An active compression/decompression CPR device includes two pressure members mounted on a common beam. When placed on the victim with one member on the chest and the other on the abdomen, pressure on one end of the beam causes compression of the thorax and decompression of the abdomen. Conversely, when pressure is applied to the other end of the beam, the abdomen is compressed and the thorax is decompressed.

1. Field of the Invention
This invention relates generally to cardiopulmonary resuscitation (CPR), and more particularly, to a device for performing CPR through alternating active compression and decompression of the thorax and abdomen.
2. Description of the Related Art
There are approximately 550,000 cases annually of cardiac arrest in the U.S. Despite advances in many other areas of medicine, the survival rate for these cases remains low. In general, for the victims to survive, it is essential that they receive proper resuscitation as soon as possible after the cardiac arrest. It is generally felt that in order for a victim to stand a reasonable chance for survival successful cardiopulmonary support must be established within ten minutes of cardiac arrest. Beyond this, any delay in providing support is likely to result in severe brain damage.
There are two general classes of cardiopulmonary support: invasive and non-invasive. Examples of invasive support devices include percutaneous bypass, direct coronary perfusion, the Anstadt cup, hemopumps, and intraortic balloon pumping. Of course since these techniques require the insertion of devices into the body, they can only be performed by trained medical personnel. In fact, these techniques are generally not suited for emergency life support outside a hospital. Even then, they generally take longer to establish than a person in cardiac arrest can ordinarily tolerate.
Non-invasive devices tend to be easier and less expensive to use and faster to implement than the invasive equipment. Non-invasive support techniques include cardiopulmonary resuscitation (CPR), leg compression, and THUMPER.RTM. devices or compression vests which mechanically compress the chest to simulate CPR. Traditional CPR provides cardiac support through a series of rhythmic compressions of the victim's thorax alternating with mouth-to-mouth ventilation. Thoracic compression is achieved by having the care giver place his or her hands on the victim's chest and pressing down. After compression has been achieved, thoracic pressure is released and mouth-to-mouth ventilation follows. The principle advantage of CPR is its relative simplicity. An individual can be trained to administer traditional CPR in only about 15 hours.
However, traditional CPR has its limitations. For one thing, it is tiring to administer. In addition, it is not very efficient, ordinarily providing insufficient cardiopulmonary support to sustain the patient until professional emergency medical care can be provided.
The THUMPER.RTM. devices and compressive vests now used for non-invasive life support have been designed to duplicate the movements used to perform CPR, the idea being to provide a mechanical substitute for a person trained to administer CPR. Examples of such devices can be found in U.S. Pat. No. 3,219,031, No. 3,509,899, No. 3,896,797, and No. 4,397,306. Each of these patents describe devices which use a reciprocable plungers to compress a victim's chest along with a means of ventilating the victim, such as a source of pressurized oxygen or a squeeze bag. However, such devices, because they are fairly complex and not easily used by untrained lay persons, are in fact less-than-ideal substitutes for a trained CPR administrator. Furthermore, they do not improve the hemodynamic efficiency of CPR.
As an alternative to the use of mechanical chest compressors, U.S. Pat. No. 2,071,215, No. 4,424,806 and No. 4,928,674 describe how to support the pulmonary and/or cardiac functions by providing an inflatable bladder around the patient's chest. In some cases, a stiff outer shell or biasing cuff surrounds the bladder so that when the bladder is periodically inflated, the patient's chest is compressed, causing expiration and inspiration.
Because none of the commercial embodiments of these devices is entirely satisfactory, CPR remains the most common resuscitative technique used by lay persons to treat cardiac arrest.
As indicated above, traditional CPR involves the use of the administrator's hands on the victim's chest followed by mouth-to-mouth ventilation. Compressing the thorax causes blood to circulate while the mouth-to-mouth ventilation ventilates the lungs. Recently certain hand held devices have been employed to serve both these functions. Indeed, the popular media have reported on the use of a suction cup plunger, often referred to as a "plumber's helper", having been used to provide enhanced CPR.
A recent study determined that where cardiac support is provided by rhythmic chest compressions, cardiac output can be significantly improved by alternating chest compressions with chest decompressions. In this study, the chest was compressed and decompressed using a rubber plunger which alternately applied pressure and suction to the patient's chest. See Cohen, T. J., et al., "Active Compression-Decompression: A New Method of Cardiopulmonary Resuscitation", J. Am. Med. Assoc. Vol. 267, No. 21, pp. 2916-23, 1992. This technique is known as active compression-decompression CPR ("ACD CPR").
ACD CPR is reported as being significantly more effective than conventional "compression-only" CPR. It provides both perfusion and ventilation, and can resuscitate some patients where conventional CPR and defibrillation fail.
Devices capable of being used to perform ACD CPR are also described in U.S. Pat. No. 5,295,481 and European Patent Application No. 92303367.4 (Publication No. 0 509 773 A1). Each of these patents shows a device which includes a suction cup and handle. In each case, the aid giver would grab the handle and alternately press down and then pull up. The downward pressure would force air out of the lungs and blood out of the heart while the pulling up on the handle would cause the suction cup to draw the chest upwardly to pull air into the lungs and blood into the heart.
Although the traditional manner of performing CPR involves only the thorax, it has also been suggested that simultaneous involvement of the abdomen might prove even more advantageous. In an article entitled "Optimization of Coronary Blood Flow During Cardiopulmonary Resuscitation (CPR)" by Lin et al. (IEEE Transactions on Biomedical Engineering, Vol. BME-34, No. 6, Jun. 1987) the authors describe a computer simulation of CPR. Based on that simulation they conclude that coronary blood flow could be significantly improved if, in addition to alternating positive and negative pressure on the thorax, negative and positive pressure could also be applied to the abdomen. In other words, their computer model suggests that when positive pressure is applied to the thorax, it should be accompanied by the application of negative pressure to the abdomen and, conversely, as negative pressure is supplied to the thorax, positive pressure should be applied to the abdomen. The Lin et al. paper, however, appears to be based solely on the authors' computer simulation, and no structure is suggested for applying these alternating positive and negative pressures.
As previously noted, emergency medical personnel have available to them a number of different ways to treat cardiac arrest. However, none of these techniques is entirely satisfactory. Thus, there is a need for a CPR resuscitation device which is simple, easy to use, and not harmful to patients. In particular there is need for such a device which will facilitate alternating application of positive and negative pressures on the thorax and abdomen.

Active compression/decompression device and method for cardiopulmonary resuscitation


The outer peripheral surface of a connector, to which a connector seal structure is applied, is provided with an engaging section that engages with a seal member. A rib of the engaging section locks the seal member in the inserting direction of the connector. The seal member is provided with a cutout section formed by cutting out a part of the rib, or a protruding section that engages with the rib.

For example, Japanese Laid-Open Patent Publication No. 2017-021899 discloses placing a sealing member in the shape of a continuous ring (belt) on the outer circumferential surface of a connector member covering a terminal portion that is connectable to a connecting object. In this case, the sealing member is placed in a groove portion formed in the outer circumferential surface of the connector member, and a locking structure is provided in a connector, the locking structure curbing sliding of the sealing member in a direction in which the connector is inserted into the object and rotation of the sealing member in the circumferential direction of the connector.


An integrated circuit for use with an external Hall sensor that permits to at least substantially cancel out the temperature drifts of the Hall sensor, as caused by the temperature drift of the current supplied to the Hall sensor, and the gain of the Sigma-Delta modulator. Specifically, the circuit provides an integrated circuit for use with an external Hall sensor, that has an analog input for application of a Hall voltage from the Hall sensor, a digital data output and a current output for connection to a current input of the Hall sensor. The integrated circuit comprises a Sigma-Delta modulator with an input connected to the analog input and an output connected to the digital data output. An internal reference voltage source is also included in the integrated circuit, and an internal current source is connected to the current output for the Hall sensor. The internal reference voltage source is used as a reference in the current source that determines the amount of current supplied to the Hall sensor, and is also used in the Sigma-Delta modulator as a reference that determines the input voltage range. Since the same reference voltage source is used by the current source for the Hall sensor and by the Sigma-Delta modulator, the temperature drifts of the Hall voltage and the gain of the Sigma-Delta modulator cancel each other. Other benefits are low noise and an excellent common mode rejection.

Electric current measurements within electric motor control are mainly based on measurement of a voltage drop across a shunt resistor. For high current applications, however, Hall sensors are used. In both cases, since the voltage to be measured is small and the environment of an electric motor control is typically noisy, the use of a Sigma-Delta modulator is advantageous because of its capability to convert low voltage inputs with high accuracy and low noise. A Sigma-Delta modulator converts an analog input signal into a digital data stream. The principles of Sigma-Delta modulation are described in "CMOS: Mixed-Signal Circuit Design, Chapter 32: Noise Shaping Data Converters" by Russel J. Baker, John Wiley & Sons.
The accuracy of current measurement with a Hall sensor and a Sigma-Delta modulator is affected by several factors. Since the Hall voltage is proportional to the current applied to the Hall sensor, a first factor is the temperature drift of the current supplied to the Hall sensor, such current being in turn dependent on the temperature behavior of a reference voltage source used in the current source that provides the current to the Hall sensor. Another factor is the temperature dependent gain drift of the Sigma-Delta modulator.

Integrated circuit for use with an external hall sensor, and hall sensor module


A battery unit includes a power supply; a connection configured to be connectable with a load for atomizing an aerosol source or heating a flavor source and a charger for charging the power supply; and a controller that performs a specific process at least selectively executable to at least temporarily disable the supply of electric power to the load from the power supply, if erroneously determining the load connected to the connection as the charger is identified.

Instead of cigarettes, non-combustion-type flavor inhalers (electronic cigarettes) for inhaling flavor without combustion have been proposed (see PTLs 1 to 6). The flavor inhaler includes at least one of an aerosol source and a flavor source, an atomizer that is an electric load for atomizing inhaling taste components contained in at least one of the aerosol source and the flavor source, a power supply configured to supply electric power to the atomizer, and a controller configured to control the atomizer and the power supply.
PTL 1 discloses that the atomizer is configured to be detachably connected to the battery unit provided with the power supply and the controller. PTL 1 discloses that the atomizer connected to the battery unit can be identified using identification information such as an ID.
PTL 2 discloses an electronic smoking apparatus in which the atomizer and a charger can be alternatively connected to a common connection (interface) of the battery unit.
PTL 3 discloses that over-current flowing in an electronic circuit in an electronic cigarette or short circuit in the electronic circuit is detected. PTL 4 discloses a fuse that prevents overheating of the atomizer in the electronic cigarette. PTL 5 discloses that when there is a system malfunction in an aerosol generating device such as an electric smoking utensil, the fuse in the electronic circuit is blown, thereby disabling the system. PTL 6 discloses that over-current and over-voltage are detected in a charging process of the battery unit of the electronic cigarette.
PTL 7 discloses a charge monitoring device configured to monitor a charged state of a battery when the battery is charged. This charge monitoring device detects an abnormal charge state by monitoring change in voltage of the battery to be charged with respect to time or change in voltage of the battery to be charged with respect to a charging electric quantity, and also monitoring a voltage value of the battery measured by the voltage measurement means.
PTL 8 discloses a user authentication technique based on the inhaling pressure in a puff action of the user in the flavor inhaler.
PTL 9 discloses a technique in which the flavor inhaler is easily disabled.

Battery unit, flavor inhaler, method of controlling battery unit, and program


The present invention provides compounds of formula

The present invention relates to adenine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
The immune system is comprised of innate and acquired immunity, both of which work cooperatively to protect the host from microbial infections. It has been shown that innate immunity can recognize conserved pathogen-associated molecular patterns through toll-like receptors (TLRs) expressed on the cell surface of immune cells. Recognition of invading pathogens then triggers cytokine production (including interferon alpha(IFNα)) and upregulation of co-stimulatory molecules on phagocytes, leading to modulation of T cell function. Thus, innate immunity is closely linked to acquired immunity and can influence the development and regulation of an acquired response.
TLRs are a family of type I transmembrane receptors characterized by an NH2-terminal extracellular leucine-rich repeat domain (LRR) and a COOH-terminal intracellular tail containing a conserved region called the Toll/IL-1 receptor (TIR) homology domain. The extracellular domain contains a varying number of LRR, which are thought to be involved in ligand binding. Eleven TLRs have been described to date in humans and mice. They differ from each other in ligand specificities, expression patterns, and in the target genes they can induce.
Ligands which act via TLRs (also known as immune response modifiers (IRMS)) have been developed, for example, the imidazoquinoline derivatives described in U.S. Pat. No. 4,689,338 which include the product Imiquimod for treating genital warts, and the adenine derivatives described in WO 98/01448 and WO 99/28321.
This patent application describes a class of 9-substituted-8-oxoadenine compounds having immuno-modulating properties which act via TLR7 that are useful in the treatment of viral or allergic diseases and cancers.
In accordance with the present invention, there is therefore provided a compound of formula (I):
wherein
R1 represents hydrogen, hydroxyl, C1-C6 alkoxy, C2-C5 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or a C6-C10 aryl, C5-C10 heteroaryl or C3-C8 cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C5 alkoxycarbonyl, amino (NH2) and di-C1-C6 alkylamino;
Y1 represents a single bond or C1-C6 alkylene;
X1 represents a single bond or an oxygen or sulphur atom or sulphonyl (SO2) or NR3;
Z1 represents a C2-C6 alkylene or C3-C8 cycloalkylene group, each of which may be optionally substituted by at least one hydroxyl;
X2 represents NR4, CONR4, NR4CO, SO2NR4, NR4CONR5 or NR5CONR4, SO2, CO, NR5CSNR5;
Y2 represents a single bond or C1-C6 alkylene;
n is an integer 0, 1 or 2;
each R2 group independently represents halogen, cyano, S(O)mR9, OR10, SO2NR10R11, CONR10R11, NR7R8, NR10SO2R9, NR10CO2R9, NR10COR9, C6-C10 aryl, C5-C10 heteroaryl group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, the latter six groups being optionally substituted by one or more substituents independently selected from halogen, cyano, S(O)mR12, OR13, SO2NR13R14, CONR13R14, NR7R8, NR13SO2R12, NR13CO2R12, NR13COR12, C1-C6 alkyl or C3-C8cycloalkyl
R3 represents hydrogen or C1-C6 alkyl;
R4 represents hydrogen or a 3- to 8-membered saturated heterocyclic ring comprising a ring group O or NR6;
or R4 represents a C1-C6 alkylene optionally substituted by one or more substituents independently selected from NR7R8 or R6;
R5 represents hydrogen or a C1-C6 alkyl or C3-C6 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl and NR7R8;
R6 represents hydrogen, CO2R9, SO2R9, COR9, SO2NR10R11, CONR10R11, a 3- to 8-membered saturated heterocyclic ring comprising a ring group NR9; or
(i) a C6-C10 aryl or C5-C10 heteroaryl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, oxo, carboxyl, S(O)mR12, OR13, SO2NR13R14, CONR13R14, NR13R14, NR13SO2R12, NR13CO2R12, NR13COR12, C1-C6 alkyl and C1-C3 haloalkyl, or(ii) a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, C3-C8 cycloalkyl, OR15, S(O)pR16, CO2R16, NR17R18, CONR17R18, NR17COR16, SO2NR17R18, NR17SO2R16 and a group as defined in (i) above;
R7, R8, R13, R14R15, R19, R22, R23, R24 and R25 each independently represent hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;
or R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, carboxyl, cyano, OR21, S(O)qR21, NR22R23, C1-C6 alkyl and C3-C8 cycloalkyl;
R9, R16 and R21 each independently represent a C1-C6 alkyl or C3-C6 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, carboxyl, hydroxyl and NR19R20;
either R10 represents hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, carboxyl, cyano, OR21, S(O)qR21, NR22R23 and C3-C8 cycloalkyl, and
R11 represents hydrogen or a C1-C6 alkyl or C3-C6 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl and NR24R25, or
R10 and R11 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring comprising at least one heteroatom or heterogroup selected from nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, carboxyl, cyano, OR21, S(O)qR21, NR22R23, C1-C6 alkyl and C3-C8 cycloalkyl;
R12 represents C1-C6 alkyl or C3-C6 cycloalkyl;
R17 and R18 are defined as for R10 and R11 respectively;
m, p and q each independently represent an integer 0, 1 or 2; and
A represents a monocyclic or bicyclic C6-C10 aryl or a monocyclic or bicyclic C5-C12 heteroaryl group containing 1-3 heteroatoms;
or a pharmaceutically acceptable salt thereof.
In the context of the present specification, unless otherwise stated, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. Examples of C1-C6 alkyl groups/moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Similarly, an alkylene group/moiety may be linear or branched. Examples of C1-C6 alkylene groups/moieties include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methylethylene, 2-methylethylene, 1,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene and 1-, 2- or 3-ethylpropylene. A C1-C6 haloalkyl or C1-C6 haloalkoxy substituent group/moiety will comprise at least one halogen atom, e.g. one, two, three, four or five halogen atoms, examples of which include trifluoromethyl, trifluoromethoxy or pentafluoroethyl. The alkyl groups in a di-C1-C6 alkylamino or alkylcarbonyl group/moiety may be the same as, or different from, one another. A C1-C6 hydroxyalkyl or C1-C6 hydroxyalkoxy substituent group/moiety will comprise at least one hydroxyl group, e.g. one, two or three hydroxyl groups. An aryl or heteroaryl substituent group/moiety may be monocyclic or polycyclic (e.g. bicyclic or tricyclic) in which the two or more rings are fused. A heteroaryl group/moiety will comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur. Examples of aryl and heteroaryl groups/moieties include phenyl, 1-naphthyl, 2-naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, isoindolyl, quinolyl, isoquinolyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl and oxazolyl.
A C2-C10 acyloxy group/moiety is exemplified by a C2-C5 alkylcarbonyloxy group, a C2-C5 alkenylcarbonyloxy group, a C2-C5 alkynylcarbonyloxy group, a C6-C9 arylcarbonyloxy group or a C5-C9 heteroarylcarbonyloxy group, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-C3 alkoxy or phenyl ring, optionally substituted by from halogen, hydroxyl, cyano, OR21, S(O)qR21 or C1-C6 alkyl, providing that the total number of carbon atoms in the acyloxy group does not exceed 10.
Preferably R1 represents hydrogen.
Preferably Y1 represents C1-C6 alkylene, more preferably C4 alkylene
Preferably X1 represents oxygen
Preferably Z1 represents C2-C6 alkylene, more preferably (CH2)3.
Preferably X2 represents NR4.
Preferably Y2 represents C1-C6 alkylene, more preferably a CH2 group.
Preferably A represents phenyl
Preferably R2 is hydrogen or C1-C6 alkoxy
Examples of compounds of the invention include:    6-Amino-9-{3-[benzyl(3-morpholin-4-ylpropyl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(4-isopropoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(4-methoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(3,4-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(4-morpholin-4-ylbenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-pyrimidin-2-ylbenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[[4-(methylthio)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl) [(2-oxo-2H-chromen-6-yl)methyl]amino}propyl)-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl) [(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)methyl]amino}propyl)-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-propoxybenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(3,5-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[(2,4-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    (4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}phenoxy)acetonitrile    6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-pyrrolidin-1-ylbenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)[4-(1H-1,2,4-triazol-1-yl)benzyl]amino}propyl)-7,9-dihydro-8H-purin-8-one    6-Amino-2-butoxy-9-{3-[[4-(methylsulfonyl)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}-N-(tert-butyl)benzenesulfonamide    6-Amino-2-butoxy-9-{3-[[4-(hydroxymethyl)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one    6-Amino-9-(3-{benzyl[2-(dimethylamino)ethyl]amino}propyl)-2-butoxy-7,9-dihydro-8H-purin-8-one    6-Amino-9-{3-[benzyl(1-methylpiperidin-4-yl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-oneand pharmaceutically acceptable salts or solvates thereof.
The present invention further provides a process for the preparation of a compound of formula (I).
The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises,
(a) reacting a compound of formula
wherein Z1, Y1, X1, R1 and R4 are as defined in formula (I), with a compound of formula
wherein Y3 represents a bond or C1-C5 alkylene group and n and R2 are as defined in formula (I) in the presence of a suitable reducing agent (e.g. sodium triacetoxyborohydride); or(b) reacting a compound of formula (II) as defined in (a) above with a compound of formula
wherein Y4 represents C1-C5 alkylene group; L1 represents a leaving group (e.g. halogen, mesylate or triflate) and n and R2 are as defined in formula (I) in the presence of a suitable base (e.g. sodium carbonate or potassium carbonate), and optionally after carrying out one or more of the following:converting the compound obtained to a further compound of the invention,removal of any protecting groups,forming a pharmaceutically acceptable salt of the compound; or
In process (a), the reaction may conveniently be carried out in an organic solvent such as 1-methyl-2-pyrrolidinone, 1,2-dichloroethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 150° C.
In process (b), the reaction may conveniently be carried out in an organic solvent such as acetonitrile, 1-methyl-2-pyrrolidinone or N,N-dimethylformamide at a temperature, for example, in the range from 0 to 150° C.
Compounds of formula (II) where R1 represents hydrogen, Y1 represents C1-C6 alkylene, and X1 represents oxygen may be prepared as illustrated in the following reaction scheme:

The compound of formula (B) is prepared by reacting the compound of formula (A) with ammonia in an organic solvent such as methanol, ethanol, propanol, butanol, tetrahydrofuran, 1,4-dioxane, diglyme, acetonitrile or an aqueous mixture of any one of the preceding solvents. The reaction may be carried out in an autoclave, and at a temperature, for example, in the range from 20 to 200° C.
Compounds of formula (C) may be prepared by reacting the compound of formula (B) with an alkanol in the presence of a base such as sodium hydride and in an organic solvent such as tetrahydrofuran, 1,4-dioxane, diglyme, N,N-dimethylformamide or dimethylsulfoxide, preferably at elevated temperature, e.g. at a temperature in the range from 20 to 150° C. Alternatively an alkali metal such as sodium may be dissolved in the alkanol and then reacted with the compound of formula (B), preferably at elevated temperature, e.g. at a temperature in the range from 20 to 150° C.
Compounds of formula (D) are prepared by brominating a compound of formula (C). The reaction may be carried out using a brominating agent such as bromine, hydroperbromic acid or N-bromosuccinimide, in an organic solvent such as carbon tetrachloride, methylene chloride, dichloroethane, diethyl ether, acetic acid or carbon disulfide. The reaction temperature will generally be in the range from 0° C. to the boiling point of the solvent.
Compounds of formula (E) are prepared by reacting a compound of formula (D) with sodium methoxide in an organic solvent such as methanol and at a temperature, for example, in the range from 20 to 150° C.
Compounds of formula (F) may be obtained by treating a compound of formula (E) with an acid such as trifluoroacetic acid in an organic solvent such as methanol.
Compounds of formula (G) are prepared by reacting a compound of formula (F) with a compound of formula LG-Z1-LG wherein LG represents a leaving group such as a halogen, mesylate or triflate and Z1 represents a C2-C6 alkylene group as defined in formula (II). The reaction may be carried out in an organic solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile with a base present, preferably at room temperature (20° C.). A base such as an alkali metal carbonate, e.g. sodium carbonate or potassium carbonate; an alkaline earth metal carbonate, e.g. calcium carbonate; a metal hydroxide, e.g. sodium hydroxide or potassium hydroxide; a metal hydrogenate, e.g. sodium hydride; or a metal alkoxide, e.g. potassium t-butoxide, may be used.
Compounds of formula (H) may be obtained by treatment of a compound of formula (G) with an acid. The reaction may be carried out in an organic solvent such as methanol using either an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid.
Compounds of formula (II) are prepared by reacting a compound of formula (H) with an amine of formula R4NH2 where R4 is as defined in formula (I). The reaction may be carried out in an organic solvent such as acetonitrile or N,N-dimethylformamide using an excess of the amine, preferably at elevated temperature, e.g. at a temperature in the range from 0 to 150° C.
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 reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or p-toluenesulphonate.
Compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired.
The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators of toll-like receptor (especially TLR7) activity, and thus may be used in the treatment of:
1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;2. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia greata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;3. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial;4. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female);5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;6. other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome and Sazary syndrome;7. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,8. infectious diseases: virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, candida, aspergillus, cryptococcal meningitis, pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
Thus, the present invention provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
In particular, the compounds of the invention may be used in the treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterial infections and dermatosis.
The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:—
(i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of5α-reductase such as finasteride;(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase);(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux®, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
The invention still further provides a method of treating, or reducing the risk of, an obstructive airways disease or condition (e.g. asthma or COPD) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
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. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).
The compounds of formula (I) and pharmaceutically acceptable salts 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 (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals—The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt 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 thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler®; 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.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention (including pharmaceutically acceptable salts) may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 micrometres (μm), and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound of the invention with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient.
For oral administration the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
In particular, for the treatment of the inflammatory diseases COPD, asthma and allergic rhinitis the compounds of the invention may be combined with agents such as tumour necrosis factor alpha (TNF-alpha) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab [Remicade®], CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (such as entanercept [Enbrel®]); non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate, lefunomide; hydroxychloroquine, d-penicillamine, auranofin or other parenteral or oral gold preparations.
The present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott®-79175; Abbott®-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca® ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
The present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT B4, LTC4, LTD4, and LTE4) selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
The present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
The present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
The present invention still further relates to the combination of a compound of the invention and a gastroprotective histamine type 2 receptor antagonist.
The present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
The present invention still further relates to the combination of a compound of the invention and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
The present invention further relates to the combination of a compound of the invention and an anticholinergic agent including muscarinic receptor (M1, M2, and M3) antagonists such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
The present invention still further relates to the combination of a compound of the invention together with a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol.
The present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
The present invention still further relates to the combination of a compound of the invention together with an insulin-like growth factor type I (IGF-1) mimetic.
The present invention still further relates to the combination of a compound of the invention and a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
The present invention still further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12.
The present invention still further relates to the combination of a compound of the invention together with modulators of chemokine receptor function such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX3CR1 for the C—X3-C family.
The present invention still further relates to the combination of a compound of the invention together with a cytokine or modulator of cytokine function, including alpha-, beta-, and gamma-interferon; interleukins (IL) including IL1 to 15, and interleukin antagonists or inhibitors, including agents which act on cytokine signalling pathways.
The present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (omalizumab).
The present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
The present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.
A compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin);(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride;(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function);(iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;(vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or(ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
The present invention will be further explained by reference to the following illustrative examples.
The following abbreviations are used;
EtOAcethyl acetateDCMdichloromethaneNMPN-methylpyrrolidineNBSN-bromosuccinamideDMFN, N-dimethylformamideDMSOdimethylsulfoxideTHFtetrahydrofuranTFAtrifluoroacetic acidmcpba3-chloroperoxybenzoic acid (Aldrich 77% max)rtroom temperaturehhoursminminutesMmolarMSmass spectrometryAPCIatmospheric pressure chemical ionisationNMRnuclear magnetic resonanceHClhydrochloric acidBOCtertiary-butoxycarbonylHOBt1-hydroxybenzotriazoleEDC1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochlorideHATUO-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluroniumhexafluorophosphonate
Unless otherwise stated organic solutions were dried over magnesium sulphate. RPHPLC denotes Reverse Phase Preparative High Performance Liquid Chromatography using Waters® Symmetry® C8, XTerra® or Phenomenex® Gemini™ columns using acetonitrile and either aqueous ammonium acetate, ammonia, formic acid or trifluoroacetic acid as buffer where appropriate. Column chromatography was carried out on silica gel. SCX denotes solid phase extraction with a sulfonic acid sorbent whereby a mixture was absorbed on a sulfonic acid sorbent and eluted with an appropriate solvent such as methanol or acetonitrile and then the free base product was eluted with aqueous ammonia/an appropriate solvent such as methanol or acetonitrile.
Biological Assay
Human TLR7 Assay
Recombinant human TLR7 was stably expressed in a HEK293 cell line already stably expressing the pNiFty2-SEAP reporter plasmid; integration of the reporter gene was maintained by selection with the antibiotic zeocin. The most common variant sequence of human TLR7 (represented by the EMBL sequence AF240467) was cloned into the mammalian cell expression vector pUNO and transfected into this reporter cell-line. Transfectants with stable expression were selected using the antibiotic blasticidin. In this reporter cell-line, expression of secreted alkaline phosphatase (SEAP) is controlled by an NFkB/ELAM-1 composite promoter comprising five NFkB sites combined with the proximal ELAM-1 promoter. TLR signaling leads to the translocation of NFkB and activation of the promoter results in expression of the SEAP gene. TLR7-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37° C. with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP production by compounds was expressed as the log of the minimal effective concentration of compound to induce SEAP release (pMEC).
Compound of Example:8pMEC7.212>7.7167.4

Abstract: wherein R1, Y1, X1, Z1, X2, Y2, A, n and R2 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.


Apparatus for actuating a hydraulic power steering system for automotive vehicles, wherein the steering shaft (1 ) is allowed to roll off on the gear rack (3) to a small degree to actuate the steering valve. To enable this rolling motion, the steering shaft (1 ) is supported in a sleeve (9) which, in turn, is supported through needle bearings (10) so as to be rotatable in relation to the steering gear housing (4). To prevent inadvertent steering maneuvers in the event of partial or complete system failure, the needle bearing axis is arranged in parallel to the center line of the steering shaft (1) as well as in one plane with the steering shaft and with the point of force transmission between pinion (2) and gear rack (3). The needle bearing axis is radially outward from the central point of the steering shaft axis than the point of force transmission. A captivated spring (24) is provided to retain the valve slide (19) in its neutral position.

The present invention relates to a device for actuating a hydraulic power steering system for automotive vehicles having the following features:
A steering shaft, non-rotatably coupled with the steering wheel, is furnished with a pinion and is supported in a sleeve, PA1 The pinion is engaged with a gear rack coupled to the wheels to be steered, PA1 The sleeve is supported in a steering gear housing so as to be pivotable about an axis, parallel in relation to the steering shaft, and it comprises a recess to enable the pinion to engage into the gear rack, and on it a pin-shaped extension is secured perpendicularly relative to the steering shaft, the extension actuating the valve slide of a steering valve designed as a linear slide valve, and PA1 A spring which presses the gear rack against the pinion and simultaneously stabilizes the support of the sleeve in the steering gear housing. PA1 The bearing between the sleeve and the steering gear housing is formed by two needles, PA1 The two needle bearings are disposed on different sides of the gear rack, and PA1 The bearing axis of the two needle bearings is farther away from the steering shaft center line than the point of force transmission between pinion and gear rack, and it is placed on the same side of the steering shaft center line as the latter point, and the valve slide is biassed by a captivated spring.
A device of this type is known from European patent application 0 291 155. In this prior art device, the sleeve is supported on that side of the steering shaft in the housing which is remote from the gear rack. The bearing is formed by a spherical indentation in the extension and a spherical shell-shaped recess in the steering gear housing. A disadvantage of this device is that high friction forces occur in the bearing because of the great radius of effect the friction force has due to the spring being pressed on. However, the strong spring is required to ensure freedom of play between gear rack and pinion. Further, the system has a tendency of being unstable since the force of the spring, which keeps the gear rack in contact with the pinion, induces a rolling motion of the steering shaft on the gear rack, the steering valve being actuated as a result. This might be a safety risk since the vehicle would be steered inadvertently in such a case.

Device for actuating a hydraulic power steering system


System and method for modular sorting stations. A sorting station may be subdivided into two or more modular bins. A modular bin may be partitioned into compartments. Each compartment may be configured to receive one order including one or more items. Modular bins may be partitioned into compartments of different sizes to receive orders of different sizes. A modular bin may be removed from a sorting station and conveyed to a packing station for packing or other sorting station to continue sorting. Picked items may be received and sorted for rebinning into the modular bins manually or using an automated sorting mechanism. A control system may direct the sorting and rebinning operation. Modular sorting stations may be located adjacent to packing stations or, alternatively, away from packing stations and, when a modular bin is complete, it may be conveyed to an appropriate packing station for packing.

1. Field of the Invention
This invention relates to materials handling systems such as order processing systems and, more particularly, to stations for receiving and sorting picked items for orders.
2. Description of the Related Art
Retailers, wholesalers, and other distributors of product (which may collectively be referred to as distributors) typically maintain an inventory of various items that may be ordered by clients or customers. This inventory may be maintained and processed at a materials handling facility which may include one or more of, but not limited to: warehouses, distribution centers, cross-docking facilities, order fulfillment facilities, packaging facilities, shipping facilities, or other facilities or combinations of facilities for performing one or more functions of material (inventory) handling. FIG. 1 illustrates a broad view of the operation of a conventional materials handling facility. Multiple customers 10 may submit orders 20 to the distributor, where each order 20 specifies one or more items from inventory 30 to be shipped to the customer that submitted the order. To fulfill the customer orders 20, the one or more items specified in each order may be retrieved or "picked" from inventory 30 (which may also be referred to as stock storage) in the materials handling facility, as indicated at 40. Picked items may be delivered to one or more stations in the materials handling facility for sorting 50 into their respective orders, packing 60, and finally shipping 70 to the customers 10. Note that a picked, packed and shipped order does not necessarily include all of the items ordered by the customer; a shipped order may include only a subset of the ordered items available to ship at one time from one inventory-storing location. Also note that a materials handling facility typically also includes a receiving operation for receiving shipments of stock from various vendors and placing the received stock into stock storage. Further, note that the various operations of a materials handling facility may be located in one building or facility, or alternatively may be spread or subdivided across two or more buildings or facilities.
FIG. 2 illustrates an exemplary physical layout of a conventional material handling facility, specifically an order fulfillment facility, or center. At any time, one or more agents of the distributor may each be picking items from inventory 30 to fulfill portions or all of one or more orders. This may result in a stream and/or batches of picked items for multiple incomplete or complete orders being delivered to a sorting station 50 for sorting into their respective orders for packing 60 and shipping 70. A stream may be a continuous or nearly continuous flow of picked items arriving at a sorting station 50, while groups of picked items arriving periodically or aperiodically at a sorting station 50 may be referred to as batches. Note that portions of an order may be received at different times, so sorting 50 and packing 60 may have to wait for one or more items for some orders to be delivered to the sorting station(s) 50 before completion of processing of the orders. The stream or batches of incoming picked items are sorted into their respective orders at the sorting station(s) 50. Conventionally, the picked items may be sorted into a fixed array of "pigeon holes" or slots, with each slot receiving one order. Once an order is completed at a sorting station 50, the order is ready to proceed to a packing station 60 to be packaged for shipping 70. Note that an order fulfillment center may also include one or more receiving stations for receiving shipments of stock from various vendors. The received stock may then be placed into stock storage. Further, note that the various operations and stations of an order fulfillment center may be located in one building or facility, or alternatively may be spread or subdivided across two or more buildings or facilities.
A materials handling facility such as an order fulfillment center 80 may implement an order fulfillment control system, or control system for short. A control system (not shown) may include hardware and software configured for assisting and/or directing agents in the order fulfillment center 80 in fulfilling customers' orders. Items in inventory 30 may be marked or tagged with a bar code, radio frequency identification (RFID) tag, Universal Product Code (UPC), Stock-Keeping Unit (SKU) code, serial number, and/or other designation (including proprietary designations) to facilitate order fulfillment center 80 operations, including, but not limited to, picking, sorting 50 and packing 60. These designations, or codes, may identify items by type, and/or may identify individual items within a type of item. The control system may include hand-held, mobile and/or fixed scanners or scanning devices that may be able to scan the marks or tags on individual items to determine and record the item and/or item type of the items.
The control system may be able to receive order information for each order specifying the item or items to be picked to fulfill the order. Each order may be assigned a unique order number for use in the order fulfillment process. Item and/or item type information, including associated item and/or item type designations or codes and possibly other descriptive information, may be entered into the control system for each item picked to fulfill each order. This information may be scanned into the control system from marks or tags on the items or, alternatively, manually entered. A combination of scanning and manual entry may be employed during picking.
Conventionally, sorting 50 may be performed using automated sorting mechanisms or manual sorting systems. Automated sorting mechanisms for sorting certain types of inventory items according to individual orders include, but are not limited to, the Crisplant® sorter, Eurosort® sorters, and automated sorting mechanisms offered by other vendors. Using an automated sorting mechanism, batches or a stream of incoming picked items for multiple different customer orders are received at the automated sorting mechanism and sorted by the automated mechanism according to individual orders. Such automated sorting mechanisms are typically expensive in both cost and floor area. Further, automated sorting mechanisms tend to be more expensive than manual sorting systems in situations where inventory throughput demands may vary significantly, for example from month to month, and/or where inventory throughput demands may increase rapidly over time, due to the need to pay for fixed automation equipment that may only be fully utilized at peak demand periods.


The present disclosure includes a headgear for a helmet. The headgear includes a front band, a back band, and an intermediate band comprising a plurality of intermediate band parts arranged between the front band and the back band. The plurality of intermediate band parts comprises first pair of band parts having a circular shape, the band parts of the first pair of band parts extending from and connecting on a first side of the headgear, a second pair of band parts having a circular shape, the band parts of the second pair of band parts extending from and connecting on a second side of the headgear, a first cross band part intersecting with and extending from the connection of the first pair of band parts, and a second cross band part intersecting with and extending from the connection of the second pair of band parts.

Welding helmets have become essential devices on welding sites for protecting welders. Welding helmets typically include a helmet shell that can be connected to a headband that is worn on the welder's head. The headgear can include one of a variety of mechanisms to securely mount the headgear to the welder's head.
For example, current iterations of headgear s include band parts that connect to one side of the headgear, go over the welder's head, and connect to the other side of the headgear. These band parts can be flat and stiff, which can have difficulty conforming to the curvature of the welder's head. Being forced to wear headgear comprising flat and stiff band parts can lead to discomfort for the welder, particularly when the welder is required to wear the headgear for an extended period of time in order to complete a welding task. As a result of the extended period of time welding tasks can take to complete, the issue of discomfort for a welder is a significant concern.
In some instances, the discomfort can be significant enough to negatively impact the welder while performing his or her tasks. For example, the discomfort can prevent a wearer from performing his or her tasks as efficiently or effectively as needed. In addition, the discomfort can lead to safety concerns. Discomfort can lead to diminished concentration, increasing the potential of exposure to harmful heat and sparks.

Headgear with curved straps for welding helmet


An implantable electrode device designed for heart stimulation and/or cardioversion/defibrillation in connection with a pacemaker or a defibrillator. The electrode device comprises a large-surface area indifferent reference electrode pole permanently implanted in the atrial septum and in electrical communication with a pacemaker or defibrillator. The electrode pole is made from biocompatible metal braiding and has a tube like opening. The electrical communication is positioned from the pacemaker/defibrillator via the right atrium of the heart through the indifferent electrode pole into the left atrium via the opening. Thus allowing electrical pulses to be delivered to the electrode pole and stimulating the heart.

1. Field of the Invention
The present invention relates to an implantable indifferent reference electrode pole and more particularly an electrode pole which can be used to facilitate both stimulation and cardioversion/defibrillation of all four heart chambers.
2. Description of Related Art
Implantable pacing leads are known since about 1960, the time when the first pacemaker was implanted. The use of pacemakers has continued to grow during the 1970s due to improved reliability and, in particular, higher breakage resistance of the electrode devices and due to good fixing of the electrode-tip in the right atrium. However, pacing therapy for treating congestive heart failure often requires left ventricular or left atrial stimulation, either alone or in conjunction with right ventricular stimulation and defibrillation usage.
Left ventricular access leads have been developed which are introduced through the coronary sinus and then advanced through the coronary veins so that an electrode can be positioned on the surface of the left ventricle near the apex of the heart.
For permanent stimulation of the left heart chambers, especially the left atrium there is as yet no simple solution. It would therefore be beneficial to provide a quick and easy access via the intra-atrial septum to the left atrium and the left ventricle further providing the possibility of exact positioning of the electrode during stimulation or cardioversion/defibrillation, thus giving the chance for a successful therapy of atrial and ventricular fibrillation.
Such conventional methods and systems have generally been considered satisfactory for their intended purpose. However, there is still a need in the art for an implantable indifferent electrode pole that allows for facilitation of stimulation for all four heart chambers. The present invention provides a solution for these problems.

Implantable indifferent reference electrode pole