This invention provides a compound of the formula (I):

This invention relates to novel N-benzenesulfonyl L-proline compounds. These compounds are useful as antagonists of bradykinin, and are thus useful in the treatment of inflammation, asthma, allergic rhinitis, pain or the like in mammalian, especially humans. The present invention also relates to a pharmaceutical composition comprising the above compounds.
Bradykinin (xe2x80x9cBKxe2x80x9d) is generated under normal conditions in mammalia by the action of various plasma enzymes such as kallikrein on high molecular weight kininogens. It is widely distributed in mammals, and relates its two receptor subtypes, B1 and B2. The actions of BK at the B2 receptor include mainly contraction of arterial and venous preparations, although it can cause relaxation of peripheral resistance vessels as well.
Many of the more important functions of BK, such as increases in vascular permeability, pain, and vasodilatation, however, are mediated by the B2 receptor. These effects at the B2 receptor are believed to be responsible for BK""s role in numerous diseases, such as inflammation, cardiovascular disease, pain, and the common cold. Hence antagonists at the B2 receptor should find considerable therapeutic applications. Most of the efforts in this area thus far have been directed at peptidic analogues of the BK structure, some of which have been studied as analgesics and antiinflammatory agents.
Numerous N-benzenesulfonyl L-proline compounds as a B2 antagonist have been synthesized, and disclosed in a number of patent publications such as international publication Nos. WO 97/41104, WO 96/13485, WO 99/00387, WO 98/24783, WO 98/03503, WO 97/24349, WO 97/07115 and WO 96/40639.
International Publication Number WO 98/24783, WO 98/03503, WO 97/24349, WO 97/07115 disclose a variety of N-benzenesulfonyl L-proline compounds as antagonists of bradykinin.
It would be desirable if there were provided a non-peptide antagonist of the B2 receptor, having an improved B2 antagonistic activity and a good metabolic stability against human liver microsomes.
The present invention provides a compound of the following formula:
or the pharmaceutically acceptable salts thereof wherein
X1 and X2 are independently halo or C1-4 alkyl;
R1 and R2 are independently hydrogen or C1-4 alkyl;
R3 and R4 are independently hydrogen or halo; and
R5 is
(a) xe2x80x94C3-9 diazacycloalkyl optionally substituted with C5-11 azabicycloalkyl;
(b) xe2x80x94C3-9 azacycloalkyl-NHxe2x80x94(C5-11, azabicycloalkyl optionally substituted with C1-4 alkyl);
(c) xe2x80x94NHxe2x80x94C1-3 alkyl-C(O)xe2x80x94C5-11 diazabicycloalkyl;
(d) xe2x80x94NHxe2x80x94C1-3 alkyl-C(O)xe2x80x94NHxe2x80x94C5-11 azabicycloalkyl, the C5-11 azabicycloalkyl being optionally substituted with C1-4 alkyl;
(e) xe2x80x94C3-9 azacycloalkyl optionally substituted with C3-9 azacycloalkyl; or
(f) xe2x80x94NHxe2x80x94C1-5 alkyl-NHxe2x80x94C(O)xe2x80x94C4-9 cycloalkyl-NH2.
The N-benzenesulfonyl L-proline compounds of this invention have an antagonistic action towards bradykinin and are thus useful in therapeutics, particularly for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer""s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or the like in mammalian, especially humans.
The N-benzenesulfonyl L-proline compounds of this invention have an antagonistic action towards bradykinin and are thus useful in therapeutics, particularly for the treatment of Amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, multiple sclerosis, stroke, head trauma, post-surgical brain edema, brain edema (general), cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), rheumatoid arthritis, osteoarthritis, migraine, neuropathic pain, pruritis, brain tumor, pseudotumor cerebri, glaucoma, hydrocephalus, spinal cord trauma, spinal cord edema, neurodegenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching, sepsis or the like in mammalian, especially humans.
The present invention provides a pharmaceutical composition for the treatment of disease conditions mediated by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer""s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or the like, which comprises a therapeutically effective amount of the N-benzenesulfonyl L-proline compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Further, the present invention also provides a pharmaceutical composition for the treatment of Amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, Multiple sclerosis, Stroke, head trauma, Post-surgical brain edema, Brain edema (general), Cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), Brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), Rheumatoid arthritis, Osteoarthritis, Migraine, Neuropathic Pain, Pruritis, Brain Tumor, Pseudotumor cerebri, Glaucoma, Hydrocephalus, Spinal cord trauma, Spinal cord edema, neurodegenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching or Sepsis, which comprises a therapeutically effective amount of a compound of formual (I) or its pharmaceutically acceptable carrier.
Also, the present invention provides a method for the treatment of disease conditions mediated by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention provides a method for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer""s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or the like, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
As used herein, the term xe2x80x9chaloxe2x80x9d is fluoro, chloro, bromo or iodo (preferably fluoro or chloro).
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl.
As used herein, the term xe2x80x9cC4-9 cycloalkylxe2x80x9d means monocyclic alkyl having 4 to 9 carbon atoms, such as cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, and the like.
As used herein, the term xe2x80x9cC3-9 azacycloalkyl, C3-9 diazacycloalkyl, C5-11 azabicycloalkyl or C5-11 diazabicycloalkyl xe2x80x9d means a group wherein one or two carbons of mono- or bicyclic alkyl ring components are substituted by nitrogen atoms, included, but not limited to, azetidinyl, piperazinyl, piperidino, piperidinyl, pyrrolidinyl, azabicyclo[3.3.0]octyl, quinuclidinyl, azabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, azabicyclo[2.2.2]octyl or diazabicyclo[3.2.1]octyl.
In the formula (I), R5 is preferably (a) xe2x80x94C3-9 diazacycloalkyl optionally substituted with C5-11 azabicycloalkyl or (c) xe2x80x94NHxe2x80x94C1-3 alkyl-C(O)xe2x80x94C5-11 diazabicycloalkyl, more preferably (a) xe2x80x94C4-8 diazacycloalkyl optionally substituted with C6-10 azabicycloalkyl or xe2x80x94NHxe2x80x94C1-3 alkyl-C(O)xe2x80x94C6-10 diazabicycloalkyl, further preferably azabicyclo[2.2.2]octyl-piperazinyl, diazabicyclo[3.2.1]octyl-oxomethylamino or diazabicyclo[3.2.1]octyl-oxoethylamino, and most preferably azabicyclo[2.2.2]octyl-piperazinyl or diazabicyclo[3.2.1]octyl-oxomethylamino.
Preferred compounds of this invention are those of the formula (I) wherein
X1 and X2 are chloro;
R1 and R2 are independently hydrogen, methyl or ethyl;
R3 and R4 are independently hydrogen or fluoro; and
R5 is
(a) xe2x80x94C4-8 diazacycloalkyl optionally substituted with C6-10 azabicycloalkyl;
(b) xe2x80x94C3-6 azacycloalkyl-NHxe2x80x94(C6-10 azabicycloalkyl optionally substituted with C1-4 alkyl);
(c) xe2x80x94NHxe2x80x94C1-3 alkyl-C(O)xe2x80x94C6-10 diazabicycloalkyl;
(d) xe2x80x94NHxe2x80x94C1-3 alkyl-C(O)xe2x80x94NHxe2x80x94C6-10 azabicycloalkyl, the C6-10 azabicycloalkyl being optionally substituted with C1-4 alkyl;
(e) xe2x80x94C4-8 azacycloalkyl optionally substituted with C4-8 azacycloalkyl; or
(f) xe2x80x94NHxe2x80x94C1-5 alkyl-NHxe2x80x94C(O)xe2x80x94C58 cycloalkyl-NH2.
Much preferred compounds of this invention are those of the formula (I) wherein
R1 and R2 are methyl; R3 and R4 are hydrogen; and
R5 is azabicyclo[2.2.2]octyl-piperazinyl, azabicylo[3.2.1]octanylaminoazetidinyl, diazabicyclo[3.2.1]octyl-oxomethylamino, diazabicyclo[3.2.1]octyl-oxoethylamino, methylazabicyclo[3.2.1]octyl-aminooxomethylamino, methylazabicyclo[3.2.1]octyl-aminooxoethylamino, ethylazabicyclo[3.2.1]octyl-aminooxomethylamino, piperidinopiperidinyl, [[(aminocyclohexyl)carbonyl]amino]propylamino or [[(aminocyclohexyl)carbonyl]amino]butylamino.
Also, preferred compounds of this invention are those of the formula (I) wherein
R5 is azabicyclo[2.2.2]octyl-piperazinyl, azabicylo[3.2.1]octanylaminoazetidinyl, diazabicyclo[3.2.1]octyl-oxomethylamino, methylazabicyclo[3.2.1]octyl-aminooxomethylamino, piperidinopiperidinyl or [[(aminocyclohexyl)carbonyl]amino]propylamino.
Preferred individual compounds of this invention are:
8-[[3-[[(2S)-2-[[4-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]carbonyl]pyrrolidinyl]sulfonyl]-2,6-dichlorobenzyl]oxy]-2,4-dimethylquinoline; and (2S)-N-[2-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-oxoethyl]-1-[[2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl]sulfonyl]-2-pyrrolidinecarboxamide, and a salt thereof.
The N-benzenesulfonyl L-proline compounds of formula (I) of this invention may be prepared by a variety of synthetic methods.
(wherein X1, X2, R1, R2, R3, R4 and R5 are as already defined; and WSC is 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, HOBt is 1-hydroxybenzotriazole hydrate.
To a stirred solution of the acid of formula (II) (150 mg, 0.294 mmol) and amine H-R5 (0.441 mmol) in CH2Cl2 (15 mL) were added HOBt (67 mg, 0.441 mmol) and WSC (84 mg, 0.441 mmol) at room temperature and the mixture was stirred overnight. To the mixture was added H2O (5 mL) and the organic layer was separated, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (NH gel, 200-350 mesh, 8 g, CH2Cl2/MeOH=99/1 to 90/10) afforded the coupling product including a compound of formula (I).
In the described method A, 1,3-diisopropylcarbodiimide in place of WSC, t-BuOHxe2x80x94CH2Cl2(1-1), DMF, or AcOEt in place of CH2Cl2 were also used. For purification process, appropriate regins or solid-phase extraction method was also utilized when the small amount of the starting material (II) (about 50 Smol) were used.
To a stirred solution of the coupling product including a compound of formula (I) (0.0964 mmol) in MeOH was added HCl-MeOH (2.9 mL) and the mixture was stirred for 15 minutes. Then the solvent was removed in vacuo to provide the HCl salt.
Alternately, the N-benzenesulfonyl L-proline compounds of formula (Ia-II) were prepared by reaction of a compound (III) with a compound of formula (IV) as indicated in the following Scheme A-II.
(wherein R is hydroxy, C1-4 alkoxy (such as methoxy and ethoxy) or R5; X3 is halo; and the other symbols are as already defined are as already defined)
This method utilizes a synthesis as described in WO97/07115. This reaction is carried out in a suitable reaction-inert solvent (anhydrous). Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, propanol and butanol; ethers such as diethyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as methylene dichloride, chloroform, dichloromethane and dichloroethane; amides such as N,N-dimethylformamide; and nitrites such as acetonitrile. This reaction is carried out at a temperature between xe2x88x9210xc2x0 C. and 100xc2x0 C., preferably from 0xc2x0 C. to 50xc2x0 C. for 5 minutes to 24 hours, preferably 30 minutes to 5 hours.
In addition, the compounds (III) and (IV) which can be used herein may be either already known or may be prepared according to the reported methods.
The compounds of formula (III) was prepared by the reaction of a compound (V) with a compound of formula (VI) as indicated in the following Scheme B.
(wherein X3 is halo; and the other symbols are as already defined)
This method utilizes a synthesis as described in WO97/07115. This reaction is carried out in the presence of base in a suitable reaction-inert solvent. Suitable base includes, for example, triethylamine. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, propanol and butanol; ethers such as diethyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; amides such as N,N-dimethylformamide; and nitrites such as acetonitrile. This reaction is carried out at a temperature between xe2x88x9210xc2x0 C. and 100xc2x0 C., preferably from 0xc2x0 C. to 40xc2x0 C. for 5 minutes to 24 hours, preferably 30 minutes to 3 hours.
The compounds of formula (I), and the intermediates above-mentioned preparation methods can be isolated and purified by conventional procedures such as recrystallization or chromatographic purification.
The optically active compounds of this invention can be prepared by several methods known to a skilled person in the art. For example, the optically active compounds of this invention may be obtained by chromatographic separation or fractional crystallization from the final compounds or the intermediates in racemic form thereof. Alternatively, the optically active compounds may be prepared by optically selective reaction, enzymatic hydrolysis or reactions using optically active intermediates.
The N-benzenesulfonyl L-proline compounds of this invention possess an asymmetric center. Hence, the compounds can exist in separated (+)- and (xe2x88x92)-optically active forms, as well as in racemic one thereof. The present invention includes all such forms within its scope. Individual isomers can be obtained by known methods, such as optically selective reaction or chromatographic separation in the preparation of the final product or its intermediate.
The present invention includes salt forms of the compounds (I) as obtained above.
Insofar as the N-benzenesulfonyl L-proline compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned N-benzenesulfonyl L-proline base compounds of this invention of formula (I) are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1.1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate). The acid addition salts can be prepared by conventional procedures.
The N-benzenesulfonyl L-proline compounds of the present invention of formula (I) exhibit significant bradykinin receptor-binding activity and therefore, are of value in the treatment of a wide variety of clinical conditions in mammals, especially human. Such conditions include inflammation, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma and the like.
Therefore, these compounds are readily adapted to therapeutic use as bradykinin antagonists for the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humans.
Also, the compounds of formula (I) may be expected more effective therapeutic effects with being co-administered with H1-antagonist.
Further, the present invention also encompasses a pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer""s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, cystitis, pancreatitis, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, multiple sclerosis, stroke, head trauma, post-surgical brain edema, brain edema (general), cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), rheumatoid arthritis, osteoarthritis, migraine, neuropathic pain, pruritis, brain tumor, pseudotumor cerebri, glaucoma, hydrocephalus, spinal cord trauma, spinal cord edema, neurodegenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching, sepsis, or the like, which comprises a therapeutically effective amount of the N-benzenesulfonyl L-proline compound of formula (I) and H1-antagonist or their pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
The compounds of the invention may advantageously be employed in combination with one or more other therapeutic ingredients selected from an antibiotic, anti-fungal, or anti-viral agent, an anti-histamine, a non-steroidal anti-inflammatory drug or disease modifying anti-rheumatic drug.
The combination with an anti-histamine (H1 antagonist) is particularly favorured for use in the prophylaxis and treatment of asthma and rhinitis. Examples of anti-histamine are chlorpheniramine, brompheniramine, clemastine, ketotifen, azatadine, loratadine, terfenadine, cetirizine, astemizole, tazifylline, levocabastine, diphenhydramine, temelastine, etolotifen, acrivastine, azelastine, ebastine, mequitazine, KA-398, FK-613, mizolastine, MDL-103896, levocetirizine, mometasone furoate, DF-1111301, KC-11404, carebastine, ramatroban, desloratadine, noberastine, selenotifen, alinastine, E-4716, efletirizine, tritoqualine, norastemizole, ZCR-2060, WY-49051, KAA-276, VUF-K-9015, tagorizine, KC-11425, epinastine, MDL-28163 terfenadine, HSR-609, acrivastine and BMY-25368.
The activity of the N-benzenesulfonyl L-proline compounds of the present invention, as bradykinin antagonists, is determined by their ability to inhibit the binding of bradykinin at its receptor sites in recombinant human bradykinin B2 receptor expressing CHO-KI cells (from Receptor Biology, Inc.) employing radioactive ligands.
The bradykinin antagonist activity of the N-benzenesulfonyl L-proline compounds is evaluated by using the standard assay procedure described in, for example, Baenziger N. L., Jong Y-J. I., Yocum S. A., Dalemar L. R., Wilhelm B., Vaurek R., Stewart J. M., Eur. J. Cell Biol., 1992, 58, 71-80. This method essentially involves determining the concentration of the individual compound required to reduce the amount of radiolabelled bradykinin ligands by 50% at their receptor sites in CHO-K1 cells, thereby affording characteristic IC50 values for each compound tested.
More specifically, the assay is carried out as follows. First, rat, guinea pig or monkey ileum tissues are minced and suspended in 25 mM piperazine-N,Nxe2x80x2-bis (2-ethanesulfonic acid (PIPES) buffer (pH 6.8) containing 0.1 mg/ml of soybean trypsin inhibitor. Then, the tissues are homogenized using a Polytron homogenizer at setting 7 for 30 seconds three times, and then rehomogenized with a Teflon-coated homogenizer. The homogenized suspension was centrifuged at 1,200xc3x97 g for 15 minutes. The pellet was rehomogenized and then centrifuged at 1,200xc3x97 g for 15 minutes. These supernatant were centrifuged at 10,000xc3x97 g for 60 minutes. The tissue pellets, CHO-K1 cell membrane are suspended in 25 mM PIPES buffer (pH6.8) containing 1.25 mM dithiothreitol, 1.75 xcexcg/ml bacitracin, 1 mM o-phenanthroline, 18.75 xcexcM captopril, 1.25 mg/ml bovine serum albumin (BSA), to prepare tissue/cell suspensions. Then, 10 xcexcl of test compound solution dissolved in phosphate buffered saline (PBS, pH 7.5) containing 2% DMSO (final) and 0.1% BSA (w/v) or 10 ml of 12.5 mM bradykinin in PBS (pH 7.5) containing 0.1% BSA (w/v) are placed in a reaction 96-well plate. 15 xcexcl of 8.3 nM [3H]bradykinin is added to the compound solution or bradykinin solution in the 96-well plate. Finally 100 xcexcl of the tissue or cell suspension are added to the mixture in the plate, and incubated at room temperature for 1 hour under the dark. After incubation, the resultant product in the reaction plates is filtered through 0.1% polyethylenimine presoaked LKB filermat. The filtrate is washed using a Skatron auto cell harvester. The tissue bound radioactivity is determined using a LKB betaplate counter. The IC50 value is determined using the equation:
Bound=Bmax/(1+[I]/IC50)
wherein [I] means the concentration of the test compound.
All compounds prepared in the working examples as described below were tested by this method, and showed an IC50 value of 0.1 nM to 4 nM in CHO-KL cells with respect to inhibition of binding at its receptor.
The most preferred compounds prepared in the working examples as described below were tested by this method, and showed an IC50 value of 0.5 nM to 3.3 nM in CHO-K1 cells with respect to inhibition of binding at its receptor.
The possibility of drugxe2x80x94drug interaction of the N-benzenesulfonyl L-proline compounds of the present invention, as bradykinin antagonists, is determined by their ability to inhibit the testosterone 6xe2x96xa1-hydroxylase activity raised by CYP3A4 which is most abundant subtype of cytochrome P-450 in human.
This method essentially involves determining the concentration of the individual compound required to reduce the amount of 67-hydroxytestosterone by 50%.
More specifically, the assay is carried out as follows. Human liver microsomes (0.2 mg/ml) were mixed with appropriate concentrations of kinin B2 antagonist. Then, incubated with the presence of 50 xcexcM testosterone, 1.3 mM NADP+, 0.9 mM NADH, 3.3 mM glucose-6-phosphate, 3.3 mM MgCl2, and glucose-6-phosphate dehydrogenase (8 units/ml) in a total volume of 0.2 ml of 100 mM potassium phosphate buffer, pH 7.4, at 37xc2x0 C. After incubation (20 minutes), 10 xcexcl of methylalchol containing internal standard was withdrawn. The medium was filtrated by membrane filter with centrifugation at 1,800xc3x97 g for 10 minutes, and the resulting filtrate was taken.
xe2x96xa1xe2x96xa16xe2x96xa1-hydroxylated metabolite of testosterone in samples was analyzed by HPLC. A sample of 20 xcexcl was injected to the HPLC system equipped with a Polymer Cl 8 column (2.0xc3x9775 mm). The mobile phase consisted of 24% to 66% acetonitorile linear gradient including 10 mM ammonium phosphate, and with a flow rate of 0.35 ml/min.
The IC50 value is determined using the equation:
Activity=Activitycontol/(1+[I]/IC50)
wherein [I] means the concentration of the test compound.
The most preferred compounds as memtined above of Working Examples showed IC50 values of more than 10 xcexcM.
T12 value against human liver microsome was calculated by conventional procedure. More specifically, human liver microsomes (0.2 mg/ml) were mixed with 1 xcexcM of kinin B2 antagonist and incubated with in the presence of 1.3 mM NADP+, 0.9 mM NADH, 3.3 mM glucose-6-phosphate, 3.3 mM MgCl2, and glucose-6-phosphate dehydrogenase (8 units/ml) in a total volume of 1.2 ml of 100 mM potassium phosphate buffer, pH 7.4, at 37xc2x0 C. At specified incubation times (0, 5, 10, 30 minutes), an aliquot of 100 xcexcl was withdrawn from the reaction mixture and mixed with 1 ml of acetonitrile containing internal standard. Protein was precipitated by centrifugation at 1,800xc3x97 g for 10 minutes, and the resulting supernatant was taken.
Bradikinin B2 antagonist in samples were analyzed by LS/MS/MS, in a Sciex API-300 mass spectrometer linked with a Hawlett-Pakkered HP1100 HPLC system. A sample of 20 xcexcl was injected to the HPLC system equipped with a Wakosil II 5C18 HG column (2.0xc3x97150 mm). The mobile phase consisted of 80% acetonitorile including 10 mM ammonium acetate, and the elution was isocratic with a flow rate of 0.3 ml/min. Part of the eluent from the HPLC column was introduced into the atmospheric ionization source via an ion spray interface. Txc2xd value is determined using the equation:
Txc2xd=0.693/k
wherein k is elimination rate constant of the test compound.
The compounds of the formula (I) exhibit excellent biological activity in vitro and in vivo as bradykinin antagonists. Additionally, the compound of the formula (I) was stable against metabolism in human liver microsomes assay experiments. The most preferred compounds of Working Examples showed T112 values of more than 10 minutes.
The compound of this invention showed a good IC50 in CHO-K1 cells and a good Txc2xd value, which are essential for a practical drug.
The N-benzenesulfonyl L-proline compounds of formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.3 mg to 750 mg per day, preferably from 10 mg to 500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, for example, a dosage level that is in the range of from 0.06 mg to 2 mg per kg of body weight per day is most desirably employed for treatment of inflammation.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

N-benzenesulfonyl L-proline compounds as bradykinin antagonists

Abstract: or the pharmaceutically acceptable salts thereof wherein X1 and X2 are halo; R1 and R2 are independently hydrogen or C1-4 alkyl; R3 and R4 are each hydrogen or halo; and

Abstract: R5 is

Abstract: (b) xe2x80x94C3-9 azacycloalkyl-NHxe2x80x94(C5-11 azabicycloalkyl optionally substituted with C1-4 alkyl);

Abstract: These compounds are useful for the treatment of medical conditions mediated by bradykinin such as inflammation, allergic rhinitis, pain, etc. This invention also provides a pharmaceutical composition comprising the above compound.


A method of using an ICF chamber may include causing a target in the ICF chamber to emit x-ray radiation; receiving the x-ray radiation through a plurality of holes in a wall of the ICF chamber; and absorbing the x-ray radiation in a gas contained in a plurality of tubes that are coupled to the plurality of holes.

Nuclear fusion by inertial confinement, Inertial Confinement Fusion ("ICF"), utilizes nuclear fusion reactions to produce energy. In most types of ICF systems, an external drive mechanism, such as a laser, delivers energy to a target containing nuclear fusion fuel. The target is designed to use this energy to compress, heat and ignite the fusion fuel within the target. If a sufficient amount of fuel is compressed sufficiently and heated sufficiently, a self-sustaining fusion reaction can occur in which energy produced by fusion reactions continues to heat the fuel. This is generally referred to as "ignition." The inertia of the compressed fuel can keep it from expanding long enough for significant energy to be produced before expansion of the fuel and the resultant cooling terminates the fusion reaction.
ICF targets release energy in the form of high-velocity subatomic particles (ions and neutrons), x-ray radiation, and kinetic energy of the expanding debris field. The target is ignited inside a vacuum chamber, which is responsible for safely containing the energy output of the target, and potentially converting it into useful form (for example, steam). In general, the required size of the containment chamber increases with the energy output of the target. High-performance targets, involving high gains and/or large output energies, may require very large containment chambers.

Structure for containment of radiation from an ICF


An upgrade of an application product is installed to a first location in a shared environment that is different than a second location in the shared environment. An indication of the newer version of the application product and an indication of the first location are recorded in a registry that comprises indications of a plurality of application products and locations corresponding thereto. Metadata and binding information are obtained from an instance of the previous version of the application product while the instance of the previous version of the application product continues running. The metadata and the binding information are instantiated for an instance of the newer version of the application product in execution space thereof. Work is diverted work from the instance of the previous version of the application product to the instance of the newer version of the application product while both instances continue running in the shared environment.

Embodiments of the inventive subject matter generally relate to the field of computer processing and, more particularly, to live install of a product with smart rebinding.
Typically, an enterprise customer runs multiple software products as a solution. The multiple software products interact to provide the solution for that enterprise customer. One software product implements a user interface, while another software products manages a database. Other software products implement web services, security, and data processing. These products are often updated on different timelines. For instance, the database manager product is updated at a time when the other software products are not updated. Upgrading one of these products is inefficient and often introduces an interruption in handling requests submitted to the software product being upgraded.

Smart rebinding for live product install

International Business Machines Corporation


Water-based diarylide pigment compositions containing diarylide pigment modified with water-soluble amines. The pigment compositions are useful in both water-based coating and ink compositions.

1. Field of the Invention
The present invention relates to water-based inks.
2. Description of the Related Art and Brief Description of the Invention
Diarylide pigments represent an important class of coloring agents used primarily in the manufacture of inks. The most utilized diarylide pigments include, but are not limited to, the following: Pigment Yellow 12, Pigment Yellow 13, Pigment Yellow 14, Pigment Yellow 17 and Pigment Yellow 83.
It is documented in the prior art literature that the addition of fatty primary amines to an aqueous slurry of Pigment Yellow 12, followed by filtration and drying at an elevated temperature, results in a pigment having superior properties (e.g., increased strength, gloss, transparency, and lower rheology) when used to make a solvent-based printing ink, especially a publication gravure type ink. (B.P. 1,080,835). There are many variations on this technology which have also been patented. Some include the use of diamines to reduce penetration (E.P. 57,880), the use of rosin amine (B.P. 1,080,116; B.P. 1,288,044), the use of heterocyclic amines (B.P. 1,334,570), etc. There are also many patents on the process of forming the azomethine additive (aka Schiff's Base or ketimine).
Thus, some patents include pre-reaction of the amine and the acetoacetanilide, followed by reaction with tetrazotized DCB (B.P 1,334,570; U.S. Pat. No. 4,643,770). Others utilize reaction of the dry Pigment Yellow 12 in a solvent to form the azomethine (U.S. Pat. No. 4,468,255), but most, simply form the additives by drying the presscake containing the amine.
Although the use of the numerous aforementioned amine treatments afford pigments with improved application properties in solvent-based inks (e.g., publication gravure, nitrocellulose packaging, solvent flexo), the use of amine modification for water-based inks has not been exploited, and is within the scope of the present invention. Accordingly, it has been determined that by producing the azomethine compounds of the present invention, diarylide pigment compositions exhibiting significantly improved application properties in water-based ink and coating compositions can be obtained. This is of increasing importance with the current trend toward the use of water-based printing inks. The use of the products of this invention by affording stronger and improved diarylide pigments for water inks, offers significant economic incentives required for printers to change from the traditionally less costly solvent inks


A video signal output circuit used in a TV set to sample the frequency level of an input video signal so that monitored pictures are automatically optimized in quality. A luminance signal is separated from the input video signal by a Y/C separator. A plurality of band-pass filters whose passing frequencies are f.sub.1, f.sub.2, f.sub.3, . . . , f.sub.n detect the frequency spectrum of the luminance signal through sampling. The detected values are sent to a controller attached to an equalizer. The equalizer is controlled so that monitored pictures based on the output video signal are optimized in quality.

Recent years have seen numerous kinds of apparatus developed and marketed as video signal sources. For example, ordinary television sets are equipped with many video input terminals for receiving video signals from a video tape recorder (VTR) and optical disk players in addition to broadcast program signals.
The characteristics of the video signal of VTR's sometimes differ from those of optical-disk players (commonly known as laser disk players). For example, the frequency characteristic of the video signal may vary depending on the performance and property of the video apparatus in question. Furthermore, recordings are sometimes made on the medium in such a manner that special visual effects are provided to enhance the contents of the program recorded.
Given these parameters of variation, a video apparatus with fixed video circuit characteristics such as a conventional television sets may not cope sufficiently with diverse video signals coming from external video sources. For example, the screen may turn high-resolution pictures into scenes of unnatural glare, or the screen may show "dulled" pictures lacking visual sharpness.

Video signal output circuit with adaptive equalizer


A hedge trimmer includes a blade unit having a plurality of teeth spaced at one spacing from each other and another plurality of teeth spaced at another spacing and distance from the first teeth whereby branches and the like having a variety of sizes can be accommodated by the hedge trimmer.

Many homeowners trim and shape the hedges, bushes and trees around their homes using a powered trimmer. These trimmers generally include a motor which is drivingly connected to a blade. The blade has a multiplicity of teeth which are moved to cut the hedge, branches, etc.
These powered trimmers work well when all of the branches are essentially the same size, and that size is within the size limits associated with the spacing between the saw blade teeth.
However, if the user has trees and/or hedges with widely varying branch sizes, a single hedge trimmer may prove to be inadequate. For this reason, many homeowners are required to own several trimmers or at least different blades, one with a large number of uniformly and closely spaced teeth for ordinary trimming, and another with teeth spaced apart for large branches. Alternatively, a user may be required to carry a chain saw to accommodate such large branches.
Accordingly, there is a need for a hedge trimmer that is adaptable for use with a wide variety of branch sizes.


To provide an image reading device capable of reading a high-quality image under the conditions such as compactness, simplification, and low power consumption, an image reading apparatus using this image reading device, and a method therefor, white reference data for white level correction is stored in a memory in correspondence with a reference temperature. A temperature near the image reading device is detected, and white reference data is corrected on the basis of the temperature difference between the detected temperature and the reference temperature. The corrected white reference data is used in white level correction of an image signal output from a CCD included in the image reading device.

1. Field of the Invention
The present invention relates to an image reading device, an image reading apparatus, and a method therefor and, more particularly, to an image reading device used in an image scanner or facsimile apparatus for reading light from an original, an image reading apparatus, and a method therefor.
2. Description of Related Art
As an image reading apparatus used in an image scanner or facsimile apparatus, an apparatus using a reduction optical system shown in FIG. 21 is known. Referring to FIG. 21, light is irradiated from a light source 5 to an original 6. The light reflected by the original 6 is deflected through 90.degree. by a mirror 4 and focused on a CCD image sensor 1 through a lens 2, thereby converting the light into an image signal. A correction plate (shading correction plate) 3 for correcting a power of cos4 of a white output waveform lens. The image signal output from the CCD image sensor 1 is A/D-converted into digital data by an analog-to-digital (A/D) converter incorporated in an IC (not shown). The digital data is subjected to an image process. An inexpensive xenon (Xe) lamp or LED is often used as a light source for this image reading apparatus.
A printer serving as an image reading apparatus is available in which a scanner unit is mounted in place of a print head unit including an ink tank detachably mounted in the printer.
The above techniques pose the following problems. Since the absolute light amount of the Xe lamp or LED used in the image reading apparatus is small, a charge accumulation time (to be simply referred to also as an accumulation time hereinafter) in reading operation in the CCD image sensor 1 must be prolonged, and the sensitivity of a reception system must be improved in order to obtain stable image information. The sensitivity characteristics of the light-receiving portion for photoelectrically converting light reflected by the original have limitations although high-speed driving of a CCD device serving as a light-receiving element has advanced. In order to obtain a sufficiently high S/N ratio, the original must be illuminated in a sufficiently large light amount.
For this purpose, to increase the light amount by increasing a drive current to the LED, the drive current changes due to the wavelength of emission light upon heating of the LED itself and a change in forward voltage. As a result, a stable emission intensity cannot be obtained.
In a printer incorporated in a notebook personal computer, when a scanner unit is mounted in place of a print head unit, the scanner unit must be made compact and simple because the printer of this personal computer is compact. In addition, a reduction in power consumption is desired in consideration of driving the notebook personal computer using a secondary battery.
To correctly set the dynamic range in reading an image, a white reference value and an offset value must be measured for each scanner unit because the respective scanner units vary in characteristics. However, in mounting a scanner unit in the built-in printer of the notebook personal computer, white reference setting for setting the white reference value and the offset value is often omitted due to downsizing and low cost. In this case, every time the white reference value and the offset value are to be set, a user must feed originals for measuring the white reference value and the offset value to allow them to read these values, and must set the white reference value and the offset value.

Image reading device, image reading apparatus, and method therefor


An endoscope includes a detachable wireless imaging device and an insertion tube having a distal end region. The attachment of the detachable wireless imaging device detachably attaches the detachable wireless imaging device to the distal end region of the insertion tube.

An endoscope is a medical device comprising a flexible tube and a camera mounted on the distal end of the tube. The endoscope is insertable into an internal body cavity through a body orifice to examine the body cavity and tissues for diagnosis. The tube of the endoscope has one or more longitudinal channels, through which an instrument can reach the body cavity to take samples of suspicious tissues or to perform other surgical procedures such as polypectomy.
There are many types of endoscopes, and they are named in relation to the organs or areas with which they are used. For example, gastroscopes are used for examination and treatment of the esophagus, stomach and duodenum; colonoscopes for the colon; bronchoscopes for the bronchi; laparoscopes for the peritoneal cavity; sigmoidoscopes for the rectum and the sigmoid colon; arthroscopes for joints; cystoscopes for the urinary bladder; and angioscopes for the examination of blood vessels.
Each endoscope, has a single forward viewing camera mounted at the distal end of the endoscope to transmit an image to an eyepiece or video camera at the proximal end. The camera is used to assist a medical professional in advancing the endoscope into a body cavity and looking for abnormalities. The camera provides the medical professional with a two-dimensional view from the distal end of the endoscope. To capture an image from a different angle or in a different portion, the endoscope must be repositioned or moved back and forth. Repositioning and movement of the endoscope prolongs the procedure and causes added discomfort, complications, and risks to the patient. Additionally, in an environment similar to the lower gastro-intestinal tract, flexures, tissue folds and unusual geometries of the organ may prevent the endoscope's camera from viewing all areas of the organ. The unseen area may cause a potentially malignant (cancerous) polyp to be missed.
This problem can be overcome by providing an auxiliary camera, which presents an image of the areas not viewable by the endoscope's main camera. The auxiliary camera can be oriented backwards to face the main camera. This arrangement of cameras can provide both front and rear views of an area or an abnormality. In the case of polypectomy where a polyp is excised by placing a wire loop around the base of the polyp, the camera arrangement allows better placement of the wire loop to minimize damage to the adjacent healthy tissue.
Unfortunately, most of the endoscopes currently in use do not have such an auxiliary camera. To replace these existing endoscopes with new endoscopes with auxiliary cameras is expensive. Therefore, it is desirable to provide the existing endoscopes with retrofit auxiliary cameras. Additionally, to avoid the costs of modifying existing endoscopes, it is desirable to provide retrofit auxiliary cameras that do not require significant modification of the existing endoscopes.
Although a channel of an endoscope can be used to accommodate an auxiliary camera that does not require modification of the endoscope, the loss of a channel may impair the endoscope's ability to perform all of its designed functions. Thus the ability of the retrofit auxiliary camera to function without using an endoscope channel is desirable.


Monomers and polymers are provided that comprise a carbon alicyclic group or heteroalicyclic group that comprises 1) one or more acid-labile ring substituents and 2) one or more ether or thioether ring substituents. Photoresists that comprise such polymers also are provided.

The invention relates generally to the manufacture of electronic devices. More specifically, this invention relates to photoresist compositions and to photolithographic processes which allow e formation of fine patterns using a negative tone development process.
Photoresists are photosensitive films used for the transfer of images to a substrate. A coating layer of a photoresist is formed on a substrate and the photoresist layer is then exposed through a photomask to a source of activating radiation. Following exposure, the photoresist is developed to provide a relief image that permits selective processing of a substrate.
Considerable effort has been made to extend the practical resolution capabilities of photoresist compositions, including though development of various resist composition materials. See JP2015111637A; US20160077429; WO2011111807A1; JP2012031381A; US20130004740A1; U.S. Pat. No. 8,841,060B2; JP5618924B2; US20120251948A1; U.S. Pat. No. 8,846,293B2; JP5572656B2; JP5775804B2.
Immersion lithography also has been explored to extend photoresist resolution. In immersion lithography, the numerical aperture of the exposure tool lens is increased through use of a fluid to focus more light into the resist film. More particularly, immersion lithography utilizes a relatively high refractive index fluid between the last surface of an imaging device (e.g. ArF stepper) and the first on a wafer or other substrate.
Electronic device manufacturers continually seek increased resolution of a patterned photoresist image. It would be desirable to have new photoresist compositions that could provide enhanced imaging capabilities.

Monomers, polymers and photoresist compositions

ROHM AND HAAS ELECTRONIC MATERIALS KOREA LTD.


Systems and methods are provided for imaging a region of interest in an obscured environment. A millimeter band radar assembly is configured to capture a radar image of the region of interest. A data source provides a representation of at least a portion of the region of interest. A data fusion module is configured to combine the radar image and the representation of the region of interest to provide an enhanced representation of the region of interest.

Individuals in emergency conditions must deal with a number of adverse conditions when attempting to leave, or assist others in leaving, the affected area. A critical factor in navigating locations in emergency conditions can be a reduced visibility caused by obscurants such as smoke or other airborne particulate matter. In very low visibility conditions, individuals unfamiliar with the environment are reluctant to evacuate through an obscurant sufficiently dense to reduce visibility below ten meters. Individuals familiar with exit routes are able to evacuate through more dense obscurants, at around five meters of visibility. At lower visibility levels, however, the behavior of individuals changes, and more reliance is placed on their feeling their way forward, while crawling along walls, as opposed to relying on visual information. It will be appreciated that this can significantly slow progression through the obscured environment and may result in prolonged exposure to toxic gases.

Imaging system for obscured environments


A heat sink for memory strips comprises two heat transfer plates respectively attached on two sides of a memory strip. The upper edges of the heat transfer plates are further provided with retaining tongues and retaining rings. The extended portion of the combined heat transfer plated above the memory strip forms a heat radiating section which further includes a multitude of radiating fins for enhancing the cooling effect.

To achieve an effect of fast cooling, two metallic plates sandwiching a memory strip are commonly used as a heat sink to transfer the heat produced in the memory strip away and thereby reduce the likelihood of memory malfunction. However, due to the upgrade of computing speed of modern computers, the heat generating rate in a memory strip increases accordingly, and therefore an improvement of the structure of the associated heat sink is necessary.


The present application provides a method and device for determining inner and outer sides of limbs, and relates to the field of wearable devices. The method comprises: acquiring first somatosensory information of a first side of a limb of a user, the first side being an inner side or an outer side of the limb; and determining whether the first side is the inner side of the limb according to the first somatosensory information and reference information. The method and device facilitate a device that the user wears to perform automatic setting according to an identification result, thereby enhancing user experience.

In recent years, with the development of wearable devices, smart wristbands, smart bracelets, smart glasses and the like have gradually entered into people's life, thus greatly enriching and facilitating people's life.
For example, a somatosensory sensor configured on a smart watch may continuously monitor the somatosensory data of a user, such as body temperature, heart rate and blood sugar, so as to provide the user with health care services. The somatosensory sensor is either embedded in the back of the dial, or embedded in the inside of the strap, according to the measurement principle. While such a somatosensory sensor can accurately measure somatosensory data of the user by closely clinging to the inside of the wrist of the user, the user must wear a smart watch in a fixed manner, thus bringing about inconvenience to the user. For example, if the somatosensory sensor is embedded in the inside of the strap, the user must wear the dial of the smart watch at the outside of the wrist, which will bring about inconvenience to users who are accustomed to wearing the dial at the inside of the wrist.

Method and device for determining inner and outer sides of limbs


A memory device includes a memory cell having a capacitor for accumulating electric charges in accordance with the logic of data, a bit line connected to the memory cell, a charge transfer circuit for transferring the electric charges in the bit line to an output node, a dummy memory cell connected to the bit line, and a control circuit for controlling the charge transfer ability of the charge transfer circuit in accordance with the change in the voltage of the bit line.

1. Field of the Invention
The present invention relates to a memory device.
2. Description of the Related Art
Recently, a readout system of a ferroelectric memory called a bit line GND sense system has been proposed (for example, refer to patent document 1 and non-patent document 1). In the readout system of this kind, in order to prevent the voltage of a bit line from varying when a voltage is applied to a plate line, electric charges to be read out from a memory cell to the bit line are transferred to a charge accumulation circuit via a charge transfer circuit called a charge transfer formed in a pre-sense amplifier, and the logic value of the data stored in the memory cell is judged in accordance with the amount of electric charges transferred to the charge accumulation circuit. The charge transfer is configured by a p channel MOS transistor. In the p channel MOS transistor, the voltage between gate and source is initially set to the same value as that of a threshold voltage before the plate line is activated. The gate of the p channel MOS transistor is controlled by an inverter amplifier that lowers the output voltage in accordance with a rise in the voltage of the bit line.
[Patent document 1] Japanese Patent Application Laid-open No. 2002-133857
[Non-patent document 1] IEEE Journal of Solid-State Circuits, Vol. 37, No. 5 pp592-597, May 2002
In the bit line GND sense system, the readout operation is performed in such a way that a control circuit causes electric charges to flow by opening the gate of the charge transfer circuit with a slight rise of the bit line and the bit line returns to the ground again.
The memory judges the difference between an increase in potential due to electric charges that come out when data "1" is read (P term) and an increase in potential due to electric charges that come out when data "0" is read (U term) by amplifying it with a sense amplifier. However, miniaturization advances and a cell is reduced in size, not only the amount of polarized electric charges Qsw(P−U) but also the respective amounts of P term and U term become smaller, therefore, the ratio in which electric charges are absorbed in a parasitic capacity in the circuit increases and the peak to which the bit line rises is reduced considerably. Due to this, the control circuit is put into a state in which it does not open the charge transfer circuit sufficiently and there arises a problem of decrease in readout margin.


The present invention relates to recombinant DNA that encodes the BsmBI restriction endonuclease as well as BsmBI methyltransferase, expression of BsmBI restriction endonuclease and BsmBI methylase in E. coli cells containing the recombinant DNA. It also relates to a method for purification of the recombinant BsmBI restriction endonuclease.

The present invention relates to recombinant DNA which encodes the BsmBI restriction endonuclease (endonuclease) as well as the BsmBI methyltransferase (methylase), expression of BsmBI endonuclease and methylase in E. coli cells containing the recombinant DNA.
BsmBI endonuclease is found in the strain of Bacillus stearothermophilus B61 (New England Biolabs"" strain collection #857). It recognizes the double-stranded DNA sequence 5xe2x80x2CGTCTC3xe2x80x2N1/N5 (SEQ ID NO:1) and cleaves at N1 (top strand) and N5 (bottom strand) downstream of the recognition sequence to generate a 4-base 5xe2x80x2 overhang (N=A, T, C, or G;/indicates the cleavage of phosphodiester bond). BsmBI methylase (M.BsmBI) is also found in the strain of Bacillus stearothermophilus B61. It recognizes the double-stranded DNA sequences 5xe2x80x2CGTCTC3xe2x80x2 (SEQ ID NO:2) (top strand) and 5xe2x80x2GAGACG3xe2x80x2 (SEQ ID NO:3) (bottom strand) and probably modifies a cytosine (5 mC) on the top strand and an adenosine (N6mA) on the bottom strand within the recognition sequences.
Type II restriction endonucleases are a class of enzymes that occur naturally in bacteria and in some viruses. When they are purified away from other bacterial/viral proteins, restriction endonucleases can be used in the laboratory to cleave DNA molecules into small fragments for molecular cloning and gene characterization.
Restriction endonucleases recognize and bind particular sequences of nucleotides (the xe2x80x98recognition sequencexe2x80x99) along the DNA molecules. Once bound, they cleave the molecule within (e.g. BamHI), to one side of (e.g. SapI), or to both sides (e.g. TspRI) of the recognition sequence. Different restriction endonucleases have affinity for different recognition sequences. Over two hundred and eleven restriction endonucleases with unique specificities have been identified among the many hundreds of bacterial species that have been examined to date (Roberts and Macelis, Nucl. Acids Res. 27:312-313, (1999)).
Restriction endonucleases typically are named according to the bacteria from which they are discovered. Thus, the species Deinococcus radiophilus for example, produces three different restriction endonucleases, named DraI, DraII and DraIII. These enzymes recognize and cleave the sequences 5xe2x80x2TTT/AAA3xe2x80x2 (SEQ ID NO:4), 5xe2x80x2PuG/GNCCPy3xe2x80x2 (SEQ ID NO:5) and 5xe2x80x2CACNNN/GTG3xe2x80x2 (SEQ ID NO:6) respectively. Escherichia coli RY13, on the other hand, produces only one enzyme, EcoRI, which recognizes the sequence 5xe2x80x2G/AATTC3xe2x80x2 (SEQ ID NO:7).
A second component of bacterial/viral restriction-modification (R-M) systems are the methylase. These enzymes co-exist with restriction endonucleases and they provide the means by which bacteria are able to protect their own DNA and distinguish it from foreign DNA. Modification methylases recognize and bind to the same recognition sequence as the corresponding restriction endonuclease, but instead of cleaving the DNA, they chemically modify one particular nucleotide within the sequence by the addition of a methyl group (C5 methyl cytosine, N4 methyl cytosine, or N6 methyl adenine). Following methylation, the recognition sequence is no longer cleaved by the cognate restriction endonuclease. The DNA of a bacterial cell is always fully modified by the activity of its modification methylase. It is therefore completely insensitive to the presence of the endogenous restriction endonuclease. Only unmodified, and therefore identifiably foreign DNA, is sensitive to restriction endonuclease recognition and cleavage. During and after DNA replication, usually the hemi-methylated DNA (DNA methylated on one strand) is also resistant to the cognate restriction digestion.
With the advancement of recombinant DNA technology, it is now possible to clone genes and overproduce the enzymes in large quantities. The key to isolating clones of restriction endonuclease genes is to develop an efficient method to identify such clones within genomic DNA libraries, i.e. populations of clones derived by xe2x80x98shotgunxe2x80x99 procedures, when they occur at frequencies as low as 10xe2x88x923 to 10xe2x88x924. Preferably, the method should be selective, such that the unwanted clones with non-methylase inserts are destroyed while the desirable rare clones survive.
A large number of type II restriction-modification systems have been cloned. The first cloning method used bacteriophage infection as a means of identifying or selecting restriction endonuclease clones (EcoRII: Kosykh et al., Mol. Gen. Genet. 178:717-719, (1980); HhaII: Mann et al., Gene 3:97-112, (1978); PstI: Walder et al., Proc. Nat. Acad. Sci. 78:1503-1507, (1981)). Since the expression of restriction-modification systems in bacteria enables them to resist infection by bacteriophages, cells that carry cloned restriction-modification genes can, in principle, be selectively isolated as survivors from genomic DNA libraries that have been exposed to phage. However, this method has been found to have only a limited success rate. Specifically, it has been found that cloned restriction-modification genes do not always confer sufficient phage resistance to achieve selective survival.
Another cloning approach involves transferring systems initially characterized as plasmid-borne into E. coli cloning vectors (EcoRV: Bougueleret et al., Nucl. Acids. Res. 12:3659-3676, (1984); PaeR7: Gingeras and Brooks, Proc. Natl. Acad. Sci. USA 80:402-406, (1983); Theriault and Roy, Gene 19:355-359 (1982); PvuII: Blumenthal et al., J. Bacteriol. 164:501-509, (1985); Tsp45I: Wayne et al. Gene 202:83-88, (1997)).
A third approach is to select for active expression of methylase genes (methylase selection) (U.S. Pat. No. 5,200,333 and BsuRI: Kiss et al., Nucl. Acids. Res. 13:6403-6421, (1985)). Since restriction-modification genes are often closely linked together, both genes can often be cloned simultaneously. This selection does not always yield a complete restriction system however, but instead yields only the methylase gene (BspRI: Szomolanyi et al., Gene 10:219-225, (1980); BcnI: Janulaitis et al., Gene 20:197-204 (1982); BsuRI: Kiss and Baldauf, Gene 21:111-119, (1983); and MspI: Walder et al., J. Biol. Chem. 258:1235-1241, (1983)).
A more recent method, the xe2x80x9cendo-blue methodxe2x80x9d, has been described for direct cloning of thermostable restriction endonuclease genes into E. coli based on the indicator strain of E. coli containing the dinD::lacz fusion (U.S. Pat. No. 5,498,535, (1996); Fomenkov et al., Nucl. Acids Res. 22:2399-2403, (1994)). This method utilizes the E. coli SOS response signals following DNA damage caused by restriction endonucleases or non-specific nucleases. A number of thermostable nuclease genes (TaqI, Tth111I, BsoBI, Tf nuclease) have been cloned by this method (U.S. Pat. No. 5,498,535, 1996). The disadvantage of this method is that some positive blue clones containing a restriction endonuclease gene are difficult to culture due to the lack of the cognate methylase gene.
There are three major groups of DNA methyltransferases based on the position and the base that is modified (C5 cytosine methylases, N4 cytosine methylases, and N6 adenine methylases). N4 cytosine and N6 adenine methylases are amino-methyltransferases (Malone et al. J. Mol. Biol. 253:618-632, (1995)). When a restriction site on DNA is modified (methylated) by the methylase, it is resistant to digestion by the cognate restriction endonuclease. Sometimes methylation by a non-cognate methylase can also confer the DNA site resistant to restriction digestion. For example, Dcm methylase modification of 5xe2x80x2CCWGG3xe2x80x2 (SEQ ID NO:8) (W=A or T) can also make the DNA resistant to PspGI restriction digestion. Another example is that CpM methylase can modify the CG dinucloetide and make the NotI site (5xe2x80x2GCGGCCGC3xe2x80x2 (SEQ ID NO:9)) refractory to NotI digestion (New England Biolabs"" Catalog, 2000-01, page 220). Therefore methylases can be used as a tool to modify certain DNA sequences and make them uncleavable by restriction enzymes.
Because purified restriction endonucleases and modification methylases are useful tools for creating recombinant molecules in the laboratory, there is a strong commercial interest to obtain bacterial strains through recombinant DNA techniques that produce large quantities of restriction enzymes. Such over-expression strains should also simplify the task of enzyme purification.
The present invention relates to a method for cloning the BsmBI restriction endonuclease from Bacillus stearothermophilus B61 into E. coli by methylase selection and inverse PCR. A methylase gene with high homology to C5 methylase was found in a DNA library after methylase selection. A second methylase gene with high homology to amino-methylases (N6-adenosine methylases) was found after sequencing the genomic DNA surrounding the first methylase gene. It was later determined that these two genes are fused together and code for a single fusion protein. This fusion gene was named BsmBI methylase gene (bsmBIM). The bsmBIM gene was amplified by PCR and cloned into pACYC184. The premodified host ER2744 [pACYC-BsmBIM] was used for BsmBI endonuclease expression.
It proved to be difficult to express BsmBI endonuclease in medium-copy-number expression vectors. When PCR DNA containing bsmBIR gene was ligated to pAII17 or pET21at, no active clones with correct insert were found, which may be due to under-methylation of BsmBI sites in E. coli genome or the vectors.
In order to construct a stable expression clone, the bsmBIM gene was amplified by PCR and cloned into pBR322, giving rise to pre-modified host ER2744 [pBR322-BsmBIM]. The bsmBIR gene was amplified by PCR and inserted into pACYC-T7ter with compatible ends. High BsmBI endonuclease activity was detected. However, the expression clone ER2744 [pBR-BsmBIM, pACYC-T7ter-BsmBIR] was not very stable because lower BsmBI activity was detected in larger amplified cultures. To further stabilize the expression clone, two strategies were used:
a. Introducing another plasmid carrying the T7 lysS gene coding for T7 lysozyme which inhibits T7 RNA polymerase and thus reduces the constitutive expression from the T7 promoter.
b. Using a non-cognate methylase BsmAI methylase to premodify the expression host (BsmAI methylase recognition sequence 5xe2x80x2GTCTC3xe2x80x2 N1/N5 (SEQ ID NO:27).
Two production strains were constructed. The first one was ER2566 [pBR322-BsmBIM, pCEF8, pACYC-T7ter-BsmBIR]. The second strain was a pre-modified strain by a non-cognate methylase, BsmAI methylase, ER2566 [pBR322-BsmAIM, pACYC-T7ter-BsmBIR]. This second strain generated the highest BsmBI production yield in amplified large cultures.

Method of cloning and expression of BsmBI restriction endonuclease and BsmBI methylase in E. coli and purification of BsmBI endonuclease


A system for self-calibrating sensors includes an electronic control unit, a first image sensor and a second image sensor communicatively coupled to the electronic control unit. The electronic control unit is configured to obtain a first image and a second image, where the first image and the second image contain an overlapping portion, determine an identity of an object present within the overlapping portion, obtain parameters of the identified object, determine a miscalibration of the first image sensor or the second image sensor based on a comparison of the identified object in the overlapping portions and the parameters of the identified object, in response to determining a miscalibration of the first image sensor or the second image sensor, calibrate the first image sensor or the second image sensor based on the parameters of the identified object and the second image or the first image, respectively.

Apparatuses, such as robots, autonomous vehicles, or the like, include sensors. such as cameras, LIDAR sensors, radar sensors, sonar sensors, or the like, that require calibration from time to time. In particular, calibration of the sensors may be required because vibrations, environmental conditions, or other factors may cause sensors to fall out of calibration. Sensors and sensor systems installed on such apparatuses may be calibrated in a controlled environment with calibration objects having known dimensions. However, when these calibrations are required, it may not be advantageous or possible to seek out a mechanic or calibration facility to complete a controlled environment calibration.
Accordingly, there is a need for systems and methods for self-calibration of sensors on a vehicle in-the-wild.

Sensor self-calibration in the wild by coupling object detection and analysis-by-synthesis


An attachment film for an electronic display, which film is used for adjusting the optical transmissivity in a variety of electronic displays and adjusting color shades. It permits the simple and easy adjustment of the reflection of a fluorescent lamp and sunlight in and from the screen thereof and can prevent the formation of air bubbles in an adhesive layer thereof. The attachment film includes a transparent substrate and an adhesive layer which contains carbon black dispersed therein and formed on one surface of a transparent substrate.

1. Field of the Invention
The present invention relates to an attachment film for use in electronic displays such as Cathode Ray Tube (CRT) and a liquid crystal display device. More specifically, it relates to a an attachment film for an electronic display, which is for adjusting the quantity of transmitted light from a light source and the scattering of transmitted light and for preventing the reflection of a fluorescent lamp and sun light in and from a display device screen.
2. Description of the Prior Art
Conventionally, a glass unit as a screen of a display device such as a plasma display or TV cathode ray tube contains a colorant such as carbon black. The colorant is used for adjusting the quantity of transmitted light from a light source. For example, in a cathode ray tube having a fluorescent material which forms a color by the irradiation with electron beams, white is formed by mixing three colors such as red, green and blue, and black is formed in a color-non-forming portion. As a result, the cathode ray tube has a characteristic that the intensity of white is high and the intensity of black is low. A glass unit as a display device screen is therefore colored in gray for controlling white and intensifying black. In recent years, there are increasingly used displays having a cathode ray tube, etc., of which the light source side is formed as a curved surface and the viewer side, i.e., the front side is formed as a flat surface. In a display of the above type, the screen of a glass unit has a small thickness in the central portion thereof, and the thickness increases toward circumferential portions. In the above glass unit having a change in thickness, the central portion is required to be colored densely, and it is required to decrease the coloring toward the circumferential portions, for accomplishing a uniform optical transmissivity and a uniform scattering ratio of the glass unit on the entire screen of the glass unit. However, the decreasing the coloring toward the circumferential portions of the glass unit makes its production process complicated and requires an additional cost. Further, it is required to alter a gray scale variously depending upon a colorant used or a display material used. The coloring of the glass unit for satisfying the above demands is liable to make the production process thereof complicated and incur an increase in its production cost. Further, with an increase in the size of a display, a fluorescent lamp and sun light is reflected in the screen to a greater extent, and it is more intensely demanded to prevent the above reflection. When the optical transmissivity and the scattering ratio of the glass unit as a display device screen does not match a display material, a black and white contrast is deteriorated, and images showing original hues can be no longer viewed. It has been also found according to further studies that an adhesive layer of a film attached to the surface of an electronic display suffers air bubbles in some cases. More specifically, it has been found that air bubbles are formed in an adhesive layer in a light resistance test using the irradiation with ultraviolet light. The formation of air bubbles downgrades displayed images.
It is an object of the present invention to provide an attachment film for an electronic display, which film is used for adjusting the optical transmissivity depending upon a variety of electronic displays and adjusting color shades.
It is another object of the present invention to provide an attachment film for an electronic display, which film permits the simple and easy adjustment of the reflection of a fluorescent lamp and sun light in and from the screen thereof.
It is further another object of the present invention to provide an attachment film for an electronic display, which film can serve to adjust the optical transmissivity, adjust color tones and prevent the reflection of a fluorescent lamp and sun light in a screen even when the electronic display is increased in size.
It is still further another object of the present invention to provide an attachment film for an electronic display, which film can prevent the formation of air bubbles in an adhesive layer thereof.
According to the present invention, there is provided an attachment film for an electronic display, which comprises an adhesive layer which contains carbon black dispersed therein and is formed on one surface of a transparent substrate.
According to the present invention, there is provided an attachment film according to the above, wherein the adhesive layer further contains a coloring pigment different from the carbon black.
According to the present invention, there is provided an attachment film according to the above, wherein the attachment film is colored in neutral gray.
According to the present invention, there is provided an attachment film according to the above, wherein the carbon black in the adhesive layer has an average particle diameter of 30 nm or less and has a BET specific surface area of at least 100 m2/g.
According to the present invention, there is provided an attachment film according to the above, wherein the adhesive layer contains an acrylic adhesive having a carboxyl group and/or a hydroxyl group and the carbon black is an acidic carbon black.
According to the present invention, there is provided an attachment film according to the above, wherein the adhesive layer further contains a photopolymerizable compound and a photopolymerization initiator.
According to the present invention, there is provided an attachment film according to the above, wherein the adhesive layer is formed on one surface of the transparent substrate and a hard coating layer and an anti-reflection layer are consecutively formed on the other surface of the transparent substrate.

Attachment film for electronic display device


A method of mutual monitoring of components of a distributed computer system for a safety-relevant application in a motor vehicle in particular. The components are interconnected by at least one communication system. To make the mutual monitoring of components as simple and comprehensible as possible and to save on additional hardware components for monitoring, in a plurality of components of the computer system an internal monitoring function which detects faults in the monitored component and a mutual monitoring function which performs a mutual check on results determined by the components and makes a majority selection from the results are implemented, and both the result of the internal monitoring function and the results of the mutual monitoring functions are taken into account in a decision as to whether there is a fault in a component.

Distributed computer systems having a plurality of components for an electronic brake system (brake-by-wire) in a motor vehicle are described in German Patent Application No. 198 26 130, German Patent Application No. 198 26 131, German Patent Application No. 198 26 132, and German Patent Application No. 198 61 144. However, uses of such computer systems and methods of mutual monitoring of components of such computer systems are not limited to use in motor vehicles. Instead, they may be used for any safety-relevant applications, e.g., in land vehicles, rail vehicles or aircraft, for example. Safety-relevant applications are applications in which fault-free output of at least one variable is absolutely essential.
In addition to an electronic brake system, it is also possible to use such computer systems in electronic steering systems (steer-by-wire) or other x-by-wire systems, where the function of a mechanical connection is taken over exclusively by electric and electronic components. Another typical application for the computer system of the aforementioned type in a motor vehicle is use in an engine controller for camshaft-free actuation of intake and exhaust valves.
The electronic brake system described in the applications cited above has wheel brakes having an electromechanical actuation. A central control unit is used to provide setpoint values for the individual wheel brakes. To permit reliable operation of the control unit and secure monitoring of the components, the control unit is equipped with a redundant computing element and an additional monitoring unit, in addition to the actual computing element for calculation of the setpoint values. This implementation in the circuitry and a mutual monitoring strategy of the computing elements contained in the control unit based on a question-response communication permit a reliable means of providing setpoint variables for activation of the wheel brakes.
The central control unit delivers the setpoint variables to electronic control units via at least one communication system, these being distributed control units located on site in the vicinity of the wheel brakes. The control units cause actuation of the brake shoes by electric motors and tightening of the brake disks on the individual wheels as a function of the setpoints. Reliable triggering of the electric motors is achieved by an additional monitoring module provided on each control unit, detecting potential faults in the monitored control unit on the basis of a coordinated question-response communication, actuating a shutdown path if necessary.
In addition, self-test routines are implemented in the control units, permitting fault recognition to a certain extent. These self-test routines may be referred to as internal monitoring functions which detect faults in the monitored control unit. To ensure the operating functionality of the control units, two independent power sources are provided to supply power to the individual electric components. Individual electric components are supplied with power either from both power sources or from only one power source at a time to maintain at least partial operation of the electric brake system in the event of failure of one power source.
It has proven to be a disadvantage of the conventional computer systems and the conventional method of mutual monitoring of components of the computer systems that a relatively great complexity is required in terms of hardware and software to meet the high reliability requirements. On the other hand, for understandable reasons, it is not readily possible to simply lower the safety requirements in the case of safety-relevant applications.

Method for mutual monitoring of components of a distributed computer system


The present application discloses a catalyst, the catalyst contains a molecular sieve, there is at least one-dimension 8-membered ring channel in the molecular sieve structure, the diameter of a diffusible substance in the direction of the 8-membered ring channel is no less than 2.0 Å, the diameter of a substance that can be accommodated in the molecular sieve structure is no more than 6 Å; the catalyst is used for a methanol and/or dimethyl ether to propylene reaction, comprising contacting methanol and/or dimethyl ether with a methanol-to-propylene catalyst to obtain propylene.

Propylene is an important chemical raw material, mainly used in the production of chemical products such as polypropylene (PP), propylene oxide (PO), acrylonitrile (AN), acrylic acid (AA), and terminal applications involving packaging, construction, automobile, spinning, and daily chemical industry and many other fields. At present, the global demand for propylene is increasing year by year, benefiting from China's economic development, China's propylene consumption is also growing rapidly.
At present, the methods for preparing propylene at home and abroad mostly use petroleum as raw materials, while China's petroleum resources are very scarce, and oil reserves and output cannot meet the needs of the rapid development of the national economy, and the contradiction between supply and demand is prominent. The technology of methanol/dimethyl ether-to-olefins (MTO) and methanol/dimethyl ether-to-propylene (MTP) from coal can make use of abundant coal and natural gas resources, and is an advantageous alternative and supplement for obtaining olefins from petroleum routes.
The key to MTP technology is the development of high performance catalysts. HZSM-5 molecular sieve is the first choice for MTP catalyst because of its suitable pore size and acid properties. In the 1990s, Lurgi company in German developed a MTP fixed bed process with high selectivity to propylene based on a modified high-silicon-aluminum ratio ZSM-5 molecular sieve. The process seeks to maximize the yield of propylene. In the process, ethylene and C4+ hydrocarbons are separated from propylene and recycled to the MTP reaction system, so that the conversion rate of raw material of methanol is greater than 99%, and the yield of propylene carbon-based is as high as 71%. In recent years, Sinopec and Tsinghua University have also developed S-MTO/MTP and FMTP technology.
The MTP catalysts currently used in the industry all use ZSM-5 as a molecular sieve catalyst. In addition, there are related reports of using SAPO-34 and SAPO-18 molecular sieves in MTP reaction. The selectivity to propylene based on these catalysts is limited, and improving the single-pass selectivity to propylene is the most important challenge in the current research on MTP reaction.

Molecular sieve catalyst, preparation method therefor and application thereof

Dalian Institute of Chemical Physics, Chinese Academy of Sciences


A master-slave flip-flop and method is provided for use with critical path circuits, for example, driving output pads on an integrated circuit. Briefly described, in architecture, the master-slave flip-flop comprises a master stage and a slave stage. The master stage includes a pass gate, an input inverter coupled to the pass gate, a feedback inverter coupled across the input inverter, and a driving inverter coupled to the output of the input inverter. The output of the driving inverter is coupled to the slave stage which includes a second pass gate through which the output of the driving inverter is applied to the master-slave flip-flop output. The above architecture results in a fast setup time and a fast clock-to-Q time without the problems associated with kickback. Also, the output of the master-slave flip-flop is tristatable.

Currently, logical circuits are employed in a nearly infinite number of applications, such as microprocessors and other integrated circuits. In the case of microprocessors, for example, these logical circuits are designed to operate at ever increasing speeds to facilitate the execution of larger and more complex software packages.
The logical circuits may be designed using a multitude of components to accomplish a specific purpose as part of a microprocessor circuit or other integrated circuit. These components may include various logical gates, registers, inverters, amplifiers, or other devices which are created using transistors such as junction field-effect transistors (JFET's) and metal-oxide semiconductor field-effect transistors (MOSFET's) and other circuit elements.
One such logical circuit is called a "master-slave flip-flop" which is often used to capture a specific logical value in a microprocessor or other complex circuit. For example, master-slave flip-flops may be used to capture and store a logical value to be applied to critical path circuits which drive output pads, for example, in a microprocessor or other integrated circuit. The capture of the logical value may be performed according to a clock pulse or other activation signal input.


Apparatus and method for modulating the phase or the amplitude of a monochromatic light beam, the apparatus including in one embodiment a Mach-Zehnder interferometer that consists of two beam splitters or beam combiners, a fully reflective mirror and an electro-optical crystal for modulation of one of two beam components. The electro-optical crystal serves as an optical resonator for the portion of the light beam admitted into the crystal material, using total internal reflection of the light beam from two or more of the crystal surfaces. The crystal has a high finesse so that a relatively small change in voltage applied across the crystal produces a large (.apprxeq.180.degree.) change in the external phase shift associated with the modulated component of the light beam. The modulated and unmodulated light beam components may be recombined for purposes of communication of information, using the mutual extinction of the two beam components when the optical phase shift between the two beam components is approximately 180.degree.. Transverse or longitudinal electro-optical materials can be used for the crystal, and the driving voltages required are less than 50 volts in some configurations. Communications at frequency up to and beyond 1 GHz. are possible.

Electro-optical modulation of light beams such as laser beams is well known in general and is described in many textbooks such as Optical Electronics by A. Yariv, Holt, Rinehart and Winston Company, 1985, pp. 274-305. Most electro-optical devices are either bulk modulators or waveguide modulators.
Bulk modulators can handle large optical powers because the laser beam diameter can be of the order of the transverse dimension of the electro-optical crystal, which may be of the order of 1 cm. Consequently, the intensity or power density, expressed in Watts/cm.sub.2, of the beam and the crystal can be held below the optical damage limit, even for high optical power systems. The power lost upon entering, propagating through and exiting from the bulk modulator can be quite small. However, the voltage required for good depth of modulation in such devices is usually hundreds to thousands of volts. Bulk electro-optical modulators are now available commercially from several crystal manufacturers.
A waveguide modulator requires much smaller voltages, on the order of 5-10 Volts for maximum depth of modulation. However, the power handling capability of these devices is limited to a few milliwatts because the laser beam is confined in a narrow portion of the modulator, typically having a width of several microns. Signal losses suffered in coupling into and out of a waveguide device are usually 6-8 dB, which is often unacceptable. Waveguide modulators are also available commercially.
One method of reducing the voltage required to provide good depth of modulation with a light modulator is to place the electro-optical crystal in a Fabry-Perot optical cavity that includes several high reflectivity surfaces. Near a resonance of this cavity, the voltage required for a given depth of modulation is reduced by the finesse of the cavity. According to one definition, finesse is the ratio of voltage required to change the resonant frequency of the cavity from one resonance to an adjacent resonance (a phase shift of 2.pi.), divided by the voltage required to change the resonant frequency between two half power points on the same resonance peak. An equivalent definition of finesse in terms of optical parameters is presented in A. Yariv, Optical Electronics, op.cit., pp. 92-94. The finesse itself may be a large, dimensionless number F>>1. For example, if the reflecting surfaces of the Fabry-Perot optical cavity have reflectivities of R=0.9, the finesse will be about 30 so that the driving voltages are reduced from several hundred volts to smaller voltages, such as 10-30 volts.
One version of a Fabry-Perot optical cavity that uses an electro-optical crystal with two reflecting surfaces is disclosed by F. Gires and P. Tournois, Comptes, Rendu, Acad. Sci. (Paris) Vol. 258 (1964) pp. 6112-6115.
Operation of an optical cavity near resonance in order to reduce the voltage requirement for an electro-optical modulator has not been widely used in the past, for several reasons. A resonantly enhanced electro-optical modulator must be used with a single frequency laser signal, and this has been hard to obtain. Further, the optical frequency of the laser source must be sufficiently stable to stay close to the desired resonance of the electro-optical modulator. A non-planar, internally reflecting ring laser, as described by Kane et al. in U.S. Pat. No. 4,578,793 and by Kane in U.S. Pat. No. 4,829,532, is a nearly ideal source for use with a resonantly enhanced electro-optical light modulator.
Use of an etalon external to a laser optical cavity for purposes of fine tuning the cavity output frequency is disclosed in U.S. Pat. No. 4,174,504, issued to Chanausky et al., in U.S. Pat. No. 4,550,410, issued to Hakini et al., and in U.S. Pat. No. 4,805,185, issued to Smith. Use of an etalon or equivalent means within an optical cavity to achieve a similar purpose is disclosed in U.S. Pat. No. 4,081,760, issued to Berg and in U.S. Pat. No. 4,284,963, issued to Allen et al. In U.S. Pat. No. 4,241,997, issued to Chraplyvy for a laser spectrometer with frequency calibration, two separate optical paths are formed, one containing a sample cell and the other containing a static etalon, with the light along each path being chopped at a different frequency to produce separate spectra for each path. None of these references discloses use of a dynamically controlled electro-optical material, functioning as an etalon in a two-path optical cavity, to control the phase and amplitude of a combination signal that issues from the cavity.
What is needed is a light modulator with low insertion loss, relatively low voltage requirements and high power handling capability. This package should also be reasonably compact.