The present invention is directed to compounds and compositions for the treatment of neurological diseases that cause neurogenic and neuropathic pain, inflammatory diseases, renal ishaemia, cardiovascular disease and other pathologies caused by the presence of endogenous cannabinoids and or other substrates resulting from the metabolic activities of fatty acid amido hydrolase (FAAH). These compounds are represented by the formula

Aryl- and -heteroarylalkylcarbamate derivatives are known to be useful in the treatment of numerous metabolic diseases in varying degrees. Their preparation and their application in therapeutics is also well documented.
Phenylalkylcarbamate and (dioxan-2-yl)alkylcarbamate derivatives, disclosed respectively in the documents FR 2850377 A and WO 2004/020430 A2, which are inhibitors of the enzyme FAAH (Fatty Acid Amido Hydrolase) are already known and are incorporated herein by reference.
However, there still exists a need to find and develop products which are inhibitors of the enzyme FAAH. The compounds of the present invention can readly acheve this objective.
The compounds of the invention correspond to the general formula (I):

in which:
A is chosen from one or more groups X, Y and/or Z;
X represents a methylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups;
Y represents either a C2-alkenylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups; or a C2-alkynylene group;
Z represents a group of formula:

m represents an integer ranging from 1 to 5;
p and q represent integers and are defined such that p+q is a number ranging from 1 to 5;
n represents an integer ranging from 1 to 7;
R1 represents an R2 group optionally substituted by one or more R3 and/or R4 groups;
R2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, 1-oxo-3,4-dihydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl or isothiazolopyridyl;
R3 represents a group chosen from halogen atoms or cyano, nitro, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl, NR5R6, NR5COR6, NR5CO2R6, NR5SO2R6, COR5, CO2R5, CONR5R6, SO2R5, SO2NR5R6, —O—(C1-3-alkylene)-O— or phenyl groups, the phenyl group optionally being substituted by one or more halogen atoms;
R4 represents a group chosen from phenyl, phenyloxy, benzyloxy, naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl groups; it being possible for the R4 group or groups to be substituted by one or more R3 groups which are identical to or different from one another;
R5 and R6 represent, independently of one another, a hydrogen atom or a C1-6-alkyl group or form, with the atom or atoms which carry them, a ring chosen from an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine ring, this ring optionally being substituted by a C1-6-alkyl or benzyl group;
R7 represents a hydrogen atom or a C1-6-alkyl group;
R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group.
In the context of the invention, the compounds of general formula (I) can thus comprise several groups A which are identical to or different from one another.
Among the compounds of general formula (I), a first subgroup of compounds is comprised of compounds for which:
A is chosen from one or more groups X and/or Y;
X represents a methylene group;
Y represents a C2-alkynylene group;
n represents an integer ranging from 1 to 5;
R1 represents an R2 group optionally substituted by one or more R3 and/or R4 groups;
R2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, indolyl, benzimidazolyl or pyrrolopyridyl;
R3 represents a group chosen from halogen atoms, more particularly chlorine and fluorine atoms, or C1-6-alkyl, more particularly methyl, C3-7-cycloalkyl, more particularly cyclopropyl, C1-6-alkoxy, more particularly methoxy, NR5R6 or phenyl groups;
R4 represents a group chosen from phenyl, naphthyl or pyridyl groups; it being possible for the R4 group or groups to be substituted by one or more R3 groups which are identical to or different from one another;
R5 and R6 represent, independently of one another, a C1-6-alkyl group, more particularly a methyl;
R7 represents a hydrogen atom or a C1-6-alkyl group;
R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group.
Among the compounds of general formula (I), a second subgroup of compounds is comprised of the compounds for which:
A, X, Y, Z, m, p, q, n, R1, R3, R4, R5, R6, R7 and R8 are as defined in the general formula (I) or in the first subgroup as defined above,
and R2 represents a group chosen from a pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl or isoquinolinyl.
Among the compounds of general formula (I), a third subgroup of compounds is comprised of the compounds for which:
A, X, Y, Z, m, p, q, n, R1, R2, R3, R4, R5 and R6 are as defined in the general formula (I) or in the subgroups as defined above;
R7 represents a hydrogen atom;
R8 represents a hydrogen atom or a C1-6-alkyl group, more particularly a methyl.
The following compounds may be mentioned among the compounds of the subgroups defined above:    2-(methylamino)-2-oxoethyl (5-phenylpyrid-2-yl)methylcarbamate    2-(methylamino)-2-oxoethyl 2-(5-phenylpyrid-2-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(2-phenylpyrimidin-5-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(5-phenylpyrimidin-2-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-[6-(4-chlorophenyl)pyrimidin-4-yl]ethylcarbamate    2-(methylamino)-2-oxoethyl 2-[6-(4-chlorophenyl)-2-methylpyrimidin-4-yl]ethylcarbamate    2-(methylamino)-2-oxoethyl 2-[6-(4-chlorophenyl)-2-(dimethylamino)pyrimidin-4-yl]ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(isoquinolin-7-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(2-phenyl-1,3-oxazol-4-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-[5-(4-chlorophenyl)isoxazol-3-yl]ethylcarbamate    2-amino-2-oxoethyl 3-(pyrid-2-yl)propylcarbamate    2-amino-2-oxoethyl 3-(pyrid-3-yl)propylcarbamate    2-amino-2-oxoethyl 3-(pyrid-4-yl)propylcarbamate    2-amino-2-oxoethyl 3-(pyrimidin-5-yl)propylcarbamate    2-(methylamino)-2-oxoethyl 3-[6-(4-chlorophenyl)pyrimidin-4-yl]propylcarbamate    2-(methylamino)-2-oxoethyl 3-[6-(4-chlorophenyl)-2-methylpyrimidin-4-yl]propylcarbamate    2-(methylamino)-2-oxoethyl 3-[6-(4-chlorophenyl)-2-(dimethylamino)pyrimidin-4-yl]propylcarbamate    2-amino-2-oxoethyl 3-(quinolin-2-yl)propylcarbamate    2-amino-2-oxoethyl 3-(quinolin-4-yl)propylcarbamate    2-amino-2-oxoethyl 3-(isoquinolin-1-yl)propylcarbamate    2-amino-2-oxoethyl 3-(isoquinolin-4-yl)propylcarbamate    2-(methylamino)-2-oxoethyl 3-[5-(4-chlorophenyl)isoxazol-3-yl]propylcarbamate    2-amino-2-oxoethyl 3-[3-(4-chlorophenyl)isoxazol-5-yl]propylcarbamate    2-(methylamino)-2-oxoethyl 3-[3-(4-chlorophenyl)isoxazol-5-yl]propylcarbamate    2-(methylamino)-2-oxoethyl 3-[3-(4-phenylphenyl)isoxazol-5-yl]propylcarbamate    2-(methylamino)-2-oxoethyl 3-[3-(naphth-2-yl)isoxazol-5-yl]propylcarbamate    2-amino-2-oxoethyl 4-(pyrid-2-yl)butylcarbamate    2-amino-2-oxoethyl 4-(pyrid-3-yl)butylcarbamate    2-amino-2-oxoethyl 4-(pyrid-4-yl)butylcarbamate    2-amino-2-oxoethyl 4-(pyrimidin-5-yl)butylcarbamate    2-(methylamino)-2-oxoethyl 4-[6-(4-chlorophenyl)pyrimidin-4-yl]butylcarbamate    2-(methylamino)-2-oxoethyl 4-[6-(4-chlorophenyl)-2-methylpyrimidin-4-yl]butylcarbamate    2-(methylamino)-2-oxoethyl 4-[6-(4-chlorophenyl)-2-cyclopropylpyrimidin-4-yl]butylcarbamate    2-(methylamino)-2-oxoethyl 4-[6-(4-chlorophenyl)-2-(dimethylamino)pyrimidin-4-yl]butylcarbamate    2-amino-2-oxoethyl 4-(quinolin-2-yl)butylcarbamate    2-amino-2-oxoethyl 4-(quinolin-4-yl)butylcarbamate    2-amino-2-oxoethyl 4-(isoquinolin-1-yl)butylcarbamate    2-amino-2-oxoethyl 4-(isoquinolin-4-yl)butylcarbamate    2-(methylamino)-2-oxoethyl 4-[5-(4-chlorophenyl)isoxazol-3-yl]butylcarbamate    2-(methylamino)-2-oxoethyl 4-[3-(4-chlorophenyl)isoxazol-5-yl]butylcarbamate    2-(methylamino)-2-oxoethyl 4-[3-(4-phenylphenyl)isoxazol-5-yl]butylcarbamate    2-(methylamino)-2-oxoethyl 4-[3-(naphth-2-yl)isoxazol-5-yl]butylcarbamate    2-amino-2-oxoethyl 5-(pyrid-2-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(pyrid-4-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(pyrimidin-5-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(quinolin-2-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(quinolin-4-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(isoquinolin-1-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(isoquinolin-4-yl)pentylcarbamate    2-amino-2-oxoethyl [3-(naphth-1-yl)prop-2-yn-1-yl]carbamate    2-(methylamino)-2-oxoethyl [3-(naphth-1-yl)prop-2-yn-1-yl]carbamate    2-amino-2-oxoethyl [5-(naphth-1-yl)pent-4-yn-1-yl]carbamate    2-(methylamino)-2-oxoethyl [5-(naphth-1-yl)pent-4-yn-1-yl]carbamate    2-(methylamino)-2-oxoethyl [5-(4-fluoronaphth-1-yl)pent-4-yn-1-yl]carbamate    2-(methylamino)-2-oxoethyl [3-(pyrid-3-yl)isoxazol-5-ylpropyl]carbamate    2-(methylamino)-2-oxoethyl [3-(4-methoxynaphth-1-yl)isoxazol-5-ylpropyl]carbamate.
Among the compounds of general formula (I), one subfamily of compounds is comprised of the compounds corresponding to the general formula (I′):

in which
A is chosen from one or more groups X, Y and/or Z;
X represents a methylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups;
Y represents either a C2-alkenylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups; or a C2-alkynylene group;
Z represents a group of formula:

m represents an integer ranging from 1 to 5;
p and q represent integers and are defined such that p+q is a number ranging from 1 to 5;
n represents an integer ranging from 1 to 7;
R1 represents an R2 group optionally substituted by one or more R3 and/or R4 groups;
R2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, 1-oxo-3,4-dihydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl or isothiazolopyridyl;
R3 represents a group chosen from halogen atoms or cyano, nitro, C1-6-alkyl, C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl, NR5R6, NR5COR6, NR5CO2R6, NR5SO2R6, COR5, CO2R5, CONR5R6, SO2R5, SO2NR5R6 or —O—(C1-3-alkylene)-O— groups;
R4 represents a group chosen from phenyl, phenyloxy, benzyloxy, naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl groups; it being possible for the R4 group or groups to be substituted by one or more R3 groups which are identical to or different from one another;
R5 and R6 represent, independently of one another, a hydrogen atom or a C1-6-alkyl group or form, with the atom or atoms which carry them, a ring chosen from an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine ring, this ring optionally being substituted by a C1-6-alkyl or benzyl group;
R7 represents a hydrogen atom or a C1-6-alkyl group;
R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group.
Among the compounds of general formula (I′), a first subgroup of compounds is comprised of the compounds for which:
A is chosen from one or more groups X and/or Y;
X represents a methylene group;
Y represents a C2-alkynylene group;
n represents an integer ranging from 1 to 5;
R1 represents an R2 group optionally substituted by one or more phenyl groups, more particularly by one phenyl;
R2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, oxadiazolyl, naphthyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, indolyl, benzimidazolyl or pyrrolopyridyl;
R7 represents a hydrogen atom or a C1-6-alkyl group;
R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group.
Among the compounds of general formula (I′), a second subgroup of compounds is comprised of the compounds for which:
A, n and R1 are as defined in the first subgroup defined above;
R7 represents a hydrogen atom;
R8 represents a hydrogen atom or a C1-6-alkyl group, more particularly a methyl.
Mention may be made, among the compounds of general formula (I′), of the following compounds:    2-(methylamino)-2-oxoethyl (5-phenylpyrid-2-yl)methylcarbamate    2-(methylamino)-2-oxoethyl 2-(5-phenylpyrid-2-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(6-phenylpyridazin-3-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(2-phenylpyrimidin-5-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(5-phenylpyrimidin-2-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(isoquinolin-7-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(4-phenyl-1H-imidazol-1-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(2-phenyl-1,3-oxazol-4-yl)ethylcarbamate    2-(methylamino)-2-oxoethyl 2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethylcarbamate    2-amino-2-oxoethyl 3-(pyrid-2-yl)propylcarbamate    2-amino-2-oxoethyl 3-(pyrid-3-yl)propylcarbamate    2-amino-2-oxoethyl 3-(pyrid-4-yl)propylcarbamate    2-amino-2-oxoethyl 3-(pyrimidin-5-yl)propylcarbamate    2-amino-2-oxoethyl 3-(quinolin-2-yl)propylcarbamate    2-amino-2-oxoethyl 3-(quinolin-4-yl)propylcarbamate    2-amino-2-oxoethyl 3-(isoquinolin-1-yl)propylcarbamate    2-amino-2-oxoethyl 3-(isoquinolin-4-yl)propylcarbamate    2-(methylamino)-2-oxoethyl 3-(4-phenyl-1H-imidazol-1-yl)propylcarbamate    2-(methylamino)-2-oxoethyl 3-(1H-benzimidazol-1-yl)propylcarbamate    2-amino-2-oxoethyl 4-(pyrid-2-yl)butylcarbamate    2-amino-2-oxoethyl 4-(pyrid-3-yl)butylcarbamate    2-amino-2-oxoethyl 4-(pyrid-4-yl)butylcarbamate    2-amino-2-oxoethyl 4-(pyrimidin-5-yl)butylcarbamate    2-amino-2-oxoethyl 4-(quinolin-2-yl)butylcarbamate    2-amino-2-oxoethyl 4-(quinolin-4-yl)butylcarbamate    2-amino-2-oxoethyl 4-(isoquinolin-1-yl)butylcarbamate    2-amino-2-oxoethyl 4-(isoquinolin-4-yl)butylcarbamate    2-(methylamino)-2-oxoethyl 4-(1H-benzimidazol-1 -yl)butylcarbamate    2-amino-2-oxoethyl 4-(1H-indol-1-yl)butylcarbamate    2-(methylamino)-2-oxoethyl 4-(1H-indol-1-yl)butylcarbamate    2-amino-2-oxoethyl 4-(1H-pyrrolo[2,3-b]pyrid-1-yl)butylcarbamate    2-(methylamino)-2-oxoethyl 4-(1H-pyrrolo[2,3-b]pyrid-1-yl)butylcarbamate    2-(methylamino)-2-oxoethyl 4-(3,4-dihydroisoquinolin-2(1H)-yl)butylcarbamate    2-amino-2-oxoethyl 4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)butylcarbamate    2-(methylamino)-2-oxoethyl 4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)butylcarbamate    2-amino-2-oxoethyl 5-(pyrid-2-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(pyrid-4-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(pyrimidin-5-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(quinolin-2-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(quinolin-4-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(isoquinolin-1-yl)pentylcarbamate    2-amino-2-oxoethyl 5-(isoquinolin-4-yl)pentylcarbamate    2-amino-2-oxoethyl [3-(naphth-1 -yl)prop-2-yn-1-yl]carbamate    2-(methylamino)-2-oxoethyl [3-(naphth-1-yl)prop-2-yn-1-yl]carbamate    2-amino-2-oxoethyl [5-(naphth-1-yl)pent-4-yn-1-yl]carbamate    2-(methylamino)-2-oxoethyl [5-(naphth-1 -yl)pent-4-yn-1-yl]carbamate.
The compounds of general formula (I) can comprise one or more asymmetric carbons. They can exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and their mixtures, including the racemic mixtures, form part of the invention.
The compounds of formula (I) can exist in the form of bases or of addition salts with acids.
Such addition salts form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids but the salts of other acids, of use, for example, for the purification or the isolation of the compounds of formula (I), also form part of the invention.
The compounds of general formula (I) can exist in the form of hydrates or of solvates, namely in the form of combinations or of associations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention.
In the context of the invention:                Ct-z, where t and z can take the values from 1 to 7, is understood to mean a carbon chain which can have from t to z carbon atoms, for example C1-3 a carbon chain which can have from 1 to 3 carbon atoms;        alkyl is understood to mean a saturated, linear or branched, aliphatic group; for example a C1-6-alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, more particularly a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl;        alkylene is understood to mean a saturated, linear or branched, divalent alkyl group, for example a C1-3-alkylene group represents a linear or branched divalent carbon chain of 1 to 3 carbon atoms, more particularly a methylene, ethylene, 1-methylethylene or propylene;        cycloalkyl is understood to mean a cyclic alkyl group, for example a C3-7-cycloalkyl group represents a cyclic carbon group of 3 to 7 carbon atoms, more particularly a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;        alkenylene is understood to mean an unsaturated divalent aliphatic group comprising 2 carbons, more particularly an ethenylene;        C2-alkynylene is understood to mean a —C≡C— group;        alkoxy is understood to mean an —O-alkyl group comprising a saturated, linear or branched, aliphatic chain;        thioalkyl is understood to mean an —S-alkyl group comprising a saturated, linear or branched, aliphatic chain;        fluoroalkyl is understood to mean an alkyl group, one or more hydrogen atoms of which have been substituted by a fluorine atom;        fluoroalkoxy is understood to mean an alkoxy group, one or more hydrogen atoms of which have been substituted by a fluorine atom;        fluorothioalkyl is understood to mean a thioalkyl group, one or more hydrogen atoms of which have been substituted by a fluorine atom;        halogen is understood to mean a fluorine, a chlorine, a bromine or an iodine.
The compounds of the invention can be prepared according to various methods illustrated by the schemes which follow.

A first method (Scheme 1) for producing the compounds of general formula (I) consists in reacting an amine of general formula (II), in which R1, A and n are as defined in the general formula (I), with a carbonate of general formula (II) in which V represents a hydrogen atom or a nitro group, R7 is as defined in the general formula (I) and R represents a methyl or ethyl group. The carbamate-ester of general formula (IV) thus obtained is subsequently converted to the compound of general formula (I) by aminolysis using an amine of general formula R8NH2, where R8 is as defined in the general formula (I). The aminolysis reaction can be carried out in a solvent, such as methanol or ethanol, or a mixture of solvents, such as methanol and tetrahydrofuran.
Another method (Scheme 2) for producing the compounds of general formula (I) consists in reacting a derivative of general formula (V), in which R1, n and A are as defined in the general formula (I) and W represents a hydroxyl, mesylate or tosylate group or a chlorine, bromine or iodine atom, with an oxazolidinedione of general structure (VI), in which R7 is as defined in the general formula (I), to provide the oxazolidinedione derivative of general structure (VII).
In the case where W represents a hydroxyl group, the reaction can be carried out according to the conditions of Mitsunobu (Synthesis, 1981, 1-28), for example, by the action of diethyl or diisopropyl azodicarboxylate in the presence of triphenylphosphine. In the case where W represents a chlorine, bromine or iodine atom or a mesylate or tosylate group, the reaction can be carried out in the presence of a base, such as 1,1,3,3-tetramethylguanidine, sodium hydride or sodium tert-butoxide, in a solvent, such as tetrahydrofuran, acetonitrile or dimethylformamide, at a temperature of between 0° C. and 80° C. The oxazolidinedione derivative of general formula (VII) thus obtained is subsequently converted to the compound of general formula (I) by aminolysis using an amine of general formula R8NH2, where R8 is as defined in the general formula (I).

The compounds of general formula (I), (IV) and (VII) in which R1 represents a group of aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type can also be prepared by reaction of the corresponding compounds of general formula (I), (IV) or (VII) for which R2 is substituted by a chlorine, bromine or iodine atom or by a triflate group in the position where the R4 group has to be introduced with an aryl- or heteroarylboronic acid derivative according to the Suzuki reaction conditions (Chem. Rev., 1995, 95, 2457-2483) or with an aryl- or heteroaryltrialkylstannane derivative according to the Stille reaction conditions (Angew. Chem. Int. Ed., 1986, 25, 504-524).
The carbonates of general formula (III) can be prepared according to any method described in the literature, for example by reaction of an alcohol of general formula HOCHR7COOR, where R represents a methyl or ethyl group, with phenyl or 4-nitrophenyl chloroformate in the presence of a base, such as triethylamine or diisopropylethylamine.
The compounds of general formulae (II), (V) and (VI) and the amines of general formula R8NH2, when their method of preparation is not described, are commercially available or are described in the literature or can be prepared according to various methods described in the literature or known to a person skilled in the art.
The compounds of general formula (IV) in which n, A, R1 and R7 are as defined in the general formula (I) and R represents a methyl or ethyl group are novel and also form part of the invention, the following compounds being excluded:    ethyl 2-[({[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino}carbonyl)oxy]propanoate;    ethyl 2-[({[2-[5-(phenylmethoxy)-1H-indol-3-yl]ethyl]amino}carbonyl)oxy]propanoate.
The compounds of general formula (IV) are of use as synthetic intermediates for the preparation of the compounds of general formula (I).
The compounds of general formula (VII) in which n, A, R1 and R7 are as defined in the general formula (I) are novel and also form part of the invention, the following compounds being excluded:    2-[2-(2,4-dioxo-3-oxazolidinyl)ethyl]-1-methylpyridinium iodide;    2-[2-(2,4-dioxo-3-oxazolidinyl)ethyl]-5-ethyl-1-methylpyridinium iodide;    4-[2-(2,4-dioxo-3-oxazolidinyl)ethyl]-1-methylpyridinium iodide;    5-methyl-3-[2-(4-pyridyl)ethyl]-2,4-oxazolidinedione hydrochloride;    5-methyl-3-[2-(2-pyridyl)ethyl]-2,4-oxazolidinedione hydrochloride;    3-[5-(imidazo[1,2-a]pyridin-5-yl)pentyl]-2,4-oxazolidinedione;    3- [2-(5-methyl-4-thiazolyl)ethyl]-2,4-oxazolidinedione;    3-[2-(1H-pyrrol-2-yl)ethyl]-2,4-oxazolidinedione;    3-[2-(2-thienyl)ethyl]-2,4-oxazolidinedione;    3-[3-(2-thienyl)propyl]-2,4-oxazolidinedione;    3-[4-(2-thienyl)butyl]-2,4-oxazolidinedione;    5-methyl-3-[2-(2-thienyl)ethyl]-2,4-oxazolidinedione;    5-ethyl-3-[2-(2-thienyl)ethyl]-2,4-oxazolidinedione;    3-[2-(3-thienyl)ethyl]-2,4-oxazolidinedione;    3-[2-(5-methyl-2-thienyl)ethyl]-2,4-oxazolidinedione;    3-[2-(5-acetyl-2-thienyl)ethyl]-2,4-oxazolidinedione;    3-[2-(5-bromo-2-thienyl)ethyl]-2,4-oxazolidinedione;    5-[2-(2,4-dioxo-3-oxazolidinyl)ethyl]-2-thiophenecarbaldehyde;    3-[3-(1-indolinyl)propyl]-2,4-oxazolidinedione;    3-[3-(1-indolinyl)propyl]-5-methyl-2,4-oxazolidinedione;    3-[2-(2-pyridyl)ethyl]-2,4-oxazolidinedione;    3-[2-(5-ethyl-2-pyridyl)ethyl]-5-methyl-2,4-oxazolidinedione;    5-ethyl-3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-oxazolidinedione;    3-[2-(5-ethyl-2-pyridyl)ethyl]-5-isopropyl-2,4-oxazolidinedione;    3-[2-(4-pyridyl)ethyl]-2,4-oxazolidinedione;    5-ethyl-3-[2-(4-pyridyl)ethyl]-2,4-oxazolidinedione;    5-ethyl-3-[2-(2-pyridyl)ethyl]-2,4-oxazolidinedione;    5-isopropyl-3-[2-(4-pyridyl)ethyl]-2,4-oxazolidinedione;    5-isopropyl-3-[2-(2-pyridyl)ethyl]-2,4-oxazolidinedione;    3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-oxazolidinedione.
The compounds of general formula (VII) are of use as synthetic intermediates for the preparation of the compounds of general formula (I).
A subgroup of compounds of general formula (VII) is composed of the compounds for which:
n, A, R1 and R7 are as defined in the general formula (I) provided that:                when R2 is a pyrrolyl, imidazo[1,2-a]pyridyl or indolinyl group, then R2 is substituted by one or more R3 and/or R4 groups;        when R2 is a pyridyl group, then R2 is substituted by one or more R3 and/or R4 groups where R3 is other than a methyl or than an ethyl;        when R2 is a thienyl group, then R2 is substituted by one or more R3 and/or R4 groups where R3 is other than a bromine, than a methyl or than a CHO or COCH3 group;        when R2 is a thioazolyl group substituted by an R3 group, then R3 is other than a methyl.
The examples which will follow illustrate the preparation of a few compounds of the invention. These examples are not limiting and only illustrate the invention. The microanalyses, the IR and NMR spectra and/or the LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) confirm the structures and the purities of the compounds obtained.
M.p. (° C.) represents the melting point in degrees Celsius.
The numbers shown in brackets in the titles of the examples correspond to those in the 1st column in the table below.

Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Abstract: alkylene group; a salt thereof, or a hydrate or a solvate of said compound or said salt; where the variables are as defined in the attached specification.


A leadless intra-cardiac medical device is configured to be implanted entirely within a heart of a patient. The device includes an intra-cardiac extension and a housing. The intra-cardiac extension includes a loop body having at least one loop segment retaining at least one coil group that is configured to one or both of receive and transmit radio frequency (RF) energy, wherein the loop body is configured to extend into a first chamber of the heart. The housing is in electrical communication within the loop body, and includes a transceiver, control logic and an energy source. The housing is configured to be securely attached to an interior wall portion of a second chamber of the heart, wherein the transceiver is configured to communicate with an external device through the RF energy.

Current implantable medical devices for cardiac applications, such as pacemakers, include a "housing" or "can" and one or more electrically-conductive leads that connect to the can through an electro-mechanical connection. The can is implanted outside of the heart, in the pectoral region of a patient and contains electronics (e.g., a power source, microprocessor, capacitors, etc.) that provide pacemaker functionality. The leads traverse blood vessels between the can and heart chambers in order to position one or more electrodes carried by the leads within the heart, thereby allowing the device electronics to electrically excite or pace cardiac tissue and measure or sense myocardial electrical activity.
To sense atrial cardiac signals and to provide right atrial chamber stimulation therapy, the can is coupled to an implantable right atrial lead including at least one atrial tip electrode that typically is implanted in the patient's right atrial appendage. The right atrial lead may also include an atrial ring electrode to allow bipolar stimulation or sensing in combination with the atrial tip electrode.
Before implantation of the can into a subcutaneous pocket of the patient, however, an external pacing and measuring device known as a pacing system analyzer (PSA) is used to ensure adequate lead placement, maintain basic cardiac functions, and evaluate pacing parameters for an initial programming of the device. In other words, a PSA is a system analyzer that is used to test an implantable device, such as an implantable pacemaker.
To sense the left atrial and left ventricular cardiac signals and to provide left-chamber stimulation therapy, the can is coupled to the "coronary sinus" lead designed for placement in the "coronary sinus region" via the coronary sinus ostium in order to place a distal electrode adjacent to the left ventricle and additional electrode(s) adjacent to the left atrium. As used herein, the phrase "coronary sinus region" refers to the venous vasculature of the left ventricle, including any portion of the coronary sinus, great cardiac vein, left marginal vein, left posterior ventricular vein, middle cardiac vein, and/or small cardiac vein or any other cardiac vein accessible by the coronary sinus.
Accordingly, the coronary sinus lead is designed to: receive atrial and/or ventricular cardiac signals; deliver left ventricular pacing therapy using at least one left ventricular tip electrode for unipolar configurations or in combination with left ventricular ring electrode for bipolar configurations; deliver left atrial pacing therapy using at least one left atrial ring electrode as well as shocking therapy using at least one left atrial coil electrode.
To sense right atrial and right ventricular cardiac signals and to provide right-chamber stimulation therapy, the can is coupled to an implantable right ventricular lead including a right ventricular (RV) tip electrode, a right ventricular ring electrode, a right ventricular coil electrode, a superior vena cava (SVC) coil electrode, and so on. Typically, the right ventricular lead is inserted transvenously into the heart so as to place the right ventricular tip electrode in the right ventricular apex such that the RV coil electrode is positioned in the right ventricle and the SVC coil electrode will be positioned in the right atrium and/or superior vena cava. Accordingly, the right ventricular lead is capable of receiving cardiac signals, and delivering stimulation in the form of pacing and shock therapy to the right ventricle.
Although a portion of the leads are located within the heart, a substantial portion of the leads, as well as the can itself are outside of the patient's heart. Consequently, bacteria and the like may be introduced into the patient's heart through the leads, as well as the can, thereby increasing the risk of infection within the heart. Additionally, because the can is outside of the heart, the patient may be susceptible to Twiddler's syndrome, which is a condition caused by the shape and weight of the can itself. Twiddler's syndrome is typically characterized by a subconscious, inadvertent, or deliberate rotation of the can within the subcutaneous pocket formed in the patient. In one example, a lead may retract and begin to wrap around the can. Also, leads may dislodge from the endocardium and cause the device to malfunction. Further, in another typical symptom of Twiddler's syndrome, the device may stimulate the diaphragm, vagus, or phrenic nerve, pectoral muscles, or brachial plexus. Overall, Twiddler's syndrome may result in sudden cardiac arrest due to conduction disturbances related to the device.
In addition to the foregoing complications, implanted leads may experience certain further complications, such as incidences of venous stenosis or thrombosis, device-related endocarditis, lead perforation of the tricuspid valve and concomitant tricuspid stenosis; and lacerations of the right atrium, superior vena cava, and innominate vein or pulmonary embolization of electrode fragments during lead extraction.
To combat the foregoing limitations and complications, small sized devices configured for intra-cardiac implant have been proposed. These devices, termed leadless pacemakers (LLPM) are typically characterized by the following features: they are devoid of leads that pass out of the heart to another component, such as a pacemaker can outside of the heart; they include electrodes that are affixed directly to the can of the device; the entire device is attached to the heart; and the device is capable of pacing and sensing in the chamber of the heart where it is implanted.
It can be appreciated, however, that a leadless pacing system needs to be compact enough to fit within the heart. At the same time, the pacing system requires a power source to operate. Accordingly, the pacer module includes a battery contained therein. Typically, the pacer module has a housing having a battery that may take up as much as 75% of the internal volume of the housing. Therefore, the pacer module itself may be bulky and occupy a relatively large volume within the heart chamber, which may adversely impact proper heart function.
Moreover, many pacing systems include telemetric subsystems that communicate with a remote programmer or patient care system. Telemetric subsystems include an antenna that communicates with the remote patient care system through radio frequency (RF) signals. Conventional antenna are relatively large, too large to fit into the housing of a leadless pacemaker.

Leadless intra-cardiac medical device with built-in telemetry system


An improved, tamper-evident label and bottle cap to be used with standard five gallon bottles; such bottle cap of the type having a central tube section capable of receiving a dispensing probe which is part of a dispensing system. A micro-thin, plastic label is heat-sealed to the face of the bottle cap, thereby protecting the central tube section from any external contaminants. An edge of the label is left unsealed to provide a means for peeling the label from the bottle cap when the bottle is to be installed. By virtue of the heat-sealing method of attachment, the tamper-evident label cannot be reattached to the face of the bottle cap, or any other surface, once it is removed.

It is commonly known and practiced within this field of art that detachable, plastic bottle caps be mounted on the neck of standard five gallon bottles. Such bottle caps seal the bottle and the contents inside prior to the bottle's installation in a dispensing system. Normally, through the use of an attached pull tab and scoreline, the bottle cap is removed from its associated bottle prior to the bottle's installation and use. Examples of such caps are shown in the following U.S. Pat. Nos. 5,392,939; 5,370,270; 5,295,518; 4,991,635 and 4,699,188.
Recent developments in the bottle cap industry include a cap which has a central tube section which is capable of receiving a specialized dispensing probe from a dispensing system. This tube section has an inner seal which prevents the liquid from escaping the bottle until such dispensing probe is inserted. With this type of arrangement, the bottle cap itself need not be removed prior to its installation into a dispensing system.
While these newer types of bottle caps do, indeed, have liquid-tight seals, the surface areas of the bottle cap face and central tube section remain susceptible to external contaminants. Some manufacturers have addressed this concern by simply placing an adhesive-backed label upon the face of the bottle cap. This attempt to prevent contamination has at least one major drawback in that the labels, once removed, can again be reattached to the face of the bottle cap. If this is done carefully, there is no evidence that the label has been tampered with.
Alternatively, users of these systems have found it convenient to simply slap these labels on the side of the bottle rather than disposing of them in a waste container. This has two disadvantages. First, its is unsightly for such litter in the form of a used label to appear on the bottle when it is inverted on to a dispenser. Second, bottlers are forced to perform the step of removing the label from the side of the bottle before reusing the bottle. The adhesives used on such labels made this task quite difficult and costly.
Another problem which sometimes arises with valved or otherwise openable bottle caps is that they occasionally, although rarely, leak. Five gallon bottles are usually shipped in the horizontal position, which puts substantial hydraulic pressure on the cap and the particular seal associated therewith. Leaks may occur because of a small defect in the seal between components of the cap, or because of assembly problems. Pressure sensitive labels currently used in the industry over the top of valved or otherwise openable caps are not effective to provide even a secondary liquid-tight seal.
In light of the safety deficiencies and additional burdens associated with the protective labels which currently exist, what is still needed in this field of art is a tamper-evident label which can be easily and inexpensively attached to a standard bottle cap, which provides a liquid-tight seal and which cannot be reattached to the cap, or any other surface, once it is removed.

Protective tamper-evident label and bottle cap


The present invention briefly provides a method of site-specific insertion in Zymomonas, comprising, providing a Zymomonas gene fragment, interrupting a DNA sequence the fragment, and transforming the Zymomonas through homologous recombination with the interrupted fragment.

1. Field of the Invention
The present invention relates to gene insertion in Zymomonas mobilis, and in particular to the insertion inactivation of specific gene products in recombinant Zymomonas mobilis strains which ferment xylose and arabinose, or both, into ethanol.
2. Description of the Related Art
Fermentation technology is useful for the conversion renewable biomass cellulose substrates into fuels and chemicals, such as ethanol. A typical substrate is comprised of 35-45% cellulose, 30-40% hemicellulose, and 15% lignin. The hydrolysis fraction contains glucose polymers, and the hemicellulose fraction contains mostly xylose. Arabinose is also a significant fermentable substrate found in biomass materials, such as switchgrass grass and corn fiber.
Z. mobilis is widely reported for its ability to rapidly and efficiently convert glucose substrates into ethanol, at a low pH, in an anaerobic culture, and in a medium which contains the inhibitory compounds typically associated with a lignocellulose-hydrolysate. A distinct disadvantage in the use of Z. mobilis is, however, that it does not ferment pentose sugars. To overcome this disadvantage, the prior art has focused on recombinant Z. mobilis strains which ferment a mixture of glucose, and xylose or arabinose, or both, using exogenous genes which catalyze the metabolism of xylose and arabinose. These strains are based on the use of multicopy plasmids capable of expression of the desired enzyme product.
U.S. Pat. No. 5,514,583 discloses a transformed Z. mobilis xylose fermenting strain (CP4/pZB4 and pZB5) having exogenous genes, and plasmid vectors (pZB4 and pZB5) encoding xylose isomerase, xylulokinase, transaldolase and transketolase, and further comprising at least one promoter (Pgap and Peno) recognized by Zymomonas which regulates the expression of at least one of said genes. The microorganism is capable of growing on xylose as a sole carbon source, and fermenting xylose to ethanol at about 88% of the maximum theoretic yield. The patent claims an integrated strain.
U.S. Pat. Nos. 5,712,133 and 5,726,053 disclose, inter alia, Z. mobilis arabinose fermenting transformants (CP4/pZB 206), containing exogenous genes that encode L-arabinose isomerase, L-ribulokinase and L-ribulose-5-phosphate-4-epimerase, transaldolase and transketolase which impart arabinose to ethanol fermentation capability. The plasmid vector (pZB 206) and a process of using the transformants for the fermentation of a glucose and arabinose containing substrate is also disclosed. The patent claims integration of the exogenous genes into the host genome.
U.S. Pat. No. 5,843,760 discloses a Z. mobilis xylose and arabinose fermenting transformant (206C/pZB301) containing exogenous genes encoding xylose isomerase, xylulokinase, L-arabinose isomerase, L-ribulokinase, L-ribulose-5-phosphate 4-epimerase, transaldolase and transketolase, and further comprising at least one promoter recognized by Zymomonas which regulates the expression of at least one of said genes, wherein said microorganism is capable of growing on arabinose and/or xylose, alone or in combination, as the carbon source and fermenting said arabinose and xylose to ethanol. The process of using the transformants together with the plasmid vectors (pZB301, pZB401, pZB402, and pZB 403) is also disclosed. This patent claims integration of the exogenous genes into the host genome.
Vital to the engineering of an economic fermentation process for the production of fuels and chemicals, from cellulose containing substrates, is to achieve a high rate of specific product formation and conversion efficiency. When using the pentose-fermenting recombinant strains of Z. mobilis, where ethanol is the specific product, the formation of the by-products lactic acid, an end product of energy formation, and xylitol lowers conversion efficiency. Thus, it is desirable to develop new metabolic engineering methods for the site-specific insertion of genes in Z. mobilis, such as for the insertion inactivation of lactate dehydrogenase, to enhance the conversion efficiency in a cellulose to ethanol process.
In Esherichia coli, the classical method for generating chromosomal inserts of foreign genes involves the use of specialized λ phage cloning vectors that can exist stable in the lysogenic state. Alternatively, site specific genes can be inserted though homologous recombination, when bracketed with E. coli chromosomal sequences, or by random transposition if the genes can be cloned in the permissive sites of a transposon. While transposition has been demonstrated in Z. mobilis, Pappas, K. M., et al., (1997) Transposon mutagensesis and strain construction in Zymomonas mobilis, Journal of Applied Microbiology, Vol. 82, p.p. 379-388 (Tn5 or mini Mμ transposition of auxotrophy or antibiotic resistance for genetic analysis in Z. mobilis) transposition is random and homologous recombination in Z. mobilis has not been demonstrated. Further, no bacteriophage has ever been isolated from Zymomonas.
In view of the foregoing, a need exists for a method of site specific insertion in Z. mobilis. One practical application of the method would be for the elimination in the formation of by-products, in a Z. mobilis fermentation, through the construction of stable recombinant strains, characterized by the insertion inactivation of genes encoding those enzymes in the specific by-product formation pathway, to be eliminated.

Method of inactivation of an end product of energy metabolism in


A method and system for sending an interrupt signal is described herein. The method may include detecting sensor data in a sensor controller and detecting a powered down port between the sensor controller and an operating system. The method may also include sending the interrupt signal from the sensor controller to the operating system. In addition, the method may include detecting the operating system has provided power to the powered down port. Furthermore, the method may include sending the sensor data from the sensor controller to the operating system.

Modern computing devices continue to incorporate a growing number of components. For example, modern computing devices may include sensors that can provide additional information to the computing device about the surrounding environment. In some examples, the sensors may include a Global Positioning System (also referred to herein as GPS) radio, a real-time clock, or a magnetometer. A GPS radio may detect the change in location of a computing device. In some embodiments, a real-time clock may detect the time for the computing device from various sources, such as the International Atomic Time, among others. A magnetometer may detect the direction the computing device is traveling. As the number of sensors included in a computing system increases, the amount of power to operate the sensors also increases.


In the manufacture of a substrate with a hydrophobic film used for a reference electrode of an ion sensor or the like, a hydrophobic film is formed on a substrate by irradiating a target consisting of a hydrophobic compound with a neutral atom beam and thereby effecting sputtering. The apparatus for effecting the sputtering comprises a target base disposed in a vacuum chamber, an atom beam gun for irradiating a target on the target base with a neutral beam, a substrate base and a shutter for controlling the passage of sputtered particles. A thin film that is manufactured is suitable for an ion sensor, such as an ISFET or the like or an enzyme sensor.

1. Field of the Invention
This invention relates to a method of forming on a substrate a thin film such as a functional film used as a reference electrode of an ion sensor, and apparatus for forming a thin film suitable for carrying out the method and a biosensor and chemical sensor such as an ISFET (ion sensitive field effect transistor) sensor having a thin film formed by the apparatus.
2. Description of the Prior Art
Ion sensors or the like generally use reference electrodes for reference potential generation. In the manufacture of this reference electrode, there have been many attempts of manufacturing hydrophobic organic thin films consisting of hydrophobic fluororesins, particularly polytetrafluoroethylene (available under a trademark "Teflon") by a dry process such as a deposition process or a sputtering process.
However, in a method of forming a thin film of a reference electrode by the prior art sputtering process or the like, it is very difficult to control film composition, directivity of film and polymerization degrees, and it has been impossible to form an organic thin film as designed on a substrate. In the sputtering process, heat is stored in a target by an accelerated beam, thus causing thermal damage to the target. This technical field is only in an initial stage, and it can be said that the selection of the kind of organic thin film and corresponding dry process determines the quality of the film and characteristics of the intended functional film.
As the above apparatus for manufacturing a thin film, used in the field of manufacture of semiconductors, there are known various CVD (chemical vapor deposition) apparatus for instance, thermal CVD, reduced pressure CVD, light CVD and plasma CVD apparatuses, sputtering apparatus and ICB (ion cluster beam) apparatus. In many of these apparatuses, film is formed in vacuum and under a somewhat high temperature condition.
Recently, there have been extensive studies with an aim of making use of organic thin films for improving the function of electronic devices. It is thought that organic thin films can find extensive applications for passivation films and sealing materials because it is possible to obtain films which have good machining properties and are chemically stable.
However, with such prior art apparatuses for dry state manufacturing of thin films it is necessary to form films at high temperatures. Therefore, it is very difficult to form organic substances capable of ready decomposition, particularly thin films of polymers. Further, it is difficult to form multi-layer bodies, laminations and mixtures of thin films.
By using the RF sputtering process or ion beam process it is possible to form multi-layer bodies and mixtures of thin films. These methods, however, lead to great damage with organic substances due to ion bombardment, and there is a high probability of fragmentation of molecules. Besides, there is a trend of introduction of ions. Further, it is impossible to form an insulating film.
As methods of forming thin film in a wet state, there are a LB (Langmuir Blodgett) process and an electrolytic process. In these processes, thin films can be formed at room temperature. However, substances which can be used for film formation are limited, and thus it is impossible to obtain a perfect insulating film.
Further, regarding a sensor using a substrate with a thin film as electrode, ion sensors utilizing MOSFETs capable of fine machining using semiconductor manufacture technology, i.e., ISFET sensors, have been developed as solid-state very small sensors, with reported sizes less than 10 microns.
While the active electrode of the sensor is capable of miniaturization in this way, miniaturization of the whole sensor requires miniaturization of the reference electrodes.
With the prior art technique, however, it is difficult to obtain miniaturized solid reference electrodes. In order to solve these problems, reference electrodes with polystyrene thin film and hydrophobic organic polymer film on a gate insulating film are disclosed in Japanese Patent Disclosures 58-103658 and 58-34352.
While various reference electrodes have been developed for miniaturization and solidification, these electrodes can readily respond to pH (hydrogen ion concentration). In addition, adsorption of and permeation to interfering substances are possible. Therefore, these reference electrodes have inferior potential stability, and difficulties are involved in their use.
As further sensors, there are enzyme sensors for measuring the substrate concentration using enzyme electrodes by an amperometric process, and particularly enzyme sensors for directly measuring enzymic reaction from oxidation/reduction reaction of electron movement media (mediators).
These kinds of enzyme sensors are mainly used for clinical chemical analysis, and those for glucose, urea and neutral and phosphoric fat as the subject of measurement are in practical use. For instance, an enzymic reaction in the case of .beta.-D-glucose (grape sugar) as the subject of measurement is expressed as ##STR1##
More specifically, B-D-glucose consumes O.sub.2 with an action of .beta.-D-glucose (GOX) to generate an organic acid (gluconolactone) and hydrogen peroxide (H.sub.2 O.sub.2). Therefore, glucose concentration can be measured from the amount of generated hydrogen peroxide and gluconolactons or amount of consumed oxygen.
Heretofore, for measuring the glucose concentration according to the amount of generated hydrogen peroxide a method has been adopted, in which the generated hydrogen peroxide is oxidized with a metal electrode, and the oxidizing current is measured. Alternatively, the generated hydrogen peroxide is reduced, and the reducing current is measured. However, these oxidizing and reducing currents are subject to the influence of oxygen. Further, a prior art detection electrode is liable to be influenced by changes in the surface state. Further, the principle of measurement by electrochemical means uses a sensor structure, which comprises an electrode substrate, liquid, enzyme fixed film and liquid under test. Therefore, miniaturization of the sensor is difficult due to liquid present between the electrode and the film.
As other methods for measuring the glucose concentration, there are
(1) one, in which hydrogen peroxide is decomposed by catalase, and the amount of oxygen is measured, and
(2) one, in which iodide ions are oxidized in the presence of enzyme (peroxidase) and inorganic catalyst (molybdenum), and the amount of iodine is measured by causing the following reaction, thereby indirectly measuring the amount of hydrogen peroxide. ##STR2##
In the above way, when measuring the glucose concentration according to the amount of generated hydrogen peroxide, the amount of consumed oxygen or amount of generated iodine is measured, and the amount of generated hydrogen peroxide is determined indirectly from the measured amount.
However, such method of measurement through two reaction stager requires a separate electrode for measuring oxygen or iodine in addition to an enzymic electrode for decomposing glucose or the like to hydrogen peroxide. In addition, the measurement is very complicated and takes a long time. Meanwhile, with the prior art electrochemical method, there are problems of contamination of the liquid under test and difficulties of miniaturization because the sensor contains inner liquid.


Embodiments described can more effectively complete complicated service transactions in a more efficient manner by having a team of well-trained professionals who are instantly “streamed” into any location as necessary. A two-way communication system can provide instant or quick access to the right expert at the right point in time, thereby converting what might otherwise be a negative customer experience into a positive sales and service opportunity. A computer implemented method for providing customer support comprises receiving, by a touchpoint device, identification information from a user of the touchpoint device; receiving the identification information; providing an electronic document to the user; receiving an input from the user requesting a session with a representative; selecting a representative based at least in part on the electronic document; providing information about the electronic document to the representative; and establishing a connection between the representative and the touchpoint device.

Financial institutions provide a vast array of financial services and products to customers and potential customers. Traditionally, the process for selling a product to a customer and servicing a customer has been predominantly in person, over the telephone, or via the Internet. When communicating with a customer service representative, even over the telephone or in person, that representative may not be able to answer a customer's questions about a particular product or service outside their area of expertise. As a result, the customer must be directed to an expert, if one is even available.
Typically, the customer must enter details about themselves and their desired transaction in order to be connected to the appropriate representative. When connecting with a call center, the customer can become frustrated and spend unnecessary time just trying to connect with a representative than can assist. Moreover, if the customer has traveled to a branch or physical location of a financial institution, that particular branch may not employ any representatives who can answer the customer's questions. Obviously, such a situation proves frustrating for customers and can result in a lost sales opportunity for the financial institution.
From the customers' point of view, customers desire a personal experience of a face-to-face interaction with an expert who can answer a question about a product or help a customer to properly complete a form. From the financial institution's point of view, the financial institution cannot reasonably expect to employ an expert on each of the vast number of products and services it offers in every branch at all times.
Accordingly, there is a need for a system and method for automatically selecting and connecting a customer service representative to a user of a financial product or service without requiring the user to enter additional information about the product or service they are using.

This patent is subject to a terminal disclaimer.

System and method for providing customer support on a user interface


A method and structure for a DRAM device which includes a trench within an insulator, a conductor within the trench, a transistor adjacent a first side of the trench, and a shallow trench isolation region formed within a top portion of the conductor on a second side of the trench, opposite the first side, wherein the top portion of the conductor has a curved shape at an edge of the shallow trench isolation region. The curved shape comprises a conductive strap and electrically connects the conductor and the single crystal where the transistor is formed, further comprising a collar oxide surrounding the top portion of the conductor, the collar oxide controlling a shape and location of the curved shape. The curved shape is formed by hydrogen annealing, and may be convex, or concave. The DRAM further comprising a collar oxide extending into the shallow trench isolation region on the second side.

1. Field of the Invention
The present invention generally relates to formation of a low resistive strap with hydrogen annealing within a DRAM structure.
2. Description of the Related Art
Conventional processing of trench dynamic random access memory (DRAM) structures forms a buried strap during the formation of a deep trench to connect the conductor in the deep trench to an adjacent transistor. The strap resistance has been shown to be a significant bottleneck in trench DRAM characteristics. The primary reason for this is that the active area (AA) to deep trench (DT) overlay is limited (by tool capability) to about 45 nm. The conventional process causes the strap to be etched away around the trench in unwanted areas during the shallow trench isolation definition leaving a sliver of silicon along the trench sidewalls to contact to the deep trench portion below the STI. This contributes significantly to the strap resistance.
Various schemes have been proposed (sometimes with an oxide cap on top of the trench as by Radens et al., U.S. Ser. No. 09/272124, referred to as a xe2x80x98Pedestalxe2x80x99 STI) leaving the polysilicon in the trench untouched but etching only the silicon outside the trench or performing the strap recess after the active area (AA) etch with a xe2x80x98Poly Planarizedxe2x80x99 STI etch. However, neither of these schemes work with a xe2x80x98lipxe2x80x99 or near surface strap which is deemed necessary to avoid a deep strap with poor array device performance.
It should also be noted that for deep trenches with high cell capacitance it is necessary to minimize the gap at the top of the trench. However, the conventional poly fill technology cannot fill perfectly vertical trenches. This constant tradeoff results quite often with voids in the top of the trench polysilicon which need to be healed to prevent them from opening up during shallow trench isolation etching.
Therefore, there is a need for a low resistance buried strap which is thicker and does not have trench voids. It is to be noted that rounding of the STI corners is preferable for good gate oxide integrity.
It is, therefore, an object of the present invention to provide a structure and method for a DRAM device which includes a trench within an insulator, a conductor within the trench, a transistor adjacent a first side of the trench, and a shallow trench isolation region formed within a top portion of the conductor on a second side of the trench, opposite the first side, wherein the top portion of the conductor has a curved shape at an edge of the shallow trench isolation region. The curved shape comprises a conductive strap and electrically connects the conductor and the transistor, further comprising a collar oxide surrounding the top portion of the conductor, the collar oxide controlling a shape and location of the curved shape. The curved shape is formed by hydrogen annealing, and may be convex, or concave. The DRAM further comprises a collar oxide extending into the shallow trench isolation region on the second side. A method of manufacturing a DRAM device includes depositing a conductor in a trench, removing a portion of the conductor to form a shallow trench isolation region, and reflowing the conductor to form a curve in the conductor adjacent the shallow trench isolation region. The reflowing comprises hydrogen annealing, the curve is convex, or concave. The reflowing increases the width of the conductive portion. The trench has a collar oxide to surround a top portion of the conductor whose removal is selective to the collar and leaves the collar oxide in place. The collar oxide contacts a shape and position of the curve, further comprising forming a transistor adjacent the trench, wherein the top portion of the conductor comprises a strap connecting the conductor to the transistor and the curve reduces the resistance of the strap.

DRAM strap: hydrogen annealing for improved strap resistance in high density trench DRAMS

International Business Machines Corporation


A time needed until measurement values are obtained in a two-frequency continuous wave radar systems is reduced.

Recently, there have been active studies that attempt to enhance driving safety by mounting on a vehicle such as an automobile a radar system that automatically detects surrounding obstacles and the like to make use of the detection results for vehicle cruise control. The radar system used in the vehicle cruise control needs to detect relative speed information on obstacles and other vehicles with high accuracy.
While such radar system detects speeds, positions, and the like of target objects by frequency-analyzing reception signals obtained by receiving incoming radio waves from the target objects, in order to improve frequency resolution in the frequency analysis of the reception signals, it is necessary to receive the signals for more than a predetermined time period. Taking more time for measurement of the reception signals, the frequency resolution is improved accordingly, which increases accuracy of measurement values outputted as the result.
A minimum measurement time required for achieving a desired velocity resolution can be determined in principle depending on a frequency analysis method to be employed. For example, in a radar system using transmission waves of wavelength λ, if reception signals are frequency-analyzed by a Fourier transformation, a minimum measurement time Tc required for obtaining a velocity resolution δV and a frequency resolution δf is known to satisfy Formula (1):
                              δ                                                              V                =                                            λ              2                                    δ                                                                          f                    =                                    λ              2                        ·                                          1                Tc                            .                                                          (        1        )
Cost reduction is a key for vehicle-mounted radars to come into widespread use. In order to achieve cost reduction of radar systems, a frequency-modulated continuous wave (FMCW) method or a two-frequency continuous wave (CW) method is likely to be advantageous that is feasible with low speed signal processing compared with a pulse radar or a pulse compression radar (spread spectrum radar) that requires a signal processing circuit of high performance.
The FMCW method is a method in which beat signals are created from transmitted signals and received signals obtained by receiving reflection waves from target objects during two measurement periods of an up-chirp and a down-chirp in frequency, to detect relative speeds of and distances to the target objects by combining beat signals obtained during the up-chirp period with those obtained during the down-chirp period. In this case, since the respective beat signals needs to be determined independently from the up-chirp and the down-chirp periods, both up-chirp and down-chirp periods have to be equal to or more than the time Tc. Accordingly, it takes at least twice the time Tc to obtain measurement values satisfying a desired velocity resolution.
On the other hand, the two-frequency CW method is a method in which transmission waves of two frequencies f1 and f2 each are emitted for a fixed time period, to detect target objects from frequency and phase information of respective received waves. In this case also, since frequency-analysis process of the received waves for the transmission waves of frequency f1 and those for the transmission waves of frequency f2 are independent of each other, it is needed that after the transmission waves of frequency f1 have been emitted at least for the time Tc and their reflection waves have been received, the transmission waves of frequency f2 are emitted at least for the time Tc and their reflection waves are received. For that reason, in order to obtain measurement values satisfying a desired velocity resolution even in the two-frequency CW method, it resultantly takes at least twice the time Tc.
Thus, either the conventional FMCW or two-frequency CW method needs a measurement time that is twice or more the time Tc in order to obtain measurement values with a desired velocity resolution. As a method of obtaining measurement values within twice the time Tc, a method is known in which relative speeds of and distances to target objects are detected by combining phase differences of reception wave beat signals obtained from transmission waves of different frequencies during either an up-chirp or a down-chirp period in an FMCW method (refer to Patent Document 1, for example).
Patent Document 1: "Method and Device for Determining Separation and Relative speed of a Distant Object"; Japanese Unexamined Patent Publication No. 2004-511783.
Patent Document 2: "Radar System"; Japanese Unexamined Patent Publication No. 2002-71793.

Abstract: An object detection system that emits transmission signals, as transmission waves, whose frequencies have been modulated successively into a plurality of stepped frequencies, and receives echoes of the transmission waves reflected from target objects, thereby calculating relative velocities of the target objects by frequency-analyzing reception signals obtained from the received echoes. The target object detection system includes: a frequency modulation component that repeatedly executes frequency-modulation processes to successively modulate the transmission signals into those of the stepped frequencies, within a minimum measurement time in which a desired velocity resolution is achieved; and a frequency-analysis component that frequency-analyzes throughout the repeated frequency-modulation processes the reception signals processed by the frequency-modulation component.


The present disclosure intends to provide an optical signal from an ONU according to a desired service usage state without using the ONU and an OLT. A simulated signal light generation apparatus 10 according to the present disclosure is a simulated signal light generation apparatus 10 for simulating an uplink signal light generated in an optical network unit (ONU) in a passive optical network (PON), and the apparatus includes a usage state control unit 11 that sets a service usage state of the ONU, a signal generation unit 12 that generates an uplink signal frame according to the usage state set by the usage state control unit 11, and an electrical/optical conversion unit 13 that converts an electrical signal from the signal generation unit 12 into an optical signal, and the optical signal from the electrical/optical conversion unit 13 is repeatedly transmitted to an optical fiber core 22.

A communication monitor has been proposed for monitoring communication of an optical line termination device in a user home, which is connected to an end of a target optical fiber core at a connection point of an outside line without entering an exchange station (for example, see Patent Literature 1). In the communication monitor in Patent Literature 1, by bending the target current optical fiber core so as not to affect communication and receiving leaked light, an uplink signal light can be acquired from the optical line termination device connected to the end of the optical fiber core, and an MAC address and service usage state of the optical line termination device can be monitored from the acquired signal.
When inspecting, verifying, and evaluating an apparatus for implementing the technique in Patent Literature 1 and training the operator, it is necessary to use an optical signal from the optical line termination device and to prepare an optical signal matching the desired service usage state.
Here, a passive optical network (PON) including a gigabit Ethernet passive optical network (GE-PON) is configured of an optical line terminal (OLT), which is a parent device and a optical line termination device, and optical network units (ONUs), which are child devices and are optical line termination devices, and the OLT controls and manages a plurality of ONUs to perform communication.
In the PON, since the OLT controls timing at which each ONU emits the uplink signal light such that the uplink signal light does not collide with an uplink signal light from another ONU, each ONU emits the uplink signal light only when connected to the OLT and receiving a downlink signal light from the OLT. Accordingly, in order to build a verification system for verification, evaluation, and the like of the above-described apparatus, it is required to prepare the ONU and the OLT and connect them, contract with a service provider, and prepare a user terminal, a phone, or the like for simulating the state of calling, IP communication, or so on. In this manner, a lot of articles need to be prepared, which is very labor intensive. In addition, the verification place is disadvantageously limited because the verification system can be constructed only at the place where the optical fiber core connected to the OLT can be connected to the ONU.

Simulation signal light generation device and simulation signal light generation method

NIPPON TELEGRAPH AND TELEPHONE CORPORATION


Eyeglasses worn in winter weather conditions are subject to fogging due to condensation of water vapor. A method of removing condensation from eyeglasses is provided. The method involves heating the lenses of the eyeglasses, by making the lenses a part of an electrical circuit. Electric current is supplied to the electric circuit from a power source external to the eyeglasses. The size and weight of the power source may be minimized by utilizing a timer or a power regulator. A smaller power source is also made possible by selectively heating the lenses, applying more power in the area of the lenses most likely to experience fogging.

1. Technical Field
This invention pertains to a method and device for removing condensation from eyeglasses.
2. Background Art
Eyeglasses used out-of-doors in cold climates are subject to fogging due to the accumulation of water vapor on the lenses. Such condensation hinders the user's ability to see through the lenses, whether the lenses are optically corrective or simply to protect the user's eyes from bright sunlight.
The use of electrical heating to prevent or remove condensation on lenses or face masks is known in the prior art. For example, U.S. Pat. No. 4,209,234 to McCooeye discloses a pair of eyeglasses in which a battery is mounted on the temples of the glasses to supply power to an electrical circuit which includes a conductive transparent film covering the lenses of the eyeglasses. Great Britain Patent No. 489,530 reveals lenses which are coated with a conductive metal paint, and which are superimposed on a second set of lenses, embedding a wire which forms a portion of an electrical circuit for heating the lenses. U.S. Pat. No. 3,160,735 to Aufricht, like McCooeye, relies on a battery mounted in the temple of eyeglasses. This miniature battery supplies power to an electrical circuit which includes a wire around each lens. Batteries mounted on the glasses themselves increase the weight of the glasses and cause the glasses to be considerably different in appearance and in construction than standard eyeglasses. Furthermore, the use of miniature batteries, which enables these designs to be comfortably worn, results in a maximum time for supplying power of approximately one to two hours under moderate fogging conditions, and no more than ten minutes in severe fogging conditions, which is significantly less than is required to permit defogging during a day of work or sports.
A number of specialized goggles and helmets are known in the prior art, which achieve defogging based on an electrical circuit supplied from an exterior power supply such as a vehicle electrical system. See, for example, U.S. Pat. No. 4,638,728 to Elenewski, U.S. Pat. No. 4,584,721 to Yamamoto, U.S. Pat. No. 3,024,341 to Ogle Jr. et al., and U.S. Pat. No. 4,682,007 to Hollander. Use of the external vehicle power source alleviates the problems associated with using a small battery pack to defog eyewear, and allows virtually limitless time periods for heating the eyewear. These designs are useful for activities involving consistent contact with a vehicle, such as snow mobiling. However, reliance on an external vehicle power source makes it impossible to utilize these defogging systems in sports such as skiing.
Goggles which may be heated to achieve defogging are revealed in U.S. Pat. No. 4,942,629 to Stadlmann, U.S. Pat. No. 3,027,561 to Senne, Great Britain Patent No. 264,280, U.S. Pat. No. 1,963,990 to Gilkeson et al., and U.S. Pat. No. 4,868,929 to Curcio. The power source used in Stadlmann is a solar cell mounted in a headband, which provides less than optimum heating capacity on cloudy days. Senne and Great Britain 264,280 are geared toward applications other than winter weather, and each relies on wires embedded in lenses to complete an electrical circuit and heat the lenses. Similarly, a wire is embedded in aircraft and ski goggles in Gilkeson and Curcio respectively, to heat the lenses and accomplish defogging.
Other eyewear or helmets with mechanisms for clearing condensation are known in the prior art. U.S. Pat. No. 4,996,981 to Elenewski et al. describes a visor to be used by a fireman or miner with an electrically activated heater or fan to prevent condensation from forming on the visor. U.S. Pat. No. 4,633,532 to Yagasaki and U.S. Pat. No. 2,888,703 to Karwowska both involve the use of miniature "windshield wipers" to remove condensation. Finally, U.S. Pat. No. 1,488,085 to Zachara discloses an electrically powered eye glass frame which is intended to be used as a light source.
While each of these mechanisms known in the prior art may be useful for its intended purpose, no mechanism is known which may be used to defog eyeglasses for a period as long as a day during use in winter weather, while achieving a customary construction, appearance, and weight for the eyeglasses. There exists a need for a defogging mechanism which can be used for a period of at least six hours during outdoor winter work or sports activities, while maintaining the comfort and typical appearance of eyeglasses. Ideally, such a defogging mechanism should permit the eyeglasses to be manufactured by existing production techniques, to avoid additional expense. Furthermore, this defogging means should utilize a convenient, portable, and economical power source.


Methods and systems for aligning an x-ray source position in an imaging system are provided. The imaging system includes a multislice detector array having a plurality of rows of detector cells displaced along a z-axis and an x-ray source for radiating an x-ray beam toward the detector array. The system is configured to determine an x-ray beam z-axis profile using the detector array, and determine an adjustment to the position of the x-ray source based on the determined x-ray beam z-axis profile.

This invention relates generally to computed tomography (CT) imaging and more particularly, to alignment of a radiation source in a CT imaging system.
In at least one known CT imaging system configuration, an x-ray source projects a fan-shaped beam which is collimated to lie within an X-Y plane of a Cartesian coordinate system and generally referred to as the "imaging plane". The x-ray beam passes through the object being imaged, such as a patient. The beam, after being attenuated by the object, impinges upon an array of radiation detectors. The intensity of the attenuated beam radiation received at the detector array is dependent upon the attenuation of the x-ray beam by the object. Each detector element of the array produces a separate electrical signal that is a measurement of the beam attenuation at the detector location. The attenuation measurements from all the detectors are acquired separately to produce a transmission profile.
In known third generation CT systems, the x-ray source and the detector array are rotated with a gantry within the imaging plane and around the object to be imaged so that the angle at which the x-ray beam intersects the object constantly changes. A group of x-ray attenuation measurements, i.e., projection data, from the detector array at one gantry angle is referred to as a "view". A "scan" of the object comprises a set of views made at different gantry angles, or view angles, during one revolution of the x-ray source and detector.
In an axial scan, the projection data is processed to construct an image that corresponds to a two-dimensional slice taken through the object. One method for reconstructing an image from a set of projection data is referred to in the art as the filtered back projection technique. This process converts the attenuation measurements from a scan into integers called "CT numbers" or "Hounsfield units", which are used to control the brightness of a corresponding pixel on a display.
To reduce the total scan time required for multiple slices, a "helical" scan may be performed. To perform a "helical" scan, the patient is moved in the z-axis synchronously with the rotation of the gantry, while the data for the prescribed number of slices is acquired. Such a system generates a single helix from a fan beam helical scan. The helix mapped out by the fan beam yields projection data from which images in each prescribed slice may be reconstructed. In addition to reducing scan time, helical scanning provides other advantages such as better use of injected contrast, improved image reconstruction at arbitrary locations, and better three-dimensional images.
To further reduce the total acquisition time, multi-slice CT has been introduced. In multi-slice CT, multiple rows of projection data are acquired simultaneously at any time instant. When combined with helical scan mode, the system generates a single helix of cone beam projection data. Similar to the single slice helical weighting scheme, the projection data can be "weighted" prior to filtered back projection. Thus, one technical effect is the generation of a volumetric CT three-dimensional (3D) image of a scanned object.
Multislice CT systems are used to obtain data for an increased number of slices during a scan. Known multislice systems typically include detectors generally known as 3-D detectors. With such 3-D detectors, a plurality of detector elements form separate channels arranged in columns and rows. Each row of detectors forms a separate slice. For example, a two-slice detector has two rows of detector elements, and a four-slice detector has four rows of detector elements. During a multislice scan, multiple rows of detector cells are simultaneously impinged by the x-ray beam, and therefore data for several slices is obtained.
The image reconstruction process relies on a very accurately positioned focal spot from which the fan-shaped x-ray beam is emitted. The focal spot is the location on the x-ray tube anode that is struck by an electron beam emanating from a cathode. Misalignment of this focal spot may result in sampling errors that reduce image resolution and produce image artifacts.
Perfect mechanical alignment of the x-ray tube focal spot is difficult to achieve in a commercial production setting and difficult to maintain in a clinical setting. Calibration and alignment procedures are used to position the x-ray tube focal spot during initial manufacture. These procedures are delicate and time consuming. However, if a detector tube fails after the scanner has been in operation, a new tube must be installed and aligned. In such a case, because of new build dimensional tolerances and/or previous detector calibration procedures being performed, the collimator and detector are assumed to be in proper alignment and only the position of the new tube (Zc) needs to be adjusted.

Methods and systems for imaging system radiation source alignment


The present invention provides improved primers for the polymerase chain reaction (PCR) amplification of a nucleic acid sequence from the gag gene of the human immunodeficiency virus type 1 (HIV-1). The primers and amplification methods of the invention enable the detection of all HIV-1 group M isolates with nearly uniform efficiency.

1. Field of the Invention
The present invention relates to the field of molecular biology and nucleic acid chemistry. More specifically, it relates to methods and reagents for detecting human immunodeficiency virus type 1 (HIV-1). The invention therefore has applications in the field of medicine generally, medical diagnostics specifically, and the field of molecular biology.
2. Description of Related Art
The invention of methods for amplifying specific sequences of nucleic acids, in particular, the polymerase chain reaction (PCR), makes possible the rapid detection of nucleic acids present in a sample in what was previously an undetectably low quantity (see U.S. Pat. Nos. 4,683,195; 4,683,202; and 4,965,188, each of which is incorporated herein by reference). The development and application of PCR are described extensively in the literature. For example, a range of PCR-related topics are discussed in PCR Technology--principles and applications for DNA amplification, 1989, (ed. H. A. Erlich) Stockton Press, New York, N.Y.; PCR Protocols: A guide to methods and applications, 1990, (ed. M. A. Innis et al.) Academic Press, San Diego, Calif.; and PCR Strategies, 1995, (ed. M. A. Innis et al.) Academic Press, San Diego, Calif.; each of which is incorporated herein by reference. Commercial vendors, such as Perkin Elmer (Norwalk, Conn.), market PCR reagents and publish PCR protocols.
The use of PCR and probe hybridization to amplify and detect HIV-1 nucleic acid is reviewed in Kwok, 1992, Ann. Med. 24:211-214; and Coutlee et al., 1991, Mol. Cel. Probes 5:241-259; both incorporated herein by reference. PCR-based HIV-1 detection assays are described in, for example, U.S. Pat. Nos. 5,008,182 and 5,176,775; Kellogg and Kwok, 1990, in PCR Protocols: A Guide to Methods and Applications, (ed. Innis et al.), Academic Press, San Diego, Calif.:337-347; Holodniy et al., 1991, J. Inf. Dis. 163:802-865; Jackson et al., 1991, AIDS 5:1463-1467; and Mulder et al, 1994, J. Clin. Microbiol. 32(2):292-300; each incorporated herein by reference.
Commercial kits for the amplification and detection of HIV-1 are commercially available from Hoffmann-La Roche (Nutley, N.J.). The Amplicor.TM. HIV-1 Test is an in vitro assay for the detection of HIV-1 proviral DNA. The AMPLICOR HIV-1 MONITORTM.TM. Test is an in vitro assay for the quantitation of HIV-1 RNA. The Amplicor HIV-1 Test product insert and the AMPLICOR HIV-1 MONITOR Test product insert are each incorporated herein by reference. Both of the Amplicor assays amplify HIV-1 nucleic acids using the primer pair SK462 (SEQ ID NO: 5) and SK431 (SEQ ID NO: 6), described in Mulder et al., 1994, J. Clin. Microbiol. 32(2):292-300, and referred to herein as the Amplicor HIV-1 primers.
HIV-1 displays considerable genomic sequence variability. Phylogenetic analysis of the nucleic acid sequences of HIV-1 gag and env genes is described in Myers et al, 1993, Human Retrovirus and AIDS 1993, Los Alamos National Laboratory, Los Alamos, N.Mex., incorporated herein by reference. Within the M group, subtypes A-J have been identified.
Conventional techniques of molecular biology and nucleic acid chemistry, which are within the skill of the art, are fully explained fully in the literature. See, for example, Sambrook et al., 1989, Molecular Cloning--A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Nucleic Acid Hybridization (B. D. Hames and S. J. Higgins. eds., 1984); and a series, Methods in Enzymology (Academic Press, Inc.), all of which are incorporated herein by reference. All patents, patent applications, and publications cited herein, both supra and infra, are incorporated herein by reference.

Gag gene primers for the detection of HIV-1


A bed apparatus having a base and two inflatable members for elevating the torso and legs of a user is provided. The inflatable members are removably attachable to the base and can be selectively spaced apart, making the bed spatially adjustable. The extent to which a user's body is elevated is controlled by inflation of the inflatable members, making the bed vertically adjustable.

The present invention generally relates to an inflatable bed and is specifically directed to an air inflatable bed apparatus that, when not inflated, is compactable for efficient portability and storage and that includes removably attachable elevated support components that are vertically and spatially adjustable so as to make the apparatus adjustable for optimum comfort and compatible with users of different physical dimensions.
Vertically adjustable beds are well known commodities. Today, most American hospital rooms are equipped with vertically adjustable beds that are electromechanically operable. Hospitalized patients who are confined to those types of beds, but who remain physically capable of controlling the beds without assistance can, at the mere press of a switch, incline their beds and raise themselves to watch television, converse with visitors and perform various other waking activities that are preferably done from upright postures. Similarly, the patients can then decline the beds and lower themselves whenever they wish to assume a more evenly horizontal position. Furthermore, vertically adjustable beds allow bedridden patients in more debilitated conditions to be raised, by their care providers, to facilitate basic activities such as feeding and bedpan use or for preventing fluid buildup in the patients' lungs without the patients having to be physically handled by multiple care providers. Therefore, in addition to enabling patients to have more comfortable hospitalization experiences, vertically adjustable beds can effectively lower a hospital's labor costs by reducing the number of care personnel that otherwise would be needed simply for lifting and lowering debilitated patients on their beds throughout the day.
From a negative standpoint, however, a contemporary electromechanical bed that is vertically adjustable can be simply too expensive for the average consumer to purchase for home use. Also, as is the case with any electromechanical device, there are risks of mechanical or electrical failure occurring. Furthermore, the sheer sizes and weights of most of these beds make it prohibitive to move them from room to room, much less transport them in vehicles.
Air inflatable beds, some of which are vertically adjustable, are also well known in the prior art. For examples, U.S. Pat. No. 6,298,511 to Collymore and U.S. Pat. No. 5,170,522 to Walker both disclose examples of such. Inflatable beds, generally, can provide multiple benefits to users. One obvious benefit, depending on the construction of the particular airbed, is that of portability. Airbeds which are compactable and devoid of any heavy or rigid parts, as are many vinyl-fabricated air mattresses, can be transported for use virtually anywhere, and their compactness allows them to be easily stored in small spaces.
Another virtue of an inflatable mattress, in comparison to a conventional bed mattress, can be the firmness that the inflatable mattress possesses when it is inflated to a high pressure. For this reason, an inflatable bed may be preferable to a more forgiving conventional mattress for a person suffering from a chronic back ailment. And an airbed that is contoured to smoothly incline a user's torso can be a considerably firmer inclined lying surface than is an inclinable conventional mattress, much less the makeshift alternative of stacked pillows for propping the head and torso. Again, for users suffering from back or neck problems, the extra firmness of the airbed can be essential to preventing further spinal and muscular aggravation. Additionally, persons suffering respiratory ailments such as asthma or emphysema and those suffering gastric problems such as acid reflux disease ("GERD") can also benefit from an airbed that elevates their torsos during rest.
However, inflatable beds of the prior art are not without their deficiencies as well. One such deficiency common to many known inflatable beds is their lack of spatial adjustability. To wit, since people of varying tallness may wish to enjoy the use of an inflatable bed, it may be necessary to allow for expansion and contraction of, for example, the space that separates the torso/head elevating segment of the airbed from its leg elevating segment, where the inflatable bed features both such segments. When an inflatable bed does not allow for this kind of spatial adjustment, the bed may be incompatible with users who are considerably taller than the typical user, as the legs of taller users may extend beyond the end of the airbed, or the leg incline segment of the airbed may not be comfortably situated relative to its torso/head incline segment. Incidentally, this inability to adjust the spacing between inclined segments of the bed is not confined to inflatable beds; it can be a drawback of mechanical adjustable beds as well.
Thus, it can be appreciated that there exists a particular need for a portable bed apparatus that is both vertically and horizontally adjustable to enable lifting and propping of the torsos and legs of users and to render it compatible with virtually all users. The portable, adjustable and inflatable bed of the present invention substantially fulfills this need.