The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor. Although a wide range of COX-II inhibitors may be employed but it is preferred to employ compounds of the Formula I:

U.S. Pat. No. 5,192,753 states inter alia that dementia in human beings may be treated with compounds selected from the non-steroidal anti-inflammatory group of cyclooxygenase inhibitors. The non-steroid anti-inflammatory drugs (NSAIDs) referred to in U.S. Pat. No. 5,192,753 are all agents which possess significant ability to inhibit cyclooxygenase type 1 (COX-1). A number of publications have also occurred in the scientific literature which disclose that agents such as acetylacetic acid and indomethecin, which are generally viewed as potent inhibitors of COX-1, can be used in the treatment of Alzheimers disease; see for example:
McGeer et al, Lancet, 1990:335, 1037;
Rogers et al, Neurology, 1993:43; 1609-1611;
McGeer et al, Neurology, 1992:42, 447-449; and
Breitner et al, Neurology, 1994, 227-232.
Cyclooxygenase (COX) exists in the human as cyclooxygenase type I (COX-I) and cyclooxygenase type II (COX-II also referred to herein as COX-2). Hitherto there has been no suggestion that COX-II plays any role in Alzheimers disease. Indeed there has been no evidence which demonstrates that COX-II plays a part in any human central nervous system disorder. COX-II is inducilible by a number of agents such as mitogen, endotoxin, cytokines and the like but none of these agents which have been demonstrated as inducing COX-II have been shown to be causitive in Alzheimers disease.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor.
The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor. Although a wide range of COX-II inhibitors may be employed but it is preferred to employ compounds of the Formula I as set out hereinafter.
In one aspect the invention encompasses a method of treating a neurodegenerative disease in a human which comprises administering to said human an effective amount of a non-steroidal COX-2 inhibitor.
Within this apsect the invention encompasses a method of treating the neurodegenerative disease, Alzheimers Disease.
Within the above aspect the invention also encompasses a method of treating stroke, cerebral ischernia and de-myelinating disorders.
Oral administration (such as by tablet or capsule) is a preferred mode of administration
Within the above aspect, there is a preferred classs of method wherein the non-steroidal COX-2 inhibitor will bind at least 100 times as well to COX-2 as to COX-1.
Within the above aspect there is a preferred class of COX-2 inhibitors, which is:
(a) 3-(4-(Aminosulfonyl) phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,
(b) 3-(4-(Aminosulfonyl) phenyl)-2-(4-fluorophenyl)thiophene,
(c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,
(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene,
(e) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl) thiophene-2-carboxylic acid,
(f) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole,
(g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one
(h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole,
(i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone,
(k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl) furan,
(l) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl) thiophene,
(n) 3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,
(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(p) 5,5-Dimethyl-3-(3fluorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(q) 5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(t) 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(v) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, and
(y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
The invention also encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases
or pharmaceutically acceptable salts thereof wherein:
X-Y-Z-is selected from the group consisting of:
(a) xe2x80x94CH2CH2CH2xe2x80x94,
(b) xe2x80x94C(O)CH2CH2xe2x80x94,
(c) xe2x80x94CH2CH2C(O)xe2x80x94,
(d) xe2x80x94CR5(R5xe2x80x2)xe2x80x94Oxe2x80x94C(O)xe2x80x94,
(e) xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5xe2x80x2)xe2x80x94,
(f) xe2x80x94CH2xe2x80x94NR3xe2x80x94CH2xe2x80x94,
(g) xe2x80x94CR5(R5xe2x80x2)xe2x80x94NR3xe2x80x94C(O)xe2x80x94,
(h) xe2x80x94CR4=CR4xe2x80x2xe2x80x94Sxe2x80x94,
(i) xe2x80x94Sxe2x80x94CR4xe2x95x90CR4xe2x80x2xe2x80x94,
(j) xe2x80x94Sxe2x80x94Nxe2x95x90CHxe2x80x94,
(k) xe2x80x94CH⊚Nxe2x80x94Sxe2x80x94,
(l) xe2x80x94Nxe2x95x90CR4xe2x80x94Oxe2x80x94,
(m) xe2x80x94Oxe2x80x94CR4xe2x95x90Nxe2x80x94
(n) xe2x80x94Nxe2x95x90CR4xe2x80x94NHxe2x80x94;
(o) xe2x80x94Nxe2x95x90CR4xe2x80x94Sxe2x80x94, and
(p) xe2x80x94Sxe2x80x94CR4xe2x95x90Nxe2x80x94;
(q) xe2x80x94C(O)xe2x80x94NR3xe2x80x94CR5(R5xe2x80x2)xe2x80x94;
(r) xe2x80x94R3Nxe2x80x94CHxe2x95x90CHxe2x80x94 provided R1 is not xe2x80x94S(O)2Me
(s) xe2x80x94CHxe2x95x90CHxe2x80x94NR3xe2x80x94 provided R1 is not xe2x80x94S(O)2Me
when side b is a double bond, and sides a an c are single bonds; and
X-Y-Z-is selected from the group consisting of:
(a) xe2x95x90CHxe2x80x94Oxe2x80x94CHxe2x95x90, and
(b) xe2x95x90CHxe2x80x94NR3xe2x80x94CHxe2x95x90,
(c) xe2x95x90Nxe2x80x94Sxe2x80x94CHxe2x95x90,
(d) xe2x95x90CHxe2x80x94Sxe2x80x94Nxe2x95x90,
(e) xe2x95x90Nxe2x80x94Oxe2x80x94CHxe2x95x90,
(f) xe2x95x90CHxe2x80x94Oxe2x80x94Nxe2x95x90,
(g) xe2x95x90Nxe2x80x94Sxe2x80x94Nxe2x95x90,
(h) xe2x95x90Nxe2x80x94Oxe2x80x94Nxe2x95x90,
when sides a and c are double bonds and side b is a single bond;
R1 is selected from the group consisting of
(a) S(O)2CH3,
(b) S(O)2NH2,
(c) S(O)2NHC(O)CF3,
(d) S(O)H)CH3,
(e) S(O)(NH)NH2,
(f) S(O)(NH)NHC(O)CF3,
(g) P(O)(CH3)OH, and
(h) P(O)(CH3)NH2,
R2 is selected from the group consisting of
(a) C1-6alkyl,
(b) C3, C4, C5, C6, and C7, cyloalkyl,
(c) mono-, di- or tri-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo,
(3) C1-6alkoxy,
(4) C1-6alkylthio,
(5) CN,
(6) CF3,
(7) C1-6alkyl,
(8) N3,
(9) xe2x80x94CO2H,
(10) xe2x80x94CO2xe2x80x94C1-4alkyl,
(11) xe2x80x94C(R5)(R6)xe2x80x94OH,
(12) xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94C1-4alkyl, and
(13) xe2x80x94C1-6alkylxe2x80x94CO2xe2x80x94R5;
(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of
(1) hydrogen,
(2) halo, including fluoro, chloro, bromo and iodo,
(3) C1-6alkyl,
(4) C1-6alkoxy,
(5) C1-6alkylthio,
(6) CN,
(7) CF3,
(8) N3,
(9) xe2x80x94C(R5)(R6)xe2x80x94OH, and
(10) xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94C1-4alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R3 is selected from the group consisting of
(a) hydrogen,
(b) CF3,
(c) CN,
(d) C1-6alkyl,
(e) hydroxyC1-6alkyl,
(f) xe2x80x94C(O)xe2x80x94C1-6alkyl,
(g) optionally substituted
(1) xe2x80x94C1-5 alkyl-Q,
(2) xe2x80x94C1-3alkylxe2x80x94Oxe2x80x94C1-3 alkylxe2x80x94Q,
(3) xe2x80x94C1-3 alkylxe2x80x94Sxe2x80x94C1-3 alkylxe2x80x94Q,
(4) xe2x80x94C1-5 alkylxe2x80x94Oxe2x80x94Q, or
(5) xe2x80x94C1-5 alkylxe2x80x94Sxe2x80x94Q,
wherein the substituent resides on the alkyl and the substituent is C1-3alkyl;
(h) xe2x80x94Q
R4 and R4xe2x80x2 are each independently selected from the group consisting of
(a) hydrogen,
(b) CF3,
(c) CN,
(d) C1-6alkyl,
(e) xe2x80x94Q,
(f) xe2x80x94Oxe2x80x94Q;
(g) xe2x80x94Sxe2x80x94Q, and
(h) optionally substituted
(1) xe2x80x94C1-5 alkylxe2x80x94Q,
(2) xe2x80x94Oxe2x80x94C1-5 alkylxe2x80x94Q,
(3) xe2x80x94Sxe2x80x94C1-5 alkylxe2x80x94Q,
(4) xe2x80x94C1-3alkylxe2x80x94Oxe2x80x94C1-3alkylxe2x80x94Q,
(5) xe2x80x94C1-3alkylxe2x80x94Sxe2x80x94C1-3alkylxe2x80x94Q,
(6) xe2x80x94C1-5 alkylxe2x80x94Oxe2x80x94Q,
(7) xe2x80x94C1-5 alkylxe2x80x94S""Q,
wherein the substituent resides on the alkyl and the substituent is C1-3alkyl, and
R5, R5xe2x80x2, R6, R7 and R8 are each independently selected from the group consisting of
(a) hydrogen,
(b) C1-6alkyl,
or R5 and R6 or R7 and R8 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or7 atoms;
Q is CO2H, CO2xe2x80x94C1-4alkyl, tetrazolyl-5-yl, C(R7)(R8)(OH), or C(R7)(R8)(Oxe2x80x94C1-4alkyl);
provided that when Xxe2x80x94Yxe2x80x94Z is xe2x80x94Sxe2x80x94CR4xe2x95x90CR4xe2x80x2, then R4 and R4xe2x80x2 are other than CF3.
One Class within this embodiment are the compounds of formula I
or pharmaceutically acceptable salts thereof wherein:
Xxe2x80x94Yxe2x80x94Zxe2x80x94 is selected from the group consisting of xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5xe2x80x2)xe2x80x94 when side b is a double bond, and sides a and c are single bonds; and
R1 is selected from the group consisting of
(a) S(O)2CH3,
(b) S(O)2NH2,
R2 is selected from the group consisting of
(a) C1-6alkyl,
(b) C3, C4, C5, C6, and C7, cycloalkyl,
(c) heteroaryl
(d) benzoheteroaryl
(e) mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo,
(3) C1-6alkoxy,
(4) C1-6alkylthio,
(5) CN,
(6) CF3,
(7) C1-6alkyl,
(8) N3,
(9) xe2x80x94CO2H,
(10) xe2x80x94CO2xe2x80x94C1-4alkyl,
(11) xe2x80x94C(R5)(R6)xe2x80x94OH,
(12) xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94C1-4alkyl, and
(13) xe2x80x94C1-6alkylxe2x80x94CO2xe2x80x94R5;
R5, R5xe2x80x2 and R6 are each independently selected from the group consisting of
(a) hydrogen,
(b) C1-6alkyl,
or R5 and R6 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with C1-6alkyl including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, C1-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, C1-6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies xe2x80x94SCH2CH2CH3.
Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
Benzoheteroaryl includes the above heteroaryl rings to which it is possible to fuse a benzene ring.
Exemplifying the invention are:
(a) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,
(b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,
(c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,
(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene,
(e) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid,
(f) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole,
(g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one
(h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole,
(i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone,
(k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan,
(1) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene, and
(n) 3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,
(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(p) 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(q) 5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(t) 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(v) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(w) 3 -(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl)phenyl)-b 2-(5H)-furanone,
(y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
In a second embodiment, the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above.
Within this embodiment the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above.
In a third embodiment, the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases, advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1 as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
For purposes of this specification a compound is said to selectively inhibit COX-2 in preference to COX-1 if the ratio of the IC50 concentration for COX-1 inhibition to COX-2 inhibition is 100 or greater.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamnine, diethylamnine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolarnine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
The Compound of Formula I is useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. Compounds of formula I may also be useful for the treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer Disease (ie Alzheimer""s dementia).
Compounds of formula I will also be useful in the treatment of Stroke, cerebral ischemia and de-myelinating disorders.
Compounds of formula I will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
By virtue of its high cyclooxygenase-2 (COX-2) activity and/or its selectivity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1) as defined above, compounds of formula I will prove useful as an alternative to conventional non-steroidal antiinflammatory drugs (NSAID""S) particularly where such non-steroidal antiinflammatory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems (including those relating to reduced or impaired platelet function); kidney disease (eg impaired renal function); those prior to surgery or taking anticoagulants; and those susceptable to NSAID induced asthma.
Similarly, compounds of formula I, will be useful as a partial or complete substitute for conventional NSAID""S in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetominophen or phenacetin; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating or non-sedating antihistamine. In addition the invention encompasses a method of treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effect amount of the compound of Formula I, optionally co-administered with one or more ofsuch ingredients as listed immediately above.
Compounds of the present invention are inhibitors of cyclooxygenase-2 and are thereby useful in the treatment of cyclooxygenase-2 mediated diseases as enumerated above. This activity is illustrated by their ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Accordingly, in one assay, the ability of the compounds of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a compound of formula I. The IC50 values represent the concentration of inhibitor required to return PGE2 synthesis to 50% of that obtained as compared to the uninhibited control. Illustrating this aspect, we have found that the Compounds of the Examples are more than 100 times more effective in inhibiting COX-2 than they are at inhibiting COX-1. In addition they all have a COX-2 IC50 of 1 nM to 1 mM. By way of comparison, Ibuprofen has an IC50 for COX-2 of 1 mM, and Indomethacin has an IC50 for COX-2 of approximately 100 nM. For the treatment of any of these cyclooxygenase mediated diseases, compounds of formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.
As indicated above, pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc:, containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor.
From another aspect this invention provides the use of a COX-II inhibitor in the manufacture of a medicament for the treatment of neurodegenerative diseases including dementia, and in particular Alzheimers disease. Risk factors include those based on Apo lipoprotein genotype, age, Mild Cognitive Impairment and family History.
When used herein the term xe2x80x9ctreatingxe2x80x9d includes treatment of existing disease and prophylactic treatment of those at risk of developing the disease.
When used herein the term xe2x80x9cCOX-IIxe2x80x9d inhibitor means a compound able to inhibit human COX-II enzyme without causing relatively significant inhibition of human COX-I enzyme. Generally compounds which bind at least 10 times as well to COX-I receptors as to COX-II receptors (ie will have a IC50 COX-II receptor only one tenth the numerical value of the COX-I receptor) are chosen for use in the invention, more aptly 20 times as well, favourably 50 times as well most favourably at least 100 times as well, and preferably at least 10.00 times as well.
The COX-II inhibitors for use in this invention are most aptly those which are highly brain penetrant so that the maximum concentration of COX-II inhibitor after administration of the anti-neurodegenerative for example the anti-alzheimer effective dose of COX-II inhibitor is at least the binding IC50 value and preferably at least 10 times that value for example at least 100 times the binding IC50 value.
The COX-II inhibitor may be of any structural type other than a steroid. However, most aptly the COX-II inhibitor employed in this invention is not a carboxylic acid or a salt thereof. Most favourably it will possess a SO2CH3, NHSO2CH3, SO2NH2, SO2CHCH3 or like substituent on an aromatic ring especially on a phenyl ring.
Our investigations and statements made in the more recent of the following patents indicate that COX-II inhibitors may be found in U.S. Pat. Nos 4,375,479; 4,590,205; 4,820,827; 5,343,991; EP 0418845; WO 91/19708; WO 94/15932 and WO 94/13635. Each of the above documents is incorporated herein by cross reference.
Thus in one aspect this invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a patient therapeutically effective amount of a compound generically disclosed (and preferably a compound specifically described) in U.S. Pat. Nos. 4,375,479; 4,590,205; 4,820,827; 5,344,991; EP 0418845; WO 91/19708; WO 94/15932 or WO 94/13635 all of which are incorporated herein by cross reference.
The invention also provides the use of such compounds in the manufacture of a medicament for the treatment of neurodegenerative disease and in particular Alzheimers disease.
Favourably the COX-II inhibitor employed is one described in WO 94/26731 (published Nov. 24, 1994), WO 94/20480 (published Sep. 15, 1994), U.S. Pat. No. 5,436,265 (issued Jul. 25, 1995), WO 95/00501 (published Jan. 5, 1995) or WO 95/18799 (published Jul. 13, 1995) all of which are incorporated herein by cross reference.
The medicaments for treating neurodegenerative disease may be formulated as described in the aforementioned referenced documents. The medicament may be employed in the doses and regimens set out in the aforementioned referenced documents with respect to the treatment of diseases which benefit from the administration of a COX-II inhibitor.
It is a great advantage of this invention that treatment may be carried out without causing gastric side effects of the type that can occur when COX I inhibitors are used for prolonged periods. Since neurodegenerative diseases such as Alzheimers disease are generally progressive treatment may need to take place for a number of years. Thus the provision of medicaments which are surprisingly effective without any significant tendency to cause gastric side effects at the therapeutic dose is of great use particularly to the elderly. The use of medicaments of this invention for the treatment of patients who are asymptotic is also envisaged especially in those cases where genetic information suggests that the patient is likely to develop Alzheimers disease or other neurodegenerative disease especially those which may be termed dementia, for example senile dementia or pre-senile dementia.
Favourably this invention provides a method of treating neurodegenerative disease without any significant tendency to cause gastric side effects which comprises the oral administration of a pharmaceutical composition which comprises an effective amount of a COX-II inhibitor and a pharmaceutical acceptable carrier therefor.
Such a method is applicable to patients with overt symptoms of disease and is applicable without overt symptoms of the disease (asymptotic patients).
Generally the oral dosage form will be administered from 1 to 6 times per day. Preferably the oral dosage form will be administered once or twice per day.

Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases


The present invention provides a central current share coordinator for use with remotely and non-remotely controllable rectifiers coupled to an output bus. In one embodiment, the central current share coordinator includes a rectifier current resolver configured to determine an existing current share condition for the remotely and non-remotely controllable rectifiers. Additionally, the central current share coordinator also includes a load share adjuster coupled to the rectifier current resolver and configured to adjust an output current of the remotely controllable rectifiers toward a target current share distribution on the output bus.

Telecommunication and data switching systems are used to route tens of thousands of calls and data connections per second. The failure of such a system, due to either an equipment breakdown or a loss of power, is generally unacceptable since it would result in a loss of millions of voice and data communications along with its corresponding revenue. The traditionally high reliability of telecommunication systems, that users have come to expect, is partially based on the use of redundant equipment including power supplies.
Primary power is normally supplied through commercially available AC voltage. Should the AC voltage become unavailable due to an AC power outage or the failure of one or more of its associated components, a backup power capability supplies the needed voltages and currents to maintain operation of the system. This backup power capability can be provided by a battery plant, which generally includes a number of backup batteries as well as corresponding rectifying, inverting and associated power distribution equipment. The backup batteries provide power to the load in the event an AC power outage occurs. During normal operation, the backup batteries are usually maintained in a substantially fully-charged state to provide as long a duration for backup power as possible.
Multiple rectifier systems are connected to the battery plant's output bus to provide the needed load current by the telecommunication systems or other load equipment and maintain the battery charge, during these normal operating periods. These multiple rectifier systems may employ a disparate collection of rectifiers ranging from older embedded legacy rectifiers, whose output voltage and current values are not remotely controllable, to newly installed rectifiers that provide remote control capability of these functions.
The ability to determine how a load current will be shared between these multiple rectifier systems is an important consideration when loads are static. However, as loads become dynamic and the load current varies significantly, the question of how the load current is shared between multiple rectifier systems may become critical to efficient or even successful plant operation.
Older rectifier systems typically provide a manually-settable current share capability that accommodates load current sharing among only the older rectifier systems. Correspondingly, newer rectifier systems provide load current share capability among only the newer rectifier systems. However, the two types of rectifier systems do not provide a common current share, either by physical bus or otherwise, and are not currently able to actively current share. This is especially true when they are provided by different vendors.
Accordingly, what is needed in the art is a way to provide load current sharing between older and newer rectifier systems having differing load current share capabilities.

Central current share coordinator, method of current sharing and battery plant employing the same


A reinforcing tape for a slide fastener and a slide fastener having a pair of fastener tapes whose end portions are reinforced with the reinforcing tapes are disclosed. On the end portion of a fastener tape to which a pin-and-box separator of a slide fastener is fitted, a transparent film layer formed of a thermoplastic elastomer or a thermoplastic resin and a fiber reinforcement layer formed of either a reticular sheet of monofilaments or a thin-layer non-woven fabric of fibers manufactured from a thermoplastic resin of the same type as the transparent film layer are superposed through the medium of an adhesive layer, with the transparent film layer constituting itself a surface layer.

1. Field of the Invention
This invention relates to reinforcing structure for the end portions of fastener tapes in a separable slide fastener, and more particularly to a reinforcing tape or reinforcing sheet material to be attached fast to each of the end portions of fastener tapes, especially to the end portions of dyed fastener tapes, adapted for attachment thereto of a pin-and-box separator and a slide fastener provided with fastener tapes having the end portions thereof reinforced therewith.
2. Description of the Prior Art
The conventional reinforcing tapes to be applied fast to the end portions of dyed fastener tapes have included those which, for the sake of obviating the necessity of preparing reinforced tapes dyed specially in various colors matched to the colors of the aforementioned dyed fastener tapes and consequently saving such time and labor as would otherwise be incurred in the inventory control, use transparent synthetic resin films in a superposed manner so as to show the colors of the dyed fastener tapes therethrough. For example, the reinforcing piece which is formed of two superposed transparent synthetic resin films having different melting points and is adapted to be applied fast to a fastener tape by melting that of the two films having a lower melting point as disclosed in Japanese Utility Model Publication No. (hereinafter referred to briefly as "JUM-B-") 44-25,843 and the lateral application tape which is formed by superposing on one side of a transparent film of nylon 6 or nylon 66 a transparent polyester copolymer film having a melting point in the range of 80 to 200.degree. so as to show the color of the base fabric of the fastener tape therethrough as disclosed in published Japanese Patent Application, KOKAI (Early Publication) No. (hereinafter referred to briefly as "JP-A-") 62-149,780 have been known to the art.
Also JP-A-08-299,033 discloses a reinforcing tape which has a transparent elastomer film used for the obverse surface layer and an adhesive layer superposed on the reverse surface thereof and U.S. Pat. No. 3,490,970 discloses a method for reinforcing the end portions of fastener tapes by causing a wire mesh of metal or synthetic resin to adhere to at least one face of each of the fastener tapes by the use of a thermoplastic resin under application of heat and pressure.
Since the reinforcing tapes formed of two layers of synthetic resin film as are disclosed in JUM-B-44-25,843 and JP-A-62-149,780 mentioned above have the component layers thereof invariably formed of film, they are at a disadvantage in being deficient in torsional strength and transverse tensile strength (laterally drawing strength). Since they are hard from the material point of view, they cannot be easily shaped by bending in conformity with the shape of the core portion of the fastener tape and, for this reason, the core portion of the fastener tape is not easily formed accurately in contour thereof. Further, these reinforcing tapes have the problem that when they are repeatedly bent, the bent lines thereof ultimately cause whitening possibly to the extent of jeopardizing the appearance of the reinforcing tapes.
The reinforcing tape disclosed in JP-A-08-299,033 forms the surface layer with an elastomer film and, therefore, is at an advantage in exhibiting due flexibility and consequently allowing itself to be easily bent in conformity with the contour of the core portion of the fastener tape. Since the component layers of this reinforcing tape are formed of film, however, the reinforcing tape has room for further improvement in terms of torsional strength and transverse tensile strength.
The reinforcing tape disclosed in U.S. Pat. No. 3,490,970 which resorts to the combination of a thermoplastic resin with a wire mesh gains in rigidity and secures satisfactory strength owing to the wire mesh. It nevertheless is at a disadvantage in assuming a rigid constituent as a whole, suffering from insufficiency in flexibility, and consequently incurring difficulty in being shaped by the kind of bending which is mentioned above.


An improved magnetoelectric composite which incorporates LaSrMn or LaCaMn oxides as a magnetostrictive composition are described. The magnetostrictive composition preferably has the formula La0.7Sr0.3MnO3 or La0.7Ca0.3MnO3. The composites preferably have a magnetostrictive layer joined to a piezoelectric layer. The composites are useful for sensors, read-heads, storage media and high frequency transducer devices.

(1) Field of the Invention
The present invention relates to magnetoelectric composites and method for preparation thereof which incorporate lanthanum manganese strontium (LaSrMn) oxides or lanthanum manganese calium (LaCaMn) oxides as the magnetostrictive composition in the composite. The composites are in layers, with layers of piezoelectric compositions.
(2) Description of Related Art
In a single-phase material, ME effects require long range ordering of atomic moments and electric dipoles. There are few such material and the effect is often weak (Astrov, D. N., Soviet phys. JETP 13 729 (1961); Rado, G. T., et al., Phys. Rev. Lett. 7, 310 (1961); Foner, S., et al., J. Appl. Phys. 34 1246 (1963); and Kornev, I., et al., Phys. Rev. B 62, 12247 (2000)). For the engineering of materials with new or improved properties Van Suchtelen proposed product-property composites (Van Suchtelen, Philips Res. Rep., 27, 28 (1972)). For example, composites with magnetostrictive (m) and piezoelectric phases (p) are expected to be magnetoelectric because of mechanical stress mediated electromagnetic coupling. Most studies in the past focused exclusively on ferrite-PZT/BaTiO3 composites. Van den Boomgaard synthesized bulk composites of CoFe2O4/NiFe2O4 and BaTiO3 (Van den Boomgaard, J., et al., J. Mater. Sci. 9, 1705 (1974); Van den Boomgaard, J., et al., Ferroelectrics 14 727 (1976); and van den Boomgaard, J., et al., J. Mater. Sci. 13 1538 (1978)). The mixed oxides yielded ME coefficients much smaller than calculated values due to leakage currents through low resistivity ferrites and microcracks that resulted from mismatch of structural parameters and thermal properties. The problem with low resistivity ferrites can be eliminated in a layered structure. Theories predict a very large ME coefficient in a bilayer of p- and m-phases due to enhanced piezoelectricity, but measured values in CoFe2O4-PZT were small (Harshe, G., et al., Int. J. App Electromag. Mater. 4 145 (1993); Avellaneda, M., et al., J. Intell. Mater. Sys. Struc. 5, 501 (1994); and Harshe, G., Magnetoelectric effect in piezoelectric-magnetostrictive composites, PhD thesis. The Pennsylvania State University, College Park, Pa. (1991)). The inventor recently reported giant ME coefficients in bilayers and multilayers of nickel ferrite-PZT (Srinivasan, G., et al., Phys. Rev. B 64, 214408 (2001)), and a record high ME effect was reported very recently in trilayer composites of PZT with Terfenol-D (Ryu, J., et al., Jpn. J. Appl. Phys. 40, 4948 (2001)). The recent theoretical model for a ferrite-PZT bilayer predicts a strong ME effects at microwave frequencies (Bichurin, M. I., et al., Phys. Rev. B, 64 094409 (2001)). Lanthanum manganites with divalent substitutions have attracted considerable interest in recent years due to double exchange mediated ferromagnetism, metallic conductivity, and giant magnetoresistance (Ramirez, A. P., J. Phys.: Condens. Mater 9, 8171 (1997)). The manganites are potential candidates for ME composites because of (i) high magnetostriction and (ii) metallic conductivity that eliminates the need for a foreign electrode at the p-m interface.
The art of magnetoelectric composites is well developed as shown by U.S. Pat. Nos. 4,769,599 and 5,130,654 to Mermelstein, U.S. Pat. Nos. 5,512,196 and 5,856,770 to Mantese et al, U.S. Pat. No. 5,675,252 to Podney and U.S. Pat. No. 6,279,406 to Li et al. Additional art is shown in U.S. publications 2001/0040450 A1 and 2001/0028245 A1 to Li et al. What is apparent from this art is that while the concepts are well developed, the composites need an improvement in the magnetoelectric properties. All of these patents and applications are incorporated by reference herein.

Magnetoelectric effects of magnetostrictive and piezoelectric layered composites


A multi-purpose automobile lock, having a rod member and a catch structure with a side of one end of the rod member provided with an elongated channel in which are drilled several latching holes and tapped holes. At the other end of the rod member is disposed a hollow channel. The catch structure comprises a U type hook and a locking member, with the U type hook having at its center a tapped hole to lock in on the side of the channel. A pair of trapped holes are also provided on the lock. When both are latched, the channel is placed on the side of the steering wheel to achieve the summary lockup. This invention also permits the removal of the hook in order for the locking member to be screwed to the inner side of the channel. With the hollow channel at the other end of the rod member holding against the hand brake lever, and the hook latched to the shift lever, the device will lock up both the hand brake lever and the shift lever.

The present invention relates to a multi-purpose automobile lock, which is comprised of a rod member and a catch structure. A side of one end of the rod member defines a channel bored with several sets of latching holes. Both sides of the other end define a hollow channel. A catch structure comprised of a U type hook and a locking member with the former having at its center a tapped hole to lock in to a corresponding tapped hole in the channel. The buckling surface of the locking member is also disposed with a pair of tapped holes so as to be located to achieve easy lockup. The latching of locking member and hook causes the channel to hold firmly to the side of the steering wheel. This invention permits the hook to be removed and the locking member screwed to an inner portion of the channel while the hollow channel at the other end of rod member may be used to hold against the hand brake lever. The hook is used to lock the device to the hand brake.
The prior art parking lock (See FIG. 4) is provided with a sleeve (6) within which is fitted a sectional tube (7) having sectional openings (72). On one end of the sleeve (6) and on one end of the sectional tube (7) are disposed inverse retaining hooks (61, 71) respectively. A locking head (8) is provided at the end where sleeve (6) receives the sectional tube (7) to control the length of extension of the sectional tube (7) from the sleeve (6). In use, said lock is placed above the steering wheel (H) as retaining hooks (61, 71) respectively at the end of the sleeve (6) and of the sectional tube (7) are held against the inner sides of the steering wheel (H) before inserting the key into the locking head (8) to lock up. However, a burglar may use one end of a hollow steel pipe(S) to deform retaining hook (61). The retaining hook (61) thus will be damaged and lock removed (See FIG. 4-1). Alternatively, a burglar may use the sawing blade (J) or other tools to cut a small portion of the steering wheel (H) and use the retaining hooks (61, 71) to exert a force on the sleeve (6) or on the sectional tube (7) to easily disengage the retaining hooks (61, 71) from where the cut off occurs. Such has been the major defect of the prior art devices in practical use. Later in the market there has been available a device referred to as "Suspension Side Stopping Lock for Automobile Steering Wheel" (See FIG. 5). Said lock comprises a wrapping tube, one hinged leaf, a lock and a stopping lever. The wrapping tube forms a receiving trunk, one end of which is provided with a recess and a latching ridge is disposed on the side abutted to said recess. Further, an arc recess is formed at the opening end inner side of the tube axially connected to the receiving trunk. On another end, the receiving trunk is provided with a hinged leaf pivoted by means of a rivet, said leaf which closing upon the receiving trunk of the wrapping tube, forms a closed round tube while allowing the arc recess to become an open end. One bottom cover is disposed on the extending hinged leaf so that, when the leaf closes upon the receiving recess, said bottom cover is locked in a recess. A lock is fixed to the bottom cover with its latch extending into a latching ridge when locked up. The stopping lever is fixed to the opening end of the wrapping tube near the arc recess for stopping involved components of the vehicle when the wrapping tube revolves along with the steering wheel. Said lock uses essentially the receiving recess of the wrapping tube in conjunction with the shape of hinged leaf to close upon the steering wheel and uses the latch at the side of the wrapping tube to extend into the latching ridge in the corresponding position at the side of the hinged leaf and the latching catch locks to the latching ridge by turning the key. However, such lock is only applicable to the steering wheel. The present invention eliminates the aforesaid disadvantages.

Assembly optional multi-purpose automobile lock


System for producing diffusion-inhibiting epitaxial semiconductor layers, by means of which thin diffusion-inhibiting, epitaxial semiconductor layers can be produced on large semiconductor substrates at a high throughput.

Epitaxially deposited semiconductor layers, preferably of SiGe or Si, involving high and sharply delimited dopings, are increasingly used in the production of high frequency devices such as for example 1-heterobipolar transistors (HBT) and in CMOS circuits. Those highly doped layers involve the problem of diffusing out during subsequent process steps at elevated temperatures within the technological procedures involved and thus degradation of the electronic properties of those layers. In order to minimize those diffusion processes the temperatures have to be reduced and additional diffusion-inhibiting materials have to be employed.
WO 98/26457 describes how the diffusion of boron in SiGe is significantly suppressed by the use of an additional, electrically non-active material, preferably an element from the 4th main group, in particular carbon, in a concentration of between 1018 cm−3 and 1021 cm−3. The production of those epitaxial diffusion-inhibiting layers, preferably of SiGeC or SiC, is effected by molecular beam epitaxy (MBE) and primarily with chemical gaseous phase deposition (CVD) processes. As described in T. I. Kamins, D. J. Meyer, Appl. Phys. Lett., 59, (1991) 178; W. B. de Boer, D. J. Meyer, Appl. Phys. Lett. 58, (1991) 1286 and B. S. Meyerson, Appl. Phys. Lett. 48 (1986) 797, single-wafer and ultra-high-vacuum (UHV) batch reactors are used in conjunction with CVD processes. In the case of the single-wafer reactors, it can be detrimentally observed that those installations do not involve hot wall reactors, in other words in single-wafer reactors the wafers are very rapidly heated by means of radiant or induction heating, in which case neither the wafer nor the reactor goes into a condition of thermodynamic equilibrium.
Because of the necessary low deposition rates in the case of Si-, SiC-, SiGe- and SiGeC-low temperature epitaxy, only a low throughput rate is to be achieved with single-wafer reactors. For typical HBT stacks the throughput rate is for example about 5 wafers per hour. That is not economically viable for an industrial process.
The sole batch reactor which has been known hitherto is an UHV hot wall reactor which operates in the temperature range of between 400° C. and 800° C. and typically at 600° C. In those hot wall reactors the wafers are heated in small batches in a condition of thermodynamic equilibrium, whereby it is admittedly possible to achieve a substantially better level of temperature homogeneity, but the high expenditure linked to the UHV process has a disadvantageous effect on the throughput rate. Thus, all peripheral process times (for example pumping and flushing sequences, handling of the wafers and so forth) are substantially longer than for example with conventional low pressure (LPCVD) installations. Therefore, the throughput rate for typical HBT stacks in the case of that UHV batch reactor is in the range of the single-wafer reactors, that is to say about 5 wafers per hour. There is also the disadvantageous effect that, because of the UHV system, it is not possible to use very high temperatures (1000° C. and higher) and thus for example in the UHV batch reactor etching and baking processes can only be implemented at low temperatures. The low H2O/O2 residual content for low temperature epitaxy, which is achieved for UHV installations and which is represented as necessary, can also be achieved by suitable measures for non-UHV installations.
Low pressure (LP) batch reactors were hitherto not used for the production of diffusion-inhibiting semiconductor layers, in particular not those of SiGeC or SiC. The reason for this is on the one hand the fact that the low oxygen and moisture content required by the men skilled in the art for low temperature epitaxy in those installations was deemed not to be a feasible proposition. On the other hand, depletion effects occur in the gaseous phase in high temperature epitaxy in the batch reactors, and those effects result in inadequate homogeneity of the deposited layers on the substrates. Therefore single wafer reactors have gained general acceptance for high temperature epitaxy (T≧1000° C.). At low temperatures however kinetic effects dominate and transport-conditioned depletion is of subordinate significance in comparison with the influence of temperature homogeneity on layer homogeneity.

Method and device for the production of thin epitaxial semiconductor layers

Abstract: The surfaces of the semiconductor substrates to be coated are first cleaned, and the substrates are then heated in a low pressure batch reactor to a first temperature (prebake temperature). The surfaces to be coated are next subjected to a hydrogen prebake operation at a first reactor pressure. In the next step the semiconductor substrates are heated in a low pressure hot or warm wall batch reactor to a second temperature (deposition temperature) lower than the first temperature, and after a condition of thermodynamic equilibrium is reached the diffusion-inhibiting semiconductor layers are deposited on the surfaces to be coated in a chemical gaseous deposition process (CVD) at a second reactor pressure higher than, equal to or lower than the first reactor pressure.


A multi-layered circuit board is provided having a buried capacitive layer and a device-specific embedded, localized, non-discrete, and distributive capacitive element. A printed circuit board is provided including (1) a first dielectric layer, (2) a first conductive layer coupled to a first surface of the first dielectric layer, (3) a second conductive layer coupled to a second surface of the first dielectric layer, and (4) a localized distributive non-discrete capacitive element adjacent the first conductive layer, wherein the capacitive element occupies a region that approximately coincides with a location over which a device to be coupled to the capacitive element is to be mounted. The embedded, localized, non-discrete, and distributive capacitive element may provide device-specific capacitance to suppress voltage/current noise for a particular device.

In the art of circuit design and circuit board manufacturing, capacitors are commonly employed in order to reduce electromagnetic interference, decouple signals, reduce or dampen resonances, suppress current/voltage noise, improve signal quality, filter signals, and several further such purposes and/or functions. A distributed interplane capacitance (or buried capacitance) is typically formed between a power and ground plane to provide global power distribution network impedance improvements to the whole printed circuit board. In addition to distributed interplane capacitance, bypass capacitors are often used with specific devices. Typically, small-valued capacitors located near the power pins of an active device are employed for high-frequency decoupling (e.g., resonance dampening, noise suppression, etc.). For example, FIG. 1 illustrates a cross-sectional view of a prior art integrated capacitive laminate structure that uses a surface mounted bypass capacitor 110 to suppress current/voltage noise for an integrated circuit device 108. A printed circuit board 100 may include multiple layers 116 along with a first conductive layer 102, a second conductive layer 104, and a dielectric layer 106 sandwiched between the first conductive layer 102 and the second conductive layer 104 to create an integrated capacitive laminate. The IC device 108 is mounted to the printed circuit board 100. In order to supply additional capacitance to the IC device 108, above and beyond the capacitance provided by the integrated capacitive laminate, a discrete, surface mounted capacitor 110 is also mounted to the printed circuit board 100. To reach the surface mounted capacitor 110, an electrical path is formed from a first terminal 112 at the IC device 108, through the first conductive layer 102, to the discrete surface mounted capacitor 110, then to the second conductive layer 104, and to a second terminal 114 at the IC device 108.
When circuit board designers do not face space constraints on the surface of a circuit board, discrete capacitors are commonly mounted to the surface of the circuit board. However, with the increased complexity of circuits and the reduction in the size of electronic devices, the space on the surface of a circuit board is often limited and does not allow room to surface mount numerous capacitors. For instance, due to manufacturing constraints, a keep out zone is maintained around the IC device 108 where no surface mounted capacitors (or any other device) can be mounted. Adding surface mounted capacitors is further undesirable because, with the addition of each capacitor, vias and/or electrical paths have to be added that result in undesirable qualities, such as additional inductance and resistance. For example, FIG. 2 is a schematic circuit diagram of the prior art integrated capacitive laminate circuit of FIG. 1. The combined electrical effects of the discrete surface mounted capacitor 110 are illustrated by an equivalence circuit showing the capacitance 202, resistance 204, and inductance 206 associated with discrete capacitor 110. Additionally, the vias and electrical paths through the circuit board also contribute additional inductance 208 and 210. These additional capacitive, resistive, and inductive elements are undesirable because they, reduce bypass bandwidth, create resonances, noise, interference, and otherwise corrupt electrical signals.
Thus, integrated capacitive laminates have been developed, wherein a thin dielectric layer between two conductor foils provides distributive capacitance to the circuit and replaces one or more conventional discrete capacitors. U.S. Pat. No. 5,079,069 to Howard et al., for example, discloses a capacitive printed circuit board (PCB) that provides capacitance to a large number of devices by a sheet of dielectric material that is sandwiched between two sheets of conductive material. Howard, thus, discloses a PCB that provides capacitance to each individual device by a portion of the capacitor laminate proportional to the individual device and borrowed capacitance from other portions of the capacitor laminate, depending upon the random firing of the devices. The PCB disclosed by Howard et al., thus, allows many of the benefits of conventional, surface mounted capacitors, while preserving space on the surface of the circuit board because the capacitance is integrated to the layers of the PCB itself.
While PCBs using integrated capacitive laminates are disclosed by Howard et al., these are generally successful in providing capacitance to a number of devices. In certain applications the capacitance supplied by such integrated capacitive laminates is insufficient. For example, because of their potential for interference and noise, certain high power, high switching speed integrated circuit (IC) devices require capacitance that exceeds that which can be supplied by integrated capacitive laminates. Circuit designers, thus, are required to employ additional localized, surface mounted capacitors in order to provide sufficient capacitance for the IC device. Such localized, surface mounted capacitors, however, are undesirable for the reasons discussed above.
Others have sought to improve upon the integrated capacitive laminates. For example, U.S. Pat. No. 6,215,373 by Novak et al., discloses a system and method for stabilizing the impedance of a circuit board by adding an embedded electrical resistance about the periphery of the circuit board. While disclosing a system and method for stabilizing a circuit board's impedance, the '373 patent fails to disclose a system for providing localized capacitance to a specific device on a circuit board.
Another such system is disclosed by U.S. Pat. No. 6,441,313 by Novak. The '313 patent discloses an apparatus for reducing power plane resonances in an integrated capacitive laminate structure. The apparatus reduces power plane resonances by employing a lossy power distribution network that is formed by a pair of parallel planar conductors separated by a dielectric layer. The '313 patent, however, also fails to disclose a system for providing localized capacitance to a specific device on a circuit board.
Thus, there remains a long felt need in the art for a providing device-specific capacitance on a circuit board without utilizing surface space or increasing overall inductance.

Enhanced localized distributive capacitance for circuit boards


A fuel transfer tube is capable of being used reliably for transferring alcohol, gasoline, or the mixure thereof. The fuel transfer tube has a polyamide resin layer containing metaxylene group, thickness of which is 0.3mm or less, and a polyolefin resin layer. The tube is formed by simultaneous extrusion method.

1. Field of the Invention
The present invention relates to a tube for transferring alcohol, gasoline or the mixture thereof (hereinafter referred to as a fuel transfer tube).
2. Prior Art
As a tube for transferring alcohol media, for example, as shown in FIG. 6, a tube composed of a polyamide layer 9 and a polyolefin layer 9' disposed inside thereof has been known.
This type of tube is used as a transfer tube such as for transferring media of an automotive brake system (containing alcohol for an antifreeze purpose), and the presence of the polyolefin layer possessing alcohol resistance and impermeability brings about the exellent safety of the brake system as compared with conventional tubes made of polyamide.
However, the tests with the tube on tranferring alcohol and gasoline respectively alone, such as a gasoline permeability test and a moisture permeability test shown below, proved that the gasoline resistance of the tube was not favorable. These test methods and results are shown below.
The tube used in the tests measured 8 mm in outside diameter and 6 mm in inside diameter, and the polyamide layer 9 of the tube was 0.9 mm in thickness and the polyolefin layer 9' thereof was 0.1 mm in thickness.


The invention enables accessing and using a Voice over Internet Protocol network, and can use a standard telephone to automatically access a VoIP network. A first aspect of the invention uses an auto dialer to transmit digits, such as a network access number, an account number and a PIN, which remain unchanged from call to call made through a given network service provider. A second aspect of the invention provides a speed dial feature for placing VoIP telephone calls. Speed dial numbers are recorded in a VoIP service provider's database on a server, which is accessible through the Internet from a personal computer (PC) or a conventional telephone. A third aspect of the invention enables callers to complete calls from conventional telephones to personal computers connected to the Internet. The VoIP network detects a flag such as leading “0,” determines that the call recipient station is a personal computer, looks up the IP address of the PC and routes the call to the PC.

When making a telephone call over a conventional Public Switched Telephone Network (PSTN), a caller uses a touch-tone telephone keypad to enter a telephone number typically consisting of eleven digits for a long distance call within the United States, or other numbers of digits in some foreign countries, which identify the call recipient. Using the number entered, the PSTN identifies the caller, sets up the telephone connection, manages the call and charges the call to the caller's or subscriber's account. The PSTN identifies the caller by identifying the telephone line used to make the call, which is assigned to a specific subscriber. However, in Internet telephony systems, callers typically are not identified by the line they call from, so they must supply this information to make VoIP telephone calls.
In order to supply account information before a telephone call can be made over a VoIP network, callers have been required to input a long series of digits by a procedure as for example illustrated in FIG. 1A. A conventional telephone handset is picked up to initiate a VoIP call. In step 110 the caller uses the telephone keypad or a computer keyboard to enter an access number of an Internet calling service, which could be a local number or a toll free national access number. Typically, in the U.S. this is an eleven digit telephone number such as 1-800-555-1234. Once a connection is established to the service, the caller in step 120 enters an account number of, say, eleven digits, followed in step 130 by entering a personal identification number (PIN) of, say, four digits. Finally, in step 140, the caller enters the desired recipient's eleven digit (or other length, depending on the country,)-telephone number. This method of making a VoIP call from a regular telephone requires callers to enter a total of approximately thirty-seven digits.
Callers accustomed to making conventional telephone calls by entering eleven digits view entering thirty-seven digits as tedious and are discouraged from using VoIP networks to make telephone calls. Therefore, a method of reducing the number of digits that are entered when placing a VoIP telephone call is needed.
Auto dialers, as shown in FIG. 1B, have been used to address the task of repeatedly transmitting strings of digits. VoIP telephone calls have the problem that only the portion of the string corresponding to the network access number, account number and PIN number is the same for all calls through a given service provider, whereas the portion corresponding to the recipient's telephone number differs for each recipient. Although auto dialer 150 has the ability to store and transmit programmed strings of digits, it does not have the flexibility to automatically modify an existing string of VoIP logon digits by appending a different telephone number string for each call recipient. It would be inefficient to have the caller program the auto dialer with the same logon string and a different telephone number string for every new call made. Also, the storage capacity of auto dialers is finite and incrementally costly.
Furthermore, when making a VoIP telephone call it. is insufficient to transmit just a string of numbers and be done. Often the caller must transmit some digits, wait for a handshake signal. from the IP network, transmit the next set of digits, and so on, until a connection is established. A conventional auto dialer 150 does not have the ability to interact with a communications network in this smart fashion. Therefore, there is a need for a smart auto dialer which can automatically modify a string of digits according to a user's input, transmit that string of digits and interact with the communications network to establish communications.

This patent is subject to a terminal disclaimer.

Method and system for routing calls from a standard telephone device to a voice over internet protocol network


A quick release anchor mechanism for tying objects to a surface. The anchor mechanism includes a bottom plate secured to a surface by a pair of riser bolts. A mounting platform defined to include a base plate with keyhole slots to fit into the riser bolts, a body extending from the base plate to a loop for attaching objects thereto, and a nape extending from the body. The nape having a spring loaded pin system that is configured to releaseably connect the mounting platform to the bottom plate.

The present invention relates generally to anchor mechanism used to tie items in place to help avoid the items being damaged when moved or tied down.
More particularly, this invention pertains to a quick release anchor mechanism that can be secured to a surface and that can be used with a latch to tie an item in place. When used as a pair positioned on either side of the item, such as a motorcycle, the quick release anchor mechanism is configured to secure the item in place. This particularly works well when the item is being transported in a trailer, truck or any other place cargo needs to be restrained.
Prior art tie downs exist but do not provide for the versatility provided in the present invention. Other tie downs require a portion of the surface to be cut or carved out for the proper fitting of the tie down base. Yet additional tie down anchor systems do not employ a keyhole slot and a spring-loaded locking pin in combination to provide a versatile product, meaning the prior art anchor system once installed cannot be easily moved to another location in the same manner.


A processing system for an input device includes a transmitter module including transmitter circuitry, a receiver module, and a determination module. The transmitter module is configured to drive the transmitter electrode with a first drive signal to produce a first voltage gradient across the transmitter electrode, wherein the first voltage gradient is non-linear. The receiver module is configured to receive a first resulting signal with a receiver electrode, the resulting signal comprising effects of the first voltage gradient. The determination module is configured to determine positional information for a plurality input objects located simultaneously within a sensing region along the transmitter electrode based on the first resulting signal.

Input devices including proximity sensor devices (also commonly called touchpads or touch sensor devices) are widely used in a variety of electronic systems. A proximity sensor device typically includes a sensing region, often demarked by a surface, in which the proximity sensor device determines the presence, location and/or motion of one or more input objects. Proximity sensor devices may be used to provide interfaces for the electronic system. For example, proximity sensor devices are often used as input devices for larger computing systems (such as opaque touchpads integrated in, or peripheral to, notebook or desktop computers).
Gradient sensors are sensors that employ a voltage variation across one or more electrodes (usually a transmitter electrode) to assist in determining positional information. While gradient sensors are advantageous in a number of respects, there remains a need for gradient sensors capable of simultaneously sensing more than one input object present within a sensing region.

System and method for sensing multiple input objects with gradient sensor devices


Disclosed herein are systems, methods, and non-transitory computer-readable storage media for presenting a machine translation and alternative translations to a user, where a selection of any particular alternative translation results in the re-ranking of the remaining alternatives. The system then presents these re-ranked alternatives to the user, who can continue proofing the machine translation using the re-ranked alternatives or by typing an improved translation. This process continues until the user indicates that the current portion of the translation is complete, at which point the system moves to the next portion.

Additional features and advantages of the disclosure will be set forth in the description which follows, and in part will be understood from the description, or can be learned by practice of the herein disclosed principles. The features and advantages of the disclosure can be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features of the disclosure will become more fully apparent from the following description and appended claims, or can be learned by the practice of the principles set forth herein.
Disclosed are systems, methods, and non-transitory computer-readable storage media for presenting a machine translation and alternative translations to a user, where a selection of any particular alternative translation results in the re-ranking of the remaining alternatives. The system then presents these re-ranked alternatives to the user, who can continue proofing the machine translation using the re-ranked alternatives or by providing an improved or alternate translation. This process continues until the user indicates that the current portion of the translation is complete, at which point the system moves to the next portion. The determination that a portion is complete can be decided by direct or indirect input from the user, upon reaching a certain level of confidence, or receiving confirmation from the user that each portion is translated correctly.
As an example, a system configured to practice the method of this disclosure generates a machine translation of a source text as well as a list of alternative translation possibilities. The system then ranks the list of alternative translation possibilities and presents the machine translation and the alternative translation possibilities to a user, who selects the machine translation or one of the alternatives as the preferred translation, or enters a their own translation. The user can be a participant in a collaborative translation of the source text with at least one other human and/or computer-based entity. If the user selects one of the alternative translations listed, the system re-orders or recreates the alternative translations list in a new order based on the user selection.

System and method for collaborative language translation


A package structure integrating a start-up component, a controller, and a power switch for a power converter, wherein the power converter has a coil having a first end and a second end, and the first end is coupled to a rectifier, the package structure including: a first die pad for carrying a chip of the controller; a second die pad for carrying a chip of the start-up component and a chip of the power switch, wherein the chip of the start-up component has a bottom surface providing a first drain contact; and the chip of the power switch has a bottom surface providing a second drain contact; and a plurality of external connection leads, of which one is connected with the second die pad via a wire and is used to couple with the second end of the coil.

1. Field of the Invention
The present invention relates to a package structure of a controller module for power conversion applications, especially to a package structure of a controller module including a start-up component, a controller, and a power switch.
2. Description of the Related Art
Please refer to FIG. 1a, which illustrates a circuit diagram of a prior art power converter, and FIG. 1b, which illustrates the package structure of a controller module applicable in the prior art power converter of FIG. 1a. As illustrated in FIG. 1a, the prior art power converter includes a PWM (pulse width modulation) controller 100, a first NMOS (n type metal oxide semiconductor) transistor 110, a second NMOS transistor 120, a primary coil 130 for transferring power to a load, and an auxiliary coil 140 for generating a supply voltage VCC; and in FIG. 1b, the controller module is in the form of an integrated circuit package having a package structure integrating a chip 100c of the PWM controller 100, a chip 110c of the first NMOS transistor 110, and a chip 120c of the second NMOS transistor 120 of FIG. 1a.
The PWM controller 100 has two contacts for connecting with the first NMOS transistor 110, one contact for connecting with the supply voltage VCC, and one contact for providing a PWM signal VPWM to switch on/off the second NMOS transistor 120 for realizing a power conversion.
The first NMOS transistor 110, having a first drain coupled to a first end A of the primary coil 130, a first gate connected to one contact of the PWM controller 100, and a first source connected to another contact of the PWM controller 100, is used as a start-up component, which is switched on to provide a current path for starting up the PWM controller 100 during an initial period after an AC power VAC is applied, and is switched off by the PWM controller 100 when the supply voltage VCC is built up. That is, when the supply voltage VCC reaches a predetermined level, the PWM controller 100 will send a low voltage to the first gate of the first NMOS transistor 110 to switch off the first NMOS transistor 110.
The second NMOS transistor 120, acting as a power switch, has a second drain coupled to a second end B of the primary coil 130, a second gate coupled with the PWM signal VPWM, and a second source connected with a current sensing resistor for generating a current sensing signal VCS according to a primary current IP. The second NMOS transistor 120 controls an on period for the primary current IP to flow through the primary coil 130 in response to the PWM signal VPWM.
The package structure in FIG. 1b includes the chip 100c of the PWM controller 100, the chip 110c of the first NMOS transistor 110, the chip 120c of the second NMOS transistor 120, a resin material 200, a first die pad 210, a second die pad 220, a third die pad 230, and eight external connection leads.
The resin material 200 is used to enclose the chip 100c of the PWM controller 100, the chip 110c of the first NMOS transistor 110, the chip 120c of the second NMOS transistor 120, the first die pad 210, the second die pad 220, and the third die pad 230.
The first die pad 210 is made of a conductor, copper for example, for carrying the chip 110c of the first NMOS transistor 110. The chip 110c of the first NMOS transistor 110 has a top surface providing a gate contact G1 and a source contact S1, and a bottom surface providing a drain contact D1 which is electrically connected with the first die pad 210.
The second die pad 220 is made of a conductor, copper for example, for carrying the chip 100c of the PWM controller 100.
The third die pad 230 is made of a conductor, copper for example, for carrying the chip 120c of the second NMOS transistor 120. The chip 120c of the second NMOS transistor 120 has a top surface providing a gate contact G2 and a source contact S2, and a bottom surface providing a drain contact D2 which is electrically connected with the third die pad 230.
The interconnections among the chip 100c, the chip 110c, the chip 120c, and the external connection leads are accomplished by wires, which can be made of copper, gold, or aluminum. As can be seen in FIG. 1b, a wire 251 connects the first die pad 210 with an external connection lead 241 of the eight external connection leads, and a wire 252 connects the third die pad 230 with an external connection lead 242 of the eight external connection leads, wherein the external connection lead 241 is used to connect electrically with the first end A of the primary coil 130, and the external connection lead 242 is used to connect electrically with the second end B of the primary coil 130.
As the die pads constitute a substantial portion of the cost of the package structure of the controller module, it is therefore desirable to reduce the number of die pads to promote the market competition ability of the controller module. However, as can be seen in FIG. 1a and FIG. 1b, the first die pad 210, the second die pad 220, and the third die pad 230 all seem to be necessary for implementing the controller module. For example, if we put the chip 110c and the chip 120c into one die pad to save one die pad, then the drain contact D1 will be in direct electrical contact with the drain contact D2, making the power module not applicable for the prior art power converter of FIG. 1a. Therefore, it is not easy to reduce the cost of the package structure of the controller module for power converters.

Package structure integrating a start-up component, a controller, and a power switch


An electrical connector assembly having a first electrical connector or header including a base and a shroud extending therefrom. The shroud defines a first opening arranged opposite the base and a second lateral opening defined between two ends thereof. A second or mating connector of the assembly includes a mating end received within the first opening of the shroud in an insertion direction. A body of the second electrical connector is received within the second lateral opening of the shroud and includes a pair of covers or hoods with channels for receiving and mechanically joining the two ends of the shroud.

Electronic components are often housed or packaged separately from a remainder of a larger electrical system in which they are utilized, promoting ease of integration and improved protection of sensitive components from harsh environmental conditions. As a result, the components must be electrically interconnected with other elements of the system. These connections are often implemented via wires or cables joining various components using complementary electrical connectors or connector assemblies, including device-mounted headers. Headers and associated mating connectors may be directional in nature, or configured to connect to a corresponding mating electrical connector such that an angular conducive pathway is realized (e.g., a right-angle or 90-degree connector assembly).
Due to packaging considerations and space constraints, it is important to minimize the size of these connector assemblies, and in particular, their profile or stand-off height from a mounting surface of the header. Achieving a low profile or low overall height, however, typically reduces retention forces between respective mated connectors, in part due to their minimal engagement length and associated reduction in engagement friction. As a result, headers typically utilize four-sided shrouds for increasing mating connector stability and retention, and/or supplemental locking features such as locking levers. However, these features add additional size, especially height, complexity and/or cost to the assemblies.
Accordingly, there is a need for improved electrical connector assemblies that remain compact, while providing sufficient stability and retention force without the need for complex locking provisions of the use of enclosed shrouds.


An image sensor includes a substrate having an active pixel sensor region defined therein, a plurality of first conductivity type photodiodes formed in the active pixel sensor region and a first conductivity-type first deep well formed in the active pixel sensor region in a location which does not include the plurality of the first conductivity-type photodiodes. Moreover, the first deep well is electrically connected to a positive voltage.

1. Technical Field
The present disclosure relates to an image sensor and a fabrication method thereof, and more particularly to an image sensor having reduced crosstalk between pixels, and a fabrication method thereof.
2. Description of the Prior Art
An image sensor is a device that may convert optical images into electrical signals. The demand for devices with image sensors having improved performance such as, for example, digital cameras, camcorders, PCSs (Personal Communication Systems), gang machines, security cameras, micro-cameras for medical applications, and robots has increased.
A metal oxide semiconductor (MOS) image sensor is driven in a simple and relatively easy manner and can be embodied using various scanning methods. Also, MOS processing technology allows for the miniaturization of products and also reduces production costs because signal processing circuits can be integrated onto a single chip. Moreover, MOS image sensors have very low power consumption, and thus can be applied to products having limited battery capacity. Furthermore, with MOS image sensors high resolution may be achieved for products used in conjunction therewith. Accordingly, the demand for the MOS image sensor is increasing.
The pixel of the MOS image sensor photoelectrically converts incident light to accumulate charges corresponding to the amount of the light in a photodiode, and then reproduces image signals in a read-out operation. However, the charges produced by incident light may not accumulate in the photodiode of the corresponding pixel, but may instead move to and accumulate in the photodiode of an adjacent pixel, causing crosstalk between pixels.
As shown in FIG. 1, crosstalk between pixels can be divided into two categories: optical crosstalk A and electrical crosstalk B. For example, optical crosstalk A refers to when light incident through a microlens and/or a color filter is not transferred to a desired pixel, but is instead transferred to the photodiode of an adjacent pixel due to refracted light resulting from refraction from the following surfaces: (a) the surface of a multilayer structure consisting of interlayer insulating films 3, 4 and 5 having different refractive indexes, (b) the surface of non-uniform films, or (c) reflected light 6 resulting from reflection from the upper or side surface of metal interconnections M1, M2 and M3. Next, electrical crosstalk B refers, for example, to when charges produced in the bottom or side of a photodiode are transferred to the photodiode 2 of the adjacent pixel due to long-wavelength incident light 7.
When crosstalk occurs, in the case of black and white image sensors, the distortion of images can occur due to a reduction in resolution. Also, in the case of color image sensors including a color filter array (CFA) having red, green and blue filters, the possibility of crosstalk due to incident long-wavelength red light is higher, thereby possibly resulting in poor tint. In addition, a blooming phenomenon, in which adjacent pixels in a picture become hazy, may also occur.
Thus, there is a need for an improved image sensor which provides reduced crosstalk between pixels and for a method of fabricating the same.

Image sensor and fabrication method thereof


In a method for manufacturing sawtooth card clothings and all-steel card clothings for processing textile fibers in a carding process, a sawtooth wire is produced by generating teeth on a wire blank sequentially behind one another in a longitudinal direction of the wire blank, wherein the teeth extend transversely to the longitudinal direction away from a base area. The sawtooth wire is subjected at least in the area of the teeth to a hardening process under exclusion of oxygen in the area of the sawtooth wire. A device for performing the method has a heating chamber having an inlet opening and an outlet opening for the sawtooth wire passing through the heating chamber. An arrangement for generating an inert gas atmosphere in the area of the sawtooth wire passing through the heating chamber is provided.

1. Field of the Invention
The invention relates to a method for manufacturing sawtooth card clothing and all-steel card clothing for processing textile fibers, in particular, in connection with a carding process. According to the method, a wire blank is provided with teeth sequentially arranged in a longitudinal direction of the wire and extending, starting at the base area, transversely to the longitudinal direction and the sawtooth wire generated accordingly is subjected, at least in the area of the teeth, to a hardening process. The invention also relates to a device for performing such a method as well as to sawtooth wire manufactured by such a method.
2. Description of the Related Art
Sawtooth wires that are manufactured by methods of the aforementioned kind from unalloyed or alloyed steels are used, for example, in cards for treating textile fibers. For this purpose, the sawtooth wires can be mounted, for example, in a coil shape on a circular cylinder support (tambour) of the card.
In modern cards, sawtooth wire having a length of several kilometers is required for producing the sawtooth card clothing or all-steel (metal) card clothing for the tambour of a card. For processing textile fibers, the tambour of the card with the wire card clothing disposed thereon is rotated about its cylinder axis so that the card clothing can pass through and clean fiber material supplied to the tambour; the tambour card clothing cooperates with stationary or oppositely driven flat cards each provided with an appropriate flat card clothing. In this type of fiber processing, for obtaining a satisfactory carding result and for preventing damage to the card it must be ensured that the sawtooth wires are mounted with high precision in such a way on the circular cylinder support that no changes of the radial spacing of the sawtooth wire tips from the axis of rotation of the tambour will result that would negatively affect the carding result or the operating reliability; even local imprecisions resulting during mounting of the wire on the tambour can cause damage of the thus formed sawtooth card clothing and all-steel card clothing that may require a complete exchange.
This is very cost-intensive in modern high-performance cards with regard to the downtimes of the machine and the required materials. Moreover, in the context of ensuring a satisfactory carding quality a random axial displacement of sequentially arranged windings must be prevented also. Moreover, for obtaining a satisfactory service life of a card, it must be ensured that an excessive wear of the sawtooth wires is prevented. For this purpose, the teeth of the sawtooth wires to be mounted on the tambour are subjected to a hardening process. For example, they can be heated by means of an open flame to their austenization temperature, respectively, and can be subsequently quenched.
In particular when heating the wire a scale or oxide layer of varying thickness can form on the wire. Such a layer presents a particular problem in regard to the required precision of the card clothing mounted in a coil shape on the support. The sawtooth wire is mounted on the rotating support by means of a wire mounting device. For ensuring the required wire mounting precision, the wire must pass through narrow guides. During this process, as a result of bending and friction of the wire in the guides, scale particles can chip off the wire surface and deposit in the mounting device and especially in the guides. Such contamination of the guides can greatly affect the wire mounting quality and the speed at which wire mounting is carried out. Moreover, because of the scale particles chipping off, it can be required to frequently interrupt the wire mounting process in order to clean the wire mounting device and, in particular, its guides. If these cleaning interruptions are not performed timely, the pulling forces acting on the wire that increase because of increasing contamination of the guides can rise to such an extent that the wire will break
In regard to these problems it has been proposed already to remove after the hardening process the scale or oxide layers produced during hardening. For this purpose, abrasive methods are known, for example, in which the wires after the hardening process are brushed with rotating metal brushes so that the adhering scale is removed as much as possible. In another method, the wire is ground by profiled grinding wheels for removing the scale layer. Finally, chemical methods are also known for removing the scale layer chemically.
However, the methods for removing the scale layer that have been proposed in view of the above mentioned problems have the disadvantage that as a result of the mechanical or chemical material removal the wire itself is also damaged to a greater or lesser degree. Moreover, the removal of the scale layer done to avoid the problems in regard to mounting the wire can also lead to the flanks and tips of the teeth of the sawtooth wire to become rounded so that the teeth lose some of the desired sharpness.

Method and device for manufacturing sawtooth card clothing and all-steel card clothing as well as sawtooth wire