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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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  • 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
  • A61P25/06—Antimigraine agents
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/22—Anxiolytics
• • 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
• • 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
  • A61P25/28—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
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to novel therapeutic agents which have affinity for 5-HT 1A and/or C and/or D 2 receptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behaviour, panic attacks, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, migraine, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, prostatic hypertrophy, drug-induced extrapyramidal symptoms and spasticity.
• central nervous system disorders for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug
• A is methylene or -O-; B is methylene or -O-; and g is 0, 1 , 2, 3 or 4;
• R-i represents, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, hydroxy, acyloxy, hydroxymethyl, cyano, aikanoyl, alkoxycarbonyi, optionally ⁇ /-substituted carbamoyl, carbamoylmethyl, sulphamoyl or sulphamoylmethyl, an amino group optionally substituted by one or two alkyl groups, or two adjacent R- ⁇ groups together with the carbon atoms to which they are attached form a fused benz ring;
• R 2 is H, alkyl or alkoxy;
• R 3 and R 4 which are the same or different, are H, or alkyl;
• U is an alkylene chain optionally substituted by one or more alkyl;
• Q represents a
• V is a bond or an alkylene chain optionally substituted by one or more alkyl
• VN is an alkylene chain optionally substituted by one or more alkyl
• X is a bond or an alkylene chain and X' is an alkylene chain, provided that the total number and carbon atoms in X and X' amounts to 3 or 4
• R 5 is H, or alkyl
• T represents an optionally substituted aromatic group which optionally contains one or more N atoms, provided that T is not 2-pyrimidinyl when A is -0-;
• the present invention provides compounds of formula
• the compounds of the present invention are advantageous over compounds known in the prior art because of their selectivity in receptor binding assays and their superior oral activity.
• Compounds of formula I may exist as salts with pharmaceutically acceptable acids.
• Examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.
• Compounds of formula I and their salts may exist in the form of solvates (for example hydrates).
• Certain compounds of formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. Certain compounds of formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
• the present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I or a salt thereof together with a pharmaceutically acceptable diluent or carrier.
• active compound denotes a compound of formula I or a salt thereof.
• the active compound may be administered orally, rectally, parenterally or topically, preferably orally.
• the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration.
• Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy.
• the compositions of the invention may contain 0.1-99% by weight of active compound.
• the compositions of the invention are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is 1-500 mg.
• the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
• compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oil suspensions.
• the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
• Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods.
• the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
• Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
• capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner.
• the tablets and capsules may conveniently each contain 1 to 500 mg of the active compound.
• Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethyl- cellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
• the active compound may be formulated into granules with or without additional excipients.
• the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion.
• the granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
• compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
• compositions of the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
• compositions for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
• a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, for example paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
• the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base.
• the amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
• the compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
• Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused.
• the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
• the amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
• the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
• the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
• compositions containing a therapeutically effective amount of a compound of formula I or a salt thereof may be used to treat depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behaviour, panic attacks, eating disorders, anorexia, cardiovascular and cerebrovascular disorders, migraine, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, prostatic hypertrophy, drug-induced extrapyramidal symptoms and spasticity in human beings.
• psychoses for example schizophrenia
• tardive dyskinesia for example schizophrenia
• Parkinson's disease for example schizophrenia
• obesity for example schizophrenia
• hypertension for example schizophrenia
• Tourette's syndrome sexual dysfunction
• drug addiction drug abuse
• cognitive disorders Alzheimer's disease
• senile dementia obsessive
• the amount of active compound administered in such treatment is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
• the ability of compounds of formula I to interact with 5-hydroxytryptamine (5- HT) receptors has been demonstrated by the following test which determines the ability of the compounds to inhibit tritiated ligand binding to 5-HT receptors in vitro and in particular to 5-HT 1A receptors.
• Hippocampal tissue from the brains of male Charles River CD rats weighing between 150-250 g were homogenised in ice-cold 50 mM Tris-HCI buffer (pH 7.7) when measured at 25°C, 1 :40 w/v) and centrifuged at 30,000 g at 4°C for 10 minutes. The pellet was rehomogenised in the same buffer, incubated at 37°C for 10 minutes and centrifuged at 30,000 g at 4°C for 10 minutes.
• the final pellet was resuspended in 50 mM Tris-HCI buffer (pH 7.7) containing 4 mM CaCI 2 , 0.1% L- ascorbic acid and 10 ⁇ M pargyline hydrochloride (equivalent to 6.25 mg wet weight of tissue/ml) and used immediately in the binding assay.
• the filters were washed with ice-cold Tris-HCI buffer and dried. The filters were punched out into vials, scintillation fluid added and radioactivity determined by liquid scintillation counting. The percentage displacement of specific binding of the tritiated ligand was calculated for the single concentration (10 "6 M) of test compound. Displacement curves were then produced for those compounds which displaced >50% of specific binding of the tritiated ligand at 10 "6 M using a range of concentrations of the compound. The concentration which gave 50% inhibition of specific binding (IC 50 ) was obtained from the curve. The inhibition coefficient Ki was then calculated using the formula
• the final pellet was resuspended in 50 mM Tris-HCI, pH 7.6 (equivalent to 12.5 mg wet weight of tissue/ml) and used immediately in the binding assay. Aliquots (400 ⁇ l; equivalent to 5 mg wet weight of tissue/tube) of this suspension were added to tubes containing the ligand (50 ⁇ l; 0.1 nM) and distilled water (50 ⁇ l; total binding) or phentolamine (50 ⁇ l; 5 ⁇ M; non-specific binding) or test compound (50 ⁇ l; at a single concentration of 10 "6 M or at 10 concentrations ranging from 10 "11 - 10 "3 M).
• the ligand was [7-methoxy- 3 H]prazosin and the mixture was incubated at 30°C for 30 minutes before the incubation was terminated by rapid filtration.
• the filters were washed with ice-cold Tris-HCI buffer and dried. The filters were punched out into vials, scintillation fluid added and radioactivity determined by liquid scintillation counting. The percentage displacement of specific binding of the tritiated ligand was calculated for the single concentration (10 "6 M) of test compound. Displacement curves were then produced for those compounds which displaced ⁇ 50% of specific binding of the tritiated ligand at 10 "6 M using a range of concentrations of the compound. The concentration which gave 50% inhibition of specific binding (IC 50 ) was obtained from the curve. The inhibition coefficient Ki was then calculated using the formula IC 50
• [ligand] is the concentration of the tritiated ligand used and K D is the equilibrium dissociation constant for the ligand.
• Tris salts buffer (equivalent to 2 mg wet weight of tissue/ml). Aliquots (720 ⁇ l; equivalent to 1.44 mg wet weight of tissue/tube) of this suspension were then added to tubes containing the ligand (40 ⁇ l; 1 nM) and Tris salts buffer (40 ⁇ l; total binding) or spiroperidol (40 ⁇ l; 10 nM; non-specific binding) or test compound (40 ⁇ l; at a single concentration of 10 "6 M or at 6 concentrations ranging from lO ' ⁇ -IO ⁇ M). The ligand was tritiated (S)-sulpiride and the mixture was incubated at 4°C for 40 minutes before the incubation was terminated by rapid filtration.
• S tritiated
• the filters were washed with ice-cold Tris-HCI buffer and dried. The filters were punched out in to vials, scintillation fluid added and were left for about 20 hours before being counted by scintillation spectrophotometry. The percentage displacement of specific binding of the tritiated ligand was calculated for the single concentration (10 *6 M) of test compound. Displacement curves were then produced over a range of concentrations for those compounds which displaced ⁇ 50% of specific binding of the tritiated ligand at 10 '6 M. The concentration which gave a 50% inhibition of specific binding (IC 50 ) was obtained from the curve. The inhibition coefficient Ki was then calculated using the formula
• [ligand] is the concentration of the tritiated ligand used and KD is the equilibrium dissociation constant for the ligand.
• mice Groups of 10 male mice weighing 18-35 g (max. range 10 g) were treated with test compound or control vehicle by po administration. 30 minutes later, mice were injected subcutaneously with apomorphine (0.88 mg/kg). Immediately after the apomorphine injection the mice were placed in the test cages and the climbing behaviour of each mouse was assessed at 10 and 20 minutes on a simple 0-2 ranking scale.
• ED o values dose causing 50% of the control score
• ED 50 values are calculated as free base equivalents and are given in Table 2 alongside Comparative Example A.
• the compounds of the present invention are more potent orally than compounds previously described. More potent compounds are advantaged as they are less likely to induce systemic toxicological effects on organs which are not the therapeutic target.
• Processes for the preparation of compounds of formula I will now be described. These processes form a further aspect of the present invention.
• the processes are preferably carried out at atmospheric pressure, at a temperature in the range 0-200°C, preferably in the range 20-150°C.
• the substituents are as defined for formula I above unless otherwise stated.
• Z is a leaving group, for example toluene-4-sulphonyloxy, with a compound of formula III in which R is as previously defined, optionally in the presence of a suitable solvent or mixture of solvents, for example a hydrocarbon, eg toluene, or a polar solvent, eg dimethylformamide, or mixtures thereof, optionally in the presence of a base, for example potassium carbonate at a temperature in the range of 0 - 250°C.
• a suitable solvent or mixture of solvents for example a hydrocarbon, eg toluene, or a polar solvent, eg dimethylformamide, or mixtures thereof, optionally in the presence of a base, for example potassium carbonate at a temperature in the range of 0 - 250°C.
• the invention is illustrated by the following Examples which are given by way of example only.
• the final product of each of these Examples was characterised by one or more of the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy.

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Citations (4)

• 1998
  • 1998-06-03 GB GBGB9811879.7A patent/GB9811879D0/en not_active Ceased
• 1999
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  • 1999-05-26 CA CA002333756A patent/CA2333756A1/en not_active Abandoned
  • 1999-05-26 JP JP2000552113A patent/JP2002517392A/ja active Pending
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  • 1999-05-26 KR KR1020007013670A patent/KR20010052526A/ko not_active Application Discontinuation
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  • 1999-05-26 EP EP99926434A patent/EP1087964A1/en not_active Ceased
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• 2001
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