AU594512B2

AU594512B2 - Hydroxy indole derivatives

Info

Publication number: AU594512B2
Application number: AU79640/87A
Authority: AU
Inventors: Rolf Bergmann; Henning Bottcher; Hans-Heinrich Hausberg; Christoph Seyfried
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1986-09-16
Filing date: 1987-09-12
Publication date: 1990-03-08
Anticipated expiration: 2007-09-12
Also published as: JPH01501548A; JPH0822859B2; KR880701709A; EP0281608A1; EP0281608B1; AU7964087A; WO1988001998A1; KR950011409B1; SG118592G

Description

rPP_ AU-.A-79640/ 87 PTWLLTORGANISATION FOR GITGSEGNU PCT InternatioUo Irog IV INTERNATIONALE ANMELDUNG VEROFFE ~C NAt D' VE RA ER DIE INTERNATIONALE ZUSAMMENARBEIT AUF 5JMl BI £'jDE ATE TWdLNS (PCT) (51)"Internationale Patentklassifikation 4 C07D 209/14, A61K 31/44 (It) Internationale Verffentlichungsnummer: WO 88/ 01998 Al (43) Internationales I e6Afentlichungsdatumn: 24. Mtirz 1988 (24.03.88) (21) Internationales Aktenzeichen: PCT/EP87/00518 I internationales Anmneldedatum: 12, September 1987 (12,09,87) (A1) Prioritiitsaktenzeichen, (32) Prioritlitsdatumn: (33) Prioritatsland: 907,909 16, September 1986 (16,09.86) (71) Anmelder cfir alle Bestimmungsstaaten ausser US):, MERCK PATENT GESELLSCHAFT MIT BE- SCHRANKTER HAFTUNG[DE/DE]; Frankfurter Strasse 250, D-6 100 Darmstadt (DE), (72) Erfinder;und Erfinder/AnmeIder (nur fiir US) H-AUSBERG, Hans- Heinrich [DE/DE]; Qdenwaldstrasse 30, D-6105 Ober-Ramstadt BOTTCHER, Henning [DE/ DEJ; Soderstrasse 95, D-6100 Darmstadt SEY- FRIED, Christoph EDE/DE]; Mathildenstrasse 6, D- 6104 Seeheim-Jugenheim BERGMANN, Rolf (DE/DE]; Birkenhag 36, D-6101 Reichelqheim (DE).

(74) Gemneinsamer Vertreter: MERCK PATENT GESELL- SCHAFTr MIT BESCHRANKTER HAFTUNG; Frankfurter Strasse 250, D-6100 Darmstadt (DE).

(81) Bestimmungsstaaten: AT (europa1isches Patent), AU, BE (europiiisches Patent), CR (europtiisches Patent), DE (europfiisches Patent), FR (europiiisches Patent), GFB (europtlisches Patent), IT (europaiisches Patent), JP, KR, LU (europtiisches Patent), NL (europdiisches Priterit), SE (europtiisches Patent), US, Verbffentlicht Kvfit internafloaalem Recherclenbericht.

Vor Ablatifde./1Th Anderungen der Ansprilche zutgelassenen Frist. Ver6fj, 'ntlich zng wird wviederholt falls Anderungen eint, effen.

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AUSTRALIAN

-7 APR 98 PATENT OFFICE P (54) Title: HYDROXYLINDOL DERIVATIVES (54) Bezeichnung: HYDROXY! NDO LD ERIVAT (57) Abstract 3.(4-(4-phenyt14,2,3,6-tetrahydro-4-pyridy)-buty].5-hydroxy-indo1-methanesulfonate can be used in the therapy of parkinisonism and has particularly good Sotlubility, (57) Zusarmenfassung 3.[4-(4-Phenyl.1,2,3,6-tetrahydro-l-pyridyl)-butyl]-5-hydroxy-indol-methansulfonat kani-. be! der Therapie von Parkinson smus verwendet werden unc st besonders gut lbstich.

pr i 1 Hydroxyindole derivative The invention relates to the new compound 3-E4- (4-phenyl--1,2,3,6-tetrahydro-l-pyridyl)-butyl]-5-hydroxyindole methanesulfonate The underlying base (II) and the corresponding hydrochloride (III) are described in DE-OS 2,910,367.

It has been found that I has considerably more favourable pharmacokinetic properties than III. Thus, for examoLe, 100 mg/kg of I administered orally to Cynomolgus monkeys already lead to a sedating reaction, whilst this effect can be achieved with III only with doses above 500 mg/kg. I also has a considerably better solubility in water (0.921 g in 100 ml) than III (0.035 g in 100 mL).

The invention accordingly relates to the new compound I and a process for its preparation, which comprises reacting the base II with methanesulfonic acid.

This reaction is advantageously carried out in an inert solvent, for example methanol or ethanol, at temperatures between 0 and 800, preferably between and 30°. Stoichiometric amounts of the starting substances are preferably used.

The compound I can be used to prepare pharmaceutical formulations, in particular by a non-chemical route. For this, they can be brought into a suitable dosage form together with at Least one solid, (iquid or semi-liquid cxcipient or auxiliary and if appropriate in combination with one or more other active compound(s).

The invention furthermore relates to pharmaceutical formulations containing the compound I. These formulations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration or topical application and do not react with the new compound, for example water, vegetable oils, benzyl alcohols, poly- .ethylere gtycgols, .gelatine, carbohydrates, such as lac- I I K Ar;^ i I 2 tose or starch, magnesium stearate, talc and vaseline.

Tablets, coated tablets, capsules, syrups, elixirs, drops or suppositories are used, in particular, for enteral administration, solutions, preferably oily or aqueous solutions, and f'rthermore suspensions, emulsions or implants, are used for parenteral administration and ointments, creams or powders are used for topical application. The new compound can also be Lyophilized and the resulting lyophilisates -an be used, for exampLe, to produce injection preparations. The formulations mentioned can be sterilized and/or contain auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs, flavouring substances and/or aroma substances. If desired, they can also contain one or more other active compounds, for example one or more vitamins.

The compound I can be administered to humans or animals, in particular mammals, such as monkeys, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in combating diseases, in particular in the therapy of Parkinsonism, extrapyramidal disturbances in neuroleptic therapy, depression and/or psychoses and side effects in the treatment of hypertension (for example with t-methyldopa).

The compound I can also be used in endocrinology and gynaecology, for example for the therapy of acromegaly, hypogonadism, secondary amenorrhoea, premenstrual syndrome, undesirable puerperal lactation and generally as a proLactin inhibitor, and furthermore 'or the therapy of cerebral disturbances (for example migraine), in particular in geriatrics in the same way as certain ergot alkaloids, and also for reducing blood pressure.

The compound I is as a rule thereby administered analogously to known commercially available preparations (for example bromocriptine and dihydroergocornine), preferably in dosages of between about 0.05 and 5 mg, in S partlcCar'.'be.tween Q..2 and 2 mg per dosage unit. The pL, daily dosage is preferably between about 0.001 and 0.1 I f .ql DIV 3 mg/kg of body weight. However, the specific dose for each particular patient depends on the most diverse factors, for example on the age, body weight, general state of health., sex, diet, administration time and method, rate of excretion, drug combination and the severity of the particular disease to which the therapy applies. Oral administration is preferred.

Preparation Example A solution of 7 g of methanesulfonic acid in 40 ml of ethanol is added to a suspension of 23 g of 3- [4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butylJ-5-hydroxyindole (II) in 340 ml of ethanol at 150C, the mixture is warmed briefly to 30 0 C and cooled to 15 0 C and the resulting 3-E4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl butyl]-5-hydroxyindole methanesulfonate is filtered off. Melt j point 176 0

C.

The following examples relate to pharmaceutical formulations containing the compound I: Example A: Tablets A mixture of 1 kg of 1, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of 'magnesium stearrte is pressed into tablets in the customary manner such that each tablet contains 1 mg of active compound.

Example B: Coated tablets Tablets are pressed analogously to Example A and are then coated in the customary manner with a coating of j) sucrose, potato starch, talc, tragacanth and dyestuff.

Example C: Capsules Hard gelatine capsules are filled with 10 kg of I in the customary manner such that each capsule contains 1 mg of active compound.

Example D: Ampoules A solution of 1 kg of I in 30 1 of doubly-dis- tilled water is subjected to sterile filtration and ampoules are filled with the solution, lyophilized under sterile conditions and subjected to sterile sealing.

Each ampoule contains 0.5 mg of active compound.

"I 1* c~ t;B

Claims

1. The acid addition salt3-[4-(4-Phenyl-l,2,3,6-tetrahydro- methanesulfonate

2. Process for the preparation of the acid addition salt (I) as defined in claim 1, characterized in that

3-[4-(4-Phenyl-l,2,3,6-tetra- hydro-l-pyridyl)-butyl] -5-hydroxy-indole is reacted with methanesulfonic acid. 3. Process for the preparation of pharmaceutical formaulations, characterized in that the acid addition salt (I) as defined in claim 1 is brought into a suitable dosage form Se* together with at least one solid, liquid or semi-liquid excipient or auxiliary and if appropriate in combination with one or more other active compounds.

4. Pharmaceutical formulation, characterized in that it contains the acid addition salt according to claim 1, in admixture with pharmaceutically acceptable excipients or auxiliaries.

5. Acid addition salt according to claim 1, when used in the therapeutic treatment of Parkinsonism, extrapyramidal *I disturbances, depression and/or psychoses, side effects in the h* treatment of hypertension, endocrinology, gynaecology and v cerebral disturbances substantially as herein before described. DATED this 17th day of October, 1989. MERCK PATENT GMBH S By Its Patent Attorneys Ok ARTHUR S. CAVE CO. 0128/RAP 01280/RAP i 1 1 v I -77 Abs tract 3-C4-(4-PhenyL-1,2,3,6-tetrahydro-l-pyr idyL)- butyL J-5-hydroxy- indoL e me thanesu f ona te can be used in the therapy of Parkinsonism and is particuLarLy readiLy soLubie.- I, I 71 INTERNATIONAL, SEARCH REPORT International Application No PCT/EP 87/00518 1. CLASSIFICATION OF SUBJECT MATTER (if several clatneif'ication symbol$ apply, Indicate all) According to International Psant Cassification (IPC) or to both Nattionai Classification and IPC Int..Cl. 4: C 07 D 209/14; A 61 K 31/44 II. FIELDS SEARCHED Minimum Documentation Searclhed 7 Classification System C1asu6fl-ation Symbols Int.Cl. 4 C 07 D 209/00 Documentation Searched other than Minimum Documentation to the Extant that such Documents are Included In the Fields Searched 8 Ill. DOCUMENTS CONSIDERD TO BE RELEVANT I Category Citation of Document, 11 with Indication, where appropriate, of the relevant passages 'it Relevant to Clim No, 13 X EP, A, 0007399 (M'AERCK PATENT GmbH) 1-7 06 February 1980, see pages 1-3; page 35, example 175; claims DE, A, 2910367 (cited in the application) Special categories of cited documents; 10 later document Published after the International fing date document defining the general state of the art which Ia i ,pt or priority data and not In conflict with the application but considered to be of particular relevance cited to understand the principle or theory undlerlying the Invewition IE" earlier document but pulljqhod on or after the Inteinstional document of particular relevance,, the claimed Invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or Involve an, Inventive step which Is cited to establish the publication date of another "YV docm~ment of Particular releverncel' the claimed Invention, citation or other special reason (ae specified) cannot be considered to Involve an Inventive step when the document referring to in oral disclosure, use, exhibition Vt document Is combined with one or more other such docu- other means otsuhcmiainbigovostapnn,!-ild "101 document published prior to the International fi'ling date but In the lfl. later than the priority date claimed -4 dodu~irent member of the same patent family IV4 CERTIFICATION___________ Date at the Actual Completion rat the International Search T 1Mailing of this Intefinational Search Report Decemnber 1987 (U5.12.81) 10Fbur 198( .28) Internationat Searching Authority ISignature of Authoried Officer EUROPEAN PATENT OFFICE1 Form PCT/ISA/2IO (second sheet) (January 1365), 7 I ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. EP 8700518 SA 18684 This, annex lists the patcnt family members relating to the patent docutm~.,ts cited in the nbove-mcntione international search report. The members are as contained in the European Patent Office EDP1 file on 28/01/88 The Europenn P~atent office is in no way liable for these particulars which are merely given fc.r tic purpose of information. Patent documecnt Publication Pa~tent family P'ublication cited in search report date member(s) date EP-A- 0007399 06-02-80 DE-A- AU-A- US-A- J P-A- AT-T- CA-A- AU-B- OE-A- 2827874 4830279 4251538 55004391 587 1133484 525995 2910367

07-02-80 03 -01-80 17 -02-8 1 12 -01-80

15-02-82 12-10-82 09-12-82 02-10-80 4 SFor more de~tails abou~t this annex see Offcial Journul of the European Patent Office, No. 12/82 INTERNATIONALER RECHERCHENBERICHT In ternationales Aktenzeichen PCT/EP 87/00518 1. KLASSIPIKATION DES ANMELOUNGSGEGENSTANDS lbej i,.hrersr' KlasifikarIorsvmbolen $Ina 41lo aflzugoanl 6 Nach der Inernationalen Patentklassifikation IIPC) oder nach der nationalen Klassifikation und der IPC C 07 D 209/14; A 61 K 31/44 11, RECHERCHIERTE SACHOEBIETE Rcecire idiirf~f K lassi fi kationssystem K lassifik atlo nssYmbol e Int CI 4C 07 D 209/00 Recharchierta nicht zumn MindesprfsToff gehorende Veroffentllchungen, soweit diese untar die recherchierten Sachgebiete fallen 8 III. EINSCHLAGIGE VERO FFENTLICHUNGEN 9 Art Kennzelch nu ng der Verb f fen tiichu ng 1 sowelt erf orderlIch u nter Angabe dermra~gebl iche n Tei le 1 2 Semr Ansoruch Nr.1 3 X EP, A, 0007399 (MERCK~ PATENT GmbH) 1-7 6. Februar 1980 siehe Seiten 1-3; Seite 35, Beispie. 175; Patentanspr~iche DE, A, 2910367 (in der An~eldung erwdhnt) aesondoro Katoqorlon Yon angogobenotn Vortdtanxdlctiungon' 0 'IAO VordffentlicIhung, die den aligemolnon Stand aq Tochnik 'IT" Sptere Ver f1ntlchung, die nach derm Internatlonalon An. dofinlon, Abor nicht als bosonders becasoa anzusehon fit meldoclatumn odor derm Prlarititidatumn vortdffentlch; warden 'IE" 31tores Ookumoent, des jodoch orort am odor nach domn intern. lit und mit dot Anmoidung nicht kolilert sondomn nur zumn tionlonAnmldealun vrdfontlch wadenIstVorwindnis des det Erfindung zUgrundelloe~nden Prlnzips IOVtfonillcAnmodietu vsovdfnlci wordmn lodo d r ugrundollegmndon Theori. angegoen it 't.~Vorffo~Ithg ,l goknot fot, alnon PriorlidutanepruI VordffntlIchung von besondoerr Bodsutunq, dlo boonspruch. zweltolhoft arschonon zu lason, odor durch dldie ioVerdf. .,kn lh l e do u r~drs~o ~g fontlichunodcatumn olnor andoron Imn Rocherchombricht go. L to fidug an niht al nudo u rldricIeTt naroiton V'dflontlichung WWbg warden "i ader dlo sa sinorn keIt beu ono trachs torde aridaron bosondeon Grund angeooe~n Ist Weo ofig@hrt) Verdftentlchung van besonderor Bidoutung: die boansprucl,. 110 Vadtfntichug, ie tchsuf ~ndich Ofenbsrug, to Erfinciung kann nicht isle Auf orfindortschor fTlgkoit be. @0n' Vorfnulung, dsi alitluf odor m ndch Onbhmn ruhorsd betrachtot wordon, vIonn dlo Vordfortfllchung mit embous ung .m utlugoo adr eioiolner odor morron endeoen Verdtfentlichungon dieteor Kate~ bozloht gorb, In Verbindung gobiracht wird urid dies. Vorbinduing for Vordffnjichung, die Yoe dorn Internationolon Anmolded.. olmen Fachmann nahollogmnd let tumn, obor lnch dom boonspruchten Prforititidaotom vordffnt, I' Vordffenvtkhling, die Mltgllod dorsolbon Patonttamlillo lit licht warden lot IV. BESCHOINIOUNO '4 AF Oatumn des Abechlusos" doe Intornationalon Recherche Dezember 1987 Irnatlonale Roctsarchon bohdrde Europilwoh Patentamt MormblotPCT/ISA/210 (91 21 (JanuG#. 1961) Absondodatum doe lrternaoalon Rochorchanbericht3 ANHANG ZUM INTERNATIONALEN RECHERCHENBERICHT OBER DIE INTERNATIONALE PATENTANMELDUNG NR. EP 8700518 SA 18684 In dJS~sem Aknhan.g sind die Nlitglieder der Patcntfamiin der hn obengenanntcn internationalen Rechtirchenbcricht angefiihrtcn Patentdokumncnte angegeben. Die Ang-,b4n uber die Familienmitglieder entsprechen deni Stand der Datei des Europiiischcn Patentais am 28/01/88 Diclle nAngabien dienen nur zur Unterrichitung und erfolgen ohne Gewihr. mIn Rechcrchenbcricht Datum der NIitglied(or) der Datumn der arigeffihrtes Patentdokunicnt Verdlfentlichung flutcntfamilie vcrbffentlichung EP-A- 0007399 06-02-80 DE-A- 2827874 07-02-80 AU-A- 4830279 03-01-80 US-A- 4251538 17-02-81 JP-A- 55004391 12-01-80 AT-T- 587 15-02-82 CA-A- 1133484 12-10-82 AU-B- 525995 09-12-82 OE-A- 2910367 02-10-80 .4P VPhr nilhero Etnzelheiten iii diescim knhang slehe Amtshlatt des Europl-sL-hen Patentamts, Nord 2/82