CA2436079A1 - Heterocyclic inhibitors of glycine transporter 2 - Google Patents
Heterocyclic inhibitors of glycine transporter 2 Download PDFInfo
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- CA2436079A1 CA2436079A1 CA002436079A CA2436079A CA2436079A1 CA 2436079 A1 CA2436079 A1 CA 2436079A1 CA 002436079 A CA002436079 A CA 002436079A CA 2436079 A CA2436079 A CA 2436079A CA 2436079 A1 CA2436079 A1 CA 2436079A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- 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
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D417/02—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 two hetero rings
- C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides compounds, compositions and methods for inhibiting the glycine transporter (2) and for affecting glycine transporter mediated neuronal activity. Useful compounds comprise compounds of Formula I : wherein n is (0, 1, 2 or 3) and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen ; X is O, S or N-R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene) ; Q may be absent or present, and when present, it is represented by the formula : in which n, R and X are as defined above ; when Q is present, W is a lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl (optionally substituted aryl)-X-CH2-or (optionally substituted heteroaryl)-X-CH2-in which X is as defined above ; or a pharmaceutically acceptable salt thereof. These compounds are particularly useful for treating diseases of the nerve and muscle, including psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like, and of muscle disorders, including diseases or conditions associated with increased muscle contraction, such as spasticity and myoclonus. In addition, the compounds may be used to discover other agents with improved activity in assays in which the compounds of the invention are active.
Description
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to the treatment of certain central and peripheral nervous system disorders by inhibition of the glycine transporter-2. The invention relates in particular to the use of a group of compounds in the treatment in humans of certain neurological disorders, for example, psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like. The invention also relates to a group of novel compounds and pharmaceutical compositions containing them which are useful in inhibition of the glycine transporter 2.
Description of Related Art Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialized structures in both the pre- and post- synaptic neuron. High affinity neurotransmitter transporters are one such component, located on the pre-synaptic terminal membranes and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1032, 1987).
Transporters sequester neurotransmitter from the synapse; thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration of action therein, which together influence the magnitude and duration of synaptic transmission. By preventing the spread of transmitter to neighboring synapses, transporters help maintain the fidelity of synaptic transmission. In addition, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization.
The amino acid glycine is a major neurotransmitter in the mammalian central nervous system (CNS), functioning at both inhibitory and excitatory synapses.
These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are referred to "strychnine-sensitive." Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
For example, enhancing inhibitory glycinergic transmission through strychinine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity. In addition, pain-related information in the spinal cord has been shown to be mediated by these receptors (Yaksh, Pain, 37, 111, 1989).
Nucleic acid sequences and transfection techniques for delivering nucleic acid message coding for glycine transporters axe disclosed in U.S. Patent Nos.
5,756,348 and 6,127,131 to Smith et al., U.S. PatentNos. 5,824,486 and 5,968,823 to Borden et al., and U.S. Patent No. 56,008,015 to Albert et al. Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT1 and GlyT2. GlyT1 is found predominantly in the forebrain, and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith et al., Neuron., 8, 927, 1992). Additional cloning experiments has determined that GlyT1 transporter has three additional variants, GlyTla, GlyTlb, and GlyTlc. GlyT2 is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors. This is consistent with the view that by regulating the synaptic levels of glycine, GlyTl and GlyT2 selectively influence the activity of the NMDA receptors and strychnine-sensitive glycine receptors, respectively.
Triazoles, as well as oxa- and thia- diazole derivatives are known in the art.
They have shown a wide variety of uses in photographic material (JP09114055, JP07005646) and in liquid crystal compositions (JP11043485). These types of heterocyclic derivatives have also been reported as pesticides, fungicides and herbicides (JP10036357, JP05202038, JP02129173, DE3717865, DE3031191, DE2533605).
There are a number of highly functionalized analogs showing activity as immunosuppressants, antiinflammatories and hepatoprotectants (US5670526, EP214732), Gp IIb/IIIa antagonists (LTS5668159), antiulcer (W09513268) and as angiotensin II antagonists (EP554107, W09111909, EP409332). All patents, both supra and is fra, are hereby incorporated by reference in their entirety.
Substituted triazoles have been reported to be neurotensin antagonists and be useful in the treatment of certain CNS and gastrointestinal disorders (GB2263635, W009830561). Recently, there have been some reports of piperidinyl-, and piperazinyl- as inhibitors of the glycine transporters (W0994501 l, W09944596) as well as diaryl-glycine derivatives have been shown to inhibit GlyT1 and GlyT2 (W09745115).
BRIEF SUMMARY OF THE INVENTION
The inventors have discovered and herein disclose that the triazoles, oxa- and thia- diazoles inhibit the glycine transporter 2 (GIyT2) and are useful in the regulation of the central and peripheral nervous systems. Thus, the invention is directed to use of these triazoles, oxa- and thia- diazoles compounds or pharmaceutical compositions containing them for inhibition of GlyT2, and to methods for inhibiting GlyT2 in mammals using these compounds and pharmaceutical compositions. The compounds, compositions and methods of the invention are particularly useful in the treatment of diseases of nerve and muscle.
Inhibition of GlyT2 diminishes the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine.
Inhibition of glycine transporters by the triazoles, oxa- and thia- diazoles is effective to alter receptor function, and can be used to provide therapeutic benefits in a variety of~disease states, including diseases of muscles and of the nervous system. Thus, for example, these compounds may be used to diminish the transmission of pain-related information in the spinal cord, to decrease muscle hyperactivity, to treat neurological disorders such as psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like, and to treat diseases or conditions associated with increased muscle contraction, such as spasticity and myoclonus.
A first aspect of this invention is related to the use of compounds of Formula I:
N N
Q-W
X S
~R)n Formula I
wherein n is 0, l, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen;
X is O, S or N-R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene);
Q may be absent or present, and when present, it is represented by the formula:
N N
/ s ~R)n formula (Q) in which n, R and X are as defined above;
when Q is present, W is a lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally subtituted heteroaryl (optionally substituted aryl~X--CHI- or (optionally subtituted heteroaryl}-X--CHZ--- in which X is as defined above; or a pharmaceutically acceptable salt thereof, for inhibition of glycine transporter-2 (GlyT2) or fox the manufacture of a medicament useful for treating a disease treatable by inhibition of GlyT2.
More specifically, the first aspect of the invention is directed to the use of a compound of Formula I in the treatment, in a mammal such as a human, of neurological disorders, including psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like, and of muscle disorders, including diseases or conditions associated with increased muscle contraction, such as spasticity and myoclonus. The treatment comprises the step of administering a therapeutically effective amount of a compound of Formula I to the mammal. Optionally, the treatment may also comprises administering a combination of this invention and other therapies to the mammal.
A second aspect of the invention relates to pharmaceutical compositions useful for the treatment of a disease treatable by administration of a glycine transporter-2 inhibitor, which compositions comprise (i) a pharmaceutically acceptable Garner and (ii) as an active ingredient, a compound of Formula I.
In a third aspect, this invention is directed to a group of novel compounds represented by Formula II (shown below) and their synthesis.
In a fourth aspect, the invention is directed to pharmaceutical compositions comprising (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of Formula II.
In a fifth aspect, the invention provides a method of inhibiting the glycine transporter 2 (GlyT2) comprising contacting a cell with a compound of Formula I, in an amount sufficient to inhibit GlyT2. Ifa vivo, the step of contacting the cells with such a compound may be effected by administering to an animal an effective amount of the compound. In vitro, the step of contacting the cells with a compound of Formula I may be effected by administering an effective amount of the compound to the cells or to a solution bathing the cells.
In a sixth aspect, this invention provides a method of inhibiting GlyT2 in cells which have a GlyT2. This method of inhibiting GlyT2 in cells which have GlyT2 comprises contacting the cells with a compound of Formula I in an amount sufficient to inhibit the GlyT2. Ira vivo, the step of contacting the cells with such a compound may be effected by administering to an animal an effective amount of the compound.
lye vitro, the step of contacting the cells with a compound of Formula I may be effected by administering an effective amount of the compound to the cells or to a solution bathing the cells.
Other aspects of the invention include methods for discovering agents which show improved activity in assays that inhibit a glycine transporter or affect glycine transporter mediated neuronal activity.
DETAILED DESCRIPTION OF THE INVENTION
(a) Definitions and General Parameters The term "alkyl" means a C1-Czo monovalent hydrocarbyl which may be linear, branched, or cyclic. "Lower alkyl", as in "lower alkyl", or "substituted lower alkyl", means a C1-G1o alkyl. The term "lower alkyl" includes methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclopropylmethyl, cyclohexyl, or cyclohexylmethyl. Cr-C6 lower alkyls are preferred.
The term "substituted lower alkyl" is a lower alkyl which is typically mono-, di-, or tri-substituted with aryl, R'-substituted aryl, heteroaryl, nitro, cyano, halo, -OR, -SR, -COR, -OC(O)R, -C(O)OR, -NR2, -SOZOR, -OS02R, -SO2NR2, -NRSOZR, -CONR2, or -NRCOR, where each R is, independently, hydrogen, lower alkyl, R'-substituted lower alkyl, aryl, R'-substituted aryl, heteroaryl, heteroaryl(Iower)alkyl, R'-substituted aryl(lower)alkyl, or aryl(lower)alkyl and each R' is, independently, hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl, or amino.
Substituted lower alkyls which are substituted with one to three of the substituents selected from the gxoup consisting of cyano, halo, lower alkyloxy, thio, nitro, amino, or hydroxy axe particularly preferred.
The term "alkoxy" or "alkyloxy" is a radical, -OR' wherein R' is alkyl having from one to the number of carbon atoms designated (e.g., (C1.~)alkyloxy includes the radicals methoxy, ethoxy, prop-1-yloxy, prop-2-yloxy, but-1-yloxy, but-2-yloxy, 2-rnethylprop-1-yloxy and 2-methylprop-2-yloxy.
The term "alkylene" is a radical represented by the formula, -CnH2"-, which may be straight or branced and include methylene (-CHz-), ethylene (-z---CZH~), n-propylene (---C3H6-) and n-butylene (-C4H$--).
The term "aryl" means an aromatic hydrocarbyl containing 6 to 20 ring carbon atoms, having a single ring (e.g., phenyl), or two or more condensed rings, preferably 2 to 3 condensed rings (e.g., naphthyl), ox two ox more aromatic rings, preferably 2 to 3 aromatic rings, which are linked by a single bond (e.g., biphenylyl).
Optionally, the aryl group may be substituted with lower alkyl, substituted lower alkyl, aryl, heteroaryl, nitro, cyano, halo, -OR, -SR, -COR, -OC(O)R, -C(O)OR, NR2, -SOZOR, -OSOZR, -SOzNR2, -NRSOZR, -CONR2, or -NRCOR; where each R is independently, hydrogen, lower alkyl, substituted lower alkyl. Aryl groups are preferably C6-C16 and even more preferably, C6 to C14.
The term "heteroaryl" means a radical derived from an aromatic hydrocarbon containing 5-14 atoms, 1-5 of which are hetero atoms selected from a group consisting of N, O and S, and includes monocyclic, condensed heterocyclic and condensed carbocyclic and heterocyclic aromatic rings (e.g., thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, benzo[b]thienyl, isobenzofuranyl, purinyl, isoquinolyl, ' pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, etc.).
The term "substituted heteroaryl" means the heteroaryl group is substituted with lower alkyl, substituted lower alkyl, aryl, heteroaryl, vitro, cyano, halo, -OR, -SR, -COR, -OC(O)R, -C(O)OR, -NR2, -S020R, -OSOZR, -SO2NR2, -NRS02R, -CONR2, or -NRGOR; where each R is independently, hydrogen, lower alkyl or substituted lower alkyl.
The term "halogen" or "halo" means fluoro, chloro or bromo.
A "pharmaceutically acceptable salt" may be any salt derived from an inorganic or organic acid or an inorganic or organic base. The term "pharmaceutically acceptable anion" refers to the anion of such acid addition salts. The term "pharmaceutically acceptable cation" refers to a cation formed by addition of a base. The salt and/or the anion or canon are chosen not to be biologically or otherwise undesirable.
A "therapeutically effective amount" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
"Treating" or "treatment" of a disease in a mammal includes (1) preventing the disease from occurring in a mammal which may be predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting its development, (3) relieving symptoms of the disease, i.e., reducing the effects of the disease, and (4) causing regression of the disease.
(b) Use for Inhibition of Glycine Transporter-2 The first aspect of the invention relates to the use of a compound represented by Formula I:
N N
Q-W
X S
~R)n Formula I
wherein n is 0, l, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen;
X is O, S or N-R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene);
Q may be absent or present, and when present, it is represented by the formula:
N N
/ s ~R)n I X
formula (Q) in which n, R and X are as defined above;
when Q is present, W is a Lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally subtituted heteroaryl (optionally substituted aryl)-X-CHz- or (optionally subtituted heteroaryl)-X--CHZ-- in which X is as defined above; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease treatable by administration of a glycine transporter-2 inhibitor.
GIyT2 inhibition is useful, for example, in the treatment of subjects with certain central and peripheral nervous system disorders, and in treatment of subjects with certain muscle disorders. More particular, examples of the use of the compounds include the treatment of psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like.
One embodiment of the invention is directed to a method of inhibiting GlyT2.
This method comprises contacting a cell with a compound of Fornmla I in an amount sufficient to inhibit GlyT2. By inhibiting GlyT2, neuronal transmission is regulated and is useful in the treatment of psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis, spasticity, myoclonus, or other disease condition. The inhibition of GlyT2 may occur either iTa vivo or iiZ vitro.
In another embodiment of the invention, GlyT2 is inhibited by contacting a cell having a glycine transporter with a compound of Formula I in an amount sufficient to inhibit GIyT2. In such a case, the contacting is effected in vivo by administering the compound, or a pharmaceutical composition thereof, to the mammal and in vitro by administering the compound, or a pharmaceutical composition thereof, to a container in which the cells are present ox to a solution bathing the cells.
A further embodiment of the invention provides a method of treating a disorder in a mammal, where the disorder may be selected from a nervous disorder and a muscle disorder, comprising administering a therapeutically effective amount of a compound of Formula I to the mammal. Optionally, the method may further comprise treating the mammal with an additional form of therapy for an autoimmune disease. For instance, one method may also comprise administering to the mammal a CNS compound in addition to the compounds of Formula I, where a CNS compound is one having pharmacological activity affecting the central nervous system (CNS).
Alternatively, the compounds of Formula I may be administered to the mammal in combination with a CNS compound or other alternative treatment for nervous system disease. The total amount of the combination of drugs administered to the mammal must be a therapeutically effective amount, although the individual amounts of each of the individual drugs may be, by themselves, suboptimal for therapeutic purposes.
For the treatment of muscle conditions, the method may also comprise administering to the mammal a muscle compound in addition to the compounds of Formula I, where a muscle compound is one having pharmacological activity affecting muscle.
Alternatively, the compounds of Formula I may be administered to the mammal in combination with a muscle compound or other alternative treatment for muscle disease.
The total amount of the combination of drugs administered to the mammal must be a therapeutically effective amount, although the individual amounts of each of the individual drugs may be, by themselves, suboptimal for therapeutic purposes.
The preferred compounds of Formula I include:
(i) when X is N R' in which R' is methyl, ethyl, pheny or benzyl;
n is 0, 1 or 2 R is chlorine or methyl;
Q is absent and W is aryl such as phenyl, optionally substituted heteroaryl such as 2-ethyl-5-methyl-3-diazolyl or (optionally subtituted heteroaryl~-X--CHZ--, such as thien-2-ylthiomethyl.
Examples of this group of compounds are:
5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole 5-benzylthio-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole 5-(4-methylbenzylthio)-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole 5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N=ethyl-1,3,4-triazole 5-benzylthio-2-(2-ethyl-5-methyl-3-diazolyl)-N-phenyl-1,3,4-triazole 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-N-benzyl-1,3,4-triazole (ii) when X is S;
n is 0, 1 or 2 R is chlorine;
Q is absent and W is aryl such as phenyl or heteroaryl such as pyridyl or pyranzinyl.
Examples of this group of compounds are:
5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole 5-(benzylthio)-2-phenyl-1,3,4-thiadiazole 5-(benzylthio)-2-pyrid-3-yl-1,3,4-thiadiazole 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-1,3,4-thiadiazole 5-(benzylthio)-2-pyrazin-2-yl-1,3,4-thiadiazole (iii) when X is O;
n is 0;
Q is present and in Formula Q, n is 0 and X is O; and W is n-butylene. .
The compound is named 2,2'-(1,4-butanediyl)bis[5-(benzylthio)-1,3,4-oxadiazole].
Patients requiring treatment to inhibit GlyT2 include patients suffering from nervous disorders and patients suffering from muscle disorders. The method of treatment comprises the administration of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical earner. The effective doses of the compound of Formula I are generally selected from the range of 0.01 to 1000 mg/kg, preferably 0.01 to 100 mg/kg and more preferably 1-30 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. The dosage units may be administered up to one to ten times daily for acute or chronic disease. No unacceptable toxicological effects are expected when compounds of Formula I are administered in accordance with the present invention.
(c) Novel Compounds of the Invention Another aspect of the present invention provides novel compounds of Formula II:
N N
W
X S
~R)n Formula II
wherein:
when X is S, n is 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is an optionally substituted heteroaryl having at least two heteroatoms; or when X is N-R' (in which R' is as defined above), n is 0, 1, 2 or 3, R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is (optionally substituted five-membered heteroaryl)-S--CH2- wherein said five-membered heteroaryl comprises one heteroatom; or a pharmaceutically acceptable salt thereof.
A most preferred compound is the compound of Formula II in which X is S, n is 2, R is chlorine and W is pyrazin-2-yl, as shown in Formula III below:
N-N CI
N
g N CI
Formula III
The compound is named 5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-triazole.
Compounds of Formula II have been found to inhibit GlyT2 and are useful for inhibiting GlyT2, including inhibiting GlyT2 in a mammal, and for treating certain mammalian neurological disorders, in particular, psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like. The compounds of Formula II, including the most preferred compound shown in Formula III, as single stereoisomers or mixtures of stereoisomers, and the pharmaceutically acceptable salts thereof, are suitable for use in pharmaceutical compositions for inhibiting GlyT2 in a mammal or for treating a mammalian with certain neurological disorders, in particular, psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like.
(d) Synthesis of Compounds of Formulae I and II
The compounds of Formulae I and II may be prepared by synthetic methods known in the art. For example, they may be prepared according to the following reaction scheme:
N-N -Q-W Y + Z ~ (R)n q W~X~S
~V) (~) (~) \ ~' (R)n In the reaction scheme, Q, W, X, n and R are as defined above, Y and Z are independently a mercapto, -SM (wherein M is an alkali metal), halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy, with the proviso when Y is a mercapto or -SM, Z is halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy or when Z is mercapto or -SM, Y is halogen, lower alkylsulfonyloxy, arylsulfonyloxy or axalkylsulfonyloxy. Examples of alkali metal represented by M in the above formula include sodium, potassium, lithium and the like.
The reactions between the compounds of Formula IV and V may be carried out in a suitable solvent in the presence of a basic compound. Any inert solvent can be used as the solvent for the reaction. Examples of the solvent are disclosed in US
Patent No. 5,670,526 which include water, alcohols, aromatic hydrocarbons, ethers, ketones, esters, aprotic solvents or a mixture thereof. Examples of the basic compound which can be used may also be found in US Patent No. 5,670,526. The reaction is carried out usually at 0-150°C, preferably at about 0-120°C, and completed in about 1 to 30 hours.
Compound of Formula (IV) is usually used in an amount of at least one mole, preferably 1-12 moles, per mole of compound of Formula (V).
The compounds of Formula (V) are usually commercially available. The compounds of Formula (IV) are either commercially available or may be synthesized by cyclization of a hydrazide. In the case of oxadiazole compounds, the cyclization of the hydrazide compounds may be carried out in the presence of CSz and a basic compound such as KOH. For the thiadiazole compounds, the cyclization of the hydrazide may be carried out in the presence of a Lawessen's reagent, CSZ and a basic compound.
These syntheses are demonstrated in the examples below.
In some cases, protective groups may be introduced and later removed in the synthesis. Suitable protective groups for amino, hydroxyl, carboxyl groups are described in Greene, et al., Protective GYOUps ira OYgar~ic SyTZ.thesis, Second Edition, John Wiley and Sons, New York, 1991. The compounds may be synthesized as shown in the examples below or by modifying the exemplified syntheses by means known to those of ordinary skill in the art.
Certain compounds of Formulae I and II may contain one or more chiral centers.
In such cases, all stereoisomers also fall within the scope of this invention.
The compounds include the individually isolated stereoisomers as well as mixtures of such stereoisomers.
Pharmaceutically acceptable salts, canons and anions of the compounds of Formulae I and II are also included in the present invention and are useful in the methods and pharmaceutical compositions described herein.
Pharmaceutically acceptable salts include salts which may be formed when acidic protons present are capable of reacting With inorganic or organic bases.
Typically, the parent compound. is treated with an excess of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing an appropriate canon. Cations, such as Na+, K+, Ca2+, Mgz+ and NHS.+, are examples of canons present in pharmaceutically acceptable salts. The Na* salts are especially useful. Acceptable inorganic bases, therefore, include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Salts may also be prepared using organic bases, such as salts of primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like.
If the compounds of Formulae I and II contain a basic group, an acid addition salt may be prepared. Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, malefic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, p-toluenesulfonic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, lactic acid, o-(4-hydroxy-benzoyl)benzoic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2.]oct-2-ene-1-carboxylic acid, glucoheptonic acid, gluconic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic)acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid, glucuronic acid, glutamic acid, 3-hydroxy-2-naphthoic acid, stearic acid, muconic acid and the like.
Certain of the compounds may form inner salts or zwitterions.
(e) Pharmaceutical Compositions of Formulae I and II
One aspect of the invention provides pharmaceutical compositions for the treatment of a disease treatable by inhibition of glycine transporter-2, which compositions comprise (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of Formula I.
Another aspect of the invention provides pharmaceutical compositions, which compositions comprise (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of Formula II.
Examples of preferred pharmaceutical compositions for the treatment of a disease treatable by inhibition of glycine transporter-2 comprise, as the active ingredient:
5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-benzylthio-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-(4-methylbenzylthio)-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-ethyl-1,3,4-triazole, 5-benzylthio-2-(2-ethyl-5-methyl-3-diazolyl)-N-phenyl-1,3,4-triazole, 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-N-benzyl-1,3,4-triazole, 5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole, 5-(benzylthio)-2-phenyl-1,3,4-thiadiazole, 5-(benzylthio)-2-pyrid-3-yl-1,3,4-thiadiazole, 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-1,3,4-thiadiazole, 5-(benzylthio)-2-pyrazin-2-yl-1,3,4-thiadiazole, or 2, 2' -( 1,4-butanediyl)bis [5-(benzylthio)-1, 3,4-oxadiazole] .
A most preferred pharmaceutical composition for this use comprises, as the active ingredient, 5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole or 2,2'-(1,4-butanediyl)bis[5-(benzylthio)-1,3,4-oxadiazole].
The pharmaceutical compositions of this invention may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are especially suitable for parenteral administration, but may also be used for oral administration. It may be desirable to add excipients such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid Garners include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid Garner varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
When a liquid carrier is use, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered orally directly or filled into a soft gelatin capsule.
Some specific examples of suitable pharmaceutical compositions are described in the Examples below.
Typically, a pharmaceutical composition of the present invention is packaged in a container with a label, or instructions, or both, indicating the use of the pharmaceutical composition in the treatment of nerve and muscle diseases, such as psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis, spasticity, myoclonus, or other disease condition.
The compounds of Formulae I and II, or pharmaceutical compositions thereof, may be administered by any route suitable to the subject being treated and the nature of the subject's condition. Routes of administration include, but are not limited to, administration by injection, including intravenous, intraperitoneal, intramuscular, and subcutaneous injection, by transmucosal or transdermal delivery, through topical applications, nasal spray, suppository and the like or may be administered orally.
Formulations may optionally be liposomal formulations, emulsions, formulations designed to administer the drug across mucosal membranes or transdermal formulations.
Suitable formulations for each of these methods of administration may be found, for example, in Remiragtota's Phaf-mczceutical Sciejaces, latest edition, Mack Publishing Company, Easton, PA.
(f) Methods for Discovering Agents for Inhibition of Glycine Transuorter Bioassays for determining glycine transporter typically measuxe glycine or radioactively labeled glycine transporter into cells having a glycine transporter. Glycine transporters are normally found in many cell types, including neuronal and glial cells and cell lines. In addition, exogenous glycine transporters may be provided to cells by transfection techniques. Nucleic acid sequences and transfection techniques for delivering nucleic acid message coding for glycine transporters are disclosed in U.S.
PatentNos. 5,756,348 and 6,127,131 to Smith et al., U.S. PatentNos. 5;824,486 and 5,968,823 to Borden et al., and U.S. Patent No. 56,008,015 to Albert et al.
Other bioassay methods for measuring glycine transporter include electrophysiological methods for measuring the strength and duration of neurotransmission at glycine synapses, both in vivo and ira vitro. Such techniques, known in the art, include intracellular recording, patch clamp recording, and extracellular recording techniques.
These electrophysiological techniques are also suitable for measuring the affects of glycine and other compounds on glycine transporter mediated neuronal activity.
The use of such bioassays, in the presence of various concentrations of glycine, labeled glycine, strychnine, compounds of Formula I, test compounds, and under various conditions are effective to detect and measure inhibition of glycine transporter, including inhibition of glycine transporter mediated by glycine transporter 2 or strychnine sensitive glycine transporters, and to detect and measure compound effects on glycine transporter mediated neuronal activity, including effects on neuronal activity mediated by glycine transporter 2 or strychnine sensitive glycine transporters.
The compounds of Formula I have been demonstrated to inhibit GlyT2 and can be useful in the treatment of certain neurological disorders. Similarly, othex compounds which show the same effects on GlyT2 can be useful for the treatment certain neurological disorders. The compounds disclosed in this application can be used as models to discover other new agents that act to inhibit GlyT2. The steps in a process in which these compounds can be utilized to discover new therapeutic agents may be achieved by the following: the compounds may be utilized to validate, optimize, and standardize assays necessary for the discovery of other compounds that inhibit GlyT2.
These compounds can be utilized as benchmarks to discover other agents that show improved activity in assays that:
1. Inhibit the glycine transporter;
2. Inhibit the glycine transporter 2;
Field of the Invention The present invention relates to the treatment of certain central and peripheral nervous system disorders by inhibition of the glycine transporter-2. The invention relates in particular to the use of a group of compounds in the treatment in humans of certain neurological disorders, for example, psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like. The invention also relates to a group of novel compounds and pharmaceutical compositions containing them which are useful in inhibition of the glycine transporter 2.
Description of Related Art Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialized structures in both the pre- and post- synaptic neuron. High affinity neurotransmitter transporters are one such component, located on the pre-synaptic terminal membranes and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1032, 1987).
Transporters sequester neurotransmitter from the synapse; thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration of action therein, which together influence the magnitude and duration of synaptic transmission. By preventing the spread of transmitter to neighboring synapses, transporters help maintain the fidelity of synaptic transmission. In addition, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization.
The amino acid glycine is a major neurotransmitter in the mammalian central nervous system (CNS), functioning at both inhibitory and excitatory synapses.
These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are referred to "strychnine-sensitive." Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
For example, enhancing inhibitory glycinergic transmission through strychinine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity. In addition, pain-related information in the spinal cord has been shown to be mediated by these receptors (Yaksh, Pain, 37, 111, 1989).
Nucleic acid sequences and transfection techniques for delivering nucleic acid message coding for glycine transporters axe disclosed in U.S. Patent Nos.
5,756,348 and 6,127,131 to Smith et al., U.S. PatentNos. 5,824,486 and 5,968,823 to Borden et al., and U.S. Patent No. 56,008,015 to Albert et al. Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT1 and GlyT2. GlyT1 is found predominantly in the forebrain, and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith et al., Neuron., 8, 927, 1992). Additional cloning experiments has determined that GlyT1 transporter has three additional variants, GlyTla, GlyTlb, and GlyTlc. GlyT2 is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors. This is consistent with the view that by regulating the synaptic levels of glycine, GlyTl and GlyT2 selectively influence the activity of the NMDA receptors and strychnine-sensitive glycine receptors, respectively.
Triazoles, as well as oxa- and thia- diazole derivatives are known in the art.
They have shown a wide variety of uses in photographic material (JP09114055, JP07005646) and in liquid crystal compositions (JP11043485). These types of heterocyclic derivatives have also been reported as pesticides, fungicides and herbicides (JP10036357, JP05202038, JP02129173, DE3717865, DE3031191, DE2533605).
There are a number of highly functionalized analogs showing activity as immunosuppressants, antiinflammatories and hepatoprotectants (US5670526, EP214732), Gp IIb/IIIa antagonists (LTS5668159), antiulcer (W09513268) and as angiotensin II antagonists (EP554107, W09111909, EP409332). All patents, both supra and is fra, are hereby incorporated by reference in their entirety.
Substituted triazoles have been reported to be neurotensin antagonists and be useful in the treatment of certain CNS and gastrointestinal disorders (GB2263635, W009830561). Recently, there have been some reports of piperidinyl-, and piperazinyl- as inhibitors of the glycine transporters (W0994501 l, W09944596) as well as diaryl-glycine derivatives have been shown to inhibit GlyT1 and GlyT2 (W09745115).
BRIEF SUMMARY OF THE INVENTION
The inventors have discovered and herein disclose that the triazoles, oxa- and thia- diazoles inhibit the glycine transporter 2 (GIyT2) and are useful in the regulation of the central and peripheral nervous systems. Thus, the invention is directed to use of these triazoles, oxa- and thia- diazoles compounds or pharmaceutical compositions containing them for inhibition of GlyT2, and to methods for inhibiting GlyT2 in mammals using these compounds and pharmaceutical compositions. The compounds, compositions and methods of the invention are particularly useful in the treatment of diseases of nerve and muscle.
Inhibition of GlyT2 diminishes the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine.
Inhibition of glycine transporters by the triazoles, oxa- and thia- diazoles is effective to alter receptor function, and can be used to provide therapeutic benefits in a variety of~disease states, including diseases of muscles and of the nervous system. Thus, for example, these compounds may be used to diminish the transmission of pain-related information in the spinal cord, to decrease muscle hyperactivity, to treat neurological disorders such as psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like, and to treat diseases or conditions associated with increased muscle contraction, such as spasticity and myoclonus.
A first aspect of this invention is related to the use of compounds of Formula I:
N N
Q-W
X S
~R)n Formula I
wherein n is 0, l, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen;
X is O, S or N-R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene);
Q may be absent or present, and when present, it is represented by the formula:
N N
/ s ~R)n formula (Q) in which n, R and X are as defined above;
when Q is present, W is a lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally subtituted heteroaryl (optionally substituted aryl~X--CHI- or (optionally subtituted heteroaryl}-X--CHZ--- in which X is as defined above; or a pharmaceutically acceptable salt thereof, for inhibition of glycine transporter-2 (GlyT2) or fox the manufacture of a medicament useful for treating a disease treatable by inhibition of GlyT2.
More specifically, the first aspect of the invention is directed to the use of a compound of Formula I in the treatment, in a mammal such as a human, of neurological disorders, including psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like, and of muscle disorders, including diseases or conditions associated with increased muscle contraction, such as spasticity and myoclonus. The treatment comprises the step of administering a therapeutically effective amount of a compound of Formula I to the mammal. Optionally, the treatment may also comprises administering a combination of this invention and other therapies to the mammal.
A second aspect of the invention relates to pharmaceutical compositions useful for the treatment of a disease treatable by administration of a glycine transporter-2 inhibitor, which compositions comprise (i) a pharmaceutically acceptable Garner and (ii) as an active ingredient, a compound of Formula I.
In a third aspect, this invention is directed to a group of novel compounds represented by Formula II (shown below) and their synthesis.
In a fourth aspect, the invention is directed to pharmaceutical compositions comprising (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of Formula II.
In a fifth aspect, the invention provides a method of inhibiting the glycine transporter 2 (GlyT2) comprising contacting a cell with a compound of Formula I, in an amount sufficient to inhibit GlyT2. Ifa vivo, the step of contacting the cells with such a compound may be effected by administering to an animal an effective amount of the compound. In vitro, the step of contacting the cells with a compound of Formula I may be effected by administering an effective amount of the compound to the cells or to a solution bathing the cells.
In a sixth aspect, this invention provides a method of inhibiting GlyT2 in cells which have a GlyT2. This method of inhibiting GlyT2 in cells which have GlyT2 comprises contacting the cells with a compound of Formula I in an amount sufficient to inhibit the GlyT2. Ira vivo, the step of contacting the cells with such a compound may be effected by administering to an animal an effective amount of the compound.
lye vitro, the step of contacting the cells with a compound of Formula I may be effected by administering an effective amount of the compound to the cells or to a solution bathing the cells.
Other aspects of the invention include methods for discovering agents which show improved activity in assays that inhibit a glycine transporter or affect glycine transporter mediated neuronal activity.
DETAILED DESCRIPTION OF THE INVENTION
(a) Definitions and General Parameters The term "alkyl" means a C1-Czo monovalent hydrocarbyl which may be linear, branched, or cyclic. "Lower alkyl", as in "lower alkyl", or "substituted lower alkyl", means a C1-G1o alkyl. The term "lower alkyl" includes methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclopropylmethyl, cyclohexyl, or cyclohexylmethyl. Cr-C6 lower alkyls are preferred.
The term "substituted lower alkyl" is a lower alkyl which is typically mono-, di-, or tri-substituted with aryl, R'-substituted aryl, heteroaryl, nitro, cyano, halo, -OR, -SR, -COR, -OC(O)R, -C(O)OR, -NR2, -SOZOR, -OS02R, -SO2NR2, -NRSOZR, -CONR2, or -NRCOR, where each R is, independently, hydrogen, lower alkyl, R'-substituted lower alkyl, aryl, R'-substituted aryl, heteroaryl, heteroaryl(Iower)alkyl, R'-substituted aryl(lower)alkyl, or aryl(lower)alkyl and each R' is, independently, hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl, or amino.
Substituted lower alkyls which are substituted with one to three of the substituents selected from the gxoup consisting of cyano, halo, lower alkyloxy, thio, nitro, amino, or hydroxy axe particularly preferred.
The term "alkoxy" or "alkyloxy" is a radical, -OR' wherein R' is alkyl having from one to the number of carbon atoms designated (e.g., (C1.~)alkyloxy includes the radicals methoxy, ethoxy, prop-1-yloxy, prop-2-yloxy, but-1-yloxy, but-2-yloxy, 2-rnethylprop-1-yloxy and 2-methylprop-2-yloxy.
The term "alkylene" is a radical represented by the formula, -CnH2"-, which may be straight or branced and include methylene (-CHz-), ethylene (-z---CZH~), n-propylene (---C3H6-) and n-butylene (-C4H$--).
The term "aryl" means an aromatic hydrocarbyl containing 6 to 20 ring carbon atoms, having a single ring (e.g., phenyl), or two or more condensed rings, preferably 2 to 3 condensed rings (e.g., naphthyl), ox two ox more aromatic rings, preferably 2 to 3 aromatic rings, which are linked by a single bond (e.g., biphenylyl).
Optionally, the aryl group may be substituted with lower alkyl, substituted lower alkyl, aryl, heteroaryl, nitro, cyano, halo, -OR, -SR, -COR, -OC(O)R, -C(O)OR, NR2, -SOZOR, -OSOZR, -SOzNR2, -NRSOZR, -CONR2, or -NRCOR; where each R is independently, hydrogen, lower alkyl, substituted lower alkyl. Aryl groups are preferably C6-C16 and even more preferably, C6 to C14.
The term "heteroaryl" means a radical derived from an aromatic hydrocarbon containing 5-14 atoms, 1-5 of which are hetero atoms selected from a group consisting of N, O and S, and includes monocyclic, condensed heterocyclic and condensed carbocyclic and heterocyclic aromatic rings (e.g., thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, benzo[b]thienyl, isobenzofuranyl, purinyl, isoquinolyl, ' pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, etc.).
The term "substituted heteroaryl" means the heteroaryl group is substituted with lower alkyl, substituted lower alkyl, aryl, heteroaryl, vitro, cyano, halo, -OR, -SR, -COR, -OC(O)R, -C(O)OR, -NR2, -S020R, -OSOZR, -SO2NR2, -NRS02R, -CONR2, or -NRGOR; where each R is independently, hydrogen, lower alkyl or substituted lower alkyl.
The term "halogen" or "halo" means fluoro, chloro or bromo.
A "pharmaceutically acceptable salt" may be any salt derived from an inorganic or organic acid or an inorganic or organic base. The term "pharmaceutically acceptable anion" refers to the anion of such acid addition salts. The term "pharmaceutically acceptable cation" refers to a cation formed by addition of a base. The salt and/or the anion or canon are chosen not to be biologically or otherwise undesirable.
A "therapeutically effective amount" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
"Treating" or "treatment" of a disease in a mammal includes (1) preventing the disease from occurring in a mammal which may be predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting its development, (3) relieving symptoms of the disease, i.e., reducing the effects of the disease, and (4) causing regression of the disease.
(b) Use for Inhibition of Glycine Transporter-2 The first aspect of the invention relates to the use of a compound represented by Formula I:
N N
Q-W
X S
~R)n Formula I
wherein n is 0, l, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen;
X is O, S or N-R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene);
Q may be absent or present, and when present, it is represented by the formula:
N N
/ s ~R)n I X
formula (Q) in which n, R and X are as defined above;
when Q is present, W is a Lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally subtituted heteroaryl (optionally substituted aryl)-X-CHz- or (optionally subtituted heteroaryl)-X--CHZ-- in which X is as defined above; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease treatable by administration of a glycine transporter-2 inhibitor.
GIyT2 inhibition is useful, for example, in the treatment of subjects with certain central and peripheral nervous system disorders, and in treatment of subjects with certain muscle disorders. More particular, examples of the use of the compounds include the treatment of psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like.
One embodiment of the invention is directed to a method of inhibiting GlyT2.
This method comprises contacting a cell with a compound of Fornmla I in an amount sufficient to inhibit GlyT2. By inhibiting GlyT2, neuronal transmission is regulated and is useful in the treatment of psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis, spasticity, myoclonus, or other disease condition. The inhibition of GlyT2 may occur either iTa vivo or iiZ vitro.
In another embodiment of the invention, GlyT2 is inhibited by contacting a cell having a glycine transporter with a compound of Formula I in an amount sufficient to inhibit GIyT2. In such a case, the contacting is effected in vivo by administering the compound, or a pharmaceutical composition thereof, to the mammal and in vitro by administering the compound, or a pharmaceutical composition thereof, to a container in which the cells are present ox to a solution bathing the cells.
A further embodiment of the invention provides a method of treating a disorder in a mammal, where the disorder may be selected from a nervous disorder and a muscle disorder, comprising administering a therapeutically effective amount of a compound of Formula I to the mammal. Optionally, the method may further comprise treating the mammal with an additional form of therapy for an autoimmune disease. For instance, one method may also comprise administering to the mammal a CNS compound in addition to the compounds of Formula I, where a CNS compound is one having pharmacological activity affecting the central nervous system (CNS).
Alternatively, the compounds of Formula I may be administered to the mammal in combination with a CNS compound or other alternative treatment for nervous system disease. The total amount of the combination of drugs administered to the mammal must be a therapeutically effective amount, although the individual amounts of each of the individual drugs may be, by themselves, suboptimal for therapeutic purposes.
For the treatment of muscle conditions, the method may also comprise administering to the mammal a muscle compound in addition to the compounds of Formula I, where a muscle compound is one having pharmacological activity affecting muscle.
Alternatively, the compounds of Formula I may be administered to the mammal in combination with a muscle compound or other alternative treatment for muscle disease.
The total amount of the combination of drugs administered to the mammal must be a therapeutically effective amount, although the individual amounts of each of the individual drugs may be, by themselves, suboptimal for therapeutic purposes.
The preferred compounds of Formula I include:
(i) when X is N R' in which R' is methyl, ethyl, pheny or benzyl;
n is 0, 1 or 2 R is chlorine or methyl;
Q is absent and W is aryl such as phenyl, optionally substituted heteroaryl such as 2-ethyl-5-methyl-3-diazolyl or (optionally subtituted heteroaryl~-X--CHZ--, such as thien-2-ylthiomethyl.
Examples of this group of compounds are:
5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole 5-benzylthio-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole 5-(4-methylbenzylthio)-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole 5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N=ethyl-1,3,4-triazole 5-benzylthio-2-(2-ethyl-5-methyl-3-diazolyl)-N-phenyl-1,3,4-triazole 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-N-benzyl-1,3,4-triazole (ii) when X is S;
n is 0, 1 or 2 R is chlorine;
Q is absent and W is aryl such as phenyl or heteroaryl such as pyridyl or pyranzinyl.
Examples of this group of compounds are:
5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole 5-(benzylthio)-2-phenyl-1,3,4-thiadiazole 5-(benzylthio)-2-pyrid-3-yl-1,3,4-thiadiazole 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-1,3,4-thiadiazole 5-(benzylthio)-2-pyrazin-2-yl-1,3,4-thiadiazole (iii) when X is O;
n is 0;
Q is present and in Formula Q, n is 0 and X is O; and W is n-butylene. .
The compound is named 2,2'-(1,4-butanediyl)bis[5-(benzylthio)-1,3,4-oxadiazole].
Patients requiring treatment to inhibit GlyT2 include patients suffering from nervous disorders and patients suffering from muscle disorders. The method of treatment comprises the administration of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical earner. The effective doses of the compound of Formula I are generally selected from the range of 0.01 to 1000 mg/kg, preferably 0.01 to 100 mg/kg and more preferably 1-30 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. The dosage units may be administered up to one to ten times daily for acute or chronic disease. No unacceptable toxicological effects are expected when compounds of Formula I are administered in accordance with the present invention.
(c) Novel Compounds of the Invention Another aspect of the present invention provides novel compounds of Formula II:
N N
W
X S
~R)n Formula II
wherein:
when X is S, n is 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is an optionally substituted heteroaryl having at least two heteroatoms; or when X is N-R' (in which R' is as defined above), n is 0, 1, 2 or 3, R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is (optionally substituted five-membered heteroaryl)-S--CH2- wherein said five-membered heteroaryl comprises one heteroatom; or a pharmaceutically acceptable salt thereof.
A most preferred compound is the compound of Formula II in which X is S, n is 2, R is chlorine and W is pyrazin-2-yl, as shown in Formula III below:
N-N CI
N
g N CI
Formula III
The compound is named 5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-triazole.
Compounds of Formula II have been found to inhibit GlyT2 and are useful for inhibiting GlyT2, including inhibiting GlyT2 in a mammal, and for treating certain mammalian neurological disorders, in particular, psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like. The compounds of Formula II, including the most preferred compound shown in Formula III, as single stereoisomers or mixtures of stereoisomers, and the pharmaceutically acceptable salts thereof, are suitable for use in pharmaceutical compositions for inhibiting GlyT2 in a mammal or for treating a mammalian with certain neurological disorders, in particular, psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like.
(d) Synthesis of Compounds of Formulae I and II
The compounds of Formulae I and II may be prepared by synthetic methods known in the art. For example, they may be prepared according to the following reaction scheme:
N-N -Q-W Y + Z ~ (R)n q W~X~S
~V) (~) (~) \ ~' (R)n In the reaction scheme, Q, W, X, n and R are as defined above, Y and Z are independently a mercapto, -SM (wherein M is an alkali metal), halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy, with the proviso when Y is a mercapto or -SM, Z is halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy or when Z is mercapto or -SM, Y is halogen, lower alkylsulfonyloxy, arylsulfonyloxy or axalkylsulfonyloxy. Examples of alkali metal represented by M in the above formula include sodium, potassium, lithium and the like.
The reactions between the compounds of Formula IV and V may be carried out in a suitable solvent in the presence of a basic compound. Any inert solvent can be used as the solvent for the reaction. Examples of the solvent are disclosed in US
Patent No. 5,670,526 which include water, alcohols, aromatic hydrocarbons, ethers, ketones, esters, aprotic solvents or a mixture thereof. Examples of the basic compound which can be used may also be found in US Patent No. 5,670,526. The reaction is carried out usually at 0-150°C, preferably at about 0-120°C, and completed in about 1 to 30 hours.
Compound of Formula (IV) is usually used in an amount of at least one mole, preferably 1-12 moles, per mole of compound of Formula (V).
The compounds of Formula (V) are usually commercially available. The compounds of Formula (IV) are either commercially available or may be synthesized by cyclization of a hydrazide. In the case of oxadiazole compounds, the cyclization of the hydrazide compounds may be carried out in the presence of CSz and a basic compound such as KOH. For the thiadiazole compounds, the cyclization of the hydrazide may be carried out in the presence of a Lawessen's reagent, CSZ and a basic compound.
These syntheses are demonstrated in the examples below.
In some cases, protective groups may be introduced and later removed in the synthesis. Suitable protective groups for amino, hydroxyl, carboxyl groups are described in Greene, et al., Protective GYOUps ira OYgar~ic SyTZ.thesis, Second Edition, John Wiley and Sons, New York, 1991. The compounds may be synthesized as shown in the examples below or by modifying the exemplified syntheses by means known to those of ordinary skill in the art.
Certain compounds of Formulae I and II may contain one or more chiral centers.
In such cases, all stereoisomers also fall within the scope of this invention.
The compounds include the individually isolated stereoisomers as well as mixtures of such stereoisomers.
Pharmaceutically acceptable salts, canons and anions of the compounds of Formulae I and II are also included in the present invention and are useful in the methods and pharmaceutical compositions described herein.
Pharmaceutically acceptable salts include salts which may be formed when acidic protons present are capable of reacting With inorganic or organic bases.
Typically, the parent compound. is treated with an excess of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing an appropriate canon. Cations, such as Na+, K+, Ca2+, Mgz+ and NHS.+, are examples of canons present in pharmaceutically acceptable salts. The Na* salts are especially useful. Acceptable inorganic bases, therefore, include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Salts may also be prepared using organic bases, such as salts of primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like.
If the compounds of Formulae I and II contain a basic group, an acid addition salt may be prepared. Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, malefic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, p-toluenesulfonic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, lactic acid, o-(4-hydroxy-benzoyl)benzoic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2.]oct-2-ene-1-carboxylic acid, glucoheptonic acid, gluconic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic)acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid, glucuronic acid, glutamic acid, 3-hydroxy-2-naphthoic acid, stearic acid, muconic acid and the like.
Certain of the compounds may form inner salts or zwitterions.
(e) Pharmaceutical Compositions of Formulae I and II
One aspect of the invention provides pharmaceutical compositions for the treatment of a disease treatable by inhibition of glycine transporter-2, which compositions comprise (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of Formula I.
Another aspect of the invention provides pharmaceutical compositions, which compositions comprise (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of Formula II.
Examples of preferred pharmaceutical compositions for the treatment of a disease treatable by inhibition of glycine transporter-2 comprise, as the active ingredient:
5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-benzylthio-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-(4-methylbenzylthio)-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-ethyl-1,3,4-triazole, 5-benzylthio-2-(2-ethyl-5-methyl-3-diazolyl)-N-phenyl-1,3,4-triazole, 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-N-benzyl-1,3,4-triazole, 5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole, 5-(benzylthio)-2-phenyl-1,3,4-thiadiazole, 5-(benzylthio)-2-pyrid-3-yl-1,3,4-thiadiazole, 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-1,3,4-thiadiazole, 5-(benzylthio)-2-pyrazin-2-yl-1,3,4-thiadiazole, or 2, 2' -( 1,4-butanediyl)bis [5-(benzylthio)-1, 3,4-oxadiazole] .
A most preferred pharmaceutical composition for this use comprises, as the active ingredient, 5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole or 2,2'-(1,4-butanediyl)bis[5-(benzylthio)-1,3,4-oxadiazole].
The pharmaceutical compositions of this invention may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are especially suitable for parenteral administration, but may also be used for oral administration. It may be desirable to add excipients such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid Garners include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid Garner varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
When a liquid carrier is use, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered orally directly or filled into a soft gelatin capsule.
Some specific examples of suitable pharmaceutical compositions are described in the Examples below.
Typically, a pharmaceutical composition of the present invention is packaged in a container with a label, or instructions, or both, indicating the use of the pharmaceutical composition in the treatment of nerve and muscle diseases, such as psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis, spasticity, myoclonus, or other disease condition.
The compounds of Formulae I and II, or pharmaceutical compositions thereof, may be administered by any route suitable to the subject being treated and the nature of the subject's condition. Routes of administration include, but are not limited to, administration by injection, including intravenous, intraperitoneal, intramuscular, and subcutaneous injection, by transmucosal or transdermal delivery, through topical applications, nasal spray, suppository and the like or may be administered orally.
Formulations may optionally be liposomal formulations, emulsions, formulations designed to administer the drug across mucosal membranes or transdermal formulations.
Suitable formulations for each of these methods of administration may be found, for example, in Remiragtota's Phaf-mczceutical Sciejaces, latest edition, Mack Publishing Company, Easton, PA.
(f) Methods for Discovering Agents for Inhibition of Glycine Transuorter Bioassays for determining glycine transporter typically measuxe glycine or radioactively labeled glycine transporter into cells having a glycine transporter. Glycine transporters are normally found in many cell types, including neuronal and glial cells and cell lines. In addition, exogenous glycine transporters may be provided to cells by transfection techniques. Nucleic acid sequences and transfection techniques for delivering nucleic acid message coding for glycine transporters are disclosed in U.S.
PatentNos. 5,756,348 and 6,127,131 to Smith et al., U.S. PatentNos. 5;824,486 and 5,968,823 to Borden et al., and U.S. Patent No. 56,008,015 to Albert et al.
Other bioassay methods for measuring glycine transporter include electrophysiological methods for measuring the strength and duration of neurotransmission at glycine synapses, both in vivo and ira vitro. Such techniques, known in the art, include intracellular recording, patch clamp recording, and extracellular recording techniques.
These electrophysiological techniques are also suitable for measuring the affects of glycine and other compounds on glycine transporter mediated neuronal activity.
The use of such bioassays, in the presence of various concentrations of glycine, labeled glycine, strychnine, compounds of Formula I, test compounds, and under various conditions are effective to detect and measure inhibition of glycine transporter, including inhibition of glycine transporter mediated by glycine transporter 2 or strychnine sensitive glycine transporters, and to detect and measure compound effects on glycine transporter mediated neuronal activity, including effects on neuronal activity mediated by glycine transporter 2 or strychnine sensitive glycine transporters.
The compounds of Formula I have been demonstrated to inhibit GlyT2 and can be useful in the treatment of certain neurological disorders. Similarly, othex compounds which show the same effects on GlyT2 can be useful for the treatment certain neurological disorders. The compounds disclosed in this application can be used as models to discover other new agents that act to inhibit GlyT2. The steps in a process in which these compounds can be utilized to discover new therapeutic agents may be achieved by the following: the compounds may be utilized to validate, optimize, and standardize assays necessary for the discovery of other compounds that inhibit GlyT2.
These compounds can be utilized as benchmarks to discover other agents that show improved activity in assays that:
1. Inhibit the glycine transporter;
2. Inhibit the glycine transporter 2;
3. Inhibit strychnine sensitive glycine transporters;
4. Affect glycine transporter mediated neuronal activity 5. Affect GlyT2 mediated neuronal activity 6. Affect strychnine sensitive glycine transporter mediated neuronal activity.
A method to discover agents that show improved activity in assays that inhibit a glycine transporter or that affect glycine transporter mediated neuronal activity comprises the steps of obtaining the results of an assay for the activity of a glycine transporter or of glycine mediated neuronal activity, obtaining the results of the assay in the presence of a plurality of concentrations of a compound of Formula I, obtaining the results of the assay in the presence of a plurality of concentrations of a test compound, comparing the results of the assays, and identifying as an agent that shows improved activity in assays that inhibits a glycine transporter or that affects glycine mediated neuronal activity a test compound from which the results obtained in the assay were improved compared to the results obtained with the compound of Formula I.
Algorithms may be used to compare structures or chemical properties of compounds, such as exemplary compounds and other test compounds. Algorithms may also be used to match structures or chemical properties within libraries of test compounds. In this way, where exemplary compounds or test compounds are known to have certain structures, properties, or activities of interest, compounds can be utilized to discover other compounds or agents that also have such structures, properties, or activities. For example, an activity of interest may be a desired activity in a bioassay.
Such algorithms are known; for example, Kauvar, U.S. Patent 5,567,317 and Kauvar et al., U.S. Patent 5,587,293 describe methods for determining the reactivity of candidate compounds with target moieties or receptors. A formula predictive of reactivity with the target receptor may be obtained from a reference set of receptors or from a panel of compounds that are systematically diverse with respect to certain properties. Compounds to be tested in this Way can be physically assessed with respect to the reference receptors, the formula applied, and the expected reactivity with the actual target receptor may be predicted. The Kauvar et al. method does not require the physical presence of the receptor.
The use of such algorithms that compare structures or chemical properties and/or match structures or chemical properties within libraries of test compounds, is effective to discover agents that display activity in bioassays. Such bioassays include bioassays to detect and measure inhibition of ghycine transporter, including inhibition of glycine transporter mediated by glycine transporter 2 or strychnine sensitive glycine transporters, and bioassays to detect and measure compound effects on glycine transporter mediated neuronal activity, including effects on neuronal activity mediated by glycine transporter 2 or strychnine sensitive glycine transporters.
Thus, when combined with algorithms that compare structures or chemical properties and/or match structures or chemical properties within libraries of test compounds, the compounds of Formula I can be utilized to discover agents that display activity in bioassays that:
1. Inhibit the glycine transporter;
2. Inhibit the glycine transporter 2;
3. Inhibit strychnine sensitive glycine transporters;
5. Affect glycine transporter mediated neuronal activity 5. Affect GlyT2 mediated neuronal activity 6. Affect strychnine sensitive glycine transporter mediated neuronal activity.
A method to discover agents that display activity in bioassays that inhibit the glycine transporter or affect glycine mediated neuronal activity, comprising applying an algorithm to compare the chemical structures or chemical properties within a library of test compounds with the chemical structure or chemical properties of a compound of Formula I, and identifying as an agent that displays activity in bioassays that inhibits the glycine transporter or affects glycine mediated neuronal activity a test compound determined by the algorithm to have a chemical structure or chemical properties similar to the compound of Formula I.
Algorithms may also be used to compare structures and/or match structures for the purpose of modeling molecular interactions. Such algorithms are known; for example, the methods of Kauvar, and of Kauvar et al., supYa, may be used to compare structures and/or match structures for the purpose of modeling molecular interactions. .
The use of such algorithms is effective to discover agents that display activity in bioassays such as bioassays to detect and measure inhibition of glycine transporter, including inhibition of glycine transporter mediated by glycine transporter 2 or strychnine sensitive glycine transporters, and bioassays to detect and measure compound effects on glycine transporter mediated neuronal activity, including effects on neuronal activity mediated by glycine transporter 2 or strychnine sensitive glycine transporters.
Thus, when combined with algorithms that compare structures and/or match structures for the purpose of modeling molecular interactions, these compounds of Formula I can be utilized to discover agents that display activity in bioassays that:
Inhibit the glycine transporter;
2. Inhibit the glycine transporter 2;
3. Inhibit strychnine sensitive glycine transporters;
6. Affect glycine transporter mediated neuronal activity Affect GlyT2 mediated neuronal activity Affect strychnine sensitive glycine transporter mediated neuronal activity.
A method to discover agents that display activity in bioassays that inhibit the glycine transporter or affect glycine transporter mediated neuronal activity, comprising applying an algorithm to compare and/or match the chemical structures within a library of test compounds with the chemical structure of a compound of Formula I for the purpose of modeling molecular interactions, and identifying as an agent that displays activity in bioassays that inhibits the glycine transporter or affects glycine transporter mediated neuronal activity a test compound determined by the algorithm to have chemical structure comparable to or matching the compound of Formula I.
EXAMPLES
The Examples which follow serve to illustrate this invention. The Examples are provided to show how to make and use compounds of the invention, and are in no way intended to limit the scope of this invention.
Examule 1 Preparation of 5-[(2,6-dichlorophenyl)methylthioj -2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 3 N-N CI
~/~\ 2,6-dichlorobenzylbromide S~N SFi Me Me _ CI
To a solution of 2 (5.0I2 gm, 20.6mmo1) in DMF (100 mL) was added, CsCO3 (13.4gm, 25 mmoL) and stirred. 2,6-Dichlorobenzylbromide (5.28gm, 22 mmoL) was added dropwise. The reaction was warmed to 80 C for 24 h. The reaction mixture cooled, partitioned between EtOAc, and 1N HCI. The aqueous layer was extracted times with EtOAc, and the combined organic layers washed with 1N HCI, brine and dried over lVIgS04. Concentration and chromatography affords a yellow solid (S.lgm, 66%).
The following compounds were prepared in a similar manner.
N-N
R~~ ~S~R3 N
R~
Compound R1 R2 R3 MW
4 2-thienylthiomethylMe benzyl 333.5 2-thienylthiomethylMe 4-methylbenzyl347.5 6 2-theinylthiomethylEt 2,6-dichlorobenzyl416.4 7 2-ethyl-5-methyl-3-diazolylPh benzyl 375.5 8 phenyl Bn 2,6-dichlorobenzyl440.3 Examule 2 Preparation of 5-[(2,6-dichlorophenyl)methylthio]
-2-pyrazin-2-yl-1,3,4-thiadiazole,12 O O O N-N
N\ O /N HZNNHz N\ N,NHZ CSZ N\ ~ S~S_~+
\ _ \
H 1. Lawessen's Reagent N/ \N N/ 2. CSp~ ICOH N/
A method to discover agents that show improved activity in assays that inhibit a glycine transporter or that affect glycine transporter mediated neuronal activity comprises the steps of obtaining the results of an assay for the activity of a glycine transporter or of glycine mediated neuronal activity, obtaining the results of the assay in the presence of a plurality of concentrations of a compound of Formula I, obtaining the results of the assay in the presence of a plurality of concentrations of a test compound, comparing the results of the assays, and identifying as an agent that shows improved activity in assays that inhibits a glycine transporter or that affects glycine mediated neuronal activity a test compound from which the results obtained in the assay were improved compared to the results obtained with the compound of Formula I.
Algorithms may be used to compare structures or chemical properties of compounds, such as exemplary compounds and other test compounds. Algorithms may also be used to match structures or chemical properties within libraries of test compounds. In this way, where exemplary compounds or test compounds are known to have certain structures, properties, or activities of interest, compounds can be utilized to discover other compounds or agents that also have such structures, properties, or activities. For example, an activity of interest may be a desired activity in a bioassay.
Such algorithms are known; for example, Kauvar, U.S. Patent 5,567,317 and Kauvar et al., U.S. Patent 5,587,293 describe methods for determining the reactivity of candidate compounds with target moieties or receptors. A formula predictive of reactivity with the target receptor may be obtained from a reference set of receptors or from a panel of compounds that are systematically diverse with respect to certain properties. Compounds to be tested in this Way can be physically assessed with respect to the reference receptors, the formula applied, and the expected reactivity with the actual target receptor may be predicted. The Kauvar et al. method does not require the physical presence of the receptor.
The use of such algorithms that compare structures or chemical properties and/or match structures or chemical properties within libraries of test compounds, is effective to discover agents that display activity in bioassays. Such bioassays include bioassays to detect and measure inhibition of ghycine transporter, including inhibition of glycine transporter mediated by glycine transporter 2 or strychnine sensitive glycine transporters, and bioassays to detect and measure compound effects on glycine transporter mediated neuronal activity, including effects on neuronal activity mediated by glycine transporter 2 or strychnine sensitive glycine transporters.
Thus, when combined with algorithms that compare structures or chemical properties and/or match structures or chemical properties within libraries of test compounds, the compounds of Formula I can be utilized to discover agents that display activity in bioassays that:
1. Inhibit the glycine transporter;
2. Inhibit the glycine transporter 2;
3. Inhibit strychnine sensitive glycine transporters;
5. Affect glycine transporter mediated neuronal activity 5. Affect GlyT2 mediated neuronal activity 6. Affect strychnine sensitive glycine transporter mediated neuronal activity.
A method to discover agents that display activity in bioassays that inhibit the glycine transporter or affect glycine mediated neuronal activity, comprising applying an algorithm to compare the chemical structures or chemical properties within a library of test compounds with the chemical structure or chemical properties of a compound of Formula I, and identifying as an agent that displays activity in bioassays that inhibits the glycine transporter or affects glycine mediated neuronal activity a test compound determined by the algorithm to have a chemical structure or chemical properties similar to the compound of Formula I.
Algorithms may also be used to compare structures and/or match structures for the purpose of modeling molecular interactions. Such algorithms are known; for example, the methods of Kauvar, and of Kauvar et al., supYa, may be used to compare structures and/or match structures for the purpose of modeling molecular interactions. .
The use of such algorithms is effective to discover agents that display activity in bioassays such as bioassays to detect and measure inhibition of glycine transporter, including inhibition of glycine transporter mediated by glycine transporter 2 or strychnine sensitive glycine transporters, and bioassays to detect and measure compound effects on glycine transporter mediated neuronal activity, including effects on neuronal activity mediated by glycine transporter 2 or strychnine sensitive glycine transporters.
Thus, when combined with algorithms that compare structures and/or match structures for the purpose of modeling molecular interactions, these compounds of Formula I can be utilized to discover agents that display activity in bioassays that:
Inhibit the glycine transporter;
2. Inhibit the glycine transporter 2;
3. Inhibit strychnine sensitive glycine transporters;
6. Affect glycine transporter mediated neuronal activity Affect GlyT2 mediated neuronal activity Affect strychnine sensitive glycine transporter mediated neuronal activity.
A method to discover agents that display activity in bioassays that inhibit the glycine transporter or affect glycine transporter mediated neuronal activity, comprising applying an algorithm to compare and/or match the chemical structures within a library of test compounds with the chemical structure of a compound of Formula I for the purpose of modeling molecular interactions, and identifying as an agent that displays activity in bioassays that inhibits the glycine transporter or affects glycine transporter mediated neuronal activity a test compound determined by the algorithm to have chemical structure comparable to or matching the compound of Formula I.
EXAMPLES
The Examples which follow serve to illustrate this invention. The Examples are provided to show how to make and use compounds of the invention, and are in no way intended to limit the scope of this invention.
Examule 1 Preparation of 5-[(2,6-dichlorophenyl)methylthioj -2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 3 N-N CI
~/~\ 2,6-dichlorobenzylbromide S~N SFi Me Me _ CI
To a solution of 2 (5.0I2 gm, 20.6mmo1) in DMF (100 mL) was added, CsCO3 (13.4gm, 25 mmoL) and stirred. 2,6-Dichlorobenzylbromide (5.28gm, 22 mmoL) was added dropwise. The reaction was warmed to 80 C for 24 h. The reaction mixture cooled, partitioned between EtOAc, and 1N HCI. The aqueous layer was extracted times with EtOAc, and the combined organic layers washed with 1N HCI, brine and dried over lVIgS04. Concentration and chromatography affords a yellow solid (S.lgm, 66%).
The following compounds were prepared in a similar manner.
N-N
R~~ ~S~R3 N
R~
Compound R1 R2 R3 MW
4 2-thienylthiomethylMe benzyl 333.5 2-thienylthiomethylMe 4-methylbenzyl347.5 6 2-theinylthiomethylEt 2,6-dichlorobenzyl416.4 7 2-ethyl-5-methyl-3-diazolylPh benzyl 375.5 8 phenyl Bn 2,6-dichlorobenzyl440.3 Examule 2 Preparation of 5-[(2,6-dichlorophenyl)methylthio]
-2-pyrazin-2-yl-1,3,4-thiadiazole,12 O O O N-N
N\ O /N HZNNHz N\ N,NHZ CSZ N\ ~ S~S_~+
\ _ \
H 1. Lawessen's Reagent N/ \N N/ 2. CSp~ ICOH N/
N-N CI
N\ / g~g /
2,6-dichlorobenzylbromide N CI
To a solution of 2-pyrazinecarboxyic anhydride (2.2 gm, 14.7 mmoL), in 20 mL
of methylene chloride was added hydrazine in THF (1M, lSmL) and allowed to stir for 24h. The reaction mixture was concentrated to an oil, diluted with methylene chloride and extracted 3 times with NaHC03. The organic layer was dried over K~C03, affording a colorless oil. The resulting hydrazide,10, was used without further purification. Compound 10 was diluted with Lawssen's reagent (2.9gm, 7.2 mmoL) in methylene chloride, and the reaction mixture heated to reflux for 12h. The mixture was filtered and washed with additional methylene chloride and concentrated in vacuo to a bright yellow solid. This crude material and powdered KOH (1 gln, 18 mmoL) were stirred in 20 mL of ethanol. CS2 (0.56 gm, 7.4 mmoL) was added dropwise, the reaction mixture was reflux for 24h. Volatiles were removed under vacuum, and the resulting solid, 11, was washed with methylene chloride/EtOH to remove soluble material.
Crude 11, was stirred with DMF and 2,6-dichlorobenzylbromide (1.76 gm, 7 mmoL). The reaction was warmed to 80 C and allowed to stir for 24h. The mixture was partitioned between methylene chloride and 1N HCl. The aqueous layer was extracted 2 times with 1N HCI, and the organic layers washed with NaHC03, brine, dried over K2C03 and concentrated to a yellow oil. Chromatography affords an off white solid (1.37 gm, 51%).
The following compounds were also prepared in a similar manner:
N-N
R ~ ~S R2 Compound Rl R2 MW
13 phenyl benzyl 284 14 3-Pyridyl benzyl 285 15 phenyl 2,6-dichlorobenzyl353 16 2-pyrazinyl benzyl 286 Examine 3 Preparation of 2,2'-(1,4-butanediyl)bis[5-(benzylthio)-1,3,4-oxadiazole]
1. oxalyl chloride HOZC 2. hydrazine HzNHNOC
COpH CONHNHp 1g 19 CSZ, KOH
NwN ~NwN
BnS~ I BnBr +K'S---(' O ( ~SBn O I ~S'K+
21 N\N 20 N\N
Adipic acid, 18, (1.46 gm, 10 mmoL) was dissolved in methylene chloride, oxalyl chloride (2.8gm, 22 mmoL) was added followed by 1 drop of DMF. The reaction mixture was allowed to stir at RT for 2h, then concentrated in vacuo. The crude oil was dissolved in methylene chloride and concentrated in vacuo. The oil was diluted in THF
and cooled to 0 C. Hydrazine in THF (1M, 2.2mL) was added slowly. The mixture was allowed to warm to RT overnight and then concentrated in vacuo to an oil. The oil was dissolved in rnethylene chloride, washed with NaHC03 and dried over K2CO3. The bishydrazide, 19, was dissolved in ethanol and powdered KOH (l.2gm, 22mmoL) was added. CS2 (1.68gm, 22mmo1) was added dropwise and the reaction was refluxed for 24h. The volatiles were removed in vacuo and washed to methylene chloride/EtOH.
The solid was placed in DMF and treated with benzyl bromide (l.7gm, 10 mmoL).
The xeaction was allowed to stir overnight at 80 C. Following an aqueous workup and chromatography affords compound 21 (0.657gm, 7.5%).
Example 4 Inhibition of glycine transporter 2 CHO cells expressing rat glycine transporter subtype 2 (GLYT2) were grown in high glucose Dulbecco's modified Eagle's medium supplemented with 10 % bovine fetal serum at 37 °C and 5 % C02. Subconfluent cells growing in 24- or 96-well plates were washed with PBS, and were preincubated at 37°C for 15 min with uptake buffer (100 mM NaCI, 2 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.5) containing sample compounds. Uptake was initiated by adding prewarmed 3H-glycine yielding a nM final glycine concentratioxi, and was terminated after 7 min by aspiration of the buffer. Cells were washed 3 times with ice-cold PBS, and radioactivity was determined by scintillation counting using TopCount.
N-N R~
Rs Cm d# W X R1 RS Gly T2 Inhib (uM) 4 . ~ s~~ N-Me Cl Cl 8.4 7 N-Ph H H 6.6 ~N
N
12 N~ '~~ S C1 C1 0.9 N
21 %~~~ O H H 1.1 Example 5 Oral pharmaceutical composition preparation - solid dosage formulation A pharmaceutical composition for oral administration is prepared by combining the following:
w/w Compound of the invention10%
Magnesium stearate 0.5%
Starch 2.0%
hydroxypropylmethylcellulose1.0%
Microcrystalline cellulose86.5%
The mixture is compressed in a press to form tablets. Optionally, the mixture is instead filled into hard gelatin capsules.
Tablets may be coated by applying a suspension of film former (e.g., hydroxypropylmethylcellulose), pigment (e.g. titanium dioxide) and plasticizer (e.g., diethyl phthalate) and drying the film by evaporation of the solvent. The film coat is 3.0 of the tablet by weight. Optionally, the film coat can comprise 2.0% to 6.0%
of the tablet weight.
Example 6 Oral pharmaceutical composition preparation - capsule A pharniaceutical composition of a compound of the invention suitable for oral administration is prepared by combining the following:
w/w Compound of the invention 20%
Polyethylene glycol 80%
The medicinal compound is dispersed or dissolved in the liquid Garner, and a thickening agent is added. The step of adding the thickening agent is optional. The formulation is then enclosed in a soft gelatin capsule.
Example 7 Pharmaceutical composition for parenteral administration Pharmaceutical compositions for parenteral administration typically comprise the pharmaceutically active ingredient and physiological saline, such as phosphate buffered saline or other water solution with pH and salt content suitable for introduction into an animal. A pharmaceutical composition for parenteral administration is prepared by combining compound 3 and Dulbecco's Phosphate Buffered Saline (D8662, Sigma Chemical Co. St. Louis, MO) as described in the following:
Amount Compound 3 1.0%
Saline 99.0%
The solution is sterilized and sealed in sterile containers.
Various modifications and variations of the present invention will be apparent to those skilled in the art without departing fiom the scope and spirit of the invention.
Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed is not limited to such specific embodiments. It will be appreciated by one of ordinary skill in the art that various modifications of the described modes for carrying out the invention are within the scope of the following claims.
N\ / g~g /
2,6-dichlorobenzylbromide N CI
To a solution of 2-pyrazinecarboxyic anhydride (2.2 gm, 14.7 mmoL), in 20 mL
of methylene chloride was added hydrazine in THF (1M, lSmL) and allowed to stir for 24h. The reaction mixture was concentrated to an oil, diluted with methylene chloride and extracted 3 times with NaHC03. The organic layer was dried over K~C03, affording a colorless oil. The resulting hydrazide,10, was used without further purification. Compound 10 was diluted with Lawssen's reagent (2.9gm, 7.2 mmoL) in methylene chloride, and the reaction mixture heated to reflux for 12h. The mixture was filtered and washed with additional methylene chloride and concentrated in vacuo to a bright yellow solid. This crude material and powdered KOH (1 gln, 18 mmoL) were stirred in 20 mL of ethanol. CS2 (0.56 gm, 7.4 mmoL) was added dropwise, the reaction mixture was reflux for 24h. Volatiles were removed under vacuum, and the resulting solid, 11, was washed with methylene chloride/EtOH to remove soluble material.
Crude 11, was stirred with DMF and 2,6-dichlorobenzylbromide (1.76 gm, 7 mmoL). The reaction was warmed to 80 C and allowed to stir for 24h. The mixture was partitioned between methylene chloride and 1N HCl. The aqueous layer was extracted 2 times with 1N HCI, and the organic layers washed with NaHC03, brine, dried over K2C03 and concentrated to a yellow oil. Chromatography affords an off white solid (1.37 gm, 51%).
The following compounds were also prepared in a similar manner:
N-N
R ~ ~S R2 Compound Rl R2 MW
13 phenyl benzyl 284 14 3-Pyridyl benzyl 285 15 phenyl 2,6-dichlorobenzyl353 16 2-pyrazinyl benzyl 286 Examine 3 Preparation of 2,2'-(1,4-butanediyl)bis[5-(benzylthio)-1,3,4-oxadiazole]
1. oxalyl chloride HOZC 2. hydrazine HzNHNOC
COpH CONHNHp 1g 19 CSZ, KOH
NwN ~NwN
BnS~ I BnBr +K'S---(' O ( ~SBn O I ~S'K+
21 N\N 20 N\N
Adipic acid, 18, (1.46 gm, 10 mmoL) was dissolved in methylene chloride, oxalyl chloride (2.8gm, 22 mmoL) was added followed by 1 drop of DMF. The reaction mixture was allowed to stir at RT for 2h, then concentrated in vacuo. The crude oil was dissolved in methylene chloride and concentrated in vacuo. The oil was diluted in THF
and cooled to 0 C. Hydrazine in THF (1M, 2.2mL) was added slowly. The mixture was allowed to warm to RT overnight and then concentrated in vacuo to an oil. The oil was dissolved in rnethylene chloride, washed with NaHC03 and dried over K2CO3. The bishydrazide, 19, was dissolved in ethanol and powdered KOH (l.2gm, 22mmoL) was added. CS2 (1.68gm, 22mmo1) was added dropwise and the reaction was refluxed for 24h. The volatiles were removed in vacuo and washed to methylene chloride/EtOH.
The solid was placed in DMF and treated with benzyl bromide (l.7gm, 10 mmoL).
The xeaction was allowed to stir overnight at 80 C. Following an aqueous workup and chromatography affords compound 21 (0.657gm, 7.5%).
Example 4 Inhibition of glycine transporter 2 CHO cells expressing rat glycine transporter subtype 2 (GLYT2) were grown in high glucose Dulbecco's modified Eagle's medium supplemented with 10 % bovine fetal serum at 37 °C and 5 % C02. Subconfluent cells growing in 24- or 96-well plates were washed with PBS, and were preincubated at 37°C for 15 min with uptake buffer (100 mM NaCI, 2 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.5) containing sample compounds. Uptake was initiated by adding prewarmed 3H-glycine yielding a nM final glycine concentratioxi, and was terminated after 7 min by aspiration of the buffer. Cells were washed 3 times with ice-cold PBS, and radioactivity was determined by scintillation counting using TopCount.
N-N R~
Rs Cm d# W X R1 RS Gly T2 Inhib (uM) 4 . ~ s~~ N-Me Cl Cl 8.4 7 N-Ph H H 6.6 ~N
N
12 N~ '~~ S C1 C1 0.9 N
21 %~~~ O H H 1.1 Example 5 Oral pharmaceutical composition preparation - solid dosage formulation A pharmaceutical composition for oral administration is prepared by combining the following:
w/w Compound of the invention10%
Magnesium stearate 0.5%
Starch 2.0%
hydroxypropylmethylcellulose1.0%
Microcrystalline cellulose86.5%
The mixture is compressed in a press to form tablets. Optionally, the mixture is instead filled into hard gelatin capsules.
Tablets may be coated by applying a suspension of film former (e.g., hydroxypropylmethylcellulose), pigment (e.g. titanium dioxide) and plasticizer (e.g., diethyl phthalate) and drying the film by evaporation of the solvent. The film coat is 3.0 of the tablet by weight. Optionally, the film coat can comprise 2.0% to 6.0%
of the tablet weight.
Example 6 Oral pharmaceutical composition preparation - capsule A pharniaceutical composition of a compound of the invention suitable for oral administration is prepared by combining the following:
w/w Compound of the invention 20%
Polyethylene glycol 80%
The medicinal compound is dispersed or dissolved in the liquid Garner, and a thickening agent is added. The step of adding the thickening agent is optional. The formulation is then enclosed in a soft gelatin capsule.
Example 7 Pharmaceutical composition for parenteral administration Pharmaceutical compositions for parenteral administration typically comprise the pharmaceutically active ingredient and physiological saline, such as phosphate buffered saline or other water solution with pH and salt content suitable for introduction into an animal. A pharmaceutical composition for parenteral administration is prepared by combining compound 3 and Dulbecco's Phosphate Buffered Saline (D8662, Sigma Chemical Co. St. Louis, MO) as described in the following:
Amount Compound 3 1.0%
Saline 99.0%
The solution is sterilized and sealed in sterile containers.
Various modifications and variations of the present invention will be apparent to those skilled in the art without departing fiom the scope and spirit of the invention.
Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed is not limited to such specific embodiments. It will be appreciated by one of ordinary skill in the art that various modifications of the described modes for carrying out the invention are within the scope of the following claims.
Claims (36)
1. Use of a compound of Formula I:
wherein n is 0, 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen;
X is O, S or N~R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene);
Q may be absent or present, and when present, it is represented by the formula:
in which n, R and X are as defined above;
when Q is present, W is a lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally subtituted heteroaryl (optionally substituted aryl)~X~CH2~ or (optionally subtituted heteroaryl)~X~CH2~ in which X is as defined above; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease treatable by administration of a glycine transporter-2 inhibitor.
wherein n is 0, 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen;
X is O, S or N~R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene);
Q may be absent or present, and when present, it is represented by the formula:
in which n, R and X are as defined above;
when Q is present, W is a lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally subtituted heteroaryl (optionally substituted aryl)~X~CH2~ or (optionally subtituted heteroaryl)~X~CH2~ in which X is as defined above; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease treatable by administration of a glycine transporter-2 inhibitor.
2. Use of Claim 1 wherein the disease is a nervous disorder.
3. Use of Claim 1 wherein the disease is a muscle disorder.
4. Use of Claim 1 wherein the disease is a disorder selected from the group consisting of psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis, spasticity and myoclonus.
5. Use of Claim 1 wherein X is N~R' in which R' is methyl, ethyl, pheny or benzyl, n is 0, 1 or 2, R is chlorine or methyl, Q is absent and W is aryl, optionally substituted heteroaryl or (optionally subtituted heteroaryl)~X~CH2~.
6. Use of Claim 5 wherein the compound is:
5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole;
5-benzylthio-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-(4-methylbenzylthio)-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-ethyl-1,3,4-triazole, 5-benzylthio-2-(2-ethyl-5-methyl-3-diazolyl)-N-phenyl-1,3,4-triazole, or 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-N-benzyl-1,3,4-triazole.
5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole;
5-benzylthio-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-(4-methylbenzylthio)-2-thien-2-ylthiomethyl-N-methyl-1,3,4-triazole, 5-[(2,6-dichlorophenyl)methylthio]-2-thien-2-ylthiomethyl-N-ethyl-1,3,4-triazole, 5-benzylthio-2-(2-ethyl-5-methyl-3-diazolyl)-N-phenyl-1,3,4-triazole, or 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-N-benzyl-1,3,4-triazole.
7. Use of Claim 1 wherein X is S, n is 0, 1 or 2, R is chlorine, Q is absent and W is aryl or heteroaryl.
8. Use of Claim 7 wherein the compound is:
5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole, 5-(benzylthio)-2-phenyl-1,3,4-thiadiazole, 5-(benzylthio)-2-pyrid-3-yl-1,3,4-thiadiazole, 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-1,3,4-thiadiazole, or 5-(benzylthio)-2-pyrazin-2-yl-1,3,4-thiadiazole.
5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole, 5-(benzylthio)-2-phenyl-1,3,4-thiadiazole, 5-(benzylthio)-2-pyrid-3-yl-1,3,4-thiadiazole, 5-[(2,6-dichlorophenyl)methylthio]-2-phenyl-1,3,4-thiadiazole, or 5-(benzylthio)-2-pyrazin-2-yl-1,3,4-thiadiazole.
9. Use of Claim 1 wherein X is O, n is 0, Q is present and in Formula Q, n is 0 and X is O; and W is n-butylene, namely 2,2'-(1,4-butanediyl)bis[5-(benzylthio)-1,3,4-oxadiazole].
10. A pharmaceutical composition for treating a disease treatable by inhibition of glycine transporter-2, which composition comprises, as the active ingredient, a compound of Formula I:
wherein n is 0, 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen;
X is O, S or N~R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene);
Q may be absent or present, and when present, it is represented by the formula:
in which n, R and X are as defined above;
when Q is present, W is a lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally subtituted heteroaryl (optionally substituted aryl)~X~CH2~ or (optionally subtituted heteroaryl)~X~CH2~ in which X is as defined above; or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
wherein n is 0, 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen;
X is O, S or N~R' (wherein R's is lower alkyl, aryl, heteroaryl, aryl-lower alkylene or heteroaryl-lower alkylene);
Q may be absent or present, and when present, it is represented by the formula:
in which n, R and X are as defined above;
when Q is present, W is a lower alkylene and when Q is absent, W is optionally substituted lower alkyl, optionally substituted aryl, optionally subtituted heteroaryl (optionally substituted aryl)~X~CH2~ or (optionally subtituted heteroaryl)~X~CH2~ in which X is as defined above; or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
11. The pharmaceutical composition of Claim 10 wherein said compound is 5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole or 2,2'-(1,4-butanediyl)bis[5-(benzylthio)-1,3,4-oxadiazole].
12. A compound of Formula II:
wherein:
when X is S, n is 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is an optionally substituted heteroaryl having at least two heteroatoms; or when X is N~R' (in which R' is as defined above), n is 0, 1, 2 or 3, R is independently hydrogen, halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is (optionally substituted five-membered heteroaryl)~S~CH2~ wherein said five-membered heteroaryl comprises one heteroatom; or a pharmaceutically acceptable salt thereof.
wherein:
when X is S, n is 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is an optionally substituted heteroaryl having at least two heteroatoms; or when X is N~R' (in which R' is as defined above), n is 0, 1, 2 or 3, R is independently hydrogen, halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is (optionally substituted five-membered heteroaryl)~S~CH2~ wherein said five-membered heteroaryl comprises one heteroatom; or a pharmaceutically acceptable salt thereof.
13. The compound of Claim 12 wherein X is S, n is 2 and R is chlorine and W is pyrazin-2-yl:
14. A pharmaceutical composition comprising, as the active ingredient, a compound of Formula II:
wherein:
when X is S, n is 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is an optionally substituted heteroaryl having at least two heteroatoms; or when X is N~R' (in which R' is as defined above), n is 0, 1, 2 or 3, R is independently hydrogen, halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is (optionally substituted five-membered heteroaryl)~S~CH2~ wherein said five-membered heteroaryl comprises one heteroatom; or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
wherein:
when X is S, n is 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is an optionally substituted heteroaryl having at least two heteroatoms; or when X is N~R' (in which R' is as defined above), n is 0, 1, 2 or 3, R is independently hydrogen, halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is (optionally substituted five-membered heteroaryl)~S~CH2~ wherein said five-membered heteroaryl comprises one heteroatom; or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
15. The pharmaceutical composition of Claim 14 wherein the compound, as the active ingredient, is 5-[(2,6-dichlorophenyl)methylthio]-2-pyrazin-2-yl-1,3,4-thiadiazole.
16. A process for the preparation of a compound of Formula II:
wherein:
when X is S, n is 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is an optionally substituted heteroaryl having at least two heteroatoms; or when X is N~R' (in which R' is as defined above), n is 0, 1, 2 or 3, R is independently hydrogen, halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is (optionally substituted five-membered heteroaryl)~S~CH2~ wherein said five-membered heteroaryl comprises one heteroatom, and a pharmaceutically acceptable salt thereof, which process comprises:
a) reacting a compound of Formula IV:
with a compound of Formula V
wherein W, Q, X, n and R are as defined above, Y and Z are independently a mercapto, -SM (wherein M is an alkali metal), halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy, with the proviso when Y is a mercapto or -SM, Z is halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy or when Z is mercapto or-SM, Y is halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy; or b) converting a compound of Formula II to a pharmaceutically acceptable salt; or c) converting a salt of Formula II to a compound of Formula II; or d) converting a salt of Formula II to a pharmaceutically acceptable salt of Formula II.
wherein:
when X is S, n is 1, 2 or 3 and R is independently halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is an optionally substituted heteroaryl having at least two heteroatoms; or when X is N~R' (in which R' is as defined above), n is 0, 1, 2 or 3, R is independently hydrogen, halogen, hydroxy, lower alkyl optionally substituted with halogen or lower alkoxy optionally substituted with halogen; and W is (optionally substituted five-membered heteroaryl)~S~CH2~ wherein said five-membered heteroaryl comprises one heteroatom, and a pharmaceutically acceptable salt thereof, which process comprises:
a) reacting a compound of Formula IV:
with a compound of Formula V
wherein W, Q, X, n and R are as defined above, Y and Z are independently a mercapto, -SM (wherein M is an alkali metal), halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy, with the proviso when Y is a mercapto or -SM, Z is halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy or when Z is mercapto or-SM, Y is halogen, lower alkylsulfonyloxy, arylsulfonyloxy or aralkylsulfonyloxy; or b) converting a compound of Formula II to a pharmaceutically acceptable salt; or c) converting a salt of Formula II to a compound of Formula II; or d) converting a salt of Formula II to a pharmaceutically acceptable salt of Formula II.
17. A method of treating a disorder in a mammal selected from a nervous disorder and a muscle disorder, comprising administering a therapeutically effective amount of a compound of Formula I to the mammal.
18. The method of Claim 17 wherein the disorder is selected from the group consisting of psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis, spasticity and myoclonus.
19. A method of inhibiting the glycine transporter 2 (GlyT2) comprising contacting a cell with a compound of Formula I in an amount sufficient to inhibit GlyT2.
20. The method of Claim 19 wherein the cell is present in a living animal, and wherein the step of contacting the cell with a compound of Formula I
comprises administering to an animal an effective amount of the compound.
21. The method of Claim 19 wherein the cell is not present in a living animal, and wherein the step of contacting the cell with a compound of Formula I
comprises administering an effective amount of the compound to the cell or to a solution bathing the cell.
comprises administering to an animal an effective amount of the compound.
21. The method of Claim 19 wherein the cell is not present in a living animal, and wherein the step of contacting the cell with a compound of Formula I
comprises administering an effective amount of the compound to the cell or to a solution bathing the cell.
21. A method of inhibiting the glycine transporter 2 (GlyT2) comprising contacting a cell having a GlyT2 with a compound of Formula I in an amount sufficient to inhibit GlyT2.
22. The method of Claim 21 wherein the cell having a glycine transporter 2 is present in a living animal, and wherein the step of contacting the cell with a compound of Formula I comprises administering to an animal an effective amount of the compound.
23. The method of Claim 21 wherein the cell having a glycine transporter 2 is not present in a living animal, and wherein the step of contacting the cell with a compound of Formula I comprises administering an effective amount of the compound to the cell or to a solution bathing the cell.
24. The method of Claim 17 further comprising another form of therapy.
25. A method to discover agents that show improved activity in assays that inhibit a glycine transporter, comprising the steps of obtaining the results of an assay for the activity of a glycine transporter, obtaining the results of the assay in the presence of a plurality of concentrations of a compound of Formula I, obtaining the results of the assay in the presence of a plurality of concentrations of a test compound, comparing the results of the assays, and identifying as an agent that shows improved activity in assays that inhibits a glycine transporter a test compound from which the results obtained in the assay were improved compared to the results obtained with the compound of Formula I.
26. The method of Claim 25 wherein the glycine transporter is selected from the group consisting of the glycine transporter 2 and a strychnine sensitive glycine transporter.
27. A method to discover agents that show improved activity in assays that affect glycine transporter mediated neuronal activity, comprising the steps of obtaining the results of an assay for glycine transporter mediated neuronal activity, obtaining the results of the assay in the presence of a plurality of concentrations of a compound of Formula I, obtaining the results of the assay in the presence of a plurality of concentrations of a test compound, comparing the results of the assays, and identifying as an agent that shows improved activity in assays that affects glycine transporter mediated neuronal activity a test compound from which the results obtained in the assay were improved compared to the results obtained with the compound of Formula I.
28. The method of Claim 27 wherein the glycine transporter mediated neuronal activity is selected from the group consisting of GlyT2 mediated neuronal activity and strychnine sensitive glycine transporter mediated neuronal activity.
29. A method to discover agents that display activity in bioassays that inhibit the glycine transporter, comprising applying an algorithm to compare the chemical structures or chemical properties within a library of test compounds with the chemical structure or chemical properties of a compound of Formula I, and identifying as an agent that displays activity in bioassays that inhibits the glycine transporter a test compound determined by the algorithm to have a chemical structure or chemical properties similar to the compound of Formula I.
30. The method of Claim 29 wherein the glycine transporter is selected from the group consisting of the glycine transporter 2 and a strychnine sensitive glycine transporter.
31. A method to discover agents that display activity in bioassays that affect glycine transporter mediated neuronal activity, comprising applying an algorithm to compare the chemical structures or chemical properties within a library of test compounds with the chemical structure or chemical properties of a compound of Formula I, and identifying as an agent that displays activity in bioassays that affects glycine transporter mediated neuronal activity a test compound determined by the algorithm to have a chemical structure or chemical properties similar to the compound of Formula I.
32. The method of Claim 31 wherein the glycine transporter mediated neuronal activity is selected from the group consisting of glycine transporter 2 mediated neuronal activity and strychnine sensitive glycine transporter mediated neuronal activity.
33. A method to discover agents that display activity in bioassays that inhibit the glycine transporter, comprising applying an algorithm to compare and/or match the chemical structures within a library of test compounds with the chemical structure of a compound of Formula I for the purpose of modeling molecular interactions, and identifying as an agent that displays activity in bioassays that inhibits the glycine transporter a test compound determined by the algorithm to have a chemical structure comparable to or matching the compound of Formula I.
34. The method of Claim 33 wherein the glycine transporter is selected from the group consisting of the glycine transporter 2 and a strychnine sensitive glycine transporter.
35. A method to discover agents that display activity in bioassays that affect glycine transporter mediated neuronal activity, comprising applying an algorithm to compare and/or match the chemical structures within a library of test compounds with the chemical structure of a compound of Formula I for the purpose of modeling molecular interactions, and identifying as an agent that displays activity in bioassays that affects glycine transporter mediated neuronal activity a test compound determined by the algorithm to have chemical structure comparable to or matching the compound of Formula I.
36. The method of Claim 35 wherein the glycine transporter mediated neuronal activity is selected from the group consisting of glycine transporter 2 mediated neuronal activity and strychnine sensitive glycine transporter mediated neuronal activity.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26789401P | 2001-02-09 | 2001-02-09 | |
| US60/267,894 | 2001-02-09 | ||
| PCT/US2002/003837 WO2002064135A1 (en) | 2001-02-09 | 2002-02-08 | Heterocyclic inhibitors of glycine transporter 2 |
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| Publication Number | Publication Date |
|---|---|
| CA2436079A1 true CA2436079A1 (en) | 2002-08-22 |
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| CA002436079A Abandoned CA2436079A1 (en) | 2001-02-09 | 2002-02-08 | Heterocyclic inhibitors of glycine transporter 2 |
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|---|---|
| US (1) | US6894054B2 (en) |
| EP (1) | EP1357913A1 (en) |
| JP (1) | JP2004522761A (en) |
| AR (1) | AR032653A1 (en) |
| AU (1) | AU2002247098B2 (en) |
| CA (1) | CA2436079A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| EP2757881A4 (en) * | 2011-09-15 | 2014-11-12 | Univ Kansas | Kappa opioid receptor effectors and uses thereof |
| CN103373993B (en) * | 2012-04-12 | 2016-03-02 | 南京大学 | One class is containing the thiadiazoles derivative of pyrazine ring and method for making thereof and purposes |
| CZ305680B6 (en) * | 2013-04-04 | 2016-02-03 | Univerzita Karlova v Praze, Farmaceutická fakulta v Hradci Králové | Substituted diazoles, their use and pharmaceutical composition containing thereof |
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| CA2276720A1 (en) | 1997-01-14 | 1998-07-16 | Gabor Berecz | 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole derivatives having an effect on the c.n.s. and the heart |
| US6008015A (en) * | 1997-04-11 | 1999-12-28 | Allelix Neuroscience Inc. | Glycine transporter |
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| GB0002666D0 (en) | 2000-02-04 | 2000-03-29 | Univ London | Blockade of voltage dependent sodium channels |
| WO2001087855A1 (en) | 2000-05-19 | 2001-11-22 | Yamanouchi Pharmaceutical Co., Ltd. | Triazole derivatives |
-
2002
- 2002-02-04 AR ARP020100370A patent/AR032653A1/en unknown
- 2002-02-05 US US10/072,308 patent/US6894054B2/en not_active Expired - Fee Related
- 2002-02-08 WO PCT/US2002/003837 patent/WO2002064135A1/en active Application Filing
- 2002-02-08 EP EP02714858A patent/EP1357913A1/en not_active Withdrawn
- 2002-02-08 CA CA002436079A patent/CA2436079A1/en not_active Abandoned
- 2002-02-08 AU AU2002247098A patent/AU2002247098B2/en not_active Ceased
- 2002-02-08 JP JP2002563929A patent/JP2004522761A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AR032653A1 (en) | 2003-11-19 |
| JP2004522761A (en) | 2004-07-29 |
| US6894054B2 (en) | 2005-05-17 |
| WO2002064135A1 (en) | 2002-08-22 |
| AU2002247098B2 (en) | 2006-06-22 |
| EP1357913A1 (en) | 2003-11-05 |
| US20030073726A1 (en) | 2003-04-17 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |