WO2001036428A1 - Composes heterocycliques silyles - Google Patents

Composes heterocycliques silyles Download PDF

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Publication number
WO2001036428A1
WO2001036428A1 PCT/EP2000/011203 EP0011203W WO0136428A1 WO 2001036428 A1 WO2001036428 A1 WO 2001036428A1 EP 0011203 W EP0011203 W EP 0011203W WO 0136428 A1 WO0136428 A1 WO 0136428A1
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WO
WIPO (PCT)
Prior art keywords
compound
acid addition
free base
addition salt
salt form
Prior art date
Application number
PCT/EP2000/011203
Other languages
German (de)
English (en)
Inventor
Joachim Nozulak
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Novartis Ag
Priority to AU23563/01A priority Critical patent/AU2356301A/en
Publication of WO2001036428A1 publication Critical patent/WO2001036428A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to novel silylated heterocyclic compounds, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • X is CH 2 or O
  • Ri is hydrogen, (C 1- )alkyl, (C 3- 5)alkenyl in which the double bond is not adjacent to the nitrogen atom, or benzyl
  • R 2 is hydroxy or (C ⁇ - ) alkoxy
  • R 3 , R 4 and R5, independently, are (C ⁇ - ) alkyl, in free base or acid addition salt form.
  • the above-defined alkyl and alkoxy groups preferably represent methyl and methoxy.
  • X is preferably CH 2 .
  • the invention includes the enantiomers as well as their mixtures, e.g. the diastereo- meric or racemic mixtures which may be present on account of the asymmetrical carbon atoms e.g. in positions 4a and 10a. In said positions the configuration is preferably trans.
  • the invention provides a process for the production of the compounds of formula I and their acid addition salts, whereby in a compound of formula II
  • X, Ri and R 2 are as defined above and R 6 is chlorine, bromine or iodine, the halogen is substituted by a trialkylsilyl group and the compounds of formula I thus obtained are recovered in free base or acid addition salt form.
  • substitution of the halogen by a trialkylsilyl group may be effected using conventional procedures, for example by halogen-metal exchange using n-butyl- lithium, and subsequent reaction with a corresponding trialkyl-halogen-silane, in an aprotic solvent such as tetrahydrofurane.
  • Acid addition salts may be produced from the free bases in known manner, and vice versa. Suitable acid addition salts include the hydrochlorides, the hydrobromines, the hydrogen maleinates and the hydrogen fumarates.
  • the starting compounds of formula II wherein X is CH 2 may be produced from compounds of formula IX according to the following reaction scheme, e.g. as described in steps a) to g) of Example 1.
  • Separation of the isomers from the racemic mixture can be effected according to known methods, for example on the level of the compounds of formula HI, e.g. as described in step f) of the Example.
  • agents of the invention exhibit interesting pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.
  • the agents of the invention behave as partial agonists at the oCi A - adrenoceptor subtype with pECso values from about 5.0 to about 9.0.
  • the agents of the invention on administration of about 1 to about 100 mg/kg p.o. prolong the wakefulness phases and reduce the REM sleep, which is indicative of attention increasing and antidepressive activity.
  • mice Triangle 21, 95-105(1982); Dixon A.K. et al., J.Clin. Psychiatry 55(9), Suppl. B, 4-7(1994)]
  • the agents of the invention at doses of about 0.01 to about 1 mg/kg increase non-social behaviour and social investigation and decrease defensive ambivalence, indicative of attention/vigilance increasing activity, suggesting an antidepressant and anxiolytic profile.
  • MCA middle cerebral artery
  • the agents of the invention are useful in the treatment of depression and related disorders including major depression, bipolar depression/ disorders, manic depression, mania, premenstrual depressive disorders, post-partum depression, post-menopausal depression; anxiety and related disorders including general anxiety disorders, sleep disorders, obsessive compulsive disorders, extreme shyness, social phobia/anxiety, simple phobia, stuttering, agoraphobia, bulimia, eating disorders, obesity, anorexia nervosa, panic disorders, suicidal attempts / ideation; stress and stress-induced disorders including post-traumatic stress disorders, hemorrhagic stress, stress-induced urinary incontinence, stress-induced psychotic episodes; furthermore stroke, post-stroke recovery and head trauma, alcohol abuse/dependency/ withdrawal, drug withdrawal, e.g. nicotine withdrawal, schizophrenia, negative symptoms of schizophrenia, attention deficit hyperactivity disorders (ADHD), sexual dysfunctions, cognitive disorders, memory deficit, senile dementia, Alzheimer's disease, narcole
  • ADHD attention deficit
  • the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.01 to about 100, preferably from about 0.1 to about 50 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from 1 to about 500, preferably from about 1 to about 100 mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • the agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
  • enterally preferably orally
  • parenterally for example in the form of injectable solutions or suspensions.
  • the preferred compound is (-)-(4aR,10aR)- 1 ,2,3,4 ,4a,5, 10, 10a-octahydro-9-methoxy-N-methyl-6-trimethylsilyl-benzo[g] quinoline.
  • Said compound has a pECso and intrinsic activity of 5.8 ⁇ 0.2 / 37 ⁇ 2% in the isolated rat vas deferens contraction model, a pECso of 5.97 ⁇ 0.20 / 107 ⁇ 17% in the assay for the 5-HT 1A receptor (calf hippocampus), a pECso of 6.37 ⁇ 0.17 / 97 ⁇ 4% in the assay for the 5-HT 1A receptor (human rec.
  • HeLa cells HeLa cells
  • a pECso of 6.75 ⁇ 0.14 / 70 ⁇ 7% in the assay for the 5-HT IB and 5-HT ID receptors (calf substantia nigra)
  • a pK ⁇ of 7.14 ⁇ 0.14 in the assay for the 5-HT 2A receptor isolated rat aorta
  • a pK ⁇ of 7.03 ⁇ 0.09 in the assay for the 5-HT 2C receptor pig choroid plexus.
  • the sleep/wakefulness cycle at 1 and 3 mg/kg p.o., it induces a long lasting increase of quiet wakefulness and a reduction in REM sleep, the classical sleep phase being mainly unchanged.
  • the intruder test at 0.03, 0.1 and 0.3 mg/kg p.o., it induces a significant increase in non-social behavior and in social investigation, as well as a significant reduction in defensive behavior, which is an index of social withdrawal.
  • the preferred indications are depression and ADHD.
  • the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of depression and ADHD.
  • the present invention furthermore provides a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent.
  • Such compositions may be manufactured in conventional manner.
  • Unit dosage forms contain, for example, from about 0.25 to about 250, preferably from about 0.25 to about 50 mg of a compound according to the invention.
  • the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above.
  • the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
  • the starting material may be prepared as follows:
  • a solution of 55 g (0.31 mols) of 8-methoxy-2-tetralone in 100 ml of dimethylformamide is added dropwise to this mixture.
  • the reaction solution is then heated under argon for 4 hours to an internal temperature of 133° and subsequently worked up.
  • the reaction mixture is divided in two and each half is added dropwise to 1.5 litres of 10% hydrochloric acid (ca. -10°). Each portion is then stirred for 30 minutes at -10°.
  • the precipitated 3- carboxy-8-methoxy-2-tetralone is filtered off and washed with one litre of ice water.
  • the starting material is prepared as follows:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé correspondant à la formule (I) dans laquelle X et R1 à R5 sont définis dans le descriptif, ainsi que sa préparation. Les composés correspondant à la formule (I) sont utiles comme agents pharmaceutiques.
PCT/EP2000/011203 1999-11-15 2000-11-13 Composes heterocycliques silyles WO2001036428A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU23563/01A AU2356301A (en) 1999-11-15 2000-11-13 Silylated heterocyclic compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19954847.1 1999-11-15
DE19954847 1999-11-15

Publications (1)

Publication Number Publication Date
WO2001036428A1 true WO2001036428A1 (fr) 2001-05-25

Family

ID=7929072

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/011203 WO2001036428A1 (fr) 1999-11-15 2000-11-13 Composes heterocycliques silyles

Country Status (6)

Country Link
AR (1) AR026451A1 (fr)
AU (1) AU2356301A (fr)
CO (1) CO5261532A1 (fr)
EC (1) ECSP003761A (fr)
PE (1) PE20011023A1 (fr)
WO (1) WO2001036428A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US11110110B2 (en) 2017-11-24 2021-09-07 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's disease
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
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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2689892A1 (fr) * 1992-04-09 1993-10-15 Rhone Poulenc Rorer Sa Dérivés de diphényl-1,1 silacyclopentane, leur préparation et les médicaments les contenant.
WO1999030694A2 (fr) * 1997-12-15 1999-06-24 Noven Pharmaceuticals, Inc. Compositions et procedes de traitement du trouble deficitaire de l'attention et de l'hyperactivite avec deficit de l'attention au moyen du methylphenidate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2689892A1 (fr) * 1992-04-09 1993-10-15 Rhone Poulenc Rorer Sa Dérivés de diphényl-1,1 silacyclopentane, leur préparation et les médicaments les contenant.
WO1999030694A2 (fr) * 1997-12-15 1999-06-24 Noven Pharmaceuticals, Inc. Compositions et procedes de traitement du trouble deficitaire de l'attention et de l'hyperactivite avec deficit de l'attention au moyen du methylphenidate

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11110110B2 (en) 2017-11-24 2021-09-07 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of Parkinson's disease
US11707476B2 (en) 2017-11-24 2023-07-25 H. Lundbeck A/S Catecholamine prodrugs for use in the treatment of parkinson's disease
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
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
US20220185839A1 (en) 2019-05-20 2022-06-16 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
US11827665B2 (en) 2019-05-20 2023-11-28 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
US11851456B2 (en) 2019-05-20 2023-12-26 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
US11858954B2 (en) 2019-05-20 2024-01-02 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
US11866410B2 (en) 2019-05-20 2024-01-09 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

Also Published As

Publication number Publication date
AU2356301A (en) 2001-05-30
ECSP003761A (es) 2002-06-26
AR026451A1 (es) 2003-02-12
CO5261532A1 (es) 2003-03-31
PE20011023A1 (es) 2001-09-27

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