sign in sign up
<<
Home , Bromerguride, Lisuride, Terguride

N° de publication : 92975

LE GOUVERNEMENT DU GRAND-DUCHÉ DE LUXEMBOURG MirtiStèi'Ç ai: s'K<Âj!-;Û:T:ie

O BREVET D'INVENTION B1

(21) N° de dépôt: 92975 (51) Int. Cl.: A61P 25/00, A61P 25/18, A61K 31/437, A61K 45/06, A61K (22) Date de dépôt: 09/02/2016 9/16, A61K9/20

(30) Priorité: ¢72) Inventeur(s): HOROWSKI REINHARD- 14552 MICHENDORF (Allemagne), KRAUSE WERNER- (43) Date de mise à disposition du public: 10/08/2017 13595 BERLIN (Allemagne), TACK JOHANNES- 13595 BERLIN (Allemagne)

(47) Date de délivrance: 10/08/2017 (74) Mandataire(s): ® Titulaire(s) : VIVOTECC GMBH - 14195 BERLIN (Allemagne)

© Use of and and its 2-Halogen Derivatives for the Treatment as . © This invention relates to the use of combinations of lisuride and/or 9,10-dihydrogenated lisuride (terguride) tt to and/or their 2-halogen analogs, e.g. 2-bromo lisuride (), either alone or in combination with a CYP2D6 inhibitor and pharmaceutical compositions thereof for the treatment of schizophrenia and all other forms of psychosis, agitation and dementia.

/

— -5

Use of Lisuride and Terguride and its 2-Halogen Derivatives for the Treatment as Antipsychotics

Background The invention comprises the use of combinations of lisuride and/or derivatives of lisuride, such as 9,10-dihydrogenated lisuride (terguride) and/or halogenated compounds (e.g. 2-bromo lisuride = bromerguride) for the treatment of psychiatric disorders such as schizophrenia, psychoses, dementia or others. The combinations of lisuride, terguride or their 2-halogen derivatives can be administered either alone or can additionally be combined with a CYP2D6 inhibitor such as , or other CYP2D6 inhibitors. Combination in the context of this patent application either means simultaneous administrations of individual formulations of the or combination within one pharmaceutical formulation. This is based upon the more recent discovery that not only classical antagonists such as and with their known severe adverse events, e.g. extrapyramidal effects, but also newer, atypical neuroleptics such as , aripiprazol, , and exert their effects by blocking central 5-HT2A receptors and thus are derived of extrapyramidal effects.

Preferentially a dopamine , e.g. lisuride, is combined with a , e.g. bromerguride. Both, lisuride and bromerguride are additionally (5-HT)2 antagonists, which is the effect that is needed for the treatment of the disorders as described. The combination of the dopamine-agonistic lisuride and the dopamine-antagonistic bromerguride therefore reduces or even eliminates all dopamine-related effects and side effects and, since both compounds are antagonists, increases the overall anti-serotonin activity. Moreover, since the different compounds bind to different serotonin subtype receptors, these combinations are able to address a much broader spectrum of psychiatric diseases and different forms of psychoses.

In order to further increase efficacy, a CYP2D6 inhibitor such as quinidine, fluoxetine, or paroxetine can added, which will result in an increased and in much less variability of pharmacokinetic parameters. If is selected as a CYP2D6 inhibitor, this will provide an additional neuroleptic efficacy component into the combination.

Fig. 1: Chemical structures of lisuride, terguride, and bromerguride (from left to right)

Lisuride is an iso- derivative, which acts as a and a for several serotonin receptors. It is an antagonist at the serotonin 5-HT2B receptor and has a high affinity for the dopamine D2, D3 and D4 receptors, as well as for serotonin 5-HT1A (as an agonist) and 5-HT2A/C receptors (as an antagonist).

Lisuride in its oral form has been approved for the prevention of attacks since 1977, for the treatment of hyperprolactinemia since 1981, and Parkinson’s disease since 1985. It has been marketed in most European and some other countries under quite a number of different tradenames, such as Dopergin, Dopergine, Dipergon, Dopagon, and Cuvalit (all Bayer, Leverkusen, Germany, formerly Schering AG, Berlin, Germany), Arolac (Lisapharm, Paris, ), Prolacam and Revanil (Cambridge Laboratories, Cambridge, UK), and Lysenil (Spofa, Prague, Czech Republic).

Terguride, a 9,10-transdihydrogenated derivative of the alkaloid lisuride, has been characterized as a potent serotonin , in particular regarding the 5-HT2A and 5-HT2B but also the 5-HT1A receptors. Additionally, the is

1 acting at the dopamine D2 receptor as a mixed agonist/antagonist depending on the 92975 location and state of the receptor and at the alpha2 receptor as an antagonist.

Terguride has been approved in Japan (Teluron; Bayer, Osaka, Japan) and in the Czech Republic (Mysalfon; Zentiva, Prague, Czech Republic) for the treatment of all forms of hyperprolactinemia.

Beneficial effects have also been reported in the treatment of Parkinson’s disease, pulmonary arterial hypertension, chronic fibro-proliferative disease, secondary Raynaud’s Syndrome, and chronic pain of various origins, to name just a few and without excluding additional indications.

Bromerguride (2-bromo-lisuride) is a dopamine antagonist and its pharmacological effects are characterized by a central depressant neuroleptic-like symptomatology. In vitro, the compound also antagonizes the decrease of cAMP accumulation produced by 5-HT and the decrease of extracellular 5-HT produced by 5-HT1A . In addition, it has strong 5-HT2A antagonistic effects. The neuroleptic efficacy of bromerguride in animal experiments such as spontaneous inhibition of locomotor activity in mice and rats was four times that of haloperidol, which also induces catalepsy in rodents.

Additional compounds in this chemical class include the 2-fluoro, 2-chloro, and 2- iodo derivatives of lisuride and the 2-fluoro, 2-chloro, 2-bromo, and 2-iodo derivatives of terguride. All lisuride or terguride analogs with a halogen substitution in the 2- position act as atypical neuroleptics with less extrapyramidal and endocrine side effects. They can be used for treating schizophrenia and other psychoses as well as psychomotor agitation.

It was now surprisingly found that combinations of these compounds such as lisuride + terguride, lisuride + bromerguride, and terguride + bromerguride are particularly useful for the treatment of psychotic disorders. Including all 2-halogen derivatives, more combinations are possible and can be used for the treatment of these disorders. By reducing or neutralizing the dopamine-related components of activity in these combinations, the doses of individual drugs can be increased significantly without observing the dopamine-related side effects such as and vomiting, which limit dosing of the individual drugs administered alone and, additionally, extrapyramidal side effects are completely avoided.

Detailed Description of the Invention

The present invention relates to the use of combinations of lisuride and/or 9,10- dihydro lisuride (terguride) and 2-halogenated (fluoro, chloro, bromo, iodo) derivatives of lisuride and terguride for the treatment of psychotic disorders. For simplicity reasons, the description will use lisuride + terguride as an example without precluding analogy of the other possible combinations. The most effective combination would be lisuride + 2-bromoterguride.

Terguride has been reported to be effective in various indications and is approved and on the market in Japan and the Czech Republic for the treatment of hyperprolactinemia. It is known to be a very safe drug.

Lisuride has been shown to be an antagonist at the 5-HT2B and 5-HT2A/C receptors and has a high agonistic affinity at the 5-HT1A receptor. Terguride is a potent serotonin receptor antagonist, in particular regarding the 5-HT2A and 5-HT2B receptors. Bromerguride is strongly antagonizing serotonin, in particular, 5-HTA1 but

2 also 5-HT2A- mediatated effects. The observed differences in concentrations 92975 necessary to affect serotonin receptors relative to other monoamine receptors such as dopamine apply to both lisuride and terguride and their 2-halogen derivatives.

It was now additionally and surprisingly found that the different ergot derivatives mentioned above can be combined in these indications, resulting in combinations such as lisuride + terguride, lisuride + a 2-halogen lisuride (such as bromerguride), lisuride + a 2-halogen terguride, terguride + a 2-halogen lisuride (such as bromerguride) or terguride + a 2-halogen terguride. This is in strong contrast to the currently used indications such as Parkinson’s disease where activity at the dopamine receptors is mandatory. In Parkinson’s disease, bromerguride, a antagonist would block the activity of lisuride, a dopamine agonist. On the other hand, some of the major side effects of lisuride, in particular emesis and vomiting but also psychosis are linked to dopamine agonistic activity. A dopamine antagonist such as bromerguride would therefore block this activity and reduce or eliminate these side effects, whereas on the other hand it would increase the serotonin-related activity, since both compounds are serotonin antagonists and act in the same direction. Another benefit of these combinations would be that different ergot derivatives affect different serotonin receptors as already mentioned above. Lisuride preferentially acts as an antagonist on the 5-HT2B receptor, terguride on the 5-HT1A and 5-HT2A/C receptors, and bromerguride on 5-HT1A. Another advantage of these combinations is that these drugs all have similar terminal half-lives, which greatly facilitates their combination in the same pharmaceutical product.

Since ergot alkaloids and their chemical derivatives are primarily metabolized by CYP2D6 resulting in a very high variability of pharmacokinetic parameters, in particular of oral ranging from nearly 0-100% (1 ), the combination with a CYP2D6 inhibitor such as quinidine, fluoxetine, paroxetine or melperone might be helpful. Melperone has the additional advantage of being itself a strong 5-HT2A antagonist.

Normally, the compounds are formulated as salts of organic or inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, methane sulfonic acid, succinic acid, tartaric acid, , etc. The preferred salt for lisuride, terguride and their 2-halogen derivatives is hydrogenmaleate.

Examples Example 1 - Treatment of Schizophrenia with a Combination of Lisuride and Terguride

Patients with florid hallucinatory schizophrenia are treated once daily with a slow- release oral formulation consisting of 0.6 mg lisuride hydrogen maleate and 6 mg terguride hydrogen maleate (or both compounds as free base) over a period of three months or until the acute symptomatology disappears.

Subsequently, these patients receive similar oral slow-release forms at half the dosages for one year or more in order to prevent relapses or new exacerbations. If these should occur despite the therapy, the full dosages as administered initially are resumed for another three months. Equivalent dosages can alternatively be administered by transdermal patches.

Example 2 - Treatment of Psychosis with a Combination of Lisuride and Bromerguride

3 Patients with psychosis and/or dementia of the Alzheimer type, Diffuse Lewy Body 92975 Dementia or with vascular dementia are treated with a daily oral dose of 0.3 mg lisuride hydrogen maleate and 3 mg of bromerguride in an oral slow-release form over an unlimited period of time in order to reduce or prevent paranoid ideation, aggressive or aberrant behavior, disturbances of the day-night rhythm or any related symptoms.

Example 3 - Treatment of Dementia with a Combination of Lisuride and Bromerguride or Bromoterguride

Patients with dementia of the Alzheimer type, with Diffuse Lewy Body Dementia or with vascular dementia are treated with an oral slow-release form of lisuride hydrogen maleate (total daily dose of 0.4 mg) combined with 20 mg of bromerguride or bromoterguride and an additional oral daily dose of 50 mg quinidine until the acute symptomatology, restlessness, disturbed day-night rhythms or aggressive and other aberrant behaviors subside.

A maintenance therapy at half the dosages described above then follows for an unlimited period of time or until extrapyramidal signs appear, which would require a further dose reduction.

Example 4 - Preparation of Micronized Bromerguride and Lisuride

The preparation will be described in detail for bromerguride and can analogously be done for lisuride so that mixtures of both drugs can be obtained. In the same way, a CYP2D6 inhibitor can be added. The particle size of, for example, bromerguride can be significantly reduced by using specific milling techniques like jet stream milling in a steel chamber under nitrogen pressure. The micronization occurs when the bromerguride powder is fed at a velocity of about 50 m/s into the milling chamber and the faster particles, accelerated by a series of jet nozzles to a speed of about 300 m/s collide with the incoming slower particles. The particle size distribution (by volume) of bromerguride, which can be achieved by the jet milling techniques described above, is about 2-3 μm (d50), 10- 12 μm (d99) and <15 μm (d100) by using Laser diffractometry. A preferred dosage form is a multiparticulate system, consisting of multiparticulates of a size of 1-3 mm, which ensures rapid gastric emptying, low variability in gastric transit time, and optimized drug absorption. Step 1. Preparation of uncoated pellets containing bromerguride. Five grams (g) of micronized bromerguride is added to a mixture of 85 grams of microcrystalline cellulose (Avicel® PH-101) and 8 grams of hydroxypropyl methylcellulose (HPMC E6). After homogenization of the dry powders, the mixture is granulated by adding an aqueous PVP (25.000 MW) solution (5%, w/w) q.s. The wet granulate obtained is extruded at room temperature at 30 rpm using a CLS Extruder 20 (2 mm orifice diameter) followed by spheronization of the extrudates using a CLS MBS 120 spheronizer with friction plate. The resulting spherical pellets are dried to a humidity of 3-5 % containing about 5% (w/w) micronized bromerguride. Step 2. Preparation of coated pellets for immediate release containing micronized bromerguride. A spray suspension of 90 ml containing 6.25 grams of amino methacrylate copolymer-NF (Eudragit® E 100), 0.625 grams of polyethylenglycol (PEG 6000) and 3.1 grams (g) of talcum, dissolved/suspended in acetone/isopropanol 1:1 is prepared

4 by using a shear mixer. Then 10 ml of destilled water was added to the suspension. 92975 The resulting spray suspension is finally passed through a 0.5 mm sieve. The suspension obtained is sprayed onto 50 grams of pellets according to Step 1 using a Caleva lab coater MCD 2. The process conditions are set to: spray rate 0.25 - 0.35 g/min, inlet temperature 42°-45° C, flow rate 60 L/min at 2 bar, air temperature 30°- 35° C. The spraying is maintained up to a 5% increase by weight due to the coating applied. The pellets are finally cured for about one hour at the air temperature of 30°- 35° C. Example 6 - Preparation of Layered Pellets for Delayed Release (of Micronized Bromerguride and Lisuride)

A spray suspension containing 5.25 grams of ammonio methacrylate copolymer (Eudragit® RL PO Type A), 17.25 grams of ammonio methacrylate copolymer (Eudragit® RS PO Typ B), 3.5 grams triethylcitrate (TEC) and 5.25 grams talcum, dissolved/suspended in 300 grams acetone/isopropanol 1:1 is prepared by using a shear mixer. The spray suspension is finally passed through a 0.5 mm sieve. The suspension obtained is sprayed onto 50 grams (g) of a 1:1 mixture (by weight) of bromerguride and lisuride pellets obtained according to Step 2 (Example 5) using a Caleva lab coater MCD 2. The process conditions are set to: spray rate 0.2 - 0.3 g/min, inlet temperature 40°-45° C, flow rate 50 L/min at 2 bar, air temperature 30°- 35° C. The spraying is maintained up to a 7% increase by weight due to the coating applied. The pellets are finally cured for about one hour at the air temperature of 30°- 35° C. In order to achieve an appropriate osmotic pressure within the coated multiparticulate, osmogens of acceptable pharmaceutical grade of hydrophilic nature will be applied. These are preferably low molecular weight sugars like fructose, sucrose, mannitol, inorganic salts like sodium phosphates, or organic acids such as citric acid or tartaric acid. Upon penetration of the gastrointestinal fluid through the membrane of the coated dosage after oral administration the dissolution of the osmogen creates an osmotic pressure, which finally leads to a rupture of the polymeric membrane and releases the drug spontaneously and completely. The compromise of the coating is influenced by the penetration rate of the gastrointestinal fluid that can be modulated by the adding hydrophilic low or large molecular weight compounds to the coating. Such modulators may be physiologically inert, water-soluble polymers, e.g., low molecular weight methylcellulose or hydroxypropyl-methylcellulose (HPMC), sugars, e.g., monosaccharides such as fructose and glucose, disaccharides such as lactose, sucrose, or polysaccharides such as cellulose, amylose and dextran. In order to achieve appropriate timing of the release pulse, the modulator may be at least 10 percent, at least about 20 weight percent of the multiparticulate, and usually not more than about 50 weight percent, preferably not more than about 40 weight percent. The polymer coating may comprise at least about 5 and not more than 50 weight percent of the multiparticulate. The exact proportion of modulator and active agent will be determined by formulation design experiments producing different types of multiparticulates for different amounts of modulator. A USP-approved method for dissolution or release test will be used to measure the rate of release (<711 >, USP 32 NF 27,2009, Vol. 1, Apparatus 1 with varying nominal capacities from 1 L to 4 L). In order to better mimic the conditions present in the digestive system and, if necessary to test under infinite sink conditions, a flow-through-cell apparatus according to the USP (Apparatus 4) can be used alternatively to determine the dissolution rate. The detection of the dissolved

5 drug as a function of time may be followed by various state of the art methods, such 92975 as spectrophotometrically, HPLC, mass spectroscopy, etc. until the absorbance becomes constant or until greater than 90% of the drug has been released. Example 7 - Preparation of Pellets for Extended Release (of Micronized Bromerguride and Lisuride)

A spray suspension containing 22.25 grams of anionic copolymers based on methacrylic acid and methyl methacrylate (Eudragit® S 100 ), 3.5 grams triethylcitrate (TEC) and 5.25 grams talcum, dissolved/suspended in 300 grams acetone/isopropanol 1:1 is prepared by using a shear mixer. Then 10 ml of destilled water is added to the suspension. The resulting spray suspension is finally passed through a 0.5 mm sieve. The suspension obtained is sprayed onto 50 grams (g) of a 1:1 mixture (by weight) of bromerguride and lisuride pellets obtained according to Step 2 (Example 5) using a Caleva lab coater MCD 2. The process conditions are set to: spray rate 0.25 - 0.35 g/min, inlet temperature 40°- 45° C, flow rate 50 L/min at 2 bar, air temperature 30°- 35° C. The spraying is maintained up to an 8% increase by weight due to the coating applied. The pellets are finally cured for about one hour at the air temperature of 30°- 35° C.

References 1. Krause, W, Dorow R, Nieuweboer B, Hasan SH; and of the ergot alkaloid, transdihydrolisuride, in man. Eur J Clin Pharmacol 27: 335-339 (1984).

6 Ansprüche 92975

1. Verwendung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid zur Behandlung von neuroleptischen Erkrankungen. 2. Verwendung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid und einem CYP2D6-Inhibitor zur Behandlung von neuroleptischen Erkrankungen. 3. Verwendung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid entsprechend den Ansprüchen 1 und 2 mit Chinidin, Fluoxetin, Paroxetin oder Melperon. 4. Langsam freisetzende Formulierungen zur oralen Verwendung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid mit einem CYP2D6-Inhibitor wie Chinidin, Fluoxetin, Paroxetin oder Melperon entsprechend den Ansprüchen 2 und 4. 5. Verwendung von Formulierungen zur transdermalen Verabreichung von Kombinationen von Lisurid, Tergurid und/oder 2-halogenierter Derivate von Lisurid oder Tergurid entsprechend den vorigen Ansprüchen. 92975

σ> LL Use of Lisuride and Terguride and its 2-Halogen Derivatives for 92975 the Treatment as Antipsychotics

Abstract This invention relates to the use of combinations of lisuride and/or 9,10- dihydrogenated lisuride (terguride) and/or their 2-halogen analogs, e.g. 2-bromo lisuride (bromerguride), either alone or in combination with a CYP2D6 inhibitor and pharmaceutical compositions thereof for the treatment of schizophrenia and all other forms of psychosis, agitation and dementia. National Application Number LE GOUVERNEMENT DU GRAND-DUCHÉ DE LUXEMBOURG Ministère de l'Économie SEARCH REPORT et du Commerce extérieur in accordance with Article 35.1 a) LO 1294 of the Luxembourg law on patents LU 92975 dated 20 July 1992

DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant CLASSIFICATION OF THE Category of relevant to claim APPLICATION (IPC) DATABASE BIOSIS [Online] 1-5 INV. BIOSCIENCES INFORMATION SERVICE, A61K31/437 PHILADELPHIA, PA, US; A61K45/06 1989, A61P25/00 NAKAMURA K ET AL: "EFFECTS IN ANIMAL A61K9/16 MODELS OF DEPRESSION OF LISURIDE ALONE AND A61P25/18 UPON COADMINISTRATION WITH Α61Κ9/2Θ ", XP002762450, Database accession no. PREV198988100594 ★ âbstfâCt * & FOLIA PHARMACOLOGICA JAPONICA, vol. 94, no. 1, 1989, pages 81-90, ISSN: 0015-5691

X ZIMMERMANN P: "Lisuride in integrated 1-5 therapeutic approach for the treatment of concomitant depression in patients with Parkinson's disease", NERVENHEILKUNDE 2000 DE, vol. 19, no. 10, 2000, pages 80-81, TECHNICAL FIELDS SEARCHED (IPC) XP0O919667, ISSN: 0722-1541 A61K * the whole document * A61P

WACHTEL H ET AL: "Central 1-5 anti dopaminergic properties of 2-bromolisuride, an analogue of the ergot dopamine agonist lisuride", LIFE SCIENCES, PERGAMON PRESS, OXFORD, GB, vol. 33, no. 26, 26 December 1983 (1983-12-26), pages 2583-2597, XP025518059, ISSN: 0024-3205, DOI: 10.1016/0024-3205(83)90342-9 [retrieved on 1983-12-26] * the whole document *

-/-

The present search report has been drawn up for all claims 2 Date of completion of the search Examiner 11 October 2016 Baumgärtner, Heike (P04C55) CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or 03.82

X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application 1503

document of the same category L : document cited for other reasons A : technological background O : non-written disclosure & : member of the same patent family, corresponding FORM P : intermediate document document EPO

page 1 of 3 National Application LE GOUVERNEMENT Number DU GRAND-DUCHÉ DE LUXEMBOURG Ministère de l'Économie SEARCH REPORT et du Commerce extérieur in accordance with Article 35.1 a) LO 1294 of the Luxembourg law on patents LU 92975 dated 20 July 1992 DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Category Relevant CLASSIFICATION OF THE of relevant passages to claim APPLICATION (IPC)

X EP 0 207 882 A2 (SCHERING AG [DE]) 1-5 7 January 1987 (1987-01-07) * the whole document *

X OLBRICH R ET AL: "AN EVALUATION OF THE 1-5 PARTIAL DOPAMINE AGONIST TERGURIDE REGARDING POSITIVE SYMPTOMS REDUCTION IN SCHIZOPHRENICS" JOURNAL OF NEURAL TRANSMISSION, SPRINGER WIEN, VIENNA, vol. 84, no. 3, 1 January 1991 (1991-01-01), pages 233-236, XP001061450, ISSN: 0300-9564, DOI: 10.1ΘΘ7/ΒF01244973 * the whole document *

X PERTZ H H ET AL: "2-Bromoterguride May Be 1-5 A Novel Antipsychotic Due to Its Complex Effects at Dopaminergic, and Receptors", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF TECHNICAL FIELDS PHARMACOLOGY, SPRINGER, DE, SEARCHED (IPC) vol. 386, no. Suppl.1, 1 February 2013 (2013-02-01), page S62, ΧΡ0Θ9191669, ISSN: 0028-1298 * the whole document *

-/-

The present search report has been drawn up for all claims

Date of completion of the search Examiner 11 October 2016 Baumgärtner, Heike (P04C55) CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or 03.82 X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application 1503

document of the same category L : document cited for other reasons A : technological background O : non-written disclosure & : member of the same patent family, corresponding FORM P : intermediate document document EPO

page 2 of 3 National Application LE GOUVERNEMENT Number DU GRAND-DUCHÉ DE LUXEMBOURG Ministère de l'Économie SEARCH REPORT et du Commerce extérieur in accordance with Article 35.1 a) LO 1294 of the Luxembourg law on patents LU 92975 dated 20 July 1992 DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant Category CLASSIFICATION OF THE of relevant passages to claim APPLICATION (IPC)

X F. JANTSCHAK ET AL: "Pharmacological 1-5 Profile of 2-Bromoterguride at Human Dopamine D2, Porcine Serotonin 5-Hydroxytryptamine 2A, and -Adrenergic Receptors, and Its Antipsychotic-Like Effects in Rats" JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 347, no. 1, 17 July 2013 (2013-07-17) , pages 57-68, XP055302933, DOI: 10.1124/jpet.113.205997 * the whole document *

X RAUSCHENBACH R ET AL: "DEVELOPMENT OF A 1-5 V79 CELL LINE EXPRESSING HUMAN CYTOCHROME P450 2D6 AND ITS APPLICATION AS A METABOLIC SCREENING TOOL", ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 3, no. 1, 1 January 1997 (1997-01-01) , pages 31-39, XP001086594, TECHNICAL FIELDS SEARCHED (IPC) ISSN: 1382-6689, DOI: 10.1016/51382-6689(96)00136-6 * the whole document *

X W0 2009/006194 Al (AVANIR PHARMACEUTICALS 1-5 [US]; FLESHER GREGORY J [US]; KATKIN KEITH A [U) 8 January 2009 (2009-01-08) * the whole document *

X DE 10 2005 041613 Al (ERGONEX PHARMA GMBH 1-5 [CH]) 8 March 2007 (2007-03-08) * the whole document *

The present search report has been drawn up for all claims 2 Date of completion of the search Examiner 11 October 2016 Baumgärtner, Heike (P04C55) CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or 03.82

X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application 1503

document of the same category L : document cited for other reasons A : technological background ...... O : non-written disclosure & : member of the same patent family, corresponding FORM P : intermediate document document EPO

page 3 of 3 ANNEX TO THE SEARCH REPORT ON LUXEMBOURG PATENT APPLICATION NO. LO 1294 LU 92975

This annex lists the patent family members relating to the patent documents cited in the above-mentioned European search report. The members are as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. 11-10-2016

Patent document Publication Patent family Publication cited in search report date member(s) date

EP 0207882 A2 07-01-1987 AT 146963 T 15-01-1997 AU 573448 B2 09-06-1988 AU 5920686 A 08-01-1987 CA 1285880 C 09-07-1991 DE 3522894 Al 02-01-1987 DK 288786 A 25-12-1986 EP 0207882 A2 07-01-1987 IE 80545 Bl 09-09-1998 IL 79207 A 04-04-1993 JP 2618375 B2 11-06-1997 JP S6259211 A 14-03-1987 US 4711891 A 08-12-1987 ZA 8604717 B 25-02-1987

W0 2009006194 Al 08-01-2009 NONE

DE 102005041613 Al 08-03-2007 NONE P0457

FORM

EPO For more details about this annex : see Official Journal of the European Patent Office, No. 12/82 LE GOUVERNEMENT DU GRAND-DUCHÉ DE LUXEMBOURG Ministère de l'Économie et du Commerce extérieur WRITTEN OPINION

File No. Filing date (day/month/year) Priority date (day/month/year) Application No. LO1294 09.02.2016 LU92975

International Patent Classification (IPC) INV. A61K31/437 Α61Κ45Ό6 Α61Ρ25Ό0 A61K9/16 A61P25/18 A61K9/20

Applicant VivoTecc GmbH

This report contains indications relating to the following items:

E3 Box No. I Basis of the opinion □ Box No. II Priority □ Box No. Ill Non-establishment of opinion with regard to novelty, inventive step and industrial applicability □ Box No. IV Lack of unity of invention H Box No. V Reasoned statement with regard to novelty, inventive step or industrial applicability; citations and explanations supporting such statement □ Box No. VI Certain documents cited □ Box No. VII Certain defects in the application □ Box No. VIII Certain observations on the application

Examiner Baumgärtner, Heike Form LU237A (Cover Sheet) (January 2007) Application No. WRITTEN OPINION LU92975

Box No. I Basis of the opinion 1. This opinion has been established on the basis of the latest set of claims filed before the start of the search.

2. With regard to any nucleotide and/or amino acid sequence disclosed in the application and necessary to the claimed invention, this opinion has been established on the basis of:

a. type of material:

□ a sequence listing

□ table(s) related to the sequence listing

b. format of material:

□ on paper

□ in electronic form c. time of filingÆurnishing:

□ contained in the application as filed.

□ filed together with the application in electronic form.

□ furnished subsequently.

3. □ In addition, in the case that more than one version or copy of a sequence listing and/or table relating thereto has been filed or furnished, the required statements that the information in the subsequent or additional copies is identical to that in the application as filed or does not go beyond the application as filed, as appropriate, were furnished. 4. Additional comments:

Box No. V Reasoned statement with regard to novelty, inventive step and industrial applicability ; citations and explanations supporting such statement

1. Statement

Novelty Yes: Claims 1-5 No: Claims

Inventive step Yes: Claims No: Claims 1-5

Industrial applicability Yes: Claims 1-5 No: Claims

2. Citations and explanations

see separate sheet

Form LU237B (January 2007) WRITTEN OPINION Application number (SEPARATE SHEET) LU92975

Re Item V

Reasoned statement with regard to novelty, inventive step or industrial applicability; citations and explanations supporting such statement

subject-matter

Claim 1 Use of combinations of lisuride, terguride and/or 2-halogenaled derivatives of lisuride or terguride for the treatment of neuroleptic disorders

Claim 2 Use of combinations of lisuride, terguride and/or 2-haiogenated derivatives of lisuride or terguride and a CYP2D6 inhibitor for the treatment of neuroleptic disorders

d3 cf combinations of lisuride, terguride or 2-halogenated derivatives of lisuride or terguride according to claims 1 and 2 with quinidine, fluoxetine, paroxetine or melperone

Claim 4 Slow-release formulations for oral use of combinations of lisuride, terguride and/or 2- halogenated derivatives of lisuride or terguride with a CYP2D6 inhibitor such as quinidine, fluoxetine, paroxetine or melperone according to claims 2 and 4(?)

Claim 5 Use of formulations for transdermal delivery of combinations of lisuride, terguride and/or 2-halogenated derivatives of lisuride or terguride according to previous claims

Reference is made to the following documents:

lisuride and indication

D1 PREV198988100594 1989 Nakamura et al. [X/IS]

Effects of lisuride, a central dopamine and serotonin agonist of the ergot type, in animal models of depression were investigated in comparison with those of , and rolipram.

D2 XP009191667 2000 Zimmermann et al. [X/IS]

Lisuride in integrated therapeutic approach for the treatment of concomitant depression in patients with Parkinson's disease

Form LU237-3 (separate sheet) (January 2007) (sheet 1) WRITTEN OPINION Application number (SEPARATE SHEET) LU92975

bromerguride and indication

D3 XP025518059 1983 Wachteletal. [X/IS]

Central anti dopaminergic properties of 2-Bromo-Lisuride an analog of the ergot dopamine agonist lisuride

terguride and indication D4 EP0207882A2 19870107 Schering [X/IS]

The use of terguride (I) or its salts for treating geriatric disorders is new. (I) is pref, administered at 0.1-1.0 mg daily, opt. in combination with galenic additives.

,(I) i.e. 3-(6-methylergolia -8alpha-yl) -1,1-diethyl-urea, is a known cpd. (DE2238540, DE3129714) previously used as nidation and lactation inhibitor and antipsychotic agent.

D5 XP001061450 1991 Olbrich et al. [X/IS]

Eleven schizophrenics (7 females) displaying an acute psychotic episode received the partial dopamine agonist terguride in doses up to 2 mg per day.

[...], the majority of the patients appeared to have benefited from terguride application.

bromoterguride and indication (analog of the ergot dopamine agonist terguride)

D6 XP009191669 Feb 2013 Pertz et al. [X/IS]

2-Bromoterguride May Be A Novel Antipsychotic Due to Its Complex Effects at Dopaminergic, Serotonergic and Adrenergic Receptors

D7 XP55302933 Oct 2013 Jantschak et al. [X/IS]

Form LU237-3 (separate sheet) (January 2007) (sheet 2) WRITTEN OPINION Application number (SEPARATE SHEET) LU92975

Pharmacological Profile of 2-Bromoterguride at Human Dopamine D-2, Porcine Serotonin 5-Hydroxytryptamine 2A, and alpha(2C)-Adrenergic Receptors, and Its Antipsychotic-Like Effects in Rats

All compounds tested behaved as antagonists at human D-2long/G alpha(o) (hD(2L)/G alpha(o)) receptors. Compared with , terguride and its derivatives displayed higher affinity at porcine 5-HT2A receptors and alpha(2C)-adrenoceptors and lower affinity at H-1 receptors. 2- Bromoterguride inhibited AIL and did not induce catalepsy in rats. Because of its in vitro and in vivo properties, 2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS.

CYP2D6 inhibitor

For CYP2D6 role in , in particular antipsychotics cf. e.g. Wikipedia entry for CYP2D6 [https://en.wikipedia.org/wiki/CYP2D6] and further the reference 17, viz.

"Flockhart DA (2007). "Drug Interactions: Cytochrome P4.w Drug Interaction Table". Indiana University School of . Retrieved on July 2011." of this entry.

This aspect of the invention appears to be of common knowledge to the skilled person, viz. to add a CYP2D6 inhibitor in order to allow for an increased plasma level of a drug that is otherwise more rapidly metabolized via CYP2D6.

D8 XP001086594 1997 Rauschenbachetal. [X/IS]

Development of a V79 cell line expressing human cytochrome P450 2D6 and its application as a metabolic screening tool

Both lisuride and terguride were monodeethylated; in case of lisuride a correlation to the in vivo situation was demonstrated comparing poor and extensive metabolizers.

D9 W02009006194A1 20090108 AVAN IR PHARMA [X/IS]

Oral preparation comprises mixed with cytochrome P450 2D6 (CYP2D6) enzyme inhibitor quinidine, viz. pharmaceutical agents capable of treating symptoms associated with neurological disease or injury, e.g., dementia or Alzheimer's disease.

Form LU237-3 (separate sheet) (January 2007) (sheet 3) WRITTEN OPINION Application number (SEPARATE SHEET) LU92975

Because of the possibility that a process involving glutamate is etiologically implicated in depression, anxiety, and related mood disorders, administration of dextromethorphan (DM) can be an effective treatment. Dextromethorphan is a noncompetitive antagonist of the N-methyl-D- aspartate-sensitive ionotropic , and it acts by reducing the level of excitatory activity. However, dextromethorphan is extensively metabolized to (DX) and a number of other metabolites. Cytochrome P450 2D6 (CYP2D6) is the key enzyme responsible for the formation of dextrorphan from dextromethorphan. A subset of the population, 5 to 10% Oi Caucasians, has reduced activity of this enzyme [...].Such individuals are referred to as "poor metabolizers" of dextromethorphan in contrast to the majority of individuals who are referred to as "extensive metabolizers" of dextromethorphan (Vetticaden et al., Pharm. Res., 1989; 6: 13-9). A number of in vitro studies have been undertaken to determine the types of drugs that inhibit CYP2D6 activity. Quinidine (Q) is one of the most potent of those that have been studied (Inaba et al., Br. J. Clin. Pharmacol, 1986; 22:199-200). These observations led to the hypothesis that concomitant dosing with quinidine could increase the concentration of dextromethorphan in plasma.

It can be advantageous to administer dextromethorphan and quinidine as an adjuvant to known therapeutic agents for the conditions to be treated according to the preferred embodiments, e.g., neu rodegenerative disorders. Anti-dementia agents include but are not limited to acetyl choliesterase inhibitors, rivastigmine and donepezil. Agents for treating Parkinson's disease include but are not limited to levodopa alone or in combination with another therapeutic agent, , COMT inhibitors such as and , dopamine agonists such as , , , , , and lisuride, mediations such as HCI, benztropine mesylate, and , and preparations such as Eldepryl(R), Atapryl(R) and Carbex(R).Agents for treating Alzheimer's disease include but are not limited to cholinesterase inhibitors such as do

oral retard formulation of a combination ergot active and CYP2D6 inhibitor

D10 DE102005041613 A1 20070308 ERGONEX PHARMA GMBH [X/IS]

Form LU237-3 (separate sheet) (January 2007) (sheet 4) WRITTEN OPINION Application number (SEPARATE SHEET) LU92975

Use of octahydro-indolo-quinoline compound in the preparation of pharmaceutical composition for the treatment and prophylaxis of gastrointestinal and endocardial disease and carcinoid syndrome

(I) is 8alpha -ergoline, 8alpha -1,6-dimethylergoline, 8alpha -1 -methylergoline, 8alpha -6-methylergoline, 8alpha -10-methoxyergoline, lisuride, d-isolysergic acid, d-lsolysergic acid amide, d-lsolysergic acid-diethylamide, proterguride or terguride.

Administration of (I) is 0.1-10 mg/dose, orally, sublingually, parenterally, buccally, cutaneously or percutaneously in the form of tablet, coated tablet, retard-oral, transdermal system, implantation, suppositories, microformulation, nano-formulation, liposomal formulation, drop, capsule, lotions, emulsion, dispersion, powder, inhalation powder, micro crystalline formulation or inhalation spray (claimed).

Compound (I) can optionally be combined with i.a. quinidine.

NB The wording of claims 1 and 2 relate to subject-matter which the EPO for instannce does not recognize as patentable claims to the use of a compound in medical treat­ ment. The EPO may allow, however, claims to a product, in particular substances or compositions for use in a first or further medical treatment.

Novelty(i) and Inventive Step(ii)

(·) None of the cited documents discloses explicitly a combination of lisuride, terguride and/or 2-halogenated derivatives thereof in the treatment of neuroleptic disorders, hence the subject-matter of claim 1 is not anticipated. Similarly, is the subject-matter of claim 2 which adds to the combination of claim 1 a CYP2D6 inhibitor not anticipated by the cited documents. The slow-release formulation for oral use of claim 4 is novel, since D10 does not explicitly combine lisuride and terguride and/or a 2-halogenated derivative, but uses merely one of the agents to be combined with i.a. a CYP2D6 inhibitor.

(H)

Form LU237-3 (separate sheet) (January 2007) (sheet 5) WRITTEN OPINION Application number (SEPARATE SHEET) LU92975

However, with regard to inventiveness it is considered that it would have been straightforward for the skilled person to consider combinations of agents that are known to be useful in the claimed indications.

So far, the application only describes the combinations (lisuride and terguride in schizophrenia - Ex1, lisuride and bromerguride in psychosis - Ex 2, lisuride and bromerguride or bromoterguride in demenitia - Ex 3) without proving an unexpected effect for the combinations. The remaining Examples are preparation examples of micronized bromerguride and lisuride (Ex4), of layered pellets for delayed release of micronized bromerguride and lisuride (Ex 6) and of pellets for extended release of micronized bromerguride and lisuride (Ex 7). NB: Presently the description refers to Examples 1-4 and 6-7. For combinations with a CYP2D6 inhibitor no examples are on file, viz. this aspect of the claimed subject-matter does not seems to be substantiated at all by evidence presently. Besides, is the effect of CYP2D6 considered very well known to the skilled person (cf. D8 and D9).

Finally, it is pointed out that also there seems to be no effect shown for all the diseases falling within the broadly claimed scope of "neuroleptic disorders" and it is doubted that indeed all possible combinations would indeed show an effect in all diseases falling possibly under such a broad definition.

To summarize: At present, the claimed subject-matter is considered to lack inventiveness.

Form LU237-3 (separate sheet) (January 2007) (sheet 6)