A compound of formula (I):

This application is a national-stage entry under 35 U.S.C. xc2xa7371 of PCT/JP99/00072, filed Jan. 11, 1999.
The present invention relates to new benzamide derivatives and salts thereof which are useful as medicaments.
Some benzamide derivatives have been known as vasopressin antagonist, for example, in PCT International Publication Nos. WO 91/05549 and WO 95/29152, EP Publication No. 0620216, and Japanese Patent Unexamined Publication Nos. 154765/1992 and 221476/1997.
This invention relates to new benzamide derivatives and salts thereof.
More particularly, it relates to new benzamide derivatives and salts thereof which exhibit activities such as vasopressin antagonistic activity, to pharmaceutical compositions comprising the same and to methods for the treatment and/or prophylaxis of cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), depressant, anxiety and the like in human beings and animals.
One object of this invention is to provide new and useful benzamide derivatives and salts thereof which possess the aforesaid activities.
Another object of this invention is to provide processes for the preparation of said benzamide derivatives and salts thereof.
A further object of this invention is to provide pharmaceutical compositions comprising, as an active ingredient, said benzamide derivatives or pharmaceutically acceptable salts thereof.
Still further object of this invention is to provide methods for the treatment and/or prophylaxis of the aforesaid diseases in human beings and animals, using said benzamide derivatives and pharmaceutically acceptable salts thereof.
The object benzamide derivatives of this invention are new and can be represented by the following formula (I):
wherein
A is an optionally substituted heterocyclic group;
R is a lower alkoxy;
Z is Cxe2x95x90O or CH2; and
B is a saturated or unsaturated condensed ring group selected from the group consisting of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, each member being optionally substituted,
preferably, by the following formula (II):
wherein A, B, R and Z are each as defined above, or a salt thereof.
The object compound (I) of the present invention can be prepared according to the following reaction schemes.
(wherein B, Z, and R are each defined above.)
(wherein A1 is a heterocyclic group substituted with an N-protective group, a protected amino or a substituent having protected amino, B1 is any one of benzazepinyl, thienoazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with an N-protective group, a protected amino or a substituent having protected amino, A2 is a heterocyclic group not substituted with an N-protective group or substituted with amino or a substituent having amino, B2 is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pryridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is not substituted with an N-protective group or substituted with amino or a substituent having amino, and Z and R are each defined above.)
(wherin B3 is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with =O, B4 is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with hydroxy, and A, Z and R are each as defined above.)
(wherein A3 is a heterocyclic group substituted with phthaloylaminoalkyl, A4 is a heterocyclic group substituted with aminoalkyl, and B, Z and R are each defined above.)
(wherein A5 is a heterocyclic group substituted with amino or aminoalkyl, A6 is a heterocyclic group substituted with (di)alkylamino or (di)alkylaminoalkyl, and B, Z and R are defined above.)
(wherein A8 is a heterocyclic group substituted with protected hydroxyalkyl, A9 is a heterocyclic group substituted with hydroxyalkyl, and B, Z and R are each as defined above.)
(wherein B5 is saturated or unsaturated benzothiazenpinyl, B6 is a saturated or unsaturated S-oxo-benzothiazepinyl, and A, Z and R are each as defined above.)
(wherein B7 is a saturated or unsaturated S,S-dioxo-benzothiazepinyl, and A, Z, B6 and R are each as defined above.)
Suitable salts of the object compound [I] are pharmaceutically acceptable, conventional non-toxic mono- or di-salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate), an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate) and a salt with an amino acid (e.g. arginine salt, aspartic acid salt, glutamic acid salt).
Suitable examples of the various definitions to be included within the scope of the invention, which are given in the description of the present specification, are explained in detail in the following.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise provided.
Suitable xe2x80x9clower alkoxyxe2x80x9d includes straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 2-ethylpropoxy and hexoxy, in which the preferred one is (C1-C4)alkoxy.
Suitable xe2x80x9cheterocyclic groupxe2x80x9d defined for A of the formula (I) includes saturated or unsaturated, monocyclic or polycyclic group such as unsaturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. 1H-azepinyl), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl), etc.;
saturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, perhydroazepinyl (e.g. perhydro-1H-azepinyl), pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl (e.g. imidazo[4,5-c]pyridyl), tetrahydroimidazopyridyl (e.g. 4,5,6,7-tetrahydroimidazo[4,5-c]pyridyl), etc.;
saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, 7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]-nonanyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl (e.g. 2-morpholinyl, 3-morpholinyl, 4-morpholino), sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s);
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.; and
unsaturated condensed heterocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl, etc.
Suitable xe2x80x9csubstituent(s)xe2x80x9d of xe2x80x9cheterocyclic groupxe2x80x9d includes lower alkyl optionally substituted with hydroxy, protected hydroxy, amino, protected amino, alkyl-substituted amino, lower alkoxy, acylamino or N-containing heterocyclic group; N-protective group; lower alkoxy; haloalkyl; amino optionally substituted with lower alkyl, acyl or N-protective group; carbamoyl optionally substituted with lower alkyl; acyl; acylamino; aminoalkylamino optionally substituted with lower alkyl or N-protective group; and N-containing heterocyclic group optionally substituted with lower alkyl, amino optionally substituted with lower alkyl or N-protective group,
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d moiety in xe2x80x9coptionally substituted with lower alkylxe2x80x9d include straight or branched (C1-C6)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-ethylpropyl and hexyl, in which the preferred one is (C1-C4)alkyl.
Suitable xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d moiety in xe2x80x9coptionally substituted with lower alkoxyxe2x80x9d include straight or branched (C1-C6)alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 2-ethylpropoxy and hexoxy, in which the preferred one is (C1-C4)alkoxy.
Suitable xe2x80x9cN-protective groupxe2x80x9d, xe2x80x9cN-protective groupxe2x80x9d moiety in xe2x80x9coptionally substituted with N-protective groupxe2x80x9d and amino-protective group of xe2x80x9ca protected aminoxe2x80x9d include aryl(lower)alkyl such as mono- or di- or triphenyl(lower)alkyl (e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl) and acyl as explained hereinbelow.
Suitable xe2x80x9cacylxe2x80x9d, xe2x80x9cacylxe2x80x9d moiety in xe2x80x9coptionally substituted with acyl or acylaminoxe2x80x9d and xe2x80x9cacylxe2x80x9d moiety in xe2x80x9cacylaminoxe2x80x9d include aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from caboxylic acid, carbonic acid, carbamic acid or sulfonic acid.
Suitable examples of the acyl group thus explained are lower alkanoyl (e.g. formyl, acetyl, propionyl, hexanoyl, pivaloyl), mono(or di or tri)halo(lower)alkanoyl (e.g. chloroacetyl, trifluoroacetyl), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl), mono(or di or tri)halo(lower)alkoxycarbonyl (e.g. chloromethoxycarbonyl, dichloroethoxycarbonyl, trichloroethoxycarbonyl), aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl), aryl(lower)alkanoyl such as phenyl-(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl), aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl), aryloxy(lower)alkanoyl such as phenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl), arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl), aryl(lower)alkoxycarbonyl which may have suitable substituent(s) such as phenyl(lower)alkoxycarbonyl which may have nitro or lower alkoxy (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxy-carbonyl, p-methoxybenzyloxycarbonyl), thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, triazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, lower alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, pentylsulfonyl, butylsulfonyl), arylsulfonyl (e.g. phenylsulfonyl, tolylsufonyl, xylylsufonyl, naphthylsufonyl) and aryl(lower)alkylsufonyl such as phenyl(lower)alkylsufonyl (e.g. benzylsufonyl, phenethylsufonyl, benzhydrylsufonyl).
Examples of preferable xe2x80x9cprotected aminoxe2x80x9d are aryl(lower)alkylamino, lower alkanoylamino and lower alkoxycarbonylamino, more preferable ones are triphenyl(Ci4)alkylamino, (C1-C4)alkanoylamino and (C1-C4)alkoxycarbonylamino, and the most preferable ones are tritylamino, formamido, acetamido and tert-butoxycarbonylamino.
Suitable xe2x80x9calkylxe2x80x9d moiety in xe2x80x9calkyl-substituted aminoxe2x80x9d, xe2x80x9chaloalkylxe2x80x9d and xe2x80x9caminoalkylaminoxe2x80x9d include straight or branched (C1-C6)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-ethylpropyl and hexyl, in which the preferred one is (C1-C4)alkyl.
Examples of preferable xe2x80x9calkyl-substituted aminoxe2x80x9d are methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino, dipentylamino, dihexylamino or the like.
Examples of preferable xe2x80x9chaloalkylxe2x80x9d are fluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl, 6-fluorohexyl, chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 4-chlorobutyl, 5-chloropentyl, 6-chlorohexyl, bromomethyl, 1-bromoethyl, 2-bromoethyl, 1-bromopropyl, 2-bromopropyl, 3-bromopropyl, 4-bromobutyl, 5-bromopentyl, 6-bromohexyl, iodomethyl, 1-iodoethyl, 2-iodoethyl, 1-iodopropyl, 2-iodopropyl, 3-iodopropyl, 4-iodobutyl, 5-iodopentyl, 6-iodohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, 2,2,2-chloroethyl tribromomethyl, triuodomethyl, or the like.
Examples of preferable xe2x80x9caminoalkylaminoxe2x80x9d and xe2x80x9caminoalkylaminoxe2x80x9d moiety in xe2x80x9coptionally substituted with aminoalkylaminoxe2x80x9d are aminomethylamino, aminoethylamino, aminopropylamino, aminoisopropylamino, aminobutylamino, aminoisobutylamino, amino-tert-butylamino, aminopentylamino, aminohexylamino, di(aminomethyl)amino, di(aminoethyl)amino, di(aminopropyl)amino, di(aminoisopropyl)amino, di(aminobutyl)amino, di(aminoisobutyl)amino, di(amino-tert-butyl)amino, di(aminopentyl)amino, di(aminohexyl)amino or the like.
Suitable xe2x80x9cN-containing heterocyclic groupxe2x80x9d and xe2x80x9cN-containing heterocyclic groupxe2x80x9d moiety in xe2x80x9coptionally substituted with N-containing heterocyclic groupxe2x80x9d include ones containing N atom(s) from among those exemplified above with regard to xe2x80x9cheterocyclic groupxe2x80x9d.
Suitable xe2x80x9cprotected hydroxyxe2x80x9d includes hydroxy protected by a conventional protective group, for example, substituted lower alkoxy such as lower alkoxy(lower)alkoxy (e.g. methoxymethoxy), lower alkoxy(lower)alkoxy(lower)alkoxy (e.g. methoxyethoxymethoxy) and substituted or unsubstituted aryl(lower)alkoxy (e.g. benzyloxy, nitrobenzyloxy); acyloxy such as lower alkanoyloxy (e.g. acetoxy, propionyloxy, pivaloyloxy), aroyloxy (e.g. benzoyloxy, fluorenecarbonyloxy), lower alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy), substituted or unsubstituted aryl(lower)alkoxycarbonyloxy (e.g. benzyloxy-carbonyloxy, bromobenzyloxycarbonyloxy), arenesulfonyloxy (e.g. benzenesulfonyloxy, tosyloxy) and alkanesulfonyloxy (e.g. methanesulfonyloxy, ethanesulfonyloxy); tri(lower)alkylsilyloxy (e.g. trimethylsilyloxy); tetrahydropyranyloxy; and the like.
Examples of preferable xe2x80x9cheterocyclic groupxe2x80x9d defined for A of the formula (I) are substituted or unsubstituted 1H-benzimidazol-4-yl such as 2-methyl-1-tert-butoxycarbonyl-1H-benzimidazol-4-yl, 2-methyl-1H-benzimidazol-4-yl, 2-phthaloylaminomethyl-1H-benzimidazol-4-yl, 2-aminomethyl-1H-benzimidazol-4-yl, 2-dimethylaminomethyl-1H-benzimidazol-4-yl, 2-methanesulfonylaminomethyl-1H-benzimidazol-4-yl, 2-(morpholin-4-yl)methyl-1H-benzimidazol-4-yl, 2-(4-tert-butoxycarbonylpiperazin-1-yl)methyl-1H-benzimidazol-4-yl, 2-(piperazin-1-yl) methyl-1H-benzimidazol-4-yl, 2-tert-butyldimethylsiloxymethyl-1H-benzimidazol-4-yl, 2-hydroxymethyl-1H-benzimidazol-4-yl, 2-(imidazol-1-yl)-1H-benzimidazol-4-yl, 2-tert-butoxycarbonylamino-1H-benzimidazol-4-yl, 2-amino-1H-benzimidazol-4-yl, 2-acetamido-1H-benzimidazol-4-yl, 2-methylsulfonylamino-1H-benzimidazol-4-yl, 2-trifluoromethyl-1H-benzimidazol-4-yl, 1,2-dimethyl-1H-benzimidazol-4-yl, 2-dimethylamino-1H-benzimidazol-4-yl, 1H-benzimidazol-4-yl, 2-methoxy-1H-benzimidazol-4-yl, 2-methoxymethyl-1H-benzimidazol-4-yl, 2-ethyl-1H-benzimidazol-4-yl, 1-tert-butoxycarbonyl-2-[2-(N-methyl-N-tert-butoxycarbonylamino)ethylamino]-1H-benzimidazol-4-yl, 2-[2-(methylamino)ethylamino]-1H-benzimidazol-4-yl, 2-n-propyl-1H-benzimidazol-4-yl, 2-(4-methylpiperazin-1-yl)-1H-benzimidazol-4-yl, 2-[N-[2-(dimethylamino)ethyl]-N-methylamino]-1H-benzimidazol-4-yl, 2-[2-(dimethylamino)ethylamino]-1H-benzimidazol-4-yl, 2-(morpholin-4-yl)-1H-benzimidazol-4-yl, 2-(imidazol-1-yl)methyl-1H-benzimidazol-4-yl, 2-[4-(dimethylamino)piperidin-1-yl]-1H-benzimidazol-4-yl, 2-(N,N-dimethylcarbamoyl)-1H-benzimidazol-4-yl, 1-tert-butoxycarbonyl-2-[N-(2-tert-butoxycarbonylaminoethyl)-N-methylamino]-1H-benzimidazol-4-yl and 2-[N-(aminoethyl)-N-methylamino]-1H-benzimidazol-4-yl;
substituted or unsubstituted 3H-benzimidazol-4-yl such as 2,3-dimethyl-3H-benzimidazol-4-yl;
substituted or unsubstituted benzoxazol-4-yl such as 2-methylbenzoxazol-4-yl; and
substituted or unsubstituted 1H-indazol-7-yl.
xe2x80x9cCondensed ring groupxe2x80x9d defined for B of the formula (I) may be saturated or unsaturated. Unsaturated condensed ring group includes partly unsaturated condensed ring group.
Suitable xe2x80x9csubstituent(s)xe2x80x9d in xe2x80x9ccondensed ring groupxe2x80x9d defined for B of the formula (I) include lower alkyl, halogen, hydroxy, N-protective group, xe2x95x90O and xe2x95x90CH2.
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9cN-protective groupxe2x80x9d are the same as those defined above with regard to the substituents of xe2x80x9cheterocyclic groupxe2x80x9d.
Suitable xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo and iodo.
Examples of preferable xe2x80x9csaturated or unsaturated condensed ring groupxe2x80x9d defined for B of the formula (I) are unsaturated benzazepinyl such as 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-5-methylene-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-7-methyl-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-7-chloro-1H-1-benzazepin-1-yl and 2,3,4,5-tetrahydro-9-methyl-1H-1-benzazepin-1-yl;
unsaturated benzodiazepinyl such as 2,3,4,5-tetrahydro-4-oxo-1H-1,5-benzodiazepin-1-yl, 2,3,4,5-tetrahydro-5-oxo-1H-1,4-benzodiazepin-1-yl, 3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-1,3-benzodiazepin-1-yl and 4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl;
unsaturated pyridoazepinyl such as 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-9-yl, 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-1-yl, 2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-5-yl and 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]azepin-1-yl;
unsaturated pyridodiazepinyl such as 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-1-yl;
unsaturated thienoazepinyl such as 2,3-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-b]azepin-8-yl and 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-yl;
unsaturated benzoxazepinyl such as 2,3,4,5-tetrahydro-1,5-benzoxazepin-5-yl and 1,2,3,5-tetrahydro-4,1-benzoxazepin-1-yl;
unsaturated benzothiazepinyl such as 2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl, 1-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl, 1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl, 1,2,3,5-tetrahydro-4,1-benzothiazepin-1-yl, 4-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-1-yl and 4,4-dioxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-1-yl;
unsaturated imidazobenzazepinyl such as 2-methyl-1,4,5,6-tetrahydro-imidazo[4,5-d][1]benzazepin-6-yl;
unsaturated pyridobenzoxazepinyl such as 5,6-dihydro-pyrido[2,3-b][1,5]benzoxazepin-6-yl; and
substituted indolinyl such as 3,3-dimethylindolin-1-yl.
The processes for preparing the object compound of the present invention are explained in detail in the following.
The object compound (I) or a salt thereof can be prepared by reacting a compound (III) or its reactive derivative at the carboxyl group or a salt thereof, with a compound (IV) or its reactive derivative at the amino group or a salt thereof.
Suitable salts of the compounds (III) and (IV) may be the same as those exemplified above with regard to the compound (I).
Suitable reactive derivative at the carboxy group of the compound (III) includes an acid halide, an acid anhydride, an activated amide and an activated ester. Examples of suitable reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid), aliphatic carboxylic acid (e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid), or aromatic carboxylic acid (e.g. benzoic acid); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N+xe2x95x90CHxe2x80x94] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester) or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole). These reactive derivatives can optionally be selected according to the kind of the compound (III) to be used.
Suitable salts of the compound (III) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
Suitable reactive derivative at the amino group of the compound (IV) includes Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IV) with a carbonyl compound such as aldehyde or ketone; a silyl derivative formed by the reaction of the compound (IV) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide or bis(trimethylsilyl)urea; and a derivative formed by reaction of the compound (IV) with phosphorus trichloride or phosgene.
Suitable salts of the compound (IV) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, an alcohol (e.g. methanol, ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylacetamide, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
In this reaction, when the compound (III) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diethylcarbodiimide; N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,Nxe2x80x2-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; phosphorus pentachloride; thionyl chloride; mesyl chloride; oxalyl chloride; lower alkyl haloformate (e.g. ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or methanesulfonyl chloride.
The reaction may also be carried out in the presence of an inorganic or organic base such as alkali metal carbonates, alkali metal hydrogencarbonates, tri(lower)alkylamine, pyridide, N-(lower)alkylmorpholine or N,N-di(lower)alkylbenzylamine.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
The object compound (Ib) or a salt thereof can be prepared by subjecting a compound (Ia) or a salt thereof to elimination reaction of the N-protective group in Axe2x80x2 and/or Bxe2x80x2.
Suitable salts of the compounds (Ia) and (Ib) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method such as hydrolysis or reduction.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base includes, for example, inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate); and organic bases such as trialkylamines (e.g. trimethylamine, triethylamine), picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene.
Suitable acid includes organic acids (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid).
The elimination using Lewis acid such as trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid) is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol).
The reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reaction method applicable to the elimination reaction includes chemical reduction and catalytic reduction.
Suitable reducing agent to be used in chemical reduction is a combination of a metal (e.g. tin, zinc, iron) or metallic compound (e.g. chromium chloride, chromium acetate) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel), cobalt catalysts (e.g. reduced cobalt, Raney cobalt), iron catalysts (e.g. reduced iron, Raney iron) and copper catalysts (e.g. reduced copper, Raney copper, Ullman copper).
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvents, and other conventional solvents such as diethyl ether, dioxane and tetrahydrofuran, or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (Id) or a salt thereof can be prepared by subjecting a compound (Ic) or a salt thereof to reduction of xe2x95x900 in B3.
Suitable salts of the compounds (Ic) and (Id) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using a reducing agent.
Suitable reducing agent includes alkali metal borohydride (e.g. sodium borohydride, sodium cyanoborohydride).
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, alcohol (e.g. methanol, ethanol, propanol), or a mixture thereof.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (If) or a salt thereof can be prepared by subjecting a compound (Ie) or a salt thereof to hydrolysis.
Suitable salts of the compounds (Ie) and (If) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using a base or an acid including Lewis acid.
Suitable base includes an inorganic or organic base such as alkaline metals (e.g. sodium, potassium), alkaline earth metals (e.g. magnesium, calcium), hydrides thereof, hydroxides thereof, carbonate salts thereof, bicarbonate salts thereof, alkylamine (e.g. methylamine, trimethylamine, triethylamine), picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene.
Suitable acid includes organic acids (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid), inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride) and acid addition salt compounds (e.g. pyridine hydrochloride).
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, dioxane, alcohol (e.g. methanol, ethanol, propanol), acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide, or a mixture thereof.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (Ih) or a salt thereof can be prepared by reacting a compound (Ig) or a salt thereof with an alkylating agent.
Suitable salts of the compounds (Ig) and (Ih) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using a conventional alkylating agent.
Suitable alkylating agent includes lower alkyl halides (e.g. methyl iodide, ethyl iodide); combination of carbonyl compounds such as aliphatic ketones (e.g. acetone, ethylmethylketone), carboaldehydes (e.g. formaldehyde, ethanal) and orthocarbonates (e.g. orthoformate), and reducting agents such as formic acid, sodium borohydride, sodium cyanoborohydride, palladium-carbon used in chemical reduction or catalytic reduction.
In case that a lower alkyl halide is used as an alkylating agent, the reaction may preferably be carried out in the presence of alkaline metals (e.g. sodium, potassium), alkaline earth metals (e.g. magnesium, calcium), hydride thereof, hydroxide thereof, carbonate salts thereof, bicarbonate salts thereof, and organic base (e.g. tri(lower)alkylamine, N,N-di(lower)alkylaniline).
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, dioxane, alcohol (e.g. methanol, ethanol, propanol), acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide, or a mixture thereof.
Additionally, in case that the above-mentioned alkylating agent or base to be used in the reaction are liquid, they can also be used as a solvent.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (Ii) or a salt thereof can be prepared by reacting a compound (Ig) or a salt thereof with an acylating agent.
Suitable salts of the compounds (Ig) and (Ii) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using a conventional acylating agent.
Suitable acylating agent includes an organic acid represented by the formula: Rxe2x80x2xe2x80x94OH wherein Rxe2x80x2 is acyl or substituted acyl as illustrated above, or its reactive derivative.
Suitable organic acid derivative includes conventional ones such as acid halides (e.g. acid chlorides, acid bromides), acid azides, acid anhydrides, activated amides and activated esters.
In case that acylating agent is used in a free acid form or its salt form, the acylation may preferably be carried out in the presence of a conventional condensing agent as explained in Process 1.
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, acetone, dioxane, chloroform, methylene chloride, acetonitrile, ethylene chloride, tetrahydrofuran, acetic acid, N,N-dimethylform-amide, pyridine, or a mixture thereof.
Additionally, the reaction may preferably be carried out in the presence of a conventional base such as triethylamine, pyridine and sodium hydroxide.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (Ik) or a salt thereof can be prepared by subjecting a compound (Ij) or a salt thereof to elimination reaction of the hydroxy-protective group in A8.
Suitable salts of the compounds (Ij) and (Ik) may be the same as those exemplified above with regard to the compound (I).
This reaction can be carried out in substantially the same manner as in Process 2, and therefore, the reaction mode and reaction conditions (e.g. base, acid, catalyst, solvent, reaction temperature) of this reaction are to be referred to those explained in Process 2.
The object compound (Im) or a salt thereof can be prepared by subjecting a compound (Il) or a salt thereof to oxidation of S atom in B5. The object compound (In) or a salt thereof can be prepared by subjecting a compound (Im) or a salt thereof to oxidation of S atom in B6.
Suitable salts of the compounds (Il), (Im) and (In) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using an oxidizing agent.
Suitable oxidizing agent includes hydrogen peroxide, Jones reagent, peracids (e.g. peracetic acid, perbenzoic acid, m-chloroperbenzoic acid), chromic acid, potassium permanganate, and alkali metal periodates (e.g. sodium periodate).
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, organic acid (e.g. acetic acid, trifluoroacetic acid), acetone, ethyl acetate, alcohol (e.g. methanol, ethanol), dichloromethane, chloroform, or a mixture thereof.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation or the like.
The object compound (I) thus obtained can be converted to a pharmaceutically acceptable salt in a conventional manner.
It is to be noted that the object compound (I) may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) or double bond(s), and all such isomers and mixtures thereof are included within the scope of this invention.
The object compound (I) and pharmaceutically acceptable salts of the present invention exhibit activities such as vasopressin antagonistic activity, vasodilating activity, hypotensive activity, activity of inhibiting saccharide release in liver, activity of inhibiting growth of mesangium cells, diuretic activity, platelet aggregation inhibitory activity, oxytocin antagonistic activity, antidepressant activity, antianxiety activity and the like, and are useful for the treatment and/or prophylaxis of hypertension, heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome, hepatocirrhosis, hyponatremia, hypokalemia, diabetes mellitus, circulation disorder, cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), Meniere""s syndrome (e.g. Meniere""s disease, etc.), motion sickness, depressant, anxiety and the like in human beings and animals.
In order to illustrate the usefulness of the object compound (I), the pharmacological data of the compound (I) are shown in the following.
Vasopressin 1 (VI) Receptor Binding
(i) Test Method
Blood was obtained from normal subject by venipuncture. Platelet-rich plasma (PRP) was prepared by centrifugation of whole blood at 200xc3x97g for 10 minutes. PRP was centrifuged at 45,000xc3x97g for 30 minutes. The remaining pellet was resuspended in 10 volume of ice-cold 100 mM Tris-HCl buffer (pH 7.4, containing 5 mM MgCl2, 0.1% bovine serum albumin and 1 mM EDTA), and again centrifuged at 45,000xc3x97g for 30 minutes. The final pellet was resuspended in 100 mM Tris-HCl buffer. The resulting suspension was used immediately for the binding assay.
Competition assays were conducted at equilibrium (15 minutes at 30xc2x0 C.) by using 1.5 nM 3H-vasopressin (40-87 Ci/mmol; New England Nuclear) in 100 mM Tris-HCl buffer (pH 7.4). Nonspecific binding was determined by using 1 xcexcM vasopressin. After incubation, the reaction was terminated by adding 5 ml of ice-cold 100 mM Tris-HCl buffer (pH 7.4), and then filtered immediately through Whatman glass filter (GF/C). The filter was washed twice with the same buffer. The glass filter was placed in a liquid scintillation cocktail, and the radioactivity thereof was counted by using a liquid scintillation counter. Competition activity of the test compound was represented by IC50 values.
(ii) Test Result
Vasopressin 2 (V2) Receptor Binding
(i) Test Method
For binding assays, a receptor cDNA was permanently expressed in Chinese hamster ovary (CHO) cells. A vector directing expression of the cDNA of a human V2 receptor was transfected into the CHO cells, and the clonal cell lines expressing the human V2 receptor were established essentially as described previously (Nakajima, Y., et. al. J. Biol. chem., 267, 2437, 1992).
DNA-transfected cells were harvested and homogenized in ice-cold 250 nm Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM EDTA and 5 xcexcg/ml p-amidinophenylmethylsulfonyl fluoride (A-PMSF). The homogenate was centrifuged at 500xc3x97g for 10 minutes. The supernatant was centrifuged at 100,00xc3x97g for 1 hour. The final pellet was suspended in 25 mM Tris-HCl buffer (pH 7.4, containing 10 mM MgCl2, 1 mM EDTA and 5 xcexcg/ml A-PMSF), and stored in small aliquots at xe2x88x9280xc2x0 C.
Competition assays were conducted at equilibrium (2 hours at 22xc2x0 C.) by using 0.5 nm 3H-vasopressin (40-87 Ci/mmol; New England Nuclear) in 100 mM Tris-HCl buffer (pH 7.4, containing 5 mM MgCl2, 5 xcexcg/ml A-PMSF, 4 xcexcg/ml leupeptin, 40 xcexcg/ml bacitracin, 20 xcexcg/ml chymostatin and 0.1% bovine serum albimin). Nonspecific binding was determined by using 1 xcexcM vasopressin. After incubation, the reaction mixture was immediately filtered through Whatman glass filter (GF/C). The filter was washed twice with the same buffer. The radioactivity was counted by using a liquid scintillation counter. Competition activity of the test compound was represented by IC50 values.
(ii) Test Result
For therapeutic purposes, the compound (I) or pharmaceutically acceptable salts threrof of the present invention can be used in the form of pharmaceutical preparation containing compound (I) or pharmaceutical acceptable salts threrof, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral or external (topical) administration. The pharmaceutical preparation may be in the form of capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included, in these preparations, auxiliary substances, stabilizing agent, wetting or emulsifying agent, buffer and other commonly used additives.
While the dosage of the compound (I) or pharmaceutically acceptable salts threrof will vary depending upon the age and condition of patients, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg or 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

Benzamide derivatives as vasopressin antagonists

Abstract: A compound of formula (I):

Abstract: wherein A is an optionally substituted heterocyclic group, R is a lower alkoxy; Z is Cxe2x95x90O or CH2; and B is benzazapinyl, which may be optionally substituted, or a salt thereof, that possesses vasopressin antagonistic activity and is useful as a vasopressin antagonist.


A semiconductor device includes first and second voltage control lines for a first memory block and third and fourth voltage control lines for a second memory block, for driving gate lines for memory transistors; a first decoder driving the first and third voltage control lines; a second decoder driving the second and fourth voltage control lines; and a control circuit controlling a voltage for the first and second decoders. The control circuit supplies a first voltage and a second voltage lower than the first voltage to the first decoder and a third voltage between the first and second voltages, and the second voltage to the second decoder, before writing operation; and supplies the first voltage and the third voltage to the first decoder and a fourth voltage between the third and second voltages, and a fifth voltage lower than the second voltage to the second decoder, in the writing operation.

This disclosure relates to a level shift circuit and further to a decode circuit that outputs an output signal having a different voltage from an input signal.
The power source used for a logic mixed non-volatile memory circuit is various. There are generally used a low voltage power source (VDD, about 1 V) in a logic circuit portion, a medium voltage power source (VCC, about 3 V) used in a peripheral circuit of a non-volatile memory, and further a positive high voltage power source (VPP, about 11 V at maximum) and a negative high voltage power source (VEE, about −8V at maximum) generated by boosting the voltage from the medium voltage power source used for writing and erasing in a memory cell (refer to Japanese Unexamined Patent Application Publication No. 2011-165269).
A low voltage MOS transistor used for the logic circuit portion is getting down in scale and miniaturization is advancing year by year. According to this, it is necessary to operate the transistor with a lower power source voltage in terms of withstand voltage, which results in decreasing the voltage of the low voltage power source.
On the other hand, a high voltage MOS transistor forming a non-volatile memory portion such as a flash memory is difficult to miniaturize and still keeps a medium voltage and a high voltage as ever.
A decode circuit that handles a high voltage needs to be basically formed by a high voltage MOS transistor. Nevertheless, the decode circuit needs to handle a signal of a low voltage power source level inside itself.
When the voltage level of a low voltage power source gets lower than the threshold voltage of the high voltage MOS transistor, there occurs such a situation that a signal having the voltage level of the low voltage power source cannot be handled normally.


The present invention discloses a portable cooking stove comprising a base portion adapted to hold a heating means, and a removable top member for supporting a cooking implement, characterised in that the base portion comprises a support member for supporting the top member, the support member comprising a plurality of leaves, the intended lower edge of each vane being pivotally connected to the circumference of the base portion such that, in use, the leaves will extend upwardly from the base portion in order to support the top member, and when not in use, the intended upper edge of the leaves are pivoted towards the centre of the base portion.

Portable stoves are used for camping or cooking in places where there is not a constant supply of fuel. Generally, portable stoves need to be lightweight and easily transportable. Existing portable stoves are often heavy or bulky and offer little wind protection for the heat source. Even existing lightweight stoves are prone to being bulky. Lack of wind protection can lead to difficulty in maintaining a heat source, and can also cause ignited fuel to blow out of the stove. Furthermore, existing stoves may be unstable on uneven ground. Generally, portable stoves do not provide an efficient heat source for cooking, with over 50% of the energy being wasted due to wind or lack of wind shield.


A device that can be worn under clothing preferably near the nape of the neck to hold the rear shoulder straps of a bra together a determined distance after the wearer establishes a desired degree of cleavage by first lifting upward on the front bra straps. The device can be rubber, plastic, cloth or other flexible material and can be adjustable to different sizes. The device can include two opposing clips that engage the bra straps holding them together to maintain the desired degree of cleavage. The device can be supplied in one or two pieces and be adjustable.

1. Field of the Invention
The present invention relates generally to the field of women's beauty enhancement and more particularly to a method and apparatus for enhancing a woman's bust-line by lifting the breasts causing more cleavage to show with a particular bra.
2. Description of the Prior Art
There are numerous brassieres (bras) in the prior art that address different aspects of the function of supporting a bust-line. There is also art that teaches hiding bra straps, matching clothing and various removable or adjustable bra features.
Hopson in U.S. Pat. No. 6,135,853 teaches a device that is used to pull bra straps together to concealing them. Scholtz in U.S. Pat. No. 5,921,845 teaches lower support straps. Robinson in U.S. Pat. No. 2,870,768 teaches a multiple strap bra. Rashkin in U.S. Pat. No. 3,334,632 teaches a torso-encircling garment. Brewster in U.S. Pat. No. 5,935,044 teaches an apparatus for securing bra straps in a particular position. Greifer in U.S. Pat. No. 4,612,935 teaches various comfort accessories for brassieres.
While the prior art teaches various aspects of bra design, what is badly needed is a device that will work with any bra to hold the bra straps together in the back to hold lift of the breasts so that a woman's appearance is enhanced by showing more cleavage (after lifting the breasts from the front straps). This would be very useful for a woman who, after work, wishes to put on an evening blouse that is low cut so that more cleavage can show, but who wishes to use the same or a standard bra, or for a woman who feels her breasts need a lift because of a natural tendency to sag.

Method and apparatus for enhancing a bustline


A flat package piezoelectric oscillator, sealed with resin, and having leads or terminals includes an IC chip mounted on one side of an island portion of a lead frame, and a piezoelectric oscillator element mounted on an opposite side of the island portion. The resin package of the oscillator has at least one hole through one of opposite surfaces of the package. An injection hole for resin injection is provided along a diagonal line extending between diametrically opposed corners of the resin package, and a cylindrical case of the piezoelectric crystal oscillator element is located such that its longitudinal axis is aligned with the diagonal line to within a range from -45.degree. to +45.degree.. The connection portions of lead terminals for the piezoelectric oscillator element and the pads of the IC chip are located adjacent to the diagonal line. The fabrication of the piezoelectric crystal oscillator is completed by sealing the above described structure with resin.

1. Field of the Invention
The present invention relates to a resin-sealed piezoelectric oscillator having leads or terminals.
2. Description of the Related Art
No conventional semiconductor devices having a flat package style also contain a piezoelectric oscillator element. FIG. 5A is a plan view showing, as an example of a flat package, a semiconductor device of QFJ (Quad Flat J-Lead Package) type. FIG. 5B is a side view of the semiconductor device of FIG. 5A. An IC chip 52 is mounted on an island portion 51 located approximately in the center of the package. Bonding wires 54 connect the pads of the IC chip 52 to the lead terminals 53 which surround the island portion 51 on its four sides. The entire structure (known as a lead frame) is then sealed with resin using transfer molding, except the outer portion of the lead terminals 53 which are left exposed. The lead terminals 53 are then subjected to cutting and bending processes.
Conventional flat package semiconductor devices (also known as plastic leaded chip carriers) cannot accommodate a piezoelectric oscillator element because the lead terminals 53 surround the island portion 51 and because the resin packages of such conventional devices are too thin.

Piezoelectric oscillator formed in resin package containing, IC chip and piezoelectric oscillator element


An instruction alignment unit is provided which is capable of routing variable byte length instructions simultaneously to a plurality of decode units which form fixed issue positions within a superscalar microprocessor. The instruction alignment unit may be implemented with a relatively small number of cascaded levels of logic gates, thus accomodating very high frequencies of operation. In one embodiment, the superscalar microprocessor includes an instruction cache for storing a plurality of variable byte-length instructions and a predecode unit for generating predecode tags which identify the location of the start byte of each variable byte-length instruction. An instruction alignment unit is configured to channel a plurality of the variable byte-length instructions simultaneously to predetermined issue positions depending upon the locations of their corresponding start bytes in a cache line. The issue position or positions to which an instruction may be dispatched is limited depending upon the position of the instruction's start byte within a line. By limiting the number of issue positions to which a given instruction within a line may be dispatched the number of cascaded levels of logic required to implement the instruction alignment unit may be advantageously reduced.

1. Field of the Invention
This invention relates to superscalar microprocessors and more particularly to the alignment and dispatch of variable byte length computer instructions to a plurality of instruction decoders within a high performance and high frequency superscalar microprocessor.
2. Description of the Relevant Art
Superscalar microprocessors are capable of attaining performance characteristics which surpass those of conventional scalar processors by allowing the concurrent execution of multiple instructions. Due to the widespread acceptance of the x86 family of microprocessors, efforts have been undertaken by microprocessor manufacturers to develop superscalar microprocessors which execute x86 instructions. Such superscalar microprocessors achieve relatively high performance characteristics while advantageously maintaining backwards compatibility with the vast amount of existing software developed for previous microprocessor generations such as the 8086, 80286, 80386, and 80486.
The x86 instruction set is relatively complex and is characterized by a plurality of variable byte length instructions. A generic format illustrative of the x86 instruction set is shown in FIG. 1. As illustrated in the figure, an x86 instruction consists of from one to five optional prefix bytes 102, followed by an operation code (opcode) field 104, an optional addressing mode (Mod R/M) byte 106, an optional scale-index-base (SIB) byte 108, an optional displacement field 110, and an optional immediate data field 112.
The opcode field 104 defines the basic operation for a particular instruction. The default operation of a particular opcode may be modified by one or more prefix bytes. For example, a prefix byte may be used to change the address or operand size for an instruction, to override the default segment used in memory addressing, or to instruct the processor to repeat a string operation a number of times. The opcode field 104 follows the prefix bytes 102, if any, and may be one or two bytes in length. The addressing mode (Mod R/M) byte 106 specifies the registers used as well as memory addressing modes. The scale-index-base (SIB) byte 108 is used only in 32-bit base-relative addressing using scale and index factors. A base field of the SIB byte specifies which register contains the base value for the address calculation, and an index field specifies which register contains the index value. A scale field specifies the power of two by which the index value will be multiplied before being added, along with any displacement, to the base value. The next instruction field is the optional displacement field 110, which may be from one to four bytes in length. The displacement field 110 contains a constant used in address calculations. The optional immediate field 112, which may also be from one to four bytes in length, contains a constant used as an instruction operand. The shortest x86 instructions are only one byte long, and comprise a single opcode byte. The 80286 sets a maximum length for an instruction at 10 bytes, while the 80386 and 80486 both allow instruction lengths of up to 15 bytes.
The complexity of the x86 instruction set poses difficulties in implementing high performance x86 compatible superscalar microprocessors. One difficulty arises from the fact that instructions must be aligned with respect to the parallel-coupled instruction decoders of such processors before proper decode can be effectuated. In contrast to most RISC instruction formats, since the x86 instruction set consists of variable byte length instructions, the start bytes of successive instructions within a line are not necessarily equally spaced, and the number of instructions per line is not fixed. As a result, employment of simple, fixed-length shifting logic cannot in itself solve the problem of instruction alignment. Although scanning logic has been proposed to dynamically find the boundaries of instructions during the decode pipeline stage (or stages) of the processor, such a solution typically requires that the decode pipeline stage of the processor be implemented with a relatively large number of cascaded levels of logic gates and/or the allocation of several clock cycles to perform the scanning operation.
A further solution to instruction alignment and decode within x86 compatible superscalar microprocessors is described within the copending, commonly assigned patent application entitled "Superscalar Instruction Decoder", Ser. No. 08/146,383, filed Oct. 29, 1993 by Witt et al., the disclosure of which is incorporated herein by reference in its entirety. The solution proposed within the above-referenced patent application involves a translation of each variable length x86 instruction into one or more fixed-length RISC-like instructions. Upon translation, each fixed-length RISC-like instruction is aligned with respect to an allocated instruction decoder. While this solution has been quite successful, it too typically requires a relatively large number of cascaded levels of logic gates. This correspondingly limits the maximum overall clock frequency of the superscalar microprocessor.

High performance superscalar alignment unit


A non-aqueous liquid plaque adsorbent oral or effervescent dentifrice composition comprising a non-aqueous carbon dioxide source selected from bicarbonate salt, carbonate salt and mixtures thereof, a non-aqueous, water soluble acid source selected from organic acid, partial salt thereof and mixtures thereof, and a carrier adsorbent. Optionally, the composition can include flavoring agent, artificial, non-caloric sweetener, surface active agent, anti-bacterial agent, astringent agent, desensitizing agent, fluoride containing anti-caries agent, gelling agent, chloropyhyllin salt, coloring agent, hydrogen peroxide source and/or excipient. The effervescent dentifrice is preferably employed as one component of a kit also including a debriding product, a hydrogen peroxide product and a bicarbonate dentifrice, the components of the kit being used in combination on a daily basis to synergistically achieve enhanced preventative and remedial oral hygiene.

Sodium bicarbonate, a bicarbonate salt, is a common household ingredient used in cooking, cleaning, and deodorizing. Sodium bicarbonate alone or in combination with other ingredients, has been recognized and used as a dentifrice since at least the turn of the century and is considered an acceptable and effective alternative dentifrice to the commercially prepared dentifrices. Dentifrice has been a very important tool of preventive dentistry. It is believed that the use of dentifrice in conjunction with a toothbrush has probably accomplished more in the prevention of oral disease than any other oral health procedure. Virtually all oral diseases of bacterial origin could be eliminated by the meticulous application of the self-administrative oral hygiene techniques now available, such as, toothbrush, toothpaste, floss, irrigation devices, and the like. Unfortunately, the average person does not use and has not used these tools effectively. One aim of preventive dentistry has therefore been to improve the efficacy of self-administered oral hygiene procedures to obtain maximum benefit with minimum effort. Various forms of dentifrices have been thought to provide one of the most productive vehicles in the achievement of this aim.
In order to maintain healthy teeth and gums, an individual must constantly battle against tooth pellicle, dental plaque, dental calculus, and food debris. The judicious use of dentifrice in conjunction with the toothbrush is currently used to control these accumulations.
Tooth pellicle is a thin proteinaceous film which forms on the teeth and is not visible to the naked eye. It forms within hours following removal by dental prophylaxis. It is believed that pellicle is formed by the adsorption by teeth enamel of proteins present in saliva. All other oral accumulations form over the pellicle. Dental pellicle and accumulations thereon are considered to be a factor for tooth stains.
Dental plaque is an accumulation that forms over tooth pellicle. After the deposition of the pellicle, micro-organisms attach to the pellicle. This is favored by the secretion of bacterial extra-cellular material. After formation, the plaque attacks and provides a suitable site for the accumulation of other substances. The acid generated by the plaque bacteria demineralizes the dental enamel resulting in carious lesions. The bacteria in the plaque are not only the leading cause of caries, they are also the leading cause of periodontal disease, that is, destruction of the gum tissue supporting the teeth. Periodontal disease is a major concern to dental hygiene since it is the major cause of tooth loss, especially in older patients.
When dental plaque mineralizes the accumulates on the tooth surface, it forms dental calculus. Calculus, once formed, is virtually impossible to remove with the toothbrush and available dentifrices. One objective of a dental hygienist is to attempt to remove formed calculus.
Food debris is an important oral accretion which can support the build-up of plaque. The food debris provides nutrients for the plaque bacteria which account for generally all dental problems. The toothbrush, a dentifrice, and floss are ideal for the removal of food debris.
Modern dentifrice comprises a mild abrasive for the removal of stains, a surface active agent or detergent to aid in the cleaning of the teeth and destruction of the plaque bacteria, an anti-caries agent, water, and, optionally, flavoring agents, sweetening agents, viscosity modifiers, desensitizers, and the like. It is still not clear whether an abrasive is needed to remove plaque and pellicle. However, it is recognized that an abrasive is required to remove stain accumulations from teeth. Up until the 1060's, the most common abrasives used in dentifrices were dicalcium phosphate dihydrate, calcium carbonate, and insoluble sodium metaphosphate. However, these abrasives since the 1960's have been gradually replaced by aluminum oxide trihydrate and forms of hydrated silica. Over half the dentifrices presently used employ hydrated silica abrasives because of their superior flavor release properties and excellent compatibility with fluoride salts. Most of the silica used is of the amorphous form since the crystalline silica structure is considered too hard to use safely with gum tissue. In addition, amorphous silicas tend to break down and shear under pressure because of their porosity and friability and, thus, are not excessively abrasive to teeth enamel or dentine. The dentifrices compounded with conventional abrasives contain about 40 to 50 percent by weight of abrasive. Dentifrices compounded with amorphous silica abrasives have a much lower abrasive loading (from about 10 to about 20 percent by weight).
The fluoride dentifrices, the anti-caries dentifrices, are normally compounded with sodium fluoride, sodium monofluorophosphate or stannous fluoride as a fluoride source. The concentration of fluoride salt is normally about 100 ppm. The function of fluoride in combating tooth decay is not fully understood nor is the mode of action fully understood. Some dental experts contend that the fluoride ion in the dentifrice interacts with tooth enamel to form a fluorophosphate structure, such as fluoratatite, which is more resistant to attack by the acids generated by dental plaque bacteria. Other experts contend that the dental enamel attached by an acid can be remineralized and that the fluoride enhances the rate of that remineralization and makes the resulting crystalline structure more resistant to further attack by acid. A third hypothesis is that the fluoride ion inhibits metabolic processes in plaque bacteria reducing their ability to produce acid. Possibly the role of fluoride in combating tooth decay combines all three of these actions.
Almost all dentifrices contain a surfactant primarily to enhance foaming action of the dentifrice. Almost all dentifrices either employ sodium lauryl sulfate or sodium dodecyl benzene sulfate as dentifrice surfactants.
In most dentifrices, the flavoring agent has no hygienic purpose. The flavoring is added to the dentifrice to make it more acceptable to the consuming public, to mask the flat taste of the other ingredients and to freshen the breath. The most common flavoring agents are mint, anise-type flavors, and cinnamon. Peppermint flavoring is slowly being phased out.
A variety of thickening agents are used in dentifrices to give the dentifrice proper body or structure. Silicas have been used extensively, especially in clear gel dentifrices, to give structure. In the opaque dentifrices, a number of organic gums are used, such as, xantham gum, carbosymethyl cellulose, acrylic acid polymers, polyacrylic acid resins, and the like. A number of dentifrices also contain desensitizing agents for patients with hypersensitive teeth. The most common desensitizers are strontium chloride and potassium nitrate. It is noteworthy that sodium citrate is also recognized as a desensitizing agent.
For ideal oral hygiene, the teeth would be brushed with a dentifrice, flossed, and irrigated following each meal and snack. Unfortunately, the time restraints in the lives of most people and the lack of convenient facilities do not allow this luxury. This is unfortunate, especially since the average life span of a typical person has increased substantially over the last 50 years. Children and young adults are the most susceptible to caries. Adults rarely get caries because of the chemical and physiological change of their saliva. However, adults are more prone to periodontal disease which is the leading cause of tooth loss. Adults are more susceptible to periodontal disease with increasing age. Plaque build-up is recognized as the principal contributor to such disease. Thus, it is very desirable to develop means for removing plaque from the teeth promptly after its formation.
It is an object of the present invention to provide a dry oral wash composition that can be inserted into the oral cavity following a meal or snack to rinse or wash the mouth free of organic debris and inhibit the formation of plaque.
It is a further object of the present invention to provide an oral non-aqueous dentifrice composition that can be taken to clean the oral cavity of organic debris and remove plaque from the teeth.
An additional object is to provide a composition that will neutralize the acids in the oral cavity.
Another object of the present invention is to provide an anti-plaque composition that will inhibit the build-up of plaque on the teeth and inhibit the population growth of plaque bacteria in the oral cavity.
Others in the field of oral hygiene have attempted to make such compositions. For example, U.S. Pat. No. 1,297,494 is directed to an effervescent, solid dentifrice comprising an acid salt and a bicarbonate salt which are mutually reactive in the presence of moisture to produce CO.sub.2 and an initially weak acid solution to contact the surface of the teeth. The solution acted primarily to dislodge plaque adhesions from enamel surface and the CO.sub.2 and the irrigation of the acid solution away from the enamel surface. The period of acid activity is limited as to preclude enamel decalcification and aids in the reactivation of the alkaline addition of the saliva in the mouth. The composition can be optionally compounded with abrasives such as calcium carbonate (chalk), surface active agent such as the soap of sodium oleate, a sweetening agent such as saccharine and flavoring agents such as oil of peppermint. The dentifrice could be employed as a dry powder or a paste compounded with thickening agent such as glycerine or gum arabic free of water. The dentifrice is to be used in conjunction with a toothbrush.

Plaque adsorbent oral composition and method


An improved leak detection system for oil and gas pipelines and the like, including submerged or buried structures, the system including an aerial- or space-based platform with GPS and Attitude Determination and Control System (ADCS) capability, the platform connected to a hyperspectral imaging sensor, the system including processor and memory structured with a vegetative index such that chemical and hydrocarbon leaks are detected within regulatorily-approved time limits based on changes in the vegetative index.

Long-Felt Need
Product spill incidents, large and small, have continued to disrupt the oil, gas and chemical industries through the years. Empirical data indicates that the total number of pipeline incidents is increasing in absolute terms. Over a quarter of all pipeline incidents are first identified and reported to the authorities by the public. Worse yet, there have been human casualties reported in numerous incidents.
Focusing on US pipeline leaks in 2016, there were over 400 reported incidents that collectively resulted in over 1,100 days of pipeline downtime. Approximately $3 billion in lost revenues have been estimated for those midstream operators in 2016 alone.
The oil and gas and chemical industries recognize the seriousness of this challenge. For example, the refining industry alone spends $9 billion annually on Operations Excellence and Integrity programs, Reputation Preservation/PR, and Leak Prevention (notably following third-party damage or right of way (ROW) changes.
Focal industry needs in hydrocarbon leak detection include:                1. efficiency, and prioritization of resources;        2. enhanced spill detection (smaller volume detection and earlier detection);        3. spill awareness generated through internal capability rather than from the Public; and        4. quicker and more efficient emergency response—spill tracking, resource deployment.
Current Systems, Problems and Industry Expectations
In terms of current alternative compliance and inspection methodologies, the oil, gas and chemical industries predominantly utilize visual air surveillance techniques and ground sensors for monitoring infrastructure and for complying with Pipeline and Hazardous Materials Safety Administration (PHMSA) and Department of Transportation (DOT) regulations.
Problems with visual air patrol are that aerial traffic is heavily regulated, subject to weather restrictions, and has limited data capture capability as compared to ground sensors. To the extent a pilot's view is relied upon, visual air perspectives may be obstructed and a pilot's conclusions may be limited to subjective visual interpretations.
Ground monitoring includes Forward Looking Infrared (FLIR), foot patrol, and electronic sensors. Electric sensors, such as fiber-optics, however, are capital intensive and implausible to install on existing underground pipelines.
Notwithstanding that the use of Drone/Unmanned Aerial Vehicle (UAV) platforms are presently hindered by low endurance and minimal coverage capability; and despite a lack of development of sufficient safety standards in automation and air traffic control; and taking into account that rapid national and global deployment of capital, operational and logistical assets would be required to capture significant market share, all of which teach away from the instant invention. The instant inventors have constructed an aerial and a space-based Hyperspectral Imaging Sensor (HSI) sensor prototype with associated equipment. The aerial and space prototypes were, and are being, evaluated for commercial viability. The incentive for developing the prototype and for the belief in the success of the invention arises out of a synergy discovered from a use of a vegetative index for leak detection with aerial or space-based HSI coverage of Targets. Secondary effects of leaks or vegetation, including importantly of buried and submerged pipelines, provide speedy reliable detection techniques.
Note: Optical Gas Imaging (OGI) and Infrared cameras are becoming more common as sensors. However, these systems capture only one data point per pixel—temperature, whereas hyperspectral sensors capture hundreds of data points per pixel—uniquely enabling chemical classification and change detection.
Existing state-of-the-art hyperspectral sensor-based detection systems are commercially utilized for various market applications including precision agriculture, mining, oil and gas surveying, and defense. These systems have been implemented on satellite or aerial platforms (airplanes, helicopters, and drones) for these uses. Commercial utilization of hyperspectral sensor systems for monitoring oil, gas and chemical assets for leak detection is believed, however, to be limited to stationary platforms and ground vehicles. The perceived high costs, complexity of required systems and questions about accuracy and reliability have discouraged the use of aerial or space-based platforms for hyperspectral sensor systems for pipeline leak detection.
Patent application publication US 2015/0323449 generally recite the possibility of detecting gas leaks by utilizing hyperspectral sensors located on satellites or airplanes, without significant details or data or analysis methods or successful test results.
Patent application publication US 2018/0046910 discloses the development of sophisticated neuro-network learning machines to predict adverse conditions in regard to structural assets, based on vegetation. A key problem addressed is the impedance of utility lines by vegetation. Hyperspectral images and a vegetation index can be involved. No possibility of debating underground/undersea problems is discussed, nor is meeting tight regulatory time limits.
Patent application publication 2009/0271719 discloses the use of hyperspectral imaging and a vegetation index to display at a customer's request a vegetative index indicating vegetation health over a geographic area.
Patent U.S. Pat. No. 9,151,864 discloses ground monitoring and detecting of materials using hyperspectral imaging where the imaging sensors are ground-based from two fixed orthogonal locations.

Aerial and space-based hyperspectral imaging system and method for hydrocarbon and chemical industry regulatory compliance, leak detection and product speciation


In embodiments of the present invention, telecommunications terminal blocks are provided for making and breaking connections between a first telecommunications conductor, a second telecommunications conductor and a service wire. The terminal block includes a housing having a first connector connected to the first telecommunications conductor and a second connector connected to the second telecommunications conductor mounted therein. A first conductor is provided in the housing, the first conductor being electrically connected to the first connector and having a service wire connector portion configured to receive the service wire. A switch electrically connects the first connector and the second connector, the switch having a first state wherein the first connector is electrically connected to the second connector and a second state wherein the first connector is electrically disconnected from the second connector. Methods are also provided.

Terminal blocks are used by telecommunications companies to connect connector wires of a multi-core cable to service wires that extend to customer residences or places of business. Such terminal blocks are typically mounted outdoors and are, thus, exposed to environmental conditions, such as rain, snow, sleet, ice, temperature fluctuations, dirt, insect infestation and similar conditions that may adversely affect the electrical connections between the service wires and the electrical connectors. Thus, some form of sealant material may be provided in such terminal blocks.
Referring now to the schematic illustration of FIG. 1, a typical telephone company (Telco) telecommunications conductor cable 20 extends from the Telco central office 22 to feed pedestals in a neighborhood or neighborhoods. The Telco telecommunications conductor cable 20 may include as many 900 or more pairs of telecommunications conductor wires. At a splice 24, one or more of the pairs of telecommunications wires are accessed. FIG. 1 illustrates a single tip line 26 and ring line 28 which are spliced at the splice 24 into a cable extending to pedestal 32. Note that, while only one pair of wires 26, 28 is illustrated, the splice typically includes bridge connections for 25 pairs of wires with a 25 pair cable 30 extending from the splice 24 to the pedestal 32. Thus, the telecommunications wire pair 26, 28 and the other 24 pairs which are bridge connected to the pedestal 32 also continue to extend within the telecommunications conductor cable 20 and are, therefore, available for use at additional pedestals further downstream from the Telco central office 22.
In the pedestal 32, the telecommunications wire pair 26, 28 is connected to a terminal block 34. It is further to be understood that, while only one terminal block 34 is illustrated, a terminal block assembly including a plurality of module stations, which may share a common base, is typically provided for all the pairs of the cable 30. The terminal block 34 provides a connection point between telecommunications wire pair 26, 28 and the customer service wires 36. A telecommunications connection may thus be provided between the customer 38 and the Telco central office 22. In addition, by utilizing a bridge connection at the splice 24, the telephone company maintains the flexibility of using ones of the pairs of wires in the telecommunications conductor cable 20 at different pedestals 32 depending upon customer requirements at various locations within a neighborhood or neighborhoods.
An example of terminal blocks 34 according to the prior art is described in U.S. Pat. No. 5,557,250 entitled "Telecommunications Terminal Block" which is incorporated herein by reference as if set forth in its entirety. Telecommunications terminal blocks may also be utilized for establishing a connection between internal wiring of the customer 38 and the customer service wires 36. An example of such a telecommunications terminal block is described in U.S. Pat. No. 5,423,694 entitled "Telecommunications Terminal Block" which is incorporated herein by reference as if set forth in its entirety.
The telecommunications infrastructure as described with reference to FIG. 1 is generally directed to providing conventional voice services to a plurality of customers 38. The conductors 20, 26, 28, 36 are typically copper wires well suited to supporting voice communications. With the increased popularity of data based communications, which are typically digital transmissions, additional demands are being placed on the telephone infrastructure. For example, the Internet is growing increasingly popular with expanding information and services available to customers utilizing the Internet. The increase in content and opportunity for utilization of the Internet further may make it desirable to provide increasing data rates for communications over the telephone infrastructure.
While conventional modems designed for use over the telephone infrastructure are suited to the systems described with reference to FIG. 1, they are typically limited in their communication rate, for example, to 56 kilo bits per second (kbps). More recently, the digital subscriber line (DSL), very high data rate DSL (VDSL), asymmetrical DSL (ADSL) and other DSL technologies have been proposed for bringing higher band width information communications to homes and small businesses over ordinary copper telephone lines such as the cable infrastructure illustrated in FIG. 1. The DSL approach is intended to provide downstream communications connections at data rates from approximately 1.544 megabits per second (mbps) through 384 kbps. However, the data rate available for any individual customer 38 may depend upon a variety of characteristics of the Telco infrastructure including the distance between the customer 38 and the Telco central office 22. The unused length of a customer's telecommunication wire pair, such as pair 26, 28, extending downstream from the splice 24 may further limit the data rate available to individual customers.

Terminal blocks and methods for making and breaking connections in a telecommunication conductor


A fuel pump assembly includes a container with the removable cover which forms an enclosure for a pump and a replaceable filter element which is disposed in coaxial surrounding relation to the pump. The filter element includes an upper end cap having an end wall forming an annulus, and a downwardly-extending side wall which forms a central cavity. The lower end of the side wall includes a radially inwardly-directed flange which defines an annular opening. A ring seal is disposed within this lower annular opening in the side wall. The filter element also includes a lower end cap which has an annular spacer collar with axially-upwardly extending tabs. A tubular filter media is disposed between the upper and lower end caps and secured thereto with a potting compound. Side wall 82 extends downwardly through the center of the filter media such that the tabs on the spacer collar on the lower end cap contact the ring seal on the upper end cap. The pump is inserted within the cavity defined by the side wall on the upper end cap such that the ring seal seals against the lower end of the pump around the pump inlet. Fuel flows radially inward and then axially downward through the filter media, radially inward and then axially upward through flow paths between the tabs on the spacer collar on the lower end cap and the ring seal, and then axially upward to the pump inlet. Outwardly-projecting ridges or spacers are provided around the circumference of the upper and lower end caps, and axially downwardly-extending fins are provided on the lower end cap, to provide an offset between the filter element and the container for fuel flow therebetween.

Various devices are known for supplying fuel from a tank to an internal combustion engine of a motor vehicle. Laue, et al., U.S. Pat. No. 5,392,750, for example, shows in one embodiment an annular filter surrounding a fuel delivery unit (pump) inside a cup-shaped supporting element. Fuel flows axially upward through the pump to an upper cover on an aggregate (housing), and then radially outward and axially downwardly through filter media, and then finally radially outward and axially upward through a raiser conduit to the internal combustion engine.
Other devices for supplying fuel to an engine include Bangs, U.S. Pat. No. 2,781,726; Von Wangenheim, U.S. Pat. No. 2,497,247; Von Wangenheim, U.S. Pat. No. 2,377,299; Niemeyer, et al., U.S. Pat. No. 3,294,025; Baltz, et al., U.S. Pat. No. 5,231,967; and Jaeger, et al., U.S. Pat. No. 5,389,245.
While the above devices appear satisfactory for certain applications, it is believed that these devices can have certain drawbacks. For example, certain of the above devices have filters which are disposed in axially-spaced relation to the pump, which can increase the overall size of the pump housing. Other of these devices do not provide a filter element which is easily accessible, such that a filter element can be quickly and easily removed and replaced when it becomes spent or otherwise unusable. Still further of these devices do not provide a simple arrangement of components which are relatively easy to manufacture and assemble. Certain of the devices also do not provide for filtering the fuel prior to the fuel entering the pump, which can cause deterioration and premature wear of the pump.
As such, it is believed that there is a demand in the industry for a fuel pump assembly which addresses the above drawbacks.

Fuel pump assembly and filter element therefor


A device for preventing melt-through of a reactor vessel comprising a first spray nozzle means disposed adjacent a bottom of the reactor vessel for spraying between 50 and 375 gpm of cooling water onto the lower bottom of the reactor vessel and for cooling and preventing melt-through of the reactor vessel; a second spray nozzle means disposed adjacent a body of the reactor vessel for spraying between 100 and 750 gpm of cooling water onto the body of the reactor vessel and for cooling and preventing melt-through of the reactor vessel; and a third spray nozzle means disposed adjacent an upper head of the reactor vessel for spraying between 50 and 375 gpm of cooling water onto the upper head of the reactor vessel and for cooling and preventing melt-through of the reactor vessel.

1. Field of the Invention
The present invention relates to a device for cooling a reactor vessel under a severe accident condition and, more particularly, to such a device having spray nozzles respectively positioned adjacent a vessel bottom, an upper head, and a body of the reactor vessel for cooling the reactor vessel and preventing melt-through.
2. Description of the Invention
In a commercial nuclear reactor, heat, from which steam and ultimately electricity are generated, is produced by fissioning of a fissible material, such as enriched uranium, contained in a reactor core which is, in turn, contained within the reactor vessel. The reactor vessel includes a flanged closure head bolted atop a flanged reactor body; the reactor vessel is entirely contained within a containment building for containing any unlikely radiation leakage within the containment building should an accident occur. A coolant, typically water, flows through the reactor core for controlling the nuclear reaction and for conveying the generated heat away from the reactor vessel.
Due to safety concerns, various safety mechanisms are present for safely shutting down the nuclear process and for containing any radiation within the reactor vessel or, as a final safety device, within the containment building. One safety concern is to contain the fissible material if the water is completely drained from the reactor vessel leaving the fissible material uncovered. This would cause the fissible material to melt which, in turn, would cause the reactor vessel body to structurally fail, generally referred to as melt-through, if the fissible material or the reactor vessel, or both, are not cooled by water.
Although not particularly directed to melt-through, in a pressurized water reactor system, one safety mechanism, a containment spray system (CSS), is for limiting the pressure in the containment building, as is well known in the art. The CSS sprays a sodium hydroxide solution of borated water into the containment building and, thus, onto the reactor vessel for limiting the pressure inside the containment building and, as a secondary effect, cooling the reactor vessel.
Although the present systems for shutting down and containing the nuclear process are satisfactory, there are areas where, due to improved technology or the like, the extent of protection for severe accidents may be expanded, for example by preventing melt-through of the reactor vessel.
Consequently, a need exists for an improved device for cooling the reactor vessel.

Device for preventing melt-through of a reactor vessel


A sink splashguard is provided and can be mounted to a sink such that it protrudes a height above a counter surface. The sink splashguard protects the user of the sink from splashes. The height of the sink splashguard above the counter surface can be easily and quickly adjusted while the sink splashguard is in use. The sink splashguard include a base with one or more than one side, and an adjustable attachment holder coupled to the base. The adjustable attachment holder adjustably couples to a splash guard coupling device, which can be a suction cup to be used to couple the splash guard within a sink. A splash guard include a curve body portion that is semi-flexible with coupling devices coupled in fixed positions to the body portion. The body portion contours to an inner wall of a sink.

Technical Field
This invention relates to sinks and wash basins and in particular to a splashguard for protecting the user of a sink from getting splashed by water from the sink.
State of the Art
Sinks and washbasins are in common use in kitchens and washrooms in homes and businesses. Sinks and washbasins are used for preparing of foods, washing dishes, washing clothes, or for washing hands and/or arms. Sinks by their nature involve the use of water, and many chores done by a sink result in the user of the sink getting splashed with water. Splashguards can be used to protect the user of a sink from getting splashed with water from the sink. Current splashguard technology does not provide a splashguard that can be easily and repeatably removed from the sink, is easy for the user to reach over and into the sink, and can be easily adjusted in height above the counter.
Accordingly, a novel sink splashguard has been developed which can be easily and repeatably attached and removed from the sink, and can be easily adjusted in height above the counter.

This patent is subject to a terminal disclaimer.


A data transfer controller connected between a device and a memory for controlling data transfer between the device and memory on the basis of a command received from a CPU. The controller includes command buffers for storing at least one data transfer command received from the CPU, an input port for reading the data transfer command from the command buffers and reading out a command packet corresponding to the data transfer command from a location within the memory instructed by the data transfer command, a packet store buffer connected to the input port for holding therein data packets and command packet read out from the memory, and a command execution circuit connected to the command buffers and the packet sore buffer for performing transfer of the data packets between the memory and device through the packet store buffer on the basis of a transfer execution flag received from the CPU. At least one data transfer command has a write command for transferring data from the memory to the device, and a read command for transferring data from the device to the memory, and the command execution circuit sends the data packets sent from the device to the packet store buffer on the basis of the data transfer command, according to a designation of the read command. When the data packet designated to be sent from the device to the packet store buffer according to the data transfer command is not held yet in the packet store buffer, the read command may not be executed. Two computer systems can be interconnected by means of respective data transfer devices to a parallel computer system as a whole.

The present invention relates to a data transfer device and a parallel computer system and more particularly, to a data transfer technique which can be effectively applied to data transfer between a memory and an I/O device in a computer system including workstations or servers or to interconnection between a plurality of such computer systems.
For example, a computer system including workstations or servers employs mainly reduced instruction set computer (RISC) processors. With improvement of such logical system as pipeline control and an operational frequency increased by advancement of semiconductor techniques, the single RISC processor has been increasingly improved.
Requirements demanded for such a system are first to increase the number of transactions processable per unit time especially for each server, and second not only to improve the performance of each CPU but also to provide a mechanism for allowing each CPU to be able to perform parallel processing operation in a plurality of computer systems and to increase the number of external memories such as disk units connectable thereto and the memory capacity thereof.
However, the numbers of CPUs, memories and I/O devices connectable to an identical bus or crossbar switch has its limit by electrical restrictions to load capacitances by which the data transfer operational speed of the bus or crossbar switch is guaranteed or by physical restrictions of manufacturing techniques for the size of a backboard forming the bus or crossbar switch.
For this reason, the hardware of a high-performance server requiring a multiplicity of I/O devices to be connected thereto has, in many cases, such a configuration that a system bus or crossbar switch for connecting a CPU and a memory is connected to I/O buses for connection of I/O devices in a hierarchically-connected relation, i.e., in a multi-layer bus connection relation. For the purpose of enhancing parallel processing capability, a plurality of computer systems each having CPUs are interconnected with each other via the I/O devices.
In order to secure a constant reliability in an overall system even when the number of I/O devices to be connected is increased, it is required that occurrence of a fault in one of the I/O devices cause the influence of the fault not to be transmitted to other CPUs, that is, to be localized.
Further, to nest buses means to make long a logical and physical distance between CPUs or memories and I/O devices. For this reason, when control of the I/O device is carried out directly from the CPU based on CPU instruction operation, there occurs such a problem that its instruction execution time becomes long and the performance of the CPU is degraded by the control of the I/O device. This also causes a data transfer latency between the memory and I/O device to become large. Thus, when data transfer is started directly from the I/O device, prefetch data from the memory or write data to the memory are required to be temporarily saved, which disadvantageously results in that the I/O device must have a large capacity of buffer, thus increasing costs for the I/O device.
Meanwhile, various sorts of devices have been developed in these years. However, sequential development of I/O devices compatible with their own computer systems is costly. Therefore, this requires the I/O devices manufactured by a third party to be built in own computer systems. Further, I/O devices manufactured by third party are generally compatible with industrial standard-based buses such as protocol control information (PCI) buses, and it is important to connect such an industrial standard-based bus as a PCI bus in own computer system, while minimizing the influence of the own computer system on its operating system.
Furthermore, communication of the own computer system with another computer system via the I/O device in order to allow the respective CPUs within the plurality of computer systems to perform parallel operation causes generation of an overhead with low efficiency, because of intervention of the control protocol of the I/O device during the communication between the computer systems. In addition, an upper limit of the data transfer rate is limited to the transfer rate of the I/O device per se.

Data transfer device for decreasing load of CPU by avoiding direct control from the CPU in parallel computer system


A lens module structure with a metal shell includes a metal shell and a lens module. The metal shell has a bottom casing and a top casing. The bottom casing has several lateral plates which have protrusions inwardly. At least two lateral plates have first locking portions. Second locking portions corresponding to the first locking portions are disposed on the side wall of the top casing. The lens module has metal portions and is assembled with the bottom casing. Each of the protrusions on the bottom casing abuts and holds the metal portions. Furthermore, the top casing is assembled with the bottom casing via locking the second locking portions with the first locking portions. The protrusions have a predetermined length. The protrusions can abut and hold the lens module with a predetermined size. Moreover, the effect of anti-electromagnetic interference is improved.

1. Field of the Invention
The present invention is related to a lens module structure with a metal shell and assembling method therefor, and more particular to an improved lens module structure with a metal shell and assembling method therefor that can save the cost for molding and can prevent electromagnetic interference.
2. Description of Related Art
Conventional lens modules are used in electrical devices like digital cameras, mobile phones or PDA (Personal Digital Assistant) which are modular products capable of taking pictures. In order to prevent electromagnetic interference (EMI), the lens modules are generally covered with a metal shell.
At present, the metal shell is usually realised by assembling a top casing with a bottom casing. The lens module is disposed in the bottom casing first and then covered with the top casing. There are bumps of the bottom casing which lock the top casing giving the shell a solid structure. The shell effectively prevents EMI of the lens module with surrounding electronic devices.
The metal shell has a predetermined size corresponding to the lens module. When the size of the lens module is variable (for example: 8 mm, 10 mm or 12 mm), different sizes of the metal shell must be provided to accommodate the lens module. Manufacturers need to manufacture several sets of metal molds (including top casing and bottom casing), and further stamp several sets of metal shells for the different size of lens module. Hence, the cost are high.
Therefore, in view of this, the inventor proposes the present invention to overcome the above problems based on his expert experience and deliberate research.

Lens module structure with a metal shell and assembling method therefor