An field programmable gate array (FPGA) includes a circuit implemented using the FPGA fabric. The FPGA further includes another circuit implemented as hardened circuitry. The FPGA also includes a configurable interface circuit that is adapted to couple together the two circuits.

FPGAs provide designers with flexibility in designing systems for information/data processing. By having the ability to program or configure the FPGA, designers can effectively change the system specifications or performance. Further, end users may configure or program the FPGA to suit their applications.
Typical FPGAs include programmable logic circuitry and interconnect in their fabric. To provide system designers or users with increased functionality or flexibility, some FPGAs also include hardened circuitry. Examples of hardened circuitry include memory controllers, memory, processors, etc.

Apparatus for configurable interface and associated methods


A magnetron sputtering system comprising a sputtering chamber. Present within the chamber are a flat cathode plate, an anode, which is cylindrical in one embodiment, and an annular auxiliary electrode. The electrodes are provided co-axially. In this embodiment the anode extends axially from a central area of the sputtering surface of the cathode plate. The auxiliary electrode extends axially from a circumferential area of the sputtering surface of the cathode plate. The anode is electrically insulated from the cathode plate. During operation the auxiliary electrode has a negative potential in relation to the anode potential. Furthermore the chamber comprises a receiving device for receiving a flat substrate to be coated with cathode plate material at a position opposite and parallel to the cathode plate. A magnetic device is provided outside the chamber for generating an electron trap around the anode, which magnetic device is surrounded by the auxiliary electrode. The magnetic device generates an asymmetric magnetic field. The auxiliary electrode enhances the interception of electrons in the electron trap.

1. Field of the Invention
The invention relates to a magnetron sputtering system comprising a chamber, and present within said chamber a flat cathode plate, an anode, an annular auxiliary electrode, which extends axially from a circumferential area of a sputtering surface of said cathode plate, is positioned co-axially with said cathode plate and during operation has a negative potential in relation to the anode potential, and a receiving device for receiving a flat substrate to be coated with cathode plate material at a position opposite and parallel to said cathode plate, and present outside said chamber a magnetic device for generating an electron trap over part of an intermediate area of the sputtering surface of the cathode plate located between a central area and said circumferential area, said device being surrounded by said annular auxiliary electrode.
2. Description of the Prior Art
A magnetron sputtering system of this type is known from European Patent 0 095 211 (the description as well as the claims and the drawing of which patent are considered to be incorporated herein by this reference).
In the known system the cylindrical electrode is a bar-shaped auxiliary electrode, and an annular anode co-axial with the cathode plate is provided, whereby the bar-shaped auxiliary electrode is disposed spaced from the substrate and a device is provided for varying the potential of the annular (tubular) auxiliary electrode in such a manner, that electrons are directed to the annular electrode during operation of the system.
The known system prevents the substrate from being damaged by electrons striking the substrate.
The known system is in particular used for the coating of substrates of temperature-sensitive optical registration carriers having a diameter of about 30 cm.
The operation of the known system will be briefly discussed below by way of supplement to the disclosure of the aforesaid patent.
A magnetron sputtering system distinguishes itself from other sputtering systems by the high rate at which cathode plate material is deposited on a substrate to be coated. This high deposition rate is achieved by an efficient trapping of electrons, as a result of which the gas discharge in the chamber of the magnetron sputtering system is able to produce a strong influx of ions to the cathode plate. This trapping of electrons is efficient because electrons moving away from the cathode plate as a result of the gas discharge are confined in a magnetic field. The magnetic field component parallel to the sputtering surface of the cathode plate, combined with the electric field perpendicular to the dark space on the sputtering surface, forces the electrons into a cycloid orbit, which, as soon as an electron leaves the dark space, changes into a circular orbit in a direction of movement perpendicular to the magnetic field component parallel to the sputtering surface as well as to the electric field. If no collisions take place, the electrons cannot move further away from the sputtering surface than the maximum height of the cycloid orbit or the radius of curvature of the circular orbit. By closing the orbit through which the electrons hop at a short distance from the sputtering surface, the electrons will remain at said short distance from the sputtering surface, unless collisions cause them to move out of the sphere of influence of the magnetic field.
Since the magnetic device is disposed on the cathode plate surface opposite the sputtering surface, the magnetic field is not uniform, which results in a magnetic field component perpendicular to the sputtering surface. More specifically, the magnetic field lines form an arc above the sputtering surface. Neither the perpendicular nor the parallel magnetic field component have a constant value between the point of entry and the point of exit of the magnetic field lines, and the perpendicular field component is reversed. The hopping which is imparted to the electrons under the influence of the parallel magnetic field component takes place in a direction perpendicular to the perpendicular magnetic field component. As a result of that a movement parallel to the sputtering surface is superposed on the hopping. Such a lateral movement is not imparted to electrons which are hopping in an orbit where the perpendicular magnetic field component is reversed, or, in other words, is zero. Electrons which start in another orbit, are subjected to a force in the direction of the orbit where the perpendicular magnetic field component is reversed. They hop and move in zigzag fashion in the closed orbit close to the sputtering surface of the cathode plate.
In the above-described manner a high-density annular plasma is formed close to the sputtering surface of the cathode plate. This plasma does not have a uniform density, however. In those places where the magnetic field component parallel to the sputtering surface becomes weaker, the distance which the electrons are able to move away from the sputtering surface becomes larger and thus the possibility of escape becomes greater. Consequently the erosion of the sputtering surface of the cathode plate does not take place in a uniform fashion. The consumptive use of cathode material is greatest in those places where the magnetic field component perpendicular to the sputtering surface is reversed. This non-uniform use is a drawback of the process of sputtering with a magnetron sputtering system. Further drawbacks resulting therefrom include a shorter life of the cathode plate, increased material costs as a consequence of a change in the plasma impedance which is greater than in the case of a uniform erosion, a reduced deposition rate, because part of the sputtered material is caught in an erosion groove, etc.
The above drawbacks become more serious as the size of the cathode plate decreases, as is for example the case when a smaller substrate is to be coated with cathode plate material, since the magnetic field gradients will increase in that case. After all, a sufficiently strong magnetic field component parallel to the sputtering surface of the cathode plate is required, whilst the distance between the points where the magnetic field intersects the sputtering surface becomes smaller. This implies that the variations in the uniformity of erosion are comparatively greater when smaller cathode plates are used.
In order to solve the above problem a comparatively large cathode plate is used for coating a small substrate so as to obtain the desired operational life of said cathode plate. A drawback of this solution is, however, that a large part of the sputtered cathode plate material does not land on the substrate to be coated, as a consequence of which the chamber needs to be opened frequently in order to remove the material from the cathode plate that has not landed on the substrate.


Aspects of the invention are provided for rate control and management of service requests. A token bucket is employed in conjunction with a capacity sharing scheme to manage processing of service requests. Each token represents the capacity reserved for a particular source of requests. Excess tokens may be shed, with the excess tokens representing available excess capacity. Similarly, a projected time at which the service request(s) may be released may be computed in the event the bucket does not contain the required quantity of tokens to process the request.

This invention relates to a rate control system in a system where it is desirable to control the rate of units of work per measure of time. More specifically, the invention is related to a demand driven model that performs a simple and precise scheduling computation for each service request.
Token bucket algorithms are metering engines that keep track of how much traffic can be sent to conform to specified traffic rates. A token, or in some cases a quantity of tokens, permits the algorithm to process a request. Tokens are granted at the beginning of a time increment according to a specified rate. Token buckets may be applied to resources of a network that are shared by multiple network devices, such as switches, routers, etc., where they are used to control data flow between network devices. Specifically, the token bucket employs credits in the form of tokens with the credits generally correlated to bandwidth.


New imidazotriazolopyrimidine derivatives of the formula

The invention relates to new imidazotriazolopyrimidines, processes for preparing them, pharmaceutical compositions comprising such compounds, and their use as medicaments for the treatment of various disease conditions.
It is known that adenosine antagonists may have a therapeutically useful effect in the treatment of diseases or pathological conditions that are somehow caused by activation of adenosine receptors.
Adenosine is an endogenous modulator with predominantly inhibitory effects in the CNS, in the heart, in the kidneys and other organs. The effects of adenosine are mediated via at least three receptor sub-types: adenosine A1, A2 and A3 receptors. Adenosine A2 receptors are further subdivided into two subtypes, A2a and A2b. The two A2 receptor subtypes can be differentiated, e.g. because specific adenosine antagonists such as CGS 21680 stimulate predominantly only the A2a subtype. It is presumed that the A2b subtype has a relatively low affinity for adenosine. For this reason, relatively high concentrations of adenosine are necessary in order to stimulate this subtype. Such high concentrations would be expected, for example, in the epithelial surface fluid in the lungs of asthmatics or in ischaemic tissue damage.
In the CNS, adenosine develops inhibitory effects mainly by activating A1 receptors: presynaptically by inhibiting the synaptic transmission (inhibiting the release of neurotransmitters such as acetylcholine, dopamine, noradrenaline, serotonin, glutamate, etc.), and postsynaptically by inhibiting neuronal activity.
A1 antagonists cancel out the inhibitory effects of adenosine and promote neuronal transmission and neuronal activity.
A1 antagonists are therefore of great interest for treating degenerative diseases of the central nervous system such as senile dementia of the Alzheimer""s type and age-related disorders of memory and learning capacity.
The disease includes, in addition to forgetfulness in its mild form and total helplessness and absolute dependence on care in its severe form, a number of other accompanying symptoms such as sleep disorders, motor co-ordination disorders ranging up to Parkinson""s syndrome, in addition to increased emotional instability and depressive symptoms. The disease is progressive and can lead to death. The treatments used hitherto have been unsatisfactory. At present there are no specific therapeutic agents at all. Attempts at treatment with acetylcholinesterase inhibitors show an effect in only a small proportion of the patients, but involve a high level of side effects.
The pathophysiology of Alzheimer""s disease and SDAT is characterised by a severe deterioration of the cholinergic system, but other transmitter systems are also affected. As a result of the loss of presynaptic cholinergic and other neurones and the resulting lack of preparation of neurotransmitters the neuronal transmission and neuronal activity in the areas of the brain essential for learning and memory are significantly reduced.
Selective adenosine A1 receptor antagonists promote neuronal transmission by the increased production of neurotransmitters, increase the excitability of postsynaptic neurones and can therefore counteract the symptoms of the disease.
The high receptor affinity and selectivity of some of the compounds claimed ought to make it possible to treat Alzheimer""s disease and SDAT with low doses, so that hardly any side effects need be expected which cannot be put down to the blockade of A1 receptors.
Another indication for centrally-acting adenosine A1 antagonists is depression. The therapeutic success of antidepressant substances appears to be linked to the regulation of A1 receptors. A1 antagonists may lead to the regulation of adenosine A1 receptors and thus offer a new therapeutic approach to the treatment of depressive patients.
Other areas of use for A2 selective adenosine antagonists, in particular, are neurodegenerative diseases such as Parkinson""s disease and also migraine. Adenosine inhibits the release of dopamine from central synaptic endings by interacting with dopamine-D2 receptors. A2 antagonists increase the release and availability of dopamine and thus offer a new therapeutic approach to the treatment of Parkinson""s disease.
In migraine, the vasodilatation of cerebral blood vessels mediated by A2 receptors appears to be involved. Selective A2 antagonists inhibit the vasodilatation and can therefore be useful in treating migraine.
Adenosine antagonists may also be used for treating peripheral indications.
For example, the activation of A1, A2 or A3 receptors in the lung may lead to bronchoconstriction. Selective adenosine A1 antagonists relax the tracheal smooth muscle, cause bronchodilatation and can thus be useful as antiasthmatic agents.
Adenosine A2b or A3 receptors are located on mast cells. Their activation causes the release of mast cell products such as histamine, tryptase or interleukin 8. Adenosine A3 receptors are found on eosinophiles and the stimulation of these receptors can influence the activation, chemotaxis and apoptosis of eosinophiles. Therefore, antagonists of A2b or A3 receptors are very promising for the treatment of allergic diseases such as e.g. rhinitis, urticaria, pruritis, allergic dermatitis, allergic eye diseases and nasal polyps. In addition, the effect of adenosine A2b or A3 antagonists on mast cells and eosinophiles may also be helpful in the treatment of asthma.
Furthermore, the anti-mast cell activity may be useful for reducing reperfusion damage after cardiac ischaemia.
By activating A2 receptors, adenosine may cause, inter alia, respiratory depression and cessation of breathing. A2 antagonists bring about respiratory stimulation. For example, adenosine antagonists (theophyllin) are used to treat respiratory distress and prevent sudden infant death in premature babies.
Adenosine stimulates the production of mucus by epithelial cells. The activation of adenosine A2b receptors on bronchial epithelial cells stimulates the chloride transportation which affects the consistency of mucus. Consequently, adenosine antagonists offer new therapeutic approaches to the treatment of diseases in which the quantity or consistency of the mucus is pathological, as in bronchitis and chronic obstructive pulmonary diseases, for example.
Adenosine A2b receptors are also located on the epithelial cells of the intestine. In the intestinal cells, too, the activation of these receptors can lead to increased chloride transportation. It is suspected that during inflammations of the intestines adenosine is released by neutrophiles, for example. The effect of the released adenosine on the chloride transportation influences the motility and absorption capacity of the intestinal epithelium. As a result, adenosine antagonists are possible therapeutic agents for inflammatory intestinal diseases and diarrhoea.
Other important therapeutic fields for adenosine antagonists are cardiovascular diseases and kidney diseases.
In the heart, adenosine inhibits electrical and contractile activity by activating A1 receptors. Combined with coronary vasodilatation mediated via A2 receptors, adenosine has a negative chronotropic, inotropic, dromotropic, bathmotropic and bradycardiac effect and reduces the volume of the heart per minute.
Adenosine A1 receptor antagonists or adenosine A3 receptor antagonists can prevent the damage caused to the heart and brain or lungs by ischaemia and subsequent reperfusion. As a result, adenosine antagonists can be used for the prevention or early treatment of damage to the heart caused by ischaemia/reperfusion e.g. after coronary bypass surgery, heart transplants, angioplasty or thrombolytic therapy of the heart and similar interventions. Moreover, adenosine antagonists can be used for the early treatment of cerebral ischaemia. The same is true of the lungs.
On the kidneys, the activation of A1 receptors causes vasoconstriction of afferent arterioles and as a result a drop in renal bloodflow and glomerular filtration. A1 antagonists act on the kidneys as powerful potassium-saving diuretics and can thus be used to protect the kidneys and to treat oedema, renal insufficiency and acute kidney failure.
On account of the adenosine antagonism on the heart and the diuretic effect, A1 antagonists can be used to therapeutic effect in various cardiovascular diseases, e.g. in cardiac insufficiency, arrythmias (bradyarrythmias) associated with hypoxia or ischaemia, transmission disorders, hypertension, ascites in liver failure (hepato-renal syndrome) and as an analgesic in circulatory disorders.
Adenosine may stimulate or inhibit cell apoptosis, via the adenosine A3 receptors and depending on the type of cell and the concentration of the receptor ligand. This effect can be reversed by adenosine A3 receptor antagonists. Consequently, adenosine A3 receptor antagonists are possible therapeutic agents for diseases in which a disruption of apoptosis is involved, such as for example inflammatory diseases such as arthritis, autoimmune diseases such as lupus erythematodes disseminatus or scleroderma and cancer. Types of cancer which overexpress the adenosine receptor would be particularly suitable for treatment with adenosine A3 receptor antagonists. Moreover, adenosine A3 receptor antagonists may be used to promote the immunological protective mechanisms against any remaining malignant cancer cells (e.g. after surgical removal of a colon carcinoma or other types of tumour).
A3 antagonists inhibit the degranulation of mast cells caused by A3 receptor activation and are therefore therapeutically useful in all disease and pathological situations connected with mast cell degranulation: e.g. as anti-inflammatory substances, in hypersensitivity reactions such as e.g. asthma, allergic rhinitis, urticaria, in myocardiac reperfusion injury, scleroderma, arthritis, autoimmune diseases, inflammatory bowel diseases and the like.
Cystic fibrosisxe2x80x94also known as mucoviscidosisxe2x80x94is an inherited metabolic (a major metabolic) disorder caused by a genetic defect on a certain chromosome. As a result of increased production and greater viscosity of the secretions of the mucosal glands in the bronchi, it may lead to severe complications in the airways. Preliminary investigations have shown that A1 antagonists increase the efflux of chloride ions, e.g. in CF PAC cells. On the basis of these findings, it may be expected that, in patients suffering from cystic fibrosis (mucoviscidosis), the compounds according to the invention will regulate the disrupted electrolyte balance of the cells and alleviate the symptoms of the disease.
In its first aspect, the invention provides new imidazotriazolopyrimidine derivatives of the formula (I)
wherein the dotted lines between the nitrogen atoms of the above general formula I indicate the existence of a double bond in one of two possible positions, so that the groups R4 and R6 and R3 and R2 need not be present simultaneously and wherein:
R1 denotes hydrogen, a C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which may optionally be mono- or polysubstituted by xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94CHO, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CHxe2x95x90NOH, xe2x80x94CHxe2x95x90NOR9, xe2x80x94NR7R8, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94NHCONHPhenyl, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R1 denotes xe2x80x94CHO, xe2x80x94COOR9, xe2x80x94CONR7R8 or NR7R8;
R1 denotes C3-7-cycloalkyl, preferably cyclopentyl or cyclohexyl, which may optionally be substituted by xe2x95x90O, xe2x80x94OR9, OCOR9 or xe2x80x94OCOPyridyl;
R1 denotes phenyl which may optionally be substituted by C14-alkyl, preferably methyl, xe2x80x94CN, xe2x80x94COOR9, NR7R8, xe2x80x94OR9, xe2x80x94OCH2COOR9, xe2x80x94OCH2CONR7R8, xe2x80x94SO3H or halogen;
R1 denotes phenyl-C1-6-alkyl, preferably phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-alkylxe2x80x94NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R1 denotes C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, wherein the cycloalkyl group may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2OCONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-Alkyl-NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, optionally methyl-substituted 1,3-dioxolane or 1,3-dioxane;
R1 denotes a norbornane, norbornene, C3-6-dicycloalkyl-methyl, preferably dicyclopropylmethyl, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R1 denotes a group of formula Axe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C2-6-alkenyl, Axe2x80x94CONHxe2x80x94C2-6-alkynyl, Axe2x80x94NHxe2x80x94COxe2x80x94C1-6-alkyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkenyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkynyl, Axe2x80x94C2-6-alkenyl, Axe2x80x94C2-6-alkynyl or Axe2x80x94, where A is a C- or N-linked 5-, 6- or 7-membered heterocycle, which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally methoxy-substituted benzyl, C1-4-alkyl, xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94COR10, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OR9, xe2x95x90O, a ketal, ethyleneketal, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94R9 or halogen;
R2 or R3 denotes a C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which may optionally be mono- or polysubstituted by xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94CHO, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CHxe2x95x90NOH, xe2x80x94CHxe2x95x90NOR9, xe2x80x94NR7R8, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94NHCONHPhenyl, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R2 or R3 denotes phenyl-C1-6-alkyl, preferably phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R2 or R3 denotes a group of formula Axe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C2-6-alkenyl, Axe2x80x94CONHxe2x80x94C2-6-alkynyl, Axe2x80x94NHxe2x80x94COxe2x80x94C1-6-alkyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkenyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkynyl, Axe2x80x94C2-6-alkenyl, Axe2x80x94C2-6-alkynyl or Axe2x80x94, where A is a C- or N-linked 5-, 6- or 7-membered heterocycle, which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally methoxy-substituted benzyl, C1-4-alkyl, xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94COR10, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OR9, xe2x95x90O, a ketal, ethyleneketal, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94R9 or halogen;
R4 or R5 denotes hydrogen, C1-4-alkyl which may optionally be substituted by xe2x80x94NR7R8, benzyl, but preferably hydrogen;
R5 denotes hydrogen, a C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which may optionally be mono- or polysubstituted by xe2x80x94CN, xe2x80x94CH2NR7R8, COOR9, xe2x80x94CONR7R8, xe2x80x94CHO, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CHxe2x95x90NOH, xe2x80x94CHxe2x95x90NOR9, xe2x80x94NR7R8, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94NHCONHPhenyl, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R5 denotes C3-7-cycloalkyl, preferably cyclopentyl or cyclohexyl, which may optionally be substituted by xe2x95x90O, xe2x80x94OH, xe2x80x94OR9, OCOR9 or xe2x80x94OCOPyridyl;
R5 denotes phenyl which may optionally be substituted by xe2x80x94OH, halogen, xe2x80x94OR9, C1-4-alkyl, preferably xe2x80x94CH3, xe2x80x94NH2, xe2x80x94COOH, xe2x80x94SO3H, xe2x80x94COOR9, xe2x80x94OCH2COOR9, xe2x80x94CN or xe2x80x94OCH2CONR7R8;
R5 denotes phenyl-C1-6-alkyl, preferably phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R5 denotes a norbornane, norbornene, C3-6-dicycloalkyl-methyl, preferably dicyclopropylmethyl, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R5 denotes xe2x80x94CHO, xe2x80x94COOR9, xe2x80x94CONR7R8 or NR7R8;
R5 denotes C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, wherein the cycloalkyl group may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2xe2x80x94OCONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-Alkylxe2x80x94NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R5 denotes a group of formula Axe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C2-6-alkenyl, Axe2x80x94CONHxe2x80x94C2-6-alkynyl, Axe2x80x94NHxe2x80x94COxe2x80x94C1-6-alkyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkenyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkynyl, Axe2x80x94C2-6-alkenylene, Axe2x80x94C2-6-alkynylene or Axe2x80x94, where A is a C- or N-linked 5-, 6- or 7-membered heterocycle, which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally methoxy-substituted benzyl, C1-4-alkyl, xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94COR10, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OR9, xe2x95x90O, a ketal, ethyleneketal, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94R9 or halogen;
R7 denotes hydrogen, C1-8-alkyl, preferably C1-4-alkyl, which may optionally be substituted by xe2x80x94COOR9, xe2x80x94COR10, xe2x80x94OR9, OCOR9, amino, phenyl, methoxy-substituted phenyl or amino, or a C3-6-cycloalkyl;
R7 denotes a 5-, 6- or 7-membered heterocycle C-linked directly or via a C1-4-alkyl chain, which contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally mono- or polysubstituted, preferably monosubstituted, by benzyl, methoxy-substituted benzyl, C1-4-alkyl, halogen, xe2x80x94OR9, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x95x90O, xe2x80x94SO3H or xe2x80x94COOR9;
R8 denotes hydrogen, C1-8-alkyl, preferably C1-4-alkyl, which may optionally be substituted by xe2x80x94COOR9, xe2x80x94COR10, xe2x80x94OR9, OCOR9, amino, phenyl, methoxy-substituted phenyl or amino, or a C3-6-cycloalkyl, or
R8 denotes a 5-, 6- or 7-membered heterocycle C-linked directly or via a C1-4-alkyl chain, which contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally mono- or polysubstituted, preferably monosubstituted, by benzyl, methoxy-substituted benzyl, C1-4-alkyl, halogen, xe2x80x94OR9, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x95x90O, xe2x80x94SO3H or xe2x80x94COOR9; or
R7 and R8 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen, oxygen or sulphur as further heteroatoms, whilst the heterocycle may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, or may carry one of the groups xe2x80x94CN, xe2x80x94COOR9, xe2x80x94CONH2, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OR9, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94R9, halogen or xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94NH2, xe2x95x90O, xe2x80x94OCH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94OCH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94C1-4-alkyl, xe2x80x94(CH2)nxe2x80x94N(C1-4-alkyl)2, xe2x80x94(CH2)nxe2x80x94NHCOOR9, wherein n=1, 2, 3 or 4;
R9 denotes hydrogen, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, a benzyl or phenyl group which may optionally be mono- or polysubstituted by xe2x80x94OCH3;
R10 denotes C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, optionally methoxy-substituted phenyl, optionally methoxy-substituted benzyl, C3-6-cycloalkyl;
R11 denotes hydrogen, C1-3-alkyl, xe2x80x94COOR9, xe2x80x94CH2OR9, xe2x80x94CH2NR7R8, xe2x80x94CONR7R8 or optionally methoxy-substituted phenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
These are adenosine antagonists and are useful for, inter alia, the treatment of senile dementia of the Alzheimer""s type.
Preferred compounds of general formula (I) are those wherein
R1 denotes hydrogen, C1-8-alkyl which may optionally be substituted by xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, xe2x80x94COxe2x80x94C1-4-alkyl, xe2x80x94CHO, xe2x80x94NR7R8, xe2x95x90NOH, xe2x80x94NHCOxe2x80x94C1-4-alkyl, xe2x80x94NHCO-phenyl, hydroxy, xe2x95x90O, C1-4-alkoxy, phenyloxy, xe2x80x94O-phenyl-C1-4-alkyloxy, benzyloxy, xe2x80x94O-benzylxe2x80x94Oxe2x80x94C1-4-alkyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-benzyl, xe2x80x94OCO-pyridyl, xe2x80x94Oxe2x80x94C2-4-alkylene or halogen;
R1 denotes xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8 or an amine of general formula NR7R8;
R1 denotes phenyl which may optionally be substituted by C1-4-alkyl, -COxe2x80x94C14-alkyl, C1-4-alkyl-NR7R8, C1-4-alkyl-OH, C1-4-alkylxe2x95x90NOH, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COOxe2x80x94phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkylxe2x80x94NH2, NR7R8, hydroxy, C1-4-alkyloxy, benzyloxy, phenyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-benzyl, xe2x80x94OCO-pyridyl, xe2x80x94Oxe2x80x94C2-4-alkenyl or halogen, preferably chlorine or fluorine;
R1 denotes a C3-6-cycloalkyl or C3-6-cycloalkyl-C1-4-alkyl group which may optionally be substituted by xe2x95x90O, hydroxy, C1-4-alkyl or C1-4-alkyloxy;
R1 denotes a norbornane, norbornene, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R1 denotes phenyl-C1-4-alkyl, preferably benzyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally be substituted by C1-4-alkyl, xe2x80x94COxe2x80x94C1-4-alkyl, C1-4-alkyl-NR7R8, C1-4-alkyl-OH, C1-4-alkylxe2x95x90NOH, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkyl-NH2, NR7R8, hydroxy, C1-4-alkyloxy, benzyloxy, phenyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-benzyl, xe2x80x94OCO-pyridyl, xe2x80x94Oxe2x80x94C2-4-alkylene or halogen, preferably chlorine or fluorine;
R1 denotes a 5- or 6-membered heterocycle optionally C- or N-linked either directly or via an alkylene bridge having 1 to 4 carbon atoms, which contains one, two or three heteroatoms selected from the group comprising nitrogen or oxygen and which is optionally mono- or polysubstituted by benzyl or C1-4-alkyl;
R2 or R3 denotes a C1-8-alkyl which may optionally be substituted by xe2x80x94NR7R8, OH or COOH; or
R2 or R3 denotes C2-8-alkenyl, phenyl-C1-4-alkyl, preferably benzyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, whilst the phenyl ring may optionally be substituted by hydroxy, C1-4-alkyl, C1-4-alkyloxy, xe2x80x94NR7R8or halogen, preferably chlorine or fluorine;
R2 or R3 denotes a 5- or 6-membered heterocycle optionally C- or N-linked either directly or via an alkylene bridge having 1 to 4 carbon atoms, which contains one, two or three heteroatoms selected from the group comprising nitrogen or oxygen and which is optionally mono- or polysubstituted by benzyl or C1-4-alkyl;
R4 or R6 denotes hydrogen, C1-4-alkyl which may optionally be substituted by xe2x80x94NR7R8, or benzyl;
R5 denotes hydrogen, C1-8-alkyl, preferably C1-6-alkyl;
R5 denotes phenyl which may optionally be substituted by C1-4-alkyl, C1-4-alkyloxy, hydroxy, xe2x80x94NR7R8 or halogen, preferably chlorine or fluorine;
R5 denotes phenyl-C1-6-alkyl, preferably benzyl, whilst the phenyl ring may optionally be substituted by C1-4-alkyl, C1-4-alkyloxy, hydroxy, xe2x80x94NR7R8 or halogen, preferably chlorine or fluorine;
R5 denotes an optionally substituted amine, preferably xe2x80x94NR7R8;
R5 denotes a 5- or 6-membered heterocycle optionally C- or N-linked either directly or via a C1-4-alkylene bridge, which contains one or more heteroatoms selected from the group comprising nitrogen or oxygen and which is optionally substituted by benzyl or C1-4-alkyl;
R5 denotes a C3-6-cycloalkyl which may optionally be substituted by xe2x95x90O, hydroxy, C1-4-alkyl or C1-4-alkyloxy;
R5 denotes a norbornane, norbornene, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R7 denotes hydrogen, a branched or unbranched C1-4-alkyl group;
R7 denotes a C-linked 5- or 6-membered heterocycle which contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally substituted by benzyl, C1-4-alkyl, C1-4-alkyloxy, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH or xe2x95x90O;
R8 denotes hydrogen, a branched or unbranched C1-4-alkyl group;
R8 denotes a C-linked 5- or 6-membered heterocycle which contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally substituted by benzyl, C1-4-alkyl, C1-4-alkyloxy, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH or xe2x95x90O; or
R7 and R8 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen or oxygen as further heteroatoms, whilst the heterocycle may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, or by a xe2x80x94(CH2)1-4-phenyl group, preferably benzyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Also preferred are the compounds of general formula (I) wherein
R1 denotes hydrogen, C1-6-alkyl, preferably C1-4-alkyl, which may optionally be substituted by xe2x80x94COxe2x80x94C1-4-alkyl, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, xe2x80x94NR7R8, xe2x80x94NHCOxe2x80x94C1-4-alkyl, xe2x80x94NHCO-Phenyl, hydroxy, xe2x95x90O, C1-4-alkoxy, phenyloxy, xe2x80x94O-phenylxe2x80x94Oxe2x80x94C1-4-alkyloxy, benzyloxy, xe2x80x94O-benzylxe2x80x94Oxe2x80x94C1-4-alkyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-pyridyl, xe2x80x94OCO-benzyl, xe2x80x94Oxe2x80x94C2-4-alkylene or halogen;
R1 denotes phenyl, whilst the phenyl ring may optionally be substituted by C1-4-alkyl, hydroxy, C1-4-alkyloxy, NR7R8, halogen, preferably fluorine or chlorine;
R1 denotes phenyl-C1-3-alkyl, preferably benzyl, whilst the phenyl ring may optionally be substituted by C1-4-alkyl, xe2x80x94COxe2x80x94C1-4-alkyl, xe2x80x94C1-4-alkyl-NR7R8, xe2x80x94C1-4-alkylxe2x80x94OH, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, NR7R8, hydroxy, C1-4-alkyloxy, benzyloxy, phenyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-benzyl, xe2x80x94OCO-pyridyl, xe2x80x94Oxe2x80x94C2-4-alkylene or halogen, preferably fluorine or chlorine;
R1 denotes a cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane linked via a single bond or via an alkylene chain having 1 to 4 carbon atoms;
R1 denotes xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94COxe2x80x94NHxe2x80x94C1-4-alkyl, xe2x80x94COxe2x80x94N(C1-4-alkyl)2 or xe2x80x94COxe2x80x94NH-phenyl;
R1 denotes an amine of general formula NR7R8;
R1 denotes a heterocycle selected from the group consisting of furan, tetrahydrofuran, xcex1-pyran, xcex3-pyran, dioxolane, tetrahydropyran, dioxane, thiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole and pyrazolidine linked via a single bond or via an alkylene chain with 1 to 4 carbon atoms;
R2 or R3 denotes C1-7-alkyl, preferably C1-5-alkyl, which may optionally be substituted by xe2x80x94NR7R8, OH or COOH; or
R2 or R3 denotes C2-5-alkenyl or phenyl-C1-3-alkyl, preferably benzyl, whilst the phenyl ring may be substituted by C1-4-alkyl, xe2x80x94NR7R8, hydroxy, C1-4-alkyloxy or halogen, preferably chlorine or fluorine;
R2 or R3 denotes a heterocycle selected from the group consisting of furan, tetrahydrofuran, xcex1-pyran, xcex3-pyran, dioxolane, tetrahydropyran, dioxane, thiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole and pyrazolidine linked via a single bond or via an alkylene chain with 1 to 4 carbon atoms;
R4 or R6 denotes hydrogen, C1-4-alkyl, preferably C1-3-alkyl, C1-3-alkyl-NR7R8 or benzyl;
R5 denotes hydrogen, C1-6-alkyl, preferably C1-4-alkyl;
R5 denotes cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane;
R5 denotes pyridyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, morpholine, piperidine or piperazine which is optionally substituted by C1-4-alkyl or benzyl;
R5 denotes a phenyl group which may optionally be substituted by C1-4-alkyl, halogen or hydroxy;
R5 denotes phenyl-C1-4-alkyl, preferably benzyl, whilst the phenyl ring may optionally be substituted by C1-4-alkyl, xe2x80x94NR7R8, hydroxy, C1-4-alkyloxy or halogen, preferably fluorine or chlorine;
R5 denotes an amine of general formula xe2x80x94NR7R8;
R5 denotes a norbornene, norbornane, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R7 denotes hydrogen, a branched or unbranched C1-4-alkyl group;
R7 denotes a C-linked heterocycle selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, imidazolidine, triazole, pyridine, piperidine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole and thiadiazole which is optionally substituted by C1-4-alkyl, xe2x80x94NO2, xe2x80x94NH2, hydroxy, C1-4-alkyloxy, chlorine or bromine;
R8 denotes hydrogen, a branched or unbranched C1-4-alkyl group, or
R denotes a C-linked heterocycle selected from the group consisiting of pyrrole, pyrrolidine, pyrazole, imidazole, imidazolidine, triazole, pyridine, piperidine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole and thiadiazole which is optionally substituted by C1-4-alkyl, xe2x80x94NO2, xe2x80x94NH2, hydroxy, C1-4-alkyloxy, chlorine or bromine; or
R7 and R8 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen or oxygen as further heteroatoms, whilst the heterocycle may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, or by a xe2x80x94(CH2)1-4-phenyl group, preferably benzyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred compounds according to the invention are compounds of general formula (I) wherein
R1 denotes hydrogen, or C1-4-alkyl, which is optionally substituted by xe2x80x94NHCOxe2x80x94C1-4-alkyl, xe2x80x94NR7R8, hydroxy, C1-4-alkyloxy, chlorine or bromine; or
R1 denotes xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl or phenyl; or
R1 denotes phenyl-C1-3-alkyl, preferably benzyl which may optionally be substituted by C1-4-alkyl, C1-4-alkyl-NR7R8, hydroxy, benzyloxy or fluorine; or
R1 denotes phenyloxy-C1-3-alkyl, preferably phenyloxymethyl, which may optionally be substituted by methoxy; or
R1 denotes benzyloxy-C1-3-alkyl, preferably benzyloxymethyl which may optionally be substituted by methoxy; or
R1 denotes benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl, N-morpholinomethyl, cyclopentyl or furyl;
R2 or R3 denote C1-5-alkyl, C2-4-alkenyl or benzyl;
R4 or R6 denote hydrogen, C1-3-alkyl, C1-3-alkylxe2x80x94NR7R8, N-morpholinoethyl or benzyl;
R5 denotes hydrogen, C1-4-alkyl, phenyl or benzyl wherein the phenyl ring may optionally be substituted by fluorine; or
R5 denotes pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzylpiperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR7R8, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl;
R7 denotes hydrogen, C1-4-alkyl or pyridyl;
R8 denotes hydrogen, C1-4-alkyl or pyridyl
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Also preferred according to the invention are compounds of general formula (I) wherein
R1 denotes hydrogen, methyl, which may optionally be substituted by xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94NMe2, xe2x80x94N(propyl)2, xe2x80x94NHAcetyl, hydroxy, methoxy, ethoxy, phenyloxy, methoxyphenyloxy, methoxybenzyloxy, piperazine, methylpiperazine, morpholine, benzoyloxy, pyridylcarbonyloxy, pyridine, pyridylamino, pyrrole or bromine; or
R1 denotes ethyl which is optionally substituted by xe2x80x94NH2 or hydroxy; or
R1 denotes benzyl which is optionally substituted by hydroxy, methoxy, benzyloxy, dimethylaminoethoxy, N-morpholinoethoxy or fluorine; or
R1 denotes n-propyl, isopropyl, n-butyl, tert.butyl, cyclopentyl, cyclohexylmethyl, phenyl, phenylethyl, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOMe, COOEt, COOPropyl, COOButyl or furan;
R2 or R3 denote methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, allyl, butenyl, n-pentyl, propargyl or benzyl;
R4 or R6 denote hydrogen, methyl, n-propyl or benzyl; or
R4 or R5 denote ethyl which is optionally substituted by morpholine;
R5 denotes hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, phenyl, benzyl, pyridyl, xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94NMe2, piperidinyl, morpholinyl; or
R5 denotes piperazinyl which is optionally substituted by methyl or benzyl; or
R5 denotes furyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornanyl or norbornenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred according to the invention are compounds of general formula (I) wherein
R1 denotes hydrogen, methyl which is optionally substituted by xe2x80x94NMe2, hydroxy, methoxy, ethoxy, phenyloxy, methoxyphenyloxy, methoxybenzyloxy, morpholine, benzoyloxy, pyridylcarbonyloxy, pyridine, pyridylamino or pyrrole; or
R1 denotes ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, cyclopentyl, cyclohexylmetyl or benzyl which is optionally be substituted by hydroxy, methoxy, dimethylaminoethoxy or fluorine;
phenyl, phenylethyl, xe2x80x94COOH, xe2x80x94COOMe or furan;
R2 or R3 denote methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl, allyl, butenyl, propargyl or benzyl;
R4 or R6 denote hydrogen;
R1 denotes hydrogen, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, phenyl, benzyl, pyridine, piperidine, morpholine, piperazine, 4-benzylpiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, xe2x80x94NMe2, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornanyl or 5-norbornenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Especially preferred according to the invention are compounds of general formula (I) wherein
R1 denotes methyl, which s optionally substituted by xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94N(iso-propyl)2, -NHAcetyl, hydroxy, phenyloxy, methylpiperazine or pyrrole; or
R1 denotes ethyl which is optionally substituted by xe2x80x94NH2 or hydroxy; or
R1 denotes benzyl which is optionally substituted by hydroxy, methoxy, benzyloxy, dimethylaminoethoxy, N-morpholinoethoxy or fluorine; or
R1 denotes cyclopentyl phenylethyl, xe2x80x94COOH, xe2x80x94COOPropyl, xe2x80x94COOButyl or furan;
R2 or R3 denote ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, allyl, butenyl or propargyl;
R4 or R6 denote hydrogen, methyl or ethyl, which is substituted by morpholine;
R5 denotes methyl, ethyl, n-propyl, tert.butyl, cyclopentyl or norbornenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are also compounds of general formula (I) wherein
R1 denotes methyl, which is optionally substituted by phenyloxy or pyrrole; or
R1 denotes benzyl which is optionally substituted by hydroxy, methoxy, dimethylaminoethoxy or fluorine; or
R1 denotes cyclopentyl, furan or phenylethyl;
R2 or R3 denote ethyl, n-propyl, allyl or propargyl;
R4 or R1 denote hydrogen;
R5 denotes methyl, n-propyl, tert.butyl, cyclopentyl or norbornenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The compounds of general formula (I) form the following isomers:
the isomers of general formulae (Ia) and (Ib) being particularly preferred, especially those wherein R4 or R6 are hydrogen or C1-4-alkyl. Particularly preferred are compounds of general formula (Ia) and (Ib) wherein R4 and R6 denote hydrogenxe2x80x94in this case the isomers (Ia) and (Ib) are tautomers. According to the invention, the particularly preferred compounds are the isomers (Ia), especially those which have a I substituent in positions 2, 4 and 7.
If desired, the compounds of general formula (I) may be converted into their salts, more particularly, for pharmaceutical use, into their physiologically acceptable salts with an inorganic or organic acid. Suitable acids include for example succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. Mixtures of the abovementioned acids may also be used.
Suitable alkyl groups (including those which are components of other groups) are branched and unbranched alkyl groups having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, hexyl, heptyl and octyl. In some cases the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are used for the abovementioned groups.
Suitable alkenyl groups (including those which are components of other groups) are branched and unbranched alkenyl groups having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, provided that they have at least one double bond, as well as the abovementioned alkyl groups, for example, provided that they have at least one double bond, such as vinyl (provided that no unstable enamines or enolethers are formed), propenyl, isopropenyl, butenyl, pentenyl and hexenyl.
Suitable alkynyl groups (including those which are components of other groups) are alkynyl groups having 2 to 8 carbon atoms, provided that they have at least one triple bond, such as ethynyl, propargyl, butynyl, pentynyl and hexynyl.
Suitable cycloalkyl groups having 3 to 6 carbon atoms include, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which may also be substituted by branched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy, and/or halogen or as hereinbefore defined. Halogen generally denotes fluorine, chlorine, bromine or iodine.
Examples of N-linked cyclic groups of general formula NR7R8 include: pyrrole, pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, preferably morpholine, piperazine and piperidine, whilst the abovementioned heterocycles may also be substituted by benzyl, alkyl having 1 to 4 carbon atoms, preferably methyl, or can be substituted as specified in the definitions.
Examples of C-linked 5- or 6-membered heterocyclic rings which may contain, nitrogen, oxygen or sulphur as heteroatoms, include, for example, furan, tetrahydrofuran, tetrahydrofuranone, -butyrolactone, -pyran, -pyran, dioxolane, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole or pyrazolidine, whilst the heterocycle may be substituted as specified in the definitions.
xe2x80x9cxe2x95x90Oxe2x80x9d denotes an oxygen atom linked via a double bond.
The compounds according to the invention may be prepared as described in the prior art (Tenor et al., Chem. Ber. Vol. 97 (1964) p. 1373-1382), to which reference is hereby made (diagram 1).
Diagram 1
The above method of synthesis already disclosed in the prior art can be used to prepare the compounds of general formula (I) according to the invention wherein the groups R2 or R3 and R4 or R6 denote hydrogen. In this case, the compounds of general formula (I) are tautomers, one tautomeric form of which is represented by formula (4) in diagram 1. The triazolopyrimidones referred to as compounds (1) in diagram 1 may be prepared by reacting cyanoacetic ester derivatives with suitably substituted 3-amino-1,2,4-triazoles as described by Tenor et al. in the introduction. The latter compounds can be obtained by methods known from the literature (J. Org. Chem. 1926, p. 1729; Org. Synthesis 26, p. 11; J. Chem. Soc. 1929, p. 816).
In order to obtain the compounds of general formula (I) wherein the groups R4 or R6 and R2 or R3 denote something other than hydrogen, the following procedure may be followed:
Before the reaction sequence described in the prior art and shown in diagram 1, the compounds (1) may be derivatised according to diagram 2. According to the invention, alkylation or benzylation is preferred as derivatisation.
Diagram 2
The alkylation or benzylation to be carried out leads to the compounds (5). The isomeric alkylation products (5xe2x80x2) may possibly be obtained as well. Any mixtures of products (5) and (5xe2x80x2) obtained can be separated into the pure alkylation products (5) and (5xe2x80x2) using purification methods known to the skilled person, such as fractional crystallisation or chromatography.
The compounds (5) and (5xe2x80x2) are then subjected to the reaction sequence described by Tenor et al., as shown diagrammatically for the reaction of compounds (5) in diagram 3.
Diagram 3
The procedure described above which can be carried out analogously to the prior art can be used to prepare the compounds of general formula (I) according to the invention wherein the groups R4 or R6 denote hydrogen. In this case, the compounds of general formula (I) are tautomers, one tautomeric form of which is represented by formula (8) in diagram 3.
Starting from the alkylation products (5xe2x80x2) the compounds (8xe2x80x2) may be obtained accordingly (diagram 4).
Diagram 4
The method of synthesis described above which can be carried out analogously to the prior art can be used to prepare the compounds of general formula (I) according to the invention wherein the groups R4 or R6 denote hydrogen. In this case, the compounds of general formula (I) are tautomers, one tautomeric form of which is represented by formula (8xe2x80x2) in diagram 4.
Compounds (Ia) and (Ib) may be obtained by re-alkylation of the compounds (8) (Diagram 5).
Diagram 5
Mostly the compounds (Ia) are isolated as the main products.
Analogously, the reaction of the derivatives (8xe2x80x2) leads to the compounds (Ic) and (Id) (Diagram 6).
Diagram 6
Mostly the compounds (Ic) are isolated as the main products.
Depending on the substitution pattern, the compounds (Ia), (Ib), (Ic) or (Id) wherein the groups R1 to R6 may be defined as hereinbefore, can be further functionalised using methods known from the literature. These functionalisations comprise the processes familiar to the skilled person, namely oxidation, reduction, ether splitting, acylation, alkylation, etc. Moreover, the use of common protecting groups, especially common hydroxyl and amino protecting groups may be necessary. It is particularly preferable to use the p-methoxybenzyl group as a protecting group for a hydroxyl function, for example, in conjunction with the benzyl group as an amino protecting group.

Imidazotriazolopyrimidines with adenosine-antagonistic activity

Abstract: Preferred are those compounds wherein:

Abstract: R4 or R6 denote hydrogen; and,

Abstract: R5 denotes methyl, n-propyl, tert.butyl, cyclopentyl or norbornenyl.

Abstract: These are adenosine antagonists are are useful for, inter alia, the treatment of senile dementia of the Alzheimer""s type.


1,5-diaryl-2-alkylpyrrole-3-substituted nitro esters, of Formula (I)

The non-steroidal anti-inflammatory drugs (NSAIDs) represent a class that is widely used in the treatment of various disorders. To date, treatment with NSAIDs is the best available therapy for pain caused by rheumatoid arthritis (RA) and osteoarthritis (OA), and other examples of common applications are treatment of fibromyalgia, of intestinal inflammation, inflammation of the urogenital tract and of the respiratory system, treatment of dysmenorrhoea and treatment of lupus erythematosus. Although the analgesic action of NSAIDs does not match in potency that of the opiates, their co-administration with usual narcotics has found wide application both for the treatment of postoperative pain and of chronic pain induced by various pathologies including tumoral pathologies. NSAIDs perform their anti-inflammatory and analgesic action via inhibition of cyclooxygenase (COX). At least two isoforms of COX are known: COX-1, expressed constitutively, and COX-2, which is absent from most tissues in physiological conditions and is expressed as a result of pro-inflammatory stimuli (e.g.: cytokines). As the traditional anti-inflammatories (tNSAIDs) are not selective, they inhibit both isoforms often with a preference for COX-1. This poor selectivity leads, with concomitant inhibition of COX-1, to inhibition of synthesis of prostanoids that are essential for maintenance of the functions of the gastric mucosa and of renal homeostasis, giving rise, especially in prolonged use, to severe gastrointestinal (GI) and renal complications. Inhibition of COX-1 by tNSAIDs leads initially to a decrease in thickness of the mucosa (erosion) and then to lesions (ulcer). At the renal level tNSAIDs are known to cause reduced glomerular filtration that gives rise to nephritides and, in particularly sensitive patients, to ischaemia and renal blockade. Clinical use of selective COX-2 inhibitors (Coxibs) has recently shown that the gastric toxicity associated with the use of tNSAIDs can be reduced considerably. Several recent clinical studies have shown that selective COX-2 inhibition, as well as giving rise to anti-inflammatories and analgesics with a safer GI profile, proves effective in the treatment of various precancerous and cancerous forms. In fact, COX-2 is overexpressed in gastric, hepatic, pancreatic, oesophageal, colon, breast, bladder, and lung tumours. However, various clinical and epidemiological studies have shown that long-term use of selective COX-2 inhibitors is associated with a higher incidence of adverse effects relating to the cardiovascular system, and in particular with an increased incidence of myocardial infarction, angina pectoris and transient ischaemic attacks. The cause of this toxicity for the cardiovascular system, which is also found with some tNSAIDs that are rather selective in inhibiting COX-2, arises from the fact that this isoform, constitutively expressed in the vascular epithelium, is fundamental to the synthesis of prostaglandin PGI2, a potent vasodilator (J. M. Dogné et al., J. Med. Chem., 2005, 48, 2251-2257). Thus, high selectivity in inhibition of COX-2 leads, in the cardiovascular system, to prevalence of the pro-aggregative and vasoconstrictive stimulus exerted by thromboxane (TxA2) no longer counterbalanced by the vasodilator effect of PGI2. The side effects associated with the use of tNSAIDs and those relating to the use of Coxibs create the need for new analgesics and anti-inflammatories that have a better profile of tolerability.
Similarly to prostacyclin (PGI2), nitric oxide (NO) at low concentrations has an important role in maintaining appropriate functionality of the cardiovascular system (J. F. Kervin et al., J. Med. Chem., 1995, 38, 4343-4362). Although the potent vasodilator effect of organic nitrates has been known for a long time, it was only discovered at the end of the 1970s that NO (Endothelium Derived Relaxing Factor, EDRF) is one of the mediators released by the vascular endothelium to control vasodilation, thrombosis, permeability and angiogenesis. NO gives rise, through activation of guanylate cyclase, to an increase in cGMP, which leads to vasodilation in smooth muscles, inhibits adhesion of leukocytes to the vessel wall and inhibits platelet aggregation, giving rise to an overall anti-thrombotic action.
It is also known that NO is of fundamental importance in maintaining good cardiac functionality and that gene knock-out experiments relating to the genes held to be responsible for expression of the enzymes capable of forming NO leads to spontaneous myocardial infarction (M. Tsutsui et al., Trends Cardiovasc. Med., 2008, 18, 8, 275-79). In the body, NO is synthesized by an enzyme known as nitric-oxide synthase (NOS), of which three isoforms are known: epithelial (eNOS), neuronal (nNOS) and inducible (iNOS). It is well known that appropriate derivatives of nitric acid (organic nitrates) as well as other organic compounds such as nitrosothiols and 1,2,5-oxadiazoles-2-oxide (furoxane N-oxide) are able to release NO of "exogenous" origin, so as to be utilizable in the treatment of cardiovascular pathologies (A. Martelli et al., Curr. Med. Chem. 2006, 13, 6, 609-25). The synthesis of molecules capable of selectively inhibiting COX-2 and at the same time of releasing NO appropriately, can give rise to new anti-inflammatory and analgesic drugs, without the cardiovascular and renal side effects that characterized the Coxibs. Some COX inhibitors that are donors of NO (CINOD: COX Inhibitors Nitric Oxide Donors) are known, for example naproxcinod (WO 9509831) and NO-flurbiprofen (WO 94012463). Although, for these products, complete absence of adverse events in the cardiovascular and renal area was recently claimed (WO 2008/132025), these compounds were designed more for overcoming the effects of gastric toxicity known for the COX-1 inhibitors than for the effects of cardiovascular and renal toxicity connected with inhibition of COX-2. In fact, protective effects exerted by NO are also known in the GI system, such as modulation of blood flow, control of permeability of the epithelium, secretion of mucus and of bicarbonate and capacity for improving the properties of self-repair in the damaged mucosa (J. L. Wallace et al., Trends Pharm. Sci., 2009, 30, 112-117). Selective COX-2 inhibitors that are at the same time NO donors have been reported, for example for rofecoxib (WO 2005/070883) or for cimicoxib (K. Chegaev et al., J. Med. Chem., 2007, 50, 1449-1457) as well as for other heterocyclic COX-2 inhibitors (C. Velazquez et al., Bioorg. & Med. Chem., 2005, 2749-2757). WO 2008/014821 describes inhibitors that are selective for COX-2, which have favourable pharmacokinetic and pharmacodynamic properties, which are reflected in excellent pharmacological properties. The possibility of combining, in these inhibitors, a function of being able to release NO appropriately, at the same time maintaining adequate activity in inhibition of COX-2, would give rise to new anti-inflammatory and analgesic drugs characterized by absence of the cardiovascular and renal effects typical of the selective COX-2 inhibitors, and would make it possible to improve their GI profile. Moreover, it should be borne in mind that although NO at high concentrations (such as the micromolar concentrations produced by iNOS) has deleterious effects on the cartilage in disorders such as OA and RA, at low concentrations (such as the nanomolar/picomolar concentrations produced by cNOS) NO has an anti-apoptotic and protective effect for the chondrocytes. Moreover, it is known that low concentrations of NO can have an important role in increasing blood flow, improving the supply of nutrients and oxygen to the synovia and to the subchondral bone. As well as the role of NO in the control of pain, via activation of cGMP in the nerve cells which, leading to hyperpolarization, consequently gives rise to blocking of pain transmission. These synergistic effects with inhibition of COX-2, exerted by release of small amounts of NO, are not only useful in the treatment of disorders such as OA and RA (I. S. Mackenzie et al., Arthritis Research & Therapy, 2008, 10: S3) but also in the treatment of various types of tumours (B. Bonavida et al., Nitric Oxide, 2008, 152-157). In fact, it was recently shown that NO-donors can inhibit the capacity of some types of tumours to metastasize as well as being able to restore apoptosis, making the tumour cell sensitive to chemotherapy. The role of nitro-aspirin (NO-ASA) in inhibiting the development of pancreatic tumour was described recently (N. Ouyang et al., Cancer Res., 2006, 66:8, 4503), as well as the efficacy of other CINODs in the treatment of colon tumour (G. K. Hagos et al., Mol. Cancer Ther., 2007, 2230-39) and prostate cancer (N. Beziere et al., Bioorganic & Med. Chem. Lett, 2008, 4655-57).

1,5-Diary1-2-alkylpyrrole-3-substituted nitro esters, selective COX-2 inhibitors and nitric oxide donors

Abstract: are provided. Such compounds are potent and selective COX-2 inhibitors which are able to release NO in concentrations that make it possible to counteract the side effects due to selective COX-2 inhibition, without giving rise to hypotensive effects. Formula (I) includes compounds wherein the groups R′ and R″ are: —H, —F, —Cl, —Br, —CH3, —CF3, —OCH3, —SCH3, R1 is methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl and the substituent in position −3 of the pyrrole ring is a chain, where the groups X, Y, Z, W and R2 are: X is a carbonyl or a group —(CHR3)—, Y is an oxygen atom or the group —NR3— and Z is a carbonyl or a group —(CHR3)—, or a [—CH(COOH)—] group, or a group —(NR3)—, W is an aliphatic chain substituted with one or two (—O—NO2) groups, R2 is: —H, —OH, —OCH3, or —NHR3. R3 is: —H, —CH3, —CH2CH3, [—CH2(CH3)2]. R′″ is methylsulphonyl or sulphonamido. Pharmaceutical formulations and methods of making an using such formulations are also provided.


A screen system used in the electro-optical reproduction of half-tone pictures in multicolor prints are generated by an algorithm which simulates a continuous tone image. There is disclosed partial screens and screen systems produced by an algorithm for use with a digitized image which provides a means of simulating a continuous tone image containing a range of gray shades from black to white or a color separation. The "Threshold equation" is the key of the invention as it calculates a threshold gray value that is compared to the desired local image value to determine whether that particular point should be "on" or "off". Which points (spots) are "on" and which are "off" is determined by the function that assigns a "threshold" value (the shade at which a pixel changes from "off" to "on") based on a pixels "x" and "y" coordinates. The generated screen comprises columns and rows of halftone dot centers, the columns and rows are geometrically orthogonal (perpendicular), but the row to row spacing and/or column to column spacing is not equal, either row to row, column to column, or row to column.

1. Field of Invention
This invention relates to a non-conventional screen system for use in a halftone generation method in digital image systems. A type of algorithm is used which is capable of generating novel halftone screen patterns which can have performance advantages. 2. Background of the Art
Algorithms are needed which can provide a means of simulating a continuous tone image containing a range of gray shades from black to white, or color separation containing a range of densities of some appropriate colorant. The practical implementation of such an algorithm must rely on a dot pattern defined within a fundamental halftone cell or "glyph" which is a relatively small rectangular array of points.
In the art of printing, half-tone systems have long been used to represent pictorial subjects where tone graduation is important. This was and frequently still is accomplished by the use of a photomechanical system in which a fine cross-hatch screen covers the pictorial image during exposure at a suitable stage in the photographic process leading to the printing plate. By this means the image is divided up into a multitude of regularly spaced very small (subliminal) dots whose size varies with the image density being reproduced. With the use of full color printing of subjects, three or four printing plates, one for each of the separate primary color images have to be prepared. The use of identical half-tone screens for each of these color separations can result in undesirable interactive visual effects including very pronounced and objectionable Moire patterns when the several successive print impressions are made. These Moire effects can be reduced to imperceptible levels by crossing the screen directions with one another. In the practice of the art it has long been known that a suitable set of screen angles for four color printing is 45.degree., 0.degree., +15.degree., and -15.degree. (See reference to this art in Chapter 13 of "Principles of Color Reproduction", by J. A. G. Yule, John Wiley & Sons Inc. N.Y., 1967).
In the conventional half-tone system, the original continuous tone picture is represented in the print by regularly spaced high density dots of ink. The dots are sufficiently closely spaced that the unaided human eye cannot distinguish them. The changing size of the dots give the impression of changing tone, and by suitable control of the process the original tones can be reproduced faithfully. With full color originals, suitable control of the process of making the individual half-tone color separations can give faithful reproductions in full color. These photomechanical processes are slow and painstaking, particularly when high quality results requiring considerable manual correction and human judgment are involved.
The transmission of images over telegraph wires based on a process of photoelectric raster scanning was introduced early in the twentieth century. It was also applied to transmitting color images (U.S. Pat. Nos. 2,185,806; 3,413,706). The application of this technique to half-tone plate making by Hardy and others (U.S. Pat. Nos. 2,136,340; 3,190,185; 2,294,644) heralded an era of faster and more automatic plate making and correction. Methods were developed for scanning colored originals (U.S. Pat. Nos. 2,165,168; 2,253,086; 2,571,322) and treating the readings and output by analog devices to produce color separations suitable for color printing plate making with a considerable saving in time.
The combination of these two techniques for the making of color half-tone images was found to suffer from interactive visual effects including the Moire pattern problem known earlier to photomechanical plate makers. Wurzburg (U.S. Pat. No. 2,185,139) made color half-tone separations by the photoelectric raster scanning devices to give different equivalent screen angles for the different colors. Screen angle choice was based on the photomechanical art already existing.
In the photoelectric raster scanning systems, conversion of analogue scanning signals to digital form was found to facilitate manipulation of the signals by computing circuits, as in the electronic formation of half-tone dot patterns (U.S. Pat. No. 3,629,496). Such methods gave color originals suffering from interactive visual effect such as Moire patterns in the resulting prints. Patterns of dots of equal size but with separation distances depending on density in the original were found to reduce the Moire patterns (U.S. Pat. Nos. 3,197,558; 3,580,995) because of the absence of repeating patterns of dots. Direction simulation of the use in color work of four contact screens at different screen angles has been achieved by computing techniques coupled with four different dot generators (U.S. Pat. No. 3,911,480). Choice of the angles used is based on earlier experience with contact screens.
A different approach has been taken to the problems presented by photoelectric scanning methods. This involves the representation of a variable size half-tone dot by a matrix of smaller dots whose number in the matrix is varied to provide half-tone dot size changes and therefore density changes. (U.S. Pat. Nos. 3,604,486; 4,439,789). No change of size or optical density of these smaller dots is involved. Only their presence or absence is considered. This system therefore lends itself to the use of digital signals and their attendant high speed computing means. Enhanced tonal reproduction has been achieved by using a variable pixel area (the area assigned to a single matrix unit) in such matrix systems (U.S. Pat. No. 4,084,259).
In four color printing the separations have been represented by matrix pixels in which the distribution of dots for the same density is varied from one separation to another. This is said to reduce Moire effects (U.S. Pat. No. 3,922,484). This technique of Moire reduction has been expanded by randomizing the distribution of dots in the pixel matrix (U.S. Pat. No. 4,468,706) building on earlier monochrome work (U.S. Pat. No. 3,629,496).
The randomized pixel matrix method of reducing Moire effects has been approached in a separate manner often termed "ordered dither". The raster scan identifies signals corresponding to all the dot positions in the pixel matrix but the presence or absence of a dot in the reproduction is determined by a predetermine matrix of threshold values--one for each dot position in the pixel matrix (U.S. Pat. Nos. 4,193,096; 4,342,051; 4,496,987).
As was reported above, U.S. Pat. Nos. 2,185,139 and 3,911,480 describe raster scan methods to reduce Moire effects which generate half-tone screen dots with different screen angles for the different color separations. This method has been enhanced in U.S. Pat. No. 4,419,690. A variation to this method has been taught in U.S. Pat. No. 4,443,060 wherein quadratic raster meshes of adjacent dots are expanded to contracted in their two diagonal directions. Different expansions/contractions are used for the different color separations.
The non-patent literature contains considerable detailed discussion of the application of raster scanning to half-tone image production. The following papers are representative: "Half-tone method with Edge Enhancement and Moire Suppression", P. G. Roetling, JOSA 66, 985 (1976). In this method, detail corresponding to the spatial frequency of the half-tone screens is suppressed. "Random Nucleated Halftone Screen," J. P. Allebach, PS and E 22.89 (1978). These screens suppress Moire effects by the introduction of random elements.
"An Optimum Algorithm for half-tone Generation for Displays and Hard Copies," T. M. Holladay, Proc. Soc. for Information Display, 21., 185 (1980). This describes electronically produced screens with different screen angles.
"A New Evaluation Method of Image Quality of Digital Halftone Images Obtained by Ordered Dither Method", K. Kinoshita et al., J. Imaging Technology, 10.181 (1984).
U.S. Pat. No. 4,758,886 approaches the problem of Moire fringes in color half-tone images from the standpoint that the mathematical functions describing the half-tone patterns for the individual separations should be orthogonal with one another. There appears to have been no earlier disclosure of such an approach and none of the mathematical investigations in the literature suggest such an approach.
The patent describes a method of designing screen functions for raster-scan generated sets of image comprising two or more color separation images, which sets of generated images have reduced Moire patterns or are free from Moire pattern problems. The method does not use the equivalent of different screen angles for the separations nor is the technique of ordered diether used. The half-tone dot matrixes in a given separation are disposed at a single uniform pitch not at variable pitch as taught in some of the known art.
U.S. Pat. No. 4,084,183 (Keller et al.) discloses a method for the electro-optical reproduction of halftone pictures in which the picture is subdivided into surface elements having covering spots therein corresponding to a tone value scale, wherein electronic recording data is produced from the surface elements and is stored, wherein by means of electro-optical scanning of a picture, signals are obtained and are used to call up the recording data for the reproduction of the picture, the improvement residing in that several raster screens on the picture are formed and the meshes and the angle of rotation of such raster screens are selected in such a manner that an orthogonally oriented parcel screen having a congruent screen structure is obtained, and the parcel screens are subdivided into smaller orthogonally oriented surface elements and recording data is obtained from such surface elements.
U.S. patent application Ser. No. 07/582,524 filed Sep. 14, 1990 describes an algorithm which simulate a continuous tone image containing a range of gray shades from black to white or a color separation. The "threshold equation" is the key of the invention as it calculates a threshold gray value that is compared to the desired local image value to determine whether that particular point should be "on" or "off". Which points (spots) are "on" and which are "off" is determined by the function that assigns a "threshold" value (the shade at which a pixel changes from "off" to "on") based on a pixels "x" and "y" coordinates. The generated screen comprises columns and rows of halftone dot centers, the columns and rows are geometrically orthogonal (perpendicular), but the row to row spacing and/or column to column spacing is not equal, either row to row, column to column, or row to column.

Perpendicular, unequal frequency non-conventional screen patterns for electronic halftone generation

Minnesota Mining and Manufacturing Company


An insect screen of increased invisibility can be created by using small wire diameter elements and/or increasing the mesh density of the screen. The combination of small wire diameter and increased mesh density provide a screen with a higher Dalquist Rating that becomes invisible at closer distances. A “sweet spot” exists at which a screen with a combination high mesh density and small wire diameter is less visible, while still providing the strength, durability, and quality desired. Further, screens with properties in proximity to this sweet spot also provide a marked increase in invisibility.

Generally, insect screens are installed on or in openings for windows and doors in homes to promote ventilation while excluding insects. Insect screens are, however, widely regarded as unattractive. From the inside of a window, some screens obstruct or at least detract from the view to the outside. From the outside, many people believe that screens detract from the overall appearance of a home or building. Homebuilders and realtors frequently remove screens from windows and/or doors when selling homes because of the improved appearance of the home from the outside. Homeowners often remove screens from windows and/or doors that are not frequently opened to improve the view from the inside and the appearance of the window and/or door.
A wide variety of insect screen materials and geometries are available in the prior art. Fiberglass, metallic and synthetic polymer screens are known. These screens suffer from reduced visual appeal due to relatively low light transmission, high reflection, or both. Standard residential insect screens include a mesh with horizontal and vertical elements. The most common insect screens have about 18 elements per inch in one direction and 16 elements per inch the other direction, often expressed as being an 18×16 mesh. Some conventional screens have an 18×14 mesh. The typical opening size is about 0.040 inch by 0.050 inch. Screens designed to exclude gnats and other very small insects usually include screen elements in a 20×20 mesh. The most common materials for the screen elements are aluminum and vinyl-coated fiberglass. Stainless steel, bronze and copper are also used for insect screen elements. Typical element diameters for insect screens are 0.011 inch for aluminum, bronze, and some stainless steel offerings, 0.016 inch for fiberglass, and 0.009 inch for galvanized steel and stainless steel.
Some products on the market advertise a black or charcoal colored screen mesh that is allegedly less visible from the inside of a house. Color coating changes and material changes have made some incremental improvements in the visual appeal of screening to the average observer, but most observers continue to object to the darkening effect and/or loss of clarity that current insect screening causes in observing scenes from inside and outside.

This patent is subject to a terminal disclaimer.


The electronic device and a corresponding signal processing method disclosed herein reduces electromagnetic noise. To that end, the electronic device includes a delay line, an oscillator, and a modulator. The delay line generates a spread spectrum clock signal from an input clock signal, where a timing jitter and a period of jitter of the spread spectrum clock signal are controlled at each period of the spread spectrum clock signal based on a digital code. The oscillator uses the spread spectrum clock signal to generate a processing signal. The modulator modulates the processing signal as a function of an audio signal.

The approaches described in this section could be pursued, but are not necessarily approaches that have been previously conceived or pursued. Therefore, unless otherwise indicated herein, the approaches described in this section are not prior art to the claims in this application and are not admitted to be prior art by inclusion in this section. Furthermore, all embodiments are not necessarily intended to solve all or even any of the problems brought forward in this section.
Audio Class-D drivers may be used in order to provide high powered audio output signal with high efficiency, typically comprised between 80 and 90%.
However, Class-D power stage also provides a lot of electromagnetic noise in the radio band, with particular frequency concentrations. This electromagnetic noise can perturb environment systems.
Electromagnetic interference (EMI) may be reduced by using solenoid inductance filters with concentrated magnetic field. However, such filters are expensive.
Electromagnetic interference (EMI) may also be reduced by using a spread-spectrum clock signal, which can be obtained with a phase locked loop or with a pseudo random noise. The use of a pseudo random noise is for example disclosed in U.S. Pat. No. 6,545,533.
However, the known systems do not permit to control the energy spectrum. As a consequence, noise is added into the audio band and reduces the dynamic range at around 91 dB/96 dB. This can be a main issue for example in case of a system given at 103 dB minimum.
There is a need for improved methods and devices for reduction of electromagnetic noise of audio Class-D drivers.


A system and method is provided for providing a relational job request queue preferably for digital imaging devices. At least one parent queue data store is created for storing a plurality of parent queue records. At least one child queue data store is also created for storing a plurality of child queue records wherein each child queue record comprises a parent queue record identifier data store. A job request data store is also created for storing a plurality of job request records. For each job request received, a job request record is created and a record related to the newly created job request record is created in at least one of the parent queues or child queues.

This invention pertains generally to job request queues, and more specifically to the implementation of a relational hierarchical job request queue.
There is a fundamental need to provide service for a variety of types of job requests in client-server systems. Modem digital imaging devices ("DID") are often capable of performing a variety of functions. DIDs suitably include devices such as printers, fax machines, scanners, copiers, multi-function peripherals ("MFPs"), and other like peripheral devices. Furthermore, a single computer can often access a plurality of different types of DIDs, which means that a single computer is capable of generating various types of job requests with various destinations. There exists a need to organize the various job requests sent from a user to any one of a plurality of types of DIDs connected to a network.
There also exists a need to provide both clients and administrators in a client-server environment with the ability to perform management functions on job request queues. It is preferable if clients have the ability to specify how a job should be processed. It is also preferable if clients have the ability to monitor jobs in a job request queue.
It is also preferable if administrators have the ability to create queues, assign priorities to queues, relate parent queues to child queues, move jobs between queues, etc.


Method and apparatus for feeding on optical waveguide through a partition device, such as a wellhead outlet are disclosed. For some embodiments, the wellhead outlet includes a first chamber having a first port, a second chamber having a second port connected by a path to the first port for feeding an optical waveguide through to the first chamber, and a strain relief member coupled with the first chamber to limit motion of the optical waveguide at or near the first port. The strain relief member can be a rigid curved tube coupled to the first port and/or a fiber management member providing one or more fiber retention pathways.

1. Field of the Invention
Embodiments of the invention relate to devices having feedthroughs for optical waveguides, and more particularly, to hermetically sealed wellhead outlets with feedthroughs that are suitable for use in high pressure, high temperature, and/or other harsh environments.
2. Background Art
In many industries and applications, there exists a need to have small diameter wires or optical waveguides penetrate a partition such as a wall, bulkhead, or wellhead outlet, wherein a high fluid or gas differential pressure can exist across a feedtrough device in the partition. Furthermore, one or both sides of the feedthrough device may be subjected to high temperatures and other harsh environmental conditions, such as corrosive or volatile gas, fluids and other materials. For example, optical sensors, particularly sensors for use in bulkheads or wellhead outlets, oil and gas exploration and production, can require use of a feedthrough device that can seal an optical waveguide at pressures of 20,000 psi and above, and temperatures of 150° C. to 250° C. The wellhead outlets can include a feedthrough where an optical waveguide is concentrically located within a cavity in a housing, and the resulting annular space is filled with a suitable sealant. U.S. Pat. No. 6,526,212, issued Feb. 25, 2003, which is incorporated herein by reference in its entirety, describes in detail an exemplary feedthrough for installation within a bulkhead.
There exist several challenges associated with constructing a feedthrough device and fiber management system for use, for example, in a wellhead outlet. One of these challenges relates to damage and breakage of the fiber at a point where the fiber enters and exits the feedthrough device. The small size of the fiber and the brittle nature of glass materials of the fiber generally make any stress points along the fiber particularly susceptible to damage. For example, damage to the fiber at a stress point where the fiber exits the feedthrough into a low pressure chamber of the wellhead outlet can occur due to a significant stress concentration at that location. Accordingly, movement of the fiber at this stress point as can occur during handling of the wellhead outlet potentially leads to damage of the fiber. Further, the fact that the fiber is rigidly held on one side of the stress point and is free on the other side of the stress point within the low pressure chamber makes the fiber susceptible to damage at the stress point due to micro-bending.
While it is typically desirable to have a length of the fiber extending from the feedthrough for purposes such as splicing, any excess fiber extending from the feedthrough presents storage issues within the wellhead outlet. For example, excess fiber disposed within the low pressure chamber can be disorderly such that the likelihood of damage to the fiber during handling of the wellhead outlet is high, particularly at the stress point discussed above. The disordered arrangement of the fiber within the low pressure chamber permits micro-bends along the length of the fiber extending from the feedthrough and can enable the fiber to become pinched during final assembly of the wellhead outlet such as when a cap is inserted on the low pressure chamber.
Therefore, embodiments of the invention provide optical waveguide feedthrough assemblies and fiber management systems, and methods of making such assemblies, which overcome one or more of the above-described drawbacks and disadvantages of the prior art.


A pixel-controlled LED light includes a plurality of LED modules and a controller. Each LED module includes at least one LED and a LED drive apparatus. The LED drive apparatus burns an ordinal number according to connection sequence thereof. The controller defines the ordinal number of the LED module as a target number, and sequentially transmits a plurality of light data whose number is greater than or equal to the target number to each of the LED modules. Each of the LED drive apparatuses sequentially receives each of the light data and counts sequence of the light data. If the sequence of the light data is equal to the ordinal number of the LED drive apparatus, the LED drive apparatuses identify the light data, and after identifying the light data, the LED drive apparatuses control the corresponding at least one LED.

Technical Field
The present disclosure relates to a LED light and a method of operating the same, and more particularly to a pixel-controlled LED light string and a method of operating the same.
Description of Related Art
The statements in this section merely provide background information related to the present disclosure and do not necessarily constitute prior art.
The statements in this section merely provide background information related to the present disclosure and do not necessarily constitute prior art.
Since light-emitting diode (LED) has the advantages of high luminous efficiency, low power consumption, long life span, fast response, high reliability, etc., LEDs have been widely used in lighting fixtures or decorative lighting, such as Christmas tree lighting, lighting effects of sport shoes, etc. by connecting light bars or light strings in series, parallel, or series-parallel.
Take the festive light for example. Basically, a complete LED lamp includes an LED light string having a plurality of LEDs and a drive unit for driving the LEDs. The drive unit is electrically connected to the LED light string, and controls the LEDs by a pixel control manner or a synchronous manner by providing the required power and the control signal having light data to the LEDs, thereby implementing various lighting output effects and changes of the LED lamp.
In the current technology, in order to drive the LEDs of the LED string variously lighting, the LEDs have different address sequence data. The LEDs receive light signals involving light data and address data. If the address sequence data of the LEDs are the same as the address data of the light signals, the LEDs light according to the light data of the light signals. If the address sequence data of the LEDs are different from the address data of the light signals, the LEDs skip the light data of the light signals.
At present, the methods of sequencing the LEDs of the LED string are mostly complicated and difficult. For example, before the LEDs are assembled into the LED string, different address sequence data need to be burned for each of the LEDs. Thereafter, the LEDs are sequentially placed and assembled into the LED string according to the address sequence data. If the LEDs are not sequentially assembled in accordance with the address sequence data, the diverse illumination of the LEDs cannot be correctly achieved.

Pixel-controlled LED light string and method of operating the same