Described herein is the use of CSF, more particularly external CSF or CSF-like compositions for the treatment and prevention of different diseases. More particularly, the application provides for the administration of CSF to the intrathecal space or the cerebral ventricles of a patient to increase intracranial pressure and/or CSF flow.

The brain and spinal cord are encased within the cranium and vertebral column inside a thin membrane known as the arachnoid. The volume of the intracranial space is on average about 1700 ml including volumes of approximately 1400 ml of brain, approximately 150 ml of intracranial blood; and approximately 150 ml of CSF. CSF circulates within the subarachnoid space and is formed principally by the choroid plexuses, which secrete about 80% of the total volume. The sources of the remainder of CSF are the vasculature of the subependymal regions, and the pia mater. The total volume of CSF is renewed several times per day, so that about 500 ml are produced every 24 hours.
CSF is absorbed through the arachnoid villi, located principally over the superior surfaces of the cerebral hemispheres. Some villi also exist at the base of the brain and along the roots of the spinal nerves. The absorptive processes include bulk transport of large molecules and as well as diffusion across porous membranes of small molecules. See, e.g., Adams et al., (1989) "Principles of Neurology," pp. 501-502.
There are several examples of low-molecular weight proteins or peptides that are known to be present in altered concentrations in CSF of persons suffering from adult-onset dementia of the Alzheimer's type. Alzheimer's disease, the most common type of dementia, is characterized neuropathologically by the presence in the brain of extracellular senile plaques and intracellular neurofibrillary tangles, along with neuronal cell loss. The major component of senile plaques is the low molecular weight peptide beta-amyloid. Neurofibrillary tangles are mainly composed of abnormally phosphorylated tau protein. Studies consistently report decreased levels of beta-amyloid (1-42) in CSF from Alzheimer patients in comparison with healthy subjects. See, e.g., Engelborghs et al., (2008) "Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia," Neurobiol. Aging 29:1143-1159. Beta-2 microglobulin is another example of a low-molecular-weight protein whose concentration in CSF increases with age and reaches high levels in patients with adult-onset dementia of the Alzheimer's type, as reported in Martinez et al., (1993) "Relationship of interleukin-1 beta and beta.sub.2—microglobulin with neuropeptides in cerebrospinal fluid of patients with dementia of the Alzheimer type," J. Neuroimmunology 48: 235-240. Beta-2 microglobulin is associated with amyloid deposits in some tissues of patients on long-term renal hemodialysis. Another substance that accumulates in CSF in patients with adult-onset dementia of the Alzheimer's type is tau, a component of the neurofibrillary tangles found in involved brain tissue. Tau concentrations in CSF are regularly increased in this syndrome with eight fold increases present in half of the patients, as reported in Arai et al., (1995) "Tau in cerebrospinal fluid: a potential diagnostic marker," Ann. Neurology 38: 649-52.
Other neurological diseases are characterized by the presence of inflammatory mediators or neurotoxins, such as central nervous infection, ischemic stroke, subarachnoid hemorrahge, intracerebral hemorrahge, multiple sclerosis, Parkinson's disease traumatic injuries and epilepsy. All of these diseases could theoretically benefit from methods which involve increased CSF turnover and the removal of the concentration of these mediators or toxins.
Previously-known devices have attempted to use filtration techniques to remove or reduce concentrations of harmful proteins from patient body fluids. For example, U.S. Pat. No. 5,334,315 to Matkovich describes a method and device that may be used to remove a body fluid from a patient, treat that fluid to remove an undesirable component, and return the fluid to the patient. Matkovich includes a partial list of the types of deleterious or undesirable substances that may be removed from a fluid, such as proteins, polypeptides, interleukins, immunoglobulins, proteases and interferon. The fluids from which these substances may be removed are described as including CSF, blood, urine and saliva, however, Matkovich does not suggest that his method and device could be used to treat patients suffering from adult-onset dementia of the Alzheimer's type.
Glaucoma is one of the leading causes of irreversible blindness. The most common type of glaucoma is primary open-angle glaucoma (POAG), which is a progressive optic neuropathy with characteristic structural changes in the optic nerve head and corresponding visual field defects. In the glaucomatous optic nerve, cupping of the optic disc reflects a loss of retinal ganglion cell (RGC) axons and a posterior bowing of the lamina cribrosa (forming the anatomic floor of the optic nerve head), accompanied by extensive remodeling of the optic nerve head.
Raised intraocular pressure is recognized as one of the most important risk factors for POAG and lowering it remains the only current therapeutic approach for slowing optic nerve damage and visual field progression in glaucoma patients. Known glaucoma therapies include medicines (e.g., prostaglandin analogues, beta-blockers, carbonic anhydrase inhibitors, and alpha-agonists), laser surgery (e.g., laser trabeculoplasty), and incisional surgery (e.g., trabeculectomy, deep sclerectomy, viscocanalostomy, and glaucoma drainage implants).
Therapy typically starts from the least invasive options, which usually involve the administration of medication. However, the administration of medication often fails for various reasons. Indeed, medicaments for the treatment of POAG typically lower the IOP by at most about 25% to 30%, which can be insufficient. Some glaucoma patients show disease progression despite of the administration of medicaments. Moreover, topical medications for glaucoma can cause side effects such as precipitation of asthma, bradycardia, impotence, and decreased exercise tolerance. There is also a significant problem in compliance with glaucoma medications due to frequent dosing regimens.
Incisional surgery is usually required when (topical) glaucoma medication and/or laser surgery fail. However, current incisional surgery techniques for treating glaucoma can lead to various complications including but not limited to choroidal effusion, hypotony maculopathy, suprachoroidal haemorrhage, and bleb infections.
Accordingly, there is a need for an alternative glaucoma treatment which mitigates at least one of the above problems.
A number of implantable pumps have been described in the art. U.S. Pat. Pub. No. 2005/0090549 (Hildebrand et al.) describes a system and method that may be used to treat pain by administering gabapentin to cerebrospinal fluid (CSF) of a patient. The system includes a pump, a catheter and a reservoir containing an effective amount of gabapentin to treat pain in the patient by pumping the gabapentin through the catheter into CSF. U.S. Pat. Pub. No. 201110021469 (Meythaler et al.) describes intrathecal delivery of baclofen to reduce spasticity. Meythaler describes using refillable programmable pump systems that are implantable and provide continuous infusion of baclofen directly into CSF of a patient. However, neither Hildebrand nor Meythaler disclose or suggest a method or system which involves increasing intracranial pressure and/or CSF turnover, nor suggest the use of such a system to treat glaucoma and/or Alzheimer's disease.

Therapeutic applications of artificial cerebrospinal fluid and tools provided therefor


One or more techniques and/or systems are provided for populating an information interface based upon social media data. For example, users may post, share, and/or discuss various information through social media sources. Accordingly, social media data may be obtained from such social media sources. The social media data may be grouped into sets of social media data based upon temporal information. Within the sets of social media data, social media entries may be clustered into topic clusters (e.g., a royal wedding topic cluster, a plane crash topic cluster, etc.). Event summaries may be generated for respective topic clusters. The event summaries may be used to populate timeslots of an information interface, such as a calendar or timeline, to create annotated timeslots. In this way, the information interface may provide users with an interactive view of events over a time period, such as a year-in-review, based upon social media data.

Many users post and share information through various social networking services. In an example, a user may use a mobile device to capture a soccer championship game photo of a player scoring a winning goal. The user may upload the soccer championship game photo to an image sharing service for other users to view, comment on, share, and/or the like. The user may tag the soccer championship game photo with a hashtag, such as #championshipgoal, which may facilitate discovery of the championship game photo by other users performing an image search. In another example, multiple users of a microblog discussion service may engage in a microblog discussion regarding a recent political debate. In this way, users may share information through image sharing services, microblog discussion services, social network profiles, and/or a variety of other social networking services.

This patent is subject to a terminal disclaimer.

Social media driven information interface


A light source apparatus is configured to generate light efficiently from a light-emitting device. The light source apparatus includes a substrate having a pair of electrodes, a light-emitting device and a transparent resin for sealing the light-emitting device. A white resist layer is formed on the substrate. The white resist layer is formed to cover apart of the electrodes. The white resist layer 6 includes an opening corresponding to the light-emitting device. A white member for controlling a shape of the transparent resin is formed on the white resist layer.

Since light-emitting diodes become able to generate high outputs in recent years, a white LED light source using a light-emitting diode (LED) is widely used to emit white light.
In particular, such white LED light source may be applied to illumination apparatuses which are requested to generate high intensity, to projector apparatuses and backlights for large-scale liquid-crystal displays. For the uses, since the white LED light source has merits that it is mercury-free to have small environmental load, it is excellent in color reproducibility, it is excellent in responsiveness, it can vary intensity and that it is long in product life, a white LED light source is expected as a white light source instead of related-art fluorescent lamps (hot cathode tube and cold cathode tube).
In order to save energy, that is, to improve efficiency in the above-mentioned white LED light source, it is important not only to improve luminous efficiency of the light-emitting diode itself but also to improve efficiency at which light can be emitted from a light-emitting diode chip.
The efficiency at which light can be emitted from the light-emitting diode chip is greatly influenced by assembly members located around the light-emitting diode chip.
Specifically, in order to improve light emitting efficiency, it is necessary to contrive assembly members located around the light-emitting diode chip.
As forms for connecting the electrodes on the substrate to the light-emitting diode chips, there may be a form in which the light-emitting diode packages are arrayed on the substrate, a form in which the light-emitting diode chips are directly mounted on the substrate and connected to the electrodes by wires or the like and a transparent resin is further formed to cover the light-emitting diode chips to seal the light-emitting diode chips (see Patent Document 1 and Patent Document 2, for example) and the like.
[Patent Document 1] Japanese Unexamined Patent Application Publication No. 10-294498
[Patent Document 2]: Japanese Unexamined Patent Application Publication No. 61-144890

Light source apparatus and display apparatus and white resist layer


There are provided novel compounds of formula (I)

This invention relates to new amidine derivatives, processes for their preparation, compositions containing them and their use in therapy.
Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classesxe2x80x94constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been implicated in the pathogenesis of inflammatory diseases. Specific regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states.
Compounds of various structures have been described as inhibitors of NOS and their use in therapy has been claimed. See, for example, WO 95/09619 (The Wellcome Foundation) and WO 95/11231 (G. D. Searle). The applicant has previously disclosed in WO 95/05363 and WO 96/01817 amidine derivatives which are NOS inhibitors which display some selectivity for inhibition of the neuronal enzyme, ncNOS.
We now disclose a group of amidines that are within the generic scope of WO 96/01817, but which are not specifically exemplified in WO 96/01817. These compounds display surprisingly advantageous properties and are the subject of the present application.
According to the invention we provide a compound of formula (I)
wherein:
R1 represents a 2-thienyl or 3-thienyl ring;
and R2 represents hydrogen or C 1 to 4 alkyl;
and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof.
Preferably R1 represents 2-thienyl.
Preferably R2 represents hydrogen, methyl or 2-propyl.
Particularly preferred compounds of the invention include:
N-(4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(4-ethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl))-2-thiophenecarboximidamide;
N-(4-propyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(4-isopropyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-thiophenecarboximidamide;
N-(4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-thiophenecarboximidamide; and pharmaceutically acceptable salts thereof.
More especially preferred compounds of the invention include:
N-(4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(4-isopropyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide; and pharmaceutically acceptable salts thereof.
Unless otherwise indicated, the term xe2x80x9cC 1 to 4 alkylxe2x80x9d referred to herein denotes a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
According to the invention, we further provide a process for the preparation of compounds of formula (I), and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof, which comprises:
(a) preparing a compound of formula (I) by reacting a corresponding compound of formula (II)
wherein R2 is as defined above,
with a compound of formula (III) or an acid addition salt thereof
wherein R1 is as defined above and L is a leaving group;
(b) preparing a compound of formula (I) by reacting a corresponding compound of formula (IV)
wherein R2 is as defined above and HA is an acid,
with a compound of formula (V)
R1xe2x80x94xe2x89xa1Nxe2x80x83xe2x80x83(V)
wherein R1 is as defined above;
(c) preparing a compound of formula (I) in which R2 represents C 1 to 4 alkyl by reacting a corresponding compound of formula (I) in which R2 represents hydrogen with a compound of formula (VI)
R3xe2x80x94Lxe2x80x83xe2x80x83(VI)
wherein R3 represents C 1 to 4 alkyl and L is a leaving group; or
(d) preparing a compound of formula (I) in which R2 represents methyl by reacting a corresponding compound of formula (I) in which R2 represents hydrogen with formaldehyde and formic acid;
and where desired or necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof, or vice versa, and where desired converting the resultant compound of formula (I) into an optical isomer thereof
In process (a), the reaction will take place on stirring a mixture of the reactants in a suitable solvent, for example, N-methyl-2-pyrrolidinone or a lower alkanol such as ethanol, isopropanol or tertiary butanol, at a temperature between room temperature and the reflux temperature of the solvent. The reaction time will depend inter alia on the solvent and the nature of the leaving group, and may be up to 48 hours; however it will typically be from 1 to 24 hours. Suitable leaving groups that L may represent include thioalkyl, sulphonyl, trifluoromethyl sulphonyl, halide, alkyl alcohols, aryl alcohols and tosyl groups; others are recited in xe2x80x98Advanced Organic Chemistryxe2x80x99, J. March (1 985) 3rd Edition, on page 315 and are well known in the art.
In process (b), the reaction is preferably performed by refluxing a mixture of the two compounds for several hours in the presence of a suitable solvent whereby the reaction temperature is high enough so that condensation takes place readily, but not sufficiently high to decompose the amidine formed. The reaction temperature can vary from room temperature to about 250xc2x0 C., although it is preferable to perform the reaction at temperatures from about 100xc2x0 C. to 200 xc2x0 C. We find that o-dichlorobenzene is a particularly suitable solvent. We also find that it is often useful to add 4-dimethylaminopyridine as a catalyst. On cooling, two layers form, the solvent may be decanted, and the reaction worked up by addition of aqueous base. Alternatively, where the reactants are soluble in the solvent, the solvent may be evaporated off under vacuum and the reaction mixture worked up by addition of water. The acid HA may be an organic or inorganic acid, for instance, hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric, phosphoric, acetic, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic or methanesulphonic acid. We prefer that HA is a hydrohalic acid.
In process (c) the reaction will take place under standard conditions, for example by reacting the two compounds in an inert solvent such as DMF under basic conditions at a suitable temperature, typically room temperature, for a period of up to 72 hours or until the reaction is complete. We have frequently found it desirable to treat the amine with NaH before reacting with the compound of formula (VI). Suitable leaving groups L are mentioned above. We prefer that L represents halide, particularly bromide.
In process (d), the reaction will typically take place on refluxing the reaction mixture for up to 4 hours or until reaction is complete.
Salts of compounds of formula (I) may be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble followed by subsequent removal of the solvent in vacuo or by freeze drying. Suitable solvents include, for example, water, dioxan, ethanol, isopropanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The reaction may be a metathetical process or it may be carried out on an ion exchange resin.
The compounds of formula (II) may be prepared by reduction of a corresponding compound of formula (VII)
wherein R2 is as defined above.
The reduction reaction may be performed under a number of conditions, for example those described in J. March xe2x80x9cAdvanced Organic Chemistryxe2x80x9d on pages 1103-1104. These include catalytic hydrogenation, use of Zn, Sn or Fe metal, AlH3xe2x80x94AlCl3, sulphides and others. We prefer to perform the reaction by hydrogenation at atmospheric pressure in the presence of a palladium and carbon catalyst until reaction is complete, typically for 3 to 6 hours, or by reduction using zinc metal in acetic acid and methanol.
Compounds of formula (VII) may be prepared by cyclising a compound of formula (VIII)
wherein R2 is as defined above and L is a leaving group, preferably fluoro;
or by cyclising a compound of formula (IX)
wherein R2 is as defined above and L is a leaving group.
Compounds of formula (VIII) may be prepared by reaction of a compound of formula (X)
wherein L is a leaving group, preferably fluoro,
with a compound of formula (XI)
wherein R2 is as defined above, by the process of reductive amination.
Other syntheses of compounds of formula (VIII) and (IX) will be readily apparent to one skilled in the art. Compounds of formula (VIII) or (IX) may cyclise directly to a compound of formula (VII) without the need for prior isolation. The cyclisation reactions may also take place on removal of protecting groups. In the above reactions it may be desirable to render the nucleophilic group xe2x80x94OH in compounds of formula (VIII) and (IX) more reactive by treatment with base.
Compounds of formula (VII) may also be prepared by nitration of a compound of formula (XII)
wherein R2 is as defined above.
The nitration reaction will take place under conditions well known to a person skilled in the art, for example, on treatment with nitric acid and sulphuric acid or potassium nitrate and sulphuric acid, optionally in an inert organic solvent.
It may also be convenient to prepare compounds of formula (VII) by nitration of a carbonyl or dicarbonyl derivative of a compound of formula (XII); which nitrated carbonyl or dicarbonyl derivative may be reduced to the desired compound of formula (VII) using, for example, diborane.
Compounds of formula (VII) and (XII), as well as certain carbonyl and dicarbonyl derivatives of compounds of formula (XII) just mentioned may also be prepared by one of the numerous methods for preparation of bicyclic heterocyclic compounds.
Compounds of formula (XII) in which R2 represents hydrogen may also be prepared by a synthesis based on ring expansion to convert a cyclic ketone into a cyclic amide (Grunewald and Dahanukar, J. Heterocyclic Chem., 1994, 31, 1609-1617).
Thus, a compound of formula (XIII)
may be converted into a compound of formula (XIV)
on treatment with sodium azide in acid. Further details of the reaction conditions may be obtained by reference to the above mentioned Grunewald and Dahanukar paper.
It will be apparent to a person skilled in the art that the compounds of formula (XIV) may also desirably be prepared in nitrated form. Nitration may be achieved by treatment of the non-nitrated analogue with nitric acid and sulphuric acid or potassium nitrate and sulphuric acid under standard conditions.
Intermediate compounds may be prepared as such or in protected form. In particular amine and hydroxyl groups may be protected. Suitable protecting groups are described in the standard text xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Edition (1991) by Greene and Wuts. Amine-protecting groups which may be mentioned include alkyloxycarbonyl such as t-butyloxycarbonyl, phenylalkyloxycarbonyl such as benzyloxycarbonyl, or trifluoroacetate. Deprotection will normally take place on treatment with aqueous base or aqueous acid.
Compounds of formula (VII), (VIII), (IX), (XI) and (XII) in which R2 represents C 1 to 4 alkyl may also be prepared by alkylating the corresponding compound in which R2 represents hydrogen following process (c) above.
Compounds of formula (IV) may be prepared by analogous processes to those described for the preparation of compounds of formula (II). Compounds of formula (IV) may be converted into corresponding compounds of formula (II) by treatment with a base. Compounds of formula (II) may be converted into corresponding compounds of formula (IV) by treatment with a protic acid HA, for example, one of those listed above.
Compounds of formula (III) are either known or may be prepared by known methods. For example, compounds of formula (III) in which L represents thioalkyl may be prepared by treatment of the corresponding thioamide of formula (XV)
wherein R1 is as defined above, with an alkylhalide under conditions well known to a person skilled in the art.
Alternatively, the acid addition salts of compounds of formula (III) wherein L is thioalkyl may be prepared by reaction of a nitrile of formula (V) with an alkyl thiol and acid, for example hydrochloric acid, in a solvent such as dichloromethane or diethyl ether.
Compounds of formula (V), (VI), (X), (XI), (XIII), (XIV) and (XV) are either known or may be prepared by conventional methods known per se.
It will be apparent to a person skilled in the art that it may be desirable to protect an amine or other reactive group in an intermediate compound using a protecting group as described in the standard text xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Edition (1991) by Greene and Wuts. Suitable amine-protecting groups are mentioned above.
The compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.
The compounds of formula (I) may exist in tautomeric, enantiomeric or diastereoisomeric forms, all of which are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation or HPLC. Alternatively, the individual enantiomers may be made by reaction of the appropriate optically active starting materials under reaction conditions which will not cause racemisation.
Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.
The compounds of general formula (I) possess useful nitric oxide synthase inhibiting activity, and in particular, they exhibit good selectivity for inhibition of the neuronal isoform of nitric oxide synthase. They are thus useful in the treatment or prophylaxis of human diseases or conditions in which the synthesis or oversynthesis of nitric oxide by nitric oxide synthase forms a contributory part. Examples of such diseases or conditions include hypoxia, such as in cases of cardiac arrest, stroke and neonatal hypoxia, neurodegenerative conditions including nerve degeneration and/or nerve necrosis in disorders such as ischaemia, hypoxia, hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia, for example, pre-senile dementia, Alzheimer""s disease and AIDS-related dementia, Sydenham""s chorea, Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Korsakoffs disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, anxiety, depression, seasonal affective disorder, jet-lag, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock. The compounds of formula (I) are also useful in the treatment and alleviation of acute or persistent inflammatory or neuropathic pain, or pain of central origin, and in the treatment or prophylaxis of inflammation. Compounds of formula (I) may also be expected to show activity in the prevention and reversal of tolerance to opiates and diazepines, treatment of drug addiction and treatment of migraine and other vascular headaches. The compounds of the present invention may also show useful immunosuppressive activity, and be useful in the treatment of gastrointestinal motility disorders, and in the induction of labour. The compounds may also be useful in the treatment of cancers that express nitric oxide synthase.
Compounds of formula (I) are predicted to be particularly useful in the treatment or prophylaxis of hypoxia or stroke or ischaemia or neurodegenerative conditions or schizophrenia or migraine or for the prevention and reversal of tolerance to opiates and diazepines or for the treatment of drug addiction or for the treatment of pain and especially in the treatment or prophylaxis of hypoxia or stroke or ischaemia or neurodegenerative disorders or schizophrenia or pain. We are particularly interested in conditions selected from the group consisting of hypoxia, ischaemia, stroke, pain, schizophrenia, Parkinson""s disease, Huntington""s disease and Amyotrophic Lateral Sclerosis.
For the treatment of pain, the compounds of formula (I) are expected to be particularly useful either alone, or in combination with other agents such as opiates, particularly morphine.
For the treatment of Parkinson""s disease, the compounds of formula (I) are expected to be particularly useful either alone, or in combination with other agents such as L-Dopa.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
Thus according to a further aspect of the invention we provide a compound of formula (I), or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
According to another feature of the invention we provide the use of a compound of formula (I) or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of the aforementioned diseases or conditions; and a method of treatment or prophylaxis of one of the aforementioned diseases or conditions which comprises administering a therapeutically effective amount of a compound of formula (I), or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, to a person suffering from or susceptible to such a disease or condition.
For the above mentioned therapeutic indications, the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.5 mg and 2000 mg (measured as the active ingredient) per day, particularly at a daily dosage of between 2 mg and 500 mg.
The compounds of formula (I), and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof, may be used on their own, or in the form of appropriate medicinal formulations. Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, or topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, xe2x80x9cPharmaceuticalsxe2x80x94The Science of Dosage Form Designsxe2x80x9d, M. E. Aulton, Churchill Livingstone, 1988.
According to the invention, there is provided a pharmaceutical formulation comprising preferably less than 95% by weight and more preferably less than 50% by weight of a compound of formula (I), or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier. The formulation may optionally also contain a second pharmacologically active ingredient such as L-Dopa, or an opiate analgesic such as morphine.
We also provide a method of preparation of such a pharmaceutical formulation which comprises mixing the ingredients.
Examples of such diluents and carriers are: for tablets and dragees: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose; for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: natural or hardened oils or waxes.
Compositions in a form suitable for oral, that is oesophageal, administration include: tablets, capsules and dragees; sustained release compositions include those in which the active ingredient is bound to an ion exchange resin which is optionally coated with a diffusion barrier to modify the release properties of the resin.
The enzyme nitric oxide synthase has a number of isoforms and compounds of formula (I), and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof, may be screened for nitric oxide synthase inhibiting activity by following procedures based on those of Bredt and Snyder in Proc. Natl. Acad. Sci., 1990, 87, 682-685. Nitric oxide synthase converts 3H-L-arginine into 3H-L-citrulline which can be separated by cation exchange chromatography and quantified by scintillation counting.
Screen for Neuronal Nitric Oxide Synthase Inhibiting Activity
The enzyme is isolated from rat hippocampus or cerebellum. The cerebellum or hippocampus of a male Sprague-Dawley rat (250-275 g) is removed following CO2 anaesthesia of the animal and decapitation. Cerebellar or hippocampal supernatant is prepared by homogenisation in 50 mM Tris-HCl with 1 mM EDTA buffer (pH 7.2 at 25xc2x0 C.) and centifugation for 15 minutes at 20,000 g. Residual L-arginine is removed from the supernatant by chromatography through Dowex AG-50W-X8 sodium form and 25 hydrogen form columns successively, and further centrifugation at 1000 g for 30 seconds.
For the assay, 25 xcexcl of the final supernatant is added to each of 96 wells (of a 96 well filter plate) containing either 25 xcexcl of an assay buffer (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl2, pH 7.4) or 25 xcexcl of test compound in the buffer at 22xc2x0 C. and 25 xcexcl of complete assay buffer (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl2, 1 mM DTT, 100 xcexcM NADPH, 10 xcexcg/ml calmodulin, pH 7.4). Following a 10 minute equilibration period, 25 xcexcl of an L-arginine solution (of concentration 18 xcexcM 1H-L-arginine, 96 nM 3H-L-arginine) is added to each well to initiate the reaction. The reaction is stopped after 10 minutes by addition of 200 xcexcl of a slurry of termination buffer (20 mM HEPES, 2 mM EDTA, pH 5.5) and Dowex AG-50W-X8 200-400 mesh.
Labelled L-citrulline is separated from labelled L-arginine by filtering each filter plate and 75 xcexcl of each terminated reaction is added to 3 ml of scintillation cocktail. The L-citrulline is then quantified by scintillation counting.
In a typical experiment using the cerebellar supernatant, basal activity is increased by 20,000 dpm/ml of sample above a reagent blank which has an activity of 7,000 dpm/ml. A reference standard, N-nitro-L-arginine, which gives 80% inhibition of nitric oxide synthase at a concentration of 1 xcexcM, is tested in the assay to verify the procedure.
Screen for Endothelial Nitric Oxide Synthase Inhibiting Activity
The enzyme is isolated from human umbilical vein endothelial cells (HUVECs) by a procedure based on that of Pollock et al in Proc. Natl. Acad. Sci., 1991, 88, 10480-10484. HUVECs were purchased from Clonetics Corp (San Diego, Calif., USA) and cultured to confluency. Cells can be maintained to passage 35-40 without significant loss of yield of nitric oxide synthase. When cells reach confluency, they are resuspended in Dulbecco""s phosphate buffered saline, centrifuged at 800 rpm for 10 minutes, and the cell pellet is then homogenised in ice-cold 50 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM phenylmethylsulphonylfluoride, 2 xcexcM leupeptin at pH 4.2. Following centrifugation at 34,000 rpm for 60 minutes, the pellet is solubilised in the homogenisation buffer which also contains 20 mM CHAPS. After a 30 minute incubation on ice, the suspension is centrifuged at 34,000 rpm for 30 minutes. The resulting supernatant is stored at xe2x88x9280xc2x0 C. until use.
For the assay, 25 xcexcl of the final supernatant is added to each of 12 test tubes containing 25 xcexcl L-arginine solution (of concentration 12 xcexcM 1H-L-arginine, 64 nM 3H-L-arginine) and either 25 xcexcl of an assay buffer (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl2, pH 7.4) or 25 xcexcl of test compound in the buffer at 22xc2x0 C. To each test tube was added 25 xcexcl of complete assay buffer (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl2, 1 mM DTT, 100 xcexcM NADPH, 10 xcexcg/ml calmodulin, 12 xcexcM tetrahydrobiopterin, pH 7.4) to initiate the reaction and the reaction is stopped after 10 minutes by addition of 2 ml of a termination buffer (20 mM HEPES, 2 mM EDTA, pH 5.5).
Labelled L-citrulline is separated from labelled L-arginine by chromatography over a Dowex AG-50W-X8 200-400 mesh column. A 1 ml portion of each terminated reaction mixture is added to an individual I ml column and the eluant combined with that from two 1 ml distilled water washes and 16 ml of scintillation cocktail. The L-citrulline is then quantified by scintillation counting.
In a typical experiment, basal activity is increased by 5,000 dpm/ml of sample above a reagent blank which has an activity of 1500 dprn/ml. A reference standard, N-nitro-L-arginine, which gives 70-90% inhibition of nitric oxide synthetase at a concentration of 1 xcexcM, is tested in the assay to verify the procedure.
In the screens for nitric oxide synthase inhibition activity, compound activity is expressed as IC50 (the concentration of drug substance which gives 50% enzyme inhibition in the assay). IC50 values for test compounds were initially estimated from the inhibiting activity of 1, 10 and 100 xcexcM solutions of the compounds. Compounds that inhibited the enzyme by at least 50% at 10 xcexcM were re-tested using more appropriate concentrations so that an IC50 could be determined.
When tested in the above screens, the compounds of Examples 1 to 7 below showed lC50 values for inhibition of neuronal nitric oxide synthase of less than 10 xcexcM and good selectivity for inhibition of the neuronal isoform of the enzyme, indicating that they are predicted to show particularly useful therapeutic activity.
When compared with other compounds, the compounds of formula (I), and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof, have the advantage that they may be less toxic, be more efficacious, be longer acting, have a broader range of activity, be more potent, be more selective for the neuronal isoform of nitric oxide synthase enzyme, produce fewer side effects, be more easily absorbed or have other useful pharmacological properties.
The invention is illustrated by the following examples:

Amidine derivatives as inhibitors of nitric oxide synthase

Abstract: wherein R1 represents a 2-thienyl or 3-thienyl ring and R2 represents hydrogen or C 1 to 4 alkyl and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are selective inhibitors of the neuronal isoform of nitric oxide synthase.


An active hybrid circuit for a full duplex channel generates a duplicated voltage at the current output stage to reduce the energy of the transmitter transmitted to the receiver. The active hybrid circuit cancels the energy of the transmitter transmitted to the receiver when it is operated in a full duplex channel with high-speed transmission. The active hybrid circuit for full a duplex channel comprises a transmit digital-to-analog converter for generating an analog transmit signal, a receive analog-to-digital converter for receiving an analog receive signal, a duplicated voltage digital-to-analog converter for generating a corresponding duplicated voltage according to the analog transmit signal of the transmit digital-to-analog converter, and a plurality of signal combiners for subtracting the duplicated voltage from the analog transmit signal to cancel the influence of analog transmit signal to the analog receive signal.

1. Field of the Invention
The present invention relates to an active hybrid circuit for use in a full duplex channel. In particular, this invention provides an active hybrid circuit to generate a duplicated voltage of a current output stage for reducing the energy of the transmitter echoing to the receiver when the hybrid circuit is operated in a full duplex channel.
2. Description of the Related Art
Due to the demand for information communication, such as the transmission of data, sound, and video, the data transmission rate has improved continually as the hardware and communication protocol have progressed to achieve high-speed and real time transmission. Information transmission and business transactions over the Internet have increased as personal computers, workstations and servers become more and more popular. For Ethernet, the transmission rate has also improved from the early original 10 Mbps of the IEEE 802.3 10BASE-T standard, 100 Mbps of the IEEE 802.3u 100BASE-T standard, to 1 Gbps of the IEEE 802.3ab 1000BASE-T standard. 1 Gbps Ethernet is also called a Gigabit Ethernet.
However, when a Gigabit Ethernet is operated over a full duplex channel, meaning a high-speed bi-directional transmission, the energy of the transmitter is coupled to the receiver of the transceiver. The signal at the receiver will be disturbed by the signal at the transmitter. If the signals are not processed appropriately, the signals at the receiver will be incorrect or the range of the transmitted signal will be shorter.
To solve the problems identified above, many hybrid circuits have been developed. Hybrid circuits can be classified into voltage output stages and current output stages. The voltage output stage includes transformer hybrids and resistive hybrids. The current output stage includes, for example, transformer hybrids, resistive hybrids, duplicated current hybrids and duplicated voltage generator hybrids.
U.S. Pat. No. 6,775,529, "Active resistive summer for a transformer hybrid", discloses an active resistive summer, as shown in FIG. 1. The active resistive summer comprises an operational amplifier 11, a feedback resistor RF1 and a plurality of resistors R11, R12, R13. A composite signal and a replica signal are inputted into the active resistive summer and a receiving signal is produced. The replica signal is subtracted from the composite signal to obtain the receiving signal. This method needs to generate a duplicated current which passes through a high-precision resistor to obtain a duplicated voltage. Therefore, a trimming operation is necessary when the IC is packaged in order to obtain the high-precision resistor in the IC.
U.S. Pat. No. 6,744,831, titled as "Adaptive electronic transmission signal cancellation apparatus for full duplex communication", discloses an adaptive electronic transmission signal cancellation apparatus. This apparatus generates a first duplicated transmission signal to cancel the signal in the receiver that comes from the transmitter. At the same time, by utilizing the characteristic of the transmitter and the first duplicated transmission signal, a second duplicated transmission signal is generated to cancel the excess current of the signal at the transmitter. In this apparatus, a trimming operation is also necessary when the IC is packaged.
U.S. Pat. No. 6,665,347, "Output driver for high speed Ethernet transceiver", discloses an output driver combination, as shown in FIG. 2. The output driver combination comprises a current driver 20, a voltage driver 21, a transformer 22 and a plurality of resistors R23, R24, R25, R26, R27, R28, R29. This driver can operate in two operation modes, including high speed and low speed. However, the output driver cannot be used at high-speed and a low supply voltage.
U.S. Pat. No. 6,792,105, "Current-mode differential active hybrid circuit", discloses a current-mode differential active hybrid circuit. The active hybrid circuit comprises a first output H-bridge (including a first transistor and a first output resistor), a drive circuit, a second output H-bridge and a second output resistor. The drawback of this device is its high pin count in the IC. Because the characteristics of the transformer are not perfect, the above method cannot completely eliminate the disturbance at the receiver caused by the transmitted signal.

Active hybrid circuit for a full duplex channel


The present invention relates to a container for cooking food in a microwave oven. The container includes a tray having a bottom wall and a side wall that is attached to the bottom wall and extends upwardly from the bottom wall to define an interior cavity and a support means to provide support for a food product and elevate the food product with respect to the bottom wall. A continuous shielding layer is provided in the bottom wall and the side wall of the tray. The bottom wall and side wall of the tray along with the bottom of the food product define a free space under the food product that totally reflects microwave beams that pass through the food product back in the direction of the food product. The container of the invention reduces the formation of temperature gradients in the food product when it is heated and accelerates the microwave reheating of the food product. The container is particularly useful for reheating large blocks of frozen food.

The present invention relates to a container for reheating frozen food products in a microwave oven. The invention is particularly useful for reheating large size frozen meals that typically require excessively long heating times.
The long length of time required to reheat large size frozen meals in a microwave oven is a real concern in the food service and catering business. For individual portions or small size frozen meals, reheating in a domestic microwave oven, can be carried out in a relatively short period of time, generally in the range of 2 to 6 minutes, depending on such factors as, for example, the type of foods, the size of the food components, and the lay-out of the various food components in the tray. For large size frozen meals, however, microwave reheating has proven to be excessively long, for example, up to 30 minutes. These long reheating times for large frozen meals renders the use of microwave ovens less attractive.
Another problem with re-heating frozen products in a microwave oven is that temperature gradients occur in the food when it is reheated in most known containers. Before the food product is thawed, the frozen product is essentially transparent to microwaves so that the microwaves are only absorbed at a very low rate, or not absorbed at all. When a frozen product is reheated in a regular microwave transparent container the microwave energy is not properly absorbed by the frozen mass. Instead the major portion of the energy is concentrated at the interface region where the container contacts the frozen product. This uneven energy distribution is not equalized by convection heat transfer and results in excessive heating at the edges of the container with the core of the frozen mass remaining at a very low temperature. The microwave heating pattern of a large frozen dish is generally characterized by the presence of large cold spots in the center of the upper surface, by a very late thawing of the inner parts of the product, and by overheating at the edges and corners of the product.
EP 348 156 to Hewitt relates to an improvement in microwave heating wherein a microwave mode is generated from underneath the food product. The food product is disposed in a tray that is transparent to microwaves and the tray is placed on a stand so that a predetermined elevation is maintained between the bottom surface of the food product and the internal bottom surface of the stand. Heating from underneath occurs by placing separated electrically conductive plates at the bottom of the stand which are made of a microwave transparent material, or by making apertures in the electrically conductive bottom of the supporting stand. The purpose is to have a majority of the microwave energy enter through the undersurface of the container and maximize the bottom heating effect.
EP 185 488 to Sugisawa discloses a container, made of a material that is transparent to microwaves for use in a microwave oven. The container has a microwave reflecting strip that partly covers the region of the container where the upper surface of the material contacts the side of the container to prevent local over-heating of the food product. The container, however, brings no significant improvements in reheating of frozen foods and simply proposes a solution to the problem of local burning at the edges of the product when the product is reheated in a conventional transparent container.
EP 471 969 to Payne relates to the use of a microwave susceptor sleeve for pizza and the like onto which the food items are placed. The susceptor, with the food product on it, is placed on a supporting base. The supporting base is elevated with respect to the bottom of the microwave oven by the use of pre-cut legs. The elevation of the base supporting the susceptor is dictated by the need to separate the susceptor from the bottom of the microwave oven sole (i.e., the bottom surface of the oven cavity) to eliminate the risk of arcing when the oven does not have a glass shelf.
WO 93 23971 A to the Campbell Soup Company relates to a microwave metallic container wherein the bottom and the whole lateral walls are externally insulated using a polymeric or glass thin layer that completely isolates the container from the metallic parts of the microwave oven. The main features of the container are that it prevents arcing by insulating the aluminum inner tray. For better convenience and for a better heat distribution within foodstuffs that do not retain their initial shape, such as liquid foodstuffs, the bottom of the aluminum container may be slightly raised or domed so that the thickness of the product in the center of the container is reduced, since it is predominately the center of the product that has a cold spot upon microwave heating. Variations in the thickness of foodstuffs are, however, generally undesirable as it might create problems when removing the foodstuff from the container. In particular, the center of the foodstuff becomes more fragile than the periphery and this may lead to portions of the foodstuff breaking off when the foodstuff is removed from the tray. The slanted bottom of the tray also results in a more acute angle between the bottom and the sidewalls of the tray that further renders it more difficult to remove the foodstuff from the tray. Finally although the thickness of the foodstuff to be heated is reduced in the center part of the tray, the slanted bottom portion of the domed tray has a tendency to reflect the microwaves in an upward diverging direction and away from the center which causes a reduction in the microwave absorption in the center part of the foodstuff, and consequently cold spots in the center part of the foodstuff.
U.S. Pat. No. 5,310,980 to Beckett discloses the incorporation of metallic patches on a microwave transparent tray in order to orient the impinging microwave energy beams selectively towards parts of the product that do not heat-up appropriately.
EP 350 660 A2 to Jaeger relates to a susceptor sheet with a microwave transparent packaging.
U.S. Pat. No. 4,642,434 to Cox et al. relates to a microwave reflecting energy concentrating spacer that includes in its lower part a microwave reflector separated from the food base by a distance of about xc2xcof a wave length, i.e., about 3 cm, since the free space wave length at the microwave emitted frequency in the microwave oven (2.45 GHz) is about 12 cm.
EP 242 026 A2 to Swiontek discloses an assembly between a susceptor which is described as a xe2x80x9cmicrowave interactive layerxe2x80x9d and the whole package.
U.S. Pat. No. 4,656,325 to Keefer refers to xe2x80x9ccold susceptorsxe2x80x9d by placing metallic patches disposed in a regular array on the cover of a pan containing the food product.
U.S. Pat. No. 4,888,459 to Keefer also refers to xe2x80x9ccold susceptorsxe2x80x9d in addition to optimizing the thickness and the dielectric permittivity of the material constituting the non-reflecting part.
U.S. Pat. No. 5,270,502 to Brown et al. relates to a combination of a microwave interactive layer that is in fact a susceptor and a supporting stand made of a microwave transparent material.
WO 95 24 110 to Gics relates to an ovenable food package comprising a microwave susceptor placed beneath the food base in order to induce crispiness in the food base.
U.S. Pat. No. 4,496,815 to Jorgensen relates to a microwave browning utensil comprising a metallic base with a ferrite layer that is a highly microwave absorbing material.
U.S. Pat. No. 4,542,271 to Tanonis et al. relates to a microwave tray comprising an absorbing material placed beneath the bottom surface of the tray.
U.S. Pat. No. 4,927,991 to Wendt et al. relates to a microwave oven package comprising a combination of a grid and susceptors inside a microwave-transparent tray that behaves like a conventional frying pan as it is heated by microwave radiation that passes through the tray.
EP-A-0 451 530 to Peleg proposes to combine a susceptor sheet and a layer of heat absorbing material to control the heat flux to the bottom surface of the food product that is placed on the arrangement.
GB 2 226 220 to Mason discloses to a microwave-transparent tray with a microwave-transparent planar insert that raises the food product with respect to the tray bottom so that excess water and the fat from the food product may be collected into the base of the container below the supporting board.
U.S. Pat. No. 5,151,568 to Rippley is similar to the previous document with a corrugated wall placed on the bottom of the tray, instead of a planar insert. An absorbing material may be placed underneath the corrugated wall. Both the container and the corrugated wall are made of stiff paperboard material that is transparent to microwaves. The apertures in the corrugated allow liquids released by the food product during the heating to drain.
U.S. Pat. No. 5,041,295 to Perry et al. discloses a device made of a susceptor sheet and a thermal insulating pad or a rigid supporting layer so that the susceptor is thermally insulated from the bottom surface of the microwave oven.
WO 92 03355 to Guillot relates to a packaging device made completely of plastic having the general form of a container with a bottom and a sidewall. The plastic container and its lid are assembled in a snap-fitting arrangement.
U.S. Pat. No. 4,661,672 to Nakanaga discloses a container made of microwave-transparent material, the bottom surface of which is maintained at a prescribed elevation with respect to the floor of the oven, and a metallic device which is placed on the upper part of the food product in the container to control the uniformity of heating by preventing the upper parts and the edges of the food product from overheating.
Other prior art documents on microwave packaging are U.S. Pat. Nos. 4,994,638 and 4,535,889.
There remains a need for a container to cook frozen food products in a microwave oven that promotes a uniform and efficient distribution of heat within the product and avoids temperature gradients within the product after it is heated. There is also a need for a container that accelerates the microwave reheating of frozen food products, in particular, large blocks of frozen food.
The present invention is directed to a container for cooking food in a microwave oven. The container includes a tray having a bottom wall and a continuous side wall attached to the bottom wall and extending upwardly from the bottom wall, wherein the bottom wall and side wall define an interior cavity. The container also includes a support means made of a material that is substantially transparent to microwave radiation to support a food having a top surface and a bottom surface in the interior cavity. The food is supported in an elevated position above the bottom wall so that the bottom surface of the food is nearest to the bottom wall and the bottom surface of the food and the bottom wall are separated by a distance. The bottom wall of the tray, the bottom of the food, and at least part of the side wall defines a free space underneath the food, wherein the bottom wall and at least that part of the side wall that defines the free space are constructed to reflect substantially all microwave radiation that passes through the food back toward the food.
The side wall can extend upwardly above the free space at least to the upper surface of the food and is constructed to reflect microwave radiation to more quickly and uniformly heat the food.
The container may have a lid. The lid may be made of a material that is transparent to microwave radiation. At least a portion of the lid may be adapted to serve as the support means after the container has been opened. The lid may include a flat member and a peripheral edge that extends downwardly from the flat member and fits inside the interior cavity with the peripheral edge contacting the bottom wall of the container. The lid may include a flat member, a peripheral edge that extends downwardly from the flat member so that it forms a cavity for receiving the food when it is turned upside down, and a side edge associated with the peripheral edge and protruding outwardly from the cavity so that the side edge abuts with and is supported by the side wall of the tray and the flat member of the lid and the bottom wall are separated by a distance to provide the free space when the lid is turned upside down and placed in the tray.
The distance between the bottom surface of the food and the bottom wall may be at least about 2 millimeters but less than about 20 mm. The bottom wall and side wall part that defines the free space may constructed of a metallic material such as aluminum or an aluminum alloy. The tray may be a single unit made entirely of a metallic material that reflects microwave radiation. The tray may also be in a multilayer arrangement with at least one layer being a metallic layer that reflects microwave radiation.
The support means may be a flat member for receiving the food and at least one spacing member between the bottom wall and the flat member. In one embodiment there are a plurality of spacing members which are substantially evenly distributed and attached to the flat member. In another embodiment the at least one spacing member may be attached to the tray. The spacing member may also be a peripheral shoulder on the side wall directed toward the interior cavity onto which the flat member is positioned or a plurality of glass or plastic marbles that directly contacts the food. The support means may be collapsible and may be an inflatable bag having a series of air cells that define interior channels that can be inflated with air before cooking.
The side wall of the container may have one or more corners that are angled and further include a microwave opaque material that spans the side walls at the corners to concentrate the microwave radiation in the corners. The container may have a lid to provide the opaque material wherein the lid has a main central portion made of a material that is transparent to microwave radiation and microwave opaque portions are attached thereto. The container may have a cavity that is at least about 1 liter, and wherein the entire sidewall is constructed to reflect microwave radiation.
In one embodiment of the container the tray is a lid that in one position covers the support means and the food and in an inverted position forms the free space beneath the food. The support means may include a side wall to form the interior cavity and be configured to have a smaller periphery that than the side wall of the lid, and include spacer means for limiting the depth that the support means can be inserted into the lid. The spacer means may be a shoulder associated with one of the side walls.
The invention is also directed to a method for uniform microwave heating of food. The method involves providing a food having a top surface and a bottom surface, placing the food on a support means that is made of a material that is substantially transparent to microwave radiation, providing a free space beneath the bottom surface of the food wherein the bottom surface of the food wherein the bottom surface of the food is separated from a bottom surface of the free space by a distance and the free space is constructed to reflect substantially all microwave radiation that passes through the food back toward the food, and exposing the food to microwave radiation for a sufficient time to cook the food. The food product may be a frozen food product. The distance between the bottom surface of the food and the bottom surface of the free space may be between about 2 and 20 mm and the thickness of the frozen food product may be between about 28 and 60 mm. The support means may be surrounded by a side wall that has corners and the method may further include providing a microwave opaque material that spans the corners of the side wall to concentrate the microwave radiation in the corners.

Container for heating rapidly and evenly frozen foods in a microwave oven


Improved techniques are disclosed for adapting signature verification systems to natural signature variations. For example, a technique for adapting a signature verification system to variations in a signature of a user includes the following steps/operations. One or more signature samples are obtained from the user. The one or more obtained signature samples are submitted by the user as part of a regular authentication procedure associated with the signature verification system. A reference set of signature samples for the user is updated through selection of one or more signature samples from the obtained signature samples, such that the updated reference set is usable by the signature verification system for verifying subsequent signature samples attributed to the user. The selection of the one or more signature samples used to update the reference set is conditioned on a false rejection rate of the user when at least one obtained signature sample of the user is authenticated and on an identification check when no obtained signature sample is authenticated.

Signature verification is a commonly used biometric authentication method. Compared with other forms of biometric authentication such as fingerprint or iris verification, signature verification has the advantage that it is a historically well-established and well-accepted approbation method and is thus perceived to be less intrusive than modern alternatives. This property makes it particularly attractive to applications in banking, retail and hospitality industries.
Signature verification is divided into two main areas: static (offline) signature verification where signature samples are optically scanned into image representations, and dynamic (online) signature verification where signature samples are collected from a digitizing tablet capable of recording pen movements during writing.
In general, the process of signature verification involves comparing a new signature submitted for testing to a set of previously collected reference signatures to determine whether the new signature is authentic. Having a set of references that captures the natural variation among different authentic signatures of the same subject is crucial for a verification system to operate effectively.
In existing systems, a number of signature samples (typically five to ten) are collected in one enrollment session and used as reference samples. However, there are a number of drawbacks with this scheme.
First, in some applications such as retail, collecting many samples during one enrollment session puts an undue burden on customers. Ideally, the number of signature samples collected during initial enrollment should be limited to no more than three.
Second, even if more samples can be collected during enrollment, samples collected in one session are typically not very representative of the natural variation exhibited by most signers. Often, a larger degree of variation is observed on samples collected from different sessions with long breaks (i.e., days) in between. Furthermore, it is known that samples collected in one session can not capture the "drift" (i.e., a slow shifting of style over a period of time) which is also common among signers.
One known solution to these problems is to first collect the reference samples over several enrollment sessions to capture the current range of variation, then have periodic "re-enrollment" sessions (e.g., once a year) to capture the signature drift. However, this is not very practical because of the extra burden placed on the customers.
Another known solution is to add to the reference set, at a time during or after the regular authentication (e.g., sign-in verification) process, any signature sample that produced a high enough score during verification. However, this policy is not very effective since setting the threshold too high will only allow the addition of samples that are very close to the initial reference samples, thus defeating the purpose of capturing more variation; while setting it too low will increase the risk of adding forgeries, thus polluting the reference set.

Method and apparatus for rolling enrollment for signature verification

International Business Machines Corporation


A post mounting system for a body mounted camera mounting system includes a grip to go about the post of the system and a vernier clamp. The vernier clamp includes a vernier ring which is slidable axially and fixed angularly to the grip. A vernier nut threadably engages the grip and is rotatable on the vernier ring. A clamp ring is integrally formed with the vernier ring and is castellated to be compressible against the post extending through the device. A split clamp ring cooperates with a cam lever for easy clamping of the clamp ring to the castellated ring. An alignment chuck is also associated with the grip for precise alignment of the post in the post mounting system.

The field of the present invention is structural hardware employed with body mounted camera equipment.
Motion isolating mounting equipment used for mounting a cinematographic camera to a cameraman has been available since the mid 1970's. Such equipment has been designed to very substantially isolate the motion of the supporting body from the camera. At the same time, such systems provide suspending support for a cinematographic camera of substantial weight. Such supported cameras are capable of being lightly guided by the hand of the camraman to exhibit relatively universal motion. A number of patents issued on such early equipment include U.S. Pat. Nos. 4,017,168; 4,156,512; 4,208,028 and 4,394,075.
The load to be carried by such mounting equipment typically includes a tube chassis, or post, with a camera platform at the upper end and batteries and other elements at the other, this assembly being referred to as a sled, and the cinematographic camera atop the platform. The post has a handle for manipulating the assembly. A three-axis gimbal mechanism, the axes being referred to as pan, tilt and roll, is attached to the post near but above the effective center of gravity of the entire assembly including the camera. The gimbal mechanism is supported by the motion isolating mounting equipment. One such assembly including a post and three axis gimbal mechanism is illustrated in U.S. Pat. No. 5,752,112, the disclosure of which is incorporated herein by reference. Motion isolating mounting equipment to carry such an assembly is disclosed in U.S. Pat. Nos. 6,030,130 and 6,347,892, the disclosures of which are incorporated herein by reference.
Because of the weight and bulkiness of such systems, proper set up is both critical and difficult. One area of concern has been the location of the gimbal relative to the center of gravity and center of moments. Some natural righting is desirable. Consequently, the gimbal is typically found slightly above the center of gravity. Obtaining that precise sweet spot can be difficult. Further, certain circumstances and shot sequences may require some adjustment to that position for advantageous effect. Clamps have been employed between the gimbal and the post. Unclamping of the gimbal from the post is typically required for adjustment to the relative location of the gimbal to the center of gravity.


A method comprising generating a surface detail model using a modeling technique, and rendering surface detail in accordance with the developed surface detail model over an object surface. The described method enables computer-generated images containing representations of hair to be rendered in real time.

Recent advances in computing power and related technology have fostered the development of a new generation of powerful software applications. Gaming applications, communications applications, and multimedia applications have all benefited from increased processing power and clocking speeds. Indeed, the field of computer graphics, leveraged by a myriad of applications, has particularly benefited by the improved processing capability found in even the most rudimentary computing devices. Examples abound, from gaming applications which once utilized simple stick figures are now capable of rendering near life-like images of people, animals, and the like. In the realm of media, movies that once relied on clumsy animation for special effects now benefit from the ability to render life-like computer images.
This ability to create and render life-like characters has added a level of realism and personality to gaming applications, modeling applications, multimedia applications, and the like. While the increased processing power/speed has improved the quality of the rendered images used in such applications, a number of problems remain in generating life-like characters in near real-time to support interactive applications such as, for example, gaming applications, multimedia applications where the user dynamically controls camera angles and proximity to subject of the media content. One major problem that remains in generating and rendering life-like characters in near real-time is the inability of current computer graphics technology to dynamically render realistic hair (used interchangeably herein with fur, scales, etc.).
One of the distinguishing characteristics of mammals is that they are covered in hair (used interchangeable herein to describe hair, fur, scales, etc.). Thus, in order to render a life-like representation of such a mammal, the application modeling the creature must attempt to cover at least select surfaces of the character in hair. Prior art approaches to modeling such surface characteristics relied on ray-tracing, Introduced by Kajiya and Kay in a presentation entitled Rendering fur with three dimensional textures, in the Proceedings of SIGGRAPH 1989, pages 271-280. In the Kajiya et al. ray-traced approach, a model with explicit geometric detail is represented as a volume of textures. While fine geometric modeling of surface features using ray tracing can provide convincing surface features, it is computationally expensive and is not, therefore, conducive to an application that supports interactive features.
Thus, a method and apparatus for modeling and rendering surface detail is presented, unencumbered by the deficiencies and limitations commonly associated with the prior art.

Method and apparatus for modeling and real-time rendering of surface detail