EP3625212A2 - Agents psychotropes et leurs utilisations - Google Patents

Agents psychotropes et leurs utilisations

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Publication number
EP3625212A2
EP3625212A2 EP18801735.4A EP18801735A EP3625212A2 EP 3625212 A2 EP3625212 A2 EP 3625212A2 EP 18801735 A EP18801735 A EP 18801735A EP 3625212 A2 EP3625212 A2 EP 3625212A2
Authority
EP
European Patent Office
Prior art keywords
previous
amisulpride
disorder
formula
condition
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP18801735.4A
Other languages
German (de)
English (en)
Other versions
EP3625212A4 (fr
Inventor
Andrew R. VAINO
Vincent T. GRATTAN
Zachary PRENSKY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LB Pharmaceuticals Inc
Original Assignee
LB Pharmaceuticals Inc
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 LB Pharmaceuticals Inc filed Critical LB Pharmaceuticals Inc
Publication of EP3625212A2 publication Critical patent/EP3625212A2/fr
Publication of EP3625212A4 publication Critical patent/EP3625212A4/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 is generally in the field of pharmaceutical compositions and methods for the treatment of neuropsychiatric and/or psychological diseases or disorders.
  • Schizophrenia is a chronic debilitating mental illness affecting about one percent of the population. The disease manifests in delusional behavior, dysfunctional thinking, agitated body movement, social withdrawal, and depression. Schizophrenia patients suffer a profoundly reduced quality of life, and are ten times more likely to commit suicide that the general population.
  • Dopamine (particularly D2 and D3) antagonists are well recognized as improving symptoms of schizophrenia, and have been used clinically as such for decades.
  • treatment of schizophrenia as with many mental illnesses, benefits from engaging multiple receptors including serotonergic and adrenergic.
  • dozens of approved drugs to treat schizophrenia the disease remains poorly treated in many patients.
  • Side effects of current medications include: dyskinesia, akathisia, weight gain, mood disturbances, sexual dysfunction, sedation, orthostatic hypotension, hypersalivation, and (in some cases) arganulocytosis.
  • Amisulpride (4-amino-/V-(((1 -ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide) is an antipsychotic patented in 1981 .
  • Amisulpride binds selectively to the human dopaminergic D2 (K 2.8 nM) and D3 (K 3.2 nM) receptor subtypes without any affinity for Di , D 4 and D5 receptor subtypes.
  • amisulpride displays low affinity for serotonin, alpha- adrenergic, histamine receptor subtypes, muscarinic receptors and sigma sites though it has also been demonstrated to bind 5-HT2B and HT a receptors with low double digit nM .
  • This ability of amisulpnde to bind 5-HT receptors is thought to result in amisulpride's ability to treat symptoms of depression (sometimes noted in schizophrenia patients).
  • amisulpride is not noted to have any activity at the 5- ⁇ 2 3 receptor.
  • the amisulpride derivatives disclosed herein are dopamine and/or serotonin antagonists.
  • the amisulpride derivatives disclosed herein have improved membrane (e.g., BBB) permeability compared to amisulpride.
  • the amisulpride derivatives can act as central nervous system (CNS) dopamine and/or serotonin antagonists.
  • CNS central nervous system
  • These amisulpride derivatives have structures of Formula I, Formula IA, Formula IB or Formula IC disclosed herein, including pharmaceutically acceptable salts thereof, and stereoisomers thereof (e.g., Formula l-S, Formula l-R, Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, and Formula IC-R).
  • pharmaceutically acceptable salts thereof e.g., l-S, Formula l-R, Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, and Formula IC-R.
  • Also provided herein are methods for delivering a serotonin (e.g., 5-HT2a, 5- HT ) receptor antagonist to the brain of a subject comprising administering to the subject an amisulpride derivative disclosed herein or a pharmaceutical composition thereof; and the serotonin receptor antagonist level in the brain is higher than administering to the subject amisulpride (racemic mixture) at a comparable dose.
  • a serotonin e.g., 5-HT2a, 5- HT
  • Also provided herein are methods for antagonizing a serotonin (e.g., 5-HT2a, 5-HT ) receptor in a subject comprising administering to a subject the R isomer of amisulpride and/or the amisulpride derivatives disclosed herein or pharmaceutical compositions thereof, either individually or in combination with other CNS active agents.
  • a serotonin e.g., 5-HT2a, 5-HT
  • administering comprising to a subject the R isomer of amisulpride and/or the amisulpride derivatives disclosed herein or pharmaceutical compositions thereof, either individually or in combination with other CNS active agents.
  • Also provided herein are methods for treating one or more conditions responsive to modulation of a serotonin (e.g., 5-HT2a, 5-HT ) receptor in a subject comprising administering to a subject the R isomer of amisulpride and/or the amisulpride derivatives disclosed herein or pharmaceutical compositions thereof, either individually or in combination with other CNS active agents.
  • a serotonin e.g., 5-HT2a, 5-HT
  • Examples of the conditions responsive to modulation of serotonin (e.g., 5- HT2a, 5-HT ) receptor and/or and the disorders associated with abnormality in levels of serotonin in the brain include, e.g., without limitation, mental illnesses.
  • Examples of the mental illnesses include, without limitation, schizophrenia, symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, depression, obsessive- compulsive disorder, Parkinson's psychosis, Alzheimer's psychosis, oppositional defiant disorder, aggression, suicidality, hostility, personality disorders, chronic fatigue syndrome, predominantly negative symptoms of schizophrenia, Charles Bonnet Syndrome, autism, and Tourette's disorder.
  • Figure 3 Binding of Compounds 102, 103, 104, and amisulpride (101 ) to 5- HT receptor.
  • Figure 4 Binding of amisulpride (Ami(rac)), R enantiomer of amisulpride (Ami(r)), and S enantiomer of amisulpride (Amid(s)) to 5-HT receptor.
  • 4-amino substituted derivatives of amisulpride (also referred to as 4-amino amisulpride derivatives and 4-amino substituted amisulpride derivatives) showed improved membrane (e.g., BBB) permeability and may be used to target relevant receptors in the brain at a lower dose with less side effects to the treated subjects compared to amisulpride.
  • membrane e.g., BBB
  • a 4-amino substituted amisulpride derivative Compound 102 (also referred to as LB-102, N-methyl amisulpride, and 4-methylamino substituted amisulpride derivative) was prepared (Examples 1 and 2) and showed unexpectedly high membrane permeability improvement compared to that of amisulpride (Example 4, 216.7 time improvement at pH 7.4, and 87.5 time improvement at pH 5).
  • Stereoisomers of Compound 102 (Compound 103 and Compound 104) were also prepared (Example 3), as were other 4-amino amisulpride derivatives Compounds 105 to 1 10.
  • the 4- amino substituted amisulpride derivatives showed effective binding to dopamine D2 receptors and various CNS receptors (Examples 5-7).
  • the 4-amino substituted amisulpride derivatives showed a2 (e.g. , a2A, a2B, and a2C) receptor antagonism (Table 4, Example 7), while amisulpride displayed low affinity for a2 receptor.
  • the 4-amino substituted amisulpride derivative showed 5-HT 2a receptor antagonism (Table 4, Example 7), while amisulpride is not noted to have any activity at the 5-HT2a receptor.
  • Compound 102 and Compound 103 were shown to restore known object exploration behavior in rats with impaired ability to discern between novel and familiar object in a Novel Object Recognition (NOR) assay (Example 8).
  • the normalized amphetamine hyperactivities of Compounds 102 and 103 were statistically superior to or indistinguishable from that of amisulpride in an amphetamine-induced Locomotor Activity (LMA) assay (Example 9). Furthermore, the stereoisomers of Compound 102 (Compound 103 and Compound 104) showed unexpectedly different K, in their binding to 5-HT receptor, with the R enantiomer (Compound 104) afforded a K, of 16 nM compared to a of > 1 ,000 nM for the S enantiomer (Compound 103) (Example 10). Unexpected the R enantiomer of amisulpride showed an unexpected lower Ki compared to the S enantiomer of amisulpride ( Figure 4).
  • X and Z are the same or different and independently selected from the group consisting of hydrogen, alkyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), alkenyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), alkynyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i- propyl, n-butyl, and s-butyl), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobut
  • the amisulpride derivative is a stereoisomer having a structure of Formula l-S:
  • the amisulpride derivative is a stereoisomer having a structure of Formula l-R:
  • the amisulpride derivative is a 4-amino substituted derivative of amisulpride having a structure of Formula IA:
  • the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IA-S:
  • the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IA-R:
  • the amisulpride derivative is a 4-amino substituted derivative of amisulpride having a structure of Formula IB:
  • the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IB-S:
  • Z is defined the same as above with respect to Formula I with the proviso that Z is not H.
  • the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IB-R:
  • Z is defined the same as above with respect to Formula I with the proviso that Z is not H.
  • the amisulpride derivative has a structure of Formula
  • the amisulpride derivative is a stereoisomer having a structure of Formula IC-S:
  • the amisulpride derivative is a stereoisomer having a structure of Formula IC-R:
  • Z is defined the same as above with respect to Formula I with the proviso that Z is not H.
  • the amisulpride derivatives disclosed herein have greater membrane (e.g. , BBB) permeability than amisulpride.
  • the amisulpride derivatives disclosed herein are dopamine and/or serotonin and/or a2 antagonists.
  • the amisulpride derivatives disclosed herein bind to dopamine D2 and/or D3 receptors.
  • the amisulpride derivatives disclosed herein more selectively bind to dopamine D2 and/or D3 receptor over dopamine Di , D 4 and/or D5 receptor.
  • the amisulpride derivatives disclosed herein are capable of interacting dopamine and/or serotonin and/or a2receptors in CNS.
  • deuterated analogs of the amisulpride derivatives disclosed herein wherein one or more hydrogens of the amisulpride derivatives are replaced by deuterium.
  • the one or more deuteriums in the deuterated analog are present in at least 100 times the natural abundance level.
  • compositions comprising one or more of the amisulpride derivatives and deuterated analogs thereof disclosed herein and a pharmaceutically acceptable carrier.
  • the one or more of the amisulpride derivatives the pharmaceutical compositions comprise are substantially enantiomerically pure, and such pharmaceutical compositions are also referred to as substantially enantiomerically pure pharmaceutical compositions.
  • substantially enantiomerically pure means enantiomerical purity of about 50% or higher, about 60% or higher, about 70% or higher, about 80% or higher, about 90% or higher, about 95% or higher, or about 98% or higher.
  • Also provided herein are methods for delivering a dopamine and/or serotonin (e.g., 5-HT2a, 5-HT ) and/or a2 receptor antagonist to the brain of a subject comprising administering to the subject one or more of the amisulpride derivatives and deuterated analogs thereof disclosed herein, or a pharmaceutical composition thereof; and the dopamine and/or serotonin (e.g., 5-HT2a, 5-HT ) and/or a2 receptor antagonist level in the brain is higher than administering to the subject amisulpride (racemic mixture) at a comparable dose.
  • the amisulpride derivatives, deuterated analogs, and/or the pharmaceutical composition are substantially enantiomerically pure.
  • Also provided herein are methods for antagonizing dopamine and/or serotonin (e.g., 5-HT 2a , 5-HT ) and/or a2 receptor in a subject comprising administering to a subject one or more of the R enantiomer of amisulpride, amisulpride derivatives and deuterated analogs thereof disclosed herein or a pharmaceutical composition thereof, either individually or in combination with other CNS active agents.
  • the amisulpride derivatives, deuterated analogs, and/or the pharmaceutical composition are substantially enantiomerically pure.
  • Also provided herein are methods for treating one or more conditions responsive to modulation of dopamine and/or serotonin (e.g., 5-HT2a, 5-HT ) and/or a2 receptor in a subject comprising administering to a subject a therapeutically effective amount of one or more of the R enantiomer of amisulpride, amisulpride derivatives and deuterated analogs thereof disclosed herein or a pharmaceutical composition thereof, either individually or in combination with other CNS active agents.
  • the amisulpride derivatives, deuterated analogs, and/or the pharmaceutical composition are substantially enantiomerically pure.
  • kits for treating one or more disorders associated with an abnormality in levels of dopamine and/or serotonin in the brain in a subject comprising administering to the subject a therapeutically effective amount of one or more of the R enantiomer of amisulpride, amisulpride derivatives and deuterated analogs thereof disclosed herein, or a pharmaceutical composition thereof.
  • the amisulpride derivatives, deuterated analogs and/or the pharmaceutical composition are substantially enantiomerically pure.
  • the therapeutically effective amount of the the R enantiomer of amisulpride, amisulpride derivatives disclosed herein or the pharmaceutical composition thereof is lower than the that of amisulpride. Accordingly, the methods disclosed herein may result in fewer adverse events to the subject treated.
  • Examples of conditions responsive to modulation of dopamine and/or serotonin (e.g., 5-HT2a, 5-HT ) and/or a2 receptor and/or disorders associated with an abnormality in levels of dopamine and/or serotonin in the brain include, e.g., without limitation, mental illnesses.
  • Examples of the mental illnesses include, without limitation, schizophrenia, symptoms of schizophrenia, schizoaffective disorder bipolar disorder, depression, obsessive-compulsive disorder, Parkinson's psychosis, Alzheimer's psychosis, oppositional defiant disorder, aggression, suicidality, hostility, personality disorders, autism, chronic fatigue syndrome, predominantly negative symptoms of schizophrenia, Charles Bonnet Syndrome, and Tourette's disorder.
  • a cell includes a plurality of cells, including mixtures thereof.
  • use of "a compound” for treatment of preparation of medicaments as described herein contemplates using one or more compounds of the invention for such treatment or preparation unless the context clearly dictates otherwise.
  • compositions and methods include the recited elements, but not excluding others.
  • a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the composition of this invention. Embodiments defined by each of the transitional terms are within the scope of this invention.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. Unless otherwise specified, the term “alkyl” refers to a group having one, two, three, four, five, six, seven, or eight carbon atoms (for example, one to six carbon atoms, or one to four carbon atoms), and which is attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, i-propyl, n-butyl, t-butyl, s-butyl, n-pentyl, and s-pentyl.
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain. Unless otherwise specified, the term “alkenyl” refers to a group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, e.g., ethenyl, 1 -propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl-1 -propenyl, 1 -butenyl, and 2-butenyl.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond. Unless otherwise specified, the term “alkynyl” refers to a group having in the range of 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 carbon atoms (for instance, 2 to 10, 2 to 10 carbon atoms), e.g., ethynyl, propynyl, and butnyl.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkylalkyl refers to a cycloalkyl group as defined above directly bonded to an alkyl group as defined above.
  • aryl refers to a mono- or multi-cyclic aromatic radical having in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5, and -C2H5C6H5.
  • heterocyclyl refers to a non-aromatic 3 to 15 member ring radical which, consists of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized.
  • heterocyclylalkyl refers to a heterocyclyl group as defined above directly bonded to an alkyl group as defined above.
  • heteroaryl refers to an optionally substituted 5-14 member aromatic ring having one or more hetero ring atoms selected from the group consisting of N, O, and S as ring atoms.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • heteroaryl ring radicals includes, but are not limited to, oxazolyl, thiazolyl imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl and isoquinolyl.
  • heteroarylalkyl refers to an heteroaryl group as defined above directly bonded to an alkyl group as defined above, e.g., -ChbCeHUN, and - C 2 H 5 C 6 H 4 N.
  • subject refers to a mammal, such as a domestic pet (for example, a dog or cat), or human. In certain embodiments, the subject is a human.
  • phrases "effective amount” refers to the amount which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.
  • Treatment includes (1 ) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
  • inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease e.g., arresting further development of the pathology and/or symptomatology
  • ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease e.g., reversing the pathology and/or symptomatology
  • pharmaceutically acceptable carrier refers to a carrier that does not cause an allergic reaction or other untoward effect in patients to whom it is administered and are compatible with the other ingredients in the formulation.
  • Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. , corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.
  • salt used herein is not limited as long as the salt is formed with a compound of the amisulpride derivatives and is pharmaceutically acceptable; preferred examples of salts include a hydrohalide salt (for instance, hydrochloride, hydrobromide, hydroiodide and the like), an inorganic acid salt (for instance, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), an organic carboxylate salt (for instance, acetate salt, maleate salt, tartrate salt, fumarate salt, citrate salt and the like), an organic sulfonate salt (for instance, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), an amino acid salt (for instance, aspartate salt, glutamate salt and the like), a quaternary ammonium salt, and the like.
  • Isomers of the amisulpride derivatives disclosed herein can be purified using general separation means, including for example recrystallization, optical resolution such as diastereomeric salt method, enzyme fractionation method, various chromatographies (for instance, thin layer chromatography, column chromatography, glass chromatography and the like) into a single isomer.
  • general separation means including for example recrystallization, optical resolution such as diastereomeric salt method, enzyme fractionation method, various chromatographies (for instance, thin layer chromatography, column chromatography, glass chromatography and the like) into a single isomer.
  • the amisulpride derivatives disclosed herein and/or deuterated analogs thereof may be administered by a variety of routes including orally and by injection (e.g. subcutaneously, intravenously, and intraperitoneally).
  • the amisulpride derivatives disclosed herein may be formulated into a pharmaceutical composition for use in the disclosed methods.
  • Such compositions are prepared in accordance with acceptable pharmaceutical procedures such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference.
  • the amisulpride derivatives disclosed herein and/or deuterated analogs thereof may be administered orally in the form of a solid or liquid dosage form.
  • the amisulpride derivatives disclosed herein compound may be coated in a material to protect it from the action of acids and other natural conditions which may inactivate the compound.
  • the amisulpride derivatives disclosed herein may be formulated as aqueous solutions, liquid dispersions, (ingestible) tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.
  • the oral dosage forms may include excipients known in the art, such as binders, disintegrating agents, flavorants, antioxidants, and preservatives.
  • Liquid dosage forms may include diluents such as saline or an aqueous buffer.
  • the amisulpride derivatives disclosed herein and/or deuterated analogs thereof may also be administered by injection.
  • Formulations suitable for injection may include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the pharmaceutical composition may be sterile and be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the pharmaceutically acceptable carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the 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 dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, and ascorbic acid.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the actual dosage amount of the compound administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
  • a human subject is administered the daily doses of from about 0.01 mg/kg to about 100 mg/kg.
  • Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the compound is administered once a day.
  • a routine schedule refers to a predetermined designated period of time.
  • the routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined.
  • the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between.
  • the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months.
  • the invention provides that the amisulpride derivatives disclosed herein or pharmaceutical compositions thereof agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake.
  • the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.
  • the amisulpride derivatives disclosed herein or pharmaceutical compositions thereof may also find use in combination therapies.
  • Effective combination therapy may be achieved with a single pharmaceutical composition or pharmacological formulation that includes both agents, or with two distinct pharmaceutical compositions or pharmacological formulations, administered at the same time, wherein one composition includes a compound of this invention, and the other includes the second agent(s).
  • the therapy may precede or follow the other agent treatment by intervals ranging from minutes to months.
  • the additional agent or agents may be selected from any agent or agents useful for treating a psychological disorder, for example any agent or agent and/or a2s useful for treating an imbalance of dopamine, serotonin, histamine, or glutamate.
  • the additional agent or agent is useful in improving psychological function, e.g., an antipsychotic, such as quetiapine, geodon, zyprexa, latuda, olanzapine, risperidone, iloperidone, ziprasidone, clozapine, haloperidol, chlorpromazine, citrlopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, desvenlafaxine, duloxetine, milnacipran, venlafaxine, vilazodone, and combinations thereof.
  • an antipsychotic such as quetiapine, geodon, zyprexa, latuda, olanzapine, risperidon
  • the amisulpride derivatives disclosed herein of the present invention can be prepared from amisulpride (4-amino-/V-((1 -ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide), which is readily available.
  • the synthesis of amisulpride is described, for example, in U.S. Patent No. 4,401 ,822.
  • the following synthesis for preparing the compounds of formula IB can be adapted to prepare other compounds of the present invention, such as compounds of Formulas I, IA and IC.
  • the compound of formula IB can be prepared by (a) treating amisulpride with a mixture of a carboxylic acid and its corresponding anhydride to obtain the corresponding amide, (b) reduction of the amide to the amine with a suitable reducing agent, for example, borane:dimethyl sulfide to form a compound of Formula IB:
  • compounds of Formula IA can be prepared by further substituting the N- in the corresponding compound of Formula IB with the corresponding X group; and compounds of Formula IC can be prepared by acylation of the aniline nitrogen in the corresponding compound of Formula IB followed by reduction.
  • 4-methylamino substituted amisulpride derivatives may be prepared by reacting amisulpride with /V,/V-dimethylformamide dimethyl acetal to provide the corresponding amide, which is then reduced by a reducing agent (e.g., NaBH 4 , DMS: BH3, Red-AI, and LiAIH 4 ) to provide the corresponding 4-methylamino substituted amisulpride derivatives.
  • a reducing agent e.g., NaBH 4 , DMS: BH3, Red-AI, and LiAIH 4
  • Stereoisomers of the amisulpride derivatives disclosed herein can be prepared similarly by using the corresponding stereoisomer of amisulpride as the starting material.
  • synthesis of ((S)-4-amino-/V-((1 -ethyl-2- pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide can be carried out as described in US Patent No. 6,169,094, which is incorporated herein by reference.
  • the S isomers of the amisulpride derivatives can be prepared using the S isomer of amisulpride (Schemes 3 and 4).
  • the R isomers of the amisulpride derivatives can be similarly prepared using the R isomer of amisulpride.
  • the amisulpride derivative (di-substituted 4-amino amisulpride derivative) may be prepared by a two-step substitution of the 4-amino group.
  • the 4-amino group is substituted with a first substitution group of Z or X as shown above to provide a mono-substituted 4-amino amisulpride derivative; and then the mono-substituted 4- amino amisulpride derivative is further substituted with a second substitution at the 4-amino to provide the desired di-substituted 4-amino amisulpride derivative. See, e.g., Examples 3C and 3D.
  • Membrane permeability of 4-methylamino-/V-((1 -ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide) was measured using a PAMPA assay at pH 5 and 7.4. Specifically, 10 mM solutions of controls ranitidine (3.5 mg in 1 mL DMSO) and propanolol (2.9 mg in 1 mL DMSO), /V-methyl amisulpride (3.3 mg in 0.8 mL DMSO), and amisulpride (3.4 mg in 0.9 mL DMSO) were prepared. Diffusion across a Pion PAMPA membrane were measured at pH 5 and pH 7.4, as shown in Table 1 , respectively
  • Example 5 Binding of Compound 102 to dopamine D2 receptors (cell-based assay)
  • Dopamine D2 receptor cells were seeded in a half a black, clear- bottomed 96 well plate. At a density of 15,000 cells/well to a volume of 25 ⁇ and were left to incubate overnight. Calcium 5 dye in HEPES buffered HBSS (Hanks' balanced salt solution) was prepared and 10 ⁇ was added to each well and the mixture was left to sit at 37 °C for 1 hour. After equilibration, 5 ⁇ ⁇ of the test compound and controls were added to the wells and incubated at room temperature for 10 minutes. Fluorescence was measured every 1 .52 seconds.
  • Membrane preparations were incubated with 3 H spiperone until equilibration. Separation of bound from free radioligand was carried out using a Packard Filtermate Harvester and glass filter plates. Radioactivity was measured using a Packard Topcount.
  • 20 ⁇ _ of D2 membranes were mixed 20 ⁇ _ of 3 H spiperone and 10 ⁇ _ test compound or reference ligand in binding buffer in a nonbinding 96 well plate, and incubated for ⁇ 120 minutes. Prior to filtration, a 96 well harvest filter plate was coated with 0.33% polyethyleneimine for 30 minutes and then washed with assay buffer. The binding reaction was transferred to the filter plate and washed three times with wash buffer, dried, scintillant added, and radioactivity counted on a Topcount NXT.
  • Example 7 Binding of Compound 102 and Compound 103 to various CNS receptors (dopamine D2, dopamine D3, 2 adrenergic, and 5-HT2a receptors) (Table 4)
  • Table 4 IC50 and Ki values for Compounds 102 (LB102) and Compound 103 (LB103) against various CNS receptors in a cell based assay.
  • Example 8 Novel Object Recognition (NOR) assay showed efficacies of Compounds 102 and 103
  • Cognitive measurements, at various PO doses test agent, were taken at 3 hours post-dose for Compound 102, 103, and amisulpride and at 30 minutes for risperidone.
  • Figure 1A shows discrimination index of the NOR study obtained by the following Equation 1 :
  • Discrimination index (time spent exploring novel - time spent exploring
  • Figures 1 A and 1 B show that all doses of Compounds 102 and 103, save one, increased the difference between novel and familiar object exploration time in a manner consistent with currently used antipsychotics amisulpride and risperidone.
  • Example 9 Amphetamine-induced Locomotor Activity (LMA) assay showed efficacies of Compounds 102 and 103
  • LMA amphetamine- induced Locomotor Activity
  • Example 10 Binding of Compound 102, 103, and 104 to 5HT7 receptors
  • the R enantiomer of amisulpride (Ami(r), solid circle, Plot A, Figure 4) showed a lower Ki than the S enantiomer of amisulpride (Ami(s), solid circle, Plot C, Figure 4).
  • the amisulpride racemic mixture (Amic(rac), solid circle, Plot B, Figure 4) had a Ki lower than that of the R enantiomer of amisulpride but higher than that of the S enantiomer of amisulpride.

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Abstract

L'invention concerne un énantiomère R d'amisulpride et de dérivé d'amisulpride ou une composition pharmaceutique de celui-ci, qui peut être utilisé pour produire une action antagoniste sur un récepteur de sérotonine (par exemple, 5-HT2a, 5-HT7) chez un sujet, soit individuellement, soit en combinaison avec d'autres agents actifs du SNC. L'énantiomère R d'amisulpride et de dérivé d'amisulpride de l'invention ou une composition pharmaceutique de celui-ci peut être utilisée pour traiter une ou plusieurs conditions sensibles à la modulation d'un récepteur de la sérotonine (par exemple, 5-HT2a, 5-HT7) chez un sujet, soit individuellement, soit en combinaison avec d'autres agents actifs du SNC. L'énantiomère R d'amisulpride et de dérivé d'amisulpride de l'invention ou une composition pharmaceutique de celui-ci peut être utilisé pour traiter un ou plusieurs troubles associés à une anomalie dans les niveaux de sérotonine dans le cerveau, soit individuellement, soit en combinaison avec d'autres agents actifs du système nerveux central (SNC).
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US20050203130A1 (en) * 2003-12-02 2005-09-15 Erik Buntinx Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US20100105755A1 (en) * 2008-09-12 2010-04-29 Auspex Pharmaceuticals, Inc. Substituted benzamide modulators of dopamine receptor
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