The present invention relates to certain imine-substituted heterocyclic compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.

1. Field of the Invention
The present invention relates to certain imine-substituted heterocyclic compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.
2. Background
Nerve cell death (degeneration) can cause potentially devastating and irreversible effects for an individual and may occur e.g. as a result of stroke, heart attack or other brain or spinal chord ischemia or trauma. Additionally, neurodegenerative disorders involve nerve cell death (degeneration) such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Down""s Syndrome and Korsakoff""s disease.
Therapies have been investigated to treat nerve cell degeneration and related disorders, e.g., by limiting the extent of nerve cell death that may otherwise occur to an individual. See, e.g., N. L. Reddy et al., J. Med. Chem., 37:260-267 (1994); and WO 95/20950.
The compound MK-801 has exhibited good results in a variety of in vivo models of stroke. See B. Meldrum, Cerbrovascular Brain Metab. Rev., 2:27-57 (1990); D. Choi, Cerbrovascular Brain Metab. Rev., 2:105-147 (1990). See also Merck Index, monograph 3392, 11th ed., 1989. For example, MK-801 exhibits good activity in mouse audiogenic tests, a recognized model for evaluation of neuroprotective drugs. See, e.g., M. Tricklebank et al., European Journal of Pharmacology, 167:127-135 (1989); T. Seyfried, Federation Proceedings, 38(10):2399-2404 (1979).
However, MK-801 also has shown toxicity and further clinical development of the compound is currently uncertain. See J. W. Olney et al., Science, 244:1360-1362 (1989); W. Koek et al., J. Pharmacol. Exp. Ther., 252:349-357 (1990); F. R. Sharp et al., Society for Neuroscience Abstr., abstr. no. 482.3 (1992).
It thus would be highly desirable to have new neuroprotective agents, particularly agents to limit the extent or otherwise treat nerve cell death (degeneration) such as may occur with stroke, heart attack or brain or spinal cord trauma, or to treat neurodegenerative disorders such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Down""s Syndrome and Korsakoff""s disease.
In a first aspect, the present invention provides imine-substituted compounds of the following Formula I:
wherein Z is sulfur, oxygen, carbon or nitrogen;
m and n are each independently an integer from 0 to 4, and the sum of m and n is at least 2, preferably is 3, 4, 5 or 6, more preferably 3, 4 or 5;
each X is independently substituted or unsubstituted alkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsilyl preferably having 1 to about 20 carbon atoms and 1 or more Si atoms; substituted or unsubstituted alkenyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy preferably having from 1 to about 20 carbon atoms, including haloalkoxy; substituted or unsubstituted alkylthio preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylamino preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl preferably having at least about 6 ring carbon atoms; substituted or unsubstituted aralkyl preferably having from 7 to about 18 carbons; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
p is an integer equal to 0 (where the ring is substituted only by the depicted xe2x80x94C(xe2x95x90NH)NH2 substituent) to 14, more typically from 0 to about 4; and pharmaceutically acceptable salts thereof.
Substituted or unsubstituted methylene (xe2x80x94CH2xe2x80x94) is a generally preferred Z ring member. Generally preferred X groups include substituted and unsubstituted alkyl, substituted and unsubstituted alkylsilyl, substituted and unsubstituted alkenyl, substituted and unsubstited alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylsulfinyl, substituted and unsubstituted alkylsulfonyl, substituted and unsubstituted aralkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaromatic or heteroalicyclic groups.
Particularly preferred X groups included substituted and unsubstituted alkyl and substituted and unsubstituted carbocyclic aryl, particularly substituted and unsubstituted naphthyl or phenyl such as naphthyl or phenyl substituted by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio and ethylthio, and alkylsilyl preferably having 1 to about 15 carbon atoms.
It is understood that the imine-substituted ring nitrogen shown in the above formula generally would not be substituted by an X group. It is further understood that the ring methylene (CH2) groups (which include Z where Z is carbon) of the above Formula I will include only a single hydrogen if the methylene unit is mono-substituted by an X group, i.e. the methylene unit will be (CHX), or the methylene unit will contain no hydrogens if di-substituted by X groups, i.e. the methylene unit will be (CXX). It is also understood the range of p values will depend in part on the sum of m and n as well as the valence of the Z ring substituent. Thus, for example, if the sum of m and n is 4 and without limitation on the Z ring member, p will be an integer of from 0 to 10, but if Z is specified to be oxygen, then p will be an integer of from 0 to 8, or if Z is nitrogen then p will be an integer of from 0 to 10.
Generally preferred compounds of Formula I include six-member ring compounds (i.e. where the sum of m and n above is four), particularly compounds of the following Formula Ia:
wherein Z and X are each the same as defined above for Formula I; pxe2x80x2 is an integer of from 0 (where the ring is substituted only by the xe2x80x94C(xe2x95x90NH)NH2 substituent) to 10, more typically from 0 to about 4; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula I are substituted piperidines of the following Formula Ib:
wherein X is the same as defined above for Formula I; pxe2x80x3 is an integer of from 0 (where the ring is substituted only by the depicted imine) to 10, more typically from 0 to about 4; and pharmaceutically acceptable salts thereof.
Preferred compounds of the invention have at least two ring substituents (pxe2x89xa72 in Formula I), particularly 2,6-substituted compounds of Formula Ia, such as the following substituted piperidine compounds of Formula Ic:
wherein W and Y are each independently substituted or unsubstituted alkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsilyl preferably having 1 to about 20 carbon atoms and 1 or more Si atoms; substituted or unsubstituted alkenyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy preferably having from 1 to about 20 carbon atoms, including haloalkoxy; substituted or unsubstituted alkylthio preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl preferably having at least about 6 ring carbon atoms; substituted or unsubstituted aralkyl preferably having from 7 to about 18 carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; and pharmaceutically acceptable salts thereof.
Generally preferred W and Y groups include substituted and unsubstituted alkyl, substituted and unsubstituted alkylsilyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylsulfinyl, substituted and unsubstituted alkylsulfonyl, substituted and unsubstituted aralkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaromatic or heteroalicyclic groups.
Particularly preferred W and Y groups included substituted and unsubstituted alkyl and substituted and unsubstituted carbocyclic aryl, particularly substituted and unsubstituted naphthyl or phenyl such as naphthyl or phenyl substituted by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio, and alkylsilyl preferably having 1 to about 15 carbon atoms.
In a second aspect, imine-substituted compounds are provided that are substituted by a group other than hydrogen on the imine or adjacent non-cyclic nitrogen. Preferred are compounds of the following Formula II:
wherein Z, X, p, m and n are the same as defined above for Formula I; R, R1 and R2 are each independently hydrogen; hydroxy; substituted or unsubstituted alkanoyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkanoyloxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylamino preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R, R1 and R2 being other than hydrogen; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula II include six-member ring compounds (sum of m and n above is four), particularly compounds of the following Formula IIa:
wherein Z and X are each the same as defined above for Formula I; p is an integer of from 0 to 10, more typically 0 to about 4; R, R1 and R2 are each the same as defined above for Formula II; and pharmaceutically acceptable salts thereof. Substituted piperidine compounds are generally preferred, i.e. where Z is carbon.
Also preferred are compounds of Formula II that have at least two ring substituents (p greater than 2 in Formula II), particularly 2,6-substituted compounds of Formula IIa, such as the following piperidine compounds of Formula IIb:
wherein W and Y are the same as defined above for Formula Ic; R, R1 and R2 are each the same as defined above for Formula II; and pharmaceutically acceptable salts thereof.
Generally preferred X, W and Y groups of compounds of Formula II, IIa and IIb include substituted and unsubstituted alkyl, substituted and unsubstituted alkylsilyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylsulfinyl, substituted and unsubstituted alkylsulfonyl, substituted and unsubstituted aralkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaromatic or heteroalicyclic groups.
Particularly preferred X, W and Y groups of compounds of Formula II, Ia and IIb include substituted and unsubstituted alkyl and substituted and unsubstituted carbocyclic aryl, particularly substituted or unsubstituted naphthyl or phenyl such as naphthyl or phenyl substituted by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio or ethylthio, and alkylsilyl preferably having 1 to about 15 carbon atoms.
Preferred R and R1 groups of compounds of Formulae II, IIa and IIb include substituted and unsubstituted carbocyclic aryl and heteroaromatic and heteroalicyclic groups. Particularly preferred R and R1 groups are substituted and unsubstituted naphthyl and phenyl groups, such as naphthyl or phenyl substituted at one or more ring positions by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio. Other preferred R and R1 groups include hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylsulfinyl, alkylsulfonyl, substituted or unsubstituted alkanoyl and substituted or unsubstituted alkanoyloxy. Generally preferred are compounds of Formulae II, IIa and IIb are those where at least of one of R and R1 is other than hydrogen, and R2 is hydrogen.
As with compounds of Formula I, it is understood with respect to the compounds of Formula II that the depicted imine-substituted ring nitrogen would not be substituted by an X group. It is further understood that the ring methylene groups (CH2) of the above Formula II will include only a single hydrogen if the methylene unit is mono-substituted by an X group, i.e. the methylene unit will be (CHX), or the methylene unit will contain no hydrogens if di-substituted by X groups, i.e. the methylene unit will be (CXX). It is also understood the range of p values will depend in part on the sum of m and n as well as the valence of the Z ring substituent.
The invention also includes both racemic mixtures and optically enriched mixtures of chiral compounds of the invention. An optically enriched mixture contains substantially more (e.g. about 60%, 70%, 80% or 90% or more) of one enantiomer or diastereoisomer than the other stereoisomer(s). Preferred optically enriched mixtures contain 97% or more, more preferably 98% or more, even more preferably 99% or more of one enantiomer or diastereoisomer than the other stereoisomer(s).
Compounds of the invention are useful for a number of therapeutic applications. In particular, the invention includes methods for treatment and/or prophylaxis of neurological conditions/injuries such as epilepsy, neurodegenerative conditions and/or nerve cell death (degeneration) resulting from e.g. hypoxia, hypoglycemia, brain or spinal chord ischemia, retinal ischemia, brain or spinal chord trauma or post-surgical neurological deficits and the like as well as neuropathic pain. The compounds of the invention are especially useful for treatment of a person susceptible or suffering from stroke or heart attack or neurological deficits relating to cardiac arrest, a person suffering or susceptible to brain or spinal cord injury, or a person suffering from the effects of retinal ischemia or degeneration. Compounds of the invention also are useful to treat and/or prevent various neurodegenerative diseases such as Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Alzheimer""s disease, Down""s Syndrome, Korsakoff""s disease, cerebral palsy and/or age-dependent dementia. Compounds of the invention will be further useful to treat and/or prevent migraines, shingles (herpes zoster), epilepsy, emesis and/or narcotic withdrawal symptoms. Also, in addition to treatment of retinal ischemia and related disorders, the invention provides methods for treatment of optic nerve injury/damage. The treatment methods of the invention in general comprise administration of a therapeutically effective amount of one or more compounds of the invention to an animal, including a mammal, particularly a human.
Particularly preferred compounds of the invention exhibit good activity in an anticonvulsant in vivo mouse audiogenic assay e.g. as disclosed in Example 6 which follows, preferably about 20% or more inhibition at a dose of a compound of the invention of 20 mg/kg, more preferably about 50% or more or 70% or more inhibition at a dose of 20 mg/kg in such an anticonvulsant in vivo audiogenic assay.
The invention also provides pharmaceutical compositions that comprise one or more compounds of the invention and a suitable carrier for the compositions.
The invention further provides methods for preparation of compounds of the invention as well as amine (particularly compounds of Formula III below), N-cyano and other compounds useful as intermediates in those preparative methods. Other aspects of the invention are disclosed infra.
The present invention provides imine-substituted compounds of the following Formulae I and II:
wherein Z, X, p, m, n, R, R1 and R2 are as defined above; and pharmaceutically acceptable salts of those compounds.
Suitable halogen substituent groups of compounds of Formulae I, Ia, Ib, Ic, II, IIa and IIb as defined above (i.e. compounds of the invention) include F, Cl, Br and I. Alkyl groups of compounds of the invention preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups of compounds of the invention. As used herein, the term alkyl unless otherwise modified refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members. Preferred alkylsilyl groups include alkylsilyl having 1 to about 15-18 carbons and 1 or about 2 Si atoms, e.g. a trialkylsilyl group such as a trimethylsilyl, triethylsilyl, a butyl(dimethyl)silyl or tributylsilyl group. Preferred alkenyl and alkynyl groups of compounds of the invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more preferably 2, 3 or 4 carbon atoms. The terms alkenyl and alkynyl as used herein refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred. Preferred alkoxy groups of compounds of the invention include groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Preferred substituted alkoxy groups include haloalkoxy such as fluoroalkoxy, e.g. trifluoromethoxy, trifluroethoxy, pentafluoroethoxy and the like. Preferred alkylthio groups of compounds of the invention include those groups having one or more thioether linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylthio groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfinyl groups of compounds of the invention include those groups having one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfonyl groups of compounds of the invention include those groups having one or more sulfonyl (SO2) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylamino groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Secondary and tertiary amine groups are generally more preferred than primary amine moieties. Preferred alkanoyl groups have from 1 to about 8 carbons and one or two carbonyl groups, with acetyl (CH3CO) and acyl being preferred. Alkanoyloxy groups preferably contain one, two or more oxygen linkages, one or two carbonyl groups and and from 1 to about 8 carbons. Preferred groups include C1-8C(xe2x95x90O)Oxe2x80x94. Suitable heteroaromatic substituent groups of compounds of the invention contain one or more N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol. Suitable heteroalicyclic substituent groups of compounds of the invention contain one or more N, O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups. Suitable carbocyclic aryl groups of compounds of the invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical carbocyclic aryl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Specifically preferred carbocyclic aryl groups include phenyl including substituted phenyl, such as 2-substituted phenyl, 3-substituted phenyl, 4-substituted phenyl or 2,3-substituted, 2,4-substituted phenyl, including where such phenyl substituents are selected from the same group as defined above in Formula I for the substituent X; naphthyl including 1-naphthyl and 2-naphthyl; biphenyl; phenanthryl; and anthracyl. As mentioned above, substituted and unsubstituted carbocyclic aryl, particularly substituted and unsubstituted naphthyl and phenyl, are preferred X, W and Y groups of compounds of the invention. Suitable aralkyl groups of compounds of the invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical aralkyl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Preferred aralkyl groups include benzyl and xe2x80x94CH2-naphthyl.
References herein to substituted X, W, Y, R, R1 and R2 groups of compounds of the invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups such as, e.g., halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkylsilyl groups such as those groups having from 1 to about 12 carbons, or more preferably 1 to about 6 carbons and 1 or Si groups; alkoxy groups including those having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylamino groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocyclic aryl having 6 or more carbons, particularly phenyl; and aralkyl having from about 7 to 14 carbon atoms such as benzyl; and heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms.
It should be understood that alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl and aminoalkyl substituent groups described above include groups where a hetero atom is directly bonded to a ring system, such as a carbocyclic aryl group or a heterocyclic group, as well as groups where a hetero atom of the group is spaced from such ring system by an alkylene linkage, e.g. of 1 to about 4 carbon atoms.
Specifically preferred compounds of the invention include the following:
N-carboximidamide-r-2, c-6-di(4-methylphenyl)piperidine;
N-carboximidamide-r-2, c-6-di(4-isopropylphenyl)piperidine;
N-carboximidamide-r-2, t-6-di(4-methylphenyl)piperidine;
N-carboximidamide-r-2, c-6-diphenylpyrrolidine;
N-(Nxe2x80x2-phenyl)carboximidamide-r-2, c-6-diphenylpiperidine;
and pharmaceutically acceptable salts thereof. See General of Organic Chemistry, vol. 56, 4833-4840 (1991) for discussion of the nomenclature of these preferred compounds. The structural formulae of these preferred compounds are also shown in the examples which follow.
Compounds of the invention can be prepared by several routes. For example, compounds of the invention can be prepared by reaction of cyanamide with a precursor derivative of Formula I that does not contain the N-substituent of xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94C(xe2x95x90NR2)NRR1, i.e. a compound of the following Formula III (where Z, X, m, n and p are each the same as defined above for Formula I):
More particularly, compounds of the invention can be suitably prepared by reaction of a precursor compound of Formula III above with cyanamide to provide compounds of Formula I, or a substituted cyanamide to provide compounds of Formula II, in a suitable solvent such as methanol, ethanol and chloroform or the like under an inert atmosphere such as argon or nitrogen. Typically, an HCl or other acid addition salt of the precursor compound III is reacted with the cyanamide. The reaction solution is suitably heated e.g. from about 100xc2x0 C. or greater for 2 to about 60 hours until reaction completion, e.g. as indicated by thin layer chromatography. The reaction solution is then cooled to room temperature, and the solvent is then removed under reduced pressure to provide the desired compound of the invention. The crude product then can be purified by recrystallization and/or column chromatography, e.g. by elution one or more times on silica gel (e.g., 60-200 mesh, 50xc3x97w/w) with suitable solvents. See Example 1, Part II which follows for exemplary conditions.
Precursor compounds of the above Formula III may be commercially available or can be prepared by reduction of the corresponding unsaturated heterocyclic nitrogen compound, e.g. by use of a reducing agent such as sodium and ethanol. See Example 1, Part 1 for exemplary conditions of such reduction. Hydrogenation also may be employed using palladium or other suitable catalyst. See Example 4, Part III. The nitrogen may be suitably activated during hydrogenation, e.g. with an oxycarbonyl group such as t-butoxycarbonyl or the like, which group can be then removed such as by acidic hydrolysis prior to reaction with cyanamide or other reagent. See Example 4 which follows for an exemplary procedure.
Substituted unsaturated cyclic amine compounds to employ in such reduction reactions can be prepared by several methods. For example, an organometallic reagent can be prepared (typically Group I or II metal, particularly Li or Mg) such as by a halogen-metal exchange reaction followed by reaction of that organometallic reagent with a halopyridine or other halogen-substituted cyclic amine. See Example 2, Part 1, Method A for an exemplary procedure.
Alternatively, a substituted pyridine or other unsaturated precursor compound can be prepared by cyclization of an intermediate compound that contains the ring substituents (i.e. groups X, W and Y in the above formulae), e.g. by cyclization of a substituted 1,5-diketopentyl compound with hydroxylamine. See Example 2, Method B which follows for exemplary conditions.
Compounds of Formulae I and II also may be prepared by reaction of a precursor compound of Formula III above with cyanogen bromide to provide the N-cyano derivative (i.e. compounds of Formula III above substituted at the depicted ring nitrogen by cyano). That cyano intermediate then may be suitably reacted an amine, particularly an ammonium salt such as an acetate salt, typically with heating to provide the N-imine substituted compound of Formula I. See Example 3 which follows for exemplary conditions. Compounds of Formula II may be prepared by reaction of the N-cyano derivative with a primary or secondary amine (to provide the desired R and R1 groups as defined above for Formula II) in the presence of a Lewis acid such as AlCl3 and the like. See Example 5 which follows for an exemplary synthesis.
Alkylsulfinyl-substituted or alkylsulfonyl-substituted reagents, that can provide correspondingly substituted compounds of the invention as described above, can be provided by oxidation (e.g., H2O2) of alkylthio-substituted reagents.
As discussed above, chiral compounds of the invention may be used as optically enriched or racemic mixtures. An optically enriched mixture contains substantially more (e.g. about 60%, 70%, 80% or 90% or more) of one enantiomer or diastereoisomer than the other stereoisomer(s). Optically enriched mixtures can be obtained by known procedures, e.g., column chromatography using an optically active binding material or formation of a salt using an optically active material, particularly an optically active acid.
As discussed above, the present invention includes methods for treating or preventing certain neurological disorders, including the consequences of stroke, heart attack and traumatic head or brain injury, epilepsy or neurodegenerative diseases comprising the administration of an effective amount of one or more compounds of the invention to a subject including a mammal, particularly a human, in need of such treatment. In particular, the invention provides methods for treatment and/or prophylaxis of nerve cell death (degeneration) resulting e.g. from hypoxia, hypoglycemia, brain or spinal cord ischemia, brain or spinal cord trauma, stroke, heart attack or drowning. Typical candidates for treatment include e.g. heart attack, stroke and/or persons suffering from cardiac arrest neurological deficits, brain or spinal cord injury patients, patients undergoing major surgery such as heart surgery where brain ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream. Candidates for treatment also will include those patients undergoing a surgical procedure involving extra-corporal circulation such as e.g. a bypass procedure.
The invention in particular provides methods for treatment which comprise administration of one or more compounds of the invention to a patient that is undergoing surgery or other procedure where brain or spinal cord ischemia is a potential risk. For example, carotid endarterectomy is a surgical procedure employed to correct atherosclerosis of the carotid arteries. Major risks associated with the procedure include intraoperative embolization and the danger of hypertension in the brain following increased cerebral blood flow, which may result in aneurism or hemorrhage. Thus, an effective amount of one or more compounds of the present invention could be administered pre-operatively or peri-operatively to reduce such risks associated with carotid endarterectomy, or other post-surgical neurological deficits.
The invention further includes methods for prophylaxis against neurological deficits resulting from e.g. coronary artery bypass graft surgery and aortic valve replacement surgery, or other procedure involving extra-corporal circulation. Those methods will comprise administering to a patient undergoing such surgical procedures an effective amount of one or more compounds of the invention, typically either pre-operatively or peri-operatively.
The invention also provides methods for prophylaxis and treatment against neurological injury for patients undergoing myocardial infarction, a procedure that can result in ischemic insult to the patient. Such methods will comprise administering to a patient undergoing such surgical procedure an effective amount of one or more compounds of the invention, typically either pre-operatively or peri-operatively.
Also provided are methods for treating or preventing neuropathic pain such as may experienced by cancer patients, persons having diabetes, amputees and other persons who may experience neuropathic pain. These methods for treatment comprise administration of an effective amount of one or more compounds of the invention to a patient in need of such treatment.
The invention also provides methods for treatment and prophylaxis against eye disorders and injury, including methods for treatment of reduced flow of blood or other nutrients to retinal tissue or optic nerve, methods for treatment of retinal ischemia and trauma and associated disorders, and methods for treatment of optic nerve damage/injury. Disorders associated with retinal or optic nerve injury or ischemia that may be treated in accordance with the invention include e.g. diabetes, significantly elevated intraocular pressures and glaucoma, diseases such as retinal artery or vein occlusion, atherosclerosis, venous capillary insufficiency, senile macular degeneration and cystoid macular edema. In such methods, a compound of the invention can be administered parenterally or by other procedure as described herein to a subject a suffering from or susceptible to ischemic insult or other injury or disorder that may adversely affect visual function. Post-ischemic or post-injury administration also may limit retinal damage. Intravitreal injection of a compound of the invention also may be a preferred administration route to provide more direct treatment to the injured retina or optic nerve.
The invention also provides methods for treatment of a subject suffering from shingles as well as treatment of a person suffering from or susceptible to migraines, particularly to alleviate the pain and discomfort associated with those disorders. These methods comprise administration of an effective amount of one or more compounds of the invention to a patient in need of treatment.
The invention further provides a method of treating Korsakoff""s disease, a chronic alcoholism-induced condition, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the disease. Compounds of the invention are anticipated to have utility for the attenuation of cell loss, hemorrhages and/or amino acid changes associated with Korsakoff""s disease.
As discussed above, the invention also includes methods for treating a person suffering from or susceptible to cerebral palsy, emesis, narcotic withdrawal symptoms and age-dependent dementia, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the condition.
As discussed above, preferred compounds of the invention are active in a standard anticonvulsant in vivo audiogenic test, such as the audiogenic mouse assay of Example 6 which follows, where DBA/2 mice about 20-23 days old are injected intraperitoneally with a test compound 30 minutes prior to being placed in a bell jar with exposure to auditory stimulus of 12 KHz sine wave at 110-120 db. References herein in vivo xe2x80x9caudiogenic assayxe2x80x9d are intended to refer to that protocol. Generally preferred compounds exhibit 20% or more inhibition (relative to subjects treated with vehicle control only) at a dose of 20 mg/kg, more preferably about 50% or more or 70% or more inhibition at a dose of 20 mg/kg in such an in vivo audiogenic assay. As discussed above, activity in the audiogenic assay has been recognized as indicative that a test compound has neuroprotective properties. See, e.g., M. Tricklebank et al., European Journal of Pharmacology, supra; T. Seyfried, Federation Proceedings, supra.
The invention also provides methods for determining binding activity of compounds of the invention as well as in vitro and in vivo binding activity diagnostic methods using one or more radiolabelled compounds of the invention, e.g., a compound of the invention that is labeled with 125I, tritium, 32P, 99Tc, or the like, preferably 125I. For instance, a compound of the invention having a phenyl or other aryl substituent that is ring substituted with one or more 125I groups can be administered to a mammal and the subject then scanned for binding of the compound. Specifically, single photon emission computed tomography (xe2x80x9cSPECTxe2x80x9d) can be employed to detect such binding. Such an analysis of the mammal could e.g. aid in the diagnosis and treatment of acute cerebral ischemia. That is, a labeled compound of the invention will selectively bind to ischemic tissue of e.g. a subject""s brain to differentiate between ischemic and non-ischemic tissue and thereby assess trauma or other injury to the brain.
Accordingly, the invention includes compounds of the invention that contain a radiolabel such as 125I, tritium, 32P, 99Tc, or the like, preferably 1251I. Such radiolabelled compounds can be suitably prepared by procedures known in the synthesis art. For example, a compound of the invention having an aromatic group, such as phenyl, that has a bromo or chloro ring substituent can be employed in an exchange labeling reaction to provide the corresponding compound having an 125I ring substituent.
Compounds of the invention may be used in therapy in conjunction with other medicaments. For example, for treatment of a stroke victim or a person susceptible to stroke, one or more compounds of the invention may be suitably administered together with a pharmaceutical targeted for interaction in the blood clotting mechanism such as streptokinase, tPA, urokinase and other agents that lyse clots. Also, one or more compounds of the invention may be administered together with agents such as heparin and related heparin-based compounds, acenocoumarol or other known anticoagulants.
Compounds of the invention also may function as prodrugs and may be metabolized in vivo to forms of enhanced activity.
The compounds of this invention can be administered intranasally, orally or by injection, e.g., intramuscular, intraperitoneal, subcutaneous or intravenous injection, or by transdermal, intraocular or enteral means. The optimal dose can be determined by conventional means. Compounds of the present invention are suitably administered to a subject in the protonated and water-soluble form, e.g., as a pharmaceutically acceptable salt of an organic or inorganic acid, e.g., hydrochloride, sulfate, hemisulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc.
Compounds of the invention can be employed, either alone or in combination with one or more other therapeutic agents as discussed above, as a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Ampules are convenient unit dosages.
For enteral application, particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a sweetened vehicle is employed. Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
Intravenous or parenteral administration, e.g., sub-cutaneous, intraperitoneal or intramuscular administration are preferred. The compounds of this invention are particularly valuable in the treatment of mammalian subjects, e.g., humans, to provide neuroprotective therapy and/or prophylaxis. Typically, such subjects include those afflicted with neurodegenerative diseases such as Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Alzheimer""s disease, Down""s Syndrome and Korsakoff""s disease. Also suitable for treatment are those subjects suffering from or likely to suffer from nervous system dysfunctions resulting from, for example, epilepsy or nerve cell degeneration which is the result of hypoxia, hypoglycemia, brain or spinal chord ischemia or brain or spinal chord trauma. As discussed above, typical candidates for treatment include heart attack, stroke, brain or spinal cord injury patients, patients undergoing major surgery where brain or spinal cord ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream.
It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the particular site of administration, etc. Optimal administration rates for a given protocol of administration can be readily ascertained by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines. In general, a suitable effective dose of one or more compounds of the invention particularly when using the more potent compound(s) of the invention, will be in the range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day, preferably in the range of from 0.01 to 20 milligrams per kilogram bodyweight of recipient per day, more preferably in the range of 0.05 to 4 milligrams per kilogram bodyweight of recipient per day. The desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 4 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule. Such sub-doses may be administered as unit dosage forms, e.g., containing from 0.05 to 10 milligrams of compound(s) of the invention, per unit dosage, preferably from 0.2 to 2 milligrams per unit dosage.
Compounds of the invention also can be useful as rubber accelerators. See U.S. Pat. No. 1,411,713 for a discussion of rubber accelerator applications.
The entire text of all documents cited herein are incorporated by reference herein. The following non-limiting examples are illustrative of the invention.
General Comments
In the following examples, all percentages reported herein, unless otherwise specified, are percent by weight. All temperatures are expressed in degrees Celsius.
Melting points were determined in open capillary tubes on a Thomas-Hoover apparatus and are uncorrected. Thin-layer chromatography was performed on Baker-flex 1B2-F silica gel plates. Compounds were visualized on TLC with 254-nM UV light or as a blue spot with bromcresol spray reagent (Sigma Chemical Co.). Preparative TLC was performed on Analtech GF precoated silica gel (1000 xcexcm) glass-backed plates (20xc3x9720 cm). NMR spectra were recorded on Varian Gemini 300 and the chemical shifts were reported in ppm (xcex4) relative to the residual signal of the deuterated solvent (CDCl3, xcex47.26; CHD2OD, xcex43.30). Elemental analyses were performed by either Galbraith Laboratories (Knoxville, Tenn.) or MHW Laboratories (Tuscon, Ariz.). High Resolution Mass spectra (HRMS) were recorded on a Finnegan MAT 90. HPLC were performed on a C18 reverse phase column using 50:50 water:acetonitrile with 0.1% TFA as a mobile phase. Chlorobenzene, ether (Et2O) and tetrahydrofuran (THF) were anhydrous quality solvents (Sure Seal) supplied by Aldrich. All other solvents were reagent grade.

Pharmaceutically active compounds and methods of use


A camera housing comprises an exterior longitudinal edge that is curved widthwise; a single opening through the exterior longitudinal edge that interrupts the exterior longitudinal edge to create a gap in the exterior longitudinal edge; and an insert having a longitudinal edge that is curved widthwise the same as the exterior longitudinal edge and configured to fit in the opening to align the longitudinal edge of the insert with the exterior longitudinal edge in order that the longitudinal edge of the insert is positioned within the gap to appear to be a continuation of the exterior longitudinal edge, and including a viewfinder window with an exterior flat face that is inclined into the longitudinal edge of the insert to at least partially interrupt the longitudinal edge of the insert in order to prevent the occurrence of image distortion when looking though the viewfinder window in the vicinity of the longitudinal edge of the insert.

The visual appearance and the compactness of a camera housing are each a critical factor in a camera's design. It is generally known to curve the longitudinal edges of the camera housing widthwise to create a pleasing soft appearance. The problem is created, however, that front and rear viewfinder windows in the camera housing usually are flat and, therefore, cannot be at one of the curved longitudinal edges. This takes away from the compactness of the camera housing. If the viewfinder window was curved in conformity with the curved longitudinal edge to provide compactness, one would see image distortion when looking through the viewfinder window in the vicinity of the curved longitudinal edge.

Camera housing with window insert conforming to housing shape


The present invention provides a system of wind turbines connected to a single unit electric generator to produce electrical power whereby the wind turbine blades rotate coaxially with a main rotor shaft instead of perpendicular to the shaft axis. In this respect, the wind turbine rotor can face the wind from any direction and does not need to be pointed into the wind to be effective, thus, eliminating the need for a yaw system. Moreover, translation of mechanical to torque of the main rotor drive allows the drive components such as the gearbox and generator to be placed near the ground of each wind turbine improving accessibility for maintenance.

The present invention relates to the generation of wind energy or wind power through multiple interconnected wind turbines.
Wind energy or wind power refers to the process by which the wind is used to generate mechanical power or electricity. Wind turbines convert the kinetic energy of the wind into mechanical power and that mechanical power is used to generate electricity. The generation of electricity by wind turbines is dependent on the strength of the wind at any given moment.
Wind farm sites are chosen after careful analysis to determine the pattern of the wind regime, including its relative strength and direction at different times of the day and year. Particular areas provide different levels of wind speed, and wind turbines are typically classified by the level of wind speed they are designed for. Small wind turbines may be designed to work at low wind speeds. Typically, small wind turbines in low wind speed areas have been underutilized.
In a conventional wind turbine, a high tower is supported below by a solid foundation fixed into the ground. The tower supports a rotor with rotating blades and a nacelle (or turbine housing) containing drive components, for example, a gearbox, generator, power electronic devices, and yaw mechanism.
U.S. Pat. No. 9,599,092 granted to the present inventor, and which is incorporated herein by specific reference for all purposes, shows a system for generating wind energy through multiple smaller wind turbines mechanically connected to each other and to a single generator. The system of multiple smaller wind turbines are connected to each other and to the single generator through a gear and chain system minimizing the number of mechanical transmissions needed between the wind turbine blades and the single generator.
Typically, a yaw drive insures that the wind turbine blades keep the rotor facing into the wind as the wind direction changes, maximizing the amount of energy produced. A yaw system may provide rotation between the nacelle and the tower (i.e., a yaw bearing) and a means to vary the orientation of the nacelle with respect to the tower (i.e., a yaw drive) using a yaw break and a control system. However, the gear and chain system of U.S. Pat. No. 9,599,092 eliminates the ability of the wind turbine blades or nacelle to rotate with respect to the tower and turn into the wind without interfering with the gear and chain system. This results in a less than optimal amount of energy from the wind translated to the wind turbine rotor and therefore the generator.

Integrated vertical axis wind power generation system


A sunvisor for a vehicle which includes a sunvisor shell. A gear drive mechanism drivingly engages at least one rack within the shell to move the shell in response to rotation of the gear drive mechanism. The sunvisor also includes at least one boot extending from a boot arm. A guide support structure is provided on the shell for each boot, each guide support structure including a slot therein having a flared circular opening upon at least one end of the slot, so that the shell will move linearly while the boot is in the slot and the shell will move radially when the boot is in one of the flared circular openings in response to rotation of the gear drive mechanism.

1. Field of the Invention
The present invention pertains to a sunvisor for a vehicle which is adjustable to a multitude of positions. In particular, the present invention pertains to a sunvisor which may be mechanically adjusted to a multitude of positions including on the front and passenger side. A glare shield panel may be placed within the sunvisor for deployment.
2. Prior Art
Sunvisors for automobiles and the like are well known. In the most common sunvisor, shaft or arms extend from or are located in the roof or headliner of the vehicle. These form an axis for rotation of the sunvisor itself which can move from a position substantially flush and parallel to the headliner to a position in angular relation therewith so that the sun is blocked from the eyes of the driver or passenger.
More recent proposals have allowed the sunvisor to move about a track such as Miyamoto et al. (U.S. Pat. No. 5,031,952).
Several arrangements have been provided whereby the movement of the sunvisor is mechanized. Prior art has failed to address an effective means of moving a visor or visor-glare shield into an in use position in a plane parallel to the roof line of a vehicle, and still have the versatility of moving the visor to the side window position by sliding or pivoting the visor to that position. The present invention addresses these problems by allowing the visor and glare shield to be operated by a simpler engagement means between the visor and glare shield components. The glare shield visor can be moved into unlimited positions using the guides, elongated slots and channels proposed in this invention.
Nothing has been suggested which provides a sunvisor arrangement having a guide support in the form of a slot with flared circular openings upon at least one end of the slot so that the shell moves linearly about the slot and moves radially about the flared circular openings.
Accordingly, it is a principal object and purpose of the present invention to provide a sunvisor having a guide support in the form of a slot or slots with flared circular openings upon at least one end of the slot so that the shell moves linearly about the slot and moves radially about the flared circular openings.


A system for improving wood strand orientation in a wood strand orienter having a plurality of orienter disks. The system includes a plurality of axially-spaced, parallel pre-orienting shafts positioned in a second plane above and substantially parallel to the orienter disks, each one of the pre-orienting shafts having a plurality of wheels mounted thereon. Each of the wheels has a hub and a plurality of outwardly-extending finger members. When the pre-orienting shafts are positioned over the disks, each one of the finger members passes, in turn, through a portion of the volume defined between the two adjacent orienter disks the wheel sits between. This permits bridged wood strands to be turned and straightened, reducing the xe2x80x9c% oversxe2x80x9d, the percentage of strands bridging the orienter disks and carried across the top of the orienter without falling through the orienter.

The present invention relates to machinery used to produce composite wood products, and in particular relates to improvements in rotating disk-type wood strand orienter machinery.
Composite wood products such as oriented strand board (xe2x80x9cOSBxe2x80x9d), particleboard and the like are produced from wood particles or strands. During the manufacturing process, strands of wood are typically formed into mats with the orientation of the wood strands controlled by strand-orienting machinery. Such strands are generally elongated (longer than they are wide), and when producing OSB it is desirable to have these strands aligned longitudinally and in a generally parallel fashion, and lying flat on the mat. Generally, the quality of a composite wood product depends in large part upon how well aligned the wood strands are in the wood strand mat produced by the orienter.
Commonly used strand orienters employ rotating disks. One type of orienter known in the art is the xe2x80x9cStokesxe2x80x9d type of orienter, which is described in detail in U.S. Pat. No. 3,115,431, which issued on Dec. 24, 1963 to Stokes et al. This orienter uses a plurality of intermeshed rotating disks mounted on a plurality of substantially parallel shafts oriented in a plane beneath a supply of wood strands. The wood strands are permitted to fall down upon the orienting disks, which, while turning, tend to align the strands longitudinally. The aligned strands fall between the disks to form a mat of strands on a platform or conveyor beneath the disks. The mat is accordingly formed of particles aligned generally longitudinally, although the strands are never perfectly aligned. The Stokes arrangement is shown in FIG. 1.
Another type of orienter known in the art, which also employs orienting disks, is the type known as the xe2x80x9cBxc3xcrknerxe2x80x9d orienter. The Bxc3xcrkner orienter is disclosed in U.S. Pat. No. 4,380,284, which issued on Apr. 19, 1983. In the Bxc3xcrkner orienter, disks on adjacent shafts are arranged in pairs in side-by-side relationship, defining passages for allowing strands of wood to pass through to form a mat. The Bxc3xcrkner arrangement is shown in FIG. 2.
The disclosures of the aforementioned Stokes and Bxc3xcrkner patents are incorporated herein by reference.
One continuing problem with wood strand orienters of the type discussed above is that many strands bridge two or more adjacent disks, riding along the tops of all of the disks and never falling through two adjacent disks onto the mat. These strands which bridge the orienting disks and which are carried along by successive disks over the orienter in its entirety are known in the art as xe2x80x9coversxe2x80x9d. It is typical to measure xe2x80x9coversxe2x80x9d as a percentage of starting material.
It is generally preferred to have adjacent disks in an orienter relatively close to one another, with narrow spacing (in the order of about 2 inches) between them. Closer disks tend to produce a mat having more highly-aligned strands. However, the closer the disks are to one another, the lower is the volume of material which is able to fall between adjacent disks. xe2x80x9cOversxe2x80x9d, therefore, are particularly problematic when the disks are relatively close together. The percentage of overs also tends to increase at higher material feed rates.
Various attempts have been made to try to ameliorate this problem. One example of a suggested solution will be found disclosed in U.S. Pat. No. 5,487,460, which issued on Jan. 30, 1986 to Barnes. In this patent, a xe2x80x9cmulti-deckxe2x80x9d orienter is described, which has three decks of orienting disk sets through which strands must fall, each successive deck purportedly aligning the strands to a greater degree. A similar arrangement may be found in U.S. Pat. No. 5,325,954, which issued on Jul. 5, 1994 to Crittenden et al. Crittenden shows a strand xe2x80x9cpre-orienterxe2x80x9d. In both the Crittenden et al and the Barnes patents, the spacing between the disks in the upper xe2x80x9cdeckxe2x80x9d is significantly larger than the spacing between the disks in the decks below them. However, it has been found Crittenden et al. and the Barnes arrangements occupy a large amount of space, and do not offer enough improvement in strand alignment over the Stokes and Bxc3xcrkner orienting arrangements to justify their implementation in commercial OSB manufacture.
A need remains, therefore, for a wood strand orienter particularly suited to orienting strands in substantially parallel relationship with a low amount of xe2x80x9coversxe2x80x9d at commercial material feed rates.
The present invention provides a system for improving wood strand orientation in a wood strand orienter having a plurality of axially-spaced, parallel orienter shafts positioned in a first plane, with each shaft bearing a plurality of axially spaced orienter disks. The system comprises a plurality of axially-spaced, parallel pre-orienting shafts positioned in a second plane above and substantially parallel to the first plane, the pre-orienting shafts substantially parallel to the orienter shafts; and a plurality of wheels mounted on each one of the pre-orienting shafts, each one of the wheels having a hub and a plurality of finger members extending radially outwardly from the hub. Each one of the wheels is positioned between two adjacent orienter disks and extends downwardly into a volume defined between the two adjacent orienter disks. Each one of the pre-orienter shafts may be positioned vertically above one of the orienter shafts.
The system of the present invention also provides means for rotating the pre-orienter shafts in a direction which causes the finger members to sweep against the direction of travel of wood strands along the tops of the orienter disks, thereby allowing the finger members to turn and straighten wood strands which are bridged over the tops of two or more of the adjacent orienter disks, allowing these strands to more readily fall between the disks. The wheels may have between 2 and 6 finger members.
In the preferred embodiment of the invention, one wheel is positioned between each pair of adjacent orienter disks, and is positioned more closely to one of the disks than to the other. The wheels may be spaced at 1.5 inch or 2 inch intervals, or at some other interval, depending upon the spacing of the orienter disks.

System for improving wood strand orientation in a wood strand orienter using rotating orienting fingers


A laundry washing machine includes a weight sensing system including a weight sensor positioned to sense at least a portion of a weight associated with a wash tub and configured to output an associated pulse width modulated (PWM) force signal having a duty cycle that varies with applied force on the weight sensor. A controller of the laundry washing machine includes a state change sensing logic circuit coupled to receive the PWM force signal from the weight sensor and execute an interrupt service routine triggered by each state transition to capture a timestamp associated with each state transition such that the duty cycle of the PWM force signal may be determined using the captured timestamps.

Laundry washing machines are used in many single-family and multi-family residential applications to clean clothes and other fabric items. Due to the wide variety of items that may need to be cleaned by a laundry washing machine, many laundry washing machines provide a wide variety of user-configurable settings to control various aspects of a wash cycle such as water temperatures and/or amounts, agitation, soaking, rinsing, spinning, etc. The settings cycle can have an appreciable effect on washing performance, as well as on energy and/or water consumption, so it is generally desirable for the settings used by a laundry washing machine to appropriately match the needs of each load washed by the machine.
Some laundry washing machines also support user selection of load types, typically based on the types of fabrics and/or items in the load. Some laundry washing machines, for example, have load type settings such as colors, whites, delicates, cottons, permanent press, towels, bedding, heavily soiled items, etc. These manually-selectable load types generally represent specific combinations of settings that are optimized for particular load types so that a user is not required to select individual values for each of the controllable settings of a laundry washing machine.
While manual load type selection in many cases simplifies a user's interaction with a laundry washing machine, such manual selection still can lead to suboptimal performance due to, for example, user inattentiveness or lack of understanding. Therefore, a significant need continues to exist in the art for an automated manner of optimizing the performance of a laundry washing machine for different types of loads, as well as reducing the burden on users when interacting with a laundry washing machine.
Automated load type selection in many instances is based at least in part on weight measurements taken of the load, e.g., when the load is dry (prior to soaking the load with water, and in some instances, after water has been dispensed into the wash tub within which the load has been placed. In addition, in some instances, it may be desirable to weigh a load while the load is spinning to account for uneven load dispersal. It has been found, however, that weight sensing can be costly, and in some instances, computationally-intensive, particularly when load cells that output pulse width modulated (PWM) force signals in which the force signals have duty cycles that vary with applied force are used as weight sensors. As such, a need also exists in the art for a more cost-effective and computationally-efficient manner of sensing weight in a laundry washing machine.

Laundry washing machine weight sensing system


The invention provides a scheduling of data blocks on multiple data carriers and a selection of data carrier to listen to. A transmitting unit simultaneously transmits, during a communication session with at least one participating receiving unit, at least a first data block on a first data carrier and a second data block on a second data carrier. The receiving unit selects which of these data carriers to listen to, i.e. whether to receive the first or second data block, based on a reception quality of a previously received data block. Furthermore, at least one of the first and second data block is based on information common to the data block and the previous data block, e.g. the first or second data block could be re-transmitted version of the previous block.

Utilization of radio resources and channels is continuously subject to much research and development in order to optimize system throughput due to the limited availability of radio resources in communications systems. This is especially true when introducing new communications services to the existing communications systems. An example of such a new communications service is Multimedia Broadcast Multicast Service (MBMS). The benefit of this MBMS service is that it enables simultaneous distribution of data to several users using the same physical channel, i.e. so-called point-to-multipoint transmission. For more information of MBMS reference is made to the 3GPP document [1].
However, although the existing communications systems, e.g. GSM (Global System for Mobile communications) and EDGE (Enhanced Data rates for GSM Evolution) communications systems, are typically dimensioned for providing guaranteed minimum C/I (carrier-to-interference) levels adapted for traditional voice services, these guaranteed minimum C/I levels are often too low to successfully provide new high bit rate services, e.g. video streaming over MBMS. Due to the demand for high bit rates, these services must often use the maximum number of allowed communications resources (time slots).
However, radio link simulations have shown that even when using the maximum number of communications resources in GSM/EDGE systems, data blocks often have to be re-transmissions many times to provide acceptable robustness down to the minimum guaranteed C/I levels. The number of such re-transmission to provide the acceptable robustness is, though, often too high in existing GSM/EDGE systems, resulting in unacceptable low throughputs.
The obvious solution to this trade-off between low robustness (due to too few re-transmissions) and low throughput (due to too many re-transmissions) is to introduce a multi-carrier EDGE solution. However, although this is possibly relatively straightforward in the base stations of existing communications systems, a multi-carrier solution would require major changes in the mobile terminals because these terminals then have to process multiple channels simultaneously, both in analogue and digital parts.


An improved interlayer is provided for use in a photoconductor element between an electrically conductive layer and a charge generation layer of the type where a dye is aggregated in a matrix polymer. The interlayer is a mixture of at least one polyester and at least one polycarbonate. The interlayer provides excellent adhesion between the conductive layer and the charge generation layer and dampens any stress to which the photoconductive element is subjected. Minimal effect on photosensitivity is achieved by optimizing interlayer thickness.

Photoconductor elements having a variety of interlayers positioned between a conductive layer and a photoconductive layer are well known. For example, interlayers have been used to bond organic photoconductive layers to electrically conductive layers.
However, photoconductive and conductive layers used in multiactive elements such as described, for example, in U.S. Pat. No. 4,175,960, exhibit unique problems. The photoconductive layer is heterogeneous and both layers tend to be brittle. When the coated and dried layers are subjected to stress, these two layers work against each other so that the photoconductive layer tends to separate from the conductive layer as a result of the stresses produced by flexing this film during handling and/or use. Conventional interlayers positioned between these layers do not appear to be useful in such structures.
New interlayer structures are needed which dampen any stress to which the photoconductor element is subjected and which provide adhesion between the photoconductive layer and the electrically conductive layer. The interlayer structure must also be free of secondary chemical or electrical effects that could deleteriously effect the overall behavior of the element.

Photoconductor elements with multiphase stress-dampening interlayers


A list of reference terms can be provided. Text and the list of reference terms can be broken down into tokens. At least one candidate can be generated in the text for mapping to at least one of the reference terms. Characters of the candidate can be compared to characters of the reference term according to one or more mapping rules. A confidence value of the mapping can be generated based on the comparison of characters. Candidates can be ranked according to their confidence value.

The present invention relates to a text analysis method, particularly for finding acronyms and variants of acronyms of reference terms in a text.
A very large proportion of all database contents are available in non-structured form, most of it in text form. The Internet, as the largest distributed text database, is assumed to have a capacity of approximately one billion static websites and approximately five hundred billion dynamically generated websites. The amount of the stored online data volume is estimated to be roughly one thousand Petabyte and is still increasing. Automated text mining methods to handle such an information load and to analyze the data are required.
Text mining generally refers to an automated process of extracting information from a text. Text mining typically involves the process of structuring the input text, deriving patterns within the structured data and, finally, evaluating and interpreting the output. Typical text mining objects include, for instance, categorization and clustering of text, extraction of concepts, production of taxonomies, sentiment analysis and the like.
Prior art methods can be applied to formal texts such as books, scientific publications, patent documents, well-managed web sites and the like, which use an accurate, formal language, to find acronyms of reference terms.
An acronym is an artificial word or sequence of letters which usually includes one or more characters of words of a word group, such as "IT" for "information technology". In formal texts, standard acronyms of compound terms are typically formed by using only initial characters. Such acronyms are usually introduced with a definition when used for the first time, which helps to identify them.
In contrast, acronyms in informal texts are frequently used without definition. One reason is that informal texts are provided for a closed group of people who typically share a common understanding of the content of the informal text so that definitions of acronyms are considered to be unnecessary. Moreover, in informal texts formation rules for building acronyms can be softened resulting in nonstandard acronyms which are variants of classical acronyms or which can even consist of a multitude of words used contextually for a nonstandard purpose.
Y. Park and R. J. Byrd describe a method for finding acronyms and their definition in "Hybrid Text Mining for Finding Abbreviations and Their Definitions", Proceedings of the 2001 Conference on Empirical Methods in Natural Language Processing, 2001. Acronyms and respective definitions are identified by using common use of rules for forming abbreviations, text markings and cue words. Candidates for acronyms are identified by heuristics such as "the initial character is either a letter or a cipher", "the potential abbreviation is at least two characters long", "the candidate includes at least one upper-case character", or "the candidate cannot be the initial word of a sentence." Additionally, the character string must not be a member of, for instance, an official dictionary, of a list of names or of a manually constructed list of stop words and the like.
Groups using informal texts can be, for instance, call center agents attending to service requests and answers related to product failures. Documents provided by such groups (call transcripts or summaries) are characterized by being prepared hastily and under time pressure. Informal texts are characterized by a high rate of typographical errors such as misspellings, typing faults, individual abbreviations, grammatically inaccurate or incomplete sentences in note form and the like.
Prior art text mining methods frequently fail to find acronyms or variants of acronyms of reference terms in such informal texts using an informal language. Prior art solutions require either an exact string matching between the acronym and the reference term or, if a fuzzy string matching is allowed, the stronger the variant deviates from the reference term, the higher the number of misfits there will be. When analyzing a text for acronyms and variants with major deviations from a classical acronym, in particular abbreviations, a user has to be involved. The user usually has to manually examine a subset of the text corpus to detect variants that differ from the reference terms by more than a minor spelling deviation and these variants found have to be collected in a list of known acronyms which is used for analyzing the text. The results have to be manually checked and probably refined. Thus, manual interaction of the user is necessary not only once but for every new text corpus because new authors may be using largely different ways of abbreviating the same terms.

Text analysis method for finding acronyms

International Business Machines Corporation


A moving image reproducing apparatus which receives moving image data transmitted through a network and reproduces the moving image data includes an analysis unit adapted to analyze first moving image data stored in a storage unit and additional information of the first moving image data, a determination unit adapted to determine a storage destination on the network which is configured to acquire second moving image data following the first moving image data on the basis of the analysis result on the additional information, an acquisition unit adapted to acquire the second moving image data from the storage destination of the second moving image data, and a reproducing unit adapted to reproduce the second moving image data acquired by the acquisition unit concurrently with finishing reproduction of the first moving image data.

1. Field of the Invention
The present invention relates to a technique of reproducing moving image data.
2. Description of the Related Art
Recently, the use of high-speed Internet connection services and wired and wireless home networks has rapidly become popular. A use method has becoming popular, which stores moving image contents converted into digital data in a home server to allow the user to view the contents on another device through a home network or receives moving image contents from a moving image distribution service on the Internet and allowing the user to view the contents. Even when a user is away from home, he/she can view moving image contents by transferring the contents to a portable reproducing device through the Internet. In order to allow a user to comfortably view these moving images, it is desired to start reproducing a moving image content immediately after the user issues a view instruction by operating the reproducing device as well as to display moving images actually reproduced and displayed with high image quality.
When downloading a moving image content on a network and reproducing it, the reproducing device starts reproducing it with a delay corresponding to the time required for data transfer with respect to when a moving image content held as a local file. In order to eliminate such a delay of the start of reproduction, a reproducing device performs streaming reproduction, i.e., storing, in the buffer of the reproducing device, moving image data in an amount that allows partial reproduction without waiting for the transfer of all the data of the moving image content, decoding the stored moving image data, and reproducing it.
Streaming reproduction makes it possible to seamlessly reproduce moving image data while hiding the time required for data transfer by decoding and reproducing partial moving image data and concurrently transferring partial moving image data to be reproduced next. In addition, even a portable reproducing device with a small storage capacity can perform streaming reproduction because it need not hold all moving image data of a large data capacity at once by using, for example, a method of discarding reproduced partial moving image data at proper timing.
As a conventional technique associated with streaming reproduction, for example, the technique disclosed in Japanese Patent Laid-Open No. 2004-080145 is available.
With regard to the first part of a moving image content to be started to be reproduced, however, reproduction cannot hide the time required for data transfer, and hence there is still a wait time between the instant at which the user issues a reproduction instruction and the instant at which reproduction starts.
The data transfer time greatly depends on the data transfer rate of a network to be used, an encoding scheme for a moving image content to be transferred, and a code amount per unit time. Recently, with the proliferation of high-speed Internet and high-speed wireless communication schemes, the data transfer rate has increased year by year. At the same time, however, the resolution and data transfer rate of moving image contents to be viewed have increased. In addition, the number of users has increased. Increases in resolution and transfer rate will cause not only increases in the congestion of the network and server load but also increases in the amount of transfer data stored until the start of reproduction. In addition, an increase in the number of users will increase the congestion of the network and the processing load on servers.
An increase in the speed of a network therefore is effective only in a use condition where the use of the network can be widely ensured, and hence provides no method of solving problems associated with the transfer and reproduction of the moving image data of moving image contents.
The present invention has been made in consideration of the problems in the prior art, and has as its object to provide a video reproduction technique which can shorten the time required for the start of reproduction of moving image data.

Moving image reproducing apparatus and method


A system for up-selling content during periods of likely viewer disinterest may include a content delivery network configured to provide media content and at least one choice of alternative content, a content viewing device, and a content processing device for interfacing the viewing device with the content delivery network. The content processing device may be configured to detect likely viewer disinterest in media content, prompt the selection of alternative content, and selectively replace the media content with the alternative content upon viewer selection. Additionally, methods for estimating a degree of likely viewer disinterest and discounting the offering price of the alternative content options are implemented by the system.

Subscriber systems, such as a cable television system and the like, may provide media content to a viewing customer according to a subscription. In addition to the standard subscription based content (e.g., scheduled network programming), specialty content may be available to the viewing customer. Specialty content may include any content that falls outside of the content available through the standard subscription, and may provide additional revenue for the subscriber system. For example, pay-per-view and pay-per-use movies, videos, music, games, etc. may be available to the viewing customer. Specialty content may further include enhancements to the subscription of the viewing customer, such as premium content channels. Additionally, specialty content may further include advertiser supported content.
Typically, the goal of any subscriber system includes maximizing revenue from subscribers while maintaining high levels of customer service and satisfaction. However, due to the remote nature of the content distribution network and the variable times that a customer may choose to receive content, there may only be limited opportunities to sell content to a viewing customer. For example, the customer may only interact with a customer service representative or salesperson at the time of subscribing or modifying a subscription. Accordingly, subscriber systems may lack the ability to up-sell specialty content to the viewing customer.

System for up-selling content during periods of likely viewer disinterest


A clamp comprising a spanner extending across a gap between first and second longitudinally extending edges of a band clamped onto a fluid conduit having a circumference orientated about an axis; a connecting assembly configured to tighten the spanner and band to the conduit and a gasket between the band and spanner and the conduit; the gasket comprising a first circumferential seal bead protruding from an inner side of the gasket and having a circumferential length that is equal to or greater than the circumference of the conduit and at least one standalone header bead protruding from the inner side of the gasket and disposed at least partially between the spanner and the conduit and having a circumferential length that is substantially less than the circumference of the conduit.

Repair clamps are used in the placement of pipes or for connecting the ends of pipes axially. Such clamps generally have a cylindrical body or band which encircles the subject pipe or pipe ends. Two opposed lugs are attached to the opposed edges of the cylindrically-shaped band, and the lugs are drawn towards each other by tightening bolts or fasteners. This reduces the effective internal diameter of the band, which in turn compresses an elastomeric sheet gasket that is typically placed between the band and the subject pipe. Compressing the gasket sheet seals the gasket to the pipe. To bridge the gap that is formed between the ends of the band, a spanner or bridge plate molded into or placed onto the outer surface of the gasket is employed to provide gasket compression across the gap. The spanner plate fits on the outer surface of the elastomeric sheet gasket and is compressed radially inward by the lugs along the opposed edges of the cylindrical band.
The range of diameters of piping for which a repair clamp may be used is typically fairly limited. For example, at present pipeline repair clamps have a range of about 0.3 to 0.4 inches for the diameter span of pipes that the repair clamp can effectively seal. The linear closure travel necessary for this range is only in the order of 1.20-1.25 inches.


The present invention relates to an epidural stimulation lead having at least one electrode that substantially encircles another electrode. Operatively, the encircling electrode can be set as an, anode and the encircled electrode can be set as a cathode to generate an electrical field therebetween. The encircling electrode functions in this capacity as an anode guard, which among other things, concentrates the electrical field about the designated cathode and limits the lateral range of a generated electrical field.

The present invention relates to an epidural stimulation lead, and in particular, to an epidural stimulation lead having at least one electrode suited to serve as an anode guard relative to a substantially encircled cathode.
Application of specific electrical fields to spinal nerve roots, spinal cord, and other nerve bundles for the purpose of chronic pain control has been actively practiced since the 1960s. While a precise understanding of the interaction between the applied electrical energy and the nervous tissue is not fully appreciated, it is known that application of an electrical field to spinal nervous tissue (i.e., spinal nerve roots and spinal cord bundles) can effectively mask certain types of pain transmitted from regions of the body associated with the stimulated tissue. More specifically, applying particularized electrical energy to the spinal cord associated with regions of the body afflicted with chronic pain can induce paresthesia, or a subjective sensation of numbness or tingling, in the afflicted bodily regions. This paresthesia can effectively mask the transmission of non-acute pain sensations to the brain.
It is known that each exterior region, or each dermatome, of the human body is associated with a particular spinal nerve root at a particular longitudinal spinal position. The head and neck regions are associated with C2-C8, the back regions extends from C2-S3, the central diaphragm is associated with spinal nerve roots between C3 and C5, the upper extremities are correspond to C5 and T1, the thoracic wall extends from T1 to T11, the peripheral diaphragm is between T6 and T11, the abdominal wall is associated with T6-L1, lower extremities are located from L2 to S2, and the perineum from L4 to S4. By example, to address chronic pain sensations that commonly focus on the lower back and lower extremities, a specific energy field can usually be applied to a region between bony level T8 and T10. As should be understood, successful pain management and the avoidance of stimulation in unafflicted regions necessarily requires the applied electric field to be properly positioned longitudinally along the dorsal column.
Positioning of an applied electrical field relative to a physiological midline is equally important. Nerve fibers extend between the brain and a nerve root along the same side of the dorsal column as the peripheral areas the fibers represent. Pain that is concentrated on only one side of the body is xe2x80x9cunilateralxe2x80x9d in nature. To address unilateral pain, electrical energy is applied to neural structures on the side of a dorsal column that directly corresponds to a side of the body subject to pain. Pain that is present on both sides of a patient is xe2x80x9cbilateral.xe2x80x9d Accordingly, bilateral pain is addressed through either an application of electrical energy along a patient""s physiological midline or an application of electrical energy that transverses the physiological midline.
Pain-managing electrical energy is commonly delivered through electrodes positioned external to the dura layer surrounding the spinal cord. The electrodes are carried by two primary vehicles: a percutaneous catheter and a laminotomy lead.
Percutaneous catheters, or percutaneous leads, commonly have three or more, equally-spaced electrodes, which are placed above the dura layer through the use of a Touhy-like needle. For insertion, the Touhy-like needle is passed through the skin, between desired vertebrae, to open above the dura layer.
For unilateral pain, percutaneous leads are positioned on a side of a dorsal column corresponding to the xe2x80x9cafflictedxe2x80x9d side of the body, as discussed above, and for bilateral pain, a single percutaneous lead is positioned along the patient midline (or two or more leads are positioned on each side of the midline).
Laminotomy leads have a paddle configuration and typically possess a plurality of electrodes (for example, two, four, eight, or sixteen) arranged in one or more columns. An example of a sixteen-electrode laminotomy lead is shown in FIG. 1.
Implanted laminotomy leads are commonly transversely centered over the physiological midline of a patient. In such position, multiple columns of electrodes are well suited to address both unilateral and bilateral pain, where electrical energy may be administered using either column independently (on either side of the midline) or administered using both columns to create an electric field which traverses the midline. A multi-column laminotomy lead enables reliable positioning of a plurality of electrodes, and in particular, a plurality of electrode columns that do not readily deviate from an initial implantation position.
Laminotomy leads require a surgical procedure for implantation. The surgical procedure, or partial laminectomy, requires the resection and removal of certain vertebral tissue to allow both access to the dura and proper positioning of a laminotomy lead. The laminotomy lead offers a more stable platform, which is further capable of being sutured in place, that tends to migrate less in the operating environment of the human body.
Percutaneous leads require a less-invasive implantation method and, with a plurality of leads, provide a user the ability to create almost any electrode array. Although likely more stable during use, laminotomy leads do not offer an opportunity for electrode array variance due to the predetermined structure which defines their electrode arrays.
To supply suitable pain-managing electrical energy, stimulation leads are connected to multi-programmable stimulation systems, or energy sources (not shown). Typically, such systems enable each electrode of a connected stimulation lead to be set as an anode (+), a cathode (xe2x88x92), or in an OFF-state. As is well known, an electric current xe2x80x9cflowsxe2x80x9d from an anode to a cathode. Consequently, using the laminotomy lead of FIG. 1 as an example, a range of very simple to very complex electric fields can be created by defining different electrodes in various combinations of (+), (xe2x88x92), and OFF. Of course, in any instance, a functional combination must include at least one anode and at least one cathode.
Notwithstanding the range of electric fields that are possible with conventional stimulation leads, in certain instances it is necessary to concentrate electrical energy at a particular point, or over a small region. As an example of such occasion, assume pain-managing electrical energy Is applied at or about T8 to address only localized lower back pain. At T8, however, spinal nervous tissue corresponding to the patient""s lower extremities commingles with the specific spinal nervous tissue associated with the lower back. Moreover, it is common that the lower back-related spinal nervous tissue is deeply embedded within the combined spinal nervous tissue. Accordingly, it becomes desirable to focus applied electrical energy to the targeted nervous tissue to (i) reach the deeply situated target nervous tissue and (ii) avoid undesirable stimulation of unafflicted regions.
Accordingly, a need exists for a stimulation lead that includes a structural arrangement that facilitates a concentration of delivered electrical energy at a point, i.e., for a given electrode, or over a small region, i.e., for a plurality of electrodes.
At least one aspect of the present invention is drawn to a stimulation lead having a plurality of terminals, a plurality of electrodes carried by a body, and a plurality of conductors, as a conductor electrically couples one terminal with a respective electrode. The plurality of electrodes includes a first electrode and a second electrode, whereby the second electrode substantially encircles at least the first electrode.
An object of the present invention is to provide a electrical stimulation lead having at least two electrodes. Unlike known stimulation leads, however, an arrangement of the electrodes of the stimulation lead should facilitate operatively concentrating delivered electrical energy at a point, i.e., for a given electrode, or over a small region, i.e., for a plurality of electrodes.
Other objects and advantages of the present invention will be apparent to those of ordinary skill in the art having reference to the following specification together with the drawings.

Spinal cord stimulation lead with an anode guard


According to various illustrative embodiments, an apparatus for redistributing release agent on a fuser surface of an image forming device is provided. The apparatus includes a fuser surface for contacting a sheet of media having an image formed thereon by the image forming device, the fuser surface moving in a traveling direction; and a flexible blade for redistributing the release agent on the fuser surface from a first post-fusing distribution to a second distribution, the flexible blade contacting the release agent on the fuser surface at a contact area and pressing the release agent against the fuser surface to redistribute the release agent from the first post-fusing distribution to the second distribution, wherein the flexible blade is adapted to redistribute the release agent such that the second distribution is more uniform across the fuser surface than the first post-fusing distribution.

The present disclosure relates generally to fuser release fluid control in imaging systems. More particularly, the present disclosure describes an apparatus, method, and system useful for reducing oil ghosting in imaging systems.
The fuser release fluid distribution on the surface of a roll or belt in an imaging system can have detrimental effects on image quality if not properly controlled. For example, if release fluid (for example, oil) is not evenly distributed on the portion of a surface (for example, a fuser roll or belt) that comes in contact with the media, oil ghosting can result in the form of a gloss band on the media. Oil ghosting can result from excess oil on, for example, the inter document zone (IDZ) of the fuser surface that exists between sheets of media, or on the outside paper path (OPP) area of the fuser surface when switching to wider media.

Redistributing release agent using a flexible blade in an image forming system


A stent comprises two serpentine bands, at least one first connector; and at least one second connector. The first and second connectors connect the two serpentine bands together. The first connector and the second each have at least a first portion of a first curvature and a second portion of a second curvature. The second portion being more flexible than the first portion. The first and second connectors are adjacent one another and the first portion of the first connector nests within the second portion of the second connector and the second portion of the second connector nests within the first portion of the first connector.

The use of stents in bodily lumen is well known. A stent is typically delivered in an unexpanded state to a desired location in a bodily lumen and then expanded. The stent may be expanded via the use of mechanical device such as a balloon or the stent may be self-expanding.
Because a stent often must be delivered through tortuous anatomy, it is desirable for the stent to be flexible and to have a low profile. In order to provide a low profile the stent is often crimped onto a balloon or catheter before entering a bodily lumen. In general, however, as a stent is crimped in order to minimize its profile, the likelihood of overlapping portions of the stent increases.
There remains a need for a stent having a low crimped profile without overlapping portions of the stent.
All US patents and applications and all other published documents mentioned anywhere in this application are incorporated herein by reference in their entirety.
Without limiting the scope of the invention in any way, the invention is briefly summarized in some of its aspects below. Additional details of the invention and/or additional embodiments of the invention may be found in the Detailed Description of the Invention below.
A brief abstract of the technical disclosure in the specification is provided as well for the purposes of complying with 37 C.F.R. 1.72.

Stent with nested flexible connectors for flexibility and crimpability