WO2000001376A2 - Pharmaceutical compositions and their uses for treatment of demyelinating disorders - Google Patents
Pharmaceutical compositions and their uses for treatment of demyelinating disorders Download PDFInfo
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- WO2000001376A2 WO2000001376A2 PCT/GB1999/002112 GB9902112W WO0001376A2 WO 2000001376 A2 WO2000001376 A2 WO 2000001376A2 GB 9902112 W GB9902112 W GB 9902112W WO 0001376 A2 WO0001376 A2 WO 0001376A2
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- 0 *=CC(NC([C@@]1*2)=O)=C(C=I=CI)C=C1C2=O Chemical compound *=CC(NC([C@@]1*2)=O)=C(C=I=CI)C=C1C2=O 0.000 description 11
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates inter alia to the treatment of demyelinating disorders.
- the majority of excitatory synaptic responses in mammalian CNS are elicited by amino acids such as L-glutamate or L-aspartate and are mediated by four different receptor subtypes.
- Three of these receptors are coupled to ionophores and are known as the N-methyl-D-aspartate (NMDA), the AMPA ⁇ -amino-3-hydroxy-5-methyl-4- isoxazole-propionate), and the kainate receptors.
- NMDA N-methyl-D-aspartate
- AMPA ⁇ -amino-3-hydroxy-5-methyl-4- isoxazole-propionate the kainate receptors.
- these receptors will be in the form of a receptor complex including for example glutamate and/or agonist binding site(s), modulatory site(s) and an ion channel, and possibly also including other moieties interacting with the function of the channel.
- the fourth receptor subtype is linked to phosphoinositol metabolism and is known as the
- the NMDA receptor is coupled to high conductance channels permeable to Na + , K + , and Ca ⁇ + (McBain CJ, Mayer M (1994): N-Methyl-D-aspartic acid receptor structure and function, Physiol. Rev., 74:723-760).
- NMDA receptor It is modulated by glycine (coagonist) and polyamines (positive modulator) and is blocked in a use- and voltage dependent manner by Mg2+
- the functional NMDA receptor is thought to be formed as a pentameric subunit assembly consisting of subunit selection from NRl (eight isoforms) and NR2 (four isoforms) families (Hollmann M, Heinemann S (1994): Cloned glutamate receptors, Annu. Rev. Neurosci. 17:31-108).
- the type of subunits fo ⁇ ning the NMDA channel determine its biophysical properties and physiological function (Sch ⁇ pfer R, Monyer H, Sommer B, Wisden W, Sprengel R, Kuner T, Lomeli H, Herb A, Kohler M, Burnashev N (1994): Molecular biology of glutamate receptors, Prog. Neurobiol. 42:353-357).
- the AMPA and kainate receptors are permeable to Na + and K + (Hollmann and Heinemann, 1994 [supra]).
- AMPA receptor-dependent ion channel is formed from four different subunits designated as GluRl to GluR4 (in two alternative splice variants - flip and flop) in a tetrameric subunit assembly (Hollmann and Heinemann, 1994 [supra]; Rosenmund C, Stern-Bach Y, Stevens C (1998): The tetrameric structure of a glutamate receptor channel, Science 280:1596-1599).
- Pharmacological properties of AMPA receptor-dependent ion channels are determined by the selection of subunits. Channel assemblies lacking GluR2 subunits are permeable to Ca 2+ in addition to Na + - and K + -permeability (Hollmann and Heinemann, 1994 [supra]).
- Kainate receptors represent the third type of ionotropic glutamate receptors (E. A. Barnard, Ionotropic glutamate receptors: new types and new concepts. Trends Pharmacol. Sci. 18: 141-148, 1997).
- the kainate receptors are formed heterometrically by GluR5-7 and KA1-2 types of subunits (Y. Paas, The macro- and microarchitectures of the ligand-binding domain of glutamate receptors. Trends in Neurosci. 21, 117-125, 1998).
- kainate receptors By being activated (opened) and desensitized (closed) by glutamate, kainate receptors modulate a passive flow of Na+, K+ and to varying degree, Ca2+ ions across the cell membrane.
- kainate receptors mediate fast synaptic transmission in the nervous system and are involved in plasticity, transmission of sensory signals and in development (E. A. Barnard, ibid). Furthermore, kainate receptors are unevenly distributed in the brain and spinal cord of rodents and primates (J. M. Henley, Trends Pharmacol. Sci. 15, 182-190, 1994). Dysfunction of kainate receptors may contribute to pathogenesis of variety of neurological and psychiatric disorders (B. Meldrum and J. Garthwaite, Trends Pharmacol. Sci. 11, 379-387, 1990).
- the present inventors have now provided evidence in support of the involvement of glutamate in the pathogenesis of demyelinating disorders. They have established a link between neuronal demyelination and glutamate-mediated cell death using accepted animal models of a demyelinating disorder.
- the present invention represents a major advance over prior art methods in the treatment of demyelinating disorders.
- an inhibitor of the interaction of glutamate with the AMPA and/or kainate receptor complex in the manufacture of a medicament for treating a demyelinating disorder.
- inhibitor of the interaction of glutamate with the AMPA and/or kainate receptor complex is used herein to include moieties that bind to the AMPA and/or kainate receptor or to glutamate so as to prevent or reduce the binding of glutamate to its binding site on the AMPA and/or kainate receptor. Such moieties may bind in a competitive or non-competitive manner. They are referred to herein as "antagonists" of the binding of glutamate to the AMPA and/or kainate receptor. A skilled person is able to identify substances that may be useful as antagonists of the present invention by binding studies.
- the AMPA and/or kainate receptor a part thereof including said glutamate binding site, or a glutamate molecule can be used to screen for substances that bind thereto, preferably in a highly specific manner.
- binding studies can be part of a screening program for identifying or designing potential therapeutic agents.
- a skilled person could identify inhibitors of the interaction of glutamate with the AMPA and/or kainate receptor complex using, for example, in vitro calcium ion-increase assays or the whole cell configuration of the patch clamp technique.
- Cells expressing the AMPA receptor complex could be obtained, for example, from dissociated cortical or hippocampal cells.
- Cells expressing the kainate receptor complex could be obtained, for example, from dissociated dorsal root ganglion cells. Inhibition of the interaction of agonists, for example glutamate, AMPA or kainate, of the AMPA and/or kainate receptor complex could be assayed by incubation of the agonist with and without antagonist and the cellular response (eg change in intra-cellular calcium ion concentration or change in membrane potential) measured.
- agonists for example glutamate, AMPA or kainate
- the cellular response eg change in intra-cellular calcium ion concentration or change in membrane potential
- inhibitor of the interaction of glutamate with the AMPA and/or kainate receptor complex also includes moieties that prevent a signal being transmitted that would otherwise occur when glutamate binds to the AMPA and/or kainate receptor.
- moieties are AMPA and/or kainate receptor channel blockers.
- AMPA and/or kainate receptor channel blocker is used herein to refer to moieties that reduce the permeability of ion channels associated with the AMPA and/or kainate receptor in vivo (preferably to Na + ,K + and/or Ca 2+ ions).
- Antagonists are within the scope of the present invention.
- Antagonists are within the scope of the present invention.
- the antagonists of the present invention include L-glutamate derivatives such as e.g. L-glutamic acid diethylester, ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate derivatives such e.g., a-amino-3-hydroxy-5-tert-buthyl-4-isoxazolepropionic acid, quinoline, quinoxaline, quinoxalinedione, quinazolinone, phenylpyridazino-indole- 1,4-dione, indeno-pyrazinone, indeno-pyrazine-carboxylic acid, indolo-pyrazinone, imidazo-pyrazinone, amino-phenyl-acetic acid, benzothiadiazine, 4-hydroxypyrrolone, 4-hydroxy-pyrrolo-pyridazinone, quinolone, amino alkanoic acid, isatin, nitroquinolone, phenyl-azolophthal
- n and m independently are 0, 1, 2 or 3;
- R 1 is selected from the group consisting of hydrogen and R 2 ;
- R 2 is selected from the group consisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, Ci to C 6 lower alkyl, C 7 to C 12 higher alkyl, aryl and aralkyl, wherein if R 2 is hydrogen, R 1 is not hydrogen;
- R 3 is selected from the group consisting of hydrogen and Ci to C 6 lower alkyl; the stereoisomers thereof in their resolved or racemic form, and pharmaceutically acceptable salts thereof.
- R 1 represents (la) wherein X represents N or R 8 C,
- R 6 represents H or alkyl, and
- R 7 and R 8 represent each H, alkyl, nitro or phenyl, or alternatively R 7 and R 8 are combined together to represent butadienylene or 1,4-butylene;
- R and R represent each H, F, cyano, acyl, nitro, alkyl, morpholino or R 1 ;
- R 4 and R 5 represent each H, hydroxy, alkyl, cycloalkyl, heterocycle, phenyl or Y-substituted alkyl;
- Y represents hydroxy, acyloxy, F- substituted methyl, cycloalkyl, tetrahydrofuryl, carboxyl, alkoxy carbonyl or NR 9 R 10 ;
- Quinoxaline compounds represented by formula (I) or (II), wherein R 1 and R 2 are independently hydrogen, C ⁇ -6 -alkyl, halogen, NO 2 , NH 2 , CN, CF 3 , SO 2 NR 4 R 5 wherein R 4 and R 5 are independently hydrogen or C ⁇ - 6 -alkyl, or COR 6 wherein R 6 is C ⁇ - 6 -alkyl; and R 3 is hydrogen, C ⁇ - 6 -alkyl or CF 3 , and compositions thereof.
- R 1 and R 2 are independently hydrogen, C ⁇ -6 -alkyl, halogen, NO 2 , NH 2 , CN, CF 3 , SO 2 NR 4 R 5 wherein R 4 and R 5 are independently hydrogen or C ⁇ - 6 -alkyl, or COR 6 wherein R 6 is C ⁇ - 6 -alkyl; and R 3 is hydrogen, C ⁇ - 6 -alkyl or CF 3 , and compositions thereof.
- R 1 is hydrogen, C ⁇ -C 6 alkyl, substituted by hydroxyl or carboxyl
- R 2 is hydrogen, C]-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, a chlorine, fluorine or bromine atom, a trihalogen methyl, cyano, or nitro group or SO 2 C ⁇ C 4 alkyl
- R 3 is COOH or a radical hydrolysable to form the carboxyl group
- n is 1 or 2.
- R 1 to R 4 have the meanings given in the description in the corresponding patent (WO 97-34896) and R 5 is a five-member optionally substituted heterocycle with between 1 and 4 nitrogen atoms or with 1 or 2 nitrogen atoms and an oxygen or sulphur atom, or an R 6 -substituted phenyl ring.
- A is the group of the formula:
- the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom (s) and double bond, and all of such isomers and a mixture thereof are included. It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
- R 1 and R 2 are identical or different and hydrogen, C ⁇ -C 6 -alkyl, nitro, halogen, cyano, the group -NR 8 R 9 , -O-C ⁇ -4- alkyl, -CF 3 , OH or Ci- ⁇ -alkanoyloxy;
- R 3 and R 4 are identical or different and hydrogen, halogen, C ⁇ -C 6 -alkoxy, hydroxy, thiocyanate, d-C ⁇ -alkylthio, cyano, COOR 12 , PO 3 R 13 R 14 , C]-C 6 -alkanoyl, C ⁇ -C 6 -alkanoyloxy, eventually with -C 4 - alkoxy or phenyl-substituted C -6 -alkynyl, eventually with or phenyl- substituted C 2- 6-alkenyl, eventually with halogen, hydroxy, C ⁇ -C 6 -alk
- R 1 stands for hydrogen, branched or linear C ⁇ -5 -alkyl or a phenyl, pyridyl or thienyl group possibly substituted by one to two chlorine atoms, a trifluoromethyl, a nitrodioxy or a methylene dioxy group
- R 2 stands for hydrogen, C ⁇ -5 -alkyl or C 3-8 -dialkylaminoalkyl
- R 3 stands for a chlorine or bromine atom, a trifluoromethyl, cyano or nitro group
- A stands for a five- membered heterocycle with 1-4 nitrogen atoms or 1-2 nitrogen atoms and one oxygen or sulphur atom possible substituted by R 4 and R 5 ; the radicals R 4 and R 5 , that may be the same or different, stand for hydrogen, C 1-5 -alkyl, C ⁇ -5 -hydroxyethyl, phenyl, phenyl
- R 1 is hydrogen, alkyl or benzyl
- X is O or NOR 2 , wherein R 2 is hydrogen, alkyl or benzyl
- Y is N-R 4 wherein R 4 is hydrogen, OH or alkyl
- n is 0 or 1
- R 6 is phenyl which is substituted one or more times with substituents selected from the group consisting of SO 2 NR'R", CONR'R", and COR'" wherein R' and R" each independently are hydrogen, alkyl, or -(CH 2 ) P -W, wherein p is 0, 1, 2, 3, 4, 5, or 6, and W is hydroxy, amino, alkoxycarbonyl, or phenyl which may be substituted one or more times with substituents selected from the group consisting or halogen, CF 3 , NO 2 , amino, alkyl, alkoxy or methylenedioxy; or wherein R' and R" together are (CH
- R 1 and R 2 are a 5- or 6-membered N- containing heterocyclic ring optionally substituted, or a fused ring system comprising a 5- or 6-membered N-containing heterocyclic ring optionally substituted; and the other of R 1 and R 2 is H, alkyl, alkoxy, halogen, NO 2 , NH 2 , CN, CF 3 , COC ⁇ -6 -alkyl or SO 2 NR'R", wherein R' and R" are independently H or alkyl and X is O or S; and pharmaceutically acceptable salts thereof.
- the present invention relates to the use of derivatives of the 2H-l,2,4-benzothiadiazrn- l,l-dioxide-3-carboxylic acid of the above formula or the salts of such compound or of intermediates of such compound for the preparation of AMPA receptor antagonists and to new componds of the formula (I), their preparation and the medications in which they are found.
- Ri is carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH 2 , -CO-NH-alk, -CO-N(alk) 2 , -CO-NHOH, -CO-N(alk)OH, -CO-NH-O-R 5 , -CO-N(alk)-OR 5 or a group that may be converted into a carboxyl moiety in vivo;
- R 2 , R 3 and t are the same or different and are selected from the group consisting of hydrogen, halogen or alkyl;
- R 5 is alkyl or phenylalkyl.
- alk refers to an alkyl or alkylene group.
- the compounds of the present invention include the tautomers of the compounds of the formula (I).
- the groups, convertible into carboxyl moieties in vivo include -CO-R ⁇ , in which R ⁇ s is O-alk-R 7 , -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R 7 , -O-alk-OH, -O-alk- O-alk, -O-alk-S-alk, -O-alk-O-R 7 , -O-alk-S-R 7 , -O-alk-COOH, -O-alk-COOalk, -O- alk-NRsR 9 , -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-
- R is alkyl or alkylene
- R 7 phenyl, Rs and R 9 are the same or different and are selected from the group consisting of hydrogen, alkyl, phenyl or phenylalkyl or form with the oxygen atom they are attached to a piperidinyl, morpholinyl or pyrrolidinyl ring.
- the halogen atoms are selected from the following: fluoride, chloride, bromide or iodide.
- the alkyl, alkoxy and alkylene groups are a straight or branched alkyl chain having one to six carbon atom, and preferably one to four carbon atoms.
- R 2 , R 3 and R 4 are hydrogen and Ri is carboxy, alkoxycarbonyl, -CO-NH 2 or -CO-NH-alk, or R a chloride or bromide atom
- R 2 and R 3 are hydrogen and Ri is carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk, or R 3 a chloride or bromide atom
- R 2 and R» are hydrogen and Ri is carboxy, alkoxycarbonyl, -CO-NH 2 or -CO-NH-alk.
- the present invention include also other compounds of the formula (I), their salts or intermediates of their salts.
- Ri is carboxy, alokoxycarbonyl, tetrazolyl, -CO-NH 2 , -CO- NH-alk, -CO-N(alk) 2 , -CO-NHOH, -CO-N(alk)OH, CO-NH-O-R 5 , CO-N(alk)-OR 5 or -CO-R6, in which Re is -O-alk-R 7 , -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O- CO-R 7 , -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R 7 , -O-alk-S-R 7 , -O-alk- COOH, -O-alk-COOalk, -O-alk-NR 8 R 9 , -NH-NH-CH
- alk refers to an alkyl or alkylene group.
- the present invention does not include the compounds of the formula (I) in which either R 2 , R 3 and R4 are hydrogen and Ri is carboxy, alkoxycarbonyl, -CO-NH 2 or -CO-NH-alk, or R 4 a chloride or bromide atom, R 2 and R 3 are hydrogen and Ri is carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk, or R 3 a chloride or bromide atom, R 2 and R4 are hydrogen and Ri is carboxy, alkoxycarbonyl, -CO-NH 2 or -CO-NH-alk .
- R 2 , R 3 , R 4 and R 5 represents hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -COR a , -CO 2 R a or -CONR a R b , and the other three of R 2 , R 3 , R 4 and R 5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -NR a R b , -NR a
- R 6 -alkyl or R 5 and R 6 or R 7 and R 8 represent a condensated benzene ring
- R 2 stands for -CO-R 3 , or -PO-XY and is present once or twice in the same or a different form.
- R ⁇ and R 2 are independently hydrogen, alkyl, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, arr noalkyl or thioalkyl; or R and R 2 are taken together to form a carbocycle or heterocycle; R 3 is hydrogen, alkyl, haloalkyl, aryl, fused aryl, a carbocychc group, a heterocyclic group, a heteroaryl group, alkenyl
- R is phenyl of the formula Ph or a five or six membered heterocycle, wherein said 6- membered heterocycle has the formula
- N is nitrogen; wherein said ring positions “K”, “L” and “M” may be independently selected from carbon or nitrogen, with the proviso that i) only one of “K, “L” or “M” can be nitrogen and ii) when “K", “L” or “M” is nitrogen then its respective R 15 , R 16 or R 17 is absent; wherein said five membered heterocycle has the formula
- R 3 is hydrogen, halo, -CN, -NO 2 , CF 3 , (C ⁇ -C 6 )alkyl or (d-C 6 )alkoxy;
- R 5 is hydrogen, (C ⁇ -C 6 )alkyl, halo, CF 3 , (d-C 6 )alkoxy or (C ⁇ -C 6 )alkylthiol;
- R 6 is hydrogen or halo;
- R 7 is hydrogen or halo;
- R 8 is hydrogen or halo;
- R 9 is hydrogen, halo, CF 3 , (Ci- C 6 )alkyl optionally substituted with one to three halogen atoms, (d-C 6 )alkoxy optionally substituted with one to three halogen atoms, (C ⁇ -C 6 )alkylthiol, arnino- CH 2 ) S -, (C 1 -C 6 )alkyl-NH-(CH 2 )s-, di(
- Z is a carbocychc fused ring having 5 to 7 carbon atoms
- X and Y are independently hydrogen, halogen, nitro, cyano, -CF 3 , -COOH, -CONR ⁇ 2 , -COR 3 , -SO 2 R , imidazolyl or lmidazolidinyl, wherein R and R are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, aralkyl or join together to form a heterocyclic ring and wherein R 3 is alkyl, haloalkyl, cycloalkyl, aryl or aralkyl;
- A is a bond, O, S, NR 4 , NR 4 CO, NR 4 CS, CONR 4 , CSNR 4 , CO or CS wherein R 4 is hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl,
- m and n are independently 0, 1, and 2, provided that (i) m is not 0 when A is 0, CN, tetrazole or CO, except when A is CO and B is a heterocyclic or when A is 0 and B is COR 5 , PO 3 R 5 2 or SO 2 R 5 ; (ii) m is not 0 or 1 when A is NR 4 , except when B is COR 5 , PO 3 R 5 2 or SO 2 R 5 ; and (iii) n is not ) when A is 0, S, NR 4 , CONR 4 and B is NR J R 2 , CN, COR 5 , or PO 3 R 5 2 .
- alk refers to an alkyl or alkylene group.
- Ar refers to a phenyl group.
- Het refers to a heterocycle which is mono or poly saturated or unsaturated with four to nine carbon atoms and one or more heteroatom (O, S, N) which may be substituted with one or more of the following: alkyl, phenyl, or phenylalkyl.
- the alkyl or aikylene groups are a straight or branched alkyl chain having one to six carbon atom
- the acyl groups have two to four carbon atoms
- the cycloalkyl groups have three to six carbon atoms
- the halogen are of the following: fluoride, chloride, bromide, or iodide.
- Het is one of the following rings: pyrrolyl, pyridyl, pyrimidinyl, imidazolinyl, thiazolyl, oxazolinyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl.
- rings can possibly be substituted by one or more of the following: alkyl, phenyl or phenylalkyl.
- the preferred substitutants are methyl, phenyl or benzyl.
- the compounds of the formula (I) in which R 7 is NO-alk, C(COOR 1 o)R2o, C(CONR 10 R 21 )R2o or CHR19 can exist as isomers (E and Z).
- the compounds of the present invention include the isomers E and Z and their mixtures.
- COORio can exist as tautomers (E and Z).
- the compounds of the present invention include the tautomers E and Z and their mixtures.
- the compounds of the present invention include the eniantomers and diastereoisomers of the compounds of the formula (I), in which R is C R 4 )Rs or CH- Re.
- alkyl Under alkyl one has to understand a linear or branched alkyl residue as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sek. butyl, pentyl, isopentyl or hexyl, which can be substituted by d-C 6 -alkoxy, halogen or d-C 6 -alkonyl. If there is a halogenated alkyl residue present, then it can be multiple halogenated or perhalogenated such as CF 3 . Under halogen one has to understand fluoride, chloride, bromide and iodide.
- the aryl- and hetaryl residue R 3 and R 4 can be single or multiple substituted with halogen, C -alkoxy or C ⁇ - 4 -alkyl.
- the alyl residue can contain 6-10 carbon atoms whereby phenyl is preferred.
- cycloalkyl one means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, respectively, particularly C 3 -5-cycloalkyl.
- alkanoyl residues are alphatic carbonic acid residues such as formyl, acetyl, propionyl, butanoyl,caproyl, valeroyl, trimethylacetyl and others. If A together with the nitrogen atom forms a 5-membered heterocycle, then is in position 4 an exocyclic double bond.
- heteroaromatics with 1-3 nitrogen atoms whereby for example A has the following meaning:
- Dihydro-2,3-benzodiazepine derivatives having general formula (I) wherein R is hydrogen or C ⁇ -C ⁇ 0 alkyl;
- X is an aromatic moiety selected from phenyl, thienyl, furyl, pyridyl, imidazolyl, benzimidazolyl, benzothiazolyl and phthalazinyl which is unsubstituted or substituted with one or more moieties chosen from the group consisting of halogen, hydroxy, cyano, nitro, C]-C 6 alkyl, , Q-Ce cycloalkyl, d-C 4 alkoxy, carboxy, d-C 6 alkoxycarbonyl, acetyl, formyl, carboxymethyl, hydroxymethyl, amino, aminomethyl, methylenedioxy and trifluoromethyl; and "Aryl” represents p-nitrophenyl, p-aminophenyl or p-(protected amino) phenyl;
- R 4 eventually substituted C ⁇ -C6-alkyl
- R 5 hydrogen or eventually substituted d-Ce- alkyl
- R 6 and R 7 are identical or different and hydrogen, eventually substituted C ⁇ -C 6 . alkyl or eventually substituted aryl
- R 8 and R 9 are identical or different and hydrogen, C ⁇ -C 6 -alkyl or the group
- R 10 hydrogen, eventually substituted d-C 6 -alkyl, eventually substituted aryl, the group -NR 1 'R 12 , -0-Ci.e-alkyl, C 3-7 -cycloalkyl, C 2 . 6 -alkenyl or -O-C 3-7 -cycloalkyl;
- R 1 and R 12 are identical or different and hydrogen, eventually substituted C ⁇ -C 6 -alkyl or eventually substituted aryl;
- R 13 Ci-Ce-alkyl and n stands for 1, 2 or 3; means as well as their isomers and pharmaceutically acceptable salts thereof.
- Heterocyclic compounds (I) in WO 95-21842 as shown in below:
- R 1 , R 2 , R 3 are the same or independently are H, alkyl, alkoxy, halogen, NO , NH 2 , CF 3 , CN, SO2CH3, SO2CF3, SO2NR'R" or a 5- or 6- membered N- containing heterocyclic ring, optionally substituted, and R', R" are independently H or alkyl; and R 4 is H or CH 2 - R 6 ; and R 6 is H, halogen, POR'"R"", NR 7 R 8 or a 5- or 6-membered N-containing heterocyclic ring optionally substituted, and R'", R"" are independently hydroxy or alkoxy; and R , R are the same or independently are H, (a) or alkyl optionally substituted; and n is 1, 2, or 3; (b) CH 2 OH, CHNOH, CN, (c) or (d) and R
- R 7 is oxygen, or NOH, NO-alk-COORio, NO-alk, CHR ⁇ 9 , R 10 , C(COOR 10 ) or C(CONR ⁇ oR 2 ⁇ )R2o
- Rs is hydrogen, alkyl, -alk-COORio, -a ⁇ k-NR ⁇ oR ⁇ , -alk-Het or phenylalkyl in which the phenyl group may be substituted by one or more of the following: halogen, alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH 2 , -COORio, and -alk-COORio, R9 is hydrogen or alkyl, R ]0 is hydrogen or alkyl, Ru is hydrogen, alkyl, (the term C ⁇ -C 9 alkyl represents a straight or branched alkyl chain having one to nine carbon atoms), alkoxy, -alk-COORio, -alk-
- alk refers to an alkyl or alkylene moiety.
- Ar refers to a phenyl moiety.
- Het refers to a heterocycle which is mono- or poly- saturated or unsaturated with one to nine carbon atoms and one or more heteroatom (O, S, N) which may be substituted with one or more of the following: alkyl, phenyl, or phenylalkyl.
- the alkyl, alkylene or alkoxy moieties are a straight or branched chain having one to six carbon atom
- the acyl moieties have two to four carbon atoms
- the cycloalkyl moieties have three to six carbon atoms
- the halogen atoms are selected from the following: fluoride, chloride, bromide or iodide.
- Het is one of the followingrings: pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, oxazolinyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl, pyrrolidinyl, piperazinyl, thienyl, furyl, azetidinyl and imidazolinyl.
- Each of these rings may be substituted by one or more of the following: alkyl, phenyl or phenylalkyl.
- the preferred substituents are methyl, phenyl or benzyl.
- the preferred polyfluoroalkoxy groups are the trifluoromethoxy groups.
- the compounds of the formula (I) in which R 7 is NO-alk, C(COORio)R2o, C(CONR ⁇ oR 2 j)R 20 or CHR ⁇ 9 can exist as isomers (E and Z).
- the compounds of the present invention include the isomers E and Z and their mixtures.
- the compounds of the formula (I), in which R is CH-Re and Re is -CO- COORio can exist as tautomers (E and Z).
- the compounds of the present invention include the tautomers E and Z and their mixtures.
- the compounds of the present invention include the eniantomers and diastereoisomers of the compounds of the formula (I), in which R is C(R 4 )R 5 or CH- Re-
- alk refers to an alkyl or alkylene moiety.
- alk' refers to an alkyl moiety.
- Het refers to a heterocycle which is mono- or poly-saturated or unsaturated with four to nine carbon atoms and one or more heteroatom (O, S, N).
- Het refers to a heterocycle which is mono- or poly-saturated or unsaturated with one to three carbon atoms and one or more heteroatom (O, S, N)may be substituted with one or - or poly- saturated or insaturated with four to nine carbon atoms and one or more heteroatom (O, S, N)may be substituted with one or more of the following: alkyl, phenyl, or phenylalkyl.
- R is CHRe
- Re is alk-Het" in which alk is alkyl (Ci) and Het" is not 2-imidazol.
- the alkyl or alkylene moieties are a straight or branched chain having one to six carbon atom
- the cycloalkyl moieties have three to six carbon atoms
- the halogen atoms are selected from the following: fluoride, chloride, bromide, or iodide.
- Het is one of the following cycles: pyrrolyl, pyridyl, pyriim ' dinyl, morpholinyl, pyrazinyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl and furyl.
- Het is one of the following: pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl, oxazolyl, pyrrolidinyl, azetidinyl, piperazinyl, piperidinyl, thienyl, oxazolinyl, furyl and imidazolinyl.
- Each of these rings may be substituted by one or more of the following: alkyl, phenyl or phenylalkyl. The preferred substitutants are methyl, phenyl or benzyl.
- the prefered polyfluoroalkoxy groups are the trifluoromethoxy groups.
- the compounds of the formula (I) in which R 3 is NO-alk, C(COOR 7 )R ⁇ 6 , C(CONR 7 R 15 )R ⁇ e or CHR 10 can exist as isomers (E and Z).
- the compounds of the present invention include the isomers E and Z and their mixtures.
- COOR 7 can exist as tautomers (E and Z).
- the compounds of the present invention include the tautomers E and Z and their mixtures.
- the compounds of the present invention include the eniantomers and diastereoisomers of the compounds of the formula (I), in which R is C(R 4 )R 5 or CH- Re.
- the preferred compounds are those with Ri in position -7 or -8.
- alk refers to an alkyl or alkylene group.
- Ar refers to a phenyl group.
- Het refers to a heterocycle which is mono or poly saturated or unsaturated with four to nine carbon atoms and one or more heteroatom (O, S, N) may be substituted with one or more of the following: alkyl, phenyl, or phenylalkyl.
- the alkyl or alkylene groups are a straight or branched alkyl chain having one to six carbon atom
- the acyl groups have two to four carbon atoms
- the cycloalkyl groups have three to six carbon atoms
- the halogen are of the following: fluoride, chloride, bromide, or iodide.
- Het is one of the following rings: pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, oxazolinyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl, furyl, azetidinyl, imidazolinyl.
- Each of these rings may be substituted by one or more of the following: alkyl, phenyl or phenylalkyl.
- the preferred substituents are methyl, phenyl or benzyl.
- the preferred polyfluoroalkoxy groups are the trifluoromethoxy groups.
- the compounds of the present invention include the isomers E and Z and their mixtures.
- the compounds of the formula (I), in which R is CH-Re and R is -CO- COORio can exist as tautomers (E and Z).
- the compounds of the present invention include the tautomers E and Z and their mixtures.
- the compounds of the present invention include the enantiomers and diastereoisomers of the compounds of the formula (I), in which R is C ⁇ Rs or CH-Re.
- R is (d -6 ) alkyl or phenyl optionally mono-, di- or trisubstituted by halogen, (C ⁇ - )alkyl, (C ⁇ -4 )alkoxy, nitro, trifluoromethyl, amino, di(C ⁇ - )alkylamino, cyano, phenylsulfonyl or sulfonylamino,
- Ri and R 2 independently are hydrogen, hydroxy, (C ⁇ - 4 )alkyl, (C ⁇ -4 )alkoxy, (C 2-5 )alkenyl, halogen, trifluoromethyl, mtro, amino, (C ⁇ - )alkylamino, benzyloxy, benzoylamino, carboxy, cyano, (C ⁇ - )alkoxy-carbonyl, (C ⁇ - )alkylsulfonyl, phenylsulfonyl, sulfonyla
- Alkyl and alkoxy groups and moieties in the compounds of formula I may be straight - or branched-chained.
- Halogen means fluorine, chlorine, bromine or iodine.
- the compounds of formula I may form cationic salts, e.g. alkali metal or ammonium salts deriving from the sulfonamido group or when a carboxyl group is present. Depending on the nature of the substituents defined above, the compounds of formula I may also form acid addition salts.
- the tautomeric forms of the compounds of formula I are also embraced. (36) 3,4-Dihydro-2H-l,2,4-benzothiadiazine l,l-dioxide-3-carboxylic acid derivatives (I) in WO 95-07899 as shown in below:
- R is an oxygen or sulphur atom or an NH or N-alk radical
- Non-competitive AMPA antagonistic compounds of the formula I wherein R 1 and R represent, independently, a hydrogen, a halo, a C M alkyl group, a C M alkoxy group, a nitro group, a trifluoromethyl group or a group of the formula -NR 8 R 9 , wherein R 8 and R 9 stand, independently, for a hydrogen, a C alkyl group or a group of the formula -COR 10 , wherein R 10 is a hydrogen, a C ⁇ .
- R 11 and R 12 mean, independently, a hydrogen, a C M alkyl group, a C 3-5 cycloalkyl group or a C 6 - ⁇ o aryl group
- R 3 represents a C M alkyl groups a C 3-5 cycloalkyl group or a group of the formula -CO-R 13 , wherein R 13 has the same definitions given in relation to R 10 , R 4 and c A 7
- R mean, independently, a hydrogen or a C ⁇ -3 alkyl group
- R and R are, independently, a hydrogen, a chloro or a bromo, with the provision that if one of R 6 and R 7 stands for a hydrogen, the other is different from hydrogen, as well as the isomers thereof and the acid addition salts of the compounds or the isomers.
- R and R independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR ⁇ -SOR a , -SO 2 R a , -SO 2 NR a R b , -NR a R b , -NR a COR b , - NR a CO 2 R b , -COR a , -CO 2 R a or -CONR a R b ; or R 1 and R 2 together represent the residue of a carbocychc or heterocyclic ring; R 3 and R 4 independently represent hydrogen, hydrocarbon, a heterocyclic group, trifluoromethyl, -OR c , -SR C , -SOR a , -SO 2 R ⁇ -SO 2 NR a R b , -COR a , -CO 2 R a or -CONR a R b , provided
- R 1 and R 2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -COR a , -CU2R a or -CONR a R b ; or R 1 and R 2 together represent the residue of a carbocychc or heterocyclic ring; R 3 , R 4 and R 5 independently represent hydrogen, hyclrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR a , -SOR a , -SO 2 R a
- R 1 and R 2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -COR a , -CO 2 R a or -CONR R b ; or R 1 and R 2 together represent the residue of a carbocychc or heterocyclic ring; R 3 , R 4 , R 5 and R 6 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR ⁇ -SOR a , -SO 2 R a , -SO
- Arylthioxaline derivatives of the formula (I) and its related salts wherein RI is hydrogen, halogen, or nitro, R2 is hydrogen, halogen, nitro, cyano, or trihalogenomethyl, R3 is hydrogen, halogen, or nitro, R4 is hydrogen, optionally substituted lower alkyl, or optionally substituted lower cycloalkyl, and Ar is optionally substituted aromatic heterocyclic ring having at least one nitrogen atom.
- the present invention relates to hydroxyquinoxalinedione derivatives of the above formula and its related salt, wherein RI is hydrogen or lower alkyl, and R2 is nitro or trifluoromethyl.
- R 3 is oxygen, NOH, NO-alk- COOK or CH-R-7
- R 4 is alkyl, -alk-Het or alk-Ar
- R 5 is alkyl, -alk-Ar, or C(R4 ) R 5 is cycloalkyl
- Re is hydroxy, alkyl, NR 8 R 9 , -alk-OH,-alk-NRs R 9 , -alk-Ar or -alk-Het
- R 7 is hydroxy, alkyl, phenyl, -alk-Ar, -alk-Ar
- R 1 is hydrogen, alkyl, or benzyl
- X is O or NOR 2 , wherein R 2 is hydrogen, alkyl or benzyl
- Y is N-R 4 wherein R 4 is hydrogen, OH or alkyl
- n is 0 or 1
- R 6 is phenyl, naphthyl, thienyl, pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen; CF 3 , NO 2 , amino, alkyl, alkoxy and phenyl;
- A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b.
- ring A a group of formula (i) or (ii) both optionally substituted by H, 1-6C alkyl, halo, CF 3 , (CH 2 ) n NH 2 , (1-6C alkyl)amino(CH 2 ) p , di(l-6C alkyl)amino(CH2)n, 1-6C alkoxy, 1-6C hydroxyalkyl, (1-6C alkyl)O(l-6C alkyl), CN, (1-6C alkyl)COO(l-6C alkyl), (1-6C alkyl)OCOO(l-6C alkyl), (1-6C alkyl)COO, OH, NO 2 , R 3 CO, R 4 OCO, di(l-6C alkyl)NCO, 1-6C cycloalkyl, R 4 NHCO or
- R 1 is hydrogen, C ⁇ - 6 -alkyl which may be branched, d -7 -cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, C ⁇ -6 -alkoxy, CH 2 CO 2
- R 2 is pyridyl or phenyl, both of which may be substituted one or more times preferably into the ortho and para positions with halogen, CF 3 , NO2, CN, phenyl, SO 2 NR"R “ wherein R " and R " independently are hydrogen, benzyl, or C ⁇ -6 -alkyl
- R 4 , R 5 independently are hydrogen, benzyl, or C ⁇ -6 -alky
- Dihydro-2,3-benzodiazepine derivatives represented by the formula I wherein R is methyl, X is acetyl and Aryl is p-nitrophenyl.
- R 1 is hydrogen, halogen, nitro or trihalomethyl
- R 2 is hydrogen, halogen, nitro, cyano, trihalomethyl, carbamoyl, carbomoyl substituted with lower alkyl, sulfamoyl, or sulfamoyl substituted with lower alkyl
- R 3 is hydrogen, nitro, or halogen
- R 4 is hydrogen, lower alkyl, substituted lower alkyl, lower cycloalkyl, or substituted lower cycloalkyl
- R 5 's are substituents independently selected from the group consisting of halogen, nitro, cyano, lower alkyl, carbamoyl, and carbamoyl substituted with lower alkyl
- n is an integer of 0 to 4.
- Heterocyclic dihydroxyquinoxaline compounds having the formula wherein R 1 is hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy, cycloalkoxy, or acyloxy; and R 5 , R 6 , R 7 and R 8 independently are hydrogen, NO 2 , halogen, CN, SO 2 NR'R', SO 2 R', CF3, or OR', wherein R' is hydrogen or C M -alkyl.
- Heterocyclic dihydroxyquinoxaline compounds having the formula wherein R is hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy, cycloalkoxy, or acyloxy; R 5 and R 6 together form a further fused ring, which may be substituted with hydrogen, halogen, or CN, and R 7 and R 8 independently are hydrogen, NO 2 , halogen, CN, SO2 NR'R', SO 2 R', CF 3 , or OR', wherein R' is hydrogen or C -alkyl; or R 7 and R 8 together form a further fused ring, which is substituted with hydrogen, halogen, or CN, and R 5 and R 6 independently are hydrogen, NO 2 , halogen, CN, SO 2 NR'R', SO 2 R', CF 3 , or OR', wherein R' is hydrogen or C M -alkyl.
- R 1 is C ⁇ .i2-alkyl, which may optionally be substituted by hydroxy, formyl, carboxy, carboxylic esters, amides or amines, C 3- s cycloalkyl, aryl, aralkyl; and wherein R 6 is hydrogen, halogen, CN, CF 3 , NO 2 , or OR', wherein R' is C M -alkyl and R 5 , R 7 and R 8 is hydrogen, provided R 6 is not CF 3 , OCH 3 , NO 2 , CL or Br when R 1 is CH 3 ; or R 6 and R 7 independently are NO2, halogen, CN, CF 3 , or OR', wherein R' is C M - lkyl and R 5 and R 8 are each hydrogen; or R 5 and R 6 together form a further fused aromatic ring, which may be substituted with halogen, NO , CN, CF 3 or OR', wherein R 6 is hydrogen, halogen, NO , CN,
- Heterocyclic dihydroxyquinoxaline compounds having the formula wherein R 1 is halogen, CN, CF 3 , ethynyl, or N 3 and R 2 is SO 2 C ⁇ -3 -alkyl, CF 3 , NO 2 , ethynyl, or CN.
- R 1 H or 1-4C alkyl
- n 0-1
- m 0-4
- R 2 H, 1-6C alkyl or phenyl (optionally mono- or di-substituted with 1-4C alkyl, OR 6 , NH 2 , NO 2 , NHCOR 6 , CN, CF 3 , OCF 3 , CO 2 R 6 , F, CI, Br, I, COR 6 or SO 2 R 6 );
- R3 F, CI, Br, I, 1-4C alkyl, OR 7 , COR 7 , NH 2 , NO 2 , NHCOR 7 , CF 3 , CN;
- R4, R5 H, 1-4C alkyl, 1- 4C alkoxy, CF 3 , OCF 3 , F, Br, I, NO , CN or an
- R9 H or 1-4C alkyl
- R H , 1-4C alkyl, phenyl, benzyl, pyridyl or benzhydryl
- R' H, 1-4C alkyl, Ph, pyridyl or 4-(R-substituted)-pi ⁇ eridin-l-yl
- Y O or N
- Z O or NH
- r 0- 4
- q 0-2
- the benzene rings in R 8 , R and R' are optionally mono- or di-substituted with NH 2 , OMe, OEt, CI, Br, OCF 3 , F, Me, Et, NO 2 , COOR 1 , CONHR 1 , CH 2 NHR 1 , CH 2 NHCOCF 3 , CH 2 NHCOMe, NHSO 2 Me, NHCOMe or NHCOCF 3 .
- R and R form, together with the adjacent nitrogen atom, a 6-membered saturated heterocyclic group containing optionally 1 or 2 additional nitrogen atoms and/or oxygen atoms (s), said ring optionally carrying a hydroxy or a hydroxy-lower alkyl group; and all of the possible mesomers, tautomeric forms and stereoisomers of the acid amides of the formula (I) and the mixtures thereof.
- R 1 -(CH 2 ) n -CR 2 H-(CH 2 ) m -Z;
- Q halo, OR 8 , NRV, SO 0 R n or COR 12 ; or aryl or heteroaryl (both optionally substituted);
- R 2 H or -(CH 2 ) q R 3 ;
- R 3 H, OH, 1-6C alkoxy or NR 19 R 20
- R 1 is hydrogen, an alkyl or an alkylaryl
- X and Y are independently hydrogen, halogen, nitro, cyano, trifluoromethyl, COOH, CONR 4 R 5 , SO 2 CF 3 , SO 2 R 4 , SONR 4 R 5 , alkyl, alkenyl, (CH 2 ) z CONR 4 R 5 , (CH 2 ) z COOR 4 , or NHCOR 4 , wherein R 4 and R 5 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl or alkylaryl, and z is an integer from 0 to 4; R 2 is alky COOR 3 , alkylamine, alkyquanidine, aryl, alkylaryl, COalkyl, COalkylaryl, CONR 3 alkyl, CONR 3 aryl, CONR 3 alkylaryl,
- -CO-alk- Ar 11 -CO-NH-Ar 11 , -CO-NH-alk-Ar 11 , -CO-Het, -CO-alk- Het, -CO-NH-Het, -CO-NH-alk-Het, -CO-NH 2 , -CO-NH-alk, -CO-N al ⁇ ahV, -CS- NH 2 , -CS-NH-alk, -CS-NH-Ar 11 , -CS-NH-Het, -alk-Het, -alk- NRe Rs, -alk- Ar 11 , -SO 2 -alk, S ⁇ 2 -Ar or -CO-cycloalkyl, where the cycloalkyl is optionally 2-substituted by a carboxy radical; or (b) a 2-pyrrolidine-5-one ring.
- R is a hydrogen atom or a -COOH or CH 2 OH radical
- Ri is a -CH-R 2 radical
- R 2 is a 3-dimethyl-lH-pyrazole-4-yl
- R is an alk-CN, -alk-COOH, alk-Het, alk- PO 3 H 2 or -alk-CO-NH- SO2R2 radical
- R2 is an alkyl or phenyl radical
- alk is an alkyl radical
- Het is a saturated or unsaturated mono- or polycyclic heterocyclic ring containing 1-9 carbon atoms and one or more heteroatoms selected from O, S and N, said heterocyclic ring optionally being substituted by one or more alkyl, phenyl or phenylalkyl radicals, with the proviso that when R is a hydrogen atom or a -COOH or - PO 3 H 2 radical,
- R is an alk-NH 2 or alk-NH-CO-R 5 radical
- R 2 is a -COOH or -COOalk radical
- R 3 is an alkyl, -alk-Ar or -alk-Het radical
- Rt is an NH 2 , -NH-alk, -N(alk)-alk', -NH-CO-alk, -NH-CO-Ar', -NH-CO-ALK-Ar', -NH-CO-Het, -NH-CO-alk-Het, -NH-CO-alk-COOH, -NH-CO-alk-COOalk', -alk- COOH, -alk-COOalk', --
- R is a hydrogen atom or a carboxy, alkoxycarbonyl, -CO-NRt R 5> -PO 3 H 2 or -CH 2 OH radical and Ri is an alk-NH 2 , -alk- NH-CO- R 3 , -alk-COORt, -alk-CO-NR 5 Re or -CO-NH-R 7 radical.
- R 1 is hydrogen, C MO alkyl, arylalkyl, alkoxycarbonyl, aryloxycarbonyl or acyl
- R 2 is hydrogen, Ci - C 6 alkyl, substituted alkyl cycloalkyl, or arylalkyl
- R 3 is a group of the formula
- R 4 is hydrogen, C M alkyl, CF 3 , phenyl, bromo, iodo, or chloro; or a pharmaceutically acceptable salt thereof.
- RI and R2 are selected from the group consisting of hydrogen, halogen, halomethyl, mtro, amino, alkoxy, hydroxyl, hydroxymethyl, CI to C6 lower alkyl and C7 to C12 higher alkyl, aryl, and aralkyl; and the pharmaceutically acceptable salts thereof.
- R is hydrogen, C ⁇ -8 -alkyl which may be branched, or cycloalkylmethyl; R 7 and R 8 are independently hydrogen, halogen, CF 3 , CN, NO , NH 2 , CM-alkyl or C M -alkoxy; and R 4 is hydrogen and R 5 is hydrogen or C ⁇ -7 alkyl; or R 4 and R 5 together signify (CH 2 ) classroom wherein n is an integer of 2-3.
- Indole-2,3-dione-3-oxime compound having the formula wherein R 1 is hydrogen, C ⁇ . 6 -alkyl which may be branched, C 3 .7 -cyclo-alkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, C ⁇ -6 -alkoxy, CH 2 CO 2 R ' wherein R is hydrogen or d.
- R 2 is (1) alkenyl of from two to six carbon atoms, preferably allyl, (2) alkynyl of from two to six carbons, preferably propargyl, (3) (CH 2 ) ⁇ -6 CO 2 H, (4) (CH 2 ) ⁇ -6 CONHR wherein R is d -6 alkyl, optionally branched; aryl which is phenyl optionally substituted by one or more of lower alkyl of from one to four carbons, halogen wherein halogen is fluoro, chloro, bromo, or iodo, trifluromenthyl, cyano, carboxy, alkoxycarbonyl wherein the alkoxy is of from one to four carbons, alkylthio wherein the al
- RI is (CH 2 ) consult- CR2H-(CH 2 ) m -Z and R5, R6, R7 and R8 together or independently are hydrogen, Cl- C6 alkyl, CF 3 , nitro, halogen, NR9R10, cyano, SO p Rll, SO 2 NR12R13, SO 3 H, SO3Ci-e-alkyl or OR14;
- R2 is hydrogen, or (CH 2 ) q -R3;
- R3 is hydrogen, OH, d -6 - alkoxy or NR15R16, and n, m and q are 0,1,2, or 3;
- Z is POXY, OPOXY, OR17, NR18R19, NH-COR20, NH-SO 2 R21, SO 2 R22, CO 2 R23, halogen, cyano or tetrazole;
- Rl l is hydrogen, C1-C6 alkyl, phenyl
- Isoquinolinyl-carboxylic acid compounds represented by the above formula wherein RI is hydrogen, C1-C10 alkyl, arylalkyl, alkoxycarbonyl, or acyl; R2 is hydrogen, Cl- C6 alkyl, substituted alkyl, cycloalkyl, or arylalkyl; R3 is CO 2 H, SO 3 H, CONHSO 2 R8, or a group of formula:
- R4 is hydrogen, C1-C4 alkyl, phenyl, or acyl;
- R5 is hydrogen, C1-C4 alkyl, CF 3 , phenyl, hydroxy, amino, bromo, iodo, or chloro;
- R6 is acyl;
- R7 is independently hydrogen, C1-C4 alkyl, phenyl, or substituted phenyl;
- R8 is C1-C4 alkyl or tetrazole- 5-yl; and n is 0, 1, or 2; provided that when Y is NR4, O, S, SO, or SO 2 , W is (CH 2 ) classroom
- Decahydroisoquinoline represented by the above formula wherein RI is hydrogen, Cl- C10 alkyl, arylalkyl, alkoxycarbonyl, aryloxycarbonyl or acyl; R2 is hydrogen, C1-C6 alkyl, substituted alkyl, cycloalkyl, or arylalkyl; R3 is a group of the formula:
- R4 is hydrogen, C1-C4 alkyl, CF 3 , phenyl, bromo, iodo, or chloro, and the pharmaceutically acceptable salts thereof.
- Cycloalkynoxalinediones represented by the above formula wherein Z is an alicychc fused ring having 5 to 7 carbon atoms; RI is hydrogen, an alkyl or an arylalkyl; X and Y are independently hydrogen, halogen, nitro, cyano, COOH, CONR2R3, SONR2R3 wherein R2 and R3 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl or aralkyl; and A is O, CH 2 , NR4, CH 2 NR4, CN, tetrazole or CO wherein R4 is hydrogen, alkyl, hydroxyalkyl, aminoalkylamine or aralkyl, wherein (i) when A is O, CH 2 , NR4, or CH 2 NR4 then B is hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aminoalkyl, heterocyclic, alkylhe
- RI or R2 are selected from the group consisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, CI to C6 lover alkyl and C7 to C12 higher alkyl, aryl, and aralkyl; and the pharmaceutically acceptable salts thereof.
- RI and R2 can be, independently from each other, hydrogen, halogen, alkyl group with 1-4 carbonic atoms, alcoxy group with 1-4 carbonic atoms, nitro group, trifluoromethyl group, or group having a general structure of -NR8R9, where the meaning of R8 and R9, can be, independently from each other, hydrogen, alkyl group with 1-4 carbonic atoms, or group having a general structure of -CORio, where R10 means hydrogen atom, alkyl group with 1-6 carbonic atoms substituted in given cases, aryl group with 6-10 carbonic atoms, alcoxy group with 1-4 carbonic atoms, cycloalkyl group with 3-5 carbonic atoms, alkenyl group with 2-6 carbonic atoms, cycloalcoxy group with 3-5 carbonic atoms, or group having a general structure of -NR11R
- Oxadiazole derivatives of formula (I), and their racemates, enantiomers, diastereomers, mixtures and acid addition salts, are new.
- One of X, Y N and the
- RI is -(CH 2 ) n CR 2 H- (CH 2 ) m - and R 5 , R 6 , R 7 and R 8 together or independently are hydrogen, Ci-e-alkyl in which one or more hydrogen atoms are replaced with halogen atoms, nitro, halogen, NR 9 R 10 , cyano, SOpR 11 , SO 2 NR 12 R 13 , SO 3 H, SO 3 Ci -6 -alkyl or OR 14 ; R 2 hydrogen or (CH 2 ) q -R 3 ; R3 hyrdogen, hydroxy, C ⁇ -6 -alkoxy or NR 15 R 16 ; n, m and q can be 0, 1, 2 or 3; Z is POXY, OPOXY, SO 2 R 17 , COR 18 , halogen, cyano or tetrazole; R 11 H, Ci-e- alkyl, phenyl;
- the inhibitors of the present invention also include AMPA and/or kainate receptor channel blockers.
- AMPA and/or kainate receptor channel blockers is used to refer to moieties that reduce the permeability of channels associated with the AMPA and/or kainate receptor to cations (preferably to Na + ,K + and/or Ca 2+ ions).
- AMPA and/or kainate receptor channel blockers can therefore be used to prevent a signal being transmitted due to ionic flux that would otherwise occur when glutamate binds to the AMPA and/or kainate receptor.
- AMPA and/or kainate receptor channel inhibitors include e.g. fluorowillardiine and Joro spider toxin. Having described the inhibitors of the present invention, their therapeutic uses will now be discussed in greater detail.
- Inhibitors of the present invention may be used in human and veterinary medicine. Treatments may be prophylactic or may be in respect of existing conditions.
- the inhibitors may be used in the manufacture of a medicament for treating a demyelinating disorder.
- demyelinating disorder is used herein to include any disorder that results in a reduced level of myelination.
- Demylinating disorders include acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- and HTLV- myelopathy, and progressive multifocal leucoencephalopathy.
- Demylinating disorders also include secondary demyelinating disorders - i.e. where bystander myelin loss occurs as a consequence of a secondary pathological insult.
- Examples of secondary demyelinating disorders are CNS lupus erythematodes, polyarteriitis nodosa, Sj ⁇ gren syndrome, sarcoidosis and isolated cerebral vasulitis.
- the present invention includes within its scope pharmaceutically acceptable compositions useful in treating demyelinating disorders which comprise an inhibitor of the present invention.
- the inhibitor will usually be provided in combination with a pharmaceutically acceptable carrier. It may be used in any suitable form, provided that it can still act in inhibiting the interaction of glutamate with the AMPA and/or kainate receptor complex.
- pharmaceutically acceptable salts, esters, hydrates, etc. may often be used.
- Pharmaceutical compositions within the scope of the present invention may include one or more of the following: preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odourants, salts, buffers, coating agents or antioxidants.
- the further therapeutically active agent may be an immunosuppresive agent (e.g. corticotrophin, a glucocorticoid, cyclophosphamide, cyclosporine, azothioprine or mitozantrone), an interferon (IFN; IFN-beta-la e.g. Rebif and Avonex; IFN-beta-lb e.g. Betaseron and Betaferon; IFN-alpha-2a e.g. Alphaferone; IFN-alpha-2b e.g.
- an immunosuppresive agent e.g. corticotrophin, a glucocorticoid, cyclophosphamide, cyclosporine, azothioprine or mitozantrone
- IFN interferon
- IFN-beta-la e.g. Rebif and Avonex
- IFN-beta-lb e.g. Betaseron and Betaferon
- a phosphodiesterase type IV inhibitor a humanised monoclonal antibody against a leukocyte adhesion molecule (e.g. Antegran), a synthetic polypeptide (e.g. glatiramer acetate, copolymer- 1) a tissue matrix metalloproteinase (MMP) inhibitor (e.g. hydroxamic acid-based inhibitors of MMPs) or a tumour necrosis factor (TNF) inhibitor (e.g. Thalidomide or TNF-receptor immunoglobulin fusion protein).
- MMP tissue matrix metalloproteinase
- TNF tumour necrosis factor
- the combination of an inhibitor of the present invention and a further therapeutically active agent may be used simultaneously, seperately or sequentially to treat a demyelinating disorder. It may provide synergistically effective combination.
- the further therapeutically active agent may be an immunosuppresive agent (e.g. corticotrophin, a glucocorticoid, cyclophosphamide, cyclosporine, azothioprine or mitozantrone), an interferon (IFN; IFN-beta-la e.g. Rebif and Avonex; IFN-beta-lb e.g. Betaseron and Betaferon; IFN-alpha-2a e.g.
- immunosuppresive agent e.g. corticotrophin, a glucocorticoid, cyclophosphamide, cyclosporine, azothioprine or mitozantrone
- IFN interferon
- MMP tissue matrix metalloproteinase
- TNF tumour necrosis factor
- a pharmaceutical composition within the scope of the present invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes.
- Such a composition may be prepared by any method known in the art of pharmacy, for example by admixing one or more active ingredients with a suitable carrier.
- a suitable carrier Preferably it will be provided in unit dosage form. It will normally be provided in a sealed, sterile container e.g. in an an ampoule, a vial, a bottle, a blister pack, etc.
- Different drug delivery systems can be used to administer pharmaceutical compositions of the present invention, depending upon the desired route of administration.
- Such systems include tablets, capsules, lozenges, pastilles, powders, solutions, suspensions, syrups, ointments, pastes, oils, aerosols, suppositories, enemas, pessaries, tampons, sprays, nebulizers, injectable compositions, etc.
- Dosages of the inhibitors of the present invention can vary between wide limits, depending upon the nature of the treatment and the age and condition of the individual to be treated. However, a daily dosage of from 0.5 mg to 1000 mg, preferably of from 50-200 mg may be suitable. The dosage may be repeated as often as appropriate. If side-effects develop, the amount and/or frequency of the dosage can be reduced, in accordance with good clinical practice.
- FIGURE 1 shows that the AMPA receptor antagonist NBQX reduces severity of paralysis during EAE in rats.
- NBQX (30mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score.
- FIGURE 3 shows that the non-competitive AMPA antagonist GYKI53773 reduces the severity of paralysis during EAE.
- GYKI53773 (30mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score.
- FIGURE 4 shows that the AMPA receptor antagonist NBQX reduces the severity of paralysis during chronic EAE.
- FIGURE 5 shows that the AMPAkainate receptor antagonist MPQX reduces the severity of paralysis during EAE.
- MPQX (lOmg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score.
- FIGURE 6 shows that the non-competitive AMPA antagonist GYKI52466 reduces the severity of paralysis during EAE.
- GYKI52466 (30mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score.
- FIGURE 7 shows that the non-competitive AMPA antagonist B1TR561 redcues the severity of paralysis during EAE.
- BHR561 (30mg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score.
- FIGURE 8 shows that the non-competitive AMPA antagonist CP465022 reduces the severity of paralysis during EAE.
- CP465022 (lOmg/kg i.p. twice daily; 10-16 dpi) significantly reduces the peak disease score.
- EAE Experimental allergic encephalomyelitis
- non-competitive AMPA antagonists (-) 1 -(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3- methylcarbamoyl-2,3-benzodiazepine (GYKI53773), l-(-aminophenyl)-4-methyl- 7,8-methylene-dioxy-5H-2,3-benzodiazepine (GYKI52466), 5-(2-[N,N- dimethylamino]oxy-phenyl)-3-phenyl-l,2,4-oxadiazol (BITR561) and 3-(2- chlorophenyl)-2-[2-[6-[(diethylamino)methyl]-2-pyridinyl]ethenyl]-6-fluoro- 4(3H)- quinazolinone (CP465022), and the AMPA/kainate receptor antagonist [1,2,3,4- tefrahyoj-o-7-mo ⁇
- mice Female Lewis rats (205 + 10 g) obtained from Charles River, Kent, UK, were housed in pairs under environmentally controlled conditions (6:00 a.m. - 6:00 p.m. light/dark cycle; 22-24°C; 45-55% humidity) and allowed free access to food and water. Experimental groups consisted of 10 animals. Female Biozzi mice (20 ⁇ 5g) obtained from Harlan, UK, were housed under the conditions described above. Experimental groups consisted of 7-10 animals.
- Rats were immunised in each hind foot with 50 ⁇ l of inoculum containing 50 ⁇ g guinea pig myelin basic protein (MBP, prepared by the method of Dunkley and Carnegie (1974); final concentration 2 mg/ml), emulsified in Freund's complete adjuvant (CFA; Sigma, UK) containing Mycobacterium tuberculosis H37Ra (final concentration 5.5 mg/ml; Difco Laboratories, UK).
- MBP myelin basic protein
- mice Spinal cords from Biozzi mice (Ab/H, H-2 dql ) were homogenised and freeze dried. Lyophilised spinal cord homogenate was reconstituted in phosphate buffered saline to a final concentration of 6.6 mg/ml. Incomplete Freund's adjuvant (IF A, Difco) was supplemented with M. tuberculosis (H37Ra, Difco) and M. butyricum (8:1). Biozzi mice were immunised subcutaneously on day 0 and day 7 in the flank at three sites with 0.3 ml of the emulsion (1 mg spinal cord homogenate, 60 ⁇ g of combined M. tuberculosis and butyricum). In addition, mice were injected i.p. with 200 ng of pertussis toxin ⁇ Bordetella pertussis, Calbiochem; 2 g/ml in phosphate buffered saline) immediately and 24 h after immunisation with neuroantigens.
- NBQX was initially dissolved in NaOH and diluted with water. pH was adjusted with HC1. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or NBQX in the dose of 30mg/kg. Mice were injected i.p. either twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation or once daily (9 a.m.) on days 26 to 42 post immunisation with either vehicle or NBQX in the dose of 30mg/kg.
- GYKI53773 administration regime GYKI53773 was suspended in 5% cremophore in saline. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or GYKI53773 in the dose of 30mg/kg.
- GYKI52466 administration regime GYKI52466 was suspended in 5% cremophore in water. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or GYKI52466 in the dose of 30mg/kg.
- BHR561 administration regime BHR561 was suspended in 5% cremophore in water. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or B1TR561 in the dose of 30mg/kg.
- CP465022 administration regime CP465022 was suspended in 5% cremophore in water. Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or CP465022 in the dose of lOmg/kg.
- MPQX administration regime MPQX was initially dissolved in NaOH and diluted with water. pH was adjusted with
- Rats were injected i.p. twice daily (9 a.m. and 5 p.m.) on days 10 to 16 post immunisation with either vehicle or MPQX in the dose of lOmg/kg. Results
- NBQX significantly reduced disease duration (pO.OOl), and peak and cumulative disease score (p ⁇ 0.01) relative to vehicle treatment.
- NBQX also conferred protection on weight loss, significantly delaying the onset until 13 dpi (p ⁇ 0.01) and decreasing the percent body weight lost at the cessation of NBQX administration (day 16; Figure 2 and Table 1).
- Table 2 Parameters of disease activity during Lewis rat acute EAE.
- b Cumulative disease score calculated by summation of individual daily disease scores, c; Calculated as the weight on cessation of experiment (20 dpi) expressed as a percent of the maximum weight before disease onset.
- NBQX was administered i.p. to immunised mice.
- Treatment with NBQX, 30mg/kg twice daily for 7 days starting on dpi 10, improved neurological outcome reducing disease severity between dpi 10 to 48 [F(l,38) 9.21, PO.OOl] (Fig. 4A).
- Table 3 Parameters of disease activity during Lewis rat acute EAE.
- Vehicle 26/26 11.2 (10-13) 4.8 (3-6) 3.5 (2.5-4) 11.0 (8-14.5) 21 (15-28) (100)
- Table 4 Parameters of disease activity during Lewis rat acute EAE.
- b Cumulative disease score calculated by summation of individual daily disease scores, c; Calculated as the weight on cessation of experiment expressed as a percent of the maximum weight before disease onset.
- Table 6 Parameters of disease activity during Lewis rat acute EAE.
- CP465022 8/9 (89) 13.4 (11-17)** 3.4 (0-5)* 2.0 (0-3.0)** 7.2 (0-13.5)** 20
- b Cumulative disease score calculated by summation of individual daily disease scores, c; Calculated as the weight on cessation of experiment expressed as a percent of the maximum weight before disease onset.
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Abstract
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JP2000557823A JP2002519373A (en) | 1998-07-02 | 1999-07-02 | Pharmaceutical compositions and their use |
EP99929545A EP1100504A2 (en) | 1998-07-02 | 1999-07-02 | Pharmaceutical compositions and their uses for treatment of demyelinating disorders |
US09/746,662 US20040204347A1 (en) | 1998-07-02 | 2000-12-22 | Treatment of demyelinating disorders |
US11/043,219 US20050130979A1 (en) | 1998-07-02 | 2005-01-26 | Treatment of demyelinating disorders |
US11/043,732 US20050182047A1 (en) | 1998-07-02 | 2005-01-26 | Treatment of demyelinating disorders |
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2000
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Also Published As
Publication number | Publication date |
---|---|
WO2000001376A3 (en) | 2001-03-22 |
US20050182047A1 (en) | 2005-08-18 |
US20040204347A1 (en) | 2004-10-14 |
JP2002519373A (en) | 2002-07-02 |
US20050130979A1 (en) | 2005-06-16 |
EP1100504A2 (en) | 2001-05-23 |
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