This invention relates to a composition for inducing smoking cessation comprising as active ingredient alkaloids from Radix ipecauanhae. In smoking cessation program using the composition, the considerable number of volunteers participated in the program became nausea and thus ultimately to have no craving for smoking.

This invention relates to a composition for inducing smoking cessation comprising as active ingredient alkaloids from Radix ipecauanhae. More specifically, it relates to a composition comprising as active ingredient basic alkaloid fraction from Radix ipecauanhae or basic emetine, optionally in combination with one or more auxiliary agents selected from Nicotiana tabacum, Fructus Phyllanthus emblica, Herba adenophorae, Herba leonuri, Herba foeniculi, Folia valerianae, Herba centellae or Circii herba. The invention also provides a method for using the same.
Nicotiana tabacum contains harmful ingredients to human body such as nicotine, tar, dioxin and the like in large quantities. It is a one""s favorite known to increase incidence of diseases related lung and cancers through long-term smoking. Various kinds of smoking cessation medicines or aids have been hitherto developed for smoking cessation. However, they have frequently adverse effects on human body or fail to successfully induce smoking cessation. Accordingly, it is absolutely needed to develop more efficient smoking cessation method or smoking cessation aid.
Radix ipecauanhae, as emetic, has been used for detoxification and the treatment of dysentery, and used as expectorant, depending upon its dosage (Deutsches Arzneibuch, British Herbal Pharmacopoeia, Gerhardt Madaus""s Lehrbuch der Biologischen Heilmittel, Georg Olms 1976). However, it has never been used for inducing smoking cessation.
The present inventors carried out extensive studies to develop a novel efficient smoking cessation composition. As a result, they found that basic alkaloid fraction from Radix ipecauanhae of its constituent emetine can efficiently induce smoking cessation after various clinical trials and thus, completed the present invention.
Accordingly, a purpose of the present invention is to provide a composition for inducing smoking cessation comprising basic alkaloid fraction from Radix ipecauanhae or emetine as active ingredient.
Another purpose of the present invention is to provide the composition comprising basic alkaloid fraction from Radix ipecauanhae or emetine as active ingredient for smoking cessation, in combination with one or more selected from Nicotiana tabacum, Fructus Phyllanthus emblica, Herba adenophorae, Herba leonuri, Herba foeniculi, Folia valerianae, Herba centellae or Circii herba.
In the composition of the present invention, alkaloid extract from Radix ipecauanhae (root of Cephaelis ipecacuanha), an emetic, is used as active ingredient. Radix ipecauanhae, one species of Rubiaceae, is known as emetic and anti-dysentery. Radix ipecauanhae contains 1.9-2.1% of total alkaloids (Deutsches Arzneibuch 9, Edition 1986; British Herbal Pharmacopoeia 1979). Emetine (6,7,10,11-tetramethoxyemethan) and cephaelin are main ingredients in the alkaloid fraction. In the present composition, ipecac extract is used in the form of basic alkaloid fraction or emetine.
A mechanism that emetine will induce vomiting is as follows: it stimulates gastrointestinal system thereby to transduce signal to 5-HT3 (5-hydroxytryptamine-receptor) in chemo-receptor trigger zone of area postremia and solitary tract nucleus. Subsequently, the transduced signal stimulates vomiting center in Medulla oblongota and then, passes through nervus vagus, phrenic nerve and abdominal muscular nerve to reach nausea followed by vomiting (Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th Edition, 1996).
Alkaloids in Radix ipecauanhae are usually in the form of salt with acid and commercial emetine is emetine hydrochloride. If smoking this salt as is, acidic moiety will transform to gaseous acid to have harmful effects on oral cavity, bronchus and lung, etc. In particular, hydrochloride may react with herbal aromatic compounds, especially, phenol and phenolic compounds, which are secondarily formed during combustion, to form poisonous dioxins. Therefore, in the present composition, ipecac alkaloid salt or salt of emetine should be converted into basic alkaloid before its use.
For conversion of salt into base, conventional alkaloid extraction method may be employed. That is, in the present invention, general alkaloid fractionation method is used for obtaining fraction, which contains mainly basic alkaloids. Specifically, the given amount of ipecac powder is degreased with hexane, and to the residual plant are added alkalis such as ammonium to basify. Subsequently, the resulting solution is extracted with water-immiscible solvent such as ether, etc. The obtained fraction contains 70-80% of total alkaloids. Further, emetine hydrochloride is dissolved in water and then, extracted with water-immiscible solvent such as ether, etc. to obtain emetine.
Generally, a daily dose of emetine for the halt of coughing and for the discharge of phlegm ranges about 1.0-1.5 mg of emetine hydrochloride. The daily dose of Radix ipecauanhae for the same purpose ranges about 0.03-0.15 g, and a single dose thereof for vomiting ranges about 0.5-1.0 g. In the present invention, it is important to adapt the dosage for inducing smoking cessation. That is, Radix ipecauanhae contained in the present composition has the practical purpose of nauseating rather than of vomiting and thus, vomiting is conversely regarded as an adverse event. In view of the fact that a single dose of Radix ipecauanhae for vomiting is 0.5-1.0 g, its amount for smoking cessation would be lesser than 0.5-1.0 g. Synergic effect with nicotine as described hereunder can lead to remarkable reduction of the inhalation amount of Radix ipecauanhae, i.e. alkaloids therefrom. In the present invention, ipecac alkaloid is preferably contained at 0.01 to 2 wt %, more preferably, 0.05 to 0.3 wt %, as basic alkaloid fraction, on the basis of the total weight of the composition. In another aspect, emetine, if employed as active ingredient, is preferably contained at 0.005 to 0.5 wt %, more preferably 0.005 to 0.15 wt %, on the basis of the total weight of the composition. In the present composition, nicotine, if employed as excipient, is contained at the residual amount excluding the active ingredient. For example, in case that the total weight of the composition is 100 g and the content of ipecac alkaloid is 2000 mg, 98 g of tobacco leaf is preferably added thereto.
If desired, the composition of the present invention may contain tobacco leaf having nicotinic ingredient. In the present composition, the tobacco leaf may not only function as excipient but also provide properties inherent in tobacco. Nicotine has complicated and unexpectable mechanism. It functions on various nerve transfer systems and further, stimulates or desensitizes receptor depending upon its dosage. Usually, nicotine inhaled into the body through smoking does not lead to desensitization, but causes stimulation and excitation of receptor. Nicotine displays vomiting effect via the same mechanism as emetine. Mechanism of vomiting in nicotine is as follows: It stimulates vomitive chemo-receptor trigger zone of area postremia in medulla oblongata thereby to activate vagal and spinal afferent which receive vomiting and reflex thereby to promote vomiting.
From the fact that emetine and nicotine pass through many common afferent areas through their reaction mechanism, these two substances are anticipated to have synergic or additive effect. Nicotine in the form of tobacco leaf may be comprised in the present composition at a conventional amount as excipient for the manufacture of tobacco. For example, in case that the total weight of the composition is 100 g and the content of emetine is 500 mg, 99.5 g of tobacco leaf may be contained. Such content of nicotine is sufficient for exhibiting synergic or additive effect.
A further aspect of the present invention is to provide a composition for inducing smoking cessation comprising smokable herbal materials instead of tobacco leaf. In this composition, as the bulk of herbal materials, Herba adenophorae, Herba centellae, Circii herba and the like, which contain less herbal phenol, may be employed. Herba adenophorae, leaf of Adenophora triphglla Var. Japonica, falls within Companulaceae and contains saponins mainly. It is known to be effective for the discharge of phlegm, lung treatment and treatment of pharyngolaryngitis, etc. In addition, Herba centellae has the effect of preventing or treating damages in epithelial tissue due to smoking.
Furthermore, the composition of the present invention may contain additional ingredients for providing gustatory, aromatic and sedative effects. Examples of such ingredients include Herba foeniculi, Fructus Phyllanthus emblica, Herba valerianae, Herba leonuri sibiricus, tobacco flavor, etc. Herba foeniculi is added for providing aroma and used as leaf of Foeniculum vulgaris of Umbelliferae. Its fruit is known to be useful as aromatic agent and to be effective for treatment of a pain in the abdomen, emmenagogue, low back pain and the like. Its root contains 3-6% of essential oils such as anethole, fenchone, phellandrene, etc. Extract from Fructus Phyllanthus emblica is added not only as gustatory ingredient but also as sedative of throat and bronchus irritated by smoking. It contains 1.0-1.8% of ascorbic acid and gallotannins. The composition may contain Herba valerianae for psychological relief. Finally, for disguise the unfamiliar taste of non-tobacco cigarette, Herba leonuri sibiricus of the bitter taste and tobacco flavors are added to the composition. Herba leonuri sibiricus contains leonuri alkaloids such as leonurine, etc. and is known effective for dysmenorrhoea, abdominal dropsy and for purifying blood and detoxification.
The above-described auxiliary agents may be used at an unlimited amount within the range of desired advantageous effects without any side effects. Such agents may be omitted, or increased or decreased considering smoker""s taste. The amount of these agents does not need to be specifically limited, but they are preferably used at the same amount as tobacco leaf. That is, in a preferable embodiment, cigarette is manufactured by mixing 0.01-2 wt % of ipecac basic alkaloid fraction obtained from Preparation 1 or 0.005-0.5 wt % of basic emetine obtained from Preparation 2 as active ingredient with the residual amount of the above auxiliary agents.
Hereunder, a process for preparing the composition of the present invention will be explained. Smoking cessation cigarettes are prepared as follows: Admixing of various concentrations of basic alkaloid fraction from Radix ipecauanhae with the given amount of tobacco leaf The alkaloid fraction or emetine is mixed with a commercial cigarette, the weight of which is 0.8-1.0 g excluding filter, at variable amounts. Alkaloid content must be adjusted within the range where it does not cause vomiting substantially regarded as adverse event in view of the purpose of the present invention. A variety of dosages of alkaloids enable to determine optimal dosage in each individual considering smoker""s sensitivity.
In the present invention, two approaches are considered for the manufacture of cigarettes. (1) Admixing ipecac basic total alkaloids or emetine with tobacco simultaneously, and (2) manufacturing cigarettes consisting of ipecac basic total alkaloids or emetine, smoking the cigarettes to pre-sensitize chemo-receptor trigger zone and smoking tobacco to induce synergic effect with nicotine after the given time.
This invention will be better understood from the following examples. However, one skilled in the art will readily appreciate the specific materials and results described are merely illustrative of, and are not intended to, nor should be intended to, limit the invention as described more fully in the claims, which follow thereafter.
Preparation 1: Preparation of Basic Alkaloid Fraction from Radix ipecauanhae
1000 g of ipecac powder was introduced into 5000 ml of Soxhlet extractor and was extracted with 2000 ml of hexane for 3 hours. Subsequently, hexane was removed by filtration and the residual hexane was removed from ipecac residue. The ipecac powder was introduced into 5000 ml of Stirring extractor and extracted with 2000 ml of methanol at 40xc2x0 C. for 5 hours. The extract was filtered and ipecac residue was extracted further twice according to the same procedure. The extracts with methanol were combined and the solvent was removed under reduced pressure to obtain 35 g of the residue. The residue was suspended in 500 ml of water and thereto was added 0.1 N sodium hydroxide to adjust pH to about 7.0-7.5. Then, the suspension was extracted twice with 500 ml of ether and filtered to obtain liquid extract with ether. The extract was washed twice with 100 ml of water and dried to obtain 18 g of alkaloid fraction (total alkaloid fraction). The fraction was analyzed, according to the procedure described in the literature Deutsches Arzneibuch 9, Ausgabe 1986 and as a result, identified to have 80% of total alkaloids.
Preparation 2: Preparation of Emetine from Emetine Dihydrochloride
5 g of Emetine dihydrochloride (5H2O) was dissolved in 100 ml of water and thereto was added 0.1 N sodium hydroxide to adjust pH to 7.5. The solution was extracted three times with 100 ml of ether. The removal of ether gave about 4 g of emetine (emetine).

Composition for inducing smoking cessation comprising alkaloids from Radix ipecauanhae


A continuous-motion decorating machine of the screen and squeegee type which receives the ware, such as glassware, from a delivery conveyor for decorating it usually with several colors. The ware, for example tapered tumblers, is delivered in upright vertical position to a loader and unloader unit of the machine which lifts it so that the ware is successively engaged by the article carrier of the machine, which consists of a spindle-carrying endless horizontal chain conveyor arranged around sprockets to provide one straight side or run with which the loader and unloader unit is associated and three other straight sides or runs with which the screen and squeegee printing units are associated. Each of the printing units consists of an upper squeegee carrier, embodying an endless squeegee-carrying vertical moving chain support, and a lower ware support assembly which also embodies a roller-carrying vertical moving chain support, along with a screen support located at a level between the lower run of the squeegee support chain arrangement and the upper run of the ware support chain arrangement.

This invention relates to a machine of the screen and squeegee type used especially for applying multi-colored decorations to glassware, particularly tapered tumblers. An example of a prior art machine for the same general purpose is illustrated in the patent to Eldred et al. U.S. Pat. No. 3,096,709, dated July 9, 1963 but this patent discloses an intermittent type machine. Continuous-motion prior art machines for this same general purpose, but designed specifically for decorating bottles, are illustrated by the following prior patents: Rudolph et al. U.S. Pat. No. 3,251,298, issued May 17, 1966; Donner et al. U.S. Pat. No. 3,518,938, issued July 7, 1970; and Killen et al. U.S. Pat. No. 3,783,777, issued Jan. 8, 1974.

Continuous-motion decorating machine of the screen and squeegee type


An agricultural harvesting system has an agricultural harvesting machine with at least one agricultural working unit that performs agricultural work, and an adjusting unit for adjusting the parameters of the particular working unit, a conveyor channel for a crop stream generated in a harvesting process by harvesting a field of crop, and an NIR sensor unit containing an NIR sensor which is configured for detecting constituents and/or properties of the crop stream. The crop stream in the conveyor channel can be guided past the NIR sensor. An on-line data processing unit controls the particular working unit, and generates control data on the basis of crop stream data which have been generated by the NIR sensor unit and correspond to the constituents and/or properties detected by the NIR sensor, and the adjusting unit carries out a parameter adjustment of the particular working unit on the basis of the control data.

The invention relates to an agricultural harvesting system comprising an agricultural harvesting machine.
The related art (EP 1 407 654 B1) describes agricultural harvesting systems comprising an agricultural harvesting machine which includes a sensor unit for detecting the constituents in the agricultural crop. The sensor unit comprises a sensor which operates on the basis of near-infrared spectroscopy (NIR sensor) and past which a crop stream can be conveyed. A crop stream is understood to mean, in this case, crop which has been harvested by means of the harvesting machine and which is transported through a conveyor channel of the harvesting machine. The NIR sensor is usually situated in a wall of the conveyor channel in this case and detects the intensity of the light reflected by the particles in the crop stream, which are flowing past, in a wavelength-resolved manner. In this case, the crop stream is acted upon by broadband, i.e., white, light. In this way, the individual light-stimulated modes of oscillation of individual constituents of the crop to be identified, which take effect via absorption, diffusion, or extinction, can be detected.
NIR sensors have proven to be particularly advantageous for the detection of constituents of the crop that are relevant for an addition of an ensilage agent. Ensilage agents are used for the preparation or handling of crop, in particular, in order to improve the fermentation process in the silo. During the harvesting process, an ensilage agent unit generally mixes an acid with water in a ratio that is dependent on the crop properties and injects the mixture into the crop stream.
In order to control the ensilage agent unit, the crop stream data measured by the NIR sensor are fed to a data processing unit which calculates the particular content of the constituents of interest (e.g., sugar content, protein content, crude ash portion, and/or raw fiber portion). The data processing unit then generates suitable control data on the basis of the crop stream data, via which the ensilage agent unit and, therefore, the addition of ensilage agent into the crop stream is controlled.
Independently thereof, it is also known with respect to harvesting machines to adjust and control various agricultural working units thereof, wherein the adjustment or control of the working units takes place on the basis of data from various further sensors. In this case, an agricultural working unit is understood to mean, in particular, an agricultural work-assisting or -performing component of the harvesting machine that mechanically acts on the crop. In the case of a forage harvester, these are, for example, the header, the cutting cylinder, feed devices, conveying and accelerating devices for the crop, the lifting mechanism for adjusting the height of the header, or the like.
With respect to the related art, it is problematic that the plurality of sensors necessary for controlling the different processes of the harvesting machine is associated with a relatively great complexity of installation and maintenance.

CLAAS Selbstfahrende Erntemaschinen GmbH


A method and apparatus which provides for holding a closure that has threads stationary and rotating the container about its longitudinal axis to apply the closure on the container. Preferably the closure and container are in inverted position. The method of cutting provides for holding the container and closure in inverted positioned, gripping the container and moving a knife transversely of the longitudinal axis of the container to sever the bottom from the container.

In one method of manufacture of such flexible tubes, a fitment defining a threaded neck is attached to an open-ended tube and then the product is filled through the other end of the tube and the other end is closed.
In another method of making such flexible tubes, a hollow container having an integral neck is formed, as by blow molding, the base of the container is severed from the container, the container is placed on a mandrel whereupon decoration is applied to the open-ended container, a closure is applied to the finish and then the ultimate user fills the container through the open end and seals the open end.
In copending application Ser. No. 08/228,048 filed Apr. 15, 1994, there is disclosed and claimed a flexible plastic tube and a method for forming a tube wherein the method of forming a flexible plastic tube for use in dispensing a viscous product comprises injection molding a finish having an opening, extruding a tube integrally with the finish by relevant movement of the finish with respect to an extruder, moving the finish axially away from the extruder while continuing continuously extruding said tube, closing a blow mold about the extruded tube, blowing said tube into an integral container body having a closed bottom, opening the molds to provide an integral container having an integral finish, a shoulder portion, a tubular body portion and a closed bottom, decorating the body portion with indicia, cutting the closed bottom of the container leaving an article having a finish, a shoulder portion and an open end tube. A closure is applied after the decorating step. Thereafter a user may fill the tube through the open end and seal the open end.
In copending application Ser. No. 08/228,055 filed Apr. 15, 1994, of which the present application is a continuation in part, there is disclosed a method and apparatus for applying the closure and for cutting the bottom from the container after the container has been subjected to one or more decorating operations. The method and apparatus provides for holding a closure which has threads stationary and rotating the container about its longitudinal axis to apply the closure on the container. Preferably the closure and container are in inverted position. The method of cutting provides for holding the container and closure in inverted positioned, gripping the container and moving a knife transversely of the longitudinal axis of the container to sever the bottom from the container.
Among the objectives of the present invention are to provide a method and apparatus for performing the method of the aforementioned application in the improved manner; wherein the containers are handled in multiples; and wherein uniformity of application of the closures and cutting of the containers can be achieved at high speeds.
In accordance with the invention there are provided a method and apparatus wherein a turret station is moved intermittently past a capping station and trimming station; wherein containers in multiples are carried by the turret past each of the stations; and wherein the capping and trimming assemblies are constructed and arranged to function to cap each container at a predetermined torque and cut each container uniformly and accurately.

Method and apparatus for forming an assembly of a flexible tube and closure


Myeloid function is enhanced by transplantation or infusion of allogeneic myeloid progenitor cells, including CMP, GMP, MEP and MKP cell subsets. Myeloid progenitors ameliorate sequelae of anemia and thrombocytopenia, and can prevent or treat gastrointestinal mucositis associated with chemotherapy, radiotherapy, and the like. The transplantation or infusion may be performed in the absence of HLA typing, and the cells may be mismatched at one or more Class I HLA loci. The transplantation may provide for treatment of ongoing disease, or prevention of disease in high risk patients.

Blood cells are derived from hematopoietic stem and progenitor cells in the bone marrow. During the process of differentiation, a pluripotential stem cell gives rise to progenitor and effector cells that have a more limited developmental repertoire, and which may give rise only to cells within a particular lineage. The common myeloid progenitor cell is the precursor of megakaryocytes, erythrocytes, granulocytes, macrophages, dendritic cells, and mast cells. These cells comprise the innate immune system, which is involved in antigen presentation, phagocytosis, and other non-antigen specific responses.
Macrophages are one of the three types of phagocytic cells in the immune system. They are the mature form of monocytes, which circulate in the blood and differentiate continuously into macrophages upon migration into the tissues. Dendritic cells are also phagocytic, and are specialized to take up antigen and display it for recognition by lymphocytes. Mast cells also differentiate in the tissues. They mainly reside near small blood vessels and, when activated, release substances that affect vascular permeability. Although best known for their role in orchestrating allergic responses, they are believed to play a part in protecting mucosal surfaces against pathogens.
There are three types of granulocyte, all of which are relatively short lived and are produced in increased numbers during immune responses, when they leave the blood to migrate to sites of infection or inflammation. Neutrophils, which are the third phagocytic cell of the immune system, are the most numerous and most important cellular component of the innate immune response: hereditary deficiencies in neutrophil function lead to overwhelming bacterial infection, which is fatal if untreated. Eosinophils are thought to be important chiefly in defense against parasitic infections, because their numbers increase during a parasitic infection. The function of basophils is probably similar and complementary to that of eosinophils and mast cells.
Patients suffering from various diseases and therapies may have a deficiency on one or more of these myeloid lineage cells, which deficiency can result in increased susceptibility to bacterial and fungal infections. Leukopenia is usually characterized by a reduced number of blood neutrophils, although a reduced number of lymphocytes, monocytes, eosinophils, or basophils may also contribute to the decreased total cell count. Neutropenia accompanied by monocytopenia and lymphocytopenia is often a more serious disorder than neutropenia alone. Thrombocytopenia can also be a problem for myelosuppressed patients, stemming from failed megakaryocyte production. Severe thrombocytopenia results in a typical pattern of bleeding. Platelet transfusions can be used, but with discretion, because they may lose their effectiveness with repeated use owing to the development of platelet alloantibodies.
For example, patients undergoing hematopoietic cell transplantation (HCT) receive myeloablative doses of chemo-radiation therapy that lead to depletion of hematopoietic stem cells (HSC), progenitor cells and mature cells, thus leading to a phase of treatment related pancytopenia. The reconstitution of a functional immune system after HCT is dependent upon the de novo regeneration of all hematopoietic lineages from HSC and progenitor cells and on the function of mature cells contained in the graft. Infections after HCT typically follow a reproducible time pattern correlating with the kinetics of immune reconstitution, and despite aggressive treatment, the mortality rate of infections in the absence of immune reconstitution can be very high.
Drugs are one of the most common causes of neutropenia. Drug-induced neutropenia has several underlying mechanisms (immune, toxic, idiosyncratic, or hypersensitivity reactions), including severe neutropenia that predictably occurs after large doses of cytoreductive cancer drugs or radiotherapy and from that caused by viral infections. Cytotoxic chemotherapy induces neutropenia because of the high proliferative rate of neutrophil precursors and the rapid turnover of blood neutrophils. Impaired neutrophil production can also occur when leukemia, myeloma, lymphoma, or metastatic solid tumors infiltrate and replace the bone marrow. Tumor-induced myelofibrosis may further extenuate neutropenia. Myelofibrosis can also occur from granulomatous infections, Gaucher's disease, and radiotherapy.
Patients whose neutropenia is secondary to acquired disorders of production arising from cancer or from chemotherapy are more likely to develop serious bacterial or fungal infections because their overall immune system is compromised. The integrity of the skin and mucous membranes, the vascular supply to tissue, and the nutritional status of the patient also influence the risk of infections in acute neutropenia. Patients may also suffer from genetic or primary deficiencies of myeloid cells and are highly susceptible to infection as is seen, for example, in children with chronic granulomatous disease.
The treatment and prevention of infections, particularly in patients suffering or at risk of myeloid cell deficiencies, are of great medical concern. The present invention addresses these issues.
Relevant Literature
U.S. Pat. Nos. 6,465,247 and 6,761,883, herein specifically incorporated by reference, characterize mammalian myeloid progenitor cells. Bitmansour et al (2002) Blood 100(13):4660-7 cotransplant congenic common myeloid progenitors (CMP) and granulocyte-monocyte progenitors (GMP) with a graft containing hematopoietic stem cells to enhance reconstitution of a tissue myeloid pool for protection against lethal challenge with fungal and bacterial pathogens. Arber et al. (2003) Blood 102:3504 provides an abstract relating to engraftment and protection with MHC-mismatched committed myeloid progenitors.

Therapeutic uses of allogeneic myeloid progenitor cells

The Board of Trustees of the Leland Stanford Junior University


A manner of generating internal voltages such as a high voltage, an intermediate voltage and an internal power supply voltage is switched in accordance with a power supply level setting signal. When the voltage level of an external power supply voltage is low, a current drive transistor receiving an output of a comparing circuit and an auxiliary drive transistor are forcedly set in a conductive state, and external power supply voltage is transmitted on an internal power supply line. At this time, the comparing operation of the comparing circuit is stopped. When the level of the external power supply voltage is high, the comparing circuit is activated down convert the external power supply voltage for generating a peripheral power supply voltage on the internal power supply line.

1. Field of the Invention
The present invention relates to a semiconductor device containing an internal voltage generating circuit for generating an internal voltage, and more particularly to an internal voltage generating circuit capable of stably generating an internal voltage in accordance with an external power supply voltage even for specifications of a plurality of external power supply voltages and a plurality of interfaces.
2. Description of the Background Art
FIG. 36 is a diagram schematically showing the configuration of an array portion of a conventional dynamic random access memory (DRAM). In FIG. 36, a memory cell MC is disposed at an intersection of bit lines BL and ZBL and a word line WL. In FIG. 36, memory cell MC disposed at the intersection of the bit line BL and word line WL is representatively shown.
Generally, in a memory array, memory cells MC are disposed in rows and columns, and word line WL is disposed corresponding to each memory cell row. For each memory cell column, a pair of bit lines BL and ZBL is disposed. A memory cell is disposed at the intersection of one of paired bit lines and a word line. Complementary data are transferred through bit lines BL and ZBL.
Memory cell MC includes a memory capacitor MQ for storing information in the form of electric charges and an access transistor MT for coupling memory cell capacitor MQ to a corresponding bit line BL (or ZBL) in accordance with a signal voltage on word line WL. Access transistor MT is usually formed of an N-channel MOS transistor (insulated gate field effect transistor), and a negative bias voltage Vbb is applied to a back gate of access transistor MT. By applying negative bias voltage Vbb to the back gate of access transistor MT, stabilization of the threshold voltage of access transistor MT, reduction in parasitic capacitance between a signal line and a substrate region, and reduction in junction capacitance of the drain and source of access transistor MT are intended to achieve.
Bit lines BL and ZBL are provided with a bit line equalizing circuit BPE for precharging and equalizing bit lines BL and ZBL to a bit line precharge voltage Vb1 level in a standby state, and a sense amplifier SA for differentially amplifying and latching the voltages on bit lines BL and ZBL.
Sense amplifier SA is provided with: a sense amplifier activating transistor ASPT that is made conductive, when a sense amplifier activate signal/SAP is activated, to couple a high-level power supply node of sense amplifier SA to a sense power supply line for transmitting an array power supply voltage Vdds; and a sense amplifier activating transistor ASNT that is made conductive, when a sense amplifier activate signal SAN is activated, to couple a low-level power supply node of sense amplifier SA to a sense ground line for transmitting a ground voltage Vss.
Bit line equalizing circuit BPE transmits bit line precharge voltage Vb1 of an intermediate voltage (Vdds/2) of array power supply voltage Vdds to bit lines BL and ZBL in accordance with a bit line equalize instruction signal BLEQ.
When selected, word line WL is driven to a high voltage Vpp level higher than array power supply voltage Vdds. By driving selected word line WL to high voltage Vpp level, without a threshold voltage loss across access transistor MT of memory cell MC, H data of array power supply voltage Vdds level is stored in a storage node of memory capacitor MQ.
Memory capacitor MQ receives a predetermined cell plate voltage Vcp at an electrode node (cell plate node) facing the storage node storing data. Usually, cell plate voltage Vcp is at the voltage level of intermediate voltage (Vdds/2) of array power supply voltage Vdds, similarly to bit line precharge voltage Vb1.
As described above, in a DRAM, a plurality of kinds of voltages of different voltage levels are used. In the case of generating the plurality of kinds of voltages externally for application to a DRAM, the scale of a system is increased and, due to loss on external wires, current consumption of the whole system also increases. In the DRAM as well, since the number of power supply pin terminals increases, the size of the package becomes large. Therefore, generally, the plurality of kinds of voltages are generated within a DRAM.
FIG. 37 is a diagram schematically showing the configuration of a portion related to internal voltages of the DRAM. In FIG. 37, the DRAM includes: a memory cell array 902 having a plurality of memory cells (memory cell MC in FIG. 36) arranged in rows and columns; a control circuit 904 for generating an operation control signal for implementing an operation mode designated by a command CMD in accordance with command CMD externally applied; a row selecting circuit 906 which is activated under control of control circuit 904 to drive a word line disposed corresponding to an addressed row in memory cell array 902 in accordance with a row address signal RA externally applied; a sense amplifier group 908 which is selectively activated by control circuit 904 to sense, amplify, and latch data of a memory cell on a row selected by row selecting circuit 906; a column selecting circuit 910 which operates under control of control circuit 904 and, when activated, selects a memory cell corresponding to an addressed column in memory cell array 902 in accordance with a column address signal CA externally applied; and an internal voltage generating circuit 900 for generating various internal voltages Vpp, Vbb, Vbl, Vcp, Vdds, and Vddp in accordance with an external power supply voltage EXVDD.
A peripheral power supply voltage Vddp from internal voltage generating circuit 900 is applied to control circuit 904 and row selecting circuit 906. A high voltage Vpp from internal voltage generating circuit 900 is also applied to row selecting circuit 906.
In row selecting circuit 906, a row selection signal is generated by a row decoding circuit which receives peripheral power supply voltage Vddp as an operation power supply voltage and, according to the row selection signal, a word line selection signal at high voltage Vpp level is transmitted by a word driver to a word line disposed corresponding to the selected row.
To memory cell array 902, bit line precharge voltage Vb1, cell plate voltage Vcp, and negative bias voltage Vbb supplied to a substrate region of memory cell array 902 are applied. To sense amplifier group 908, array power supply voltage Vdds is applied as an operation power supply voltage via the sense power supply line.
To column selecting circuit 910, usually, peripheral power supply voltage Vddp is applied as an operation power supply voltage. However, a column selection signal output from column selecting circuit 910 may be at the array power supply voltage Vdds level. Usually, peripheral power supply voltage Vddp is at a voltage level higher than array power supply voltage Vdds.
By causing peripheral circuits such as control circuit 904 to operate with peripheral power supply voltage Vddp and causing sense amplifier group 908 associated with memory cell array 902 to operate in accordance with array power supply voltage Vdds, the peripheral circuits are operated at high speed to achieve high-speed access, and the dielectric breakdown of the access transistor and memory cell capacitor of a memory cell is secured to store data stably.
In a semiconductor device, as the system scale increases, to prevent heat generation and the like, low power consumption is more strongly required. Particularly, in applications of portable equipment using a battery as a power source, current consumption has to be reduced from the viewpoint of battery's life as well. Particularly, as to a standby state in which no data access is performed, the time period of the standby state is longer than the time period in which a data processing is actually performed. A DRAM is required, in the standby state, only to hold data, and reduction in current consumption in the standby state is strongly required.
As a method of reducing current consumption in such a standby state, an operation mode called a power down mode is used. In the power down mode, supply of the operation power supply voltage is stopped in the circuitry not related to data retention such as an address input buffer circuit. By cutting off a DC (direct current) path of the circuitry that is non-related to data retention, a leakage current of the circuitry is reduced, and current consumption is reduced.
In uses of portable equipment and the like, recently, reduction in standby power is further demanded. To accommodate for such demand of a very low standby current, a mode called a "deep power down mode" is used. In the deep power down mode, an internal voltage generating operation of internal voltage generating circuit 900 is stopped. Since the power down mode is set by an external command, a power supply voltage is applied to circuitry related to release of the power down mode such as a command decoder receiving command CMD.
When the deep power down mode instruction is applied, as shown in FIG. 37, a power cut signal PCUT is generated from control circuit 904. Power cut signal PCUT is at the level of peripheral power supply voltage Vddp. In order to stop the operation of the circuitry for generating an internal voltage from external power supply voltage EXVDD, by a level converting circuit 915, power cut signal PCUT is converted to a power cut enable signal PCUTe having an amplitude of the external power supply voltage EXVDD level. Power cut enable signal PCUTe is supplied to the peripheral circuits such as row selecting circuit 906 and column selecting circuit 910 and the current path of each of the peripheral circuits is cut off.
Power cut enable signal PCUTe is applied to the circuit portion other than a circuit for controlling an operation related to the deep power down mode also in control circuit 904, and the current path of the circuit portion is cut off.
In the deep power down mode, current is consumed by only the necessary circuitry and the current path of unnecessary circuitry is cut off, thereby preventing occurrence of leakage current to reduce current consumption greatly.
A DRAM is used in various systems. In the systems, various power supply voltages exist. For example, as external power supply voltage EXVDD, 3.3V and 2.5V exist. As interfaces, not only an LVTTL, there is a 1.8VIO interface. In the 1.8VIO interface, although the external power supply voltage is 2.5V or 3.3V, the amplitude of an input signal is set to 1.8V. VIH and VIL are set to, for example, 0.8VDDQ and 0.2VDDQ on the basis of an output power supply voltage VDDQ.
In a DRAM, in the case where an internal voltage is generated from a different external power supply voltage with the same circuit configuration, since an operation condition of the internal voltage generating circuit vary according to the external power supply voltage level, such a problem occurs that the internal voltage at an optimum voltage level cannot be efficiently generated.
In the case of designing an internal voltage generating circuit in accordance with each external power supply voltage level or interface specification, to be simply adapted to the voltage level of an external power supply voltage, a plurality of kinds of chips, the same in configuration of main internal circuitry but different in configuration of the internal voltage generating circuit, have to be fabricated. It results in problems that the manufacturing efficiency deteriorates and the cost increases.
Therefore, from the viewpoints of product management and cost, it is preferable to implement an internal voltage generating circuit adapted to an external power supply voltage level or interface specification by use of mask interconnection or fixing of a voltage at a bonding pad in a slice process while manufacturing a common circuit part for a plurality of kinds external power supply voltages and interfaces in a master process.

Semiconductor device having internal voltage generated stably


An electronic lockset that allows for remote monitoring includes a locking mechanism, a motion sensor, a camera, and a wireless communication module. The locking mechanism is movable between a locked position and an unlocked position. The motion sensor is configured to detect a person in proximity to the electronic lockset. The camera is configured to capture media content of the person detected by the motion sensor. The wireless communication module is configured to wirelessly transmit the captured media content to an electronic device.

Electronic locks have gained increasing acceptance and widespread use in residential and commercial markets. These locksets control ingress through doors in a building by requiring certain electronic credentials. For example, these locksets typically include a control circuit that determines whether to unlock the lockset based on credentials provided by the user, such as using a keypad, etc., without requiring a mechanical key.
In some cases, electronic locks can be configured to communicate wirelessly with other devices, such as part of a security system. For example, it is known to remotely control (i.e., lock/unlock) an electronic lock using a wireless device, such as a mobile phone. However, the capabilities of electronic locks to communicate with other electronic devices are generally limited to status information and control of the lock. Therefore, there is a need for a novel electronic lock that allows remote monitoring not limited to lock status/control information.


Systems and methods for treating or manipulating biological tissues are provided. In the systems and methods, a biological tissue is placed in contact with an array of electrodes. Electrical pulses are then applied between a bias voltage bus and a reference voltage bus of a distributor having switching elements associated with each of the electrodes. The switching elements provide a first contact position for coupling electrodes to bias voltage bus, a second contact position for coupling electrodes to the reference voltage bus, and a third contact position for isolating electrodes from the high and reference voltage buses. The switching elements are operated over various time intervals to provide the first contact position for first electrodes, a second contact position for second electrodes adjacent to the first electrodes, and a third contact position for a remainder of the electrodes adjacent to the first and second electrodes.

1. Field of the Invention
The present invention is directed to the field of treatment of biological tissues using high voltage pulses, and more specifically to a multi-electrode pulse delivery system for the treatment of biological tissues using high voltage pulses.
2. Background
Cancer is one of the leading causes of disease, being responsible for over half a million deaths in the United States each year. For example, breast cancer is the most common form of malignant disease among women in Western countries and, in the United States, is one of the most common causes of death among women between 40 and 55 years of age. The incidence of breast cancer is increasing, especially in older women, but the cause of this increase is unknown. Malignant melanoma is another form of cancer whose incidence is increasing at a frightening rate, at least sixfold in the United States since 1945, and is the single most deadly of all skin diseases. One of the most devastating aspects of cancer is the propensity of cells from malignant neoplasms to disseminate from their primary site to distant organs and develop into metastases. Despite advances in surgical treatment of primary neoplasms and aggressive therapies, many cancer patients die as a result of metastatic disease.
To treat such cancers, several cancer therapies have been developed that are based on the application of electric fields to a tumor containing malignant cancerous cells. Some of these therapies involve the use of radiofrequency or microwave devices to cause heating of the tumor to kill cancerous cells via hyperthermia. Other therapies use electrical pulses to permeabilize the cancerous cells in the tumor to allow the introduction of toxic drugs. In yet other therapies, short, high voltage electrical pulses can be used as a purely standalone cancer therapy that kills tumors and abnormal cells without hyperthermia or drugs.
Unfortunately, a typical tumor generally extends over an area that exceeds the area that can be efficiently and/or effectively treated covered using conventional electrical pulse treatment systems. Conventional systems typically rely on electrode devices that are either needles, which are inserted into the tissue, or pins, which are placed on top of the tissue. Needles generally allow electric fields to be formed at any depth, limited primarily by the length of the needles. In contrast, pins allow the electric field to penetrate only a limited depth of the tissues, determined by the extent of the fringe electric field.
In many conventional electrical pulse systems, a pair of electrodes is typically used to generate electric fields using voltage pulses. In operation, the electrodes are manually placed on or near the tissue to be treated. Thereafter, a voltage pulse is applied across the electrodes to form an electric field for providing treatment. However, a two electrode arrangement can effectively only cover an area or volume having a generally elliptical shape with boundaries for electroporation or nanoporation determined by the electrode distance (generally limited to between 0.5 cm and 1.0 cm) and the applied voltage. Although a larger gap or spacing can be provided, such an arrangement can require application of a higher voltage pulse to generate the necessary electric field and/or providing longer pulse durations at the electrodes to ensure that a therapeutic electric field intensity is provided to all tissues to be treated. Further, such a configuration will require higher voltage generators and additional cabling requirements, which can lead to an overall higher cost.
To provide for treatment of a larger area or volume, some conventional systems use a larger number of electrodes. In a typical configuration, one electrode is provided that is surrounded by other electrodes. An electric field is then generated by applying a voltage pulse between the center electrode and the surrounding electrodes. Although such an arrangement allows a larger area or volume to be treated, such a configuration has several drawbacks. First, to expand the treatment area, a power supply providing a higher current (i.e., a larger power) would be needed. Second, even when such power supplies are available, the area or volume that can be treated can also be limited by the maximum voltage per distance between electrodes. An alternative is to use multiple power supplies with the multiple electrodes. However, the use of multiple power supplies requires a greater amount of power and complexity for managing the multiple power supplies.

Multi-electrode electrical pulse delivery system for treatment of biological tissues

OLD DOMINION UNIVERSITY RESEARCH FOUNDATION


A bolt support member for use in cutting lock bolts of security containers. The bolt support member has a hook-shaped portion at one end for engaging a lock bolt, and threaded portion at another end. The hook-shaped portion is inserted into a hole in the container near the lock bolt and is clamped between the lock bolt and the surface of the container by a pair of knobs positioned on the threaded portion of the bolt support member. The bolt support member constrains the lock bolt from bending under cutting pressure and thus prevents binding against the cutter.

The present invention pertains to devices for gaining access to security containers, and more particularly to devices that can be used to cut a lock bolt of a security container.
Various types of security containers are used for such purposes as storing confidential or sensitive documents, valuables, and the like. Typical of such security containers are secure filing cabinets having combination locks to prevent unauthorized access. Occasionally, it becomes necessary to gain access to such containers by use of force, such as by drilling the lock bolt, usually when the combination has been lost or when the lock mechanism has malfunctioned.
The use of a power drill to gain access to a locked security container is known in the art. U.S. Pat. No. 5,984,594 describes an apparatus and method for drilling a small hole near the lock mechanism to allow a locksmith to observe the inner workings of the lock. Drilling into the lock itself is generally undesirable due to the considerable expense involved in repairing or replacing the lock. Therefore, it is preferable to gain access to and cut the lock bolts of such a container. Typically, a carbide-tipped hole-saw is used to cut through a front surface of the container, such as the front surface of a drawer, and then through the lock bolts behind the front surface. Often these lock bolts are formed from one-inch diameter cylindrical rods of hardened steel. Because the lock bolts are generally supported only near their ends, they tend to bind against a hole-saw under the considerable pressure required to cut through them. This binding generates excessive heat and tool chatter which can damage the carbide tips of a hole-saw and makes cutting the bolts difficult.
Referring to FIGS. 1 and 2, the prior art method of cutting a lock bolt will now be described. FIG. 1 shows a security container 10, in the form of a secure filing cabinet, with access drawer 12 that can be secured in a closed position by a pair of lock bolts 14 and 16. In a closed and locked state, ends 18 and 20 of lock bolts 14 and 16 engage apertures 19 and 21 in container 10 that are adapted to receive the lock bolts and prevent opening of the drawer. A combination dial 22 is used to actuate a locking mechanism 24 to provide an unlocked state, whereby lock bolts 14 and 16 may be retracted from the container apertures by actuation of a lever 26, or alternatively by rotation of the dial 22.
In the event that lock mechanism 24 has malfunctioned or the combination has been lost, entry into container 10 is often obtained by cutting lock bolts 14 and 16 using a carbide-tipped hole saw 28. Typically, the hole-saw 28 is advanced through a front panel 29 of drawer 12, creating panel hole 57, and subsequently through lock bolt 14 by using a drill rig 30. A typical drill rig used for such purposes is the MAG457100 Bullet Rig and L2021 Tower Assembly, available from Lockmasters, Inc. A drill plate 32 is fastened to drawer panel 29 in a location near lock bolt 14 using self-tapping screws 34. Stand-offs 36 support a flanged mounting plate 38 secured by cap screws 40. A first tube 42 has internal threads (not shown) and is slidably attached to the flanged mounting plate 38 by a quick-release locking collar 44. Detents 46 on the first tube 42 engage the locking collar 44 to lock first tube 42 in place at various positions along the axial length of the tube.
A second tube 48 is fitted inside first tube 42 and has external threads (not shown) which operatively engage the internal threads of the first tube 42 such that the second tube can be advanced or retracted axially along first tube 42 by manual operation of a wheel 50 fixed to the end of second tube 48. A freely rotating spindle 52 is positioned in the bore of second tube 48 and has a tool chuck 54 fixed to one end for holding hole saw 28. The spindle 52 is fixed axially relative to the second tube 48 by thrust bearings (not shown) so that the spindle 52 moves with the second tube 48 as wheel 50 is manipulated. A driven end 56 of spindle 52 is adapted to receive a driver whereby spindle 52 may be rotated using a power drill (not shown).
According to the prior art method of cutting lock bolt 14, drill plate 32 is attached to drawer panel 29 generally near lock bolt 14 and drill rig 30 is secured to drill plate 32. Locking collar 44 is manipulated to allow first tube 42 to be adjusted such that hole-saw 28 is adjacent the surface of the drawer panel 29. A power drill with an appropriate driver is fitted to the driven end 56 of spindle 52 and the drill is energized to rotate the spindle 52 and hole-saw 28 while being advanced through the surface of drawer panel 29 and subsequently through lock bolt 14 by hand manipulation of wheel 50. A typical security container utilizes at least two lock bolts, operating in tandem, thus the prior art method stated above must generally be repeated on the second lock bolt 16 before access to the drawer can be gained.
FIG. 2 shows a partial section view of the prior art cutting method of FIG. 1 taken along line 2xe2x80x942. Hole-saw 28 has penetrated the surface of drawer panel 29 and has advanced part way through lock bolt 14. As depicted in FIG. 2, lock bolt 14 is substantially unsupported along its length and the cutting force applied by hole-saw 28 causes lock bolt 14 to bend in a direction away from the hole-saw 28. The bending of lock bolt 14 in turn causes ends 58 of groove 60, cut into lock bolt 14, to pinch against hole-saw 28, binding the hole-saw from rotation and damaging the carbide tips.
Accordingly, there is a need for an apparatus and methods for drilling through the lock bolt of a security container without the typical binding action which creates the various problems discussed above.
The present invention provides a method and apparatus for supporting a lock bolt of a security container while the lock bolt is being cut with a hole-saw to gain access to the container. The invention provides various advantages over previous methods and apparatus for cutting such lock bolts by constraining the lock bolt from bending and binding against the cutter. For example, the present invention reduces heat generation and tool chatter. The invention thus provides more efficient cutting and extends the service life of the cutter.
In one aspect of the present invention, a lock bolt support member has an engagement portion shaped to engage the surface of a lock bolt for a security container. The engagement portion of the support member may be inserted through an access hole that has been formed in a surface of the security container, near the lock bolt. A connecting portion of the support member remains outside the security container and mates with a locking mechanism such that the support member may be clamped between the lock bolt and the surface of the security container, thereby preventing the lock bolt from moving while it is being cut.
In another aspect of the invention, the engagement portion of the lock bolt support member is generally hook-shaped.
In another aspect of the invention, the connecting portion of the lock bolt support member includes screw threads. Accordingly the locking mechanism includes a first nut with screw threads that operatively engage the threads of the connecting portion. The locking mechanism thus can be adjusted with respect to the connecting portion so that the bolt support member can be clamped against the surface of the security container.
In yet another aspect of the invention, the locking mechanism includes a second nut with screw threads that operatively engage the threads on the connecting portion of the bolt support member such that the first nut is tightened to secure the lock bolt support member in position relative to the lock bolt and the second nut is tightened to retain the first nut from loosening.
In a further aspect of the invention, the first and second nuts of the locking mechanism comprise knobs that can be manually manipulated.
In yet another aspect of the invention, a method for cutting a lock bolt concealed behind a panel of a security container includes forming a hole in the panel near the lock bolt, inserting a lock bolt support member through the hole, supporting at least one side of the lock bolt with the lock bolt support member, cutting the lock bolt with a cutting tool that is forced against the lock bolt, and inhibiting movement of the lock bolt in a direction away from the cutter using the lock bolt support member while the lock bolt is being cut.
These and other advantages, objectives and features of the invention will become more readily apparent to those of ordinary skill upon review of the following detailed description of an illustrative embodiment of the invention.

Security container drilling apparatus and method of cutting the lock bolt of a security container


The invention provides substituted phenyl compounds of general formula

The present invention relates to substituted phenyl compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1xcex2 (IL-1xcex2) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes and mesangial cells.
Certain substituted acetamide compounds are known from EP-A-382 216 having anti-allergic activity.
It would be desirable to make compounds effective as P2X7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X7 receptor may play a role.
In accordance with the present invention, there is therefore provided a compound of general formula
wherein:
each R1 independently represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom, or a trifluoromethyl, cyano, nitro, C1-C6 alkyl or C1-C6 alkoxy group;
T represents an oxygen atom or, preferably, a group NH;
U represents an oxygen or sulphur atom or a group NH, preferably an oxygen or sulphur atom;
Ar represents a group
X represents a bond, an oxygen atom or a group CO, CH2, CH2O, O(CH2)m, CH2OCH2, NR5, CH2NR5, NR5CH2, CH2NR5CH2, CONR5, S(O)n or SO2NR5;
m is 1, 2or 3;
n is 0, 1 or 2;
one of R2 and R3 represents a halogen, cyano, nitro, amino, hydroxyl, or a group selected from C1-C6 alkyl optionally substituted by at least one C3-C6 cycloalkyl, C3-C8 cycloalkyl, C1-C6 alkyloxy optionally substituted by at least one C3-C6 cycloalkyl, C3-C8 cycloalkyloxy, S(O)pC1-C6 alkyl or S(O)qC3-C8 cycloalkyl, each of these groups being optionally substituted by one or more fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen atom or a methyl group;
p is 0, 1 or 2;
q is 0, 1 or 2;
R4 represents di(C1-2 alkyl)N(CH2)t where t is 0, 1 or 2 or imidazolyl, or R4 represents a 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, C1-C6 alkyl, acetyl, hydroxy C1-C6 alkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7, xe2x80x94CONR6R7 and pyrimidinyl, or R4 represents a 3- to 8-membered saturated carbocyclic ring system substituted by one or more substituents independently selected from NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7 the ring system being optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl;
r is 1, 2, 3, 4, 5 or 6;
R5 represents a hydrogen atom or a C1-C6 alkyl or C3-C8 cycloalkyl group; and
R6 and R7 each independently represent a hydrogen atom or a C1-C6 alkyl or C3-C8 cycloalkyl group, or R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring, provided that when R3 represents a cyano group, then X is other than a bond;
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched. When one of R2 and R3 represents a C1-C6 alkyl/C1-C6 alkyloxy optionally substituted by at least one C3-C6 cycloalkyl, it should be understood that one or both of the alkyl and cycloalkyl moieties may be optionally substituted by fluorine atoms. A 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms may be a monocyclic or bicyclic ring system. Similarly, a 3- to 8-membered saturated carbocyclic ring system may be a monocyclic or bicyclic ring system. The hydroxyl moiety in a hydroxyalkyl substituent group may be located in any suitable position in the alkyl group. Typically, the hydroxyl moiety will be located on a terminal carbon atom in a straight chain alkyl group. The alkyl groups in a dialkylamino moiety may be the same or different.
Preferably, at least one group R1 is other than a hydrogen atom, especially a halogen atom such as a fluorine or chlorine atom.
Preferably X represents a bond, an oxygen atom or a group CONH, CH2 or O(CH2)m.
One of R2 and R3 represents a halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, nitro, amino, hydroxyl, or a group selected from C1-C6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) optionally substituted by at least one (e.g. 1, 2 or 3) C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C3-C8 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C1-C6 alkyloxy (e.g. methoxy, ethoxy, isopropoxy or tert-butoxy) optionally substituted by at least one(e.g. 1, 2 or 3) C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C3-C8 cycloalkyloxy (e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), S(O)pC1-C6 alkyl (e.g. S(O)pmethyl, -ethyl, -propyl, -butyl, -pentyl or -hexyl) or S(O)qC3-C8 cycloalkyl (e.g. S(O)qcyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl), each of these groups being optionally substituted by one or more (e.g. 1, 2, 3 or 4) fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom or a methyl group.
Preferably, one of R2 or R3 represents a halogen (especially chlorine) atom or a C1-C6 alkyl (especially methyl) group and the other of R2 or R3 represents a hydrogen atom.
In one aspect, R4 may represent a 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl, C1-C6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), acetyl, hydroxyC1-C6 alkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl or hydroxyhexyl), xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7, xe2x80x94CONR6R7 and pyrimidinyl.
The 3- to 9-membered saturated heterocyclic ring system in the group R4 may be a monocyclic ring system such as a pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl or 3-pyrrolidinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl), piperazinyl (e.g. 1-piperazinyl) or homopiperazinyl ring, or a bicyclic ring system such as
In another aspect, R4 may represent a 3- to 8-membered saturated carbocyclic ring system substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from NR6R7, xe2x80x94(CH2)rNR6R7, and xe2x80x94CONR6R7, the ring system being optionally further substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl).
The 3- to 8-membered saturated carbocyclic ring in the group R4 is preferably a monocyclic ring system such as a cyclopentyl or cyclohexyl ring.
Specific examples of groups R4 include:
When X represents a bond or a group CO, CH2 or SO2, R4 preferably represents a group:
When X represents an oxygen or sulphur atom or a group CH2O O(CH2)m, CH2OCH2, NR5, CH2NR5, NR5CH2, CH2NR5CH2, CONR5, SO or SO2NR5, R4 preferably represents a group:
R5 represents a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or C3-C8, preferably C3-C6, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) group.
R6 and R7 each independently represent a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or C3-C8, preferably C3-C6, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) group, or R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring such as a pyrrolidinyl or piperidinyl ring.
Preferred compounds of the invention include:
2-(3,4-Difluorophenylamino)-N-(2-methyl-5-piperazin-1-ylmethyl-phenyl)-acetamide, trihydrochloride,
2-(3,4-Difluoro-phenylamino)-N-(2-methyl-5-piperazin-1-ylmethyl-phenyl)-thioacetamide,
2-(3,4-Difluoro-phenylamino)-N-(2-methyl-4-piperazin-1-ylmethyl-phenyl)-acetamide, trihydrochloride,
N-(2-Chloro-5-piperazin-1-yl-phenyl)-2-(3,4-difluoro-phenyl amino)-acetamide, trihydrochloride,
(S)-2-(3,4-Difluoro-phenylamino)-N-[2-methyl-4-(2-pyolidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetamide, trihydrochloride,
2-(3-Chloro-4-fluorophenylamino)-N-{2-methyl-5-[3-(4-methylpiperazin-1-yl)-propoxy]phenyl}acetamide,
(+/xe2x88x92)-2-(3-Chloro-4-fluoro-phenylamino)-N-[2-methyl-5-(piperidin4-yloxy)-phenyl]-acetamide, dihydrochloride,
2-(3,4-Difluoro-phenylamino)-N-[2-methyl-4-(piperidin-4-yloxy)-phenyl]-acetamide, dihydrochloride,
(xc2x1)N-[5-(3-Amino-pyrrolidin-1-yl)-2-methyl-phenyl]-2-(3,4-difluoro-phenylamino)-acetamide, trihydrochloride,
2-(3,4-Difluoro-phenylamino)-N-(2-methyl-5-piperazin-1-yl-phenyl)-acetamide, trihydrochloride,
(S)-2-(3,4-Difluoro-phenylamino)-N-(2-methyl-5-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-phenyl)-acetamide,
(S)-2-(3,4-fluoro-phenylamino)-N-[5-(2-hydroxymethyl-pyrrolidin-1-ylmethyl)-2-methyl-phenyl]-acetamide,
2-(3,4-Difluoro-phenylamino)-N-[2-methyl-5-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-phenyl]-acetamide,
2-(3,4-Difluorophenylamino)-N-[2-methyl-3-(piperidin-4-yloxy)phenyl]acetamide trifluoroacetate,
3-[2-(3,4-Difluorophenylamino)acetylamino]-N-(2-dimethylaminoethyl)-2-methylbenzamide,
N-[3-(4-Acetyl-piperazin-1-ylmethyl)-2-methylphenyl]-2-(3,4-difluorophenylamino)acetamide,
2-(3,4-Difluorophenylamino)-N-(3-imidazol-1-ylmethyl-2-methylphenyl)acetamide, and
2-(3,4-Difluorophenylamino)-N-(3-dimethylaminomethyl-2-methylphenyl)acetamide.
The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises:
(i) when U represents an oxygen atom, X represents a CH2 group and R4 represents a 3- to 8-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, C1-C6 alkyl, hydroxyC1-C6 alkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7, xe2x80x94CONR6R7 and pyrimidinyl, reacting a compound of general formula
wherein one of R10 and R11 represents a hydrogen atom and the other of R10 and R11 represents a group xe2x80x94CH2L1 in which L1 represents a leaving group (e.g. a halogen atom), and T, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Hxe2x80x83xe2x80x83(III)
xe2x80x83in the presence of a base (e.g. diisopropylethylamine), wherein R4xe2x80x2 represents a 3- to 8-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, C1-C6 alkyl, hydroxyC1-C6 alykl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7, xe2x80x94CONR6R7 and pyrimidinyl and wherein R6 and R7 are as defined in formula (I); or
(ii) when U represents an oxygen atom and X represents an oxygen atom or a group O(CH2)m, reacting a compound of general formula
wherein one of R12 and R13 represents a hydrogen atom and the other of R12 and R13 represents a hydroxyl group, and T, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Yxe2x80x94OHxe2x80x83xe2x80x83(V)
xe2x80x83wherein Y represents a bond or a group (CH2)m and m and R4 are as defined in formula (I), in the presence of 1,1-(azodicarbonyl)dipiperidine and tributylphosphine (under conditions of the Mitsunobu reaction: Tetrahedron Lett. (1993), 34, 1639); or
(iii) when U represents an oxygen atom and X represents a bond, an oxygen atom or a group O(CH2)m, NR5, NR5CH2, CO, CONR5, SO2 or SO2NR5 reacting a compound of general formula
wherein one of R14 and R15 represents a group xe2x80x94Xxe2x80x2xe2x80x94R4 and the other of R14or R15 represents a hydrogen atom, Xxe2x80x2 represents a bond, an oxygen atom or a group O(CH2)m, NR5, NR5CH2, CO, CONR5, SO2 or SO2NR5, and m, R2, R3, R4 and R5 are as defined in formula (I), with a compound of general formula
wherein T and R1 are as defined in formula (I), in the presence of a coupling reagent such as isobutylchloroformate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate and a base (e.g. diisopropylarmine); or
(iv) when U represents an oxygen atom and X represents a bond or a group NR5 or NR5CH2, reacting a compound of general formula
wherein one of R16 or R17 represents a leaving group, L2, such as a halogen atom and the other of R16 or R17 represents a hydrogen atom and T, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Zxe2x80x83xe2x80x83(IX)
xe2x80x83wherein Z represents a hydrogen atom or a group NHR5 or CH2NHR5 and R4 and R5 are as defined in formula (I), optionally in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BINAP) and a base (e.g. cesium carbonate); or
(v) when U represents an oxygen atom and X represents a group CH2O reacting a compound of formula (II) as defined in (i) above with a compound of formula (V) as defined in (ii) above wherein Y represents a bond, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (e.g. silver trifluoromethanesulfonate); or
(vi) when U represents an oxygen atom and X represents a group CH2NR5, reacting a compound of formula (II) as defined in (i) above with a compound of formula (IX) as defined in (iv) above wherein Z represents a group NHR5; or
(vii) when U represents an oxygen atom and X represents a group CH2OCH2, reacting a compound of formula (II) as defined in (i) above with a compound of formula (V) as defined in (ii) above wherein Y represents a group CH2, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (e.g. silver trifluoromethanesulfonate); or
(viii) when U represents an oxygen atom and X represents a group CH2NR5CH2, reacting a compound of formula (II) as defined in (i) above with a compound of formula (IX) as defined in (iv) above wherein Z represents a group CH2NHR5; or
(ix) when U represents an oxygen atom, X represents a group CH2 and R4 represents an unsubstituted 4- to 6-membered saturated heterocyclic ring system containing one nitrogen atom, reacting a compound of formula (II) as defined in (i) above, with a compound of general formula
wherein s and t independently represent 1 or 2; or
(x) when U represents an oxygen atom and X represents a sulfur atom, reacting a compound of formula (VIII) as defined in (iv) above, with n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x80x94Sxe2x80x94Sxe2x80x94R4xe2x80x83xe2x80x83(XI)
wherein R4 is as defined in formula (I); or
(xi) when U represents an oxygen atom and X represents a CH2 group, reacting a compound of formula (VIII) as defined in (iv) above, with n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x80x94CHOxe2x80x83xe2x80x83(XII)
wherein R4 is as defined in formula (I), followed by a reduction reaction, e.g. with triethylsilane and trifluoroacetic acid or by treatment with methyloxalylchloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile; or
(xii) when U represents an oxygen atom and X represents a bond, reacting a compound of formula (VIII) as defined in (iv) above, with n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4=Oxe2x80x83xe2x80x83(XIII)
wherein R4 is as defined in formula (I), followed by a reduction reaction, e.g. with triethylsilane and trifluoroacetic acid or by treatment with methyloxalylchloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile; or
(xiii) when U represents a sulphur atom, reacting a corresponding compound of formula (I) in which U represents an oxygen atom with a thiolating agent (such as Lawessons"" reagent) at a temperature, for example, in the range from 0xc2x0 to 100xc2x0 C.;
(xiv) when U represents a group NH, reacting a corresponding compound of formula (I) in which U represents a sulphur atom with a suitable alkylating agent (e.g. methyl iodide) followed by reaction with ammonium chloride or ammonia;
(xv) when U represents an oxygen atom and X represents CONR5, reacting a compound of general formula
wherein one of Rxe2x80x2 or Rxe2x80x3 represents a hydrogen atom and the other of Rxe2x80x2 or Rxe2x80x3 represents a carboxyl group and T, R1, R2 and R3 are as defined in formula (I), with a compound of general formula (XIIIB), R4xe2x80x94NHR5, wherein R4 and R5 are as defined in formula (I); or
(xvi) when U represents an oxygen atom, X represents CH2 and R4 is bonded to X through a nitrogen atom, reacting a compound of general formula
wherein T, R1, R2 and R3 are as defined in formula (I), with methane sulphonyl chloride followed by reaction with a compound of general formula (XIIID), R4xe2x80x3xe2x80x94H, wherein R4xe2x80x3 is defined as for R4 in formula (I) other than:
di(C1-2 alkyl)N(CH2)t where t is 1 or 2, and
3- to 8-membered saturated carbocyclic ring system substituted by one or more substituents independently selected from NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7, the ring system being optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl;
and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv) or (xvi) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as dichloromethane, tetrahydrofuran, dioxane, xylene or dimethylformamide, at a temperature, e.g. in the range from xe2x88x9278 to 200xc2x0 C., preferably in the range from 0 to 150xc2x0 C.
Compounds of formula (II) in which L1 represents, for example, a chlorine atom may be prepared by reacting a compound of general formula
wherein one of R18 or R19 represents a hydrogen atom and the other of R18 and R19 represents a protected benzylalcohol group (the protecting group used may, for example, be tertbutyldimethylsilyl) and R2 and R3 are as defined in formula (II), with a compound of formula (VII) as defined above, in the presence of a coupling reagent such as isobutylchloroformate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate and a base (e.g. diisopropylamine), followed by deprotection and reaction with methanesulphonyl chloride in the presence of a base such as diisopropylamine.
Compounds of formula (IV) may be prepared by reacting a compound of general formula
wherein R2, R3, R12 and R13 are as defined in formula (IV), with a compound of formula (VII) as defined above, in the presence of a coupling reagent such as isobutylchloroformate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate and a base (e.g. diisopropylamine)
Compounds of formula (VI) may conveniently be prepared by reacting a compound of general formula
wherein L3 represents a leaving group (e.g. a hydroxyl group) and R2, R3, R14 and R15 are as defined in formula (VI), with diphenylphosphoryl azide in the presence of a base such as triethylamine.
Compounds of formula (XVI) in which X represents a bond, an oxygen atom or a group O(CH2)m, NR5 or NR5CH2 can be prepared by reacting a compound of general formula
wherein R20 represents a hydrogen atom or a C1-C6 alkyl group, one of R21 and R22 represents a leaving group, L4, such as a halogen atom (e.g. bromine or iodine) or a trifluoromethanesulfonate group and the other of R21 or R22 represents a hydrogen atom, and R2 and R3 are as defined in formula (XVI), with a compound of general formula
Hxe2x80x94Xxe2x80x3xe2x80x94R4xe2x80x83xe2x80x83(XVIII)
wherein Xxe2x80x3 represents a bond, an oxygen atom or a group O(CH2)m, NR5 or NR5CH2 and R4 is as defined in formula (I), in the presence of a palladium catalyst (1996 J. Am. Chem. Soc., 7215-6; 1997 J. Am. Chem. Soc., 3395), followed by a hydrolysis reaction (e.g. with sodium hydroxide).
Compounds of formula (XVI) in which X represents CO, CONR5, SO2 or SO2NR5 can be prepared by reacting a compound of general formula
wherein R23 represents a hydrogen atom or a C1-C6 alkyl group, one of R24 and R25 represents a group COL5 or SO2L5 and the other of R24 or R25 represents a hydrogen atom, L5 represents a leaving group (e.g. a halogen atom) and R2 and R3 are as defined in formula (XVI), with a compound of formula (IX) in which Z represents a hydrogen atom or a group NHR5, in the presence of a base such as diisopropylethylamine and catalytic N,N-dimethylaminopyridine, followed by a hydrolysis reaction (e.g. using sodium hydroxide).
Compounds of formula (VII) may be conveniently prepared by reacting a compound of general formula
wherein R26 represents a hydroxyl group or a protected nitrogen atom (protected by, for example, a tertbutyloxycarbonyl group) and R1 is as defined in formula (I), with an alkylating agent (e.g. methyl bromoacetate) followed by a saponification reaction.
Compounds of formula (VIII) may be prepared in an analogous manner to compounds of formula (IV) using, instead of the intermediate compound of formula (XV), an intermediate compound of general formula
R2, R3, R16 and R17 are as defined in formula (VIII).
Compounds of formula (X) can be prepared as described in Syn. Lett. (1998) 379-380.
Compounds of formulae (XIIIA) and (XIIIC) may be prepared by processes analogous to those already described.
Compounds of formulae (III), (V), (IX), (XI), (XII), (XIII), (XIIIB), (XIIID), (XIV), (XV), (XVII), (XVIII), (XIX), (XX) and, (XXI) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, compounds of formula (I) in which one of R2 and R3 represents a nitro group can be converted to compounds of formula (I) in which one of R2 and R3 represents an amino group by reduction using iron powder and ammonium chloride in ethanol/water under reflux conditions. The latter compounds can in turn be converted into compounds of formula (I) in which one of R2 and R3 represents a halogen atom, e.g. chlorine, by diazotization (e.g. with sodium nitrite) and reaction with copper chloride. Compounds of formula (I) in which R6 or R7 represents a hydrogen atom can be converted to compounds of formula (I) in which R6 or R7 represents a C1-C6 alkyl, C3-C8 cycloalkyl or a 3- to 8-membered saturated heterocyclic ring by standard chemical procedures.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve at a certain stage the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of the present invention are advantageous in that they possess pharmacological activity. They are therefore indicated as pharmaceuticals for use in the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn""s disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer""s disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term xe2x80x9ctherapyxe2x80x9d also includes xe2x80x9cprophylaxisxe2x80x9d unless there are specific indications to the contrary. The terms xe2x80x9ctherapeuticxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d should be construed accordingly.
The invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
The invention also provides a method of treating an obstructive airways disease (e.g. asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (I)/salt/solvate (active ingredient) may be in the range from 0.001 mg/kg to 30 mg/kg.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w, more preferably from 30 to 99.90% w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.

Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions

Abstract: wherein R1, T, U and Ar are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.


An impact power tool for use in supporting a tool tip for hand-working operations comprises a body presenting a bore and having first and second ends. A piston is received within the bore and is shiftable relative to the body, and an anvil is received within the bore at a first end of the body and is shiftable relative to the body along the longitudinal axis thereof. The anvil includes a recess extending in a direction substantially parallel with the axis of the bore so as to define a receptacle in the anvil adjacent the first end of the bore. A tool carrier block is provided which is shaped for receipt in the recess of the anvil and which includes a set screw for permitting attachment of the carrier block to a tool tip to be supported on the impact power tool. The carrier block is retained in the anvil by friction-fit engagement sufficient to retain the carrier block in the receptacle and to permit manual removal of the carrier block. Further, the axial position of the anvil relative to the bore is fixed by a transverse member interposed between the anvil and the body. The transverse member is rigidly supported on the anvil and is resiliently supported on the body so that the anvil is capable of limited axial movement relative to the body.

1. Field of the Invention
The present invention relates generally to impact power tools and, more particularly, to a handheld impact power tool for use in delicate hand-working operations such as those performed by a jeweler.
2. Description of the Prior Art
An impact power tool is known from U.S. Pat. No. 4,903,784, to Glaser, which may be used for engraving, carving and delicate stone setting operations.
This known power tool is adapted for use with a tool driving system of known type such as that disclosed in U.S. Pat. No. 3,393,755 to Glaser et al., and U.S. Pat. No. 4,694,912 to Glaser. A construction of the device is described in these two patents are incorporated herein by reference so as to obviate the need for further discussion of the types of devices with which the present invention may be employed.
Although the known impact power tool discussed above provides improved control of delicate hand-working operations not previously available in power tools, it would be desirable to provide a power tool which is lighter and easier to handle than known tools, and which includes a muffling system for reducing noise of the power tool which is generated during use by movement of an internal piston of the tool.
Further, although use of known power tools permits a reduction in manual effort by as much as 90% in hand-working operations relative to manually driven tools, such power tools require time consuming effort to replace the tip of the tool with an alternate tip since the tip must be secured to the tool by a threaded connection or the like. This additional required effort represents a disadvantage of known power tools since a craftsman may use as many as ten or more tips for any given job, and is thus unable to simply reach between any of a number of different tools while focusing his attention on the work at hand.


A method for synthesizing 4-(Hydroxymethyl)benzoic acid using P-xylene (PX) as a raw material, including: dissolving PX in an organic solvent to undergo an oxidation reaction with an oxidizing agent under an action of an M-MOF catalyst; and after the oxidation reaction, performing a post-treatment to obtain the 4-(Hydroxymethyl)benzoic acid; wherein, the metal element M in the M-MOF catalyst is Fe, Cu, Cr, Mn, Cu/Fe, Cu/Cr, Cu/Mn, Fe/Mn, Cr/Fe or Cr/Mn. The by-product produced in the reaction process is little, the yield is high, and the separation is convenient. The acid-base neutralization is not required in the reaction process, reducing pollution. A one-step reaction is employed which has mild reaction conditions, short reaction time, low pollution and is convenient for industrialized mass production; and the obtained 4-(Hydroxymethyl)benzoic acid can be used for preparing medicines and liquid crystal materials having wide applications.

P-xylene (PX) is a key organic chemical raw material mainly employed in preparing important organic intermediates, such as terephthalic acid, etc., for producing polymers. The p-xylene has relatively abundant sources and a low price, which can be obtained by methods such as disproportionation of toluene, isomerization of xylene, aromatization of methanol, and reaction of 2,5-dimethylfuran with ethylene, etc. At present, a productive capacity of p-xylene is about 15 million tons/year in China. Therefore, it will greatly promote the development of p-xylene industry by expanding a development and utilization of downstream products of the p-xylene.
With the continuous recognition and broad application of oxygen-containing aromatic compounds, oxygen-containing organic compounds, such as terephthalic acid, 2,5-dihydroxyterephthalic acid, 4-(Hydroxymethyl)benzoic acid, etc., play more and more prominent roles in human production and living. These organic compounds are mainly used for synthesizing polymers, novel lithium batteries, drugs, etc. Although these oxides are widely used, the oxides such as 2,5-dihydroxyterephthalic acid, 4-(Hydroxymethyl)benzoic acid, etc. are rarely synthesized by a one-step oxidation using p-xylene which has a low price and abundant sources as a raw material, except that the terephthalic acid is obtained by an oxidation of the p-xylene.
In recent years, 4-(Hydroxymethyl)benzoic acid has been widely used in the synthesis and application of drugs, pharmaceutical intermediates, photocatalytic materials and optoelectronic materials (The Journal of organic chemistry, 2012, 78(1): 83-92; Angewandte Chemie International Edition, 2011, 50(33): 7599-7603; Crystal Growth & Design, 2011, 11(5): 1502-1511; Chemical Communications, 2012, 48(10): 1526-1528; Angewandte Chemie International Edition, 2012, 51(27): 6631-6634), and 4-(Hydroxymethyl)benzoic acid is considered to be an extremely high-value chemical intermediate.
Although the application of 4-(Hydroxymethyl)benzoic acid has attracted widespread attention, synthesis methods of 4-(Hydroxymethyl)benzoic acid have no big breakthrough. Conventional synthesis methods are as follows. 4-(Hydroxymethyl)benzoic acid is obtained by reacting 4-methylbenzoic acid with bromine to form 4-bromomethylbenzoic acid, and then hydrolyzing the 4-bromomethylbenzoic acid (FIG. 1, A). Alternatively, 4-(Hydroxymethyl)benzoic acid is obtained by selectively oxidizing 1,4-benzenedimethanol using a catalyst (FIG. 1, B) (ChemCatChem, 2010, 2(10): 1286-1295; U.S. Pat. No. 9,328,050B1). For the above two methods, many reaction steps are needed. It is necessary to first obtain 4-methylbenzoic acid or 1,4-dicarboxybenzene by methods such as oxidizing p-xylene, etc., and then next reaction can be performed, which causes a lot of by-products. Moreover, bromides produced in the reaction cause corrosion to devices or expensive catalysts are used in the above methods, which deviates from the concept of green chemistry. Therefore, a more convenient, efficient, and inexpensive synthesis method is needed for producing large amounts of 4-(Hydroxymethyl)benzoic acid.
In view of the above problems, it is quite necessary to develop a milder and greener method for synthesizing 4-(Hydroxymethyl)benzoic acid. M. G. Bramucci et al. obtain 4-(Hydroxymethyl)benzoic acid by using a xylene monooxygenase as a catalyst to perform a biomimetic catalytic oxidation on p-xylene (U.S. Pat. No. 20030073206A1). However, this method has problems such as long reaction time, low yield, and complicated cultivation of biocatalyst.

Method for synthesizing 4-(hydroxymethyl)benzoic acid by using P-xylene (PX) as raw material


The present invention provides an escalator braking system and an escalator braking control method, belonging to the field of escalator braking control technology. In the escalator braking system and the escalator braking control method according to the present invention, a braking mode is determined based on the classification of failure information in combination with the corresponding image information, and a braking device is controlled based on the braking mode, so that the braking is more intelligent, scientific and accurate, the occurrence of security problems caused by the failure can be effectively prevented, and the probability of accident is reduced.

During operation, the escalator is prone to a safety risk due to various failure problems (e.g., over speed, sudden reversal of running direction, etc.). Therefore, there is a need to monitor the failure information and to control the braking of the escalator to avoid accidents as much as possible when the failure occurs.
At present, the braking of the escalator is mainly performed by braking a rotor of an electric motor for driving the operation of the escalator in a mechanical braking manner, for example, by controlling a brake lining to brake on the rotor of the electric motor. However, this braking method at least has the following problems:
firstly, the braking force of the brake lining needs to be applied by an elastic element such as a spring, in the case of different braking forces, the braking distances are different, and it is relatively difficult to control the braking force and more difficult to achieve the adjustment of the braking force according to the different types of failure; and
secondly, the elastic element applying the brake force is unstable, for example, it is easy to change after usage for a certain period of time; therefore, not only the braking distance is not easily controlled, but also the maintenance operation such as adjustment or replacement needs to be often performed on the elastic element.
Moreover, controlling the braking of the escalator only by monitoring the failure information easily results in that the braking control is not applicable to the actual scene of the escalator, which is easy to bring about safety risks.

Escalator braking system and escalator braking control method