Compounds of formula (I) in which R1 is halo-C1-10 alkyl; halo-C2-10 alkenyl; or (CH2)nY in which n is 1 or 2 and Y is OH, CN, N3, OR3, SH, S(O)pR4, S(O)3H, NH2, NHR5, NR6R7, NHCOR8, NO2, CO2H, CONHR9, 1H-tetrazol-5-yl, 5-phenyltetrazol-2-yl or PO3H2; R3, R5, R6, R7, R8 and R9 are each selected independently from C1-4 alkyl, aryl and aryl-C1-4 alkyl; R4 is selected from C1-4 alkyl, aryl, aryl-C1-4 alkyl, and 1H-tetrazol-5-yl, carboxy-(1-4C)alkyl and 1H-tetrazol-5-yl-C1-4 alkyl; and p is 0, 1, 2 or 3; or a salt or ester thereof, provided that R1 is not methoxymethyl, modulate metabotropic glutamate receptor function and are useful in treating disorders of the central nervous system.

In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Comas, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropicxe2x80x9d. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D or C, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
The metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. Compounds which modulate the function of these receptors, in particular agonists and antagonists of glutamate, are useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant, and anti-emetic agents.
Pellicciari et al., J. Med. Chem., 1996, 39, 2259-2269 refers to compounds known as metabotropic glutamate receptor agonists, in particular (2S,1xe2x80x2S,2xe2x80x2S)-2-(2-carboxycyclopropyl)glycine, also known as L-CCG-I; (2S, 1xe2x80x2S,2xe2x80x2R,3xe2x80x2R)-2-(2xe2x80x2-carboxy-3xe2x80x2-(methoxymethyl)cyclopropyl-glycine, also known as cis-MCG-I; (2S,1xe2x80x2S,2xe2x80x2R,3xe2x80x2S)-2-(2xe2x80x2-carboxy-3xe2x80x2-(methoxymethyl)cyclopropylglycine, also known as trans-MCG-I; and (2S,1xe2x80x2R,2xe2x80x2R,3xe2x80x2R)-2-(2xe2x80x2,3xe2x80x2-dicarboxy-cyclopropyl)glycine, also known as DCG-IV. The paper also describes the synthesis of the sixteen possible stereoisomers of 2-(2xe2x80x2-carboxy-3xe2x80x2-phenylcyclopropyl)glycine and their evaluation as excitatory amino acid receptor ligands. The compound (2S,1xe2x80x2S,2xe2x80x2S,3xe2x80x2R)-2-(2xe2x80x2-carboxy-3xe2x80x2-phenylcyclopropyl)glycine, also known as PCCG 4 is reported to be a metabotropic glutamate receptor antagonist.
Japanese patent application publication number JP 06179643 discloses MCG and generically discloses (2S,1xe2x80x2S,2xe2x80x2R)-2-(2-carboxy-3-alkoxymethyl- and 3-aralkoxymethyl-cyclopropyl)glycines as glutamate receptor agonists.
International patent application publication number WO 97/19049 discloses PCCG 4 and also generically discloses various 2-carboxy-3-arylcyclopropylglycines having affinity for metabotropic glutamate receptors.
International patent application publication number WO 98/00391 discloses 2-carboxy-3,3-dihalocyclopropylglycines, including (2S,1xe2x80x2S,2xe2x80x2S)-2-(2-carboxy-3,3-difluoro)-cyclopropylglycine as metabotropic glutamate receptor agonists.
European patent application, publication number EP-A1-0870760 discloses that certain 3-substituted 2-carboxycyclopropyl glycine derivatives are modulators of metabotropic glutamate receptor function. The preferred compounds are said to be those in which the substituents at the 1 and 2 positions are in a trans relationship. The examples illustrate such compounds in which the substituents at the 1 and 3 positions are also in a trans relationship. One such compound is (2S,1xe2x80x2S,2xe2x80x2S,3xe2x80x2S)-2xe2x80x2-carboxy-3xe2x80x2-methylcyclopropylglycine.
Surprisingly, novel 3-substituted 2-carboxycyclopropyl glycine derivatives have now been found which are potent agonists of glutamate at metabotropic glutamate receptors.
Accordingly, the present invention provides a compound of the formula:
in which:
R1 is halo-C1-10 alkyl; halo-C2-10 alkenyl; or (CH2)nY in which n is 1 or 2 and Y is OH, CN, N3, SH, S(O)pR4, S(O)3H, NH2, NHR5, NR6R7, NHCOR8, NO2, CO2H, CONHR9, 1H-tetrazol-5-yl, 5-phenyltetrazol-2-yl, or PO3H2; R3, R5, R6, R7, R8 and R9 are each selected independently from C1-4 alkyl, aryl and aryl-C1-4 alkyl; R4 is selected from C1-4 alkyl, aryl, aryl-C1-4 alkyl, 1H-tetrazol-5-yl, carboxy-C1-4 alkyl and 1H-tetrazol-5-yl-C1-4 alkyl; and p is 0, 1, 2 or 3;
or a salt or ester thereof.
Compounds of the invention have been found to be agonists of glutamate at metabotropic glutamate receptors and are therefore useful in the treatment of diseases of the central nervous system such as neurological diseases, for example neurodegenerative diseases, and as antipsychotic, anxiolytic, drug-withdrawal, antidepressant, anticonvulsant, analgesic and anti-emetic agents.
It will be appreciated that the compounds of formula (I) contain at least four asymmetric carbon atoms, three being in the cyclopropane ring and one being at the xcex1-carbon of the amino acid group. Accordingly, the compounds of the invention may exist in and be isolated in enantiomerically pure form, in racemic form, or in a diastereoisomeric mixture.
Preferred compounds of the invention are those of the formula
The amino acid moiety preferably has the natural amino configuration. Accordingly, preferred compounds according to the invention are those of the formula:
As used herein, the term halogen atom, as such or as halo, for example as in haloalkyl, includes a fluorine or chlorine atom; a C1-10 alkyl group includes a C1-4 alkyl group and can be straight or branched chain, such as, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl, and is preferably methyl or ethyl. A C2-10 alkenyl group includes, for example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and isopropenyl, and an alkenyl group can contain more than one double bond and, in addition, one or more triple bonds. A preferred alkenyl group is of the formula Rxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)rxe2x80x94 where Rxe2x80x2 is hydrogen or C1-4 alkyl and r is 0, 1 or 2. An aryl group, as such or in an aryl-C1-4 alkyl may be, for example, a phenyl group or a substituted phenyl group, for example with one or two substituents selected independently from halogen, C1-4 alkyl and C1-4 alkoxy. An example of an aryl group is phenyl or 3-chlorophenyl. An example of an aryl-C1-4 alkyl group is benzyl.
A particular sub-group of compounds of formula I is that in which R4 is selected from C1-4 alkyl, aryl, aryl-C1-4 alkyl and 1H-tetrazol-5-yl-C1-4 alkyl.
Examples of particular values for R1 are: for a halo-C1-10 alkyl group: fluoromethyl; trifluoromethyl; 2-fluoroethyl; trifluorethyl, such as 2,2,2-trifluoroethyl; chloromethyl; 2-chloroethyl; trichloromethyl; and trichloroethyl, such as 2,2,2-trichloroethyl; for a halo-C2-10 alkenyl group: 2-fluorovinyl and 2,2-difluorovinyl; for a (CH2)nY group: hydroxymethyl, 2-hydroxyethyl, 2-benzyloxyethyl, cyanomethyl, 2-cyanoethyl, azidomethyl, 2-azidoethyl, 2-methoxyethyl, mercaptomethyl; 2-mercaptoethyl, methanethiomethyl, 2-methanethioethyl, 1H-tetrazol-5-ylthiomethyl, carboxymethylthiomethyl, phenylthiomethyl, methanesulfinylmethyl, 2-methanesulfinylethyl, methanesulfonylmethyl, phenylsulfinylmethyl, phenylsulfonylmethyl, 2-methanesulfonylethyl, 2-phenylthioethyl, 2-benzylthioethyl, aminomethyl, acetylaminomethyl, benzoylaminomethyl, 3-chlorobenzoylaminomethyl, benzylamidomethyl, methylaminomethyl, nitromethyl, 2-nitroethyl, 1H-tetrazol-5-ylmethyl, 2-(1H-tetrazol-5-yl)ethyl, 5-phenyltetrazol-2-ylmethyl, carboxymethyl, 2-carboxyethyl, aminocarbonylmethyl, phosphonomethyl, acetamidomethyl, benzamidomethyl and 2-benzamidoethyl.
Examples of particular values for R3, R5, R6, R7, R8 and R9 are:
for a C1-4 alkyl group: methyl or ethyl;
for an aryl group: phenyl or 3-chlorophenyl; and for an aryl-C1-4 alkyl group: benzyl.
Examples of particular values for R4 are:
for a C1-4 alkyl group: methyl;
for an aryl group: phenyl;
for an aryl-C1-4 alkyl group: benzyl;
for a carboxy-C1-4 alkyl group: carboxymethyl; and
for a 1H-tetrazol-5-yl-C1-4 alkyl group: 1H-tetrazol-5-ylmethyl.
Preferably R1 is selected from fluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, 2-chloroethyl, trichloromethyl, 2,2,2-trichloroethyl, 2-fluorovinyl, 2,2-difluorovinyl, hydroxymethyl, 2-hydroxyethyl, 2-benzyloxyethyl, cyanomethyl, 2-cyanoethyl, azidomethyl, 2-azidoethyl, mercaptomethyl, 2-mercaptoethyl, methanethiomethyl, 2-methanethioethyl, 1H-tetrazol-5-ylthiomethyl, carboxymethylthiomethyl, phenylthiomethyl, methanesulfinylmethyl, 2-methanesulfinylethyl, methanesulfonylmethyl, phenylsulfinylmethyl, phenylsulfonylmethyl, 2-methanesulfonylethyl, 2-phenylthioethyl, 2-benzylthioethyl, aminomethyl, acetylaminomethyl, benzoylaminomethyl, 3-chlorobenzoylaminomethyl, benzylamidomethyl, methylaminomethyl, nitromethyl, 2-nitroethyl, 1H-tetrazol-5-ylmethyl, 2-(1H-tetrazol-5-yl)ethyl, 5-phenyltetrazol-2-ylmethyl, carboxymethyl, 2-carboxyethyl, aminocarbonylmethyl, phosphonomethyl, acetamidomethyl, benzamidomethyl, and 2-benzamidoethyl.
A particular sub-group of compounds of formula I is that in which R1 is selected from fluoromethyl, 2-fluoroethyl, trifluoromethyl, trichloromethyl, trichloroethyl, 2-trichloroethyl, 2-fluorovinyl, 2,2-difluorovinyl, hydroxymethyl, cyanomethyl, 2-cyanoethyl, azidomethyl, 2-azidoethyl, 2-benzyloxyethyl, mercaptomethyl, methanethiomethyl, 2-methanethioethyl, 1H-tetrazol-5-ylthiomethyl, methanesulfinylmethyl, 2-methanesulfinylethyl, methanesulfonylmethyl, 2-methanesulfonylethyl, aminomethyl, acetylaminomethyl, nitromethyl, 1H-tetrazol-5-ylmethyl, aminocarbonylmethyl, phosphonomethyl, acetamidomethyl and benzamidomethyl. Especially preferred are compounds in which R1 is hydroxymethyl.
Particularly preferred compounds are:
(2SR,1xe2x80x2SR,2xe2x80x2RS,3xe2x80x2RS)-2-(3xe2x80x2-hydroxymethyl-2xe2x80x2-carboxycyclopropyl)glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-hydroxyethyl)-2xe2x80x2-carboxy)cyclopropyl]glycine;
(2SR,1xe2x80x2RS,2xe2x80x2RS,3xe2x80x2RS)-2-[3xe2x80x2-mercaptomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2RS,2xe2x80x2RS,3xe2x80x2RS)-2-[3xe2x80x2-carboxymethylthiomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2RS,2xe2x80x2RS,3xe2x80x2RS)-2-[3xe2x80x2-(1H-tetrazol-5-ylthiomethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-mercaptoethyl)-2xe2x80x2-carboxy)cyclopropyl]glycine;
(2SR,1xe2x80x2RS,2xe2x80x2RS,3xe2x80x2RS)-2-[3xe2x80x2-methylthiomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2RS,2xe2x80x2RS,3xe2x80x2RS)-2-[3xe2x80x2-phenylthiomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-phenylthioethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-benzylthioethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2RS,2xe2x80x2RS,3xe2x80x2RS)-2-[3xe2x80x2-methylsulfonylmethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2RS,2xe2x80x2RS,3xe2x80x2RS)-2-[3xe2x80x2-phenylsulfonylmethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[3xe2x80x2-azidomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-fluoroethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-chloroethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[3xe2x80x2-acetylaminomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[3xe2x80x2-benzoylaminomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[3xe2x80x2-aminomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[3xe2x80x2-benzylcarbonylaminomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[3xe2x80x2-(m-chlorobenzoyl)aminomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[3xe2x80x2-methylaminomethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2RS,2xe2x80x2RS,3xe2x80x2RS)-2-[3xe2x80x2-trifluoromethyl-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-(1H-tetrazol-5-yl)ethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-azidoethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-nitroethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[(3xe2x80x2-(2xe2x80x3-benzyloxyethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-[3xe2x80x2-(5-phenyltetrazol-2-yl)methyl-2xe2x80x2-carboxycyclopropyl]glycine,
and pharmaceutically acceptable salts and esters thereof.
A compound of especial interest is: (2S,1xe2x80x2S,2xe2x80x2R,3xe2x80x2R)-2-(3xe2x80x2-hydroxymethyl-2xe2x80x2-carboxycyclopropyl)glycine, as well as the pharmaceutically acceptable salts thereof.
This compound has been found to be highly potent as an agonist of glutamate at Group II metabotropic glutamate receptors (mGluR2 and mGluR3). It is believed to be the most highly potent 2xe2x80x2-carboxycyclopropyl)glycine (CCG) compound made to date.
The present invention includes salts of the formula (I) compounds. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammnonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula (I). The alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula (I).
The salts of the compounds of formula I may be pharmaceutically-acceptable salts. However, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically-acceptable, acid addition salts, or are useful for identification, characterisation or purification.
Acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicylic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid.
The present invention includes esters of the formula (I) compounds, such esters being for example aliphatic esters such as alkyl esters.
The esters of the compounds of formula I may be pharmaceutically acceptable metabolically labile esters of compounds of formula I. These are ester derivatives of compounds of formula I that are hydrolyzed in vivo to afford said compound of formula I and a pharmaceutically acceptable alcohol. Examples of metabolically labile esters include esters formed with (1-6C) alkanols in which the alkanol moiety may be optionally substituted by a (1-8C) alkoxy group, for example methanol, ethanol, propanol and methoxyethanol. The most preferred esters are alkyl esters derived from (1-4C) alkanols, especially methyl and ethyl esters.
The invention also comprises a process for preparing a compound according to formula (I), or a salt or ester thereof, which comprises:
(a) deprotecting a compound of formula
in which R10 and R11 each independently represents hydrogen or a carboxyl protecting group, and R12 represents hydrogen or an amine protecting group;
(b) hydrolysing a compound of formula
in which R13 represents a hydrogen atom or a carboxyl protecting group, and R14 and R15 each independently represents a hydrogen atom, a C1-4 alkyl group, or a phenyl C1-4 alkyl group in which the phenyl group is unsubstituted or substituted by halo, C1-4 alkyl, C1-4 alkoxy or C3-4 alkenyl; or
(c) hydrolysing a compound of formula
in which R16 represents a hydrogen atom or a carboxy protecting group, and R17 represents a hydrogen atom or an amine protecting group;
followed when necessary by recovering a diastereomer or isomer of the compound, or
forming a salt or ester thereof.
The protection of carboxylic acid groups is described in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973, and Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd. Ed., John Wiley and Sons, NY, 1991. Examples of carboxy protecting groups include C1-C6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aryl(C1-C4)alkyl groups such as benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, benzhydryl and trityl; silyl groups such as trimethylsilyl and t-butyldimethylsilyl; and allyl groups such as allyl and 1-(trimethylsilylmethyl)prop-1-en-3-yl.
Examples of amine protecting groups include acyl groups, such as groups of formula R18CO in which R18 represents C1-6 alkyl, C3-10 cycloalkyl, phenyl C1-6 alkyl, phenyl, C1-6 alkoxy, phenyl C1-6 alkoxy, or a C3-10 cycloalkoxy, wherein a phenyl group may be optionally substituted, for example by one or two of halogen, C1-C4 alkyl and C1-C4 alkoxy. Preferred amino protecting groups include t-butoxycarbonyl (Boc) and benzyl.
Examples of particular values for R10, R11, R13 and R16 are hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, benzyl, 4-methoxybenzyl, phenylethyl and phenylpropyl.
Examples of particular values for R12 and R17 include acetyl and tert-butoxycarbonyl.
Examples of particular values for R14 and R15 are hydrogen and benzyl.
The compounds of formula (II) may be deprotected by conventional methods. Thus, an alkyl carboxyl protecting group may be removed by hydrolysis. The hydrolysis may conveniently be performed by heating the compound of formula (II) in the presence of either a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkaline metal hydroxide, such as barium hydroxide or an acid such as hydrochloric acid. The hydrolysis is conveniently performed at a temperature in the range of from 20xc2x0 C. to 300xc2x0 C. An aralkyl carboxyl protecting group may conveniently be removed by hydrogenation. The hydrogenation may be effected by reacting the compound of formula (II) with hydrogen in the presence of a Group VIII metal catalyst, for example a palladium catalyst such as palladium on charcoal. Suitable solvents for the reaction include alcohols such as ethanol. The reaction is conveniently performed at a temperature in the range of from 0xc2x0 C. to 100xc2x0 C.
An acyl, amine protecting group is also conveniently removed by hydrolysis, for example as described for the removal of an alkyl carboxyl protecting group. Thus, a tert-butoxycarbonyl, amine protecting group may conveniently be removed in the presence of an acid, for example hydrochloric acid or trifluoroacetic acid. The hydrolysis is performed in the presence of a solvent such as water, ethyl acetate or dichloromethane and at a temperature in the range of from 20xc2x0 C. to 100xc2x0 C.
The compounds of formula III are conveniently hydrolyzed in the presence of a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide such as barium hydroxide. Suitable reaction media include water. The temperature is conveniently in the range of from 50xc2x0 C. to 150xc2x0 C.
The compounds of formula IV are conveniently hydrolyzed in the presence of an acid, such as hydrochloric acid or sulfuric acid, or a base, such as an alkali metal hydroxide, for example sodium hydroxide. The hydrolysis is conveniently performed in an aqueous solvent such as water, or in an alkanol such as methanol or ethanol, and at a temperature in the range of from 20xc2x0 C. to 200xc2x0 C.
Compounds of formula I in the form of diastereomeric mixtures or isomers may be obtained in a conventional manner, for example by chiral synthesis using chiral starting materials, or by using conventional separation techniques, for example by forming a crystalline salt with a chiral acid or base, or by chiral hplc.
Compounds of formula (II) in which R11 represents hydrogen may be prepared by a procedure analogous to that described in Ohfune Y., et al., J. Med. Chem., 1996, 39, 407-423. Thus they may be prepared by reacting a compound of formula
with an oxidising agent. Convenient oxidising agents include Jones Reagent.
Compounds of formula (V) may be prepared by reacting a compound of formula
with a sulfonic acid, such as camphorsulfonic acid (CSA) and an alkanol, such as methanol.
Compounds of formula (VI) may be prepared by reacting a compound of formula
with a strong base, such as potassium bis(trimethylsilyl)amide.
Compounds of formula (VII) may be prepared by reacting a compound of formula
with acetone dimethyl ketal in the presence of a sulfonic acid, such as camphorsulfonic acid.
Compounds of formula VIII may be prepared by selectively deprotecting a compound of formula
in which R19 represents a hydroxyl protecting group, such as a tert-butyldimethylsilyl (TBS) group. A convenient reagent for removing a TBS group is camphorsulfonic acid in methanol.
The compounds of formula (IX) may be prepared by reacting a compound of formula
with a base, such as lithium hydroxide, for example in tetrahydrofuran, followed by introduction of the protecting group R10, for example by treatment with diazomethane (to afford a compound in which R10 is methyl).
Compounds of formula (X) may be prepared by treating a compound of formula
with an ion exchange resin, such as DOWEX 50Wx8, followed by introduction of the protecting groups R12 and R19, for example by stepwise reaction with tributylsilyl chloride in the presence of imidazole, followed by Boc2O in the presence of triethylamine and 4-dimethylaminopyridine.
Compounds of formula (XI) may be prepared by reacting a compound of formula
with palladium (II) acetate.
Compounds of formula (XII) may be prepared by diazotizing a compound of formula
for example by reaction with sodium nitrite.
Compounds of formula (XIII) may be prepared by selectively deprotecting a compound of formula
in which R20 represents an amine protecting group, such as t-butoxycarbonyl. For example a t-butoxycarbonyl (Boc) group may conveniently be removed by treatment with trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine.
The compounds of formula (XIV) may be prepared by reacting a compound of formula
with an N-protected glycinate, such as N-hydroxysuccinimide N-(tert-butoxycarbonyl)glycinate, followed by reaction with acetone dimethylketal in the presence of a sulfonic acid such as p-toluenesulfonic acid.
The compounds of formula (XV) may be prepared by reacting a compound of formula
in which R21 represents an amine protecting group, such as t-butoxycarbonyl, with a triphenylphosphine halide of formula Ph3P+CH2R1 Axe2x88x92, in which Axe2x88x92 represents a halide ion such as bromide, in the presence of a strong base, such as potassium bis(trimethylsilyl)amide, followed by removal of the amine protecting group, and hydrolysis of the acetonide, for example by reaction with methanolic HCl.
Compounds of formula (II) in which R1 represents (CH2)nY in which n is 1 or 2 may alternatively be prepared by reacting a compound of formula
in which n is 1 or 2 and Z1 represents a leaving atom or group, such as a halogen atom, for example a chlorine atom, an organosulfonyloxy group, for example a p-toluenesulfonyloxy group or a diphenylphosphoryloxy group, with a salt of formula MY in which M represents an alkali metal such as sodium or potassium.
The compounds of formula (XVII) in which Z1 represents a halogen atom or an organosulfonyloxy group may be prepared by reacting a compound of formula
with a halogenating or sulphonating reagent such as p-toluenesulfonyl chloride.
Compounds of formula (XVII) in which Z1 represents a diphenylphosphoryloxy group may be prepared by reacting a compound of formula (XVIII) with diphenyl-phosphoryl azide in the presence of diazabicyclo[5.4.0]-undec-7-ene. Convenient solvents include aromatic hydrocarbons, such as toluene. The reaction is conveniently effected at a temperature of from 0 to 100xc2x0 C.
Compounds of formula (XVIII) may be converted directly into compounds of formula (II) in which R1 represents (CH2)nY and Y is N3 by reaction with diethylazodicarboxylate and triphenylphosphine followed by diphenylphosphoryl azide. The reaction is conveniently conducted in an anhydrous ether solvent, such as tetrahydrofuran and under an inert atmosphere, such as nitrogen. The temperature is conveniently in the range of from xe2x88x9250 to 40xc2x0 C.
Compounds of formula (XVII) in which Z1 represents a diphenylphosphoryloxy group, may be also converted into compounds of formula (II) in which R1 represents (CH2)nY and Y is N3 by reaction with sodium azide. The reaction is conveniently conducted in an anhydrous solvent, such as N,N-dimethylformamide and under an inert atmosphere, such as nitrogen. The temperature is conveniently in the range of from 0 to 100xc2x0 C.
Compounds of formula (XVIII) may be converted directly into compounds of formula (II) in which R1 represents (CH2)nY and Y is F by reaction with a fluorinating agent, such as (diethylamino)sulfur trifluoride. Convenient solvents for the reaction include halogenated hydrocarbons, such as dichloromethane. The reaction is conveniently performed at a temperature of from 0 to 100 xc2x0 C.
Compounds of formula (XVIII) may be converted directly into compounds of formula (II) in which R1 represents (CH2)nY and Y is Cl by reaction with a chlorinating agent, such as carbon tetrachloride and triphenylphosphine. Convenient solvents for the reaction include amides, such as dimethylformamide. The reaction is conveniently performed at a temperature of from 0 to 100xc2x0 C.
Compounds of formula (XVIII) may be converted directly into compounds of formula (II) in which R1 represents (CH2)nY and Y is S(O)pR4 and p is 0 by reaction with a compound of formula R4SH, diethylazodicarboxylate and triphenylphosphine. The reaction is conveniently conducted in an anhydrous ether solvent, such as tetrahydrofuran and under an inert atmosphere, such as argon. The temperature is conveniently in the range of from xe2x88x9210 to 100xc2x0 C. If, instead of a compound of formula R4SH, thioacetic acid is used, the resultant compound is a compound of formula (II) in which Y is SCOCH3 and this, on deprotection according to process step (a) above, affords a compound of formula (I) in which Y is SH. Alternatively the compound of formula (XVIII) may be reacted with a disulfide of formula (R4S)2 and tributylphosphine. The reaction is conveniently conducted in an anhydrous ether solvent, such as tetrahydrofuran and under an inert atmosphere, such as argon. The temperature is conveniently in the range of from xe2x88x9210 to 100xc2x0 C. Compounds of formula (II) in which R1 represents (CH2)nY, Y is S(O)pR4 and p is 0 may be converted into the corresponding compounds in which p is 1 or 2 by reaction with a peracid, such as m-chloroperbenzoic acid. Convenient solvents include halogenated hydrocarbons, such as dichloromethane. The reaction is conveniently performed at temperature in the range of from xe2x88x9210 to 50xc2x0 C.
Compounds of formula (XVIII) may be converted directly into compounds of formula (II) in which R1 represents (CH2)nY and Y is 5-phenyltetrazol-2-yl by reaction with 5-phenyl-1H-tetrazole, diethyl azodicarboxylate and triphenylphosphine. The reaction is conveniently conducted in an anhydrous ether solvent, such as tetrahydrofuran and under an inert atmosphere, such as nitrogen. The temperature is conveniently in the range of from 0 to 100xc2x0 C.
The compounds of formula XVIII may be prepared either by hydrolysing a compound of formula XIX
for example using HCl in aqueous ethanol, followed by protecting the amino group, for example by reaction with Boc2O in tetrahydrofuran or dioxane in the presence of NaHCO3, or by hydrolysing a compound of formula XX
in the presence of a base, for example sodium hydroxide, in an aqueous solution at an elevated temperature, for example about 100xc2x0 C., followed by protecting the carboxylic acid groups, for example using HCl in anhydrous ethanol, and protecting the amino group, for example by reaction with Boc2O in tetrahydrofuran or dioxane in the presence of NaHCO3.
The compounds of formula XIX may be prepared by reacting a compound of formula XXI
with ammonium chloride and potassium cyanide in the presence of aluminium oxide. A convenient solvent is acetonitrile.
The compounds of formula XX may be prepared by hydrolysing a compound of formula XXI with an alkali metal hydroxide, for example using sodium hydroxide in aqueous ethanol, followed by treatment with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and ammonium carbonate in an aqueous alcohol, such as aqueous ethanol. Conveniently the reaction is performed at a temperature of from 35xc2x0 C. to 150xc2x0 C.
Compounds of formula XXI in which n is 1 may be prepared by oxidising a compound of formula XXII
for example by employing a Swern oxidation.
Compounds of formula XXII may be prepared by reacting a compound of formula
in which R22 represents a hydrogen atom, a C1-4 alkyl group or a phenyl group, with HCl or camphorsulphonic acid in an alkanol such as ethanol.
Compounds of formula XXIII may be prepared by reacting a compound of formula
with N2CHCO2R10 in the presence of Rh2(OAc)4. A convenient solvent is pentane.
Compounds of formula XXI in which n is 2 may be prepared by reducing a compound of formula
for example using diisobutylaluminium hydride.
Compounds of formula (XXIg) may be prepared by reacting a compound of formula
with a peracid, such as m-chloroperbenzoic acid.
After they have been prepared, compounds of formula (II) may be converted into other compounds of formula (II) prior to deprotection according to process step (a) hereinabove. For example, a compound of formula (II) in which R1 is (CH2)nY and Y is N3 may be reduced in the presence of an alkylating, such as a C1-4 alkyl or aryl-C1-4 alkyl halide to afford a compound of formula (II) in which R1 is (CH2)nY, Y is NHR5, and R5 is C1-4 alkyl or aryl-C1-4 alkyl. The reduction is conveniently performed by catalytic hydrogenation in the presence of a Group VIII metal catalyst, such as palladium on carbon or platinum oxide. Similarly, a compound of formula (II) in which R1 is (CH2)nY and Y is NHCOR8 may be prepared by reducing a compound of formula (II) in which R1 is (CH2)nY and Y is N3 in the presence of an anhydride of formula (R8CO)2CO. The reduction is conveniently performed by catalytic hydrogenation in the presence of a Group VIII metal catalyst, such as palladium on carbon or platinum oxide. Alternatively, the reduction and alkylation or acylation steps may be performed sequentially. It will be appreciated by those skilled in the art that deprotection of a compound of formula (II) in which R1 is (CH2)nY and Y is NHCOR8 according to process step (a) may, depending upon the reaction conditions selected, afford a compound of formula (I) in which Y is NHCOR8 or NH2.
A compound of formula (II) in which R1 is (CH2)nY and Y is CN may be converted directly into a compound of formula (I) in which R1 is (CH2)nY and Y is COOH by acid catalysed hydrolysis, for example using hydrochloric acid.
A compound of formula (II) in which R1 is (CH2)nY and Y is CN may be converted into a compound of formula (II) in which R1 is (CH2)nY and Y is 1H-tetrazol-5-yl by reaction with a trialkyltin azide such as tributyltin azide.
A compound of formula (II) in which R1 is (CH2)nY and Y is NH2 may be converted into a compound of formula (II) in which R1 is (CH2)nY and Y is NO2 by reaction with a peracid, such as m-chloroperbenzoic acid.
The compounds of formula (III) may be prepared by reacting a compound of formula
with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and ammonium carbonate in an aqueous alcohol, such as aqueous ethanol. Conveniently the reaction is performed at a temperature of from 35xc2x0 C. to 150xc2x0 C. If desired, the compounds of formula (III) may then be alkylated, for example using a compound of formula R14Cl or R15Cl. The alkylated compounds are readily separated into their diastereomers.
Compounds of formula (IV) may be prepared by reacting a compound of formula (XXV), in which R16 is as defined for R13, with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and an ammonium halide, such as ammonium chloride. It has been found advantageous to perform the reaction in the presence of ultrasound. Thus, the ammonium halide and alkali metal cyanide are advantageously mixed with chromatography grade alumina in the presence of a suitable diluent, such as acetonitrile. The mixture is then irradiated with ultrasound, whereafter the compound of formula XXV is added, and the mixture is again irradiated.
The resultant mixture of diastereoisomeric aminonitriles may then be reacted with an acylating agent, such as acetyl chloride in the presence of a suitable base, for example an amine such as diisopropylamine, and in the presence of a suitable solvent such as dichloromethane, to afford a mixture of diastereomeric acylaminonitriles. The desired stereoisomer may conveniently be separated from this mixture, for example by chromatography.
The compounds of formula (XXV) may be prepared by oxidising a compound of formula
for example by a Swern oxidation or by reaction with tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in the presence of a molecular sieve (4 xc3x85).
A compound of formula (XXV) having the configuration
may be converted into a mixture of compounds of formula (XXV) containing a compound of the configuration
by treatment with methanolic sodium hydroxide, if necessary followed by reintroduction of the protecting group R16, for example by reaction with diazomethane to afford a compound in which R16 is methyl.
The compounds of formula (XXVI) may be prepared by selectively deprotecting a compound of formula
in which R23 represent a hydroxyl protecting group, for example a benzyl group. The deprotection may be performed in a conventional manner. For example, a benzyl group may be removed by catalytic hydrogenation using palladium on charcoal as catalyst.
Compounds of formula (XXVI) having the configuration
may be prepared by reacting a compound of formula
with an alkali metal hydroxide, such as lithium hydroxide, to afford a compound in which R16 represents hydrogen, followed by followed by introducing a protecting group R16, for example by reaction with diazomethane to produce a compound in which R is methyl.
The compounds of formula (XXVIII) may be prepared by reacting a compound of formula
with Cu(TBS)2.(copper (II) N-(tert-butyl)salicylaldimine).
The compounds of formula (XXIX) may be prepared by reacting a compound of formula
with a sulfonyl azide such as p-acetamidobenzenesulfonyl azide in the presence of a base, such as triethylamine, followed by reaction with an aqueous alkali metal hydroxide, such as lithium hydroxide.
The compounds of formula (XXX) may be prepared by reacting a compound of formula
with diketene in the presence of an alkali metal acetate, such as sodium acetate.
Compounds of formula (XXV) in which R1 represents fluoromethyl may be prepared by protecting one hydroxy group in a diol compound of formula (XXII), for example with a benzyl group, followed either by reaction with a fluorinating agent, such as (diethylamino)sulfur trifluoride, or by functionalization of the remaining hydroxyl group with a leaving atom or group such as an iodine atom or p-toluenesulfonyloxy group then reaction with an alkali metal fluoride), followed by removal of the hydroxy protecting group.
Compounds of formula (II) may also be prepared by reacting a compound of formula
with a Wittig reagent. For example, a compound of formula (XXXII) may be reacted with a haloalkyl triphenylphosphonium bromide to afford a compound of formula (II) in which R1 represents a haloalkenyl group. The resultant product may then, if desired, be converted into another compound of formula (II), for example by catalytic hydrogenation to convert a haloalkenyl group to a haloalkyl group.
Compounds of formula (XXXII) may be prepared by Swern oxidation of a compound of formula (II) in which R1 represents hydroxymethyl.
It will be appreciated that in order to obtain a compound of formula I which is in the configuration of formula Ia, the intermediates must be prepared in the appropriate configurations. The following formula illustrate the respective configurations for each of the intermediates.
As described hereinabove, the compounds of the invention are useful for the treatment of disorders of the central nervous system.
According to another aspect therefore, the present invention provides a method of treating a patient suffering from or susceptible to a disorder of the central nervous system, which comprises administering an effective amount of a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof.
The particular effective amount or dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
A variety of physiological functions have been shown to be subject to influence by excessive or inappropriate stimulation of excitatory amino acid transmission. The formula I compounds of the present invention are believed to have the ability to treat a variety of neurological disorders in patients associated with this condition, including acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. The formula I compounds are believed to have the ability to treat a variety of chronic neurological disorders, such as Alzheimer""s disease, Huntington""s Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, and idiopathic and drug-induced Parkinson""s. The present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof.
The formula I compounds of the present invention are also believed to have the ability to treat a variety of other neurological disorders in patients that are associated with glutamate dysfunction, including muscular spasms, convulsions, migraine headaches, urinary incontinence, psychosis, (such as schizophrenia), drug tolerance and withdrawal (such as nicotine, opiates and benzodiazepines), anxiety and related disorders, emesis, brain edema, chronic pain, and tardive dyskinesia. The formula I compounds are also useful as antidepressant and analgesic agents. Therefore, the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of formula I, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof.
The term xe2x80x9ctreatingxe2x80x9d for purposes of the present invention, includes prophylaxis, amelioration or elimination of a named condition once the condition has been established.
The term xe2x80x9cpatientxe2x80x9d for purposes of the present invention is defined as any warm blooded animal such as, but not limited to, a mouse, guinea pig, dog, horse, or human. Preferably, the patient is human.
According to another aspect, the present invention provides a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
According to yet another aspect, the present invention provides the use of a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder of the central nervous system.
The ability of compounds to modulate metabotropic glutamate receptor function may be demonstrated by examining their ability to influence either cAMP production (mGluR 2, 3, 4, 6, 7 or 8) or phosphoinositide hydrolysis (mGluR 1 or 5) in cells expressing these individual human metabotropic glutamate receptor (mGluR) subtypes. (D. D. Schoepp, et al., Neuropharmacol., 1996, 35, 1661-1672 and 1997, 36, 1-11).
In these tests the compound of Example 1 of the present application was found to reverse [3H] LY341495 binding with a Ki of 66.1 nM at mGluR2 and 7.9 nM at mGluR3 (average result from several tests). The compound of Example 22, which is an anantiomer of the compound of Example 1, was found to give a Ki of 30.5 nM for mGluR2 and 5.1 nM for mGluR3. (LY341495 is described in Ornstein et al., J. Med. Chem., 1998, 41, 346-357 and J. Med. Chem., 1998, 41, 358 to 378).
The ability of compounds to function as agonists of glutamate at metabotropic glutamate receptors may be determined by measuring their ability to decrease forskolin-stimulated cAMP in cells expressing mGluR receptors. The compound of Example 1 gave an EC50 in this test of 5.2 nM for mGluR2 and 11.5 nM for mGluR3.
The ability of compounds of formula I to treat anxiety and related disorders may be demonstrated using the well known fear-potentiated startle and elevated plus maze models of anxiety, as described in Davis, Psychopharmacology, 62:1; 1979, Lister, Psychopharmacology, 92: 180-185; 1987 and U.S. Pat. No. 5,750,566. The compound of Example 1 has been found to be highly potent in an animal model of anxiety.
The compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I, a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier, diluent, or excipient. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Excitatory amino acid receptor modulators


An apparatus for dispensing paper. The apparatus allows for the use of an existing wall-mounted dispenser without requiring any modification to the existing wall-mounted unit. The apparatus can also be free-standing or portable. The apparatus will accommodate rolled paper or sheets of paper. The apparatus also comprises an automated system for moistening and/or cleansing which enables the user to optionally moisten the paper and/or apply a cleansing agent to the paper if so desired. The degree (i.e.; the amount) of moistening or cleansing agent applied may be controlled by the user.

This invention relates to an apparatus for dispensing paper. This invention is especially useful for dispensing disposable paper products such as tissue and toweling.
U.S. Pat. No. 4,901,889 issued to Mitchell on Feb. 20, 1990 purports to teach an apparatus for rotatably mounting a roll of tissue in a holder and for dispensing a flowable substance.
U.S. Pat. No. 5,697,577 issued to Ogden on Dec. 16, 1997 purports to teach an apparatus for dispensing a roll of flushable, premoistened tissue paper.
U.S. Pat. No. 5,887,759 issued to Ayigbe on Mar. 30, 1999 purports to teach a liquid dispenser consisting of an H-shaped structure in which the central section and the end sections together serve as a reservoir for the liquid. The dispenser fits over a roll of toilet tissue and the central section includes a spray pump for directing a fine mist spray onto sheets of toilet tissue.
The drawback of these teachings is that the user has no means to control the degree of tissue moistening. Furthermore, the user is only able to utilize tissue which is in roll form. Yet further, the prior art dispensers are not readily attachable to an existing roll holder and require separate hardware for this purpose. Even further yet, the prior art dispensers require a user to make direct contact with the dispenser in order to moisten the tissue.
The benefits of the present invention include the ability to easily adapt the dispensing apparatus to different dispensing modes (i.e.; the apparatus can be easily attached to an existing roll holder, it can be used as a free-standing dispenser, or it can be used as a portable dispenser). Thus the dispenser is easily attachable and detachable from an existing roll holder and does not require separate hardware for this purpose. Furthermore components such as a moistening and/or cleansing system can be easily adapted to fit the dispenser of the present invention.
Additional benefits of the present invention include enhanced convenience and control for the user. The user controls whether the tissue is used dry or moist. The user also controls the degree to which the tissue is moistened. Furthermore, if the user chooses to moisten the tissue, the process of moistening the tissue can be automated using the dispenser of the present invention. Yet further, the present invention provides a wide variability in the type of moistening/cleansing agent which can be used and the format in which it is applied to the substrate (i.e.; foam, mist, spray, etc.). Yet even further, depending upon the user""s preference, the tissue may be dispensed either in roll or discrete sheet form.
Even further yet, the dispensing apparatus can be attached to an existing roll holder without requiring additional hardware, plumbing, or an external power source. Hence, the apparatus can be used without requiring any modification to the existing wall-mounted unit. The apparatus will accommodate rolled paper or sheets of paper. Standard size rolls of paper as well as oversized rolls of paper (for example oversized rolls of bath tissue, paper towel, or the like) can also be used.
The dispensing apparatus also comprises an automated (i.e.; xe2x80x9ctouchlessxe2x80x9d) system for moistening and/or cleansing which enables the user to optionally apply a cleansing agent to the paper if so desired without the need to contact the dispenser. The amount of cleansing agent applied may be controlled by the user.
The present invention relates to an apparatus for dispensing disposable paper products. The apparatus comprises an adapter. The adapter is comprised of a top wall, a bottom wall, a front wall, and a back wall all joined together. Both the top wall and the bottom wall comprise an attachment means whereby the top wall of the adapter is attachable to a first dispenser and the bottom wall of the adapter is attachable to a second dispenser.
The adapter may comprise a sleeve which is formed by the walls of the adapter. The sleeve is capable of containing a tissue roll holder spindle. The adapter may be releasably attachable to both the first dispenser and the second dispenser. Preferably the top wall and bottom wall attachment means of the adapter comprise slots and the bottom base of the first dispenser and the top base of the second dispenser comprise protuberances wherein the protuberances of the first dispenser are releasably joined to the slots of the top wall of the adapter and the protuberances of the second dispenser are releasably joined to the slots of the bottom wall of the adapter.
The first dispenser may comprise a disposable paper products dispenser, a cleanser dispenser, or a combination of both. Likewise, the second dispenser may comprise a disposable paper products dispenser, a cleanser dispenser, or a combination of both.
It is preferable that the cleanser dispenser be an automated dispenser which is activated by a user without requiring the user to touch the dispenser.


A system and method of allocating contiguous real memory in a data processing system. A memory controller within system memory receives a request from a data processing system component for a contiguous block of memory during operation of the data processing system. In response to receiving the request, the memory controller selects a candidate contiguous block of memory. Then, after temporarily restricting access to the candidate contiguous block of memory, the memory controller identifies a set of frames currently in use within the candidate contiguous block of memory, relocates the set of frames, and allocates the candidate block of memory for exclusive use by the requesting data processing component. The allocation of contiguous real memory occurs dynamically during the operation of the data processing system.

1. Technical Field
The present invention relates in general to the field of data processing systems. More particularly, the present invention relates to memory management within data processing systems. Still more particularly, the present invention relates to a system and method of allocating memory in data processing systems.
2. Description of the Related Art
Virtually all modern data processing systems utilize a virtual memory system to address memory space that greatly exceeds the size of actual, physical system memory. This virtual memory system frequently includes several levels of memory media, with smaller capacity, faster access memory units (e.g., caches, random-access memory) for storing recently-accessed data and larger capacity, slower access memory units (e.g., hard disk drives or other high-capacity storage units) that are only accessed when requested data is not found in the smaller-capacity memory units. Also, the virtual memory system typically includes a central memory controller for coordinating the transfer of data and instructions between the several levels of memory media. In this manner, the virtual memory system simulates a single, very large-capacity memory unit within the data processing system.
Processors access system memory via effective addresses that are later translated into physical addresses that reveal the actual, physical location of requested data or instructions. Because of the different levels of memory media, data or instructions located at contiguous effective addresses may not necessarily be located at contiguous physical addresses. For example, a first element of data may be located in the processor cache hierarchy because the first element was recently accessed by the processor. The second element of data may be located on the hard disk drive. Therefore, if the processor requires both elements for processing of a current task, the processor must wait for the central memory controller to retrieve the second element from the hard disk drive before processing of the current task can continue.
However, some data processing system components require the utilization of contiguous physical (also known as "real") memory regions. Components that require contiguous physical memory regions for operation are typically performance-oriented. The performance of such components would be compromised if the component would be required to halt operation during retrieval of necessary data from various levels of the virtual memory systems hierarchy. An example of such performance-oriented components are high-speed communication interconnect switches, which maintain control data in contiguous real memory regions.
Other reasons for maintaining contiguous real memory regions include system components that share large regions of memory for communication. For example, an operating system may share memory regions with system firmware. System firmware, unlike the operating system, cannot access memory via the virtual memory system.
A method well-known in the art for maintaining contiguous real memory regions involves reserving a static contiguous real memory region at system start up. However, there are many significant drawbacks to this prior art solution. First, the contiguous memory region must be statically sized at some default value or set by a system administrator based upon projected contiguous real memory usage requirements. The default value may not be appropriate for a particular system environment, which requires the system administrator to manually set a new value for the contiguous real memory region size. Also, since contiguous real memory region requirements vary over time, system administrators tend to conservatively oversize the allocated contiguous real memory region, which results in wasted system memory resources.
Another disadvantage to the prior art method is that since the contiguous real memory region is statically reserved from system memory, it is not available for general memory utilization. For example, if the current task consumes all available system memory earmarked for general utilization, any addition memory requirements cannot be satisfied from the contiguous real memory region, even if free memory is available within the contiguous real memory region.
Still another disadvantage to the prior art method is that any change in the size of the contiguous real memory region requires a system reboot. This results in interruption of the services provided by the data processing system.
Accordingly, there is a need for a system and method of dynamically allocating contiguous real memory regions.

This patent is subject to a terminal disclaimer.

System and method of allocating contiguous memory in a data processing system

International Business Machines Corporation


A cryogenic inertial Micro-Electro-Mechanical System (MEMS) device is provided. The device may include a vibratory gyroscope operable to sense a rotational acceleration. The device may also include a pre-amplifier co-located in a close proximity to the vibratory gyroscope. The device may be operated at substantially low temperatures, such as cryogenic temperatures, to reduce electrical noise and improve stability of outputs of the system.

A. Field of Invention
The present invention relates to MEMS devices, and more particularly, to cryogenic inertial MEMS devices.
B. Description of Related Art
Micro mechanics, micro-machines, or more commonly, Micro-Electro-Mechanical Systems (MEMS) are an integration of mechanical elements, such as sensors and actuators, and/or electronics on a common substrate through the utilization of micro-fabrication technology. While the electronics are fabricated using Integrated Circuit (IC) process sequences (e.g., CMOS, Bipolar, or BICMOS processes), micro-mechanical components are fabricated using compatible xe2x80x9cmicro-machiningxe2x80x9d processes that selectively etch away parts of a silicon wafer or add new structural layers to form mechanical and electromechanical devices.
Micro mechanical sensors include a mechanical structure and a sensing device. The mechanical structure is typically deformed and the sensing device transforms the deformation into an electrical signal. The mechanical structure deformation depends upon the shape of the structure, and also on the mechanical properties of the structure, such as Young""s Modulus, the Poisson ratio, and mechanical load distribution. Furthermore, environmental parameters, such as pressure, temperature, humidity, acceleration, rotation, etc., dictate a deformation of the mechanical structure. Mechanical properties and environmental parameters such as these can largely affect operation of a MEMS device due to a small size and shape of the MEMS device.
The sensing device within micro mechanical sensors may include electrically conducting bodies in close proximity with each other. Altering an arrangement of the electrically conducting bodies causes a change in capacitance that can be detected by a variation in voltage. Alternatively, MEMS devices may also operate based on temperature and heat conduction effects. Two metal plates may be placed in close proximity to each other and a heat transfer through a medium in a gap between the plates can be measured by a temperature resistance effect observed on the plates. Thus, methods of operation can be affected due to inherent electrical and mechanical properties of a MEMS.
MEMS operation presents obstacles due to these challenges present within the micro-machine domain. Empirical laws known to be true but insignificant at a macro level can be significant at a micro level. For example, a typical electrical conductor, such as gold, includes intrinsic electronic noise, which leads to inherent resistance, which can dominate operation of MEMS.
MEMS devices also include intrinsic fluctuations of operation due to thermal dynamical properties of the MEMS. For example, in operation of vibratory MEMS, such as a MEMS tuning fork gyroscope, the performance of the MEMS may be limited due to physical limitations of materials used within the MEMS, such as electrical conductors. For instance, Johnson noise (e.g., thermal noise) may be present within electrical conductors. Johnson noise is an inherent property among electrical conductors because it is substantially always present due to a random thermal motion of electrons. The Johnson noise power per unit bandwidth is proportional to absolute temperature and is independent of frequency, therefore operation of a MEMS at higher temperatures induces a larger Johnson noise. In addition, typical operation of a MEMS may be affected due to the Seebeck effect. The Seebeck effect produces a voltage between dissimilar conducting materials in the presence of a non-uniform temperature. In this situation, fluctuations in the temperature can produce voltage noise in MEMS devices. Finally, Brownian motion is present in substantially all devices due to fluctuating thermal mechanical forces. In devices with a small mass, such as MEMS devices, Brownian motion is especially significant. Brownian motion is a fundamental limitation to the ability to measure the position of a MEMS device. For example, the output of a MEMS gyroscope or MEMS accelerometer is determined by measuring the distance between two capacitor plates, at least one of which is located on the MEMS device.
Consequently, typical operation of a MEMS may be limited by inherent mechanical and electrical properties. As such, existing MEMS may not be able to meet manufacturing requirements and/or desired applications of MEMS. Thus, it would be desirable to provide a MEMS device that is able to overcome inherent mechanical and electrical property limitations.
In view of the above, some of the problems within MEMS operation associated with thermal and mechanical noise are overcome. In an exemplary embodiment, a method of operating an inertial Micro-Electro-Mechanical System (MEMS) device at a cryogenic temperature is provided. The inertial MEMS device may include cryogenic and/or super conducting materials to enhance operation at cryogenic temperatures. In addition, a method of operating an inertial Micro-Electro-Mechanical-System (MEMS) device is provided by providing a housing and an inertial MEMS device coupled to a pre-amplifier. The method further includes co-locating the inertial MEMS device and the pre-amplifier within a close proximity of the housing and operating the inertial MEMS device at cryogenic temperatures.
These as well as other features and advantages of the present invention will become apparent to those of ordinary skill in the art by reading the following detailed description, with appropriate reference to the accompanying drawings.

Cyrogenic inertial micro-electro-mechanical system (MEMS) device


A multi-party security protocol that incorporates biometric-based authentication and withstands attacks against any single party (e.g., mobile phone, cloud, or the user). The protocol involves the function split between mobile and cloud and the mechanisms to chain-hold the secrets. A key generation mechanisms binds secrets to a specific device or URL (uniform resource locator) by adding salt to a master credential. An inline CAPTCHA (Completely Automated Public Turing test to tell Computers and Humans Apart) handling mechanism uses the same sensor modality as the authentication process, which not only improves the usability, but also facilitates the authentication process. This architecture further enhances existing overall system security (e.g., handling untrusted or compromised cloud service, phone being lost, impersonation, etc.) and also improves the usability by automatically handling the CAPTCHA.

The emergence of the mobile Internet, highly available cloud services, and mobile phones with rich on-phone sensing capabilities have significantly changed the landscape of mobile computing. Mobile Internet is gaining popularity with such magnitude that the number of users that connect to the Internet using mobile devices is expected to exceed that of desktop PCs within the few years.
Current security mechanisms that use passwords are appropriate for keyboard-equipped desktop PCs, but inconvenient for most mobile devices that typically have a much smaller form factor. As a best practice, secure websites unanimously enforce, or at least advise, the use of strong passwords that require both a minimum password length and diversity on the character set used (e.g., characters are a mix of upper and lower case letters, digits and non-alphanumeric characters). Stronger passwords improve security. However, it further increases the difficulty of inputting password on a mobile device, which usability drawbacks may eventually result in users counteracting practices, and hence, fail the original goal of security.

Usable security of online password management with sensor-based authentication


A two-stage fluid control valve includes a first stage electronically switchable, bi-stable two-port valve movable between an open position and a leak-free closed position, and a second stage microvalve configured to control the flow of fluid through a fluid outlet of the two-stage fluid control valve when the first stage electronically switchable, bi-stable two-port valve is in the open position. The electronically switchable, bi-stable two-port valve is disposed between the second stage microvalve and a fluid inlet of the two-stage fluid control valve.

This invention relates in general to fluid control valves. In particular, this invention relates to an improved two-stage fluid control valve that includes a first stage electronically switchable, bi-stable two-port valve configured to control fluid flow to a second stage microvalve, such as for use in a system that requires a positive shut-off function.
MEMS (Micro Electro Mechanical Systems) are a class of systems that are physically small, having features with sizes in the micrometer range, i.e., about 10 μm or smaller. These systems have both electrical and mechanical components. The term "micromachining" is commonly understood to mean the production of three-dimensional structures and moving parts of MEMS devices. MEMS originally used modified integrated circuit (computer chip) fabrication techniques (such as chemical etching) and materials (such as silicon semiconductor material) to micromachine these very small mechanical devices. Today, there are many more micromachining techniques and materials available. The term "micromachined device" as used in this application means a device having some features with sizes of about 10 μm or smaller, and thus by definition is at least partially formed by micromachining. More particularly, the term "microvalve" as used in this application means a valve having features with sizes of about 10 μm or smaller, and thus by definition is at least partially formed by micromachining. The term "microvalve device" as used in this application means a micromachined device that includes a microvalve, and that may include other components. It should be noted that if components other than a microvalve are included in the microvalve device, these other components may be micromachined components or standard sized (larger) components. Similarly, a micromachined device may include both micromachined components and standard sized (larger) components.
Various microvalve devices have been proposed for controlling fluid flow within a fluid circuit. A typical microvalve device includes a displaceable member or valve component movably supported by a body for movement between a closed position and a fully open position. When placed in the closed position, the valve component substantially blocks or closes a first fluid port that is otherwise in fluid communication with a second fluid port, thereby preventing fluid from flowing between the fluid ports. When the valve component moves from the closed position to the fully open position, fluid is increasingly allowed to flow between the fluid ports.
U.S. Pat. Nos. 6,523,560; 6,540,203; and 6,845,962, the disclosures of which are incorporated herein by reference, describe microvalves made of multiple layers of material. The multiple layers are micromachined and bonded together to form a microvalve body and the various microvalve components contained therein, including an intermediate mechanical layer containing the movable parts of the microvalve. The movable parts are formed by removing material from the intermediate mechanical layer (by known micromachined device fabrication techniques, such as, but not limited to, deep reactive ion etching) to create a movable valve element that remains attached to the rest of the part by a spring-like member. Typically, the material is removed by creating a pattern of slots through the material to achieve the desired shape. The movable valve element will then be able to move in one or more directions an amount roughly equal to the slot width.
U.S. Pat. No. 7,156,365, the disclosure of which is also incorporated herein by reference, describes a method of controlling the actuator of a microvalve. In the disclosed method, a controller supplies an initial voltage to the actuator which is effective to actuate the microvalve. Then, the controller provides a pulsed voltage to the actuator which is effective to continue the actuation of the microvalve.
Conventional gas ranges and gas ovens use fluid control valves to control the flow of process gas or propane to one or more burners on a stovetop and in an oven, respectively. These conventional gas ranges and ovens require precise flame or temperature control and a positive shut-off function in the flow control valve to prevent an unwanted and potentially hazardous flow of process gas or propane when the gas range or oven burners are in an off position and wherein gas pressure is about 0.5 psi or lower. Additionally, the process of controlling the flow of fluid, such as process gas in silicon fabrication, such as in the fabrication of silicon wafers for MEMS microvalves, microchips, and the like, also requires a positive shut-off function to prevent defects in the fabrication process.
Conventional MEMS microvalves are known to provide very accurate fluid flow control, but typically experience a small amount of fluid leakage during normal operation, and are therefore unsuitable as a stand-alone flow control valve for use in a gas range application.
It would therefore be desirable to provide a two-stage fluid control valve that includes a first stage electronically switchable, bi-stable two-port valve configured to control fluid flow to a second stage microvalve.

Two-stage fluid control valve having a first stage bi-stable two-port valve and a second stage microvalve


A unitized, switch activating mechanism for use in keyboard assemblies for activating snap dome or similar type switches. The mechanism includes a relatively hard actuating tip portion disposed intermediate an elastomeric conical skirt portion and a light guide portion. The conical skirt functions both as a light reflector and as a return spring. The light guide portion is constructed from a diffused translucent, relatively hard elastomeric material which functions as a highly efficient light guide for uniformly illuminating the key legend of the key board assembly with which the light guide interfaces.

1. Field of the Invention
The present invention relates generally to mechanisms for activating electrical switches. More particularly, the invention concerns an improved switch actuating mechanism for use with a keyboard assembly having a light source and embodying snap dome or similar type electrical switches.
2. Discussion of the Invention
A number of different kinds of switch actuating mechanisms for use in various keyboard applications have been suggested. These include elastomeric key pad actuators in a key matrix format and multiple, single function, discrete component switch activating assemblies. These latter assemblies are relatively complex and comprise a number of separate and discrete single function components such as light guides, light plates, plungers, return springs, contact pins, and contact actuating elements.
The prior art elastomeric key pad actuators typically comprise a "waffle-like" sheet which is provided with a number of actuator key elements arrayed in rows and columns. While these types of actuators are of simple design and include a minimum number of discrete components, they typically lack the ability to pipe sufficient light from adjacent light sources to effectively illuminate the actuating keys.
Other prior art switch actuating mechanisms include capactive, touch-type activators, optical interrupted beam type actuators and piezo-electric-type activators. As a general rule, these latter types of devices have limited applicability and are appropriate for only certain specialized applications.
As will better be appreciated from the discussion which follows, the switch actuating mechanism of the present invention exhibits numerous advantages over the prior art. For example, the device of the present invention is extremely simple in design, is highly reliable, is very inexpensive to manufacture and includes highly novel integrated light management features not found in any of the prior art switch actuating devices.


The present disclosure concerns a belt conveyor roller wear liner superposable against an outer peripheral surface of a roller cylindrical body, the roller wear liner comprising: a shock-absorbing matrix; and a plurality of inserts, spaced-apart from one another and embedded in the shock-absorbing matrix with external surfaces of the inserts and the shock-absorbing matrix, extending between the inserts, being exposed outwardly, the roller wear liner being substantially ring-shaped. It also concerns a corresponding belt conveyor roller assembly, a corresponding belt conveyor and a corresponding method.

Belt conveyor rollers are designed for use on belt conveyors as means to drive, redirect, provide tension to, support, or help track a conveying belt thereof. Due to their permanent contact with an inner face of the conveying belt and the friction inbetween, the belt conveyor rollers might get quickly worn out and/or might wear the inner face of the conveying belt.
In view of the above, there is a need for a belt conveyor roller which would be able to overcome or at least minimize some of the above-discussed prior art concerns.

Belt conveyor roller wear liner, belt conveyor roller and conveyor including same and corresponding method


A method for fixing a fuel level sensor in a fuel tank having an upper and a lower wall, the sensor having a foot and a top. The method fixedly secures the foot of the sensor to the bottom wall of the fuel tank through a molded-in retainer, and elastically fixes the tubular top of the sensor to the top wall of the tank through a molded-in retainer as well.

I. Field of the Invention
The present invention relates to a level sensor mounting.
II. Description of Related Art
Typically automotive fuel systems use a rotary resistive fuel level sensor that is mounted directly to the fuel pump module to measure remaining fuel inside the tank.
The fuel tank is becoming more complex as many OEM's are packaging other components such as batteries, exhaust and driveline components around or through the fuel tank. A major advantage of a plastic fuel tank is it offers car manufacturers the ability to optimize and utilize available vehicle environment for fuel storage. However, because of this advancement many fuel systems are being designed with pump modules which are located below the full fuel level. This is known as a wet pump mounting. Wet mountings often inhibit the rotary fuel level sensor from sweeping to the full stop fuel level. Improving the measurement range requires a longer sensor float arm rod or an extension bracket to reposition or extend the sensor mounting off of the pump module. This can increase the difficulty of installing the pump module assembly inside the tank and can also decrease the accuracy of the measurement. Often it is not possible to reach the optimum sweep for the rotary fuel level sensor float arm even with an extension.
Other issues related to resistive rotary fuel level sensors are damage to the resistive circuit card due to aggressive fuels, limited resolution, and wear or damage of moving parts.
Because of these issues, car manufactures prefer to have a fuel level sensor with no moving parts.
Although many technologies have existed which have no moving parts, the cost has typically been two to five times higher than a resistive rotary gage. Introduction of non-moving part fuel level sensors for production applications has been limited to specialty vehicles due to high cost.
Another issue with some non-moving part fuel level sensors is that they are not bottom referenced (meaning they cannot measure to the bottom, empty level of the fuel tank) because they are usually only fixed to the top of the fuel tank, and not to the bottom.
For instance, U.S. Pat. No. 4,679,431 teaches the fixation of a capacitance fuel level sensor to the top of the tank only, using a specific, rather complicated system with a plurality of discs.
The problem of poor measuring accuracy owed to the lack of bottom referencing was already addressed in document FR 2,560,167, which solves the problem with a fixing method through which the gauge extends outside the tank which is nowadays avoided for permeability (environmental) reasons.

Inergy Automotive Systems Research (Societe Anonyme)


Provided is a method for manufacturing a semiconductor device. An insulation layer is formed on a bottom structure of a semiconductor substrate. Then, a trench and a via hole are formed by selectively etching the insulation layer, and a copper layer is deposited to fill the via hole and the trench. Next, a copper line is formed by a CMP (chemical mechanical polishing) process to planarize the copper layer, and a plasma process is performed to form a plasma-treated surface layer of the semiconductor substrate. The plasma-treated surface layer is then removed.

1. Field of the Invention
The present invention relates to a method for manufacturing a semiconductor device.
2. Description of the Related Art
When copper is applied as a metal line of a semiconductor device, a dual damascene process is generally performed to form a trench and a via hole in a line shape.
FIG. 1 is a sectional view illustrating a method for manufacturing a copper line according to a related art.
Referring to FIG. 1, an insulation layer 12 is formed on a bottom structure 11 where a predetermined process has been performed. Then, the insulation layer 12 is etched by performing a dual damascene process to form a dual damascene pattern 13.
Next, a copper line 14 is formed using electroplating etc. until the dual damascene pattern 13 is filled.
Next, a chemical mechanical polishing (CMP) process is performed to planarize and/or separate adjacent copper line layers 14.
The above process is called a Cu CMP process. After the Cu CMP process, a cleaning process is performed to remove floating or extraneous matter and slurry generated during the CMP process.
However, according to a related art, copper corrosion 15 may form on the copper line layer 14 by photo corrosion or galvanic corrosion after cleaning, or copper remainder 16 may remain on the surface of a wafer after cleaning.
When an intermetal dielectric (IMD) layer is deposited without removing the copper corrosion 15 or the copper remainder 16, adhesion of the subsequently deposited IMD may be weakened. Additionally, copper atoms in the copper remainder 16 may diffuse into the IMD layer, thereby increasing the possibility of causing a short between the copper line layers 14.
Accordingly, the related art process may require an additional cleaning process to remove particles that may not be removed during the cleaning process or that may be generated after the cleaning process. If the IMD layer is deposited when the particles remain, copper may diffuse between the dielectric layers due to an insufficient adhesion.
Especially, because it is difficult to remove certain copper residue such as the copper corrosion generated by photo corrosion or galvanic corrosion and the copper remainder caused by an uneven wafer surface in the related art process, a new cleaning process is in demand.

Method for manufacturing semiconductor device


A light source unit includes: a light source part that supplies light; an optical element that changes an optical path of the light from the light source part; and a wavelength conversion element that converts a wavelength of the light from the optical element. The optical element is movable, and the optical path of the light entering the wavelength conversion element from the light source part is shifted by moving the optical element.

1. Technical Field
The present invention relates to a light source unit, an illumination device, an image display apparatus, and a monitor apparatus, and specifically, to a laser light source unit technology of supplying laser light.
2. Related Art
Recently, as a light source unit for a projector, a technology using a laser light source that supplies laser light has been proposed. As a laser light source, not only one that directly supplies fundamental wave light from a light emitting part but also one that converts the wavelength of the fundamental wave light and supplies it is known. As a wavelength conversion element that converts the wavelength of fundamental wave light, for example, a second-harmonic generation (SHG) element is used. As the SHG element, for example, a nonlinear optical crystal is used. Within the nonlinear optical crystal that performs second harmonic generation, nonlinearly-polarized wave and SHG wave propagate because of nonlinear polarization induced by a strong photoelectric field. The SHG element can generate SHG wave efficiently when the phase matching condition depending on generation wavelength or the like is satisfied. Phase matching refers to matching of phases between the nonlinearly-polarized wave and SHG wave. Phase matching includes angular phase matching of entering the fundamental wave at an incident angle at which the refractive index at the wavelength of the fundamental wave and the refractive index at the wavelength of the SHG wave are equal, for example. In a related art, a technology of adjusting the phase matching angle has been proposed for efficient SHG wave generation (e.g., see JP-A-2000-250082). The phase matching angle refers to the incident angle of the fundamental wave that satisfies the phase matching condition.

Light source unit, illumination device, image display apparatus, and monitor apparatus


Disclosed is a novel transition metal compound represented by the following formula: ##STR1## wherein M is a transition metal, X is halogen or the like, R.sup.1 is a hydrocarbon group or the like, R.sup.2 is an aryl group substituted with a halogenated hydrocarbon group, and Y is a divalent silicon-containing group or the like.. Also disclosed are an olefin polymerization catalyst component comprising the transition metal compound, an olefin polymerization catalyst comprising the olefin polymerization catalyst component, and a process for olefin polymerization using the olefin polymerization catalyst.. An olefin polymerization catalyst component having high polymerization activity can be formed from the transition metal compound. By the use of the olefin polymerization catalyst or the process for olefin polymerization, polyolefins having a high melting point and a high molecular weight can be prepared with high polymerization activity.

The "Kaminsky catalyst" is well known as a homogeneous catalyst system for olefin polymerization. This catalyst has an extremely high polymerization activity, and provides a polymer having a narrow molecular weight distribution.
Of the transition metal compounds used for the Kaminsky catalyst, for example, ethylenebis(indenyl)zirconium dichloride and ethylenebis(4,5,6,7-tetrahydroindenyl)zirconium dichloride has been known to be used for producing isotactic polyolefins, as described in Japanese Patent Laid-Open Publication No. 130314/1986. However, polyolefins prepared by the use of such catalyst generally have a low stereoregularity and a low molecular weight. If low temperatures are used, polymers having a high stereoregularity or a high molecular weight can be obtained, but a problem of low polymerization activity is involved.
It has been known that use of hafnium compounds in place of the zirconium compounds makes it possible to prepare high molecular polymers, as described in Journal of Molecular Catalysis, 56 (1989), pp. 237-247, but this process involves a problem of low polymerization activity. Further, compounds such as dimethylsilylbis-substituted cyclopentadienylzirconium dichloride have also been known from Japanese Patent Laid-Open Publication No. 130704/1989 and Polymer Preprints, Japan, vol. 39, No. 6, pp. 1,614-1616 (1990), but there is a problem in that they do not satisfy all of the high polymerization activity, and the high melting point and molecular weight at the same time.
Japanese Patent Laid-Open Publication No. 268307/1992 describes an olefin polymerization catalyst formed from a metallocene compound represented by the following formula ##STR2## and an aluminoxane.
Further, EP 0 530 648 Al describes another olefin polymerization catalyst formed from a metallocene compound represented by the following formula ##STR3## wherein A is a lower alkyl group, and an aluminoxane.
However, the polyolefins obtained by the use of these catalysts are still insufficient in the melting point, the molecular weight, etc. In this connection, a catalyst containing a compound of the above formula wherein A is a phenyl group is disclosed by Hoechst AG. in 40 YEARS ZIEGLER CATALYSIS IN HONOR OF KARL ZIEGLER AND WORKSHOP (Sep. 1-3, 1993). However, there remains a problem that the polyolefins obtained by the use of this catalyst still have a low melting point and a low molecular weight.
Under these circumstances, the advent of an olefin polymerization catalyst and a process for olefin polymerization, each of which shows a high olefin polymerization activity and produces polyolefins of excellent properties, is desired. Further, also desired is the advent of a catalyst component which can be used for such olefin polymerization catalyst and a novel transition metal compound which can be used as the olefin polymerization catalyst component.

Transition metal compound, olefin polymerization catalyst component comprising the transition metal compound, olefin polymerization catalyst comprising the olefin polymerization catalyst component, and process for olefin polymerization


Disclosed is a process for treating body tissues such as vascular structures to remove barriers to recellularization before and after implantation in a human host. The body tissue, for example a heart valve, is subjected to a hypotonic/hypertonic treatment, then treated with enzymes to provide a collagen- and elastin-containing matrix suitable for recellularization.

Currently available prostheses for the replacement of defective heart valves and other vascular structures may be classified as mechanical or bioprosthetic. Mechanical structures such as heart valves are manufactured from biocompatible metals and other materials such as Silastic.RTM., graphite, titanium, and Dacron.RTM.. Although mechanical valves have the advantage of proven durability in decades of use, they frequently are associated with a high incidence of blood clotting on or around the valve. This can lead to acute or subacute closure. For this reason, patients with implanted mechanical valves generally must remain on anticoagulants for as long as the valve remains implanted. Anticoagulants are inconvenient to take and impart a 3-5% annual risk of significant bleeding.
Bioprosthetic valves were introduced in the early 1960's and are typically derived from pig aortic valves or are manufactured from other biological materials such as bovine pericardium. Xenograft heart valves invariably are tanned in glutaraldehyde prior to implantation. A major rationale for the use of autologous or heterologous biological material for heart valves is that the profile and surface characteristics of this material are optimal for laminar, nonturbulent blood flow. The result is that intravascular clotting is less likely to occur than with mechanical valves. This concept has been proven in clinical use with the well-documented reduced thrombogenicity of current versions of glutaraldehyde-fixed bioprosthetic valves.
Unfortunately all such valves are limited by the tendency to fail, often catastrophically, beginning about 7 years after implantation. Few bioprosthetic valves remain functional after 12 years. Valve degeneration is particularly rapid in the young and during pregnancy. Replacement of a degenerating valve prosthesis is particularly hazardous in the elderly and in situations of emergency replacement. As a consequence, there are few real indications and many contraindications to the use of bioprosthetic valves.
Clearly, solving the problem of bioprosthetic valve degeneration would be highly desirable. Calcification appears to be the primary insult leading to degeneration. Efforts to address the calcification problem have included treating glutaraldehyde-fixed valves with compounds such as toluidine blue, sodium dodecyl sulfate and diphosphonate to reduce calcium nucleation. However, these efforts have been unsuccessful in vivo. Other approaches include removal of reactive glutaraldehyde moieties from the tissue by a chemical process. Still other approaches have included development of alternate fixation techniques, since evidence suggests that the fixation process itself contributes to calcification and mechanical deterioration. Finally, since nonviable cells present in transplanted tissue are sites for calcium deposition, various processes have been developed to remove cells from the valve matrix prior to implantation. Most of these processes appear to reduce calcification in animal models in short-term use, but clinical data are not yet available.
Another major disadvantage to bioprosthetic devices is the failure of such devices to be self-maintaining. Neither cadaveric allografts nor glutaraldehyde-fixed xenografts have significant populations of viable cells, and glutaraldehyde is highly cytotoxic. Since viable cells in the valve provide protection against the insudation of calcium, it is likely that any devitalized bioprosthesis will undergo calcification over time. Hence it is essential to the development of a durable prosthetic device that it support ingrowth and colonization of cells 1) from the host during the period after implantation, 2) from autologous or allogeneic sources before implantation, e.g., during a period of in vitro culture prior to implantation, or 3) from both the host after implantation and from various sources prior to implantation.
Various detergents and nucleases have been used in the past to obtain extracellular matrix from body sources for use as potential graft materials. Detergent treatment of a glutaraldehyde-fixed body structure is disclosed in U.S. Pat. No. 4,323,358 as a method for retarding mineralization after implantation. Decellularization of unfixed, untreated body structures by detergent methods is disclosed in U.S. Pat. No. 4,352,887 as a means for producing a substrate for cell culture, and in U.S. Pat. No. 4,801,299 as a means for producing sterile body implants. U.S. Pat. No. 4,776,853 discloses a specific process for achieving decellularization by a combination of nonionic and anionic detergents, deoxyribonuclease (DNAse) and ribonuclease (RNAse).
The field of tissue and organ transplantation is growing rapidly as a result of a number of advances in the areas of organ preservation, surgical techniques, and immunosuppressive agents. As a result, shortages of implantable material are often the major obstacle in the use of bioprosthetic implants. As used herein, the term "autologous" refers to cells, tissues or other biological structures derived from the same individual designated to receive the implant. The term "allogeneic" refers to cells, tissues or other biological structures taken from other members of the same species. The term "xenogeneic" refers to cells, tissues or other biological structures taken from a member of a species other than the species of the individual receiving the implant.
Shortages of implantable materials for human patients are particularly acute for heart valves, where autologous structures such as the pulmonic valve can only infrequently be used as a source of replacement material, and allogeneic implantable materials are limited. Improved methods of cryopreservation have increased the number of available allogeneic bioprosthetic implants. Extending the use of cryopreservation to xenogeneic body sources is disclosed in U.S. Pat. No. 5,336,616. That patent describes a method for processing and preserving acellular collagen-based tissue matrix for transplantation that includes a detergent-based decellularization step. Decellularization is followed by cryopreservation and dehydration. On rehydration, the tissue is inoculated with viable autologous or allogeneic cells.
A number of specific conditions that affect use of xenogeneic material for heart valve implantation have yet to be fully addressed. These include the exacting requirements for mechanical integrity in short- and long-term use, as unscheduled replacement of these structures is difficult and risky. Long-term durability is affected not only by the harvesting and decellularization processes, but by the ability of cells to enter and carry out maintenance functions in the implanted tissue. That viable cells are an essential determinant of valve survival is clear from longitudinal studies in allograft recipients. In these studies, proper allograft preservation can maximize the number of viable cells remaining in the tissue as determined by matrix protein synthesis. Preservation techniques that do not promote cell survival, such as long term storage at 4.degree. C., are associated with reduced in vivo durability and increased reoperation rates.
The repopulation of matrix by contiguous cells in the host, or by inoculated autologous or allogeneic cells in tissue culture, can be critical to development of a successful implant. In turn, the characteristics of the matrix can be critical to the repopulation ("recellularization") process. For example, failure to effectively reduce the dense cellularity of the donor aortic root is likely to be a significant obstacle to cell ingrowth, due to the physical barrier created by the cellular architecture of the root, or to the effect of contact inhibition between in-migrating host cells and the remaining in situ donor cells.
Previously described processing methods have been developed and tested with the goals of reducing antigenicity and mineralization of the xenograft, but have dealt only incidentally with the problem of recellularization. Thus, the adequacy of decellularization and the ability of the decellularized matrix to support ingrowth by autologous or allogeneic cells remains to be demonstrated. Moreover, the physical constraints imposed by the method of implantation have not been considered in envisioning how host cells may migrate into and repopulate a decellularized matrix following implantation. For example, methods of implantation may include use of a Dacron.RTM. sewing ring in the case of xenograft heart valves, or freehand attachment via the root structure in the case of allogeneic heart valves. Each of these methods presents distinctive challenges for obtaining adequate recellularization of the decellularized matrix. The methods disclosed herein provide a useful substrate for ingrowth by host cells following implantation due to enhanced removal of cells from the host/graft interface.

Matrix substrate for a viable body tissue-derived prosthesis and method for making the same