(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`1111111111111111 IIIIII IIIII IIII I II Ill lllll lllll lllll lllll llll 1111111111111111111
`
`(43) International Publication Date
`7 December 2000 (07.12.2000)
`
`PCT
`
`(10) International Publication Number
`WO 00/72832 A2
`
`(51) International Patent Classification 7:
`
`A61K 31/00
`
`(21) International Application Number:
`
`PCT/EP00/04376
`
`(22) International Filing Date:
`
`16 May 2000 (16.05.2000)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`99109295.8
`
`English
`
`English
`
`27 May 1999 (27.05.1999) EP
`
`(71) Applicant (for all designated States except US): MERCK
`PATENT GMBH [DE/DE]; Frankfurter Strasse 250,
`D-64293 Darmstadt (DE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BARTOSZYK,
`Gerd [DE/DE]; Kreuzstrasse 57, D-64331 Weiterstadt
`(DE). SEYFRIED, Christoph [DE/DE]; Mathilden(cid:173)
`strasse 6, D-64342 Seeheim (DE). VAN AMSTER(cid:173)
`DAM, Christoph [DE/DE]; Schepp Allee 47, D-64295
`Darmstadt (DE). BOTTCHER, Henning [DE/DE];
`Theodor-Heuss-Strasse 13, D-64287 Darmstadt (DE).
`SEDMAN, Ewen [GB/GB]; The Barley House, Dene Lea,
`Ropley, Alresford, Hampshire SO24 0BH (GB).
`
`(74) Common Representative: MERCK PATENT GMBH;
`Postfach, D-64271 Darmstadt (DE).
`
`(81) Designated States (national): AE, AL, AM, AT, AU, AZ,
`BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE,
`ES, Fl, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD,
`MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD,
`SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ,
`VN, YU, ZA, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent
`(AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent
`(AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU,
`MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`Without international search report and to be republished
`upon receipt of that report.
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`---==
`iiiiiiii -iiiiiiii -
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`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine or a physiologically acceptable
`
`~ (54) Title: NOVEL USE OF 1-[4-(5-CYANOINDOL-3-YL)BUTYL]-4-(2-CARBAMOYL-BENZOFURAN-5-YL)-PIPERAZINE
`00 AND ITS PHYSIOLOGICALLY ACCEPTABLE SALTS
`N t: (57) Abstract:
`g salt thereof is used for the manufacture of a medicament for the treatment of sub-type anxiety disorders chosen from the
`0 posttraumatic stress disorder, acute stress indication or generalized-anxiety disorder, bipolar disorders, mania, dementia,
`
`sub-types panic disorder with or without agoraphobia, agoraphobia, obsessive-compulsive spectrum disorders, social phobia,
`
`:;, substance-related disorders, sexual dysfunctions, eating disorders, obesity, anorexia and fibromyalgia. A preferred salt is
`;;,;-,,- 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride.
`Argentum EX1005
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`Novel use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5-yl)-piperazine and its physiologically acceptable salts
`
`The present invention relates to the use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-
`(2-carbamoyl-benzofuran-5-yl)-piperazine or a physiologically acceptable
`salt thereof, for the manufacture of a medicament for the treatment of sub(cid:173)
`
`type anxiety disorders.
`
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine,
`physiologically acceptable salts thereof (US 5,532,241, column 7, lines 30
`to 58) and a process (US 5,532,241, Example 4) by which it/they can be
`prepared are known from U.S. Patent US 5,532,241. The compound which
`is referred to herein is described in the patent as a combined selective
`serotonin (5-HT) reuptake inhibitor (SSRI) and 5-HT1A receptor agonist.
`Therefore, the use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl(cid:173)
`benzofuran-5-yl)-piperazine and its physiologically acceptable acid addition
`salts for the manufacture of a medicament for the treatment of depressive
`disorders, including the sub-type disorders major depressive disorder and
`dysthymic disorder, for the treatment of anxiety disorders, for the treatment
`of psychiatric disorders like psychoses, schizophrenia or schizoaffective
`disorder, for the treatment of cerebral infarct like stroke and cerebral
`ischemia, for the treatment of CNS disorders such as tension, for the
`therapy of side-effects in the treatment of hypertension (e.g. with a(cid:173)
`methyldopa) and for the prophylaxis and therapy of cerebral disorders (e.g.
`migraine) is disclosed. Additionally, the use in endocrinology and
`gynecology is described, e.g. for the treatment of acromegaly,
`hypogonadism, secondary amenorrhea, premenstrual syndrome or
`
`undesired puerperal lactation.
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`Furthermore, it is known that they have a useful potential utility for the
`
`treatment of sleep disorders, including dyssomnias and narcolepsy.
`
`The invention had the object of providing novel uses for 1-(4-(5-cyanoindol-
`
`5
`
`3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and its
`
`physiologically acceptable salts having significantly better pharmacological
`
`properties than compounds of the prior art.
`
`It has been found that 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`
`10
`
`benzofuran-5-yl)-piperazine also has activity against sub-type anxiety
`
`disorders chosen from the sub-types panic disorder with and/or without
`
`agoraphobia, agoraphobia, obsessive-compulsive spectrum disorders,
`
`social phobia, specific phobia including neophobia, posttraumatic stress
`
`disorder, acute stress indication or generalized-anxiety disorder.
`
`15
`
`Accordingly, the present invention relates to the use of 1-[4-(5-cyanoindol-
`
`3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine or a physiologically
`
`acceptable salt thereof, for the manufacture of a medicament for the
`
`treatment of sub-type anxiety disorders chosen from the sub-types panic
`
`20
`
`disorder with or without agoraphobia, agoraphobia, obsessive-compulsive
`
`spectrum disorders including obsessive compulsive disorders, social
`
`phobia, specific phobia including neophobia, posttraumatic stress disorder,
`
`acute stress indication and/or generalized-anxiety disorder.
`
`25
`
`It is known that 5-HT reuptake inhibitors such as fluoxetine (L. Solyom, C.
`
`Solyom, B. Ledwidge, Can. J. Psychiatry, 1991, 36: 378-380) or 5-HT,A
`
`receptor agonists such as geprione (J.C. Pecknold, L. Luthe, M.H. Scott(cid:173)
`Fleury, S. Jenkins, J. Clin. Psychopharmacology, 1993, 13: 145-149) are
`
`clinically effective in panic disorders. It has been found that a combined
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`selective 5-HT reuptake inhibitor and 5-HT,A receptor agonist which
`includes both mechanisms leads to an advantage in clinical practice.
`
`A typical model for panic disorder is the Mouse Defense Test Battery
`according to G. Griebel, D.C. Blanchard, R.J. Blanchard, Prag.
`Neuropsychopharmacol. & Biol. Psychiat., 1996, 20: 185-205.
`The mouse defence battery test consists of an oval runway of 2 m straight
`segments joint by two 0.4 m curved segments separated by a median wall.
`A mouse is placed in the runway for a 3 min familiarization period. Then, a
`hand-held anaesthetized rat is introduced into the runway and brought up
`to the mouse. Approach is terminated when contact with the mouse was
`made or the mouse runs away from the approaching rat. If the subject runs
`away, avoidance distance and the number of avoidances after five
`approaches are recorded. Immediately after these approaches, the rat
`chases the mouse for a distance of 15 m, and flight speed is recorded.
`
`A typical model for Agoraphobia is named Elevated Plus Maze according to
`S. Pellow, P. Chopin, S.E. File, M. Briley, J. Neurosci. Meth., 1985, 14:
`145-167.
`
`The apparatus consists of an X-shaped platform elevated from the floor,
`with two "open" unprotected arms and two "closed" protected arms, with
`animals having free access to both arms. The rat or mouse is placed in the
`centre of the arms, and the number of entires made and the time spent on
`the open arms is measured in a 3 min test period. Normal animals have
`very low basal levels, i.e. avoid entering the open arms and stay only a for
`a very brief period on open arms.
`1-( 4-( 5-cya n oi nd ol-3-yl) butyl ]-4-(2-ca rbamoyl-be nzofura n-5-yl)-p iperazine
`or one of its physiologically acceptable salts, in particular 1-(4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride, following oral application dose-dependently increased both
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`the number of entries and the time spend on open arms. For example, in
`mice the dose of 10 mg/kg p.o. increased the number of entires by 157%
`and time spent on open arms by 105%. In rats, a dose of 10 mg/kg p.o.
`increased number of entries by 56% and time spent on open arms by 76%.
`
`It is known that 5-HT reuptake inhibitors such as paroxetine (A.K.
`
`Cardogan, I.K. Wright, I. Combs, C.A. Marsden, D.A. Kendall, I. Tulloch,
`Neurosci. Lett. 42: S8) or 5-HT1A receptor agonists such as geprione (V.
`Motta, S. Maisonnette; S. Morato; P. Castrechini; M.L. Brandao,
`Psychopharmacology, 1992; 107: 135-139) or 8-OH-DPAT (8-hydroxy(cid:173)
`dipropylaminotetralin) (N. Collinson, G.R. Dawson, Psychopharmacology,
`1997, 132: 35-43) have been shown to be effective in the elevated plus
`maze test. It has been found that a combined selective 5-HT reuptake
`
`5
`
`10
`
`inhibitor and 5-HT1A receptor agonist which includes both mechanisms
`leads to therapeutic advantages.
`
`15
`
`Obsessive Compulsive Disorders (OCDs) are characterized by unwanted
`intrusive, recurring thoughts, images, or actions which generate an
`
`irrational dread (obsession) of germs, dirt, contamination, apprehension of
`acting on violent or aggressive impulses, feeling overly responsible for the
`
`20
`
`safety of others, e.g. unreasonable dread of having run over someone with
`a car, abhorrent religious (blasphemous) and sexual thoughts, inordinate
`concern with order, arrangement, or symmetry, inability to discard useless
`or worn out possessions.
`
`25
`
`This often results in the repetitive performance of rituals (compulsions),
`such as excessive washing (particularly hand-washing or bathing),
`
`touching, counting, arranging and ordering, checking, cleaning and
`
`hoarding which persons suffering from OCD feel they can not control.
`Performing these rituals, however, provides only temporary relief. This
`person is almost always aware that their strange compulsive behaviour
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`makes no sense, but feels helpless to stop it. This person can have a few
`
`or many of these symptoms, which can vary during the course of the
`
`disorder. The patterns may be repeated as much as 100 times or for
`
`several hours per day, and renders the person unable to function normally
`
`5
`
`(for review e.g. Dolberg et al., Clin. Neuropharmacol. 1996, 19: 129 or F.
`
`Tallis, Br. J. Clin. Psycho!. 1997, 36: 3).
`
`Obsessive Compulsive Spectrum Disorders (OCSDs) share common
`
`features with OCDs including overlapping symptom profiles, demographics,
`
`10
`
`family history, comorbidity, clinical course and response to anti-obsessional
`
`treatment.
`
`OCSDs include e.g. somatoform disorders (e.g. body dysmorphobia,
`
`hypochondriasis), tic disorders (e.g. Gilles de la Tourette's syndrome),
`
`impulsive personality disorders (e.g. antisocial personality disorder),
`
`15
`
`impulse control disorders (e.g. trichotillomania, kleptomania, pyromania,
`
`pathological gambling, sexual compulsions such as exhibitionism,
`
`voyeurism, fetishism), schizo-obsessive disorders(e.g. obsessional
`
`schizophrenia, schizotypic OCD, delusional OCD), dissociative disorders
`
`(e.g. autism, torticolis, Sydenham's Chorea, Asperger's syndrome) [for
`
`20
`
`review e.g. E. Hollander and C. Wong, J. Clin. Psychiatry 1995, 56 (suppl.
`
`4): 3 or McElroy et al., J. Clin. Psychiatry 1994, 55 (suppl. 10): 33].
`
`A typical model for OCSD including OCD is the Marble Burying Test
`
`according to Y. lchimaru, T. Egawa, A. Sawa, Jpn. J. Pharmacol. 1995, 68:
`
`25
`
`65-70.
`
`The apparatus consists of an open cubic box with 25 clean glass marbles
`
`evenly spaced on sawdust. Individual mice are placed in the test box, and
`
`the number of glass marbles left uncovered after 20 minutes are counted.
`
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
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`or one of its physiologically acceptable salts, in particular 1-[4-(5-
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`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`
`hydrochloride, following subcutaneous application inhibits mable burying in
`
`mice dose-dependently. For example, a dose of 3 mg/kg of 1-[4-(5-
`
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`
`5
`
`hydrochloride nearly completely (92%) inhibits marble burying;
`
`equieffective doses of conventional serotonin reuptake inhibitors are e.g.
`
`20 mg/kg for fluvoxamine or 17 mg/kg for fluoxetine and an equieffective
`
`dose of the 5-HT,A agonist ipsapirone is 10 mg/kg.
`
`10
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`It is known that 5-HT reuptake inhibitors or 5-HT,A receptor agonists inhibit
`
`marble burying, e.g. fluvoxamine, citalopram or 8-0H-DAPT, gepirone (K.
`
`Njung'e, S.L. Handley, Br. J. Pharmacol., 104: 105-112; ). So-far the
`
`selective serotonine reuptake inhibitors (SSRls) are chosen for the
`
`treatment of OCSD (W.K. Goodman, L.H. Price, P.L. Delgado, Arch. Gen.
`
`15
`
`Psychiatry 1990, 47: 577-585). It has been found that a combined selective
`
`5-HT reuptake inhibitor and 5-HT,A receptor agonist has an increased
`
`activity and a faster onset of action.
`
`A model for social phobia is the Social Interaction Test according to S. File,
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`20
`
`J.R.G Hyde, J. Pharm. Pharmacol. 1977, 29: 735-738.
`
`Pairs of rats not familiar with each other are placed in an open test box
`
`brightly lit (aversive condition), and the number and duration of social
`
`contacts during a 5 min test session are recorded.
`
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`
`25
`
`or one of its physiologically acceptable salts, in particular 1-[4-(5-
`
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`
`hydrochloride, increase the time spent in social interaction. For example,
`
`for an oral dose of 10 mg/kg of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride the pairs of rats
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`unfamiliar to each other spend 144 sec of the 300 sec of total time with
`
`social interaction compared to 116 sec for the vehicle treated pairs of rats.
`
`It is known that the 5-HT reuptake inhibitor paroxetine (S. Lightowler, I.J.R.
`
`5
`
`Williamson, J. Hegarty, G.A. Kennett, RB. Fears, I.F. Tulloch, Br. J.
`
`Pharmacol. 1992, 106: 44P) or the 5-HT1A receptor agonists 8-0H-DPAT or
`ipsapirone (G.A. Higgins; A.J. Bradbury; B.J. Jones; N.R. Oakley,
`
`Neuropharmacology, 1988, 27: 993-1001) increase social interaction
`
`behaviour. It has been found that a combined selective 5-HT reuptake
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`10
`
`inhibitor and 5-HT1A receptor which includes both mechanisms leads to
`therapeutic advantages.
`
`A model for specific phobia is the Shock-Probe Test according to D. Treit,
`
`M.A. Fundytus, Pharmacol. Biochem. Behav. 1988, 30: 1071-1075.
`
`15
`
`Individual rats are habituated for 30 min each of 4 days to an open box
`
`filled with sawdust. On the test day, a continuously electrified probe is
`
`inserted 2 cm above the ground. The number of contacts with the probe is
`
`counted and the attemps to cover the probe with sawdust are recorded.
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`20
`
`It is known that the serotonin reuptake inhibitor imipramine (T.F. Meert,
`
`F.C. Colpaert, Psychopharmacology, 1986, 88: 445-450) or 5-HT1A
`receptor agonists, e.g. 8-0H-DPAT (D. Treit; A. Robinson; S. Rotzinger; C.
`
`Pesold, Behav-Brain-Res., 1993, 54: 23-34) or ipsapirone (S.M. Korte, B.
`
`Bohus, Eur. J. Pharmacol., 1990, 181: 307-10) demonstrated efficacy in
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`25
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`this model. It has been found that a combined selective 5-HT reuptake
`
`inhibitor and 5-HT1A receptor which includes both mechanisms leads to
`therapeutic advantages.
`
`In a typical model for neophobia, mice deprived from food for 18 h are
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`30
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`given access to unfamiliar food in a novel environment [P. Soubrie et al.,
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`Psychopharmacologica, 1975, 45: 203-21 O]. 1-[4-(5-cyanoindol-3-yl)butyl]-
`
`4-(2-carbamoyl-benzofuran-5-yl)-piperazine or one of its physiologically
`
`acceptable salts, in particular 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl(cid:173)
`
`benzofuran-5-yl)-piperazine hydrochloride, following oral application
`
`5
`
`increased food intake by 21% at the dose of 3 mg/kg.
`
`Animal models of anxiety associated with posttraumatic stress in rats utilize
`
`the long-lasting behavioural changes induced by exposure to a native
`
`stressor. The therapeutic effects of a compound effective for the acute
`
`10
`
`treatment of anxiety associated with posttraumatic stress are modelled by
`
`administration of the compound after exposure to the stressor. The
`
`therapeutic effects of a compound effective for the prophylactic treatment
`
`of anxiety associated with posttraumatic stress are modelled by
`
`administration of the compound before exposure to the stressor. Amongst
`
`15
`
`the several behavioral test procedures, the following is most validated [R.E.
`
`Adamec and T. Shallow, Physiology Behavior, 1993, 54: 101-109; R.E.
`
`Adamec et al., Behav. Neurosci. 1997, 111: 435-449]. In general, a rat is
`
`exposed to a cat for five minutes, and seven days later the rat can be
`tested in a battery of tests, i.e. the hole board test, the elevated plus maze
`
`20
`
`and the acoustic startle test. The hole board consists of a box (60 cm x 60
`
`cm) with four evenly spaced holes; the number of poking its head into a
`
`hole is counted for 5 minutes. The elevated plus maze consists of an X(cid:173)
`
`shaped platform elevated from the floor, with two "open" unprotected arms
`
`and two "closed" protected arms, with rats having free access to both arms.
`
`25
`
`The rat is placed in the centre of the arms, and the frequency of attempts to
`
`enter an open arm (risk assessment) as well as the time spent on the open
`
`and closed arms are measured. In the acoustic startle test, the rat is placed
`
`in a plexiglass cylinder, and a series of 20 white noise bursts of 120 dB out
`
`of a background noise of 60 dB is applied, and the latency to and the peak
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`30
`
`startle amplitude are measured. In general, rats exposed to the a stressor
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`like a cat show a reduced number of head dips into the holes, have a lower
`risk assessment and spend less time on the open arms, and the startle
`
`response is increased.
`1-[ 4-( 5-cya n oi nd o 1-3-yl) b utyl]-4-(2-carbamoyl-benzofu ra n-5-yl)-p iperazin e
`or one of its physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride, are effective in the models for anxiety associated with
`posttraumatic stress when given after (acute treatment) and before
`
`(prophylactic treatment) the cat stressor.
`
`A typical clinical study for post traumatic stress disorder is described in the
`
`following.
`Twenty (20) male or female patients aged 18-65 years suffering from non(cid:173)
`combat related chronic post traumatic stress disorder as defined by DSM-
`IV (Diagnostic and Statistical Manual for Mental Disorders, Fourth Version)
`will be treated for a 12 week period. Ten patients will be assigned randomly
`to receive 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)(cid:173)
`piperazine or a physiologically acceptable salt thereof and 10 patients will
`receive matched placebo in a double-blind fashion.
`Outcome will be assessed by the treating physician and the patient with the
`use of the Hamilton Depression Rating Scale , the Montgomery-Asberg
`Depression Rating Scale, The Clinical and Patient Global Impression
`Scales, general symptoms and specific rating of PTSD core symptoms
`using the Clinician Administered PTSD Scale according to D. Blake et al,
`Behavioral Therapy 1990, 13: 187-188 and TOP-8 scale according to
`J.R.T. Davidson et al, International Clinical Psychopharmacology 1997, 12:
`
`41-45.
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`A typical model for acute stress indication is the Four Plate Test according
`
`to C. Aron, P. Simon, C. Larousse, J.R. Boissier, Neuropharmacology
`
`1971, 10: 459-469.
`
`The apparatus consists of small box with a floor made up of four metal
`
`5
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`plates. Each time the mouse crosses from one plate to another, it is given a
`
`brief electric footshock reducing the amount of exploratory behavior. The
`
`number of punished crossings from one plate to another (i.e. number of
`
`shocks accepted by the animal) is recorded during a five minute test
`
`period. Normal mice make only few punished crossings, i.e. accept only a
`
`10
`
`few foots hocks.
`
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`
`hydrochloride following and oral dose of 3 mg/kg increased the number of
`
`punished crossings by 41 %.
`
`15
`
`This model has been validated with clinically active benzodiazepines in the
`
`literature (e.g. D.N. Stephens, W. Kehr, Psychopharmacology 1985, 85:
`
`143-147; G.D. Bartoszyk, U. Schoenherr, Behav. Neural Biol. 1987, 48:
`
`317-9). It has been found that a combined selective 5-HT reuptake inhibitor
`
`and 5-HT1A receptor leads to therapeutic advantages because it avoids the
`sedative properties of benzodiazepines.
`
`20
`
`A typical model for generalized anxiety disorders is the Light-Dark Chaise
`
`Test (Passive Avoidance Test) according to J.N. Crawly, Pharmacol.
`
`Biochem Behav. 1981, 15: 695-699.
`
`25
`
`The light-dark chaise apparatus consists of two connected boxes with one
`
`box darkened and the other one highly illuminated. A mouse is placed in
`
`one box, and the time spent in lit box and the number of transitions
`
`between boxes are measured over a period of 5 min. Normal mice only
`
`have low numbers of entries to the lit compartment and spent most time in
`
`30
`
`the dark compartment.
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`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`or one of its physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride, following oral application dose-dependently increase the
`number of transitions and time spent in lit compartment. For example, an
`oral dose of 1 0mg/kg of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl(cid:173)
`benzofuran-5-yl)-piperazine hydrochloride increased the number of
`transitions by 73% and time spent in lit compartment by 31 %.
`
`It is known from the 5-HT reuptake inhibitors, imipramine (R. Young, D.N.
`Johnson, Pharmacol. Biochem. Behav., 1991, 40: 739-743), or the 5-HT,A
`receptor agonists e.g. 8-OH-DPAT and ipsapirone (B. Costall; A.M.
`Oomeney, A.J. Farre; M.E. Kelly; L. Martinez; R.J. Naylor, J. Pharmacol.
`Exp. Ther., 1992, 262: 90-98) that they increase time spent in illuminated
`compartment and number of transitions between compartments. It has
`been found that a combined selective 5-HT reuptake inhibitor and 5-HT,A
`receptor which includes both mechanisms leads to therapeutic advantages.
`
`5
`
`10
`
`15
`
`A preferred salt of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`
`20
`
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride.
`Therefore the invention relates to the use for the manufacture of a
`medicament for the treatment of sub-type anxiety disorders in which the
`pharmacologically acceptable salt is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride.
`
`Additionally, the invention relates to the use of a pharmaceutical
`composition containing at least one compound of 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and/or one of its
`biocompatible salts together with at least one solid, liquid or semiliquid
`
`25
`
`30
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`excipient or adjunct for the treatment of sub-type anxiety disorders chosen
`
`from the sub-types panic disorder with and/or without agoraphobia,
`
`agoraphobia, obsessive-compulsive spectrum disorders, social phobia,
`
`specific phobia including neophobia, posttraumatic stress disorder, acute
`
`5
`
`stress indication or generalized-anxiety disorder.
`
`Thus the invention provides a pharmaceutical preparation for the treatment
`
`of such sub-type anxiety disorders characterized in that it contains at least
`
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`
`10
`
`or one of its pharmaceutically acceptable salts.
`
`The compounds, 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`
`5-yl)-piperazine and its pharmaceutically acceptable salts, according to the
`
`invention are preferably administered in analogy to other known
`
`15
`
`commercially available preparations for the treatment of sub-type anxiety
`
`disorders (e.g. fluoxetine, fluvoxamine). A unit dose will generally contain
`
`from 0.1 to 1000 mg, preferably between approximately 0.1 and 500 mg, in
`
`particular 5, 10, 20, 30, 40, 50, 100, 150, 200, 250 and 300 mg. The
`
`composition may be administered once or more times a day for example 2,
`
`20
`
`3 or 4 times daily. The daily dose is preferably between approximately 0.01
`
`and 50 mg/kg of body weight. However, the specific dose for each patient
`
`depends on all sorts of factors, for example on the activity of the specific
`
`compound employed, on the age, body weight, general state of health, sex,
`
`on the diet, on the time and route of administration, on the excretion rate,
`
`25
`
`pharmaceutical substance combination and severity of the particular
`
`disorder to which the therapy relates. Oral administration is preferred, but
`
`also peroral routes of administration (e.g. intraveneous or transdermal) can
`
`be utilized.
`
`30
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`Page 13
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`Additionally, it has been surprisingly found that 1-[4-(5-cyanoindol-3-
`
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine also has activity
`
`against bipolar disorders and/or mania.
`
`5
`
`A typical animal model of mania/bipolar disorders is the hyperactivity
`
`induced by a mixture of dexamphetamine and chlordiazepoxide according
`
`to A.L. Vale and F. Ratcliffe, Psychopharmacology, 1987; 91: 352-355. and
`B.J. Cao and N.A. Peng, Eur. J. Pharmacol., 1993; 237: 177-181. The
`
`dexamphetamine-chlordiazepoxide mixture induces strong hyperactivity in
`
`10
`
`mice or rats.
`
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-'5-yl)-piperazine
`
`or one of its physiologically acceptable salts, in particular 1-[4-(5-
`
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`
`hydrochloride, inhibit the hyperactivity induced by the mixture to the same
`
`15
`
`degree as do lithium and valproate, the standard treatments for mania and
`
`bipolar disorders.
`
`Accordingly, the present invention relates to the use of 1-[4-(5-cyanoindol-
`
`3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine or a physiologically
`
`20
`
`acceptable salt thereof, for the manufacture of a medicament for the
`
`treatment of bipolar disorders and/or mania.
`
`A typical clinical study for bipolar disorders and/or mania is described in the
`
`following.
`
`25
`
`Twenty ( 20 ) male or female patients aged 18-65 years suffering from an
`
`acute hypomanic episode as part of a Bipolar II Disorder as diagnosed by
`
`DSM-IV will be treated for a 3 week period with either 1-[4-(5-cyanoindol-3-
`
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine or one of its
`
`physiologically acceptable salts or lithium in a double-blind fashion.
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`30
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`Page 14
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`Clinical improvement will be assessed by means of the Mania sub-scale of
`
`the SADS-C according to R.R. Lewine et al., Schizophr. Bull. 1983, 9(3):
`
`368-76, the Young Mania Rating Scale according to R.G. Cooke et al, Biol(cid:173)
`
`Psychiatry. 1996, 40(4): 279-83, the Hamilton Depression Rating Scale
`
`5
`
`according to M. Hamilton, Journal of Neurology, Neurosurgery and
`
`Psychiatry 1960, 23: 56-62, the Global Assessment Scale according to J.
`
`Endicott et al., Arch. Gen. Psychiatry, 1976, 33(6): 766-71 and the Clinical
`
`Global Improvement Scale according to W. Guy (ed.), ECDEU Assessment
`
`for Psychopharmacology, 1976, 217-222 at weekly intervals.
`
`10
`
`The results of this study will be used to determine if 1-[4-(5-cyanoindol-3-
`
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine or one of its
`
`physiologically acceptable salts exhibit acute anti-manic properties, prior to
`
`a long-term prophylaxis study.
`
`15
`
`The invention relates furthermore to the use for the manufacture of a
`
`medicament for the treatment of bipolar disorders and/or mania in which
`
`the pharmacologically acceptable salt is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride.
`
`20
`
`Thus the invention relates to the use of a pharmaceutical composition
`
`containing at least one compound of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`
`carbamoyl-benzofuran-5-yl)-piperazine and/or one of its biocompatible salts
`
`together with at least one solid, liquid or semiliquid excipient or adjunct for
`
`the treatment of bipolar disorders and/or mania.
`
`25
`
`30
`
`Thus the invention provides a pharmaceutical preparation for the treatment
`
`of bipolar disorders and/or mania characterized in that it contains at least 1-
`
`[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine or
`
`one of its pharmaceutically acceptable salts.
`
`Page 15
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`
`The compounds according to the invention are preferably administered in
`
`analogy to other known commercially available preparations for the
`
`treatment of bipolar disorders and/or mania (e.g. fluoxetine, fluvoxamine),
`
`preferably in doses of between approximately 0.1 and 500 mg, in particular
`
`5
`
`between 5 and 300 mg per dose unit. The daily dose is preferably between
`
`approximately 0.01 and 10 mg/kg of body weight. However, the specific
`
`dose for each patient depends on all sorts of factors, for example on the
`
`activity of the specific compound employed, on the age, body weight,
`
`general state of health, sex, on the diet, on the time and route of
`
`10
`
`administration, on the excretion rate, pharmaceutical substance
`
`combination and severity of the particular disorder to which the therapy
`
`relates. Oral administration is preferred, but also peroral routes of
`
`administration (e.g. intraveneous or transdermal) can be utilized.
`
`15
`
`Additionally, it has been surprisingly found that 1-[4-(5-cyanoindol-3-
`
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine also has activity
`
`against dementia, including Alzheimer's disease and multi-infarct.
`
`Accordingly, the present invention relates to the use of 1-[4-{5-cyanoindol-
`
`20
`
`3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine or a physiologically
`
`acceptable salt thereof, for the manufacture of a medicament for the
`
`treatment of dementia.
`
`Typical models for dementia, Alzheimer's disease and multi-infarct are the
`
`25
`
`Passive Avoidance test in rats [S.D. Glick and B. Zimmerberg, Behav. Biol.,
`
`1972, 7: 245-254; D.K. Rush, Behav. Neural Biol., 1988, 50: 255-27 4] and
`
`the testing of mermory functions in the Morris Water Maze in aged rats [R.
`
`Morris, J. Neurosci. Methods, 1984, 11: 47-60; F.H. Gage et al.; Neurobiol.
`
`Aging. 1984, 5: 43-48].
`
`30
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`Page 16
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`For the Passive Avoidance test, the apparatus is a runway separated from
`a dark compartment by a small door. The amnestic drug scopolamine is
`administerd before the animal is submitted to an aquisition trial: the rat is
`placed on the entry of the runway opposite to the dark compartment, the
`latency to enter the dark compartment is recorde