WO2011107583A1

WO2011107583A1 - Substituted 4-phenyl-n-alkyl-piperidines for preventing onset or slowing progression of neurodegenerative disorders

Info

Publication number: WO2011107583A1
Application number: PCT/EP2011/053275
Authority: WO
Inventors: Nicholas Waters; Susanna Waters
Original assignee: Nsab, Filial Af Neurosearch Sweden Ab, Sverige
Priority date: 2010-03-04
Filing date: 2011-03-04
Publication date: 2011-09-09

Abstract

The present invention relates to the use of a certain group of substituted 4-phenyl-N-alkyl-pipehdines for preventing onset or slowing progression of neurodegenerative disorders.

Description

SUBSTITUTED 4-PHENYL-N-ALKYL-PIPERIDINES FOR PREVENTING ONSET OR SLOWING PROGRESSION OF NEURODEGENERATIVE DISORDERS

5

TECHNICAL FIELD

The present invention relates to the use of a certain group of substituted 4- phenyl-N-alkyl-piperidines, belonging to a novel class of psychomotor stabilizing drugs, 10 for preventing onset or slowing progression of neurodegenerative disorders.

BACKGROUND ART

Compounds belonging to the class of substituted 4-phenyl-N-alkyl-

15 piperidines have previously been reported. Among these compounds, some are inactive in the CNS, some display serotonergic or mixed serotonergic/dopaminergic pharmacological profiles, while some are full or partial dopamine receptor agonists or antagonists with high affinity for dopamine receptors.

Drugs that act, directly or indirectly, at central dopamine receptors are

20 commonly used in the treatment of neurologic and psychiatric disorders, e.g.

Parkinson's disease and schizophrenia. They may also be used to improve cognitive functions and related emotional disturbances in neurodegenerative and developmental disorders as well as after brain damage.

WO 01/46145, WO 01/46146, WO 2005/121087, WO 2007/042295 WO

25 2008/127188 and WO 2008/155357 all describe substituted 4-phenyl-N-alkyl- piperazines and 4-phenyl-N-alkyl-piperidines, reported to be modulators of dopamine neurotransmission, and to be useful in treatment of symptoms of various disorders of the central nervous system. Neurological indications contemplated according to these publications include the treatment of Huntington's disease and other movement

30 disorders, as well as movement disorders induced by drugs.

While these publications are concerned with multiple compounds for the treatment of multiple therapeutic indications, and in particular for the treatment of the symptoms arising from such therapeutic indications, the use of a small subgroup of these compounds for preventing onset or delay onset or preventing the progression or

35 slowing progression of neurodegenerative disorders have never been reported. SUMMARY OF THE INVENTION

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease dependent of a CAG (cytosine-adenine-guanine tri-nucleotide) repeat in one of the alleles of the huntingtin (htt) gene, located on the short arm of chromosome four, leading to polyglutamine (polyQ) expansion at the N-terminal end of the huntingtin protein. Most people have a CAG repeat count of between 7 and 35 repeats. Huntington's disease gene carriers, i.e. subjects susceptible to Huntington's disease, have CAG repeat lengths exceeding 36, which leads to the appearance of toxic huntingtin protein and development of Huntington's disease. Generally, the longer the repeat length, the earlier is the onset of disease, and the higher the rate of progression.

Symptoms of Huntington's disease include severe motor dysfunctions, cognitive decline and psychiatric disturbances. CNS neuropathological changes observed in Huntington's disease include progressive loss of neurons in the caudate nucleus located in the corpus striatum, as well as thinning of the cerebral cortex and enlarged cerebral ventricles. Symptoms of Huntington's disease generally manifest in the third or fourth decade of life. The age of symptom onset correlates with the extent of polyQ expansion.

There is presently no treatment available that can prevent or delay the onset of Huntington's disease, or slow down the rate of progression (Mestre T, Ferreira J, Coelho M M, Rosa M, Sampaio C: Therapeutic interventions for disease progression in Huntington's disease; Cochrane Database of Systematic Reviews 2009 (3) Art. No.: CD006455. DOI: 10.1002/14651858.CD006455.pub2). Existing efforts to develop such disease modifying treatments include compounds affecting sodium channels, glutamatergic or gabaergic neurotransmission (riluzole remacemide, memantine), antioxidant compounds (creatine, coenzyme Q), and the antibiotic minocycline.

Dyhring et a/.; Molecular and Cellular Pharmacology 2010 628 19-26 describe a compound for use according to the present invention, which is currently in development for symptomatic treatment of Huntington's disease.

Only one treatment is currently available that has been approved for the treatment of symptoms in Huntington's disease patients, i.e. tetrabenazine, which has been shown to reduce chorea (Mestre T, Ferreira J, Coelho M M, Rosa M, Sampaio C: Therapeutic interventions for symptomatic treatment in Huntington's disease; Cochrane Database of Systematic Reviews 2009 (3) Art. No.: CD006456. DOI: 10.1002/14651858.CD006456.pub2).

According to the present invention it has now been found that compounds belonging to a particular subgroup of substituted 4-phenyl-N-alkyl-piperidines, belonging to a novel class of psychomotor stabilizing drugs, are capable of preventing the effects on the expanded CAG repeat on the motor function decline associated with Huntington's disease, suggesting a disease modifying action.

Eye movement symptoms are considered a marker of disease progression in Huntington's disease, and following a clinical study it was found that compounds representative for use according to the invention significantly improved eye movement abnormalities after six months of treatment. This observation would be consistent with a neuro-protective effect of such compounds, leading to a decreased rate of neuronal degeneration, and reflected by a reduction in eye movement abnormalities compared to placebo-treated subjects.

A series of experiments aimed at assessing the effects of compounds representative for use according to the invention, as well as a set of reference compounds known to antagonise NMDA receptors, on gene expression, have demonstrated that compounds representative for use according to the invention induced expression of the Arc gene, reflecting enhancement of synaptic NMDA receptor signalling. This has recently been shown to constitute a neuro-protective mechanism in that stimulation of synaptic NMDA receptors promotes neuronal survival and protects from neuronal death. Therefore, the effects on Arc suggest that the compounds could enhance neuronal survival in neurodegenerative disorders such as Huntington's disease, thereby slowing the neuronal degeneration and the clinical symptoms of the disease progress.

Likewise, it has been demonstrated that compounds can induce BDNF mRNA, further supporting neuronal survival promoting effects. In vitro binding data are also presented, showing significant affinity at adrenergic alpha2 receptors, associated with neurotrophic effects, and histamine H3 receptors, associated with neuroprotective effects, demonstrating two novel mechanisms by which the compounds could exert therapeutical effects leading to improved neuronal survival and hence a retardation of the disease progress in Huntington's disease.

DETAILED DISCLOSURE OF THE INVENTION

Substituted 4-phenyl-N-alkyl-piperidines

While conventional treatments suggested for combating Huntington's disease are all concerned with symptomatic treatment there is presently no treatment available that can prevent or delay the onset of Huntington's disease, or prevent or slow down the rate of progression in manifest Huntington's disease. The significance of the present invention resides in the fact that a particular group of compounds belonging to a novel class of psychomotor stabilizing drugs, and exemplified by substituted 4-phenyl-N-alkyl-piperidines, have proven capable of preventing onset of Huntington's disease, and able to slow down the rate of progression of Huntington's disease.

Therefore, in its first aspect, the invention relates to the use of a substituted 4-phenyl-N-alkyl-piperidine represented by Formula I

an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein

R¹ represents hydrogen or fluoro; and

R² represents ethyl or propyl.

In a more preferred embodiment the substituted 4-phenyl-N-alkyl-piperidine for use according to the invention is represented by Formula I, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein R¹ is attached to the 2- or 5-position.

In another preferred embodiment the substituted 4-phenyl-N-alkyl-piperidine for use according to the invention is represented by Formula I, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein

R¹ represents hydrogen; and

R² represents ethyl or propyl.

In a third preferred embodiment the substituted 4-phenyl-N-alkyl-piperidine for use according to the invention is represented by Formula I, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein

R¹ represents fluoro; and

R² represents ethyl.

In a fourth preferred embodiment the substituted 4-phenyl-N-alkyl-piperidine for use according to the invention is

4-(3-methylsulfonylphenyl)-1 -propyl-piperidine;

an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof.

In an even more preferred embodiment the substituted 4-phenyl-N-alkyl- piperidine for use according to the invention is

4-(3-methylsulfonylphenyl)-1 -propyl-piperidine hydrochloride salt; or an N-oxide thereof.

In a fifth preferred embodiment the substituted 4-phenyl-N-alkyl-piperidine for use according to the invention is

1 -Ethyl-4-(2-fluoro-3-methanesulfonyl-phenyl)-piperidine; an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

1 -Ethyl-4-(2-fluoro-3-methanesulfonyl-phenyl)-piperidine hydrochloride salt; or an N-oxide thereof.

In a sixth preferred embodiment the substituted 4-phenyl-N-alkyl-piperidine for use according to the invention is

1 -Ethyl-4-(3-fluoro-5-methanesulfonyl-phenyl)-piperidine;

an N-oxide thereof, or a pharmaceutically acceptable salt thereof. In an even more preferred embodiment the substituted 4-phenyl-N-alkyl- piperidine for use according to the invention is

1 -Ethyl-4-(3-fluoro-5-methanesulfonyl-phenyl)-piperidine hydrochloride salt; or an N-oxide thereof. Gene-positive pre-manifest Huntington's disease subjects

The present invention is concerned with preventing onset or delaying onset or preventing the progression or slowing progression of the symptoms arising from Huntington's disease. Therefore, in one particular embodiment, the invention relates to the use of a compound of Formula I, as defined above, for preventing onset or delaying onset or preventing the progression or slowing progression of the symptoms of Huntington's disease in a subject not having any symptoms of Huntington's disease.

Caused by a gene mutation that leads to a toxic accumulation of protein in the brain, Huntington's disease is inherited from either one or both parents. Every child of a parent who carries the Huntington's disease gene has a 50% chance of inheriting the abnormal gene. Pre-symptomatic testing can determine whether someone is likely to develop the disease. A child who inherits the Huntington's gene will eventually develop the illness, although onset typically does not occur until ages 35-50 or later.

Genetic testing can diagnose Huntington's disease at every stage of the life cycle. Generally, there are three categories for testing:

· Prenatal testing, either amniocentesis (a sample of fluid from around the fetus), or chorionic villus sampling (CVS, a sample of fetal cells from the placenta), will indicate whether the baby has inherited the gene for Huntington's.

• Pre-symptomatic testing is available to people who are at risk of inheriting Huntington's disease from a parent, but don't have symptoms and don't know whether or not they carry the gene.

• Confirmatory testing determines whether a person showing what appear to be the symptoms of Huntington's disease, actually has the disease. Neurological and psychological tests are also conducted to arrive at a conclusive diagnosis of Huntington's disease. Therefore, in one particular embodiment, the invention relates to the use of a compound of Formula I, as defined above, preventing onset or delaying onset or preventing the progression or slowing progression of Huntington's disease in a Huntington's disease gene-positive subject not having any symptoms of Huntington's disease, i.e. a pre-manifest Huntington's disease subject.

In the context of this invention, a Huntington's disease gene-positive subject is a human diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene, and thus being Huntington's disease gene carrier.

Also, in the context of this invention, a pre-manifest Huntington's disease subjects are patients diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene, and thus being Huntington's disease gene carrier, but not (yet) affected by the symptoms of Huntington's disease, i.e. before onset of any symptoms, i.e. a gene-positive pre-manifest subject. Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats

Therefore, in a one specific embodiment the invention relates to the use of a compound of Formula I, as defined above, for preventing onset or delaying onset or preventing the progression or slowing progression of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

In another specific embodiment the invention relates to the use of a compound of Formula I, as defined above, for preventing onset or delaying onset of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

In a third specific embodiment the invention relates to the use of a compound of Formula I, as defined above, for preventing the progression of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene. In a fourth specific embodiment the invention relates to the use of a compound of Formula I, as defined above, for delaying progression of symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

In a fifth specific embodiment the invention relates to the use of a compound of Formula I, as defined above, for slowing progression of symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

In a more specific embodiment the compound of Formula I for use according to the invention is applied to a subject diagnosed to have CAG repeats in excess of 40 in one of the alleles of the huntingtin (htt) gene.

In another more specific embodiment the compound of Formula I for use according to the invention is applied to a subject diagnosed to have CAG repeats in excess of 45 in one of the alleles of the huntingtin (htt) gene.

In a third more specific embodiment the compound of Formula I for use according to the invention is applied to a subject diagnosed to have CAG repeats in excess of 50 in one of the alleles of the huntingtin (htt) gene.

In a fourth more specific embodiment the compound of Formula I for use according to the invention is applied to a subject diagnosed to have CAG repeats in excess of 55 in one of the alleles of the huntingtin (htt) gene.

In an alternative embodiment the invention relates to the use of a compound of Formula I, as defined above, for delaying or slowing progression of symptoms of Huntington's disease in a subject having symptoms of Huntington's disease, i.e. delaying progression in a manifest Huntington's disease subject.

It is at present contemplated that a suitable dosage of the active pharmaceutical ingredient (API), calculated as the free base, is within the range of from about 0.1 to about 1000 mg API per day, more preferred of from about 10 to about 500 mg API per day, most preferred of from about 25 to about 250 mg API per day, dependent, however, upon the exact mode of administration, the form in which it is administered, the indication considered, the subject and in particular the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.

The compound for use according to the invention may be administered in one or several doses per day. A dosage regime of one or two doses per day is considered beneficial.

In a particular embodiment the compound for use according to the invention is given once daily (q.d.), each morning, to a subject in need therefore. In another particular embodiment the compound for use according to the invention is given twice daily (b.i.d.), morning and evening, to a subject in need therefore.

In a more preferred embodiment a dosage of 45 mg of the compound for use according to the invention is given once (q.d.) or twice (b.i.d.) daily to a subject in need therefore.

In another more preferred embodiment a dosage of 45 mg of the compound for use according to the invention is given twice daily (b.i.d.) to a manifest Huntington's disease subject.

Any combination of two or more of the embodiments described herein is considered within the scope of the present invention.

Pharmaceutically acceptable salts

The compound for use according to the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms, an N-oxide or a deuterated analog of the compound.

Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulphonate derived from methane sulphonic acid, the naphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the succinate derived from succinic acid, the tartrate derived from tartaric acid, the toluene-p-sulphonate derived from p-toluene sulphonic acid, and the like. Such salts may be formed by procedures well known and described in the art. Deuterated analogs

The compounds for use according to the invention may be provided in the form of their deuterated analogs. Deuterium forms bonds with carbon that vibrate at a lower frequency and are thus stronger than C-H bonds. Therefore "heavy hydrogen" (deuterium) versions of drugs may be more stable towards degradation and last longer in the organism.

Pharmaceutical Compositions

In another aspect the invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, as described above, together with at least one pharmaceutically acceptable carrier or diluent, for the treatment of a neurodegenerative disorder.

While the compound for use according to the invention may be administered in the form of the raw compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.

The actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing of from about 1 to about 500 mg of active ingredient per individual dose, preferably of from about 10 to about 100 mg, most preferred of from about 25 to about 50 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses per day.

Methods of Therapy

In another aspect the invention provides a method for preventing onset or delaying onset or preventing or slowing progression the progression of Huntington's disease in a Huntington's disease gene-positive subject not having any symptoms of Huntington's disease, i.e. a pre-manifest Huntington's disease subject, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound of a substituted 4-phenyl-N-alkyl- piperidine represented by Formula I

R¹ represents hydrogen or fluoro; and

R² represents ethyl or propyl.

In a more specific embodiment, the method of the invention is for preventing onset or delaying onset or preventing the progression of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

In another specific embodiment, the method of the invention is for preventing onset or delaying onset of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

In a third specific embodiment, the method of the invention is for preventing the progression of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

In a fourth specific embodiment, the method of the invention is for delaying progression of symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

In a more specific embodiment, the method of the invention is applied to a subject diagnosed to have CAG repeats in excess of 40 in one of the alleles of the huntingtin (htt) gene.

In another more specific, the method of the invention is applied to a subject diagnosed to have CAG repeats in excess of 45 in one of the alleles of the huntingtin (htt) gene.

In a third more specific, the method of the invention is applied to a subject diagnosed to have CAG repeats in excess of 50 in one of the alleles of the huntingtin (htt) gene.

In a fourth more specific, the method of the invention is applied to a subject diagnosed to have CAG repeats in excess of 55 in one of the alleles of the huntingtin (htt) gene.

In an alternative embodiment the invention provides a method for delaying or slowing progression of symptoms of Huntington's disease in a subject having symptoms of Huntington's disease, i.e. delaying progression in manifest Huntington's disease, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound of use of a compound of Formula I, an N-oxide thereof, a deuterated analog thereof, or a 5 pharmaceutically acceptable salt thereof, as defined above.

It is at present contemplated that suitable dosage ranges are within 0.1 to 1000 milligrams daily, preferably 10 to 500 milligrams daily, and more preferred of from 25 to 250 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, 10 the subject involved, the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.

Methods of producing substituted 4-phenyl-N-alkyl-piperidines

The compounds for use according to the invention, i.e. compounds of 15 Formula I, and N-oxides thereof, and pharmaceutically acceptable salts thereof, may be prepared by conventional methods for chemical synthesis, and in particular those described in e.g. WO 01/46145, WO 01/46146, WO 2005/121087, WO 2007/042295, WO 2006/040155 and WO 2006/040156, and N-oxides of the compounds for use according to the invention may be obtained as described in e.g. and WO 2008/127188.

20

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further illustrated by reference to the accompanying drawing, in which:

25 Fig. 1 shows a plot of the change from baseline in mMS to week 26 versus

CAG repeat length by randomised treatment; Triangles = placebo (control); Squares = 45 mg q.d. of ACR16; Circles = 90 mg (= 45 mg b.i.d.) of ACR16. The regression lines drawn for each treatment group suggest a steeper slope, i.e. a stronger correlation between the CAG repeat length and the 6-months change in mMS, in the placebo treated

30 subjects, compared to subjects treated with ACR16 45 mg q.d. or 45 mg b.i.d. This implies that the influence of CAG repeat length on the progression of motor decline is blunted in ACR16 treated patients;

Fig. 2 shows the effect of pridopidine, at 1 1 , 33 and 100 microgram/kg given s.c., on Arc gene mRNA levels in the striatum and frontal cortex of rat brains, dissected

35 60 minutes after administration of test compound. Shown are means ± SEM expressed as percentage of control means. ^** denotes p <0.01 , ^***p<0.001 by students t-test. Pridopidine dose dependently increases Arc in the striatum and frontal cortex, suggesting increased NMDA receptor signalling in these regions;

Fig. 3 shows the effect of ordopidine, at 1 1 , 33 and 100 microgram/kg given s.c., on Arc gene mRNA levels in the striatum and frontal cortex of rat brains, dissected 60 minutes after administration of test compound. Shown are means ± SEM expressed as percentage of control means. ^** denotes p <0.01 , ^***p<0.001 by students t-test. Ordopidine dose dependently increases Arc in the striatum and frontal cortex, suggesting increased NMDA receptor signalling in these regions;

Fig. 4 shows the effect of memantine, at 30, 90 and 270 mg/kg given s.c, on Arc and BDNF gene mRNA levels in the striatum (Arc) and frontal cortex (Arc and BDNF) of rat brains, dissected 60 minutes after administration of test compound. Shown are means ± SEM expressed as percentage of control means. ^* denotes p <0.05 by students t-test. Memantine dose dependently increases Arc in the striatum and frontal cortex, suggesting increased NMDA receptor signalling in these regions. Given that memantine is a NMDA receptor antagonist preferentially blocking extrasynaptic receptors it follows that this increase in Arc arises due to enhanced signalling at synaptic NMDA receptors. Furthermore, memantine at the highest dose increases cortical BDNF mRNA suggesting triggering of neuronal survival pathways;

Fig. 5 shows the effect of ifenprodil, at 3.3, 10 and 30 mg/kg given s.c, on Arc gene mRNA levels in the striatum and frontal cortex of rat brains, dissected 60 minutes after administration of test compound. Shown are means ± SEM expressed as percentage of control means. Ifenprodil tends to dose dependently increase Arc in the striatum and frontal cortex, suggesting effects similar to memantine, ie increased NMDA receptor signalling in these regions;

Fig. 6 shows the effect of MK-801 , at 0.2 mg/kg given i.p.., on Arc gene mRNA levels in the striatum and frontal cortex of rat brains, dissected 60 minutes after administration of test compound. Shown are means ± SEM expressed as percentage of control means. ^** denotes p <0.01 , ^***p<0.001 by students t-test. MK-801 reduces Arc expression in the striatum and frontal cortex, suggesting reduced NMDA receptor signalling in these regions; and

Fig. 7 shows the effect of ordopidine, at 100 and 300 microgram/kg given s.c, on Arc and BDNF gene mRNA levels in the frontal cortex of rat brains, dissected 60 minutes after administration of test compound. Shown are means ± SEM expressed as percentage of control means. ^* denotes p<0.05 by students t-test. Ordopidine (300 micromol/kg) increases Arc and BDNF in the frontal cortex, suggesting activation of neuronal survival pathways. This supports neuroprotective effects of ordopidine, that could lead to retarded progress of Huntington's disease in patients receiving ordopidine. EXAMPLES

The invention is further illustrated with reference to the following examples, which are not intended to be in any way limiting to the scope of the invention as claimed. Example 1

Biological activity

A compound for use according to the invention, i.e. 4-(3- methylsulfonylphenyl)-1 -propyl-piperidine hydrochloride salt, also designated ACR16 or pridopidine, was investigated in a randomized, double-blind, placebo controlled Phase 3 study (Multinational European Multi-center ACR16 study In Huntington's Disease; Study No ACR16C008, ClinicalTrials.gov identifier: NCT00665223) being conducted in eight European countries (Austria, Belgium, France, Germany, Italy, Portugal, Spain and the UK).

Eligible patients were randomized equally to receive ACR16 45 mg once daily (q.d.) with a placebo capsule in the afternoon (n = 148), ACR16 45 mg twice daily (b.i.d.) (n = 145), or placebo (b.i.d., n = 144), according to the same scheme. Thus, a total of 437 patients were enrolled in the study. The duration of the double-blind phase was 6 months. Patients must be 30 years of age or older and have a sum score of > 10 points on the modified motor score (mMS; See below for details) at the screening visit.

The primary efficacy outcome was the effect of ACR16 on voluntary motor function, as measured by the sum score of items included in the mMS. The mMS is a subscale of the Unified Huntington's Disease Rating Scale (UHDRS, Huntington Study Group, Unified Huntington's Disease Rating Scale: Reliability and consistency; Movement Disorders 1996 11 (2) 136-142) and comprises 10 of the 15 items on the UHDRS (items 4-10 and 13-15, i.e. dysarthria, tongue protrusion, finger taps, pronate/supinate hands, luria - fist-hand-palm sequencing, rigidity - arms, body bradykinesia, gait, tandem walking, and retropulsion pull test).

The individual CAG repeat length was taken from the patient's medical records if available, or otherwise assessed according to standard procedures at a genetic testing laboratory as selected by the responsible investigator. The change in mMS vs baseline was calculated for each individual in the three treatment groups and correlated to each subjects number of CAG repeats (see Figure 1 ). It was found that in the placebo treated subjects, the rate of decline in motor function, as measured by the sum of the items in the mMS, over six months was strongly correlated to the CAG repeat length, which is in accordance with previously published longitudinal data (see Rosenblatt The association of CAG repeat length with clinical progression in Huntington disease; Neurology 2006 66 1016-1020; Ravina et al. The Relationship Between CAG Repeat Length and Clinical Progression in Huntington's Disease; Movement Disorders 2008 23 (9) 1223-1227).

In contrast, in the ACR16 45 mg q.d. and b.i.d. treatment groups, this correlation was abolished (Fig. 1 ; For statistics see Table 1 )].

Table 1

Correlation coefficients CAG vs change in UHDRS mMS by treatment.

*n.s.: not significant

To further investigate this finding, the mMS change vs baseline over 6 months was analysed by means of analysis of covariance (ANCOVA), including terms for the categorical effect for treatment, baseline mMS and an interaction between treatment and CAG repeat count (as a continuous variable). The analysis was performed in SAS version 9.1 .3 (SAS Institute Inc., Cary, NC, USA.)

The ANCOVA model of mMS change from baseline demonstrated a significant interaction between CAG repeat length and treatment (p = 0.014), signifying that the difference between the treatment groups with respect to the influence of CAG repeat length on the rate of decline in mMS was statistically significant. Hence, in subjects treated with ACR16, the influence of CAG repeat length on the rate of progression is significantly reduced. The results of this analysis are presented in Table 2, showing the estimated slopes of the CAG vs mMS change regression lines for each treatment group. Table 2

Summary of ANCOVA of Change in UHDRS mMS

Interaction model: CAG by Treatment

CAG Coefficient Estimates (Slope CAG vs mMs change) and Confidence Intervals

^*n.s.: not significant These data strongly suggests that treatment with ACR16 not only gives symptomatic relief in Huntington's disease, but also has disease modifying effects, leading to prevention, or slowed progression, of the clinical symptoms.

Example 2

Biological activity

To investigate the efficacy and safety of 4-(3-methylsulfonylphenyl)-1 - propyl-piperidine hydrochloride salt, also designated ACR16 or pridopidine, in patients with HD a 6-month randomized, double-blind, placebo-controlled European study was initiated.

Eligible patients were aged >30 years with a score of >10 points in the modified motor score (mMS) at screening. The mMS is a validated subscale of the UHDRS total motor score (UHDRS-TMS) equal to the UHDRS-TMS excluding eye movements, dystonia and chorea. Patients were randomized 1 :1 :1 to pridopidine 45 mg once or twice (b.i.d.) daily or placebo. The primary outcome was the effect of pridopidine on voluntary motor function (mMS).

After 26 weeks, pridopidine 45 mg b.i.d. improved the mMS by 0.99 points (full analysis set [FAS]; n = 437; p = 0.042 vs placebo; not significant), as analyzed by analysis of covariance (ANCOVA), including terms for the categorical effect for treatment, baseline mMS (as a continuous variable), a categorical term for co- treatment with neuroleptics, and a term for sex (male/female). The analysis was performed in SAS version 9.1 .3 (SAS Institute Inc., Cary, NC, USA.)

When a term for CAG repeat count by treatment was included in the ANCOVA model, in addition to the terms for treatment, baseline mMS, sex and neuroleptic cotreatment, the mMS change from baseline with pridopidine 45 mg b.i.d. was -1 .20 points (FAS; n = 393; p < 0.02 vs placebo). Pridopidine 45 mg b.i.d. significantly improved the UHDRS-TMS (change from baseline vs placebo -3.51 points; FAS; n = 437; p < 0.001 ) with improvements in the eye movements and dystonia sub domains (not chorea). With placebo, there was a significant correlation (p = 0.0051 ) between CAG repeats and rate of motor symptom progression (0.3 points on the mMS per CAG repeat after 26 weeks). The correlation was not significant in either pridopidine group. Effects were similar regardless of whether patients were taking neuroleptics. Pridopidine was well tolerated and had an adverse event profile similar to placebo.

This study suggests a beneficial effect of pridopidine 45 mg b.i.d. on motor function in patients with HD as reflected in the improvement vs placebo on mMS and UHDRS-TMS. Furthermore, the changes in mMS per CAG, ie the abolished dependence of increase in mMS on CAG repeat length observed in the pridopidine treated subjects, suggests an effect on motor symptom progression, rather than a pure symptomatic effect by pridopidine. Such slowing of symptom progression could be related to slowing of the underlying pathogenetic processes in HD, ie inhibition of the mechanisms causing the disease. Example 3

Biological activity

A compound for use according to the invention, i.e. 4-(3- methylsulfonylphenyl)-1 -propyl-piperidine hydrochloride salt, also designated ACR16 or pridopidine, was investigated in a randomized, double-blind, placebo controlled Phase 3 study (Multinational European Multi-center ACR16 study In Huntington's Disease; Study No ACR16C008, ClinicalTrials.gov identifier: NCT00665223). Eligible patients were aged >30 years with a score of >10 points in the modified motor score (mMS) at screening. Patients were randomized 1 :1 :1 to pridopidine 45 mg once (q.d.) or twice (b.i.d.) daily or placebo.

The mMS is a validated subscale of the UHDRS total motor score (UHDRS-

TMS) equal to the UHDRS-TMS excluding eye movements, dystonia and chorea.

The primary outcome variable was the mMS. However, analysis of other UHDRS motor items revealed that pridopidine 45 mg b.i.d. significantly improved eye movement abnormalities, measured as the sum of items 1 -6 on the UHDRS motor scale (FAS, n = 437, 1 .07 points improvement vs. placebo, p=0.007, analyzed by an ANCOVA model including terms for the categorical effect for treatment, baseline eye movement scores (as a continuous variable), a categorical term for co-treatment with neuroleptics, and a term for sex (male/female). The analysis was performed in SAS version 9.1 .3 (SAS Institute Inc., Cary, NC, USA.). Eye movement abnormalities are considered to reflect the degree of degenerative changes in Huntington's disease, and hence the improvement vs placebo after six months of treatment with pridopidine may reflect a slowing of the disease progress rather than a direct symptomatic effect.

Example 4

Biological activity

To investigate potential effects of two of the dopamine stabilizers for use according to the invention, i.e. 4-(3-methylsulfonylphenyl)-1 -propyl-piperidine hydrochloride salt, also designated ACR16 or pridopidine, and 1 -Ethyl-4-(2-fluoro-3- methanesulfonyl-phenyl)-piperidine, also designated ordopidine, on cortical and striatal NMDA receptor related synaptic signaling, Arc mRNA induction was assessed upon acute administration of pridopidine and ordopidine.

Arc Arc/Arg3.1 (activity regulated cytoskeleton-associated protein/activity- regulated gene 3.1 ) is an immediate early gene (IEG), induced by synaptic activity, whose expression and localization at synaptic sites is believed to be triggered specifically by NMDA receptor activation, and strongly related to neural plasticity

Two different NMDA receptor antagonists, memantine and ifenprodil, known to preferentially block extrasynaptic NMDA receptors, as well as the potent, unselective NMDA antagonist MK801 , were tested in a similar set-up to allow up-front comparisons, and to enable elucidation of the receptor population (extrasynaptic vs synaptic NMDA receptors) involved.

Pridopidine and ordopidine dose dependency increased the expression of the Arc gene, see Figs. 2, 3 and 7. Likewise, memantine dose dependency increased cortical Arc, see Fig. 4. Ifenprodil displayed a similar trend of increased cortical Arc, see Fig. 5. In contrast, the potent, non-selective NMDA antagonist MK-801 reduced Arc mRNA in both the striatum and the frontal cortex, see Fig. 6.

This indicates that the increase in Arc observed with pridopidine and ordopidine arises due to synaptic, rather than extrasynaptic, NMDA receptor enhancement, since the two extrasynaptic blockers did not reduce, but rather increase Arc expression.

Synaptic NMDA receptor stimulation has recently been shown to promote neuronal survival and plasticity, as opposed to extrasynaptic NMDA receptor stimulation which triggers neurotoxic effects and neuronal death. As an example, the extrasynaptic antagonist memantine has been shown to exert neuroprotective effects in an huntington's disease model in vivo. Hence, the enhancement of synaptic NMDA receptor signalling observed upon treatment with pridopidine and ordopidine constitutes a neuroprotective mechanism that could be of therapeutic value to slow down disease progression in neurodegenerative disorders including Huntington's disease.

It should be noted that neither pridopidine nor ordopidine has shown any significant affinity at NMDA receptors in vitro. However, both pridopidine and ordopidine produce increased levels of dopamine in the frontal cortex and the striatum measured by in vivo microdialysis. For example, ordopidine at a dose of 50 micromol/kg s.c. increased extracellular levels in the frontal cortex to approximately 300% of baseline levels.

Stimulation of dopamine D1 receptors, which are abundant in these brain regions, is believed to lead to enhanced NMDA responses given the well-established interaction between DA, D1 and NMDA-R signalling. Therefore, the effect of pridopidine and ordopidine to enhance synaptic NMDA stimulation is most likely an indirect effect related to stimulation of D1 receptors. Example 5

Biological activity

In this example a compound for use according to the invention, i.e. 1 -Ethyl- 4-(2-fluoro-3-methanesulfonyl-phenyl)-piperidine, also designated ordopidine, was further investigated with respect to the effects on the neurotrophic biomarker BDNF (Brain derived nerve growth factor). BDNF is considered crucial for neuronal survival and plasticity.

Ordopidine significantly increased BDNF mRNA levels in the frontal cortex, see Fig. 7.

Also, the neuroprotective compound memantine, preferentially blocking extrasynaptic NMDA receptors, produced increased BDNF mRNA in this experimental set-up, reflecting that a shift in the balance from extrasynaptic to synaptic NMDA receptor signalling may upregulate neuronal survival pathways, see Fig. 4.

Example 6

Biological activity

It has previously been reported that the compounds for use according to the invention function as competitive antagonists at dopamine D2 receptors. Recent data show that pridopidine and ordopidine may also display significant affinity at Histamine H3 receptors and adrenergic alpha2 receptors.

Histamine is a neurotransmitter and neuromodulator in the central nervous system (CNS). The histamine H3 receptor is participating in the modulation of arousal, learning and memory and food intake by their autoreceptors and heteroreceptors. Furthermore, the histamine H3 receptor is involved in the regulation of forskolin- stimulated cAMP formation and extracellular calcium inflow. In addition clobenpropit, a compound with affinity to histamine H3 receptors, has been shown to protect from NMDA-induced excitotoxicity in rat cultured cortical neurons. Excitotoxicity in neurons is a toxic consequence of the actions of excitatory amino acids (EAAs), whether endogenous or exogenous (in the cases of some chemical models in animals or in vitro). Since glutamate is the major excitatory neurotransmitter, excitotoxicity in the central nervous system (CNS) is considered to result from glutamate exposure for prolonged periods or in excessive concentrations.

We have recently discovered that pridopidine and ordopidine have affinity to histamine H3 receptors, see Table 3 below. As a compound with histamine H3 affinity, clobenpropit, has been shown to protect from NMDA-induced excitotoxicity, we propose that pridopidine and ordopidine could also be neuroprotective by means of their affinity to histamine H3 receptors.

Norepinephrine is a neurotransmitter in the central nervous system (CNS) also in the peripheral sympathetic nervous system. Norepinephrine act at adrenergic receptors (adrenoreceptors), e.g. at the adrenergic alpha2 receptors. Adrenergic alpha2 receptors have been shown to be involved in regulation of adult hippocampal neurogenesis, a critical form of cellular plasticity that is greatly influenced by neural activity. Yohimbine, a compound with affinity to adrenergic alpha2 receptors, was able to accelerate hippocampal neurogenesis and expression of brain derived neurotrophic factor (BDNF) in rats treated with the antidepressant imipramine. Furthermore, a recent study has shown that norepinephrine directly activates adult hippocampal precursors in mice.

Pridopidine and ordopidine have been shown to increase extracellular levels of norepinephrine in rat. Moreover, we have recently discovered that pridopidine and ordopidine have affinity to adrenergic alpha2 receptors, see Table 3 below.

Table 3

In Fig. 7 it is shown that ordopidine produces increased BDNF mRNA. This finding supports that pridopidine and ordopidine are neuroprotective through accelerated neurogenesis and expression of BDNF, possibly mediated to some extent by affinity to adrenergic alpha2 receptors and by enhanced extracellular levels of norepinephrine, and is in support of a disease modifying effect.

Claims

1 . A substituted 4-phenyl-N-alkyl-piperidine represented by Formula I

R¹ represents hydrogen or fluoro; and

R² represents ethyl or propyl;

for use as a medicament for preventing onset or delaying onset or preventing or slowing the progression of Huntington's disease in a Huntington's disease gene-positive subject not having any symptoms of Huntington's disease, i.e. a pre-manifest Huntington's disease subject.

2. The substituted 4-phenyl-N-alkyl-piperidine according to claim 1 , an N- oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein R¹ is attached to the 2- or 5-position.

3. The substituted 4-phenyl-N-alkyl-piperidine according to either one of claims 1 -2, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein

R¹ represents hydrogen; and

R² represents ethyl or propyl.

4. The substituted 4-phenyl-N-alkyl-piperidine according to either one of claims 1 -2, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein

R¹ represents fluoro; and

R² represents ethyl.

5. The substituted 4-phenyl-N-alkyl-piperidine according to claim 1 , an N- oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein

4-(3-methylsulfonylphenyl)-1 -propyl-piperidine; an N-oxide thereof, a deuterated analog thereof, or a pharnnaceutically acceptable salt thereof.

6. The substituted 4-phenyl-N-alkyl-piperidine according to claim 1 , an N- oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein

7. The substituted 4-phenyl-N-alkyl-piperidine according to claim 1 , an N- oxide thereof, or a pharmaceutically acceptable salt thereof; wherein

1 -Ethyl-4-(2-fluoro-3-methanesulfonyl-phenyl)-piperidine;

an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

8. The substituted 4-phenyl-N-alkyl-piperidine according to claim 1 , an N- oxide thereof, or a pharmaceutically acceptable salt thereof; wherein

9. The substituted 4-phenyl-N-alkyl-piperidine according to claim 1 , an N- oxide thereof, or a pharmaceutically acceptable salt thereof; wherein

1 -Ethyl-4-(3-fluoro-5-methanesulfonyl-phenyl)-piperidine;

an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

10. The substituted 4-phenyl-N-alkyl-piperidine according to claim 1 , an N- oxide thereof, or a pharmaceutically acceptable salt thereof; wherein

1 -Ethyl-4-(3-fluoro-5-methanesulfonyl-phenyl)-piperidine hydrochloride salt; or an N-oxide thereof.

1 1 . The substituted 4-phenyl-N-alkyl-piperidine according to any one of claims 1 -10, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for preventing onset or delaying onset or preventing or slowing the progression of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

12. The substituted 4-phenyl-N-alkyl-piperidine according to any one of claims 1 -10, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for preventing onset or delaying onset of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

13. The substituted 4-phenyl-N-alkyl-piperidine according to any one of claims 1 -10, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for preventing or slowing the progression of the symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

14. The substituted 4-phenyl-N-alkyl-piperidine according to any one of claims 1 -10, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for delaying or slowing progression of symptoms of Huntington's disease in a subject diagnosed to have CAG repeats in excess of 36 in one of the alleles of the huntingtin (htt) gene.

15. The substituted 4-phenyl-N-alkyl-piperidine according to any one of claims 1 -14, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament according to the invention is applied to a subject diagnosed to have CAG repeats in excess of 40 in one of the alleles of the huntingtin (htt) gene.

16. The substituted 4-phenyl-N-alkyl-piperidine according to any one of claims 1 -14, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament according to the invention is applied to a subject diagnosed to have CAG repeats in excess of 45 in one of the alleles of the huntingtin (htt) gene.

17. The substituted 4-phenyl-N-alkyl-piperidine according to any one of claims 1 -14, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament according to the invention is applied to a subject diagnosed to have CAG repeats in excess of 50 in one of the alleles of the huntingtin (htt) gene.

18. The substituted 4-phenyl-N-alkyl-piperidine according to any one of claims 1 -14, an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament according to the invention is applied to a subject diagnosed to have CAG repeats in excess of 55 in one of the alleles of the huntingtin (htt) gene.

19. The substituted 4-phenyl-N-alkyl-piperidine according to claim 1 , an N- oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for delaying or slowing progression of symptoms of Huntington's disease in a subject having symptoms of Huntington's disease, i.e. delaying progression in a manifest Huntington's disease subject.

20. A pharmaceutical composition comprising a therapeutically effective amount of a therapeutically effective amount of a substituted 4-phenyl-N-alkyl- piperidine represented by Formula I

R¹ represents hydrogen or fluoro; and

R² represents ethyl or propyl;

together with at least one pharmaceutically acceptable carrier or diluent, for preventing onset or delaying onset or preventing or slowing the progression of Huntington's disease in a Huntington's disease gene-positive subject not having any symptoms of Huntington's disease, i.e. a pre-manifest Huntington's disease subject.

21 . A method for preventing onset or delaying onset or preventing or slowing the progression of Huntington's disease in a Huntington's disease gene- positive subject not having any symptoms of Huntington's disease, i.e. a pre-manifest Huntington's disease subject, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a substituted 4-phenyl-N-alkyl-piperidine represented by Formula I

an N-oxide thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof; wherein R¹ represents hydrogen or fluoro; and R² represents ethyl or propyl.