WO1997023202A1 - Ligands du recepteur n-methyl-d-aspartate selectifs de sous-type - Google Patents

Ligands du recepteur n-methyl-d-aspartate selectifs de sous-type

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Publication number
WO1997023202A1
WO1997023202A1 PCT/US1996/020086 US9620086W WO9723202A1 WO 1997023202 A1 WO1997023202 A1 WO 1997023202A1 US 9620086 W US9620086 W US 9620086W WO 9723202 A1 WO9723202 A1 WO 9723202A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
group
alkyl
hydrogen
aryl
Prior art date
Application number
PCT/US1996/020086
Other languages
English (en)
Inventor
Sui Xiong Cai
John F. W. Keana
Nancy C. Lan
Gian Luca Araldi
Amir Tamiz
Zhang-Lin Zhou
Richard M. Woodward
Edward R. Whittemore
Eckard Weber
Original Assignee
STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITYA ND THE UNIVERSITY OF OREGON, EUGENE OREGON
Acea Pharmaceuticals, Inc.
Cocensys, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITYA ND THE UNIVERSITY OF OREGON, EUGENE OREGON, Acea Pharmaceuticals, Inc., Cocensys, Inc. filed Critical STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITYA ND THE UNIVERSITY OF OREGON, EUGENE OREGON
Priority to AU14639/97A priority Critical patent/AU1463997A/en
Publication of WO1997023202A1 publication Critical patent/WO1997023202A1/fr

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    • C07D207/04—Heterocyclic 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
    • C07D207/08—Heterocyclic 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/52—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
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    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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    • C07D207/04—Heterocyclic 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
    • C07D207/06—Heterocyclic 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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    • C07D207/18—Heterocyclic 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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic 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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D211/10—Heterocyclic 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
    • C07D211/16—Heterocyclic 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 acylated ring nitrogen atom
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Definitions

  • the invention is in the field of medicinal chemistry.
  • the invention relates to subtype-selective NMDA receptor ligands and the use thereof to treat or prevent conditions mediated by the excitatory amino acids such as neuronal loss, for example that occurs during ischemia: neurodegenerative conditions such as Parkinson's disease; glaucoma; CMV retinitis, urinary incontinence; convulsions; pain; opiate tolerance, to treat opiate withdrawal; to treat or prevent aminoglycoside-induced hearing loss; and to enhance cognition.
  • neurodegenerative conditions such as Parkinson's disease; glaucoma; CMV retinitis, urinary incontinence; convulsions; pain; opiate tolerance, to treat opiate withdrawal; to treat or prevent aminoglycoside-induced hearing loss; and to enhance cognition.
  • Ar, and Ar 2 which may be the same or different, independently represent phenyl or phenyl substituted by one or more of amino, nitro, halogen, hydroxy, Cl to 6 alkoxy, Cl to 6 alkyl or cyano;
  • R represents hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy-carbonyl
  • R 2 represents hydrogen or COCH 2 NH 2
  • R 3 represents hydrogen or Cl to 6 alkyl
  • R 2 represents hydrogen either one or both of Ar
  • Ar 2 may also represent 2-, 3- or 4-pyridinyl and R, may also represent trihalomethyl; or a pharmaceutically acceptable salt thereof.
  • the compounds having Formula I are reportedly useful for treating neurological disorders such as epilepsy, stroke and cerebral ischemia, as well as a number of neurodegenerative diseases.
  • X is -(CH 2 ) q -, wherein q is 1 -6;
  • C,-C 6 alkyl (wherein Z is hydrogen); and Z is hydrogen, aryl, an aryl-substituted carboxylic acid group, heteroaryl or cycloalkyl, wherein aryl, heteroaryl and cycloalkyl can be optionally substituted; -
  • R, R 2 , a and b as defined above, may be the same or different;
  • Cy is C -C 8 cycloalkyl and Ar, R', n, R, X, and Z are defined as above;
  • R 5 and R 6 are independently a C,. g alkyl group
  • R 7 is hydrogen or a C,_ alkyl group substituted by an arylacetoxy group
  • X is as defined above.
  • the compounds having Formula II-VI are reportedly useful for treating central nervous system disorders, drug abuse, gastrointestinal disorders, hypertension, migraine, angina and depression.
  • Cinnamides 1-3 are reported to be potent EGFR-K inhibitors with high antiproliferative activity (Gazit et al., J. Med. Chem. 34: 1896 (1991)). Cinnamate 4 is reported to be an extremely potent inhibitor of 12-lipoxygenase (Cho et al., J. Med. Chem. 34:1503 (1991)).
  • U.S. Patent 5,463,125 discloses that certain phenyl alcohol amides have anticonvulsant activity. Examples of such compounds include 2-hydroxy-2- phenylbutyramide and 3-hydroxy-3-phenylpentamide.
  • the compounds are said to lower the blood pressure of anesthetized dogs and to generalize central depression in mice.
  • U.S. 786383 discloses l-substituted-3-phenoxypyrrolidines described by the formula:
  • R is C,. g alkyl, alkoxy, alkenyl, or alkynyl, carbamoyl, carbamoyloxy, PhO, BzO, atpha-HO-Bz, styryl, HO, 1,2-diHO-ethyl, amidino, COOalk or Ph.
  • R is H, lower alkyl or alkoxy, CF 3 , MeCO, F, Cl, or Br, n is 0-4.
  • the compounds are said to be useful as major tranquillisers, anti-convulsants and muscle relaxants. But there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
  • nitrogen heterocycles can be 3-8 member rings and substituted in 2-4 positions.
  • Ar and ' Ar are opionally mono or disubstituted phenyl.
  • the compounds are said to be useful to treat arrhythmia and tachycardia. But there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
  • injury to neurons is caused, at least in part, by overstimulation of receptors for the excitatory amino acids, which include glutamate and aspartate.
  • Such receptors include the N-methyl-D-aspartate
  • NMDA neurotrophic lateral sclerosis
  • Antagonists of the NMDA receptor are considered useful in treating or preventing a number of neurologic disorders which are caused by overstimulation by the excitatory amino acids. These include domoic acid poisoning; cerebral ischemia; stroke; hypoxia; anoxia; poisoning by carbon monoxide, manganese or cyanide; hypoglycemia; mechanical trauma to the nervous system, epileptic seizures; and such chronic neurodegenerative diseases such as Huntington's disease, AIDS dementia, neuropathic pain syndrome, olivopontocerebral atrophy, Parkinson's disease, amyotrophic lateral sclerosis, mitochondrial abnormalities, Alzheimer's disease, hepatic encephalopathy,
  • U.S. Patent 5,352,683 discloses the treatment of chronic pain with a compound which is an antagonist of the NMDA receptor.
  • U.S. Patent 4,902,695. discloses certain competitive NMDA antagonists that are useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative diseases such as Alzheimer's disease and Huntington ' s disease.
  • U.S. Patent 5,192,751 discloses a method of treating urinary incontinence in a mammal which comprises administering an effective amount of a competitive NMDA antagonist.
  • NMDA receptor comprises a class of such receptors with different subunits.
  • Molecular cloning has revealed the existence of at least five subunits of the NMDA receptors designated NRl & NR2A through 2D. It has been demonstrated that the co-expression of NRl with one of
  • NR2 subunits forms a receptor with a functional ion channel. (Ann. Rev. Neurosci. 77:31-108 (1994)). It is thought that NMDA receptors with different subunit composition generate the different NMDA receptor subtypes found in the mammalian brain. Summary of the Invention
  • the invention relates to a subtype-selective NMDA receptor ligand having the Formula (VII):
  • E and E' are independently (CR a R b ) r -G s -(CR c R d ) radical wherein R,, R b , R, and Rj may differ with each repetitive methylene and are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2 or O 2 C), carbonyl (CO), or NR., wherein R,, is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is
  • Y is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
  • R is hydrogen, alkyl, aryl or aralkyl; and m is 0, 1, 2, or 3.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (VIII):
  • W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group
  • X is a bond, (CH 2 ) m , carbonyl (CO), oxygen, or NR;
  • E is (CR a R b ) r -G s -(CR c R d ) t , wherein R_, R,,, R, and Rj may differ with each repetitive methylene and are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
  • G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2 or O 2 C), carbonyl, or NR e , wherein R e is hydrogen, alkyl or aryl; r and t are independently 0, 1 , 2, 3, 4, or 5; and s is 0 or 1 ; with the proviso that at least one of r, s and t is other than 0;
  • Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryioxy, optionally substituted arylthioxy, optionally substituted aroyl, ⁇ -Y
  • , -Y
  • R is hydrogen, alkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (IX):
  • W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group
  • X is a bond, (CH 2 ) m , carbonyl, oxygen, sulfur or NR;
  • E is (CR a R b ) r -G s -(CR c R d ) office wherein R_, RNase, R_ and R_ may differ with each repetitive methylene and are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2 or O 2 C), carbonyl, or NR statement wherein R e is hydrogen, alkyl or aryl; r and t are independently 0, 1. 2, 3, 4, or 5; and s is 0 or 1 ; with the proviso that at least one of r, s and t is other than 0;
  • Y is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, optionally substituted cycloalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group, an aminoalkyl group, an amidoalkyl group,
  • R is hydrogen, hydroxy, an optionally substituted aryl group, an optionally substituted aralkyl group, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, a heteroaryl group, a heteroaryl substituted alkyl group, a fused cycloalkyl group, a fused cycloalkyl group which is further fused to an optionally substituted benzene ring, a carboxy group or an alkyl carboxy (ester) group; m is 0, 1, 2, or 3; and p is 0, 1 or 2.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (X):
  • Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryioxy, optionally substituted arylthioxy, optionally substituted aroyl, ⁇ -Y
  • , -Y
  • Y is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, optionally substituted cycloalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
  • R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
  • R is hydrogen, hydroxy, an optionally substituted aryl group, an optionally substituted aralkyl group, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, a heteroaryl group, a heteroaryl substituted alkyl group, a fused cycloalkyl group, a fused cycloalkyl group which is further fused to an optionally substituted benzene ring, a carboxy group or an alkyl carboxy (ester) group; m is 0, 1 or 2; and
  • E is (CR a R b ) r -G s -(CR c R d ) t , wherein R., R b , R,. and R d may differ with each repetitive methylene and are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2 or O 2 C), carbonyl, or NR-, wherein R e is hydrogen, alkyl or aryl; r and t are independently 0, 1 , 2, 3, 4, or 5; and s is 0 or 1.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (XI):
  • W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
  • X is a bond, (CH 2 ) m , carbonyl, oxygen, or NR; E is (CR a R b ) r -G s -(CR I R d ) utilizat wherein R_, R_, R.
  • R naph may differ with each repetitive methylene and are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2 or O 2 C), carbonyl, or NRj, wherein R e is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1; with the proviso that at least one of r, s and t is other than 0;
  • Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryioxy, optionally substituted arylthioxy, optionally substituted aroyl, ⁇ -Y
  • , -Y t , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
  • Y is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
  • R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
  • R is hydrogen, hydroxy. alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group; m is 0, 1, 2, or 3; and p is 0, 1 or 2.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (XII):
  • R g and R h are independently hydrogen or alkyl
  • R,-R 3 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
  • E is (CR a R b ) r -G s -(CR c R d ) office wherein R,, R restroom, R- and Rj may differ with each repetitive methylene and are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2 or O 2 C), carbonyl, or NR e , wherein R e is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1 ; with the proviso that at least one of r, s and t is other than 0;
  • the invention relates to a subtype-selective NMDA receptor ligand having the Formula (XIII)
  • R,-R 4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN) 2 , guanadino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
  • E and E' are independently (CR a R b ) r -G s -(CR c R d ) radical wherein R hinder, R ⁇ R_ and R_ may differ with each repetitive methylene and are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2 or O 2 C), carbonyl, or NR-., wherein R_ is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1 ; with the proviso that at least one of r, s and t is other than 0;
  • R 5 is hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group; p is 0, 1, 2, or 3;
  • oximo amidino, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and
  • Y is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (XIV):
  • E is (CR a R b ) r -G s -(CR c R d ) architect wherein R., R restroom, R- and Rj may differ with each repetitive methylene and are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2 or O 2 C), carbonyl, or NR C , wherein R c is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1 ; with the proviso that at least one of r, s and t is other than 0;
  • Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryioxy, optionally substituted arylthioxy, optionally substituted aroyl, ⁇ -Y
  • , -Y, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido. ureido, or guanidino; and
  • Yi is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.
  • the invention also relates to the quaternary ammonium salts of any one of the compounds above obtained by reacting the compound with a lower alkyl halide, preferable, methyl iodide or methyl sulfate.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (XV):
  • X is NR, O, or CHR', wherein R and R 1 are independently hydrogen, alkyl or aralkyl;
  • X I is NR 2 , O, S or (CHR 3 ) m , wherein R 2 and R 3 are independently hydrogen, alkyl or aralkyl and m is 0, 1, 2. 3, 4 or 5; or where R or R 1 together with R 2 or R 3 is (CH 2 ) p , wherein p is 0, 1, 2, 3 or 4; n is O, 1, 2, 3, 4, 5 or 6;
  • Z and Z' are independently substituted or unsubstituted aromatic or heteroaromatic groups, adamantyl, hydroxy, or guanidino; -__- ⁇ - can be a single or double bond; and
  • Y is CN or hydrogen.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (XVI):
  • n 0, 1, 2, 3, 4 or 5
  • m 0, 1, 2, 3 or 4
  • p 0, 1, 2, 3 or 4
  • Z and Z' are independently substituted or unsubstituted aromatic or heteroaromatic groups, or adamantyl.
  • the invention also relates to a method of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and
  • Down's syndrome treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, treating or preventing aminoglycoside antibiotic-induced hearing loss, treating anxiety, convulsions, chronic pain, glaucoma, CMV retinitis, migraine headache and inducing anesthesia, as well as enhancing cognition, treating glaucoma, treating or preventing opiate tolerance, and treating opiate withdrawal, comprising administering to an animal in need of such treatment an effective amount of any one of the subtype-selective NMDA receptor ligands of the present invention, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to the discovery of new compounds which are subtype-selective ligands of the NMDA receptor. Such subtype selective ligands will allow for the treatment of various conditions mediated through binding to the NMDA receptor, while minimizing unwanted side effects.
  • Electrophysiological assays may be utilized to characterize the actions of potential subtype-selective ligands at NMDA receptors expressed in Xenopus oocytes.
  • the ligand may be assayed at the different subunit combinations of cloned rat NMDA receptors corresponding to the four putative NMDA receptor subtypes (Moriyoshi et al, Nature (Lond.) 354:3 -31 (1991); Monyer et al.
  • the inhibitory potency of a putative subtype-selective ligand may be assayed at the NMDA receptors assembled from NR1A/2A, NR1A/2B, NR1A/2C and NR1A/2D subunit combinations.
  • the subtype selective NMDA receptor ligands are limited efficacy NMDA receptor antagonists.
  • Such limited efficacy antagonists are attractive because such drugs have built-in safety margins; no matter how high the dosage only a certain fraction of the response can be blocked. This could be particularly important for analgesic, anticonvulsant, anti-psychotic, antimigraine, headache, anti-Parkinson's disease and antiglaucoma indications, where overdosage of full antagonists may result in sedation. It is also likely that low efficacy NMDA receptor antagonists, particularly those showing subtype-selectivity, will not induce such profound memory deficits as full antagonists.
  • Certain of the subtype-selective NMDA receptor ligands are expected to be able to mediate either inhibition or potentiation of membrane current response. Which type of effect predominates appears to be dependent upon the subunit composition of the receptors.
  • the 1A/2A and 1 A/2B subtypes are mainly in the forebrain.
  • the 1A/2C and 1A/2D are mainly in cerebellum.
  • Such drugs could show therapeutic potential as cognitive-enhancers in treatments of neurodegenerative conditions such as Alzheimer's disease. Furthermore, there is potential of developing drugs that selectively potentiate some subtypes of NMDA receptor while simultaneously having inhibitory effects at other subtypes. Such compounds could be important for adjusting imbalances in subtype activity and may have therapeutic potential as psychotropic agents.
  • Typical .,, aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • Typical halo groups include fluorine, chlorine, bromine and iodine.
  • Typical C alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert.-butyl groups. Also contemplated is a trimethylene group substituted on two adjoining positions on any benzene ring of the compounds of the invention.
  • Typical C 2 . alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec.-butenyl.
  • Typical C 2 . 4 alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups.
  • Typical arylalkyl groups include any of the above-mentioned C alkyl groups substituted by any of the above-mentioned C 6 ., 4 aryl groups.
  • Typical arylalkenyl groups include any of the above-mentioned C 2 _, alkenyl groups substituted by any of the above-mentioned C 6 ., 4 aryl groups.
  • Typical arylalkynyl groups include any of the above-mentioned C 2.4 alkynyl groups substituted by any of the above-mentioned C 6 ., 4 aryl groups.
  • Typical haloalkyl groups include C,. 4 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 , 1 -difluoroethyl and trichloromethyl groups.
  • Typical hydroxyalkyl groups include C,. 4 alkyl groups substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.
  • Typical alkoxy groups include oxygen substituted by one of the C,_ 4 alkyl groups mentioned above.
  • Typical alkylthio groups include sulphur substituted by one of the C alkyl groups mentioned above.
  • Typical acylamino groups include any C,. 6 acyl (alkanoyl) substituted nitrogen, e.g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as aryl-substituted C 2 . 6 substituted acyl groups.
  • Typical acyloxy groups include any C,__ acyloxy groups, e.g. acetoxy, propionoyloxy. butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
  • Typical heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperizinyl, pyrrolidinyl, imidazolindinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, mo ⁇ holinyl, isochromanyl, chromanyl, pyrazolidinyl and pyrazolinyl groups.
  • Typical heteroaryl groups include any one of the following which may be optionally substituted with one or more alkyl, halo, or hydroxy groups: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, c
  • heteroaryl group contains a nitrogen atom in a ring
  • nitrogen atom may be in the form of an N-oxide, e.g. a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and the like.
  • Typical amino groups include -NH 2 , -NHR 14 , and -NR I4 R 15 , wherein R M and R 15 are C alkyl groups as defined above.
  • Typical carbonylamido groups are carbonyl groups substituted by -NH 2 , -NHR 14 , and -NR I4 R 15 groups as defined above.
  • any one of the nitrogen atoms may be substituted independently by hydrogen, alkyl, or aryl groups.
  • Optional substituents on the aryl, aralkyl, aryioxy, arylthioxy, aroyl, heterocyclic, heterocycloxy, heteroaryl, heteroaryloxy, cycloalkyl, and cycloalkoxy groups listed above include any one of the typical halo, haloalkyl, aryl, fused aryl, heterocyclic, heteroaryl, alkyl, alkenyl, alkynyl. arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido. hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, and alkylthiol groups mentioned above.
  • the group E is a linker group between the nitrogen, e.g. pyrrolidine nitrogen, and the terminal group Y.
  • Hydrazine groups (-N-N-) are contemplated as possible linkers.
  • the group E is an optionally substituted methylene linker.
  • the group E is a methylene linker
  • the group Y is an N-hydroxyalkyl (e.g., hydroxypropyl) group, which is expected to provide a reduction in affinity to the ⁇ , receptor, thereby resulting in less hypotension when the compounds are administered to animals.
  • N-hydroxyalkyl e.g., hydroxypropyl
  • halo group such as a -chlorophenyl group may be employed to give compounds having a prolonged in vivo activity.
  • the compounds of the invention may be prepared by reaction of an appropriately substituted amino compound with a suitable electrophile in an aprotic solvent such as toluene or acetonitrile.
  • a base such as potassium carbonate or pyridine may be added.
  • suitable electrophiles include, for example, an alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, or heteroaralkyl halide, sulfate, sulfonate, or isocyanate.
  • electrophiles include ethyl 3-bromoethoxyphenyl acetate, methyl 5-bromovalerate, ethyl 4-bromobutyrate, 3-butyn-l-methanesulfate, ethyl crotonate, 1 -chloro-4-phenylbutane, 3-phenoxypropyl bromide, 4-chloro-4 '-fluorobutyrophenone, 4-chlorobutyrophenone, 2-phenylethyl bromide, l-bromo-3-phenylpropane, 3-phenoxypropyl bromide, ⁇ -bromo-phenetole, 3-phenoxypropyl bromide, 3-phenylpropyl bromide, 1,3-propanesulfone, phenylisocyanate, 4-nitrophenylisocyanate, allyl iodide, bromomethylcyclopropane, 3-bromo-l-propano
  • a general procedure for reaction of the amino compound with an alkyl chloride, bromide, tosylate or mesylate involves forming a mixture of a free base of the amino compound and an alkyl chloride or bromide in toluene, acetonitrile, DMF. acetone or ethanol, in the presence of Nal.
  • the reaction may be refluxed for 1 -10 h then cooled to room temperature, filtered and washed with hexane.
  • the filtrate is evaporated, and the residue chromatographed over silica gel to give the product.
  • the product is a solid, it may be crystallized, for example, from hexane or hexane-ethyl acetate.
  • the product is an oil, it may be dissolved in acetone and 4N HCl solution in 1 ,4-dioxane or concentrated HCl may be added until the mixture becomes strongly acidic (pH ⁇ 2). It may then be rota-evaporated, and co-evaporated until a solid residue is obtained. The solid may then be recrystallized from acetone to give the hydrochloride.
  • hydrobromide or other acid addition salts may be prepared by substitution of, for example, HBr or maleic acid for HCl.
  • compounds having Formula VII may be prepared by the reaction of an appropriate amino compound EYNHR with a suitable electrophile XE' Y'.
  • Examples of such compounds include N-(2-phenylethyl)-N-(3- pheny lpropyl)amine, N-( 1 -methyl-2-hydroxy-2-phenylethyl)-N-(3- pheny lpropyl)amine, N-(3 -phenoxypropy l)-N-( 1 -pheny lcyclohexyl)amine, bis- N,N-(2-(4-fluorophenoxy)ethyl)-N-(2-(4-hydroxyphenyl)ethyl)amine hydrochloride, N-(3-(4-chlorophenyl) propyl)-N-(2-(2-fluorophenoxy)ethyl)-N- (3 -hydroxypropyl)amine hydrochloride, N-(3-(4-chlorophenyl)propy l)-N-(2- (4-__uorophenoxy)ethyl)-N-(3-hydroxypropyl)amine
  • Y is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
  • R is hydrogen, alkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl; and n is 0, 1, 2, 3, 4, 5, or 6.
  • Compounds having Formula IX may be prepared by reaction of the corresponding pyrrolidine with an electrophile as described above. See Scheme 2 for methods of prepciring 2-benzyl pyrrolidines.
  • This route may be used as a general entry into 2-substituted azetidines and pyrrolidines.
  • pyrrolidines may be used as well.
  • fused pyrrolidine ring system F described in Haadsma-Svensson, S. R., et al,J. Med Chem 38:125 (1995) to prepare a family of subtype selective ligands.
  • electrophilic aikylating agents as described above may be used to alkylate F.
  • One example compound is Compound G, shown below. The bromine atom may then be replaced with a carboxamide group by analogy to work done in the cited paper, giving Compound H.
  • W is an adamantyl group
  • the compounds may be prepared as shown in Scheme 5.
  • adamantyl groups are 1 -adamantyl.
  • the compounds may be prepared using an aryl lithium or grignard reagent as shown in Scheme 6.
  • R,-R 5 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol; n is 1, 2, 3, 4, 5, or 6;
  • Y is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.
  • Another example includes compounds having the Formula (IXb):
  • W is optionally substituted aryl
  • X is a bond, (CH 2 ) m , oxygen, sulfur, or NR
  • R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
  • R is hydrogen, hydroxy, aryl, or aralkyl; n is 1, 2, 3, 4, 5, or 6;
  • carbon ring is not part of a naphthyl group.
  • the present invention also relates to compounds having the Formula
  • Y is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl; and n is 0, 1, 2, 3, 4, 5, or 6; and each R is a lower alkyl or lower aralkyl group.
  • the invention relates as well to azetidine-based compounds having Formula XI in which the A ring is a 2- or 3- or 2,3-(di)substituted azetidine.
  • Compounds Q and R are examples. These compounds may be prepared according to Scheme 12:
  • Compounds having Formula XII may be prepared by N-alkylation of one of the following benzodiazepine derivatives:
  • Compounds having Formula XIII may be prepared by reaction of the corresponding 2-amino substituted anthranilamide with chloroacetyl chloride to give the l-substituted-3,5(2H,4H)dione-l,4- benzodiazepine. Reduction with lithium aluminum hydride gives the 1 -substituted- lH-2,3,4,5-tetrahydro- 1,4- benzodiazepine. Finally, reaction with one of the electrophilic reagents listed above gives the compound having Formula XIII
  • Examples of compounds having Formula XIII include l -benzyl-4-(3-phenoxypropyl)-l H-2,3,4,5-tetrahydro-l ,4-benzodiazepine, 1 -benzyl-4-(3-hydroxypropyl)- 1 H-2,3,4,5-tetrahydro- 1 ,4-benzodiazepine and l-benzyl-4-(2-phenoxyethyl)-lH-2,3,4,5-tetrahydro-l,4-benzodiazepine.
  • Examples of such aza crown ethers include l-aza-12-crown-4, 1 -aza- 15 -crown- 5, and l-aza-18-crown-6.
  • the invention also relates to a subtype-selective NMDA receptor ligand having the Formula (XV):
  • X is NR, O, or CHR', wherein R and R 1 are independently hydrogen, alkyl or aralkyl; X 1 is NR 2 , O, S or (CHR 3 ) m , wherein R 2 and R 3 are independently hydrogen, alkyl or aralkyl and m is 0, 1, 2, 3, 4 or 5; or where R or R' together with R 2 or R 3 is (CH 2 ) P , wherein p is 0, 1, 2, 3 or 4; n is O, 1, 2, 3, 4, 5 or 6; Z and Z' are independently substituted or unsubstituted aromatic or heteroaromatic groups, adamantyl, hydroxy, or guanidino; -r _- r -- can be single or double bond; and
  • Y is CN or hydrogen.
  • R and R' are independently any one of a number of optional substituents.
  • Other particular examples include N-(4-phenylbutyl)-3,4- dihydroxycinnamide, N-(4-phenylbutyl)cinnamide, N-(4-phenylbutyl)- 4-hydroxycinnamide, 4'-benzylpiperidinyl-4-hydroxycinnamide, N-(4- phenylbutyl)-3-(4-hydroxyphenyl)propionamide, l ,3-bis-(4-hydroxy- benzylidene)acetone, 4-chloro-N-(2-(4-hydroxyphenyl) ethyl)cinnamide, 4-chloro-N-( l -(indol-3-yl)prop-2-yl)cinnamide, 4-chloro-N-(3- phenylpropyl)cinnamide, 4-chloro-N-(3-hydroxypropyl)cin
  • ⁇ -cyano-3.4-dihydroxy-N-(3-phenylpropyl)cinnamide and 2-(2-thienyl)ethyl- ⁇ -cyano-3.4-dihydroxycinnamate are subtype selective NMDA receptor antagonists.
  • the known subtype selective NMDA receptor antagonists such as ifenprodil and eliprodil all contain a piperidine basic amino group.
  • the cinnamide and cinnamate should have very different chemical and pharmacological properties from the piperidines and should have a completely different side effect profile from that of ifenprodil.
  • the cinnamides have been found to be inactive at ⁇ l receptors.
  • non-cyclized amine such as nylidrin and isoxsuprine are subtype selective NMDA receptor antagonists. This demonstrated that the cyclic piperidine structure in the known subtype selective NMDA receptor antagonists.
  • NMDA receptor antagonists such as ifenprodil and eliprodil is not essential for activity.
  • the invention also relates to compounds having the Formula (XVI):
  • n O, 1, 2, 3, 4 or 5
  • m O, 1, 2, 3 or 4
  • p 0, 1, 2, 3 or 4
  • Z and Z' are independently substituted or unsubstituted aromatic or heteroaromatic groups, or adamantyl.
  • the compounds of the present invention are active in treating or preventing neuronal loss, neurodegenerative diseases, chronic pain, are active as anticonvulsants and inducing anesthesia. They are also useful for treating epilepsy and psychosis.
  • the therapeutic and side effect profiles of subunit-selective NMDA receptor antagonists and agonists are expected to be markedly different from the more non-selective types of inhibitors.
  • the subtype-selective ligands of the present invention are expected to exhibit little or no untoward side effects caused by non-selective binding with other receptors, particularly, the PCP and glutamate bindings sites associated with the NMDA receptor.
  • selectivity for different NMDA receptor subtypes is expected to result in reduced side effects such as sedation that are common to non-subtype-selective NMDA receptor antagonists.
  • the compounds of the present invention are effective in treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, e.g. those which are involved in the NMDA receptor system, by preventing the ligand-gated cation channels from opening and allowing excessive influx of Ca ++ into neurons, as occurs during ischemia.
  • Neurodegenerative diseases which may be treated with the compounds of the present invention include those selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease. Parkinson's disease and Down's syndrome.
  • the compounds of the present invention find particular utility in the treatment or prevention of neuronal loss associated with multiple strokes which give rise to dementia. After a patient has been diagnosed as suffering from a stroke, the compounds of the present invention may be administered to ameliorate the immediate ischemia and prevent further neuronal damage that may occur from recurrent strokes.
  • the compounds of the invention find particular utility in treating or preventing the adverse neurological consequences of surgery.
  • coronary bypass surgery requires the use of heart-lung machines which tend to introduce air bubbles into the circulatory system which may lodge in the brain. The presence of such air bubbles robs neuronal tissue of oxygen, resulting in anoxia and ischemia.
  • Pre- or post- surgical administration of the compounds of the present invention will treat or prevent the resulting ischemia.
  • the compounds of the invention are administered to patients undergoing cardiopulmonary bypass surgery or carotid endarterectomy surgery.
  • the compounds of the present invention also find utility in treating or preventing chronic pain. Such chronic pain may be the result of surgery, trauma, headache, arthritis, pain from terminal cancer or degenerative diseases.
  • the compounds of the present invention also find particular utility in the treatment of phantom pain that results from amputation of an extremity.
  • the compounds of the invention are also expected to be useful in inducing anesthesia, either general or local anesthesia, for example, during surgery.
  • Aminoglycoside antibiotics have been used successfully in the treatment of serious Gram-negative bacterial infections. However, prolonged treatment with these antibiotics will result in the destruction of sensory hair cells of the inner ear and consequently, permanent loss of hearing.
  • the compounds of the present invention with NMDA receptor antagonist activity will be useful in preventing aminoglycoside antibiotic-induced hearing loss by antagonizing their interaction with the receptor.
  • the subtype-selective NMDA receptor antagonists, agonists and modulators may be tested for in vivo anticonvulsant activity after iv or ip injection using a number of anticonvulsant tests in mice (audiogenic seizure model in DBA-2 mice, pentylenetetrazol-induced seizures in mice, maximum electroshock seizure test (MES) or NMDA-induced death).
  • the compounds may also be tested in drug discrimination tests in rats trained to discriminate PCP from saline. It is expected that most of the compounds of the present invention will not generalize to PCP at any dose. In addition, it is also expected that none of the compounds will produce a behavioral excitation in locomotor activity tests in the mouse.
  • NMDA receptor antagonists and agonists of the present invention do not show the PCP-like behavioral side effects that are common to NMDA channel blockers such as MK-801 and PCP or to competitive NMDA antagonists such as CGS 19755.
  • Elevated levels of glutamate have been associated with glaucoma.
  • glaucoma management particularly protection of retinal ganglion cells, can be achieved by administering to a patient a compound capable of reducing glutamate-induced excitotoxicity in a concentration effective to reduce the excitotoxicity.
  • the compounds of the present invention which are expected to cross the blood-retina barrier, are also expected to be useful in the treatment of glaucoma.
  • the invention is directed to the treatment of patients which have primary open-angle glaucoma, chronic closed-angle glaucoma, pseudoexfoliation, or other types of glaucoma or ocular hypertension.
  • the compound is administered over an extended period (e.g. at least six months and preferably at least one year), regardless of the changes in the patient's intraocular pressure over the period of administration.
  • the compounds of the present invention are also useful in treating CMV retinitis, particularly in combination with antiviral agents.
  • CMV afflicts the ganglion cell layer which may result in higher levels of glutamate.
  • NMDA receptor antagonists could block retinitis by blocking the toxicity effect of high levels of glutamate. It is well known to use opiates, e.g., morphine, in the medical field to alleviate pain.
  • opiates is intended to mean any preparation or derivative of opium, especially the alkaloids naturally contained therein, of which there are about twenty, e.g., morphine, noscapine, codeine, papaverine, and thebaine, and their derivatives.
  • morphine noscapine
  • codeine codeine
  • papaverine papaverine
  • thebaine a pharmaceutically acceptable carrier
  • Huidobro et al Huidobro et al, J.
  • NMDA receptor antagonists are useful for inhibiting opioid tolerance and some of the symptoms of opioid withdrawal.
  • the present invention is also directed to the administration of the compounds described herein to inhibit opiate tolerance and to treat or ameliorate the symptoms of opiate withdrawal by blocking the glycine co-agonist site associated with the NMDA receptor.
  • the compounds of the present invention Eire also expected to show potent activity in vivo after intraperitoneal injection suggesting that these compounds can penetrate the blood/brain barrier and are systemically bioavailable.
  • the present invention is directed to compounds having preferred binding to a particular subtype NMDA receptor and, low binding to other sites such as dopamine and other catecholamine receptors, and ⁇ sites. According to the present invention, those compounds having preferred binding to a particular subtype NMDA receptor and, low binding to other sites such as dopamine and other catecholamine receptors, and ⁇ sites. According to the present invention, those compounds having preferred binding to a particular subtype NMDA receptor and, low binding to other sites such as dopamine and other catecholamine receptors, and ⁇ sites. According to the present invention, those compounds having preferred binding to a particular compounds having preferred binding to a particular subtype NMDA receptor and, low binding to other sites such as dopamine and other catecholamine receptors, and ⁇ sites. According to the present invention, those compounds having preferred binding to a particular subtype NMDA receptor and, low binding to other sites such as dopamine and other catecholamine receptors, and ⁇ sites. According to the present invention, those compounds having preferred binding to a particular sub
  • NMDA subtype exhibit an IC 50 of about 100 ⁇ M or less in an NMDA subunit binding assay (see the Examples).
  • the compounds of the present invention exhibit an IC 50 of 10 ⁇ M or less.
  • the compounds of the present invention exhibit an IC 50 of about 1.0 ⁇ M or less.
  • the efficacy of the NMDA subtype selective antagonists to inhibit glutamate neurotoxicity in rat brain cortex neuron cell culture system may be determined according to Choi. D.W., J. Neuroscience 7:357 (1987).
  • the anticonvulsant activity of the antagonists may be assessed in the audiogenic seizure model in DBA-2 mice as follows.
  • DBA-2 mice may be obtained from Jackson Laboratories, Bar Harbor, Maine. These mice at an age of ⁇ 27 days develop a tonic seizure within 5-10 seconds and die when they are exposed to a sound of 14 kHz (sinus wave) at 1 10 dB (Lonsdale, D., Dev. Pharmacol Ther. 4:2% (1982)).
  • Seizure protection is defined when animals injected with drug 30 minutes prior to sound exposure do not develop a seizure and do not die during a 1 minute exposure to the sound. 21 day old DBA-2 mice are used for all experiments.
  • Dose response curves are constructed by giving increasing doses of drug from 1 mg/kg to 100 mg/kg. Each dose group (or solvent control) consists of at least six animals.
  • the anticonvulsant activity of the antagonists may be evaluated in the Maximal Electroshock-induced Seizure (MES) test. Seizures are induced by application of current (50 mA, 60 pulses/sec, 0.8 sec pulse width, 1 sec duration, d.c.) through saline-coated corneal electrodes using a Ugo Basile
  • ECT device (Model 7801). Mice are restrained by gripping the loose skin on their dorsal surface, electrodes were held lightly against the two cornea, then current was applied and mice were observed for a period of up to 30 sec for the occurrence of a tonic hindlimb extensor response.
  • a tonic seizure is defined as a hindlimb extension in excess of 90 degrees from the plane of the body. Results are treated in a quantal manner.
  • the anticonvulsant efficacy of the antagonists may also be assessed in the pentylenetetrazol (PTZ)-induced seizure test according to WO94/00124 and U.S. 5,514,680.
  • the efficacy of NMDA antagonists to protect mice from NMDA-induced death may be assessed according to WO94/00124 and U.S. 5,514,680.
  • NMDA antagonists of the invention may be conducted on doses of the NMDA antagonists of the invention to determine the biological activity of the compounds both in normal gerbils and in animals exposed to 5 minutes of bilateral carotid occlusion. SeeWO94/00124 and U.S. 5,514,680.
  • NMDA receptors are critically involved in the development of persistent pain following nerve and tissue injury.
  • the effects of the NMDA receptor antagonists of the present invention on pain may be evaluated according to WO94/00124 and U.S. 5,514,680.
  • the compounds of the present invention are useful in treating headaches, in particular, migraine headaches.
  • migraine attack a sensory disturbance with unique changes of brain blood flow will result in the development of characteristic migraine auras. Since this unique phenomena has been replicated in animal experiments with cortical-spreading depression (CSD) of Lea ⁇ ,
  • CSD CSD is considered an important phenomena in the pathophysiology of migraine with aura (Tepley et al, In: Biomagnetism, eds. S. Williamson, L. Kaufmann, pp. 327-330, Plenum Press, New York (1990)).
  • the CSD is associated with the propagation (2 ⁇ 6 mm/s) of transient changes in electrical activity which relate to the failure of ion homeostasis in the brain, efflux of excitatory amino acids from the neurons and increased energy metabolism (Lauritzen, M., Acta Neurol. Scand. 76 (Suppl 113) :4-40 (1987)).
  • Subtype selective NMDA antagonists will be therapeutically useful for migraine headache because of their expected low side effects, their ability to cross blood brain barrier and their systemic bioavailability.
  • Bladder activity is controlled by parasympathetic pregnaglionic neurons in the sacral spinal cord (DeGroat et al, J. Auton. Nerv. Sys. 3:135-160 (1981)).
  • NMDA receptors in the spinal cord are located at sacral level, including those areas that putatively contain bladder parasympathetic pregnaglionic neurons (Shaw et al, Brain Research 559:164-168 (1991)). Because NMDA receptors are excitatory in nature, pharmacological blockade of these receptors would suppress bladder activity. It has been shown that the noncompetitive NMDA receptor antagonist MK801 increased the frequency of micturition in rats (Vera and Nadelhaft, Neuroscience Letters 134: 135- 138 (1991)).
  • Non-competitive NMDA receptor antagonist M 801 has been shown to be effective in a variety of animal models of anxiety which are highly predictive ofhuman anxiety (Clineschmidt, B.V. et al, Drug Dev. Res. 2:147-163 (1982)).
  • NMDA receptor glycine site antagonists are shown to be effective in the rat protentiated startle test (Anthony, E.W., Eur. J. Pharmacol 250:317-324 (1993)) as well as several other animal anxiolytic models (Winslow, J. et al, Eur.
  • Glycine site antagonists (+) HA-966 and 5,7-dichlorokynurenic acid were found to selectively antagonize d-amphetamine induced stimulation when injected into rat nucleus accumbens but not in striatum (Hutson, P.H. et al, Br.
  • the anxiolytic activity of any particular compound described herein may be determined by use of any of the recognized animal models for anxiety.
  • a preferred model is described by Jones, B.J. et al, Br. J. Pharmacol. 93:985-993 (1988). It has been shown that in an animal model of Parkinson's disease — MPP + or methamphetamine-induced damage to dopaminergic neurons — can be inhibited by NMDA receptor antagonists (Rojas et al, Drug Dev. Res. 29:222-226 (1993); and Sonsalla et al. Science 2 3:398-400 (1989). In addition, NMDA receptor antagonists have been shown to inhibit haloperidol-induced catalepsy (Schmidt, W.J.
  • compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is with the skill of the art.
  • the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for psychosis or anxiety disorders, e.g., generalized anxiety disorder, phobic disorders, obsessional compulsive disorder, panic disorder, and post traumatic stress disorders.
  • a suitable intramuscular dose would be about
  • the pharmaceutical compositions of the invention may comprise the compounds of the present invention at a unit dose level of about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1-4 times per day.
  • the compounds of the invention When used to treat chronic pain, to induce anesthesia, or to treat or prevent glaucoma, migraine headache, urinary incontinence, or opiate tolerance or withdrawal, the compounds of the invention may be administered at a unit dosage level of from about 0.01 to about 50mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1 -4 times per day.
  • a unit dosage level of from about 0.01 to about 50mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1 -4 times per day.
  • the exact treatment level will depend upon the case history of the animal, e.g., human being, that is treated. The precise treatment level can be determined by one of ordinary skill in the art without undue experimentation.
  • the unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound.
  • the unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.
  • the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient.
  • non-toxic pharmaceutically acceptable salts of the compounds of the present invention are also included within the scope of the present invention.
  • Acid addition salts are formed by mixing a solution of the particular NMDA subunit selective antagonist or agonist of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
  • Basic salts are formed by mixing a solution of the particular haloperidol analog of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
  • compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
  • animals are mammals, e.g., humans, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, marmitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, marmitol or sorbitol
  • cellulose preparations and/or calcium phosphates for example tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and or dextran.
  • the suspension may also contain stabilizers.
  • NMDA ligands of the present invention may be used to characterize the NMDA subunits and their distribution.
  • Particularly preferred NMDA subunit selective antagonists and agonists of the present invention which may be used for this purpose are isotopically radiolabelled derivatives, e.g. where one or more of the atoms are replaced with 3 H, "C, l4 C, ,5 N, or 18 F.
  • a fluorescent group Y may be employed. Examples of such groups include 4-nitrobenzofurazan:
  • the HBr salt was prepared as a white solid (0.12 g, 89%); mp 147- 149°C. 'H NMR (DMSO): 3.1-3.7 (m, 6H), 4.3-4.65 (m, 6H), 5.219 (bs, 4H), 6.9-7.1 (m,
  • A) 2,5-Dichlorocinnamic acid A mixture of 1 ,4-dichloro-2-iodobenzene (2.8 g, 10 mmol), acrylic acid (890 mg, 12 mmol), palladium(II)acetate (22 mg, 0.10 mmol) and Et 3 N (2.6 g, 26 mmol) in CH 3 CN (4 mL) was heated under N 2 in a sealed tube at 100°C for 1 h. The reaction was allowed to cool to rt and was diluted with HCl (10% in water, 250 mL).
  • 3-(4-Me.hylbenzyl)pyrroIidine was prepared from 4-methyIbenzyItriphenylphosphonium bromide (8.1 g, 0.018 mol) and
  • B)l-[2-(4-BenzyIoxyphenoxy)ethyl]-3-(4-methylbenzyl)pyrrolidine hydrochloride was prepared from a mixture of 2-(4-benzyloxyphenoxy)ethyl bromide (0.61 g, 2.0 mmol), 3-(4-methylbenzyl)pyrrolidine (0.35 g, 2.0 mmol), potassium carbonate (0.69 g, 5.0 mmol) in 30 mL of acetonitrile as a white solid (0.23 g, 26%), mp 148-151°C.
  • N-(2-(4-Hydroxyphenyl)ethyl)-4-phenylbutylamide 4-Phenylbutyric acid (1.0 g, 6.1 mmol), 1,3-dicyclohexylcarbodiimide (1.27 g, 6.2 mmol), 1-hydroxy- benzotriazole (837 mg, 6.2 mmol) and tyramine (849 mg, 6.2 mmol) in DMF (10 mL) was stirred at rt for 3 h then at 80°C for 24 h. The solid was removed by filtration. The solution was diluted with H 2 O (150 mL) and the yellow oil was extracted with CH 2 C1 2 (3 x 20 mL).
  • N-(2-(4-Hydroxyphenyl)ethyl)cinna_nide From cinnamic acid (1.0 g , 6.8 mmol), 1,3-dicyclohexylcarbodiimide (1.42 g, 6.9 mmol), 1 -hydroxy - benzotriazole (932 mg, 6.9 mmol) and tyramine (945 mg, 6.9 mmol) in DMF (10 mL) was obtained 1.62 g (89%) of the title compound as off-yellow solid, mp
  • N-(2-(4-Hydroxyphenyl)ethyl)-3-phenylpropylamine N-(2-(4-Hydroxyphenyl)ethyl)cinnamide (1.0 g, 3.7 mmol) was reduced by
  • N-(2-phenylethyI)-(3-(4-hydroxyphenyl)propylamide (1.0 g, 3.7 mmol) was reduced by LiAlH 4 (1.0 g, 26 mmol) and worked up to give the title compound as a yellow oil (800 mg, 84%) which solidified upon standing.
  • N-(2-(4-Hydroxyphenyl)e_hyl)cyanoace.amide A mixture of tyramine (5.00 g, 36.5 mmol) and ethyl cyanoacetate (4.10 g , 36.3 mmol) in DMF (50 mL) was stirred at 120°C for 4 h. The mixture was diluted with water (300 mL) and the solution was extracted with ethyl acetate (3 x 100 mL). Combined organic layers were washed with water (100 mL), dried over Na 2 SO 4 , and the solvent was removed using a rotor evaporator. A yellow solid was obtained.
  • 1,3-dicyclohexylcarbodiimide (0.99 g , 7.32 mmol) and 1-hydroxybenzotriazole (0.99 g , 7.32 mmol) in DMF (25 mL) was stirred at rt for 3 h.
  • Tyramine (1.00 g, 7.32 mmol) was added and the reaction mixture was stirred at 120°C for 12 h.
  • the precipitate was removed by filtration.
  • the solution was diluted with water (300 mL). The solid formed was separated by filtration and dissolved in ethyl acetate (250 mL), washed with acetic acid (2 N in water, 3 x 100 mL). dried over Na 2 SO 4 , and the volume reduced to 150 mL.
  • RNA Preparation of RNA.
  • cDNA clones encoding the NR1A, NR2A, NR2B, NR2C and NR2D rat NMDA receptor subunits were provided by Dr. P. H. Seeburg (see. Moriyoshi et al, Nature (Lond.) 354:31-31 (1991); Kutsuwada et al, Nature (Lond.) 355:36-41 (1992); Monyer et al, Science (Washington, D. C.)
  • the clones were transformed into appropriate host bacteria and plasmid preparations were made with conventional DNA purification techniques. A sample of each clone was linearized by restriction enzyme digestion and cRNA was synthesized with T3 RNA polymerase. The cRNA was diluted to 400 ng/ml and stored in 1 ml aliquots at -80°C until injection.
  • the Xenopus oocyte expression system Mature female Xenopus laevis were anaesthetized (20-40 min) using 0.15% 3-aminobenzoic acid ethyl ester (MS-222) and 2-4 ovarian lobes were surgically removed. Oocytes at developmental stages IV-VI (Dumont, J.N., J. Morphol 736:153-180 (1972)), were dissected from the ovary. Oocytes were micro-injected with 1 : 1 mixtures of cRNA:NR!A + NR2A, 2B, 2C or 2D; injecting ⁇ 2, 5, or 20 ng of RNA encoding each receptor subunit. NRl A encoding cRNA was injected alone at -20 ng. Oocytes were stored in Barth's medium containing (in mM): NaCl, 88;
  • Oocytes were defolliculated by treatment with collagenase (0.5 mg/ml Sigma Type I for 0.5-1 hr) (Miledi and Woodward, J. Physiol (Lond.) 416:601-621 (1989)). Electrical recordings were made using a conventional two-electrode voltage clamp (Dagan TEV-200) over periods ranging between 3-14 days following injection.
  • collagenase 0.5 mg/ml Sigma Type I for 0.5-1 hr
  • Electrical recordings were made using a conventional two-electrode voltage clamp (Dagan TEV-200) over periods ranging between 3-14 days following injection.
  • Oocytes were placed in a 0.1 ml recording chamber continuously perfused (5-15 ml min 1 ) with frog Ringer's solution containing (in mM): NaCl, 115; KC1, 2; CaCl 2 , 1.8; HEPES, 5; pH 7.4, or perfused by zero-Ca 2+ /Ba 2+ Ringer had the composition (in mM): NaCl. 1 15; KCl, 2; BaCl 2 , 1.8; HEPES, 5; pH 7.4. Drugs were applied by bath perfusion. Intraoocyte injections were made by pneumatic pressure-pulse ejection from micropipettes (Miledi and Parker, J.
  • Drugs The drugs were synthesized as described in the Examples above). Drugs were initially dissolved at concentrations of 10- 100 mM in DMSO. Dilutions were then made to generate a series of DMSO stock solutions over the range 10 mM to 100 mM. Working solutions were made by 1000-3000 fold dilution of stocks into Ringer. At these dilutions DMSO alone had no measurable effects on membrane current responses. DMSO stock solutions were stored for up to two weeks in the dark at 4°C without apparent reductions in potency. Ringer solutions of drugs were made up fresh each day of use.
  • the MES test for anticonvulsant activity was carried out as described infra.
  • the alpha 1 adrenoreceptor binding assay was carried out as described in
  • the membrane suspension was incubated for 45 min at room temperature in a total vol of 1ml with [ 3 H]-prazosin (final concentration 1.6 nM).
  • the incubation medium was immediately filtered through a GF/C glass fiber using a Brandel Cell Harvester followed by three, 3 ml washes with ice-cold buffer.
  • the filters were transferred to scintillation vials and 5 ml of scintillation cocktail was added, vials were shaken overnight and the radioactivity was counted by liquid scintillation spectroscopy.
  • the specific binding was determined by subtracting the non-specific binding in the presence of 10 uM phentolamine from the total.
  • Inhibition dose response curves were performed using increasing concentration of various compounds (5 nM-100 uM).

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Abstract

Cette invention a trait à des ligands du récepteur N-méthyl-D-aspartate (NMDA) sélectifs de sous-type et à leur utilisation dans le traitement ou la prévention de la dépopulation neuronale associée à un ictus, une ischémie, une lésion du système nerveux central, une hypoglycémie et à un acte chirurgical, ainsi que dans le traitement de maladies neurodégénérescentes, au nombre desquelles la maladie d'Alzheimer, la sclérose latérale amyotrophique, les maladies d'Huntington et de Parkinson ainsi que le syndrome de Down. Ces ligands sont également utilisés dans le traitement et la prévention des conséquences préjudiciables d'une stimulation excessive d'acides aminés excitateurs, le traitement de l'anxiété, de psychoses, de convulsions, de douleurs chroniques, du glaucome, de la rétinite à cytomégalovirus, de l'incontinence urinaire et pour le déclenchement de l'anesthésie ainsi que comme tonique cérébro-actif. Ces ligands sont, en outre, utilisés dans le traitement et la prévention de l'accoutumance opiacée et le traitement du sevrage des dépendances aux opiacés ainsi que pour le traitement et la prévention du déficit auditif provoqué par des aminoglycosides.
PCT/US1996/020086 1995-12-22 1996-12-20 Ligands du recepteur n-methyl-d-aspartate selectifs de sous-type WO1997023202A1 (fr)

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JP2017505779A (ja) * 2014-01-29 2017-02-23 ニューロポア セラピーズ インコーポレイテッド タンパク質凝集の阻害剤としてのヘテロアリールアミド
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US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
US11498896B2 (en) 2014-12-19 2022-11-15 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10874636B2 (en) * 2016-01-27 2020-12-29 Tasly Pharmaceutical Group Co., Ltd. Application of substituted cinnamamide derivatives in preparation of anti-anxiety medication
CN111065619A (zh) * 2017-08-29 2020-04-24 浙江海正药业股份有限公司 (E)-α,β-不饱和酰胺化合物及其制备方法和用途
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