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  • 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
  • C07D221/06—Ring systems of three rings
  • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
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  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
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  • 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
• • 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
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
  • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
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  • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
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  • C07—ORGANIC CHEMISTRY
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
  • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • 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
  • C07D221/06—Ring systems of three rings
  • C07D221/08—Aza-anthracenes
• • 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
  • C07D221/06—Ring systems of three rings
  • C07D221/10—Aza-phenanthrenes
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
  • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

• the present invention relates to new chemical compounds representing a new prodrug principle for the generation of catecholamines, in particular catecholethylamines, to processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
• Parkinson's disease is a disorder of the brain which is characterized by tremor and difficulty with walking, movement, and coordination.
• Parkinson's disease appears to be caused by a progressive deterioration of dopamine-containing neurons in the sub- stantia nigra zona compacta of the brain.
• Dopamine is a chemical neurotransmitter which is utilized by brain cells to transmit impulses to control or modulate peripheral mus- cle movement.
• the loss of the dopamine-containing neurons results in reduced amounts of dopamine available to the body. Insufficient dopamine is thought to disturb the balance between dopamine and other neurotransmitters such as acetylcholine .
• nerve cells cannot properly transmit impulses, resulting in a loss of muscle control and function.
• Parkinson's disease Treatments are typically aimed at controlling the symptoms of Parkinson's disease, primarily by replacing the dopamine, with either L-DOPA which is metabolized to dopamine, or by administering chemical agents that stimulate dopamine receptors.
• Current treatments to slow the progression of the disease include compounds such as deprenyl (Selegeline) , a selective monoamine oxidase inhibitor, and amantadine, a compound that appears to decrease dopamine uptake into pre- synaptic neurons.
• hydroxylated (mono-phenolic or catechols) phenyl- ethylamines are known to have useful dopaminergic activity. However, their clinical use is limited because they have low or no bioavailability (high first-pass effect) .
• the active drug may be ( ⁇ ) -5-OH-DPAT (see Formula B below) . Consequently, the compound of Formula II, falling within the generally claimed structure of Formula I, is provisoed from the present invention.
• the preferential dopamine autoreceptor antagonists (+) -AJ76 and (+) -UH232 possessed the highest preference for the D3 site.
• the D3 receptor appears to occur both pre- and postsynaptically, and the regional distribution (high preference in limbic brain areas) differs from that of the Dl and D2 receptors .
• Drugs acting as agonists or antagonists on central DA transmission are clinically effective in treating a variety of central nervous system disorders such as parkinsonism, schizophrenia, Huntington's disease and other cognitive dysfunctions .
• the nigro-neostriatal hypo- function can be restored by an increase in postsynaptic DA receptor stimulation (see above) ) .
• the condition can be normalized by achieving a decrease in postsynaptic DA receptor stimulation.
• Classical antipsy- chotic agents directly block the postsynaptic DA receptor. The same effect can be achieved by inhibition of intraneu- ronal presynaptic events essential for the maintenance of adequate neurotransmission, transport mechanism and trans- mitter synthesis.
• Direct DA receptor agonists like apomorphine (a mixed DA D1/D2 agonist) are able to activate the DA autoreceptors as well as the postsynaptic DA receptors.
• the effects of autoreceptor stimulation appear to predominate when 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 anti- psychotic and antidyskinetic effects in man of low doses of apomorphine are likely due to the autoreceptor-stimulator properties of this DA receptor agonist. This body of knowledge indicates DA receptor stimulants with a high selectiv- ity for central nervous DA autoreceptors would be valuable in treating psychiatric disorders.
• geriatrics for preventing bradykinesia and depression and in the improvement of mental functions (e.g. cognition) . It can have an effect in depressed patients. It can be used in obesitas as an anorectic agent. It can improve minimal brain dysfunction (MBD) , narcolepsy and negative symptoms of schizophrenia and, in addition, impotence, erectile dysfunction and restless legs. Thus, improvement of sexual functions is another indication (in both women and men) . Disclosure of the invention
• rings B, C, D and E may be present or not and, when present, are combined with A as A+C, A+E, A+B+C, A+B+D, A+B+E, A+C+E, A+B+C+D or A+B+C+D+E, rings B, C and E being aliphatic whereas ring D may be aliphatic or aromatic/hetero- aromatic, and wherein X is -(CH 2 ) m -, in which m is an integer 1-3, to form a ring E or, when E is absent, a group Ri bound to the nitrogen atom, wherein Ri is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 3 carbon atoms, cycloalkyl (alkyl) groups of 3 to 5 carbon atoms (i.e.
• R 2 is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms, cycloalkyl (alkyl) groups of 3 to 7 carbon atoms, alkenyl or alkylnyl groups of 3 to 6 carbon atoms, arylalkyl, heteroarylalkyl having 1 to 3 carbon atoms in the alkyl moiety, whilst the aryl/heteroaryl nucleus may be substituted, pro- vided that when rings B, C, D and E are absent NR X R 2 is different from dimethylamino, N-methyl-N-e
• R l t R 2 , m and n are defined as above.
• rings A to E are A+B+C (formula Ie) , A+B+C+D (formula Ig) , A+B+E (formula If) , A+E (formula lb) and A+C+E (formula Id) , the most preferred combination being that of A+B+C (formula Ie) .
• Ri and R 2 is n-propyl .
• compounds of this invention contain one or several chiral centers.
• the compounds of Formula I contain asymmetric carbon atoms in the alphatic ring moieties.
• the scope of this invention includes all (theoretically possible) R/S-combinations of the compounds of Formula I in their pure form.
• the flatter a molecule of Formula I is the more potent it is as a dopaminergic agonist, provided it has a suitable n-alkyl substituent.
• Flat molecules of Formula I are those which have trans- fused ring systems.
• R lf R 2 , m and n are defined as above
• the prodrugs according to the present invention display useful therepeutic effects for the treatment of diseases like (in the central nervous systen (CNS) ) : Parkinson's disease, psychoses (e.g. schizophrenia), Huntington's disease, impotence; (in the periphery) : renal failure, heart failure and hypertension.
• diseases like (in the central nervous systen (CNS) ) : Parkinson's disease, psychoses (e.g. schizophrenia), Huntington's disease, impotence; (in the periphery) : renal failure, heart failure and hypertension.
• Other fields of therapeutically active catecholamines are adrenergic, anti-adrenergic compounds .
• Some of the compounds according to the invention have both pre- and postsynaptic antagonistic effects. Compounds possessing more of the postsynaptic effects can be used to alleviate the symptoms (both positive and negative) of schizophrenia and for the rehabilitation of drug addicts. Other disturbances of interest in this context is "jet lag", sleep disorders and early stages of Parkinsonism. Another indication for the compounds of this invention are diseases with a disturbed cognition, e.g. Huntington's disease and Alzheimer's disease.
• RLS restless legs syndrome
• erectile dysfunction impotence in men
• sexual stimulation e.g. menopausal women
• erectile dysfunction impotence in men
• sexual stimulation e.g. menopausal women
• striatal tissue concentration of compounds of the present invention can also be used to treat psychoses (e.g. schizo- phrenia; see above) .
• the compounds of Formula I may be converted to their respective "built-in” 3 , 4-di-OH-phenylethylamines, (Formula II), in vivo in the CNS and/or the periphery.
• Compounds of formula II may also possess properties of catechol-O ⁇ methyl-transferase (COMT) inhibition, an effect which may synergistically augment the dopaminergic effects of the catechols generated.
• CCT catechol-O ⁇ methyl-transferase
• the compounds of the present invention can be administered to a patient either alone or as a part of a pharmaceutical composition.
• patient means all animals includ- ing humans. Examples of patients include humans, rodents, and monkeys .
• a pharmaceutical composition which as the active principle contains a compound of formula I as de- fined above, however with no disclaimer in the meaning of NR X R 2 when rings B, C, D and E are absent, or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, diluent, or excipient.
• compositions of the present invention can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutane- ously) , intracisternally, intravaginally, intraperito- neally, intravesically, locally (powders, ointments, or drops) , or as a buccal or nasal spray.
• a preferred route of administration is oral, although par- enteral and transdermal administration are also contem- plated.
• Controlled release formulations particularly in the form of skin patches and the like, are particularly well- suited treating elderly patients.
• compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• suitable aqueous and nonaqueous carriers, diluents solvents or vehicles include water, etha- nol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable (such as olive oil, sesame oil and viscoleo) and injectable organic esters such as ethyl oleate .
• Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the surfactants.
• compositions may also contain adjuvants such as preserving, emulsifying, and dispensing agents.
• adjuvants such as preserving, emulsifying, and dispensing agents.
• Prevention of the action of microorganisms be controlled by addition of any of various antibacterial and antifungal agents, example, parabens, chlorobutanol , phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, ) ) ) ) »— *
• the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.01 to about 1,000 mg per day.
• a dosage in the range of about 0.001 to about 100 mg per kilogram of body weight per day is preferable.
• the specific dosage used can vary.
• the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacol- ogical activity of the compound being used. The determination of optimum dosages for a particular patient is well- known to those skilled in the art.
• the compounds of Formula I, utilized in the method of the present invention are ideally suited for several reasons. Firstly, the compounds are stable, making them excellent candidates for oral administration. Secondly, the compounds are long acting, thereby enabling effective treatment with fewer dosing intervals, which is of significant importance for elderly patients. Thirdly, the compounds of the present invention have excellent oral bioavailabilities .
• the present invention provides the compounds of formula (I) as defined above, how- ever with no disclaimer in the meaning of NR X R when rings B, C, D and E are absent, and the pharmaceutically acceptable salts thereof, for therapeutical use.
• the present invention comprises the use of the compounds of formula (I) as defined above, however with no disclaimer in the meaning of NR ⁇ R 2 when rings B, C, D and E are absent, and the pharmaceutically acceptable salts thereof for the manufacturing of pharmaceutical compositions for the treatment of Parkinson's disease, psychoses, Huntington's disease, impotence, renal failure, heart failure or hypertension.
• the lower scheme represents a Birch reduction.
• Example 2 The same procedure was used as in Example 1 but using di- ethylamine. Destination at 120°C, 0.01 mmHg afforded a colorless oil that was converted to the hydrochloride salt. Recrystallization from isopropyl ether/isopropyl alcohol yielded: 1.3 g, 5.6 mmol (91%), mp 148-149 °C.
• Example 2 The same procedure was used as in Example 1 but using dibutyl- amine. Purification by column chromatography (silica, ethyl acetate) yielded a colorless oil that was converted to the hydrochloride salt. Recrystallisation from isopropyl ether/isopropyl alco- hoi gave 1.3 g, 5.6 mmol (91%), mp 115-117°C. IR (KBr) 2959,
• Example 2 The same procedure was used as in Example 1 but using N- propyl-2-phenylethylamine . Purification by column chromatography (silica, ethyl acetate) yielded a colorless oil that was converted to the hydrochloride salt. Recrystallisation from ether/ethanol gave 1.8 g, 5.6 mmol (91%), mp 110-112°C.
• Reagents (a) H 2 , Pd/C; (b) SOCl 2 , RNH 2 ; (c) LiAlH 4 ; (d) Li, NH 3 ; (e) Et0 2 C (CH 2 ) 3 P (Ph) 3 Br, K'OBu; (f) PPA.
• N- (3- (4-methoxyphenyl) -propyl) -N-propyl amine (6.15 g, 31.45 mmol) (from b) above) was dissolved in THF (60 mL) , t-BuOH (4.65 g, 5.93 mL, 62.89 mmol). The mixture was cooled to -60°C and liquid NH 3 (60 mL) was introduced. Then Li metal (1.70 g, 0.24 mol) was gradually added in small portions and the blue mixture was stirred at -60°C for 4h. The color was discharged by addition of a MeOH/aqueous NH 4 C1 (sat) solution (1:1, 20 mL) and the cooling bath removed.
• Cis isomer Yield 0.07 g, 0.3 mmol (6%).
• Example 7 1-Propyl- trans-2 , 3 , 4 , 4a, 5 , 7 , 8 , 9, 10 , 10a- decahydrobenzo [g] quinolin-6-one (GMC6650) and 1-Propyl-cis- 2, 3, 4, 4a, 5, 7, 8, 9, 10, lOa-decahydrobenzo [g] quinolin-6-one (GMC6651)
• GMC6650 -Maleate mp 186°C
• (-) -GMC6650 -Maleate mp 192°C.
• Reagents (a) Chloropropyl-alkylamine; (b) NaBH 3 CN ) > t t o O ⁇ y ⁇ o
• 3-Aminophenylacetic acid ethyl ester hydrochloride (2.7 g, 13 mmol) was added to n-propylamine (20 mL) while stirring and cooling to 0°C. After stirring for 45 min the reaction mixture was evaporated to give a colorless solid of the amide product.
• the amide was dissolved in tetrahydrofuran (20 mL) and 2N BH 3 • SMe 2 in tetrahydrofuran (20 mL) was added at -10 °C. After stirring at that temperature for 2h the mixture was refluxed for 48h. The mixture was extracted to give the amine which was converted to the hydrochloride salt.
• both individuals displayed the same pattern of biological activity: after 10 minutes the rats became sedated, closing or partly closing their eyes. After 15 min- utes obvious dopaminergic effects were seen, i.e. chewing, sniffing, licking, penile grooming, grooming, and after 30 minutes both rats showed clear signs of stereotypy.
• Stereotypy was intense and was registered for several hours by visual inspection. After 10 hours both rats were still showing signs of stereotypy. The next morning, the SC rat was still active, while the PO rat was resting. Duration of action was thus ⁇ 10 h for both sc and po administration of 1 ⁇ mol/kg.

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  • 2001-04-17 AU AU2001248982A patent/AU2001248982B2/en not_active Ceased
  • 2001-04-17 PL PL365113A patent/PL204661B1/pl unknown
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