WO2009156458A1 - Nouvelles amines phénoliques et catécholiques et leurs promédicaments - Google Patents

Nouvelles amines phénoliques et catécholiques et leurs promédicaments Download PDF

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Publication number
WO2009156458A1
WO2009156458A1 PCT/EP2009/057928 EP2009057928W WO2009156458A1 WO 2009156458 A1 WO2009156458 A1 WO 2009156458A1 EP 2009057928 W EP2009057928 W EP 2009057928W WO 2009156458 A1 WO2009156458 A1 WO 2009156458A1
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Prior art keywords
hexahydro
naphtho
propyl
oxazin
methoxy
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PCT/EP2009/057928
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English (en)
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Ask Püschl
Morten JØRGENSEN
Benny Bang-Andersen
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H Lundbeck AS
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H Lundbeck AS
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Priority to CN200980133807XA priority Critical patent/CN102131790A/zh
Priority to EP09769306A priority patent/EP2303851A1/fr
Priority to JP2011515379A priority patent/JP2011525893A/ja
Publication of WO2009156458A1 publication Critical patent/WO2009156458A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to new phenolic and catecholic amines as well as to prodrug derivatives for their formation in vivo; to processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.
  • PD Parkinson's disease
  • Parkinson's disease appears to be caused by a progressive deterioration of dopamine-containing neurons in the substantia nigra zona compacta of the brain.
  • Dopamine (DA) is a chemical neurotransmitter, which is utilized by brain cells to transmit impulses to control or modulate peripheral muscle movement. The loss of dopamine-containing neurons results in reduced amounts of dopamine available to the body. This process is thought to disturb nerve cell function such that impulses are not transmitted properly, resulting in a loss of muscle control and function.
  • L-DOPA is a cheap and efficacious drug, but with a poor PK profile leading to dyskinesia and other response fluctuations.
  • Selective D 2 -agonists e.g. pramipexole
  • D 2 -agonists give less dyskinesia, and are the preferred first-line treatment of PD.
  • Certain hydro xylated (phenols or catechols) phenylethylamines are known to possess useful dopaminergic activity at least in animal models. However, their clinical use is limited because they have low or no oral bioavailability.
  • Apomorphine is used clinically [for clinical experiences, see for example: Manson et al, Brain 124, 331 (2001) and Neef and van Laar, Clin. Pharmacokinet., 37, 257 (1999)].
  • Several clinical studies are ongoing with alternative delivery strategies for apomorphine, e.g. using intranasal and sublingual formulations; however, these efforts have not yet resulted in an option for the clinical treatment of PD [for general discussions, see: Stacy and Factor (Eds) Neurology, 62 (Supplement 4), Sl (2004) and Neef and van Laar, Clin. Pharmacokinet., 37, 257 (1999)].
  • DA receptor agonists are able to activate the DA autoreceptors as well as the postsynaptic DA receptors.
  • the effects of autoreceptor stimulation appear to predominate when, for example, apomorphine is administered at low doses, whereas at higher doses the attenuation of DA transmission is outweighed by the enhancement of postsynaptic receptor stimulation.
  • the antipsychotic and antidyskinetic effects in humans of low doses of, for example, apomorphine are likely due to the autoreceptor-stimulator properties of this DA receptor agonist. This body of knowledge indicates that DA receptor stimulants with a high selectivity for central nervous DA autoreceptors would be valuable in treating psychiatric disorders.
  • DA receptor stimulants can have an effect in depressed patients, and can be used in the treatment of obesities as an anorectic agent. DA receptor stimulants can improve minimal brain dysfunction (MBD), narcolepsy, and negative and cognitive symptoms of schizophrenia. Restless leg syndrome and periodic limb movement disorder are other indications which are clinically treated with DA-agonists [for a discussion, see: Lesage and Hening, Seminars in Neurology, 24, 249 (2004)]. In addition, impotence and erectile dysfunction are also likely to be improved by treatment with a DA-agonist (in both women and men). In this context, it is noteworthy that apomorphine when given sublingually is used clinically to improve erectile dysfunction in men.
  • DA is involved in regulation of the cardiovascular and renal systems, and accordingly, renal failure and hypertension can be considered further indications for the compounds of the invention.
  • DA receptor agonists are used in the treatment of hyperprolactinemia to lower the amount of prolactin in the blood [For a recent review see: Chanson, P. et al, Annales d'Endocrinologie 68(2-3), 113 (2007)].
  • One example of such a DA receptor agonist is the selective D2 agonist quinagolide (Norprolac®). Therefore, hyperprolactinemia can also be considered as an additional indication for the compounds of the invention.
  • the present invention relates to compounds of Formula I:
  • Ri and R 2 are independently selected from hydrogen; Ci-C 6 alkanoyl; C 6 -CiO aryl- Ci-C 6 alkanoyl such as phenylacetyl or benzoyl; or Ri and R 2 are fused and form a methylene (CH 2 ) group.
  • Ri is selected from hydrogen; Ci-C 6 alkyl, Ci-C 6 alkanoyl; C 6 - Cio aryl-Ci-C 6 alkanoyl such as phenylacetyl or benzoyl; and R 2 is hydrogen.
  • R 3 is selected from the group consisting of hydrogen; Ci -C 4 alkyl such as methyl, ethyl, n-propyl, cyc/o-propyl-methyl, allyl, or propargyl; C 3 -C 4 cycloalkyl such as cyc/o-propyl and cyc/o-butyl; hydroxyalkyl such as hydroxyethyl; C 2 -C 3 fiuoroalkyl such as 3-fiuoro- n-propyl and 2-fiuoroethyl, • R 4 is selected from the group consisting of hydrogen; Ci-C 6 alkyl such as methyl; C 6 -CiO aryl-Ci-C 6 alkyl such as benzyl; heteroaryl-Ci-C 6 alkyl such as 1-imidazolyl-methyl; di(Ci-C 6 alkyl)amino-Ci-C 6 alkyl such as dimethylamin
  • the invention relates to compounds of Formula I in the form of a substantially pure single enantiomer or single diastereomer.
  • the invention relates to compounds of Formula I in the form of a mixture of enantiomers, a mixture of diastereomers, or a substantially pure polymorph.
  • the invention relates to compounds of Formula I which have transfused ring systems.
  • Ri and R 2 are both hydrogen and X, R 3 and R 4 are as defined above.
  • Ri and R 2 are fused and form a methylene (CH 2 ) group, and X, R3 and R 4 are as defined above.
  • at least one of Ri and R 2 is Ci-C 6 alkanoyl, phenylacetyl or benzoyl, and X, R3 and R 4 are as defined above.
  • Ri is hydrogen and X, R 2 , R3 and R 4 are as defined above.
  • Ri is Ci-C 6 alkanoyl, phenylacetyl or benzoyl, and X, R 2 , R3 and R 4 are as defined above.
  • R 4 is hydrogen, and X, R 1 , R 2 , R3 are as defined above.
  • R 4 is not hydrogen, and X, R 1 , R 2 , R3 are as defined above.
  • R 3 is Ci -C 4 alkyl, such as methyl, ethyl or n-propyl, and X, R 1 , R 2 and R 4 are as defined above.
  • X is oxygen
  • R 1 , R 2 , R3 and R 4 are as defined above.
  • X is absent, and R 1 , R 2 , R3 and R 4 are as defined above.
  • R 4 is heteroaryl-Ci-C 6 alkyl wherein the heteroaryl group is pyrazol or substituted pyrazole. In a further embodiment of the invention R 4 is heteroaryl-Ci-C 6 alkyl wherein the heteroaryl group is imidazol. In another embodiment of the invention R 4 is heteroaryl-Ci-C 6 alkyl wherein the heteroaryl group is 1,2,4-triazol.
  • the compound of Formula I is in the form of a substantially pure enantiomer. In another embodiment the compound of Formula I is in the form of a substantially pure diastereomer.
  • R 4 is hydrogen
  • the compound of Formula I is in the form of the substantially pure (4aR,10aR)-enantiomer.
  • R 4 is hydrogen, and the compound of Formula I is in the form of the substantially pure (4aS,10aS)-enantiomer. In a separate embodiment of the invention R 4 is not hydrogen, and the compound of Formula I is in the form of the substantially pure (2R, 4aR,10aR)-enantiomer.
  • R 4 is not hydrogen, and the compound of Formula I is in the form of the substantially pure (2S, 4aR,10aR)-enantiomer.
  • R 4 is not hydrogen, and the compound of Formula I is in the form of the substantially pure (2R, 4aS,10aS)-enantiomer.
  • R 4 is not hydrogen, and the compound of Formula I is in the form of the substantially pure (2S, 4aS,10aS)-enantiomer.
  • R 4 is hydrogen
  • Ri and R 2 are fused and form a methylene (CH 2 ) group
  • the compound of Formula I is in the form of the substantially pure (6aR, 1 OaR)-enantiomer.
  • R 4 is hydrogen
  • Ri and R 2 are fused and form a methylene (CH 2 ) group
  • the compound of Formula I is in the form of the substantially pure (6aS,10aS)-enantiomer.
  • R 4 is not hydrogen
  • Ri and R 2 are fused and form a methylene (CH 2 ) group
  • the compound of Formula I is in the form of the substantially pure (2R,6aR, 1 OaR)-enantiomer.
  • R 4 is not hydrogen
  • Ri and R 2 are fused and form a methylene (CH 2 ) group
  • the compound of Formula I is in the form of the substantially pure (2R,6aS, 1 OaS)-enantiomer.
  • R 4 is not hydrogen
  • Ri and R 2 are fused and form a methylene (CH 2 ) group
  • the compound of Formula I is in the form of the substantially pure (2S,6aR, 1 OaR)-enantiomer.
  • R 4 is not hydrogen
  • Ri and R 2 are fused and form a methylene (CH 2 ) group
  • the compound of Formula I is in the form of the substantially pure (2S,6aS, 1 OaS)-enantiomer.
  • the compound of Formula I is selected among the following specific compounds, either as the free base, tautomers thereof or as a pharmaceutically acceptable acid addition salt thereof.
  • Each of the compounds constitutes an individual embodiment of the present invention:
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt hereof, as a medicament.
  • the compound of Formula I may be administered in any suitable way e.g. orally, buccally, sublingually, non-orally or parenterally, and the compound may be presented in any suitable form for such administration, e.g. orally in the form of tablets, capsules, powders, syrups, solutions or dispersions, non-orally in the form of eg. transdermal patches or parenterally in the form of dispersions or solutions for injection.
  • the compound of Formula I is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule.
  • the compounds of Formula I form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids. Such salts also constitute aspects of the present invention.
  • a pharmaceutically acceptable acid addition salt of the compound of Formula I is formed from a pharmaceutically acceptable acid, as is well known in the art.
  • Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66,2-19 (1977) and are known to the skilled person.
  • Inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, hypophosphoric, metaphosphoric, pyro- phosphoric, and the like.
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include the chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-l,4-dicarboxylate, hexyne-l,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate, teraphthalate, propiolate, propionate,
  • Tablets may thus be prepared by mixing the active ingredient with ordinary adjuvants, fillers and diluents and subsequently compressing the mixture in a convenient tabletting machine.
  • adjuvants, fillers and diluents comprise microcrystalline cellulose, corn starch, potato starch, lactose, mannitol, sorbitol talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives such as colourings, aroma, preservatives, etc., may also be used provided that they are compatible with the active ingredients.
  • the tablet compositions according to the invention may be prepared by direct compression of a compound of Formula I in admixture with conventional adjuvants or diluents.
  • a wet granulate or a melt granulate of a compound of Formula I, optionally in admixture with conventional adjuvants or diluents may be used for compression of tablets.
  • Solutions of a compound of Formula I for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilisation of the solution and filling in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, solubilising agents, etc.
  • the active ingredient eg. as the free base, may be dissolved in a digestible or non-digestible oil, mixtures hereof or similar, to prepare an intramuscular depot composition capable of releasing the active ingredient over a prolonged period of time.
  • compositions of the compound of Formula I to be used in transdermal applications may optionally contain permeation activators to facilitate the passage of the active ingredient through the skin.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier or diluent, wherein X is absent, Ri is selected from hydrogen; Ci-C 6 alkyl, Ci-C 6 alkanoyl and aryl- Ci-C 6 alkanoyl such as phenylacetyl or benzoyl; and R 2 is hydrogen.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier or diluent, for non-oral administration, such as transdermal, nasal, buccal, intramuscular ⁇ parenteral, or subcutaneous administration.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier or diluent, wherein the compound of Formula I is in the form of a substantially pure diastereoisomer or a substantially pure enantiomer.
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of neurodegenerative disorders, such as Parkinson's disease and Huntington's disease.
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of psychoses, impotence, renal failure, heart failure, hyperprolactinemia or hypertension.
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of cognitive impairment in a mammal.
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of cognitive impairment associated with a disorder or disease selected from schizophrenia, Parkinson's Disease, dementia such as AIDS dementia, anxiety disorder, age associated memory impairment, depression, Alzheimer's Disease, attention deficit hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD).
  • a disorder or disease selected from schizophrenia, Parkinson's Disease, dementia such as AIDS dementia, anxiety disorder, age associated memory impairment, depression, Alzheimer's Disease, attention deficit hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD).
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of restless legs syndrome (RLS) or periodic limb movement disorder (PLMD).
  • RLS restless legs syndrome
  • PLMD periodic limb movement disorder
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of movement disorders, poverty of movement, gait disorders or intention tremor in a mammal.
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof for the treatment of neurodegenerative disorders such as Parkinson's disease and Huntington's disease.
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof for the treatment of psychoses, impotence, renal failure, heart failure, hyperprolactinemia or hypertension.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, for the treatment of cognitive impairment in a mammal.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof for the treatment of cognitive impairment associated with a disorder or disease selected from schizophrenia, Parkinson's Disease, dementia such as AIDS dementia, anxiety disorder, age associated memory impairment, depression, Alzheimer's Disease, attention deficit hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD).
  • a disorder or disease selected from schizophrenia, Parkinson's Disease, dementia such as AIDS dementia, anxiety disorder, age associated memory impairment, depression, Alzheimer's Disease, attention deficit hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD).
  • ADHD attention deficit hyperactivity disorder
  • PTSD posttraumatic stress disorder
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, for the treatment of restless legs syndrome (RLS) or periodic limb movement disorder (PLMD).
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, for the treatment of movement disorders, poverty of movement, gait disorders or intention tremor in a mammal.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of medicaments, which are intended for oral administration, or for non-oral administration.
  • the invention also provides a method of treating a mammal suffering from a neurodegenerative disorder, such as Parkinson's disease and Huntington's disease, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof.
  • a neurodegenerative disorder such as Parkinson's disease and Huntington's disease
  • the invention also provides a method of treating a mammal suffering from psychoses, impotence, renal failure, heart failure, hyperprolactinemia or hypertension, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof.
  • the invention provides a method of treating a mammal suffering from a cognitive impairment, comprising administering to the mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof.
  • the invention also relates to a method of treating a mammal suffering from restless legs syndrome (RLS) or periodic limb movement disorder (PLMD), comprising administering to the mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable addition salt thereof.
  • RLS restless legs syndrome
  • PLMD periodic limb movement disorder
  • the invention also relates to a method of treating a mammal suffering from movement disorders, poverty of movement, gait disorders or intention tremor comprising administering to the mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof.
  • the mammal is a human subject
  • the therapeutically effective amount of a compound of Formula I, calculated as the daily dose of the compound of Formula (I) as the free base, is suitably between 0.01 and 125 mg/day, more suitably between 0.05 and 100 mg/day, e.g. preferably between 0.1 and 50 mg/day.
  • the daily dose of the compound of Formula I is between 1 and 10 mg/day.
  • the daily dose of the compound of Formula I is less than about 1 mg/day.
  • the daily dose of the compound of Formula I is about 0.1 mg/day.
  • the invention provides an oral composition comprising from 0.001 mg to 125 mg of a compound of Formula I.
  • the invention provides an oral composition comprising from 0.001 mg to 0.1 mg of a compound of Formula I.
  • the invention provides an oral composition comprising from 0.01 mg to 1 mg of a compound of Formula I.
  • the invention provides an oral composition comprising from 0.1 mg to
  • Figure 1 Crystal structure of (+)-(4aS,10aS)-4-cjc/o-propylmethyl-3,4,4a,5,10,10a-hexahydro- 2H-naphtho[2,3-b][l,4]oxazin-9-ol hydrochloride (example 5d2). Absolute configuration determined by the anomalous scattering of the 'heavy' chlorine atom.
  • Figure 2 Crystal structure of (2R,4aR,10aR)-2-methylsulfanylmethyl-4-/?-propyl- 3,4,4a,5,10,10a-hexahydro-2H-naphtho [2,3-b][l,4]oxazin-9-ol hydrochloride, (example 5j).
  • Figure 3 Crystal structure of toluene-4-sulfonic acid (2R,4aS,10aS)-9-methoxy-4-propyl- 3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][l,4]oxazin-2-ylmethyl ester (intermediate VB).
  • 2R,4aS,10aS Crystal structure of toluene-4-sulfonic acid
  • Ci-C 6 alkyl refers to a straight chained or branched saturated hydrocarbon having from one to six carbon atoms inclusive. Examples of such groups include, but are not limited to, methyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-l- butyl and n-hexyl.
  • Ci -C 4 alkyl refers to a straight chained or branched saturated hydrocarbon having from one to four carbon atoms inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, 1 -butyl and 2-butyl.
  • Ci-C 6 alkanoyl refers to a straight-chain or branched-chain alkanoyl group containing from 1 to six carbon atoms, examples of which include a formyl group, an acetyl group, a pivaloyl group, and the like.
  • Ci-C 6 alkoxy refers to a straight chain or branched saturated alkoxy group having from one to six carbon atoms inclusive with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n- hexyloxy.
  • Ci-C 6 alkylthio refers to a straight chain or branched saturated alkylthio group having from one to six carbon atoms inclusive with the open valency on the sulphur. Examples of such groups include, but are not limited to, methylthio and ethylthio.
  • C 6 -CiO aryl refers to a mono- or polycyclic aromatic group, which contains from 6 to 10 ring carbon atoms, and partially saturated variants thereof.
  • Typical examples which should not be considered limiting, comprise phenyl, indenyl, indanyl, naphthyl and tetrahydronaphthyl.
  • C 6 -CiO aryl-Ci-C 6 alkanoyl refers to a Ci-C 6 alkanoyl as defined above, which is attached to a C 6 -CiO aryl group as defined above.
  • Typical examples which should not be considered limiting, comprise benzoyl and phenylacetyl
  • Ci-C 6 -C 6 -CiO aryl refers to a Ci-C 6 group as defined above, which is attached to a C 6 -CiO aryl group as defined above.
  • Ci-C 6 alkylthio-Ci-C 6 alkyl refers to a Ci-C 6 alkylthio group as defined above, which is attached to a Ci-C 6 alkyl group as defined above. Examples of such groups include, but are not limited to, methylthiomethyl and ethylthiomethyl.
  • heteroaryl group refers to a mono- or polycyclic aromatic group which contains up to 10 ring atoms of which 1 to 4 are selected from N, O or S, and the remaining atoms are carbon, and wherein the ring atoms selected from N, O or S may be placed in one or more rings, and partially saturated variants thereof.
  • Typical examples comprise pyridyl, thienyl, furyl, indolyl, pyranyl, benzofuranyl, benzothienyl, quinoline, isoquinoline, naphthyridyl, dihydroquinolinyl, chromenyl, thiochromenyl, benzoquinolinyl and acridinyl.
  • Ci-C 6 alkyl-heteroaryl refers to a heteroaryl group as defined above, which is attached to a Ci-C 6 alkyl group as defined above.
  • the compounds of the present invention are all trans-fused morpholines, which contains at least two chiral centers (denoted with * below), while the compounds of the present invention with R 4 different from H also have a third chiral center (denoted with ⁇ below).
  • the compounds of Formula I have been found to behave as orally active Apomorphine, which renders them potentially useful in relation to treatment of Parkinson's disease and other diseases/disorders which responds favorably to an increased dopaminergic turnover.
  • the specific metabolic pathway differs with the substitution pattern, and is not yet completely understood.
  • X oxygen and Ri and R 2 are ester groups such as Ci-C 6 alkanoyl and C ⁇ -Cio-aryl-Ci-C ⁇ alkanoyl
  • the metabolism amounts to a hydrolysis of the ester groups.
  • X oxygen and Ri and R 2 are fused and form a methylene (CH 2 ) group
  • the conversion to the catecholamine occurs through an oxidation of the methylene group, presumably followed by a hydro lytic step.
  • a specific embodiment of the present invention relates to the use of a compound of Formula I or a pharmaceutically acceptable addition salt thereof for improving cognition in a mammal in a condition of cognitive impairment wherein the condition is associated with schizophrenia.
  • the condition is associated with Parkinson's Disease.
  • the condition is associated with dementia, such as AIDS dementia.
  • the condition is associated with an anxiety disorder.
  • the condition is associated with age associated memory impairment.
  • the condition is associated with depression, including major depression, in particular in elderly.
  • the condition is associated with the use of benzodiazepines.
  • the condition is associated with the use of tricyclic antidepressants.
  • the condition is associated with Alzheimer's Disease.
  • the condition is associated with attention deficit hyperactivity disorder (ADHD).
  • PTSD posttraumatic stress disorder
  • the present invention relates to the use of a compound of Formula I or a pharmaceutically acceptable addition salt thereof for the treatment of a mammal suffering from depression, such as major depression, bipolar disorder or anxiety.
  • the invention also relates to compounds of Formula I to be used as imaging ligands, in particular PET and SPECT ligands or as precursors therefore.
  • the desired radiolabel can be introduced by reacting precursors of PET or SPECT ligands with radio-labeled reactants, including n C-labelled reactants such as [ n C]methyl iodide, [ n C]methyl triflate, etc.
  • the compounds may also be labeled with 3 H, 18 F or 123 I.
  • radiolabeled compounds of Formula I wherein Ri and R 2 are both hydrogen are particularly preferred as radioligands.
  • the invention relates to a radiolabeled compound of Formula I wherein
  • X oxygen, Ri and R 2 are both hydrogen and R3 is 3-( 18 F)-fluoropropyl or 2-( 18 F)-fluoroethyl.
  • the invention relates to a radiolabeled compound of Formula I wherein X is a bond, Ri is hydrogen and R3 is chosen from 3-( 18 F)-fluoropropyl, 2-( 18 F)- fiuoroethyl, ( 11 CH 3 )-, ( 11 CH 3 CH 2 )- or ( 11 CH 3 CH 2 CH 2 )-.
  • R 4 is chosen from 3-( 18 F)-fluoropropyl, 2- ( 18 F)-fiuoroethyl, ( 11 CH 3 )-, ( 11 CH 3 CH 2 )- or ( 11 CH 3 CH 2 CH 2 )-.
  • trans-diastereomeric excess means that the ratio of the trans- to the c ⁇ -diastereoisomer is 55:45 in the mixture in question
  • the terminology "cis " and "trans” relates exclusively to the configuration of the two carbons (marked with an * below) joining the morpholine ring with the central ring of the compounds of Formula I:
  • trans-diastereoisomers of the present invention always have either (R,R) or (S, S) configuration, whereas the c ⁇ -diastereoisomers (which are not comprised by the present invention) have either (R, S) or (S, R) configuration.
  • Further embodiments relate to the free base of a compound of Formula I or a salt thereof, or a pharmaceutical composition thereof and to the uses as described herein, wherein the compound of Formula I has an enantiomeric excess of at least 10% (for example, 10% enantiomeric excess for a compound of Formula I having (4aR,10aR) configuration means that the ratio between the (4aR,10aR)- and (4aS,10aS)-enantiomers is 55:45 in the mixture in question), at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, preferably at least 98%.
  • 10% enantiomeric excess for a compound of Formula I having (4aR,10aR) configuration means that the ratio between the (4aR,10aR)- and (4aS,10aS)-enantiomers is 55:45 in the mixture in question
  • the present invention relates to compounds of Formula I wherein the catechol moiety is masked as a methylenedioxy (MDO) prodrug derivative, which may be metabolized in vivo to generate the free catecholamines:
  • MDO methylenedioxy
  • the present invention further comprises unsymmetrical di-ester derivatives of the compounds of Formula I, wherein Ri and R 2 are two different substituents.
  • the compound of Formula (I) when specifying the compound of Formula (I) to be substantially enantiomerically or diastereomerically pure, then the compound is relatively stereochemically pure.
  • the enantiomeric or diastereomeric excess is at least 60%, at least 70%, and more preferably at least 80% (80% enantiomeric excess means that the ratio of eg. (4aR,10aR) to (4aS,10aS) is 90:10 in the mixture in question), at least 90%, at least 96%, or preferably at least 98%.
  • Preparation of Markush 2A constitutes of the cleavage of the methoxy group of Markush IA.
  • One method of cleaving the methoxy group is by using L-selectride in THF at high temperature.
  • Another method involves treatment with thiophenol and KF in DMA at high temperature.
  • Scheme 2 depicts the preparation of the compounds of this invention, for which X is absent and R 4 is different from hydrogen.
  • the pure enantiomer compound 7A is produced from compound 2 in a similar manner as described for compound 6 A prepared from compound 5.
  • Compound 7 A can be converted to compound 8 A for example by cleavage of the BOC group with acid, followed by acylation with benzoylchloride and then LAH reduction of the intermediate amide.
  • Alkylation of compound 8 A with R-(-)-epichlorohydrin followed by boiling in dilute NaOH furnishes both compound 9A and compound 1OA, which can be separated by chromatography.
  • Markush 3A can be prepared from compound 9A [eg. by hydrogeno lysis of the benzyl group as described in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, Wiley Interscience, (1991) ISBN 0471623016].
  • Markush 3A is then prepared from the resulting compound HA as described for Markush IA above.
  • Markush 4A can be prepared from Markush 3 A for example by reaction with tosyl-chloride followed by displacement of the leaving group with a nucleophile. This nucleophile can e.g. be an alkoxide, an alkyl thiolate, or an amine.
  • Markush 5A can be prepared from Markush 4A using L-selectride as described for Markush 2A. or using thiophenol and KF in e.g. DMA at high temperatures.
  • Method 25 API 150EX and Shimadzu LCIOAD/SLC-IOA LC system. Column: dC-18
  • Method 101 API 150EX and Shimadzu LC8/SLC-10A LC system. Column: C-18 4.6x30mm,
  • Method 102 API 150EX and Shimadzu LC8/SLC-10A LC system. Column: dC-18 4.6x30mm,
  • Method 111 API 150EX and Shimadzu LC8/SLC-10A LC system. Column: C-18 4.6x30mm,
  • Method 350 API 300 and waters UPLC system.
  • chromatography refers to HPLC, "silica gel chromatography”, or to “chiral SFC”.
  • Preparative HPLC-purif ⁇ cation was performed on the same instrument with atmospheric pressure chemical ionisation.
  • Column 50 x 20 mm YMC ODS-A with 5- ⁇ m particle size.
  • Method linear gradient elution with 80% A to 100% B in 7 min and with a flow rate of 22.7 mL/min. Fraction collection was performed by split-flow MS detection.
  • sica gel chromatography (EtO Ac/heptane) has the following meaning:
  • the compound to be purified was usually dissolved in a small amount of DCM and loaded onto a column pre-packed with silica gel and eluted using a mixture of EtOAc and heptane, either in a isocratic fashion or with a gradient such as 0-100% of EtOAc in heptane.
  • a column loaded with silica gel used is "ISOLUTE SPE COLUMNS" [e.g. 2Og FLASH Si 70 mL from International sorbent technology].
  • classical manual chromatographic purifications were performed using silica gel [e.g.
  • Compounds were visualized by illumination using a UV lamp (254 nm) or by charring after dipping in a solution of ammonium molybdate (6.25 g) and cerium(IV)sulfate (2.5 g) in 10% aqueous sulphuric acid (250 mL).
  • Microwave-accelerated reactions were performed in sealed microwave reactor vials. The experiments were performed on a Smith Synthesizer from Personal Chemistry.
  • lyophilized refers to the freeze-drying of a material using a Christ Alpha 2-4 LSC instrument from WWR International.
  • dried (Na 2 SO 4 ) and “dried (Mg 2 SO 4 )” refers to the removal of water from organic layers by the addition of dry Na 2 SO 4 or Mg 2 SO 4 , respectively, followed by stirring for an appropriate amount of time to ensure an effective drying process. Then the solid is removed by filtration, and the filtrate is typically concentrated in vacuo (see below).
  • the term "concentrated in vacuo '" has the following meaning: The volatile components were removed from the mixture using a standard rotary evaporator at reduced pressure.
  • the term “dried in vacuo at 40 0 C” refers to the use of a standard vacuum oven heated to 40 0 C connected to an oil pump.
  • the term “dried in vacuo” refers to a drying process in which the material to be dried is placed in a flask connected directly to an oil pump for a sufficient period of time to remove volatile components.
  • X-ray crystal structure determinations were performed as follows.
  • the crystal of the compounds was cooled to 120 K using a Cryostream nitrogen gas cooler system.
  • the data were collected on a Siemens SMART Platform diffractometer with a CCD area sensitive detector.
  • the structures were solved by direct methods and refined by full-matrix least-squares against F 2 of all data.
  • the hydrogen atoms in the structures could be found in the electron density difference maps.
  • the Flack x-parameters are in the range 0.0(I)-0.05(1), indicating that the absolute structures are correct.
  • Programs used for data collection, data reduction and absorption were SMART, SAINT and SADABS [cf. "SMART and SAINT, Area Detector Control and Integration Software", Version 5.054,Bruker Analytical X-Ray Instruments Inc., Madison, USA (1998), Sheldrick "SADABS, Program for Empirical Correction of Area Detector Data” Version 2.03, University of G ⁇ ttingen, Germany (2001)].
  • SHELXTL [cf.
  • Intermediates HB and IHB were prepared from compound 7B in several steps, in a similar manner as described for the enantiomer 7A using S-(+)-epichlorohydrin. Intermediates HB and IHB were also prepared from compound 14B in a similar manner as described for the enantiomer 14A, using either S-(+)-epichlorohydrin or R-(-)-epichlorohydrin.
  • example 5b2 The procedure described for example 5al was followed starting from example 2b2 (102 mg) to give example 5b2. Yield: 60 mg as a white solid, mp dec>300 0 C; 1 H NMR data identical to the data reported for example 5bl.
  • Anal. Calcd for C I5 H 2I NO 2 -HCIO ⁇ H 2 O: C, 62.48; H, 7.88; N, 4.86. Found: C, 62.67; H, 7.78; N, 5.00. ⁇ D +111.4 (C 0.5, DMSO).
  • example 5al The procedure described for example 5al was followed starting from example 2cl (117 mg) to give example 5cl. Yield: 28 mg as a white solid, mp dec>280 0 C; LC/MS (method 25): RT 0.74 min, ELSD 99%, UV 96%. MH + : 246.2.
  • example 5al The procedure described for example 5al was followed starting from example 2dl (107 mg) to give example 5dl. Yield: 79 mg as a white solid, mp dec>280 0 C; LC/MS (method 25): RT 0.80 min, ELSD 99%, UV 98%. MH + : 260.2.
  • Example 5d2 The compound of Example 5d2 was subjected to X-ray analysis in order to determine the absolute configuration of the two stereocenters (cf. Figure 1).
  • Example 5i can be prepared from example 3c using the method described for the preparation of example 5g. 5j .
  • example 3d example 5j (2R, 4aR, 1 OaR) (2R, 4aR, 1OaR)
  • the procedure described for example 5g was followed starting from example 3d (2.3 mg) to give example 5j. Yield: 0.8 mg as a clear oil.
  • MH + 308.3.
  • Example 5j hydrochloride was subjected to X-ray analysis in order to determine the absolute configuration of the two stereocenters (cf. Figure 1).
  • Example 5m can be prepared from example 3f using the method described for the preparation of example 5g.
  • Example 5n can be prepared from example 3g using the method described for the preparation of example 5g.
  • Example 5o can be prepared from example 3h using the method described for the preparation of example 5g.
  • Example 6
  • Example 3jl (27 mg, 0.08 mmol) was dissolved in DMA (2.5 mL) and KF (9 mg, 0.16 mmol) and thiophenol (0.04 mL, 0.40 mmol) were added. The solution was heated to 210 0 C for Ih in a sealed microwave process vial. After cooling to rt, the crude product was purified by silicagel chromatography (Eluent 0-100% EtOAc in heptane, 0-10% MeOH in EtOAc), and then by HPLC. Yield: 7.5 mg of 6al as an oil.
  • LC/MS (method 350): RT 0.40 min, ELSD 99.9 %, UV 100 %. MH + : 328.0.
  • example 31 example 6c (2R, 4aR, 1 OaR) (2R, 4aR, 1OaR)
  • Example 31 (8 mg, 0.02 mmol) was dissolved in DMA (0.7 mL) and KF (2 mg, 0.04 mmol) and thiophenol (0.01 mL, 0.11 mmol) were added. The solution was heated to 220 0 C for Ih in a sealed microwave process vial. After cooling to rt, the solvent was evaporated off, and the residue was purified by silicagel chromatography and then by HPLC. Yield: 2.6 mg of example 6c as a white solid.
  • LC/MS (method 350): RT 0.48 min, ELSD 100 %, UV 100 %. MH + : 362.4.
  • Example 3n (60 mg, 0.14 mmol) was dissolved in DMA (0.7 mL) and KF (16 mg, 0.28 mmol) and thiophenol (0.07 mL, 0.70 mmol) were added. The solution was heated to 220 0 C for Ih in a sealed microwave process vial. After cooling to rt, the solvent was evaporated off, and the residue was purified by chromatography (Eluent: 0-100% EtOAc in heptane), and then by HPLC. Yield: 15.6mg of example 6e as oil.
  • LC/MS (method 350): RT 0.57 min, ELSD 99.5 %, UV 85.6 %. MH + : 404.3.
  • Example 8 6aR, 1 OaR)- 7-Methyl-6a, 7, 8, 9, 1 Oa, ll-hexahydw-6H-l, 3, 10-t ⁇ oxa- 7-aza-cyclopenta[a] anthracene trifluoroacetate
  • ClAcCl chloroacethyl chloride (e.g. Aldrich 10,449-3).
  • CS 2 CO 3 cesium carbonate (Aldrich 441902).
  • DA dopamine.
  • Dl dopamine Dl receptor.
  • D2 dopamine D2 receptor.
  • D3 dopamine D3 receptor.
  • D4 dopamine D4 receptor.
  • D5 dopamine D5 receptor.
  • DCM dichloromethane / methylene chloride.
  • DMF dimethyl formamide.
  • DMSO dimethyl sulfoxide.
  • L-DOPA (levo)-3,4- dihydroxy phenylalanine.
  • EC50 concentration required to induce a response halfway between the baseline and the maximum response for the compound in question.
  • ELSD evaporative light scattering detection.
  • EtsN triethyl amine.
  • Et 2 NH diethyl amine.
  • EtOAc ethyl acetate.
  • EtOH absolute ethanol.
  • Ethyl magnesium bromide used as a 3M solution in Et 2 O; e.g. Aldrich 18,987-1).
  • Et 2 O diethyl ether. [(l-Ethoxy-cyc/o-propyl)-oxy]trimethylsilane (Aldrich 332739).
  • H 2 O 2 35% aqueous solution of hydrogen peroxide (e.g. Aldrich 34,988-7).
  • HCl aqueous solution of hydrogen chloride (unless noted specifically as a Et 2 O solution, which is commercially available, e.g. Aldrich 45,518-0).
  • HMPA hexamethylphosphorous triamide.
  • 1-Iodopropane e.g. Aldrich 17,188-3).
  • K2CO3 potassium carbonate (e.g.
  • KMnO 4 potassium permanganate (e.g. Aldrich 39,912-4).
  • KO knock-out.
  • LC/MS high-performance liquid chromatography / mass spectrometer.
  • LAH lithium aluminium hydride (used as a IM THF solution; e.g. Aldrich 21,277-6).
  • L-Selectride lithium tri-s-butylborohydride (used as a IM THF solution; Aldrich 17,849-7).
  • MDO methylene-di-oxy.
  • MED minimal effective dose.
  • MEDNemonap ⁇ de minimal effective dose in the presence of Nemonapride.
  • MeOH methanol.
  • Methoxyacetyl chloride e.g.
  • NaCNBH 3 sodium cyanoborohydride (e.g. Aldrich 15,615-9).
  • NaH sodium hydride (used as a 60% dispersion; e.g. Aldrich 45,291-2).
  • 1 M / 9 M NaOH 1 M / 9 M aqueous solution of sodium hydroxide.
  • NaOMe sodium methoxide (used as a ca. 5 M solution in methanol; e.g. Aldrich 15,625-6).
  • 6-OHDA 6-hydroxydopamine.
  • PBS phosphate buffered saline (0.02 M sodium phosphate buffer with 0.15 M sodium chloride, pH adjusted to 7.4).
  • PD Parkinson's disease.
  • PFC prefrontal cortex.
  • Pd/C palladium-on-charcoal (e.g. Aldrich 20,569-9).
  • PK pharmacokinetic.
  • PLMD periodic limb movement disorder. Propionaldehyde (e.g. Aldrich 58,812-4).
  • RT retention time.
  • sat. NaHCO 3 saturated aqueous solution of sodium hydrogen carbonate
  • sat. NH 4 Cl saturated aqueous solution of ammonium chloride.
  • SC subcutaneous.
  • SFC supercritical flash chromatography.
  • tert tertiary.
  • TBAI tetra-n-butyl ammonium iodide (e.g. Aldrich 14,077-5).
  • TFA trifluoroacetic acid.
  • THF tetrahydrofuran (dried over 4 A molecular sieves).
  • UV ultraviolet purity (at 254 nm unless noted differently).
  • the ability of the compounds to either stimulate or inhibit the Dl receptor mediated cAMP formation in CHO cells stably expressing the human recombinant Dl receptor was measured as follows. Cells were seeded in 96-well plates at a concentration of 11000 cells/well 3 days prior to the experiment.
  • the ability of the compounds to either stimulate or inhibit the D2 receptor mediated inhibition of cAMP formation in CHO cells transfected with the human D2 receptor was measure as follows. Cells were seeded in 96 well plates at a concentration of 8000 cells/well 3 days prior to the experiment. On the day of the experiment the cells were washed once in preheated G buffer (1 mM MgCl 2 , 0.9 mM CaCl 2 , 1 mM IBMX in PBS) and the assay was initiated by addition of 100 micro-1 of a mixture of 1 micro-M quinpirole, 10 microM forskolin and test compound in G buffer (antagonism) or 10 micro-M forskolin and test compound in G buffer (agonism).
  • the cells were incubated 20 minutes at 37 °C and the reaction was stopped by the addition of 100 micro-1 S buffer (0.1 M HCl and 0.1 mM CaCl 2 ) and the plates were placed at 4 °C for Ih. 68 micro-L N buffer (0.15 M NaOH and 60 mM Sodium acetate) were added and the plates were shaken for 10 minutes.
  • 100 micro-1 S buffer 0.1 M HCl and 0.1 mM CaCl 2
  • 68 micro-L N buffer (0.15 M NaOH and 60 mM Sodium acetate
  • 60 micro-L of the reaction were transferred to cAMP FlashPlates (DuPont NEN) containing 40 micro-L 60 mM NaOAc pH 6.2 and 100 micro-L IC mix (50 mM NaOAc pH 6.2, 0.1 % Sodium azide, 12 mM CaCl 2 , 1% BSA and 0.15 micro-Ci/ml 125 I-cAMP) were added. Following an 18h incubation at 4 °C the plates were washed once and counted in a Wallac TriLux counter.
  • Dopamine agonists can have activity at either the Dl -like receptors, the D2-like receptors, or both.
  • Human D5 (hD5) expression construct was made using a modified pEXJ vector.
  • a stable cell line expressing a promiscuous human Galphal ⁇ G protein (CHO-GaI 6) was purchased from (Molecular Devices, Sunnyvale, CA). The cells were cultured in HAMS F-12 media (Invitrogen, Carlsbad, CA) containing 10% FSB, 1% L-glutamine and 1% penicillin/streptomycin (P/S) at 37 °C in 5% CO 2 . 48h before assay, CHO-GaI 6 cells were transiently transfected with hD5 receptor DNA using a lipofectamine Plus method (Invitrogen, Carlsbad, CA), and allow to grow for 1 day in serum and P/S free media.
  • HAMS F-12 media Invitrogen, Carlsbad, CA
  • P/S penicillin/streptomycin
  • hD5 transfected CHO-Ga 16 cells were seeded at a density of 10,000 cells per well into black walled clear-base 384-well plates pretreated with poly-D-Lysine (Becton Dickinson, USA). The cells were then cultured in HAMS F-12 cell growth media containing 1.5% FBS, 1% L-glutamine and 1% penicillin/streptomycin (P/S) at 37 °C in 5% CO 2 .
  • HAMS F-12 cell growth media containing 1.5% FBS, 1% L-glutamine and 1% penicillin/streptomycin (P/S) at 37 °C in 5% CO 2 .
  • Cryopreserved pooled male rat hepatocytes (Sprague Dawley) and pooled human hepatocytes from 10 donors (male and female) were purchased from In Vitro Technologies Inc., BA, USA. Cells were thawed at 37 0 C in a water bath, live cells counted and seeded in a total of 100 micro- L in Dulbecco's modified Eagle medium (high glucose) with 5 mM Hepes buffer in 96 well plates, each well containing 250.000 and 500.000 cells/mL for rat and human hepatocytes, respectively.
  • Dulbecco's modified Eagle medium high glucose
  • Incubations were started after 15 min of pre-incubation and stopped at time points of 0, 5, 15, 30 and 60 min for rats and at 0, 30, 60, 90 and 120 min for human hepatocytes. Incubations were stopped by addition of an equal volumes of ice-cold acetonitrile containing 10% 1 M HCl. Following centrifugation, 20 micro-L of the supernatants were injected on a HPLC Column Atlantis dC18 3 micro-m, 150 x 2.1 mm i.d. (Waters, MA, USA). The mobile phase had the following composition: A: 5% acetonitrile, 95% H 2 O, 3.7 ml/1 25% aq. NH 3 , 1.8 mL/L formic acid.
  • Mobile phase B 100% acetonitrile and 0.1% formic acid.
  • the flow rate was 0.3 ml/min.
  • the gradient operated from 0% to 75 % B from 5 min to 20 min and the eluate was analyzed using a Q-TOFmicro mass spectrometer (Waters, MA, USA). Formation of the product/metabolite was confirmed by accurate mass measurements and comparison with a synthesized standard giving coinciding retention times.
  • the EC50 values for most the compounds in the present invention, exemplified above, at either the human Dl and D2 receptor was determined to be about 5.0 ⁇ M or less.
  • the binding affinities for many of the compounds were determined to be about 1.0 ⁇ M or less.
  • the binding affinities for several compounds were determined to be about 500 nM or less.
  • the binding affinities for several compounds were determined to be 100 nM or less.

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Abstract

Cette invention concerne de nouvelles amines phénoliques et catécholiques de formule I, des procédés permettant de les préparer, des compositions pharmaceutiques les contenant, leur utilisation en traitement et leur utilisation en marqueurs radioactifs sous forme de ligands de PET ou SPECT.
PCT/EP2009/057928 2008-06-27 2009-06-24 Nouvelles amines phénoliques et catécholiques et leurs promédicaments Ceased WO2009156458A1 (fr)

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US12226428B2 (en) 2017-11-24 2025-02-18 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's disease
US12319710B2 (en) 2019-05-21 2025-06-03 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's diseases
US12384765B2 (en) 2019-05-21 2025-08-12 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's Disease
US12391650B2 (en) 2019-05-21 2025-08-19 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's disease
US12398106B2 (en) 2019-05-21 2025-08-26 H. Lundbeck A/S Catecholamine carbamate prodrugs for use in the treatment of parkinson's disease
US12398169B2 (en) 2019-05-20 2025-08-26 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
US12421271B2 (en) 2019-05-20 2025-09-23 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
US12479801B2 (en) * 2019-05-20 2025-11-25 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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Cited By (8)

* Cited by examiner, † Cited by third party
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US12226428B2 (en) 2017-11-24 2025-02-18 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's disease
US12398169B2 (en) 2019-05-20 2025-08-26 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
US12421271B2 (en) 2019-05-20 2025-09-23 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
US12479801B2 (en) * 2019-05-20 2025-11-25 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
US12319710B2 (en) 2019-05-21 2025-06-03 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's diseases
US12384765B2 (en) 2019-05-21 2025-08-12 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's Disease
US12391650B2 (en) 2019-05-21 2025-08-19 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's disease
US12398106B2 (en) 2019-05-21 2025-08-26 H. Lundbeck A/S Catecholamine carbamate prodrugs for use in the treatment of parkinson's disease

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CN102131790A (zh) 2011-07-20
EP2303851A1 (fr) 2011-04-06

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