A compound of the formula (I)

The present invention relates to a novel 2,3-disubstituted pyridine derivative exhibiting a phosphodiesterase IV (hereinafter, referred to as PDE IV) inhibitory activity being useful as a medicament, a process for the preparation thereof, a pharmaceutical composition containing the same, and an intermediate therefor.
Hitherto, theophylline or various chemical mediator antagonists have been used as an agent for treatment of asthma, but these agents have defects, for example, they cannot exhibit a sufficient inhibitory effect on bronchoconstriction or a sufficient effect on airway inflammatory and they cannot show a sufficient selectivity from their side effects on the cardiovascular system. Steroids also have been used as an agent for treatment of asthma, and their effects on the airway inflammation are potent but their inhibitory effects on bronchoconstriction is weak, and in addition, serious side effects of steroids have also been predicted. Therefore, it has been desired to develop a novel agent exhibiting an inhibitory effect on bronchoconstriction as well as an effect on the airway inflammation.
PDE IV widely distributes onto the bronchial smooth muscle and inflammatory cells including eosinophil, and it is an enzyme catalyzing the destruction of cyclic AMP (hereinafter, occasionally referred to as cAMP). It has widely been known that by inhibiting PDE IV, the constriction of the bronchial smooth muscle is prevented, and the activation of inflammatory cells is prevented (Current Medicinal Chemistry, vol. 2, p. 561-572 (1995)).
The compounds of the following formulae, for example, Rolipram (U.S. Pat. No. 4,193,926), RP-73401 (WO 92 12961), SB-207499 (WO 93 19749), are exemplified as a representative compound having a PDE IV inhibitory activity.
In addition, EP 773024 discloses that an N-substituted nicotinamide compound of the following formula (A) exhibits a PDE IV inhibitory activity.
wherein R3 is 1-piperidyl, phenyl, benzyl, etc., Y is hydrogen, fluoro or chloro, and X is hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, carboxy, methylcarbamoyl, dimethylcarbamoyl or a carbo(C1-C4)alkoxy.
In addition, WO 9845268 discloses that a nictoninamide compound of the following formula (B) exhibits a PDE IV inhibitory
wherein m is 0 or 1, n is 0 or 1, o is 0, 1, 2, 3, or 4, p is 0 or 1, q is 0, 1, 2, or 3, r is 0, 1, 2, 3, or 4, t is 0 or 1, A is an oxygen atom,  greater than NH, etc., B is an oxygen atom or NH, D is an oxygen atom or NR9, E is CH2, an oxygen atom, NH or S(O)a, R1 is a hydrogen atom, a (C1-C6)alkyl group, a (C3-C7)heterocyclic group, etc., R2, R3 and R4 are a hydrogen atom, a hydroxy group, etc., R1 is a (C3-C7)heterocycle, R6, R7 and R8 are a hydrogen atom, a (C1-C6)alkyl group, etc.
However, conventional PDE IV inhibitors cannot show a sufficient bronchodilating activity, and under such circumstances, it has been desired to develop a novel PDE IV inhibitor exhibiting more potent bronchodilating activity as well as effects on the airway inflammation.
On the other hand, a compound of the above formula (A) or (B) wherein the 3-substituent of the pyridine ring is a pyridyalkyleneoxy group has never been known.
An object of the present invention is to provide a novel 2,3-disubstituted pyridine derivative and a pharmaceutically acceptable salt thereof, which show an excellent PDE IV inhibitory activity.
The present invention relates to a 2,3-disubstituted pyridine derivative of the following formula (I) or a pharmaceutically acceptable salt thereof, a phosphodiesterase IV inhibitor containing said compound as an active ingredient, and a pharmaceutical composition containing the same.
wherein A is an oxygen atom, a sulfur atom, CHR1 or NR2, R1 and R2 are a hydrogen atom or a lower alkyl group;
X1 and X2 are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyl group, a lower acyloxy group, an ammo group, a lower acylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be converted into a hydroxy group in vivo;
Y1 is a hydrogen atom or a lower alkyl group;
Z1 and Z2 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be convereted into a hydroxy group in vivo; and n is an integer of 2 to 4.
The pharmaceutically acceptable salt includes a pharmaceutically acceptable acid addition salt, an alkali metal salt, an alkaline earth metal salt or a salt with an organic base. For example, the acid addition salt includes a salt with an inorganic acid such as a hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc., or a salt with an organic acid such as oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, etc. The alkali metal salt includes, for example, a salt with an inorganic alkali metal such as sodium salt, potassium salt, and the alkaline earth metal salt includes, for example, calcium salt, magnesium salt. The salt with an organic base includes, for example, a salt with ammonia, methylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, dicyclohexylamine.
The present compound of the formula (I) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and/or a solvate, and the present invention also includes these hydrates and solvates as well.
The present compounds of the formula (I) may optionally have one or more asymmetric carbon atoms, and the present invention also includes these stereoisomers and a mixture thereof.
When Z1 or Z2 is a hydroxy group and these groups attach to the 2-position or the 4-position of the pyridine ring, the present compounds of the formula (I) may have a keto-enol tautomer, and the present invention also includes these tautomers, and a mixture thereof.
In the compound (I), the group being able to be converted into a hydroxy group in vivo means a group which can be enzymatically or non-enzymatically destructed to a hydroxy group in vivo, for example, one wherein a hydroxy group is acylated, carbonated or carbamated by an acetyl group, a propionyl group, a benzoyl group, an ethoxycarbonyl group, a carbamoyl group, an amino acid residue, etc. Hereinafter, compounds having such groups may occasionally be referred as a prodrug.
The present invention also relates to an intermediate for preparing a 2,3-disubstituted pyridine derivative of the above formula (I), i.e., a pyridine derivative of the following formula (II):
wherein Z3 is a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower acyl group, a benzyl group, a benzoyl group, or a mono- or di-lower alkoxy-substituted benzoyl group, Z4 is a hydrogen atom, a halogen atom, a cyano group, a lower alkoxycarbonyl group, a lower acyloxy group, a lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, an amino group, a lower alkoxycarbonylamino group, or a lower alkylsulfonylamino group.
The terms used in the specification are explained below.
The xe2x80x9clower alkyl groupxe2x80x9d and the xe2x80x9clower alkyl moietyxe2x80x9d include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl, etc.
The xe2x80x9chalogeno-lower alkyl groupxe2x80x9d and the xe2x80x9chalogeno-lower alkyl moietyxe2x80x9d include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, which is substituted by a halogen atom, for example, trifluoromethyl group.
The xe2x80x9ccyclo-lower alkyl groupxe2x80x9d and the xe2x80x9ccyclo-lower alkyl moietyxe2x80x9d include a cyclic alkyl group having 3 to 6 carbon atoms, for example, cyclopentyl and cyclohexyl.
The xe2x80x9clower acyl groupxe2x80x9d and the xe2x80x9clower acyl moietyxe2x80x9d include a straight chain or branched chain alkanoyl group having 1 to 5 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, and pivaloyl.
The xe2x80x9chalogen atomxe2x80x9d is fluorine atom, chlorine atom, bromine atom, and iodine atom.
The xe2x80x9clower alkoxy groupxe2x80x9d and the xe2x80x9clower alkoxy moietyxe2x80x9d include a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and hexyloxy.
The xe2x80x9ccyclo-lower alkoxy groupxe2x80x9d and the xe2x80x9ccyclo-lower alkoxy moietyxe2x80x9d include a cyclic alkoxy group having 3 to 6 carbon atoms, for example, cyclopentyloxy and cyclohexyloxy.
The xe2x80x9clower alkenyl groupxe2x80x9d and the xe2x80x9clower alkenyl moietyxe2x80x9d include a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, for example, allyl, 2-butenyl, and 3-methyl-2-butenyl.
Among the present compounds (I) of the present invention, preferable one is a compound of the formula (I) wherein A is an oxygen atom, a sulfur atom, CH2 or NH, Z1 and Z2 are the same or different and each a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxyl-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, or a group which can be converted into a hydroxy group in vivo, or a pharmaceutically acceptable salt thereof.
More preferable compounds are compounds of the formula (Ia) or a pharmaceutically acceptable salt thereof.
wherein A1 is an oxygen atom, a sulfur atom, CH2 or NH;
X11 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower allyl group, a halogeno-lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, or a lower acyl group;
X21 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group;
Y1 is a hydrogen atom or a lower alkyl group;
Z11 and Z21 are the same or different and each a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonyl-amino group, a lower alkylsulfonylamino group, a carbamoyl group, or a group which can be converted into a hydroxy group in vivo.
Especially preferable compounds are the following compounds or a pharmaceutically acceptable salt thereof.
2-phenoxy-3-[3-(pyridin-4-yl)propoxy]pyridine;
2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;
2-(3-fluorophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;
2-(3-fluorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]-pyridine;
2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]-pyridine;
2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]-pyridine;
2-(3-chlorophenoxy)3-[3-(3-aminopyridin-4-yl)propoxy]pyridine;
2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;
2-phenoxy-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]-pyridine;
2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-5-yl)propoxy]-pyridine;
2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy) -3-[3-(3-methylsulfonylaminopyridin-4-yl)propoxy]pyridine; and
2-(3-bromophenylthio)-3-[3-(pyridin-4-yl)propoxy]pyridine.
The representative compounds (I) of the present invention are the compounds as listed in the following Table 1 or a pharmaceutically acceptable salt thereof, in addition to the compounds of Examples as disclosed hereinbelow.
Note: Attaching position means the position at which the alkylene group is bonded to the pyridine ring. In Table 1, the following abbreviations are used in order to simplify the description. Me: methyl group, Ac: acetyl group.
The compounds (I) of the present invention may be prepared, for example, by the following processes (a) and (b), as explained below.
Process (a):
The compound of the formula (I) wherein A is an oxygen atom, a sulfur atom or CHR1 may be prepared, if necessary, by protecting by a conventional method a compound of the formula (III):
wherein A2 is an oxygen atom, a sulfur atom or CHR1, X12 and X22 are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkoxycarbonyl group, a lower acyl group or a lower acyloxy group, and R1 and Y1 are as defined above, and a compound of the formula (IV):
wherein Z12 and Z22 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkoxycarbonyl group, a lower acyloxy group, a benzyloxy group, a benzoyloxy group, a mono- or di-lower alkoxy-substituted benzoyl group, a mono- or di-lower alkoxy-substituted benzoyloxy group, an amino group, a lower alkoxycarbonyl-amino group or a lower alkylsulfonylamino group, and n is as defined above, followed by condensing these compounds in the presence of a triphenylphosphine and a dialkyl azodicarboxylate in a suitable solvent, then, if necessary, by removing the protecting groups from the resultant, and further converting the substituents X12, X22, Z12, Z22 to other substituents by a conventional method, if required.
The dialkyl azodicarboxylate,includes, for example, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, etc. In addition, a trialkylphosphine such as tri-n-butylphosphine, etc. may be used instead of triphenylphosphine. The reaction is preferably carried out at a temperature of from xe2x88x9250xc2x0 C. to 120xc2x0 C., more preferably at a temperature of from 0xc2x0 C. to 80xc2x0 C. The solvent may be tetrahydrofuran, toluene, xylene, dichloromethane, etc.
The compound of the formula (IV) may include a compound of the above formula (II), i.e., a compound of the (IV) wherein one of Z12 and Z22 is bonded to the 3-position of the pyridine ring as OZ3, and the other is bonded to the 4- or 5-position of the pyridine ring as Z4, and a hydroxyalkylene group wherein n is 3 is bonded to the 4- or 5-position of the pyridine ring to which the above Z4 is not bonded.
Process (b):
The compound of the formula (I) wherein A is an oxygen atom, a sulfur atom or NR2 may be prepared by reacting a compound of the formula (V):
wherein L is a halogen atom or a nitro group, Z13 and Z23 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, or a lower alkoxycarbonyl group, and Y1 and n are as defined above, with a compound of the formula (VI):
wherein A3 is an oxygen atom, a sulfur atom or NR2, and R2, X12 and X22 are as defined above, in the presence of a base and a copper catalyst in a suitable solvent, and if necessary, by removing the protecting groups from the resulting compound, and then further followed by converting the substituents X12, X22, Z13, Z23 to other substituents by a conventional method, if required. The base is preferably an alkali metal hydride, an alkali metal carbonate, etc. The copper catalyst may preferably be cuprous iodide, cuprous bromide, cuprous chloride, copper powder, cuprous oxide, cupric bromide, etc. The reaction is carried out at a temperature of from 80xc2x0 C. to 220xc2x0 C., preferably at a temperature of from 100xc2x0 C. to 180xc2x0 C. The solvent may preferably be dimethylformamide, dimethylimidazolidinone, dimethylsulfoxide, dimethylacetamide, pyridine, toluene, xylene, etc.
Processes for preparing the starting compounds for Processes (a) and (b), i.e., the compounds of the formulae (II) to (VI), are explained below.
Process for Preparing the Compound of the Formula (III):
The compound of the formula (III) which is a starting compound for Process (a) wherein A is an oxygen atom, i.e., the compound of the formula (1-4), may be prepared according to the following Scheme 1. Namely, a compound of the formula (1-1) and a compound of the formula (1-2) are reacted in the presence of a base and a copper catalyst in a suitable solvent, and the resulting compound of the formula (1-3) is deprotected to give a compound of the formula (1-4).
wherein Q is a lower alkyl group, a cyclo-lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkenyl group, a benzyl group, or a tetrahydropyranyl group, and L, X12, X22 and Y1 are as defined above.
The compound of the formula (1-1) or (1-2) may be commercially available ones or may be prepared by a conventional method. The base may be an alkali metal hydride, an alkali metal carbonate, etc. The copper catalyst may preferably be cuprous iodide, cuprous bromide, cuprous chloride, copper powder, cuprous oxide, cupric bromide, etc. The reaction is carried out at a temperature of from 80xc2x0 C. to 220xc2x0 C., preferably at a temperature of from 100xc2x0 C. to 180xc2x0 C. The solvent may be dimethylformamide, dimethylimidazolidinone, dimethylsulfoxide, dimethylacetamide, pyridine, toluene, xylene, etc.
The starting compound for Process (a), a compound of the formula (III) wherein A is a sulfur atom, i.e., a compound of the formula (2-3) may be prepared according to the following Scheme 2. Namely, a compound of the formula (2-1) and a compound of the formula (2-2) are reacted in a suitable solvent to give a compound of the formula (2-3).
wherein L, X12, X22 and Y1 are as defined above.
The compound of the formula (2-1) or (2-2) may be commercially available ones or may be prepared by a conventional method. The reaction is carried out at a temperature of from 0xc2x0 C. to 200xc2x0 C., preferably at a temperature of from 50xc2x0 C. to 130xc2x0 C. The solvent may be dimethylformamide, dimethylimidazolidinone, dimethylsulfoxide, dimethylacetamide, toluene, xylene, tetrahydrofuran, etc.
The starting compound for Process (a), a compound of the formula (III) wherein A is CHR1, i.e., a compound of the formula (3-6) or (3-8) may be prepared according to the following Scheme 3. Namely, a compound of the formula (3-1) is converted to a lithium salt compound of the formula (3-1a), which is further reacted with a compound of the formula (3-2) to give a compound of the formula (3-3). When R1 is a hydrogen atom, a compound of the formula (3-3) is oxidized to give a compound of the formula (3-4), which is further subjected to reduction to give a compound of the formula (3-5). The compound (3-5) is further deprotected to give a compound of the formula (3-6). When R1 is a lower alkyl group, the compound (3-3) is subjected to reduction to give a compound of the formula (3-7), which is further deprotected to give a compound of the formula (3-8).
wherein L1 is a bromine atom or a iodine atom, and R1, Q, X12, X22 and Y1 are as defined above.
The compound of the formula (3-1) or (3-2) may be commercially available ones or may be prepared by a conventional method. The compound of the formula (3-1) can be converted to a corresponding lithium salt thereof by reacting with a base such as n-butyl lithium in a suitable solvent. The reaction is preferably carried out at a temperature of from xe2x88x92150xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9280xc2x0 C. to 0xc2x0 C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.
A compound of the formula (3-2) is added to a reaction solution containing the compound of the formula (3-1a) thus obtained and reacted. The reaction is carried out at a temperature of from xe2x88x92150xc2x0 C. to 100xc2x0 C., preferably at a temperature of xe2x88x9280xc2x0 C. to 0xc2x0 C.
The compound of the formula (3-4) is obtained by reacting a compound of the formula (3-3) wherein R1 is a hydrogen atom in the presence of an oxidizing agent such as activated manganese dioxide, etc. in a suitable solvent. The reaction is carried out at a temperature of from xe2x88x9220xc2x0 C. to 120xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 100xc2x0 C. The solvent may be toluene, tetrahydrofuran, dioxane, methylene chloride, hexane, etc.
The reduction of the compound of the formula (3-4) is carried out in the presence of hydrazine and a base in a suitable solvent. The base may be an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., and the solvent may be ethylene glycol, diethylene glycol, etc. The reaction is carried out at a temperature of from 0xc2x0 C. to 220xc2x0 C., preferably at a temperature of from 100xc2x0 C. to 200xc2x0 C.
The compound of the formula (3-7) is obtained by subjecting a compound of the formula (3-3) wherein R1 is a lower all group to catalytic reduction in the presence of palladium carbon, and if necessary, in the presence of an acid catalyst such as hydrochloric acid, acetic acid, perchloric acid, etc. in a suitable solvent under hydrogen atmosphere. The reaction is carried out at a temperature of from xe2x88x9240xc2x0 C. to 110xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 70xc2x0 C. The solvent may be methanol, ethanol, ethyl acetate, toluene, xylene, tetrahydrofuran, dioxane, etc.
The removal of a protecting group from the compound (3-5) and the compound (3-7) is carried out in the presence of a suitable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, camphor-sulfonic acid, etc. in a suitable solvent such as water, methanol, ethanol, isopropanol, acetic acid, etc. The reaction is carried out at a temperature of from xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably at a temperature of from 20xc2x0 C. to 70xc2x0 C.
Process for Preparing a Compound of the Formula (II) or the Formula (IV):
The starting compound for Process (a), i.e. the compound of the formula (IV) may be commercially available one or may be prepared according to the following Scheme 4. Besides, the compound of the formula (II) which is within the scope of the compound of the formula (IV), i.e., the compound of the formula (IV) wherein one of Z12 and Z22 is bonded to the 3-position of the pyridine ring as OZ3, and the other is bonded to the 4- or 5-position of the pyridine ring as Z4, and a hydroxyalkylene group wherein n is 3 is bonded to the 4- or 5-position of the pyridine ring to which said Z4 is not bonded may be prepared similarly.
wherein E is a bromine atom or a iodine atom, G is a lower alkyl group, a lower alkoxy-substituted lower all group, an allyl group, a benzyl group or a tetrahydropyranyl group, Z14, Z24 are a halogen atom, Z15, Z25 are the same or different and each a halogen atom, a cyano group, a lower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxycarbonyl group, or a benzyloxy group, and Z13, Z23 and Q are as defined above.
Among the starting compounds (IV) for Process (a), the compound of the formula (IV) wherein n is 2 or 4 is obtained by reacting a compound of the formula (4-1) with trimethylsilylmethyl magnesium chloride in a suitable solvent, converting the resulting product into a compound of the formula (4-2) by placing it under acidic conditions, further by subjecting the compound (4-2) to hydroboronation reaction, and to subsequently oxidation and hydrolysis to give a compound of the formula (4-3), and if necessary, followed by converting Z13 and Z23 by a conventional method.
The compound of the formula (4-1) may be commercially available one or may be prepared by a conventional method. The reaction of the compound (4-1) with trimethylsilylmethyl magnesium chloride is preferably carried out at a temperature of from xe2x88x92150xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9270xc2x0 C. to 0xc2x0 C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.
The compound (4-2) thus obtained is subjected to hydroboronation in the presence of a hydroboronating agent such as a complex of borane-pyridine, a complex of borane-tetrahydrofuran, or 6-borabicyclo[3.3.1]nonane, etc. in a suitable solvent, and then further subjected to oxidation and a subsequent hydrolysis under basic conditions. The hydroboronation reaction is carried out at a temperature of from xe2x88x92150xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9270xc2x0 C. to 50xc2x0 C. The solvent may be tetrahydrofuran, diethyl ether, dioxane, etc. The oxidation reaction and the subsequent hydrolysis are carried out by adding an aqueous solution of an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc. to the reaction solution of hydroboronation, and then by using an aqueous hydrogen peroxide solution. The reaction is carried out at a temperature of from xe2x88x92100xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9270xc2x0 C. to 50xc2x0 C.
Among the starting compounds (IV) for Process (a), the compound of the formula (IV) wherein n is 3 is prepared by reacting a compound (4-4) with an alkali metal salt of a trialkylphosphonoacetate in a suitable solvent to give the compound (4-5), which is further subjected to catalytic hydrogenation, and further subjecting the resulting compound (4-6) to hydride reduction to give the compound (4-7), and if necessary, followed by converting Z13, Z23 by a conventional method.
The compound (4-4) may be commercially available one or may be prepared by a conventional method. The reaction of the compound (4-4) is carried out by reacting an alkali metal salt of a trialkylphosphonoacetate, which is obtained by reacting a trialkylphosphonoacetate such as trimethylphosphonoacetate, triethylphosphonoacetate, etc. with an alkali metal hydride such as sodium hydride, potassium hydride, etc. in a suitable solvent. The reaction is carried out at a temperature of from xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9220xc2x0 C. to 70xc2x0 C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.
The compound (4-5) thus obtained may be converted into a compound of the formula (4-6) by catalytic reduction in the presence of a palladium carbon under hydrogen atmosphere. The reaction is carried out at a temperature of from xe2x88x9240xc2x0 C. to 110xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 70xc2x0 C. The solvent may be methanol, ethanol, ethyl acetate, toluene, xylene, tetrahydrofuran, dioxane, etc.
Further, the compound (4-6) is subjected to reduction by using a reagent such as lithium aluminum hydride, diisobutyl aluminum hydride, etc., in a suitable solvent. The reaction is carried out at a temperature of from xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 70xc2x0 C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.
Among the starting compounds (IV) for Process (a), the compound of the formula (IV) wherein n is 3 may also be prepared by reacting a compound of the formula (4-8) with ethylene oxide in the presence of a base to give a compound of the formula (4-7), and if necessary, followed by converting Z13 and Z23 by a conventional method.
The compound (4-8) may be commercially available one or may be prepared by a conventional method. The compound (4-8) may be converted into a compound of the formula (4-7) by treating with a base such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium amide, etc. in a suitable solvent to give a corresponding alkali metal salt thereof, followed by reacting with ethylene oxide. The reaction is carried out at a temperature of from xe2x88x92120xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9280xc2x0 C. to 20xc2x0 C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.
Among the starting compounds (IV) for Process (a), the compound of the formula (IV) wherein n is 3 and the 4-position of the pyridine ring is a propanol group may be prepared by reacting a compound of the formula (4-9) with a compound of the formula (4-10) in the presence of a base, if necessary, converting Z14 of the resulting compound of the formula (4-11) by a conventional method, and removing a protecting group to give a compound of the formula (4-12), if necessary, followed by converting Z15 and Z25 by a conventional method.
The compound (4-9) and the compound (4-10) may be commercially available ones or may be prepared by a conventional method. The compound of the formula (4-11) may be prepared by treating the compound of the formula (4-9) with a base such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium amide, etc. in a suitable solvent to give an alkali metal salt thereof, and further reacting with the compound of the formula (4-10). The reaction is carried out at a temperature of from xe2x88x92120xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9280xc2x0 C. to 20xc2x0 C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.
Process for Preparing a Compound of the Formula (V):
The starting compound (V) for Process (b), which is the same compound as a compound of the formula (5-3), may be prepared according to the following Scheme 5. Namely, a compound of the formula (5-1) and a compound of the formula (5-2) are reacted in the presence of a triphenylphosphine and a dialkyl azodicarboxylate in a suitable solvent to give a compound of the formula (5-3).
wherein L, Y1, Z13, Z23 and n are as defined above.
The compound (5-1) may be commercially available one or may be prepared by a conventional method. The dialkyl azodicarboxylate includes dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, etc. A trialkylphosphine such as tri-n-butylphosphine, etc., may be used instead of a triphenylphosphine. The reaction is carried out at a temperature of from xe2x88x9250xc2x0 C. to 120xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 80xc2x0 C. The solvent may be tetrahydrofuran, toluene, xylene, dichloromethane, etc.
The compound (5-2) may be commercially available one or may be prepared according to the reaction scheme as shown in Scheme 4, in a similar manner as the preparation of the compound of the formula (4-3), the compound (4-7) and the compound (4-12) as mentioned above.
Process for Preparing a Compound of the Formula (VI):
The starting compound (VI) for Process (b) may be commercially available one or may be prepared by a conventional method.
The pharmacological experiments were done on the representative compounds of the present compounds. The results and the pharmacological activities of the present compounds are explained as follows.
Experiment 1: PDE IV Inhibitory Activity Test
The PDE IV inhibitory activity test was carried out according to a method using eosinophils prepared from the abdomen of guinea pig (Souness, J. E. et al., Biochem. Pharmacol. vol. 42, p. 937 (1991)). That is, a homogenizing buffer (10 ml, components: 20 mM Tris-HCl buffer (pH 7.5); 2 mM magnesium chloride; 1 mM dithiothreitol, 5 mM ethylenediamine tetraacetate disodium; 250 mM sucrose; 20 xcexcM p-tosyl-l-lysine-chloromethylketone; 10 xcexcg/ml Leupeptine) was added to 5xc3x97107 cells, and the mixture was centrifuged. To the residue was added a solubilizing buffer (10 ml, sodium deoxycholate (final concentration: 0.5%) and sodium chloride (final concentration: 100 mM) were added to the above homogenizing buffer), and the mixture was centrifuged again. The supernatant was subjected to ultrafiltration using Molcut-II (manufactured by Japan Millipore Limited), and the fraction on the membrane was collected by adding a homogenizing buffer (10 ml) to give an enzyme preparation. Inhibitory activity against the enzyme was determined by comparing the hydrolysis rates of a substrate, cAMP (manufactured by Nacalai Tesque Inc.), by the above enzyme fraction between in the test compound-treated group and the vehicle group. In addition, a 50% inhibitory concentration, .i.e., IC50, was obtained from a concentration activity curve of a test compound. The compounds of Examples of the present invention as listed in Table 2 were used as a test compound, and Rolipram, RP-73401 and SB-207499, which are known to exhibit a PDE IV inhibitory activity, were used as a control compound. The results are shown in Table 2.
As is clear from Table 2, the present compounds of the formula (I) exhibit a potent inhibitory activity against PDE IV isolated and purified from guinea pig eosinophils.
Experiment 2: Inhibitory Effect on Antigen-induced Bronchoconstriction
Hartley male guinea pigs were actively sensitized by intraperitoneally administering an ovalbumin (manufacture by Sigma). Four weeks thereafter, the animals were anesthetized with Nembutal (50 mg/kg, i.p., manufactured by Dainabot Co., Ltd.), and a cannula was inserted at the airway, and the bronchoconstriction response of the animals under artificial respiration was observed. The response of the airway was measured by Konzett-Roessler method (Naunyn-Schmiedeberge, Arch. Exp. Pathol. Pharmacol., vol. 195, p. 71 (1940)). A test compound (the compounds of Examples of the present invention as listed in Table 3) was orally administered to the animals one hour prior to the administration of the antigen (i.e., ovalbumin, 0.05%/physiological saline solution, i.v.). Only the compound of Example 31 was orally administered 2 hours prior to the administration of the antigen. The inhibitory rate (%) caused by the test compound was calculated by comparing the bronchoconstriction response of the test calculated-treated group with that of the control group to which only a solvent was administered. The results are shown in Table 3.
As is shown in Table 3, the present compounds of the formula (I) exhibited a potent inhibitory activity against the bronchoconstriction of guinea pig induced by the antigen.
As is clear from the above Pharmacological Experiments, the compounds (I) of the present invention show a potent PDE IV inhibitory activity as well as an excellent bronchodilating activity.
Besides, the present compounds (I) of the present invention are low toxic. In an acute toxicity test, for example, the compound of Example 31 never showed any toxicity even at a dose of 2000 mg/kg.
The compounds (I) of the present invention can be administered as a PDE IV inhibitor either orally, parenterally or rectally. The compounds of the present invention can also be administered by transpulmonary infiltration, oral mucous administration, trans-nasal mucous administration. The dose of the compounds of the present invention varies according to the administration routes, the conditions, ages of the patients, etc., or by the object of the administration, i.e., prophylaxis or treatment, but it is usually in the range of 0.01-100 mg/kg/day, preferably in the range of 0.1-50 mg/kg/day.
The compounds (I) of the present invention are usually administered in the form of a pharmaceutical preparation, which is prepared by mixing thereof with a pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent may be any conventional ones being usually used in the pharmaceutical field, and do not react with the compounds (I) of the present invention. Suitable examples of the pharmaceutically acceptable carrier or diluent are, for example, lactose, glucose, mannitol, dextrin, starch, white sugar, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxylmethylcellulose, ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl-pyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium laurylsulfate, glycerin, glycerin fatty acid ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, nonionic surfactant, propyleneglycol, water, etc.
The pharmaceutical preparation is, for example, tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injection preparations, inhalants, nasal drops, etc. These preparations may be prepared by a conventional method. In the preparation of liquids, the compound of the present invention may be dissolved or suspended in water or a suitable other solvent, when administered. Tablets and granules may be coated by a conventional method. In the injection preparations, it is preferable to dissolve the compound (I) in water, but if necessary, by using an isotonic agent, and further, a pH adjuster, a buffering agent or a preservative may be added thereto.
These preparations may contain the compound (I) of the present invention at a ratio of at least 0.01%, preferably at a ratio of 0.05-70%. These preparations may also contain other therapeutically effective compounds as well.
In addition, these preparations may be used together with an antiallergic agent, a steroid, a xcex22-stimulant, an anticholinergic agent, if necessary.

2,3-disubstituted pyridine derivative, process for the preparation thereof, pharmaceutical composition containing the same, and intermediate therefor

Abstract: A compound of the formula (I)

Abstract: wherein A is O, S, CHR1 or NR2, R1 and R2 are H, lower alkyl, X1 and X2 are H, halogen, nitro, cyano, etc., Y1 is H, lower alkyl, Z1 and Z2 are H, halogen, cyano, hydroxy, lower alkyl, etc., and n is an integer of 2 to 4, a pharmaceutically acceptable salt thereof, a process for preparing the same, a pharmaceutical composition containing the same as an active ingredient, and an intermediate therefor. The compounds (I) of the present invention show a potent PDE IV inhibitory activity as well as an excellent bronchodilating activity, and hence, they are widely useful as a PDE IV inhibitor in the treatment or prophylaxis of allergic inflammatory diseases or organ inflammatory diseases, especially in the treatment or prophylaxis of pulmonary diseases accompanied by airway obstruction such as asthma.

Dainippon Pharmaceutical Company, Limited


A fluorescent image analyzer stores a reference fluorescent-sample image and a subject fluorescent-sample image. The reference fluorescent-sample image is an image obtained by illuminating a reference fluorescent sample about which relation of in-plane fluorescence intensities is known with linearly polarized light and capturing a first specific polarization component of fluorescence from the reference fluorescent sample. The subject fluorescent-sample image is an image obtained by illuminating a subject fluorescent sample with linearly polarized light and capturing a second specific polarization component of fluorescence from the subject fluorescent sample. The fluorescent image analyzer is configured to determine correction coefficients to correct non-uniformity in measurement of light intensities among pixels of a captured image based on the reference fluorescent-sample image, and correct light intensities of the pixels of the subject fluorescent-sample image based on the correction coefficients.

This disclosure relates to a fluorescent image analyzer.
Fluorescent image analysis is widely used to assess various states of various molecules. A fluorescent image is obtained by illuminating a fluorescently labeled sample with polarized light as excitation light and extracting a specific polarization component from the fluorescence. For example, a fluorescence depolarization method calculates a fluorescence polarization value from the polarization components of the fluorescence that are parallel and perpendicular to the polarization direction of the excitation light to analyze a sample. The fluorescence polarization value (fluorescence anisotropy) teaches information on molecules, such as the size, the shape, the concentration, and the viscosity.


Some embodiments relate to an apparatus for metallic particulate detection. The apparatus comprises: an entry stage defining an input chamber to receive an element having particulate matter thereon; a sensor defining a passage in fluid communication with the input chamber to receive the particulate matter from the input chamber and to detect the particles in the particulate matter; a vented recovery stage defining a recovery chamber to receive and capture at least some of the particulate matter passing through the passage; and at least one air outlet positioned in the input chamber to direct pressurized air from the at least one air outlet to impinge on the element to remove the particulate matter from the element.

Machinery, such as aircraft machinery, can generate debris as a function of wear of the machinery components during operation. Where the debris is relatively large, this can provide an indication of the possible failure of the machinery. Extraction of wear debris from a lubrication system filter can be an effective tool for the identification of incipient failure of oil-wetted components. Traditional wear debris analysis methods, such as Spectrometric oil Analysis, suffer from particle size limitations (i.e. they typically detect particles less than 8 microns), and fine filtration present in modern aircraft machinery further reduces the effectiveness of this limited technique. In some cases, an oil filter may be used to capture wear debris in order to obtain information about wear-related failure modes of the machinery. Extraction of debris from such filter elements can be cumbersome and rely heavily on manual extraction and visual inspection of debris, which can be error-prone and inaccurate. Similarly, ferromagnetic particles captured on magnetic chip detectors can be difficult to accurately quantify.
It is desired to address or ameliorate one or more shortcomings or disadvantages associated with existing techniques for quantifying wear debris in particulate form, or to at least provide a useful alternative thereto.

Apparatus for metallic particulate quantification


Process for manufacturing an electrically programmable non-volatile memory device having electrically programmable non-volatile memory cells comprising floating-gate MOS transistors, a first kind of MOSFETs, and a second kind of MOSFETs capable of substaining gate voltages higher than that sustainable by the MOSFETs of the first kind. The process includes forming a first gate oxide layer for the floating-gate MOS transistors, a second gate oxide layer for the MOSFETs of the first kind, and a third gate oxide layer for the MOSFETs of the second kind. The first gate oxide layer further comprises a tunnel oxide region. The process provides for: forming over the surface of a semiconductor material a first layer of oxide; selectively removing the first layer of oxide from regions of said surface dedicated to the MOSFETs of the first kind, but not from the regions dedicated to the floating-gate MOS transistors nor to the MOSFETs of the second kind; forming a second layer of oxide over the first layer of oxide and over said regions dedicated to the MOSFETs of the first kind; simultaneously removing the first and the second layer of oxide only from the tunnel oxide region of the floating-gate MOS transistors; and forming over the second layer of oxide and over said tunnel region oxide for the floating-gate MOS transistors a tunnel oxide layer. The third gate oxide layer and said first gate oxide layer, except in the tunnel oxide region, are formed by the superposition of the first layer of oxide, while the second layer of oxide and the tunnel oxide layer, said second gate oxide layer being formed by the superposition of the second layer of oxide and the tunnel oxide layer.

It is known that for the manufacturing of these memory devices it is necessary to provide for layers of different of different thickness in the active areas of the devices forming the memory cells.
For forming such oxide layers, a selective removal of the different layers that are successively grown in the active areas is necessary. To this purpose, several chemical etching processes are performed to remove the unnecessary layers from the silicon surface.
Examples of electrically programmable non-volatile memory cells are the double polysilicon level (DP) FLOTOX EEPROM memory cells, one of which is shown in FIGS. 1 and 2 and includes a floating-gate MOS transistor 2 and a selection MOSFET 3. The floating-gate MOS transistor 2 comprises an N type source region 4 and an N type drain region 5 both formed in a P type semiconductor substrate or well 6, spaced apart from each other. The portion of P type substrate or well comprised between the source and drain regions 4 and 5 forms a channel region, and a floating gate electrode 7 (formed in a first polysilicon level) is placed over the channel region and part of the drain region 5, with the interposition of a gate oxide layer 8 having typically a thickness of 200 .ANG.. At the drain region 5, the gate oxide 8 has a thinner portion 9, with typical thickness of about 70 .ANG., called tunnel oxide. The drain region 5 comprises, under the tunnel oxide 9, a region 10 heavily doped of the N type. A control gate electrode 11 (formed in a second polysilicon level) is placed over the floating gate electrode 7 with the interposition of a dielectric layer 100.
The selection MOSFET 3 of each memory cell is connected in series to the respective floating-gate MOS transistor 2, and comprises an N type source region coincident with the drain region 5 of the floating-gate MOS transistor 2, and an N type drain region 12 formed in the P type substrate or well 6. The region of the substrate or well 6 comprised between the drain region 12 and the source region 5 of MOSFET 3 forms a channel region, over which two polysilicon electrodes 13, 14 are placed, forming the gate of MOSFET 3. The first electrode 13 is separated from the channel region by a gate oxide layer 80. The second electrode 14 is separated from the first electrode 13 by a dielectric layer 101.
Conventionally, as far as the selection transistors 3 are concerned, the two polysilicon electrodes 13, 14 belong to respective lines formed from the first and the second polysilicon levels, and said lines are electrically short-circuited in a region of the array not shown in FIG. 1.
The oxide layer 80 is generally thicker than the oxide layer 8 (typically the oxide layer 80 is 300 .ANG. thick), since the former must be capable of sustaining the voltages involved in the process of programming the memory cells, voltages which are higher than the supply voltage.
With reference to FIGS. 3 to 6, the conventional process for the fabrication of an EEPROM memory device includes using FLOTOX EEPROM memory cells and MOSFETs 90 for the circuitry. The process provides for defining active areas for the memory cells and the MOSFETs of the circuitry; the formation of a sacrificial oxide layer; the implantation of an N type dopant for forming the regions 10 of the memory cells, and a thermal diffusion process for diffusing the dopant; and the subsequent removal of the sacrificial oxide.
By means of a thermal oxidation a first gate oxide layer 15 is formed, having a thickness of about 200 .ANG.. The oxide layer 15 is formed over the active areas of both the memory cells 1 and the MOSFETs 90 of the circuitry (FIG. 3).
By means of a conventional photolithographic process, providing for the deposition of a photoresist 16 and the selective etching thereof, the first oxide layer 15 is removed from the active area region wherein the floating-gate MOSFET 2 will be formed, and from the active areas where low-voltage (LV) transistors 90 of the circuitry will be formed (FIG. 4).
By means of thermal oxidation a second gate oxide layer 800 is formed having a thickness of about 170 .ANG.. By means of a conventional photolithographic technique, providing for the deposition of another photoresist layer 17 and the selective etching thereof, the second oxide layer 800 is selectively removed from the tunnel region of the memory cell (FIG. 5). By means of a further thermal oxidation the tunnel oxide layer 9 is formed, having a typical thickness of about 70 .ANG..
The memory cell 1 and the MOSFETs 90 of the circuitry are then conventionally completed by defining their gates, forming the source and drain regions, forming insulating spacers, and so on.
As it will be appreciated, the gate oxide layer 80 of the selection MOSFET 3, as well as the gate oxide layer of the high-voltage (HV) MOSFETs of the circuitry that, as the selection MOSFET 3 have to sustain the high voltages involved in the programming operation, is formed by a stack of the three oxide layers 15, 800 and 9. The gate oxide layer 8 of the floating-gate MOS transistor 2, as well as the gate oxide layer of the low-voltage (LV) MOSFETs of the circuitry is instead formed by a stack of the two oxide layers 800 and 9.
A drawback of this process is due to the fact that the surface of the silicon where the tunnel oxide 9 is grown is affected by the removal of the first and second oxide layers. The twice removal increases the probability of damaging the silicon surface, negatively affecting the reliability of the tunnel oxide subsequently grown, and thus negatively affecting the reliability of the memory device.

Process for the manufacturing of an electrically programmable non-volatile memory device


A mold closing unit for use in an injection molding machine for processing plastic materials for removal of moldings is provided with a device for actuating at least two first identical parts of an injection mold, which are transferred alternately into the space between the mold carriers of the mold closing unit on a guideway that runs transversally with respect to the closing direction for creation of an injection mold. Since all parts of the injection mold together with their corresponding swivel arms constitute a single oscillating crank with multiple arms, which transfers the first parts of the injection mold substantially in the parting plane of the mold closing unit, and since the position of the oscillating crank in the mold stressing chamber is determined by the mold closure itself, at least one of the first part of an injection mold being located outside the injection mold is fixed in a precise position that can be repeated for each injection cycle, the moldings can be handed over to a removal device and shorter production times with a faster ejection of moldings is obtained.

1. Field of the Invention
This invention relates to a mold closing unit for use in an injection molding machine for synthetic materials, comprising a device for moving at least two first identical parts of an injection mold, each of them mounted on a swivel arm, which is rotatable around an axis parallel disposed with respect to the closing direction, whereby the first parts of an injection mold are transferred alternately into at least one parting plane in the mold stressing chamber between the mold carriers of the mold closing unit on a transfer path vertically disposed with respect to the closing direction, for production of an injection mold.
2. Description of the Prior Art
German Published Patent Application 40 08 310 discloses a unit in which the parts of the injection mold are swivelled into the parting plane. The parts of the injection mold can be swivelled around a separate axis, whereby each part is individually swivelled. An axial displacement of the two parts against one another is necessary, so that one part can be moved into the parting plane inside the mold. As a result, the moldings can be taken out relatively quick from the injection mold, however, a separate drive to make the movement possible is required for each first part of the injection mold, which means that the removal position is changed for every injection cycle. However, since it should be avoided to touch the moldings during the removal process, the changing position is or no special importance in this case. The costs involved for the removal of the moldings from the mold cavity are increased in so far as separate drives are required for each first part of the injection mold.
A further installation for removal of moldings from the mold cavity is for example known from European Published Patent Application 359 013 A2. For removal installations of that kind it is, however, basically necessary, that a grab of the removal installation dips into the space between the stationary and the movable mold carrier, in order to withdraw the moldings from the mold cavities. That is why the opening width between the two mold carriers is mainly determined by the size of the grab to be introduced. However, the larger the necessary distance between stationary and movable mold carrier has to be for removal of the moldings, the more time is needed for bringing both mold carriers into the position with the required distance. Practice shows that at causes time and again problems, if the grab does not immediately get properly hold of the moldings during the removal process, which aggravates the circumstances additionally. This over and over again results in idle time, which counteracts a quick and troublefree production.
German Patent 12 68 365 furthermore discloses a system which is utilized for two-color injection. To this end the first parts of the injection mold are turned inside the injection mold around an axis disposed transversally with respect to the closing direction. It is possible to support the turning movement for example by an eccentric to the effect that the mold chambers are in the corresponding positions desired. However, the only purpose of this invention is, to make the mold accessible to the two-color injection and it is not possible to carry out moldings from the injection mold with this installation, since such a disposition of the swivel axis transversally to the closing direction, still would mean that the total opening distance had to be covered by the mold closing unit.

Mold closing unit for use in an injection molding machine for synthetic material


The present invention discloses a pad and an electronic device employing the same, wherein the pad has an accommodating groove, a ditch disposed around the periphery of the accommodating groove, and at least one guiding groove disposed between the ditch and the accommodating groove, and one end of the guiding groove coupled to the ditch and the other end coupled to the accommodating groove; such that if a glue for attaching the pad with an electronic device is melted by heat, the melted glue will flow into the ditch, and thus can achieve the effects of preventing the melted glue flowing out from the body as well as guiding and collecting the melted glue within the body.

Personal computers lead to a fast development of information products, and the demand for information products grows unceasingly every year. As the information industries develop and advance, related electronic products tend to be developed in a high-frequency high-speed data processing model and a light, thin, short and compact stylish design becomes the mainstream of electronic products. Although the reduced model brings a smaller size to the internal components and chips, the design also causes a higher density of heat sources of the electronic components. The heat dissipation for related electronic products and the way of controlling the influence of the produced heat to electronic products are the determining factors of the product stability for electronic product manufacturers.
In early stage, the design of internal circuits in a computer is simpler; the computer has less application programs and a slower operating speed; and thus the operations of a computer system will not run out of order due to the heat produced. However, the present computers require higher memory capacity and faster computational speed for powerful functions, and thus the operating temperature of the system is increased accordingly. The size of chips installed in a computer system gradually gets smaller, and the density of the heat sources of electronic components becomes higher. The design and appearance of the computer system is getting smaller according to the trend and convenience, and the hot air inside the chassis usually cannot be discharged successfully, and thus will cause a large temperature rise to the whole computer and affect the components and structure of the computer.
A prior-art pad is installed at the bottom surface of a notebook computer, such that when the notebook computer is placed on a disposing surface, the pad provides a buffer for the notebook computer for a reaction exerted on the disposing surface so as to avoid damaging the electronic components in the notebook computer due to collisions. One side of the pad is in contact with the disposing surface and the other side is attached onto the bottom surface of the notebook computer by glue. However, the foregoing heat generating problem not only produces a high temperature to the electronic components, but also affects every part of the notebook computer. Therefore, the glue will be melted easily due to a high temperature produced by the notebook computer. Furthermore, the weight of the notebook computer and the force from the user's palm and the key strokes of the notebook computer squeeze the melted glue to one side of the pad and the disposing surface, and thus the pad and disposing surface adhere dust and dirt easily. It is not easy to clean the dust and dirt since the composition of the glue is very special. As a result, the disposing surface of the notebook computer is contaminated by the remains of the glue, so that when the melted glue flows out excessively, the cohesion between the bottom surface and the pad will no long exist and cause the pad to fall off.
To solve the aforementioned problem, a prior art changes the composition of the glue, so that the glue can stand a higher temperature. However, the heat resisting effect of the glue is not as good after a long use of the notebook computer. Furthermore, it is not easy to change the composition of the glue to achieve a higher heat resisting effect. Therefore, there is a need for a simple and cost-saving method to prevent the glue from flowing out.

Pad and electronic device employing the same


An electrolytic cell 1 comprises electrolysis chambers 5 and 6 arranged opposite to each other through a diaphragm 11, raw water feed means 8 and 7, electrodes 12a and 12b arranged in the electrolysis chambers 5 and 6 in a manner sandwiching the diaphragm 11, and electrolyzed water take-out means 9 and 10 for taking out electrolyzed water obtained by electrolyzing raw water. The electrolytic cell 1 comprises a membrane-electrode assembly 2 formed so as to cause the electrodes 12a and 12b to respectively adhere to both surfaces of the diaphragm 11, mesh current collectors 13 and 14 respectively arranged opposite to the electrodes 12a and 12b, and a plurality of protrusions 15 and 16. The electrolytic cell 1 comprises connecting members 17 and 18 connecting the mesh current collectors 13 and 14 to an external electric power supply in a manner penetrating the outer walls of the electrolysis chambers 5 and 6, and resilient members 25 for energetically pressing the connecting members 17 and 18 toward the mesh current collectors 13 and 14. The electrolytic cell 1 comprises a plurality of the protrusions 15 and 16, and the connecting members 17 and 18, respectively at positions opposite to each other on both sides of the membrane-electrode assembly 2. The current collectors 13 and 14 are formed of a corrosion resistant conductive material. The electrodes 12a and 12b are formed of a porous material containing a conductive powder.

1. Field of the Invention
The present invention relates to an electrolyzed water generator which produces acidic and alkaline electrolyzed water, by electrolyzing raw water fed into a pair of electrolysis chambers arranged opposite to each other through an ion permeable diaphragm, and by applying a voltage to a pair of electrodes respectively arranged in the electrolysis chambers in a manner sandwiching the diaphragm. More specifically, the present invention relates to an electrolytic cell in the electrolyzed water generator.
2. Description of the Related Art
There is known an electrolyzed water generator which produces electrolyzed water by use of an electrolytic cell comprising a pair of electrolysis chambers arranged opposite to each other through an ion permeable diaphragm and a pair of electrodes respectively arranged in the electrolysis chambers in a manner sandwiching the diaphragm. In the electrolyzed water generator, electrolyte-containing raw water is fed into each of the electrolysis chambers, the raw water is electrolyzed by applying a voltage to the pair of electrodes, and consequently, acidic electrolyzed water can be produced in the anodic electrolysis chamber, and on the other hand, alkaline electrolyzed water can be produced in the cathodic electrolysis chamber.
In the electrolytic cell in the electrolyzed water generator, the electrodes are each arranged usually with a space from the diaphragm. However, in this structure, the electrodes arranged in a manner sandwiching the diaphragm are separated from each other with a large space therebetween, and hence the electric resistance between the electrodes is large, resulting in a problem that the electrolysis efficiency in relation to the applied electric power is low.
For the purpose of solving the above described problem, for example, there has been proposed an electrolytic cell in which the electrodes are separated from each other with a reduced space by bringing the diaphragm into contact with the electrodes each formed by laminating a porous electrode material made of a plain-woven wire mesh and a punched metal sheet (for example, see Japanese Patent Laid-Open No. 2001-73177). According to this electrolytic cell, raw water is made to circulate inside the porous electrode material, and consequently the contact area between the raw water and each of the electrodes can be made large. In addition, according to this electrolytic cell, the electrolysis efficiency can be improved to some extent in relation to the applied electric power.
However, in the electrolytic cell disclosed in the above publication, the circulation resistance is large, and hence when the amount of electrolyzed water produced in a unit time is increased, the equipment concerned inevitably becomes large insize. The mentioned large circulation resistance is caused by the fact that raw water is made to circulate inside the porous electrode material.
Under these circumstances, the present inventors have proposed an electrolytic cell in which a pair of electrodes are formed so as to respectively adhere to both surfaces of an ion permeable diaphragm, and there is used a membrane-electrode assembly in which the electrodes themselves are provided with ion permeability (see Japanese Patent Laid-Open Nos. 2005-144239 and 2005-144240). According to the membrane-electrode assembly, only the diaphragm intervenes between both electrodes, so that the electrolysis efficiency in relation to the applied electric power can be enhanced, and in addition, the equipment can be downsized.
However, in the above described membrane-electrode assembly, it is not easy to connect lead wires to the electrodes, and it is not easy to supply electric power through the lead wires. It is possible to make current collectors, in place of the lead wires, in contact with the surfaces of the electrodes. However, when the electrodes are formed of a porous material having fine pores, namely, so-called a microporous material, the surface resistance of the electrodes is high. Accordingly, even when the current collectors are brought into contact with the electrode surfaces, it is not easy to supply electric power from the current collectors to the electrodes, and hence further improvement is desired.

Electrolytic cell for electrolyzed water generator


An intake apparatus includes an intake pipe, a resonator and a blowby gas recirculation pipe. The resonator includes a volume portion having a volume chamber therein and a connecting pipe connecting the volume portion and the intake pipe and having a connecting passage connecting the volume chambera and the intake passage. The blowby gas recirculation pipe includes an internal passage therein. The blowby gas recirculation pipe is connected to an axially midway portion of the connecting pipe, and an exit of the internal passage is connected to the connecting passage of the connecting pipe.

Japanese Patent Publication 2003-214263 discloses the following (i) and (ii) intake apparatuses:    (i) An intake apparatus 1a illustrated in FIG. 3 where a blowby gas recirculation pipe 4 is connected to a volume portion 3a of a resonator 3. In FIG. 3, reference numerals or alphabets 2, 2a, 2b and E illustrate an intake pipe, an intake passage of the intake pipe, an air cleaner and an engine, respectively.    (ii) An intake apparatus 1b illustrated in FIG. 4 where a blowby gas recirculation pipe 4 is connected directly to the intake pipe 2 without via the resonator 3. In FIG. 4, reference numerals or alphabets 2a, 2b and E illustrate the intake passage of the intake pipe, the air cleaner and the engine.
However, there are the following problems with the conventional intake apparatuses: With the intake apparatus of (i) above (the intake apparatus of FIG. 3), oil (oil mist) and water (steam) that have flowed through the blowby gas recirculation pipe 4 may stay stagnant in the volume portion 3a of the resonator 3 without flowing into the intake passage 2a of the intake pipe 2. With the intake apparatus of (ii) above (the intake apparatus of FIG. 4), two apertures, including an aperture 2c for the resonator 3 and an aperture 2d for the blowby gas recirculation pipe 4, have to be provided at the intake pipe 2, which causes a disadvantage from the viewpoint of cost.


An oil guiding device for hydraulic brake lever assembly having a brake lever includes a seat connected to the brake lever. The seat has an oil reservoir disposed thereon. The oil reservoir has an oil chamber defined therein. An oil guiding base is disposed in the oil chamber. The oil guiding base has an oil inlet and an oil outlet defined therein. An oil guiding unit engages with the oil guiding base. The oil guiding unit has a pipe disposed thereon and an oil hole defined therein. The pipe and the oil hole are communicated with the oil outlet and the oil inlet respectively. A cover panel engages with the oil reservoir. The pipe sucks up the hydraulic oil gathered in the oil chamber and supplies the hydraulic oil through the oil outlet; the returned hydraulic oil flows into the oil chamber through the oil inlet.

1. Field of the Invention
The present invention relates to a hydraulic brake lever assembly, and more particularly to an oil guiding device for hydraulic brake lever assembly having a brake lever for preventing formation of air bubbles in hydraulic oil during operation.
2. Description of Related Art
The braking system of a bicycle is the key component for controlling speed of the bicycle and maintaining the safety for riding. A conventional hydraulic brake assembly for bicycle rim brake includes an oil tank for containing oil, a brake lever pivotally connecting to one end of the oil tank, and a tube for connecting with a caliper body is engaged to another end of the oil tank. When the brake lever is exerted, the oil stored in the oil tank is pressured into to the tube, thereby forcing the caliper body to push toward a rim until the rim is forced to brake. The hydraulic brake assembly is widely applied on various types of bicycles for the outstanding braking effect it can achieve.
In the conventional hydraulic brake assembly, the oil tank includes a chamber and an oil storage unit respectively formed in two laterals thereof The chamber is adapted for receiving a piston assembly which is slidably movable therein. The oil storage unit is adapted for storing oil which is provided for braking. A first guiding hole and a second guiding hole are defined between the chamber and the oil storage unit such that the chamber and the oil storage unit are communicated for the oil to flow therein between. The first guiding hole and the second guiding hole have different diameters. Thereby when a rider exerts the brake lever, the piston assembly pressured the oil in the chamber to the caliper body through the tube, when the rider releases the brake lever, the oil in the oil storage unit passes through the first guiding hole to the chamber such that oil in the chamber is maintained in a sufficient level for braking and preventing malfunction due to insufficient oil.
However, despite the effect it provides, the conventional hydraulic brake assembly has the following drawbacks. Usually the brake lever is downwardly and inclinedly positioned relative to the bicycle handlebar for gripping purpose such that the oil tank is also downwardly and inclinedly positioned relative to the bicycle handlebar. When the oil tank is inclinedly positioned, the oil in the chamber would flow into the caliper body through the tube, causing excessive oil to accumulate in the caliper body. In addition, due a tilted position of the oil tank, air may enter into the hydraulic oil through first and second guiding holes causing formation of air bubbles in the hydraulic oil, which results in a "spongy brake" operation and would influence the performance of the hydraulic brake assembly as hydraulic pressure can no longer be distributed accurately and may consequently lead to serious injuries of the rider.
The present invention has arisen to obviate/mitigate the disadvantages of the conventional hydraulic brake assembly.

Oil guiding device for hydraulic brake lever assembly having a brake lever


The nonvolatile memory device may include a substrate including a first region and a second region. A string line group may be disposed on the substrate in the first region, and a bias interconnection group may be disposed above the substrate in the second region. The bias interconnection group may include a string select bias interconnection, cell bias interconnections, and a ground select bias interconnection, which may be respectively electrically connected to a string select line, word lines, and a ground select line of the string line group. The string select bias interconnection may be disposed between the ground select bias interconnection and the cell bias interconnections of the bias interconnection group.

The present disclosure herein relates to semiconductor devices, and more particularly, to nonvolatile memory devices.
Semiconductor memory devices may be classified into volatile memory devices and nonvolatile memory devices. The volatile memory devices have a volatile characteristic that loses all data stored therein when power is cut off. The volatile memory devices may include DRAM devices and SRAM devices. Nonvolatile memory devices have a characteristic that it retains stored data even if power supply is interrupted. Examples of the nonvolatile memory devices may include PRAM devices, MRAM devices and/or flash memory devices.
Flash memory devices may electrically rewrite or erase data. Such a flash memory device may be classified as a NOR type flash memory device or a NAND type flash memory device. The NOR type flash memory device enables high-speed random access, and thus, it may be widely used for a device in which high-speed operation is required. The NAND type flash memory device has faster programming and erasing speed and advantage of easy high integration. Thus, the NAND type flash memory may be used for a large-capacity memory device.
As the semiconductor industries are developed rapidly, line widths and/or distances of patterns for realizing nonvolatile memory devices are being reduced more and more. Accordingly, reliability of the nonvolatile memory devices is being reduced. As semiconductor and electronic industries develop, high-integration and superior reliability of nonvolatile memory devices are being required more and more.


Systems and methods for developing, customizing, and deploying applications for devices are provided through a application development and deployment platform. Preferably, these systems and methods are implemented in an Internet based environment that allows non-technical users to build sophisticated, highly-customizable cross-platform applications. The platform allows users to select, input, create, customize, and combine various content, design characteristics, and application components, such as modules, some of which utilize features and functionality associated with various devices capable of running applications, operating systems, and app-enabled accessories. In certain embodiments, the platform allows users to compile and generate a configuration file for the application that can be distributed to end users for execution on various devices and operating systems. When the application is installed on, or executed by the device, the configuration file may enable the retrieval of various data associated with the application.

Mobile devices, such as smart-phones, tablet PCs, and other handheld devices have become widespread and important to the daily activities of many consumers and businesses. Traditionally, these type of devices have primarily served as communications devices. Recently, however, consumers are increasingly relying upon these devices as an integral tool in the performance of a wide-range of personal and work-related tasks. In response, mobile phones and other wireless handheld devices have evolved into complex computing devices with equally complex computer hardware and software.
While many of these mobile devices continue to be used for various forms of communication (e.g., voice calls and text messaging) they also generally provide other various functionalities, including accessing and displaying websites, sending and receiving e-mails, taking and displaying photographs and videos, playing music and other forms of audio, etc. These, and numerous other functionalities, are generally performed by software applications either in the form of software components that are built-in to the device's mobile operating system or separate mobile applications (mobile apps) that run on top of the operating system. Recently, the development and use of mobile apps has become prolific and thousands of apps now exist across a wide array of mobile devices.
Numerous competing manufacturers, developers, and other service providers have entered the mobile device space in recent years, offering hardware, software in the form of mobile operating systems, or in some cases a combination of both hardware and software. This, in turn, has resulted in the development of a number of dissimilar and incompatible mobile device platforms and environments. Some of the differences among these devices include their hardware components, operating systems and input and output capabilities. In fact, many of the most widely used mobile devices, such as Blackberrys, iPhones and Android-based devices, use different operating systems (e.g., Symbian, iOS, Android and webOS), many of which have their own programming environments and software development tools.
Typically, developing mobile applications for these different operating systems and devices requires the use of varying design techniques and programming languages, as well as separate operating system or device specific software code and compilations. As a result, it is often challenging for developers to write software applications that are portable across multiple types of mobile devices. Instead, mobile app developers are frequently forced to rewrite all or at least substantial portions of the software in order to support different devices.
In order to encourage and facilitate the development of mobile apps for certain types of mobile operating systems and/or devices, the manufacturers and developers of these systems and devices frequently distribute software development kits (SDKs) that are associated with their devices and/or operating systems (or particular versions or releases thereof). Among other things, these SDKs allow application developers to write programs or applications for users of the supported mobile devices and/or mobile operating systems. While these SDKs assist with the development of mobile apps, in order to utilize these SDKs a significant degree of technical knowledge and expertise in software programming and mobile devices is typically required. In particular, use of these SDKs requires programmers to possess an understanding of and experience with both the programming language and the specific mobile operating system platform for which the application is being developed.
In addition to the challenges associated with building mobile apps, deploying these applications and distributing them to end users can often be a complex and involved process. In part, this is due to the fact that many of the mobile device and operating system manufacturers and developers require that all mobile apps to be used with their devices and operating systems must be distributed through their digital distribution platform (e.g., iOS's App Store, Android's Google Play, webOS's App Catalog). Typically, the apps must also be approved by the manufacturers or developers prior to being included in their distribution platforms. Obtaining such approvals for a mobile applications can be a time-consuming and complex process. As a result, an understanding of, and experience with, the requirements and restrictions imposed by manufacturers is often necessary in order to deploy and distribute applications to mobile device users successfully and efficiently.
Similarly, these manufacturers and developers often require that any additional data associated with the application, such as updates, plug-ins, extensions, and content, also be distributed through their digital distribution platforms. In some cases, certain types of updates are also subject to separate approval by the manufacturers. Thus, these restrictions can further complicate and slow-down the distribution and management of mobile applications.
As an increasing number of mobile applications have been developed for mobile handheld devices, and as consumers have come to rely on mobile applications in an increasing number of situations, devices other than handheld mobile devices have provided additional platforms for running applications. For example, many vehicles now include infotainment systems that support a variety of applications. Other devices, such as video game consoles, satellite navigation systems, digital media receivers, and other home appliances, such as refrigerators, can also support certain mobile applications. As with development for mobile devices, developing applications for these other devices often requires developers to have a significant degree of technical knowledge as well as experience in software programming and the SDKs for the particular device for which the application is developed.
Given the high level of skill and expertise needed to create, deploy and update mobile applications, many non-technical individuals, as well as individuals lacking experience in a particular programming language or mobile operating system or digital distribution platform, have are not able to develop and/or distribute mobile applications. Although there have been attempts to make mobile application development more accessible to a wider public through software systems that allow persons who do not have significant experience in programming or specific mobile operating system platforms to create mobile applications, these systems have exhibited a number of drawbacks and limitations which have resulted in their failure to be widely adopted by consumers.
For example, one drawback is that many of these software systems allow non-technical users to create applications for only one mobile operating system, such as, for example, iOS, Android, webOS, or Symbian, (or a restricted subset of the operating systems). In light of the number of different mobile operating systems, including a number of which are widely used, the ability to develop an application that can be easily ported across all mobile operating systems (or at least those with meaningful consumer bases) is a crucial in promoting efficient and simplified mobile application development.
Another drawback is that many of these software systems still require substantial technical knowledge and expertise and, therefore, these systems do not simplify the process to the degree necessary to make mobile app development accessible to non-technical users. Some of these systems are not intuitive to use, involve user training and/or require at least a base level of technical knowledge, such as exposure to application programming and design.
Yet another drawback is that many of these software systems place significant limitations on the types of applications that can be built using the system. For example many of these systems only provide users with the ability to create simple, non-flexible applications that prohibit the utilization of the wide-range of features and specific functionalities included within many mobile devices and their respective mobile operating systems, such as a compass, GPS, gyroscope, touch screen, camera, speaker, microphone, Bluetooth, Wi-Fi, USB connectivity, and proximity sensor. In addition, many products, such as app-enabled accessories, are designed to interact with mobile applications on mobile devices, and such products may be configured, controlled, and/or monitored by mobile devices through mobile applications. Many of the software systems for developing mobile applications do not provide the ability to interact with app-enabled accessories. As a result, with these types of systems, special programming skills and expertise is needed to use/install additional components, plug-ins, modules, or emulators, in order to create more sophisticated mobile apps that utilize these features and functionalities. Also, some of the resulting applications built using existing systems or development tools are only usable while the user's device is "online." In addition, some of these systems require the user to download updates for the application from a third party, such as the mobile operating system's digital distribution platform, rather that from the application developer directly.
There is, therefore, a need for a system that simplifies and streamlines the development, deployment and update of mobile software applications, thereby making the process accessible to non-technical users through an enhanced, user-friendly experience. There is also an need for a system that allows users to develop an application that can run on any mobile device operating system. There is also a need for a system that allows users to develop an application that can run on other devices that support mobile and other specialized applications. There is further a need for a system that allows users to create sophisticated applications that utilize a customized combination of mobile device and mobile operating system features and functionality, as well as features and functionality provided by app-enabled accessories. There is still further a need for a system that is web based while also enabling users to access applications developed through the platform off-line. There is still further a need for a system that provides users with updates associated with applications directly without the need to access the mobile operating system's digital distribution platform.

This patent is subject to a terminal disclaimer.

Systems and methods for a specialized application development and deployment platform


An antifuse structure and methods of forming contacts within the antifuse structure. The antifuse structure includes a substrate having an overlying metal layer, a dielectric layer formed on an upper surface of the metal layer, and a contact formed of contact material within a contact via etched through the dielectric layer into the metal layer. The contact via includes a metal material at a bottom surface of the contact via and an untreated or partially treated metal precursor on top of the metal material.

The present invention relates to integrated circuit (IC) structures, and more specifically, to antifuses for in line circuit modification.
Fuses and antifuses have been used in integrated circuits for tailoring circuit parameters for optimal performance. Fuses increase the resistance of a circuit path when subjected to a programming current. Fuses typically include a fuse link and contact regions at both ends of the fuse link including a plurality of contacts of a uniformed size. The fuse has an underlying polycrystalline layer formed over a substrate and an overlying silicide layer. Fuses are "blown" by applying a voltage across the fuse structure. This voltage causes a current to flow and the structure to open, resulting in a permanent open circuit. Fuses are structures in which resistance is increased during programming and antifuses are structures in which resistance is decreased during programming.
Antifuses are structures that, when first fabricated, are an open circuit. When the antifuse is "fused," the open circuit becomes closed and conduction across the antifuse becomes possible. Thus, antifuses are used to perform the opposite function of a fuse. Typically an antifuse is fused by applying a sufficient voltage, called a "fusing voltage" across the antifuse structure. This voltage causes a current to flow and the structure to fuse together, resulting in a permanent electrical connection.
Each contact formed on the contact regions is typically formed by etching a contact via to a surface of the substrate and depositing a metal material such as titanium (Ti) and organic carrier material within the via to the surface of the substrate by a chemical vapor deposition (CVD) process thereby evaporating the organic material and leaving the metal material on the surface of the substrate. This process is performed at a temperature of approximately 400 degrees Celsius. The processing temperature may be too low to completely evaporate the organic material; therefore, the metal material and any residual carbon containing material are then treated by an N2/H2 plasma to break a bond of the metal material and the carbon containing material. During this treatment, hydrogen reacts with the carbon containing material thereby evaporating the residual carbon containing material and the nitrogen reacts with the metal material and leaves a metal precursor which acts a liner within the contact via. Contact material is then deposited within the contact via to form the contact.

Antifuse structure for in line circuit modification

International Business Machines Corporation


A source of gas for inflating a vehicle occupant restraint comprises a container. Gas generating material in said container comprises an alkali metal azide and a metal oxidizer. When ignited, the gas generating material produces heated nitrogen gas. A supply of pressurized nitrogen gas is also in the container. Structure is provided for separating the supply of pressurized nitrogen gas from the gas generating material. The separating structure is releasable to enable the heated nitrogen gas and the stored nitrogen gas to commingle. The source of gas also includes structure for directing the stored nitrogen gas and the heated nitrogen gas through a tortuous path toward the vehicle occupant restraint so as to remove particulates from the gases.

1. Technical Field
The present invention relates to an apparatus for supplying gas to inflate a vehicle occupant restraint, such as an airbag, and particularly to an apparatus for supplying generated gas along with stored gas. Description of the Prior Art
Typically, an inflatable vehicle occupant restraint is inflated solely by gas which is generated by ignition of gas generating material. The gas generating material is generally volatile and must be handled carefully. Some have suggested that inflatable restraints be inflated by gas which is stored under pressure and by gas which is generated through ignition of gas generating material. In this way, the amount of gas generating material used can be reduced
U.S. Pat. No. 3,723,205 discloses an apparatus for supplying gas to inflate a vehicle occupant restraint. The apparatus comprises gas generating material in combination with stored pressurized gas. The stored gas can be nitrogen, air, carbon-dioxide or helium. The gas generating material, when ignited, generates a hot gas. The gas generating material comprises a halogen free alkali metal salt, an inorganic oxidizer, and a polyvinyl chloride binder. Suitable inorganic oxidizers include alkali metal chlorates and perchlorates, such as ammonium perchlorate, and alkaline earth metal nitrates. Examples of halogen-free alkali metal salts are alkali metal oxalates, carbonates, bicarbonates, and azides, e.g., KN.sub.3, The generated gas ruptures a seal and is directed into the pressurized stored gas. This increases the temperature and thus the pressure of the stored gas causing the commingled stored gas and generated gas to rupture a second seal. The commingled gas then flows into an inflatable device.
In U.S. Pat. No. 3,723,205 the ignition of the gas generating material creates relatively small particles which flow with the gas directly into the inflatable device. Removing these relatively small particles apparently was considered unnecessary because the patent does not disclose a technique for removal of these particles.


A method and system is disclosed for evaluating a chat message sent between users of an online environment. The method may include receiving a chat message and parsing the message into words. The method determines the acceptability of the message by matching the message to a plurality of acceptable messages stored in a data structure. Upon determining the message does not match any acceptable messages, the method replaces each word in the message with grammatical metadata. The method may use templates to determine if the message has acceptable word combinations based on the metadata. The method may also compare the metadata to rules wherein the rules determine if the message has unacceptable word combinations based on the metadata. The method may send the message to a user upon determining words in the message do not match any word in a list of unacceptable words.

Field
Embodiments of the invention are generally directed to online communication. More specifically, embodiments of the invention are directed to a variety of techniques for managing the content of chat messages exchanged between users in online environments.
Description of the Related Art
Multiplayer video games and virtual worlds have rapidly become popular forms of online entertainment. Both generally provide users with access to a virtual environment where they may interact with one another. For example, avatars are frequently used to provide a graphical representation of each user present within a virtual environment and users interact with one another through their avatars. Users control the actions of their avatar to navigate the virtual environment, e.g., achieve gaming objectives as well as to communicate or chat with other users. Such an environment may be persistent where events occur and users interact with each other regardless of the presence of any particular user. Alternatively, such an environment may be game or session based, e.g., where a group of users participate in a match of a first-person shooter game.
Chatting is a prominent feature within these kinds of online environments. For example, a user may chat directly with other users present in the same virtual location by typing characters into a text-field on a user interface. To promote civility and safety among users, a service provider hosting an online environment may desire to prevent the use of obscene language or other inappropriate communication, particularly in online environments developed for minors. In such a case, chat software may filter chat messages by removing swear words, slurs, or other known terms of disparagement. Blacklist filtering does not detect semantically unsafe messages; it can only filter individual words. Because phrases going through a blacklist filter are allowed by default unless blocked by a specific word in the blacklist, this approach allows guests to say a nearly infinite number of phrases which, in turn, makes it vulnerable to guests saying unsafe words using alternate spellings (replacing "S" with "$" or "cks" with "x").
Whitelist filtering allows only safe words (or phrases), which prevents unsafe alternate spellings, but like blacklist filtering, does not detect semantically unsafe messages which can be formed using safe words. Further, whitelist filtering blocks at the word (or phrase) level, so words which are safe in some contexts but unsafe in others are blocked.
While such whitelist chat is safe, it is limited in the number of phrases it allows. Severely impacting user expressivity.
To protect a user's safety in online worlds, providers engage in continuous monitoring and filtering of chat. At a base level, providers filter out and prevent the sending of obvious profanity. The challenge is that people are very good at getting around the sort of filters which are typically used to detect and block unsafe messages. Every time a guests finds a way around one of the filter entries, a new entry must be made to block the unsafe phrases they are now saying. The system ends up flooded with filter entries put into place after-the-fact (meaning the damage is done by the time the filters are updated), often with entries which exist only because it was a work-around to another filter and which no one has tried to get around since it was first introduced. The race to detect and block unsafe message is a continuous, expensive process and in the end never provides a reliably safe environment for our guests. Additionally, the more complex a system becomes, the longer it takes for a phrase to be validated.

Real-time search and validation of phrases using linguistic phrase components


A semiconductor device includes a test pattern decoding unit and a scan chain unit. The test pattern receives a scan-in pattern from an external test device and generates a test pattern based on the scan-in pattern and a scan-out pattern. The scan-in pattern is decoded based on a seed pattern and an expectation pattern. The scan chain unit performs logical operation based on the test pattern and feedbacks the scan-out pattern to the test pattern decoding unit.

1. Field
Exemplary embodiments relate generally to scan testing for semiconductor devices, and more particularly, to a semiconductor device enabled to undergo a scan test and a test system for testing a semiconductor device.
2. Description of the Related Art
The type of semiconductor testing technique used to test a semiconductor device is as much a design/production consideration as improving density and a complexity of the semiconductor device itself. Reduction of time and cost as well as improvement of testability is considered for mass production of semiconductor devices. Thus, a design-for-testability (DFT) scheme is widely used to improve efficiency of testing during a design phase of the semiconductor device. Scan tests have been important as one of the DFT schemes for testing the semiconductor devices.

Semiconductor device and test system for testing the same