A color field 1 detector includes analog and digital processor sections, wherein the analog processor section receives a video signal input and provides the digital signals necessary to drive the digital processor section. A timing generator receives a free-running reference clock and supplies an internal reference signal of subcarrier frequency starting at the falling edge of composite sync. A burst phase comparator compares the incoming color burst phase to the internal reference signal phase and generates logic signals indicative of the phase relationships therebetween to thus indicate whether the color burst is in phase, 180.degree. out of phase, or if any phase error exists. A state machine receives the logic signals and detects the sequence of occurrence of the states of the color burst relative to the internal reference signal. The sequence is indicative of the subcarrier-to-composite sync phase of the video signal input for the particular color television standard. The state machine provides a field reference signal in the form of a selected logic level which identifies the color field 1 of the color field sequence for the standard.

The invention relates to color field sequence detection and, in particular, to a digital circuit for detecting a specific color field in the color field sequence of a color television signal, for NTSC, PAL or PAL-M color television standards, wherein the usual phase locked loop is eliminated.
In the field of color television, the detection and identification of a specific color field in the color field sequence of an NTSC, PAL, or PAL-M color television standard, is a well known process that is required when performing such processes as color field editing, color framing of videotape recorders, time base correction of color signals, etc. For example, a time base corrector must convert any off-tape field to the field type dictated by the station reference. Likewise, the proper color field must be known when performing an edit process to prevent the generation of undesirable picture shifts.
In turn, color field detection requires the identification of a phase relationship between the color subcarrier signal and the horizontal sync. This relationship for the color fields of the color field sequence in an incoming video reference signal, differs in accordance with the standard.
Because of the television raster scan system of interlace, adjacent fields are offset vertically by one-half scan line. In addition, the color encoding structure is not identical on corresponding lines of different fields. Thus, for example, in NTSC there are two unique color frames each having two interlaced fields. The fields are normally indicated as fields 1 and 2 of color frame A and fields 3 and 4 of color frame B. Fields 1 and 3 differ in that the encoding chroma subcarrier phase will be 180.degree. offset for a given line on field 1 compared to the corresponding line on field 3. The same is true when fields 2 and 4 are compared. In PAL, the sync-to-subcarrier relationship and the V axis phase gives four unique frames (eight unique fields).
Typically, detection of the phase relationship of previous mention is performed in an analog domain by using color burst as a reference to synthesize phase coherent subcarrier, and comparing the latter signal to the edge of horizontal sync during the proper line of each video frame. When the comparison meets the selected specification for subcarrier-to-horizontal sync (ScH) phase, detection of the specified color field, generally color field 1, can be made consistently.
Analog color field sequence detectors presently found, for example, in videotape recorders, editors, etc., require significant analog circuitry. This, in turn, maximizes the susceptibility of the detector to the noise, drift, etc., problems commonly associated with analog circuits. In addition, most of the circuitry must be duplicated for each standard which is handled by the apparatus, thus increasing the components, the complexity, the space required and the costs.
In the analog system, a phase locked loop is employed to continuously re-generate the color subcarrier in a phase locked condition over successive intervals of horizontal lines. The synthesized phase coherent subcarrier then is compared to the edge of horizontal sync during the proper line of each video field. As is well known, phase locked loops are susceptible to the problems of noise, drift, added component count and difficulty in board layout.
The present invention circumvents the disadvantages of the above analog detector circuits while providing the inherent advantages of an all-digital circuit which is fast enough to make the subcarrier-to-sync comparison in the same horizontal line, thereby eliminating the need for a phase locked loop and its inherent disadvantages. To this end, in a preferred embodiment, a reference signal of subcarrier frequency is generated internally, starting with a known phase relationship at the leading edge of H sync. The phase of this reference signal then is compared to incoming burst of the same line when it occurs. Since burst occurs a relatively short time after H-sync, a free-running time base is sufficient to make an accurate phase comparison, and all phase locking circuitry is eliminated.
More particularly, an analog processor section includes a sync stripper and an odd/even field detector to provide composite sync and odd field signals, and a burst processor to provide a squared burst signal. A digital processor section includes a line selector circuit for determining a selected video line signal, and further includes a timing generator responsive to the selected line signal, the composite sync and an NTSC/PAL standard signal for internally generating the reference signal of subcarrier frequency, starting at the leading edge of composite sync. In addition, the timing generator provides a state clock signal, and one or more sample pulses for timing the subsequent phase comparison to be made by a burst phase comparator. The phase comparator also receives the squared burst and, under control of the sample pulses, compares its phase to that of the reference subcarrier signal, whereby the phase relationship may be determined. A state machine circuit receives the phase comparison results and, in response to the standard signal and the state clock, supplies a field reference signal which selectively becomes active to identify the presence of color field 1.
Thus, it may be seen that the reference signal generation, phase detection, sequence detection and timing generation all are performed in the digital domain with its inherent advantages of ease of board layout, lower component count, less board space requirements, adaptability to multiple color television standards and operating stability, as well as the elimination of the phase locked loop as previously mentioned. The invention further lends itself to gate array implementation.

Circuit for and method of detecting a color field sequence of a color video signal


In column domain dictionary compression, column values in one or more columns are tokenized by a single dictionary. The domain of the dictionary is the entire set of columns. A dictionary may not only map a token to a tokenized value, but also to a count (“token count”) of the number of occurrences of the token and corresponding tokenized value in the dictionary's domain. Such information may be used to compute queries on the base table.

Data in a relational or object-relational database is stored as relations comprising rows or tuples that share the same columns. There are several formats of storing rows, which are row-major and column-major. In row-major format, column values of a single row are stored contiguously within a unit of persistent storage, such as a data block. In column-major format, values of a column of multiple rows are stored contiguously. Row-major format or column-major format are collectively referred to herein as major formats.
Each major format has its advantageous. For example, column-major format is advantageous for queries that require scanning a single column to generate aggregate values for those columns. Such queries occur often in the context of data warehousing and decision support systems. On the other hand, row-major format is advantageous for queries that return rows with multiple columns or for modifications to a few number of rows. The major format of a column and the compression technique used, if any, is referred to herein as a storage format.
Described herein are techniques that provide advantages of both row-major and column-major format.


A document conveyance apparatus for conveying a document to an exposing surface of a copying apparatus, and conveying the document out from the exposing surface after an exposure to copy the document. The apparatus including a driving roller unit for supporting and driving a conveyance belt, including (i) at least a pair of driving rollers, rotatably mounted on a conveyance frame with first supporters, for driving the conveyance belt suspended thereon, wherein at least one of the driving rollers is driven by a driving motor, (ii) the first supporters for supporting both ends of the driving rollers, wherein each of the driving rollers is supported movable in the direction of its axis of rotation so that at least one end of the driving rollers is capable of being removed from the roller supporters, and (iii) a positioner for being mounted on each of the driving rollers so that each of the driving rollers is positioned in the direction of its axis of rotation.

The present invention relates to an automatic conveyance apparatus for a document in a copying machine such as an machine, and particularly to the mechanism for replacing a document-conveying endless belt.
A document conveyance apparatus is normally used, after being installed on the document table of a copying machine or the like, to convey the sheet type documents (hereinafter called a document) automatically. When it is in an open state, the manual operation for documents is possible.
Documents loaded on the document feeding table (sheet feeding tray) are fed out one by one by means of a sheet-feeding section of a document conveyance apparatus, and each of them is fed and positioned, by means of a conveyance belt in the conveyance section, on the document-placing table glass (platen glass) where the document is exposed to light from the exposure lamp provided in the main body of a copying machine, and then is further ejected onto the document-exit tray.
On a document conveyance apparatus such as this, there are provided many rollers rotatably supported on frame side plates, such as, for example, conveyance rollers composed of a belt-driving roller, a driven roller, a tension roller, a pressure roller or the like as well as a sheet-feeding roller and a sheet-exit roller. A conveyance belt composed of one or a plurality of belts used for the conveyance of a document is spread between the aforesaid conveyance rollers.
In such a mechanism of a document conveyance apparatus, when removing and replacing the aforesaid conveyance belt and various rollers on the occasion of assembly, periodic inspection or apparatus troubles, there have been required complicated procedures and much labor and time have been consumed and it has been difficult to keep the assembling accuracy stably. In particular, the surface of the aforesaid conveyance belt which must be kept white constantly needs to be replaced with a new one occasionally, because it is easily soiled and scratched while it is used. Further, after the conveyance belt is used for a long time, it also needs to be replaced with a new one because of its deformation and change in quality.
In one of the conventional methods for replacing a conveyance belt, the outer casings of a document conveyance apparatus are removed first, then bearings and others are removed from the roller-supporting side plate, and all rollers passing through the inside of a loop shaped conveyance belt are removed, thereby the loop of a conveyance belt is released.
In this method, the side plate of a frame is separated in advance occasionally. Further, a driving roller naturally needs to be removed. Therefore, a mechanism for separating the driving roller from the driving system needs to be prepared, which causes a complicated mechanism and difficult work.
Even in the case of a document conveyance apparatus of a monocoque structure type wherein outer casings play a role of a structural member, bearings for each roller, various panels located at the bottom of an apparatus and casings need to be removed first, and then, all rollers are removed for the replacement of a conveyance belt.
Furthermore, when replacing a conveyance belt, a driven roller and others need to be moved for adjusting to a proper belt tension because there is a difference between the incoming and outgoing conveyance belts in terms of a total length of an endless belt. Even in this case, disassembling work identical to the above has been needed.
From the viewpoint of an easy process for replacing a conveyance belt and rollers and of an assurance of functions after the replacement, it is desired that the replacing work is easy, the time required for the replacement is short and readjustments for sensors and parts are not needed. Namely, the mechanism that makes a simple and efficient replacement possible is desired.
The conventional mechanism, however, does not always satisfy fully the above desired points due to its weak points mentioned previously.

Document conveyance apparatus facilitating conveyance belt replacement


The alkali blue dry toner comprises 60 to 98 weight percent alkali blue pigment particles, 1 to 20 weight percent of di- and tri-decyl phosphate esters of free acids, and 1-20 weight percent of dehydroabietyl amine. The toner exhibits a high strength and soft texture in comparison with prior art pigment compositions made from similar ingredients.

1. Field of the Invention
The present invention is related to specific types of pigment compositions which are especially suited to both oil-based and water-based systems, as well as processes for flexographic printing using these pigment compositions. More particularly, the pigment composition of the present invention comprises an alkali blue pigment. The pigment composition of the present invention exhibits a high strength and soft texture in comparison with prior art pigment compositions made from similar ingredients.
2. The Related Art
The closest related art of which applicants are aware includes the following U.S. Pat. Nos.: 4,456,485; 4,383,865; 4,032,357.
U.S. Pat. No. 4,383,865, to Iyengar, discloses a process for preparing a soft textured, high strength Alkali Blue pigment composition which comprises insolubilized amines. This composition is made by mixing a solution of alkali blue crude first with an alkaline solution of an alkyl aryl sulfonic acid, then with an acidic solution having from 3 to 36 carbon atoms, following which the pigment composition is recovered. In the '865 patent the preferred group of alkyl aryl sulfonic acids has from 1 to 14 carbon atoms. The most preferred alkyl aryl sulfonic acid appears to be dodecylbenzene sulfonic acid.
U.S. Pat. No. 4,456,485, also to Iyengar, discloses a process for preparing easily dispersible high color strength powdered alkali blue pigments by precipitating the pigment in the presence of various acids and/or amines, and/or esters, and/or alcohols, etc., as well as the product of these processes.
U.S. Pat. No. 4,032,357, assigned to Sherwin-Williams Company, discloses a substantially anhydrous, free-flowing alkali blue pigment composition having an organic anionic dispersant coprecipitated therewith. Furthermore, the pigment and dispersant are admixed with an oil phase in order to reduce the hydrophilic aggregation of the coprecipitated pigment and dispersant. The specific organic dispersants used in the '357 patent are Gafac.RTM. RS-710 and Gafac.RTM. RS-610.
As can be seen in the appended claims, the scope of the present invention is limited to pigment compositions comprising alkali blue pigment in combination with:
(1) di- and tri- decyl phosphate esters of free acids; and PA0 (2) dehydroabietyl amine. PA0 (a) between 60 percent, by weight, and 98 percent, by weight, alkali blue pigment particles; PA0 (b) between 1 percent by weight and 20 percent by weight of a surfactant selected from the group consisting of di- and tri- decyl phosphate esters of free acids; PA0 (c) between 1 percent by weight and 20 percent, by weight, of dehydroabietyl amine, said weights based on the total composition.
In contrast, none of the related patents listed above recites this specific combination of elements. Furthermore, none of these related patents refers to flexographic printing.

High strength alkali blue pigment toner useful in both oil-based and water-based systems


A class of substituted or 6,7-ring fused [1, 2, 3]triazolo[1,5-xcex1]-pyrimidine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 3-position and an amino moiety at the 5-position, are selective ligands for GABAA receptors, in particular having high affinity for the xcex12 and/or xcex13 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of disorders of the central nervous system, including anxiety and convulsions.

This application is a U.S. National Phase application under 35 U.S.C. xc2xa7371 of PCT Application No. PCT/GB00/04654, filed Dec. 5, 2000, which claims priority under 35 U.S.C. xc2xa7119 from GB Application No. 9929587.3, filed Dec. 15, 1999.
The present invention relates to a class of substituted triazolo-pyrimidine derivatives and to their use in therapy. More particularly, this invention is concerned with substituted [1,2,3]triazolo[1,5-xcex1]pyrimidine derivatives which are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six xcex1 subunits, four xcex2 subunits, three xcex3 subunits, one xcex4 subunit, one xcex5 subunit and two xcfx81 subunits.
Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an xcex1 subunit, a xcex2 subunit and a xcex3 subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, xcex4, xcex5 and xcfx81 subunits also exist, but are present only to a minor extent in GABAA receptor populations.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one xcex1, one xcex2 and one xcex3 subunit from a repertoire of seventeen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include, amongst many others, xcex11xcex22xcex32, xcex12xcex22/3xcex32, xcex13xcex2xcex32/3, xcex12xcex2xcex31, xcex15xcex23xcex32/3, xcex16xcex2xcex32, xcex16xcex2xcex4 and xcex14xcex2xcex4. Subtype assemblies containing an xcex11 subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing xcex12 and xcex13 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an xcex15 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat.
A characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the xcex11 subunit in combination with a xcex2 subunit and xcex32. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain.
Two other major populations are the xcex12xcex2xcex32 and xcex13xcex2xcex32/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain xcex15-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.
It is now believed that agents acting as BZ agonists at xcex11xcex22, xcex12xcex2xcex32 or xcex13xcex2xcex32 subtypes will possess desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as xe2x80x9cGABAA receptor agonistsxe2x80x9d. The xcex11-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAA receptors containing the xcex11 subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the xcex12 and/or xcex13 subunit than with xcex11 will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at xcex11 might be employed to reverse sedation or hypnosis caused by xcex11 agonists.
The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work.
Further disorders for which selective ligands for GABAA receptors may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing loss. Selective ligands for GABAA receptors may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.
WO 99/37645 describes a class of substituted and 7,8-ring fused [1,2,4]triazolo[4,3-b]pyridazine derivatives which are stated to be selective ligands for GABAA receptors beneficial in the treatment and/or prevention of neurological disorders including anxiety and convulsions. There is in that publication, however, no disclosure nor any suggestion that the central triazolo-pyridazine ring system can be replaced by any other ring system. In particular, there is no disclosure nor any suggestion in that publication that the specified triazolo-pyridazine ring system can be replaced by a [1,2,3]triazolo[1,5-xcex1]pyrimidine ring system.
Co-pending International Patent Application No. PCT/GB99/01827, published on Dec. 23, 1999 as WO 99/65907, describes a class of substituted and 6,7-ring fused [1,2,3]triazolo[1,5-xcex1]pyrimidine derivatives which are stated to be selective ligands for GABAA receptors beneficial in the treatment and/or prevention of neurological disorders including anxiety and convulsions. However, the compounds described therein all possess a substituted alkoxy moiety at the 5-position, none of the compounds described therein being substituted at the 5-position by a substituted amino moiety.
The present invention provides a class of triazolo-pyrimidine derivatives which possess desirable binding properties at various GABAA receptor subtypes The compounds in accordance with the present invention have good affinity as ligands for the xcex12 and/or xcex13 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the xcex12 and/or xcex13 subunit than with the xcex11 subunit. Desirably, the compounds of the invention will exhibit functional selectivity in terms of a selective efficacy for the xcex12 and/or xcex13 subunit relative to the xcex11 subunit.
The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the xcex12 and/or xcex13 subunit, as measured in the assay described hereinbelow, of 100 nM or less, typically of 50 nM or less, and ideally of 10 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the xcex12 and/or xcex13 subunit relative to the xcex11 subunit. However, compounds which are not selective in terms of their binding affinity for the xcex12 and/or xcex13 subunit relative to the xcex11 subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of a selective efficacy for the xcex12 and/or xcex13 subunit relative to the xcex11 subunit.
The present invention provides a compound of formula I, or a salt or prodrug thereof:
wherein
Y represents hydrogen or C1-6 alkyl; and
Z represents C1-6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-8 bicycloalkyl, aryl, C3-7 heterocycloalkyl, heteroaryl, C2-7 alkoxycarbonyl or di(C1-6)alkylamino, any of which groups may be optionally substituted; or
Y and Z are taken together with the two intervening carbon atoms to form a ring selected from C5-9 cycloalkenyl, C6-10 bicycloalkenyl, tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be optionally benzo-fused and/or substituted;
R1 represents C3-7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted;
R2 represents hydrogen, C1-6 alkyl, hydroxy(C1-6)alkyl or C1-6 alkoxy(C1-6)alkyl; and
R3 represents C1-6 alkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted; or
R2 and R3 are taken together with the intervening nitrogen atom to form a ring of formula (a), (b), (c), (d), (e), (f), (g), (h), (j) or (k):
wherein
X represents oxygen, sulphur, Nxe2x80x94R5 or CR6R7;
R4 represents hydrogen, C1-6 alkyl, aryl, C2-7 alkoxycarbonyl or aryl(C1-6)alkoxy(C1-6)alkyl;
R5 represents hydrogen, C1-6 alkyl, di(C1-6)alkylamino(C1-6)alkyl, C2-6 alkenyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, C2-7 alkylcarbonyl or C2-7 alkoxycarbonyl;
R6 represents hydrogen, halogen, hydroxy, C1-6 alkoxy, di(C1-6)alkylamino, C2-7 alkoxycarbonyl, or an optionally substituted or phenyl ring-fused C3-7 heterocycloalkyl group; and
R7 represents hydrogen, C1-6 alkyl, or an optionally substituted aryl or aryl(C1-6)alkyl group.
The present invention also provides a compound of formula I as depicted above, or a salt or prodrug thereof, wherein
Y, Z and R1 are as defined above;
R2 represents hydrogen, C1-6 alkyl, hydroxy(C1-6)alkyl or C1-6 alkoxy(C1-6)alkyl; and
R3 represents C1-6 alkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted; or
R2 and R3 are taken together with the intervening nitrogen atom to form a ring of formula (a), (b), (c), (d), (e), (f), (g) or (h) as depicted above, wherein
X, R4 and R7 are as defined above;
R5 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, aryl, heteroaryl, C2-7 alkylcarbonyl or C2-7 alkoxycarbonyl; and
R6 represents hydrogen, halogen, hydroxy, di(C1-6)alkylamino, C3-7 heterocycloalkyl or C2-7 alkoxycarbonyl.
Where Y and Z are taken together with the two intervening carbon atoms to form a ring, the resulting compounds of formula I above incorporate the relevant cycloalkenyl, bicycloalkenyl, tetrahydropyridinyl, pyridinyl or phenyl ring fused to the central triazolo-pyrimidine ring system as depicted in formula I.
Where Y and Z are taken together with the two intervening carbon atoms to form a C5-9 cycloalkenyl ring, this ring may be a cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl or cyclononenyl ring, suitably cyclohexenyl or cycloheptenyl.
Where Y and Z are taken together with the two intervening carbon atoms to form a C6-10 bicycloalkenyl ring, this ring may be a bicyclo[2.1.1]hex-2-enyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[3.2.2]non-6-enyl or bicyclo[3.3.2]dec-9-enyl ring, suitably bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]oct-2-enyl or bicyclo[3.2.2]non-6-enyl, and especially bicyclo[2.2.2]oct-2-enyl.
Where Y and Z are taken together with the two intervening carbon atoms to form a ring, this ring may be optionally benzo-fused. By way of illustration, Y and Z taken together with the two intervening carbon atoms may represent a benzo-fused cyclohexenyl ring, whereby the resulting ring is dihydronaphthyl.
The groups Y, Z, R1, R3, R6and R7 may be unsubstituted, or substituted by one or more, suitably by one or two, substituents. In general, the groups Y, Z, R1, R3, R6 and R7 will be unsubstituted or monosubstituted. Examples of optional substituents on the groups Y, Z, R1, R3, R6 and R7 include C1-6 alkyl, aryl(C1-6)alkyl, pyridyl(C1-6)alkyl, halogen, halo(C1-6)alkyl, cyano, cyano(C1-6)alkyl, hydroxy, hydroxymethyl, C1-6 alkoxy, C3-7 cycloalkyl(C1-6)alkoxy, C3-7 cycloalkoxy, amino(C1-6)alkyl, di(C1-6)alkylamino(C1-6)alkyl, di(C1-6)alkylaminocarbonyl(C1-6)alkyl, N-(C1-6)alkylpiperidinyl, pyrrolidinyl(C1-6)alkyl, piperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl, di(C1-6)alkylmorpholinyl(C1-6)alkyl and imidazolyl(C1-6)alkyl. Representative substituents include C1-6 alkyl, aryl(C1-6)alkyl, halogen, cyano, hydroxy, hydroxymethyl, C1-6 alkoxy and C3-7 cycloalkyl(C1-6)alkoxy. Particular substituents include methyl, ethyl, fluoro, chloro, hydroxy and methoxy. Additional substituents include oxo; and C2-7 alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl. Specific substituents include methyl, fluoro, hydroxy, methoxy, oxo and ethoxycarbonyl.
As used herein, the expression xe2x80x9cC1-6 alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert-butyl and 1,1-dimethylpropyl. Derived expressions such as xe2x80x9cC1-6 alkoxyxe2x80x9d are to be construed accordingly.
Typical C2-6 alkenyl groups include vinyl and allyl.
Typical C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The expression xe2x80x9cC3-7 cycloalkyl(C1-6)alkylxe2x80x9d as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
Typical C4-7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl and cyclohexenyl.
Typical aryl groups include phenyl and naphthyl, preferably phenyl.
The expression xe2x80x9caryl(C1-6)alkylxe2x80x9d as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and diazepanyl groups.
A typical phenyl ring-fused C3-7 heterocycloalkyl group is 1,2,3,4-tetrahydroisoquinolinyl.
A typical C3-7 heterocycloalkyl(C1-6)alkyl group is pyrrolidinylethyl.
Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The expression xe2x80x9cheteroaryl(C1-6)alkylxe2x80x9d as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Suitably, Y represents hydrogen or methyl, especially hydrogen.
Examples of suitable values for the substituent Z include methyl, ethyl, isopropyl, tert-butyl, 1,1-dimethylpropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, bicyclo[2.1.1]hex-1-yl, bicyclo[2.2.1]heptan-1-yl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl, methoxycarbonyl and diethylamino, especially tert-butyl, cyclobutyl or phenyl.
In a particular embodiment, the substituent Z represents C3-7 cycloalkyl, either unsubstituted or substituted by C1-6 alkyl, especially methyl. Favourably, Z represents cyclobutyl.
When Y and Z are taken together with the two intervening carbon atoms to form a ring, representative compounds according to the invention include those of structure IA to IL:
wherein R1, R2 and R3 are as defined above;
R8 represents hydrogen, C1-6 alkyl, aryl(C1-6)alkyl, halogen, cyano, hydroxy, hydroxymethyl or C1-6 alkoxy; and
R9 represents hydrogen or C1-6 alkyl.
Suitably, R8 represents hydrogen, C1-6 alkyl or halogen, especially hydrogen, methyl, fluoro or chloro. Particular values of R8 include hydrogen and fluoro, especially hydrogen.
Suitably, R9 represents hydrogen or methyl
Favoured ring-fused triazolo-pyrimidine derivatives according to the present invention include the compounds represented by formula IL as depicted above.
Examples of typical optional substituents on the group R1 include methyl, fluoro and methoxy, especially fluoro.
Representative values of R1 include cyclopropyl, phenyl, methylphenyl, fluorophenyl, difluorophenyl, trifluorophenyl, methoxyphenyl, furyl, thienyl, methyl-thienyl and pyridinyl. More particularly, R1 may represent unsubstituted or monosubstituted phenyl. Most particularly, R1 represents phenyl or fluorophenyl, especially fluorophenyl. A specific value of R1 is 2-fluorophenyl.
Suitably, R2 represents hydrogen, methyl, hydroxyethyl or methoxyethyl. Specific values of R2 include 2-hydroxyethyl and 2-methoxyethyl.
Suitably, R3 represents aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, either of which groups may be optionally substituted.
Suitable values for the substituent R3 in the compounds according to the invention include cyclohexylmethyl, benzyl, pyrazolylmethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, benzimidazolylmethyl, oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl, any of which groups may be optionally substituted by one or more substituents.
Suitably, R3 represents an optionally substituted triazolylmethyl group.
Examples of suitable optional substituents on the group R3 include C1-6 alkyl, aryl(C1-6)alkyl, pyridyl(C1-6)alkyl, halogen, halo(C1-6)alkyl, cyano, cyano(C1-6)alkyl, hydroxymethyl, C1-6 alkoxy, C3-7 cycloalkyl(C1-6)alkoxy, amino(C1-6)alkyl, di(C1-6)alkylamino(C1-6)alkyl, di(C1-6)alkylaminocarbonyl(C1-6)alkyl, N-(C1-6)alkylpiperidinyl, pyrrolidinyl(C1-6)alkyl, piperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl and di(C1-6)alkylmorpholinyl(C1-6)alkyl, especially C1-6 alkyl.
Specific illustrations of particular substituents on the group R3 include methyl, ethyl, in-propyl, benzyl, pyridinylmethyl, chloro, chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl, morpholinylmethyl and dimethylmorpholinylmethyl, especially methyl or ethyl, and more especially methyl.
Representative values of R3 include hydroxymethyl-cyclohexylmethyl, cyanobenzyl, hydroxymethyl-benzyl, pyrazolylmethyl, dimethyl-pyrazolylmethyl, methyl-isoxazolylmethyl, thiazolylmethyl, methyl-thiazolylmethyl, ethyl-thiazolylmethyl, methyl-thiazolylethyl, imidazolylmethyl, methyl-imidazolylmethyl, ethyl-imidazolylmethyl, benzyl-imidazolylmethyl, benzimidazolylmethyl, methyl-oxadiazolylmethyl, triazolylmethyl, methyl-triazolylmethyl, ethyl-triazolylmethyl, propyl-triazolylmethyl, benzyl-triazolylmethyl, pyridinylmethyl-triazolylmethyl, cyanomethyl-triazolylmethyl, dimethylaminomethyl-triazolylmethyl, aminoethyl-triazolylmethyl, dimethylaminoethyl-triazolylmethyl, dimethylaminocarbonylmethyl-triazolylmethyl, N-methylpiperidinyl-triazolylmethyl, pyrrolidinylethyl-triazolylmethyl, piperazinylethyl-triazolylmethyl, morpholinylethyl-triazolylmethyl, methyl-tetrazolylmethyl, pyridinylmethyl, methyl-pyridinylmethyl, dimethyl-pyridinylmethyl, ethoxy-pyridinylmethyl, cyclopropylmethoxy-pyridinylmethyl, pyridazinylmethyl, chloro-pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl
Particular values of R3 include methyl-triazolylmethyl and ethyl-triazolylmethyl.
A favoured value of R3 is methyl-triazolylmethyl.
In an alternative embodiment, R3 suitably represents a substituted C1-6 alkyl group. In a particular aspect of this embodiment, R3 represents ethyl substituted by hydroxy or methoxy. Specific values of R3 in this context include 2-hydroxyethyl and 2-methoxyethyl.
In a further embodiment, R3 suitably represents an optionally substituted C3-7 heterocycloalkyl group. In a particular aspect of this embodiment, R3 represents piperidinyl, either unsubstituted or substituted by C1-6 alkyl, e.g. methyl. A specific value of R3 in this context is 1-methylpiperidin-4-yl.
Where R2 and R3 are taken together with the intervening nitrogen atom to form a ring, this is suitably a ring of formula (a), (b), (d), (f), (g) or (h) as depicted above.
Suitably, R4 may represent hydrogen or C2-7 alkoxycarbonyl. Particular values of R4 include hydrogen and ethoxycarbonyl, especially hydrogen.
Suitably, R5 may represent hydrogen, C1-6 alkyl, aryl or heteroaryl. Typical values of R5 include hydrogen, methyl, ethyl, n-propyl, dimethylaminoethyl, allyl, cyclopropylmethyl, phenyl, pyrrolidinylethyl, pyridinyl, acetyl, propionyl, trimethylacetyl and ethoxycarbonyl. Specific values of R5 include hydrogen, methyl, ethyl, n-propyl, allyl, phenyl, pyridinyl, acetyl, propionyl, trimethylacetyl and ethoxycarbonyl. Particular values of R5 include hydrogen, methyl, phenyl and pyridinyl.
Suitably, R6 may represent hydrogen, hydroxy, di(C1-6)alkylamino, C3-7 heterocycloalkyl or C2-7 alkoxycarbonyl. Typical values of R6 include hydrogen, hydroxy, methoxy, dimethylamino, pyrrolidinyl, piperidinyl, ethoxycarbonyl-piperidinyl, morpholinyl, diazepanonyl, 1,2,3,4-tetrahydroisoquinolinyl and ethoxycarbonyl. Particular values of R6 include hydrogen, hydroxy, dimethylamino, pyrrolidinyl, piperidinyl and ethoxycarbonyl.
An example of a typical optional substituent on the group R7 is halogen, suitably chloro. Particular values of R7 include hydrogen and C1-6 alkyl, especially hydrogen or methyl.
A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof:
wherein
R1 is as defined above;
R18 represents hydrogen or halogen; and
Q represents the residue of a ring of formula (a), (b), (c), (d), (e), (f), (g), (h), (j) or (k) as defined with reference to formula I above.
The present invention also provides a compound of formula IIA as depicted above, or a salt or prodrug thereof, wherein
R1 and R18 are as defined above; and
Q represents the residue of a ring of formula (a) to (h) as defined with reference to formula I above.
Particular values of R18 include hydrogen and fluoro, especially hydrogen.
Particular rings of which Q is the residue include the rings of formula (a), (b), (d), (f), (g) and (h) as depicted above.
A further sub-class of compounds according to the invention is represented by the compounds of formula IIB, and salts and prodrugs thereof:
wherein
R1 and R2 are as defined with reference to formula I above;
R18 is as defined with reference to formula IIA above;
n is 1 or 2; and
R13 represents hydroxy or C1-6 alkoxy, or an optionally substituted aryl or heteroaryl group.
In one embodiment of the compounds of formula IIB above, n is 2, and R13 represents hydroxy or C1-6 alkoxy. In a particular aspect of this embodiment, n is 2, and R13 represents hydroxy or methoxy.
In another embodiment of the compounds of formula IIB, n is 1 or 2, typically 1, and R13 represents an optionally substituted aryl or heteroaryl group.
Suitably, R13 represents phenyl, pyrazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl or quinoxalinyl, any of which groups may be optionally substituted.
A particular value of R13 is optionally substituted triazolyl.
Examples of typical substituents on the group R13 include C1-6 alkyl, aryl(C1-6)alkyl, pyridyl(C1-6)alkyl, halogen, cyano, cyano(C1-6)alkyl, hydroxymethyl, C1-6 alkoxy, C3-7 cycloalkyl(C1-6)alkoxy, di(C1-6)alkylamino(C1-6)alkyl, amino(C1-6)alkyl, di(C1-6)alkylaminocarbonyl(C1-6)alkyl, N-(C1-6)alkylpiperidinyl, pyrrolidinyl(C1-6)alkyl, piperazinyl(C1-6)alkyl and morpholinyl(C1-6)alkyl, especially C1-6 alkyl
Illustrative values of specific substituents on the group R13 include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl and morpholinylmethyl, especially methyl or ethyl, and more especially methyl.
Representative values of R13 include cyanophenyl, hydroxymethyl-phenyl, pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl, methyl-thiazolyl, ethyl-thiazolyl, imidazolyl, methyl-imidazolyl, ethyl-imidazolyl, benzyl-imidazolyl, benzimidazolyl, methyl-oxadiazolyl, triazolyl, methyl-triazolyl, ethyl-triazolyl, propyl-triazolyl, benzyl-triazolyl, pyridinylmethyl-triazolyl, cyanomethyl-triazolyl, dimethylaminomethyl-triazolyl, aminoethyl-triazolyl, dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyl-triazolyl, N-methylpiperidinyl-triazolyl, pyrrolidinylethyl-triazolyl, piperazinylethyl-triazolyl, morpholinylethyl-triazolyl, methyl-tetrazolyl, pyridinyl, methyl-pyridinyl, dimethyl-pyridinyl, ethoxy-pyridinyl, cyclopropylmethoxy-pyridinyl, pyridazinyl, chloro-pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl.
Particular values of R13 include methyl-triazolyl and ethyl-triazolyl.
A favoured value of R13 is methyl-triazolyl.
A particular subset of the compounds of formula IIB above is represented by the compounds of formula IIC, and pharmaceutically acceptable salts thereof:
wherein
R1 and R2 are as defined with reference to formula I above;
R18 is as defined with reference to formula IIA above; and
R23 represents hydrogen, methyl or ethyl.
Suitably, R23 represents methyl or ethyl, especially methyl.
Another sub-class of compounds according to the invention is represented by the compounds of formula IID, and salts and prodrugs thereof:
wherein
R1 and Q are as defined above; and
Z1 represents C1-6 alkyl, C3-7 cycloalkyl or aryl, any of which groups may be optionally substituted.
Examples of typical substituents on the group Z1 include C1-6 alkyl, especially methyl.
Illustrative values for the group Z1 include methyl, ethyl, isopropyl, tert-butyl, 1,1-dimethylpropyl, cyclopropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl and phenyl.
Particular values of Z1 include tert-butyl, cyclobutyl and phenyl.
In a specific embodiment, Z1 represents cyclobutyl. In another embodiment, Z1 represents phenyl.
An additional sub-class of compounds according to the invention is represented by the compounds of formula IIE, and salts and prodrugs thereof:
wherein
R1, R2, n, R13 and Z1 are as defined above.
A particular subset of the compounds of formula IIE above is represented by the compounds of formula IIF, and salts and prodrugs thereof:
wherein
R1 and R2 are as defined with reference to formula I above;
R23 is as defined with reference to formula IIC above; and
Z1 is as defined with reference to formula IID above.
Specific compounds within the scope of the present invention include:
3-(2-fluorophenyl)-5-(morpholin-4-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-[5,6-dihydroimidazo[1,2-xcex1]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-[5,6-dihydroimidazo[1,5-xcex1]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-[5,6-dihydro[1,2,4]triazolo[1,5-xcex1]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-(3-oxo-4-phenylpiperazin-1-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-(4-ethoxycarbonylpiperazin-1-yl)-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-(3-ethoxycarbonylpiperidin-1-yl)-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-(4-ethoxycarbonylpiperidin-1-yl)-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-(4-hydroxypiperidin-1-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-[4-(pyridin-4-yl)piperazin-1-yl]-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-[4-(pyridin-2-yl)piperazin-1-yl]-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-(4-acetylpiperazin-1-yl)-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-[2-oxopiperazin-4(1H)-yl]-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-(1-methyl-2-oxopiperazin-4-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-[5,6-dihydroimidazo[1,2-xcex1]pyrazin-7(8H)-yl]-7-fluoro-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-[bis(2-methoxyethyl)amino]-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-(thiomorpholin-4-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-[4-(dimethylamino)piperidin-1-yl]-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-[4-(pyrrolidin-1-yl)piperidin-1-yl]-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-[4-(piperidin-1-yl)piperidin-1-yl]-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-[bis(2-hydroxyethyl)amino]-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-(4-oxopiperidin-1-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
5-(1-ethyl-2-oxopiperazin-4-yl)-3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-(2-oxo-1-propylpiperazin-4-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-[2-oxo-1-(2-propenyl)piperazin-4-yl]-[1,2,3]triazolo-[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-(4-hydroxy-4-methylpiperidin-1-yl)-[1,2,3]triazolo-[1,5-xcex1]quinazoline;
1-{4-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]piperazin-1-yl}propan-1-one;
2,2-dimethyl-1-{4-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]piperazin-1-yl}propan-1-one;
N-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]-N-methyl-N-(1-methylpiperidin-4-yl)amine;
1-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]-[1,4]diazepan-5one;
3-(2-fluorophenyl)-5-(piperidin-1-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-[4-(morpholin-4-yl)piperidin-1-yl]-[1,2,3]triazolo[1,5-xcex1]quinazoline;
4-(2-dimethylaminoethyl)-1-[3-(2-Fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]-[1,4]diazepan-5-one;
1xe2x80x2-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]-[1,4xe2x80x2]bipiperidinyl-4-carboxylic acid ethyl ester;
5-[4-(3,4-dihydro-1H-isoquinolin-2-yl)piperidin-1-yl]-3-(2-fluorophenyl)-[1,2,3]triazolo [1,5-xcex1]quinazoline;
1-{1-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]piperidin-4-yl}[1,4]diazepan-5-one;
N,N-dimethyl-N-{1-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]pyrrolidin-3-yl}amine;
3-(2-fluorophenyl)-5-{4-[2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl}-[1,2,3]triazolo[1,5-xcex1]quinazoline;
3-(2-fluorophenyl)-5-(4-methoxypiperidin-1-yl)-[1,2,3]triazolo[1,5-xcex1]quinazoline;
1-cyclopropylmethyl-4-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-xcex1]quinazolin-5-yl]piperazin-2-one;
and salts and prodrugs thereof.
Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof.
Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The binding affinity (Ki) of the compounds according to the present invention for the xcex13 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The xcex13 subunit binding affinity (Ki) of the compounds of the invention is ideally 10 nM or less, preferably 2 nM or less, and more preferably 1 nM or less.
The compounds according to the present invention will ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the xcex13 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the xcex11 subunit of the human GABAA receptor.
The potentiation of the GABA EC20 response in stably transfected cell lines expressing the xcex13 and xcex11 subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al., Mol. Pharmacol., 1996, 50, 670-678. The procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltkxe2x88x92 fibroblast cells.
The compounds according to the present invention exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al., J. Psychopharmacol., 1996, 10, 206-213).
The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501.
In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called xe2x80x9cblood-brain barrierxe2x80x9d. Preferably, the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of anxiety, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
The compounds of formula I as defined above may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV:
wherein Y, Z, R1, R2 and R3 are as defined above, and L1 represents a suitable leaving group.
The leaving group L1 is suitably an arylsulphonyloxy group such as p-toluenesulphonyloxy (tosyloxy).
The reaction between compounds III and IV is conveniently effected by stirring the reactants at an elevated temperature under basic conditions, for example triethylamine in N,N-dimethylformamide at a temperature in the region of 50xc2x0 C.
The intermediates of formula III above wherein L1 represents tosyloxy may be prepared by reacting a compound of formula V:
wherein Y, Z and R1 are as defined above; with a tosylating agent, e.g. a tosyl halide such as tosyl chloride.
The reaction is conveniently carried out by stirring at ambient temperature in the presence of a base such as triethylamine, typically in a solvent such as N,N-dimethylformamide.
The intermediates of formula V above, in particular those wherein Y and Z are taken together with the two intervening carbon atoms to form a ring (e.g. a phenyl ring), may be prepared by reacting an azide derivative of formula VI with an acetonitrile derivative of formula VII:
wherein Y, Z and R1 are as defined above.
The reaction between compounds VI and VII is conveniently effected under basic conditions in a suitable solvent, for example sodium ethoxide in ethanol, typically at an elevated temperature.
The intermediates of formula VI may be prepared by diazotisation of a compound of formula VIII:
wherein Y and Z are as defined above; followed by displacement with azide ion.
The diazotisation/displacement procedure is conveniently effected by treating compound VIII with sodium nitrite at 0xc2x0 C. in the presence of a mineral acid, e.g. hydrochloric acid, then with sodium azide, typically in the presence of sodium acetate.
In an alternative approach, the intermediates of formula V above, in particular those wherein Y and Z represent pendant groups (i.e. are not taken together with the intervening carbon atoms to form a ring), may be prepared by cyclising a compound of formula IX:
wherein Y, Z and R1 are as defined above, L2 represents a suitable leaving group, and Ph is an abbreviation for phenyl.
The leaving group L2 is typically a halogen atom, especially chloro.
The cyclisation of compound IX is conveniently effected by treatment with a strong base, e.g. potassium bis(trimethylsilyl)amide, in the presence of a suitable solvent, e.g. tetrahydrofuran, typically at a temperature in the region of xe2x88x9278xc2x0 C.
The intermediates of formula IX may be prepared by reacting a compound of formula X with a compound of formula XI:
wherein Y, Z, R1 and L2 are as defined above, and Hal represents a halogen atom; followed by oxidation of the phenylthio group.
The halogen atom Hal in the compounds of formula XI is typically chloro.
The reaction between compounds X and XI is conveniently carried out in a solvent such as N,N-dimethylformamide, typically in the presence of pyridine, and suitably at a temperature in the region of 0xc2x0 C. Subsequent oxidation of the phenylthio group is conveniently accomplished by treatment with ozone, typically in dichloromethane at a temperature in the region of xe2x88x9278xc2x0 C.
The intermediates of formula X above may be prepared by reacting a compound of formula VII as defined above with a compound of formula XII:
wherein Y is as defined above.
The reaction between compounds VII and XII is conveniently carried out by stirring the reactions in a suitable solvent, e.g. dimethylsulphoxide, typically in the presence of a base such as potassium carbonate.
Where they are not commercially available, the starting materials of formula IV, VII, VIII, XI and XII may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. For example, a compound of formula I initially obtained wherein R3 is unsubstituted may be converted into a corresponding compound wherein R3 is substituted, typically by standard alkylation procedures, for example by treatment with a haloalkyl derivative in the presence of sodium hydride and N,N-dimethylformamide, or with a hydroxyalkyl derivative in the presence of triphenylphosphine and diethyl azodicarboxylate. Furthermore, a compound of formula I initially obtained wherein the R3 substituent is substituted by a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein the R3 substituent is substituted by a di(C1-6)alkylamino moiety by treatment with the appropriate di(C1-6)alkylamine, typically with heating in a solvent such as 1,4-dioxane in a sealed tube. A compound of formula I wherein R5 is hydrogen initially obtained may be converted into the corresponding compound of formula I wherein R5 represents C1-6 alkyl, C3-6 alkenyl or C3-7 heterocycloalkyl(C1-6)alkyl, typically by standard alkylation procedures, e.g. by treatment with the appropriate alkyl or alkenyl halide in the presence of a base such as sodium hydride or triethylamine and a solvent such as N,N-dimethylformamide. Moreover, a compound of formula I wherein R5 is hydrogen initially obtained may be converted into the corresponding compound of formula I wherein R5 represents C2-7 alkoxycarbonyl by conventional acylation procedures, e.g. by treatment with the appropriate acyl halide. A compound of formula I wherein R6 is hydroxy initially obtained may be converted into the corresponding compound of formula I wherein R6 represents C1-6 alkoxy by standard alkylation methods, e.g. by treatment with the appropriate alkyl halide, e.g. methyl iodide, in the presence of sodium hydride and N,N-dimethylacetamide. A compound of formula I initially obtained wherein xe2x80x94NR2R3 represents a ring of formula (d) may be converted by reductive amination into a compound of formula I wherein xe2x80x94NR2R3 represents a ring of formula (a) in which X is CR6R7, wherein R7 is hydrogen and R6 represents an N-linked heterocycloalkyl moiety, by treatment with the appropriate heterocycloalkane reagent, e.g. morpholine, in the presence of a reducing agent such as sodium triacetoxyborohydride.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following Examples illustrate the preparation of compounds according to the invention.
The compounds in accordance with this invention potently inhibit the binding of [3H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the xcex12 or xcex13 subunit stably expressed in Ltkxe2x88x92 cells.
Reagents
Phosphate buffered saline (PBS).
Assay buffer: 10 mM KH2PO4, 100 mM KCl, pH 7.4 at room temperature.
[3H]-Flumazenil (18 nM for xcex11xcex23xcex32 cells; 18 nM for xcex12xcex23xcex32 cells; 10 nM for xcex13xcex23xcex32 cells) in assay buffer.
Flunitrazepam 100 xcexcM in assay buffer.
Cells resuspended in assay buffer (1 tray to 10 ml).
Harvesting Cells
Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cmxc3x9725 cm) of cells.
Assay
Can be carried out in deep 96-well plates or in tubes. Each tube contains:
300 xcexcl of assay buffer.
50 xcexcl of [3H]-flumazenil (final concentration for xcex11xcex23xcex32: 1.8 nM; for xcex12xcex23xcex32: 1.8 nM; for xcex13xcex23xcex32: 1.0 nM).
50 xcexcl of buffer or solvent carrier (e.g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to determine non-specific binding), 10 xcexcM final concentration.
100 xcexcl of cells.
Assays are incubated for 1 hour at 40xc2x0 C., then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3xc3x973 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be calculated for each test compound.
The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [3H]-flumazenil from the xcex12 and/or xcex13 subunit of the human GABAA receptor of 100 nM or less.

Triazolo-pyrimidine derivatives as ligands for gaba receptors


A software and/or hardware facility is described that enables searches for transient multimedia resources that are contained in real-time multimedia streams. Because real-time data streams are not archived for subsequent access, transient resources contained in the streams are preferably quickly identified, characterized in a database, and indexed so that the facility can locate transient resources that are responsive to search queries. Stream listeners are disclosed that are configured to monitor data streams and identify transient resources within the streams based on associated metadata. Various techniques are disclosed to optimize the operation of the stream listeners. In response to a search query, search results are generated by the facility that include transient multimedia resources that are accessible via a network at the time that the search query is received.

Searching refers to a process in which a user submits a query, such as a list of keywords, and receives in return a search result. The search result is a set of one or more resources in a search domain that are determined to be responsive to the query by a search algorithm. It is typical for queries to be processed against a search index that corresponds to a desired search domain. For example, a query may be applied against a search index corresponding to a search domain of web documents, such as web pages or other textual documents available via the Internet, to produce a result containing a list of links to web documents satisfying the query. A query may similarly be applied against a search index corresponding to a multimedia search domain, to produce a result containing a list of links to multimedia resources satisfying the query. For example, the search query "Santana" applied against a multimedia search index could identify a link to a multimedia resource corresponding to the song "Smooth" by the band Santana.
The conventional approach to indexing a search domain involves populating the search index using web crawling techniques. Such web crawling techniques typically involve automatically examining all or portions of the World Wide Web in a methodical manner to identify resources, and queuing information about visited resources for later processing to add these resources to an index. Depending on the scope of the crawl, such techniques can involve long update cycles—for example, the web crawl might run every three days and therefore the index would only be updated every three days. Because of the time required to complete the crawl, this method of indexing is better suited for indexing some types of resources over others. For example, this method of indexing is generally quite suitable for identifying multimedia resources that are available for relatively long periods of time. An example of a multimedia resource that may be accessible for an extended period is a link to a Santana song on Santana's homepage (santana.com). As long as the band Santana continues to enjoy consumer success, it is likely that a user will be able to select and play a Santana audio or video clip from the website at any time during the future (whether weeks, months, or years).
In contrast to such "static" multimedia resources that are available for long periods of time, some publishers make available transient multimedia resources as part of a data stream. For example, a publisher may offer programming from a radio station over the Internet as a digitized stream so that listeners do not have to be in geographic proximity to a broadcast tower in order to enjoy the station programming. When provided over the Internet as an audio stream, the programming is typically "real-time" in the sense that the station does not store or archive the transmitted content in a manner that can be easily accessed by users in the future. Instead, users are only able to receive and play the content that is presently being broadcast by the station. That is, a user accessing a station via the Internet half-way through the broadcast of a song is usually precluded from "rewinding" or otherwise listening to the song from the start. Instead, the user is only able to listen to the remaining portion of the song that hasn't been broadcast. In this sense, all of the multimedia resources contained in a real-time data stream—whether they are songs, interviews, traffic reports, weather updates, or any other content in audio, video, audio/video, and/or other form—may be considered to be "transient" since they are only accessible via the Internet for an instant of time. Unless stored by the user, each multimedia resource can only be accessed for the period that the resource is broadcast. Of course, real-time multimedia data streams vary significantly between publishers and may be produced in any of a variety of media types, in various encoding formats, and at various quality levels. Some multimedia resources broadcast in a real-time data stream may be "live" in the sense that the media content is being created contemporaneously with its broadcast, while other multimedia content may be preexisting content that is presented in the real-time data stream.
Because transient multimedia resources are only accessible for a brief instant of time, conventional indexing techniques used to identify static multimedia resources are not suitable for transient multimedia resources for at least two reasons. First, conventional indexing techniques that identify a real-time multimedia data stream are often only able to index the data stream based on general metadata associated with that stream. For example, a stream might be identified as "swing music from the 40s," but the indexing would not be able to identify particular artists or song titles that are included in the stream. As a result, users searching for a particular artist may not know about the inclusion of the artist in a particular data stream because the metadata associated with the stream does not include such information. Second, even if the indexing technique was able to identify a particular artist that was being played on the stream at the time of indexing, because of the delay associated with most crawls such an index would quickly become out of date. Users searching for a particular artist would be unable to find the artist in a particular data stream because all or some of the results may be stale (meaning that a user selecting a search result and being redirected to a stream would not find the artist they were seeking in the stream) or no results may be returned even though the artist should be found in a stream if the stream were being indexed in a timely fashion. In each case, the user is unable to locate a desired result responsive to their search query.
In view of the above-discussed disadvantages of conventional approaches, a more effective approach to indexing transient multimedia resources would have substantial utility.

Searching for transient streaming multimedia resources


An electrostatically actuated oscillating structure includes a first stator subregion, a second stator subregion, a first rotor subregion and a second rotor subregion. Torsional elastic elements mounted to the first and second rotor subregions define an axis of rotation. A mobile element is coupled to the torsional elastic elements. The stator subregions are electrostatically coupled to respective regions of actuation on the mobile element. The stator subregions exhibit an element of structural asymmetry such that the electrostatic coupling surface between the first stator subregion and the first actuation region differs from the electrostatic coupling surface between the second stator subregion and the second actuation region.

Known to the art are micromechanical mirror structures (or reflectors) made, at least in part, of semiconductor materials exploiting MEMS (microelectromechanical systems) technology.
MEMS reflectors are designed to receive an optical beam and to vary the direction of propagation thereof, in a periodic or quasi-periodic way. For this purpose, MEMS reflectors include mobile elements formed by mirrors, the positions of which in space are electrically controlled by an appropriate oscillation control signals.
In greater detail, in a generic MEMS reflector comprising a respective mirror, the control of position of the mirror is of particular importance for enabling scanning of a portion of space with an optical beam, which is made to impinge on the mirror. In particular, the control of position of the mirror is crucial in the case of resonant MEMS reflectors, in which, in use, the mirror is made to oscillate in a substantially periodic way about a resting position, the period of oscillation being as close as possible to the resonance frequency of the mirror in order to maximize the angular distance covered by the mirror during each oscillation, and thus maximize the extent of the portion of space scanned.
For example, United States Patent Application Publication No. 2011/0109951 (incorporated by reference) describes a circuit for control of the position of the mirror of a MEMS reflector of a resonant type, said mirror being arranged for rotating, under the action of a motor of an electrostatic type, about an axis of rotation. In particular, the MEMS reflector according to US2011/0109951 comprises a fixed support body, of semiconductor material, and a mirror, which is constrained to the fixed support body by a first spring and a second spring.
The fixed support body comprises a first stator subregion and a second stator subregion, which are connected, respectively, to a first stator electrode and a second stator electrode, and a first rotor subregion and a second rotor subregion, which are connected, respectively, to a first rotor electrode and a second rotor electrode. The first and second stator electrodes enable biasing, respectively, of the first and second stator subregions, whereas the first and second rotor electrodes enable biasing, respectively, of the first and second rotor subregions.
The mirror is mechanically set between the first and second springs, each of which has a respective end that is fixed with respect to the fixed support body. In particular, the first and second springs are fixed, respectively, with respect to the first and second rotor subregions. The mirror and the first and second springs thus form a resonant system, which has a respective mechanical resonance frequency. In general, the mechanical resonance frequency varies in time, for example on account of variations in temperature.
In greater detail, according to the patent application No. US2011/0109951, the voltages of the rotor electrodes and of the stator electrodes, and consequently the voltages of the stator and rotor subregions, are set in such a way as to cause oscillation of the mirror about the axis of rotation. For this purpose, the first and second rotor electrodes are set at a biasing voltage (Vpol), while the first and second stator electrodes receive a same electrical control signal.
To bring about oscillation of the mirror with a mechanical oscillation frequency that is as close as possible to the mechanical resonance frequency, it is necessary to know the mechanical resonance frequency, and it is necessary to generate the pulses of the electrical control signal with an appropriate frequency and phase, as a function of the position of the mirror.
In greater detail, on the basis of the teachings contained in US2011/0109951, it is possible to control the position of the mirror using an electronic driving circuit. In particular, the stator electrodes are considered as being electrically equivalent to, and coinciding with, a node S, and the first and second rotor electrodes are set at the biasing voltage Vpol. The mirror is thus electrically equivalent to a capacitor with variable capacitance Cm which has a first terminal, electrically coinciding with the node S, and a second terminal, set at the biasing voltage, which is generated by an amplifier according to the virtual-ground principle. The capacitance of the capacitor with variable capacitance Cm depends upon the torsion to which the first and second springs are subjected, and thus is inversely proportional to the angular distance of the mirror from the resting position, where by "resting position" is meant the position of the mirror to which there corresponds a zero torsion of the first and second springs. During driving, the node S receives electrical voltage pulses. Since the electrical pulses are at a high positive voltage having a value higher than the biasing voltage Vpol, a torque of an electrostatic nature is exerted on the mirror; in this way, the mirror is kept in oscillation.
However, application of the biasing voltage Vpol to the first and second rotor electrodes does not make it possible to drive the mirror in oscillation with a pre-set phase. In practice, the oscillation phase is substantially random or, at least in part, subject to offsets that derive from manufacturing steps that may not be determined beforehand.
The knowledge of the oscillation phase is important since the orientation of the mirror defines, in use, the direction of the images projected. Thus, it is necessary to know the orientation (or phase) of the mirror to generate correct images. According to an embodiment of a known type, described in US 2011/0181931, the motion of the mirror is detected by a microphone configured to transduce into an electrical signal the pressure waves generated by oscillation of the mirror. In this way, according US 2011/0181931, it is possible to recognize in which position the mirror is in use, and, consequently, derive the oscillation phase thereof.
Even though this system and method provide reliable results, they require integration of a MEMS microphone in the same package as the one that houses the mirror, with consequent increase in costs and difficulty in containment of the dimension of the final package.
Further, the oscillation phase is not known immediately, but only after oscillation of the mirror has started, at the end of the starting transient.
There is accordingly a need to provide an electrostatically actuated oscillating structure with control of the absolute oscillation starting phase, and corresponding manufacturing method and driving method, that will overcome at least in part the drawbacks of the known art, and in particular will make it possible to govern start of oscillation of the oscillating structure of the MEMS device with a pre-set and known phase.

Electrostatically actuated oscillating structure with oscillation starting phase control, and manufacturing and driving method thereof


A method for providing a desktop environment solution is provided. The method may include providing a client information handling system and authenticating the client to a network. Furthermore, a hardware configuration of the client may be dynamically examined, and an appropriate desktop environment solution may be selected based on the hardware configuration.

As the value and use of information continues to increase, individuals and businesses seek additional ways to process and store information. One option available to users is an information handling system (IHS). An information handling system generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes thereby allowing users to take advantage of the value of the information. Because technology and information handling needs and requirements vary between different users or applications, information handling systems may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in information handling systems allow for such systems to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. In addition, information handling systems may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
Currently, numerous desktop environment solutions exist in large enterprise networking systems. A desktop environment solution may be intuitive mechanism for a user to interact with the information handling system using icons, windows, and other graphic user interface (GUI) components. Thus, a desktop environment solution may be a method of providing an IHS user interface to a remote user without it being physically installed on a client IHS. To this end, a desktop environment solution may be delivered over a network from a server to a client IHS. However, different desktop environment solutions may be suitable for different client IHS devices depending on the hardware configurations and resources of the client IHS. Furthermore, the type of network connection used to couple the server and the client IHS may also affect the performance of certain desktop environment solutions. Further still, the security of the client IHS may also be a determining factor since user data may be compromised if the client IHS can be hacked by malicious users. Therefore, depending on the type of client IHS and other external factors, one or more desktop environment solutions may not be appropriate. Thus, a need exists for dynamic methods, systems, and media to determine the most appropriate desktop environment solution for a particular client IHS.

Desktop environment solutions methods and systems


Device for indicating the angular position between a first part and a part which is rotatable relative to the first part. Each of these parts exhibits a grating (15, 16) consisting of a pattern which, in each grating, comprises opaque lines separated by interspaces, the gratings together being arranged to provide an easily readable moire pattern which indicates whether the opaque lines in the one grating are at a certain position relative to the opaque lines of the other grating. The interspaces of each grating (15, 16) exhibit mutually differing widths, with a width which gradually increases over the height of the one grating (15) in a direction transverse to the longitudinal direction of the interspaces and a width which gradually decreases over the height of the other grating (16) transverse to the longitudinal direction of the interspaces and in the same direction.

The Swedish patent specifications SE 7,307,577-2 and 7,611,511-2 are examples of a practical application of angle gauges which are founded on the technique used in the present invention, namely, the moire effect. In these known devices a moire pattern arises by two gratings being provided on parts which are rotatable relative to one another, whereby a pattern arises which indicates whether the two parts are located at a desired angular position relative to one another or whether they deviate from this angular position. The angle gauges can be provided with a graduated angular scale, by means of which the gauge can be used to obtain a directly readable value, for example, for an object, such as a parabolic antenna, which can be adjusted for different angular positions. The angular position relative to the horizontal plane is arrived at by the one part being made unbalanced so that it continually strives to assume a position which is unchanging relative to the horizontal plane. In these cases it may prove difficult, using the previously known devices, to achieve both a high degree of adjustment accuracy and simplicity of adjustment due to the fact that a high degree of adjustment accuracy is associated with undesirably quick and large motions of the moire pattern for each angular change.
The object of the present invention is to provide a device by means of which a high degree of adjustment accuracy, as well as simplicity of adjustment, can be achieved.


Disclosed is a touch screen panel for improving touch sensitivity, the screen panel comprising a first electrode in a first direction; and a second electrode, insulated from the first electrode, in a second direction perpendicular to the first direction, wherein the first electrode includes a plurality of first patterns, and a second pattern formed as one body with the plurality of first patterns so as to connect the plurality of first patterns in the first direction; the second electrode includes a plurality of third patterns, and a fourth pattern formed as one body with the plurality of third patterns so as to connect the plurality of third patterns in the second direction; and the first pattern is provided at a predetermined distance in a horizontal direction from the third pattern, the second pattern crosses the fourth pattern, and an area of the first electrode is larger than an area of the second electrode.

1. Field of the Disclosure
The present disclosure relates to a touch screen panel, and more particularly, to a capacitive type touch screen panel.
2. Discussion of the Related Art
With a development of various portable electronic devices such as a mobile phone and a notebook computer, a demand for flat display devices to be applied to the various portable electronic devices has been increased steeply.
For example, the flat display devices may include a liquid crystal display apparatus, a plasma display panel, a field emission display device, and a light emitting diode display device. Among the above flat display devices, an application of the liquid crystal display apparatus is gradually increased owing to advantageous of mass production technology, easy driving, high quality image with good resolution, and large-sized screen.
A touch screen is widely used as a substitute for an input device such as a mouse or a keyboard according to the related art, wherein the touch screen facilitates to directly input information to a screen through the use of finger or pen.
The touch screen panel is largely classified into a resistive type and a capacitive type. In this case, the resistive type senses a change of resistance value according to a contact between two substrates if a pressure is applied to a screen by the use of finger or stylus pen. Meanwhile, the capacitive type senses a change of capacitance according to a user's touch.
The capacitive type is advantageous in that it can decrease a thickness of the touch screen panel in comparison with that of the resistive type, it can improve endurance of a touch pad, and it can reduce malfunction caused by an external pressure. Furthermore, the capacitive type enables to perform a multi-touch function by freely expanding or reducing an image with two fingers. Accordingly, there is a recent trend toward high preference of the capacitive type.
FIG. 1 illustrates a flat display device with a capacitive type touch screen panel according to the related art.
Referring to FIG. 1, the capacitive type touch screen panel according to the related art includes a first electrode 120 formed in a first direction, a second electrode 130 formed in a second direction being perpendicular to the first direction, a connection line 140, and a touch pad 150.
The touch screen panel senses a change of capacitive between the first electrode 120 and the second electrode 130 according to whether or not there is a user's touch, to thereby sense a user's touch position.
The first electrode 120 is driven as a driving electrode to which a touch driving signal for sensing a user's touch is applied, and the first electrode 120 is connected with the touch pad 150 through the connection line 140. In this case, the touch pad 150 is connected with a driving electrode driver (not shown) for supplying the touch driving signal for sensing a user's touch through an FPC.
The second electrode 130 is driven as a sensing electrode for sensing a change of capacitance according to a user's touch, and the second electrode 130 is connected with the touch pad 150 through the connection line 140. In this case, the touch pad 150 is connected with a sensing electrode driver (not shown) for sensing a change of capacitance according to a user's touch by the use of FPC.
The sensing electrode driver (not shown) senses a user's touch position by comparing the sensed touch capacitance with a reference capacitance, and outputs the sensed touch position.
The touch screen panel is provided on a liquid crystal panel 110. As shown in FIG. 1, a predetermined portion of the second electrode 130 of the touch screen panel, which is not overlapped with the first electrode 120, is exposed to the liquid crystal panel 110, whereby the exposed portion of the second electrode 130 is influenced by noise generated in the liquid crystal panel 110.
Thus, the touch screen panel has problems of low touch sensitivity and accuracy. For example, since the capacitive type touch screen panel senses the change of capacitance according to a user's touch, it is very sensitive to the noise. That is, even though the capacitive type touch screen panel is not touched by a user, there might be malfunction or error of sensing a user's touch.