A control arrangement decoupled two driven inputs for driven belt web accumulators using gear trains, gear trains with torque feed-forward control or gear trains with toque feed-forward control and velocity feedback control.

The present invention relates in general to web accumulators for accumulating and discharging a reserve portion of a continuous web passing through the accumulator to enable continuous operation of processing stations on either or both sides of the accumulator when the speed of the web moving through the processing stations temporarily varies between the two stations. More particularly, the present invention relates to a control arrangement for belt-powered web accumulators that limits torque disturbances between the input and output rollers of such accumulators.
A typical web accumulator consists of sets of fixed and movable web rollers with the web path passing around these rollers so that the length of accumulated web increases when the moveable rollers move away from the fixed rollers and decreases when the moveable rollers move toward the fixed rollers. In order to accumulate web, the velocity of the web flowing into the accumulator must exceed the velocity of the web flowing out of the accumulator. Similarly, to discharge web, the velocity of the web flowing out of the accumulator must exceed the velocity of the web flowing into the accumulator. The input and output rollers of accumulators may be powered by servomotors or drive shafts, while the remaining rollers in the accumulator are idler-rollers that are rotated by the web moving over the rollers.
Since idler rollers have inertia and a coefficient of drag associated with their rotary motion, a force must be imparted by the web to accelerate, maintain radial velocity, and decelerate each idler roller. Therefore, each idler roller in the accumulator induces undesired tension variations in the web. Because web tension is proportional to web strain, any tension variation also creates a strain variation.
For processes that are to deliver fixed amounts of relaxed web per unit time wherein the web is elastic and exhibits elastic behavior at least for strain values, it is common to define and elastic modulus E that describes the relationship between strain, ε, in the direction of web flow, and tension, T, per unit width of web. For a given width of web, a web modulus, Ew, is defined which describes the relationship between web tension, T, and web strain, ε, in the direction of web-flow. This relationship is: T=εEw. For many materials, Ew, and therefore T, vary even within a particular lot of material. Such variations are no problem provided strain remains within the elastic region of the web; and, therefore, the primary objective for processes that deliver fixed amounts of relaxed web per unit time is to maintain target strain, rather than target tension, within acceptable limits.
In processes where strain variations need to be kept to a minimum and for weak webs in general, the size of the accumulator is limited by the number of idler rollers that can be turned by the web without the web being over-strained. Singh, U.S. Pat. No. 4,009,814, which is incorporated herein by reference, solves the strain problem resulting from idler rollers by introducing a chain or belt that is wrapped around sprockets or pulleys associated with the rollers in the accumulator so that each roller in the accumulator is powered by the same power sources that drive input and output rollers, respectively. Further, the rate of web accumulation or discharge is controlled by the difference in velocity between the input roller and the output roller. Herein, the Singh type of driven accumulator will be referred to as a belt-powered accumulator.
It is known to use servo-drives to drive belt-powered accumulators. However, unless the load inertia reflected onto each servomotor is negligible compared to the motor inertia, a substantial torque coupling can exist between the input and output roller servo drives. This torque coupling induces undesired speed variations on the input roller and the output roller when the opposing torque between the input roller and the output roller changes.
There is thus a need to provide a control arrangement for driven belt accumulators that limits torque disturbances between the input and output rollers of the accumulators.

Web accumulator having limited torque disturbance


A computer-implemented method according to one embodiment includes identifying code word interleaved (CWI)-4 entries to be re-written to a data storage cartridge, selecting a subset of the CWI-4 entries to be included within a first CWI-4 set, where a plurality of the CWI-4 entries within the subset are associated with a single sub data set (SDS), and re-writing the first CWI-4 set to the data storage cartridge.

The present invention relates to data storage systems, and more specifically, this invention relates to performing a re-write of data to a data storage cartridge.
Data storage cartridges are used for providing cost effective storage and retrieval of large quantities of data. Data storage cartridges are commonly termed "removable media." Data storage cartridge media may comprise any type of media on which data may be stored and which may serve as removable media, including but not limited to magnetic media (such as magnetic tape or disks). An example of a data storage cartridge that is widely employed in automated data storage libraries for mass data storage is a magnetic tape cartridge.
After data is written to a data storage cartridge by a data storage drive, it is reviewed (e.g., as part of a read-while-write operation). If a portion of the data that is written contains more than a predetermined amount of errors, the portion is scheduled to be re-written to the data storage cartridge. However, current methods for implementing this re-writing are inefficient.

Prioritized sourcing for efficient rewriting

International Business Machines Corporation


A device for holding lateral tabs of box blanks filing along a conveyor particularly in a folder-gluer. At least one rotary support is actuated in synchronicity with the passage of said blanks the activation being via a drive member arranged on an adjustable bearing structure. At least one sensor detects the blanks. The sensor is connected to an electronic control unit that commands the drive member which is rendered autonomous.

The subject of the present invention is a device for holding lateral tabs of box blanks passing through a folder-gluer, the machine commonly used in the packaging industry to make up boxes from cardboard blanks.
A folder-gluer machine generally comprises a series of modules, each intended to carry out a given operation so that the box blanks introduced at the input of the machine in a feeder, reemerge in the form of folded boxes ready for use. Typically, the operations carried out in a folder-gluer are in sequence: pre-breaking of certain fold lines of the blank, folding of parts such as the lateral tabs, folding of the front and rear tabs, coating the tabs with glue, pressing of the blanks once folded and glued, and their receipt at the end of the production line.
The box blanks are generally conveyed through the various modules of the machine via a belt conveyor which, through friction, holds the blanks either between lower and upper belts or between lower belts and upper press rollers.
It is in the module that folds the rear tabs that the device of the present invention finds its use. The folding of the rear tabs is a relatively complicated operation performed by one or more horizontal-axis rotary folders. These folders generally comprise two hooks mounted in opposition on a central hub which are able to move along a drive shaft positioned transversely to the direction of travel of the blanks. In a movement that is synchronized with the rate of travel of these blanks, these hooks each in turn emerge from the plane of passage of the blanks, in the space separating two consecutive blanks. Each hook is temporarily given a speed higher than the speed at which the blanks are moving, so that the hook is able, at a given moment, to catch the rear tab of the blank and fold it completely onto the rear part of the box blank.
To be able to carry out this folding operation, it is generally necessary to interrupt the belts or rollers of the upper conveyor which holds the lateral parts already folded, pressed against the lower conveyor. Without the action of the upper conveyor, these lateral tabs have the tendency to open up. This effect is more pronounced when the rear tab is being folded, during which operation, the rear of the blank is predisposed to being lifted by the rotary folder.
To prevent the lateral tabs from opening out or the lifting of the blank at the time of the folding of the rear tab, recourse to rotary supports is known. Such supports are described in patent CH 457 114 that describes a similar device. These supports consist of two diametrically opposed flexible fins or blades mounted in continuous rotation about a drive shaft so as to form a helix. The rotational speed of this shaft is directly dependent on the rate of travel of the blanks through the machine. To achieve this, the drive shaft is mechanically connected by a drive line either to the drive of the rotary hooks or to the main drive of the folder-gluer or alternatively to a so-called "synchronous" feeder so that it is always in perfect synchronicity with the rate at which the blanks pass through the machine.
A synchronous feeder is a mechanical entity that is able to synchronize the start of the blanks by means of feed guides mounted on toothed belts. This feeder is said to be "synchronous" because of its function that compensates for any delay on the part of the blank as a result of unwanted slippage against the conveyor.
The chief disadvantage with such a device for holding the lateral tabs lies in the fact that its operation is completely dependent on its drive system. This dependency prevents any time delay between the enaction of the rotary supports with respect to the folding of the rear tab by the rotary hook. Now, it has been found that, depending on the type of box being made up, the lateral tabs are not always positioned the same distance away from the rear tab. In such cases, the folded lateral parts of the blank are not always held in place at the most opportune moment.
According to another device known to those skilled in the art, the supports are not mounted on a spindle in continuous rotation but on the leaf of a hinge that allows the support to move back and forth. This support moves from one position to another by means of a return spring for example. The chief disadvantage with such a system lies in the fact that the mechanism is not rapid and reliable enough to sustain high production rates.
Another solution might be to provide a mechanical cam in the drive of the rotary supports, a mechanical cam allowing a predefined delay or advance to be introduced into the action of the rotary supports, depending on the boxes being processed. Such a solution would, however, suffer from a major disadvantage associated with the fact that it would then become necessary to provide as many specific cams as there are types of box to be processed. From an economic standpoint, such a solution is of course inconceivable.

Device for maintaining side tabs of box blanks running through a folder-gluer


A casino card game using a deck of cards having a number of value cards and a number of subsets of cards. A first subset constitutes value cards which have value in the play of the game to provide winning combinations according to the game rules. A second subset are wild cards that assume the value of another value card in a players hand. A third subset of cards are player specific cards which when matching an identifier separately associated with the player, assumes special meaning in the players hand. A fourth subset termed worthless cards which have no value and occupies space in the hand. A fifth subset are losing cards which causes a hand to immediately lose. A sixth subset is termed contingent cards which causes the player to receive additional payoff when the player has a winning combination of value cards. A last subset are win cards which causes the hand to immediately win. During the play of the game, the deck of cards are shuffled and a player analyzes the hand for a winning combination of value cards.

1. Field of the Invention
The present invention relates to casino card games and, more particularly, to a variation of poker.
2. Background of the Invention
U.S. Pat. No. 4,807,885 is a card game wherein the cumulative value of the discards are continually added up to a chosen value "99" to be reached in the game. FIG. 4 of the '885 patent has special "pass" cards, "wild" cards, "reverse" cards, "no play joker" cards, and "automatic ninety-nine" cards. The "pass" card allows a player to pass to the next player; with a "reverse" card, a player shifts the direction of play; a "no play joker" card cannot be played thereby effectively reducing the playable cards in a player's hand, and "automatic ninety-nine" card moves the count of the discard stack to ninety-nine. The "wild" cards allow the player to adjust the cumulative value of the discard stack.
WO 92/16269 is a conventional gaming card game with added symbols for separate wagers. In one embodiment, two additional "no value" playing cards are added to the deck for an additional wager on if the two "no value" cards will be dealt consecutively during play of the underlying game.
U.S. Pat. No. 5,605,333 has a card game with a standard deck of cards wherein face cards and the ten card have a value of zero, and numbered cards retain their natural value except for fours and fives which are removed from the deck. To win one must come close to a target value in a suit.
U.S. Pat. No. 5,431,408 permits a player upon receiving a wild card to optionally reserve it for use in a subsequent hand. If the player elects this option, he/she receives a replacement card.
U.S. Pat. No. 5,308,065 has a standard card deck for poker, and each player receives a hand of five cards. A sixth card, not a part of the hand, is delivered to the player face down. The player has the right to improve the ranking of the dealt five-card hand by discarding up to five cards and replacing them. Thereafter, any cards in the hand with the same value as the sixth card are wild.
3. Statement of the Problem
Live card games continue to be popular in casinos around the world. One popular casino card game is poker and variations on poker have occurred over the years which have increased participation and excitement by players of these games at casinos. A need exists to provide variants on the game of poker.
A number of well-known board games, not generally suited for the casino environment, have also entertained the populace for a large number of years. A need exists to adapt such well-known board games to the casino environment. In general, such board games normally take a long period of time to play in the family or home setting. In the casino environment, such periods of time are too long and, in adopting a board game to the casino environment, a need exists to speed up the game while preserving the excitement and popularity of the board game.
In card games in general, all cards in the card games have value with respect to the play of the game. For example, in poker, each card in the deck has at least one value (i.e., rank or suit). When certain winning combinations of cards exist in a poker hand, the player wins. Conventional house banked poker games have straights and flushes as winning combinations which pay back winnings (usually multiples of the ante) to the player. While such combinations add variety to the game, a player must study the hand in order to play for these combinations. A need exists to simplify such analysis in order to provide a modified poker game which eliminates such straights and flushes winning combinations and the payoffs for them.
The use of a subset of cards in a casino card game called "wild cards" is conventionally known to exist. Wild cards also provide excitement to the game since a player, based upon the other value cards in the hand can select a value for a wild card appearing in his or her hand. A need exists for other "subsets" of cards in a card deck to make the casino card game more exciting to players.
Hence, an overall need exists to provide a new card game adapted for the casino environment which preferably adapts popular board games to the casino environment, which provides a poker-type card game with "straights and flushes" eliminated and which provides entirely new and different card subsets, all of which are designed to add excitement, speed, and rewards to players of such games at casinos.
4. Solution to the Problem
The present invention provides a solution to the aforesaid needs. The card game disclosed herein is a form of modified poker in which "straights and flushes" are eliminated. Furthermore, the card game provides a structure in which the play of a conventional board game may be adopted into. In the preferred embodiment, the conventional board game is MONOPOLY.RTM..
The card game of the present invention incorporates several new subsets of cards in a deck which have application to casino card games in general and, in specific, to the adaption of a board game in a modified form as discussed herein. The first subset of cards is termed "worthless" in that they constitute a predetermined number of cards that have no value in a game. The second subset of cards is termed "loser" in that the receipt of such a card causes the player to immediately lose the hand. A third subset of cards is termed "player specific" cards. When the player receives the special player card and the card corresponds to a separate identifier of the player, the card assumes special meaning--e.g., a wild card. If it does not correspond, it assumes a different meaning--e.g., a "worthless" card in the play of that hand. A fourth subset of cards is termed "contingent" cards. When the player receives the contingent card and the player has a winning hand (for example, a winning like-kind group of cards) the presence of a contingent card in his or her hand adds additional payoff value. If the player does not have a winning combination in the hand, the card is worthless. Hence, the contingent card has a value contingent on what other cards are present in the hand. A final subset of cards is termed "win" cards. When the player receives the win card, the player automatically wins.


A composite article includes a ceramic part, a plastic part, and an adhesive layer connecting the ceramic part to the plastic part. The adhesive layer includes polyvinyl acetate, polyvinyl alcohol, dibutyl phthalate, and sec-butyl acetate.

1. Technical Field
The present disclosure relates to composite articles, especially to a ceramic-and-plastic composite article and a method for making the composite article.
2. Description of the Related Art
A typical process for joining a ceramic part and a plastic part may include the following steps: (1) the ceramic part is coated with a liquid adhesive on the combined surface; (2) the plastic part is attached to the combined surface of the ceramic part under a certain pressure to combine the ceramic part and the plastic part together. However, during the joining process, the liquid adhesive usually flows out of the combined surface, which adversely affects the appearance of the composite article. Furthermore, the bonding strength between the ceramic part and the plastic part is not strong enough due to a poor adhesive property of the current liquid adhesive.
Therefore, there is room for improvement within the art.

Composite article and method for making same

SHENZHEN FUTAIHONG PRECISION INDUSTRY CO., LTD.


The invention relates to 3-hydroxy-and 3-keto-cyclohetero-substituted leucine compounds that are inhibitors of cysteine proteases, particularly cathepsin K, and are useful in the treatment of diseases in which inhibition of bone loss is a factor. The 3-hydroxy-or 3-keto-moiety is bonded to a tetrahydrothiophene, tetrahydrothiopyran, tetrahydrofuran or tetrahydropyran ring.

This invention relates to novel protease inhibitors, particularly inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases. The compounds of this invention even more particularly relate to those compounds which inhibit cysteine proteases of the papain superfamily, and particularly cysteine proteases of the cathepsin family. In the most preferred embodiment, this invention relates to compounds which inhibit cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
Cathepsin K is a member of the family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Pat. No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F. H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
Cathepsin K has been variously denoted as cathepsin O, cathepsin X or cathepsin O2 in the literature. The designation cathepsin K is considered to be the more appropriate one (name assigned by Nomenclature Committee of the International Union of Biochemistry and Molecular Biology).
Cathepsins of the papain superfamily of cysteine proteases function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have been implicated in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like. See International Publication Number WO 94/04172, published on Mar. 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 A1, and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.
Cathepsin K is believed to play a causative role in diseases of excessive bone or cartilage loss. Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated. Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface. This creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane, and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget""s disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle. Ultimately, this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget""s disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium. Thus, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.
It now has been discovered that a novel class of compounds are protease inhibitors, most particularly inhibitors of cathepsin K, and these compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis and periodontal disease.
An object of the present invention is to provide protease inhibitors, such as inhibitors of cysteine and serine proteases. In particular, the present invention relates to compounds which inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily. Preferably, this invention relates to compounds which inhibit cysteine proteases of the cathepsin family and particularly, compounds which inhibit cathepsin K. The compounds of the present invention are useful for treating diseases, which may be therapeutically modified by altering the activity of such proteases.
Accordingly, in the first aspect, this invention provides a compound according to formula (I):
In another aspect, this invention provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
In yet another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, such as cysteine and serine proteases. In particular, the method includes treating diseases by inhibiting cysteine proteases, and particularly cysteine proteases of the papain superfamily. More particularly, the inhibition of cysteine proteases of the cathepsin family, such as cathepsin K is described.
In another aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
The present invention provides compounds of formula (I):
wherein:
R1 is Rxe2x80x3, Rxe2x80x3C(O), Rxe2x80x3C(S), Rxe2x80x3SO2, Rxe2x80x3OC(O), Rxe2x80x3Rxe2x80x2NC(O), or Rxe2x80x3OC(O)NRxe2x80x2CH(R6)C(O);
R2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R3 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R4 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
each R5 independently is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R6 is H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl-C0-6-alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
Rxe2x80x2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
Rxe2x80x3 is C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, Ar-C2-6alkenyl or Het-C2-6alkenyl;
X is O or S; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to formula (I) in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. According to the instant invention, the S-form at the furan ring junction of formula (I) compounds is preferred.
In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
The meaning of any substituent at any one occurrence in formula (I) or any subformula thereof is independent of its meaning, or any other substituent""s meaning, at any other occurrence, unless specified otherwise.
With respect to formula (I):
Suitably, R2 and R4 are H and R3 is C1-6alkyl or C2-6alkenyl. Preferably, R3 is i-butyl.
Suitably, each R5 is H.
Suitably, R1 is Rxe2x80x3OC(O), Rxe2x80x3SO2 or Rxe2x80x3C(O), in which Rxe2x80x3 is Ar-C0-6alkyl or Het-C0-6alkyl, and, most preferably, Rxe2x80x3 is
in which B2 is OH, CN, OCF3, OC1-6alkyl, OAr, SO2C1-6alkyl, C1-6alkyl or halo.
Suitably, n is 1 or 2. Preferably, n is 1.
Suitably, X is O.
In one particular embodiment, this invention is a compound of formula (II):
Preferably, the formula (I) compound of this invention is a compound of formula (IIa):
Alternately, the formula (I) compound of this invention is a compound of formula (IIb):
In another embodiment, this invention is a compound of formula (IIc):
Specific representative compounds of this invention are:
4-(R,S)-Amino-N-[(3,4-methylenedioxybenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(3,4-dichlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(2-quinolinecarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(8-quinolinecarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-2,2-dibenzyl-tetrahydrofuran-3-one;
4-(R,S)-Amino-N[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(indole-6-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(benzofuran-2-ylcarbonyl)-S-leucine)-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(5-aminobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(5-chlorobenzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(5-methoxybenzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(3-bromobenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(4-bromobenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(5-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(4-fluorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(4-phenoxybenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(4phenylbenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(6-trifluoromethylbenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(4-ethyllbenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(4-(tert-butyl)benzoyl)-S-leucine]-tetrahydrofuran-3-one ;
4-(R,S)-Amino-N-[(5-methoxybenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(4-nitrobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(6-bromobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(5-bromobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(6-methoxybenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(benzo(b)thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-R-Amino-N-[(benzo(b)thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(2-napthoyl)-S-leucine]-tetrahydrofuran-3-one;
4-R-Amino-N-[(2-napthoyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(quinoline-2-carbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-R-Amino-N-[(quinoline-2-carbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(5-methoxybenzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[((4-pyrid-3-yl)benzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[((4-pyrid-2-yl)benzoyl)-S-leucine]-tetrahydrofuran-3-one,
4-S-Amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(benzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(4-[6-methylpyrid-3-yl]benzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(5-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[((4-pyrid4-yl)benzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(2-chlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(4-bromobenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(4-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(4-benzylpiperidin-1-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(3,4-dichlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-S-Amino-N-[(3-chlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one;
4-(R,S)-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydropyran-3-one;
4-(R,S)-Amino-N-[(4-phenoxybenzoyl)-S-leucine]-tetrahydropyran-3-one;
4-(R,S)-Amino-N-[(quinolin-2-ylcarbonyl)-S-leucine]-tetrahydropyran-3-one;
4-(R,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydropyran-3-one:
4-(R,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydropyran-3-one; and
4-(R,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrothiophen-3-one;
or a pharmaceutically acceptable salt thereof.
In yet another aspect, this invention provides novel intermediates useful in the preparation of formula (I) compounds represented by formulae (III), (IV) and (V):
wherein:
R1 is Rxe2x80x3, Rxe2x80x3C(O), Rxe2x80x3C(S), Rxe2x80x3SO2, Rxe2x80x3OC(O), Rxe2x80x3Rxe2x80x2NC(O), or Rxe2x80x3OC(O)NRxe2x80x2CH(R6)C(O);
R2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R3 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R4 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
each R5 independently is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R6 is H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl-C0-6-alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
Rxe2x80x2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
Rxe2x80x3 is C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, Ar-C2-6alkenyl or Het-C2-6alkenyl; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, or
wherein:
R1 is Rxe2x80x3, Rxe2x80x3C(O), Rxe2x80x3C(S), Rxe2x80x3SO2, Rxe2x80x3OC(O), Rxe2x80x3Rxe2x80x2NC(O), or Rxe2x80x3OC(O)NRxe2x80x2CH(R6)C(O);
R2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R3 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R4 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
each R5 independently is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R6 is H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl-C0-6-alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
Rxe2x80x2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
Rxe2x80x3 is C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, Ar-C2-6alkenyl or Het-C2-6alkenyl; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, or
wherein:
R1 is Rxe2x80x3, Rxe2x80x3C(O), Rxe2x80x3C(S), Rxe2x80x3SO2, Rxe2x80x3OC(O), Rxe2x80x3Rxe2x80x2NC(O), or Rxe2x80x3OC(O)NRxe2x80x2CH(R6)C(O);
R3 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R4 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
each R5 independently is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R6 is H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl-C0-6-alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
Rxe2x80x2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
Rxe2x80x3 is C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, Ar-C2-6alkenyl or Het-C2-6alkenyl;
X is O or S; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
Representative intermediates of this invention are:
trans-4-(R,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3-hydroxytetrahydrofuran;
trans-4-(R,S)-Amino-N-[(tert-butoxycarbonyl)-S-leucine]-3-hydroxytetrahydrofuran;
trans-4-(R,S)-Amino-N-(S-leucine)-3-hydroxytetrahydrofuran;
trans-4-(R,S)-Amino-N-[(3,4-methylenedioxybenzoyl)-S-leucine]-3-hydroxytetrahydrofuran;
trans-4-(R,S)-Amino-N-[(3,4-dichlorobenzoyl)-S-leucine]-3-hydroxytetrahydrofuran;
trans-4-(R,S)-Amino-N-[(2-quinolinecarbonyl)-S-leucine]-3-hydroxytetrahydrofuran;
trans-4-(R,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3-hydroxytetrahydropyran;
trans-4-(R,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-hydroxytetrahydropyran;
trans-4-(R,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-hydroxytetrahydrofuran;
trans-4-(R,S)-Amino-N-[(indole-6-ylcarbonyl)-S-leucine]-3-hydroxytetrahydrofuran;
trans-4-(R,S)-Amino-N-[(5-aminobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-hydroxytetrahydrofuran
trans-4-Amino-3-hydroxytetrahydrofuran;
trans-3-Hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran;
4-Benzyloxycarbonylamino-tetrahydrofuran-3-one;
3,3-Dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran;
3,3-Dimethoxy-4-amino-tetrahydrofuran
trans-4-S-Amino-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-(S-leucine)-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(3,4-dichlorobenzoyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(2-quinolinecarbonyl)-S-leucine]-3-R-hydroxytetrahydrofuran,
trans-4-S-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(benzofuran-2-ylcarbonyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(2-naphthoyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(5-methoxybenzofuran-2-ylcarbonyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(5-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(4-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(4-bromobenzoyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(4-(pyrid-2-yl)benzoyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S Amino-N-[(4-(pyrid-3-yl)benzoyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-S-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-3-R-hydroxytetrahydrofuran;
trans-4-Amino-3-hydroxytetrahydropyran;
trans-4-(R,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3-hydroxytetrahydropyran;
trans-4-(R,S)-Amino-N-(S-leucine)-3-hydroxytetrahydropyran;
trans-4-(R,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-hydroxytetrahydropyran;
N-benzo[b]thiophene-2-ylcarbonyl-L-leucine methyl ester;
N-benzo[b]thiophene-2-ylcarbonyl-L-leucine;
N-benzo[b]thiophene-2-ylcarbonyl-L-leucine-S-(methoxycarbonylmethyl)-L,D-cysteine ethyl ester; and
2-Methoxycarbonyl-4-(R,S)-Amino-N-[(benzo[b]thiophene-2-ylcarbonyl)-S-leucine]-tetrahydrothiophene-3-one;
or salts thereof.
These intermediates are prepared using methods analogous to that described in Schemes 1-4 and the Examples described hereinafter.
Prodrugs of compounds of the present invention may be a prodrug of the ketone functionality of formula (I) compounds, specifically ketals or hemiketals, of the formula (VI):
wherein:
R1 is Rxe2x80x3, Rxe2x80x3C(O), Rxe2x80x3C(S), Rxe2x80x3SO2, Rxe2x80x3OC(O), Rxe2x80x3Rxe2x80x2NC(O), or Rxe2x80x3OC(O)NRxe2x80x2CH(R6)C(O);
R2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R3 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R4 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
each R5 independently is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R6 is H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl-C0-6-alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
Rxe2x80x2 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
Rxe2x80x3 is C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, Ar-C2-6alkenyl or Het-C2-6alkenyl;
X is O or S;
n is 1, 2 or 3; and
Ra and Raxe2x80x2 independently are H or C1-2alkyl, with the proviso that when one of Ra and Raxe2x80x2 is H, the other is C1-2alkyl; or together are (CH2)2-3 forming a 5- or 6-membered ring;
or a pharmaceutically acceptable salt thereof.
Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). The term xe2x80x9camino acidxe2x80x9d as used herein refers to the D- or L-isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
xe2x80x9cC1-6alkylxe2x80x9d as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any C1-6alkyl group may be optionally substituted independently by one or two halogens, SRxe2x80x2, ORxe2x80x2, N(Rxe2x80x2)2, C(O)N(Rxe2x80x2)2, carbamyl or C1-4alkyl, where Rxe2x80x2 is H or C1-6alkyl. C0alkyl means that no alkyl group is present in the moiety. Thus, Ar-C0alkyl is equivalent to Ar.
xe2x80x9cC3-6cycloalkylxe2x80x9d as applied herein is meant to include substituted (i.e., alkyl, OR, SR or halogen) and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
xe2x80x9cC2-6alkenylxe2x80x9d as applied herein means an alkyl group of 2 to 6 carbons,
wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2-6alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
xe2x80x9cC2-6alkynylxe2x80x9d means an alkyl group of 2 to 6 carbons, wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C2-6alkynyl includes acetylene, 1-propync, 2-propyne, 1-butyne, 2-butyne, 3-butyne, and the simple isomers of pentyne and hexyne.
xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d means F, Cl, Br, and I.
xe2x80x9cArxe2x80x9d or xe2x80x9carylxe2x80x9d means unsubstituted phenyl or naphthyl; or phenyl or naphthyl substituted by one or more of Ph-C0-6alkyl, Het-C0-6alkyl, C1-6alkoxy, Ph-C0-6alkoxy, Het-C0-6alkoxy, OH, (CH2)1-6NRxe2x80x2Rxe2x80x2, O(CH2)1-6NRxe2x80x2Rxe2x80x2; wherein each Rxe2x80x2 independently is H, C1-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl; or phenyl or naphthyl substituted by one to three moieties selected from C1-4alkyl, ORxe2x80x2, N(Rxe2x80x2)2, SRxe2x80x2, CF3, NO2, CN, CO2Rxe2x80x2, CON(Rxe2x80x2)2, F, Cl, Br and I, or substituted by a methylenedioxy group.
As used herein xe2x80x9cHetxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C1-4alkyl, ORxe2x80x2, N(Rxe2x80x2)2, SRxe2x80x2, CF3, NO2, CN, CO2Rxe2x80x2, CON(Rxe2x80x2)2, F, Cl, Br and I, where Rxe2x80x2 is as defined herein before. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, thienyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, isothiazolyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzopyranyl, benzoxazolyl, benzofuranyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl, 1,6napthyridinyl, 1,7-napthyridinyl, 1,8-napthyridinyl, tetrazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl.
Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical; Boc or BOC refers to the tbutyloxycarbonyl radical; Fmoc refers to the fluorenylmethoxycarbonyl radical; Ph refers to the phenyl radical; and Cbz or CBZ refers to the benzyloxycarbonyl radical.
Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodiimide; EDC or EDCI refers to N-ethyl-Nxe2x80x2(dimethylaminopropyl)-carbodiimide. HOBT or HOBt refers to 1-hydroxybenzotriazole; DMF refers to dimethyl formamide; DIEA refers to di-isopropylethylamine; Lawesson""s reagent is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide; TFA refers to trifluoroacetic acid; and THF refers to tetrahydrofuran.
Compounds of the formula (I) are generally prepared by:
(i) reacting a compound of the formula (III):
wherein R1, R2, R3, R4, R5 and n are as defined in formula (I), with any reactive functional groups protected, with an oxidizing agent; or
(ii) decarboxylating a compound of the formula (IV):
wherein R1, R2, R3, R4, R5 and n are as defined in formula (I), with any reactive functional groups protected; or
(iii) reacting a compound of the formula (V):
wherein R1, R3, R4, R5 and n are as defined in formula (I), with any reactive functional groups protected, with an acid;
and thereafter removing any protecting groups and optionally forming a pharmaceutically acceptable salt.
Compounds of the formula (I) are prepared by methods analogous to those described in the solution synthesis method of Scheme 1, or the solid support method of Scheme 2, or the solution synthesis method of Scheme 3.
a) NaN3, ammonium chloride, methanol:water; b) 10% Pd/C, EtOH, H2; ethanolic HCl; c) trimethylacetyl chloride, N-BOC-leucine, DIEA, CH2Cl2; d) TFA, CH2Cl2; e) RCOCl, sodium hydrogen carbonate, 1,4-dioxane; f) Dess-Martin periodinane, CH2Cl2
Compounds of the general formula (I), wherein n is 1 and R1 is Rxe2x80x3C(O) are prepared by methods shown in Scheme 1. Treatment of the known epoxide 1-Scheme-1 with sodium azide and ammonium chloride in aqueous methanol at elevated temperatures provides the azide 2-Scheme-1. Reduction of the azide 2-Scheme-1 utilizing methods that are known in the art, such as reduction with palladium on carbon in ethanol under an atmosphere of hydrogen, provides the amine salt 3-Scheme-1 after treatment with ethanolic hydrogen chloride. The amine salt 3-Scheme-1 may be coupled with a carboxylic acid by methods that are known in the art, such as acylation with an acid chloride or coupling with an acid in the presence of EDC and HOBT, to provide the amide 4-Scheme-1. The tert-butoxycarbonyl group may be removed by treatment with a strong acid, such as TFA, in an aprotic solvent, such as dichloromethane, to provide 5-Scheme-1. The salt 5-Scheme-1 may be acylated with an acid chloride in 1,4-dioxane in the presence of an aqueous base, such as saturated sodium hydrogen carbonate, to yield 6-Scheme-1. The alcohol 6-Scheme-1 may be oxidized by methods known in the art, such as by treatment with Dess-Martin periodinane, in an aprotic solvent, such as dichloromethane.
Compounds of the general formula (I), wherein R1 is C(O)Rxe2x80x2, R2 is H, R4 is H, R5 is H, X is O, and n is 1, are prepared by the solid support synthesis (SPS) method shown in Scheme 2. In particular, in the first step, sodium triacetoxyborohydride is added to a stirred solution of Ellmans resin in DMF containing 1% HOAc, and then the xcex1-amino acid, methyl ester is added to give rise to 2-Scheme-2. The amine group is coupled with a carboxylic acid by using known methods, such as by the addition of the carboxylic acid with EDC, to give rise to the amide, 3-Scheme-2. Thereafter, the ester group is hydrolysed, for example, with potassium trimethylsilanoate in THF, and the liberated acid group is coupled with 3,3-dimethoxy-4-amino-tetrahydofuran using, for example, EDC in NMP, to give rise to 4-Scheme-2. The blocking group is then removed by known cleaving methods, such as by the addition of 7:2:1 TFA/CH2Cl2/H2O, to give rise to the desired compound, 5-Scheme-2.
Compounds of the general formula (I), wherein R1 is C(O)Rxe2x80x2, R2 is H, R4 is H, R5 is H, X is O, and n is 2, are prepared by the solid support synthesis (SPS) method shown in Scheme 2, except 3,3-dimethoxy-4-aminotetrahydropyran is substituted for 3,3-dimethoxy-4-amino-tetrahydofuran.
(a) L-Leu methyl ester, iPr2NEt, CH2Cl2; (b) LiOH, THF/H2O; (c) (i)ClCO21Pr, Et3N, CH2Cl2 (ii) L-Cys ethyl ester (iii) BrCH2CO2Me; (d) (i)NaOMe, MeOH, (ii) AcOH/HCl, H2O
Scheme 4, hereinafter, shows the preparation of certain formula (I) compounds which are S-diastereomers at the furan ring junction.
The R-diastereomer is prepared in an identical way from the opposite 3-azido4-hydroxytetrahydrofuran enantiomer:
The intermediates of the present invention, such as 3,3-dimethoxy4-amninotetrahydofuran, can be prepared according to the method of Scheme 5.
The steps in Scheme 5 are presented as follows. First, a nitrogen-protecting group is added by reacting 3-hydroxy4-aminotetrahydofuran with benzychloroformate in dioxane containing aqueous sodium carbonate. Thereafter, the alcohol group is oxidized by known methods, such as by the addition of bleach containing sodium bicarbonate in the presence of sodium bromide and TEMPO in EtOAc, toluene, and water, to give rise to the ketone. The ketone is converted to the dimethylketal by the addition of trimethyl-orthoformate in the presence of paratoluenesulphonic acid in methanol. Finally, the protecting group is removed by hydrogenation using, for example, palladium an charcoal in the presence of ethanol under an atmosphere of hydrogen.
excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget""s disease; hypercalcemia of malignancy, and metabolic bone disease.
Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
The present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of the present invention. The present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof, an inhibitor of cathepsin K, including a compound of the present invention. The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget""s disease, hypercalcemia of malignancy, and metabolic bone disease.
This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of formula (I), alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.
In accordance with this invention, an effective amount of the compounds of formula (I) is administered to inhibit the protease implicated with a particular condition or disease. Of course this dosage amount will further be modified according to the type of administration of the compound. For example, xe2x80x9ceffective amountxe2x80x9d for acute therapy, parenteral administration of a compound of formula (I) is preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K. The compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day. The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
Prodrugs of compounds of the present invention may be prepared by any suitable method. For those compounds in which the prodrug moiety is a ketone functionality, specifically ketals and/or hemiacetals, the conversion may be effected in accordance with conventional methods.
The compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.
No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
The compounds of this invention may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect.
Determination of Cathepsin K Proteolytic Catalytic Activity
All assays for cathepsin K were carried out with human recombinant enzyme. Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 xcexcM final substrate concentration in the assays. All assays contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature. Product fluorescence (excitation at 360 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product.
Inhibition Studies
Potential inhibitors were evaluated using the progress curve method. Assays were carried out in the presence of variable concentrations of test compound. Reactions were initiated by addition of enzyme to buffered solutions of inhibitor and substrate. Data analysis was conducted according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors. For those compounds whose progress curves were linear, apparent inhibition constants (Ki,app) were calculated according to equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140):
v=VmA/[Ka(1+I/Ki,app)+A]xe2x80x83xe2x80x83(1)
where v is the velocity of the reaction with maximal velocity Vm, A is the concentration of substrate with Michaelis constant of Ka, and I is the concentration of inhibitor.
For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give kobs according to equation 2:
[AMC]=vSSt+(v0xe2x88x92vSS)[1xe2x88x92exp (xe2x88x92kobst)]/kobs xe2x80x83xe2x80x83(2)
where [AMC] is the concentration of product formed over time t, v0 is the initial reaction velocity, and vSS is the final steady state rate. Values for kobs were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (kobs/inhibitor concentration or kobs/[I]) describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61, 201).
One skilled in the art would consider any compound with a Ki of less than 50 micromolar to be a potential lead compound. Preferably, the compounds used in the method of the present invention have a Ki value of less than 1 micromolar. Most preferably, said compounds have a Ki value of less than 100 nanomolar. 4-(R,S)-Amino-N-[(8-quinolinesulfonyl)-S-leucine]-3-tetrahydrofuran-3-one, a compound of formula (I), has a Ki value that is greater than 10 micromolar.
Human Osteoclast Resorption Assay
Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37xc2x0 C. and washed xc3x971 in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4xc2x0 C.). The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated for 30 minutes on ice. The cell suspension was mixed frequently.
The cells were washed xc3x972 with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4xc2x0 C.) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber.
Sufficient magnetic beads (5/mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.
The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xc3x9710. The bead-coated cells were discarded.
The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample. The cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xc3x97104/mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7 g/liter of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 xcexcM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL). The, tubes were incubated at 37xc2x0 C. for 30 minutes.
0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37xc2x0 C. for 2 hours. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL/well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37xc2x0 C. for 48 hours. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 minutes, following which they were washed in water and incubated in buffer for 5 minutes at 37xc2x0 C. The slices were then washed in cold water and incubated in cold acetate buffer/fast red garnet for 5 minutes at 4xc2x0 C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
The TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.


A method for manufacturing a magnetic head of a metal-in-gap type in which a soft magnetic film is provided in a gap of a ferrite core comprising the steps of: forming a first layer comprising a metallic magnetic film containing nitrogen on magnetic ferrite; forming a second layer comprising a metallic magnetic film containing nitrogen in an amount less than said first layer; and forming a third layer comprising a metallic magnetic film containing nitrogen in an amount more than said second layer.

1. Field of the Invention
The present invention relates to a magnetic head, and more particularly, to a method for manufacturing a magnetic head of a MIG type in which a magnetic material of a high saturation magnetic flux density and a high magnetic permeability is provided in the magnetic gap.
2. Description of the Related Arts
In recent years, improvements in video, acoustic, and information equipment have been remarkably progressing. Magnetic recording plays a very important role in these equipments. Accordingly, there are growing demands for the development of magnetic recording technology. For example, the development of technology for carrying out a high density recording is strongly demanded. As a result, the recording medium of these equipments have increased in magnetic coercive force. A conventional magnetic head made of ferrite is not enough to record a signal favorably on a medium having such a high magnetic coercive force. Therefore, researches have been made on a metallic soft magnetic materials of a high saturation magnetic flux density such as Sendust, Co-base amorphous, and Fe-base alloy. Further, magnetic heads of various types, such as laminated types or thin film types, which are made of these metallic soft magnetic material, have been energetically developed.
A magnetic head of a metal-in-gap (MIG) type is superb in that it is low in manufacturing cost and preferably has wear resistance. The above-described MIG head means that a magnetic head made of ferrite in which a metallic magnetic material of a high saturation magnetic flux density and a high magnetic permeability is provided in the magnetic gap. Of MIG heads, a MIG head of a parallel gap type particularly has a favorable productivity, namely, a magnetic head in which the magnetic gap is parallel with the boundary surface between the ferrite and the metallic magnetic film of a high saturation magnetic flux density and a high magnetic permeability. But the parallel gap type MIG head is inferior in practicability in that a pseudo signal is produced due to the generation of a pseudo gap in the boundary region between the ferrite and the metallic magnetic film caused by reaction or diffusion in heat treatment. But recently, researches have been made to manufacture a metallic film which is hardly diffused and hardly reacts with the ferrite or the nonmagnetic reaction preventing film. The parallel gap type MIG heads comprising such films are practically used, which is described in, for example, "Japanese applied magnetics society magazine", 12, 103-106 (1988) or 13, 277-280 (1989).
The conventional parallel gap type MIG head has a disadvantage in its structure in the metallic magnetic film of a high saturation magnetic flux density and a high magnetic permeability in practical use does not have the necessary reactivity or only exhibits the property of diffusion in a slight degree. Accordingly, it is necessary to provide a parallel gap type MIG head comprising such a metallic magnetic film with a composition suitable for the metallic magnetic film. Otherwise, it is necessary to form a reaction preventing layer between the metallic magnetic film and the ferrite. If the reaction preventing layer is nonmagnetic, the reaction preventing layer itself serves as a magnetic gap. Consequently, the reaction preventing layer causes a pseudo gap.

Matsushita Electric Industrial Co., Ltd.


A thresher element adapted for securement to a combine rotor for threshing crop materials. The thresher element has a generally L-shaped configuration including first and second portions which angle away from each other. The second portion of each thresher element is configured to impact with crop materials moving therepast while the first portion deflects crop material from impacting with thresher element mountings on the rotor. The first and second portions of the thresher elements are each provided with a smooth outer material engaging surface extending thereover to inhibit abrading action between the crop material and the thresher elements. The smooth outer material engaging surface extending over the second portion of the thresher element preferably has a curved configuration. A smooth spike can extend outwardly from the second portion of the thresher element to facilitate handling of crop material during the threshing process.

A conventional agricultural combine includes a header assembly for severing and collecting crop materials as the combine is driven through a field and a feeder mechanism for advancing and elevating the crop materials to a threshing area on the combine. In the threshing area of the combine, the crop material is threshed as it passes between a rotor assembly and a stationary generally cylindrical housing.
A typical rotor assembly includes an elongated rotor including a series of metallic thresher elements peripherally arranged thereabout. An outer surface on the thresher elements is arranged proximate to the cylindrical housing. The rotor is mounted on a frame of the combine and is rotatably driven at variable speeds depending on the crop material being harvested. Conventional thresher elements have a rasp or tooth-like configuration on the outer surface which impacts with crop materials as the rotor assembly is driven.
The impact of the crop materials against any of the multitude of edges on the rasp or tooth-like outer surface on the thresher elements naturally tends to cause damage to the crop materials. That is, the impact of the slower moving crop materials against and coupled with the relative movement between the threshing element edges and the crop material naturally results in some level of abrasive action which typically damages the crop material. As used herein, the term "damage" is meant to include splitting, cracking, nicking, scratching, and/or marring of the harvested crop materials.
As will be appreciated, damaged crop material is an inferior grade of product which quickly spoils and, therefore, only a relatively small percentage (typically 7-10%) is permitted by volume in those products intended for human consumption. Because only a relatively small percentage of damaged material is permitted in those products intended for human consumption such as corn, soybeans, kidney beans, peas and others, farmers are paid a premium price for crop materials having a relatively low damage content by volume at a collection station.
Reducing the operational speed of the rotor assembly has been proposed to limit crop material damage by the thresher elements of the combine. As will be appreciated, reducing the speed of the rotor assembly likewise reduces the overall capacity of the combine and, thus, detracts from productivity and, therefore, the profits the farmer may realize for the harvested crop material will be effected.
Another proposal to reduce damage to crop materials involves facing or plating the rasp-like configured threshing elements with chrome or other forms of metal. During combine operation, the threshing elements are subjected to considerable abrasive action by reason of dust and gritty materials brought into the threshing area from the field. Due to the speed of the rotor which must be maintained for efficient threshing, coupled with the abrasive material, rapid wear of the facing or plating on the threshing elements typically occurs. Unless new threshing elements are held in inventory, considerable down time of the combine is incurred. Adding new thresher elements to the rotor assembly is also expensive. Moreover, the damage to the grain is not readily perceivable by the farmer and, thus, he will not be able to tell if new parts are required until the harvested grain is graded at the collection point.
Thus, there remains a need and a desire for threshing elements which are designed to inhibit damage to crop materials impacting with and moving past the threshing elements thereby enhancing combine performance.


This invention provides a coating composition which utilizes a free radical initiator and an organic tintability additive which remains substantially unpolymerized even after the remainder of the coating composition is cured. Superior tintability and adhesion to polycarbonate makes this coating particularly suitable for making tinted opthalmic lenses.

The present invention relates to a coating composition, which when applied to a substrate, forms a protective, abrasion-resistant coating thereon, and which coated substrate has been found to be readily tintable. More particularly, the present invention relates to a colloidal silica coating composition employing a free radical initiator and an organic tintability additive which remains substantially unpolymerized even after the remainder of the coating composition is cured onto the substrate.
It is known in the art that colloidal silica can be included in abrasion-resistant coating compositions, also referred to as hardcoating compositions. Examples of such colloidal silica hardcoating compositions are Chung U.S. Pat. No. 4,348,462; Perkins et al. U.S. Pat. No. 5,221,560; and Perkins et al. U.S. Pat. No. 5,296,295.
Chung U.S. Pat. No. 4,348,462 discloses a colloidal silica hardcoat composition. Chung also discloses that additives, such as pigments or dyes, can be added to the composition. The present invention relates to a change in color or light transmittance brought about by adding a color additive, e.g. dye, after the composition already has been cured onto a substrate, not by adding the color additive to the coating composition before curing.
Perkins et al. U.S. Pat. Nos. 5,221,560 and 5,296,295 disclose a tintable hardcoat composition but the tintable additive in Perkins et al. is polymerized. In addition, the Perkins et al. patents refer to cationic-type initiators, used alone or in combination with a free radical initiator. The Perkins et al. patents do not disclose the use of a free radical initiator alone. The present invention, on the other hand, requires only a free radical initiator. Further, the tintability additive of this invention remains substantially unpolymerized. It has been discovered that the compositions of this invention result in improved tintability without any appreciable loss in abrasion resistance.

Abrasion resistant, curable hardcoating compositions and tinted articles made therefrom


A self-contained device for rapid and repetitive delivery and collection of a fluid. The device includes a container having resilient walls and a lower portion in which the walls converge to form an inverted, generally elliptical frustum that pools the fluid stored in the container. The device also includes a nozzle having a funnel-shaped opening which facilitates discharge and collection of the fluid.

The present invention relates to a device for delivering and collecting fluids and, more particularly, to a self-contained manual device adapted for rapid and repetitive delivery and collection of a fluid.
Oftentimes, as part of a medical procedure, a physician is required to collect a specimen for culture (typically a fluid secretion) from a body cavity of a patient. The medical procedure may, for example, require that a specimen be taken from the patient's nasopharynx.
Typically, these specimens are obtained by direct swabbing of the affected area. However, a more accurate and preferred method for collecting a specimen involves the delivery of a quantity of irrigating solution to the nasopharynx (thereby dissolving the secretion in the solution) and the subsequent collection of such solution for analysis in a laboratory.
The goal of the above-described collection technique is to obtain a specimen having a high concentration of fluid secretion. This task is preferably accomplished by repeatedly lavaging the nasopharynx with the irrigating solution. Accordingly, it is important that the lavaging step be conducted with only a minimal loss of irrigating solution. Further, the process is preferably accomplished by employing only a relatively small volume of irrigating solution. In this fashion, the collected secretion does not become overly diluted in the irrigating solution and hinder the analysis stage. Finally, the process is preferably accomplished without causing undue discomfort or trauma to the patient.
The devices and techniques currently available are unable to simultaneously accomplish these goals. For example, at least one of the devices currently available for sampling the nasopharynx requires substantial wall suction that may prove uncomfortable and traumatic to the patient. Other devices such as bulb syringes are unable to effectively deliver fluid against gravity and, further, are not adapted for aspiration of the dispensed fluid. Moreover, typical sampling techniques require substantial cooperation from and movement by the patient, thereby rendering such techniques useless in children and the elderly.
One technique currently employed by physicians involves the construction of a collection device from a syringe, which is then filled with saline and fitted with a section of flexible catheter. The patient is placed in a generally horizontal position and, thereafter, the flexible catheter is advanced into the nasal cavity. The solution is then dispersed into the nasal cavity from the syringe and, thereafter, is aspirated back into the syringe. As might be expected, it is difficult to recollect the solution in the syringe because the solution tends to run back along the nasal passage. Further, the flexible catheter employed to deliver the solution does not facilitate the recovery process and, in fact, hinders the process due to the rather small diameter of its opening. Finally, the above-described procedure can be quite discomforting to the patient and is difficult to perform on children and the elderly.
It is also necessary, at times, to obtain specimens from such body cavities as the ear, vagina or rectum. For example, vaginal or rectal sampling is often required to check for local infections. These samples, which are currently obtained by swabbing the affected area or by sampling excrement, would prove more accurate and be accomplished in a less invasive manner by use of the above-described collection technique.
There is also a need in the medical field for a device which can deliver medication to a body cavity. The device is preferably capable of delivering a relatively large volume of medication to a body cavity. The particular procedure may also require that the delivered medication be promptly removed from the body cavity of the patient. For example, when treating a cancer of the nasal passage, it may prove medically desirable to deliver a relatively large volume, high concentration of a toxic agent to the passage. This agent must be quickly and entirely delivered to the nasal cavity and then quickly and entirely withdrawn. Again, the devices currently available are unable to accomplish this task.
There is a further need in the art for a device which would allow cleansing of a surface through repetitive lavaging of such surface with an irrigating solution. Accordingly, this same device must be capable of readily collecting the discharged solution once such solution has pooled.


A waterproof shoe gasket insole strip comprising a stiff textile material gasket sheet coated with a selected thermoplastic polymer. The insole gasket is located between the insole and the outer sole. Due to its stiff, but flexible nature, it is easy to apply during lasting procedures.

In shoe constructions in which waterproof breathable uppers are used, it is convenient to attach the combination to an insole. But due to construction and cost considerations, it is not feasible to bring the upper and liner across the bottom of the shoe. Accordingly, an insole supplement, frequently called an insole gasket, is used to bridge the area not covered by the combination, and to provide a waterproof buffer between the insole and the outer sole. However, it is difficult to bond across the opening. Many gasket materials tend to wrinkle during bonding. Others are too limp and pliant. Many need to have adhesive applied thus creating a separate step. In addition to these requirements, the insole gasket needs to be waterproof.
It would be desirable to have a waterproof insole gasket that is flexible but stiff so that it can be easily positioned in place without wrinkling or become misshaped, that is strong but lightweight, that is self-adhering so that a separate adhesive need not be applied thus making use of solvent and means for solvent removal unnecessary.


A system (100) and method deliver audible caller identification information when standard Caller ID information can not be provided. A calling party is prompted by an announcement to provide the audible caller identification information. The announcement may be tailored by changing the language of the announcement, for example, to conform to the majority of calls received by the called party. A special designator may be stored in association with account information when the service is ordered. The designator is read before the announcement is played to the calling party. The audible caller identification information is recorded and played to the called party in a message. The message may be tailored by changing the language or format of the announcement.

The present invention relates generally to telecommunications services and more particularly to caller identification.
Telecommunications service providers typically offer services that attempt to provide customers with information that enables them to determine whether or not to accept a call before answering the call. One service that provides such information is caller identification (xe2x80x9cCaller IDxe2x80x9d). Standard Caller ID services generally provide a customer with an indication of who is calling without requiring the customer to answer the call. These systems typically retrieve information about the calling party from a database and provide that information to the called party. Customer premise equipment (CPE) in the form of a display device is generally used to provide the called party with a visual readout of the name and/or telephone number associated with the calling party.
However, the effectiveness of Caller ID systems can be reduced due to a number of different occurrences. One such occurrence is the inability of a service provider to provide the standard Caller ID information for a particular incoming call. A service provider may not be able to provide the standard Caller ID information if the Caller ID information is blocked by the calling party, or if the Caller ID information is unavailable or incomplete. This may occur, for example, if the calling party pressed *67 when initiating the call
When the standard Caller ID information cannot be provided, the called party is not adequately informed about who is calling and cannot determine whether or not to accept the incoming call before answering the call. Because the effectiveness of Caller ID systems is greatly reduced when information cannot be provided, an improved system and method for providing caller identification information that overcome these deficiencies are needed.
Patent application Ser. No. 09/122,484, filed Jul. 24, 1998 and commonly assigned to the assignee of the present application, is incorporated herein by reference. This patent application discloses a method and system for providing a called party with audible caller identification information when standard caller identification cannot be provided. When standard caller identification cannot be provided, the call is blocked and a request for audible caller identification is transmitted to the calling party. The audible information is subsequently transmitted to the called party.
Patent application Ser. No. 09/253,339, filed Feb. 19, 1999, is also incorporated herein by reference. This application discloses a method for providing enhanced caller identification information when per line blocking of Caller ID is present. When per line blocking is activated for a subscriber line, the Caller ID information for that line is never transmitted by the system.
In the systems disclosed in the incorporated patents, a standard message is played to the calling party when standard caller identification cannot be provided. The standard message includes a request for audible caller identification. Similarly, a standard notification is played to the called party when the audible caller identification is conveyed to the called party. However, such a standard message and standard notification may not be suitable for all applications and all customers. For example, a customer may receive a majority of calls from calling parties who primarily speak a language other than English, so a standard message in the English language will not be as effective as required.
Accordingly, there is a need for a system and method which permit tailored announcements to be made to the calling party requesting audible caller identification information for presentation to the called party, and for tailored notifications to be made to the called party.

Method and system for providing enhanced caller identification information including tailored announcements


A bearing seal for earth boring bits is disclosed. A supporting ring is located in a groove formed in the earth boring bit. An annular cavity between the outer circumference of the supporting ring and the bottom of the groove is connected with the outside. An O-ring made of rubber is provided in an annular space defined by the sidewalls of the groove, the inner circumference of the supporting ring and the cylindrical surface of the bearing shaft of the head section to form a seal comprising a radial and axial seal. Compressive deformation of the O-ring does not depend on the eccentric rotation of the cone. Therefore, the working life of the seal is increased and the compressive deformation is decreased, thus facilitating use at high rotating speeds.

The invention relates to a bearing sealing means of earth boring bits used in well drilling, the petroleum industry, geologic surveys and the like.
Because of limited space in bearings of earth boring bits, an O-ring has been used as a radial seal for such bearings due to its simple structure and safe property. Such radial seals for bearings of earth boring bits are described in U.S. Pat. No. 3,397,928. In general, clearances of bearings in earth boring bits are greater (usually 0.08 to 0.23 mm) since the working temperature of such bits is higher. However, the greater clearance brings unfavorable effects when O-rings are used as radial seals. Significant compressive deformation is required to fit with the eccentric rotation of a loaded cone, however this causes increased heat generation due to the sliding friction of the O-ring. If the temperature becomes too great, the O-ring can be permanently deformed. For these reasons, an O-ring made of rubber cannot be used, otherwise its working life will be shortened when the bit is operated at high speed.
Attempts have been made to improve the sealing structures of bearing in earth boring bits, however none have been satisfactory. For example, a sealing assembly is disclosed in U.S. Pat. No. 4,623,028, which comprises a static and softer O-ring, a dynamic and harder O-ring and a rigid supporting ring. A smaller compressive deformation is designed for the dynamic O-ring, while a greater compressive deformation is designed for the static to compensate the eccentric rotation of the cone. Due to this structure, the sealing assembly can be used at high operating speed. Unfortunately, use of the assembly was limited because of its complex structure and large volume. A floating seal for earth boring bits is disclosed in U.S. Pat. No. 4,428,687. The seal comprises a groove formed on the bearing shaft of a head section. A split supporting ring is located in the groove. An O-ring is provided in an annular space defined by sidewalls of the groove, the outer circumference of the supporting ring, and the circumferential surface of the shaft so that a seal structure comprising radial and axial seals is formed. After forming the axial seal on the sidewall of the groove, there is air in the floating clearance between the inner circumference of the supporting ring and the bottom of the groove; and the floating clearance has been closed. During drilling, the pressure of drilling liquid is much greater than that of air located in the floating clearance. This causes the O-ring to be pressed partially into the groove, and thus deforms the supporting ring. This will cause the seal to no longer function. In practice the technical solution of the above patent is not satisfactory.

Bearing sealing means of earth boring bits


A microcatheter for delivery of embolic fluids includes an outer member dimensioned for insertion within a blood vessel adjacent an embolization site. The outer member defines a first longitudinal lumen, and an inner member is selectively positionable within the first longitudinal lumen of the outer member. The inner member defines a second longitudinal lumen and has a delivery port in fluid communication with the second longitudinal lumen for passage and delivery of embolic fluids toward the embolization site. A valve is disposed within the outer member. The valve is dimensioned to establish a substantial seal about the inner member, to minimize entry of the embolic fluids within the first longitudinal lumen of the outer member subsequent to delivery thereof toward the embolization site.

1. Technical Field
The present disclosure generally relates to intravascular devices and methods for facilitating delivery of an embolic composition into a blood vessel of a patient. In particular, the disclosure relates to an apparatus, system and method for the containment and restraint of a fluid embolic composition to or within an embolization site.
2. Description of Related Art
The delivery of fluid embolic compositions that solidify in vivo is particularly useful for a variety of reasons including treatment of blood vessels, tumors, aneurysms, arteriovenous malformations ("AVMs"), and arteriovenous fistulas ("AVF"). Delivery of such compositions is preferably accomplished via catheter techniques that permit the selective placement of the catheter at the delivery site. In practice, the catheter tip is directed to the vascular delivery site by use of conventional visualization techniques such as fluoroscopy, which allow the clinician to visualize the catheter tip. After placement of the catheter, the composition is introduced into the catheter and delivered to this site. Upon delivery, a biocompatible solvent of the composition dissipates into the blood, fluid, or tissue, and a water insoluble polymer of the composition precipitates to form a coherent mass, which solidifies in vivo. In the treatment of an AVM, for example, depending on the rate at which the liquid embolic composition is delivered and the amount of blood flow present, the dissipation of the biocompatible solvent may be sufficiently slow to permit the polymer, in liquid form, to migrate away from the AVM or embolization site. This migration may cause the occlusion of undesired locations in the vasculature, or the undesired occlusion of an intravascular device provided for delivering the liquid embolic composition.
Accordingly, it would be desirable to provide an apparatus for delivery of a liquid embolic composition to an AVM or aneurysm to prevent the embolic composition from passing outside of the desired embolization site into the vasculature.
Similarly, it would be desirable to provide an apparatus for delivery of a liquid embolic composition to an aneurysm that prevents backflow or reflux of the embolic composition into the vasculature.

Apparatus and method for delivering an embolic composition


Methods and systems are described for providing status monitor capability to a networked printer. The methods and systems, upon receipt of a print job, embed status monitor instructions in print data of the print job, send the print data from an information server to the printer while monitoring the status of the printer, and return status monitor information regarding the printer.

1. Field
The present disclosure relates to systems and methods for providing status monitor capability to printing devices.
2. Background
Printers having network capability may fall into two categories with respect to a distributed printing service (for example a cloud printing service). Some printing devices are capable of connecting and communicating with a distributed printing service directly, are capable of self-registration with a distributed printing service, and/or may receive print jobs directly from the distributed printing service. Other printing devices require an intermediary to perform such functions, for example a computing device, such as a thin-client and/or a proxy, that operates a driver for the printing device and that mediates communication between the printing device and the distributed printing service. The former printing devices may be termed "cloud-aware" printers, whereas the latter may be termed "legacy" printers.
Distributed printing may be device independent and therefore not require any specific printer drivers. The "cloud-aware" printer may connect to the distributed printing service directly and consume print data sent from the print server of the distributed printing service, while the "legacy" printer may require connection to an intermediary on which a proxy has been installed to communicate with the distributed printing service and to pass the print data from the print server of the distributed printing service to the "legacy" printer.
However, regardless of whether the printer is directly or indirectly connected to the distributed printing service, due to the inherent and intentional limitations of state-of-the-art distributed printing services, distributed printing services do not know the status of the printer, and intervention during printing or correction of printer errors is therefore not possible.

Systems and methods for providing status monitor capability to printing devices


A synchronous data interface circuit which is reduced in scale and low in power consumption is provided. A bit clock amplitude detector measures the amplitude of a bit clock signal transmitted thereto through a signal line and outputs to a set of equalizers a signal representing a ratio corresponding to the measured amplitude. The equalizers also respectively receive an NRZ data signal, a frame signal and a bit clock signal on lines of the same length and made of the same material. The equalizers thus individually set equalizing amounts and compensate for amplitude distortion of the individual signals. In this instance, each equalizing amount is set in accordance with the signal received from the bit clock amplitude detector. Discriminators receive signals after this amplitude compensation and reproduce the original signals as output.

1. Field of the Invention
This invention relates to a method of equalizing synchronous digital data when such synchronous digital data are transmitted through lines of an arbitrary length and also to a synchronous data interface circuit to which the equalizing method is applied.
2. Description of Related Art
When a non-return to zero (NRZ) data signal is transmitted through a line of an arbitrary length, deterioration of the transmission characteristics, particularly of the amplitude distortion characteristic, of the line will cause distortion of the signal waveform, resulting in deterioration of the eye pattern at the signal receiving end of the line. Therefore, in order to minimize the deterioration represented by the eye pattern, conventional synchronous data interface circuits first pass a received NRZ data signal through an equalizer to compensate for amplitude distortion of the NRZ data signal, and then reproduce its original signal by a discriminator. Further, in order to receive a plurality of NRZ data signals, equalizers are provided for individual signal paths, and they perform compensating processing for amplitude distortion independently of each other.
In these conventional synchronous data interface circuits, since the equalizers operate independently of each other to compensate for amplitude distortion of data signals, each equalizing circuit is large in scale, and particularly when a plurality of NRZ data signal paths are provided, total volume of interface circuit becomes great in size and the power consumption is also high.

Synchronous data interface circuit and method of equalizing synchronous digital data therefor


An integrated circuit output section has a controller that controls a plurality of drivers to transmit data signals over output lines in a group staggered manner to substantially reduce the generation of inductive noise or ground and power bounce. The controller staggers the transmission of the data signals in each group relative to the other groups to achieve a reduction in inductive noise of greater than 25% using relatively short total staggering times of less than five times the transition switching time of a driver for the groups of data signals. Also, an enhanced reduction in inductive noise is achieved with a total staggering time equal to or less than a driver transition switching time, wherein at least one group has a different number of data signals than the other groups.

Presently, inductive noise caused by many switching simultaneously is a major design and performance limitation of high-speed, high pin-out integrated circuit chips. Inductive noise, also referred to as ground bounce, is attributed to when a large number of chip output drivers switch simultaneously. The simultaneous switching causes a substantial transient current to appear in the chip's ground and power distribution systems. This transient current causes a corresponding transient voltage difference to develop between the ground in the chip and the ground in an associated printed wiring board (PWB). This voltage difference can cause false switching of integrated circuit devices and corresponding system errors or loss of data. A more detailed discussion of inductive noise is provided in A. J. Rainal, "Computing Inductive Noise of Chip Packages", AT & T Bell Laboratories Tech. J., Vol. 63, No. 1, (1984), which is incorporated by reference herein.
Although a pin-out array size of 256 .times.256 can be fabricated on a single chip, such a large array is presently impractical because of the inductive noise that would be generated by the large number of output drivers that provide data signals on corresponding output leads. Various techniques for reducing inductive noise are known. One such technique uses a pair of leads and corresponding balanced circuit drivers for transmitting each data signal. An exemplary balanced driver system is described in A. J. Rainal, "Eliminating Inductive Noise of External Chip Interconnections", IEEE Journal of Solid-State Circuits, Vol. 29, No. 2, pp. 126-129 (1994), which is incorporated by reference herein. In such a system, a data signal is transmitted by causing the current traversing a first output lead of the pair to have the same amplitude but opposite polarity of the current traversing the other output lead to negate inductive noise. However, balanced driver techniques tend to be difficult to implement in CMOS integrated circuits because of the inherent difficulty in causing two CMOS drivers to switch simultaneously in controlling the current traversing the balanced output lead pair. This is especially the case for data signal rise times on the order of less than three nanoseconds.
Thus, a need exists for a integrated circuit driver technique that reduces inductive noise and can be implemented in a variety of different types of semiconductor devices including CMOS devices.

Integrated circuit having reduced inductive noise