A knee ice pack for cooling the affected area of a knee including a body member having left, center and right compartments open along the top portions thereof and adapted to receive ice therein, the center compartment having a through opening intended to be aligned with the patella to preclude the patella from being subjected to the cooling effects of the ice, a closure fastener for permitting opening and closing of the top portions of the compartments to provide access thereto, and a fastener for securing the ice pack to the knee.

1. Field of the Invention
This invention relates to devices used in the application of heat or cold to various portions of the appendages of the human body. More particularly, this invention relates to ice packs designed to be fitted about an appendage of the human body to effectuate the application of cold to an affected area such as the knee.
2. Description of the Prior Art
Presently there exist many types of devices designed to be filled with a cold or hot medium and then applied to an affected area of the human body or an animal such as a horse. The most basic of such devices consists of a hot water bag in which a bladder is filled with hot water and then applied to the affected area. Another most basic type of these devices include ice packs in which a bladder is filled with ice and then applied to the affected area. The more common forms of such devices consist of generally rectangular bladders having a filling cap at one end or a generally circular bladder with a fill cap at its center. It has long been recognized that one major disadvantage to these types of devices is their inability to be easily secured about the affected area of the appendage so that the person could freely move about without constantly holding the device into position.
With somewhat limited success, various methods have been invented which seek to affix the devices to the affected area of the body. For example, U.S. Pat. No. 3,889,684 discloses a hot and cold pack comprising an encapsulated absorbent pad positioned within a cover. A plurality of fasteners is attached to the edges of the cover allowing the pack to be positioned over a large body portion such as the back, shoulder or stomach or to be applied to other body members such as the ankle, neck or face. U.S. Pat. No. 4,044,773 discloses a similar cold pack which comprises a supply of water encapsulated within a relatively thin polyurethane bladder. After the freezing of the water within the bladder, the resulting thin layer of ice is fragmented into small particles, thereby allowing the pack to be more appropriately fitted about the affected area of the appendage. U.S. Pat. No. 2,949,914 discloses an ice pack for an ankle which basically comprises an ice containing bag which is fitted about the ankle by means of a draw-string. In a similar fashion, U.S. Pat. No. 3,491,761 discloses an ice bag harness including several pockets adapted to receive an ice bag. The harness includes tie strap allowing the harness to be fitted about an appendage and tied.
In addition to the devices disclosed in the foregoing patents, there has also been developed ice packs which function in the conventional manner as an ice pack but also function as a splint to immobilize the appendage to which the ice pack is affixed. For example, U.S. Pat. Nos. 3,548,819 and 3,561,435 disclose an ice pack including an air fillable bladder which functions as a splint.
Therefore, it is an object of this invention to provide an apparatus which overcomes the aforementioned inadequacies of the prior art devices and provides an improvement which is a significant contribution to the advancement of the ice pack art.
Another object of this invention is to provide an ice pack adapted to be filled with ice and then fitted about the knee of a person.
Another object of this invention is to provide an ice pack having a design which, when fitted about the knee of a person, remains in proper position about the knee even while the person is walking or is otherwise mobile.
Another object of this invention is to provide an ice pack having a plurality of individualized compartments for receiving the ice to be used during treatment to assure that the cooling effects of the ice is concentrated to each area of the affected area to be treated.
Another object of this invention is to provide an ice pack having individualized compartments for receiving ice in such a manner that a certain degree of bending motion is allowed while the person is wearing the knee ice pack.
Another object of this invention is to provide a knee ice pack having a recessed area located proximate to the patella area (kneecap) of the knee to prevent the patella area from being subject to the cold treatment while allowing the affected areas of the knee to be treated.
Another object of this invention is to provide a knee ice pack having a cut-out recess to assure that the ice positioned within the individualized compartments will not come in thermal contact with the patella area of the knee.
Another object of this invention is to provide a knee ice pack having an opening at the upper portion thereof to facilitate easy filling of the ice pack with ice.
Another object of this invention is to provide a knee ice pack having an opening at its upward end which includes a zipper.
Another object of this invention is to provide a knee ice pack having individualized compartments which are insulated from the ambient air to concentrate the cooling effects of the ice to the affected area of the knee rather than being lost to the ambient air.
Another object of this invention is to provide a knee ice pack including fastener means which permits the ice pack to be easily fitted about the knee of the injured person.
Another object of this invention is to provide a knee ice pack which can be worn by the injured person for significant periods of time without excessive melting of the ice contained therein due to the ambient environment.
Another object of this invention is to provide a knee ice pack in which the fastener comprises the fastener sold under the trademark "Velcro" to permit the ice pack to be easily positioned about the knee or removed therefrom.
The foregoing has outlined some of the more pertinent objects of the invention. These objects should be construed to be merely illustrative of some of the more prominent features and applications of the intended invention. Many other beneficial results can be attained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a fuller understanding of the invention may be had by referring to the summary of the invention and the detailed description of the preferred embodiment in addition to the scope of the invention defined by the claims taken in conjunction with the accompanying drawings.


A water irrigation restriction violation system includes a geostationary satellite to collect soil surface moisture data and rain data throughout a given day for a geographic region. A processor and a memory coupled to the processor are configured to store water irrigation restrictions for governmental jurisdictions for the geographic region, receive the soil surface moisture data and rain data from the geostationary satellite, and determine a water irrigation restriction violation based upon the stored water irrigation restrictions and the received soil surface moisture data and rain data. A violation notification is then sent to a corresponding governmental jurisdiction for the determined water irrigation restriction violation.

One of the main purposes of water irrigation is to grow crops. Unlike some states in the Midwest, certain geographic regions in California, for example, do not receive enough rain during the summer. This makes water irrigation a necessity.
Agricultural irrigation districts in California utilize local rivers, and store the water in reservoirs. The irrigation season usually runs from approximately March 15 to October 15, depending on the weather and water supplies.
Even in geographical regions other than in California, severe drought is causing local governmental jurisdictions to issue water irrigation restrictions. Water irrigation restrictions are typically in the form of allowed or not allowed watering days of the week, and/or times of the day.
Discovery of water irrigation restriction violations is difficult due to the large land areas involved and the transient nature of "wet" soil. One approach is for local authorities to use drones to patrol the geographical regions subjected to water irrigation restrictions. A drawback of using drones is that it is cost prohibitive to provide around the clock aerial coverage due to manpower and equipment costs.
Another aerial approach is to use satellites. Even though the use of satellites may be economically viable, a drawback is that the same geographical region is not observed often enough. Soil surfaces may dry between satellite passes, for example. In addition, the spatial resolution of the satellites is typically too coarse.
Consequently, there is a need to help governmental jurisdictions to discourage local agribusinesses from violating water irrigation restrictions.

Water irrigation restriction violation system and associated methods


The present invention provides a monitoring method for monitoring a semiconductor wafer, in a chemical mechanical polishing (CMP) process. The CMP process is used to polish a dielectric layer of the semiconductor. The monitoring method comprises: 1. exposing the dielectric layer of the semiconductor wafer to an input light beam of fixed wavelength at a predetermined angle to generate a reflected light beam within a predetermined time period after performing the CMP process, the intensity of the reflected light beam undergoing periodic changes in response to the gradual thinning of the dielectric layer during the CMP process, 2. monitoring the intensity of the reflected light beam at a starting period within the predetermined time period and obtaining a periodic change rule according to the periodic changes of the intensity of the reflected light beam, and 3. monitoring the intensity of the reflected light beam throughout the rest of the predetermined time period and generating an output signal to stop the CMP process if the change of the intensity of the reflected light beam is not in accordance with the periodic change rule.

1. Field of the Invention
The present invention relates to a method for monitoring a semiconductor wafer, and more particularly, to a method for monitoring a semiconductor wafer in a chemical mechanical polishing process.
2. Description of the Prior Art
In semiconductor processing, chemical-mechanical polishing (CMP) is a planarization technique for uniformly removing a deposited layer from the surface of a semiconductor wafer. When performing the CMP process, proper monitoring is essential to avoid any manufacturing or polishing errors that may affect the yield. In the prior art, a CMP end-point detection system uses an optical theorem to monitor the dielectric layer to decide when to stop polishing, i.e., the end-point of polishing. However, the prior art monitoring method is not continuous. It lacks the ability to know, at any given time, if the polishing process is complete or to standard. Consequently, if any mistakes occur before the end-point of the polishing is reached, there is insufficient time to stop the process.
In the prior art, a supporting stand is used during the CMP process. This stand comprises a pedestal for supporting the semiconductor wafer and a polishing pad installed on the pedestal for polishing the surface of the semiconductor wafer. There is a hole in the polishing pad. The stand is connected to a liquid transmitting system. The liquid transmitting system is responsible for directing the necessary polishing slurry to the stand for use in the CMP process. During CMP processing of the deposited layer, such as a dielectric layer, the semiconductor wafer is first positioned horizontally on the pedestal. The pedestal then spins at a certain speed. The polishing slurry is uniformly sprayed onto the surface of the spinning semiconductor wafer and undergoes chemical reactions with the dielectric layer. At the same time, the polishing pad above the pedestal presses downward upon the surface of the semiconductor wafer to perform a mechanical polishing. The chemical reaction of the polishing slurry in conjunction with the mechanical polishing of the polishing pad, and with the parameters of the process properly set, can remove the portion of the dielectric layer that lies on the surface of the semiconductor wafer. The end-point detection system determines the polishing end-point of the dielectric layer in the CMP process. This is accomplished by monitoring the reflected light beam from the dielectric layer via the hole in the polishing pad.
Please refer to FIG. 1. FIG. 1 is a graph of intensity versus time of the reflected light beam in a prior art method for monitoring a dielectric layer in a chemical mechanical polishing process. In the prior art method, the end-point detection system exposes the dielectric layer of the semiconductor wafer to an input light beam of fixed wavelength at a predetermined oblique angle to generate a reflected light beam that passes through the hole of the polishing pad when performing the CMP process. The intensity of the reflected light beam is detected. Measuring and recording the intensity of the reflected light beam continues at every time point. In FIG. 1, t2 in the figure denotes the predetermined point in time to stop the CMP process. The CMP process automatically stops at t2. However, as the polishing time increases, and before the time t2 is reached, the dielectric layer becomes thinner, which results in variations in the intensity of the reflected light beam. Such a change is depicted in the region between a time t1 and the predetermined end-point time t2, the region xcex94t2. When the surface of the semiconductor wafer becomes excessively polished to the extent that the layer below the dielectric layer is reached, the intensity of the reflected light beam changes sharply due to the differences in the properties of the different materials. In order to avoid over-polishing, the CMP process must stop as soon as the sharp change of the intensity of the reflected light beam is discovered. So, in the prior art method of monitoring a semiconductor wafer in a chemical mechanical polishing end-point detection system, changes of the intensity of the reflected light beam within the time period xcex94t2 are detected so as to determine the end-point of polishing of the dielectric layer and to monitor the accuracy of the CMP process.
The end-point detection system for a dielectric layer in the CMP process starts detecting at t1 and stops detecting at t2. Using the theorem of window logic, the change in the slope of the curve within a fixed window 19 at every time point within the time period xcex94t2 is detected. If the change of the slope of the curve is larger than a predetermined value within the window 19, an output signal is generated to stop the CMP process. Alternatively, if the change of the slope of the curve is always smaller than the predetermined value, the CMP process will automatically stop at the end-point time t2.
The prior art method does not detect the performance of the CMP process within the time period xcex94t1, which is before the time point t1. When errors in the CMP process occur within the time period xcex94t1, they go undetected and an incorrect CMP process will continue to be performed on the semiconductor wafer. This may cause irreversible damage such that the semiconductor wafer must be discarded. This obviously affects the yield of the entire process.
It is therefore a primary objective of the present invention to provide a method for monitoring a semiconductor wafer in a chemical mechanical polishing process to solve the above mentioned problem.
In a preferred embodiment, the present invention provides a monitoring method for monitoring a semiconductor wafer in a chemical mechanical polishing (CMP) process, the CMP process being used to polish a dielectric layer of the semiconductor, the monitoring method comprising:
exposing the dielectric layer of the semiconductor wafer with an input light beam of fixed wavelength at a predetermined angle to generate a reflected light beam within a predetermined time period after performing the CMP process, the intensity of the reflected light beam undergoing periodic changes in response to the gradual thinning of the dielectric layer during the CMP process;
monitoring the intensity of the reflected light beam at a starting period within the predetermined time period and obtaining a periodic change rule according to the periodic changes of the intensity of the reflected light beam; and
monitoring the intensity of the reflected light beam throughout the rest of the predetermined time period and generating an output signal if the change of the intensity of the reflected light beam is not in accordance with the periodic change rule.
It is an advantage of the present invention that the method for monitoring a semiconductor wafer in a chemical mechanical polishing process can detect the performance of the CMP process of a dielectric layer and prevent incorrect CMP processes, thereby improving productivity.

Method for monitoring a semiconductor wafer in a chemical mechanical polishing process


A compound of the formula

The present invention relates to arylsulfonyl hydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (TNF) and as such are useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (hereinafter NSAID""S) and analgesics for the treatment of arthritis, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, in the treatment of cancer.
The invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to pharmaceutical compositions useful therefor.
There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases. Matrix-degrading metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in tissue matrix degradation (e.g. collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget""s disease and osteoporosis), tumor metastasis or invasion, as well as HIV-infection (J. Leuk. Biol., 52 (2): 244-248, 1992).
Tumor necrosis factor is recognized to be involved in many infectious and auto-immune diseases (W. Fiers, FEBS Letters, 1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al., Clinical Immunology and Immunopathology, 1992, 62 S11).
The present invention relates to a compound of the formula
or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond;
X is carbon, oxygen, sulfur, SO, SO2 or nitrogen;
Y is carbon, oxygen, sulfur, SO, SO2 or nitrogen;
R1, R2, R3, R4 R5, R6, R7, R8 and R9 are selected from the group consisting of hydrogen, hydroxy, (C1xe2x80x94C6)alkyl optionally substituted by one or two groups selected from (C1xe2x80x94C6)alkylthio, (C1xe2x80x94C6)alkoxy, trifluoromethyl, halo, (C6xe2x80x94C10)aryl, (C2xe2x80x94C9)heteroaryl, (C6xe2x80x94C10)arylamino, (C6xe2x80x94C10)arylthio, (C6xe2x80x94C10)aryloxy, (C2xe2x80x94C9)heteroarylamino, (C2xe2x80x94C9)heteroarylthio, (C2xe2x80x94C9)heteroaryloxy, (C6xe2x80x94C10)aryl(C6xe2x80x94C10)aryl, (C3xe2x80x94C6)cycloalkyl, hydroxy, piperazinyl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy, (C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkoxy, (C1xe2x80x94C6)acylamino, (C1xe2x80x94C6)acylthio, (C1xe2x80x94C6)acyloxy, (C1xe2x80x94C6)alkylsulfinyl, (C6xe2x80x94C10)arylsulfinyl, (C1xe2x80x94C6)alkylsulfonyl, (C6xe2x80x94C10)arylsulfonyl, amino, (C1xe2x80x94C6)alkylamino or ((C1xe2x80x94C6)alkyl)2amino; (C2xe2x80x94C6)alkenyl, (C6xe2x80x94C10)aryl(C2xe2x80x94C6)alkenyl, (C2xe2x80x94C9)heteroaryl(C2xe2x80x94C6)alkenyl, (C2xe2x80x94C6)alkynyl, (C6xe2x80x94C10)aryl(C2xe2x80x94C6)alkynyl, (C2xe2x80x94C9)heteroaryl(C2xe2x80x94C6)alkynyl, (C1xe2x80x94C6)alkylamino, (C1xe2x80x94C6)alkylthio, (C1xe2x80x94C6)alkoxy, perfluoro(C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)aryl, (C2xe2x80x94C9)heteroaryl, (C6xe2x80x94C10)arylamino, (C6xe2x80x94C10)arylthio, (C6xe2x80x94C10)aryloxy, (C2xe2x80x94C9)heteroarylamino, (C2xe2x80x94C9)heteroarylthio, (C2xe2x80x94C9)heteroaryloxy, (C3xe2x80x94C6)cycloalkyl, (C1xe2x80x94C6)alkyl(hydroxymethylene), piperidyl, (C1xe2x80x94C6)alkylpiperidyl, (C1xe2x80x94C6)acylamino, (C1xe2x80x94C6)acylthio, (C1xe2x80x94C6)acyloxy, R10(C1xe2x80x94C6)alkyl or a group of the formula
wherein
n is 0 to 6;
y is 0 or 1;
W is oxygen or  greater than NR24;
Z is xe2x80x94OR11, xe2x80x94NR24R11, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a bridged diazabicycloalyl ring selected from the group consisting of
wherein
r is 1, 2 or 3;
m is 1 or 2;
p is 0 or 1; and
V is hydrogen, (C1xe2x80x94C3)alkyl, (C1xe2x80x94C6)alkyl(Cxe2x95x90O)xe2x80x94, (C1xe2x80x94C6) alkoxy(Cxe2x95x90O)xe2x80x94, (C6xe2x80x94C10)aryl(Cxe2x95x90O)xe2x80x94, (C6xe2x80x94C10)aryloxy(Cxe2x95x90O)xe2x80x94, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl(Cxe2x95x90O)xe2x80x94, (C6xe2x80x94C10)aryl-(C1xe2x80x94C6)alkoxy(Cxe2x95x90O)xe2x80x94, or (C1xe2x80x94C6)alkoxy(Cxe2x95x90O)xe2x80x94Oxe2x80x94;
wherein each heterocyclic group (i.e., each Z cyclic group containing one or more heteroatoms) may optionally be independently substituted by one or two groups selected from hydroxy, (C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)alkoxy, C1xe2x80x94C10)acyl, (C1xe2x80x94C10)acyloxy, (C6xe2x80x94C10)aryl, (C2xe2x80x94C9)heteroaryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl, (C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkyl, hydroxy(C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)alkoxy(C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)acyloxy(C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)alkylthio, (C1xe2x80x94C6)alkylthio(C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)arylthio, (C6xe2x80x94C10)arylthio(C1xe2x80x94C6)alkyl, R12R13Nxe2x80x94, R12R13NSO2xe2x80x94, R12R13N(Cxe2x95x90O)xe2x80x94, R12R13N(Cxe2x95x90O)xe2x80x94(C1xe2x80x94C6)alkyl, R14SO2xe2x80x94, R14SO2NHxe2x80x94, R15(Cxe2x95x90O)xe2x80x94[N(R12)]xe2x80x94, R16O(Cxe2x95x90O)xe2x80x94, or R16O(Cxe2x95x90O)xe2x80x94(C1xe2x80x94C6)alkyl;
wherein R10 is (C1xe2x80x94C6)acylpiperazinyl, (C6xe2x80x94C10)arylpiperazinyl, (C2xe2x80x94C9)heteroarylpiperazinyl, (C1xe2x80x94C6)alkylpiperazinyl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkylpiperazinyl, (C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkylpiperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, (C1xe2x80x94C6)alkylpiperidyl, (C6xe2x80x94C10)arylpiperidyl, (C2xe2x80x94C9)heteroarylpiperidyl, (C1xe2x80x94C6)alkylpiperidyl(C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)arylpiperidyl(C1xe2x80x94C6)alkyl, (C2xe2x80x94C9)heteroaryl-piperidyl-(C1xe2x80x94C6)alkyl or (C1xe2x80x94C6)acylpiperidyl;
R11 is hydrogen, (C6xe2x80x94C10)aryl, (C2-C9)heteroaryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl, (C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)alkyl(C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl(C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkyl, 5-indanyl, xe2x80x94CHR17Oxe2x80x94(Cxe2x95x90O)xe2x80x94R18 or xe2x80x94CH2(Cxe2x95x90O)xe2x80x94NR19R20;
R12 and R13 are each independently hydrogen, (C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)aryl, C2xe2x80x94C9)heteroaryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl or (C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkyl or R12 and R13 may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring;
R14 is trifluoromethyl, (C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)aryl, (C2xe2x80x94C9)heteroaryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl or (C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkyl;
R15 is hydrogen, (C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)alkoxy, (C6xe2x80x94C10)aryl, (C2xe2x80x94C9)heteroaryl, (C1xe2x80x94C6)aryl(C1xe2x80x94C6)alkyl(C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy or (C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkyl;
R16 is (C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)aryl, (C2xe2x80x94C9)heteroaryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl, 5-indanyl, xe2x80x94[CH(R17)]Oxe2x80x94(Cxe2x95x90O)xe2x80x94R18, xe2x80x94CH2(Cxe2x95x90O)xe2x80x94NR19R20, or R21O(C1xe2x80x94C6)alkyl;
R17 is hydrogen or (C1xe2x80x94C6)alkyl;
R18 is (C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)alkoxy or (C6xe2x80x94C10)aryl;
R19 and R20 are each independently hydrogen or (C1xe2x80x94C6)alkyl or may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomopholinyl ring;
R21 is H2N(CHR22)(Cxe2x95x90O)xe2x80x94;
R22 is the side chain of a natural D- or L-amino acid;
R23 is hydrogen, (C1xe2x80x94C6)acyl, (C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl, (C2xe2x80x94C9)heteroaryl(C1xe2x80x94C6)alkyl or (C1xe2x80x94C6)alkylsulfonyl;
R24 wherever it occurs is independently hydrogen or (C1xe2x80x94C6)alkyl;
or R1 and R2, or R3 and R4, or R5 and R6 may be taken together to form a carbonyl;
or R1 and R2, or R3 and R4, or R5 and R6, or R7 and R8 may be taken together to form a (C3xe2x80x94C6)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula
Q is (C1xe2x80x94C10)alkyl, (C6xe2x80x94C10)aryl, (C6-C10)aryloxy(C6xe2x80x94C10)aryl, (C6xe2x80x94C10)aryl(C6xe2x80x94C10)aryl, (C6xe2x80x94C10)aryl(C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C1xe2x80x94C6)alkyl, (C6xe2x80x94C10)aryloxy(C2xe2x80x94C9)heteroaryl, (C2xe2x80x94C9)heteroaryl, (C1xe2x80x94C6)alkyl(C6xe2x80x94C10)aryl, (C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl, (C2xe2x80x94C9)heteroaryloxy(C6xe2x80x94C10)aryl, (C1xe2x80x94C6)alkyl(C2xe2x80x94C9)heteroaryl, (C1xe2x80x94C6)alkoxy(C2xe2x80x94C9)heteroaryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C2xe2x80x94C9)heteroaryl, (C2xe2x80x94C9)heteroaryloxy(C2xe2x80x94C9)heteroaryl, (C6xe2x80x94C10)aryloxy(C1xe2x80x94C6)alkyl, (C2xe2x80x94C9)heteroaryloxy(C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)alkyl(C6xe2x80x94C10)aryloxy(C6xe2x80x94C10)aryl, (C1xe2x80x94C6)alkyl(C2xe2x80x94C9)heteroaryloxy(C6xe2x80x94C10)aryl, (C1xe2x80x94C6)alkyl(C6xe2x80x94C10)aryloxy(C2xe2x80x94C9)heteroaryl, (C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryloxy(C6xe2x80x94C10)aryl, (C1xe2x80x94C6)alkoxy(C2xe2x80x94C9)heteroaryloxy(C6xe2x80x94C10)aryl or C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryloxy(C2xe2x80x94C9)heteroaryl optionally substituted by fluoro, chloro, (C1xe2x80x94C6)alkyl, (C1xe2x80x94C6)alkoxy or perfluoro(C1xe2x80x94C3)alkyl;
with the proviso that when y is zero, Q is other than (C6xe2x80x94C10)aryl(C6xe2x80x94C10)aryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl or (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C2xe2x80x94C9)heteroaryl, and anyone of R1-R9 is a group of formula II then Z must be substituted when defined as azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, piperazinyl, (C1xe2x80x94C10)acylpiperazinyl, (C1xe2x80x94C6)alkylpiperazinyl, (C6xe2x80x94C10)arylpiperazinyl, (C2xe2x80x94C9)heteroarylpiperazinyl or a bridged diazabicycloalkyl ring;
with the proviso that when y is zero, Q is other than (C6xe2x80x94C10)aryl(C6xe2x80x94C10)aryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl or (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C2xe2x80x94C9)heteroaryl, then at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 must be defined as the group of formula II;
with the proviso that when Q is (C6xe2x80x94C10)aryl(C6xe2x80x94C10)aryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl or (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C2xe2x80x94C9)heteroaryl, then R1-R9 may be other than formula II but when R1, R2, R3, R4, R5, R6, R7, R8, and R9 are all defined by hydrogen or (C1xe2x80x94C6)alkyl, either X or Y is oxygen, sulfur, SO, xe2x80x94SO2xe2x80x94 or nitrogen, or the broken line represents a double bond;
with the proviso that R7 is other than hydrogen only when R8 is other than hydrogen;
with the proviso that R6 is other than hydrogen only when R5 is other than hydrogen;
with the proviso that R3 is other than hydrogen only when R4 is other than hydrogen;
with the proviso that R2 is other than hydrogen only when R1 is other than hydrogen;
with the proviso that when R1, R2 and R9 are a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 2- or 6-positions of the ring;
with the proviso that when X is nitrogen, R4 is not present;
with the proviso that when X is oxygen, sulfur, SO, SO2 or nitrogen and when one or more of the group consisting of R1, R2, R5 and R6, is a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 4- or 6-positions;
with the proviso that when Y is oxygen, sulfur, SO, SO2 or nitrogen and when one or more of the group consisting of R3, R4, R7 and R8, are independently a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 3- or 5-positions;
with the proviso that when X is oxygen, sulfur, SO or SO2, R3 and R4 are not present;
with the proviso that when y is 1 and W is NR24 or oxygen, Z cannot be hydroxy;
with the proviso that when Y is oxygen, sulfur, SO or SO2, R5 and R6 are not present;
with the proviso that when Y is nitrogen, R6 is not present;
with the proviso that when the broken line represents a double bond, R4 and R6 are not present;
with the proviso that when R3 and R5 are independently a substituent comprising a heteroatom when the broken line represents a double bond, the heteroatom cannot be directly bonded to positions X and Y;
with the proviso that when either the X or Y position is oxygen, sulfur, SO, SO2 or nitrogen, the other of X or Y is carbon;
with the proviso that when X or Y is defined by a heteroatom, the broken line does not represent a double bond.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, (C1xe2x80x94C6)alkoxy, (C6xe2x80x94C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C1xe2x80x94C6)alkyl.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents independently selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1xe2x80x94C6)alkoxy, (C6xe2x80x94C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C1xe2x80x94C6)alkyl.
The term xe2x80x9cacylxe2x80x9d, as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy (such as methyloxy carbonyl), aryl, arylalkyl or arylalkyloxy and the terms xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d are as defined above.
The term xe2x80x9cacyloxyxe2x80x9d, as used herein, includes O-acyl groups wherein xe2x80x9cacylxe2x80x9d is defined above.
The term xe2x80x9cD- or L-amino acidxe2x80x9d, as used herein, unless otherwise indicated, includes glycine, alanine, valine, leucine, isoleucine, phenylalanine, asparagine, glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, cystine, methionine, aspartic acid, glutamic acid, lysine, arginine or histidine.
The positions on the ring of formula I, as used herein, are defined as follows:
The preferred conformation of the compound of formula I includes hydroxamic acid axially disposed in the 2-position.
The compound of formula I may have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
Preferred compounds of formula I include those wherein Y- is carbon.
Other preferred compounds of formula I include those wherein Q is (C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl, or (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C1xe2x80x94C6)alkyl wherein each terminal aryl group is optionally substituted by fluoro.
Other preferred compounds of formula I include those wherein R2, R3, R6, R7 and R9 are hydrogen.
More preferred compounds of formula I include those wherein Y is carbon; Q is (C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl, (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C6xe2x80x94C10)aryl, or (C6xe2x80x94C10)aryl(C1xe2x80x94C6)alkoxy(C1xe2x80x94C6)alkyl.
Specific preferred compounds of formula I include the following:
(2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid;
(2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoly-piperidine-4-carboxylic acid methyl ester;
(2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid;
(2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester;
(2R,3S)-{1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3-yl}-carbamic acid isopropyl ester;
3-(S)-4-(4xe2x80x2-Fluorobiphenyl-4-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
3-(S)-4-[4-(4-Fluorobenzyloxy)benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(2R,4S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; and
(2R,4R)-1-(4-Methoxybenzenesulfonyl)-4-(piperazine-1-carbonyl)-piperidine-2-carboxylic acid hydroxyamide hydrochloride.
Other compounds of the invention include:
(3S)-4-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(3S)-2,2-Dimethyl-4-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
(3S)-2,2-Dimethyl-4-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
(3S)-4-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(3S)-2,2-Dimethyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
(3S)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(3S)-2,2-Dimethyl-4-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
(3S)-2,2-Dimethyl-4-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
(2R,3S)-{1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3-yl}-carbamic acid methyl ester;
(2R,3S)-{2-Hydroxycarbamoyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidin-3-yl}-carbamic acid methyl ester;
(2R,3S)-{2-Hydroxycarbamoyl-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-piperidine-3-yl}-carbamic acid methyl ester;
(2R,3S)-{1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidine-3-yl}-carbamic acid methyl ester;
(2R,3S)-(1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2-hydroxycarbamoyl-piperidin-3-yl)-carbamic acid methyl ester;
(2R,3S)-{2-Hydroxycarbamoyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidin-3-yl}-carbamic acid methyl ester;
(2R,3S)-{1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3-yl}-carbamic acid methyl ester;
(2R,3S)-{2-Hydroxycarbamoly-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-piperidin-3-yl}-carbamic acid methyl ester;
(2R,3S)-{2-Hydroxycarbamoyl-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidin-3-yl}-carbamic acid methyl ester;
(2R,3S)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-1-{4-[2-(4-Fluroophenyl)-ethoxy]-benzenesulfonyl}-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)3-Hydroxy-3-methyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-3-methyl-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-3-methyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-3-methyl-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-3-Hydroxy-3-methyl-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(3R)-4-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2,2-dimethyl-morpholine-3-carboxylic acid hydroxyamide;
(3R)-2,2-Dimethyl-4-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(3R)-2,2-Dimethyl-4-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(3R)-4-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2,2-dimethyl-morpholine-3-carboxylic acid hydroxyamide;
(3R)-4-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2,2-dimethyl-morpholine-3-carboxylic acid hydroxyamide;
(3R)-2,2-Dimethyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(3R)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2,2-dimethyl-morpholine-3-carboxylic acid hydroxyamide;
(3R)-2,2-Dimethyl-4-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(3R)-2,2-Dimethyl-4-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(2R,4R)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid;
(2R,4R)-2-Hydroxycarbamoyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid;
(2R,4R)-2-Hydroxycarbamoyl-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid;
(2R,4R)-1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2-hydroxycarbamoyl-piperidine-4-carboxylic acid;
(2R,4R)-2-Hydroxycarbamoyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid;
(2R,4R)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid;
(2R,4R)-2-Hydroxycarbamoyl-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-piperidine-4-piperidine-4-carboxylic acid;
(2R,4R)-2-Hydroxycarbamoyl-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid;
(3R)-4-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-3-methyl-morpholine-3-carboxylic acid hydroxyamide;
(3R)-3-Methyl-4-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(3R)-3-Methyl-4-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(3R)-4-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-methyl-morpholine-3-carboxylic acid hydroxyamide;
(3R)-4-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-3-methyl-morpholine-3-carboxylic acid hydroxyamide;
(3R)-3-Methyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(3R)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-3-methyl-morpholine-3-carboxylic acid hydroxyamide;
(3R)-3-Methyl-4-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(3R)-3-Methyl-4-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide;
(2R)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2-methyl-3-oxo-piperidine-2-carboxylic acid hydroxyamide;
(2R)-2-Methyl-3-oxo-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R)-2-Methyl-3-oxo-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-methyl-3-oxo-piperidine-2-carboxylic acid hydroxyamide;
(2R)-1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2-methyl-3-oxo-piperidine-2-carboxylic acid hydroxyamide;
(2R)-2-Methyl-3-oxo-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2-methyl-3-oxo-piperidine-2-carboxylic acid hydroxyamide;
(2R)-2-Methyl-3-oxo-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R)-2-Methyl-3-oxo-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R,4S)-1-(4-Benzyloxy-benzenesulfonyl)-4-butylaminomethyl-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,4S)-4-Butylaminomethyl-1-[4-(4-fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,4S)-4-Benzylamino-1-(4-benzyloxy-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxyamide;
(2R,4S)-4-Benzylamino-1-[4-(4-fluorobenzyloxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide;
(2R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-oxo-piperidine-2-carboxylic acid hydroxyamide;
(2R,4R)-1-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid hydroxyamide;
(2R,5S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,5S)-1-(4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,5R)-1-(4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,5R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,3S)-1-(4-Benzyloxy-benzenesulfonyl)-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,4S)-1-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
(2R,4S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide;
1-(4-Butoxy-benzenesulfonyl)-3-(morpholine-4-carbonyl)-piperidine-2-carboxylic acid hydroxyamide;
1-[4-(4-Fluoro-benzyloxy)-benzenesulfonyl)-3-(morpholine-4-carbonyl)-piperidine-2-carboxylic acid hydroxyamide;
1-[3-(Fluoro-benzyloxy)-propane-1-sulfonyl]-3-(morpholine-4-carbonyl)-piperidine-2-carboxylic acid hydroxymide;
1-(4-Butoxy-benzenesulfonyl)-3-(pyrrolidine-1-carbonyl)-piperidine-2-carboxylic acid hydroxyamide;
1-[4-(4-Fluoro-benzyloxy)-benzyloxy)-benzenesulfonyl)-3-(pyrrolidine-1-carbonyl)-piperidine-2-carboxylic acid hydroxyamide;
1-[3-(4-Fluoro-benzyloxy)-propane-1-sulfonyl)-3-(pyrrolidine-1-carbonyl)-piperidine-2-carboxylic acid hydroxyamide; and
1-[4-(4-Fluoro-benzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid.
The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, synergy with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, in combination with standard NSAID""S and analgesics and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier.
The present invention also relates to a method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, compounds of formula I may be used in combination with standard NSAID""S and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition.
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated R1, R2, R3, R4, R5, R6, R7, R8, R9, n and Ar in the reaction Schemes and the discussion that follow are defined as above.
Preparation 1 refers to the preparation of intermediates of the formula VI. Compounds of the formula VI are converted to compounds of the formula I according to the methods of Scheme 1. The starting materials of formula XVI can be prepared according to methods well known to those of ordinary skill in the art.
In reaction 1 of Preparation 1, the compound of formula XVI is converted to the corresponding hydroxy ester compound of formula VI by first reacting XVI with an arylsulfonylhalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at a temperature between about 20xc2x0 C. to about 30xc2x0 C., preferably at room temperature. The compound so formed is further reacted with a compound of the formula
wherein R25 is carbobenzyloxy, (C1-C6)alkyl, benzyl, allyl or tert-butyl, in the presence of sodium hexamethyldisilazane and a tetrahydrofuran-dimethylformamide solvent mixture at a temperature between about xe2x88x9220xc2x0 C. to about 20xc2x0 C., preferably about 0xc2x0 C., to form the hydroxy ester compound of formula VI.
Preparation 2 refers to an alternate method of preparing compounds of the formula VI. The starting materials of formula XVIII can be prepared according to methods well known to those of ordinary skill in the art. In reaction 2 of Preparation 2, the amine compound of formula XVIII, wherein R25 is as defined above, is converted to the corresponding arylsulfonyl amine compound of formula XVII by (1) reacting XVIII with an arylsulfonylhalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran, or dioxane, at a temperature between about 20xc2x0 C. to about 30xc2x0 C., preferably at room temperature, (2) reacting the compound so formed with a compound of the formula
in the presence of sodium hexamethyldisilazane and a tetrahydrofuran-dimethylformamide solvent mixture at a temperature between about xe2x88x9220xc2x0 C. to about 20xc2x0 C., preferably about 0xc2x0 C., and (3) further reacting the compound so formed with ozone in a methylene chloride-methanol solution at a temperature between about xe2x88x9290xc2x0 C. to about xe2x88x9270xc2x0 C., preferably about xe2x88x9278xc2x0 C. The unstable ozonide compound so formed is then reacted with triphenylphosphine to form the arylsulfonyl amine compound formula XVII. In Reaction 2 of Preparation 2, the arylsulfonyl amine compound of formula XVII is converted to the corresponding hydroxy ester compound of formula VI by reacting XVII with a compound of the formula
wherein W is lithium, magnesium, copper or chromium.
Scheme 1 refers to the preparation of compounds of the formula II, which are compounds of the formula I, wherein X and Y are carbon; R4, R6 and R7 are hydrogen; and the dashed line between X and Y is absent. In reaction 1 of Scheme 1, the compound of formula VI, wherein the R25 protecting group is carbobenzyloxy, (C1-C6) alkyl, benzyl, allyl or tert-butyl, is converted to the corresponding morpholinone compound of formula V by lactonization and subsequent Claisen rearrangement of the compound of formula VI. The reaction is facilitated by the removal of the R25 protecting group from the compound of formula VI and is carried out under conditions appropriate for that particular R25 protecting group in use. Such conditions include: (a) treatment with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, where R25 is carbobenzyloxy, (b) saponification where R25 is lower alkyl, (c) hydrogenolysis where R25 is benzyl, (d) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid, where R25 is tert-butyl, or (e) treatment with tributyltinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium (II) chloride where R25 is allyl.
In reaction 2 of Scheme 1, the morpholinone compound of formula V is converted to the carboxylic acid compound of formula IV by reacting V with lithium hexamethyldisilazane in an aprotic solvent, such as tetrahydrofuran, at a temperature between about xe2x88x9290xc2x0 C. to about xe2x88x9270xc2x0 C., preferably about xe2x88x9278xc2x0 C. Trimethylsilyl chloride is then added to the reaction mixture and the solvent, tetrahydrofuran, is removed in vacuo and replaced with toluene. The resulting reaction mixture is heated to a temperature between about 100xc2x0 C. to about 120xc2x0 C., preferably about 110xc2x0 C., and treated with hydrochloric acid to form the carboxylic acid compound of formula IV.
In reaction 3 of Scheme 1, the carboxylic acid compound of formula IV is converted to the corresponding hydroxamic acid compound of formula III by treating IV with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenztriazole in a polar solvent, such as dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methylmorpholine. Alternatively, a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as a tert-butyl, benzyl or allyl ether, may be used in the presence of (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorphosphate and a base, such as N-methylmorpholine. Removal of the hydroxylamine protecting group is carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium (II) chloride. N,O-bis(4-methoxybenzyl)hydroxylamine may also be used as the protected hydroxylamine derivative where deprotection is achieved using a mixture of methanesulfonic acid and trifluoroacetic acid.
In reaction 4 of Scheme 1, the hydroxamic acid compound of formula III is converted, if desired, to the corresponding piperidine compound of formula II by treating III with hydrogen and a hydrogenation catalyst, such a 10% palladium on carbon.
Scheme 2 refers to the preparation of compounds of the formula VII, which are compound of the formula I wherein Y is nitrogen; X is carbon; R1, R2, R3, R4, R7 and R8 are hydrogen, and R6 is absent. The starting materials of formula IX can be prepared according to methods well known to those of ordinary skill in the art. In reaction 1 of Scheme 2, the arylsulfonylpiperazine compound of formula IX, wherein R26 is carbobenzyloxy, benzyl or carbotertbutyloxy, is converted to the compound of formula VIII by reacting IX with a protected derivative of hydroxylamine of the formula
R27OHN2.HCl
wherein R27 is tertbutyl, benzyl or allyl, in the presence of dicylohexylcarbodiimide, dimethylaminopyridine and an aprotic solvent, such as methylene chloride. The R26 protecting group is chosen such that it may be selectively removed in the presence of an without loss of the R27 protecting group, therefore, R26 cannot be the same as R27. Removal of the R26 protecting group from the compound of formula IX is carried out under conditions appropriate for that particular R26 protecting group in use. Such conditions include; (a) treatment with a hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, where R26 is carbobenzyloxy, (b) hydrogenolysis where R26 is benzyl or (c) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid where R20 is carbotertbutyloxy.
In reaction 2 of Scheme 2, the compound of formula VIII is converted to the corresponding hydroxamic acid compound of formula VII, wherein R5 is hydrogen or (C1-C6)alkyl, by reacting, if desired, VIII with an alkylhalide when R5 is (C1-C6)alkyl. Subsequent removal of the R27 hydroxylamine protecting group is carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium (II) chloride.
Scheme 3 refers to the preparation of compounds of the formula X, which are compounds of the formula I wherein Y is nitrogen; X is carbon; R2, R7, R8 and R9 are hydrogen; R3 and R4 taken together are carbonyl; R5 is hydrogen, and R6 is absent. In reaction 1 of Scheme 3, the arylsulfonylamine compound of formula XII, wherein R26 is as defined above, is converted to the corresponding piperazine compound of formula XI by reacting XII with a carbodiimide and a base, such as triethylamine. The compound of formula XI is further reacted to give the hydroxamic acid compound of formula X according to the procedure described above in reaction 3 of Scheme 1.
Scheme 4 refers to the preparation of compounds of the formula XIII. The starting materials of formula XVIII can be prepared according to methods well known to those of ordinary skill in the art. Compounds of the formula XIII are compounds of the formula I wherein X is carbon, and the dotted line between X and Y is absent. In reaction 1 of Scheme 4, removal of the R26 protecting group and subsequent reductive amination of the compound of formula XXII, wherein Y is oxygen, sulfur or carbon, to give the corresponding imine compound of formula XXI is carried out under conditions appropriate for that particular R26 protecting group in use. Such conditions include those used above for removal of the R26 protecting group in reaction 1 of Scheme 2.
In reaction 2 of Scheme 4, the imine compound of formula XXI is converted to the corresponding piperidine compound of formula XX by reacting XXI with a nucleophile of the formula R2M wherein M is lithium, magnesium halide or cerium halide. The reaction is carried out in ether solvents, such as diethyl ether or tetrahydrofuran, at a temperature between about xe2x88x9278xc2x0 C. to about 0xc2x0 C., preferably about xe2x88x9270xc2x0 C.
In reaction 3 of Scheme 4, the sulfonation of the piperidine compound of formula XX to given the corresponding arylsulfonylpiperidine compound of formula XIX is carried out by reacting XX with an arylsulfonylhalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at a temperature between about 20xc2x0 C. to about 30xc2x0 C., preferably at room temperature.
In reaction 4 of Scheme 4, the arylsulfonylpiperidine compound of formula XIX is converted to the hydroxamic acid compound of formula XIII according to the procedure described above in reaction 3 of Scheme 1.
Scheme 5 refers to the preparation of compounds of the formula XIV, which are compounds of formula I wherein Y is nitrogen, X is carbon, the dotted line between X and Y is absent, R5 is hydrogen and R6 is absent. In reaction 1 of Scheme 5, the compound of formula XXVI, wherein the R29 and R31 protecting groups are each independently selected from the group consisting of carbobenzyloxy, benzyl and carbotertbutyloxy and R30 is carbobenzyloxy, (C1-C6)alkyl, benzyl, allyl or tert-butyl, is converted to the corresponding imine compound of formula XXV by the removal of the R29 protecting group and subsequent reductive amination of the compound of formula XXVI. The R29 protecting group is chosen such that it may be selectively removed in the presence of and without loss of R31 protecting group. Removal of the R29 protecting group from the compound of formula XXVI is carried out under conditions appropriate for that particular R29 protecting group in use which will not affect the R31 protecting group. Such conditions include; (a) treatment with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, where R29 is carbobenzyloxy and R31 is tert-butyl, (b) saponification where R29 is (C1-C6)alkyl and R31 is tert-butyl, (c) hydrogenolysis where R29 is benzyl and R31 is (C1-C6) alkyl or tert-butyl, (d) treatment with a strong acid such as trifluoracetic acid or hydrochloric acid where R29 is tert-butyl and R31 is (C1-C6)alkyl, benzyl or allyl, or (e) treatment with tributyltinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium (II) chloride where R29 is allyl and R31 is (C1-C6)alkyl, benzyl or tert-butyl. The R30 protective group may be selected such that it is removed in the same reaction step as the R29 protecting group.
In reaction 2 of Scheme 5, the imine compound of formula XXV is converted to the corresponding compound of formula XXIV by reacting XXV with a nucleophile of the formula R2M wherein M is lithium, magnesium halide or calcium halide. The reaction is carried out in ether solvents, such as diethyl ether or tetrahydrofuran, at a temperature between about xe2x88x9278xc2x0 C. to about 0xc2x0 C., preferably about xe2x88x9270xc2x0 C.
In reaction 3 of Scheme 5, the sulfonation of the piperidine compound of formula XXIV to give the corresponding arylsulfonylpiperidine compound of formula III is carried out according to the procedure described above in reaction 3 of Scheme 4.
In reaction 4 of Scheme 5, the arylsulfonylpiperidine compound of formula XXIII is converted to the hydroxamic acid compound of formula XIV by (1) removing the R30, if needed, and R31 protecting groups from XXIII followed by (2) reacting XXIII according to the procedure described above in reaction 3 of Scheme 1. Removal of the R30 and R31 protecting groups from the compound of formula XXIII is carried out under conditions appropriate for that particular R30 and R31 protecting group in use. Such conditions include those used above for removal of the R25 protecting group in reaction 1 of Scheme 1.
Pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium slats, such as ammonium, trimethyl-ammonium, diethylammonium, and tris(hydroxymethyl)-methylammonium salts.
Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids e.g. hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.
The ability of the compounds of formula I or their pharmaceutically acceptable salts (the compounds of the invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, consequently, demonstrate their effectiveness for treating diseases characterized by matrix metalloproteinase or the production of tumor necrosis factor is shown by the following in vitro assay tests.
Human recombinant collagenase is activated with trypsin using the following ratio: 10 xcexcg trypsin per 100 xcexcg of collagenase. The trypsin and collagenase are incubated at room temperature for 10 minutes then a five fold excess (50 xcexcg/10 xcexcg trypsin) of soybean trypsin inhibitor is added.
10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted using the following Scheme:
10 mMxe2x86x92120 xcexcMxe2x86x9212 xcexcMxe2x86x921.2 xcexcMxe2x86x920.12 xcexcM
Twenty-five microliters of each concentration is then added in triplicate to appropriate wells of a 96 wells microfluor plate. The final concentration of inhibitor will be a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are set up in wells D1-D6 and blanks (no enzyme, no inhibitors) are set in wells D7-D12.
Collagenase is diluted to 400 ng/ml and 25 xcexcl is then added to appropriate wells of the microfluor plate. Final concentration of collagenase in the assay is 100 ng/ml.
Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is made as a 5 mM stock in dimethyl sulfoxide and then diluted to 20 xcexcM in assay buffer. The assay is initiated by the addition of 50 xcexcl substrate per well of the microfluor plate to give a final concentration of 10 xcexcM.
Fluorescence readings (360 nM excitation, 460 nm emission) were taken at time 0 and then at 20 minute intervals. The assay is conducted at room temperature with a typical assay time of 3 hours.
Fluorescence vs time is then plotted for both the blank and collagnease containing samples (data from triplicate determinations is averaged). A time point that provides a good signal (the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC50 values. The zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data. Data is plotted as inhibitor concentration vs % control (inhibitor fluorescence divided by fluorescence of collagenase alonexc3x97100). IC50""s are determined from the concentration of inhibitor that gives a signal that is 50% of the control.
If IC50""s are reported to be  less than 0.03 xcexcM then the inhibitors are assayed at concentrations of 0.3 xcexcM, 0.03 xcexcM and 0.003 xcexcM.
Inhibition of gelatinase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2 substrate (10 xcexcM) under the same conditions as inhibition of human collagenase (MMP-1).
72 kD gelatinase is activated with 1 mM APMA (p-aminophenyl mercuric acetate) for 15 hours at 4xc2x0 C. and is diluted to give a final concentration in the assay of 100 mg/ml. Inhibitors are diluted as for inhibition of human collagenase (MMP-1) to give final concentrations in the assay of 30 xcexcM, 3 xcexcM, 0.3 xcexcM and 0.03 xcexcM. Each concentration is done in triplicate.
Fluorescence readings (360 nm excitation, 460 emission) are taken at time zero and then at 20 minutes intervals for 4 hours.
IC50""s are determined as per inhibition of human collagenase (MMP-1). If IC50""s are reported to be less than 0.03 xcexcM, then the inhibitors are assayed at final concentrations of 0.3 xcexcM, 0.03 xcexcM, 0.003 xcexcM and 0.003 xcexcM.
Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (Weingarten, H. and Feder, J., Spectrophotometric Assay for Vertebrate Collagenase, Anal. Biochem. 147, 437-440 (1985)). Hydrolysis of the thio peptolide substrate [Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H5] yields a mercaptan fragment that can be monitored in the presence of Ellman""s reagent.
Human recombinant prostromelysin is activated with trypsin using a ratio of 1 xcexcl of a 10 mg/ml trypsin stock per 26 xcexcg of stromelysin. The trypsin and stromelysin are incubated at 37xc2x0 C. for 15 minutes followed by 10 xcexcl of 10 mg/ml soybean trypsin inhibitor for 10 minutes at 37xc2x0 C. for 10 minutes at 37xc2x0 C. to quench trypsin activity.
Assays are conducted in a total volume of 250 xcexcl of assay buffer (200 mM sodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6.0) in 96-well microliter plates. Activated stromelysin is diluted in assay buffer to 25 xcexcg/ml. Ellman""s reagent (3-Carboxy-4-nitrophenyl disulfide) is made as a 1M stock in dimethyl formamide and diluted to 5 mM in assay buffer with 50 xcexcl per well yielding at 1 mM final concentration.
10 mM stock solutions of inhibitors are made in dimethyl sulfoxide and diluted serially in assay buffer such that addition of 50 xcexcL to the appropriate wells yields final concentrations of 3 xcexcM, 0.3 xcexcM, 0.003 xcexcM, and 0.0003 xcexcM. All conditions are completed in triplicate.
A 300 mM dimethyl sulfoxide stock solution of the peptide substrate is diluted to 15 mM in assay buffer and the assay is initiated by addition of 50 xcexcl to each well to give a final concentration of 3 mM substrate. Blanks consist of the peptide substrate and Ellman""s reagent without the enzyme. Product formation was monitored at 405 nm with a Molecular Devices UVmax plate reader.
IC50 values were determined in the same manner as for collagenase.
Human recombinant MMP-13 is activated with 2 mM APMA (p-aminophenyl mercuric acetate) for 1.5 hours, at 37xc2x0 C. and is diluted to 400 mg/ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20 xcexcM zinc chloride, 0.02% brij). Twenty-five microliters and diluted enzyme is added per well of a 96 well microfluor plate. The enzyme is then diluted in a 1:4 ratio in the assay by the addition of inhibitor and substrate to give a final concentration in the assay of 100 mg/ml.
10 mM stock solution of inhibitors are made up in dimethyl sulfoxide and then diluted in assay buffer as per the inhibitor dilution scheme for inhibition of human collagenase (MMP-1): Twenty-five microliters of each concentration is added in triplicate to the microfluor plate. The final concentrations in the assay are 30 xcexcM, 3 xcexcM, 0.3 xcexcM, and 0.03 xcexcM.
Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH3) is prepared as for inhibition of human collagenase (MMP-1) and 50 xcexcl is added to each well to give a final assay concentration of 10 xcexcM. Fluorescence readings (360 nM excitation; 450 emission) are taken at time 0 and every 5 minutes for 1 hour.
Positive controls consist of enzyme and substrate with no inhibitor and blanks consist of substrate only.
IC50""s are determined as per inhibition of human collagenase (MMP-1). If IC50""s are reported to be less than 0.03 xcexcM, inhibitors are then assayed at final concentrations of 0.3 xcexcM, 0.03 xcexcM, 0.003 xcexcM and 0.0003 xcexcM.
The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay:
Human mononuclear cells were isolated from anti-coagulated human blood using a one-step Ficoll-hypaque separation technique, (2) The mononuclear cells were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2xc3x97106/ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells in these preparations.
180xcexc of the cell suspension was allquoted into flate bottom 96 well plates (Costar). Additions of compounds and LPS (100 ng/ml final concentration) gave a final volume of 200 xcexcl. All conditions were performed in triplicate. After a four hour incubation at 37xc2x0 C. in an humidified CO2 incubator, plates were removed and centrifuged (10 minutes at approximately 250xc3x97g) and the supernatants removed and assayed for TNFxcex1 using the RandD ELISA Kit.
For administration to mammals, including humans, for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), a variety of conventional routes may be used including orally, parenterally and topically. In general, the compounds of the invention will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
The compounds of the invention can be administered in a wide variety of different dosage forms. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration level ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; performed materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. In the case of animals, they are advantageously contained in an animal feed or drinking water in a concentration of 5-5000 ppm, preferably 25 to 500 ppm.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. In the case of animals, compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 divided doses.
The present invention is illustrated by the following examples, but it is not limited to the details thereof.

Arylsulfonyl hydroxamic acid derivatives

Abstract: A compound of the formula

Abstract: wherein R1, R2 R3, R4 R5, R6, R7, R8, R9 and Q are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID""S) and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.


A cutter and stripper assembly of a shredder has a lower housing part injection-molded with a receptacle in which an injection-molded stripper block is received. The stripper block has fingers reaching between the blades of the blade shaft and braced by ribs injection-molded on the upper part of the housing.

A paper shredder generally comprises a pair of blade shafts in a shredder housing, the shafts having interdigitating rotating blades into which the paper or other sheet material carrying information is fed so that the information carrier will be cut up into strips and collected in a bin, chamber or other collector with which the cutting assembly is associated. Additional cutter elements may also be provided to further subdivide the strips.
Generally between the blades of each shaft in the cutter zone stripper bars or fingers may be provided to prevent the cut-up information carriers from collecting around the blade shaft and for guiding the cut material into a collector. A collecting of the comminuted material between the blades can lead to an interruption in the operation of the shredder.
In German Open Application DE 0S 36 16 554, a stripper element in the form of a bar grate is provided in one piece and is fastened at the lateral points of the cutter assembly at which the bearings of the blade shafts are mounted. This system can be complex and expensive.

Blade and stripper assembly for a paper shredder


An improved color space (YHB model) for compressing image files is provided. An example method includes storing a sum of an unweighted first color value and an unweighted second color value for each pixel in a plurality of pixels of an image as a first channel, subsampling, among the plurality of pixels, a difference between the first color value and the second color value as a second channel, subsampling, among the plurality of pixels, a third color value as a third channel, and storing the first channel, the second channel, and the third channel as the compressed image. In some implementations, the original image may be split into a low frequency version and a high frequency version. The system may apply the YHB model to the high frequency version and apply a conventional model or a second variation of the YHB model to the low frequency version.

Digital images are often captured in an RGB color space with a red component, a green component, and a blue component. To reduce image size, some systems use lossy compression, which reduces the amount of information stored for the image. Conventionally lossy compression includes keeping intensity information for an image and losing some of the color information. One example of lossy compression is the JPEG image format, which uses a YUV color space, specifically YUV 420. This color space dates back to the transition of black-and-white TV to the color era, carrying luminance information on the Y channel, and chroma information on the U and V channels. With the separate channels, black-and-white sets could easily separate out the luminance information. The YUV color space also assumes highest spatial sensitivity for a mixture that is highest on the green component.


A power supply device of controlling feedback synchronization is connected to an electric power source for obtaining an input power and includes first and second converters for modulating the input power. The first and second converters include first and second output terminals for providing first and second output power respectively. The power supply device further includes a feedback synchronization unit electrically coupled to the first and second output terminals of the first and second converters for obtaining first and second feedback signals, and producing and transmitting a synchronous feedback signal to the second converter according to a voltage difference of the first and second feedback signals to synchronizing output voltage level of the second converter with the first converter. The aforementioned circuit can control the synchronization of a voltage boost time and output time of the first and second converters.

Most power supply devices provide one or more output power to meet a load requirement or generate two output power for a backup or compensation of power. However, a majority of the traditional power supply devices use a tap winding of a transformer or a plurality of winding couplings to achieve the function of providing a plurality of output power to drive different loads. An "Alternate-current distributed power supply device" is disclosed in R.O.C. Pat. No. M244645, FIG. 2 of the patent specification shows the structure of the aforementioned traditional power supply device, and FIG. 5 further discloses a transformer that uses a circuit structure having a plurality of windings to provide different voltages through a multiple of output paths, but the tap winding of the transformer or the structure of a plurality of windings actually involves a complicated manufacturing procedure, slows down the production rate, and increases the cost. To avoid using components of a higher cost, manufacturers provide another multi-output power circuit structure that uses two converters for generating two output power as shown in FIG. 1. FIG. 1 shows a circuit block diagram of a traditional power supply device, wherein the power supply device is connected to an electric power source 1 for obtaining input power. After going through a rectifier unit 2 and a power correction unit 3, the power correction unit 3 obtains the input power and modulates its voltage or power factor. The power correction unit 3 is connected to a first converter 4 and a second converter 5, and the first and second converters 4, 5 obtain the input power from the power correction unit 3 to generate a first output power and a second output power and output the first and second power from a first output terminal 41 and a second output terminal 51 respectively. The first and second converters 4, 5 obtain a feedback signal from the first output power or the second output power to control the output timing and power independently. Although the power supply devices can back up each other independently to avoid the use of components of a higher cost, theoretically the output timing of the two converters should be synchronous, and the boost time and step-down time of the voltage of the first output power and the second output power should be equal, yet there is a time difference between the timings of the voltages of the two converters from the startup to the final stage, so that the boost time and the step-down time cannot be synchronized. Obviously, the prior art requires improvements.

Power supply device of controlling feedback synchronization


The invention relates to a power supply unit (3) for supplying power to an on-board electrical network of a vehicle, including: at least two DC-to-DC converters (9A, 9B) which are interleaved and reversible between an opera-ting mode for lowering voltage and an operating mode for raising voltage, the converters (9A, 9B) being intended for being connected to a power storage device (ST2) and being capable of supplying current to the on-board network; and a switch (K) enabling a power source (STI) to supply power to the on-board network when the switch (K) is in a first state, and enabling the power storage device (ST2) to supply power to the on-board network when the switch (K) is in a second state. The unit is characterized in that the converters (9A, 9B) are variable-frequency converters, and in that the power supply unit (3) also includes a synchronization unit (200) configured such as to synchronize the operation of the converters (9A, 9B) operating at variable frequencies and the current generation of the converters.

The present invention relates in general manner to a power supply unit for supplying an on-board network of a vehicle.
Units for supplying an on-board network of a vehicle with electrical energy existing in the automotive industry include interlaced multi-phase converters working at a fixed frequency (e.g. 150 kHz for each phase). For example, the document FR2970094 describes a unit for supplying electrical energy in an on-board network including a plurality of interlaced converters also working at a fixed frequency.
However, for such a unit, the conducted and radiated emissions are present on a narrow spectrum in radio frequency and filters are thus necessary to meet EMI standards required for the components of a vehicle.
In addition, the converters operating at a fixed frequency do not maintain the stability of the control function for a duty cycle higher than 50% and this limits the output power of the converters and of the unit.
In addition, these interlaced fixed frequency converters, by principle, need to have a minimum duty cycle of minimal control (e.g. 1%) to keep the phase-lock loop stability of the output voltage. This principle involves consuming, at minimum, a load current of a few amperes, which implies poor performance.
In addition, variations in the input voltage of the unit are not taken into account by the regulator of the unit so that the unit operation may become unstable.

Power supply unit for supplying power to an on-board electrical network of a vehicle


The present invention provides for an apparatus and method of use for a hydraulic shifting tool to be used in a sealed volume in a subsurface well completion to actuate a downhole device, without a fluid return to surface or the well annulus.

1. Field of Invention
The present invention pertains to shifting tools used in subsurface well completions, and particularly to hydraulic shifting tools used in closed hydraulic volumes.
2. Related Art
Shifting tools are commonly used in well completions in which actuation of a tool is brought about by relative movement of a tool element. This can be, for example, opening or closing a valve (e.g., sleeve, ball, or flapper), setting a packer, or initiating an explosive train. The earliest shifting tools were simple mechanical devices that engaged a profile in the tool element to be moved, and the tool element was moved as an operator manipulated the shifting tool.
More sophisticated shifting tools use hydraulic pressure to apply a force to a moveable element, such as a piston, to induce motion of the element. Existing hydraulic shifting tools generally require a fluid path to the surface or well annulus to permit movement of relatively incompressible well fluids. If such tools are run into a sealed volume, the tool will be stopped from advancing, and the piston will be prevented from moving, unless the fluid within the volume is routed to the surface or well annulus.


A method and system for playing background music and key tone based on an embedded browser, and a digital television receiving terminal. The method comprises: analyzing and downloading web data, intercepting protocol registration events, and sending a background music start command when the background music need to be played; analyzing transport stream (TS) data pushed by a server, obtaining data required for playing the background music, and playing the background music; and receiving a key operation command from a user, analyzing the TS data pushed by the server when playing the background music, obtaining data required for playing key tone, and playing the key tone instructed in the key operation command. With the preceding method, system and digital television receiving terminal, defects in concurrently playing multi-channel audio data are overcome and the background music and key tone can be played concurrently.

With the constant development of the digital television technologies, the Internet Protocol Television (IPTV) technology is increasingly mature. With this technology, users can watch digital television programs and browse web pages using a set top box (STB). When watching television programs, users can browse the program guide using a remote controller. Except the focus de-selection mode to prompt key switching, no other operations to prompt key switching are available. To satisfy the multi-functionality demand on the STB, the digital television, IPTV, and even mobile phone platform all require the support from an embedded browser.
With the key tone for prompting the key operations provided by the embedded browser, the defect that no tone is played for browsing web pages is overcome. In addition, with the implementation of background music playing using the embedded browser, the issue that beautiful background music cannot be enjoyed by users is also addressed. However, the current key tone and key switching operation are based on single thread.
The background music are played by establishing a connection control channel with the player system. A background music playing request is sent to the player system. Upon receiving the request, the player system selects to establish a media transfer channel to play the transferred data or deny the request according to its status (whether the player system is idle or not). This satisfies the users' demands on the background music.
Accordingly, the background music and key tone are played in two independent threads. The system cannot play the background music and responds to the user keys when users are browsing the program guide. In addition, the operation effects on the screen are not blocked.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and in adequacies.

Method and system for playing background music and key tone based on embedded browser


A LED lighting device is disclosed, which includes a LED lighting source, a printed circuit board, a heat sink and a transparent cover. The LED lighting source is provided on the printed circuit board, and the cover is attached to the heat sink for protecting the LED lighting source and the printed circuit board. The LED lighting device further includes a rivet made of plastics, which is used to fix the printed circuit board to the heat sink.

Currently, the LED-based T8/T5 tubes are emerging as a replacement for traditional fluorescent lamps which can be widely used in the application sites, such as offices, shops and homes. The LED lighting device of the prior art generally includes a LED aluminum based board/printed circuit board, a LED lighting source, a transparent cover or a scattering cover, a heat sink and a heat conducting medium (for example, a heat conducting silicon). The printed circuit board is fixed to the heat sink typically by a plurality of screws in order to obtain perfect heat conductivity between the printed circuit board and the heat sink. Since the distance between the electrical element and the circuit of the printed circuit board and the screws is restricted critically, the plurality of screws used on the circuit board can affect the routing design of the circuit seriously. In addition, the use of the plurality of screws results in additional difficulties for the manufacture and maintenance of the products.
In the prior art, another solution is to connect the printed circuit board to the heat sink by means of a type of adhesive heat conducting glue. But this is not practical, because the T8/T5 tubes are relatively longer, the adhesive glue may cause reliability problems due to the thermal expansion during using, for example, the potential separation or curving of the printed circuit board and the heat sink.

LED lighting device and manufacturing method thereof


An apparatus for sensing exhaust gas comprising: first and second tubular passages; a solid plug through which the first and second tubular passages pass and to which the tubular passages are sealingly engaged; a sampling chamber mounted to and in flow contact with the first and second tubular passages, wherein the first tubular passage provides gas flow into the sampling chamber and the second tubular passage takes gas flow out of the sampling chamber; and a flow passage having a tubular wall with an opening therein to which the solid plug is sealingly engaged, wherein the first and second tubular passages extend from inside the flow passage, through the plug, to the sampling chamber mounted outside of the flow passage.

In a known manner, exhaust gas oxygen sensors are used in automotive exhaust management systems to monitor the performance of the engine and/or catalytic converter in controlling vehicle emissions. In some examples, the exhaust gas oxygen sensors are used as feedback for engine control.
In a typical system, the oxygen sensor is mounted in a catalytic converter or in an exhaust gas flow pipe such as a manifold pipe or post-converter flow pipe. The sensor body is mounted in the pipe or converter wall with the sensing area of the sensor extending into the exhaust gas flow stream within the pipe to sense the oxygen content thereof. In such systems, the body of the sensor projects out of the converter or pipe perpendicular to the flow axis of the converter or pipe. This configuration requires clearance, for example in the vehicle floor pan, for the sensor projecting out of the converter or pipe.


The current document is directed to an integrated application-aware load-balancing component of a distributed computer system. The integrated application-aware load-balancing component is, in a described embodiment, incorporated within a distributed application that serves as a control component of multiple physical computers within a distributed computer system. The integrated application-aware load-balancing component includes a layer-4 load-balancing subcomponent that distributes communications connections initiated by remote client computers among computational nodes within the distributed computer system in order to balance the computational load applied to the distributed application and distributed computer system by the remote client computers. The integrated application-aware load-balancing component additionally includes a layer-7 load-balancing subcomponent that periodically and locally computes weights for each computational node and redistributes client requests according to the computed weights among cluster nodes within the distributed computer system in order to enhance balancing of the computational load applied to the distributed service application and distributed computer system by the remote client computers. Operation of the layer-4 and layer-7 load balancers are controlled and/or adjusted by rules and policies informed by performance and operational characteristics of the distributed service application and distributed computer system.

For many years following the advent of electronic computer systems, application programs were executed locally within a single mainframe computer or minicomputer. Initially, applications were encoded on large sets of Hollerith cards and were executed one at a time in batch-mode processing either without the benefit of an operating system or, as computer systems evolved, using primitive operating-system-like functionality. Subsequently, modern operating systems were developed to allow many different application programs to execute concurrently within a single computer system, using techniques including time-division multiplexing to provide the appearance of simultaneous execution on a single-processor computer system. Ultimately, as computer networking, operating systems, virtualization layers, and computer hardware evolved, it became possible to execute large, compute-intensive distributed applications across multiple networked computer systems. Currently, large distributed computer systems, including cloud-computing facilities, provide users with the ability to execute large, distributed applications across multiple distributed computer centers located in different geographical locations. As one example, many large e-commerce websites execute as distributed web-server applications that execute in multiple cloud-computing facilities, each including hundreds to thousands of server computers, network-attached storage systems, multiple internal networks, and other distributed-computing-system components. Computational bandwidth and storage resources are now offered as services by large cloud-computing providers much like electricity and water are provided by utility companies.
While there has been remarkable progress in computer hardware, distributed operating systems and virtualization platforms, computer networking, and tools and techniques for designing and implementing distributed applications, many technological hurdles and problems associated with distributed applications remain. As one example, when a distributed application offers a service, through a client/response protocol or web interface, the distributed service application often supports many different internet-protocol ("IP") addresses or uniform resource locators ("URLs") to which requests for the service can be directed from client computers. The multiple IP addresses or URLs may be distributed across many different front-end server computers within many different computer centers so that the request traffic is distributed across multiple computer centers and multiple front-end servers within each of the computer centers. However, use of multiple IP addresses or URLs does not, by itself, generally provide effective balancing of the total workload applied by remote clients to the distributed service application among the many different servers or virtual servers within a distributed computer system on which the distributed service application runs. In one approach to attempting to balance the computational load over multiple servers or virtual servers, an external load-balancer system is used to distributed incoming service requests among multiple computational nodes. However, external load balancers ("ELBs") are relatively expensive, complicated to set up and operate, and are generally unable to be easily scaled as the number of servers or virtual servers that execute a distributed service application increase. Moreover, ELBs generally cannot access distributed-application-state information needed to effect anything close to an even distribution, over time, of the computational load applied by remote client devices to the distributed service application among the many servers or virtual servers controlled, at least in part, by the distributed service application. Designers and developers of distributed applications and distributed computer system continue to seek methods and systems for more efficient and robust support of distributed-application-program execution within distributed computer systems.

Node selection for message redistribution in an integrated application-aware load balancer incorporated within a distributed-service-application-controlled distributed computer system