A variable sampling-rate digital channel phase detector for reading synchronous data recordings from magnetic or optical media. All-digital implementation allows multiplexing of several parallel channels on a single monolithic chip for tape storage systems or other magnetic or optical data storage systems. The ASDD channel signal processing is entirely digital and includes A/D converter, digital filter and equalizer, digital differentiator and zero-crossing detector, peak amplitude estimator, zero-crossing qualifier and zero-crossing position (phase) estimator. The ASDD input is an analog waveform and the output includes two flags for qualified negative and positive waveform threshold-crossings and a digital signal encoding a waveform threshold-crossing position within the current sampling clock interval. The ASDD operates over a wide continuous range of channel data rates and provides accurate phase detection at relatively low sampling rates. It is suitable for monolithic CMOS implementation, which provides low power dissipation and small size.

1. Field of the Invention
This invention relates generally to data recording channel signal detectors and, more specifically, to a digital system for detecting waveform peaks or threshold-crossings in an asynchronously-sampled data signal.
2. Discussion of the Related Art
In the data storage arts, binary data is encoded and stored on optical or magnetic media as a series of optical or magnetic threshold-crossings. Retrieval of stored data requires a detecting and decoding system in the recording channel to reconstruct the original binary data and synchronous clock from the self-clocking analog signal waveform created by the magnetic or optical transducer adjacent to the storage medium. Practitioners in the art have proposed many solutions to the problems associated with extracting synchronous clock and data signals from a self-clocking data signal. These problems include discrimination between actual threshold-crossings and mere noise pulses and precise reconstruction of the synchronous data clock signal for decoding the phase-encoded data.
Analog pulse detectors known in the art suffer from the usual disadvantages of analog electronic apparatus. They are expensive, bulky and subject to calibration drift over time. Moreover, analog pulse detectors are generally suited to a narrow predetermined range of channel data rates, imposing severe channel data rate restrictions on storage media data retrieval systems. Digital implementations of data pulse or threshold-crossing phase detectors known in the art usually rely on discrete-signal embodiments of the well-known analog detection techniques. For instance, the analog signal waveform is first sampled and digitized using well-known phase-locked loop (PLL) techniques. These samples are then processed digitally to remove unwanted frequency components and to reconstruct the synchronous clock and data.
Such a discrete-signal equivalent of a phase-locked loop circuit is disclosed by Antonia C. Van Rens, et al in U.S. Pat. No. 4,912,729. Van Rens et al disclose a digital method for detecting data pulse transitions in an asynchronously-sampled signal waveform, but their technique is restricted to controlling estimated signal threshold-crossing phase errors using a discrete-time oscillator under the control of a digital sequential filter to hold the phase error to substantially zero. The Van Rens et al digital PLL method requires asynchronous sampling rates substantially higher than the expected channel data rate. Also, if the data signal threshold-crossings temporarily drop out, their discrete-time oscillator drifts off-clock very rapidly, creating relocking delays when the data signal resumes. This also limits the variety of Run-Length Limiting (RLL) codes suitable for their device.
There is a clearly felt need in the art for a fully digital implementation of a channel waveform threshold-crossing phase detector that can accurately detect self-clocking data pulses in a recording channel data signal over a wide range of data rates. The crucial need is for accurate synchronous data detection at moderate asynchronous sampling rates because high-speed sampling techniques are disadvantageously expensive. Although decimation and interpolation techniques are available for translating sampling rates from one level to another, these techniques alone do not facilitate detection at unrestricted data rates in a data recording channel. Moreover, such sampling rate translation overhead militates against rapid, efficient decoding of phase-encoded data signals.
Digital computer programs are known in the art for simulating the functions of analog recording channels but these techniques require high sampling rates, making implementation in real-time hardware expensive and difficult as discussed above. Many of the difficulties known for digital implementation can be overcome by reducing the asynchronous analog signal sampling rate. A practical method for accurate digital phase detection at low sampling rates has not been known until now. These and other unresolved problems and deficiencies are clearly felt in the art and are solved by this invention in the manner described below.

Asynchronous sampling digital detector system for magnetic and optical recording channels

International Business Machines Corporation


An arthroscopic tenodesis kit, including a guide with an elongate member having a length with a distal portion having a notch configured to releasably engage a suture; a cannulated fixation screw having a longitudinal cannula configured to receive the guide; and an inserter. The inserter includes an elongate cannulated body having an interior bore having a blind end and an open end configured to slidingly receive the guide. The body of the inserter has a length that is shorter than the length of the guide, so that the distal portion of the guide remains spaced from the bore when the guide is fully received within the bore.

Improvement is desired in the field of tenodesis or surgical fixation or anchoring of tendons to bone. Improvement is particularly desired in regards to arthroscopic fixation of tendons to bone.
Current devices often require a dedicated interference screw or fixation device and cannot be used with a wide variety of cannulated interference screws. Current devices also are hampered by the large size of the inserter and implant assembly that blocks arthroscopic view of the tunnel and impedes surgeon performance. Currently available devices also do not enable temporary fixation of the tendon to bone prior to implant insertion. Therefore, the tendon has a tendency to wrap around the interference screw as it is being inserted. This makes insertion of the screw more complex and also impedes visibility of the surgeon. Alternatively, current devices undesirably utilize a second separate implant (other than the fixation screw) which adds cost to the procedure, and is undesirable in that a second implant remains in the body after the procedure.
The disclosure advantageously provides apparatus and methods for arthroscopic tenodesis that does not require a dedicated interference screw or fixation device, but is suitable for use with a wide variety of cannulated interference screws. The apparatus and methods according to the disclosure also advantageously enable temporary distal fixation to the bone, avoid the need for any implant beyond the fixation screw, improve surgeon visibility, and reduce operating room time and costs by reducing the number of steps required as compared to conventional tenodesis procedures.


A method and device are provided for adjusting a focus bias of an objective lens of an optical pickup for an optical disc using a level of a tracking error signal. The level of the tracking error signal outputted when the optical disc is rotated and driven is detected for a predetermined period of time. An operation of adjusting the focus bias of the objective lens is carried out on the basis of the detected level of the tracking error signal. A focus bias adjustment value is set as an optimum focus bias value at a time when the detected level of the tracking error signal is maximized. In accordance with the method, a period of time for adjusting the focus bias is very short, on the order of “0” to several hundred milliseconds, in comparison with periods of time for adjusting the focus bias in conventional methods, such that the focus bias can be quickly adjusted. Moreover, the method moves the objective lens to an optimum focus point where the thickness of a substrate in the optical disc is thinner or thicker than the standard thickness (e.g., 0.6 mm in the case of a DVD (Digital Versatile Disc)), thereby enabling a normal playback operation.

1. Field of the Invention
The present invention relates to a method and device for adjusting a focus bias of an objective lens for an optical disc on the basis of a level of a tracking error signal detected when the optical disc is driven.
2. Description of the Related Art
Conventionally, where the thickness of a substrate of an optical disc is thinner or thicker than the standard thickness, a high-frequency playback signal on a focus error zero point is weakened, a level of a tracking error signal is abruptly degraded, and the amount of jitter of the high-frequency playback signal is abruptly increased, when a general focus point, on the optical disc, of an objective lens (focus lens) arranged within an optical pickup, is not correct. Accordingly, it is necessary that the focus bias must be adjusted such that the focus point of the objective lens on the optical disc is optimally located.
A conventional focus bias adjustment method detects an error rate of playback data when the optical disc is reproduced, and adjusts the focus bias such that the error rate can be minimized. However, the conventional focus bias adjustment method is inefficient, because a single layer DVD (Digital Versatile Disc) needs about 3 seconds to adjust the focus bias, and a dual layer DVD needs about 6 seconds or more to adjust the focus bias.
Another conventional focus bias adjustment method using the jitter carries out a focusing-on operation, a tracking-on operation and a PLL (Phase-Locked Loop) lock operation, measures the amount of jitter from playback data, and adjusts the focus bias such that the amount of jitter can be minimized. But this conventional focus bias adjustment method using the jitter is also inefficient in that the amount of time for adjusting the focus bias increases.

Method and device for adjusting focus bias in optical disc apparatus


One end of each of five resistors is connected to each of the two ends and the respective intermediate points of a cascade of four depression-type FETs, while the other ends of the five resistors are provided with a predetermined voltage. This configuration fixes the source-drain potential of the four FETs. This fixing of the source-drain potential of the FETs permits stable application of a bias voltage for turning ON the FETs between the gate and the source each FET, so as to ensure the ON-OFF switching of the FETs.

1. Technical Field
The present invention relates to a high frequency switch circuit built in a switch semiconductor integrated circuit or a communication terminal device. In particular, the invention is preferably applicable in a high frequency switch circuit which needs to have low insertion loss, high isolation, and low distortion characteristics, as well as in a communication terminal device using this switch circuit. This high frequency switch circuit is used, for example, as an antenna switch in a portable phone.
2. Prior Art
In these days, mobile telecommunication business such as in car telephones and portable phones is growing in remarkable rapidness. In many countries in the world, various mobile telecommunication systems have commenced operations. Meanwhile, in these mobile telecommunication systems, semiconductor field effect transistors (FETs) are used widely in signal processing units in major portable terminals. In particular, in order to improve the portability in portable terminals, considerable efforts are devoted into the development of monolithic microwave ICs (MMICs) using GaAs-FETs which are expected to serve as semiconductor integrated circuit devices permitting all of size reduction, low voltage driving, and power consumption reduction. Among these MMICs, high frequency switches for switching a high frequency signal in a portable terminal are important as a target of development.
When an FET is used as a switching device, a bias voltage applied to the gate terminal of the FET needs to be controlled. For example, when a gate bias sufficiently higher than the pinch-off voltage is applied to the gate terminal, the drain-source impedance is reduced, so that the FET is controlled to go ON. On the contrary, when a gate bias sufficiently lower than the pinch-off voltage is applied to the gate terminal, the drain-source impedance is increased, so that the FET is controlled to go OFF.
When such a single FET is used as a switching device, a GaAs-FET has a low insertion loss, but has a difficulty in increasing the isolation. The isolation in a single FET is increased by reducing the gate width of the FET. Nevertheless, the reduction of the gate width causes an increase in the ON resistance, and hence causes the problem of an increase in the insertion loss. Thus, a low insertion loss and a high isolation are difficult to be achieved simultaneously.
As such, a low insertion loss and a high isolation are difficult to be achieved simultaneously in a single FET. However, this problem is addressed by using a combination of FETs.
An example of a high frequency switch circuit having such configuration is an SPDT (single pole dual throw) switch composed of a series FET and a shunt FET connected respectively in series and in shunt relative to the signal path (for example, see JP-A-H08-213893 (pp. 2–3 and FIG. 2)). The series FET is an FET connected in an inserted configuration into the signal line. The shunt FET is an FET connected between the signal line and the ground.
According to this configuration, an RF signal having been leaked through a parasitic capacitance component in the series FET in an OFF state is drawn into the ground via the shunt FET in an ON state. This realizes a high isolation.
Further, this single stage FET circuit composed of one series FET and one shunt FET for reducing the signal leakage through the series FET in the OFF state may be duplicated into a cascade of multistage. This configuration further reduces the signal leakage through this single stage FET circuit.
Nevertheless, in the configuration of such a multistage cascade of the FET circuits, the voltage is undetermined in the intermediate connection points between a plurality of these series FETs. This causes instability in the operation of the series FETs, and hence prevents reliable ON-OFF switching based on the gate voltage control.
In order to resolve this problem, a modification is proposed that in the multistage cascade of the FET circuits, the source and the drain of each FET are interconnected through a resistor (for example, see JP-A-2000-277703 (pp. 4–5 and FIG. 1)). This configuration is shown in FIG. 9. In FIG. 9, numerals 111–114 indicate FETs interconnected in series. Numerals 211–214 indicate resistors one end of each of which is connected to the gate of each FET 111–114. Numerals 215–218 indicate resistors each of which interconnects the source and the drain of each FET 111–114. Numerals 311 and 312 indicate high frequency signal input and output terminals. Numeral 411 indicates a control terminal connected in common to the other terminals of the resistors 211–214 so as to receive a control signal for controlling the ON-OFF of the FETs 111–114.
As such, in this configuration, the source and the drain of each FET 111–114 are interconnected through each resistor 215–218, so that the voltage is fixed at the intermediate connection points between a plurality of the series FETs 111–114. This stabilizes the operation of the FETs.
In this configuration of the prior art, in the multistage cascade of the FET circuits, the voltage is fixed at the intermediate connection points between the FETs. Never the less, this voltage has a value arbitrarily determined by the gate voltage of the FET as well as the gate-source resistance Rgs and the gate-drain resistance Rgd of the FET.
When the FETs are to be set OFF by an arbitrary voltage, the gate voltage is changed, and so is the voltage in the intermediate connection points. This can result in a situation that the signal inputted through the high frequency signal input and output terminal 311 or the other is not shut off reliably. In particular, when a large signal is inputted, the FETs cannot reliably be set OFF, so that the signal can leak.
Described below is the reason why the FETs cannot reliably be set OFF when a large signal is inputted. When a high frequency signal is inputted to the high frequency switch circuit composed of the FETs, the voltage amplitude depends on the input power. When a signal of a high power is inputted, the voltage amplitude becomes accordingly large. This results in a situation that at the timing near the peak of the high frequency voltage waveform, the gate-source voltage of the FETs cannot be maintained in a reverse bias state. This causes temporary conduction in the FETs near the peak of the high frequency voltage waveform. This mechanism is described in detail in JP-A-H07-106937.
For example, when FETs are used in an antenna switch, the highest priority is assigned to the reduction of the insertion loss. The reduction of the insertion loss requires the reduction of the ON resistance of the FETs. When the FETs are used in a forward bias state, the ON resistance of the FETs can be reduced. Nevertheless, in the above-mentioned configuration of the prior art, the voltage of the intermediate connection points is arbitrarily determined as described above. This has prevented the high frequency switch circuit from being used in a state of the lowest ON resistance.

Matsushita Electric Industrial Co., Ltd.


This invention is related to substituted 2-aminoacetamides represented by Formula II:

1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to substituted 2-aminoacetamides and the discovery that these compounds act as blockers of sodium (Na+) channels.
2. Related Background Art
Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine, have been shown to share a common mechanism of action by blocking or modulating Na+ channel activity (Catterall, W. A., Trends Pharmacol Sci. 8:57-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Na+ ions.
Recently, other Na+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British Pharmacol. 115:1425-1432 (1995); SCRIP 1870:8 (1993); SCRIP 1773:14 (1992)).
The neuroprotective activity of Na+ channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na30  channel blockers prevent hypoxic damage to mammalian white matter (Stys et al., J. Neurosci. 12:430-439 (1992)). Thus, they may offer advantages for-treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.
Another example of clinical use of a Na+ channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al., New Engl. J. Med. 330:585-591 (1994)) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76 (1994)).
It has been established that there are at least five to six sites on the voltage-sensitive Na channels which bind neurotoxins specifically (Catterall, W. A., Science 242:50-61 (1988)). Studies have further revealed that therapeutic antiarrhythmics, anticonvulsants and local anesthetics whose actions are mediated by Na+ channels, exert their action by interacting with the intracellular side of the Na+ channel and allosterically inhibiting interaction with neurotoxin receptor site 2 (Catterall, W. A., Ann. Rev. Pharmacol Toxicol. 10:15-43 (1980)).
PCT International Published Application WO 90/14334 and WO 97/05102 disclose 2-(4-substituted)-benzylamino-2-methyl-propanamide derivatives represented by Formula I:
where n is 0-3; X is O, S, CH2 or NH; each of R and R1 independently is hydrogen, C, alkyl, halogen, hydroxy, C1-4 alkoxy, or trifluoromethyl; each of R2, R3 and R4 independently is hydrogen, C1-6 alkyl or C3-7 cycloalkyl: The compounds are disclosed to be useful as antiepileptics, in the treatment of Parkinson""s disease and as neuroprotective agents, e.g. preventing or treating neuronal loss associated with stroke, hypoxia, ischemia, CNS trauma, hypoglycemia or surgery, and in treating and preventing neurodegenerative diseases such as Alzheimer""s disease, amyotrophic lateral sclerosis, Down""s syndrome, Huntington""s disease, dementia caused by acquired immunodeficiency syndrome (AIDS), infarctual dementia and infections or inflammations in the brain; they can also be used as antidepressants, hypnotics, and antispastic agents and in treating ocular damage and retinopathy. However, their mechanism of action was not disclosed.
The present invention is related to treating a disorder responsive to the blockade of sodium channels in a mammal suffering from excess activity of said channels by administering an effective amount of a compound of Formula I. The present invention is also related to treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom by administering an effective amount of a compound of Formula II as described herein.
The present invention is also directed to the use of a compound of Formulae I or II for the treatment of neuronal damage following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy and for the treatment of pain including chronic pain.
The present invention also is directed to the process for preparing novel substituted 2-aminoacetamide of Formula II.
A first aspect of the present invention is directed to the use of compounds of Formulae I or II as blockers of sodium channels.
A second aspect of the present invention is to provide a method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating pain including chronic pain; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing or ameliorating manic depression; inducing local anesthesia; and treating arrhythmias by administering a compound of Formulae I or II to a mammal in need of such treatment.
A number of compounds within the scope of the present invention are novel compounds. Therefore, a third aspect of the present invention is to provide novel compounds of Formula II, and to also provide for the use of these novel compounds for treating, preventing or ameliorating convulsions.
A fourth aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the blockade of sodium ion channels, containing an effective amount of a compound of Formulae I or II in a mixture with one or more pharmaceutically acceptable carriers or diluents.
A fifth aspect of the present invention is directed to methods for preparing novel compounds of Formulae II.
The present invention arises out of the discovery that compounds of Formulae I and II act as blocker of the Na+ channel. In view of this discovery, compounds of Formulae I and II are useful for treating disorders responsive to the blockade of sodium ion channels.
The compounds useful in this aspect of the present invention are substituted 2-aminoacetamides represented by Formula II:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1, R2, R3 and R4 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
R5, R6 and R7 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R5, is defined as above, and R6 and R7 together with the nitrogen atom to which they are attached form a heterocycle;
A1 and A2 are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted;
X is one or O, S, NR8, CH2, C(O), NR8C(O), C(O)NR8, SO, SO2 or a covalent bond; where
R8 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
n is 0, 1, 2 or 3.
Preferred compounds falling within the scope of Formula II include compounds wherein A1 and A2 are both aryl moieties, preferably both phenyl moieties, that are each optionally independently substituted by one or two substituents independently selected from the group consisting of halogen, nitro, amino, C1-6 alkyl, C3-8cycloalkyl, cyano, C1-6 alkoxy or C6-10aryloxy; R1 is hydrogen, C1-6 alkyl, C3-8cycloalkyl or C6-10aryl; O or S.
Preferred compounds within Formula II also include those compounds where A1 is an optionally substituted aryl group selected from the group consisting of phenyl and naphthyl, and A2 is an optionally substituted heteroaryl or aryl group selected from the group consisting of pyridyl. pyrimidinyl, 1,3,5-triazinyl, furanyl, thiophenyl, naphthyl, quinolyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl, biphenylmethyl, triphenylmethyl and quinoxalinyl.
Additional preferred compounds within Formula II also include those compounds where A1 is an optionally substituted aryl group selected from the group consisting of phenyl or naphthyl, and A2 is an optionally substituted carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl, adamantyl, exo-norbomyl and cyclopentenyl.
Additional preferred compounds within Formula II include those compounds where A1 is an optionally substituted heteroaryl or aryl group selected from the group consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl, and thiophenyl, and A2 is an optionally substituted heteroaryl or aryl group selected from the group consisting of phenyl, furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and naphthyl.
Additional preferred compounds within Formnula II include those compounds where A1 is an optionally substituted, saturated or partially unsaturated carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl, and A2 is an optionally substituted aryl or heteroaryl group selected from the group consisting of phenyl, furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl, or naphthyl.
Exemplary preferred compounds that may be employed in this method of invention include, without limitation:
2-(4-(2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(3,4-methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-propanamide;
2-(4-cyclohexyloxybenzylamino)-2-methyl-propanamide;
2-(4-(5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methyl-propanamide;
2-(4-(2-adamantanoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-Chloro-2-fluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(3,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(6-bromo-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-nitrophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-tetrahydropyranoxy)benzylamino)-2-methyl-propanamide;
2-(4-(3,5-difluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-chlorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-methylphenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(2-chloro-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(5-indanoxy)benzylamino)-2-methyl-propanamide;
2-(4-cycloheptoxybenzylamino)-2-methyl-propanamide;
2(4-(1-methyl-4-piperidinoxy)benzylamino)-2-methyl-propanamide,
2-(4-(exo-2-norbornoxy)benzylamino)-2-methyl-propanamide;
2(3-(4-fluorophenoxy)-5-pyridylmethylamino)-2-methyl-propanamide;
2-(4-(4-pyridinoxy)benzylamino)-2-methyl-propanamide;
2-(3-fluoro-4-(4-fluorophenyl)benzylamino)-2-methyl-propanamide,
2-(4-(2-pyrimidinoxy)benzylamino)-2-methyl-propanamide;
2-(4-(6-quinolinoxy)benzylamino)-2-methyl-propanamide;
2-(4-(N,N-diphenylamino)benzylamino)-2-methyl-propanamide;
2-(4-diphenylmethoxy)benzylamino-2-methyl-propanamide; and
2-(4-triphenylmethoxy)benzylamino-2-methyl-propanamide.
Since the compounds of Formula I and II are blockers of sodium (Na30 ) channels, a number of diseases and conditions mediated by sodium ion influx can be treated employing these compounds. Therefore, the invention is related to a method of treating, preventing or ameliorating neuronal loss associated with stroke, global and focal ischemia, CNS trauma, hypoglycemia and surgery, spinal cord trauma, as well as treating or ameliorating neurodegenerative diseases including Alzheimer""s disease, amyotrophic lateral sclerosis, Parkinson""s disease, treating or ameliorating anxiety, convulsions, glaucoma, migraine headache, and muscle spasm. The compounds of Formula I and II are also useful as antimanic depressants, as local anesthetics, and as antiarrhythmics; as well as for treating, preventing or ameliorating pain including surgical, chronic and neuropathic pain. In each instance, the methods of the present invention require administering to an animal in need of such treatment an effective amount of a sodium channel blocker of the present invention, or a pharmaceutically acceptable salt or prodrug thereof.
The present invention is also directed to novel compounds within the scope of Formula II. These compounds include those compounds of Formula II where:
R1, R2, R3 and R4 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
R5, R6 and R7 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R5, is defined as above, and R6 and R7 together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine;
A1 and A2 are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted;
X is one or O, S, NR8, CH2, C(O), NR8C(O), C(O)NR8, SO, SO2 or a covalent bond, where
R8 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
n is 1, 2 or 3,
provided that:
when X is O, S, CH2 or NH; R1 and R2 are hydrogen, R3 and R4 are methyl or ethyl, then A1 and A2 are not both phenyl.
Specifically, preferred substituted 2-aminoacetamides are represented by Formulae III-VIII. In particular, a preferred embodiment is represented by Formulae III and IV:
or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, X, n, A1 and A2 are as defined previously with respect to Formula II; and
R9, R10, R11 and R12 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or
R9, and R10, or R11 and R12 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle. Examples of bridges formed by R9 and R10 or R11 and R12 taken together are xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCF2Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2)4xe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94, xe2x80x94CH2N(R18)CH2xe2x80x94, xe2x80x94CH2CH2N(R18)CH2xe2x80x94, xe2x80x94CH2N(R18)CH2CH2xe2x80x94 and xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; where R18 is hydrogen, alkyl or cycloalkyl;
provided that when A1 in Formula III is an optionally substituted phenyl, then R9 and R10 or R11 and R12 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle.
R13, R14, R15, R16 and R17 independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or
one of R13 and R14, or R14 and R15, or R15 and R16, or R16 and R17 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle. Examples of bridges formed by R13 and R14, or R14 and R15, or R15, and R16, or R16 and R17 taken together are xe2x80x94OCH2xe2x80x94, xe2x80x94OCF2Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94, xe2x80x94CH2N(R18)CH2xe2x80x94, xe2x80x94CH2CH2N(R18)CH2xe2x80x94, xe2x80x94CH2N(R18)CH2CH2xe2x80x94 and xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; where R18 is hydrogen, alkyl or cycloalkyl.
provided that when A1 in Formula IV is an optionally substituted phenyl, then R13 and R14, or R14 and R15, or R15 and R16, or R16 and R17 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle.
Preferred values of A2 in Formula III include furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl, and naphthyl.
Preferred values of A1 in Formula IV include furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and naphthyl.
Another preferred embodiment of the invention includes substituted 2-aminoacetamides represented by Formula V and Formula VI:
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R1xe2x80x94R7, R9-R12, R13-R17, n and X are as defined previously with respect to Formulae II, III and IV; and
A, B, C, D and E are independently nitrogen or carbon, provided that no more than three of A, B, C, D and E are nitrogen, and there is no substituent, except for oxygen (when the nitrogen is present as a N-oxide), present on A, B, C, D or E when said A, B, C, D or E represents nitrogen.
Preferred compounds of Formula V are those where one, two or three of A through E are nitrogens. Preferred compounds of Formula VI are those where one or two of A through D are nitrogens.
Another preferred embodiment of the invention includes substituted 2-aminoacetamide represented by Formula VII and Formula VIII:
or a pharmaceutically acceptable salt or prodrug thereof, wherein R1-R7, R9-R12, R13-R17, n and X are as defined previously with respect to Formulae II, III and IV; and
B1 is an optionally substituted saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle; and
B2 is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle.
Preferred B1 and B2 independently include cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl.
Generally, preferred compounds of Formulae II-VIII are those compounds where R1 and R2 is hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, and where R3 and R4 are independently hydrogen or C1-4 alkyl.
Preferred values of X in Formulae II-VIII are O and S.
Preferred values of R5-R7 with respect to Formulae II-VIII are hydrogen or C1-4 alkyl.
Preferred values of R9-R12, and R13-R17, with respect to Formulae II-VIII include hydrogen, halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10aryl(C,xe2x80x94C6)alkynyl, C1-C6 hydroxyalkyl, nitro, amino, ureido, cyano, C1-C6 acylamido, hydroxy, thiol, C1-C6 acyloxy, azido, C1-C6 alkoxy, and carboxy. Alternatively, R9 and R10 or R11, and R12, or two adjacent R13 through R17 can form a bridge selected from the group consisting of xe2x80x94OCH2Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94, xe2x80x94CH2N(R18)CH2xe2x80x94, xe2x80x94CH2CH2N(R18)CH2xe2x80x94, xe2x80x94CH2N(R18)CH2CH2xe2x80x94, and xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, where R18 is hydrogen or C1-C6 alkyl. Most preferably, at least one, two or three of R9, R10, R11, R12 are hydrogen. Most preferably, at least one, two or three of R13 through R17 are hydrogen.
With respect to the novel methods of treatment of the present invention, an additional preferred subset of substituted 2-aminoacetamide compounds includes compounds of Formula II, wherein A1 and A2 are phenyl moieties, that A2 is substituted by one or two substituents independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, hydroxy, C1-4 alkoxy, or trifluoromethyl; each of R1 and R2 are hydrogen; R3 and R4 are methyl; and R5-R7 are independently C1-6 alkyl or C3-7cycloalkyl.
Useful compounds in this aspect of the present invention include:
2-(4-(2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(3,4-methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-propanamide.
2-(4-cyclohexyloxybenzylamino)-2-methyl-propanamide;
2-(4-(5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methyl-propanamide;
2-(4-(2-adamantanoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-Chloro-2-fluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(3,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(6-bromo-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-nitrophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-tetrahydropyranoxy)benzylamino)-2-methyl-propanamide;
2-(4-(3,5-difluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-chlorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(4-methylphenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(2-chloro-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;
2-(4-(5-indanoxy)benzylamino)-2-methyl-propanamide;
2-(4-cycloheptoxybenzylamino)-2-methyl-propanamide;
2-(4-(1-methyl-4-piperidinoxy)benzylamino)-2-methyl-propanamide;
2-(4-(exo-2-norbornoxy)benzylamino)-2-methyl-propanamide;
2-(3-(4-fluorophenoxy)-5-pyridylmethylamino)-2-methyl-propanamide;
2-(4-(4-pyridinoxy)benzylamino)-2-methyl-propanamide;
2-(3-fluoro4-(4-fluorophenyl)benzylamino)-2-methyl-propanamide;
2-(4-(2-pyrimidinoxy)benzylamino)-2-methyl-propanamide;
2-(4-(6-quinolinoxy)benzylamino)-2-methyl-propanamide;
2-(4-(N,N-diphenylamino)benzylamino)-2-methyl-propanamide;
2-(4-diphenylmethoxy)benzylamino-2-methyl-propanamide; and
2-(4-triphenylmethoxy)benzylamino-2-methyl-propanamide.
Useful aryl groups are C6-14 aryl, especially C6-10 aryl. Typical C6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
Useful cycloalkyl groups include C3-8 cycloalkyl groups. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyctopentyl and cyclohexyl and cycloheptyl.
Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as defined above, as well as cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
Useful alkyl groups include straight-chained and branched C1-10 alkyl groups, more preferably C1-6 alkyl groups. Typical C1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylene group substituted on two adjoining positions on the benzene ring of the compounds of the invention.
Useful alkenyl groups include C2-6 alkenyl groups, preferably C2-4 alkenyl. Typical C2-4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec.-butenyl.
Useful alkynyl groups include C2-6 alkynyl groups, preferably C2-4 alkynyl. Typical C2-4 alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups.
Useful arylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned C6-14 aryl groups. Typical groups include benzyl, phenethyl and naphthylmethyl.
Useful arylalkenyl groups include any of the above-mentioned C2-4 alkenyl groups substituted by any of the above-mentioned C6-14 aryl groups.
Useful arylalkynyl groups include any of the above-mentioned C2-4 alkynyl groups substituted by any of the above-mentioned C6-14 aryl groups. Typical groups include phenylethynyl and phenylpropynyl.
Useful cycloalkylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned cycloalkyl groups.
Useful haloalkyl groups include C1-10 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups.
Useful hydroxyalkyl groups include C1-10 alkyl groups substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.
Useful alkoxy groups include oxygen substituted by one of the C1-10 alkyl groups mentioned above.
Useful alkylthio groups include sulphur substituted by one of the C1-10 alkyl groups mentioned above.
Useful acylamino groups are any C1-6 acyl (alkanoyl) attached to an amino nitrogen, e.g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as aryl-substituted C2-6 substituted acyl groups.
Useful acyloxy groups are any C1-6 acyl (alkanoyl) attached to an oxy (xe2x80x94Oxe2x80x94) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperizinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl and pyrazolinyl groups.
Useful heterocycloalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned heterocyclic groups.
Useful heteroaryl groups include any one of the following: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl. isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, 5aH-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl. isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocownarin, pyrido[1,2-a]pyrimidin4-one, 1,2-benzoisoxazol-3-yl, 4-nitrobenzofurazan. benzimidazolyl, 2-oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g. a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and the like.
Useful heteroarylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned heteroaryl groups.
Useful heteroarylalkenyl groups include any of the above-mentioned C2-4 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.
Useful heteroarylalkynyl groups include any of the above-mentioned C2-4 alkynyl groups substituted by any of the above-mentioned heteroaryl groups.
Useful amino groups include xe2x80x94N2H, xe2x80x94NHR19, and xe2x80x94NR19R20, wherein R19 and R20 are C1-10 alkyl or cycloalkyl groups as defined above.
Useful aminocarbonyl groups are carbonyl groups substituted by xe2x80x94NH2, xe2x80x94NHR19, and xe2x80x94NR19R20, wherein R19 and R20 are C1-10 alkyl groups.
Optional substituents on any of the aryl, heterocyclic, heteroaryl, and cycloalkyl rings in Formulae II-VIII include any one of halo, haloalkyl, aryl, heterocycle, cycloalkyl, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, aminocarbonyl, and alkylthiol groups mentioned above. Preferred optional substituents include: halo, haloalkyl, hydroxyalkyl, aminoalkyl, nitro, alkyl, alkoxy and amino.
Certain of the compounds of Formula II may exist as optical isomers and the invention includes both the racemic mixtures of such optical isomers as well as the individual entantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, acetic acid, dichloroacetic acid and oxalate.
Examples of prodrugs include esters or amides of Formula II with R1-R7 as hydroxyalkyl or aminoalkyl, and these may be prepared by reacting such compounds with anhydrides such as succinic anhydride.
The invention is also directed to a method for treating disorders responsive to the blockade of sodium channels in animals suffering thereof. Particular preferred embodiments of the substituted 2-aminoacetamide for use in method of this invention are represented by previously defined Formula II.
The compounds of this invention may be prepared using methods known to those skilled in the art, or by the novel methods of this invention. The methods described in PCT published application WO97/05102, can be employed to synthesize compounds within the scope of the invention.
Compounds with Formulae II-VIII can be prepared as illustrated by exemplary reactions in Schemes 1-5.
The compounds of the present invention were assessed by electrophysiological assays in dissociated hippocampal neurons for sodium channel blocker activity. These compounds also could be assayed for binding to the neuronal voltage-dependent sodium channel using rat forebrain membranes and [3H]BTX-B.
Sodium channels are large transmembrane proteins that are expressed in various tissues. They are voltage sensitive channels and are responsible for the rapid increase of Na+ permeability in response to depolarization associated with the action potential in many excitable cells including muscle, nerve and cardiac cells.
One aspect of the present invention is the discovery of the mechanism of action of the compounds herein described as specific Na+ channel blockers. In one aspect of the present invention it has been discovered that compounds disclosed in international published application WO 97/05102 are specific Na+ channel blockers. Based upon the discovery of this mechanism, these compounds, as well as novel compounds described herein, are contemplated to be useful in treating or preventing neuronal loss due to focal or global ischemia, and in treating or preventing neurodegenerative disorders including ALS, anxiety, and epilepsy. They are also expected to be effective in treating, preventing or ameliorating neuropathic pain, surgical pain and chronic pain. The compounds are also expected to be useful as antiarrhythmics, anesthetics and antimanic depressants.
The present invention is directed to compounds of Formulae II that are blockers of voltage-sensitive sodium channels. According to the present invention, those compounds having preferred sodium channel blocking properties exhibit an IC50 of about 100 xcexcM or less in the electrophysiological assay described herein. Preferably, the compounds of the present invention exhibit an IC50 of 10 xcexcM or less. Most preferably, the compounds of the present invention exhibit an IC50 of about 1.0 xcexcM or less. Substituted 2-aminoacetamide disclosed in WO 97/05102, as well as novel compounds of the present invention, may be tested for their Na+ channel blocking activity by the following electrophysiological and binding assays.
Electrophysiological Assay
Cell preparation: Acute cultures of rat hippocamnpal neurons were prepared daily using a modification of procedures described previously (Kuo and Bean, Mol. Pharm. 46:716-725 (1994)). Briefly, hippocampi were isolated from 3-11 day old rat pup brains (Sprague-Dawley; Charles River) and were sectioned, by hand, into 0.5-1 mm thick transyerse slices (Whittemore and Koerner, Eur. J. Pharm. 192:435-438 (1991)). Slices were incubated for at least 30 min at room temperature (20-24xc2x0 C.) in an oxygenated medium (124 mM NaCl, 3.3 mM KCl, 2.4 mM MgSO4, 2.5 mM CaCl2, 1.2 mM KH2PO4, 26 mM NaHCO3, pH=7.4) continuously bubbled with 5% CO2/95% O2. Prior to recording, 4-5 slices were transferred to an oxygenated dissociation medium (82 mM NaSO4, 30 mM K2SO4, 3 mM MgCl2, 2 mM HEPES, 26 mM NaHCO3, 0.001% phenol red, pH=7.4) containing 3 mg/mL protease XXIII (Sigma, St. Louis, Mo.) and incubated for 10-15 min at 37xc2x0 C., while continuously bubbling with 5% CO2/95% O2. Enzymatic digestion was terminated by transferring the slices to dissociation medium without bicarbonate, supplemented with 1 mg/mL bovine serum albumin and 1 mg/mL trypsin inhibitor (Sigma, St. Louis, Mo.). Slices were then transferred to a 35 mm culture dish containing dissociation medium without bicarbonate, and triturized with a fire-polished glass Pasteur pipette to release single cells. Cells were allowed to settle in this dish for 30 minutes and were then used for making electrical recordings.
Patch-clamp recordings of voltage-sensitive Na+ currents: Whole-cell voltage-clamp recordings were made using conventional patch-clamp technique (Hamill et al., Pfluegers Arch. 391:85-100 (1981)) with an Axopatch 200A amplifier (Axon Instruments, Foster City, Calif.). Recordings were made within 2-3 hours after neuron dissociation. The recording chamber was continuously superfused with Tyrode""s solution (156 mM NaCl, 3.5 mM KCl, 2 mM CaCl2, 5 mM NaHCO3, 10 mM HEPES, 10 mM glucose, pH 7.4) at a speed of about 1 ml/min. Thin-walled pipettes were pulled from 100-xcexcl Clay Adams Accu-Fill 90 Micropet disposable pipettes (Becton, Dickenson and Company, Parsipanny, N.J.), fire-polished and sylgarded (Dowxe2x80x94Coming, Midland, Mich.). The pipette resistances ranged from 1 to 3 Mxcexa9 when the pipettes were filled with internal solution containing (in mM): 130 CsF, 20 NaCl, 1 CaCl2, 2 MgCl2, 10 EGTA, 10 HEPES, pH adjusted to 7.4 with CsOH. Drugs and intervening wash-outs were applied through a linear array of flow pipes (Drummond Microcaps, 2-xcexcl, 64-mm length). Compounds are dissolved in dimethylsulfoxide (DMSO) to make a 10 mM stock solution, which was subsequently diluted into Tyrode""s solution to give final concentrations of 0.1-20 xcexcM. At the highest (1%) concentration. DMSO inhibited the size of Na+ current only slightly. Currents were recorded at room temperature (22-25xc2x0 C.), filtered at 5 kHz with 4-pole Bessel filter, digitized at 20-50-xcexcs intervals, and stored using Digidata 1200 analog/digital interface with Pclamp6/Clampex software (Axon Instruments). Residual series resistance ranged from 0.4 to 0.8 Mxcexa9 after partial compensation (typically xcx9c90%). The inhibitory potency of drugs was assessed by measuring reductions in the peak amplitude of Na30  currents induced by increasing concentrations of compounds tested. Na30  currents were elicited by stepping membrane voltage from holding potentials over the range xe2x88x92100 mV to xe2x88x9250 mV, to a pulse potential of xe2x88x9210 mV. The test pulse duration was 5-10 msec, repeated at a frequency xe2x89xa61 Hz. Concentration-inhibition curves were fitted with equation 1:
I/Icontrol=1/(1+([compound]/IC50))xe2x80x83xe2x80x83Eq. 1
where Icontrol is the maximal Na+ current in the absence of antagonist, [compound] is the drug concentration, and IC50 is the concentration of compound that produces half maximal inhibition.
Binding Assay
The ability of compounds of the present invention to modulate either site 1 or site 2 of the Na+ channel was determined following the procedures fully described in Yasushi, J. Biol. Chem. 261:6149-6152 (1986) and Creveling, Mol. Pharmacol. 23:350-358 (1983), respectively. Rat forebrain membranes were used as sources of Na+ channel proteins. The binding assays were conducted in 130 xcexcM choline chloride at 37xc2x0 C. for 60-minute incubation with [3H] saxitoxin and [3H] batrachotoxin as radioligands for site 1 and site 2, respectively.
The compounds of the present invention may be tested for in vivo anticonvulsant activity after iv or ip injection using a number of anticonvulsant tests in mice (audiogenic seizure model in DBA-2 mice, pentylenetetrazol-induced seizures in mice, maximum electroshock seizure test (MES)).
The compounds may be tested for their neuroprotective activity after focal and global ischemia produced in rats or gerbils according to the procedures described in Buchan et al. (Stroke, Suppl. 148-152 (1993)) and Sheardown et al. (Eur. J. Pharmacol. 236:347-353 (1993)) and Graham et al. (J. Pharmacol. Exp. Therap. 276:1-4 (1996)).
The compounds may be tested for their neuroprotective activity after traumatic spinal cord injury according to the procedures described in Wrathall et. al. (Exp. Neurology 137:119-126 (1996)) and Iwasaki et. al. (J. Neuro Sci. 134:21-25 (1995)).
Compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for epilepsy, neurodegenerative diseases, anesthesia, arrhythmia, manic depression, and pain. For intramuscular injection, the dose is generally about one-half of the oral dose.
In the method of treatment or prevention of neuronal loss in global and focal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia, status epilepsy and surgery, the compound can be administrated by intravenous injection at a dose of about 0.025 to about 10 mg/kg.
The unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.
In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. Preferably, the preparations, particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient.
Also included within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of the particular 2-aminoacetamide of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, flumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like. Basic salts are formed by mixing a solution of the particular 2-aminoacetamide of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide,. choline hydroxide, sodium carbonate and the like.
The pharmaceutical compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic. talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.

Substituted 2-aminoacetamides and the use thereof

Abstract: R1, R2, R3 and R4 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; R5, R6 and R7 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R5, is defined as above, and R6 and R7 together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; A1 and A2 are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; X is one or O, S, NR8, CH2, C(O), NR8C(O), C(O)NR8, SO, SO2 or a covalent bond; where R8 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3. The invention also is directed to the use substituted 2-aminoacetamides for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), and for the treatment, prevention or amelioration of pain, as anticonvulsants, and as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.


Disclosed are an ASPECT score estimating system and a method thereof which estimate an ASPECT score which is a factor for identifying the stroke diseases from the brain CT images and a configuration including a pre-processing step of normalizing and standardizing a feature of an image dataset; a segmenting step of separating each lesion from an CT image which is classified into a supra ganglionic level and a ganglionic level; and a determining step of determining whether the lesion is a stroke by independently building a neural network which learns a positive/negative image for each lesion is provided to estimate an ASPECT score which is an objective indicator for diagnosing a condition of the stroke patient using a brain CT image of the patient.

Stroke is a disease which causes brain damages due to blockage or rupture of blood vessels which supply blood to the brain, and thus causes physical disability. The stroke is an important cause of death worldwide and classified as a high risk disease which causes permanent disability even though it does not lead to death.
Conventionally, the stroke has been mainly regarded as a disease of the elderly. However, recently, as the stroke frequently occurs even in the thirties and forties, the stroke is recognized as a very dangerous disease which broadly occurs not only in the elderly, but also in young adults and middle-aged people (see Non-Patent Documents 1 and 2).
There are two types of stroke including "ischemic stroke" which is caused by the blockage of blood vessels which supply blood to the brain and "cerebral hemorrhage" which causes bleeding due to the bursting of blood vessels which are connected to the brain.
The ischemic stroke accounts for about 80% of the total strokes and most of the ischemic stroke is generated due to the blockage of the blood vessel, which supplies oxygen and nutrients to the brain, caused by thrombosis which is a coagulated blood clot.
In order to diagnose the stroke, various tests have been developed and among the various tests, a method which utilizes computed tomography (CT) may allow the test to be quickly performed.
Therefore, the test method based on the CT has an advantage of being able to test quickly, so that it is considered as a test method suitable for a characteristic of the stroke disease for which prompt response is essential.
Further, the cerebral hemorrhage can be observed through the CT immediately after the bleeding occurs. Therefore, in order to treat the ischemic stroke, the CT is useful as a tool which surely identifies cerebral hemorrhage prior to the use of thrombolytic which dissolves the clots to unclog the blood vessels.
Further, the CT is also important for the progress observation of the cerebral hemorrhage after the usage of thrombolytic.
In the meantime, as a representative indicator of the stroke, the Alberta stroke program early CT (ASPECT) score is used.
The ASPECT score divides a middle cerebral artery (MCA) region into 10 predefined anatomical regions and assess the presence of early infarct signs with substantial low risk for NCCT (see Non-Patent Document 3).
The ASPECT score has been proved as a powerful predictor to diagnose a condition of the stroke patients.
However, determination of early signs of ischemia and conversion to the ASPECT score have significant interrater variability, which is influenced by post experience among other factors (See Non-Patent Document 4).
That is, the ASPECT score assesses the disease by calculating a degree of the stroke progression of the user to be 0 to 10 points and this allows medical staffs to use the ASPECT score as a key indicator to determine a treatment method of the user and predict a prognosis of the user.
However, when a medical specialist estimates the ASPECT score, an estimation value may vary depending on the career and experience of the medical specialist due to the user's initial sign and complexity of the image.
Such scoring variability has a negative influence on a decision making process for patient clinical outcomes.
Therefore, it is demanded to develop a technology which objectifies and automates the ASPECT score based on the image processing and deep learning technology to estimate the ASPECT score.

Aspect score estimating system and method


A method and a system for improving operation of a hybrid vehicle are presented. In one example, operation of a transmission torque converter lockup clutch is adjusted by way of adjusting a transfer function based on torque supplied by an electric machine to improve engine starting control. The approach may improve engine starting and vehicle drivability.

A driveline of a hybrid vehicle may include and engine and a motor that are selectively coupled together. The engine and motor may be selectively coupled together via a disconnect clutch. The engine and motor may also be coupled to an automatic transmission that includes a torque converter and lockup clutch. The automatic transmission may also include a torque converter and a plurality of fixed gear ratios.
The transmission torque converter lockup clutch may be selectively applied to improve driveline efficiency. The torque converter may also be applied during engine starting while the transmission is in gear to improve vehicle drivability. For example, the lockup clutch may be applied to shape engine speed and an amount of engine torque that is transferred to vehicle wheels or a vehicle chassis when the transmission is in a tied-up state (e.g., when two or more transmission clutches are engaged to couple the transmission input shaft to the transmission case). In particular, the torque converter clutch may be initially open or in controlled slip where little torque converter clutch pressure is applied. As engine speed increases and reaches a desired speed, the torque converter clutch application pressure or force may be increased to improve driveline efficiency. However, if the torque converter application force or pressure is greater than desired during engine run-up or after the engine reaches a desired speed, vehicle drivability and/or emissions may be degraded.
The inventors herein have recognized the above-mentioned issues and have developed a hybrid powertrain operating method, comprising: rotating at least a portion of an electric machine in a driveline; and adjusting operation of a torque converter lockup clutch in response to a current supplied to the electric machine.
By rotating an electric machine and applying a transmission torque converter lockup clutch, it may be possible to improve lockup clutch operation. In particular, it may be possible to accurately determine an amount of torque transferred across a torque converter lockup clutch so that the lockup clutch may be applied with more precision. In one example, an amount of electric current supplied to the electric machine may be a basis for determining the amount of torque transferred across the lockup clutch. During subsequent lockup clutch application, the lockup clutch closing may be scheduled based on a transfer function that was adjusted in response to an amount of torque transferred across the torque converter lockup clutch.
The present description may provide several advantages. Specifically, the approach may improve engine starting by improving engine speed control during engine starting. Further, the approach may reduce lockup clutch wear. Further still, the approach may improve vehicle drivability.
The above advantages and other advantages, and features of the present description will be readily apparent from the following Detailed Description when taken alone or in connection with the accompanying drawings.
It should be understood that the summary above is provided to introduce in simplified form a selection of concepts that are further described in the detailed description. It is not meant to identify key or essential features of the claimed subject matter, the scope of which is defined uniquely by the claims that follow the detailed description. Furthermore, the claimed subject matter is not limited to implementations that solve any disadvantages noted above or in any part of this disclosure.

Method and system for adapting operation of a hybrid vehicle transmission torque converter lockup clutch


Platelets are concentrated from the blood of a patient. The platelets are treated by a method such as ultrasound or agitation to obtain platelet releasate. This releasate as a whole or a component thereof is formulated into an injectable formulation which is administered to the same patient the platelets were extracted from in order to treat the patient's cancer.

Formulations and methods of the invention can be applied to the treatment of a variety of different diseases and abnormalities. Although the present invention is not limited to such, it can be used in the treatment of cancer, wound healing, and a variety of chronic inflammatory diseases. In general, each is presently treated directly by physical means such as surgical removal of cancerous tissue, suturing of wounds and surgical removal of inflamed joints. Further, each can be treated by chemical means. Chemotherapy is applied to cancers, growth hormones are applied to wound healing and anti-inflammatory drugs are applied to treating chronic inflammatory conditions. These, and related treatments are directed, in general, to treating the cancerous, injured, or inflamed tissue using active compounds not native to the patient's body. The present invention can be used along with all or any of these treatments. However, in order to provide an understanding on how the present invention departs from conventional treatment modalities a brief and general description of current treatment technologies in these areas is provided.

Method of treating cancer using platelet releasate


The present invention generally relates to a filtration system having one or more apparatuses for filtering gases, liquids, or fluids (e.g., water) to remove particulate matter, and methods of making and using the apparatus. More particularly, embodiments relate to apparatuses and methods for applying centrifugal force(s) to push a fluid or gas to be filtered through a porous membrane or filter within the apparatus to separate particulate matter therefrom. The present invention takes advantage of the Coriolis effect within a cylindrical filter radiating out from a rotating central body. The filtration apparatus provides an energy efficient system for microfiltration (or other filtration process) to remove contaminants from gases and fluids, such as waste water.

Microfiltration, ultra filtration, and reverse osmosis all involve the physical separation particulate matter from a fluid. In general, particulate contaminants may be removed by mechanical filtration methods, provided the filter has pores small enough to exclude the particles. Substances that are larger than the pores in membranes are fully removed. Substances that are smaller than the pores of the membranes are partially removed, depending on the structure or construction of a refuse or filtrate layer on the membrane.
In the case of water purification (e.g., industrial, municipal, and/or residential water purification), the extent to which dissolved solids, turbidity, microorganisms, and ions are removed is determined by the size of the pores in the membranes. FIG. 7 provides a scale of various pore sizes and/or size ranges along with the types of materials (e.g., particulate matter) that can be filtered from a fluid by a filter membrane having the identified pore sizes. Microfiltration utilizes membranes with a pore size of 0.1 to 10 microns, which can remove virtually all bacteria from the water to be filtered. Ultra-filtration (UF) membranes typically have pore sizes in the range of 0.01 to 0.10 microns and can efficiently remove bacteria and most viruses, colloids (e.g., lead), and silt.
Separation efficiency is increased with filters containing smaller pore sizes, although higher pressures are needed to maintain flow through the filter. Thus, a filter having a smaller pore size requires a high-pressure pump or other means of creating high pressure. Such equipment typically requires and consumes a relatively large amount of energy to carry out the filtration process, and may require relatively complex and/or costly techniques to clean the filters.
A method commonly used to separate solids from liquids includes passing a mixture of solids and liquids through a tubular membrane or filter. Such filters are typically used, for example, in reverse osmosis processes. Such separation processes require high fluid pressures to push the liquid through the filter and separate the liquid from contaminants. Typically, the high fluid pressure is achieved by using a high-pressure pump. These high-pressure pumps consume large amount of energy in creating adequate filtration pressures, especially as the amount of particulate matter blocking the pores increases. There is a continuing need for more energy-efficient fluid filtration systems.
Centrifuges and other machines that use centrifugal force (and optionally, a filter) to separate fluid components from solid-phase materials (e.g., a washing machine) provide energy efficiencies with regard to the inertia created by the spin of the drum or rotor around a central drive shaft. There are known centrifugal filtration systems (e.g., a household washing machine) for separating liquids (water) from solids (fabric/clothing). However, application of this type of apparatus to perform other tasks such as wastewater treatment, recycling industrial solvents, pharmaceutical and blood product purification, and water purification in food product industries encounter several technical difficulties and limitations. For example, practical applications of a centrifugal system for separating particulate contaminants from water in waste water treatment are generally limited by the filter(s) and their suitability for separating certain types of particulate matter (e.g., the holes may be too large to separate most of the suspended solids in the waste water).
Therefore, a need still exists in the art for new and improved systems, configurations and operational processes that can separate particulate matter from relatively high volumes of fluid or gas with greater efficiency, scalability, and ease of cleaning.

Dynamic filtration device using centrifugal force


An antenna switch is provided on a portable telecommunication instrument, such as a cellular telephone, to enable operation of the keypad of the instrument when the antenna is extended. In one arrangement, an antenna switch comprises a pair of antenna position sensing contacts disposed on a printed circuit board at a position where electrical continuity is established between the contacts by an electrically conductive member on the antenna when the antenna is in an extended position. The present invention solves the problem of inadvertent activation of the instrument when the antenna is retracted. Thus, the instrument does not require a closeable cover over the keypad to prevent inadvertent actuation of the instrument.

1. Technical Field
This invention relates generally to an apparatus for enabling the keypad of an electronic instrument such as a cellular telephone, and more particularly to such an apparatus which enables operation of the keypad in response to extension of an antenna.
2. History of Related Art
It is very easy to inadvertently depress the keypad of an electronic instrument, such as a cellular telephone, while carrying the phone in a pocket or purse. This is particularly true with today's small cellular telephones. The inadvertent activation of the telephone can lead to a number of problems, ranging from low battery life due to excessive current drain to missing calls because the phone was accidentally turned off.
Heretofore, the only solution to inadvertent activation of the keypad has been to incorporate a "flip" cover over the keypad in order to protect the keys when the phone is carried in a purse, briefcase or pocket. However, flip covers present a number of problems. The three most troublesome problems include the additional steps required to answer a telephone equipped with a flip cover, increased thickness that a flip cover adds to the instrument, and the extra cost added to the instrument as a result of the cover and other added components. More specifically, when a telephone is equipped with a flip cover, the telephone must be removed from a pocket or other place of storage, the flip cover must be opened, the antenna extended, and the "SEND" key depressed to answer the call unless the flip cover is equipped with a switch which automatically answers the call when the cover is opened. The increased thickness added to the instrument as a result of the flip cover decreases the comfort and compactness of the instrument when carried in a pocket. The extra cost added to the manufacture of an instrument equipped with a flip cover does not result in any additional utility of the instrument.
One attempt to reduce the inadvertent activation of the keypad is described in U.S. Pat. No. 4,845,772 issued Jul. 4, 1989 to Metroka et al. In the Metroka radiotelephone, the flip cover activates a hook switch which establishes power to the phone when moved to an open position. While this arrangement is somewhat beneficial, use of the phone to receive or transmit calls still requires extension of the antenna. Furthermore, if the antenna is not extended to its full length, not only is signal reception and transmission quality diminished, but also the antenna will be in undesirably close proximity to the user's head, thereby increasing the user's specific absorption rate (SAR) of electromagnetic energy emitted from the antenna.
It is therefore desirable to have a method of preventing inadvertent activation of a keypad of an instrument without adding steps required to answer a call. It is further desirable to have such an instrument that enables the user to answer a call simply by removing the phone from the user's pocket or other place of temporary storage and fully extending the antenna to its intended operational position. When the antenna is at it's correct operational position, the user can directly respond to the incoming call with assurance that the antenna is at its properly spaced from the user's head and that the signal will not break up due to insufficient antenna length. Furthermore, on outgoing calls it is desirable to have an instrument with a keypad that is enabled simply by extending the antenna of the instrument. It is still further desirable to have such an instrument that has a thin profile and can be comfortably carried in the pocket of a jacket or shirt. It is further desirable to have such an instrument that is economical to produce and does not add significant complexity or cost to the instrument.

Apparatus for enabling a keypad in response to antenna extension