WO2006052546A2 - Pyrazolylmethyl heteroaryl derivatives - Google Patents
Pyrazolylmethyl heteroaryl derivatives Download PDFInfo
- Publication number
- WO2006052546A2 WO2006052546A2 PCT/US2005/039488 US2005039488W WO2006052546A2 WO 2006052546 A2 WO2006052546 A2 WO 2006052546A2 US 2005039488 W US2005039488 W US 2005039488W WO 2006052546 A2 WO2006052546 A2 WO 2006052546A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- gaba
- receptor
- salt according
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 350
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9406—Neurotransmitters
- G01N33/9426—GABA, i.e. gamma-amino-butyrate
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates generally to pyrazolylmethyl heteroaryl derivatives that have useful pharmacological properties.
- the invention further relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment of central nervous system (CNS) disorders.
- CNS central nervous system
- GABA A receptors are composed of five protein subunits. A number of cDNAs for these GABA A receptor subunits have been cloned and their primary structures determined. While these subunits share a basic motif of 4 membrane-spanning helices, there is sufficient sequence diversity to classify them into several groups. To date, at least six ⁇ , three ⁇ , three ⁇ , one ⁇ , one ⁇ and two p subunits have been identified. Native GABA A receptors are typically composed of two ⁇ subunits, two ⁇ subunits and one ⁇ subunit. Various lines of evidence (such as message distribution, genome localization and biochemical study results) suggest that the major naturally occurring receptor combinations are ⁇ i ⁇ 2 ⁇ 2, 0 ⁇ 372.
- the GABA A receptor binding sites for GABA are formed by amino acids from the ⁇ and ⁇ subunits. Amino acids from the ⁇ and ⁇ subunits together form one benzodiazepine site per receptor, at which benzodiazepines exert their pharmacological activity.
- the GABA A receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site and a barbiturate site.
- the benzodiazepine site of the GABA A receptor is a distinct site on the receptor complex that does not overlap with the sites of interaction for other classes of drugs or GABA.
- GABA A receptor antagonists In a classic allosteric mechanism, the binding of a drug to the benzodiazepine site alters the affinity of the GABA receptor for GABA.
- Benzodiazepines and related drugs that enhance the ability of GABA to open GABA A receptor channels are known as agonists or partial agonists, depending on the level of GABA enhancement.
- Other classes of drugs, such as ⁇ -carboline derivatives, that occupy the same site and negatively modulate the action of GABA are called inverse agonists.
- Those compounds that occupy the same site, and yet have little or no effect on GABA activity, can block the action of agonists or inverse agonists and are thus referred to as GABA A receptor antagonists.
- R 2 and R 3 are independently chosen from Rc; or (ii) Z is nitrogen and R 2 is taken together with Z to form a fused, 5-membered heteroaryl that contains 2 or 3 ring nitrogen atoms, with remaining ring atoms being carbon, and that is substituted with from 0 to 3 substituents independently chosen from R 4 ; or (iii) X is nitrogen and R 2 is taken together with X to form a fused, 5-membered heteroaryl that contains 1, 2 or 3 ring nitrogen atoms, with remaining ring atoms being carbon, and that is substituted with from 0 to 3 substituents independently chosen from R 4 ; and R 3 is chosen from Rc; or (iv) Y is nitrogen and R 3 is taken together with Y to form a fused 5-membered heteroaryl that contains 2 or 3 ring nitrogen atoms, with remaining ring atoms being carbon, and that is substituted with from 0 to 3 substituents independently chosen from R 4 ; Each R 4 is independently chosen from
- R 8 represents 0, 1 or 2 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, Ci-C 4 alkyl, Ci-C 4 alkoxy, mono- and di(Ci-C 4 alkyl)amino, C 3 -C 7 Cycloalkyl, Ci-C 2 haloalkyl and
- Ci-C 2 haloalkoxy Each Rc is independently chosen from:
- L is absent, a single covalent bond or CpCgalkylene
- R B O ,0 (e.g., N-S- ); wherein m is 0, 1 or 2;
- R A and each R B are independently selected from: (i) hydrogen;
- Ci-C 8 alkyl C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, (3- to 7- membered heterocycloalkyl)Co-C 4 alkyl, (C 6 -Cioaryi)Co-C 2 alkyl and (5- to 10- membered heteroaryl)Co-C 2 alkyl, each of which is optionally substituted, and is preferably substituted with from O to 4 substituents independently selected from halogen, hydroxy, nitro, cyano, amino, oxo, Ci-C 4 alkyl, Ci-C 4 alkoxy, C)-C 4 alkanoyl, mono- and di(C r C 4 alkyl)amino, Ci-C 4 haloalkyl and Ci-C 4 haloalkoxy; and
- Ar represents phenyl, naphthyl or 5- to 10-membered heteroaryl, each of which is optionally substituted, and is preferably substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, aminocarbonyl, Ci-C 8 alkyl, Ci-C 8 alkenyl, CpQalkynyl,
- such compounds are GABA A receptor modulators provided herein that modulate GABA A receptor activation and/or GABA A receptor-mediated signal transduction.
- GABA A receptor modulators are preferably high affinity and/or high selectivity GABA A receptor ligands and act as agonists, inverse agonists or antagonists of GABA A receptors, such as human GABA A receptors. As such, they are useful in the treatment of various CNS disorders.
- the present invention provides pharmaceutical compositions comprising one or more compounds or salts as described above in combination with a pharmaceutically acceptable carrier, diluent or excipient.
- the present invention further provides, within other aspects, methods for treating patients suffering from certain CNS disorders, such as anxiety, depression, a sleep disorder, sleepwalking, attention deficit disorder, schizophrenia or a cognitive disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Formula I.
- CNS disorders such as anxiety, depression, a sleep disorder, sleepwalking, attention deficit disorder, schizophrenia or a cognitive disorder
- the invention provides methods of potentiating the action of other CNS active compounds. These methods comprise administering to a patient a therapeutically effective amount of a compound or salt of Formula I in conjunction with the administration of a therapeutically effective amount of a different CNS active compound.
- the present invention further relates to the use of compounds and salts of Formula I as probes for the localization of GABA A receptors in sample (e.g., a tissue section).
- GABA A receptors are detected using autoradiography.
- the present invention provides methods for determining the presence or absence of GABA A receptor in a sample, comprising the steps of: (a) contacting a sample with a compound or salt of Formula I under conditions that permit binding of the compound to GABA A receptor; (b) removing compound or salt that is not bound to the GABA A receptor and (c) detecting compound or salt bound to GABA A receptor.
- the present invention provides methods for preparing the compounds disclosed herein, including the intermediates.
- the present invention provides compounds and salts of Formula I.
- Certain preferred compounds bind to GABA A receptor, preferably with high selectivity; more preferably such compounds further provide beneficial modulation of brain function.
- GABA A receptor preferably with high selectivity; more preferably such compounds further provide beneficial modulation of brain function.
- Such compounds may be used in vitro or in vivo to determine the location of GABA A receptors or to modulate GABA A receptor activity in a variety of contexts.
- isotopes of hydrogen include tritium and deuterium
- isotopes of carbon include 11 C, 13 C and 14 C.
- a “pharmaceutically acceptable salt” is an acid or base salt form of a compound, which salt form is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication.
- Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
- Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH 2 ) n -COOH where n is 0- 4, and the like.
- acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric
- pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
- pharmaceutically acceptable salts for the compounds provided herein, including those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985).
- a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, EtOAc, EtOH, isopropanol or acetonitrile, is preferred.
- nonaqueous media such as ether, EtOAc, EtOH, isopropanol or acetonitrile
- prodrugs of the compounds of Formula I are a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound of Formula I, or other formula provided herein.
- Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino or sulfhydryl group, respectively.
- a prodrug may be an acylated derivative of a compound of Formula I.
- prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
- Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
- a “substituent,” as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest.
- a “ring substituent” may be a moiety such as a halogen, alkyl group, haloalkyl group or other substituent discussed herein that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member.
- substitution refers to replacing a hydrogen atom in a molecular structure with a substituent as described above, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.
- 2 hydrogens on the atom are replaced.
- aromatic moieties are substituted with an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring.
- a pyridyl group substituted with oxo is a pyridone.
- alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups; where specified, such a group has the indicated number of carbon atoms.
- Ci-C 6 alkyl indicates an alkyl group having from 1 to 6 carbon atoms.
- Co-C 4 alkyl refers to a single covalent bond or a C r C 4 alkyl group.
- Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-Csalkyl), from 1 to 6 carbon atoms (Ci-C 6 alkyl) and from 1 to 4 carbon atoms (Ci-C 4 alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.
- preferred alkyl groups are methyl, ethyl, propyl, butyl and 3-pentyl.
- Alkylene refers to a divalent alkyl group, as defined above.
- C 0 -C 3 alkylene is a single covalent bond or an alkylene group having 1, 2 or 3 carbon atoms.
- Alkenyl refers to a straight or branched hydrocarbon chain comprising one or more carbon- carbon double bonds, such as ethenyl and propenyl.
- Alkenyl groups include C 2 -C 8 alkenyl, C 2 - C ⁇ alkenyl and C 2 -C 4 alkenyl groups (which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively), such as ethenyl, allyl or isopropenyl.
- Alkynyl refers to straight or branched hydrocarbon chains comprising one or more carbon- carbon triple bonds.
- Alkynyl groups include C 2 -Csalkynyl, C 2 -C 6 alkynyl and C 2 -C 4 alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
- Alkynyl groups include, for example, groups such as ethynyl and propynyl.
- alkoxy as used herein, is meant an alkyl group as described above attached via an oxygen bridge.
- Alkoxy groups include Ci-Cgalkoxy and Ci-C 4 alkoxy groups, which have from 1 to 6 or 1 to 4 carbon atoms, respectively.
- Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-bntoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy are specific alkoxy groups.
- alkylthio refers to an alkyl group attached via a sulfur bridge.
- a “cycloalkyl” is a saturated or partially saturated cyclic group in which all ring members are carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, and partially saturated variants of any of the foregoing, such as cyclohexenyl.
- Cycloalkyl groups typically contain from 3 to about 10 ring carbon atoms; in certain embodiments, such groups have from 3 to 7 ring carbon atoms (i.e., C 3 - C 7 cycloalkyl). If substituted, any ring carbon atom may be bonded to any indicated substituent.
- (cycloalkyl)alkyl In the term "(cycloalkyl)alkyl,” "cycloalkyl” and “alkyl” are as defined above, and the point of attachment is on the alkyl group. Certain such groups are (C 3 -C 8 cycloalkyl)Co-C 4 alkyl and (C 3 - C 7 cycloalkyl)C 0 -C 4 alkyl, in which the cycloalkyl group of the indicated ring size is linked via a single covalent bond or a Ci-C 4 alkylene group. This term encompasses, for example, cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.
- (C 3 -C 7 cycloalkyl)Ci-C 4 alkoxy refers to a C 3 - C 7 cycloalkyl group linked via a C [ ⁇ alkoxy, in which the oxygen atom is the point of attachment (/.e., (C 3 -C 7 cycloalkyl)CrC 4 alkyl-O-).
- alkanoyl refers to an alkyl group as defined above attached via a carbonyl bridge
- alkyl ether refers to a linear or branched ether substituent linked via a carbon- carbon bond.
- Alkyl ether groups include C 2 -Cgallcyl ether, C 2 -C ⁇ alkyl ether and C 2 -C 4 alkyl ether groups, which have 2 to 8, 6 or 4 carbon atoms, respectively.
- a C 2 alkyl ether group has the structure -CH 2 -O-CH 3 .
- Alkoxycarbonyl groups include Ci-C 8 , C 1 -C 6 and Q- C 4 alkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group.
- Ci-C 8 C 1 -C 6 and Q- C 4 alkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group.
- Ci-C 8 Ci-C 8 , C 1 -C 6 and Q- C 4 alkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group.
- “Mono- or di-(C r C 6 alkyl)aminocarbonyl” is an aminocarbonyl group in which one or both of the hydrogen atoms is replaced with Ci-C 6 alkyl. If both hydrogen atoms are so replaced, the Ci-C ⁇ alkyl groups may be the same or different.
- Alkylamino refers to a secondary or tertiary amine substituent having the general structure
- each alkyl may be the same or different.
- groups include, for example, mono- and di-(Ci-C 6 alkyl)amino groups (in which each alkyl may be the same or different and may contain from 1 to 6 carbon atoms), as well as mono- and di-(C r C 4 alkyl)amino groups and mono- and di-(Ci-C 2 alkyl)amino groups.
- Alkylaminoalkyl refers to an alkylamino group linked via an alkyl group (i.e., a group having the general structure -alkyl-NH-alkyl or -alkyl-N(alkyl)(alkyl)). Such groups include, for example, mono- and di-(Ci-C 8 alkyl)aminoCi-C 8 alkyl, in which each alkyl may be the same or different. "Mono- or di-(Ci-C 8 alkyl)aminoCo-C 8 alkyl” refers to a mono- or di-(C r C8alkyl)amino group linked via a single covalent bond or a CpCgalkylene group. The following are representative alkylaminoalkyl groups:
- halogen refers to fluorine, chlorine, bromine and iodine.
- a “haloalkyl” is a branched or straight-chain alkyl group, substituted with 1 or more halogen atoms (e.g., "Ci-Cghaloalkyl” groups have from 1 to 8 carbon atoms; "Ci-C 2 haloalkyl” groups have from 1 to 2 carbon atoms).
- aryl indicates aromatic groups containing only carbon in the aromatic ring(s). Such aromatic groups may be further substituted with carbon or non-carbon atoms or groups. Typical aryl groups contain 1 to 3 separate, fused, spiro or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. Preferred aryl groups are 6- to 12- membered groups and 6- to 10-membered groups, such as phenyl, naphthyl (including 1-naphthyl and 2-naphthyl) and biphenyl.
- Arylalkyl groups are aryl groups linked via an alkylene.
- Such groups include, for example, (C 6 -Cioaryl)C 0 -C 2 alkyl groups, which are 6- to 10-membered groups liked via a single covalent bond or a methylene or ethylene moiety.
- Arylalkoxy groups are aryl groups linked via an alkoxy moiety.
- phenylCi-C 2 alkoxy refers to benzyloxy or phenylethoxy (also known as phenethyloxy).
- heterocycle or “heterocyclic group” is used to indicate saturated, partially unsaturated or aromatic groups having 1 or 2 rings, with 3 to 8 atoms in each ring, and in at least one ring from 1 to 4 heteroatoms independently chosen from oxygen, sulfur and nitrogen.
- heteroaryl groups include pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl and 5,6,7,8-tetrahydroisoquinoline.
- Bicyclic heteroaryl groups may, but need not, contain a saturated ring in addition to the aromatic ring (e.g., tetrahydroquinolinyl or tetrahydroisoquinolinyl).
- a "5- or 6-membered heteroaryl” is a monocyclic heteroaryl having 5 or 6 ring members.
- heterocycloalkyl i.e., saturated or partially saturated heterocycles, that do not contain a heteroaryl group.
- Heterocycloalkyl groups generally have from 3 to about 8 ring atoms, and more typically from 3 to 7 (or from 5 to 7) ring atoms. Examples of heterocycloalkyl groups include morpholinyl, thiomorpholinyl, piperazinyl, piperadinyl and pyrrolidinyl.
- a (3- to 7-membered heterocycle)Co-C 4 alkyl is a heterocycle having from 3 to 7 ring members that is linked via a single covalent bond or a Ci-C 4 alkylene group.
- a (3- to 7-membered heterocycloalkyl)Co-C 4 alkyl group is a heterocycloalkyl group having from 3 to 7 ring members that is linked via a single covalent bond or a Ci-C 4 alkylene group.
- a (5- to 10-membered heterocycloalkyl)Co-C 2 alkyl group is a heteroaryl group having from 5 to 10 ring members that is linked via a single covalent bond or a methylene or ethylene group.
- GABA A receptor subtypes that fall within the scope of the term "GABA A receptor.” These subtypes include, but are not limited to, ⁇ 2 ⁇ 3 g2 , ⁇ 3 ⁇ 3 $ z, ⁇ 5 ⁇ 3 g2 and ⁇ i ⁇ 2 g2 receptor subtypes.
- GABA A receptors may be obtained from a variety of sources, such as from preparations of rat cortex or from cells expressing cloned human GABA A receptors. Particular subtypes may be readily prepared using standard techniques (e.g., by introducing mRNA encoding the desired sub units into a host cell, as described herein).
- An "agonist" of a GABA A receptor is a compound that enhances the activity of GABA at the
- An "inverse agonist" of a GABA A receptor is a compound that reduces the activity of GABA at the GABA A receptor. Inverse agonists, but need not, may also inhibit binding of GABA to the GABA A receptor. The reduction of GABA-induced GABA A receptor activity may be determined from an electrophysiological assay such as the assay of Example 9.
- GABA A receptor antagonist activity may be determined using a combination of a suitable GABA A receptor binding assay, such as the assay provided in Example 8, and a suitable functional assay, such as the electrophysiological assay provided in Example 9, herein.
- a GABA A receptor modulator is said to have "high affinity” if the K 1 at a GABA A receptor is less than 1 micromolar, preferably less than 100 nanomolar or less than 10 nanomolar.
- a representative assay for determining K 1 at GABA A receptor is provided in Example 8, herein. It will be apparent that the K 1 may depend upon the receptor subtype used in the assay. In other words, a high affinity compound may be "subtype-specific" (i.e., the K 1 is at least 10-fold greater for one subtype than for another subtype). Such compounds are said to have high affinity for GABA A receptor if the K 1 for at least one GABA A receptor subtype meets any of the above criteria.
- a GABA A receptor modulator is said to have "high selectivity" if it binds to at least one subtype of GABAA receptor with a Kj that is at least 10-fold lower, preferably at least 100-fold lower, than the K, for binding to other (i.e., not GABA A ) membrane-bound receptors.
- a compound that displays high selectivity should have a K 1 that is at least 10-fold greater at the following receptors than at a GABA A receptor: serotonin, dopamine, galanin, VRl, C5a, MCH, NPY, CRF, bradykinin and tackykinin.
- a “CNS disorder” is a disease or condition of the central nervous system that is responsive to GABA A receptor modulation in the patient.
- Such disorders include anxiety disorders (e.g., panic disorder, obsessive compulsive disorder, agoraphobia, social phobia, specific phobia, dysthymia, adjustment disorders, separation anxiety, cyclothymia and generalized anxiety disorder), stress disorders (e.g., post-traumatic stress disorder, anticipatory anxiety acute stress disorder and acute stress disorder), depressive disorders (e.g., depression, atypical depression, bipolar disorder and depressed phase of bipolar disorder), sleepwalking, sleep disorders (e.g., primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression, anxiety and/or other mental disorders and substance-induced sleep disorder), cognitive disorders (e.g., cognition impairment, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), schizophrenia, traumatic brain injury, Down's Syndrome, neuro
- a “therapeutically effective amount” is an amount that, upon administration to a patient, results in a discernible patient benefit (e.g., diminution of one or more symptoms of a CNS disorder or inducing a desired effect on sleep). Such an amount or dose generally results in a concentration of compound in cerebrospinal fluid that is sufficient to inhibit the binding of GABA A receptor ligand to GABA A receptor in vitro, as determined using the assay described in Example 8. It will be apparent that the therapeutically effective amount for a compound will depend upon the indication for which the compound is administered, as well as any co-administration of other CNS agent(s).
- a "patient” is any individual treated with a compound provided herein. Patients include humans, as well as other vertebrate animals such as companion animals and livestock. Patients may be afflicted with a CNS disorder, or may be free of such a condition (i.e., treatment may be prophylactic or soporific).
- Rs represents 0 substituents or 1 substituent selected from halogen, C r C 2 alkyl and d-C 2 alkoxy.
- Ar within certain compounds of Formula I and other formulas provided herein, is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, hydroxy, amino, cyano, aminocarbonyl, Ci-C 4 alkyl, Ci-C 4 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, C 2 -C 4 alkanoyl, (C 3 - C 7 cycloalkyl)Co-C 2 alkyl, C r C 4 ammoalkyl, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy and 5-membered heteroaryl.
- Ar represents phenyl, pyridin-2-yl, l,3-thiazol-2-yl, thien-2-yl or pyridazin-3-yl, each of which is substituted with from 0 to 3 substituents independently selected from fluoro, chloro, bromo, hydroxy, aminocarbonyl, thiazolyl, aminomethyl, methyl, ethyl, cyano, methoxy and ethoxy.
- Ar groups include, for example, 3-cyano-phenyl, pyridin-2-yl, 3-fluoro-pyridin-2-yl, 3-bromo- pyridin-2-yl, 3-chloro-pyridin-2-yl, 3-cyano-pyridin-2-yl, 3-aminomethyl-pyridin-2-yl, 3- aminocarbonyl-pyridin-2-yl, 3-thiazolyl-pyridin-2-yl, 6-fluoro-pyridin-2-yl and 6-cyano-pyridin-2-yl.
- R 1 , R 2 and R 3 are independently selected from:
- R A and R B are independently selected from (1) hydrogen and (2) Ci-C ⁇ alkyl, C 2 - C 6 alkenyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl, phenylCo-Qalkyl and (5- or 6-membered heteroaryl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, cyano, amino, C r C 2 alkyl and d-Caalkoxy.
- Ri, R 2 and R 3 are independently selected from hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl, nitro, Q-C ⁇ alkyl, CrC ⁇ alkenyl, CpC ⁇ alkoxy, C 2 - C 6 alkyl ether, C 3 -C 7 cycloalkylC 0 -C 4 alkyl, C 3 -C 7 cycloalkylCi-C 4 alkoxy, Ci-C 4 hydroxyalkyl, Q- C 6 haloalkyl, Ci-C ⁇ haloalkoxy, mono- or di-(C r C 6 alkyl)amino CpCealkanoyl, Ci-C ⁇ alkoxycarbonyl, mono- and di-(C r C 4 alkyl)amino, phenylC 0 -C 4 alkyl, phenylC r C 4 alkoxy, thienyl, pyridyl, pyrimidiny
- Certain compounds of Formula I further satisfy Formula II, in which Y is N, Z is CR 3 , and R 3 is taken together with Y to form a fused 5-membered heteroaryl:
- Z u Z 2 and Z 3 are independently nitrogen or CR 4 such that exactly one or two of Zi, Z 2 and Z 3 are nitrogen. In certain such compounds, Zi and Z 3 are nitrogen and Z 2 is CR 4 (i.e., compounds of Formula Ha).
- Zi is nitrogen and Z 2 and Z 3 are independently chosen from CR 4 (i.e., compounds of Formula lib).
- FormulaIIb Within further compounds of Formula II, Zi is CR 4 , Z 2 is nitrogen and Z 3 is CR 4 (i.e., compounds of Formula lie).
- Z ⁇ and Z 2 are CR 4 , and Z 3 is nitrogen (i.e., compounds of Formula He) .
- W is CH 2 .
- Certain compounds of Formula I further satisfy Formula III, in which Z is N, Y is CR 2 , and R 2 is taken together with Z to form a fused 5-membered heteroaryl: Formula III
- Z,, Z 2 and Z 3 are independently nitrogen or CR 4 such that exactly one or two of Z], Z 2 and Z 3 are nitrogen.
- Zi is CR 4 and Z 2 and Z 3 are nitrogen.
- Zi is nitrogen
- Z 2 is CR 4
- Z 3 is nitrogen
- Zi is CR 4
- Z 2 is nitrogen
- Z 3 is CR 4 .
- Zi and Z 2 are CR 4 , and Z 3 is nitrogen.
- Zi and Z 2 are independently nitrogen or CR 4 such that exactly one or two of Zi and Z 2 are nitrogen.
- R 1 if present, is hydrogen, methyl or ethyl
- GABA A receptor preparation is incubated with labeled ⁇ e.g., 3 H) ligand, such as Flumazenil, and unlabeled test compound. Incubation with a compound that detectably modulates ligand binding to GABA A receptor will result in a decrease or increase in the amount of label bound to the GABA A receptor preparation, relative to the amount of label bound in the absence of the compound.
- labeled ⁇ e.g., 3 H
- ligand such as Flumazenil
- preferred compounds provided herein have favorable pharmacological properties, including oral bioavailability (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose, preferably less than 2 grams, more preferably less than or equal to one gram or 200 mg, can provide a detectable in vivo effect), low toxicity (a preferred compound is nontoxic when a therapeutically effective amount is administered to a subject), minimal side effects (a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject), low serum protein binding, and a suitable in vitro and in vivo half-life (a preferred compound exhibits an in vivo half-life allowing for Q. I. D. dosing, preferably T.I. D.
- certain preferred compounds do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP 1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to the EC 5 0 or IC 50 for the compound.
- Such compounds are identical to those described above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that can be incorporated into compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
- the present invention also provides pharmaceutical compositions comprising at least one compound or salt of Formula I, together with at least one physiologically acceptable carrier or excipient.
- Such pharmaceutical compositions may be used to treat patients in which GABA A receptor modulation is desirable (e.g., patients undergoing painful procedures who would benefit from the induction of amnesia, or those suffering from CNS disorders such as anxiety, depression, sleepwalking, sleep disorders or cognitive impairment).
- compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide appealing and palatable preparations.
- Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
- excipients include, for example, inert diluents to increase the bulk weight of the material to be tableted (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents that modify the disintegration rate in the environment of use (e.g., corn starch, starch derivatives, alginic acid and salts of carboxymethylcellulose), binding agents that impart cohesive qualities to the powdered material(s) (e.g., starch, gelatin, acacia and sugars such as sucrose, glucose, dextrose and lactose) and lubricating agents (e.g., magnesium stearate, calcium stearate, stearic acid or talc). Tablets may be formed using standard techniques, including dry granulation, direct compression and wet granulation. The tablets may be uncoated or they may be coated by known techniques.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).
- an inert solid diluent e.g., calcium carbonate, calcium phosphate or kaolin
- an oil medium e.g., peanut oil, liquid paraffin or olive oil
- Aqueous suspensions comprise the active materials in admixture with one or more suitable excipients, such as suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate).
- suspending agents e.g., sodium
- Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents and/or flavoring agents may be added to provide palatable oral preparations.
- Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.
- compositions may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil (e.g., olive oil or arachis oil) or a mineral oil (e.g., liquid paraffin) or a mixture thereof.
- Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
- sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
- a pharmaceutical composition may be prepared as a sterile injectible aqueous or oleaginous suspension.
- the compound(s) provided herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
- Such a composition may be formulated according to the known art using suitable dispersing, wetting agents and/or suspending agents such as those mentioned above.
- suitable dispersing, wetting agents and/or suspending agents such as those mentioned above.
- the acceptable vehicles and solvents that may be employed are water, 1,3- butanediol, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils may be employed as a solvent or suspending medium.
- any bland fixed oil may be employed, including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.
- compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofluoromethane).
- a conventional propellant e.g., dichlorodifluoromethane or trichlorofluoromethane.
- Pharmaceutical compositions may be formulated as controlled release formulations (i.e., a formulation such as a capsule, tablet or coated tablet that slows and/or delays release of active ingredient(s) following administration), which may be administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at a target site.
- a controlled release formulation comprises a matrix and/or coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and thereby provides a delayed action or a sustained action over a longer period.
- One type of controlled-release formulation is a sustained-release formulation, in which at least one active ingredient is continuously released over a period of time at a constant rate.
- the therapeutic agent is released at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic levels, over a period of time that is at least 4 hours, preferably at least 8 hours, and more preferably at least 12 hours.
- Controlled release may be achieved by combining the active ingredient(s) with a matrix material that itself alters release rate and/or through the use of a controlled-release coating.
- the release rate can be varied using methods well known in the art, including (a) varying the thickness or composition of coating, (b) altering the amount or manner of addition of plasticizer in a coating, (c) including additional ingredients, such as release-modifying agents, (d) altering the composition, particle size or particle shape of the matrix, and (e) providing one or more passageways through the coating.
- the amount of modulator contained within a sustained release formulation depends upon, for example, the method of administration (e.g., the site of implantation), the rate and expected duration of release and the nature of the condition to be treated or prevented.
- the matrix material which itself may or may not serve a controlled-release function, is generally any material that supports the active ingredient(s).
- a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
- Active ingredient(s) may be combined with matrix material prior to formation of the dosage form (e.g., a tablet).
- active ingredient(s) may be coated on the surface of a particle, granule, sphere, microsphere, bead or pellet that comprises the matrix material. Such coating may be achieved by conventional means, such as by dissolving the active ingredient(s) in water or other suitable solvent and spraying.
- additional ingredients are added prior to coating (e.g., to assist binding of the active ingredient(s) to the matrix material or to color the solution).
- the matrix may then be coated with a barrier agent prior to application of controlled-release coating. Multiple coated matrix units may, if desired, be encapsulated to generate the final dosage form.
- a controlled release is achieved through the use of a controlled release coating (i.e., a coating that permits release of active ingredient(s) at a controlled rate in aqueous medium).
- the controlled release coating should be a strong, continuous film that is smooth, capable of supporting pigments and other additives, non-toxic, inert and tack-free.
- Coatings that regulate release of the modulator include pH-independent coatings, pH-dependent coatings (which may be used to release modulator in the stomach) and enteric coatings (which allow the formulation to pass intact through the stomach and into the small intestine, where the coating dissolves and the contents are absorbed by the body).
- pH dependent coatings include, for example, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid ester copolymers and zein.
- Representative aqueous dispersions of ethylcellulose include, for example, AQUACOAT ⁇ (FMC Corp., Philadelphia, PA) and SURELEASE® (Colorcon, Inc., West Point, PA), both of which can be applied to the substrate according to the manufacturer's instructions.
- Representative acrylic polymers include, for example, the various EUDRAGIT® (Rohm America, Piscataway, NJ) polymers, which may be used singly or in combination depending on the desired release profile, according to the manufacturer's instructions.
- the physical properties of coatings that comprise an aqueous dispersion of a hydrophobic material may be improved by the addition or one or more plasticizers.
- Suitable plasticizers for alkyl celluloses include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin.
- Suitable plasticizers for acrylic polymers include, for example, citric acid esters such as triethyl citrate and tributyl citrate, diputyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
- Controlled-release coatings are generally applied using conventional techniques, such as by spraying in the form of an aqueous dispersion.
- the coating may comprise pores or channels or to facilitate release of active ingredient. Pores and channels may be generated by well known methods, including the addition of organic or inorganic material that is dissolved, extracted or leached from the coating in the environment of use.
- Compounds provided herein are generally present within a pharmaceutical composition in a therapeutically effective amount, as described above.
- Compositions providing dosage levels ranging from about 0.1 mg to about 140 mg per kilogram of body weight per day are preferred (about 0.5 mg to about 7 g per human patient per day).
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
- Optimal dose for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time and route of administration; the rate of excretion; any simultaneous treatment, such as a drug combination; and the type and severity of the particular disease undergoing treatment. Optimal dosages may be established using routine testing and procedures that are well known in the art.
- compositions may be packaged for treating a CNS disorder such as anxiety, depression, sleepwalking, a sleep disorder, attention deficit disorder or a cognitive disorder such as short-term memory loss or Alzheimer's dementia.
- Packaged pharmaceutical preparations include a container holding a therapeutically effective amount of at least one compound as described herein and instructions (e.g., labeling) indicating that the contained composition is to be used for treating the CNS disorder.
- a dosage regimen of 4 times daily or less is preferred.
- a single dose that rapidly reaches a concentration in cerebrospinal fluid that is sufficient to inhibit the binding of GABA A receptor ligand to GABA A receptor in vitro is desirable.
- Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
- compounds provided herein are used to treat patients with an existing CNS disorder.
- such patients are treated with a therapeutically effective amount of a compound of Formula I (or a pharmaceutically acceptable salt thereof); preferably the amount is sufficient to alter one or more symptoms of a CNS disorder.
- Compounds that act as agonists at 0 ⁇ 3 7 2 and oi 3 p 3 Y 2 receptor subtypes are particularly useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress and acute stress disorders.
- CNS disorders that can be treated using compounds and compositions provided herein include:
- Sleepwalking and Sleep disorders e.g., primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, and substance induced sleep disorder.
- Representative treatable symptoms of sleep disorders include, for example, difficulty falling asleep, excessive waking during the night, waking too early and waking feeling unrefreshed.
- Neurodegenerative Disorders e.g., Alzheimer's disease, Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), reflex sympathetic dystrophy (RSD), spastic paralysis, hypokinesia, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke (e.g., acute thromboembolic stroke, focal ischemia, global ischemia, transient cerebral ischemic attacks and other cerebrovascular problems accompanied by cerebral ischemia), traumatic brain injury, spinal cord trauma, asphyxia, injury from general anoxia, hypoxia, hypoglycemia or hypotension, AIDS associated dementia, and dementia associated with depression, anxiety and psychosis (including schizophrenia and hallucinatory disorders).
- Alzheimer's disease Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), reflex sympathetic dystrophy (RSD), spastic paralysis, hypokinesia, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke (e.g., acute
- Speech and Movement Disorders e.g., motor tic, clonic stuttering, dysfiuency, speech blockage, dysarthria, Tourette's Syndrome and logospasm, restless leg syndrome, periodic limb movements in sleep (PLMS), periodic limb movement disorder (PLMD), muscle spasm, essential tremor, acquired nystagmus, post-anoxic myoclonus, spinal myoclonus, spasticity, chorea and dystonia.
- PLMS periodic limb movements in sleep
- PLMD periodic limb movement disorder
- muscle spasm e.g., anoxic myoclonus, spinal myoclonus, spasticity, chorea and dystonia.
- the present invention provides methods for potentiating the action (or therapeutic effect) of other CNS agent(s). Such methods comprise administering a therapeutically effective amount of a compound provided herein in combination with a therapeutically effective amount of another CNS agent.
- the present invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by co-administering a therapeutically effective amount of a GABA A agonist compound provided herein in combination with an SSRI.
- a therapeutically effective amount of compound, when co-administered with another CNS agent, is an amount sufficient to result in a detectable change in patient symptoms, when compared to a patient treated with the other CNS agent alone.
- the present invention also pertains to methods of inhibiting the binding of benzodiazepine compounds (i.e., compounds that comprise the benzodiazepine ring structure), such as RO15-1788 or GABA, to GABA A receptor.
- benzodiazepine compounds i.e., compounds that comprise the benzodiazepine ring structure
- Such methods involve contacting cells expressing GABA A receptor with a concentration of compound provided herein that is sufficient to inhibit the binding of GABA A receptor ligand to GABA A receptor in vitro, as determined using the assay described in Example 8.
- This method includes, but is not limited to, inhibiting the binding of benzodiazepine compounds to GABA A receptors in vivo (e.g., in a patient given an amount of a GABA A receptor modulator provided herein that results in a concentration of compound in cerebrospinal fluid that is sufficient to inhibit the binding of benzodiazepine compounds or GABA to GABA A receptor in vitro).
- a GABA A receptor modulator provided herein that results in a concentration of compound in cerebrospinal fluid that is sufficient to inhibit the binding of benzodiazepine compounds or GABA to GABA A receptor in vitro.
- Such methods are useful in treating benzodiazepine drug overdose.
- the amount of GABA A receptor modulator that is sufficient to inhibit the binding of a benzodiazepine compound to GABA A receptor may be readily determined via a GABA A receptor binding assay as described in Example 8.
- the present invention provides a variety of in vitro uses for the GABA A receptor modulators provided herein.
- such compounds may be used as probes for the detection and localization of GABA A receptors, in samples such as tissue sections, as positive controls in assays for receptor activity, as standards and reagents for determining the ability of a candidate agent to bind to GABA A receptor, or as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
- PET positron emission tomography
- SPECT single photon emission computerized tomography
- Such assays can be used to characterize GABA A receptors in living subjects.
- Such compounds are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to GABA A receptor.
- a sample may be incubated with a compound as provided herein under conditions that permit binding of the compound to GABA A receptor.
- the amount of compound bound to GABA A receptor in the sample is then detected.
- the compound may be labeled using any of a variety of well known techniques ⁇ e.g., radiolabeled with a radionuclide such as tritium, as described herein), and incubated with the sample (which may be, for example, a preparation of cultured cells, a tissue preparation or a fraction thereof).
- a suitable incubation time may generally be determined by assaying the level of binding that occurs over a period of time.
- unbound compound is removed, and bound compound detected using any method suitable for the label employed (e.g., autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods may be used to detect luminescent groups and fluorescent groups).
- a matched sample may be simultaneously contacted with radiolabeled compound and a greater amount of unlabeled compound. Unbound labeled and unlabeled compound is then removed in the same fashion, and bound label is detected. A greater amount of detectable label in the test sample than in the control indicates the presence of GABA A receptor in the sample.
- Detection assays including receptor autoradiography (receptor mapping) of GABA A receptors in cultured cells or tissue samples may be performed as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York.
- compounds provided herein may be used for detecting GABA A receptors in cell or tissue samples. This may be done using matched cell or tissue samples that have not previously been contacted with a GABA A receptor modulator, at least one of which is prepared as an experimental sample and at least one of which is prepared as a control sample.
- An experimental sample is prepared by contacting (under conditions that permit binding of RO 15- 1788 to GABA A receptors within cell and tissue samples) a sample with a detectably-labeled compound of Fo ⁇ nula I.
- a control sample is prepared in the same manner as the experimental sample, except that it is also is contacted with unlabelled compound at a molar concentration that is greater than the concentration of labeled modulator.
- the detectably-labeled GABA A receptor modulator used in this procedure may be labeled with a radioactive label or a directly or indirectly luminescent label.
- tissue sections are used in this procedure and the label is a radiolabel, the bound, labeled compound may be detected autoradiographically.
- Compounds provided herein may also be used within a variety of well known cell culture and cell separation methods. For example, compounds may be linked to the interior surface of a tissue culture plate or other cell culture support, for use in immobilizing GABA A receptor-expressing cells for screens, assays and growth in culture. Such linkage may be performed by any suitable technique, such as the methods described above, as well as other standard techniques.
- Compounds may also be used to facilitate cell identification and sorting in vitro, permitting the selection of cells expressing a GABA A receptor.
- the compound(s) for use in such methods are labeled as described herein.
- a compound linked to a fluorescent marker such as fluorescein
- FACS fluorescence activated cell sorting
- methods are provided for modulating binding of ligand to a GABA A receptor in vitro or in vivo, comprising contacting a GABA A receptor with a sufficient amount of a GABA A receptor modulator provided herein, under conditions suitable for binding of ligand to the receptor.
- the GABA A receptor may be present in solution, in a cultured or isolated cell preparation or within a patient.
- the GABA A receptor is a present in the brain of a mammal.
- the amount of compound contacted with the receptor should be sufficient to modulate ligand binding to GABA A receptor in vitro within, for example, a binding assay as described in Example 8.
- An effect on signal- transducing activity may be detected as an alteration in the electrophysiology of the cells, using standard techniques.
- the amount or concentration of a compound that is sufficient to alter the signal- transducing activity of GABA A receptors may be determined via a GABA A receptor signal transduction assay, such as the assay described in Example 9.
- the cells expressing the GABA receptors in vivo may be, but are not limited to, neuronal cells or brain cells. Such cells may be contacted with one or more compounds provided herein through contact with a body fluid containing the compound, for example through contact with cerebrospinal fluid.
- Intracellular recording or patch-clamp recording may be used to quantitate changes in electrophysiology of cells.
- a reproducible change in behavior of an animal given a compound as described herein may also be taken to indicate that a change in the electrophysiology of the animal's cells expressing GABA A receptors has occurred.
- starting materials are generally readily available from commercial sources, such as Sigma-Aldrich Corp. (St. Louis, MO), and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using known synthetic methods. Representative examples of methods suitable for preparing intermediates are set forth below in Examples 1-7.
- Scheme 1 illustrates the synthesis of compounds of formulas 6 and 7.
- Compound 1 is prepared essentially as described in J. Heterocycl. Chem. (1974) 11:295-297.
- Compound 3 is prepared essentially as described in Chem. Ber. (1985) 118:741-752 or Farmaco (1990) 45:167-186.
- Iodination of 1 with Nal/HI affords 2.
- Treatment of 3 with NaH in DMSO, followed by reaction with 2 provides 4.
- Hydrolysis and decarboxylation of 4 with 6 N HCl gives 5. Reduction of 5 with H 2 under Pd/C catalytic conditions provides 7.
- Compound 5 is converted to 6 by Suzuki or Stille coupling, or by other nucleophilic substitution.
- Scheme 2 illustrates the synthesis of compounds of formulas 10 and 11.
- Compound 8 is prepared essentially as described in Tetrahedron Lett. (1999) 40: 1405-1408 or Eur. J. Med. Chetn. Chim. Titer. (1989) 24:435-446. 8 is treated with NaH, followed by reaction with 2 to give 9. Reduction of 9 with H 2 under Pd/C catalytic conditions provides 10. 9 is converted to 11 by Suzuki or Stille coupling, or by other nucleophilic substitution.
- Scheme 3 illustrates the synthesis of pyrazines 17 and 18.
- Chloropyrazine 12 is prepared essentially as described in J. Am. Chem. Soc. (1952) 74:1580-1582.
- mCPBA treatment of 12 selectively oxidizes the nitrogen meta to the chlorine to provide 13.
- 13 reacts with 3 in the presence of NaH to produce 14, which is hydrolyzed and decarboxylated with 6 N HCl to give 15.
- 15 reacts with POCI 3 to afford chloride 16.
- Reduction of 16 with H 2 under Pd/C catalytic conditions provides 18. 16 is converted to 17 by Suzuki or Stille coupling, or by other nucleophilic substitution.
- Scheme 4 illustrates the synthesis of pyridines 26, 27 and 29.
- Nitration of 19 gives 20, which is converted to 21 by diazotization to give the diazonium bromide and thermal decomposition thereof.
- Reaction of 21 with 3 in the presence of NaH gives 22.
- Hydrolysis and decarboxylation of 22 provides 23, which is reduced with SnCl 2 to give 24.
- Diazotization of 24 in 5% H 2 SO 4 affords 25, which is reacted with alkyl halide to give 26.
- Compound 27 is prepared by diazotization of 24 to give the diazonium tetrafluoroborate and thermal decomposition.
- Diazotization of 24 in concentrated H 2 SO 4 followed by treatment with CuBr provides 28.
- 28 is converted to compounds 29 by Suzuki or Stille coupling, or by other nucleophilic substitution.
- Scheme 5 illustrates the synthesis of pyridines 26, 27 and 29.
- Scheme 11 illustrates the synthesis of triazole fused pyrazines 56.
- Treatment of 16 with hydrazine gives 55, which upon refluxing with a carboxylic acid provides 56.
- Pd/C (10%, 10 mg) is added to a solution of [2-(3-fluoro-pyridin-2-yl)-2H-pyrazol-3-yl]-(6- iodo-5-propyl-pyrimidin-4-yl)-acetic acid ethyl ester (104) (80 mg) in EtOH (10 mL). The mixture is stirred under H 2 overnight. The catalyst is removed by filtration and the filtrate is evaporated in vacuo to give 105.
- Step 3 7- ⁇ [ 1 -(3-fluoropyridin-2-yl)- 1 H-pyrazol-5-yl]methyl ⁇ -2-methyl-8-propyl[ 1 ,2,4]triazolo[ 1 ,5- c]pyrimidine (125)
- the compound 176 is synthesized via a procedure similar to that illustrated by Example ID
- Compound 180 is synthesized via a procedure similar to that illustrated by Example ID (step 3) using compound 179 as a starting material.
- Step 1 7-[2-(3-fluoro-pyridin-2-yl)-2H-pyrazol-3-ylmethyl]-8-propyl-[1.2.4]triazolo[l ,5- c]pyrimidine-2-carbaldehyde (182)
- Tributyltinthioazole (57 nig) and Pd(Ph 3 P) 4 (20 mg) are added to a solution of (2-bromo-8- propyl-[ 1 ,2,4]triazolo[l ,5-c]pyrimidin-7-yl)-[2-(3-fluoro-pyridin-2-yl)-2H-pyrazol-3-yl]-acetic acid ethyl ester (199) (50 mg) in toluene (10 niL). The mixture is degassed for 10 minutes, and then heated at 11O 0 C overnight. The solvent is removed, neutralized with 37% KF solution, and extracted with EtOAc. The combined organic layers are dried, solvent removed to give crude product, which is purified by TLC with 5% MeOH in DCM to give the product 200.
- Step 4 7- ⁇ [ 1 -(3 -fluoropyridin-2-yl)- 1 H-pyrazol-5-yl]methyl ⁇ -8-propyl-2-( 1 ,3 -thiazol-2- yl)[ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidine (201)
- the compound 201 is synthesized via the method provided in Example 2A (step 3) using compound 200 as starting material.
- 1 H NMR ⁇ (CDCl 3 ) 1.01 (t, 3H), 1.58-1.74 (m, 2H), 2.98 (t, 2H), 4.48 (s, 2H), 6.21 (s, IH), 7.33-7.38 (m, IH), 7.55 (d, IH), 7.62 (t, IH), 7.71 (s, IH), 8.05 (d, IH), 8.33 (s, IH), 9.12 (s, IH).
- Step 1 7- ⁇ [ 1 -(3-bromopyridin-2-yl)- 1 H-pyrazol-5-yl]methyl ⁇ -2-chloro-8-propyl[ 1 ,2,4]triazolo[ 1 ,5- c]pyrimidine (202)
- Step 2 7- ⁇ [ 1 -(3-bromopyridin-2-yl)- 1 H-pyrazol-5-yl]methyl ⁇ - ⁇ -propyl- ⁇ -pyrrolidin- 1 - yl[l,2,4]triazolo[l,5-c]pyrimidine (203)
- Compound 204 is synthesized via a procedure similar to that illustrated by Example ID (step 3) using compound 203 as a starting material.
- Step 1 7- ⁇ [l-(3-bromopyridin-2-yl)-lH-pyrazol-5-yl]methyl ⁇ -2-methoxy-8-propyl[l,2,4]triazolo[l,5- c]pyrimidine (208)
- Compound 209 is synthesized via a procedure similar to that illustrated by Example ID (step 3) using compound 208 as a starting material.
- Compound 210 is synthesized via a procedure similar to that illustrated by Example ID (step 3) using compound 202 as a starting material.
- Step 1 1 -(6- ⁇ [ 1 -(3-Fluoropyridin-2-yl)- 1 H-pyrazol-5-yl]methyl ⁇ -5-propylpyrimidin-4-yl)ethanone (216)
- Tributyltinvinylethylether (0.186 g) and Pd(Ph 3 P) 4 (40 mg) are added to a solution of [2-(3- fluoro-pyridin-2-yl)-2H-pyrazol-3-yl]-(6-iodo-5-propyl-pyrimidin-4-yl)-acetic acid ethyl ester (104) (0.17 g) in toluene (30 mL).
- the mixture is degassed for 10 minutes, and then heated at 110 0 C overnight.
- the solvent is removed under vacuum to obtain the crude product, which is then dissolved in 6N of HCl (10 mL) and the mixture is stirred at 6O 0 C for 3 hours.
- This compound is synthesized via a procedure similar to that illustrated in Example 5A.
- the desired compound 311 is synthesized via a similar procedure illustrated by Example ID (step 3) using compound 310 as a starting material.
- Compound 312 is synthesized following the synthetic procedure of 311 using sodium isopropoxide.
- 1 H NMR ⁇ (CDCl 3 ) 0.95 (t, 3H), 1.32 (s, 3H), 1.34 (s, 3H), 1.71 (h, 2H), 2.64 (t, 2H), 4.53 (s, 2H), 5.24 (h, IH), 6.02 (d, IH), 7.33 (dd, IH), 7.70 (d, IH), 7.80 (d, IH), 8.14 (d, IH), 8.59 (dd, IH).
- Tributyltinthioazole (30 mg) and Pd(Ph 3 P) 4 (15 mg) are added to a solution of 2-[5-(5-chloro- 3-propyl-pyrazin-2-ylmethyl)-pyrazol-l-yl]-nicotinonitrile (305) (20 mg) in toluene (10 mL). The mixture is degassed for 10 minutes, and then heated at 110 0 C overnight. The solvent is removed, neutralized with a 37% KF solution, and extracted with EtOAc. The combined organic layers are dried, and solvent is removed to give crude product, which is purified by TLC with 5% MeOH in DCM to give the product 321.
- 3-Propyl-5-nitro-pyridin-2-ylamine (404) (13.2 g, 72.8 mmol) is added to hydrobromic acid (48%, 41 mL, 362 mmol) in portion at O 0 C with vigorous stirring. The mixture is stirred until the internal temperature has dropped to -15 to -2O 0 C with an ice-salt-EtOH bath. To the mixture is added bromine (10.9 mL, 215 mmol) dropwise over 15 minutes to maintain the internal temperature below O 0 C. The resulting mixture is stirred at this temperature for 90 minutes, and to the mixture a solution of sodium nitrite (17.5 g, 253 mmol) in 25 niL of water is added dropwise.
- Compound 414 is synthesized via a procedure similar to that illustrated by Example ID (step 3) using 413.
- Procedure 1 Frozen rat cortex is homogenized in ice cold 50 mM Tris 7.4 (1 g cortex/150 mL buffer) using a POLYTRON homogenizer (setting 5 for 30 seconds). The suspension is poured into centrifuge tubes, and then centrifuged for 15 minutes at 20,000 rpm in a SS34 rotor (48,000 x g). The supernatants are discarded and the pellets are washed twice with same buffer and centrifuge speed. The final pellets are stored in covered centrifuge tubes at -8O 0 C. Prior to use, the washed rat cortical membrane is thawed and re-suspended in ice cold 50 mM Tris 7.4 (6.7 mg frozen cortex weight/mL buffer).
- the pellet is then thawed and resuspended in 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000 x g and the supernatant decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of Buffer A.
- Buffer A original wt/vol
- Method 1 Incubations are carried out at 1.2 mg membrane/well. Duplicate samples containing 180 ⁇ L of membrane suspension, 20 ⁇ L of 3 H-Rol5-1788 ( 3 H-Flumazenil (PerkinElmer Life Sciences, Boston, MA) and 2 ⁇ L of test compound or control in DMSO (total volume of 202 ⁇ L) are incubated at 4 0 C for 60 minutes. The incubation is terminated by rapid filtration through untreated 102x258 mm filter mats on Tomtec filtration manifold (Hamden, CT) and the filters are rinsed three times with ice cold 50 mM Tris 7.4.
- 3 H-Rol5-1788 3 H-Flumazenil (PerkinElmer Life Sciences, Boston, MA)
- test compound or control in DMSO total volume of 202 ⁇ L
- radioligand 0.5 nM 3 H-RO 15- 1788, specific activity 80 Ci/mmol
- test compound or control see below
- Preferred compounds exhibit Kj values of less than 100 nM and more preferred compounds exhibit K; values of less than 10 nM.
- test compound for the benzodiazepine site Specificity of a test compound for the benzodiazepine site is determined following completion of a concentration/effect curve. After washing the oocyte sufficiently to remove previously applied test compound, the oocyte is exposed to GABA + 1 ⁇ M RO 15- 1788, followed by exposure to GABA + 1 ⁇ M RO 15- 1788 + test compound. Percent change due to addition of compound is calculated as described above. Any percent change observed in the presence of RO15-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 ⁇ M RO15-1788. These net values are used for the calculation of average efficacy and EC 50 values by standard methods. To evaluate average efficacy and EC 50 values, the concentration/effect data are averaged across cells and fit to the logistic equation.
- EXAMPLE lO. MDCK TOXICITY ASSAY This Example illustrates the evaluation of compound toxicity using a Madin Darby canine kidney (MDCK) cell cytotoxicity assay. 1 ⁇ L of test compound is added to each well of a clear bottom 96-well plate (PACKARD, Meriden, CT) to give final concentration of compound in the assay of 10 micro molar, 100 micromolar or 200 micromolar. Solvent without test compound is added to control wells.
- MDCK Madin Darby canine kidney
- MDCK cells ATCC no. CCL-34 (American Type Culture Collection, Manassas, VA), are maintained in sterile conditions following the instructions in the ATCC production information sheet.
- Confluent MDCK cells are trypsinized, harvested and diluted to a concentration of 0.1 x 10 6 cells/mL with warm (37 0 C) medium (VITACELL Minimum Essential Medium Eagle, ATCC catalog # 30- 2003). 100 ⁇ L of diluted cells is added to each well, except for five standard curve control wells that contain 100 ⁇ L of warm medium without cells. The plate is then incubated at 37 0 C under 95% O 2 , 5% CO 2 for 2 hours with constant shaking. After incubation, 50 ⁇ L of mammalian cell lysis solution is added per well, the wells are covered with PACKARD TOPSEAL stickers, and plates are shaken at approximately 700 rpm on a suitable shaker for 2 minutes.
Abstract
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EP (1) | EP1807417A2 (en) |
WO (1) | WO2006052546A2 (en) |
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WO2006093911A2 (en) * | 2005-03-02 | 2006-09-08 | Neurogen Corporation | Thiazolylmethyl and oxazolylmethyl heteroaryl derivatives |
WO2006093911A3 (en) * | 2005-03-02 | 2007-01-04 | Neurogen Corp | Thiazolylmethyl and oxazolylmethyl heteroaryl derivatives |
US8431596B2 (en) | 2007-10-10 | 2013-04-30 | Cancer Research Technology Limited | [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds and their use |
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US9394301B2 (en) | 2007-10-10 | 2016-07-19 | Cancer Research Technology Limited | [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds and their use |
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WO2010055884A1 (en) * | 2008-11-13 | 2010-05-20 | 日本農薬株式会社 | Method for producing pyrazine derivative and intermediate thereof |
US10457648B2 (en) | 2014-09-26 | 2019-10-29 | Genentech Inc. | Process for preparing (cyclopentyl[d]pyrimidin-4-yl)piperazine compounds |
US10870626B2 (en) | 2014-09-26 | 2020-12-22 | F. Hoffman-La Roche Ag | Process for preparing (cyclopentyl[d]pyrimidin-4-yl)piperazine compounds |
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WO2006052546A3 (en) | 2006-07-20 |
EP1807417A2 (en) | 2007-07-18 |
US20080004269A1 (en) | 2008-01-03 |
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