Backup file recovery from multiple data sources is described. A system determines whether each of multiple data sources stores a corresponding copy of a backup file associated with a data object, in response to receiving a request to recover the backup file associated with the data object. The system allocates multiple portions of the backup file to corresponding multiple data streams, if each of the multiple data sources stores the corresponding copy of the backup file associated with the data object. The system recovers the backup file by concurrently recovering the multiple data streams from the corresponding multiple data sources.

If a software error corrupts a data object, or if erroneous data updates the data object, a data protection administrator may restore the data object to a previous state that does not include the corrupted or erroneous data. A backup/restore application executes a backup operation either occasionally or continuously to enable this restoration, storing a copy of each desired data object state (such as the values of data and these values' embedding in a database's data structures) within dedicated backup files. When the data protection administrator decides to return the data object to a previous state, the data protection administrator specifies the desired previous state by identifying a desired point in time when the data object was in this state, and instructs the backup/restore application to execute a restore operation to restore a copy of the corresponding backup files for that state to the data object.
A data object may be stored on a storage array, which is a disk storage system that includes multiple disk drives. Unlike a disk enclosure, a storage array has cache memory and advanced functionality, such as virtualization and Redundant Array of Independent Disks (RAID). A data protection administrator may manage a backup/restore application to create backups files of data objects and store the backup files of data objects on multiple storage arrays.


A facial validation sensor includes an imaging element, a validating unit and a feedback unit. The validating unit performs validation of an individual to be validated based on facial image data of the individual, imaged by the imaging element, and facial image data registered in advance. The feedback unit guides a face of the individual to be within an imaging range that is imaged by the imaging element. The feedback unit is an indicator providing unit that provides an indicator that is viewable from a specific direction within the imaging range that is imaged by the imaging element.

As sensors for validating individuals there are facial validation sensors for validating a user through the use of an image of a face or the use of a feature quantity extracted from an image of a face (hereinafter termed, in general, "facial image data").
This type of facial validation sensor validates a user by matching facial image data, obtained through the use of a camera to image the face of the individual to be validated (input facial image data), with facial image data that has been registered in advance (registered facial image data).
Consequently, in order to perform accurate validation using facial image data, preferably, when obtaining the input facial image data, the orientation of the face in the input facial image data in the imaging region of the facial validation sensor is always the same orientation (for example, "face forward") as in the registered facial image data. Given this, the facial validation sensor must have a feedback unit that guides the face of the person to be validated into the imaging region that is imaged by the camera.
In conventional facial validation sensors there has been a proposal, such as in Japanese Unexamined Patent Application Publication 2007-4613 ("the JP '613"), for the placement of a convex mirror in the vicinity of a wide-angle camera to enable each individual to be validated to visually check his or her own face in a portion of the mirror, so that the face will reliably be facing the convex mirror and the wide-angle camera when the face is imaged, in order to capture facial images that are facing the same direction even when there is variability in the stature of the individuals to be validated, as the feedback unit that guides the face of the individual to be validated into the imaging region that is imaged by the camera.
However, even though the technology disclosed in the JP '613 is able to cause the individual to be validated to direct his or her face in a specific direction, the region that is reflected in the convex mirror changes depending on the distance from the convex mirror, thus making it difficult to ensure a distance from the camera wherein the face of the individual to be validated will be within the imaging region of the facial validation sensor, and thus there was the danger that the face of interest would extend outside of the imaging region of the facial validation sensor, producing variability in the validation results.
Given this, the object of the present invention is to provide a facial validation sensor that is both able to cause the face of the individual to be validated to face in a specific direction, and able to induce the face of the individual to be validated into the imaging region of the facial validation sensor regardless of the distance between the individual to be validated and the camera.


Sulfonamide lactams of the following formula

The present invention relates to sulfonamide lactam inhibitors of the enzyme Factor Xa which are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses.
In accordance with the present invention, novel lactam derivatives are provided which are inhibitors of the enzyme Factor Xa and have the structure I
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein
X is defined as:
xe2x80x94(CH2)mxe2x80x94
where m is an integer between 1 and 3 and which may be optionally mono- or di-substituted on 1 to 3 of the methylenes with oxo, lower alky, and aryl;
R1 is selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl and substituted cycloheteroalkyl;
R2 and R3 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl;
R4, R4a, R5,and R5a are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy,
R6 and R6a are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloheteroalkyl;
R7 and R8 are independently chosen from
xe2x80x94(CH2)nxe2x80x94H
where n is an integer between 1 and 4 and which may be optionally mono- or di-substituted on 1 to 4 of the methylenes with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;
or R7 and R8 together with the nitrogen atom to which they are attached may form an optionally substituted cycloheteroalkyl group;
Ra and Rb are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, substituted alkyl-carbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, substituted alkylaminocarbonyl, dialkylaminocarbonyl, and substituted dialkylaminocarbonyl.
Compounds within the scope of the present invention include compounds of the following formula II
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein
Y and Ya are independently a bond, alkyl, alkenyl or alkynyl;
X and Xa are independently
xe2x80x94(CH2)mxe2x80x94
where m is an integer between 1 and 3 and where each methylene group of X may be optionally substituted with oxo, or mono- or di-substituted with lower alkyl or aryl;
Q is a group A or B
xe2x80x83where
(1) n, p, q and r are each independently 0 to 2, provided that at least one of n, p, q and r is other than zero;
(2) X1 is xe2x80x94Oxe2x80x94, xe2x80x94CR14R15xe2x80x94, xe2x80x94NR14xe2x80x94, or xe2x80x94S(O)txe2x80x94 where t is 1 or 2;
(3) the group B ring system optionally contains one or more double bonds where valence allows; and
(4) optionally fused to the group B ring system is an optionally substituted cycloalkyl ring, an optionally substituted cycloheteroalkyl ring, an optionally substituted heteroaryl ring, or an optionally substituted aryl ring;
R1 and R1a are independently aryl, heteroaryl, cycloalkyl or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z1, Z2 or Z3;
R2, R2a, R3 and R3a are independently selected from
(1) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl any of which may be optionally substituted with one or more groups Z1a, Z2a or Z3a; or
(2) xe2x80x94C(O)tH, or C(O)tZ6 where t is 1 or 2; or
(3) xe2x80x94Z4xe2x80x94NZ7Z8;
R4, R4a, R4b, R4c, R5, R5a, R5b and R5c are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy,
xe2x80x83any of which may be optionally substituted with one or more groups Z1b, Z2b or Z3b;
R6 and R6a are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z1c, Z2c or Z3c;
R7 and R8 are independently chosen from optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl or
xe2x80x94(CH2)nxe2x80x94H,
where n is an integer between 1 and 4 and wherein 1 to 4 of the methylene groups may be optionally mono- or di-substituted with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;
or R7 and R8 together with the nitrogen atom to which they are attached may form an optionally substituted cycloheteroalkyl group;
Ra and Rb are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl.
R9 is H, Z3d or when a group R11 is present R9 combines with R11 to form a bond;
R10 is H, Z1f, xe2x80x94Y2xe2x80x94R11, xe2x80x94Y2xe2x80x94N(R11)(Z4xe2x80x94Z9a), xe2x80x94Y2xe2x80x94OR11, xe2x80x94Y2xe2x80x94C(O)R11, xe2x80x94Y2xe2x80x94C(O)OR11, xe2x80x94Y2xe2x80x94OC(O)R11, xe2x80x94Y2xe2x80x94N(Z4xe2x80x94Z9a)xe2x80x94C(O)R11, xe2x80x94Y2xe2x80x94N(Z4xe2x80x94Z9a)xe2x80x94C(O)OR11, xe2x80x94Y2xe2x80x94S(O)tR11 where t is 0 to 2, or xe2x80x94Y2xe2x80x94R12;
Y2 is xe2x80x94(CH2)uxe2x80x94, xe2x80x94Oxe2x80x94(CH2)uxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)uxe2x80x94, xe2x80x94C(O)Oxe2x80x94(CH2)uxe2x80x94, xe2x80x94OC(O)xe2x80x94CH2)uxe2x80x94 where u is 0 to 3;
R11 when present combines with R9 to form a bond;
R12 is
R13 is H, Z2f,
R14 is H, Z3f or a group D
or R13 and R14 combine to form xe2x95x90O or xe2x95x90S;
Z1, Z1a, Z1b, Z1c, Z1d, Z1e, Z1f, Z2, Z2a, Z2b, Z2c, Z2d, Z2e, Z2f, Z3, Z3a, Z3b, Z3c, Z3d, Z3e, Z3f, Z13 and Z14 are each independently
(1) hydrogen or Z6, where Z6 is
(i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl;
(ii) (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of Z1 through Z3f,
(2) xe2x80x94OH or xe2x80x94OZ6,
(3) xe2x80x94SH or xe2x80x94SZ6,
(4) xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, or xe2x80x94Oxe2x80x94C(O)Z6,
(5) xe2x80x94SO3H, xe2x80x94S(O)tZ6, or S(O)tN(Z9)Z6,
(6) halo,
(7) cyano,
(8) nitro,
(9) xe2x80x94Z4xe2x80x94NZ7Z8,
(10) xe2x80x94Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8,
(11) xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6,
(12) xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H,
(13) oxo,
Z4 and Z5 are each independently
(1) a single bond,
(2) xe2x80x94Z11xe2x80x94S(O)txe2x80x94Z12xe2x80x94,
(3) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Z12xe2x80x94,
(4) xe2x80x94Z11xe2x80x94C(S)xe2x80x94Z12xe2x80x94,
(5) xe2x80x94Z11xe2x80x94Oxe2x80x94Z12xe2x80x94,
(6) xe2x80x94Z11xe2x80x94Sxe2x80x94Z12xe2x80x94,
(7) xe2x80x94Z11xe2x80x94Oxe2x80x94C(O)xe2x80x94Z12xe2x80x94,
(8) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Oxe2x80x94Z12xe2x80x94,
(9) xe2x80x94Z11xe2x80x94C(xe2x95x90NZ9a)xe2x80x94Z12xe2x80x94, or
(10) xe2x80x94Z11xe2x80x94C(O)xe2x80x94C(O)xe2x80x94Z12xe2x80x94
Z7, Z8, Z9, Z9a and Z10
(1) are each independently hydrogen or a group provided in the definition of Z6,
(2) Z7 and Z8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the defintion of Z1 through Z3,
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the defintion of Z1 through Z3, or
(4) Z7 and Z8 or Z9 and Z10 together with the nitrogen atom to which they are attached may combine to form a group xe2x80x94Nxe2x95x90CZ13Z14;
Z11 and Z12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene.
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating cardovascular diseases associated with thromboses is provided, wherein a compound of formula I or II is administered in a therapeutically effective amount which inhibits Factor Xa.
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 20 carbons, preferably 1 to 12 carbons, more preferably 1 to 8 carbons in the normal chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the various additional branched chain isomers thereof. The term xe2x80x9clower alkylxe2x80x9d includes both straight and branched chain hydrocarbons containing 1 to 4 carbons.
The term xe2x80x9calkenylxe2x80x9d as employed herein alone or as part of another group includes both straight and branched hydrocarbons having one or more double bonds, preferably one or two, and being of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain. Examples include
The term xe2x80x9calkynylxe2x80x9d as employed herein alone or as part of another group includes both straight and branched hydrocarbons having one or more triple bonds, preferably one or two, and being of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain. Examples include
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted lower alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d and xe2x80x9csubstituted alkynylxe2x80x9d refer to such groups as defined above having one, two, or three substituents independently selected from the groups listed in the description of T1, T2 and T3.
The term xe2x80x9chaloxe2x80x9d refers to chloro, bromo, fluoro and iodo.
The term xe2x80x9ccycloalkylxe2x80x9d as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds and/or 1 or 2 triple bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 12 carbons forming the rings. Also included within the definition of xe2x80x9ccycloalkylxe2x80x9d are such rings fused to an aryl, cycloheteroalkyl, or heteroaryl ring and bridged multicyclic rings containing 5 to 20 carbons, preferably 6 to 12 carbons, and 1 or 2 bridges. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, cyclooctynyl, etc. Cycloalkyl groups may be optionally substituted with one, two or three substituents independently selected from the groups listed in the description of T1, T2 and T3.
The term xe2x80x9carylxe2x80x9d or xe2x80x9carxe2x80x9d as employed herein alone or as part of another group refers to phenyl, 1-naphthyl, and 2-naphthyl as well as such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl ring.
Examples include
etc.
Aryl rings may be optionally substituted with one, two or three substituents independently selected from the groups listed in the description of T1, T2 and T3.
The term xe2x80x9ccycloheteroalkylxe2x80x9d as used herein alone or as part of another group refers to 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated rings which includes 1 or more hetero atoms such as nitrogen, oxygen and/or sulfur (preferably 1 to 3 heteroatoms), linked through a carbon atom or an available nitrogen atom. Also included within the definition of cycloheteroalkyl are such rings fused to a cycloalkyl or aryl ring and spiro cycloheteroalkyl rings. One, two, or three available carbon or nitrogen atoms in the cycloheteroalkyl ring can be optionally substituted with substituents listed in the description of T1, T2 and T3. Also, an available nitrogen or sulfur atom in the cycloheteroalkyl ring can be oxidized. Examples of cycloheteroalkyl rings include
etc. Depending on the point of attachment, a hydrogen may be missing from the nitrogen atom in the above rings.
The term xe2x80x9cheteroarylxe2x80x9d as used herein alone or as part of another group refers to a 5- 6- or 7-membered aromatic rings containing from 1 to 4 nitrogen atoms and/or 1 or 2 oxygen or sulfur atoms provided that the ring contains at least 1 carbon atom and no more than 4 heteroatoms. The heteroaryl ring is linked through an available carbon or nitrogen atom. Also included within the definition of heteroaryl are such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or another heteroaryl ring. One, two, or three available carbon or nitrogen atoms in the heteroaryl ring can be optionally substituted with substituents listed in the description of T1, T2 and T3. Also an available nitrogen or sulfur atom in the heteroaryl ring can be oxidized. Examples of heteroaryl rings include
Again, depending on the point of attachment, a hydrogen may be missing from the nitrogen atom in the above rings.
The term xe2x80x9calkoxYxe2x80x9d as employed herein alone or as part of another group includes xe2x80x9calkylxe2x80x9d groups as defined above bonded to an oxygen. Similarly, the term xe2x80x9calkylthioxe2x80x9d as employed herein above or as part of another group includes xe2x80x9calkylxe2x80x9d groups as defined above bonded to a sulfur.
Unless otherwise indicated, the term xe2x80x9csubstituted aminoxe2x80x9d as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl (optionally substituted), aryl (optionally substituted), arylalkyl (optionally substituted), arylalkyl (optionally substituted), heteroaryl (optionally substituted), heteroarylalkyl (optionally substituted), cycloheteroalkyl (optionally substituted), (cycloheteroalkyl)alkyl (optionally substituted), cycloalkyl (optionally substituted), cycloalkylalkyl (optionally substituted), haloalkyl (optionally substituted), hydroxyalkyl (optionally substituted), alkoxyalkyl (optionally substituted) or thioalkyl (optionally substituted). In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, substituted alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl or substituted aryl.
T1, T2 and T3 are each independently
(1) hydrogen or T6, where T6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, cycloheteroalkyl, (cylcloheteroalkyl)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T1, T2 and T3,
(2) xe2x80x94OH or xe2x80x94OT6,
(3) xe2x80x94SH or xe2x80x94ST6,
(4) xe2x80x94C(O)tH, xe2x80x94C(O)tT6, or xe2x80x94Oxe2x80x94C(O)T6,
(5) xe2x80x94SO3H, xe2x80x94S(O)tT6, or S(O)tN(T9)T6,
(6) halo,
(7) cyano,
(8) nitro,
(9) xe2x80x94T4xe2x80x94NT7T8,
(10) xe2x80x94T4xe2x80x94N(T9)xe2x80x94T5xe2x80x94NT7T8,
(11) xe2x80x94T4xe2x80x94N(T10)xe2x80x94T5xe2x80x94T6,
(12) xe2x80x94T4xe2x80x94N(T10)xe2x80x94T5xe2x80x94H,
(13) oxo,
T4 and T5 are each independently
(1) a single bond,
(2) xe2x80x94T11xe2x80x94S(O)txe2x80x94T12xe2x80x94,
(3) xe2x80x94T11xe2x80x94C(O)xe2x80x94T12xe2x80x94,
(4) xe2x80x94T11xe2x80x94C(S)xe2x80x94T12xe2x80x94,
(5) xe2x80x94T11xe2x80x94Oxe2x80x94T12xe2x80x94,
(6) xe2x80x94T11xe2x80x94Sxe2x80x94T12xe2x80x94,
(7) xe2x80x94T11xe2x80x94Oxe2x80x94C(O)xe2x80x94T12xe2x80x94,
(8) xe2x80x94T11xe2x80x94C(O)xe2x80x94Oxe2x80x94T12xe2x80x94,
(9) xe2x80x94T11xe2x80x94C(xe2x95x90NT9a)xe2x80x94T12xe2x80x94, or (10) xe2x80x94T11xe2x80x94C(O)xe2x80x94C(O)xe2x80x94T12xe2x80x94
T7, T8, T9 and T10
(1) are each independently hydrogen or a group provided in the definition of T6, or
(2) T7 and T8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1, T2 and T3, or
(3) T7 or T8, together with T9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1, T2 and T3, or
(4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached may combine to form a group xe2x80x94Nxe2x95x90CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6;
T11 and T12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
The compounds of formula I can be prepared as salts, in particular pharmaceutically acceptable salts. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, with amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluene sulfonic acid. Corresponding acid addition salts can also be formed if the compounds of formula I have an additional basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.
Preferred salts of the compounds of formula I include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
It should be understood that the present invention includes a prodrug forms of the compounds of formula I such as alkylesters of acids or any known prodrugs for lactam derivatives.
The compounds of the instant invention may, for example, be in the free or hydrate form, and may be obtained by methods exemplified by the following descriptions.
The compounds of formula I may be prepared by the exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples.
The compounds of formula I can be prepared using the reactions shown in the schemes below using techniques known to those skilled in the art of organic synthesis. Additional compounds within formula I can be generated from compounds disclosed in the schemes through conversion of the substituent groups to other functionality by the usual methods of chemical synthesis. In generating compounds of the present invention one skilled in the art will recognize that it may be necessary to protect reactive functionalilty such as hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in reactions. The introduction and removal of protecting groups are well known to those skilled in the art (for example see Green, T. W., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons 1991).
In one method, lactam II, the preparations of which are know in the literature to those skilled in the art, shall be protected on the nitrogen atom alpha to the carbonyl by the Cbz group to produce lactam III. The Boc and other protecting groups may also be used. Lactam III may then be derivatized by alkylation with appropriately substituted alpha-halo esters such as methyl bromoacetate, methyl 2-bromopropionate, or methyl 2-bromo-2-phenylacetate to yield lactam IV, where X is defined as in structure I. Hydrolysis of the ester with LiOH and the like will give the acid V.
The coupling of V with various amines to produce product amides can be accomplished using numerous procedures known to those skilled in the art. A suitable example employs ethyl 3-(dimethylamino)propylcarbodiimide hydrochloride (WSC, EDCI) and 1-hydroxybenzotriazole hydrate (HOBt).
The Cbz protecting group can be removed, for example with hydrogen over palladium, to give amine compound VII. Reaction of VII with sulfonyl chlorides in the presence of triethylamine or other base will provide the product VIII.
Alternatively, the Cbz-protecting group of compound IV can be removed with hydrogen and palladium to give compound IX. This compound can then be sulfonylated to yield compound X, which can be hydrolyzed with lithium hydroxide and the like to produce the acid XI. Compound XI can then be coupled with various amines as described above to yield products of formula VIII.
In addition to the methods already described, compounds of formula I wherein R2 is other than hydrogen can be prepared as shown in the following scheme. Compounds of formula VIIIa are sequentially treated with a base such as NaH or the like and then with an alkylating agent R2-halogen (for example; methyl iodide, methyl bromoacetate, benzyl bromide and the like) to provide the title compounds. Similarly, compounds of formula VIIIa are treated with an acylating agent, for example methyl chloroformate, to provide the title compounds.
In a similar fashion, compounds of formula IVa are treated with a base (cesium carbonate and the like) and an alkylating agent such as is methyl iodide to provide compounds of formula IV which are transformed using aformentioned procedures.
R2 other then Hydrogen may also be introduced by reductive amination procedures. For example, compounds of formula IXa are treated with an aldehyde and a reducing agent such as sodium triacetoxyborohydride to produce compounds of the type IXb. The aldehyde may be attached to a polymer support to provide resin-bound intermediates which can be treated using the other described procedures. Resin cleavage techniques are well known to those skilled in the art.
In a similar fashion compounds of formula VIIa may be resin bound or functionalized to produce compounds of formula VIIb.
Preferred compounds of this invention are those of Claim 1 including a pharmaceutically acceptable salt thereof wherein:
X is CH2;
R1 is selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, cycloheteroalkyl, and heteroaryl;
R2 is H, alkyl or substituted alkyl;
R3, R4, R4a, R5, R5a, R6, and R6a are H or alkyl;
R7 and R8 are independently chosen from
xe2x80x94(CH2)nxe2x80x94H
where n is an integer between 1 and 4 and which may be optionally mono- or di-substituted on 1 to 4 of the methylenes with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;
or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted cycloheteroalkyl group;
More preferred compounds of this invention are those of formula I or a pharmaceutically acceptable salt thereof wherein:
X is CH2;
R1 is selected from, substituted alkyl (especially (heteroaryl)alkyl or (aryl)alkyl), substituted alkenyl (especially (heteroaryl)alkenyl or (aryl)alkenyl), substituted alkynyl (especially (heteroaryl)alkynyl or arylalkynyl), substituted cycloalkyl, aryl, cycloheteroalkyl, and heteroaryl;
R2 is H, alkyl or substituted alkyl;
R3, R4, R4a, R5, R5a, R6, and R6a are H.
R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted cycloheteroalkyl group (especially pyrolidine, piperadine, piperazine, morpholine, thiomorpholine or thiazolidine).
More preferred compounds include compounds of formula II wherein
X is CH2;
Y is a bond or alkyenyl (when alkenyl, Y is preferably xe2x80x94CHxe2x95x90CHxe2x80x94, and more preferably
R1 is aryl or heteroaryl, either of which may be optionally substituted with one or more groups Z1, Z2, Z3 (especially where Z1, Z2 and Z3 are independently halo, cyano, xe2x80x94OH, xe2x80x94OZ6, alkyl, aryl, heteroaryl, or xe2x80x94Z4xe2x80x94NZ7Z8, any of which may be further substituted where valence allows as provided in the definition of Z1, Z2 and Z3);
R2 is H, alkyl, xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, xe2x80x94Z4xe2x80x94NZ7Z8, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, or -(alkyl)-Z4xe2x80x94NZ7Z8;
R3, R4, R4a, R5, R5a, R6, and R6a are H;
Q is a group B;
R9 is H, Z3d or when a group R11 is present R9 combines with R11 to form a single bond;
R10 is H, Z1f, xe2x80x94Y2xe2x80x94R11, Y2xe2x80x94R12 or xe2x80x94Y2xe2x80x94N(R11)xe2x80x94Z4xe2x80x94Z9a;
Y2 is xe2x80x94(CH2)uxe2x80x94 or xe2x80x94C(O)xe2x80x94(CH2)xe2x80x94;
Z3d and Z1f are each independently H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, xe2x80x94OH, xe2x80x94OZ6, xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, xe2x80x94S(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, -(alkyl)-S(O)tZ6, xe2x80x94Z4xe2x80x94NZ7Z8, xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, xe2x80x94Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5Z6, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, or -(alkyl)-Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8 any of which may be optionally further substituted where valence allows as provided in the respective definitions of Z3d and Z1f;
R14 is a group D or H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, xe2x80x94OH, xe2x80x94OZ6, xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, xe2x80x94S(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, -(alkyl)-S(O)tZ6, xe2x80x94Z4xe2x80x94NZ7Z8, xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, xe2x80x94Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, or -(alkyl)-Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8 any of which may be optionally further substituted where valence allows as provided in the definition of R14;
Z4 is a bond xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NZ9a)xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94 or xe2x80x94C(O)Oxe2x80x94; and
Z5 is xe2x80x94C(O)xe2x80x94 or xe2x80x94SO2xe2x80x94.
The most preferred compounds are those of formula I or a pharmaceutically acceptable salt thereof wherein:
X is CH2;
R1 is selected from, optionally substitued heteroaryl, optionally substituted (heteroaryl)alkenyl, optionally substituted aryl or optionally substituted (aryl)alkenyl (especially where the aryl and heteroaryl groups are optionally substituted with one or more halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl);
R2 is H, alkyl or substituted alkyl;
R3, R4, R4a, R5, R5a, R6, and R6a are H;
R7 and R8 together with the nitrogen atom to which they are attached form a cycloheteroalkyl group (especially pyrrolidine) which may be optionally substituted (especially with one or more (amino)alkyl, or (substituted amino)alkyl.
Most preferred compounds include compounds of formula II wherein
X is CH2;
Y is a bond or
R1 is aryl or heteroaryl, either of which may be optionally substituted with one or more halo, cyano, xe2x80x94OH, xe2x80x94OZ6 (especially alkoxy), optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or xe2x80x94Z4xe2x80x94NZ7Z8;
R2 is H, alkyl, xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, xe2x80x94Z4xe2x80x94NZ7Z8, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, or -(alkyl)-Z4xe2x80x94NZ7Z8,
R3, R4, R4a, R5, R5a, R6, and R6a are H;
Q is a group B;
R9 is H, Z3d or, when a group R11 is present R9 combines with R11 to form a single bond;
R10 is H, Z1f, xe2x80x94Y2xe2x80x94R11 or xe2x80x94Y2xe2x80x94R12;
Y2 is xe2x80x94(CH2)uxe2x80x94 or xe2x80x94C(O)xe2x80x94(CH2)xe2x80x94;
Z3d and Z1f are each independently H, alkyl, heteroaryl, -(alkyl)-cycloheteroalkyl, -(alkl)-Z4xe2x80x94NZ7Z8, xe2x80x94Z4xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, -(alkyl)-Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8, xe2x80x94C(O)tZ6, -(alkyl)-C(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, or xe2x80x94S(O)tZ6;
R14 is a group H, -(alkyl)-cycloheteroalkl, -(alkyl)-Z4xe2x80x94NZ7Z8, xe2x80x94Z4xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, -(alkyl)-Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8, xe2x80x94C(O)tZ6, -(alkyl)-C(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, xe2x80x94S(O)tZ6 or a group D;
Z4 is a bond xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NZ9a)xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(O)Oxe2x80x94; and
Z5 is xe2x80x94C(O)xe2x80x94 or xe2x80x94SO2xe2x80x94.
The compounds of the present invention are inhibitors of the activated coagulation serine protease known as Factor Xa and thus are useful for the treatment or prophylaxis of those processes which involve activation of the coagulation cascade and especially those which involve the production and/or action of Factor Xa. Thus the compounds of the present invention are useful in the prevention and treatment of all Factor Xa-associated conditions. An xe2x80x9cFactor Xa-associated conditionxe2x80x9d is a disorder which may be prevented, partially alleviated or cured by the administration of an inhibitor of Factor Xa. Such diseases include arterial thrombosis, coronary artery disease, acute coronary syndromes, myocardial infarction, unstable angina, ischemia resulting from vascular occlusion cerebral infarction, stroke and related cerebral vascular diseases (including cerebrovascular accident and transient ischemic attack). Additionally, the compounds are useful in treating or preventing formation of atherosclerotic plaques, transplant atherosclerosis, peripheral arterial disease and intermittent claudication. In addition, the compounds can be used to prevent restenosis following arterial injury induced endogenously (by rupture of an atherosclerotic plaque), or exogenously (by invasive cardiological procedures such as vessel wall injury resulting from angioplasty).
In addition, the inventive compounds are useful in preventing venous thrombosis, coagulation syndromes, deep vein thrombosis (DVT), disseminated intravascular coagulopathy, Kasabach-Merritt syndrome, pulmonary embolism, cerebral thrombosis, atrial fibrillation, and cerebral embolism. The compounds are useful in treating peripheral arterial occlusion, thromboembolic complications of surgery (such as hip replacement, endarterectomy, introduction of artificial heart valves, vascular grafts, and mechanical organs), implantation or transplantation of organ, tissue or cells, and thromboembolic complications of medications (such as oral contraceptives, hormone replacement, and heparin, e.g., for treating heparin-induced thrombocytopenia). The inventive compounds are useful in preventing thrombosis associated with artificial heart valves, stents, and ventricular enlargement including dilated cardiac myopathy and heart failure. The compounds are also useful in treating thrombosis due to confinement (i.e. immobilization, hospitalization, bed rest etc.).
These compounds are also useful in preventing thrombosis and complications in patients genetically predisposed to arterial thrombosis or venous thrombosis (including activated protein C resistance, FVleiden, Prothrombin 20210 elevated coagulation factors FVII, FVIII, FIX, FX, FXI, prothrombin, TAFI and fibrinogen), elevated levels of homocystine, and deficient levels of antithrombin, protein C, and protein S. The inventive compounds may be used for treating heparin-intolerant patients, including those with congenital and acquired antithrombin III deficiencies, heparin-induced thrombocytopenia, and those with high levels of polymorphonuclear granulocyte elastase.
The present compounds may also be used to inhibit blood coagulation in connection with the preparation, storage, fractionation, or use of whole blood. For example, the compounds may be used to maintain whole and fractionated blood in the fluid phase such as required for analytical and biological testing, e.g., for ex vivo platelet and other cell function studies, bioanalytical procedures, and quantitation of blood-containing components. The compounds may be used as anticoagulants in extracorpeal blood circuits, such as those necessary in dialysis and surgery (such as coronary artery bypass surgery); for maintaining blood vessel patency in patients undergoing transluminal coronary angioplasty, vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, tumor cell metastesis, and organ, tissue, or cell implantation and transplantation. The inventive compounds may also be inhibitors of the activated coagulation serine proteases known as Factor VIIa, Factor XIa, and thrombin and also inhibit other serine proteases, such as trypsin, tryptase, and urokinase. Thus, the compounds are useful for treating or preventing those processes, which involve the production or action of Factor VIIa, Factor XIa, thrombin, trypsin, and/or tryptase. Inventive compounds with urokinase inhibitory activity are useful as metastasis inhibitors in treating cancer. As used herein with reference to the utilities described below other than metastasis, the term xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d encompasses prevention, partial alleviation, or cure of the disease or disorder.
In view of their above-referenced serine protease inhibitory activity, the inventive compounds are useful in treating consequences of atherosclerotic plaque rupture including cardiovascular diseases associated with the activation of the coagulation cascade in thrombotic or thrombophilic states. The inventive compounds with tryptase inhibitory activity are useful as anti-inflammatory agents, in treating chronic asthma, allergic rhinitis, inflammatory bowel disease, psoriasis, conjunctivitis, atopic dermatitis, pancreatis, rheumatoid arthritis, osteoarthritis, septic shock, and chronic inflammatory joint diseases, diseases of joint cartilage destruction, and/or vascular damage due to bacterial and/or viral infections. Additionally, the inventive compounds may be useful for treating diabetic retinopathy or motor neuron diseases such as a amyotrophic lateral sclerosis, progressive muscular atrophy, and primary lateral sclerosis. Additionally, the inventive compounds may a be useful for tissue remodeling diseases and for treating plaque instability and sequelli. In addition, these compounds may be useful for treating fibrotic diseases and conditions, for example, fibrosis, scleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, and hypertrophic scars.
In addition, the compounds of the present invention are useful in treating cancer and preventing the prothrombotic complications of cancer. In view of their metastasis inhibition activity, the compounds are useful in treating tumor growth, as an adjunct to chemotherapy, and for treating diseases involving metastases including, but not limited to cancer, more particularly, cancer of the lung, prostate, colon, breast, ovaries, and bone. These compounds may also be useful in preventing angiogenesis.
The inventive compounds may also be used in combination with other antithrombotic or anticoagulant drugs such as thrombin inhibitors, platelet aggregation inhibitors such as aspirin, clopidogrel, ticlopidine or CS-747, warfarin, low molecular weight heparins (such as LOVENOX), GPIIb/GPIIIa blockers, PAI-1 inhibitors such as XR-330 and T-686, inhibitors of xcex1-2-antiplasmin such as anti-xcex1-2-antiplasmin antibody and thromboxane receptor antagonists (such as ifetroban), prostacyclin mimetics, phosphodiesterase (PDE) inhibitors, such as dipyridamole or cilostazol, PDE inhibitors in combination with thromboxane receptor antagonists/thromboxane A synthetase inhibitors (such as picotamide), serotonin-2-receptor antagonists (such as ketanserin), fibrinogen receptor antagonists, hypolipidemic agents, such as HMG-CoA reductase inhibitors, e.g., pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin (Nissan/Kowa), and compounds disclosed in U.S. provisional applications No. 60/211,594 filed Jun. 15, 2000, and No. 60/211,595 filed Jun. 15, 2000; microsomal triglyceride transport protein inhibitors (such as disclosed in U.S. Pat. Nos. 5,739,135, 5,712,279 and 5,760,246), antihypertensive agents such as angiotensin-converting enzyme inhibitors (e.g., captopril, lisinopril or fosinopril); angiotensin-II receptor antagonists (e.g., irbesartan, losartan or valsartan); and/or ACE/NEP inhibitors (e.g., omapatrilat and gemopatrilat); xcex2-blockers (such as propranolol, nadolol and carvedilol), PDE inhibitors in combination with aspirin, ifetroban, picotamide, ketanserin, or clopidogrel and the like. The inventive compounds are also useful in combination with anti-arrhythmic agents such as for atrial fibrillation, for example, amiodarone or dofetilide.
The inventive compounds may be used in combination with prothrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, and the like. The inventive compounds may also be used in combination with xcex2-adrenergic agonists such as albuterol, terbutaline, formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol; anticholinergics such as ipratropium bromide; anti-inflammatory cortiocosteroids such as beclomethasone, triamcinolone, budesonide, fluticasone, flunisolide or dexamethasone; and anti-inflammatory agents such as cromolyn, nedocromil, theophylline, zileuton, zafirlukast, monteleukast and pranleukast.
The inventive compounds may also be useful in combination with other anticancer strategies and chemotherapies such as taxol and/or cisplatin.
The compounds may act synergistically with one or more of the above agents. For example, the inventive compounds may act synergistically with the above agents to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. Thus, reduced doses of thrombolytic agent(s) may be used, therefore minimizing potential hemorrhagic side effects.
The compounds of this invention may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Systematic treatment is typically preferred for cancerous conditions, although other modes of delivery are contemplated. The compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; sublingually; bucally; transdermally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.
The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art. The specific dose level and frequency of dosage for any particular subject may vary and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. An exemplary effective amount of compounds of formula I may be within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses.
The ability of compounds of the present invention to inhibit Factor Xa can be determined using methods well known to those skilled in the art, such as methods that measure FXa amidolytic (Balasubramanian et al., J. Med. Chem. 36:300-303, 1993;Combrink et al., J. Med. Chem. 41:4854-4860, 1998), clotting time (Balasubramanian, N. et al., J. Med. Chem. 36:300-303, 1993) and in vivo models of arterial and venous thrombosis (Schumacher et al., Eur. J. Pharm. 259:165-171, 1994).
General Experimental and Definitions
The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto. Abbreviations and terms employed herein are defined below.
brine=saturated aqueous sodium chloride
Dess-Martin periodinane=1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-Benziodoxol-3(1H)-one
DMF=N,N-dimethylformamide
EDCI=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.
PS-PB-CHO=1% Cross linked polystyrene with (4-formyl-3-methoxyphenoxy)methyl linker.
PyBOP=(T-4)-(1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-phosphorus(1+)hexafluorophosphate(1xe2x88x92)=Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
TFA=trifluoroacetic acid
TFFH=Tetramethylfluoroformamidinium hexafluorophosphate.
THF=tetrahydrofuran
WSC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.
Unless otherwise noted all mass spectral data are positive ion spectra.
The following conditions were used for HPLC:
Method 1: columnxe2x80x94YMC S5 C18 ODS 4.6xc3x9750 mm; flowxe2x80x944.0 mL/min.; detection at 220 nm; solventxe2x80x94A=90:10/water:methanol+0.2% phosphoric acid, B=10:90/water:methanol+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 4 min and hold at 100% B for 1 min.
Method 2: columnxe2x80x94YMC (ODS) S-5, 4.6 mmxc3x9733 mm; flowxe2x80x945.0 mL/min.; detection at 220 nm; solventxe2x80x94A=10% methanol/water+0.2% phosphoric acid, B=90% methanol/water+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 2 min and 100% B for 1 min.
Method 3: columnxe2x80x94YMC A-ODS S-5, 4.6 mmxc3x9750 mm; flowxe2x80x944 mL/min.; detection at 220 nm; solventxe2x80x94A=90:10 water:methanol, solvent B=10:90 water:methanol (both containing 0.1% trifluoroacetic acid); 0% B to 100% B (4 min linear gradient) and 100% B for 1 min.
Method 4: columnxe2x80x94YMC (ODS-A) S-5, 4.6 mmxc3x9733 mm; flowxe2x80x945 mL/min.; detection at 220 nm; solventxe2x80x94A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; gradient-linear, 0% B to 100% B over 2 min and 100% B for 1 min.
Method 5: columnxe2x80x94YMC (S3 ODS column) 3 mmxc3x9750 mm; detection at 220 nm; flowxe2x80x945 mL/min; solventxe2x80x94A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 2 min and 100% B for 1 min.
Method 6: columnxe2x80x94Phenomenex (5 micron ODS column) 4.6 mmxc3x9730 mm; detection at 220 nm; flowxe2x80x945 mL/min.; solventxe2x80x94A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 2 min and 100% B for 1 min.
Method 7: columnxe2x80x94Shimadzu VP-ODS, 4.6 mmxc3x9750 mm; flowxe2x80x944 mL/min.; detection at 220 nm; solventxe2x80x94A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 4 min and 100% B for 2 min.
Method 8: Luna (5micron ODS column) 2xc3x9730 mm; flowxe2x80x941 ml/min; detection at 220 nm; solventxe2x80x94A=10 mM ammonium acetate in 98% water/acetonitrile; solvent B=10 mM ammonium acetate in 90% MeCN/water; 3 min linear gradient 0%-100% B and 0.4 min hold at 100% B.
Method 9: columnxe2x80x94Waters Xterra, 4.6 mmxc3x9750 mm; flowxe2x80x945.0 mL/min.; detection at 220 nm; solventxe2x80x94A=10% methanol/water+0.2% phosphoric acid, B=90% methanol/water+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 2 min.
Method 10: columnxe2x80x94YMC S5 C18 ODS 4.6xc3x9750 mm; flowxe2x80x942.5 mL/min.; detection at 220 nm; solventxe2x80x94A=90:10/water:methanol+0.2% phosphoric acid, B=10:90/water:methanol+0.2% phosphoric acid; gradient-linear, 40% B to 60% B over 10 min.

Sulfonamide lactam inhibitors of FXa and method

Abstract: wherein X, R1, R2, R3, R4, R4a, R5, R5a, R6, R6a, R7 and R8 are as described herein, are provided which inhibitors of Factor Xa and are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses.


A bootstrap capacitor charging circuit comprising first and second power switching transistors arranged in a half bridge arrangement such that the first and second transistors are disposed between a high side potential and a low side potential, a driver circuit for driving the first and second transistors, a bootstrap capacitor adapted to be charged from a potential source and for providing a voltage source to power an electronic circuit, a charging circuit providing a charging path from one of the high and low side potentials to the bootstrap capacitor, first and second series connected switches arranged between a common node of the first and second transistors and one of the high and low side potential, the bootstrap capacitor having a first terminal coupled to be charged by the charging circuit and a second terminal coupled to a common node between the first and second series connected switches; and a control circuit operating in first and second modes, wherein in a first mode when the first and second power switching transistors are switching at a rate above a predetermined frequency, a first of the switches connected to the common node of the first and second power switching transistors is controlled on and the second switch is controlled off; and wherein, when the first power switching transistor is on for a duration of time exceeding a preset duration, the control circuit operates in a second mode wherein the first and second switches are alternately turned on and off for first and second predefined periods of time whereby the bootstrap capacitor charges through the second switch and the charging circuit during the second predefined period of time.

The present invention relates to power switching circuits and, in particular, to driver circuits for driving power switching circuits. In particular, the present invention relates to a bootstrap capacitor power supply refresh circuit utilized in a driver circuit for driving a power switching circuit, for example, a half bridge power switching circuit driving a load.
Bootstrap capacitors are often employed in driver circuits to provide an additional fkiatubg voltage from an existing power supply or from an existing voltage source or from a pulsed signal source. In particular, as shown in FIG. 1, which shows a driver IC for driving a half bridge switching circuit comprising two power MOSFETs M1 and M2 driving a load, as shown there, the half bridge transistors M1 and M2 are arranged between a voltage source VBAT and ground. The voltage supply is also provided to the driver IC (IC) at a voltage input VCC to provide power to the driver IC. VBAT may be a different, higher voltage than VCC, or it may be the same voltage. Typically, VCC is different than VBAT because of high voltage spikes on VBAT. VCC may be derived from VBAT by an internal or external regulator circuit. The driver IC includes a driver HO and a driver LO which drive the respective high side and low side transistors M1 and M2. In addition, an external bootstrap capacitor CBOOT is provided between a terminal VB and the terminal VS which is coupled to the load and which is the common connection between the transistors M1 and M2. A supply voltage VBOOT is thus provided across the bootstrap capacitor. A diode D is disposed either internally to the IC or external to it to allow the bootstrap capacitor CBOOT to charge up from VCC when transistor M2 is on. The bootstrap supply is used to supply a votlage to the high side driver.
A problem arises when there is a permanent conduction of transistor M1. By "permanent conduction" is meant a relatively lengthy on time for transistor M1, for example, more than 200 usecs. In such a circumstance, transistor M2 is off and accordingly, the bootstrap capacitor cannot charge through transistor M2 during such operation. Accordingly, the circuit of FIG. 1 cannot be used if transistor M1 has relatively lengthy on times, for example conduction times greater than 200 usec. Transistor M2 will simply not be on long enough to allow the bootstrap capacitor to charge up and therefore provide a power source to circuits either internal to the IC or external to it that are powered by VBOOT.
It is therefore necessary to provide a solution to this problem, and particularly one that is useful in automotive applications.


An optical element includes a liquid crystal layer; and at least one alignment layer in contact with the liquid crystal layer, the at least one alignment layer being formed from a mixture including a first reactive mesogen and a second reactive mesogen. Each of the first and second reactive mesogens have at least one polymerizable functional group, and a number of polymerizable functional groups of the second reactive mesogen is smaller than that of the first reactive mesogen. A ratio of the second reactive mesogen to the first reactive mesogen in the mixture is determined so as to provide a predetermined pretilt angle with liquid crystal molecules in the liquid crystal layer.

1. Field of the Invention
This invention relates to a liquid crystal optical element and to a liquid crystal device incorporating same, and is more particularly concerned with a liquid crystal optical element comprising a liquid crystal layer and at least one alignment layer for alignment and tilt angle control of adjacent liquid crystal molecules in the liquid crystal layer. This invention is particularly, but not exclusively, concerned with active liquid crystal devices, i.e. liquid crystal devices having a liquid crystal layer which is field-switchable to change an optical property of the layer.
2. Description of the Related Art
It is very well known to provide a rubbed alignment layer to control the alignment and pretilt angle of adjacent liquid crystal molecules in a liquid crystal layer. However, the control of the pretilt angle requires the use of specific combinations of the liquid crystal layer and the alignment layer. It can be difficult to achieve very high pretilt angles with sufficient control by this method.
Various other methods, which do not require rubbing of the alignment layer in contact with the liquid crystal layer, have also been previously proposed.
EP-A-0689084 discloses liquid crystal devices having multiple alignment layers. One alignment layer is a photo-orientated polymer network (PPN) layer which is cured using linearly polarised light to effect anisotropic polymerisation of a monomer. Another alignment layer is formed of a photo-cured mixture of diacrylate liquid crystal monomers. The use of such a mixture is to provide a supercoolable nematic mixture which allows the LC layer to be produced at room temperature. Such alignment layer is produced by dissolving the diacrylate liquid crystal monomers with a photoinitiator in a solvent and applying the mixture to a previously-produced rubbed lower alignment layer by spin coating. This is followed by photo-curing so as to fix the orientation imparted to the liquid crystal monomer molecules by the underlying lower alignment layer. However, there is no teaching concerning control of the tilt angle produced by any of the alignment layers.
EP-A-0 506 175 provides an alignment layer consisting of an oriented polymer network in which a non-reactive liquid crystalline material is dispersed. The alignment layer is formed from a mixture of a reactive liquid crystalline material and a non-reactive liquid crystalline material. There is no teaching concerning control of the tilt angle produced by the alignment layer.
U.S. Pat. No. 5,528,401 relates to controlling the tilt angle produced by an alignment layer. The material from which the alignment layer is formed comprises a liquid crystal material and a polymerising material. The tilt angle is controlled by polymerising the polymerisable material while applying an electric or magnetic field to control the tilt angle of the liquid crystal molecules.
In M. Schadt et al, Nature, Vol. 381 May 16, 1996, pages 212 to 215, there is disclosed a modification of the PPN technique wherein, to enable pretilt angle control, novel photo-prepolymer molecules containing a coumarin moiety are employed. These photo-prepolymer molecules not only polymerise at a polymerisable moiety at one end of the molecule, but they also cross-link by fusing together in various configurations at the pyrone ring of the coumarin moiety. However, this technique requires the use a specialised monomer and also requires directional control over the incident cross-linking UV radiation.
EP-A-0467456 discloses that the pretilt angle of liquid crystal molecules in an adjacent liquid crystal layer can be controlled by controlling the thickness of a liquid crystalline auxiliary alignment layer which is spin formed on a glass substrate to which a polyimide alignment layer has been applied. The auxiliary alignment layer contains a diacrylate liquid crystal monomer, a photoinitiator and a liquid crystal material having a surface-active group such as an aliphatic chain which is directed towards an exposed surface of the auxiliary alignment layer. This can enable relatively high pretilt angles (i.e. relatively high angles relative to the plane of the alignment layer) to be achieved for liquid crystal molecules in the adjacent active liquid crystal layer. However, control of the pretilt angle requires a precise control over the thickness of the spun layer, which is difficult.
In some instances, it is desired for the molecules of the liquid crystal active layer to align on a surface with their long molecular axes normal to the surface (so called "homeotropic alignment"). Methods of achieving homeotropic alignment of common liquid crystal materials are described by L. M. Blinov et al in "Electrooptic Effects in Liquid Crystal Materials", Springer Verlag, New York Inc--Chapter 3, 1994.
In some instances, it is desirable to achieve a slight tilt (typically 1-10.sup.0) away from the homeotropic (90.degree.) alignment. Dyed guest-host displays utilising tilted-off homeotropic alignment and negative dielectric anisotropy liquid crystal mixtures have a number of attractive features including slightly improved multiplexibility and brightness. Although this "tilted-off" homeotropic alignment can be achieved via the oblique evaporation of a layer of silicon oxide onto a glass substrate [see T. Uchida et al, Japanese journal of Applied Physics, Vol. 19, No. 11, November 1980, pp 2127-2136, T. Uchida et al, IEEE Transactions on Electronic Devices, Vol. Ed-26, No. 9, September 1979, pp 1373-1374, T. J. Scheffer, Phil. Trans. R. Soc. Lond., A 309, 189-201 (1983), and U.S. Pat. No. 4,635,051], it requires special equipment and there is generally no reliable way of reproducibly achieving such tilted-off homeotropic alignment over large areas.

Liquid crystal optical element and liquid crystal device incorporating same


The present invention relates to a method for controlling a pressurized water reactor (100) comprising the steps that involve measuring the effective power (Pe) of the nuclear reactor; acquiring a reference value for the desired power (Pc); acquiring an estimated duration (DURATION) for the increase in power in order to achieve said reference value of the target power (Pc) desired, said estimated duration (DURATION) corresponding to the time taken for the power to increase from said effective power (Pe) to said reference value for the target power (Pc); determining the reference position (Z) of at least one control rod cluster among said plurality of control rod clusters (40) in order to achieve said reference value for said target power (Pc) desired as a function of said estimated duration (DURATION), of said measured effective power (Pe) and of said reference value for said target power (Pc); monitoring the position of said at least one control rod cluster so as to position it in its reference position (Z).

FIG. 1 schematically illustrates such a pressurized water nuclear reactor 1, which comprises in a conventional manner:                a core 2 divided into an upper area and a lower area and producing power,        steam generators 3, a single generator being represented,        a turbine 4 coupled to an electric power generator 5, and        a condenser 6.
The reactor 1 also comprises a primary circuit 8 equipped with pumps 9, a single pump being represented, and in which pressurized water circulates, along the path indicated by the arrows. This water rises particularly to the core 2 to be heated therein while assuring the cooling of the core 2. The water also assures a function of moderation, in other words of slowing down the neutrons produced by the nuclear fuel.
The primary circuit 8 further comprises a pressuriser 10 making it possible to regulate the pressure of the water circulating in the primary circuit 8.
The water of the primary circuit 8 also supplies the steam generators 3 where it is cooled while assuring the vaporisation of water circulating in a secondary circuit 12.
The steam produced by the generators 3 is channelled by the secondary circuit 12 to the turbine 4 then to the condenser 6 where said steam is condensed by indirect heat exchange with the cooling water circulating in the condenser 6.
The secondary circuit 12 comprises, downstream of the condenser 6, a pump 13 and a heater 14.
The core 2 comprises fuel assemblies 16 which are loaded in a vessel 18. A single assembly 16 is represented in FIG. 1, but the core comprises a plurality of assemblies 16.
The fuel assemblies 16 comprise nuclear fuel rods formed, in a conventional manner, of an alloy cladding, based on zirconium, enclosing a stack of nuclear fuel pellets based on uranium oxide or a mixture of uranium oxide and plutonium oxide.
The reactor 2 comprises control rods 20, also known as control rod clusters, for controlling the reactivity of the core, which are arranged in the vessel 18, above certain assemblies 16, and which are capable of occupying a plurality of insertion positions in the core. A single rod 20 is represented in FIG. 1, but the core 2 comprises several tens of control rod clusters 20. The control rods 20 can be moved vertically by mechanisms 22 so as to be inserted, in different insertion positions, in the fuel assemblies 16 that they overhang.
In a conventional manner, each control rod 20 comprises a plurality of control pencils made of neutron absorbing material.
Thus, the vertical movement, or insertion state, of each rod 20 inside the fuel assemblies 16 makes it possible to regulate the reactivity of the core of the reactor 1, thereby authorising variations in the overall power supplied by the core 2, from zero power up to rated power (hereafter noted RP).
It may prove to be useful, in fact, particularly in countries such as France where 80% of the electricity is produced by nuclear reactors, that the overall power supplied by the reactors varies in order to adapt to the needs of the grid that they supply; this is then known as grid monitoring or load follow.
During load follow, the power produced by the reactor is regulated so as to correspond to a programme pre-established by the service operating the grid.
The adjustment of the power supplied by the reactor is achieved by operating means positioning control rods constituted of neutrophage element in different insertion positions in the core so as to absorb more or less the neutrons and/or by optionally adjusting the concentration of a neutron absorbing compound, such as boron, in the primary coolant, as a function of the desired power and/or measurements from the instrumentation of the core of the reactor.
For example, the operating means are formed of a set of electronic and electrical equipment which, from measurements from instrumentation chains and by comparing them to limit levels, elaborate orders of movement of control rods 20 and/or modification of the boron concentration in the primary coolant by injection of water (dilution) or boron (boronation).
Different modes of operating a pressurized water nuclear reactor are known. Generally speaking, the operation consists in controlling and regulating to the minimum the average temperature of the primary coolant Tav and the distribution of power (thermal and neutronic) and in particular the axial distribution of power DA in order to avoid the formation of a power imbalance between the upper area and the lower area of the core.
The methods of regulation of these parameters vary as a function of the different operating modes used. Generally speaking, the average temperature Tav is regulated by the movement of the control rods 20 as a function of different parameters such as the power required at the turbine, the standard value of the temperature of the coolant, and/or optionally by modification of the boron concentration in the primary coolant, which makes it possible indirectly to adapt the positions of the control rods 20 to a desired position, particularly in order to obtain an axial distribution of desired power DA and/or a capacity of rapid rise in the power of the core to the desired power.
The choice of the mode for operating a nuclear reactor is determined by taking into consideration the fact that the action of the control rods has immediate effects, whereas the action by injection of boron in solution is comparatively slower.
Moreover, the increase in the boron concentration in solution in the primary coolant requires boric acid storage and injection means and thus imposes additional design constraints.
Thus, there is a tendency only to use the injection of boron or water in solution to correct the long term effects on the operating reactivity of the reactor, in other words essentially the xenon effect and the ageing of the fuel.
In order to meet the needs of the grid, the operation of the reactor is thus preferentially carried out by the movement of the control rods.
However, the insertion of the control rods affects, in a prejudicial manner, the axial distribution of power produced in the reactor. This may result in the formation of power peaks in the core as well as the development of oscillations of the xenon concentration in the longer term, favourable to the accentuation of these power peaks, factors intervening in a restrictive manner in the operating procedure and imposing a corrective recourse by modifying the boron concentration in the primary coolant.
Yet, in load follow, in other words with a power production level following a daily curve, and even in slave mode, by remote control, the variations in power production multiply the control actions, with the aforementioned unfavourable consequences, engaging in an important manner the control rod mechanisms and leading to considerable volumes of effluents due to repeated operations of dilution and boronation of the coolant.
In order to meet these difficulties, methods for operating a pressurized water reactor have been developed determining the positions of the control rods in the core, making it possible to limit perturbations of the axial power distribution and resorting to the use of boron, the concentration of which is adjusted so as to mainly compensate the effects of the release of xenon and the ageing of the fuel rods.
However, this operating method is not always optimised and does not always make it possible to minimise the volumes of effluents as well as the movement of the control rod clusters. In addition, the minimisation of the volumes of effluents as well as the engaging of the control rod insertion mechanisms remains a permanent concern of the operator.

Method for operating a pressurized water reactor during load monitoring


A wireless IC device includes a wireless IC chip, a feeder circuit substrate which is coupled to the wireless IC chip and includes a feeder circuit including an inductance element, and a radiation plate. The inductance element includes a plurality of stacked layers having coil conductors electrically connected, and a coil conductor electrically connected in a middle portion of the inductance element is arranged at an end position in the coil axis direction and faces a coupling portion of the radiation plate.

1. Field of the Invention
The present invention relates to wireless IC devices.
In particular, the present invention relates to a wireless IC device used in an RFID (radio frequency identification) system and to an electromagnetic coupling module included in the wireless IC device.
2. Description of the Related Art
An RFID system has been developed and used as an article management system. The RFID system includes a reader/writer that generates an induction field and communicates in a non-contact manner with an IC tag (also referred to as a wireless IC device) which stores specific information and is attached to an article. Thus, information is transmitted between the reader/writer and the IC tag. A wireless IC device used in such an RFID system is disclosed in PCT International Publication WO2009/081719. As illustrated in FIG. 11A, a wireless IC device includes two inductance elements L1 and L2 (helically connected coil conductors) that are electrically connected to a wireless IC chip 10 and electromagnetically coupled to radiation plates 30A and 30B.
However, in the above-described wireless IC device, coil conductors on the bottom layer which face the radiation plates 30A and 30B are arranged in the vicinity of connection points to the wireless IC chip 10 having a high impedance, as illustrated in FIG. 11B. Such arrangement increases the impedance of the inductance elements L1 and L2, which makes it difficult to ensure impedance matching between the wireless IC chip 10 and the radiation plates 30A and 30B. In FIG. 11B, the connection point X of the inductance elements L1 and L2 serves as a virtual ground.

Wireless IC device and electromagnetic coupling module


There is disclosed printing apparatus composed essentially of molded plastics material which has relatively few parts, is easy to manufacture and maintain, and is lightweight and portable. The apparatus is illustrated as being of the table top type which can print both standard type tags and labels, string tags and pin tickets. The apparatus has a print head operable in conjunction with an impression control device, a feed finger assembly with a registration adjustment, a simple drive arrangement operated by a cam with a single cam path, and a reel positionable at different attitudes, and the construction of the apparatus is readily adaptable to both manually operated and motorized versions.

1. Field of the Invention
The invention relates to the art of printing apparatus.
2. Brief Description of the Prior Art
Prior art printing apparatus is disclosed in U.S. Pat. No. 1,715,290 granted May 28, 1929 to Henry, Jr. and in U.S. Pat. No. 2,271,840 granted Feb. 3, 1942 to Kohnle. Prior art impression control devices are disclosed in U.S. Pat. No. 2,265,584 granted Dec. 9, 1941 to Stiegler, U.S. Pat. No. 3,601,042 granted Aug. 24, 1971 to Paul H. Hamisch, Sr., U.S. Pat. No. 4,280,862 granted July 28, 1981 to Paul H. Hamisch, Jr. and U.S. Pat. No. 4,290,840 granted Sept. 22, 1981 to Pabodie et al.


An ohmic contact includes a metal boride layer on a semiconducting diamond layer. The metal boride preferably includes boron and a transition metal and, more preferably, a refractory metal. Heating of the metal boride layer and diamond during fabrication forms a highly boron-doped surface portion of the semiconductor diamond by boron diffusion. Alternately, the highly doped surface portion may be formed by selective ion implantation, annealing to form a graphitized surface portion, and removing the graphitized surface portion by etching to thereby expose the highly doped surface portion. The highly doped surface portion lowers the electrical resistivity of the contact. In addition, an interface region of a carbide may also be readily formed by heating. The carbide interface region enhances mechanical adhesion of the metal boride and also serves to lower the electrical resistance of the contact. The ohmic contact may be incorporated into many semiconductor devices including, for example, transistors, diodes, and other devices.

Diamond is a preferred material for semiconductor devices because it has semiconductor properties that are better than traditionally used silicon, germanium, or gallium arsenide. Diamond provides a higher energy band gap, a higher breakdown voltage and a greater saturation velocity than these traditional semiconductor materials. These properties of diamond yield a substantial increase in projected cutoff frequency and maximum operating voltage compared to devices fabricated using conventional semiconductor materials. For example, silicon is typically not used at temperatures higher than about 200.degree. C. and gallium arsenide is not typically used above 300.degree. C. These temperature limitations are caused, in part, because of the relatively small energy band gaps for silicon (1.12 eV at ambient temperature) and gallium arsenide (1.42 eV at ambient temperature). Diamond, in contrast, has a large band gap of 5.47 Ev at ambient temperature, and is thermally stable up to about 1400.degree. C.
Diamond has the highest thermal conductivity of any solid at room temperature and exhibits good thermal conductivity over a wide temperature range. The high thermal conductivity of diamond may be advantageously used to remove waste heat from an integrated circuit, particularly as integration densities increase. In addition, diamond has a smaller neutron cross-section which reduces its degradation in radioactive environments. In other words, diamond is also a "radiation-hard" material.
Because of the advantages of diamond as a material for semiconductor devices, there is at present an interest in the growth and use of diamond for high temperature and radiation-hardened electronic devices. Key to many of such devices, such as diodes and field effect transistors (FET's), is an ohmic contact having good electrical and mechanical characteristics even at relatively high operating temperatures. Consequently, the fabrication of ohmic contacts on diamond will play an important role in the development of future diamond-based semiconductor devices.
Ohmic contacts have reportedly been obtained on semiconducting diamond. For example, U.S. Pat. No. 5,055,424, to Zeidler et al. discloses a refractory metal layer forming an ohmic contact on semiconducting diamond. The patent to Zeidler et al. also discloses a refractory metal carbide interface region between the diamond layer and the refractory metal layer formed by heating the structure. Similarly, Moazed et al. in A Thermally Activated Solid State Reaction Process for Fabricating Ohmic Contacts to Semiconducting Diamond, J. App. Phys., 68(5), Sept. 1990, discloses annealing a refractory metal, that is, molybdenum, at 950.degree. C. to grow carbide precipitates at an original diamond/metal interface to provide an electrical contact with good electrical performance and with good mechanical adhesion at relatively high operating temperatures.
The electrical resistivity of ohmic contacts to diamond has also been improved by highly doping the surface region of the diamond underlying a metal contact as disclosed, for example, by Tsai et. al., in Diamond MESFET Using Ultrashallow RTP Boron Doping, IEEE, Electron Dev. Letters., Vol. 12, No. 4, Apr. 1991. The Tsai et al. article discloses using cubic boron nitride in a solid state diffusion process including rapid thermal annealing for more highly doping the surface portion of the diamond layer. An article to Prins entitled Preparation of Ohmic Contacts to Semiconducting Diamond, pp. 1562-1564, July 1989, discloses ion implantation to more highly boron dope a surface of diamond underlying a metal contact layer to lower resistivity.
Another approach to obtaining a highly doped diamond surface portion adjacent a metal contact layer is disclosed in an article by Grot et al. in The Effect of Surface Treatment on the Electrical Properties of Metal Contacts to Boron-Doped Homoepitaxial Diamond Film, IEEE Electron Dev. Letters. Vol. 11, No. 2, Feb. 1990. The article discloses placing boron powder near edges of a diamond substrate and then exposing the powder and the diamond to a hydrogen plasma to thereby highly dopes the diamond surface portion with boron.
Ishii et al., in U.S. Pat. No. 5,075,757 teaches a non-metal ohmic contact formed by a highly boron-doped silicon layer on a diamond layer, wherein the silicon is amorphous or polycrystalline including microcrystalline silicon phase. The diamond region underlying the silicon layer becomes more highly doped by boron diffusion from the silicon layer into the diamond surface.
Despite continuing attempts to obtain low resistivity ohmic contacts to diamond also having good mechanical adhesion even at elevated temperatures, there still exists a need for such contacts which may be readily fabricated.

Metal boride ohmic contact on diamond and method for making same


A process for selectively extracting and ultimately recovering copper from acidic chloride solutions containing the same wherein an acidic chloride solution containing copper is initially contacted with an extractant to selectively extract copper, as copper chloride, therefrom. The loaded extractant is contacted with a suitable aqueous stripping solution to strip copper therefrom. Thereafter, the pregnant aqueous stripping solution is contacted with an active hydrogen ion exchange extractant, such as hydroxy oxime, a beta diketone or mixture thereof dissolved in an inert organic carrier solvent. The active hydrogen ion exchange extractant selectively extracts copper from the pregnant aqueous stripping solution with hydrochloric acid being formed. An aqueous acidic stripping solution is utilized to strip copper from the loaded hydrogen ion exchange extractant, the copper being recoverable from the pregnant aqueous acidic stripping solution as cathode copper by electrowinning and/or copper sulfate by crystallization. The hydrochloric acid formed during extraction of copper by the hydrogen ion exchange extractant is preferably neutralized to provide predetermined pH by the addition of a suitable base to efficiently and effectively utilize the hydrogen ion exchange extractant without any localized precipitation of copper.

1. Field of the Invention
The present invention relates to a process for the selective extraction and ultimate recovery of copper from an acidic chloride solution containing copper, and more particularly to a process for selectively extracting and ultimately recovering copper from both a spent cupric chloride etch and a spent ammoniacal etch, both of which are derived from etching copper from printed circuit boards in the electronic industry.
2. Description of the Prior Art
Selective recovery of copper from solutions containing the same has become a major concern of the metals industry in recent years. Solvent extraction is one technique for recovering copper from solutions which has achieved increasing popularity and acceptance, in particular, liquid-liquid type solvent extraction. Liquid-liquid solvent extraction involves contacting a copper-containing, aqueous feed solution with an organic extractant. The organic extractant has an active organic extractant for selectively extracting copper dissolved in an inert organic solvent (carrier), such as kerosene. Hydroxy oximes, beta diketones and tertiary amines are examples of active, selective organic extractants. Multistage liquid-liquid extraction may be employed to achieve substantially complete extraction of copper from a solution containing copper. The copper-containing aqueous feed solution and the organic extractant flow countercurrently between the extraction stages. In each stage, the active organic extractant selectively extracts copper from the solution containing the same, resulting in a copper loaded organic phase and a raffinate from which copper has been removed. Each stage constitutes a mixer-settler system wherein the aqueous feed and organic extractant are mixed for a period of time and then permitted to settle so as to separate the phases. The copper from the loaded organic extractant is selectively stripped therefrom by contact with a suitable stripping solution.
Several patents relate to processes which involve, at least in part, the use of liquid-liquid extraction to selectively recover copper. Examples of such patents are U.S. Pat. No. 3,224,873 issued to Swanson on Dec. 21, 1965, U.S. Pat. No. 3,761,249 issued to Ritcey et al on Sept. 25, 1973, U.S. Pat. No. 3,849,269 issued to Hartwig et al on Nov. 19, 1974, U.S. Pat. No. 3,853,981 issued to Hadzeriga on Dec. 10, 1974, U.S. Pat. No. 3,855,090 issued to Skarbo on Dec. 17, 1974, U.S. Pat. No. 3,872,209 issued to Hazen et al on Mar. 18, 1975, U.S. Pat. No. 3,887,679 issued to Wegstol et al on June 3, 1975, U.S. Pat. No. 3,907,966 issued to Skarbo on Sept. 23, 1975, U.S. Pat. No. 3,927,169 issued to Goren et al on Dec. 16, 1975, U.S. Pat. No. 3,950,487 issued to Pemsler et al on Apr. 13, 1976, U.S. Pat. No. 3,971,652 issued to Bryson on July 27, 1976, U.S. Pat. No. 3,981,966 issued to Baucom on Sept. 21, 1976, U.S. Pat. No. 3,988,151 issued to Skarbo on Oct. 26, 1976, U.S. Pat. No. 4,023,964 issued to DeMarthe et al on May 17, 1977, U.S. Pat. No. 4,036,639 issued to Yarko on July 19, 1977 and German Pat. No. 26 15 287 issued to Perschke et al on Oct. 6, 1977.
As copper reserves dwindle under increased copper demand, and therefore exploitation, it has become imperative to recycle "waste" copper. One source of such "waste" copper is copper contained in spent etches derived from the etching of copper from printed electronic circuit boards. Conventionally, aqueous solutions of hydrochloric acid and sodium chlorate or aqueous solutions of ammonia and ammonium chloride are employed to etch copper from printed electronic circuit boards. The resultant spent etch solution contains relatively large quantities of copper in solution. Currently, these spent etch solutions are waste streams in the electronic industry, and in fact, many firms pay other concerns to properly dispose the spent etch solutions.
U.S. Pat. No. 3,440,036 issued to Spinney on Apr. 22, 1969 relates to a process for liquid-liquid ion exchange extraction of copper from a ammonium sulfate-ammonium peroxy-disulfate etch solution with hydroxy oximes as the extraction agent. The pH of the etch solution must range from about 5.5 to about 7.5 when utilizing a hydroxy oxime to effectively extract copper therefrom. U.S. Pat. No. 4,083,758 issued to Hamby et al on Apr. 1, 1978 discloses a process for recovering copper values from a solution containing such values along with chloride ions, particularly spent, ammoniacal etching solutions derived from the manufacture of printed electronic circuit boards. The process comprises removing copper from the solution utilizing conventional liquid-liquid extraction techniques employing a LIX reagent, organic extractants manufactured by Henkel Corporation, in an organic vehicle as the extractant. The copper values are thereafter stripped from the extractant by contacting the extractant with a strong sulfuric acid solution as conventionally known. An electrowinning circuit is provided to recover "wire-grade" metallic copper from the acidic stripping solution.
These processes do not provide for product selectivity from diverse copper-containing feed streams and, therefore, have limited marketability. Nor do these processes encompass a plurality of diverse feed streams which may be concurrently processed thereby. Thus, it can be appreciated that a need exists for an improved process for selectively extracting copper from solution(s) containing the same.

Selective extraction and recovery of copper


Disclosed is an adhesive composition in which a solid component is dissolved in a solvent, the solid component being dissolved in the solvent to have a solid component content of not less than 20% by weight with respect to a total amount of the solid component and the solvent, the solid component containing resin obtained by polymerizing a monomer composition that contains a cycloolefin monomer, the solvent having no carbon-carbon double bond, and an alcohol content contained in the solvent being not more than 0.45% by weight with respect to an entire amount of the solvent.

A thin semiconductor silicon chip is manufactured, for example, in a method as follows: (i) a high purity single crystal silicon or the like is sliced to a wafer form, (ii) a predetermined circuit pattern is formed on a surface of the wafer by photoresist, (iii) a back surface of the semiconductor wafer thus obtained is subjected to grinding, and (iv) after the semiconductor wafer is grinded to a predetermined thickness, the semiconductor wafer is diced so as to form a chip shape. In such a manufacturing process, the thin wafer itself is fragile and easily breakable; hence, it is necessary to reinforce the thin wafer. Furthermore, it is also necessary to prevent the circuit pattern formed on the surface of the wafer from being contaminated due to grinding dust and the like generated in the grinding process. Methods such as the following are known as methods of preventing the breakage of the wafer and protecting the circuit pattern provided on the surface of the wafer: a method in which the wafer is grinded in a state in which the supporting body is temporally fastened to the adhesive layer, and thereafter the supporting body is stripped off (see for example Patent Literature 1 and Patent Literature 2); and a method in which the wafer is grinded in a state in which an adhesive film having an adhesive layer is adhered on the surface of the wafer on which the circuit pattern is provided, and thereafter the adhesive film is stripped off (see for example Patent Literature 3 and Patent Literature 4).
In recent years, demands have been increasing for achievement of small sized, thin, and highly functioned electronic apparatuses. In this trend, in replacement of the wire bonding technique that conventionally has been the main current as a wiring technique for connecting electrodes (bumps) and a circuit board in a System in Package (SiP) for example, a through-hole formation technique has been gaining attention as the wiring technique. The through-hole formation technique is a technique in which a chip formed with a through-hole electrode is stacked to form a bump on a back side of the chip. In order to employ the through-hole formation technique, it is necessary to manufacture a chip having a through-hole electrode, by forming a through-hole electrode on a semiconductor wafer which is grinded to a predetermined thickness. The forming of the through-hole electrode on the semiconductor wafer requires going through many processes, including high temperature processing and high vacuum processing.
If the grinding process is carried out in the methods disclosed in Patent Literatures 1 to 4 upon adhering the supporting body or adhesive film to the semiconductor wafer, and the through-hole electrode is formed thereafter, the adhesive layer becomes exposed to a high temperature while the semiconductor wafer is subjected to the process of forming the through-hole electrode. However, the adhesive used in the adhesive layer for temporally fastening the supporting body, and the adhesive used in the adhesive layer for adhering the adhesive film, each in the methods of Patent Literatures 1 to 4, do not have sufficient thermal resistance. As a result, problems occur caused by the adhesive layer being exposed to high temperature, such as that the resin of the adhesive layer deteriorates thereby causing a decrease in its adhesive strength, or that moisture absorbed by the adhesive layer evaporates as gas under the high temperature, which gas causes the adhesive layer to peel off at these bubbles of air, thereby causing poor adhesion. Furthermore, even when the adhesive layer is to be stripped off (the supporting body or adhesive film is stripped off), once the adhesive layer is exposed to high temperature, poor stripping easily occurs, such as having residue remaining when the adhesive layer is stripped off. Moreover, in a case where the forming of the through-hole electrode requires carrying out a process in a high temperature high vacuum environment, not only does the gas generated by decomposition of the adhesive layer itself in the high temperature and the gas generated from the moisture in the adhesive layer cause the poor adhesion as described above, but also these gases hinder the maintaining of the vacuum environment.
In view of the problems, an adhesive composition whose main component is a specific acrylic resin has been proposed as an adhesive composition which has good thermal resistance and which exhibits sufficient adhesive strength in a high temperature environment (see for example Patent Literature 5). Moreover, an adhesive composition containing (i) an alicyclic structure-containing polymer having a specific molecular weight and (ii) a low molecular weight compound having a specific molecular weight has been proposed as a thermally resistant adhesive resin composition, for use in adhering an electronic component and a substrate (Patent Literature 6).
Meanwhile, norbornene resin is known for its outstanding transparency, thermal resistance, low moisture absorbency, low birefringence, moldability, and the like; reports have been made which disclose that norbornene resin is used for optical disk substrates, and molding of optical films such as a phase difference compensating film and a polarizing plate protective film (for example, see Patent Literatures 7 to 9).