The present invention relates to novel imidazole derivatives having a positive allosteric GABAB receptor (GBR) modulator effect, methods for the preparation of said compounds and to their use, optionally in combination with a GABAB agonist, for the inhibition of transient lower esophageal sphincter relaxations, for the treatment of gastroesophageal reflux disease, as well as for the treatment of functional gastrointestinal disorders and irritable bowel syndrome (IBS). The compounds are represented by the general formula (I) wherein R1, R2, R3 and Y are as defined in the description. For example, R1 may be phenyl, R2 may be dimethylamino, R3 may be alkoxy and Y may be a thioylamino- or methyl eneamino- linked substitutuent containing an aryl group.

The lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
Gastroesophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy aims at reducing gastric acid secretion, or at neutralizing acid in the esophagus. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, recent research (e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535) has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESR), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
Consequently, there is a need for a therapy that reduces the incidence of TLESR and thereby prevents reflux.
GABAB-receptor agonists have been shown to inhibit TLESR, which is disclosed in WO 98/11885 A1.
GABAB Receptor Agonists
GABA (4-aminobutanoic acid) is an endogenous neurotransmitter in the central and peripheral nervous systems. Receptors for GABA have traditionally been divided into GABAA and GABAB receptor subtypes. GABAB receptors belong to the superfamily of G-protein coupled receptors (GPCRs).
The most studied GABAB receptor agonist baclofen (4-amino-3-(p-chlorophenyl)butanoic acid; disclosed in CH 449046) is useful as an antispastic agent. EP 356128 A2 describes the use of the GABAB receptor agonist (3-aminopropyl)methylphosphinic acid for use in therapy, in particular in the treatment of central nervous system disorders.
EP 463969 A1 and FR 2722192 A1 disclose 4-aminobutanoic acid derivatives having different heterocyclic substituents at the 3-carbon of the butyl chain. EP 181833 A1 discloses substituted 3-aminopropylphosphonic acids having high affinities towards GABAB receptor sites. EP 399949 A1 discloses derivatives of (3-aminopropyl)methylphosphinic acid, which are described as potent GABAB receptor agonists. Still other (3-aminopropyl)methylphosphinic acids and (3-aminopropyl)phosphinic acids have been disclosed in WO 01/41743 A1 and WO 01/42252 A1, respectively. Structure-activity relationships of several phosphinic acid analogues with respect to their affinities to the GABAB receptor are discussed in J. Med. Chem. (1995), 38, 3297-3312. Sulphinic acid analogues and their GABAB receptor activities are described in Bioorg. & Med. Chem. Lett. (1998), 8, 3059-3064. For a more general review on GABAB ligands, see Curr. Med. Chem.-Central Nervous System Agents (2001), 1, 27-42.
Positive Allosteric Modulation of GABAB Receptors
2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930) and 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-dimethylpropanal (disclosed in U.S. Pat. No. 5,304,685) have been described to exert positive allosteric modulation of native and recombinant GABAB receptor activity (Society for Neuroscience, 30th Annual Meeting, New Orleans, La., Nov. 4-9, 2000: Positive Allosteric Modulation of Native and Recombinant GABAB Receptor Activity, S. Urwyler et al.; Molecular Pharmacol. (2001), 60, 963-971).
N,N-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine has been described to exert positive allosteric modulation of the GABAB receptor (The Journal of Pharmacology and Experimental Therapeutics, 307 (2003), 322-330).
For a recent review on allosteric modulation of GPCRs, see: Expert Opin. Ther. Patents (2001), 11, 1889-1904.
Outline of the Invention
The present invention relates to a compound of the general formula (I)
wherein    R1 represents C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, SO3R7, halogen(s), hydroxy, mercapto, carboxylic acid, CONR5R9, NR5COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or    R1 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10C alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups, wherein any aryl or heteroaryl group used in defining R1 may be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy, wherein said C1-C10 alkyl may be further substituted by one or two aryl or heteroaryl groups;    R2 represents C1-C6 alkyl, C1-C6 alkoxy or NR5R6; optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups;    R3 represents C1-C10 alkoxy, optionally substituted by one or more of C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups;    C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or    R3 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or    R3 represents amino, optionally mono- or disubstituted with C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl or C3-C10 cycloalkyl;    Y represents
    R4 represents C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C1-C10 alkoxy; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, keto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, COR10, nitrile, SO2NR8R9, SO2R11, NR8SO2R9, NR8C═ONR9 or one or two aryl or heteroaryl groups; or    R4 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR5R9, NR8COR9, CO2R10, SO3R7, nitrile or one or two aryl or heteroaryl groups, wherein said aryl or heteroaryl group used in defining R4 may be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy, wherein said C1-C10 alkyl may be further substituted by one or two aryl or heteroaryl groups;    R5 represents hydrogen, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, CONR5R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups;    R5 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR5R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups;    R6 represents hydrogen, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups;    R6 represents aryl or heteroaryl, each optionally substituted by C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C1 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups;    or R5 and R6 together form a ring consisting of from 3 to 7 atoms selected from C, N and O, wherein said ring is optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, keto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups;    R7 each and independently represents C1-C10 alkyl;    R8 each and independently represents hydrogen, C1-C10 alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy;    R9 each and independently represents hydrogen, C1-C10 alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy;    R10 each and independently represents C1-C10 alkyl, optionally substituted by aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy;    R11 represents C1-C10 alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy;    wherein each of alkyl, alkenyl, alkynyl and cycloalkyl used in defining R1 and R3-R11 may independently have one or more carbon atom(s) substituted for O, N or S; wherein none of the O, N or S is in a position adjacent to any other O, N or S;    wherein each of alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl may independently have one or more carbon atom(s) substituted by fluoro;    with the proviso that R2 may only represent alkoxy if Y represents NHSO2 or NHCS;    as well as pharmaceutically and pharmacologically acceptable salts thereof, and enantiomers of the compound of formula (I) and salts thereof.
According to one embodiment of the present invention R1 represents C1-C4 alkyl, optionally substituted by one aryl or two heteroaryl groups.
According to another embodiment of the present invention, R1 represents aryl, optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, SO3R7, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrite or one or two aryl or heteroaryl groups.
In another embodiment of the present invention, R1 represents unsubstituted phenyl.
In yet another embodiment of the present invention, R2 represents C1-C4 alkyl.
In a further embodiment of the present invention, R3 represents C1-C4 alkoxy, optionally substituted by one or more of C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrite or one or two aryl or heteroaryl groups.
In another embodiment of the present invention, R3 represents C1-C10 alkyl, optionally substituted by one or more of C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrite or one or two aryl or heteroaryl groups.
In a further embodiment of the present invention R4 represents C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl or C3-C7 cycloalkyl, optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrite, SO2NR8R9, NR8SO2R9, NR8C═ONR9 or one or two aryl or heteroaryl groups, wherein any aryl or heteroaryl group used in defining R4 may be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy, wherein said C1-C10 alkyl may be further substituted by one or two aryl or heteroaryl groups.
According to a further embodiment of the present invention, R4 represents C1-C4 alkyl, optionally substituted by one or two aryl or heteroaryl groups.
According to another embodiment of the present invention, R4 represents C1-C4 alkyl, substituted by one or two aryl or heteroaryl groups.
In a further embodiment of the present invention, R4 represents aryl or heteroaryl, optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups.
In yet another embodiment of the present invention, R5 represents C1-4 alkyl.
In one embodiment of the present invention, R5 represents methyl.
In yet another embodiment of the present invention, R6 represents C1-4 alkyl.
In a further embodiment of the present invention, R6 represents methyl.
According to another embodiment of the present invention R5 and R6 form a ring consisting of 5 or 6 atoms selected from C, O and N.
In one embodiment of the present invention Y represents

In another embodiment of the present invention, Y represents

According to another embodiment of the present invention,    R1 represents aryl;    R2 represents NR5R6;    R3 represents C1-C10 alkoxy;    Y represents
    R4 represents C1-C10 alkyl; optionally substituted by one aryl; or    R4 represents aryl or heteroaryl, each optionally substituted by one halogen;    R5 represents hydrogen or C1-C10 alkyl;    R6 represents hydrogen or C1-C10 alkyl;    or R5 and R6 together form a ring consisting of from 3 to 7 atoms selected from C or N;    wherein the alkyl used in defining R4 may have one carbon atom substituted for O.
According to yet another embodiment of the present invention,    R1 represents aryl;    R2 represents NR5R6;    R3 represents C1-C4 alkoxy;    Y represents
    R4 represents C1-C10 alkyl; optionally substituted by one aryl; or    R4 represents aryl or heteroaryl, each optionally substituted by one halogen;    R5 represents C1-C4 alkyl;    R6 represents hydrogen, C1-C4 alkyl;    or R5 and R6 together form a ring consisting of from 5 to 6 atoms selected from C or N;    wherein the alkyl used in defining R4 may have one carbon atom substituted for O.
The present invention also relates to a compound selected from    tert-butyl 4-{[(4-chlorophenyl)carbonothioyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;    tert-butyl 4-{[(1Z)-(4-chlorophenyl)(pyrrolidin-1-yl)methylene]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate;    tert-butyl 4-[(2,3-dihydro-1,4-benzodioxin-2-ylcarbonothioyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate; and    tert-butyl 4-{[2-(benzyloxy)ethanethioyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate.
The compounds of formula (I) above are useful as positive allosteric GABAB receptor modulators as well as agonists.
The molecular weight of compounds of formula (I) above is generally within the range of from 300 g/mol to 700 g/mol.
It is to be understood that the present invention also relates to any and all tautomeric forms of the compounds of formula (I).
The general terms used in the definition of formula (I) have the following meanings:    C1-C10 alkyl is a straight or branched alkyl group, having from 1 to 10 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, hexyl or heptyl. The alkyl groups may contain one or more heteroatoms selected from O, N and S, i.e. one or more of the carbon atoms may be substituted for such a heteroatom. Examples of such groups are methyl-ethylether, methyl-ethylamine and methyl-thiomethyl. The alkyl group may form part of a ring. One or more of the hydrogen atoms of the alkyl group may be substituted for a fluorine atom.
C1-C4 alkyl is a straight or branched alkyl group, having from 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl. The alkyl groups may contain one or more heteroatoms selected from O, N and S, i.e. one or more of the carbon atoms may be substituted for such a heteroatom. Examples of such groups are methyl-ethylether, methyl-ethylamine and methyl-thiomethyl. One or more of the hydrogen atoms of the alkyl group may be substituted for a fluorine atom.
C2-C10 alkenyl is a straight or branched alkenyl group, having 2 to 10 carbon atoms, for example vinyl, isopropenyl and 1-butenyl. The alkenyl groups may contain one or more heteroatoms selected from O, N and S, i.e. one or more of the carbon atoms may be substituted for such a heteroatom. One or more of the hydrogen atoms of the alkenyl group may be substituted for a fluorine atom.
C2-C10 alkynyl is a straight or branched alkynyl group, having 2 to 10 carbon atoms, for example ethynyl, 2-propynyl and but-2-ynyl. The alkynyl groups may contain one or more heteroatoms selected from O, N and S, i.e. one or more of the carbon atoms may be substituted for such a heteroatom. One or more of the hydrogen atoms of the alkynyl group may be substituted for a fluorine atom.
C3-C10 cycloalkyl is a cyclic alkyl, having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkyl may also be unsaturated. The cycloalkyl groups may have one or more heteroatoms selected from O, N and S, i.e. one or more of the carbon atoms may be substituted for such a heteroatom. One or more of the hydrogen atoms of the cycloalkyl group may be substituted for a fluorine atom.
C1-C10 alkoxy is an alkoxy group having 1 to 10 carbon atoms, for example methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentoxy, hexoxy or a heptoxy group. The alkoxy may be cyclic, partially unsaturated or unsaturated, such as in propenoxy or cyclopentoxy. The alkoxy may be aromatic, such as in benzyloxy or phenoxy.
C1-C4 alkoxy is an alkoxy group having 1 to 4 carbon atoms, for example methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, secondary butoxy, tertiary butoxy. The alkoxy may be cyclic, partially unsaturated or unsaturated, such as in propenoxy or cyclopentoxy.
C1-C10 thioalkoxy is a thioalkoxy group having 1 to 10 carbon atoms, for example thiomethoxy, thioethoxy, n-thiopropoxy, n-thiobutoxy, thioisopropoxy, thioisobutoxy, secondary thiobutoxy, tertiary thiobutoxy, thiopentoxy, thiohexoxy or thioheptoxy group. The thioalkoxy may be unsaturated, such as in thiopropenoxy or aromatic, such as in thiobenzyloxy or thiophenoxy.
The term "aryl" is herein defined as an aromatic ring having from 6 to 14 carbon atoms including both single rings and polycyclic compounds, such as phenyl, benzyl or naphtyl. Polycyclic rings are saturated, partially unsaturated or saturated.
The term "heteroaryl" is herein defined as an aromatic ring having 3 to 14 carbon atoms, including both single rings and polycyclic compounds in which one or several of the ring atoms is either oxygen, nitrogen or sulphur, such as furanyl, thiophenyl or imidazopyridine. Polycyclic rings are saturated, partially unsaturated or saturated.
Halogen(s) as used herein is selected from chlorine, fluorine, bromine or iodine.
The term "keto" is defined herein as a divalent oxygen atom double bonded to a carbon atom. Carbon atoms are present adjacent to the carbon atom to which the divalent oxygen is bonded.
When the compounds of formula (I) have at least one asymmetric carbon atom, they can exist in several stereochemical forms. The present invention includes the mixture of isomers as well as the individual stereoisomers. The present invention further includes geometrical isomers, rotational isomers, enantiomers, racemates and diastereomers.
Where applicable, the compounds of formula (I) may be used in neutral form, e.g. as a carboxylic acid, or in the form of a salt, preferably a pharmaceutically acceptable salt such as the sodium, potassium, ammonium, calcium or magnesium salt of the compound at issue.
The compounds of formula (I) are useful as positive allosteric GBR (GABAB receptor) modulators. A positive allosteric modulator of the GABAB receptor is defined as a compound which makes the GABAB receptor more sensitive to GABA and GABAB receptor agonists by binding to the GABAB receptor protein at a site different from that used by the endogenous ligand. The positive allosteric GBR modulator acts synergistically with an agonist and increases potency and/or intrinsic efficacy of the GABAB receptor agonist. It has also been shown that positive allosteric modulators acting at the GABAB receptor can produce an agonistic effect. Therefore, compounds of formula (I) can be effective as fall or partial agonists.
A further aspect of the invention is a compound of the formula (I) for use in therapy.
As a consequence of the GABAB receptor becoming more sensitive to GABAB receptor agonists upon the administration of a positive allosteric modulator, an increased inhibition of transient lower esophageal sphincter relaxations (TLESR) for a GABAB agonist is observed. Consequently, the present invention is directed to the use of a positive allosteric GABAB receptor modulator according to formula (I), optionally in combination with a GABAB receptor agonist, for the preparation of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).
A further aspect of the invention is the use of a compound of formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the prevention of reflux.
Still a further aspect of the invention is the use of a compound of formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment of gastroesophageal reflux disease (GERD).
Effective management of regurgitation in infants would be an important way of preventing, as well as curing lung disease due to aspiration of regurgitated gastric contents, and for managing failure to thrive, inter alia due to excessive loss of ingested nutrient. Thus, a further aspect of the invention is the use of a compound of formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment of lung disease.
Another aspect of the invention is the use of a compound of formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the management of failure to thrive.
Another aspect of the invention is the use of a compound of formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment or prevention of asthma, such as reflux-related asthma.
A further aspect of the invention is the use of a compound of formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment or prevention of laryngitis or chronic laryngitis.
A further aspect of the present invention is a method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to subject in need of such inhibition.
Another aspect of the invention is a method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such prevention.
Still a further aspect of the invention is a method for the treatment of gastroesophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
Another aspect of the present invention is a method for the treatment or prevention of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
Yet another aspect of the invention is a method for the treatment or prevention of regurgitation in infants, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
Still a further aspect of the invention is a method for the treatment, prevention or inhibition of lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment. The lung disease to be treated may inter alia be due to aspiration of regurgitated gastric contents.
Still a further aspect of the invention is a method for the management of failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
A further aspect of the invention is a method for the treatment or prevention of asthma, such as reflux-related asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
A further aspect of the invention is a method for the treatment or prevention of laryngitis or chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
A further embodiment is the use of a compound of formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment of a functional gastrointestinal disorder (FGD). Another aspect of the invention is a method for the treatment of a functional gastrointestinal disorder, whereby an effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject suffering from said condition.
A further embodiment is the use of a compound of formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment of functional dyspepsia. Another aspect of the invention is a method for the treatment of functional dyspepsia, whereby an effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject suffering from said condition.
Functional dyspepsia refers to pain or discomfort centered in the upper abdomen. Discomfort may be characterized by or combined with upper abdominal fullness, early satiety, bloating or nausea. Etiologically, patients with functional dyspepsia can be divided into two groups:                1- Those with an identifiable pathophysiological or microbiologic abnormality of uncertain clinical relevance (e.g. Helicobacter pylori gastritis, histological duodenitis, gallstones, visceral hypersensitivity, gastroduodenal dysmotility)        2- Patients with no identifiable explanation for the symptoms.
Functional dyspepsia can be diagnosed according to the following:
At least 12 weeks, which need not be consecutive within the preceding 12 months of                1- Persistent or recurrent dyspepsia (pain or discomfort centered in the upper abdomen) and        2- No evidence of organic disease (including at upper endoscopy) that is likely to explain the symptoms and        3- No evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool frequency or form.
Functional dyspepsia can be divided into subsets based on distinctive symptom patterns, such as ulcer-like dyspepsia, dysmotility like dyspepsia and unspecified (non-specific) dyspepsia.
Currently existing therapy of functional dyspepsia is largely empirical and directed towards relief of prominent symptoms. The most commonly used therapies still include antidepressants.
A further aspect of the invention is the use of a compound according to formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS.
A further aspect of the invention is a method for the treatment or prevention of irritable bowel syndrome (IBS), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
IBS is herein defined as a chronic functional disorder with specific symptoms that include continuous or recurrent abdominal pain and discomfort accompanied by altered bowel function, often with abdominal bloating and abdominal distension. It is generally divided into 3 subgroups according to the predominant bowel pattern:                1- diarrhea predominant        2- constipation predominant        3- alternating bowel movements.
Abdominal pain or discomfort is the hallmark of IBS and is present in the three subgroups. IBS symptoms have been categorized according to the Rome criteria and subsequently modified to the Rome II criteria. This conformity in describing the symptoms of IBS has helped to achieve consensus in designing and evaluating IBS clinical studies.
The Rome II diagnostic criteria are:                1- Presence of abdominal pain or discomfort for at least 12 weeks (not necessarily consecutively) out of the preceding year        2- Two or more of the following symptoms:        a) Relief with defecation        b) Onset associated with change in stool frequency        c) Onset associated with change in stool consistency
A further aspect of the invention is the use of a compound according to formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment or prevention CNS disorders, such as anxiety.
A further aspect of the invention is a method for the treatment or prevention of CNS disorders, such as anxiety, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
A further aspect of the invention is the use of a compound according to formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment or prevention of depression.
A further aspect of the invention is a method for the treatment or prevention of depression, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
A further aspect of the invention is the use of a compound according to formula (I), optionally in combination with a GABAB receptor agonist, for the manufacture of a medicament for the treatment or prevention of dependency, such as alcohol or nicotine dependency.
A further aspect of the invention is a method for the treatment or prevention of dependency, such as alcohol dependency, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of such treatment.
For the purpose of this invention, the term "agonist" should be understood as including full agonists as well as partial agonists, whereby a "partial agonist" should be understood as a compound capable of partially, but not fully, activating GABAB receptors.
The wording "TLESR", transient lower esophageal sphincter relaxations, is herein defined in accordance with Mittal, R. K, Holloway, R. H., Penagini, R., Blackshaw, L. A., Dent, J, 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 109, pp. 601-610.
The wording "reflux" is defined as fluid from the stomach being able to pass into the esophagus, since the mechanical barrier is temporarily lost at such times.
The wording "GERD", gastroesophageal reflux disease, is defined in accordance with van Heerwarden, M. A., Smout A. J. P. M., 2000; Diagnosis of reflux disease. Bailliére's Clin. Gastroenterol. 14, pp. 759-774.
Functional gastrointestinal disorders, such as functional dyspepsia, can be defined in accordance with Thompson W G, Longstreth G F, Drossman D A, Heaton K W, Irvine E J, Mueller-Lissner S A. C. Functional Bowel Disorders and Functional Abdominal Pain. In: Drossman D A, Talley N J, Thompson W G, Whitehead W E, Coraziarri E, eds. Rome I I: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, V A: Degnon Associates, Inc.; 2000:351-432 and Drossman D A, Corazziari E, Talley N J, Thompson W G and Whitehead W E. Rome I I: A multinational consensus document on Functional Gastrointestinal Disorders. Gut 45(Suppl. 2), II1-II81.9-1-1999.
Irritable bowel syndrome (IBS) can be defined in accordance with Thompson W G, Longstreth G F, Drossman D A, Heaton K W, Irvine E J, Mueller-Lissner S A. C. Functional Bowel Disorders and Functional Abdominal Pain. In: Drossman D A, Talley N J, Thompson W G, Whitehead W E, Coraziarri E, eds. Rome I I: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, V A: Degnon Associates, Inc.; 2000:351-432 and Drossman D A, Corazziari E, Talley N J, Thompson W G and Whitehead W E. Rome II: A multinational consensus document on Functional Gastrointestinal Disorders. Gut 45(Suppl. 2), II1-II81.9-1-1999.
A "combination" according to the invention may be present as a "fix combination" or as a "it of parts combination".
A "fix combination" is defined as a combination wherein (i) a compound of formula (I); and (ii) a GABAB receptor agonist are present in one unit. One example of a "fix combination" is a pharmaceutical composition wherein (i) a compound of formula (I) and (ii) a GABAB receptor agonist are present in admixture. Another example of a "fix combination" is a pharmaceutical composition wherein (i) a compound of formula (I) and (ii) a GABAB receptor agonist; are present in one unit without being in admixture.
A "kit of parts combination" is defined as a combination wherein (i) a compound of formula (I) and (ii) a GABAB receptor agonist are present in more than one unit. One example of a "kit of parts combination" is a combination wherein (i) a compound of formula (I) and (ii) a GABAB receptor agonist are present separately. The components of is the "kit of parts combination" may be administered simultaneously, sequentially or separately, i.e. separately or together.
The term "positive allosteric modulator" is defined as a compound which makes a receptor more sensitive to receptor agonists by binding to the receptor protein at a site different from that used by the endogenous ligand.
The term "therapy" and the term "treatment" also include "prophylaxis" and/or prevention unless stated otherwise. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Pharmaceutical Formulations
The compound of formula (I) can be formulated alone or in combination with a GABAB receptor agonist.
For clinical use, the compound of formula (I), optionally in combination with a GABAB receptor agonist, is in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations. Thus, the compound of formula (I), optionally in combination with a GABAB receptor agonist, is formulated with a pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of a solid, semi-solid or liquid diluent.
In the preparation of oral pharmaceutical formulations in accordance with the invention, the compound of formula (I), optionally in combination with a GABAB receptor agonist, to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets.
Soft gelatine capsules may be prepared with capsules containing a mixture of a compound of formula (I), optionally in combination with a GABAB receptor agonist, with vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain a compound of formula (I), optionally in combination with a GABAB receptor agonist, in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains a compound of formula (I), optionally in combination with a GABAB receptor agonist, in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing a compound of formula (I), optionally in combination with a GABAB receptor agonist, and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of formula (I), optionally in combination with a GABAB receptor agonist, in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispersed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
In one aspect of the present invention, a compound of formula (I), optionally in combination with a GABAB receptor agonist, may be administered once or twice daily, depending on the severity of the patient's condition. A typical daily dose of the compounds of formula (I) is from 0.1 to 100 mg per kg body weight of the subject to be treated, but this will depend on various factors such as the route of administration, the age and weight of the patient as well as of the severity of the patient's condition.
Methods of Preparation
The compounds according to formula (I) of the present invention, wherein Y=—NH—Z—R4 and wherein R1, R2, R1 and R4 are defined as above, Z is —SO2— or —C(S)—, may be prepared by the following general method (Scheme 1; related literature: Tetrahedron (1982), 38:1435-1441).
wherein aminoimidazoles (II) efficiently are converted into (Ia), using acyl chlorides, sulfonylchlorides, isocyanates or other electrophiles (typically 1.5-2.5 equivalents) in organic solvents such as THF or the like. The reaction is performed in the presence of polymer-supported diisopropylethylamine (PS-DIPEA; 1.5-3 equivalents) at ambient temperature to 50° C. with agitation over 4-18 hours. Filtration of the reaction mixture over the nucleophilic anion exchange resin Isolute-NH2, elution with THF and evaporation in vacuo yields the desired products as oils or amorphous solids.
When
the compounds according to formula (I) of the present invention may be prepared analogously to the synthesis described in Examples 1-2, i.e. following schemes 8 and 9.
The aminoimidazoles (II) are prepared from intermediates (III) or (IV) by heating the reagents under basic conditions with an alpha halo carbonyl compound (Scheme 2; literature: Tetrahedron Lett. (1966), 1885-1889 and Monatshefte für Chemie (1976), 107:1413-1421)

Intermediate (III) is prepared by substitution of the thiomethoxy group in intermediate (IV) by the R2 group according to Scheme 3.

Intermediate (IV) is prepared by treating dimethylcyanodithioimidocarbonate in ethanol with 1-2 equivalent of the primary amine and reflux for 3-5 hours (see Scheme 4). The reaction mixture is allowed to cool, evaporated in vacuo and then the desired compounds are either collected by filtration directly or subsequently after the product has precipitated out by the addition of water.

An alternative route to intermediate (II) is the treatment of intermediate (IV) with an alpha halo carbonyl compound in the presence of a base such as potassium carbonate providing intermediate (V). Subsequent treatment of intermediate (V) with nucleophiles such as e.g. alkoxy or thioalkoxy derivatives (e.g. NaOMe, NaOEt) provides intermediate (II) via thiomethyl group substitution and ring closure.

Imidazole derivatives for the treatment of gastrointestinal disorders


Software deployment systems and techniques allow unattended and virtually real-time provisioning of a data item, such as a set of commands, a patch, update, or upgrade, of a product on one or more client computing devices. An example product may be a large-scale software application, such as a development environment. Update engines are used in conjunction with policy files so that the product's versions and updates on the client computing devices are consistent with each other and with the main development environment as represented by a main policy file.

Large-scale software applications, such as development environments, that are packaged and distributed to client computing devices, are becoming larger and more complex. An example development environment may be 4-8 Gigabytes or larger. Such a large development environment is too large to transmit over a network to client computing devices (e.g., programmers' or developers' desktop computers) using a conventional packaging tool.
Network installation may be used, but this is problematic because clients, such as the individual programmers or developers, may subsequently download and install patches, updates, and future versions without system administrator authorization. Because of this, the client computing devices do not remain consistent, as some are updated, some are not, etc. This leads to a non-heterogenous client computing device environment.
Additionally, some programmers would then be producing code that may account for updates that they had personally installed on their computing device, but the update may not yet have been installed systemwide. In this manner, the update level of the production code, which gets shipped out, is not in sync with the update level of the development environment.
Product license compliance is also challenging because manual loads by frustrated users in need of productivity tools make monitoring difficult.

Systems and methods for product updates with provisioning of data items

United States Automobile Association (USAA)


Disclosed is a hydraulic control system for an automatic transmission including a plurality of friction elements associated with respective transmission speeds. The hydraulic control system includes a hydraulic fluid source, a line pressure controller, a reducing pressure controller, a range controller, a shift controller, a hydraulic pressure controller, and a hydraulic pressure distributor. The hydraulic pressure distributor further includes a 3-4 shift valve, a 1-2 shift valve, a 2-3/4-3 shift valve, a 4-2 shift valve for realizing port conversion during a 4-2 skip-shifting process to selectively supply/exhaust the control pressure to/from at least one of the friction elements corresponding to the respective transmission speeds, a control switch valve for realizing port conversion to selectively supply/exhaust hydraulic pressure from the shift controller and the control pressure via the 1-2 shift valve to at least one of the friction elements corresponding to the respective transmission speeds, and a solenoid valve for controlling the control switch valve in accordance with a control signal from a transmission control unit.

Generally, a conventional automatic transmission used in a vehicle includes a torque converter, a multistage gear shift mechanism connected to the torque converter, and a plurality of friction elements actuated by hydraulic pressure for selecting a gear shift stage of the gear shift mechanism.
The conventional automatic transmission is provided with a hydraulic control system which controls the automatic transmission.
In such a hydraulic control system, hydraulic pressure generated by a hydraulic pump is selectively supplied to each friction element by a plurality of control valves such that automatic shifting is realized in accordance with a driving state of the vehicle and engine throttle opening.
The above described hydraulic control system generally comprises a line pressure controller for regulating hydraulic pressure generated by the hydraulic pump to line pressure, a damper clutch controller for actuating a damper clutch of the torque converter, a reducing pressure controller for reducing line pressure, a range controller for selectively supplying line pressure to lines corresponding to respective shift ranges, a shift controller for supplying hydraulic pressure from the range controller to lines corresponding to respective shift ranges, a hydraulic pressure controller for duty-controlling hydraulic pressure from the range controller into operational pressure operating the friction elements, and a hydraulic pressure distributor for determining a hydraulic flow path corresponding to each shift range by operating valves according to the hydraulic pressure from the shift controller, and suitably distributing the operational pressure to each friction element.
The shift controller operates spool valves of the hydraulic pressure distributor under the control of a transmission control unit, such that the hydraulic flow path corresponding to each shift range is determined to realize shifting.
When changing shift stages, the timing of exhausting hydraulic pressure from one set of friction elements and supplying hydraulic pressure to another set of friction elements through the hydraulic flow path, determined by the shift controller in accordance with each shift range, greatly influences shift quality. However, mis-timing can cause an abrupt increase in engine revolutions or locking of the shift mechanism. Further, abrupt changes in hydraulic pressure levels in the hydraulic flow path decreases the life span of the automatic transmission.
In order to improve shift quality and durability of the transmission by both accurately controlling the timing of pressure supply and minimizing changes in hydraulic pressure levels, a method of modifying shift valve structure has been developed. However, such a method complicates both the structure of the shift valves and the control process.

Hydraulic control system for an automatic transmission used in vehicles


This invention relates to a method and an apparatus for generating an image description vector, an image detection method and apparatus. The method for generating an image description vector comprising: an encoding step of encoding each of a plurality of pixel regions of an image into M pieces of N-bit binary codes, wherein each bit of an N-bit binary code represents a neighboring pixel region which is in neighborhood of a corresponding pixel region; and a generating step of generating an image description vector of the image based on matching at least one of the M pieces of N-bit binary code of each pixel region of the plurality of pixel regions with a particular code pattern, where M is an integer of 3 or larger, and N is an integer of 3 or larger.

1. Field of the Invention
The present invention relates to a method and an apparatus for generating an image description vector, as well as an image detection method and an image detection apparatus.
2. Description of the Related Art
Great progress has been made for detection technology of specific objects or targets (such as people, faces, cars, etc.) in the last few decades. In order to describe morphology of an image, discriminative features or patterns can be extracted from the image to form an image descriptor (image description vector). In some techniques, a training process which uses a large quantity of samples is necessary. While for more general or training-free object detection, an effective and robust feature descriptor (description vector) is very important.
Traditional image regional description method uses a feature vector which represents the global distribution of the feature of the image without any spatial or structure related information, thus it has limited discrimination and be liable to false positive.
Recently, image partition based methods have been introduced. Generally, the image partition based methods firstly partition the whole image into pre-defined regions; then generate a feature vector for each of the partitioned image regions independently; and finally combine all the generated feature vectors into a single descriptor for the whole image. Therefore, the single descriptor for the whole image integrates spatial or structure related information of the image and will be more powerful to represent the image.
In particular, two kinds of image partition based methods have been widely used. One image partition based method is called grid based image partition method, as shown in FIG. 1. The grid based image partition method firstly divides the image into multiple regular grids, for example, square grids, then extracts feature vector in each grid region and finally assembles all the grid region feature vectors into a single feature vector sequentially to obtain the descriptor for the image.
The single descriptor for the whole image is commonly illustrated in form of histogram as shown in FIG. 1, in which the abscissas axis indicates the color component in a predetermined color space in bin, and the vertical axis indicates the appearance frequency of the pixels corresponding to each color component, which usually can be represented by the number of the pixels.
However, the grid based image partition method is sensitive to in-plane rotation, for example when the image is rotated by 90°, the histogram of the descriptor will be much different. That is, the descriptor generated by the grid based image partition method is sensitive to in-plane rotation and not so robust.
Another image partition based method is called circular based image partition method, as shown in FIG. 2. The circular based image partition method divides the image into multiple concentric ring regions, and the center of the multiple concentric ring regions is the image center. Thus the descriptor generated by the circular based image partition method is robust against in-plane rotation. But the circular based image partition method does not consider the image characters, which limits its robustness. Furthermore, the method is sensitive to out-plane rotation and deformation.
As seen from the above description, although the image partition based method can generate an image descriptor which includes spatial or structure related information on the image and may somewhat powerfully present the image, the image partition based method is sensitive to rotation of the image, such as the in-plane or out-plane rotation, and thus the robustness of the descriptor generated by the image partition based method is limited.
Currently, pixel classification based methods have been proposed to overcome the drawbacks of the image partition based methods and to achieve more robust descriptor. The pixel classification based methods firstly classify the pixels included in the image into several categories, then generate feature vectors for the categories and finally combine all the feature vectors into a single descriptor.
Two kinds of pixel classification based color feature description method have been introduced and widely used in content-based image retrieval.
One pixel classification based method is called as BIC (Border/Interior Color) method as cited in Document 3. The BIC method first quantizes pixels in a specified color space with a predefined quantization schema; after that, classifies the pixels as border or interior pixels. A pixel is classified as border when it is at border of the image itself (e.g. pixels at image outlier borders shown in FIG. 3) or at least one of its 4 neighbors has a different quantization color (e.g. pixels at the quantized borders); a pixel is classified as interior when all its 4 neighbors have the same quantization color. Finally, generate a descriptor constituted by two color histograms (shown in FIG. 3), the two color histograms representing statistic color distribution for interior and border pixels separately.
However, although the robustness of the descriptor generated by BIC method is somewhat improved, the descriptor is sensitive to illumination variation and noise since the image border is sensitive to illumination variation and noise. Furthermore, since the quantized border depends on color quantization schema, which makes the classification process to couple with color features, the descriptor is also feature dependent.
Another pixel classification based method is called as CCV (Color Coherent Vector) method as cited in Document 4. The CCV classification method is based on the size of the connected components and an pre-defined empirical size threshold is introduced. When a pixel is part of a contiguous region with size being bigger than the pre-defined threshold, classify the pixel as coherent pixel (e.g. Red (dark grey) and green (light grey) pixels in FIG. 4); otherwise, classify the pixel as incoherent pixel (e.g. Blue (medium grey) pixels in FIG. 4).
Based on the above states, only when at least one color of the image is full of texture or constitutes small scattered patches, the CCV method is efficient; otherwise, it will reduce to the simple global color histogram (GCH). Furthermore, the descriptor generated by the method is has no spatial or topology information, thus it is a little more effective than GCH.
As seen from the above description, although the pixel classification based methods are robust with respect to the in-plane or out-plane rotation, such methods may be sensitive to illumination variance and noise. Furthermore, the BIC method and CCV method both perform quantization before pixel classification, and thus the generation result of the two methods depend on color quantization schema, which make the classification process of the two method couple with color features. Therefore, the descriptor generated by the pixel classification method is further limited to color features of the image, that is, feature dependent.
In view of the above, few prior techniques can obtain descriptor for image which is robust against illumination variance, view-point change, non-rigid deformation, etc. and is feature independent.
Recently, Local Binary Pattern (LBP) descriptors and Local Ternary Pattern (LTP) descriptors are proposed as powerful grey-scale invariant local texture descriptors for describing microstructures of images (please see, for example, T. Ojala, M. Pietikainen and T. Maenpaa, "Multi-resolution Gray-Scale and Rotation Invariant Texture Classification with Local Binary Patterns", IEEE Transaction on pattern analysis and machine intelligence, 24(7), 2002, and Xiaoyang Tan and Bill Triggs, "Enhanced Local Texture Feature Sets for Face Recognition Under Difficult Lighting Conditions", IEEE Transactions on Image Processing, pp. 1635-1650, 19(6), 2010). These two patterns (image descriptors) are widely used in the field of face recognition and have achieved great success.
Now the LBP descriptor and the LTP descriptor will be described briefly with reference to FIGS. 5 and 6.
FIG. 5 is a schematic diagram showing the principle of the LBP descriptor.
As shown in FIG. 5, the LBP method encodes each pixel in an image into one piece of 8-bit binary code. More specifically, for a 3×3 matrix of pixels, if a neighbouring pixel has a pixel value larger than or equal to that of the centre pixel, a bit representing this neighbouring pixel in the 8-bit binary code is set to "1", and if a neighbouring pixel has a pixel value smaller than that of the centre pixel, a bit representing this neighbouring pixel in the 8-bit binary code is set to "0". In this way, the 8-bit binary code for the centre pixel is formed by thresholding the eight neighbouring pixels with respect to the pixel value of the centre pixel. In FIG. 5, white dots indicate binary bit "1" and black dots indicate binary bits "0". The LBP feature can describe texture structures around the encoded pixel (centre pixel).
However, the single threshold and the two-pixel comparison make the LBP method very sensitive to noise, and the reliability will decrease significantly under intensive illumination. In addition, the encoding schema limits the LBP feature to present only a small set of texture structures, like lighter or darker edges and dots. Furthermore, the structures represented by the LBP features merely capture the surrounding features of the pixel, while the feature of that pixel itself is lost.
FIG. 6 is a schematic diagram showing the principle of the LTP descriptor.
As shown in FIG. 6, the LTP method encodes each pixel in an image into an 8-bit ternary code. More specifically, for a 3×3 matrix of pixels, if a neighbouring pixel has a pixel value larger than an upper threshold, a bit representing this neighbouring pixel in the 8-bit ternary code is set to "1", if a neighbouring pixel has a pixel value not larger than the upper threshold and not smaller than a lower threshold, a bit representing this neighbouring pixel in the 8-bit ternary code is set to "0", and if a neighbouring pixel has a pixel value smaller than the lower threshold, a bit representing this neighbouring pixel in the 8-bit ternary code is set to "−1". The upper threshold can be set as (centre pixel value +T), and the lower threshold can be set as (centre pixel value −T), where T is a constant margin which can be set as appropriate. In this way, the 8-bit ternary code for the centre pixel is formed by double-thresholding the eight neighbouring pixels with respect to the pixel value of the centre pixel. In FIG. 6, white dots indicate ternary bits "1", black dots indicate ternary bits "−1" and grey dots indicate ternary bits "0".
By using double-thresholding, the LTP feature can describe texture structures around the encoded pixel (centre pixel) with improved robustness, and can preserve more detailed structure of the image than the LBP feature.

Method and apparatus for generating image description vector, image detection method and apparatus


A film digital radiological imaging apparatus to capture the image formed on a dental x-ray film during its developing process and convert it into a video and digital image, while allowing the completed development of the x-ray film, comprising a reaction tank having a window of tinted-clear material to allow a video camera to capture the image forming on a film during its development. A computer programmed to accept the image and to allow the image to be digitized for storage, modification, and transmission to a video monitor for display, or to a printer for printing is also provided. A method for capturing the image forming on dental x-ray film during the opaque stage of the development process and converting it into a video and digital image comprising developing the film to form an opaque image, capturing the image with a video camera, and transferring the image to a computer for digitizing, to a monitor for viewing, zooming, or further enhancing, and to a printer for printing is further provided.

Current technology for creating a digital radiological image of a patient's teeth utilizes a sensor card which is configured to be sensitive to x-rays and electronically connected to a computer thence to a video monitor and/or a printer. The sensor card is placed in the patient's mouth behind the area to be x-rayed. An x-ray head is then aimed at the teeth in question. The x-ray head is then activated, the radiation going through the teeth and onto the sensor card. The sensor card sends the image created to a computer. The computer then digitizes the image. Once it is digitized, it can then be sent to a printer for the production of a hard copy "picture". Or, it can be sent to a video monitor. Because the image is digitized, it can be further enhanced for greater clarity. It can be zoomed in or out, inverted, contrasted with different intensities, or color switched, black to white, and white to black.
Advantages of digital radiology over film radiology are: (1) The fact that a darkroom is not needed for hard copy production. (2) The image is rapidly produced on a video screen, saving the operator time. (3) It has the ability to send the image via E-mail or the internet to insurance companies or other practitioners for diagnosis and consultation due to the fact that the image is digitized. (4) It uses an extremely small dosage of radiation. (5) Patients can see problems on a picture on hard copy paper or a monitor much more readily than on a small and negative film radiograph, making case presentations much more understandable.
The disadvantages of digital radiological imaging are the following: (1) The pictures which appear on the video screen are quite fuzzy and not of clear quality. (2) The hard copy produced is also of poor quality. It is difficult for the practitioner to see much detail. Film radiographs are far superior in quality and resolution. (3) Digital radiological imaging is advantageous for only one or two films. It is not possible to take a full set of radiographs, eighteen to twenty-two films, (or even four bite-wing films) and view them clearly on a video monitor. Each individual radiograph is too small when all are viewed as a whole, considering the comparatively poor quality of video imaging. It is very difficult to be constantly zooming in and out to different individual pictures. When a dentist has a full set of "film" radiographs in front of him, his eyes can be constantly scanning from film to film to contrast and compare different areas, which greatly aids him in the diagnosis. This just cannot be done when a full set of radiographs is on a video screen. (4) Ergonomically, the hard copies produced on the printer are extremely difficult to view and diagnose, when in groups of eighteen to twenty-two, and to store. Viewing the pictures is like viewing a stack of photographs. The bigger the stack gets, the more awkward the handling. Storing the hard copies in the patients' charts, which must be done in case the computer hard disk breaks down or is destroyed, becomes cumbersome over time, because the stack of hard copies gets thicker and more cluttered. (5) While, at the writing of this patent, the inventor realizes that the costs of technology usually gets less expensive as time goes on, the current digital radiological technology is electronically complex and prohibitively expensive, and is simply out of reach for a majority of practitioners. (6) The sensor card, which goes into the patient's mouth, is an extremely fragile and costly piece of equipment which cannot be sterilized or it would be destroyed. It must be covered by a small baggie every time it is used to prevent transmission of pathogens from patient to patient. This technique is of questionable safety, considering pathogens can be transferred from baggie to baggie as they are changed. Because it is a piece of electronic equipment, it cannot be bent to conform to the patient's mouth, as can a piece of film. This may cause great discomfort to the patient.

Apparatus for producing a video and digital image directly from dental x-ray film


A method and apparatus are provided that support enhanced international dialing in cellular systems using handset based code dialing. According to one aspect, the handset analyzes the dialed digits before sending the dialed number to the network. If the dialed digits begin with the country code of the area from which the call is placed, the country code will be removed and a national access code will be added in front of the digit strings. For international calls the dialed number may begin with a + indicator, followed by a country coded, an area code, and a customer number. The digit string is automatically translated into a new number based on the numbering plan of the area in which a call is being placed. The new number can then be sent to the network to set up the call.

1. Field
The present invention relates generally to communications, and more specifically, to systems and techniques for supporting international dialing while roaming across multiple network platforms in a wireless communications system.
2. Background
Roaming refers to the ability to make and receive calls outside of a user's home network. More specifically, international roaming is the ability make and receive calls from a foreign country, using the user's own handset and the foreign country's wireless network. Typically, international roaming requires a user to dial an international access code to reach a telephone number outside of the country where the user is located. International access codes are specific to each country and, in some cases, to the carrier whose network supports the call. For example, a user in the United States must dial "011" on his handset in order to use the international roaming feature to place an international call. A user in France would dial "00," "40," or "70," or another international access code, depending on which carrier he chooses to utilize, in order to place an international call from France. Users who frequently travel must keep track of a variety of different international access codes in order to use their handsets to make phone calls in different countries. Because many countries have different international access codes, and because the international access codes within a single country may vary according to carrier, accurate knowledge of the codes may be a significant burden on travelers.
The "+ Code" Dialing Feature
A feature, sometimes referred to as the "+ code" dialing feature, enables international dialing in a cellular system. The Global System for Mobile Communications (GSM) standard for wireless networks supports a version of this international dialing feature in which users may dial a (+) key on their handset in lieu of dialing the international access code. Dialing the (+) key marks the call as an international call, instructing the local switching system to route the call to an international switch. The "+" indicator means the dialed digit string is an international number. For example, with + code dialing, a subscriber making an international call can dial "+CountryCode-AreaCode-Customer Number". According to this approach, the handset translates the "+" code into "international number type", the network recognizes the "international number type" and routes the call to international gateway, if the country code (CC) in the dialed number is different from the area of operation. By contrast, if the dialed digit string begins with the country code of the current serving system, then the network (MSC) should remove the CC from dialed number and set up the call as a local or national call.
To illustrate how some of these terms are commonly used, some examples will now be provided. When placing a call to a given phone number, the phone number dialed by a user can be in several different formats depending upon where the user is located and what network the user is calling from. For example, assume three callers located in different regions of the world would like to call someone in San Diego who has a customer/local number 658-2598. Further assume that the first caller is located in San Diego in a region with the same area code, the second caller is located in the United States but outside San Diego, and the third caller is located outside the United States, for instance, in China.
The first caller can simply dial the customer number or local number, 658-2598. If the first caller is still in San Diego, but calls from a region with a different area code the first caller might need to dial 858-658-2598, where the digits "858" are the area code. The second caller would have to dial 1-858-658-2598, where the digit '1' is the national access code, the digits "858" are the area code, and the digits "658-2598" are the customer number or local number. This is also known as a "long-distance" call. The third caller would have to dial 00-1-858-658-2598, where the digits "00" are international access code, the digit "1" is the country code for the United States (as opposed to the national access code in the preceding example), the digits "858" are the area code, and the digits "658-2598" are the customer number or local number. This call will be routed to an international gateway and then directed to the USA. Accordingly, with an international call, before the user dials the number, the user must know where they are making the call, and the international access code.
To help eliminate the need to know this information, in some networks, a feature known as enhanced international dialing can be used to simplify the dialing. According to this feature, all numbers can be expressed in the format "+ country code-area code-customer number), where "+" means the number is an international number type. The digits after + are the "country code". Thus, in the example above, the third caller can simply dial +1-858-658-2598, and does not need to know the international access.code.
Unfortunately, users whose handsets include the GSM-supported (+) key cannot utilize this function in areas that are not covered by a GSM network. If a mobile user dials a national call with international number type, some systems cannot correctly analyze the number to set up the call. For example, all code division multiple access (CDMA) systems do not support a + code dialing feature and do not recognize or support the mark accompanied by a call that has been placed with a (+) key, and therefore cannot route the call to an international switch. Instead, in order to route an international call, CDMA systems require the appropriate international access code to accompany the call. For example, a CDMA user typically must dial "IAC-CC-AC-CustomerNumber" to make international call, and the network routes the call to international gateway after recognizing the IAC. This requires that CDMA subscribers know the International Access Code (IAC) to make international calls and the National Access Code (NAC) to make national calls when roaming to other countries.
There has recently been an increasing demand for simplified access procedures when roaming internationally. To help alleviate these issues, patent application Ser. No. 10/315,673 entitled "International Dialing In Cellular Networks" filed Dec. 9, 2002, assigned to the assignee hereof and hereby expressly incorporated by reference herein, describes, among other things, an automated international dialing feature. This feature allows users to engage in international roaming, regardless of the network supporting the call, without knowing and entering the proper international access code.
Operators appreciate that Standard +code dialing will require roaming partners' to upgrade their networks to support this feature. These upgrades may not be deployed until some future time. In the interim, there is a need in the art for enhanced international dialing features that can help alleviate this problem. It would be desirable if such a feature could be implemented without the need to upgrade the serving networks.

Method and apparatus for supporting enhanced international dialing in cellular systems


The present invention relates to targeted polymerized liposomes for oral and/or mucosal delivery of vaccines, allergens and therapeutics. In particular, the present invention relates to polymerized liposomes which have been modified on their surface to contain a molecule or ligand which targets the polymerized liposome to a specific site or cell type in order to optimize the immune response to the encapsulated antigen or the efficacy of the encapsulated drug.

2.1. DRUG DELIVERY
Drug delivery takes a variety of forms, depending on the agent to be delivered and the administration route. The most convenient way to administer drugs into the body is by oral administration. However, many drugs, in particular proteins and peptides, are poorly absorbed and unstable during passage through gastrointestinal (G-I) tract. The administration of these drugs is generally performed through parenteral injection.
Although oral vaccination is more convenient, vaccines are generally given through injection. This is particularly true with killed or peptidic vaccines, because of their low absorbability and instability in the G-I tract. A problem with systemic immunization is that it may not effectively induce mucosal immune responses, particularly production of IgA, that are important as the first defense barrier to invaded microorganisms. For this reason, it would be beneficial to provide oral vaccination, if the problems of low absorbability and instability could be overcome.
Controlled release systems for drug delivery are often designed to administer drugs to specific areas of the body. In the gastrointestinal tract it is important that the drug not be eliminated before it has had a chance to exert a localized effect or to pass into the bloodstream.
Enteric coated formulations have been widely used for many years to protect drugs administered orally, as well as to delay release. Several microsphere formulations have been proposed as a means for oral drug delivery. For example, PCT/US90/0643 and PCT/US90/06433 by Enzytech discloses the use of a hydrophobic protein, such as zein, to form microparticles; U.S. Pat. No. 4,976,968 to Steiner et al. discloses the use of "proteinoids" to form microparticles; and European Patent Application 0,333,523 by the UAB Research Foundation and Southern Research Institute discloses the use of synthetic polymers such as polylactic acid-glycolic acid to form in microspheres.
Particles less than ten microns in diameter, such as the microparticles of EPA 0,333,523, can be taken up by cells in specialized areas, such as Peyer's patches and other intestinal mucosal lymphoid aggregates, located in the intestine, especially in the ileum, into the lymphatic circulation. Entrapping a drug or antigen in a microparticulate system can protect the drug or antigen from acidic and enzymatic degradation, yet still allow the drug or antigen to be administered orally, where they are taken up by the specialized uptake systems, and release the entrapped material in a sustained manner or are processed by phagocytic cells such as macrophages. When the entrapped material is a drug, elimination of the first-pass effect (metabolism by the liver) is highly advantageous.
2.2. LIPOSOMES
Liposomes have been proposed for use as an oral drug delivery system, for example, by Patel and Ryman, FEBS Letters 62(1), 60-63 (1976). Liposomes are typically less than 10 microns in diameter, and, if they were stable to passage through the G-I tract, may be absorbed through Peyer's patches. Liposomes also have some features that should be advantageous for a particulate system for oral drug or antigen delivery. The phospholipid bilayer membrane of liposomes separates and protects entrapped materials in the inner aqueous core from the outside. Both water-soluble and -insoluble substances can be entrapped in different compartments, the aqueous core and bilayer membrane, respectively, of the same liposome. Chemical and physical interaction of these substances can be eliminated because the substances are in these different compartments. Further, liposomes are easy to prepare. However, liposomes are physically and chemically unstable, and rapidly leak entrapped material and degrade the vesicle structure. Without fortifying the liposomes, they are not good candidates for oral drug or antigen delivery.
Several methods have been tried to fortify liposomes. Some methods involved intercalating cholesterol into the bilayer membrane or generating the liposomes in the presence of polysaccharides. These methods are not useful in making liposome for oral delivery since during oral delivery liposomes are exposed to an acidic pH in the stomach and bile salts and phospholipases in intestine. These conditions break down the cholesterol and polysaccharide in the liposomes.
Investigators have explored the improved stability of polymerized liposomes, however in the area of drug delivery their ultimate utility remains uncertain (Regen, 1987 in Liposomes From Biophysics to Therapeutics, edit. Ostro, Marcel Dekker, N.Y.). Polymerized liposomes have been developed in attempts to improve oral delivery of encapsulated drugs (Chen et al. WO 9503035). The ability of liposomes derivatized with wheat germ agglutinin to better survive the G-I tract has also been investigated (Chen et al., 1995, Proceed. Internat. Symp. Control. Rel. Bioact. Mater. 22; Chen et al., 1995 Proc. 3rd U.S. Japan Symposium on Drug Delivery).
However, to the inventors' knowledge, to date the utility of conventional liposomes for oral delivery is still questionable. Similarly, whether polymerized liposomes are more advantageous than conventional or unpolymerized liposomes for oral drug delivery is still unclear since improved stability alone may not be sufficient for oral drug delivery, particularly oral vaccination. Thus, there remains a need for drug and antigen delivery devices that can survive the harsh conditions in the G-I tract, and effectively deliver the drug, antigen or any other therapeutic.

Targeted polymerized liposomes for improved drug delivery


The present invention deals with the composition of matter and the utilization of certain amine oxides of meadowfoam amido propyl dimethyl amine. These materials are useful in personal care applications.

1. Field of the Invention
The present invention deals with surface active compounds that are the amine oxide of meadowfoam amidopropyl dimethyl amine. The compounds of the present invention possess conditioning properties when applied to hair. The process for their use comprises contacting the hair with an effective conditioning amount of a novel amine oxide based upon meadowfoam. The term meadowfoam as used here refers to compounds derived from meadowfoam oil, meadowfoam acid or meadowfoam methyl ester. The introduction of the meadowfoam portion of the molecule into the compounds of the present invention results in improved conditioning in personal care formulations as well as improved odor stability in the formulation.
2. Description of the Art Practices
Amine oxides are known in the art. Variation of carbon chain lengths in amido amine has direct effect upon the conditioning properties of the compound. While amido amines based upon short chain fatty acids can be made, they do not produce conditioning effects on hair. The use of fatty acids having 18 or more carbon atoms result in compounds that provide conditioning. If the compounds are saturated, like stearyl amido amine oxide the aqueous product is solid. The selection of a oleyl amido amine gives a liquid product, which is highly desirable but the compound undergoes a process of oxidative instability referred to as rancidity, producing low molecular weight aldehydes with mal odor. The availability of a liquid, oxidatively stable amido amine salts that can be used in personal care systems has been elusive prior to the compounds of the present invention.
The recent availability of meadowfoam oil, with it's 20 to 22 carbon atoms and the specific location of it's double bonds, and it's reaction to make betaines results in the preparation liquid stable betaines, having outstanding emulsifying properties and are very acceptable for use in personal care applications.
None of the prior amido amine possess the critical meadowfoam carboxy moiety. Molecules of the current invention have the meadowfoam alkyl group in the surfactant.
The parent case Ser. No. 847,202 filed May 1, 1997, discloses the procedure and processes needed to make the intermediate necessary to make the compound of the present.


A method is described that involves generating an update to an object-oriented model of an information system from information that describes a new state of the information system. The generating includes applying a synchronization rule for a sub-system identified within the information system. The synchronization rule indicates whether a new component within the sub-system that appears within the information is merged within the sub-system or replaces a component within the sub-system.

An information system (also referred to as an "IS system") is an orchestrated collection of computing and networking hardware and software components designed to collectively support some kind of organization (e.g., a partnership, a corporation or a government institution). Advanced information system (IS) configuration and maintenance software tools are migrating to an environment in which detailed object oriented models for specific IS features (e.g., clients, servers, routers, software installations, hardware installations, etc.) are used to effect intelligent and automatic configuration and/or maintenance tasks. Examples include the efforts of the Web-Based Enterprise Management (WBEM) initiative and the Common Information Model (CIM) specification(s) (e.g., the Common Information Model (CIM) Specification published by the Distributed Management Task Force, Inc., Version 2.2, Jun. 14, 1999).
FIG. 1 shows an exemplary depiction of such an object oriented model 100. According to the depiction of FIG. 1, an object is used to represent a server having a dispatcher and worker nodes. Object 101 represents the dispatcher. Objects 102-105 represent the worker nodes and objects 106-109 represent associations between the worker nodes and the dispatcher.
In order to successfully implement maintenance and/or configuration tasks, live "tracking" of the state of an IS system (where, the IS system has two or more IS components having at least one association between them, where, a "component" is some identifiable unit of functionality) is often beneficial. A problem, however, is that the specific changes made to an IS system (e.g., by some kind of "event" (like a failure or bring-up)) may be "lost" or otherwise not presentable for purposes of updating a detailed object oriented model of the IS system to reflect the changes. If so, all that is available is the "new" state of the IS system (i.e., the state of the IS system after the change).

Synchronization method for an object oriented information system (IS) model


Multilayer, thin film multijunction integrated micropotentiometers are formed in an integral multifilm membrane form over a through opening in a nonmagnetic, dielectric substrate. Through the use of conventional photolithographic and etching techniques, integrated structures are formed to include either single elongate heater elements, bifilar heater elements, or trifilar heater elements with multiple return paths. Multijunction thermopiles and resistors are formed with the heater. The individual layers of silicon oxide or silicon nitride, are formed with conventional chemical vapor deposition, sputtering and other known techniques.

The addition of one or more previously formed resistors in series with the heater element of a thermal converter forms a micropotentiometer. The highest performance thermal converters are multijunction thermal converters (MJTCs).
Micropotentiometers are very precise standards for determining a low voltage output over a wide range of frequencies for ac-dc and RF-dc applications. To meet this need, integrated .mu.pots require physical ruggedness, ability to withstand stresses associated with thermal cycling and in-use exposure to a wide range of temperatures locally, and an error-free structure, e.g., minimization of capacitances or inductances developed between the heater and thermopiles and/or the contact pads.
The best combination for structural elements for forming MJTCs and the output resistors required for the corresponding .mu.pots includes: low stress sandwich-type multifilm membranes; low stress metal films for forming the heater element, thermopiles, contact-pads, and the like; minimization of capacitances between heater and thermopiles or between contact pads by precise definition of form and structure; a coaxial design, use of a relatively thick film nonmagnetic mounting substrate to support a chip containing thinner films constituting the heater element, thermopiles, resistors and contact pads; optional provision of guard thermocouples at both ends of each thermopile; and careful selection of materials so that, for example, the resistance heaters have a very low thermal coefficient of resistance and Thompson effect. The present invention incorporates such features in novel and highly reliable structures.
These and other related objects of this invention are described more fully hereinbelow, as are structural details of the preferred embodiments of this invention and methods of forming the same. Persons of ordinary skill in the art, upon understanding the following disclosure and the accompanying drawing figures may consider implementing obvious modifications and variations of this invention, and the claims appended hereto are intended to comprehend such variations of the explicitly disclosed embodiments.

Multilayer thin film multijunction integrated micropotentiometers

The United States of America as represented by the Secretary of Commerce


An inductor structure including a first helix winding, a second helix winding, and a shielding structure is provided. The first helix winding has a first exterior wire connecting with a first interior wire in series. The second helix winding and the first helix winding are intercoiled about a symmetric plane. The second helix winding has a second exterior wire connecting with a second interior wire in series and connects with the first interior wire. The shielding structure includes a first shielding layer disposed between the first exterior wire and the substrate corresponding to a projection of the first exterior wire and a second shielding layer disposed between the second exterior wire and the substrate corresponding to a projection of the second exterior wire. The first shielding layer and the second shielding layer are grounded individually, and are in symmetry about the symmetric plane.

1. Field of the Invention
The present invention relates to an inductor structure. More particularly, the present invention relates to an inductor structure that can improve Q value.
2. Description of Related Art
Generally speaking, an inductor has energy storage and discharge functions through electromagnetic conversion, so the inductor can be used as an element for stabilizing current. Further, the inductor can be widely utilized, for example, in a radio frequency (RF) circuit. In an integrated circuit (IC), the inductor is a very important and challenging passive device. For the performance of an inductor, the requirement on the quality of the inductor is high, i.e., the inductor must have a high quality factor, which is represented by the Q value. The Q value is defined as follows:Q=ω×L/R
where ω is the angular frequency, L is the inductance of a coil, and R is the resistance at a specific frequency taking the inductance loss into account.
Currently, many methods and techniques are available to combine inductors with IC processes. However, in the IC, the restriction on the thickness of the inductor conductor and the interference of the silicon substrate to the inductor will also lead to poor quality of the inductor. In the conventional art, a thick metal is disposed on the top of the inductor to reduce the conductor loss, so as to improve the Q value of the inductor. However, when the thickness of the metal increases to a certain extent, the improvement on the Q value becomes insignificant. Further, as the inductor is often disposed near the silicon substrate, the parasitic capacitance generated between the silicon substrate and the inductor will increase, and the resistance of the inductor will increase accordingly. Thus, much energy must be consumed, and the quality of the inductor is degraded. As a result, it has become the key point of the vigorous development in the industry to solve the problems in the process to raise the Q value of the inductor and reduce the conductor loss.


A high-purity silicone ladder polymer of high molecular weight which contains 1 ppm or less of sodium, potassium, iron, copper, lead, magnesium, manganese and chlorine, and 1 ppb or less of uranium and thorium; and whose polymerization degree is 600 to 10000. Trialkoxysilane compounds or trichlorosilane compounds are hydrolyzed to produce a high-purity silicone ladder prepolymer whose polymerization degree is 5 to 600. The silicone ladder prepolymer is subjected to dehydrative condensation by using a nucleophilic reagent as a catalyst, and then purified in a dissolution/reprecipitation method to yield the silicone ladder polymer.

1. Field of the Invention
This invention relates to a high-purity silicone ladder polymer of high molecular weight having hydrogen atoms in side chains, a silicone ladder prepolymer, and processes for producing them. A silicone ladder polymer of the invention can be advantageously used as a material for making protective films, inter-level insulation films, etc in semiconductors and other electronic devices.
2. Description of the Prior Art
Because of its unique molecular structure, a silicone ladder polymer excels in heat resistance, electrical insulating properties and chemical resistance. It have been conventionally been used as a material for making protective films and inter-level insulation films in electronic parts or semiconductor devices, etc.
For example, a conventional process for producing such a conventional silicone ladder polymer is described in Japan Patent Laid-open (Kokai) No. 124943/85. In this process, triethoxysilane is hydrolyzed in an organic solution and polymerized under a reduced pressure. The terminal thereof is modified with dimethylchlorosilane. The resultant is then purified with an organic solvent to yield a silicone ladder polymer.
The conventional process for producing a silicone ladder polymer had a problem that a silicone ladder polymer obtained contained large amounts of impurities or by-products. This is because the purification after modifying a terminal is not sufficient and the reaction after hydrolysis is conducted under conditions where impurities or by-products are hardly removed, e.g., at a high temperature of 35.degree. C. Further, since the molecular weight of the silicone ladder polymer obtained is as low as 100000 or less, there is another problem that the formation of a thick film is difficult.

Silicone ladder polymer and process for producing the same