WO1990012574A1 - Composes agonistes de la dopamine - Google Patents

Composes agonistes de la dopamine Download PDF

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Publication number
WO1990012574A1
WO1990012574A1 PCT/US1989/001747 US8901747W WO9012574A1 WO 1990012574 A1 WO1990012574 A1 WO 1990012574A1 US 8901747 W US8901747 W US 8901747W WO 9012574 A1 WO9012574 A1 WO 9012574A1
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Prior art keywords
compound
accordance
acid
substituted
lower alkyl
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PCT/US1989/001747
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English (en)
Inventor
John L. Neumeyer
Sten Ramsby
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Northeastern University
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Priority to PCT/US1989/001747 priority Critical patent/WO1990012574A1/fr
Publication of WO1990012574A1 publication Critical patent/WO1990012574A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings

Definitions

  • aporphine compounds have therapeutic activity.
  • APO apomorphine
  • APO apomorphine
  • NPA N-n-propylnorapormorphine
  • Such aporphine compounds have been used clinically, especially in neurological and psychiatric disorders, but their clinical use has been limited by their poor oral bio-availability and short duration of action.
  • a dopamine agonist compound which has two adjacent hydroxy groups on an aromatic nucleus and which has a therapeutic effect when administered subcutaneously or intraperitoneally can be converted into an orally effective therapeutic compound by bridging the hydroxy groups to form a dioxy group as for example, methylenedioxy.
  • the dioxy group is cleaved in vivo to provide the compound with two adjacent hydroxy groups.
  • Such compounds include novel aporphine compounds.
  • R 1 is lower alkyl, substituted lower alkyl, cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lover alkyl, phenyl lower alkenyl and phenyl lower alkynyl.
  • R 2 is hydrogen, hydroxy.
  • R 3 and R 4 are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl, phenyl lower alkynyl, or COR 5 , where R 5 is methyl or lower alkyl; and pharmaceutically acceptable addition salts thereof .
  • This invention is generally applicable to dopamine agonist compounds which have two hydroxy groups on adjacent positions on an aromatic nucleus and which have dopamine agonist activity when administered subcutaneously or interperitoneally.
  • dopamine agonist compounds which have two hydroxy groups on adjacent positions on an aromatic nucleus and which have dopamine agonist activity when administered subcutaneously or interperitoneally.
  • Such compounds include not only aporphine compounds but also non-aporphine compounds , as for example , compounds of the following structures :
  • R 1 and R 2 are hydrogen, methyl and lower alkyl
  • R 1 and R 2 are hydrogen, methyl and lower alkyl
  • R 1 and R 2 are hydrogen, methyl and lower alkyl.
  • aporphine compounds are described which are orally effective in treating neurological and psychiatric disorders.
  • aporphine compounds are described which are effective in the prevention and treatment of duodenal ulcers and can be administered orally, subcutaneously or peritoneally.
  • Preferred examples of these novel compounds with dioxy groups have the following structures:
  • R 1 is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl
  • R 2 and R 3 are hydrogen, methyl, lover alkyl, substituted lover alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lover alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lover alkenyl and phenyl lover alkynyl and pharmaceutically acceptable acid additional salts thereof.
  • lower-alkyl means saturated monovalent aliphatic radicals, including straight and branched- chain radicals, of from two to six carbon atoms, as illustrated by, but not limited to ethyl, propyl, isopropyl, butyl, sec- butyl, amyl, or hexyl.
  • lower-alkenyl means monovalent, aliphatic radicals of from three to seven carbon atoms which contain at least one double bond, and are either straight or branched-chain, as illustrated by, but not limited to 1-(2- propenyl), 1-(3-methyl-2-propenyl), 1-(1,3-dimethyl-2-propenyl), or 1-(2-hexanyl).
  • lower-alkynyl means monovalent, alphatic radicals of from three to seven carbon atoms which contain at least one triple bond, and are either straight or branched, as illustrated by, but not limited to 1-(2-pro ⁇ ynyl), 1-(1-methyl-2-propynyl), or 1- (2-heptynl).
  • cycloalkyl means cyclic, saturatd aliphatic radicals of from three to eight ring carbon atoms, as illustrated by, but not limited to cyclopropyl, cyclobutyl, 2- methylcyclobutyl, cyclohexyl, 4-methycyclohexyl, or cyclooctyl.
  • phenyl- lower-alkyl As used herein, the terms "phenyl- lower-alkyl,” “phenyl- lower-alkenyl,” and “phenyl-lower-alkynyl” mean monovalent radicals consisting of a phenyl nucleus bonded to the rest of the molecule through, respectively, a divalent lower-alkylene radical of from one to four carbon atoms, as illustrated by, but not limited to methylene, 1, 1-ethylene, 1, 2-ethylene, 1,3- propylene, 1,2-propylene, or 1,3-butylene; or through a divalent lower-alkynylene radical of from two to four carbon atoas, as illustrated by, but not limited to 1,2-ethyny 1 ene, 1,3- propynylene, 1,3-(1-butynylene), and the like.
  • benzene ring of such phenyl- lower-alkyl, phenyl-lower-alkenyl, and phenyl-lower-alkynyl radicals can be substituted by one or more substituents selected from the group consisting of lower- alkyl, lower-alkoxy, halo (chloro, bromo, iodo, or fluoro), nitro, lower-alky Imercapto, methylenedioxy, and trifluoromethyl.
  • Apropriate acid addition salts are those derived fro ⁇ such diverse acids as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, 1-naphtha lenecarboxy 1 ic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonie acid, acetylene dicar boxy lie acid, sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxyl ic acid, 2-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, benzenesulf inic acid, buty
  • diethylphosphinic acid diethylphosphinic acid, p-aminophenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride, and the like.
  • N-substituted noraporphines of this invention may be prepared from the readily available opium alkaloid thebaine by the synthesis scheme illustrated in Figure 1.
  • thebaine is N-demethy lated to northebaine ⁇ seing diethylazodicarboxylate according to the method disclosed in British Patent 1,124, -441 (August 21, 1968).
  • the rearrangement of the northebaine to normorphothebaine is accomplished with concentrated HCI in a sealed pressure bottle on a steam bath for 2.5 hours according to a published procedure
  • N-R 1 - normorphothebaine Formation of the N-R 1 - normorphothebaine. HCI is carried out in the presence of an acid acceptor (e.g., Na 2 CO 3 or NaHCO 3 ) using the appropriate
  • ester derivatives wherein R 2 ,R 3 or R 4 are -C-R 5 and R 5 is lower alkyl are conveniently prepared by reacting the appropriate N-R 1 -2,10,11-trihydroxynoraporphine HBr or free base with an appropriate acyl halide to give the substituted triacyl noraporphine.
  • the free base and acid addition salts may thus be converted from one form to the other and one acid addition salt may be converted to another by regenerating the free base and acidifying it.
  • Aporphines were administered, as described below, freshly dissolved in ImM citric acid mixed with 0.9t (w/v) saline (1:4 vols) this solvent was also used as a vehicle ("placebo") control.
  • Haloperidol was given in the same medium; 2-diethyl aminoethyl-2,2 diphenyl va lerate HCI (SKF-525A) was given in saline.
  • Locomotor activity was evaluated by use of a printing electronic activity monitor (EAM, Soelting Co., Chicago, IL) within a sound-attenuated chamber, typically for 60 min., as previously described (Stewart, Campbell, Sperk and Baldessarini, 1979,
  • Catalepsy was assessed as described in detail elsewhere (Campbell and Baldessarini, 1981a; 1981b, Life Sciences 29 1341- 46). Briefly, rats were evaluated every 10 min. by timing (stopwatch) their maintenance of an abnormal posture with forelimbs on a 1 cm-diameter steel bar parallel to, and 8cm above the bench, so that the rate rested on its hindquarters only; 60 sec. was taken as a maximum and nearly all normal untreated rats remained on the bar for less than 5 sec. Ratings were made as follows: O, remaining on the bar 0-10 sec; 1, 10-29 sec; 2, 30-59 sec; 3, 60 sec. Thus, in a typical 60 min. session, the maximunm score was 18.0.
  • rats were given as injection of vehicle and then allowed to rest for 15 min. to adapt to non-specific arousal effects, prior to a second injection of test agent or
  • halo and amino compounds were tested for their ability to displace 3 H-spiperone in porcine anterior pituitary gland. [George, S.R., M. Watanabe, and P. Seeman. Dopamine D 2 receptors in pituitary: A single population without reciprocal agonist/antagonist states. J. Neurochem. 44:1168-1177 (1985)].
  • Examples 1-10 and 15-22 describe preparation of compounds made in accordance with this invention.
  • Examples 11-14 describe biological testing.
  • Tables 1-12 describe biological activity.
  • Normorphothebaine hydrochloride was prepared from thebaine using the synthesis scheme outlined above and according to the teaching of British Patent 1,124,441 and Granchelli et al. Four
  • N- R 1 -normorphothebaines wherein R 1 is phenyl lower alkyl, phenyllower alkenyl or phenyl lower alkynyl are advantageously prepared by reaction, in the presence of an acid acceptor, of the normorphothebaine CHCl 3 with an appropriate phenyl lower alkyl halide, phenyl lower alkenyl halide or phenyl lower alkyny halide.
  • the hydrochloride salt was prepared by dissolving the free base in 200 milliliters of anhydrous ether and the solution was treated with an excess of ethereal HCI. Filtration of the mixture gave a white solid (1.09 grams, 80%) with m.p. 179-183oC, and a structure confirmed by NMR and infrared spectra.
  • N-Propargyl-2,10,11-trihydroxynorapnrphine A mixture of normorphothebaine hydrochloride (1.5 g, 4.7 moles) in 481 HBr was heated at 130oC under nitrogen for 3 hours and evaporated to a dry residue in vacoo. The residue was taken up with minimal amount of absolute methanol and the solution added dropwise to 200 mL of ethyl ether to give a precipitate. Filtration of the mixture yielded the intermediate 2,10,11- trihydroxynoraporphine (1.55 g).
  • Emetic efficency was measured in alert dogs with three particulate (15 um spheres) and three soluble markers (phenol red theophylline and tobramycin) instilled 5, 25, and 55 minutes before rapid intraveneous injection of the emetic. Apomorphine was used as a control emetic. Measurements included time interval to first emesis and recovery in the vomitus of the particulate and soluble markers.
  • Example 6 made up in a solution of physiological saline or other suitable vehicle and administered in doses ranging between 0.005 and 1mg/kg body weight, produced emesis in conscious dogs within two minutes of an intraveneous injection. Even at the high dosage level of 1 mg/kg there was no evidence of cardiovascular, central nervous system or respiratory toxcity. At a dosage level of 0.1 mg/kg the ( - ) N - n - propyl -2, 10, 11- trihydroxynorapomorphine.HBr was found to be 50 times more potent that apomorphine.
  • mice 18.28 show a fixed sequence of seizure phenomena in response to a loud sound.
  • Dopamine agonists prevent the later stages of this response (Tabl e 10 )
  • (-)-2, 10, 11-trihydroxy-N-propylnorapomorphine (TNPA) has a prolonged sedative action.
  • TNPA is equipotent with apomorphine (tested 30 minutes after drug administration).
  • Dopamine agoni s ts protect agins t pa roxysma l EEG and myoc Ionic responses to photic stimulation in Papio Papio (Table
  • TNPA 0.02 mg/kg
  • iv produced a mi ld sedative effect but did not modify tuyoclonic responses to photic stimulation.
  • complete protection was seen for 3-7 hours after TNPA, 0.5 and 2.5 mg/kg, given intravenously.
  • TNPA 0.02 mg/kg
  • iv produced a mi ld sedative effect but did not modify tuyoclonic responses to photic stimulation.
  • complete protection was seen for 3-7 hours after TNPA, 0.5 and 2.5 mg/kg, given intravenously.
  • These doses are a l so fol lowed by pupi l di lation, yawning, s lowing of EEG background rhythms, and at the highest dose, by excess salivation and piloerection.
  • the crude propionic acid derivative 5 (4.0 g) was dissolved in 50 mL of SO 2 Cl 2 and stirred at room temperature overnight.
  • the amide 6 (3.0 g, 7.8mmol) was dissolved in 50 mL of dry HMPT and NaH (50% in oil. 0.42 g) was added under N 2 at room temperature. The solution was heated at 100oC for 1 h with stirring. The reaction mixture was cooled and poured into ice- water and extracted with AcOEt. The combined extracts were washed with water and dried (MgSO 4 ). Removal of the solvent gave 3.6 g of crude hydroxy amide, 7.
  • Haloperidol or its vehicle was given 30 min before MDO-NPA (both dissolved in the same citric acid-saline vehicle).
  • Th e grours consisted of 3-4 Spragu e-Dewley female rats (160-180g) . Each experiment was repeated at least twice and the results of those gropes were pooled.
  • the dopemine agonists were injected s. c. once daily for seven days prior to the administration of cysteamine HCl (Aldrieh) 26mg/100g . p.o. three times with 3 hr intervals. The animals were killed 46 hr after the duodenal ulcer- ogen.
  • MDO-NPA is converted in vivo to NPA eg N-n-propylnorapomorphine .

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Abstract

Sont décrits des composés agonistes de la dopamine efficaces oralement et notamment de nouveaux composés d'aporphine. Ces composés possèdent un groupe dioxy sur un noyau aromatique qui est clivé in-vivo pour libérer des composés présentant deux groupes hydroxy adjacents sur le noyau aromatique. Sont également décrits de nouveaux composés d'aporphine agonistes de la dopamine dans lesquels le groupe hydroxyl phénolique est remplacé par des groupes amino, bromo ou fluoro.
PCT/US1989/001747 1989-04-25 1989-04-25 Composes agonistes de la dopamine WO1990012574A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997030977A1 (fr) * 1996-02-23 1997-08-28 Pharm-Eco Laboratories, Incorporated Agonistes selectifs et agonistes/antagonistes partiels du recepteur de la dopamine d1
JP2004506041A (ja) * 2000-08-17 2004-02-26 アクソン・バイオケミカルズ・ビー・ブイ 新規アポルフィンエステルおよび治療におけるそれらの使用
EP1634596A1 (fr) * 2003-06-19 2006-03-15 Lotus Pharmaceutical Co., Ltd. Aporphine et oxoaporphine et leur utilisation a des fins medicales
EP1737458A2 (fr) * 2004-04-13 2007-01-03 The McLean Hospital Corporation Derives de r(-)-11-hydroxyaporphines et utilisations de ces derives
EP1744758A2 (fr) * 2004-04-23 2007-01-24 Perkinelmer Las, Inc. Produit radiopharmaceutique, ses methodes de synthese et d'utilisation
WO2010039920A2 (fr) * 2008-10-02 2010-04-08 Osteogenex Inc. Composés à base de boldine pour favoriser la croissance osseuse
US8431591B2 (en) 2007-07-12 2013-04-30 The Mclean Hospital Corporation R(−)-2-methoxy-11-hydroxyaporphine and derivatives thereof
JP2014111635A (ja) * 2007-08-31 2014-06-19 H Lundbeck As カテコールアミン誘導体およびそのプロドラッグ
WO2020041683A3 (fr) * 2018-08-23 2020-03-26 Sunovion Pharmaceuticals Inc. Sels d'addition d'acides d'apomorphine, compositions pharmaceutiques en contenant et leurs procédés d'utilisation
US11104697B2 (en) 2019-05-20 2021-08-31 H. Lundbeck A/S Process for the manufacture of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4AR,10AR)-7-hydroxy-1- propyl-1,2,3,4,4A,5,10,10A-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid
US11111263B2 (en) 2019-05-20 2021-09-07 H. Lundbeck A/S Process for the manufacture of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid
US11110110B2 (en) 2017-11-24 2021-09-07 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's disease
US11130775B2 (en) 2019-05-20 2021-09-28 H. Lundbeck A/S Solid forms of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4A,5,10,10A-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid
US11168056B2 (en) 2019-05-20 2021-11-09 H. Lundbeck A/S Process for the manufacturing of (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4′,5′:5,6]benzo[1,2-G]quinoline and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[G]quinoline-6,7-diol

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EP1634596A1 (fr) * 2003-06-19 2006-03-15 Lotus Pharmaceutical Co., Ltd. Aporphine et oxoaporphine et leur utilisation a des fins medicales
EP1634596A4 (fr) * 2003-06-19 2006-06-21 Lotus Pharmaceutical Co Ltd Aporphine et oxoaporphine et leur utilisation a des fins medicales
EP1737458A4 (fr) * 2004-04-13 2010-08-04 Mclean Hospital Corp Derives de r(-)-11-hydroxyaporphines et utilisations de ces derives
EP1737458A2 (fr) * 2004-04-13 2007-01-03 The McLean Hospital Corporation Derives de r(-)-11-hydroxyaporphines et utilisations de ces derives
JP2007532670A (ja) * 2004-04-13 2007-11-15 ザ マクレーン ホスピタル コーポレーション Ｒ（−）−１１−ヒドロキシアポルフィン誘導体およびその使用方法
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EP1744758A2 (fr) * 2004-04-23 2007-01-24 Perkinelmer Las, Inc. Produit radiopharmaceutique, ses methodes de synthese et d'utilisation
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