AU737095B2 - Pharmaceutical for treating of neurological and neuropsychiatric disorders - Google Patents

Pharmaceutical for treating of neurological and neuropsychiatric disorders Download PDF

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AU737095B2
AU737095B2 AU31510/97A AU3151097A AU737095B2 AU 737095 B2 AU737095 B2 AU 737095B2 AU 31510/97 A AU31510/97 A AU 31510/97A AU 3151097 A AU3151097 A AU 3151097A AU 737095 B2 AU737095 B2 AU 737095B2
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ring
alkyl
substituted
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nitrogen
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Stanley Charles Bell
Laurence Borden
Vassil Iliya Ognayanov
Jing Zhang
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Shire NPS Pharmaceuticals Inc
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Allelix Neuroscience Inc
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02Muscle relaxants, e.g. for tetanus or cramps
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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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    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40Oxygen atoms
    • C07D211/42Oxygen atoms attached in position 3 or 5
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems

Description

WO 97/45423 PCT/US97/09346 -1- PHARMACEUTICAL FOR TREATING OF NEUROLOGICAL AND NEUROPSYCHIATRIC DISORDERS The present invention relates to a class of substituted cyclic amines, pharmaceutical compositions and methods of treating neurological and neuropsychiatric disorders.
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. Highaffinity neurotransmitter transporters are one such component, located on the pre-synaptic terminal 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 therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighboring synapses, transporters maintain the fidelity of synaptic transmission.
Last, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization.
Neurotransmitter transport is dependent on extracellular sodium and the voltage difference across the membrane; under conditions of intense neuronal firing, as, for example, during a seizure, transporters can function in reverse, releasing neurotransmitter in a calciumindependent non-exocytotic manner (Attwell et al., Neuron, 11, 401-407 (1993)). Pharmacologic modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of neurological and psychiatric disturbances.
The amino acid glycine is a major neurotransmitter in the mammalian central nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. 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 thus referred to as "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.
Glycine functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the central nervous system. See Johnson and Ascher, Nature, 325, 529-531 (1987); Fletcher et al., Glycine Transmission, (Otterson and Storm-Mathisen, WO 97/45423 PCT/US97/09346 -2eds., 1990), pp. 193-219. Specifically, glycine is an obligatory co-agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMDA) receptor. Activation of NMDA receptors increases sodium and calcium conductance, which depolarizes the neuron, thereby increasing the likelihood that it will fire an action potential. NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT-1 and GlyT-2. GlyT-1 is found predominantly in the forebrain, and its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 927-935 (1992)). Molecular cloning has further revealed the existence of three variants of GlyT-1, termed GlyT-la, GlyT-1b and GlyT-1c (Kim, et al., Molecular Pharmacology, 608-617 (1994)), each of which displays a unique distribution in the brain and peripheral tissues. These variants arise by differential splicing and exon usage, and differ in their N-terminal regions. GlyT-2, in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J Biological Chemistry, 268, 22802-22808 (1993); Jursky and Nelson, J. Neurochemistry, 64, 1026- 1033 (1995)). These data are consistent with the view that, by regulating the synaptic levels of glycine, GlyT-1 and GlyT-2 selectively influence the activity of NMDA receptors and strychninesensitive glycine receptors, respectively.
Compounds that inhibit or activate glycine transporters would thus be expected to alter receptor function, and provide therapeutic benefits in a variety of disease states. For example, inhibition of GlyT-2 can be used to diminish the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine, thus diminishing the transmission of pain-related nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors. Yaksh, Pain, 3Z, 111-123 (1989). Additionally, enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity, which is useful in treating diseases or conditions associated with increased muscle contraction, such as spasticity, myoclonus, and epilepsy (Truong et al., Movement Disorders, 3, 77-87 (1988); Becker, FASEB 4, 2767-2774 (1990)).
Spasticity that can be treated via modulation of glycine receptors is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system.
NMDA receptors are critically involved in memory and learning (Rison and Stanton, Neurosci. Biobehav. Rev., 19, 533-552 (1995); Danysz et al., Behavioral Pharmacol., 6, 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to -3underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996). Thus, agents that inhibit GlyT-1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes. Conversely, over-activation of NMDA receptors has been implicated in a number of disease states, in particular the neuronal death associated with stroke and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma. Coyle Puttfarcken, Science, 262, 689-695 (1993); Lipton and Rosenberg, New Enal. J. of Medicine, 330, 613-622 (1993); Choi, Neuron, 1, 623-634 (1988). Thus, pharmacological agents that increase the activity of GlyT-1 will result in decreased glycine-activation of NMDA receptors, which activity can be used to treat these and related disease states. Similarly, drugs that directly block the glycine site on the NMDA receptors can be used to treat these and related disease states.
SUMMARY OF THE INVENTION By the present invention, a class of compounds has been identified that inhibit •20 glycine transport via the GlyT-1 or GlyT-2 transporters, are precursors, such as prodrugs, to compounds that inhibit such transport, or are synthetic intermediates for S" preparing compounds that inhibit such transport. Thus, the present invention S provides a compound of one of the following formulas I and II: .o.A R RR 2 R
E
I R Ra
R
R y R or a pharmaceutically acceptable salt thereof, 190M6O1,ct10184.speci,3 -4wherein: X is nitrogen or carbon, and R 2 is not present when X is nitrogen;
R
2 is hydrogen, (C1-C6) alkyl, (CI-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (Cl-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, comprises (where R 1 is not -O-R8or -S-R 8 hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, forms a double bond with an adjacent carbon or nitrogen from one of either R 1
R
x b or Ry, is oxygen forming an oxa linkage with R' or is R 2a linked by R 2 b to X; Rx is a ring-containing structure R linked by R X to X;
R
y is a ring-containing structure R" linked by R to X; R" and R 2 a are independently aryl, heteroaryl, adamantyl or a 5 to 7membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein: aryl is phenyl or naphthyl, heteroaryl comprises a five-membered ring, a six-membered ring, a sixmembered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a sixmembered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon, each of R x
R
a and R 2 a can be independently substituted with one of R R'O- or wherein R'and Rs are independently aryl, heteroaryl, Sadamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for R x and 25 Ra, R 2 R R' and Rs can be substituted or additionally substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (CI-C6) N-alkyl substitutions, adamantyl, (Cl- C12) alkyl, (C1-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2- C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino 19/0601,cf10184.speci,4 that can independently substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl, wherein: the substitutions of R" x
R
y and R 2 a can be combined to form a second bridge between two of R Y and R 2 a comprising (C1-C2) alkyl or alkenyl, which can be independently substituted with one or more (C1-C6) alkyl, sulfur, oxygen, amino, which can be substituted for hydrogen with one (C1-C6) alkyl, carbonyl, (6) which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, -CH 2 which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) 24 wherein R 24 is hydrogen or (C1-C6) alkyl, (10) -CH 2 NH-, which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) which can be substituted for hydrogen with (Cl- C6) alkyl, or wherein two of Rx, R" and R 2 a can be directly linked by a single bond; (2v) R x and R 2 b are independently a single bond or (C1-C2) alkylene; (2v) Ry is a single bond, oxa, (C1-C2) alkylene, ethenylene or -CH= (where the double bond is with thia, methyleneoxy or methylenethio, or either -N(R 6 or 6
-CH
2
-N(R
6 wherein R 6 and R 6 are hydrogen or (C1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom;
R
1 comprises: a single bond; a straight-chained (C1-C3) aliphatic group; or (where X is carbon and Rb does not include a heteroatom attached to X) -O-R 8 or
-S-R
8 wherein either R 8 or R 8 is, (C1-C3) alkylene or (C2-C3) alkenylene and O or S is bonded to X: wherein R 1 can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen, or (where R 1 is -O-R 8 and X is carbon) an oxa linkage to X forming a 1,3-dioxolane, 1906/01 ,cf10184.speci,5 -6wherein the alkyl or alkylidene substituents of R 1 can be linked to form a 3 to 7-membered non-aromatic ring, and wherein if X is nitrogen, X is linked to R 1 by a single bond and the terminal carbon of R' that links R 1 to N is saturated; n is 0 or 1, and where if n is 1, R 3 is either (C1-C6) alkyl (with the attached nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon; wherein ring D is a 3 to 8-membered ring, a 3 to 8-membered ring substituted with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens: wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (Cl-C6) alkylidene, hydroxyl, (C1-C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for R" or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and wherein R 1
R
3 and G are such that at least two atoms separate X and the illustrated ring nitrogen; wherein ring E is a 3 to 8-membered ring, a 3 to 8-membered ring substituted S with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens: wherein the carbon and nitrogen ring atoms of ring E can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, i (C1-C6) alkoxy, oxo, hydroxycarbonyl, (C1-C6) alkoxycarbonyl, aryl wherein the aryl is as defined for Ra, or heteroaryl wherein the heteroaryl is as defined for R a with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms 19 u s f OFP\ c^19/06s/1,c«0184.speci,6 -7substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and wherein G and R 1 8 are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to Rx and RY; when G* is a sixmembered ring;
R
19 forms a double bond with R 1
R
3 or G, is hydrogen is (Cl C3) alkyl or alkylene, or is incorporated into a fused ring;
R
4 and R 4 are independently hydrogen or (C1-C6) alkyl, or one of R 4 and R 4 can be (C1-C6) hydroxyalkyl; and
R
5 is (CO)NRR14, (CO)OR 15
(CO)SR
1 6 (SO)NR17R 2 6 (PO)(OR2)(OR 2 (CR2)(OR23)(OR4), CN or tetrazol-5-yl, wherein R 13
R
14
R
15
R
16
R
17
R
26
R
29 and
R
20 are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R 15 or the sulfur of R 1 6 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is C1 to C6, aryl or heteroaryl, R 22 is hydrogen or OR 25 and R 23
R
24 and R 25 are (C1-C6) alkyl, phenyl, benzyl, acetyl or, where R 2 2 is hydrogen, the alkyls of R 23 and
R
24 can be combined to include 1,3-dioxylane or 1,3-dioxane: wherein the aryl is phenyl or naphthyl and the heteroaryl is a fivemembered ring, a six-membered ring, a six-membered ring fused to a five- Smembered ring, a five-membered ring fused to a six-membered ring, or a six- S* membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon; Swherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) 19106/01,cf10184.speci,7 -8alkyl, (C1-C6) alkylsulfonyl, amidino that can substituted with up to three (Cl- C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl; and wherein R 1 3 and R 14 together with the nitrogen can form a 5 to 7membered ring that can contain one additional heteroatom selected from oxygen and sulfur.
In a preferred embodiment, at least one of R and R 2 a is substituted with fluoro, chloro, bromo, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, (C3-C8) alkyl, R RsS-, or the ring structures of R and R 2 a, including substituents thereto, otherwise include at least two aromatic ring structures that together include from 15 to 20 ring atoms. Preferably, at least one of R R" and R 2 a is substituted with fluoro, trifluoromethyl, trifluoromethoxy, nitro, cyano, or (C3-C8) alkyl. Preferably, at least one of R Y and R 2 a is substituted with Rq, or RSS-.
Preferably, an aryl or heteroaryl of at least one of R" and R 2 a is phenyl.
Preferably, Rb is oxa, methyleneoxy, thia, methylenethia. Preferably, Rb is oxa or thia. Preferably, R s is (CO)NR 1 3
R
4
(CO)OR
5 or (CO)SR 16 Preferably, R' 1 is (C2- C6) alkyl, (C2-C4) hydroxyalkyl, phenyl, phenylalkyl wherein the alkyl is C1-C3, or aminoalkyl where the alkyl is C2-C6 and the amino can be substituted with up to two i. independent (C1-C3) alkyls, wherein the phenyl or the phenyl of phenylalkyl can be S substituted. Preferably, n is zero. Preferably, R 15 is hydrogen. Preferably, R 4 is ee* ooooo
,US
190/1,f 14.pc, 8ahydrogen, methyl or hydroxymethyl and R 4 is hydrogen. Preferably, at least one of R and R 2 a is a heteroaryl comprising diazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiolyl, diazinyl, triazinyl, benzoazolyl, benzodiazolyl, benzothiazolyl, benzoxazolyl, benzoxolyl, benzothiolyl, quinolyl, isoquinolyl, benzodiazinyl, benzotriazinyl, pyridyl, thienyl, furanyl, pyrrolyl, indolyl, isoindoyl or pyrimidyl. Preferably, R 1 is -O-R 8 or -S-R 8 Preferably, the second bridge between two of Rx, R y and R 2 is L, and satisfies the following formula:
L
A c
X
wherein A and B are aryl or heteroaryl groups of R and RO, respectively.
Preferably, and X form:
R
21
R
bonded to R 1 and wherein R 21 either completes a single bond linking two aryl or heteroaryl rings of R" gee o* *oo *o* 1 /06/01,cf10184.speci,a WO 97/45423 PCT/US97/09346 -9and R
Y
is (C1-C2) alkylene or alkenylene, (iii.) is sulfur or is oxygen, and wherein Rx and
R
Y can be substituted as set forth above. Preferably, R 2 1 is CH 2
CH
2 or CH=CH. Preferably, the alkylenedioxy substitution of Rx a
R
ya or R 2a is as follows: 0 iO wherein the alkylenedioxy can be substituted with up to two independent (C1-C3) alkyl.
Preferably, ring D is according to one of formulas A' and B': A' B' wherein Z represents carbon or nitrogen, wherein for each of formulas A' and B' up to two of the bonds indicated with the hashed lines can be double bonds provided no two double bonds are adjacent, and wherein the ring of formulas A' and B' can be substituted as set forth above for ring D. Preferably, the ring system comprising G is according to one of formulas C' and D' 'Ar N 'Ar 2Ar 2Ar Z C' D' ,wherein Z represents carbon or nitrogen, wherein for formula C' up to one of the bonds indicated with the hashed lines can be double bond and for formula D' up to two of the bonds indicated with the hashed lines can be double bonds, and wherein the ring can be substituted as set forth above for ring E. Preferably, ring D or ring E is substituted with up to three substituents. Preferably, Rxa and R ya together can be substituted with up to six substituents, R 2 a Rq, R' and Rs can each be substituted with up to 3 substituents, and wherein the presence of WO 97/45423 PCT/US97/09346 10 each of R q R' or Rs is considered a substitution to the respective ring structure of Rxa, R ya and
R
2a Preferably, the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl of R 1 3
R
1 4
R
1 5
R
16
R
17
R
1 8
R
19 or R 20 is substituted with up to three substituents. Preferably, the compound is an optically pure enantiomer. Preferably, the compound is an optically pure enantiomer at least about 80% ee, preferably at least about 90% ee, more preferably at least about 95% ee).
Preferably, the invention provides a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. Preferably, the compound of the invention is present in an effective amount for: treating or preventing schizophrenia, (2) enhancing treating or preventing dementia, treating or preventing epilepsy, treating or preventing spasticity, treating or preventing muscle spasm, treating or preventing pain, (7) preventing neural cell death after stroke, preventing neural cell death in an animal suffering from a neurodegenerative disease, treating or preventing mood disorders such as depression, enhancing memory or learning, or (11) treating or preventing learning disorders. The invention further provides a method of treating or preventing schizophrenia comprising administering a schizophrenia treating or preventing effective amount of a compound, of treating or preventing dementia comprising administering a dementia treating or preventing effective amount of a compound, of treating or preventing epilepsycomprising administering an epilepsy treating or preventing effective amount of a compound, of treating or preventing spasticity comprising administering a spasticity treating or preventing effective amount of a compound, of treating or preventing muscle spasm comprising administering a muscle spasm treating or preventing effective amount of a compound, of treating or preventing pain comprising administering a pain treating or preventing effective amount of a compound, of preventing neural cell death after stroke comprising administering a neural cell death preventing effective amount of a compound, of preventing neural cell death in an animal suffering from a neurodegenerative disease, treating or preventing mood disorders such as depression, enhancing memory or learning, or (11) treating or preventing learning disorders, comprising administering an amount effective for said treating, preventing or enhancing of the compound.
Preferably, the spasticity treated or prevented is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury or dystonia. Preferably, the neurodegenerative disease treated or prevented is Alzheimer's disease, multi-infarct dementia, AIDS dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or stroke or head trauma such as results in neuronal cell death.
WO 97/45423 PCT/US97/09346 11 The comprising:
A)
1) invention also provides a method of synthesizing a compound of the invention reacting a compound of the formula
R
4
R
,wherein 'L is a nucleophilic substitution leaving group, with a compound of the formula Rx R 2
Y
R
Y
or B) reacting a compound of the formula 1) with a compound of the formula R 4 R wherein 2 L is a nucleophilic substitution leaving group.
The invention also provides a method of synthesizing a compound of the invention comprising reductively alkylating RdNH 2 with a compound of the formula WO 97/45423 PCT/US97/09346 12- G R 4 O0 R19 R NR R4
R
c ,wherein Rc and R d are independently the same as defined for Rx, and wherein R 1 has the same definition as R 1 except that it does not include a nitrogen, oxygen or sulfur, and does not include any double bonds conjugated with the above-illustrated carbonyl.
The invention also provides a method of synthesizing a compound of the invention comprising reacting RfOH or RfSH with a compound of the formula
L
6
G
SN
R
RR
4 to form an ether or a thioether, respectively, wherein R' and R r are independently the same as defined for Rx, and wherein R' has the same definition as R 1 except that it does not include a nitrogen, oxygen or sulfur, and does not include any double bonds at the atom bonded to the above-illustrated L -substituted carbon. Preferably, the method further comprises synthesizing the compound of formula
L
6 G 1. 1 9 G
R
4 by replacing the hydroxyl of formula OH G..
R
4 with another nucleophilic substitution leaving group. Preferably, the method comprises reacting a compound of formula WO 97/45423 PCT/US97/09346 13-
OH
Rc with an azodicarboxylate in the presence of a phosphine compound.
The invention also provides a method of synthesizing a compound of the invention comprising reacting ReM with a compound of the formula
R
4 to form a compound of the formula ,wherein R e is independently the same as defined for Rx, wherein M is a metal-containing substituent such that ReM is a organometallic reagent.
The invention also provides a method of synthesizing a compound of the invention comprising dehydrating a compound of the formula OH G G 259
R
4 to form a compound of the formula R R
R
4 wherein C (the tertiary carbon marked with an adjacent has a double bond with an adjacent carbon, wherein R 27 and R 27 have the same definition as R 1 except that R 27 and R 2 7 do not include a nitrogen, oxygen or sulfur.
WO 97/45423 PCT/US97/09346 14- The invention also provides a method of synthesizing a compound of the invention comprising reducing a compound of the formula ReG RD'f N R 5 wherein C has a double bond with an adjacent carbon, to Rc R f-R 4 2 3 R form a compound of the formula Re Rc 27 RI9 2< 3 I-4R R R 4 The invention also provides a method of synthesizing a compound of the invention comprising reducing a compound of one of the following formulas
R
4
R
4 4'
R
R\ R 2
R
4 Rx R 2 I' ii- or c CxP I 5 C RR.
X ROO, R 28 i* R/ 28 2 to reduce a double bond in ring C" or ring wherein R 28 is the same as R 1 except that the bond to the ring is not a double bond, wherein ring C" is mono or di-unsaturated at one or more of the bonds indicated with the dased lines with the double bonds formed between ring carbons and no two double bonds are adjacent, wherein ring C" or ring C i x can include a fused phenyl and can be substituted as follows the carbon and nitrogen ring atoms of ring C" or ring C" can be substituted with up to two substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, and (C2-C7) alkyloxycarbonyl, and wherein I is a negative counter-ion.
Preferably, the compound reduced is that containing ring C".
The invention also provides a compound according to the following formula
R
4 RX R 2 XC R c
R
R 28
R
Y
S
WO 97/45423 PCT[US97/09346 15 that can be used to synthesize a compound of the invention. The invention also provides a method of synthesizing this compound comprising reacting a compound of the formula R\ R 2 rN I c' I X RZ 28 with a compound of the formula R4 4L R4*
R
wherein L 4 is a nucleophilic substitution leaving group and wherein ring C' can be fused with phenyl or substituted, the same as defined for ring C".
The invention also provides a compound of the invention according to the following formula
R
4 Rx
R
2 R cx I X R R 28
RY
wherein ring can be fused with phenyl or substituted, the same as defined for ring and is mono or di-unsaturated at one or more of the bonds indicated with the dased lines with the double bonds formed between ring carbons and no two double bonds are adjacent.
The invention also provides a compound of the following formula WO 97/45423 PCT/US97/09346 16
R
4 S cv R Rx 28 that can be used to synthesize a compound of the invention, wherein I is a negative counter-ion, wherein R 28 is a (C1-C3) aliphatic group that can be substituted as defined for R 1 wherein ring C"v can be fused with phenyl or substituted, the same as defined for ring The invention also provides a method of synthesizing this compound comprising reacting a compound of the formula O N
RX
with a compound of the formula
R
4 L R4"
R
,wherein L 5 is a nucleophilic substitution leaving group, wherein ring CV' can be fused with phenyl or substituted, the same as defined for C".
The invention also provides a compound of the following formula
R
4 WO 97/45423 PCT/US97/09346 17 that can be used to synthesize a compound of the invention, wherein ring C"'1 can be fused with phenyl or substituted, the same as defined for ring C. The invention also provides a method of synthesizing this compound, the method comprising reducing a compound of the following formula
R
4 I"
R
4 2
RX
to reduce the double bonds in ring wherein ring C vi can be fused with phenyl or substituted, the same as defined for ring C".
The invention also provides a method of synthesizing a compound that can be used to synthesize the compound of the invention, the method comprising synthesizing a compound of formula G
R
4 0 D NI R 4 FR L
R
155
RC
by reacting a compound of the formula
G
O D NH P R 19
RC
with a compound of the formula
R
4
L
3
R
4
R
WO 97/45423 PCT/US97/09346 18- The invention also provides a method of synthesizing of a compound of the invention, the method comprising reacting a compound of formula with Ar-Q wherein Ar is aryl which is substituted with an electron-withdrawing group or heteroaryl and is substituted with an electron-withdrawing group, and wherein Q is halide (preferably fluoro or chloro), to form Ar O G RC 3 The invention also provides a method of synthesizing a compound that can be used to synthesize the compound of the invention, the method comprising synthesizing a compound of formula X: Rd /SO 2 Ar Rca 1 "rR
R
4 x X by reacting a compound of formula: OH G, with RdNHSO 2 Ar, wherein Ar is aryl or heteroaryl. Preferably, the method further comprises converting the compound of formula X to: WO 97/45423 PCT/US97/09346 19- Rd d NH G The invention also provides a method of synthesizing a compound that can be used to synthesize the compound of the invention, the method comprising reacting a compound of formula HO NH R 27
R
R
Rc with a compound of formula R4 4L R4
R
wherein L4 is a nucleophilic substitution leaving group, to form a compound of formula OH G
R
0 R R4 The invention also provides a method of synthesizing a compound that can be used to synthesize the compound of the invention, the method comprising synthesizing the compound of formula: WO 97/45423 PCT/US97/09346 20 said synthesis comprising reducing the ketone of a compound of formula S R19 The invention also provides a compound of the following formula
HO
that can be used to synthesize a compound of the invention, wherein I is a negative counter-ion, wherein R 28 is the same as R 1 except that the bond to the ring is not a double bond, wherein ring C x can be fused with phenyl or substituted, the same as defined for ring The invention also provides a method of synthesizing this compound, comprising reacting a compound of the formula HO N R 28 with a compound of the formula WO 97/45423 PCT/US97/09346 21
R
4 sL R4'
R
,wherein L 5 is a nucleophilic substitution leaving group, wherein ring Cx can be fused with phenyl or substituted, the same as defined for C".
The invention also provides a compound of the following formula
R
4 4 HO RN R R R/ 2 8
X"
Rx s that can be used to synthesize a compound of the invention, wherein R 28 is the same as R 1 except that the bond to the ring is not a double bond, wherein ring C x can be fused with phenyl or substituted, the same as defined for ring The invention also provides a method of synthesizing this compound, the method comprising reducing a compound of the following formula
R
4 4 +is. R 4 HO N[ CX R Rx R to reduce the double bonds in ring Cx, ring Cx can be fused with phenyl or substituted, the same as defined for ring C".
BRIEF DESCRIPTION OF THE DRAWING Figure depicts several reactions that can be employed in the synthesis of the compounds of the invention.
DEFINITIONS
The following terms shall have the meaning set forth below: accounting for ring heteroatoms If two rings are linked to form a bicyclic ring system, then a nitrogen located at one of the junctions is considered a heteroatom of each of the component rings.
WO 97/45423 PCT/US97/09346 -22 Sexcipient Excipients are pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral oral or inhalation) or topical application that do not deletereiously react with the active compositions. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, benzyl alcohols, gelatine, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, hydroxymethylcellulose, polyvinylpyrrolidone, and the like.
effective amount The meaning of "effective amount" will be recognized by clinicians but includes amount effective to reduce, ameliorate or eliminate one or more symptoms of the disease sought to be treated, induce a pharmacological change relevant to treating the disease sought to be treated, or prevent or lessen the frequency of occurrence of a disease.
neuronal cell death prevention Neuronal cell death is "prevented" if there is a reduction in the amount of cell death that would have been expected to have occurred but for the administration of a compound of the invention.
oxo substitution References to oxo as a "substituent" refer to substitutions.
DETAILED DESCRIPTION The compounds of the invention are generally prepared according to one of the following synthetic schemes, although alternative schemes will be recognized by those of ordinary skill.
Reaction 1
SR
4 R NH
R
R' R 3 Rx R 2 D R4 /19 3 R 1 9 D 1 WO 97/45423 PCT/US97/09346 23 Reaction 2 G H R 4 G*s R R 4 R E NH 2LR 4 E R 4 R 1 R
R
R
Y
R
Y
In Reaction 1 and Reaction 2, L 1 and L 2 are good nucleophilic substitution leaving groups such as a halide, especially a bromide, a tosylate, a brosylate (p-bromobenzenesulfonate), and the like. The reaction is preferably conducted in the presence of a base such as potassium carbonate or a tertiary amine such as diisopropylethylamine. Where the leaving group is a halide, the reaction can be conducted in the presence of an iodide salt such as potassium iodide.
Suitable organic solvents include, for example, methanol, dioxane, acetonitrile or dimethyformamide. The reaction is favorably conducted at a temperature range of about 15*C to about 40°C. Avoiding more elevated temperatures helps avoid producing the quaternary ammonium salt resulting from bis-alkylation.
Reaction 3
R
4 RX R 2 N 4 4 R R 28 RY R 4 Rx R 2 4 i R 4
RY
Reaction 4 WO 97/45423 PCT/US97/09346 -24-
R
4 S/R24
R
4 Rx R 2
R
Cmpun I' can be |u furthec" f R 5 sR 8 28 Ii
R
4 RX R 2 N R 4 X R I R 28
R
Y
Cmpound I' can be reduced further, for instance in a Reaction 5 that produces: R 4 R' R 2
IN
R 4 Xv
R
S 28
RY
i"l A further Reaction 6 can be used to fully reduce ring In the above-described Reactions 3 to 6, the bond between R 1 and the ring is either at the 2, 3 or 4 position of the ring. In the alkylation of Reaction 3, L 4 is a good nucleophilic substitution leaving group such as a halide, especially a bromide. Although not indicated above, the ring C can be substituted. Suitable organic solvents include, for example, those that effectively solubilize the starting materials and are unreactive to the alkylation reagent. Depending on the reactants, such solvents can include benzene, acetonitrile, tetrahydrofuran or ethanol. The reaction is favorably conducted at a temperature range of about 20°C to about 100"C.
In Reactions 4 and 5, the ring C is reduced by one of a number of reduction procedures known in the art, such as, for instance, reaction with a metal hydride such as sodium borohydride. See R.M. Acheson, G. Paglietti, J. Chem. Soc.. Perkin I, p. 45, 1976. It will be recognized that, while the above reaction schemes describe the separate formation of various WO 97/45423 PCT/US97/09346 25 partially reduced compounds such as I" and the ratio of these products and the ease with which they can be isolated will vary with each case, depending on such factors as the type of metal hydride used and the solvent used. In Reaction 6, the ring Cv is further reduced by one of a number of reduction procedures known in the art, such as, for instance, hydrogenation in the presence of an appropriate hydrogenation catalyst. For example, in many cases the hydrogenation can be conducted with a Pd/C catalyst and in an alcohol solvent.
In Reaction 7, shown in the Figure, Rc and Rd are independently the same as defined for Rx. The starting material III can be synthesized, for instance, using the chemistry of Reaction (similar to Reaction as follows: Reaction o D NH 3 L R4 RC R G R 0 R D R 4
RC
III
wherein R 1 has the same definition as R 1 except that it does not include a nitrogen, does not include an oxygen linked to the above-illustrated carbonyl and does not include any double bonds conjugated with the above-illustrated carbonyl, and wherein L 3 is a good nucleophilic substitution leaving group such as a halide, especially a bromide, a tosylate, a brosylate (pbromobenzenesulfonate), and the like.
In Reaction 7, shown in the Figure, Rd-NH 2 is reacted with III to form IV under conditions that effect a reductive alkylation. The reductive alkylation can be effected by several known methods (see, for example, "Reductive Alkylation," W.S. Emerson in Organic Reactions, Vol. 4, John Wiley Sons, 1948, p. 174 etseq.) including reaction with hydrogen in the presence of a catalyst such as palladium on carbon, reaction with sodium cyanoborohydride or reaction with sodium triacetoxyborohydride when groups labile to catalytic hydrogenation are present. It will be recognized that an intermediate Schiffs base is formed in the reaction, which Schiffs base is reduced to form the linkage. The intermediate Schiffs base can be isolated and then reduced in WO 97/45423 PCT/US97/09346 -26 a separate reaction. Solvent selection will vary with such factors as the solubility of the starting materials, the degree to which the solvent favors the dehydration reaction forming the Schiffs base, and the suitability of the solvent in the reduction process. Suitable solvents using catalytic hydrogenation to reduce the Schiffs base include ethanol. Suitable solvents using a borohydride to reduce the Schiffs base include alcoholic solvents such as methanol or ethanol. In some cases, a drying process can be employed during the reaction to promote the dehydration reaction that forms the Schiffs base that is reduced. Such drying processes include refluxing under conditions selected to remove water as an azeotrope or the use of molecular sieves or other drying reagents. Suitable reaction temperatures include the range from about 20"C to the reflux temperature of the solvent employed.
Alternatively, IV can be synthesized via Reaction 16, shown in the Figure, by reacting Rd-NH 2 with X under the conditions described for Reaction 1 or Reaction 2. In another alternative, starting material III' is prepared as follows: Reaction 17
R
4 5L R4
L
L 0
I,^
Reaction 18
R
4
R
4 x 5 R" >4R
R
RC RC R $i' These Reactions 17 and 18 use chemistry described above for Reactions 3 and 6, respectively.
This compound III' can be substituted for III in Reactions 7, 8 and 12, shown in the Figure.
WO 97/45423 PCT/US97/09346 27- In Reaction 8, shown in the Figure, R e is independently the same as defined for R 1 In Reaction 8, III or II' is reacted with a organometallic reagent such as an aryllithium or an aryl or arylalkyl Grignard reagent to form V, as described, for instance, in Section 5.1.2 of Cary and Sundberg, Advanced Organic Chemistry, Part 2, Plenum, New York, 1977, pp. 170-180, and references cited therein. Those of ordinary skill will be aware that in some cases where R includes an ester, the organometallic reagent may react with the ester group; in those such cases where the yield of the desired product is too low, the solvent, the organometallic reagent or the ester substitution can be varied.
In Reaction 9, shown in the Figure, V is subjected to conditions suitable for dehydration to form a double bond. Such conditions are, for instance, those described in H. Weiland, Ber.
484 et seq. (1912), wherein V is refluxed with acetic anhydride. In the illustration, the double bond forms with the adjacent carbon atom of R 1 The double bond will typically form with this orientation where Rc and R e are aryl or heteroaryl and the adjacent carbon of R 1 is saturated and not fully substituted, but other orientations are possible depending on the composition of Rc,
R
e and R 1 In reaction 10, shown in the Figure, VI is is reduced, for instance using any of a number of known methods for reducing carbon-carbon double bonds, such as catalytic hydrogenation in the presence of an appropriate catalyst.
In reaction 11, shown in the Figure, V is acylated, for instance, with acetic anhydride in the presence of an acylation catalyst such as 4-dimethylaminopyridine.
In reaction 12, shown in the Figure, the ketone moiety of III or III' is reduced, for instance by any of a number of known methods for selectively reducing ketones, such as reaction with lithium tri-tert-butoxyaluminohydride. For reaction 13, shown in the Figure, the hydroxyl of IX is replaced by a leaving group L 6 wherein the leaving group is, for instance, chloro or bromo, by reacting IX with, for instance, thionyl chloride or thionyl bromide. For reaction 14, shown in the Figure, R' independently satisfies the definition of RX. X is reacted with R'OH in the presence of a base such as K 2
CO
3 or sodium hydride. Alternatively, the thio-containing analog of XI can be synthesized by reacting X with R'SH.
In reaction 19, IX is reacted with RdNHSO 2 Ar to yield XII, for instance for instance under the conditons of Mitzunobu reaction, and further converted into IV by reacton 20, analogously to the procedure described in J.R. Henry et al., Tetrahedron Letters 30: 5709-5712, 1989.
A number of other well-known synthetic approaches can be applied. For instance, acids can be formed by the hydrolysis of the corresponding esters. Amine derivatives can be formed by the alkylation of primary, secondary or tertiary amines. A number of double bond containing compounds can be hydrogenated to form the corresponding single bond.
WO 97/45423 PCT/US97/09346 28 Compounds of the invention may also be prepared by adapting the classical solution chemistries outlined above into solid-phase synthetic techniques. For example, R' 3
R
1 5
R
1 6
R
1 7 and R 20 can be residues other than hydrogen representing functionalized resin or suitably selected. linker attached to functionalized resin. The linker and the functional group represented by R 5 should be stable under the conditions employed for the above-described reactions. The compounds of the invention where R 1 3
R
1 5
R
1 6
R
1 7 is R 2 0 is hydrogen, are then cleaved from the resin or the linker leaving the remainder of the molecule intact. For example, solid-phase synthesis of peptoids [oligo(N-substituted glycines)] using robotic synthesizer was described by Zuckermann et al., J. Am. Chem. Soc., 114, 0646-10647, (1992) and Spellmeyer et al, WO 95/04072). Under analogous conditions, acylation reaction of Rink amide polystyrene resin with bromoacetic acid in the presence of N,N'-diisopropylcarbodiimide followed by displacement of the bromine with the amine component of reaction 1 or reaction 2, and cleavage can provide N-substituted glycinamides (R 1 3 and R 1 4 are hydrogen).
In some cases, the chemistries outlined above may have to be modified, for instance by use of protective groups, to prevent side reactions due to reactive groups, such as reactive groups incorporated into heterocyclic rings or attached as substituents. Using the reactions described herein, hydrolysis of esters, alkylation of amines, or hydrogenation reactions, the following compounds of the invention have been synthesized: WO 97/45423 WO 9745423PCT/US97/09346 29 cl C2 C3 C4 Cs 0 D nN Q 0-\ X/ OH 0
HN
0
F
C7 0
N
C8 h
CC
H CI
OH
dlo WO 97/45423 PCT/US97/09346 C11 N/ OH C14 O
AO
C1
OH
It will be recognized that numerous salt forms of the compounds herein described are available and suitable for use in the invention or during the synthesis of compounds of the invention. The invention contemplates that in certain instances where stereoisomers are available that one such isomer can be more active than another; in such a case, it will be desirable to isolate the particular isomeric form. The invention, of course, encompasses both the particular stereoisomers and racemic mixtures. As described herein, chemical approaches, starting with for example commercially available, optically pure starting materials (or made using enantioselective reactions), can also used to synthesize optically pure versions of the compounds of the invention.
It will be recognized that such optically pure compounds are within the invention. Enantiomeric excess can be enhanced by purification techniques such as crystallization or chromatography on chiral supports. Enantiomeric excess can be quantitated by a number of analytic techniques including NMR, optical rotation measurements and appropriate chromatography.
Additional, related compounds are described in U.S. Patent Applications were filed concurrently with the parents hereof as U.S. Serial No. 08/656,063 (Docket No. 317743-103, Ognyanov et al.) U.S. Serial No. 08/655,912 (Docket No. 317743-106, Ognyanov et U.S.
Serial No. 08/807,754 (PHARMACEUTICAL FOR TREATMENT OF NEUROLOGICAL AND NEUROPSYCHIATRIC DISORDERS, Docket No. 317743-103A, Ognyanov et al.) and U.S. Serial WO 97/45423 PCTIUS97/09346 31 No. 08/807,682 (PHARMACEUTICAL FOR TREATMENT OF NEUROPSYCHIATRIC AND NEUROLOGICAL DISORDERS, Docket No. 317743-106A, Ognyanov et which applications are also incorporated herein by reference in their entirety. Further incorporated by reference in their entirety are U.S. Application No. 08/655,847 (Docket No. 317743-107, Ognyanov et al.) and U.S. Application No. 08/807,681 (Docket No. 317743-107A, Ognyanov et the parents of the present application.
It will be recognized that some combinations of components of the compounds of the invention will be less stabile than others. For example, when the ring D or the ring E is fully saturated any two ring heteroatoms should typically be separated by at least two ring carbons to maintain stability. The compounds having sufficient stability to be useful as pharmaceuticals are of greater usefulness.
In a preferred embodiment, the D ring or the E ring is substituted with at most one of aryl or heteroaryl.
The glycine transporter genes and their respective gene products are responsible for the reuptake of glycine from the synaptic cleft into presynaptic nerve endings or glial cells, thus terminating the action of glycine. Neurological disorders or conditions associated with improperly controlled glycine receptor activity, or which could be treated with therapeutic agents that modulate glycine receptor activity, include spasticity (Becker, FASEB Journal, 4, 2767-2774 (1990)) and pain realization (Yaksh, Pain, 37, 111-123 (1989)). Additionally, glycine interacts at N-methyl-D-aspartate (NMDA) receptors, which have been implicated in learning and memory disorders and certain clinical conditions such as epilepsy, Alzheimer's and other cognition-related diseases, and schizophrenia. See Rison and Stanton, Neurosci. Biobehav. Rev., 19, 533-552 (1995); Danysz et al., Behavioral Pharmacol., 6, 455-474 (1995).
Compounds that inhibit GlyT-1 mediated glycine transport will increase glycine concentrations at NMDA receptors, which receptors are located in the forebrain, among other locations. This concentration increase elevates the activity of NMDA receptors, thereby alleviating schizophrenia and enhancing cognitive function. Alternatively, compounds that interact directly with the glycine receptor component of the NMDA receptor can have the same or similar effects as increasing or decreasing the availability of extracellular glycine caused by inhibiting or enhancing GlyT-1 activity, respectively. See, for example, Pitkanen et al., Eur. J. Pharmacol., 253, 125-129 (1994); Thiels et al., Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J. Neurosci., 16, 1561-1569 (1996). Compounds that inhibit GlyT-2 mediated glycine transport will increase glycine concentrations at receptors located primarily in the brain stem and spinal cord, where glycine acts as an inhibitor of synaptic transmission. These compounds are WO 97/45423 PCT/US97/09346 32effective against epilepsy, pain and spasticity, myospasm and other such conditions. See, for example, Becker, FASEB 4, 2767-2774 (1990) and Yaksh, Pain, 37, 111-123 (1989).
The compounds of the invention are, for instance, administered orally, sublingually, rectally, nasally, vaginally, topically (including the use of a patch or other transdermal delivery device), by pulmonary route by use of an aerosol, or parenterally, including, for example, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intravenously or intrathecally.
Administration can be by means of a pump for periodic or continuous delivery. The compounds of the invention are administered alone, or are combined with a pharmaceutically-acceptable carrier or excipient according to standard pharmaceutical practice. For the oral mode of administration, the compounds of the invention are used in the form of tablets, capsules, lozenges, chewing gum, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents such as magnesium stearate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. If desired, certain sweetening and/or flavoring agents are added. For parenteral administration, sterile solutions of the compounds of the invention are usually prepared, and the pHs of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers. Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzylchromium chloride, and the usual quantities of diluents and/or carriers. For pulmonary administration, diluents and/or carriers will be selected to be appropriate to allow the formation of an aerosol.
Suppository forms of the compounds of the invention are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include theobroma oil, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weight and fatty acid esters of polyethylene glycol. See, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms. Analogous gels or cremes can be used for vaginal, urethral and rectal administrations.
WO 97/45423 PCT/US97/09346 33- Numerous administration vehicles will be apparent to those of ordinary skill in the art, including without limitation slow release formulations, liposomal formulations and polymeric matrices.
Examples of pharmaceutically acceptable acid addition salts for use in the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic and arylsulphonic acids, for example. Examples of pharmaceutically acceptable base addition salts for use in the present invention include those derived from non-toxic metals such as sodium or potassium, ammonium salts and organoamino salts such as triethylamine salts. Numerous appropriate such salts will be known to those of ordinary skill.
The physician or other health care profesional can select the appropriate dose and treatment regimen based on the subject's weight, age, and physical condition. Dosages will generally be selected to maintain a serum level of compounds of the invention between about 0.01 pg/cc and about 1000 pg/cc, preferably between about 0.1 pg/cc and about 100 pg/cc. For parenteral administration, an alternative measure of preferred amount is from about 0.01 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg, will be administered.
For oral administrations, an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg. For administrations in suppository form, an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg.
For use in assaying for activity in inhibiting glycine transport, eukaryokic cells, preferably QT-6 cells derived from quail fibroblasts, have been transfected to express one of the three known variants of human GlyT-1, namely GlyT-la, GlyT-lb or GlyT-ic or human GlyT-2. The sequences of these GlyT-1 transporters are described in Kim et al., Molec. Pharm. 45: 608-617, 1994, excepting that the sequence encoding the extreme N-terminal of GlyT-la was .merely inferred from the corresponding rat-derived sequence. This N-terminal protein-encoding sequence has now been confirmed to correspond to that inferred by Kim et al. The sequence of the human GlyT-2 is described by Albert et al., U.S. Application No. 08/700,013, filed August 20, 1996, which is incorporated herein by reference in its entirety. Suitable expression vectors include pRc/CMV (Invitrogen), Zap Express Vector (Stratagene Cloning Systems, LaJolla, CA; hereinafter "Stratagene"), pBk/CMV or pBk-RSV vectors (Stratagene), Bluescript II SK Phagemid Vectors (Stratagene), LacSwitch (Stratagene), pMAM and pMAM neo (Clontech), among others. A WO 97/45423 PCT/US97/09346 -34suitable expression vector is capable of fostering expression of the included GlyT DNA in a suitable host cell, preferably a non-mammalian host cell, which can be eukaryotic, fungal, or prokaryotic. Such preferred host cells include amphibian, avian, fungal, insect, and reptilian cells.
As discussed above, the compounds of the invention have a number of pharmacological actions. The relative effectiveness of the compounds can be assessed in a number of ways, including the following: comparing the activity mediated through GlyT-1 and GlyT-2 transporters. This testing identifies compounds that are more active against GlyT-1 transporters and thus more useful in treating or preventing schizophrenia, increasing cognition and enhancing memory or that are more active against GlyT-2 transporters and thus more useful in treating or preventing epilepsy, pain, spasticity or myospasm.
testing for NMDA receptor binding. This test establishes whether there is sufficient binding at this site, whether antagonist or agonist activity, to warrant further examination of the pharmacological effect of such binding.
testing the activity of the compounds in enhancing or diminishing calcium fluxes in primary neuronal tissue culture. A test compound that increases calcium flux either has little or no antagonist activity at the NMDA receptor and should not affect the potentiation of glycine activity through GlyT-1 transporter inhibition or if marked increases are observed over GlyT-1 inhibitors used for comparison and that have little direct interaction with NMDA receptors, then the compound is a receptor agonist. In either of the above-described cases, the test confirms activity in treating or preventing schizophrenia, increasing cognition, or enhancing memory. In contrast, a test compound that decreases calcium flux has a net effect wherein receptor antagonist activity predominates over any activity the compound has in increasing glycine activity through inhibiting glycine transport. In this case, the test confirms activity in limiting or preventing the cell damage and cell death arising after stroke or other ischemiainducing conditions, or in limiting or preventing the cell damage associated with neurodegenerative diseases.
All animal methods of treatment or prevention described herein are preferably applied to mammals, most preferably humans.
The following examples further illustrate the present invention, but of course, should not be construed as in any way limiting its scope.
WO 97/45423 PCT/US97/09346 Example 1 Synthesis of 3-bis(4-fluorophenyl)methoxvpiperidin-1-vl acetic acid ethyl ester (compound A mixture of 0.170 g (0.5 mmol) of 3 -bis(4-fluorophenyl)methoxypiperidine [prepared in three steps from 3-hydroxypiperidine hydrochloride (Aldrich) using the synthetic scheme described by E. Falch, P. Krogsgaard-Larsen, Eur. J. Meod Chem. 1991, 26, 69-78, for the synthesis of 3diphenylmethoxypiperidine], 0.092 g (0.55 mmol) ethyl bromoacetate (Aldrich) and 0.276 g (2 mmol) potassium carbonate in 1 ml acetonitrile was stirred under argon for 20 hours. The reaction mixture was filtered, the solvent evaporated and the residue purified by preparative TLC with 30% ethyl acetate in hexanes to give 0.150 g (yield 77%) 3-bis(4-fluorophenyl) methoxypiperidin-1-yl acetic acid ethyl ester (compound C5) as an oil. NMR spectra of the product showed: 'H NMR (CDCI 3 300 MHz) s 7.60 7.35 4 7.35 7.00 4 5.72 1 4.38 2 3.90 3.65 1 3.42 (br. s, 2 3.25 1 2.97 1 2.42 (dt, 2 2.17 1 2.00 1.80 1 1.70 (dt, 1 1.60 -1.50 1 1.46 3 H), 3 C NMR (CDCI3, 75 MHz) 8 170.16, 163.52, 160.27, 138.14, 138.11, 128.50, 128.40, 115.13, 114.85, 79.30, 72.45, 60.27, 59.31, 57.83, 52.80, 30.06, 23.12, 14.01.
Example 2 Additional Syntheses for Reactions 1 and 2: Compounds were synthesized using Reaction 1 or Reaction 2, as follows: Compound Reaction Amine Reagent Solvent Yield C3 1 2 A X 38% C4 2 1 A X 58% C6 2 3 A X 86% 1 4 A X 89% C14 2 5 B X 1 6 A X 67% Amine: 1) 4,4-diphenylpiperidine Wetzel et al., J. Med. Chem., 38: 1579-1581, 1995); 2) a,a-diphenyl-4-piperidinomethanol (Acros, Pittsburgh, PA); 3) 2,2-diphenyl-4A,5,6,7,8,8A-hexahydro-4H-1,3-dioxino[5,4-b]pyridine (Sigma-Aldrich Library of Rare Chemicals); 4) perhexiline maleate [2-(2,2-dicyclohexylethyl)piperidyne] (Sigma, St. Louis); 5) 3,3-diphenyl-2-ethylpyrrolidine [prepared by sodium borohydride reduction of 3,3-diphenyl-2ethyl-1-pyrroline (Sigma-Aldrich Library of Rare Chemicals)]; 6) 2,2-diphenyl-1,3-dioxolan-4yl)piperidine hydrochloride (Sigma-Aldrich Library of Rare Chemicals)].
Reagen: A) ethyl bromoacetate (Aldrich); B) benzyl 2-bromoacetate (Aldrich).
WO 97/45423 PCT/US97/09346 36- Solvent: X) acetonitrile.
Example 3 Synthesis of 3-Diphenylmethyl-1,2,3.6.-tetrahydropyridin-1-yl acetic acid ethyl ester (Compound C1) Step 1: A mixture of 0.490 g (2 mmol) 3-diphenylmethylpyridine (Sigma-Aldrich Library of Rare Chemicals) and 0.334 g (4 mmol) ethyl bromoacetate (Aldrich) in 2 ml acetonitrile was heated under reflux for 1 hour. The solvent was evaporated, the residue suspended in diethyl ether and filtered to give 0.8 g 1-ethoxycarbonylmethyl-3-diphenylmethylpyridinium bromide as a yellow powder. 'H NMR (CD 3 OD, 300 MHz) 8 8.87 1 8.77 1 8.42 1 8.10 (dd, 1 7.50 7.10 10 5.96 1 5.55 2 4.28 2 1.29 3 H).
Step 2: To an ice cooled solution of 0.206 g (0.5 mmol) 1-ethoxycarbonylmethyl-3diphenylmethylpyridinium bromide (from step 1) was added 0.034 g (0.92 mmol) sodium borohydride in small portions with stirring over one hour. The solvent was evaporated, the residue dissolved in diethyl ether, washed with water and dried with magnesium sulphate. After evaporation of the solvent, the residue was chromatographed on silica gel column with 30% ethyl acetate in hexanes to give 0.107 g 3-diphenylmethyl-1,2,3,6-tetrahydropyridin-1-yl acetic acid ethyl ester (compound C1) as a pale yellow oil. NMR spectra showed: 'H NMR (CDCI 3 300 MHz) a 7.40 7.10 10 5.22 (br. s, 1 4.61 1 4.12 2 3.25 2 H), 3.03 2 2.68 2 2.22 (br. s, 2 1.19 3 "C NMR (CDCl3 75 MHz) 8 170.24, 141.86, 137.89, 129.11, 128.10, 126.19, 123.24, 60.31, 58.79, 56.24, 55.13, 49.51, 25.64, 14.05.
EI-MS: 335 (10, C 22
H
25 262 Example 4 Additional Syntheses: Compound C8 was prepared in 29% yield by sodium borohydride reduction of the corresponding quaternary salt of 4-diphenylmethylpyridine (Aldrich) using the methodology of Example 3.
Example 5 Hydrogenation of compound C1 to form 3-diphenlmethylpiperidin-l-yl acetic acid ethyl ester (compound C2) 0.041 g (0.122 mmol) or 3-diphenylmethyl-1,2,3,6 -tetrahydropyridin-1-yl acetic acid ethyl ester (compound C1) was hydrogenated with 0.040 g 10% Pd/C in 4 ml ethanol at 40 psi for 6 hours at room temperature. The mixture was filtered from the catalyst through celite and the solvent evaporated to give 0.038 g (yield 93%) 3-diphenylmethylpiperidin-l-yl acetic acid ethyl ester (compound C2) as an oil. NMR spectra of the product showed: 'H NMR (CDC,, 300 MHz) s 7.40 7.10 10 4.11 2 3.52 1 3.10 2 2.87 1 2.72 (d, 1 2.65 2.40 1 2.20 2.00 1 1.87 1 1.70 1.50 3 1.17 3 H), WO 97/45423 PCT/US97/09346 37- 1.00 0.8 1 "C NMR (CDCI 3 75 MHz) 8 168.89, 142.11, 141.81, 126.92, 126.90, 126.36, 126.28, 124.58, 124.50, 58.78, 58.47, 57.29, 55.34, 52.05, 37.97, 27.86, 23.58, 12.57.
EI-MS: 337 C 2 2
H
2 7
NO
2 264 Example 6A Additional syntheses: Compound C7 is prepared by hydrogenation of compound C8 using the methodology of Example Example 6B Additional Syntheses Using the Procedure of Example 6A Compound C13 was prepared by hydrogenation of compound C14 (using the methodology of Example 6A), followed by acidification with HCI.
Example 6C Synthesis of 2-(2.2-Dicyclohexylethyl)piperidin-1-vl acetic acid hydrochloride (Compound C9) To a solution of 0.413 g (1.136 mmol) 2-(2,2-dicyclohexylethyl)piperidin-1-yl acetic acid ethyl ester (Compound C10) in 4 ml methanol was added 8 ml 1N sodium hydroxide and the mixture was heated under reflux for one hour. The reaction mixture was concentrated to half volume, acidified with 4N hydrochloric acid, and extracted four times with methylene chloride.
The combined extracts were dried and evaporated to give 0.400 g (yield 95%) 2-(2,2dicyclohexylethyl)piperidin-1-yl) acetic acid hydrochloride (Compound C9).
Example 6D Additional Syntheses Using the Procedure of Example 6C Compound C11 was prepared by hydrolysis of Compound C2, followed by acidification with HCI.
Compound C12 was prepared by hydrolysis of Compound C1, followed by acidification with HCI.
Example 7 Preparation of Cells Expressing GlyT-1 and GlyT-2 This example sets forth methods and materials used for growing and transfecting QT-6 cells.
QT-6 cells were obtained from American Type Culture Collection (Accession No. ATCC CRL-1708). Complete QT-6 medium for growing QT-6 is Medium 199 (Sigma Chemical Company, St. Louis, MO; hereinafter "Sigma") supplemented to be 10% tryptose phosphate; fetal bovine serum (Sigma); 1% penicillin-streptomycin (Sigma); and 1% sterile dimethylsulfoxide (DMSO; Sigma). Other solutions required for growing or transfecting QT-6 cells included: DNA/DEAE Mix: 450 pl TBS, 450 pl DEAE Dextran (Sigma), and 100 pl of DNA (4 pg) in TE, where the DNA includes GlyT-la, GlyT-lb GlyT-ic, or GlyT-2, in a suitable expression vector The DNA used was as defined below.
WO 97/45423 PCT/US97/09346 38- PBS: Standard phosphate buffered saline, pH 7.4 including 1 mM CaCI 2 and 1 mM MgCI, sterilized through 0.2 p filter.
TBS: One ml of Solution B, 10 ml of Solution A; brought to 100 ml with distilled H 2 0; filter-sterilized and stored at 4°C.
TE: 0.01 M Tris, 0.001 M EDTA, pH DEAE dextran: Sigma, #0-9885. A stock solution was prepared consisting of 0.1% (1 mg/ml) of the DEAE dextran in TBS. The stock solution was filter sterilized and frozen in 1 ml aliquots.
Chloroquine: Sigma, #C-6628. A stock solution was prepared consisting of 100 mM chloroquine in H 2 0. The stock solution was filter-sterilized and stored in 0.5 ml aliquots, frozen.
Solution A NaCI 8.00 g KCI 0.38 g Tris base 3.00 g Na 2 HPO, 0.20 g The solution was adjusted to pH 7.5 with HCI, brought to 100.0 ml with distilled H 2 0, and filter-sterilized and stored at room temperature.
Solution B (100X): CaCI2-2HO 1.5 g MgCI, 2 6H0O 1.0 g The solution was brought to 100 ml with distilled H20, and filter-sterilized; the solution was then stored at room temperature.
HBSS: 150 mM NaCI, 20 mM HEPES, 1 mM CaCI,, 10 mM glucose, 5 mM KCI, 1 mM MgCI 2
*H
2 0; adjusted with NaOH to pH 7.4.
Standard growth and passaging procedures used were as follows: Cells were grown in 225 ml flasks. For passaging, cells were washed twice with warm HBSS (5 ml each wash). Two ml of a 0.05% trypsin/EDTA solution was added, the culture was swirled, then the trypsin/EDTA solution was aspirated quickly. The culture was then incubated about 2 minutes (until cells lift off), then 10 ml of QT-6 media was added and the cells were further dislodged by swirling the flask and tapping its bottom. The cells were removed and transferred to a 15 ml conical tube, centrifuged at 1000 xg for 10 minutes, and resuspended in 10 ml of QT-6 medium. A sample was removed for counting, the cells were then diluted further to a concentration of 1 x 10 cells/ml using QT-6 medium, and 65 ml of the culture was added per 225 ml flask of passaged cells.
WO 97/45423 PCT/US97/09346 39 Transfection was accomplished using cDNA's prepared as follows: The rat GlyT-2 (rGlyT-2) clone used contains the entire sequence of rGlyT-2 cloned into pBluescript SK+(Stratagene) as an Eco RI Hind III fragment, as described in Liu et al., J. Biol.
Chem. 268, 22802-22808 (1993). GlyT-2 was then subcloned into the pRc/RSV vector as follows: A PCR fragment corresponding to nucleotides 208 to 702 of the rGlyT-2 sequence was amplified by PCR using the oligonucleotide: 5'GGGGGAAGCTTATGGATTGCAGTGCTCC 3' as the 5' primer and the oligonucleotide: GGGGGGGTACCCAACACCACTGTGCTCTG 3' as the 3' primer. This created a Hind III site immediately upstream of the translation start site. This fragment, which contained a Kpn I site at the 3' end, along with a Kpn 1 Pvu II fragment containing the remainder of the coding sequence of rGlyT-2, were cloned into pBluescript SK+ previously digested with Hind III and Sma I, in a three part ligation. A Hind III Xba 1 fragment from this clone was then subcloned into the pRc/RSV vector. The resulting construct contains nucleotides 208 to 2720 of the rGlyT-2 nucleic acid in the pRc/RSV expression vector.
The human GlyT-la (hGlyT-la) clone used contains the sequence of hGlyT-la from nucleotide position 183 to 2108 cloned into the pRc/CMV vector (Invitrogen, San Diego, CA) as a Hind Ill-Xba 1 fragment as described in Kim et al., Mol. Pharmacol., 45, 608-617, 1994. This cDNA encoding GlyT-la actually contained the first 17 nucleotides (corresponding to the first 6 amino acids) of the GlyT-la sequence from rat. To determine whether the sequence of human GlyT-la was different in this region, the 5' region of hGlyT-la from nucleotide 1 to 212 was obtained by rapid amplification of cDNA end using the 5' RACE system supplied by Gibco BRL (Gaithersburg, MD). The gene specific primer: 5' CCACATTGTAGTAGATGCCG 3' corresponding to nucleotides 558 to 539 of the hGlyT-la sequence, was used to prime cDNA synthesis from human brain mRNA, and the gene specific primer: 5' GCAAACTGGCCGAAGGAGAGCTCC 3', corresponding to nucleotides 454 to 431 of the hGlyT-la sequence, was used for PCR amplification. Sequencing of this 5' region of GlyT-la confirmed that the first 17 nucleotides of coding sequence are identical in human and rat GlyT-la.
The human GlyT-1b (hGlyT-lb) clone used contains the sequence of hGlyT-lb from nucleotide position 213 to 2274 cloned into the pRc/CMV vector as a Hind III Xba I fragment as described in Kim et al., Mol. Pharmacol., 45, 608-617, 1994.
The human GlyT-1c (hGlyT-lc) clone used contains the sequence of hGlyT-lc from nucleotide position 213 to 2336 cloned into the pRc/CMV vector (Invitrogen) as a Hind III Xba I fragment as described in Kim et al., Mol. Pharmacol., 45, 608-617, 1994. The Hind III Xba WO 97/45423 PCT/US97/09346 fragment of hGlyT-lc from this clone was then subcloned into the pRc/RSV vector. Transfection experiments were performed with GlyT-1c in both the pRc/RSV and pRc/CMV expression vectors.
The following four day procedure for the tranfections was used: On day 1, QT-6 cells were plated at a density of 1 x 106 cells in 10 ml of complete QT- 6 medium in 100 mm dishes.
On day 2, the media was aspirated and the cells were washed with 10 ml of PBS followed by 10 ml of TBS. The TBS was aspirated, and then 1 ml of the DEAE/DNA mix was added to the plate. The plate was swirled in the hood every 5 minutes. After 30 minutes, 8 ml of 80 pM chloroquine, in QT-6 medium was added and the culture was incubated for 2.5 hours at 37°C and 5% CO2. The medium was then aspirated and the cells were washed two times with complete QT-6 media, then 100 ml complete QT-6 media was added and the cells were returned to the incubator.
On day 3, the cells were removed with trypsin/EDTA as described above, and plated into the wells of 96-well assay plates at approximately 2x10 5 cells/well.
On day 4, glycine transport was assayed as described in Example 8.
Example 8 Assay of Transport Via GlyT-1 or GlyT-2 transporters This example illustrates a method for the measurement of glycine uptake by transfected cultured cells.
Transient GlyT-transfected cells grown in accordance with Example 7 were washed three times with HEPES buffered saline (HBS). The cells were then incubated 10 minutes at 37*C, after which a solution was added containing 50 nM 3 H]glycine (17.5 Ci/mmol) and either no potential competitor, 10 mM nonradioactive glycine or a concentration of a candidate drug.
A range of concentrations of the candidate drug was used to generate data for calculating the concentration resulting in 50% of the effect the IC 5 oS, which are the concentrations of drug inhibiting glycine uptake by The cells were then incubated another 10 minutes at 37*C, after which the cells were aspirated and washed three times with ice-cold HBS. The cells were harvested, scintillant was added to the cells, the cells were shaken for 30 minutes, and the radioactivity in the cells was counted using a scintillation counter. Data were compared between the same cells contacted or not contacted by a candidate agent, and between cells having GlyT-1 activity versus cells having GlyT-2 activity, depending on the assay being conducted.
Example 9 Assay of Binding to NMDA Receptors This example illustrates binding assays to measure interaction of compounds with the glycine site on the NMDA receptor.
WO 97/45423 PCT/US97/09346 41 Direct binding of ([H]glycine to the NMDA-glycine site was performed according to the method of Grimwood et al., Molecular Pharmacology, 41, 923-930 (1992); Yoneda et al., J.
Neurochem, 62, 102-112 (1994).
Preparation of membranes for the binding test required application of a series of standard methods. Unless otherwise specified, tissues and homogenates were kept on ice and centrifugations were conducted at 4"C. Homogenizations were conducted with an effort to minimize resulting rise in tissue/homogenate temperature. The membrane preparation included the following steps: 1. Sacrifice and decapitate four rats; remove cortices and hippocampi.
0 2. Homogenize tissue in twenty volumes of 0.32 M sucrose/5 mM Tris- Acetate (pH 7.4) with 20 strokes of a glass/teflon homogenizer.
3. Centrifuge tissue at 1000 x g, 10 minutes. Save supernatant.
Resuspend pellet in small volume of buffer and homogenize again.
Centrifuge the homogenized pellet and combine the supernatant with the previous supernatant.
4. Centrifuge the combined supernatants at 40,000 x g, for 30 minutes.
Discard the supernatant.
Resuspend the pellet in 20 volumes of 5 mM Tris-Acetate (pH 7.4).
Stir the suspension on ice for one hour. Centrifuge the suspension at 40,000 x g for 30 minutes. Discard the supernatant and freeze the pellet for at least 24 hours.
6. Resuspend the pellet from step 5 in Tris Acetate buffer (5 mM, pH 7.4) containing 0.1% saponin Sigma Chemical Co., St. Louis) to a protein concentration of 1 mg/ml. Leave on ice for 20 minutes.
Centrifuge the suspension at 40,000 x g for 30 minutes. Resuspend the pellet in saponin-free buffer and centrifuge again. Resuspend the pellet in Tris-Acetate buffer at a concentration of.10 mg/ml and freeze in aliquots.
7. On day three, remove an aliquot of membranes and thaw on ice.
Dilute the suspension into 10 ml Tris-Acetate buffer and centrifuge at 40,000 x g for 30 minutes. Repeat the wash step twice more for a total of 3 washes. Resuspend the final pellet at a concentration of 1 mg/ml in glycine-free Tris-Acetate buffer.
WO 97/45423 PCT/US97/09346 -42- The binding test was performed in eppendorf tubes containing 150 pg of membrane protein and 50 nM 3 H]glycine in a volume of 0.5 ml. Non-specific binding was determined with 1 mM glycine. Drugs were dissolved in assay buffer (50 mM Tris-acetate, pH 7.4) or DMSO (final concentration of Membranes were incubated on ice for 30 minutes and bound radioligand was separated from free radioligand by filtration on Whatman GF/B glass fiber filters or by centrifugation (18,000 x g, 20 min). Filters or pellet was washed three times quickly with ice-cold mM Tris-acetate buffer. Filters were dried and placed in scintillation tubes and counted.
Pellets were dissolved in deoxycholate/NaOH (0.1 N) solution overnight, neutralized and radioactivity was determined by scintillation counting.
A second binding test for the NMDA-glycine site used 3 H]dichlorokynurenic acid (DCKA) and membranes prepared as above. See, Yoneda et al., J. Neurochem., 60,634-645 (1993).
The binding assay was performed as described for 3 H]glycine above except that 3 H]DCKA was used to label the glycine site. The final concentration of 3 H]DCKA was 10 nM, and the assay was performed for 10 minutes on ice.
A third binding test used for the NMDA-glycine site used indirect assessment of affinity of ligands for the site by measuring the binding of 3 H]MK-801 (dizocilpine). See, Palmer and Burns, J. Neurochem., 62, 187-196 (1994). Preparation of membranes for the test was the same as above. The binding assay allowed separate detection of antagonists and agonists.
The third binding test was operated to identify antagonists as follows: 100 pg of membranes were added to wells of a 96-well plate, along with glutamate (10 pM) and glycine (200 nM) and various concentrations of the ligand to be tested. The assay was started by the addition of 5 nM [3H]MK-801 (23.9 Cilmmol), which binds to the ion channel associated with NMDA receptors. The final volume of the assay was 200 pl. The assay was performed for 1 hour at room temperature. Bound radioactivity was separated from free by filtration, using a TOMTEC harvester. Antagonist activity was indicated by decreasing radioactivity associated with the NMDA receptor with increasing concentration of the tested ligand.
The third binding test was operated to identify agonists by performing the test as above, except that the concentration of glycine was 200 nM. Agonist activity was indicated by increasing radioactivity associated with the NMDA receptor with increasing concentration of the tested ligand.
Example 10 Assay of Calcium Flux This example illustrates a protocol for measuring calcium flux in primary neuronal calls.
The calcium flux measurement is performed in primary neuronal cell cultures, which are prepared from rat fetal cortices dissected from pregnant rats using standard procedures and techniques that require sterile dissecting equipment, a microscope and defined medium. The WO 97/45423 PCT/US97/09346 43protocol used was adapted from Lu et al., Proc. Nat'l. Acad. Sci. USA, 88, 6289-6292 (1991).
Defined medium is prepared in advance in accordance with the following recipe: Components Source (catalogue Final Concentration D-glucose Sigma (G-7021) 0.6% transferrin Sigma (T-2252) 100 pg/ml insulin Sigma (1-5500) 25 pg/ml progesterone Sigma (P-6149) 20 nM putrescine Sigma (P-7505) 60 pM selenium Sigma (S-5261) 30 nM pen-strep' GIBCO (15070-014) 0.5 U-0.5 pg/ml L-glutamine* GIBCO (25030-016) 146 mg/I MEM GIBCO (11095 or 11090) 500 ml/I F-12 GIBCO (11765) 500 ml/I A pen-strep: 5,000 Ulml penicillin and 5,000 pg/ml steptomycin add only when MEM without L-glutamine is used o with L-glutamine or without L-glutamine, respectively Before starting the dissection, tissue culture plates were treated with polylysine (100 pg/ml for at least 30 minutes at 37*C) and washed with distilled water. Also, a metal tray containing two sets of sterile crude dissecting equipment (scissors and tweezers) and several sets of finer dissecting tools was autoclaved. A pair of scissors and tweezers were placed into a sterile beaker with 70% alcohol and brought to the dissecting table. A petri dish with cold phosphate buffered saline (PBS) was placed on ice next to the place of dissection.
A pregnant rat (E15 or 16 on arrival from Hilltop Lab Animals (Scottdale, PA), E17 or 18 at dissection) was placed in a CO 2 dry ice chamber until it was unconscious. The rat was removed, pinned to a backing, the area of dissection was swabbed with 70% alcohol, and skin was cut and removed from the area of interest. A second pair of scissors was used to cut through and remove the prenatal pups in their sacs. The string of sacs was placed into the cold PBS and transported to a sterile hood.
The prenatal pups were removed from the sacs and decapitated. The skulls were then removed and the brains were carefully dislodged and placed into a clean petri dish with cold PBS. At this point, it was necessary to proceed with a dissecting microscope. The brain was turned so that the cortices were contacting the plate and the tissue between the dissector and the cortex (striatum and other brain parts) was scooped out. The hippocampus and olfactory bulb were cut away from the cortex. Then the tissue was turned over and the meninges were removed with tweezers. The remaining tissue (cortex) was placed in a small petri dish with defined media.
DOCKET NO. 1743-107BWO -44- The tissue was chopped with a scalpel and then triturated with a glass pipet that had been fire polished. The chopped, triturated tissue was then transferred to a sterile plastic tube and continued to be triturated with a glass pipet with a finer opening. Cells were counted in a suitable counting chamber. Cells were plated at roughly 40,000 cells/well in 100 pJ of defined medium for 96-well plates, 200,000 cells/well in 500 pl in 24-well plates, 400,000 cells/well in 1 ml in 12-well plates, 1.5 x 108 cells/35 mm dish in 1.5 ml and 10 x 108 cells/100 mm dish in ml. To inhibit glia growth, cultures were treated with 100 pM 5-flouro-2-deoxyuridine (FDUR, Sigma (F-0503)) or 50/pM uridine (Sigma (U-3003)) and 50 pM FDUR.
The cortical cultures for the standard calcium flux assay were grown in 24-well plates in 10 the defined medium described above for 7 days and fed once with serum containing media heat inactivated fetal calf serum, 0.6% glucose in MEM) by exchanging half of the medium.
Cultures were used after 12 days of incubation in vitro. The cultures were rinsed three times with HCSS HEPES-buffered control salt solution, containing 120 mM NaCI, 5.4 mM KCI, 1.8 mM CaCl 2 25 mM HEPES, and 15 mM glucose, in HPLC water and adjusted to pH 7.4 by NaOH, which was also made in HPLC water). In the third wash, the culture was incubated at 37*C for to 30 minutes.
Solutions containing 45 Ca" (5000 dpm/ml) and drugs for testing or controls were 0@ prepared in HCSS. Immediately before the above 45 Ca" solutions were added, cultures were washed twice with HCSS, and 250 pl of 4 5 Ca" solution per well was added, one plate at a time.
The cultures were incubated for 10 minutes at room temperature, rinsed three times with HCSS, and 1 ml scintillation liquid per well was added, followed by shaking for at least 15 minutes.
Retained radioactivity was counted in a scintillation counter.
While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations in the preferred compositions and methods may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the claims that follow.
Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of S one or more other feature, integer, step, component or group thereof.

Claims (12)

1. A compound of formula I or II: R 4 G R R 219 R 3 /n G N RX R' Rx8J /n x II RY R or a pharmaceutically acceptable salt thereof, wherein: X is nitrogen or carbon, and R 2 is not present when X is nitrogen; R 2 is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is independently Cl to C6, comprises (where R' is not -O-R 8 or -S-Rs*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, forms a double bond with an S adjacent carbon or nitrogen from one of either R 1 Rxb or Ryb, is oxygen forming an oxa linkage with R' or ring D or is R 2 a linked by R 2 b to X; Rx is a ring-containing structure Rxa linked by Rxb to X; 15 (2 i R Y is a ring-containing structure Rya linked by Ryb to X; (2111) Rxa, Rya and R 2a are independently aryl, heteroaryl, adamantyl or a 5 to 7- membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein: aryl is phenyl or naphthyl, S: 20 heteroaryl comprises a five-membered ring, a six-membered ring, a six- membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six- membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon, -46- each of Rxa, Rya and R 2 a can be independently substituted with one of R' RrO- or RsS-, wherein R, R r and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for Rxa, and Rxa, Rya, R 2 a, Rq Rr and Rs can be substituted or additionally substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (Cl-C6) N-alkyl substitutions, adamantyl, (C1-C12) alkyl, (C1-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl is independently Cl to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1- C6) alkylsulfonyl, amidino that can independently substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl, wherein: "i the substitutions of Rxa, Rya and R 2 a can be combined to form a 20 second bridge between two of Rxa, Rya and R 2 a comprising (1) 1-C2) alkyl or alkenyl, which can be independently substituted with one or more (C1-C6) alkyl, sulfur, oxygen, amino, which can be substituted for hydrogen with one (C 1-C6) alkyl, carbonyl, -CH 2 which can be substituted for hydrogen 25 with up to two independent (C1-C6) alkyl, CH 2 which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, 24 wherein R 24 is hydrogen or (C1-C6) alkyl, (10) -CH 2 which can be substituted for hydrogen with up to three (C 1-C6) alkyl, or (11) CH=N-, which can be substituted for hydrogen with (C1-C6) alkyl, or wherein two of Rxa, Rya and R 2a can be directly linked by a single bond; (2 iv Rxb and R 2 b are independently a single bond or (C1-C2) alkylene; -47- R yb is a single bond, oxa, (C1-C2) alkylene, ethenylene or -CH= (where the double bond is with thia, methyleneoxy or methylenethio, or either -N(R 6 or -CH2- N(R 6 wherein R 6 and R 6 are hydrogen or (C 1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom; R' comprises: a single bond; a straight-chained (C1-C3) aliphatic group; or (where X is carbon and Ryb does not include a heteroatom attached to X) -O-R 8 or -S- R 8 wherein either R 8 or R 8 is (C1-C3) alkylene or (C2-C3) alkenylene and O or S is bonded to X: wherein R' can be substituted with up to one hydroxy, up to one (Cl-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen, or (where R' is -0-R 8 and X is carbon) an oxa linkage to X forming a 1,3-dioxolane, wherein the alkyl or alkylidene substituents of R' can be linked to form a 3 to 7-membered non-aromatic ring, and wherein if X is nitrogen, X is linked to R' by a single bond and the terminal carbon of R' that links R' to N is saturated; *i n is 0 or 1, and where ifn is 1, R 3 is either (C1-C6) alkyl (with the attached 20 nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon; wherein ring D is a 3 to 8-membered ring, a 3 to 8-membered ring substituted with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6- membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens: 25 wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C 1-C6) alkylidene, hydroxyl, (Cl- C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for Ra or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and hD Z'?\\cC3 I OWp~
48- wherein R 3 and G are such that at least two atoms separate X and the illustrated ring nitrogen; wherein ring E is a 3 to 8-membered ring, a 3 to 8-membered ring substituted with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6- membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens: wherein the carbon and nitrogen ring atoms of ring E can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C C6) alkoxy, oxo, hydroxycarbonyl, (C 1-C6) alkoxycarbonyl, aryl wherein the aryl is as defined for Ra, or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and wherein G* and R' 8 are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to Rx and R y when G* is a six-membered ring; R 1 9 forms a double bond with R 3 or G, is hydrogen is (Cl C3) 20 alkyl or alkylene, or is incorporated into a fused ring; O"0: R 4 and R 4 are independently hydrogen or (C 1-C6) alkyl, or one of R 4 and R 4 o* can be (C1-C6) hydroxyalkyl; and R 5 is (CO)NR' 3 R' 4 (CO)SR 1 6 (S0 2 )NR' 7 R 26 (PO)(OR 2 9 )(OR 20 (CR 2 2 )(OR 23 )(OR 24 CN or tetrazol-5-yl, wherein R' 3 R 1 4 R 1 5 R 16 R 1 7 R 26 R 29 and 25 R 20 are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R 15 or the sulfur of R 16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is Cl to C6, aryl or heteroaryl, R 22 is hydrogen or OR 25 and R 23 R 24 and R 25 are (C1-C6) alkyl, phenyl, benzyl, acetyl or, where R 22 is hydrogen, the alkyls of R 23 and R 24 can be combined to include 1,3-dioxalane or 1,3-dioxane: -49 wherein the aryl is phenyl or naphthyl and the heteroaryl is a five- membered ring, a six-membered ring, a six-membered ring fused to a five- membered ring, a five-membered ring fused to a six-membered ring, or a six- membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon; wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C 1-C6) N-alkyl substitutions, (C 1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently Cl to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) alkyl, (C 1-C6) alkylsulfonyl, amidino that can substituted with up to three (C1- C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl; and 20 wherein R 3 and R' 4 together with the nitrogen can form a 5 to 7- S" membered ring that can contain one additional heteroatom selected from oxygen and sulfur. 2. The compound of claim 1, wherein: 25 when D is a 3-8 member ring containing at least one N, (ii) R 2 is OH, (iii) Rx is Rxa, and (iv) R y is R y a then Rxa and Rya are not phenyl, phenyl substituted with fluoro, chloro, bromo, hydroxy, trifluoromethyl, C1-C8 alkyl, C1-C6 alkoxy, or not pyridyl, and R 5 is not (CO)NR' 3 R' 4 or (CO)OR" 5 when R 3 R 14 and R 1 5 are independently hydrogen, C1-C8 alkyl, phenyl, or phenyl substituted with fluoro, chloro, bromo, C 1-C6 alkyl or C 1-C6 alkoxy; when D is piperidine, (ii) X is carbon, (iii) R' is OR 8 or SR 8 (iv) R 5 is (CO)OR 1 5 Rx is Rxa and (vi) R y is R ya then Rxa and Rya are not both phenyl or phenyl substituted with fluoro, chloro, bromo, C1-C4 alkyl or C1-C4 alkoxy and R' 5 is not hydrogen or C1-C4 alkoxy. 3. The compound of claim 1, wherein at least one of Rxa, Rya and R 2 a is substituted with fluoro, chloro, bromo, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, (C3-C8) alkyl, Rq, RsS-, or the ring structures of Rxa, Rya and R 2 a including substituents thereto, otherwise include at least two aromatic ring structures that together include from 15 to 20 ring atoms. 4. The compound of claim 2, wherein at least one ofRxa, Rya and R 2a is substituted with fluoro, trifluoromethyl, trifluoromethoxy, nitro, cyano, or (C3-C8) alkyl. 5. The compound of claim 1, wherein at least one of Rxa, Rya and R 2a is substituted with Rq RrO-, or RSS-. 6. The compound of claim 1, wherein an aryl or heteroaryl of at least one of Rxa, Rya and R 2a is phenyl. 7. The compound of claim 1, wherein Ryb is oxa, methyleneoxy, thia, methylenethia. 8. The compound of claim 6, wherein Ryb is oxa or thia. 9. The compound of claim 1, wherein R 5 is (CO)NR' 3 R' 4 (CO)OR 1 5 or (CO)SR 16 The compound of claim 8, wherein R 1 5 is (C2-C6) alkyl, (C2-C4) S 20 hydroxyalkyl, phenyl, phenylalkyl wherein the alkyl is C1-C3, or aminoalkyl where the alkyl is C2-C6 and the amino can be substituted with up to two independent (C1 -C3) alkyls, wherein the phenyl or the phenyl of phenylalkyl can be substituted. 11. The compound of claim 8, wherein R 15 is hydrogen. 12. The compound of claim 1, wherein R 4 is hydrogen, methyl or 25 hydroxymethyl and R 4 is hydrogen. 13. The compound of claim 1, wherein at least one of Rxa, Rya and R2a is a heteroaryl comprising diazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, diazinyl, triazinyl, benzoazolyl, benzodiazolyl, benzothiazolyl, benzoxazolyl, S' quinolyl, isoquinolyl, benzodiazinyl, benzotriazinyl, pyridyl, thienyl, furanyl, pyrrolyl, indolyl, isoindoyl or pyrimidyl. 14. The compound of claim 1, wherein R' is -0-R 8 or -S-R 8 The compound of claim 1, wherein said second bridge between two of Rxa, R ya and R 2a is L, and satisfies the following formula: -51 L wherein A and B are aryl or heteroaryl groups of R xa and Rya, respectively. 16. The compound of claim 14, wherein Ra-RbR"-, Rya-Ryb- and X form: 21 R ]D Y wherein Y is a carbon bonded to R' by a single or double bond or a nitrogen that is bonded to R 1 and wherein R 21 either completes a single bond linking two aryl or heteroaryl rings of RX and R y is (C1-C2) alkylene or alkenylene, (iii.) is sulfur or is oxygen, and wherein RX and R y can be substituted as set forth above. 17. The compound of claim 15, wherein R 21 is CH 2 CH 2 or CH=CH. 18. The compound of claim 1, wherein the alkylenedioxy substitution of Rxa, Got* Rya or R 2 a is as follows: 0 *S S or •oor wherein the alkylenedioxy can be substituted with up to two independent (C1-C3) alkyl. S.oo.. S S
52- 19. The compound of claim 1, wherein ring D is according to one of formulas A' and B': N -RR A' B' wherein Z represents carbon, wherein for each of formulas A' and B' at least one and up to two of the bonds indicated with the hashed lines can be double bonds provided no two double bonds are adjacent, and wherein the ring of formulas A' and B' can be substituted as set forth above for ring D. The compound of claim 1, wherein the ring system comprising G* is according to one of formulas C' and D' N *000 S 0 S 0O S @6 OS 4 S 4 S 9 *000 .9 0 0 4555 00 wherein Z represents carbon, wherein for formula C' up to one of the bonds indicated with the hashed lines can be double bond and for formula D' up to two of the bonds indicated with the hashed lines can be double bonds, and wherein the ring can be 20 substituted as set forth above for ring E.
53- 21. The compound of claim 1, wherein ring D or ring E is substituted with up to three substituents. 22. The compound of claim 1, wherein Rxa and Rya together can be substituted with up to six substituents, R 2 a, Rq Rr and Rs can each be substituted with up to 3 substituents, and wherein the presence of each of Rq Rr or Rs is considered a substitution to the respective ring structure of Rxa, Rya and R 2 a. 23. The compound of claim 1, wherein the aryl of arylalkyl or the heteroaryl of heteroarylalkyl of R 1 3 R 1 4 R 1 5 R 1 6 R 1 7 R 2 6 R 29 or R 20 is substituted with up to three substituents. 24. The compound of claim 1, wherein the compound is an optically pure enantiomer. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient. 26. The pharmaceutical composition of claim 25, wherein the compound of claim 1 is present in an effective amount for: treating schizophrenia comprising administering a schizophrenia treating effective amount of a compound, of treating epilepsy comprising administering an epilepsy treating effective amount of a compound, treating spasticity comprising administering a spasticity treating effective amount of a compound, treating muscle spasm comprising administering a muscle spasm treating effective amount of a compound, treating pain comprising administering a pain treating effective amount of a compound, treating mood disorders comprising administering a mood disorder treating effective amount of a compound, enhancing memory or learning comprising administering a memory or learning enhancing effective amount of a compound, or (8) 25 treating learning disorders. 27. A method treating schizophrenia comprising administering a schizophrenia treating effective amount of a compound, of treating epilepsy comprising administering an epilepsy treating effective amount of a compound, (3) treating spasticity comprising administering a spasticity treating effective amount of a compound, treating muscle spasm comprising administering a muscle spasm treating effective amount of a compound, treating pain comprising administering a pain treating effective amount of a compound, treating mood disorders comprising administering a mood disorder treating effective amount of a compound, enhancing
54- memory or learning comprising administering a memory or learning enhancing effective amount of a compound, or treating learning disorders, comprising administering an amount effective for said treating, preventing or enhancing of a compound of claim 1. 28. A method treating schizophrenia comprising administering a schizophrenia treating effective amount of a compound, of treating epilepsy comprising administering an epilepsy treating effective amount of a compound, (3) treating spasticity comprising administering a spasticity treating effective amount of a compound, treating muscle spasm comprising administering a muscle spasm treating effective amount of a compound, treating pain comprising administering a pain treating effective amount of a compound, treating mood disorders comprising administering a mood disorder treating effective amount of a compound, enhancing memory or learning comprising administering a memory or learning enhancing effective amount of a compound, or treating learning disorders, comprising administering an amount effective for said treating, preventing or enhancing of a compound of formula I or II: 4R R D o3 G N R5 G* R S* 2 R .R* x SR RJ n or a II RY R or a pharmaceutically acceptable salt thereof, wherein: X is nitrogen or carbon, and R 2 is not present when X is nitrogen; R 2 is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is independently Cl to C6, comprises (where R' is not -O-R 8 or -S-R 8 hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, forms a double bond with an adjacent carbon or nitrogen from one of either Rxb or Ryb, is oxygen forming an oxa linkage with R' or ring D or is R 2 a linked by R 2 b to X; Rx is a ring-containing structure Rxa linked by Rxb to X; R y is a ring-containing structure Rya linked by Ryb to X; Rxa, R ya and R 2a are independently aryl, heteroaryl, adamantyl or a 5 to 7- membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein: aryl is phenyl or naphthyl, heteroaryl comprises a five-membered ring, a six-membered ring, a six- membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six- membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon, each of Rxa, Rya and R 2 a can be independently substituted with one of Rq RrO or RsS wherein R q Rr and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for Rxa, and Rxa, Rya, R 2 a, R R r and Rs can be substituted or additionally substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can 20 have up to two independent (Cl-C6) N-alkyl substitutions, adamantyl, (C1-C12) alkyl, (C1-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl is independently C to C6, (C 1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be 25 substituted for hydrogen with up to two independent (C 1-C6) alkyl, (C1- C6) alkylsulfonyl, amidino that can independently substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two I: oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl, wherein: the substitutions of Rxa, Rya and R 2 a can be combined to form a second bridge between two of Rxa, Rya and R 2a comprising (1) (C 1-C2) alkyl or alkenyl, which can be independently substituted
56- with one or more (C1-C6) alkyl, sulfur, oxygen, amino, which can be substituted for hydrogen with one (C1-C6) alkyl, carbonyl, -CH 2 which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, CH 2 which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, wherein R 24 is hydrogen or (C1-C6) alkyl, (10) -CH 2 which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) CH=N-, which can be substituted for hydrogen with (C1-C6) alkyl, or wherein two of Rxa, Rya and R 2 a can be directly linked by a single bond; Rxb and R 2 b are independently a single bond or (C1-C2) alkylene; Ryb is a single bond, oxa, (C1-C2) alkylene, ethenylene or -CH= (where the double bond is with thia, methyleneoxy or methylenethio, or either -N(R 6 or -CH 2 N(R 6 wherein R 6 and R 6 are hydrogen or (C 1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom; R' comprises: a single bond or double bond; a straight-chained (C1-C3) aliphatic group; or (where X is carbon and Ryb does not include a heteroatom attached to X) -0- R 8 or -S-R 8 wherein either R 8 or R 8 is a single bond, (C1-C3) alkylene or (C2-C3) alkenylene and O or S is bonded to X: wherein R' can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C 1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is 25 bonded to a nitrogen or oxygen, or (where R' is -0-R 8 and X is carbon) an oxa linkage to X forming a 1,3-dioxolane, wherein the alkyl or alkylidene substituents of R' can be linked to form a 3 to 7-membered non-aromatic ring, and wherein ifX is nitrogen, X is linked to R' by a single bond and the terminal carbon of R' that links R' to N is saturated; n is 0 or 1, and where if n is 1, R 3 is either (C1-C6) alkyl (with the attached nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon;
57- wherein ring D is a 3 to 8-membered ring, a 3 to 8-membered ring substituted with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6- membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens: wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C 1-C6) alkylidene, hydroxyl, (C1- C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for Ra or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and wherein R 3 and G are such that at least two atoms separate X and the illustrated ring nitrogen; wherein ring E is a 3 to 8-membered ring, a 3 to 8-membered ring substituted with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6- membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens: wherein the carbon and nitrogen ring atoms of ring E can be substituted 20 with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C 1-C6) alkylidene, hydroxyl, (C- C6) alkoxy, oxo, hydroxycarbonyl, (C1-C6) alkoxycarbonyl, aryl wherein the aryl is as defined for Ra, or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or 25 oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and wherein G* and R' are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to Rx and R Y when G* is a six-membered ring; R' 9 forms a double bond with R 1 R 3 or G, is hydrogen is (Cl C3) alkyl or alkylene, or is incorporated into a fused ring;
58- R 4 and R 4 are independently hydrogen or (C 1-C6) alkyl, or one of R 4 and R 4 can be (C1-C6) hydroxyalkyl; and R s is (CO)NR 3 R' 4 (CO)OR 1 5 (CO)SR 1 6 (SO2)NR 7 R 26 (PO)(OR 29 )(OR 20 (CR 22 )(OR 23 )(OR 2 4 CN or tetrazol-5-yl, wherein R 1 3 R 1 4 R 1 5 R 1 6 R 17 R 26 R 2 9 and R 20 are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R 1 5 or the sulfur of R 16 has no more than secondary branching and (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is Cl to C6, aryl or heteroaryl, R 22 is hydrogen or OR 25 and R 23 R 24 and R 2 5 are (C -C6) alkyl, phenyl, benzyl, acetyl or, where R 22 is hydrogen, the alkyls of R 23 and R 24 can be combined to include 1,3-dioxalane or 1,3-dioxane: wherein the aryl is phenyl or naphthyl and the heteroaryl is a five- membered ring, a six-membered ring, a six-membered ring fused to a five- membered ring, a five-membered ring fused to a six-membered ring, or a six- membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon; wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of 20 heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C 1-C6) **alkyl, (C 1-C6) alkylsulfonyl, amidino that can substituted with up to three (C 1l- C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C -C6) alkyl; and
59- wherein R 13 and R 14 together with the nitrogen can form a 5 to 7- membered ring that can contain one additional heteroatom selected from oxygen and sulfur. 29. The method of claim 28, wherein the spasticity is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury or dystonia. The method of claim 28, wherein the neurodegenerative disease is Alzheimer's disease, multi-infarct dementia, AIDS dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or stroke or head trauma. 31. A method of synthesizing a compound of claim 1 comprising: A) reacting a compound of the formula 1) R 4 lt--(RA wherein 'L is a nucleophilic substitution leaving group, with a compound of the formula 2) 2 G or B) reacting a compound of the formula G* 2) :R L R* p Sor B) reacting a compound of the formula /R wherein 2L is a nucleophilic substitution leaving group. 32. A method of synthesizing a compound of claim 1 comprising reductively alkylating RdNH 2 with a compound of the formula oG R ,wherein Rc and Rd are independently the same as defined for Rx, and wherein R has the same definition as R' except that it does not include a nitrogen, oxygen or sulfur, and does not include any double bonds conjugated with the above-illustrated carbonyl. 33. A method of synthesizing a compound of claim 1 comprising reacting RfOH or RPSH with a compound of the formula L 6 R c f R-N Rs I 3 C <R R 4 to form an ether or a thioether, respectively, wherein R f and R P are independently the same as defined for Rx, and wherein R has the same definition as R' except that it does not include a nitrogen, oxygen or sulfur, and does not include any double bonds at the S 20 atom bonded to the above-illustrated L 6 -substituted carbon. 34. The method of claim 31, further comprising synthesizing the compound of formula L 6 G R 4 by replacing the hydroxyl of formula SOH G D N= R RCaS R4 with another nucleophilic substitution leaving group. 35. The method of claim 33, comprising reacting a compound of formula -61 OH G- with an azodicarboxylate in the presence of a phosphine compound. 36. A method of synthesizing a compound of claim 1 comprising reacting ReM with a compound of the formula to form a compound of the formula OH G R' 4 ,wherein Re and Re are independently the same as defined for Rx, wherein M is a metal- containing substituent such that ReM is a organometallic reagent and wherein has the *same definition as R' except that it does not include a nitrogen, oxygen.or sulfur, and 20 does not include any double bonds conjugated with the above-illustrated carbonyl. 37. A method of synthesizing a compound of claim 1 comprising dehydrating a compound of the formula OH G iD RS R3 R4" R 19 R4 o. to form a compound of the formula o *o*
62- wherein C* has a double bond with an adjacent carbon, wherein R and Re are independently the same as defined for Rx, wherein R 27 and R 27 have the same definition as R' except that R 27 and R 27 do not include a nitrogen, oxygen or sulfur. 38. A method of synthesizing a compound of claim 1 comprising reducing a compound of the formula Re DG R1 9 R 4 wherein C* has a double bond with an adjacent carbon, to form a compound of the formula RI R 4 ,wherein RC and Re are independently the same as defined for Rx, wherein R 27 and R 27 have the same definition as R 1 except that R 27 and R 27 do not include a nitrogen, oxygen or sulfur. 39. A method of synthesizing a compound of claim 1 comprising reducing a compound of one of the following formulas R 4 R .0 0 R R v or to reduce a double bond in ring C" or ring Cix, wherein R 28 is the same as R' except that the bond to the ring is not a double bond, wherein ring C" i is mono or di-unsaturated at one or more of the bonds indicated with the dashed lines with the double bonds formed between ring carbons and no two double bonds are adjacent, wherein ring C" or ring C" i can include a fused phenyl and can be substituted as follows the carbon and nitrogen ring atoms of ring C" or ring C" i can be substituted with up to two substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, and (C2-C7) alkyloxycarbonyl, and wherein I is a negative counter-ion. S\ 40. The method of synthesizing a compound of claim 37, wherein the S compound reduced is that containing ring C". iS -63- 41. A precursor to the compound of claim 1 having the following formula Fe R 4 R 25 I o wherein I is a negative counter- ion, wherein R 28 is the same as R 1 except that the bond to the ring is not a double bond, wherein ring C" can include a fused phenyl and can be substituted as follows: the carbon and nitrogen ring atoms of ring C" can be substituted with up to two substituents selected from (C 1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, and (C2-C7) alkyloxycarbonyl. 42. A method of synthesizing a compound of claim 41, comprising reacting a compound of the formula R\ R 2 with a compound of the formula *wherein L 4 is a nucleophilic substitution leaving group and wherein ring C' can be fused :with phenyl or substituted, the same as defined for ring C. 25 43. A compound of claim 1 according to the following formula R4 xI CIX+ 20 8 wherein L 4 is tha nucleophilic substitution leaving group and wherein ring Ca dou can be fused wherein ring C" is mono or substituted, the i-usatrme as defined for more of the bonds indicated with theC. dashed lines with the dcompoubend of claim 1 aormed between ring carbons and no two double following formula (!,cHN wherein R 28 is the same as R n except that the bond to the ring is not a double bond, wherein ring C i is mono or di-unsaturated at one or more of the bonds indicated with the dashed lines with the double bonds formed between ring carbons and no two double -64- bonds are adjacent, wherein ring C' x can include a fused phenyl and can be substituted as follows the carbon and nitrogen ring atoms of ring D can be substituted with up to 2 substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, and (C2-C7) alkyloxycarbonyl. 44. A precursor to the compound of claim 1 having the following formula R' o wherein I is a negative counter- ion, wherein R 28 is a (C1-C3) aliphatic group that can be substituted as defined for R', wherein ring C V can include a fused phenyl and can be substituted as follows the carbon and nitrogen ring atoms of ring C v can be substituted with up to 2 substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, and (C2-C7) alkyloxycarbonyl. A method of synthesizing a compound of claim 44 comprising reacting a compound of the formula 0 c N RR with a compound of the formula R 4 25 L R wherein L 5 is a nucleophilic substitution leaving group, wherein ring C vi can be fused with phenyl or substituted, the same as defined for 46. A precursor to the compound of claim 1 having the following formula 65 wherein R 28 is a (C1-C3) aliphatic group that can be substituted as defined for wherein ring C'vi can include a fused phenyl and can be substituted as follows the carbon and nitrogen ring atoms of ring can be substituted with up to 2 substituents selected from (C 1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, and (C2-C7) alkyloxycarbonyl. 47. A method of synthesizing the compound of claim 46, the method comprising reducing a compound of the following formula I R, N^ R 0 5, ,to reduce the double bonds in ring wherein I is a negative counter-ion, and wherein ring C V can be fused with phenyl or substituted, the same as defined for ring 48. A method of synthesizing a precursor to the compound of claim 1, having the following formula 2 0 R O? R R R ,wherein RC is independently the same as wherein RI has the same definition as R' except that it does not include a nitrogen, oxygen or sulfur, and does not include any double bonds at the atom bonded to the above-illustrated L 6 -substituted carbon, which method comprises reacting a compound of the formula G D with a compound of the formula R 4 *L R R R 4 3 4
66- wherein L 3 is a nucleophilic leaving group. 49. A method of synthesizing of a compound of claim 1, the method comprising reacting a compound of formula substituted with an electron-withdrawing group or heteroaryl and is substituted with an electron-withdrawing group, and wherein Q is fluoro or chloro, to form Aro wherein R 27 has the same definition as R 1 except that R 27 does not include a nitrogen, oxygen or sulfur. :1 50. A method of synthesizing a precursor to the compound of claim 1, having the following formula X: a 250 hc eho opie reatn a.compunAfomua R R 4 OH/ G a 3 w~ithern wr i independently the same as R d Are isaylo e. which mero tho d comprises reacting a compound of for mula: t r ilentOHr Go r Re* /I 19 R C.A 15 R 4 o o* with RdNHSO2Ar, wherein R c and R d 1 are independently the same as R x and Ar is aryl or heteroaryl, and wherein R 27 has the same definition as R except that R 27 does not include a nitrogen, oxygen or sulfur.
67- 51. The method of claim 50, further comprising converting the compound of formula X to: RdN NH G 52. A method of synthesizing a precursor to the compound of claim 1, the method comprising reacting a compound of formula D H HO N H Rc R 19 with a compound of formula 4 R wherein L4 is a nucleophilic substitution leaving group and Rc is independently the same as Rx, and wherein R 27 has the same definition as R' except that R 27 does not 20 include a nitrogen, oxygen or sulfur, to form a compound of formula F G 27RC 19 R *oooo R 25 53. A method of synthesizing a precursor to the compound of claim 1, the method comprising synthesizing the compound of formula: 4 0* O 9O r1; 68 wherein Rc is independently the same as Rx and has the same definition as R' except that does not include a nitrogen, oxygen or sulfur and does not include any double bonds at the atom bonded to the above-illustrated hydroxyl-substituted carbon, said synthesis comprising reducing the ketone of a compound of formula 0 R 4 Ro R's RS 54. A precursor to the compound of claim 1 having the following formula HO i. wherein I is a negative counter- ion, wherein R 28 is the same as R' except that the bond to the ring is not a double bond, wherein ring Cx can include a fused phenyl and can be substituted as follows the carbon and nitrogen ring atoms of ring C" can be substituted with up to 2 substituents selected from (C 1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, 20 trifluoromethyl, and (C2-C7) alkyloxycarbonyl A method of synthesizing a compound of claim 54, comprising reacting a Scompound of the formula N HO I 25 R" with a compound of the formula 30 sR :R ,wherein L s is a nucleophilic substitution leaving group, wherein ring C i can be fused r with phenyl or substituted, the same as defined for Cx. 69 56. A precursor to the compound of claim 1 having the following formula 24 HO N R RE wherein R 28 is the same as R' except that the bond to the ring is not a double bond, wherein ring Ci" can include a fused phenyl and can be substituted as follows the carbon and nitrogen ring atoms of ring Cx" can be substituted with up to 2 substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, and (C2-C7) alkyloxycarbonyl. 57. A method of synthesizing the compound of claim 56, the method comprising reducing a compound of the following formula to reduce the double bonds in ring Cx, wherein I is a negative counter-ion, and wherein ring Cx can be fused with phenyl or substituted, the same as defined for ring Cii. 58. The use of a compound of claim 1 in the preparation of a medicament to treat schizophrenia, epilepsy, spasticity, muscle spasm, pain, mood disorders, enhance memory or learning or treat learning disorders. 59. The use of a compound of the formula I or II: 4 R 4 G R N D R 3 3)n 2R I 9 E I R 2 is hydrogen, (C1-C6) alkyl, (C-C6) alkoxy, cyano, (C2-C7) alkanoyl, Is ot* 6** 0 0, or a pharmaceutically acceptable salt thereof, 0:000: X is nitrogen or carbon, and R 2 is not present when X is nitrogen; **Ofe: R 2 is hydrogen, (C 1 -C6) alkyl, (C 1 -C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is indepenenntly C1 to C6, comprises (where R I is not -O-Ror -S-R 8 hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, forms a double bond with an adjacent carbon or nitrogen from one of either R xb or Ryb, is oxygen forming an oxa linkage with R' or ring D or is R 2 a linked by R 2 b to X; *0 19/06/01 ,c10184.daims,70 -71- Rx is a ring-containing structure Rxa linked by Rx b to X; R Y is a ring-containing structure Rya linked by Ryb to X; Rxa, Rya and R Z are independently aryl, heteroaryl, adamantyl or a 5 to 7- membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein: aryl is phenyl or naphthyl, heteroaryl comprises a five-membered ring, a six-membered ring, a six- membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six- membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon, each of R"a, Rya and R 2 a can be independently substituted with one of R q rO- or RsS wherein R' R' and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for Rxa, and Rxa, Rya, R 2 a, R, Rr and Rs can be substituted or additionally substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can 20 have up to two independent (CI-C6) N-alkyl substitutions, adamantyl, (C1-C 12) alkyl, (C -C 12) alkenyl, amino, (C 1-C6) alkylamino, dialkylamino wherein each alkyl is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be 25 substituted for hydrogen with up to two independent (C 1-C6) alkyl, (C 1 C6) alkylsulfonyl, amidino that can independently substituted with up to three (C -C6) alkyl, or methylenedioxy or ethylenedioxy with the two o ^oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with 30 up to two independent (C -C6) alkyl, wherein: the substitutions of Rxa, Rya and R 2 a can be combined to form a second bridge between two of Rxa, R ya and R 2a comprising (1) A (C 1-C2) alkyl or alkenyl, which can be independently substituted -72- with one or more (C1-C6) alkyl, sulfur, oxygen, amino, which can be substituted for hydrogen with one (C -C6) alkyl, carbonyl, -CH 2 which can be substituted for hydrogen with up to two independent (C 1-C6) alkyl, CH 2 which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, 24 wherein R 24 is hydrogen or (C1-C6) alkyl, (10) -CH 2 which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) CH=N-, which can be substituted for hydrogen with (C1-C6) alkyl, or wherein two of Rxa, Rya and R can be directly linked by a single bond; (2 i v) Rxb and R 2 b are independently a single bond or (C1-C2) alkylene; Ryb is a single bond, oxa, (C1-C2) alkylene, ethenylene or -CH= (where the double bond is with thia, methyleneoxy or methylenethio, or either -N(R 6 or -CH 2 N(R 6 wherein R 6 and R 6 are hydrogen or (C 1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom; R' comprises: a single bond or double bond; a straight-chained (C1-C3) aliphatic group; or (where X is carbon and Ryb does not include a heteroatom attached to X) -0- R 8 or -S-R 8 wherein either R 8 or R 8 is a single bond, (Cl-C3) alkylene or (C2-C3) 20 alkenylene and O or S is bonded to X: wherein R' can be substituted with up to one hydroxy, up to one (C 1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C 1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is 25 bonded to a nitrogen or oxygen, or (where R' is -0-R 8 and X is carbon) an oxa linkage to X forming a 1,3-dioxolane, wherein the alkyl or alkylidene substituents of R' can be linked to form a S 3 to 7-membered non-aromatic ring, and wherein if X is nitrogen, X is linked to R' by a single bond and the 0 terminal carbon of R' that links R' to N is saturated; n is 0 or 1, and where if n is 1, R 3 is either (C 1-C6) alkyl (with the attached nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon; -73- wherein ring D is a 3 to 8-membered ring, a 3 to 8-membered ring substituted with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6- membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens: wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C 1-C6) alkylidene, hydroxyl, (C1- C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for Ra or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and wherein R 3 and G are such that at least two atoms separate X and the illustrated ring nitrogen; wherein ring E is a 3 to 8-membered ring, a 3 to 8-membered ring substituted with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6- membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens: wherein the carbon and nitrogen ring atoms of ring E can be substituted 20 with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C 1-C6) alkylidene, hydroxyl, (C- C6) alkoxy, oxo, hydroxycarbonyl, (C -C6) alkoxycarbonyl, aryl wherein the aryl is as defined for Ra, or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or 25 oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and wherein G* and R' 8 are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to Rx and R y when G* is a six-membered 30 ring; R 1 9 forms a double bond with R 3 or G, is hydrogen is (Cl C3) alkyl or alkylene, or is incorporated into a fused ring; -74- R 4 and R 4 are independently hydrogen or (C 1-C6) alkyl, or one of R 4 and R 4 can be (C -C6) hydroxyalkyl; and R 5 is (CO)NR" 3 R 1 4 (CO)OR Is (CO)SR 1 6 (SO 2 )NR 7 R 26 (PO)(OR 2 9 )(OR 20 (CR2)(OR)(OR 24 CN or tetrazol-5-yl, wherein R 1 3 R 1 4 R is R 1 6 R 17 R 26 R 29 and R 20 are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R' 5 or the sulfur of R 1 6 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is Cl to C6, aryl or heteroaryl, R" is hydrogen or OR 25 and R 2 R 24 and R 25 are (C -C6) alkyl, phenyl, benzyl, acetyl or, where R 22 is hydrogen, the alkyls of R 2 and R 24 can be combined to include 1,3-dioxalane or 1,3-dioxane: wherein the aryl is phenyl or naphthyl and the heteroaryl is a five- membered ring, a six-membered ring, a six-membered ring fused to a five- membered ring, a five-membered ring fused to a six-membered ring, or a six- membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon; wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of 20 heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C 1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently Cl to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) 25 alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C 1-C6) 1 alkyl, (C1-C6) alkylsulfonyl, amidino that can substituted with up to three (Cl- C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy *0 or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl; and wherein R 13 and R 14 together with the nitrogen can form a 5 to 7- membered ring that can contain one additional heteroatom selected from oxygen and sulfur in the preparation of a medicament to treat schizophrenia, epilepsy, spasticity, muscle spasm, pain, mood disorders, to enhance memory or learning, or to treat learning disorders. 60. The use of claim 59, wherein the spasticity is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury or dystonia. 61. The use of claim 59, wherein the neurodegenerative disease is Alzheimer's disease, multi-infarct dementia, AIDS dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or stroke or head trauma. 62. A compound of any one of claims 1 to 24 or claim 43, substantially as herein described with reference to any one of the Examples. 63. A pharmaceutical composition of claim 25 or claim 26, substantially as herein described with reference to any one of the Examples. 64. A method of any one of claims 27 to 30 which method is substantially as herein described with reference to any one of the Examples. A method of any one of claims 31 to 40, 42, 45, 47 to 53, 55, or 57 which method is substantially as herein described with reference to any one of the Examples. 66. A precursor compound of claim 41, claim 44, claim 46, claim 54, or claim 56, substantially as herein described with reference to any one of the Examples. 20 67. The use of any one of claims 58 to 61, substantially as herein described with reference to any one of the Examples. DATED this 19" h day of June, 2001. ALLELIX NEUROSCIENCE, INC. By their Patent Attorneys: CALLINAN LAWRIE 19106/01,cf10184.daims.75
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