NZ721697B2 - Use of benzimidazole-proline derivatives - Google Patents

Abstract

The present invention relates to compounds of the formula (I), wherein Ar1 and Ar2 are as described in the description and to their use as pharmaceuticals for the treatment of sundown syndrome. The invention also relates to the preparation of such compounds and of pharmaceutically acceptable salts thereof. hereof.

Description

Use of benzimidazole-proline derivatives The present disclosure relates to novel benzimidazole-proline derivatives of formula (I) and their use as pharmaceuticals for the treatment of sundown syndrome. Also described are processes for the preparation of the compounds and ceutical compositions containing one or more compounds of formula (I).

Sundown syndrome is a late-day circadian syndrome of increased confusion and restlessness, generally in a patient with some form of dementia. Cardinal clinical signs include increased agitation, l confusion and mood swings that typically develop as natural light begins to fade. This disruptive behavior worsening in the late afternoon or early evening among ia patients or elderly institutionalized patients has been reported in the medical literature for more than 60 years (Bachman & Rabins, Annu. Rev. Med. 2006. 57:499–511). Terms used to be this phenomenon e sundowning, afternoon sundowning, sundowner syndrome, or sundowning syndrome.

In contrast to delirium which is generally acute in onset and fluctuating in the course of the day, sundown syndrome is defined by its temporal pattern (late-day onset and termination).

Sundown syndrome seems to occur more frequently during the middle stages of Alzheimer dementia. ts are generally able to understand that this behavioral pattern is abnormal.

Sundown syndrome seems to subside with the progression of a patient's dementia.

About half of dementias (44%) are of Alzheimer's type ing Alzheimer dementia (presenile dementia or senile dementia), subcortical dementia, diffuse Lewy body ia, and frontotemporal dementia. About 20–45% of Alzheimer type patients will experience some sort of sundowning ion. Further 47% of dementias are of vascular type including vascular ia, multi-infarct dementia, Binswanger's dementia, boxer's dementia, and osclerotic dementia. Remaining types of dementia (9%) are of other etiologies such as paralytic ia, substance-induced persisting dementia, dialysis dementia, hydrocephalic dementia, tumors, subdural hematoma, normal pressure hydrocephalus, vasculitis, Vitamin deficiency, or endocrine and metabolic disease.

Possible etiology of sundown syndrome es the particular histopathological signs of degeneration that are ed into Ventro l Pre-Optic area (VLPO) and Supra- Chiasmatic Nucleus (SCN) in dementias. The SCN pacemaker is severely affected in Alzheimer e, whereas pineal is essentially unaffected (Swaab DF, Fliers E, Partiman TS. "The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia". Brain Res 1985; 342: 37–44; Zhou JN, Hofman MA, Swaab DF. "VIP neurons in the human SCN in relation to sex, age, and Alzheimer's disease". Neurobiol Aging 1995; 16: 571–576; Swaab DF, Grundke-Iqbal I, Iqbal Ket al. "Tau and ubiquitin in the human hypothalamus in aging and Alzheimer's disease". Brain Res 1992; 590: 9; Stopa EG, Volicer L, Kuo-Leblanc Vet al. "Pathologic evaluation of the human suprachiasmatic s in severe dementia". J Neuropathol Exp Neurol 1999; 58: 29–39). SCN is ated with ting wakefulness and sleep patterns by maintaining circadian s. These rhythms are synchronized with external dark cues and involve complex iological regulation within the brain. Histopathological signs of geriatric disturbance in brain ian oscillators such as SCN have been observed across several mammalian species.

The most widely prescribed pharmacological treatments for sundown syndrome - atypical antipsychotics - have a modest but significant beneficial effect in the short-term treatment (over 6–12 weeks) of aggression, less so on symptoms of agitation, and have limited benefits in longer term y. Concerns are growing over the ial for serious adverse outcomes with these treatments, including stroke and death (Ballard et al., Nat. Rev. Neurol. , 245–255, 2009).

Previous clinical work has been published and describes medical technology with protocols for evaluating drug s in sundown me patients; a review on trials and methodology in agitation and aggression in dementia can be found in Ballard et al., Nat. Rev.

Neurol. 5, 245–255, 2009 (see especially table 1). Published studies are for example: a) Cohen-Mansfield J, Garfinkel D, Lipson S. Melatonin for treatment of sundowning in elderly persons with dementia – a preliminary study. Arch Gerontol Geriatr 2000; 31: 65–76. b) Brusco LI, Marquez M, Cardinali DP. Melatonin treatment izes chronobiologic and cognitive symptoms in Alzheimer's disease. Neuroendocrinol Lett 2000; 21: 39–42. c) de Jonghe A, Korevaar JC, van Munster BC, de Rooij SE. Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia. Are there ations for delirium? A systematic review. Int J Geriatr Psychiatry. 2010 Dec; 25(12):1201-8. d) ti AE. Risperidone for control of agitation in dementia patients. Am J Health Syst Pharm. 2000 May 1;57(9):862-70.

Partial effectiveness of melatonin or bright light exposure has been reported to decrease behavioral symptoms in sundown syndrome. Consistent sleeping schedule and daily routine can also reduce confusion and agitation. Reduction of daytime napping is recommended as unintentionally getting too much sleep will affect nighttime sleep. ion of caffeine intake is recommended to sundown syndrome patients.

Neuronal afferences and efferences connect alamic orexin neurons to brain areas involved in circadian rhythm regulation (receiving day-night signals) and in cortical activation (inducing and maintaining ess); orexin neurons also receive afferent physiological and emotional inputs of limbic and metabolic origin. Activated orexin neurons thus regulate alertness for adapting the organism to environmental and circadian requirements and for accurate maintenance of homeostatic balance (Saper et al., Nature 437: 1257, 2005). The Ventro Lateral Pre-Optic area (VLPO) and the Supra-Chiasmatic Nucleus (SCN) are important brain clock regions that exert major inhibition on ty of orexin neurons during the nocturnal phase. It is hypothesized that abnormally hyperactive orexin s significantly contribute to cortical overdrive mediating hyperalertness at a given time point in the ian cycle. Pathological orexin hyperactivity may result from deficient inhibitory input from VLPO and SCN that should start to gradually establish in late afternoon.

Caffeine administration ses orexin levels in rat brain. Caffeine may be used as a tool to experimentally simulate deficient tory VLPO-SCN input to hypothalamic orexin neurons.

The pharmacological action of caffeine, an adenosine A1 and A2A receptor antagonist, is to block adenosinergic inhibition exerted by adenosinergic s upon orexin s.

It is an object of the present invention to go someway towards overcoming the prior art problems and/or to at least provide the public with a useful chopice. The orexin receptor antagonists disclosed herein may reverse late-day agitation simulated in animals by afternoon caffeine administration. Electroencephalographic recordings confirm the oral symptoms of agitation which were reduced by two of the exemplified compounds when administered orally to rats and / or dogs.

Short description of the s: Figure 1 shows the effect of the nd of example 7 in a coffein-induced agitation model in the rat.

Figure 2 shows the effect of the compound of example 11 in a coffein-induced agitation model in the rat.

Figure 3 shows the effect of the compound of example 7 in a coffein-induced agitation model in the dog.

Summary of the invention In a first aspect present invention provides a uUse of a compound of the formula (I): Formula (I) or of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of sundown syndrome; wherein the compound of formula (I) is in absolute configuration (S); Ar1 represents , , or ; and Ar2 represents , , , , , , , , or .

Brief Description Orexin receptor antagonists sing a 2-substituted saturated cyclic amide derivatives (such as 2-substituted pyrrolidinecarboxamides) are known for example from WO2008/020405, /038251, WO2008/081399, WO2008/087611, WO2008/117241, WO2008/139416, WO2009/004584, WO2009/016560, WO2009/016564, WO2009/040730, WO2009/104155, WO2010/004507, WO2010/038200, WO2001/096302, WO2002/044172, WO2002/089800, /090355, WO2003/002559, WO2003/032991, WO2003/041711, WO2003/051368, WO2003/051873, WO2004/026866, WO2004/041791, /041807, WO2004/041816, /003993, WO2009/003997, WO2009/124956, WO2010/060470, WO2010/060471, WO2010/060472, WO2010/063662, /063663, WO2010/072722, WO2010/122151, and WO2008/150364. A particular pyrrolidine derived compound is sed in Langmead et. al, Brit. J. Pharmacol. 2004, 141, 340-346 as being highly orexin-1 selective. WO2003/002561 discloses certain l cyclic amine derivatives, encompassing benzimidazolyl-methyl substituted pyrrolidine tives, as orexin receptor antagonists.

There is no mention of sundown syndrome in WO2003/002561. e the great number of prior art orexin receptor antagonist compounds and their high structural ility, all compounds share a common ural feature, i.e. in position 2 of the saturated cyclic amide a linker group such as at least a methylene group (or longer groups such as -CH2-NH-CO-, -CH2-NH-, -CH2-O-, -CH2-S-, etc.) link the cyclic amide to the respective aromatic ring system substituent. It has now surprisingly been found that, despite the ntial conformational changes that may be expected from the removal of a linker between two rigid structural elements, the present compounds, that have a idazole ring directly attached to a pyrrolidine amide in position 2, are potent orexin receptor antagonists.

Also described are certain benzimidazole-proline derivatives, which are potent non-peptide antagonists of human orexin receptors for use in the prevention or treatment of sundown syndrome. 1) A first embodiment described herein relates to compounds of the formula (I): Formula (I) for use in the prevention or treatment of sundown syndrome; wherein the compounds of formula (I) are in absolute configuration (S); Ar1 represents , , or ; and Ar2 represents , , , , , , , , or . 2) A second embodiment relates to compounds of formula (I) according to embodiment 1) for use according to embodiment 1), wherein the compound is: -(5-Chloromethyl-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methylpyrimidinyl-phenyl)- methanone; [(S)(5-Bromomethyl-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(S)(5-Bromomethyl-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methylpyrimidinyl-phenyl)- methanone; [(S)(5-Chloromethyl-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methoxy[1,2,3]triazolylphenyl )-methanone; [(S)(6-Bromofluoro-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(S)(5,6-Dimethoxy-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(S)(5,6-Dimethoxy-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methylpyrazolyl-phenyl)- one; [(S)(5,6-Dimethoxy-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methoxy[1,2,3]triazolyl-phenyl)- methanone; [(S)(6-Chlorotrifluoromethyl-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methyl[1,2,3]triazolylphenyl )-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(S)methyl(5-trifluoromethyl-1H-benzoimidazolyl)-pyrrolidinyl]- methanone; or (5-Methyl[1,2,3]triazolyl-phenyl)-[(S)methyl(5-trifluoromethoxy-1H-benzoimidazolyl)-pyrrolidinyl]- methanone. 3) A third ment relates to compounds according to embodiment 1) for use according to embodiment 1), n the compound is: [(S)(5-Bromomethyl-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methylpyrimidinyl-phenyl)- methanone. 4) A fourth embodiment relates to compounds according to embodiment 1) for use according to embodiment 1), wherein the compound is: [(S)(5-Chloromethyl-1H-benzoimidazolyl)methyl-pyrrolidinyl]-(5-methoxy[1,2,3]triazolylphenyl )-methanone.

The compounds of formula (I) n at least one stereogenic center which is situated in on 2 of the pyrrolidine moiety. The absolute configuration of the pyrrolidine moiety of the present compounds is as depicted in formula (I); i.e. said chiral center is in te (S) configuration.

In addition, it is well understood that the benzimidazole moiety Ar2 of the present nds ents tautomeric forms. Thus, substituents of the benzimidazole moiety may be ed in the position(s) ortho to the bridgehead atoms (i.e. attached in position(s) 4 and/or 7), and/or in the position(s) meta to the bridgehead atoms, (i.e. attached in position(s) 5 and/or 6). It is understood that the two ortho, and, respectively, the two meta positions are considered equivalent. For example, the group 5-chloromethyl-1H-benzoimidazolyl is understood to signify the same group as 6-chloromethyl-1H-benzoimidazolyl, 5-chloro- 4-methyl-3H-benzoimidazolyl and 6-chloromethyl-3H-benzoimidazolyl.

In this patent ation, a dotted line shows the point of attachment of the radical drawn.

For example, the radical drawn below represents a 5-methyl(2-triazolyl)-phenyl group.

Where the plural form is used for compounds, salts, ceutical compositions, diseases and the like, this is ed to mean also a single compound, salt, or the like.

Any reference to compounds of a (I) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject nd. For reference see for e ook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quéré (Eds.), RSC Publishing, 2012. A preferred pharmaceutically acceptable salt is the hydrochloric acid salt.

Sundown syndrome is defined as a late-day (i.e. afternoon and / or evening hours, especially afternoon hours) circadian syndrome of increased confusion and restlessness in a patient, wherein in general said t has some form of dementia. Cardinal clinical signs include increased agitation, general confusion and mood swings that typically develop as natural light begins to fade. The term "late day" ed to herein relates to the afternoon and evening, notably the time about sunset and later (but not including the night / the sleep time); for example the time from about 4 pm to about 10 pm, especially from about 4 pm to about 9 pm. In one sub-embodiment, the term relates to the oon, especially from about 4 pm to about 7 pm; in r sub-embodiment the term relates to the evening, especially from about 7 pm to about 10 pm.

Dementias include notably dementias of Alzheimer's type ing: Alzheimer dementia (presenile ia or senile dementia), subcortical ia, diffuse Lewy body dementia, and frontotemporal dementia. Dementias further include dementias of vascular type such as: vascular dementia, multi-infarct dementia, Binswanger's dementia, boxer's dementia, osclerotic dementia. Remaining types of dementia (9%) are of other gies such as paralytic dementia, substance-induced persisting dementia, dialysis dementia, hydrocephalic ia, and dementias due to tumors, subdural hematoma, normal pressure hydrocephalus, vasculitis, Vitamin deficiency, or endocrine or metabolic disease. In the context of the present disclosure, the term preferably refers to dementias of Alzheimer's type, especially mer dementia.It is understood that the term dementia also includes any combination of the above listed types of dementias.

In a sub-embodiment, dementia especially refers to middle stages of dementias of Alzheimer's type (especially to middle stages of mer dementia) in which stages n syndrome appears to occur more frequently and / or of mixed dementia [a form of dementia combining neuropathological protein deposits (associated with Alzheimer dementia) with a dementia of vascular type]. In a preferred sub-embodiment, dementia refers to middle stages of dementias of Alzheimer's type (especially to middle stages of Alzheimer dementia).

Stages of dementias of mer's type may be defined as follows in the entioned middle stages of dementias of Alzheimer's type (especially middle stages of Alzheimer dementia) refer to stages 3 to 6, preferably stages 3 to 5, in particular to stages 3 and 4 as defined below, and n pre-senile dementia may be defined as corresponding to stages 1 to 4, in particular to stages 3 and 4, below): Stage 1: No ment (normal function); The person does not experience any memory problems. An interview with a medical professional does not show any evidence of symptoms of dementia. Stage 2: Very mild cognitive decline (may be normal age-related s or earliest signs of a dementia, e.g. of Alzheimer's type): The person may feel as if he or she is having memory lapses (e.g. forgetting familiar words or the location of everyday objects). But at this stage, no symptoms of dementia can be detected during a medical examination or by friends, family or co-workers. Stage 3: Mild ive decline (dementia, e.g. of Alzheimer's type can be diagnosed in some, but not all duals with these symptoms): Friends, family or co-workers begin to notice difficulties. During a detailed medical interview, doctors may be able to detect problems in memory or tration.

Common stage 3 difficulties include: noticeable problems coming up with the right word or name; trouble remembering names when introduced to new people; having noticeably greater difficulty performing tasks in social or work settings; forgetting material that one has just read; losing or misplacing a valuable object; increasing trouble with planning or organizing. Stage 4: Moderate cognitive decline: At this point, a careful medical interview should be able to detect clear-cut symptoms in several areas: forgetfulness of recent events; impaired ability to perform challenging mental arithmetic; greater difficulty ming complex tasks, such as planning dinner for guests, paying bills or managing finances; forgetfulness about one's own personal history; becoming moody or withdrawn, especially in socially or mentally challenging situations. Stage 5: Moderately severe cognitive decline: gaps in memory and ng are noticeable, and individuals begin to need help with day-today activities. At this stage, those with a dementia, e.g. of Alzheimer's type may be unable to recall their own address or one number or the high school or college from which they graduated; become confused about where they are or what day it is; have trouble with less nging mental arithmetic; need help choosing proper clothing for the season or the occasion; still remember significant details about themselves and their family; still require no assistance with eating or using the toilet. Stage 6: Severe cognitive decline: Memory continues to worsen, personality changes may take place and individuals need extensive help with daily activities. At this stage, individuals may lose awareness of recent ences as well as of their surroundings; remember their own name but have difficulty with their personal history; distinguish ar and unfamiliar faces but have trouble remembering the name of a spouse or caregiver; need help dressing properly and may, without supervision, make mistakes such as putting pyjamas over daytime clothes or shoes on the wrong feet; experience major changes in sleep patterns (e.g. sleeping during the day and becoming ss at night); need help handling s of toileting; have increasingly frequent trouble controlling their bladder or bowels; experience major personality and behavioral changes, including suspiciousness and ons (such as ing that their caregiver is an impostor) or compulsive, repetitive behavior like hand-wringing or tissue shredding; tend to wander or become lost. Stage 7: Very severe cognitive decline: In the final stage of e.g. Alzheimer dementia, individuals lose the ability to respond to their environment, to carry on a conversation and, eventually, to control movement. They may still say words or phrases. At this stage, individuals need help with much of their daily personal care, including eating or using the . They may also lose the ability to smile, to sit without support and to hold their heads up. Reflexes become abnormal, muscles grow rigid, swallowing impaired. 5) A fifth ment thus relates to compounds according to any one of embodiments 1) to 4) for use according to embodiment 1), n the compound is used for the prevention or treatment of sundown syndrome in a patient who has some form of dementia.

Medical factors which may contribute to the development of sundown syndrome said patients expressing some form of dementia may be chronic pain (e.g. due to arthritis or malignancy) organ systemic disorders (e.g. tive heart failure, ischemic heart se, asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, incontinence, benign prostatic hypertrophy), psychiatric conditions (e.g. depression, anxiety, sis), and effects of medication. 6) A r ment relates to compounds according to any one of embodiments 1) to 4) for use according to embodiment 5), wherein said patient has a dementia of Alzheimer's type. 7) A further embodiment relates to nds according to any one of embodiments 1) to 4) for use according to embodiment 5), n said patient has Alzheimer dementia. 8) A further embodiment relates to compounds according to any one of embodiments 1) to 4) for use according to embodiment 5), wherein said patient has middle stage dementia of Alzheimer's type (especially middle stage Alzheimer dementia). 9) A further embodiment relates to compounds according to any one of embodiments 1) to 4) for use according to any one of embodiments 1) to 8), wherein said sundown syndrome is afternoon sundown syndrome (wherein afternoon is especially defined as the intervall from about 4 pm to about 7 pm).

) A further ment relates to compounds according to any one of embodiments 1) to 4) for use according to any one of embodiments 1) to 8), wherein said n syndrome is evening sundown syndrome (wherein afternoon is especially defined as the intervall from about 7 pm to about 10 pm).

Also described are compounds of the formula (I) as d in embodiment 1), or to such compounds further limited by the characteristics of any one of ments 2) to 4), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments in the ent of sundown syndrome according to any one of embodiments 1) to 10). For avoidance of any doubt, the following embodiments are thus possible and intended and herewith specifically disclosed in individualized form: 1, 2+1, 3+1, 4+1, 5+1, 5+2+1, 5+3+1, 5+4+1, 6+5+1, 6+5+2+1, 6+5+3+1, 6+5+4+1, 7+5+1, 7+5+2+1, 7+5+3+1, 7+5+4+1, 8+5+1, 8+5+2+1, 8+5+3+1, 1, 9+1, 9+2+1, 9+3+1, 9+4+1, 9+5+1, 9+5+2+1, 9+5+3+1, 9+5+4+1, 1, 9+6+5+2+1, 3+1, 4+1, 9+7+5+1, 9+7+5+2+1, 9+7+5+3+1, 9+7+5+4+1, 9+8+5+1, 9+8+5+2+1, 9+8+5+3+1, 9+8+5+4+1, 10+1, 10+2+1, 10+3+1, 10+4+1, 10+5+1, 10+5+2+1, 10+5+3+1, +5+4+1, 10+6+5+1, 10+6+5+2+1, 10+6+5+3+1, 10+6+5+4+1, 10+7+5+1, 10+7+5+2+1, 10+7+5+3+1, 10+7+5+4+1, 10+8+5+1, 10+8+5+2+1, 10+8+5+3+1, 10+8+5+4+1.

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The ent individualized embodiments are separated by . In other words, “10+7+5+1” for example refers to embodiment 10) depending on embodiment 7), depending on embodiment 5), depending on embodiment 1), i.e. embodiment “10+7+5+1” corresponds to the compounds of formula (I) according to embodiment 1) further limited by all the features of the embodiments 5), 7), and 10).

The compounds of formula (I) according to any one of embodiments 1) to 4) and their ceutically acceptable salts can be used as medicaments for the prevention or treatment of sundown syndrome, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral stration ding topical ation or inhalation).

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person d in the art (see for e Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formulae (I), (II) and (III) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical stration form together with suitable, non-toxic, inert, eutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

Also described is a method for the ent of a er mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) as defined in any one of embodiments 1) to 4).

In a red embodiment of the disclosure, the administered amount of such a compound of formula (I) according to any one of embodiments 1) to 4) is comprised between 1 mg and 1000 mg per day, ularly between 5 mg and 400 mg per day, more particularly n mg and 200 mg per day.

Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 ºC and 80 ºC, this means that the end points 40 ºC and 80 ºC are ed in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.

The term “about” placed before a cal value “X” refers in the current application to an al extending from X minus 10% of X to X plus 10% of X, and ably to an interval ing from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10ºC to Y plus 10ºC, and preferably to an interval extending from Y minus 5ºC to Y plus 5ºC. Besides, the term “room temperature” as used herein refers to a temperature of about 25°C. In the particular case of time points, the term “about” placed before a certain time point “Y” refers in the current application to an interval extending from the time point Y minus 1 hour to Y plus 1 hour, and preferably to an interval extending from Y minus 30 minutes to Y plus 30 s.

For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.

Preparation of compounds of formula (I): The compounds of formula (I) can be prepared by the methods given below, by the methods given in the experimental part below or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. In some cases the final product may be further modified, for example, by manipulation of substituents to give a new final product. These lations may include, but are not limited to, reduction, oxidation, alkylation, ion, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the following reaction s, and/or reaction steps, may be varied to facilitate the reaction or to avoid unwanted reaction products.

Compounds of formula (I) described herein can be prepared according to the general sequence of reactions outlined below wherein Ar1 and Ar2 are as defined for formula (I). The generic substituent (R)n refers to the tuents of the benzimidazole group Ar2 as defined for the compounds of formula (I).

There are two general tic approaches towards the compounds of formula (I).

OH CH3 N OH H H N N O N a b Boc O c (R)n Boc O H CH3 N H N N CH3 N H N H N Ar1 O N N (R)n x HCl f (R)n d Boc N (R)n A first synthetic approach 1 may start with a Boc-protection of the respective proline tive a under standard conditions, e.g. by dissolving the proline a in a solvent such as DCM or THF and adding a base to the solution, for example DIPEA, TEA or aq. Na2CO3 followed by the addition of Boc2O. The reaction is performed at RT and is usually complete within a few hours and results in the Boc-protected proline derivative b. The protected proline derivative b (which is also cially available) is then coupled under standard amide coupling conditions with the appropriate phenylene-diamine derivative, e.g. in a t such as THF, DCM or DMF in the presence of a ng agent such as HBTU or TBTU or the like and a base, for example DIPEA or TEA to give compound c. Ring closure to obtain the benzimidazole derivative d is achieved for example by dissolving the precursor c in AcOH and heating at 100°C for 1 h. Compound d is Boc-deprotected under rd acidic conditions such as 4M HCl in dioxane, or TFA in DCM, to give precursor e which is converted into the final compound f by an amide ng on with Ar1-COOH, e.g. in a solvent such as THF, DMF or DCM in the ce of a coupling agent such as TBTU, HBTU, HATU, EDC or the like and a base such as DIPEA, TEA or N-methylmorpholine.

CH3 CH3 CH3 N O O H N O H a O g O h Ar1 O H CH3 H CH3 N N N OH O (R)n N Ar1 O (R)n Ar1 O O H2N Ar1 O i An alternative synthetic ch 2 may start with an esterification (usually methyl ester formation) of the proline derivative a, e.g. by dissolving the starting material in THF and adding 5 equivalents of the respective alcohol (usually MeOH) followed by the addition of EDC and DMAP. The methyl-ester derivative g (which is also commercially ble) is then ed with Ar1-COOH using standard amide coupling conditions such as those described above to result in intermediate h. Ester hydrolysis under standard conditions, e.g. by dissolving the ester derivative h in THF / MeOH =