Classifications

• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • 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
• • 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

Definitions

• N-oxides are known since 1894. By now it is very well known that N-oxides are metabolites of many tertiary amines, and in most cases are also intermediates between tertiary amines and their N-dealkylated analogs. Most, but not all, tertiary amine drugs give rise to N- oxides. This is for instance the case with morphine, imipramine, promazine, cinnarizine and nicotine, to name just a few. How much N-oxidation takes place varies from trace amounts to a near quantitative conversion. Some N-oxides were shown to be more potent than their corresponding tertiary amines.
• N-oxides were found to be less potent than their corresponding tertiary amines, and N-oxidation is most commonly regarded to be metabolic deactivation. Whilst N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines and in other cases the conversion is a mere trace reaction or even completely absent (Bickel, 1969).
• N-oxides and their corresponding tertiary amines are unpredictable. Once formed, N-oxides may be more active than their corresponding tertiary amines, less active or even completely inactive. N-oxides may be reduced to the corresponding tertiary amines or not. When they are, the reaction may be a mere trace or nearly quantitative.
• pyridine-N-oxides of SLV313 or its analogs are approximately equipotent with their parent compounds, and, dependent on the route of administration, also in vivo they offer the same therapeutic possibilities as disclosed for these compounds (EP 0 908 458).
• N- oxides formed by oxidation of the tertiary N-atoms of piperazine or piperidine rings are virtually inactive in vitro. But upon oral administration they act as prodrugs: They are rapidly converted to their parent compounds.
• the present invention relates to N-oxides of compounds of the general formula (a):
• - A represents a heterocyclic group of 5-7 ring atoms comprising 1-3 heteroatoms from the group O, N and S
• - R 1 is hydrogen or fluoro
• - F* 2 is C- ⁇ - 4 -alkyl , d- 4 -alkoxy or an oxo group
• p is 0, 1 or 2
• - Z represents carbon or nitrogen, and the dotted line is a single bond when Z is nitrogen, and a single or double bond when Z is carbon,
• R 3 and R 4 independently are hydrogen or d- 4 -alkyl, - n has the value 1 or 2,
• R 5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R ⁇ )q,
• - Y is phenyl, furanyl or thienyl, which groups may be substituted with 1-3 substituents of the group hydroxy, halogen, CF 3 , Ci -4 -alkoxy, Ci -4 -alkyl, cyano, aminocarbonyl, mono- or di-Ci- 4 -alkylaminocarbonyl,
• R 6 is halogen, hydroxy, Ci -4 -alkoxy or Ci -4 -alkyl, and q is 0, 1 , 2 or 3,
• the oxidized nitrogen atom may be the nitrogen atom in the pyridyl ring of R 5 , or the nitrogen atom in the piperidine ring (when Z is carbon) or either one of the nitrogen atoms in the piperazine ring (when Z is nitrogen), or both the nitrogen atom connected to R 5 via a methylene group, and the nitrogen atom in the pyridyl ring of R 5 , and tautomers, stereoisomers, pharmacologically acceptable salts, hydrates and solvates thereof.
• N-oxides of the present invention may be substantially free of 3-[[4-(2,3-dihydro-1 ,4-benzodioxin-5- yl)-1 -piperazinyl]-methyl]-5-(4-fluorophenyl) pyridine.
• the invention relates to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (a), as well as to hydrates and solvates thereof.
• Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid or an organic acid.
• Preferred compounds according to the invention are N-oxides of compounds of the formula (a) wherein the oxidized nitrogen atom is the nitrogen atom in the pyridyl ring of R 5 , the 'pyridine N-oxides' of N-oxides of compounds of formula (a), and tautomers, stereoisomers, pharmacologically acceptable salts, hydrates and solvates thereof.
• N-oxides of compounds of the formula (a) wherein the oxidized nitrogen atom is the nitrogen atom connected to R 5 via a methylene group are also preferred.
• N-oxides of the compounds of the invention of the general formula (a), as well as the pharmacologically acceptable salts thereof, have dopamine-D 2 receptor antagonistic and 5- HT 1A receptor agonistic activity. They are useful in treating Parkinson's disease, aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, and in particular schizophrenia, and other psychotic disorders.
• the invention also embraces: pharmaceutical compositions for treating, for example, a disorder or condition treatable by antagonizing dopamine-D 2 receptors and/or activating 5-HT 1A receptors, the compositions comprising an N-oxide of a compound of formula (a) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; methods of treating a disorder or condition treatable by antagonizing dopamine-D 2 receptors and/or activating 5-HT 1A receptors, the methods comprising administering to a mammal in need of such treating an N-oxide of a compound of formula (a) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions for treating, for example, a disorder or condition selected from the group consisting of Parkinson's disease, aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, and in particular schizophrenia, and other psychotic disorders; methods of treating a disorder or condition selected from the group consisting of the disorders listed herein, the methods comprising administering to a mammal in need of such treating
• the invention also provides the use of an N-oxide of a compound according to formula (a), or a salt thereof, for the manufacture of medicament.
• the invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed.
• Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the compounds of the invention.
• the invention also provides compounds, pharmaceutical compositions, kits and methods for treating Parkinson's disease, aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, and in particular schizophrenia, and other psychotic disorders, the method comprising administering to a patient in need of such treating an N-oxide of a compound of formula (a) or a pharmaceutically acceptable salt thereof.
• the compounds of the invention possess dopamine-D 2 receptor antagonistic and 5- HT 1A receptor agonistic activity.
• the (ant)agonizing activities of the compounds of the invention is readily demonstrated, for example, using one or more of the assays described herein or known in the art.
• the invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.
• the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Depending on the nature of the various substituents, the molecule can have additional asymmetric centers. Each such asymmetric center will independently produce two optical isomers. All of the possible optical isomers and diastereomers, in mixtures and as pure or partially purified compounds, belong to this invention. The present invention comprehends all such isomeric forms of these compounds.
• Formula (a) shows the structure of the class of compounds without preferred stereochemistry. The independent syntheses of these diastereomers, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed therein.
• Racemic mixtures of the compounds can be separated into the individual enantiomers by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
• the coupling often consists of the formation of salts using an enantiomerically pure acid or base, for example (-)-di-p-toluoyl-D-tartaric acid and/or (+ )-d i-p-tol uoy l-L-tartaric acid.
• the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
• the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases: Methods well-known in the art.
• any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well- known in the art.
• Cis and trans isomers of N-oxides of a compound of formula (a), or a pharmaceutically acceptable salt thereof also belong to the invention, and this also applies to tautomers of N-oxides of N-oxides of compounds of formula (a) or a pharmaceutically acceptable salt thereof.
• Some of the crystalline forms for the compounds may exist as polymorphs: as such intended to belong to the invention.
• some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such solvates also fall within the scope of this invention.
• N-oxides of a compound of formula (a) or pharmaceutically acceptable salts thereof including N-oxides of N-oxides of compounds of formula (a) isotopically-labeled to be detectable by PET or SPECT, also fall within the scope of the invention.
• compounds of the present invention may be provided substantially free of parent compound 3-[[4-(2,3-dihydro-1 ,4-benzodioxin-5-yl)-1 -piperazinyl]methyl]-5-(4-fluorophenyl) pyridine (SLV-313).
• substantially free is meant that compound of the present invention contains less than about 50%, 40%, 30%, 20%, 10%, 1 %, 0.5% or is, within detectable limits, free of 3-[[4-(2,3-dihydro-1 ,4-benzodioxin-5-yl)-1-piperazinyl]methyl]-5-(4- fluorophenyl) pyridine (SLV-313) as an impurity.
• SLV-313 3-[[4-(2,3-dihydro-1 ,4-benzodioxin-5-yl)-1-piperazinyl]methyl]-5-(4- fluorophenyl) pyridine
• Pharmaceutical compositions containing N-oxides of SLV-313 which are substantially free of SLV-313 are envisioned in accordance with the present invention.
• 'alkyl' refers to straight or branched saturated hydrocarbon radicals.
• 'Ci.3-Alkyl' means methyl, ethyl, n-propyl or isopropyl
• 'Ci. 4 -alkyl' means 'methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl'.
• 'Halo' or 'Halogen' means chloro, fluoro, bromo or iodo; 'hetero' as in 'heteroalkyl, heteroaromatic' etc.
• 'heteroalkyl' includes alkyl groups with heteroatoms in any position, thus including N-bound O-bound or S-bound alkyl groups.
• oxy means containing one or more N, O or S atoms
• thio includes alkyl groups with heteroatoms in any position, thus including N-bound O-bound or S-bound alkyl groups.
• oxy means containing one or more N, O or S atoms
• 'heteroalkyl' includes alkyl groups with heteroatoms in any position, thus including N-bound O-bound or S-bound alkyl groups.
• amino refers to a nitrogen atom that may be either terminal, or a linker between two other groups, wherein the group may be a primary, secondary or tertiary (two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogen atom, respectively) amine.
• composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
• this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
• pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
• the pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases.
• the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
• the term 'combination preparation' comprises both true combinations, meaning an N-oxide of a compound of formula (a) or a pharmaceutically acceptable salt thereof, and other medicaments physically combined in one preparation such as a tablet or injection fluid, as well as 'kit-of-parts', comprising an N-oxide of a compound of formula (a) or a pharmaceutically acceptable salt thereof, and SLV313 or another medicament in separate dosage forms, together with instructions for use, optionally with further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings.
• the pharmacotherapy by definition is simultaneous.
• the contents of 'kit-of-parts' can be administered either simultaneously or at different time intervals.
• Dose The affinity of the compounds of the invention for dopamine-D 2 and 5-HT 1A receptors was determined as described below. From the binding affinity measured for a given compound of formula (a), one can estimate a theoretical lowest effective dose. At a concentration of the compound equal to twice the measured K-value, nearly 100% of the receptors likely will be occupied by the compound.
• the dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician.
• the dosage will preferably be in the range of from 0.01 mg/kg to 10 mg/kg.
• the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
• oral and parenteral dosages will be in the range of 0.1 to 1 ,000 mg per day of total active ingredients.
• therapeutically effective amount refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic, preventative or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating or preventing the conditions listed herein.
• the precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration.
• pharmaceutically acceptable salt refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.
• treatment refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1 ) preventing the disease or condition from occurring in a subject predisposed to the disease, but not yet diagnosed as having it, (2) inhibiting the disease or condition, i.e., arresting its development, (3) relieving the disease or condition, i.e., causing the condition to regress, or (4) stopping the symptoms of the disease.
• the term “medical therapy” intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
• subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
• the LC-MS system consists of 2 Perkin elmer series 200 micro pumps.
• the pumps are connected to each other by a 50 ⁇ l tee mixer, connected to a Gilson 215 auto sampler.
• the method is as follows:
• step total time flow ( ⁇ l/min) A(%) B(%)
• the auto sampler has a 2 ⁇ l injection loop.
• the auto sampler is connected to a Waters Atlantis C18 30 * 4.6 mm column with 3 ⁇ m particles.
• the column is thermo stated in a Perkin Elmer series 200 column oven at 40° C.
• the column is connected to a Perkin Elmer series 200 UV meter with a 2.7 ⁇ l flowcel.
• the wavelength is set to 254 nm.
• the UV meter is connected to a Sciex API 150EX mass spectrometer.
• the mass spectrometer has the following parameters: Scanrange: 150-900 a.m.u.; polarity: positive; scan mode: profile ; resolution Q1 : UNIT ; step size: 0.10 a.m.u.; time per scan: 0.500 sec; NEB: 10; CUR: 10; IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10.
• the light scattering detector is connected to the Sciex API 150.
• the light scattering detector is a Sedere Sedex 55 operating at 50° C and 3 bar N 2 .
• the complete system is controlled by a G3 powermac.
• EXAMPLE 2 SYNTHESES OF SPECIFIC COMPOUNDS
• Step 1 oxidation of pyrifenchloride (2) with H 2 O 2 :
• the residue is dissolved in 100ml of dichloromethane. Addition of 50 ml of a 10% aqueous sodium carbonate solution is followed by separation of the layers. The organic layer is extracted with 100 ml of dichloromethane and 50 ml of dichloromethane, respectively. The combined organic layers are concentrated under reduced pressure using a rotary evaporator. The crude product is purified using PrepHPLC (Inertsil ODS-3 column, eluens gradient from 10/90% acetonitrile/ water to 90/10% acetonitrile/water containing 0.1 % HCOOH) to obtain 1.48 g (29 mmol, 30% yield) of the corresponding N-oxide (3).
• PrepHPLC Inertsil ODS-3 column, eluens gradient from 10/90% acetonitrile/ water to 90/10% acetonitrile/water containing 0.1 % HCOOH
• Step 1 a oxidation of pyrifenchloride (2) with metachloroperbenzoic acid (mCPBA)
• the combined organic layers are concentrated using a rotary evaporator.
• the crude product is purified using PrepHPLC (Inertsil ODS-3 column, eluens gradient from 10/90% acetonitrile/water to 90/10% acetonitrile/water with 0.1 % HCOOH) to obtain 1.83 g (4.34 mmol, 70% yield) of the corresponding SLV313-N-oxide: 1- (2,3-dihydro-1 ,4-benzodioxin-5-yl)-4-[[5-(4-fluorophenyl)-1-oxido-3-pyridinyl]-methyl]-pipera- zine M.p. (DSC): 171 0 C.
• 155 ml of water is added to a stirred suspension of 155 g (652 mmole) of N-oxide 3, 167.5 g (1 equivalent) of eltoprazine. HCI (4), 108.2 g (781 mmole) of powdered potassium carbonate and 2.5 I of 2-butanone.
• the mixture is refluxed (76 0 C) for 3 hours.
• the mixture is cooled to about 5O 0 C and is extracted three times with 500 ml of water at this temperature.
• the combined water layers are extracted with 200 ml of MEK.
• the organic layers are combined and 1.6 I of 2-butanone is distilled of.
• the mixture is cooled to O 0 C.
• the solution is seeded at 35 0 C.
• mCPBA is dissolved in 20 ml of DCM. This solution is added to the stirred SLV313 suspension in DCM/water during 1 minute. The mixture is stirred for 2.5 hours at room temperature. The layers are separated. The water layer is extracted with 10 ml of EtOAc. The combined organic layers are extracted with 25 ml of water and with 10 ml of 2N NaOH. The organic layer is concentrated until dry. The crude product (2.83 g) is crystallized from 40 ml of acetonitrile. The solid material is isolated by filtration.
• N-oxides of the compounds of the invention of the general formula (a), as well as the pharmacologically acceptable salts thereof, are alternatives for the parent compounds or prodrugs thereof, having dopamine-D 2 receptor antagonistic activity combined with 5-HT 1A receptor agonistic activity. They are useful in the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotinergic systems, for example: Parkinson's disease, aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory and in particular schizophrenia and other psychotic disorders.
• SLV313 When administered to mice (i.v. or p.o.) SLV313 to a marginal extend is metabolized to its pyridine N-oxide: The concentration thereof never exceeds 1 - 2% of that of the parent compound. When the N-oxide itself is administered it is only to a very small extend (less than 1 %) reduced to its parent compound. In mice, the pyridine N-oxide is an alternative to, rather than a prodrug of, SLV313.
• SLV313 When administered to mice (i.v. or p.o.), SLV313 is not metabolized to its piperazine-N- oxide. When the piperazine-N-oxide itself is administered, within half an hour the concentration thereof in the plasma exceeds that of the parent molecule. The piperazine-N-oxide evidently is a prodrug of SLV313.
• V 0 The volume of distribution (V 0 ), also known as the 'apparent volume of distribution', is a pharmacological term used to quantify the distribution of a drug throughout the body after oral or parenteral dosing. It is defined as the volume in which the amount of drug would need to be uniformly distributed in to produce the observed concentration (Widmark, 1919).
• the volume of distribution of SLV313 and its pyridine N-oxide was measured in mice, using the standard procedure well known in the art:
• the volume of distribution is not a physiological volume, but rather the ratio between the total amount of drug in the body and its concentration in plasma. It is generally accepted that the volume of distribution is more or less the same across species, making it a parameter that, when measured in laboratory animals, has a high predictive value towards man.
• the value of 350 L, calculated for an average person weighing 70 kg, is much larger than that person's body volume, indicating that the compound must be extensively distributed into tissues, leaving low concentrations in the plasma.
• the pyridine N-oxide of SLV313 has a calculated volume of distribution of 70 L in a person weighing 70 kg, indicating a distribution largely confined to total body water.
• Partition coefficients (log P) of SLV313 and its N-oxides were calculated and determined (at pH 7.0) by methods well known in the art.
• the N-oxides of SLV313 are less lipophilic than their parent compound.
• the N-oxides When given orally, in equal doses, the N-oxides will enter the bloodstream slower than SLV313, and their peak concentrations will be lower than those observed after SLV313.
• the SLV313-bis-N-oxide (the 'piperazine N-oxide of the pyridine N-oxide') can be found inactive in vitro, but equipotent with its corresponding parent molecule: the pyridine N-oxide.
• the 'bis-N-oxide' is a prodrug of an active metabolite.
• N-oxides of compounds of formula (a) are formulated into pharmaceutical compositions that are important and novel embodiments of the invention because they contain the compounds, more particularly specific compounds disclosed herein.
• Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
• the compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer.
• the pharmaceutical formulation contains at least one compound of formula (a) in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
• the total amount of active ingredients suitably is in the range of from about 0.1 % (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w).
• the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
• auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
• auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
• the mixture may then be processed into granules or pressed into tablets.
• the active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation.
• the active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
• Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
• Hard gelatin capsules may contain granules of the active ingredients.
• Hard gelatin capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
• Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
• Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g.
• liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents.
• Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use.
• Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.
• formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy.
• container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
• formulations of the present invention in the manufacture of medicaments for use in treating a condition in which antagonism of dopamine-D 2 receptors and/or activation of 5-HT 1A receptors is required or desired, and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one compound of formula (a), either as such or, in the case of prodrugs, after administration, to a patient suffering from, or susceptible to, a condition in which antagonism of dopamine-D 2 receptors and/or activation of 5-HT 1A receptors is required or desired.

Landscapes

• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Psychology (AREA)
• Pain & Pain Management (AREA)
• Otolaryngology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (9)

Applications Claiming Priority (4)

Publications (1)

Family

ID=37198739

Family Applications (1)

Country Status (16)

Cited By (4)

Citations (2)

• 2007
  • 2007-04-25 AU AU2007247251A patent/AU2007247251B2/en not_active Ceased
  • 2007-04-25 UA UAA200813798A patent/UA96756C2/ru unknown
  • 2007-04-25 EP EP07728504A patent/EP2024363B1/en active Active
  • 2007-04-25 MX MX2008013887A patent/MX2008013887A/es unknown
  • 2007-04-25 JP JP2009508315A patent/JP2009535374A/ja not_active Withdrawn
  • 2007-04-25 WO PCT/EP2007/054048 patent/WO2007128694A1/en not_active Ceased
  • 2007-04-25 CN CNA2007800157788A patent/CN101432279A/zh active Pending
  • 2007-04-25 EA EA200870492A patent/EA200870492A1/ru unknown
  • 2007-04-25 BR BRPI0710792-7A patent/BRPI0710792A2/pt not_active IP Right Cessation
  • 2007-04-25 CA CA002649479A patent/CA2649479A1/en not_active Abandoned
  • 2007-04-30 CL CL200701245A patent/CL2007001245A1/es unknown
  • 2007-05-01 TW TW096115482A patent/TW200811150A/zh unknown
  • 2007-05-02 PE PE2007000537A patent/PE20080064A1/es not_active Application Discontinuation
  • 2007-05-02 SA SA07280218A patent/SA07280218B1/ar unknown
  • 2007-05-02 AR ARP070101891A patent/AR060832A1/es not_active Application Discontinuation
• 2008
  • 2008-10-23 ZA ZA200809112A patent/ZA200809112B/xx unknown

Patent Citations (2)

Also Published As

Similar Documents

Legal Events