).

X-axis: time (hours); Y-axis: plasma concentration of Compound (I) obtained after oral dosing of the compound (la-i) (pg/mL).

DETAILED DESCRIPTION OF THE INVENTION

The compound (6aR,10aR)-7-n-Propyl-6,6a,7,8,9,10,10a,ll-octahydro-l,3-dioxa-7- aza-cyclopenta[a]anthracene with the formula (la-i) below is disclosed in WO 2009/026934 as an MDO prodrug derivative of (4aR,10aR)-l-n-Propyl-l,2,3,4,4a,5,10,10a-octahydro- benzo[g]quinoline-6,7-diol [compound (I)]. While Compound (la-i) does not possess any dopamine agonist activity, Compound (I) is a dual D1/D2 agonist (Example 1, Table 1).

(la-i)

The properties of compound (la-i) as a prodrug of compound (I) has been demonstrated in WO 2009/026934 and WO 2010/097092 indicating in in vitro conversion to

Compound (I) rat and human hepatocytes. This was further substantiated in WO

2010/097092 demonstrating activity shown in rodent and marmoset Parkinson's Disease models after oral dosing of compound (la-i). The PK profile in Figure 1 obtained according to Example 3, illustrates plasma concentrations of Compound (I) obtained after oral dosing of compound (la-i) to Wistar rats.

The inventors have now found that compound (la-i) is a 5-HT2B receptor agonist (Example 2, table 1). Since 5-HT2B receptor agonists have been linked to pathogenesis of valvular heart disease (VHD) after long term exposure, such compounds are not suitable for use in the treatment of chronical diseases (Rothman et al., Circulation. 2000; 102-2836- 2841; and Cavero and Guillon, J. Pharmacol. Toxicol. Methods. 2014. 69: 150-161). It is expected that replacing one or both hydrogens at the MDO bridge with an alkyl substituent maintains the prodrug activity (GB2105323). Therefore, the inventors decided to explore whether alkylation of the MDO bridge could solve the problem of 5-HT2B agonism.

However, it was found that the two new methylated derivatives (la-ii) and (la-iii) were also 5-HT2B agonists (table 1).

Therefore, the present invention relates to the combined administration of optionally substituted MDO derivatives of compound (I) and pharmaceutically acceptable salts thereof, and a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; to avoid unwanted side effects arising from administration of the optionally substituted MDO derivatives. Said optionally substituted MDO derivatives are herein denoted "compounds of formula (la)". In a particular embodiment, the invention relates to the combined

administration of compound (la-i) or a pharmaceutically acceptable salt thereof, and a 5- HT2B antagonist or a pharmaceutically acceptable salt thereof.

The combined administration of a compound of formula (la) or a pharmaceutically acceptable salt thereof; and a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; is useful in the treatment of neurodegenerative diseases and disorders such as Parkinson's disease and/or other conditions for which treatment with a dopamine agonist is therapeutically beneficial.

The inventors have found that oral dosing of compound (la-i) to Wistar rats (Figure 1) results in an early and high peak concentration of compound (I) which is likely to be associated with peripheral dopaminergic side effects such as for example nausea, vomiting and light headedness. Such side effects may be reduced or avoided by co-administration of a peripheral dopamine antagonist. Thus, in a separate embodiment of the present invention, a compound of formula (la) is administered in combination with a peripheral dopamine agonist or a pharmaceutically acceptable salt thereof. In a combined further embodiment, a compound of formula (la) or a pharmaceutically acceptable salt thereof is administered in combination with a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof which is also a dopamine antagonist with the ability to antagonize peripheral dopamine receptors. Amisulpride processes the properties of being both a 5-HT2B antagonist and a dopamine antagonist. Thus, in a particular embodiment the invention relates to the combined administration of a compound of formula (la) or a pharmaceutically acceptable salt thereof; and amisulpride or a pharmaceutically acceptable salt thereof. The present invention also relates the new substituted MDO derivatives of compound (I) and salts thereof, which derivatives are denoted "compounds of formula (la')".

Embodiments of the invention

In the following, embodiments of the invention are disclosed. The first embodiment is denoted El, the second embodiment is denoted E2 and so forth.

El. 1) A first compound of formula (la)

wherein

R1 and R2 are selected independently from the group consisting of H, Ci-e alkyl and saturated monocyclic C cycloalkyl, or one of R1 and R2 is H and the other is phenyl, or R1 and R2 are connected to form a saturated monocyclic 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof; and 2) a second compound which is a 5-HT2B antagonist, or a pharmaceutically acceptable salt thereof; wherein 1) and 2) are for combined use in therapy.

E2. The compounds for use according to embodiment 1, wherein R1 and R2 are individually selected from H and methyl.

E3. The compounds for use according to embodiment 1, wherein R1 and R2 are both H.

E4. The compounds for use according to embodiment 1, wherein R1 is H, and R2 is selected from Ci-e alkyl and saturated monocyclic C3-6 cycloalkyl.

E5. The compounds for use according to any of embodiments 1 or 4, wherein R1 is H, and R2 is methyl.

E6. The compounds for use according to embodiment 1 wherein R1 is selected from Ci-₆ alkyl and saturated monocyclic C3-6 cycloalkyl, and R2 is H.

E7. The compounds for use according to any of embodiments 1 or 6, wherein R1 is methyl, and R2 is H.

E8. The compounds according to embodiment 1, wherein said first compound is selected from the group consisting of:

(la-i): (6aR,10aR)-7-n-Propyl-6,6a,7,8,9,10,10a,ll-octahydro-l,3-dioxa-7-aza- cyclopenta[a]anthracene; (la-ii): (2R,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro- [l,3]dioxolo[4',5':5,6]benzo[l,2-g]quinoline; and

(la-iii): (2S,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro- [l,3]dioxolo[4',5':5,6]benzo[l,2-g]quinoline; or a pharmaceutically acceptable salt of any of these compounds.

E9. A first compound as described in any one of embodiments 1-8 or a pharmaceutically acceptable salt thereof, and a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; wherein said first and second compound are for combined use in the treatment of a neurodegenerative disease or disorder such as

Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

E10. The first and second compound according to any of embodiments 1-9, wherein said second compound is used in an amount that is at least sufficient to antagonize any 5-HT2B agonism caused by said first compound.

Ell. The first and second compound according to any of embodiments 1-10, wherein said second compound is selected from the group consisting of amisulpride, agomelatine, tegaserod, naluzotan, PRX-3140, BW-723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER-082, BF-1, lisuride, SB-200646A, vabicaserin, SB- 221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

E12. The first and second compound according to any of embodiments 1-11, wherein said second compound is amisulpride. E13. A method for the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; which method comprises the administration of a therapeutically effective amount of a first compound as described in any one of embodiments 1-8 or a pharmaceutically acceptable salt thereof, and a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; to a patient in need thereof.

E14. The method according to embodiment 13, wherein said second compound is to be administered in an amount that is at least sufficient to antagonize any 5-HT2B agonism caused by said first compound in said patient.

E15. The method according to any of embodiments 13-14, wherein said second compound is selected from the group consisting of amisulpride, agomelatine, tegaserod, naluzotan, PRX-3140, BW-723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER-082, BF-1, lisuride, SB-200646A, vabicaserin, SB-221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

E16. The method according to any of embodiments 13-15, wherein said second compound is amisulpride.

E17. Use of a first compound as described in any one of embodiments 1-8 or a

pharmaceutically acceptable salt thereof, and a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder such as

Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction. E18. Use of a first compound as described in any one of embodiments 1-8 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease,

Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; wherein said medicament is to be used together with a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof.

E19. The use according to any of embodiments 17-18, wherein said second compound is used an amount that is at least sufficient to antagonize any 5-HT2B agonism caused by said first compound.

E20. The use according to any of embodiments 17-19, wherein said second compound is selected from the group consisting of amisulpride, agomelatine, tegaserod, naluzotan, PRX- 3140, BW-723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER-082, BF-1, lisuride, SB-200646A, vabicaserin, SB-221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

E21. The Use according to any of embodiments 17-20, wherein said second compound is amisulpride.

E22. A pharmaceutical composition comprising

1) a therapeutically effective amount of a first compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof; and

2) a second compound which is a 5-HT2B antagonist, or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, diluents and excipients.

E23. The pharmaceutical composition according to embodiment 22, wherein said second compound present in an amount that is at least sufficient to antagonize any 5-HT2B agonism caused by said first compound.

E24. The pharmaceutical composition according to any of embodiments 22-23, wherein said second compound is selected from the group consisting of amisulpride, agomelatine, tegaserod, naluzotan, PRX-3140, BW-723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER-082, BF-1, lisuride, SB-200646A, vabicaserin, SB- 221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

E25. A kit comprising

1) a first compound as described in any one of embodiments 1-8 or a pharmaceutically acceptable salt thereof, and

2) a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof.

E26. The kit according to embodiment 25, which is adapted for simultaneous

administration of said first compound and said second compound.

E27. The kit according to embodiment 26, which is adapted for independent

administration of said first compound and said second compound. E28. The kit according to any of embodiments 25-27, wherein said second compound is present in an amount that is at least sufficient to antagonize any 5-HT2B agonism caused by said first compound.

E29. The kit according to any of embodiments 25-28, wherein said second compound is selected from the group consisting of amisulpride, agomelatine, tegaserod, naluzotan, PRX- 3140, BW-723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER-082, BF-1, lisuride, SB-200646A, vabicaserin, SB-221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

E30. The pharmaceutical composition according to any of embodiments 22-24 or the kit according to any of embodiments 25-29, wherein said pharmaceutical composition and said kit are for use in the treatment of a neurodegenerative disease or disorder such as

E31. A compound according to formula (la')

wherein

R1 and R2 are selected independently from the group consisting of H, Ci-₆ alkyl and saturated monocyclic C3-6 cycloalkyl, or one of R1 and R2 is H and the other is phenyl, or R1 and R2 are connected to form a saturated monocyclic 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof; with the proviso that both R1 and R2 cannot be H at the same time.

E32. The compound according to embodiment 31, wherein R1 is H, and R2 is selected from Ci-₆ alkyl and saturated monocyclic C3-6 cycloalkyl.

E33. The compound according to any of embodiments 31-32, wherein R1 is H, and R2 is methyl.

E34. The compound according to embodiment 31, wherein R1 is selected from Ci-₆ alkyl and saturated monocyclic C3-6 cycloalkyl, and R2 is H.

E35. The compound according to any of embodiments 31 and 34, wherein R1 is methyl, and R2 is H.

E36. The compound according to embodiment 31, wherein said compound is selected from the group consisting of:

(la-ii): (2R,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro- [l,3]dioxolo[4',5':5,6]benzo[l,2-g]quinoline; and

(la-iii): (2S,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro- [l,3]dioxolo[4',5':5,6]benzo[l,2-g]quinoline; or a pharmaceutically acceptable salt of any of these compounds. E37. A pharmaceutical composition comprising a compound according to any one of embodiments 31-36 or a pharmaceutically acceptable salt thereof.

E38. The compound according to any of embodiments 31-36 or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

E39. A method for the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; which method comprises the administration of a therapeutically effective amount of a compound according to any of embodiments 31-36 or a

pharmaceutically acceptable salt thereof.

E40. Use of a compound according to any of embodiments 31-36 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, and should not be construed as limiting the invention in any way. The description herein of any aspect or aspect of the invention using terms such as "comprising", "having," "including" or "containing" with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of", "consists essentially of" or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

The use of any and all examples, or exemplary language (including "for instance", "for example", "e.g.", and "as such") in the present specification is intended merely to better illuminate the invention, and does not pose a limitation on the scope of invention unless otherwise indicated.

It should be understood that the various aspects, embodiments, implementations and features of the invention mentioned herein may be claimed separately, or in any combination.

The present invention includes all modifications and equivalents of the subject- matter recited in the claims appended hereto, as permitted by applicable law.

Compounds of formula (la)

Table 1: Exemplified compounds of formula (la)

EXPERIMENTAL SECTION

Preparation of the compounds of formula (la)

The compounds of formula (la) may be prepared by methods described below, together with synthetic methods known in the art of organic chemistry, or modifications that are familiar to those of ordinary skill in the art. The starting materials used herein are available commercially or may be prepared by routine methods known in the art, such as those methods described in standard reference books such as "Compendium of Organic Synthetic Methods, Vol. I-XN" (published with Wiley-lnterscience). Preferred methods include, but are not limited to, those described below. The examples are representative of methods useful in synthesizing the compounds of the present invention. They are not intended to constrain the scope of the invention in any way.

Compound of formula (la-i): (6aR,10aR)-7-n-Propyl-6,6a,7,8,9,10,10a,ll-octahydro-l,3- dioxa-7-aza-cyclopenta[a]anthracene

The compound (la-i) can be prepared from compound (I) as disclosed in WO 2009/026934.

Exemplified new compounds of formula (la)

Synthesis of:

Compound of formula (la-ii): (2R,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll- octahydro-[l,3]dioxolo[4',5':5,6]benzo[l,2-g]quinoline, and

Compound of formula (la-iii): (2S,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll- octahydro-[l,3]dioxolo[4',5':5,6]benzo[l,2-g]quinoline.

(la-ii) (la-iii)

Compound (I) HCI salt [(4aR,10aR)-l-propyl-l,2,3,4,4a,5,10,10a- octahydrobenzo[g]quinoline-6,7-diol hydrochloride] (0.500 g), cesium carbonate (1.31 g) and ascorbic acid (0.017 g) added to a 20 mL vial and mixed with N,N-dimethylformamide (10 mL) and 1-bromo-l-chloroethane (0.29 mL). The vial was capped, evacuated and backfilled with nitrogen twice before the mixture was heated at 100 °C. More 1-bromo-l- chloroethane (0.20 mL) was added after 6 hours and the mixture was heated to 100 °C for an additional 4 hours and then stirred at ambient temperature for 2 days. The crude mixture was poured onto a silica gel column and eluted with ethyl acetate/heptane/triethylamine (10:9:1) to afford 190 mg of an oil that solidified on standing. This material was separated by Supercritical Fluid Chromatography (SFC; performed on a Berger Multigram II operating at 35 °C and 100 bar back pressure with a flow of 50 mL/min using stacked injections. The column was a Chiralcel OJ-H (250 x 21.2 mm, 5 micrometer particles). The eluent was C0₂ (90 %) and 2-propanol + 0.2 % diethylamine (10%)) to afford two product fractions corresponding to compounds (la-ii) and (la-iii).

First peak: Fractions containing the 1. peak concentrated in vacuo. The residue was chromatographed as before to afford 68 mg oil (solidified slowly on standing) of either (2R,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro- [l,3]dioxolo[4',5':5,6]benzo[l,2-g]quinoline (la-ii) or (2S,6aR,10aR)-2-methyl-7-propyl- e^a^S^lO^Oa^l-octahydro-Il^jdioxolo^S'^ejbenzoll^-gjquinoline (la-iii).

LC/MS: retention time 0.49 min; UV-purity 96%; ELS-purity 100%; mass observed 288.5.

Second peak: Fractions containing the 2. peak concentrated in vacuo. The residue was chromatographed as before to afford 57 mg of either (2R,6aR,10aR)-2-methyl-7-propyl- 6,6a,7,8,9,10,10a,ll-octahydro-[l,3]dioxolo[4',5':5,6]benzo[l,2-g]quinoline (la-ii) or (2S,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro- [l,3]dioxolo[4',5^,:5,6]benzo[l,2-g]quinoline (la-iii) as a solid.

LC/MS: retention time 0.49 min; UV-purity 97%; ELS-purity 100%; mass observed 288.5.

LC/MS was run on Waters Aquity UPLC-MS consisting of Waters Aquity including column manager, binary solvent manager, sample organizer, PDA detector (operating at 254 nM), ELS detector, and TQ.-MS equipped with APPI-source operating in positive ion mode. LC- conditions: The column was Acquity UPLC BEH C18 1.7pm; 2.1x50mm operating at 60°C with 1.2 ml/min of a binary gradient consisting of water + 0.05 % trifluoroacetic acid (A) and acetonitrile + 5% water + 0.05 % trifluoroacetic acid. Gradient: 0.00 min 10% B; 1.00 min 100% B; 1.01 min 10% B; 1.15 min 10% B. Total run time: 1.15 min.

To determine the absolute stereochemistry for the compounds of the first and second eluted peaks, methods known in the art such as X-ray crystallography or vibrational circular dichroism can be used.

In vitro and in vivo characterization of compounds of formula (I) and formula (la).

Example 1: Dopamine agonist activity

Dopamine D1 receptor agonism

Dopamine D1 receptor agonism was measured using a HTRF cAMP from CisBio using the protocol developed by HD Biosciences (China). Briefly, the assay is a homogeneous time resolved-fluorescence resonance energy transfer (HTRF) assay that measures production of cAMP by cells in a competitive immunoassay between native cAMP produced by cells and cAMP-labeled with XL-665. A cryptate-labeled anti-cAMP antibody visualizes the tracer. The assay was performed in accordance with instructions from manufacturer.

Test compounds were added to wells of microplates (384 format). HEK-293 cells expressing the human D1 receptor were plated at 1000 cells /well and incubated 30 min at room temperature. cAMP-d2 tracer was added to wells and followed by addition of Anti- cAMP antibody-cryptate preparation and incubated for lh at room temperature in dark. HTRF cAMP was measured by excitation of the donor with 337 nm laser (the "TRF light unit") and subsequent (delay time 100 microseconds) measurement of cryptate and d2 emission at 615 nm and 665 nm over a time window of 200 microseconds with a 2000 microseconds time window between repeats /100 flashes). HRTF measurements were performed on an Envision microplate reader (PerkinElmer). The HTRF signal was calculated as the emission-ratio at 665 nm over 615 nm. The HTRF ratio readout for test compounds was normalized to 0% and 100% stimulation using control wells with DMSO-solvent or 30uM dopamine. Test compound potency (EC50) was estimated by nonlinear regression using the sigmoidal dose-response (variable slope) using Xlfit 4 (IDBS, Guildford, Surrey, UK, model 205). y ⁼ (A+((B-A)/(I+((C/X)^AD)))) where y is the normalized HTRF ratio measurement for a given concentration of test compound, x is the concentration of test compound, A is the estimated efficacy at infinite compound dilution, and B is the maximal efficacy. C is the EC50 value and D is the Hill slope coefficient. EC50 estimates were obtained from an independent experiment and the logarithmic average was calculated.

Dopamine D2 receptor agonism

Dopamine D2 receptor agonism was measured using a calcium mobilization assay protocol developed by HD Biosciences (China). Briefly, HEK293/G15 cells expressing human D2 receptor were plated at a density of 15000 cells/well in clear-bottomed, Matrigel-coated 384-well plates and grown for 24 hours at 37°C in the presence of 5% C0₂. The cells were incubated with calcium-sensitive fluorescent dye, Fluo8, for 60-90 minutes at 37°C in the dark. Test compounds were prepared at 3-fold concentrated solution in lxHBSS buffer with Ca²⁺ and Mg²⁺. Calcium Flux signal was immediately recorded after compounds were added from compound plate to cell plate at FLIPR (Molecular Devices). The fluorescence data were normalized to yield responses for no stimulation (buffer) and full stimulation (1 mM of dopamine) of 0% and 100% stimulation, respectively. Test compound potency (EC50) was estimated by nonlinear regression using the sigmoidal dose-response (variable slope) using Xlfit 4 (IDBS, Guildford, Surrey, UK, model 205). y ⁼ (A+((B-A)/(I+((C/X)^AD)))) where y is the normalized ratio measurement for a given concentration of test compound, x is the concentration of test compound, A is the estimated efficacy at infinite compound dilution, and B is the maximal efficacy. C is the EC50 value and D is the Hill slope coefficient. EC50 estimates were obtained from independent experiment and the logarithmic average was calculated.

Example 2: 5-HT2B agonist activity

5-HT2B agonist activity assay

Evaluation of the agonist activity of compounds (I), (la-i), (la-ii) and (la-iii) at the human 5-HT2B receptor was performed by Eurofins/Cerep (France) measuring the compound effects on inositol monophosphate (I PI) production using the HTRF detection method. Briefly, the human 5-HT2B receptor was expressed in transfected CHO cells. The cells were suspended in a buffer containing 10 mM Hepes/NaOH (pH 7.4), 4.2 mM KCI, 146 mM NaCI, 1 mM CaCI₂, 0.5 mM MgCI2, 5.5 mM glucose and 50 mM LiCI, then distributed in microplates at a density of 4100 cells/well and incubated for 30 min at 37°C in the presence of buffer (basal control), test compound or reference agonist. For stimulated control measurement, separate assay wells contained 1 mM 5-HT. Following incubation, the cells were lysed and the fluorescence acceptor (fluorophen D2-labeled I PI) and fluorescence donor (anti-IPl antibody labeled with europium cryptate) were added. After 60 min at room temperature, the fluorescence transfer was measured at lambda(Ex) 337 nm and lambda(Em) 620 and 665 nm using a microplate reader (Rubystar, BMG). The IP1 concentration was determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). For compounds (I) and (la-i) the results were expressed as a percent of the control response to 1 pM 5-HT. The standard reference agonist was 5-HT, which was tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value is calculated as described above for dopamine functional assays. Table 1. In vitro activities for the compound of formula (I), (la-i), (la-ii) and (la-iii).

Example 3: PK experiment in rats

Blood samples of approximately 0.68 mL were drawn from the tail or sublingual vein and put into K3EDTA tubes that had been pre-cooled and prepared with stabilizing solution consisting of 80 pL ascorbic acid and 40 pL 100 mM D-saccharic acid 1,4 lactone in water.

The tubes were inverted gently 6-8 times to ensure thorough mixing and then placed in wet ice. The collecting tube was placed in wet ice for up to 30 minutes until centrifugation. Once removed from the wet ice the centrifugation was initiated immediately. Immediately after end of centrifugation the samples were returned to wet ice. Three sub-samples of 130 pL plasma were transferred to each of three appropriately labelled cryo tubes containing 6.5 pL pre-cooled formic acid (20%) (the tubes were pre-spiked and stored refrigerated prior to use). The tube lid was immediately replaced, and the plasma solution was thoroughly mixed by inverting gently 6-8 times. The samples were stored frozen at nominally -70°C within 60 minutes after sampling. Centrifugation conditions at 3000 G for 10 minutes at 4°C. Plasma was placed on water-ice following collection. Final storage at approximately -70°C.

Plasma samples were analyzed by solid phase extraction or direct protein

precipitation followed by UPLC-MS/MS. MS detection using electrospray in the positive ion mode with monitoring of specific mass-to-charge transitions for compound (I) using internal standards for correcting the response. The concentration-time data was analyzed, using standard software using appropriate noncompartmental techniques to obtain estimates of the derived PK parameters. Instrumentation used for analysis of compound (l)from dosing of compound (la-i):

Mass spectrometer (LC-MS/MS) Waters Acquity -Sciex API 5000. Analytical column Waters BEH UPLC Phenyl 100 x 2.1 mm column, 1.7 pm particle size. Mobile phase A: 20 mM ammonium formate (aq) + 0.5% formic acid. Mobile phase B: Acetonitrile. Gradient run from 95/5% to 2/98 in 6.1 min. Flow rate 0.5 mL/min. MRM monitoring of test item and the added analytical standards.

Dosing and blood sampling: Han Wistar rats were supplied by Charles River Laboratories,

UK. An artificial, automatically controlled, light and dark cycle of 12 hours was maintained. The rats received a standard laboratory diet (Teklad 2014C Diet.). The rats had unrestricted access to the diet. During the study (a 26-week toxicity study) the rats received once daily doses of (la-i) orally by gavage. From rats given 300 pg/kg (la-i), blood samples from 3 male satellite animals were collected on the following time points at day 182: 0.5, 1, 2, 4, 8 and 24 hours after dosing.

Table 2. PK parameters for (4aR,10aR)-l-n-Propyl-l,2,3,4,4a,5,10,10a-octahydro- benzo[g]quinoline-6,7-diol [the compound offormla (I)] after oral dosing of 0.300 mg/kg of compound (la-i), to Wistar rats according to Example 3.

Claims

1. 1) A first compound of formula (la)

wherein

R1 and R2 are selected independently from the group consisting of H, Ci-e alkyl and saturated monocyclic C3-6 cycloalkyl, or one of R1 and R2 is H and the other is phenyl, or R1 and R2 are connected to form a saturated monocyclic 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof; and 2) a second compound, which is a 5-HT2B antagonist, or a pharmaceutically acceptable salt thereof; wherein 1) and 2) are for combined use in therapy.

2. The compounds for use according to claim 1, wherein R1 and R2 are selected independently from H and methyl.

3. The compounds for use according to claim 1, wherein R1 and R2 are both H.

4. The compounds for use according to claim 1, wherein R1 is H, and R2 is selected from Ci-₆ alkyl and saturated monocyclic C3-6 cycloalkyl.

5. The compounds for use according to claim 1 wherein R1 is selected from Ci-e alkyl and saturated monocyclic C cycloalkyl, and R2 is H.

6. The compounds for use according to claim 1, wherein said first compound is selected from the group consisting of:

(la-i): (6aR,10aR)-7-n-Propyl-6,6a,7,8,9,10,10a,ll-octahydro-l,3-dioxa-7-aza- cyclopenta[a]anthracene;

(la-ii): (2R,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro- [l^ldioxololA'^'^^lbenzoll^-glquinoline; and

(la-iii): (2S,6aR,10aR)-2-methyl-7-propyl-6,6a,7,8,9,10,10a,ll-octahydro- [l^ldioxololA'^'^^lbenzoll^-glquinoline; or a pharmaceutically acceptable salt of any of these compounds.

7. The compounds for use according to any one of claims 1-6, wherein 1) and 2) are for combined use in the treatment of a neurodegenerative disease or disorder such as

8. The compounds for use according to any of claims 1-7, wherein said second compound is selected from the group consisting of amisulpride, agomelatine, tegaserod, naluzotan, PRX-3140, BW-723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER-082, BF-1, lisuride, SB-200646A, vabicaserin, SB-221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

9. A method for the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; which method comprises the administration of a therapeutically effective amount of a first compound as described in any one of claims 1-6 or a

pharmaceutically acceptable salt thereof, and a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; to a patient in need thereof.

10. The method according to claim 9, wherein said second compound is selected from the group consisting of amisulpride, agomelatine, tegaserod, naluzotan, PRX-3140, BW- 723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER- 082, BF-1, lisuride, SB-200646A, vabicaserin, SB-221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

11. A pharmaceutical composition comprising

1) a therapeutically effective amount of a first compound as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof; and

2) a second compound which is a 5-HT2B antagonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, diluents and excipients.

12. The pharmaceutical composition according to claim 11, wherein said second compound is selected from the group consisting of amisulpride, agomelatine, tegaserod, naluzotan, PRX-3140, BW-723C86, PF-03800130, piromelatine, RP-5063, terguride, metadoxine, ER-21027, SDZ-SER-082, BF-1, lisuride, SB-200646A, vabicaserin, SB-221284, SB-206553, PRX-8066, AMAP-102, RQ-00310941, AM-1030, LY-266097, LY-287375, F-16615, LY-272015, MW-071 and MT-500.

12. A compound according to formula (la')

wherein

R1 and R2 are selected independently from the group consisting of H, Ci-e alkyl and saturated monocyclic C3-6 cycloalkyl, or one of R1 and R2 is H and the other is phenyl, or R1 and R2 are connected to form a saturated monocyclic 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof; with the proviso that both R1 and R2 cannot be H at the same time.

13. The compound according to claim 12, wherein said compound is selected from the group consisting of:

14. A pharmaceutical composition comprising a compound according to any one of claims 12-13 or a pharmaceutically acceptable salt thereof.

15. The compound according to any of claims 12-13 or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or disorder such as Parkinson's Disease, Huntington's disease, Restless leg syndrome or Alzheimer's disease; or a neuropsychiatric disease or disorder such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.